Tesis Doctoral - Alicia Monleon Ventura

SO2Cl2
HN
HO
HO
O
HN
Ph
O
O
Ph
Et
Alquinilacin enantioselectiva de iminas:

CH2Cl2
Desarrollo de CH2Cl2
mtodos
catalticos y
aplicaciones sintticas
Te
Cbz
HN
Ph
Ph
Tesis doctoral
Alicia Monlen Ventura
Cl
ClSe
O
HN
Ph
Ph
Ph
Cl2
Cl HN
O
HN
Et
Et NH2
HN
Me H
NH
N
Me
O
HN
Me2Zn
O
O2
F3C
O
SO2Tol
OMe
O
O
Ph CF3
O
O
Ph
SO2Tol
ClCH2CH2Cl
Ph
Br2
F3C
HO
HO
O
H

FACULTA
F
ADDEQ
QUMICA
A
Departtamento
odeQumicaOrgnica
Program
madedocctorado:
Qumicaorgnicaenlaaindustriaaqumicofarmacuutica
Alqu
uinilacinenaantioselectivadeimiinas:
D
Desarro
ollodemtodoscataalticos yapliccacione
es
sintticaas.
TessisDocto
oral
AliciaM
A
onlenVenturra
D
Directore
es
Jos
R.Ped
droyGo
onzaloB
Blay
Vallencia,20
013
AGRADECIMIENTOS
Esdifcilagradecerenpocaslneasatodaslaspersonasquedeunmodouotromehan
ayudadoalograresteobjetivo.Sinduda,hedecomenzarmostrandomiagradecimientoalos
directores de esta tesis, el profesor Jos Ramn Pedro, por su gran confianza, dedicacin y
paciencia todos estos aos, y el profesor Gonzalo Blay, por estar siempre dispuesto a
ayudarmeyensearme.TambinquierodarlasgraciasaIsabelFernndezyM.LuzCardona
porsusconsejosyentretenidacompaa.
AlaGeneralitatValencianaporlaconcesindelabecapredoctoralBFPI.
AtodoelpersonaldeSecretara,alostcnicosdelDepartamentoydelSCSIE.Tambin
a Luis Domingo por la realizacin de los clculos tericos y a M. Carmen Muoz por la
resolucindelasestructurasdeRayosX.
IwouldliketoexpressmygratitudetoProfessorCarstenBolmandDr.EvaHeviafor
givingmetheopportunitytoworkintheirgroupsandfortheirkindattention.
Gracias a todos los compaeros de laboratorio porque de todos ellos he aprendido
algo y han hecho que los largos das de trabajo fueran ms agradables y llevaderos. Sobre
todo, gracias a Carlos porque me supo transmitir su pasin por la investigacin y porque
hemos compartido experiencias inolvidables. A Santi y a Uxu, porque incluso en la distancia,
siempreestnpresentes.Aloscompaerosdeotroslaboratorios,portanbuenosratosjuntos,
porvuestraayudayconsejos.GraciasaRosaL.yVioporvuestraamistady portantosratos
divertidos.ARosaA.,micompaeradeviajeyburocracias,perosobretodo,miamiga.
A todas las personas que, aunque no aparecen aqu con nombre y apellidos, han
estadopresentesdealgunaformaduranteeldesarrollodeestetrabajo,especialmenteamis
amigos, que han sabido disculpar mis ausencias, por todo el nimo y comprensin durante
estosaos.
A mi familia, mi pilar fundamental. Sobre todo a mis padres y mi hermana, por
apoyarme en todas las decisiones que he tomado a lo largo de mi vida y por ensearme a
luchar por lo que quiero. Gracias por compartir mis alegras y animarme en momentos de
frustracin.
A Pau, por estar incondicionalmente a mi lado. Por su amor, amistad y paciencia.
Gracias por acompaarme en este viaje y sufrirlo y disfrutarlo tanto como yo. Juntos
seguiremosalcanzandosueos.
Atodos,gracias.
NDICE
Captulo1.Introduccinyobjetivosgenerales
1.1.INTRODUCCINGENERAL............................................................. 5
1.2.OBJETIVOSGENERALES...................................................................13
1.3.REFERENCIAS..................................................................15
Captulo2.Adicinenantioselectivadealquinosterminalesa
N(difenilfosfinoil)iminas
2.1.ANTECEDENTES 19
2.1.1.Procedimientosenantioselectivosestequiomtricos.. 19
2.1.2.Procedimientosenantioselectivoscatalticos 20
2.1.2.1.Adicionesenantioselectivascatalizadasporcobre. 20
2.1.2.2.Adicionesenantioselectivascatalizadasporotrosmetales. 43
2.2.OBJETIVOS 53
2.3.RESULTADOSYDISCUSIN.. 55
2.3.1.SntesisdeN(difenilfosfinoil)iminas.. 55
2.3.2.Optimizacindelascondicionesdereaccin..... 56
2.3.3.Alcanceylimitacionesdelareaccin.... 59
2.3.4.DesproteccindelaagrupacinN(difenilfosfinoil)amina... 62
2.3.5.Determinacindelaestereoqumicaabsoluta.... 62
2.3.6.PropuestamecansticaparalaalquinilacindeN(difenilfosfinoil)iminas. 63
2.4.CONCLUSIONES 65
2.5.SECCINEXPERIMENTAL.. 67
2.5.1.Tcnicasgenerales... 67
2.5.1.1.Tcnicasfsicasyespectroscpicas.. 67
2.5.1.2.Tcnicascromatogrficas.. 68
2.5.1.3.Disolventes... 68
2.5.1.4.Reactivos..... 69
2.5.1.5.Reacciones.... 69
2.5.2.Procedimientosgeneralesdesntesisycaracterizacindenuevos
productos... 69
2.5.2.1.SntesisycaracterizacindeN(difenilfosfinoil)iminas1.. 69
2.5.2.2SntesisycaracterizacindelprecursordeN(difenilfosfinoil)
2feniletilaldimina7... 72
2.5.2.3.SntesisycaracterizacindeP,Pdifenilfosfinamidasproparglicas3.. 73
2.5.2.4.Sntesisycaracterizacinde(S)1,3difenilprop2inamina(4)87
2.6.REFERENCIAS..................................................................89
Captulo3.Adicinenantioselecitvadealquinosterminalesaamido
sulfonas
3.1.ANTECEDENTES 95
3.1.1.Amidosulfonascomoprecursoresdeiminas.. 95
II
3.1.2.Utilizacindeciclopropilacetilenoenreaccionesdealquinilacinde
iminas. 101
3.2.OBJETIVOS... 105
3.3.RESULTADOSYDISCUSIN..... 109
3.3.1.Sntesisdeamidosulfonas...... 109
3.3.2.Optimizacindelascondicionesdereaccin...... 111
3.3.3.Alcanceylimitacionesdelareaccin...... 123
3.3.4.Modificacionessintticas...... 130
3.3.5.Determinacindelaconfiguracinabsoluta........ 132
3.3.6.Propuestamecansticaparalaalquinilacindeiminasgeneradasinsitu
apartirdeamidosulfonas......... 132
3.4.CONCLUSIONES 135
3.5.SECCINEXPERIMENTAL.. 137
3.5.1.Tcnicasgenerales... 137
3.5.2.Procedimientosgeneralesdesntesisycaracterizacindenuevos
productos... 137
3.5.2.1.Sntesisycaracterizacindeamidosulfonas8.... 137
3.5.2.2SntesisycaracterizacindelasNbenciloxicarbonilaminas
proparglicas11ydesusderivados..... 146
3.6.REFERENCIAS.................................................................... 183
III
Chapter4.Additionofzincalkyloxygenatedspeciestoamidosulfones
4.1.ANTECEDENTS 187
4.1.1.Oxidationofdialkylzincreagents... 187
4.1.2.Applicationofdialkylzincoxygenationreactionsinorganicsynthesis 192
4.2.OBJECTIVES.... 205
4.3.RESULTSANDDISCUSSION..... 207
4.3.1.Additionofzincalkylperoxidestoamidosulfones...... 207
4.3.1.1.Optimizationofreactionconditions........ 207
4.3.1.2.Scopeandlimitationsofthereaction.......... 209
4.3.1.3.Proposedmechanismfortheadditionofdialkylzincoxygenated
speciestoamidosulfonesintheabsenceofligand.... 214
4.3.2.Additionofzincalkoxidestoamidosulfones.. 215
4.3.2.1.Optimizationofreactionconditions.. 215
4.3.2.2.Scopeandlimitationsofthereaction. 217
speciestoamidosulfonesinthepresenceofligand.. 219
4.4.CONCLUSIONS.......... 221
4.5.EXPERIMENTALSECTION.......... 223
4.5.1.Generaltechniques... 223
4.5.2.Generalsyntheticproceduresandcharacterizationofnewproducts 223
4.5.2.1.Alkylperoxidationofamidosulfones8withEt2Zn.. 223
IV
4.5.2.2.Alkylperoxidationofamidosulfones8withnBu2Zn.. 229
4.5.2.3.Alkylperoxidationofamidosulfones8withiPr2Zn.. 232
4.5.2.4.Alkoxylationofamidosulfones8withEt2Zn.. 234
4.5.2.5.Alkoxylationofamidosulfones8withnBu2Zn.... 236
4.5.2.6.Alkoxylationofamidosulfones8withMe2Zn.. 238
4.6.REFERENCES...................................................................... 241
Chapter5.HalogenandchalcogenmediatedcyclizationofNCbz
protectedpropargylicamines
5.1.ANTECEDENTS 247
5.1.1.Activationofalkynestowardnucleophilicattack.... 247
5.1.1.1.Activationofalkynesbytransitionmetals.. 248
5.1.1.2.Activationofalkynesbyelectrophiles. 258
5.1.2.Synthesisofcycliccarbamatesbyelectrophiliccyclizationofalkynes 274
5.2.OBJECTIVES.... 279
5.3.RESULTSANDDISCUSSION..... 281
5.3.1.RegioselectivehalogenmediatedcyclizationofNCbzprotected
propargylicamines.Synthesisof5halo1,3oxazin2ones 281
5.3.1.1.Optimizationofreactionconditions.. 281
5.3.1.2.Scopeandlimitationsofthereaction.... 283
5.3.1.3.Theoreticalcalculationsonthebromoandchlorocyclization
reactionsofprotectedpropargylicamines...... 291
5.3.2.RegioselectivechalcogenmediatedcyclizationofNCbzprotected
propargylicamines.Synthesisof5phenylchalco1,3oxazin2ones. 303
5.3.2.1.Optimizationofreactionconditions..... 303
5.3.2.2.Scopeandlimitationsofthereaction..... 304
5.3.2.3.Structureelucidationofthechalcocyclizationproducts.. 307
5.3.2.4.Theoreticalcalculationsontheselenocyclizationreactionof
protectedpropargylicamines... 310
5.4.CONCLUSIONS.......... 317
5.5.EXPERIMENTALSECTION.......... 319
5.5.1.Generaltechniques... 319
5.5.2.Generalsyntheticproceduresandcharacterizationofnewproducts 319
5.5.2.1.SynthesisandcharacterizationofNbenzyloxycarbonyl1
phenylbut2yn1amine(11aq).. 319
5.5.2.2.Synthesisandcharacterizationof5iodo1,3oxazin2ones33. 320
5.5.2.3.Synthesisandcharacterizationof5bromo1,3oxazin2ones34. 326
5.5.2.4.Synthesisandcharacterizationof5chloro1,3oxazin2ones35 330
5.5.2.5.Synthesisandcharacterizationof5phenylselanyl1,3oxazin
2ones36....... 332
5.5.2.6.Synthesisandcharacterizationof5phenylsulfenyl1,3oxazin
2ones37............ 335
5.5.2.7.Synthesisandcharacterizationof5phenyltellanyl1,3oxazin
2ones38......... 339
VI
5.5.2.8.Synthesisandcharacterizationof(S)4,6diphenyl5((S)
phenylsulfinyl)3,4dihydro2H1,3oxazin2one(42).. 342
5.5.3.Additionalcomputationaldata.. 344
5.6.REFERENCES...................................................................... 347
Anexos
I.Alquinos. 355
II.Aldehdos.. 356
III.Relacindepublicacionesderivadasdeestatesis... 357
VII
VIII
ABREVIATURAS/ABBREVIATIONS
angstrom
ancho
Ac
acetilo
AcO
acetato/acetate
Ar
arilo/aryl
aq.
aqueous
au
atomicunits
BINAP
2,2'bis(difenilfosfino)1,1'binaftil
BINOL
1,1binaftil2,2diol/1,1binaphthyl2,2diol
Bn
bencilo/benzyl
Boc
tercbutiloxicarbonilo/tertbutyloxycarbonyl
BOX
bisoxazolina
Bu
butilo/butyl
br
broad
Bz
benzolo
concentracin/concentration(g/100mL)
CAN
nitratodecerioyamonio
Cbz
benciloxicarbonilo/benzyloxycarbonyl
CCF
cromatografadecapafina
coll
collidine
conc.
concentrado
doblete/doublet
DABCO
1,4diazabicyclo[2.2.2]octane
dba
dibenzylideneacetone
DBU
1,8diazabicyclo[5.4.0]undec7ene
DEPT
distortionlessenhancementbypolarizationtransfer
DMSO
dimetilsulfxido/dimethylsulfoxide
DMSOd6
dimetilsulfxidodeuterado/deuterateddimethylsulfoxide
electrophile
ee
excesoenantiomrico/enantiomericexcess
equiv
equivalente/equivalent
IX
ESI
ionizacinporelectroespray/Electrosprayionization
Et
etilo/ethyl
eV
electronvolts
gramo/gram
GP
grupoprotector
hora/hour
HPLC
highperformanceliquidchromatography
HRMS
highresolutionmassspectrum
Hz
hertzio/hertz
IN
intermediate
constantedeacoplamiento/couplingconstant
ligando/ligand
multiplete/multiplet
molar
MC
molecularcomplex
MCPBA
cidometacloroperbenzoico
Me
metilo/methyl
min
minuto/minute
mL
mililitro/milliliter
mmol
milimol/millimol
mp
puntodefusin/meltingpoint
NaHMDS
Sodiumbis(trimethylsilyl)amide
NBS
Nbromosuccinimide
NIS
Niodosuccinimide
NMR
nuclearmagneticresonance
p.
pgina/page
PMB
parametoxibencilo
PG
protectinggroup
PMP
parametoxifenilo
ppm
partespormilln/partspermillion
Pr
propilo/propyl
py
piridina/pyridine
PyBIM
piridinabisimidazolina
PyBOX
bis(oxazolinil)piridina
cuadruplete/quartet
QUINAP
1(2difenilfosfino1naftil)isoquinolina
rendimiento
RMN
resonanciamagnticanuclear
rt
roomtemperature
singulete/singlet
salen
N,Netilenebis(salicilimina)
sat.
saturated
tiempo/time
triplete/triplet
temperatura/temperature
ta
temperaturaambiente
TBAF
tetranbutylammoniumfluoride
Tf
triflato(trifluorometanosulfonato)
THF
tetrahidrofurano/tetrahydrofuran
TLC
thinlayerchromatography
TMS
trimetilsililo/trimethylsilyl
Tol
tolueno/toluene
Ts
tosilo(ptoluenosulfonilo)/tosyl(ptoluenesulfonyl)
TS
transitionstate
VIH
virusdelainmunodeficienciahumana
[]
rotacinespecfica/specificrotation
desplazamientoqumico/chemicalshift
micro
XI
CH2Cl2
CAPTULO 1
Introduccin y objetivos generales
O
Ph
P
N
Ph
O
i Pr
HN
Ph
Et2Zn
2Z
OH
MeO
Br
Me
Me HN
OH
O
Ph
HN
O
O
O
H
OH
OH
Se
CH2Cl2
Captulo1
1.1.INTRODUCCINGENERAL
La bsqueda de nuevos mtodos dirigidos a la obtencin de sustancias
enantiomricamentepurashasupuestounodelosprincipalesdesafosdelaqumica
orgnica durante las ltimas dcadas debido a la influencia que la estereoqumica
absoluta de las molculas ejerce sobre su actividad biolgica, as como en las
propiedadesdelosmateriales.Estaimportanciadelaquiralidadsehaceevidenteen
multitud de productos naturales, as como en los receptores moleculares de los
sistemas biolgicos. Por ello es necesario el desarrollo de procedimientos de sntesis
decompuestosenantiomricamentepurosconunaconfiguracindeterminada,yaque
deestadependernsuspropiedadesfisiolgicasyfarmacolgicas.1
Tradicionalmente,
los
mtodos
de
obtencin
de
sustancias
enantiomricamente puras se basaban en la utilizacin de fuentes naturales

procedentes del chiralpool y en la resolucin de mezclas racmicas. Sin embargo,
nuevosaspectosquesedebentenerencuentaenlasntesisorgnicamoderna,tales
como la eficiencia sinttica, el consumo de quiralidad o la necesidad de mayor
selectividad, han hecho emerger la catlisis asimtrica como una nueva metodologa
sinttica con un potencial de crecimiento enorme. Su mayor ventaja radica en la
obtencindeproductosenriquecidosenantiomricamenteconunaelevadapureza,un
bajoconsumodequiralidadyunamenorproduccinderesiduos.2
LaaplicacindelacatlisisasimtricaenreaccionesdeformacindeenlacesC
C es de gran importancia debido a que permite obtener centros estereognicos con
unaconfiguracindeterminadaenmolculasestructuralmentecomplejas.As,sehan
utilizado en multitud de reacciones tales como Friedel Crafts, DielsAlder, reacciones
de alquilacin, Henry, etc.35 En concreto, la adicin enantioselectiva de alquinos
terminales a grupos carbonilo e imina permite la obtencin de alcoholes y aminas
proparglicas quirales respectivamente, cuya funcionalizacin es de gran valor en la
sntesisdemolculasconelevadacomplejidad.6
Las aminas proparglicas han emergido en los ltimos aos como precursores
verstiles en la sntesis de un amplio abanico de compuestos nitrogenados como
Captulo1
alilaminas,pirrolidinas,oxazolesypirroles,7ysehanutilizadocomointermediosenla
preparacindeproductosnaturales,farmacuticos,herbicidasyfungicidas.810
Asimismo,lapropiaestructuraaminoproparglicaseencuentrapresenteenun
considerablenmerodecompuestosconactividadbiolgicayfarmacolgica.11As,por
ejemplo,estaestructuraestpresenteencompuestosconpropiedadesinhibidorasde
la enzima monoamida oxidasa B (MAOB),12 antagonistas de un subtipo selectivo del
receptordelNmetilDaspartato(NMDA)13(Figura1a),inhibidorasdelaagregacinde
plaquetas,14 inhibidoras de la degradacin del cido aminobutrico (GABA),15
antibiticos,16inhibidorasdelaacetilCoAoxidasa(ACC)17(Figura1b),inhibidoresdela
transcriptasadeVIH(Figura1c)18oherbicidasentreotros.19
Me
O
NHCOCH3
F3C
Ar
Cl
NH
N
H
Ph
Ph
Figura1.1.(a)AntagonistadelreceptordeNmetilDaspartato(NMDA).(b)Inhibidordela
acetilCoAoxidasa(ACC).(c)InhibidornonuclesidoreversodelatranscriptasadeVIH,DPC
961.
En trminos generales, son cuatro los mtodos que permiten la sntesis de

aminas proparglicas quirales (Esquema 1.1): la sustitucin nucleoflica de alcoholes
proparglicos quirales con reactivos nitrogenados nucleoflicos20 (aproximacin a), la
reduccinselectivadeldobleenlaceC=Nencetiminas,insaturadas21(aproximacin
b), la adicin 1,2 de reactivos carbonados nucleoflicos a iminas ,insaturadas22
(aproximacinc)ylaadicindealquinosnucleoflicosaiminas23(aproximacind).
Captulo1
Esquema1.1.Aproximacionesgeneralesparalasntesisdepropargilaminas.
En esta ltima aproximacin, se aprovecha la acidez del protn acetilnico

terminal para formar un reactivo alquinilmetlico que acta como un carbono
nuclefilo.LaadicinnucleoflicaalosdoblesenlacesC=Nesunodelosmtodosms
practicados para la sntesis de derivados nitrogenados. Sin embargo,mientras que la
adicindeacetilenosacompuestoscarbonlicoshasidoobjetodeungrannmerode
publicaciones,laalquinilacinasimtricadeiminasysusderivadossuponeundesafo
sintticodebidoalamenorelectrofiliadeltomodecarbonoazometnicocomparada
con el tomo de carbono carbonlico de aldehdos y cetonas. No obstante, la
reactividaddeldobleenlaceC=Npuedeincrementarsemedianteelusodenitronas,la
generacin in situ de iones iminio o a travs de la introduccin de grupos electrn
atrayenteseneltomodenitrgenodelaimina.Lautilizacindeestasestrategiasha
permitidolasntesisdeaminasproparglicasmediantelareaccindealquinilacin.
Aunque es posible la sntesis de aminas proparglicas quirales a travs de
procedimientos diastereoselectivos recurriendo a la introduccin de sustituyentes
quirales en el tomo de nitrgeno, especialmente, mediante la utilizacin de
sulfiniliminas quirales, en los ltimos aos la sntesis de aminas proparglicas se ha
centradoenprocedimientosenantioselectivos,especialmente,enaquellosbasadosen
metodologas catalticas por las ventajas sealadas anteriormente y a ellos se les
prestaratencinenlapresentetesisdoctoral.
Captulo1
La utilizacin de complejos de metales de transicin y ligandos quirales como

catalizadores, junto con el empleo de organocatalizadores, constituye una de las
estrategias ms comnmente extendidas para llevar a cabo con xito las reacciones
enantioselectivas. Durante las ltimas dcadas se han desarrollado multitud de
ligandos eficientes, a algunos de los cuales se les ha catalogado como ligandos
privilegiados por su capacidad de mediar enantioselectivamente reacciones de
diversanaturaleza.AestegrupodeligandospertenecenlosdenominadosBINOL,BOX,
Salen,BINAPoDuPhos,entreotros.24
Figura1.2.Ligandosprivilegiados.
Los ligandos de tipo BINOL, en los que nuestro grupo de investigacin tiene
experiencia,23 presentan un eje axial con simetra C2 y han sido empleados en
reacciones enantioselectivas de formacin de enlace CC junto con cidos de Lewis
comoTi,Zr,AloZn.23,2527Concretamente,elcomplejoquiralformadoporZn(II)BINOL
ha demostrado ser una herramienta poderosa en la reaccin de alquinilacin
enantioselectiva de Ntosiliminas (Esquema 1.2).23 Por ello, se ha escogido este
sistemacatalticoparallevaracabolasreaccionesdeadicindealquinosterminalesa
iminasenestetrabajo.
Captulo1
Esquema1.2.AlquinilacinenantioselectivadeNtosiliminaspromovidaporMe2Znyligandos
detipoBINOL.
Uno de los inconvenientes derivados de la utilizacin de iminas es su posible

enolizacin. Esta reaccin adversa dificulta cualquier reaccin de adicin eficiente y,
adems,puedeproducirlaisomerizacindeldobleenlaceC=N.
Unaposibleaproximacinparasuperaresteobstculoeslaformacininsitude
Naciliminas a partir de amidas con un buen grupo saliente en que pueda ser
fcilmenteeliminadoenlascondicionesadecuadas,tantobsicascomoenpresencia
deuncidodeLewis(Esquema1.3).28
Esquema1.3.FormacindeionesNaciliminioyNaciliminasapartirdeamidasconunbuen
gruposalienteen.
Lasamidosulfonas(X=SO2R4)sonunejemplodeestetipodesustratosque
hasidoutilizadoenlareaccinnoenantioselectivadeadicindealquinos29ypueden
utilizarsecomoprecursoresdeiminasenpresenciadelsistemacatalticoformadopor
dialquilzincyBINOL.
9
Captulo1
Los reactivos de dialquilzinc reaccionan con oxgeno molecular dando lugar a

especiesoxigenadas.Debidoalcarcterradicalariodelasespeciesintermediasdeesta
reaccin,siempresehaconsideradounprocesodedifcilcontrolenelquesepuede
oxidar uno o los dos enlaces ZnC para dar lugar tanto a los alcxidos como a los
alquilperxidosdezinc.Noobstante,algunosestudiosrecientesdelgrupodeLewinski
demuestrancmoesposiblellevaracabolaoxigenacincontroladadelosaductosde
dialquilzincconligandosdadores(Esquema1.4).30
Esquema1.4.OxidacincontroladadetBu2Zn.
Las especies obtenidas tras la oxidacin controlada de los reactivos de

dialquilzinc pueden ser utilizadas en reacciones de adicin a amido sulfonas,
generandoasaminasoxigenadasenlaposicin.Estas,especialmentesicontienenla
agrupacinperxido, son muy interesantes tanto desde elpunto de vista estructural
como de sus aplicaciones, ya que los peroxocompuestos presentan caractersticas
antitumoralesyantimalricas(Figura1.3)yseutilizancomoantibacterianos.31
Figura1.3.Artesunatodesodio.
10
Captulo1
Por otra parte, las aminas proparglicas obtenidas en la reaccin de

alquinilacin poseen una elevada funcionalizacin, lo que hace que estos sustratos
sean susceptibles de experimentar diversas transformaciones, proporcionando una
granversatilidadsintticaaestetipodecompuestos.As,porejemplo,lareduccindel
tripleenlaceosuozonlisispermitenlaobtencindederivadosamnicosqueamplan
laaplicabilidadsintticadelosproductosdealquinilacin.
Adems, la activacin electroflica del triple enlace frente al ataque de un
nuclefiloaumentalasposibilidadesdetransformacindelasaminasproparglicas.El
ataqueintramoleculardeungruponucleoflicoprximoalaagrupacinacetilnicaes
unmtodoexcelentequeconducealasntesisdeestructurascclicas.Lautilizacinde
metalesdetransicin,especialmenteAu,AgyPt,comoactivadoresdeltripleenlaceC
C ha demostrado ser una estrategia muy til en la sntesis de diversos compuestos
heterocclicoscomooxazoles,imidazolesobenzoxazinas(Esquema1.5).32
Esquema1.5.CiclacinelectroflicamediadaporAu(I).
Asimismo, la ciclacicin electroflica mediada por halgenos o calcgenos a

travsdelaformacindeunionhalonioocalconio,resultaenlaformacindehaloy
calcoderivados heterocclicos o carbocclicos altamente funcionalizados y de gran
versatilidadenposterioresprocesossintticos(Esquema1.6).33
Esquema1.6.Ciclacinelectroflicamediadaporyodo.
La regioselectividad de estas ciclaciones electroflicas no siempre se consigue

confacilidaddebidoalacompetenciaentrelosmodosdeciclacinexoyendo.
11
Captulo1
1.2.OBJETIVOSGENERALES
La adicin nucleoflica a dobles enlaces C=N es uno de los mtodos ms
utilizados para la sntesis de derivados nitrogenados. La utilizacin de alquinos
terminales como nuclefilos constituye una herramienta sinttica de gran inters,ya
que la adicin enantioselectiva de los mismos a iminas o precursores de iminas
permite la sntesis de aminas proparglicas quirales con un enorme valor en la
formacindeunaampliavariedaddeproductosnaturalesyfarmacuticos.Adems,la
elevada funcionalizacin de las aminas proparglicas hace posible la obtencin de
productosderivadosdegranintersenqumicaorgnica.
Porotraparte,elsistemacatalticoformadoporreactivosdedialquilzinccomo
cidosdeLewisyderivadosde1,1binaftil2,2diol(BINOL)comoligandosquiralesha
demostrado inducir un elevado estereocontrol en numerosas transformaciones
sintticas.
Teniendo en cuenta estas consideraciones, en la presente tesis se han
planteadolossiguientesobjetivosgenerales:
Adicin enantioselectiva de alquinos terminales aN(difenilfosfinoil)iminas

catalizadaporcomplejosdetipoBINOLZn.
Adicinenantioselectivadealquinosterminalesaiminasgeneradasinsitua
partirdeamidosulfonascatalizadaporcomplejosdetipoBINOLZn.
Adicindeespeciesdezincalquiloxigenadasaamidosulfonas.
Ciclacin regioselectiva de aminas proparglicas NCbzprotegidas mediada

porhalgenosycalcgenos.
13
Captulo1
1.3.REFERENCIAS
(1) Gruttadauria, M.; Giacalone, F. Catalytic Methods in Asymmetric Synthesis, John
Wiley&Sons,Inc.,Hoboken,NewJersey,2011.
(2) Anastas, P. T.; Williamson, T. C. Green Chemistry, Frontiers in Benign Chemical Syntheses
andProcesses,OxfordUniversityPress,Oxford,UK,1998.
(3)deVries,J.G.ScienceofSynthesis:StereoselectiveSynthesis1,StereoselectiveReactionsof
CarbonCarbonDoubleBonds,Vol.1,GeorgThiemeVerlag,Stuttgart,Germany,2011.
(4)Molander,G.A.ScienceofSynthesis,StereoselectiveSynthesis2:StereoselectiveReactions
ofCarbonylandIminoGroups,Vol.2,GeorgThiemeVerlag,Stuttgart,Germany,2011.
(5) Evans, P. A. Science of Synthesis: Stereoselective Synthesis 1, Stereoselective Reactions of
CarbonCarbonDoubleBonds,Vol.3,GeorgThiemeVerlag,Stuttgart,Germany,2011.
(6)Trost,B.M.;Weiss,A.H.Adv.Synth.Catal.2009,351,963983.
(7)Yamamoto,Y.;Hayashi,H.;Saigoku,T.;Nishiyama,H.J.Am.Chem.Soc.2005,127,10804
10805.
(8)Jiang,B.;Xu,M.Angew.Chem.Int.Ed.2004,43,25432546.
(9)Fleming,J.J.;DuBois,J.J.Am.Chem.Soc.2006,128,39263927.
(10)Hoepping,A.;Johnson,K.M.;George,C.;FlippenAnderson,J.;Kozikowski,A.P.J.Med.
Chem.2000,43,20642071.
(11)Young,S.;Britcher,S.;Tran,L.;Payne,L.;Lumma,W.;Lyle,T.;Huff,J.;Anderson,P.;Olsen,
D.;Carroll,S.Antimicrob.AgentsChemother.1995,39,26022605.
(12)Yu,P.H.;Davis,B.A.;Boulton,A.A.J.Med.Chem.1992,35,37053713.
(13)Wright,J.L.;Gregory,T.F.;Kesten,S.R.;Boxer,P.A.;Serpa,K.A.;Meltzer,L.T.;Wise,L.
D.;Espitia,S.A.;Konkoy,C.S.;Whittemore,E.R.;Woodward,R.M.J.Med.Chem.2000,
43,34083419.
(14)Nicholson,N.S.;PanzerKnodle,S.G.;Salyers,A.K.;Taite,B.B.;Szalony,J.A.;Haas,N.F.;
King,L.W.;Zablocki,J.A.;Keller,B.T.;Broschat,K.;Engleman,V.W.;Herin,M.;Jacqmin,
P.;Feigen,L.P.Circulation1995,91,403410.
(15)Tabor,A.B.;Holmes,A.B.;Baker,R.J.Chem.Soc.,Chem.Commun.1989,10251027.
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132136.
(17) Shinde, P.; Srivastava, S. K.; Odedara, R.; Tuli, D.; Munshi, S.; Patel, J.; Zambad, S. P.;
Sonawane,R.;Gupta,R.C.;Chauthaiwale,V.;Dutt,C.Bioorg.Med.Chem.Lett.2009,19,
949953.
15
Captulo1
(18) Huffman, M. A.; Yasuda, N.; DeCamp, A. E.; Grabowski, E. J. J. J. Org. Chem. 1995, 60,
15901594.
(19)Swithenbank,C.;McNulty,P.J.;Viste,K.L.J.Agr.FoodChem.1971,19,41721.
(20)Holmes,A.B.;Tabor,A.B.;Baker,R.J.Chem.Soc,Chem.Commun.1991,33013306.
(21)Graves,C.R.;Scheidt,K.A.;Nguyen,S.T.Org.Lett.2006,8,12291232.
(22)Josephsohn,N.S.;Carswell,E.L.;Snapper,M.L.;Hoveyda,A.H.Org.Lett.2005,7,2711
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(23)Blay,G.;Cardona,L.;Climent,E.;Pedro,J.Angew.Chem.Int.Ed.2008,47,55935596.
(24)Zhou,Q.PrivilegedChiralLigandsandCatalysts,WileyVCH,Weinheim,Germany,2011.
(25)Majer,J.;Kwiatkowski,P.;Jurczak,J.Org.Lett.2011,13,59445947.
(26)Blay,G.;Fernandez,I.;Monleon,A.;Pedro,J.R.;Vila,C.Org.Lett.2009,11,441444.
(27)Li,P.;Yamamoto,H.J.Am.Chem.Soc.2009,131,1662816629.
(28)Petrini,M.Chem.Rev.2005,105,39493977.
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16
CH2Cl2
CAPTULO 2
Adicin enantioselectiva de alquinos

terminales a N-(difenilfosfinoil)iminas
O
Ph
P
NH
Ph
O
O
O
0 C
H
S
H
Br
OH
OH
Br
O
Ph
P
N
Ph
H
Tolueno
O
Ph
HP
N
Ph
Cl
H
O
Ph
P
N
Ph
Me2Zn
Me O
Me
OMe
NH2
HN
Captulo2
2.1.ANTECEDENTES
Unodelos mtodosquemayorimportanciahaadquiridoenlosltimosaos
paralaobtencindeaminasproparglicasquiraleseslaalquinilacinenantioselectiva
de iminas. Este procedimiento se ha desarrollado tanto en condiciones
estequiomtricas como catalticas, aunque es esta ltima metodologa la que resulta
ms atractiva y ha sido ms explorada recientemente. A continuacin se realiza una
revisinbibliogrficasobreestetipodereaccin.
2.1.1.Procedimientosenantioselectivosestequiomtricos
El primer ejemplo de alquinilacin enantioselectiva no cataltica de iminas se
describi en 1995. Huffman y colaboradores1 llevaron a cabo por primera vez la
adicinenantioselectivadeacetiluroaNacilcetiminascclicasutilizandoelalcxidode
litio de la quinina como aditivo quiral estequiomtrico (Esquema 2.1). Una
optimizacin extensa mostr que la enantioselectividad dependa tanto de la
concentracin como de la temperatura de la reaccin. La utilidad de esta reaccin
qued demostrada en la sntesis de un inhibidor nonuclesido de la transcriptasa
inversadeVIH.
Esquema2.1.AlquinilacinenantioselectivadeNacilcetiminascclicas.
Aligualqueenelejemploanterior,muchosprocesosdiseadosparalasntesis
de propargilaminas quirales utilizaban reactivos bsicos fuertes incompatibles con
sustratossensibles,locualconducaalanecesidaddellevaracaboladesprotonacin
19
Captulo2
delalquinoenunpasoprevio.Porotraparte,laelevadareactividaddelosalquiniluros
delitio,magnesiooaluminioresultantesnosiemprepermitaunbuenestereocontrol
delareaccin,repercutiendodeformanegativaenlaenantioselectividaddelproceso
de alquinilacin. Este problema se solucion generando in situ los reactivos
organometlicos acetilnicos a partir de un precursor metlico adecuado que
permitiera la adicin directa de los acetilenos a las iminas bajo condiciones
compatiblesconotrosgruposelectroflicos.Paraello,sehanutilizadoconxitoalquil
cupratos,boranos,estannanosoreactivosorganozncicos.
Chongycolaboradores2publicaronunejemplodeadicindealquinilboronatos
a Naciliminas en presencia de cantidades estequiomtricas de 2,2binaftoles 3,3
disustituidos (Esquema 2.2). Los mejores resultados en trminos de rendimiento y
estereoselectividad se alcanzaron con los binaftoles 3,3difenil disustituidos, con
diversos alquil y aril acetilenos, pero nicamente con iminas no enolizables. Esta
reaccinmostrsuutilidadenlasntesisde()Nacetilcolchinol.
Esquema2.2.AlquinilacinenantioselectivadeNacetilaldiminasconalquinilboronatos.
2.1.2.Procedimientosenantioselectivoscatalticos
2.1.2.1.Adicionesenantioselectivascatalizadasporcobre
La primera reaccin cataltica de alquinilacin enantioselectiva de iminas la
llevaronacaboWeiyLi3en2002,quienesemplearonsalesdeCu(I)yligandosdetipo
N,N(Figura2.1)enlaadicindefenilacetilenoaNfenilbenzaldiminasenagua.
20
Captulo2
Figura2.1.(ayb)Ligandosdetipobisoxazolina(BOX).(c,dye)Ligandosdetipo2,6
bis(oxazolin2il)piridina(PyBOX).
LacombinacindeligandosdetipoPyBOXytriflatodecobre(I)diolosmejores
resultados. Se examin la reaccin con un conjunto de iminas aromticas y
fenilacetileno en las condiciones optimizadas, obtenindose las correspondientes
propargilaminas con enantioselectividades elevadas y buenos rendimientos tanto en
aguacomoentolueno(Esquema2.3).
Esquema2.3.Adicinenantioselectivadefenilacetilenoaiminasaromticascatalizadapor
CuOTfPyBOX.
Enuntrabajoposterior,estosmismosautoresutilizaronestesistemacataltico
con alquinos alifticos,4 con los cuales se obtuvieron peores rendimientos y
enantioselectividadesqueconfenilacetileno(Esquema2.4).Elestudiotambinmostr
lagraninfluenciadeldisolventesobrelaenantioselectividaddelareaccin.
21
Captulo2
Esquema2.4.AdicinenantioselectivadealquinosalifticosaNfenilbenzaldiminacatalizada
porCuOTfPyBOX.
Variosaosmstarde,en2007,LiyChan5consiguierondisminuireltiempode
reaccin requerido para la reaccin desarrollada por Wei y Li en agua mediante la
adicindecidoestericocomosurfactante(Esquema2.5).Lareaccindeadicinde
fenilacetileno a Nfenilbenzaldimina se complet en la mitad de tiempo
proporcionando el compuesto deseado con un 86% rendimiento y 85% ee, que eran
ligeramente superiores a los obtenidos sin surfactante (71%, 84% ee). Adems, el
catalizadorpodareutilizarsetraslaextraccindelosproductosdelafaseacuosacon
hexano.Aunqueseobservunaligeraprdidadelaactividadconlossucesivosciclos,
laenantioselectividadsemantuvoconsistente.
Esquema2.5.AlquinilacinenantioselectivadeNariliminasconCu(I)PyBOXycidoesterico
enagua.
Chan y colaboradores emplearon un sistema cataltico similar para la

alquinilacin enantioselectiva de imino steres.6,7 El desarrollo de esta reaccin se
22
Captulo2
bas en un estudio previo realizado por estos mismos autores sobre la sntesis de
aminasproparglicasracmicas.8Enl,llevaronacabolaadicindealquinosalifticos
terminales a imino steres en presencia de cantidades catalticas de sales de Ag(I)
paradarloscorrespondientes,alquinilaminocidos.
Enlaversinenantioselectiva,losautoresexaminaronlareaccinentre4fenil
1butino y el imino ster etlico derivado del cido glioxlico en presencia de Ag(I)
(Esquema2.6),sinencontrarresultadossatisfactorios.Porestemotivo,centraronsus
esfuerzosenotrosmetalesdetransicin.Lautilizacindeiminasderivadasdelapara
metoxianilina(PMPNH2),CuOTf0,5C6H6yunligandoquiraldetipoPyBOXderivadode
1amino2indanol con gran congestin estrica proporcionaron el producto deseado
con90%derendimientoy85%ee.
Esquema2.6.Adicinenantioselectivade4fenil1butinoaiminosteres.
Los autores propusieron un mecanismo (Esquema 2.7) que implica la

coordinacin del sustrato y el alquino al centro metlico para producir el
correspondiente intermedio, en el que el tomo de nitrgeno del imino ster acta
como base en la formacin del alquiniluro de Cu(I) y el ion metlico se coordina al
triple enlace. A continuacin, se produce la transferencia intramolecular de protn y
alquinoparaalcanzarelcomplejofinalcuyadescoordinacinsuponelaliberacindel
productoylaregeneracindelcatalizador.
23
Captulo2
Esquema2.7.Mecanismopropuestoparalaalquinilacindeiminosteres.
Posteriormente,estosmismosautores,describieronlaadicindefenilacetileno
almismoiminosterempleandocondicionessimilaresalasanterioresenpresencia
de parametoxianilina como aditivo.9,10 Sin embargo, el producto se obtuvo con un
rendimiento moderado (51%) y baja enantioselectividad (41% ee) tras 48 h de
reaccin, haciendo evidente la diferencia de reactividad entre alquinos alifticos y
aromticos.Losresultadosmejoraroncuandosellevacabolareaccinenausencia
de aditivo (64% rendimiento, 61% ee). El ligando difenil PyBOX result ser el ms
eficiente(Esquema2.8).Porotraparte,seobservqueunpequeoexcesodeligando
disminua la enantioselectividad, mientras que un exceso de cobre resultaba
beneficioso. Adems, el estudio mecanstico de la reaccin indicaba la presencia
moderadadeefectosnolinealespositivos.11
24
Captulo2
Esquema2.8.Adicinenantioselectivadefenilacetilenoaiminosteres.
En 2009, estos mismos autores publicaron la primera adicin cataltica

enantioselectivadealquinosaiminosterespromovidaporligandosdetipoPyBOXy
CuOTf0,5Tol.12 Tanto alquinos alifticos como aromticos reaccionaron dando el
producto de alquinilacin con rendimientos elevados y buena enantioselectividad
(Esquema2.9).
Esquema2.9.AdicindealquinosaiminosterescatalizadaporCu(I)yPyBOX.
Debido a la baja estabilidad que presentan los imino steres, Chan y

colaboradores pensaron en la posibilidad de generar estos sustratos in situ y de
disearunsistemacatalticoeficaztantoconalquinosalifticoscomoaromticos.As,
desarrollaron la adicin enantioselectiva de tres componentes utilizando un ceto
ster,pmetoxianilinayunalquinoterminalconducentea,alquinilaminocidos
mediante la utilizacin de un ligando de tipo PyBOX derivado de 1amino2indanol,
congrancongestinestrica,yCuOTf0,5C6H6(Esquema2.10).Lareaccintranscurri
25
Captulo2
con rendimientos buenos (6180%) y enantioselectividades moderadas tanto con

alquinosalifticoscomoaromticos(6674%ee).13
Esquema2.10.Adicinenantioselectivadetrescomponentescatalizadaporunligando
detipoPyBOXyCuOTf0,5C6H6.Sintesisde,alquinilaminocidos.
El grupo de Maruoka14 ha utilizado el sistema cataltico formado por
Cu(I)/PyBOX en la adicin enantioselectiva de alquinos terminales a sales de iminio
derivadas de dihidroisoquinolena (Esquema 2.11). Independientemente de la
naturalezaelectrnicadelossustituyentesydesuposicinenelanilloaromticodela
sal de iminio, se obtuvieron rendimientos casi cuantitativos (9399%) y elevados
excesosenantiomricos(8594%ee).Enestareaccinseevaluarondiversosalquinos
aromticos y alifticos con rendimientos (8299%) y enantioselectividades elevados
(8996%ee),aexcepcindelareaccinconel2tolilacetilenoy1heptino(43%y75%
ee,respectivamente).
Esquema2.11.Adicinenantioselectivadealquinosasalesdeiminioderivadasdela
dihidroisoquinolena.
26
Captulo2
Los autores tambin llevaron a cabo la alquinilacin enantioselectiva de sales

deiminioderivadasdeladihidroisoquinolenasustituidasenelC1.Paraello,aplicaron
lascondicionesdereaccinanterioresutilizandouncidodeBrnstedquiralcomoco
catalizador (Figura 2.2). Las tetrahidroisoquinolenas quirales se obtuvieron con
buenosrendimientos(8599%)yenantioselectividades(7995%ee).
Figura2.2.cidodeBrnstedquiral.
Con el objetivo de mejorar los resultados de las reacciones de alquinilacin

catalticaenantioselectivadeiminas,diversosgruposhancentradosusinvestigaciones
en la especie activa formada por complejos de Cu(I) y ligandos de tipo PyBOX
modificados.
En 2006, Bisai y Singh15 desarrollaron la adicin enantioselectiva de tres
componentesempleandounamezcla1:1:1,5debenzaldehdo,anilinayfenilacetileno
enpresenciadeCu(I)PyBOX(Esquema2.12).
Esquema2.12.AlquinilacinenantioselectivadetrescomponentescatalizadaporCu(I)PyBOX.
Los mejores resultados se alcanzaron con 5 mol % de CuPF6 y el ligando

altamente sustituido mostrado en el Esquema 2.12 en CHCl3, aunque se obtuvieron
enantioselectividades similares utilizando otras sales como CuOTf o incluso Cu(OTf)2.
27
Captulo2
Lareaccincondistintosaldehdos,aminasyalquinosdemostrlaampliaaplicabilidad
deestaestrategiacataltica.Seobservaronenantioselectividadessuperioresa91%ee
empleando aldehdos con sustituyentes de distinta naturaleza electrnica, anilina y
fenilacetileno.
OtrosautorestambinhanpreparadonuevosligandosdetipoPyBOXalosque
hanincorporadoestructurasdecarbohidratoscomofuentedequiralidad.Elgrupode
Boysen dise y sintetiz un ligando de este tipo a partir de Dglucosamina (Figura
2.3).16
Figura2.3.LigandoglucoPyBOX.
Los autores han descrito la utilizacin del complejo formado por el ligando
glucoPyBOX y CuOTf0,5C6H5 en la reaccin entre benzaldehdo y anilina con
fenilacetilenoendiclorometanoconunaexcelenteenantioselectividad(99%ee),pero
con un rendimiento del 69% (Esquema 2.13). Cuando se ensayaron las condiciones
optimizadasutilizandodiferentesbenzaldehdossustituidos,anilinayfenilacetileno,la
reaccintuvolugarconbuenosrendimientosyenantioselectividadesentre7080%ee.
Noobstante,laadicindetrimetilsililacetileno,aunqueconbuenaenantioselectividad
(90%ee),transcurriconunrendimientobajo(21%).Apesardenoserunresultado
excelente,eraelmejoreeobtenidoenlasreaccionesdescritashastaesemomentocon
eltrimetilsililacetileno.
Esquema2.13.AlquinilacinenantioselectivadeiminasconelligandoglucoPyBOX.
28
Captulo2
En 2010, Boysen sintetiz un nuevo ligando quiral de tipo PyBOX en el que

tambin haban incorporado estructuras de carbohidratos como fuente de
quiralidad.17Enconcretosintetizlabisespiro(isoxazolina)quesemuestraenlaFigura
2.4.Sinembargo,suaplicacinenlaalquinilacindeNfenilbenzaldiminadiolaamina
proparglicaconunrendimientodel52%yunaenantioselectividaddel17%ee.
Figura2.4.Ligandoespirobisespiro(isoxazolina)derivadodecarbohidratos.
DebidoalxitoalcanzadoporloscomplejosdeCu(I)yligandosdetipoPyBOX
en la alquinilacin de iminas, algunos autores centraron su atencin en nuevas
estrategiasencaminadasalreciclajeyreutilizacindelcatalizador.
Afonso y colaboradores publicaron la primera aproximacin basada en la
inmovilizacindelcatalizadorenlquidosinicos.18Seobservunafuertedependencia
entrelaestructuradelcatinylaenantioselectividad,peronoseapreciaroncambios
significativos en la enantioselectividad con respecto a la estructura del anin. Los
mejores resultados para la reaccin entre fenilacetileno y Nfenilbenzaldimina en
presencia de Cu(I) y el ligando quiral PyBOX se obtuvieron con el lquido inico 1n
butil3metilimidazolio bis(trifluorometilsulfonil)imida ([bmim][NTf2]) (74%, 94% ee)
(Esquema 2.14), similares a los obtenidos por Li y colaboradores3 en tolueno, pero
mejores que los obtenidos en agua. Se ensayaron diversas iminas, alcanzndose en
todosloscasosbuenosrendimientos(7492%)yenantioselectividades(8699%).
29
Captulo2
Esquema2.14.AlquinilacinenantioselectivadeiminasconCu(I)PyBOXinmovilizado
enlquidoinico[bmim][NTf2].
Losautoresdemostraronlaeficienciadelcatalizadortrasserrecicladodurante
6ciclosporextraccindelproductoconhexano.
En2005,Portoyycolaboradores19prepararonunconjuntodeligandosdetipo
PyBOX soportados sobre poliestireno. Tras incubarlos con CuOTf, llevaron a cabo la
reaccin de adicin de fenilacetileno a Nfenilbenzaldimina (Esquema 2.15). Se
observ una gran influencia del sustituyente de la oxazolina sobre la
enantioselectividad, aumentando esta al aumentar el tamao del sustituyente.
Sorprendentemente, el ligando que dio los mejores resultados en disolucin, fue el
quediolospeoresresultadoscuandoseutilizsoportadosobrepoliestireno.Elmejor
resultado se obtuvo con el ligando con sustituyentes tercbutilo (63% rendimiento,
83% ee). Desafortunadamente, la utilizacin en ciclos posteriores de catalizador
recuperadocondujoaunadisminucindelareactividad.Laadicindecidoascrbico
permitilacompletarecuperacindelcatalizadorensucesivosciclos,peroacostade
unaprdidatotaldelaenantioselectividad.
30
Captulo2
Esquema2.15.AlquinilacinenantioselectivadeiminasconCu(I)PyBOXsoportadosobre
poliestireno.
Moberg y Levacher disearon un nuevo ligando PyBOX unido a polmero de

poliestireno mediante clickchemistry.20 Este se ensay en la alquinilacin de
diversasiminasaromticas(Esquema2.16).Aunquelaenantioselectividadfuemenora
la lograda bajo condiciones homogneas, super los resultados observados con el
catalizador soportado de Portnoy (Esquema 2.15) y sus posibilidades de reciclaje
fueron superiores. La selectividad se reestableci recargando el polmero con triflato
decobre.
Esquema2.16.AlquinilacinenantioselectivadeiminasconelcatalizadorCu(I)PyBOXunidoal
polmeromedianteclickchemistry.
31
Captulo2
En2007,OLearyycolaboradoresestudiaronelsistemaformadoportriflatode
Cu(I) y Cu(II)fenil PyBOX inmovilizado electrostticamente en tolueno (Esquema
2.17).21
Esquema2.17.Alquinilacinenantioselectivadeiminasutilizandouncatalizadorinmovilizado
electrostticamente.
Los resultados fueron similares a los hallados en disolucin homognea. El

Cu(II) proporcion enantioselectividades superiores y mayor capacidad de
reutilizacin,yaqueaunqueenlossucesivoscicloslosrendimientosdisminuyeron,la
enantioselectividadnovari.
En 2011, Li y colaboradores22 disearon un catalizador de tipo Cu(I)PyBOX
soportado sobre nanopartculas de Fe3O4 que fue utilizado con xito en la adicin
enantioselectiva de alquinos aromticos a iminas aromticas (Esquema 2.18). La
principal ventaja de este catalizador es su fcil recuperacin por decantacin con
ayudadeunimnexterno.
Esquema2.18.Alquinilacinenantioselectivadeiminasutilizandouncatalizadorsoportado
sobrenanopartculasdeFe3O4.
32
Captulo2
En2010,elgrupodeNakamura23llevacabolareaccindetrescomponentes
entrealdehdos,aminasyalquinosalifticoscatalizadaporcomplejosdetipoPyBIMy
(CuOTf)2tolueno para dar lugar a las aminas proparglicas con rendimientos y
enantioselectividades elevadas independientemente de la naturaleza electrnica y
estricadelsustituyenteunidoalgrupocarbonilodelaldehdo(8998%ee)(Esquema
2.19). El valor ms bajo de exceso enantiomrico se obtuvo cuando se emple 3
metilbutanaly4fenil1butino(81%ee).
Esquema2.19.Sntesisdetrescomponentesdeaminasproparglicasquiralescatalizadapor
PyBIMyCu(OTf)2tolueno.
El grupo de Benaglia24,25 introdujo un nuevo tipo de catalizadores quirales

diferentesalosPyBOXparaalquinilacionesenantioselectivasdeiminas.Estosautores
sintetizaronunaseriedebisiminasconsimetraC2(Figura2.5)ylasexaminaronenla
adicin de fenilacetileno a Nfeniliminas derivadas del benzaldehdo con triflato de
cobre(I).
Figura2.5.BisiminasconsimetraC2.
Los mejores resultados se consiguieron con la bisimina en la que el

sustituyenteariloeselgrupopentafluorofenilo,CuOTfytoluenocomodisolvente(98%
rendimiento,81%ee)(Esquema2.20).Elsistemacatalticotambinfuncionconotras
iminas con diferentes sustituyentes aromticos unidos tanto al N como al C con
33
Captulo2
rendimientos entre buenos y excelentes y enantioselectividades hasta 80% ee. La

aplicabilidad de la reaccin pudo extenderse a alquinos alifticos, pero no mostr
enantioselectividadessatisfactoriasconpropiolatodemetiloytrimetilsililacetileno.
Esquema2.20.AdicinenantioselectivadefenilacetilenoaNfenilbenzaldiminapromovidapor
elcomplejodebisimina/Cu(I).
Estos autores aplicaron el mismo sistema cataltico a una versin de tres

componentesdelareaccinutilizandodiferentesligandos.26nicamentelautilizacin
como ligando de la bisimina con el grupo 2hidroxifenilo condujo a resultados
satisfactorios y solo en el caso del 2hidroxibenzaldehdo. Sin embargo, el resto de
aldehdosyaminasdieronresultadosinferioresquelareaccindedoscomponentes.
Tambin se ensayaron ligandos de tipo bisaminas en la reaccin con N
fenilbenzaldiminas.27 Solamente el ligando binaftil diamina (BINAM) proporcion los
productos de alquinilacin con buenos rendimientos y enantioselectividades
moderadas(Esquema2.21).
Esquema2.21.Adicinenantioselectivadefenilacetilenoaiminassustituidaspromovidacon
complejodebisamina/Cu(I).
34
Captulo2
ElgrupodeIsharadesarrollunnuevotipodeligandosenlosqueincorporaron
ungrupofenilaminoalaestructuraquiraldebinaftilo.28Ensayaronsueficienciaenla
alquinilacin de Nfenilbenzaldimina en presencia de Cu(I). Se observ una fuerte
dependenciadelaenantioselectividadrespectoalasustitucinenelanillodeanilina
del ligando, presentndose el ligando mostrado en el Esquema 2.22 como el ms
eficiente (73% rendimiento, 82% ee). No obstante, cuando se realiz la reaccin con
iminas sustituidas se obtuvieron rendimientos bajos y enantioselectividades
comprendidas entre 11 y 46% ee. Otros alquinos como pbromofenilacetileno o
trimetilsililacetileno mostraron una reactividad escasa o nula (16% y 0%,
respectivamente).
Esquema2.22.Adicinenantioselectivadefenilacetilenoaiminaspromovidaporelligando
binaftiloanilina/Cu(I).
En 2007, Chan y Li29,30 disearon una nueva clase de ligandos quirales

tridentados con estructura de Ntosilaminosalicilaldimina (Esquema 2.23). Estos
ligandos fueron capaces de catalizar la reaccin entre el reactivo de alquinilzinc
formadoapartirdefenilacetilenoyMe2ZneiminasaromticasenpresenciadeCu(II).
Sinembargo,laaplicabilidaddeestareaccinestlimitadaaaldiminasaromticas.
35
Captulo2
Ph
Ph
NH
SO2
N
HO
N
Ar1
Ar2
H
+ Ph
Ligando (20 mol %)

Cu(OTf)2 (20 mol %)
Me2Zn/tolueno
HN
Ar2
Ar1
Ph
42-89%
73-92% ee
Esquema2.23.Adicinenantioselectivadefenilacetilenoaiminassustituidaspromovidaporel
ligandoNtosilaminosalicilaldiminoyCu(OTf)2.
Simultneamente al trabajo pionero desarrollado por Wei y Li,3,4 el grupo de

Knochelpubliclaprimeraadicinenantioselectivadealquinosaenaminascatalizada
porCuBrQUINAPentoluenoatemperaturaambiente(Esquema2.24).31,32
Esquema2.24.AlquinilacinenantioselectivadeenaminascatalizadaporQUINAP/CuBr.
La enantioselectividad de la reaccin aument con el tamao de los grupos

unidosaltomodenitrgeno,dandomejoresresultadosconlasN,NdibencilyNalil
NbencilenaminasqueconlasN,Ndialilenaminas.Alquinosaromticosproporcionaron
enantioselectividades superiores a 80% ee, mientras que con alquinos
heteroaromticosoalifticosseobservaronenantioselectividadescomprendidasentre
54 y 72% ee. Los autores realizaron un estudio mecanstico que determin que el
protnacetilnicodelalquinosetransfierealaposicindelaenamina.Teniendoen
36
Captulo2
cuenta este hecho, propusieron un mecanismo de reaccin (Esquema 2.25) segn el

cual el complejo dimrico de cobre se disocia dando las especies de cobre
monomricas. A esta especie se coordinan sucesivamente el alquino y la enamina
formndose un intermedio zwitterinico que, tras la transferencia intramoleculardel
alquino al ion iminio, se disocia produciendo la amina proparglica libre y la
regeneracindelcatalizador.
Esquema2.25.Mecanismopropuestoparalasntesisenantioselectivadepropargilaminasa
partirdeenaminasconQUINAP/CuBr.
Con el objetivo de evitar la preparacin de enaminas sensibles y extender la

aplicabilidaddelareaccinanterioraaldehdosnoenolizabes,estosmismosautores
publicaron en 2003 la sntesis enantioselectiva de tres componentes utilizando el
mismosistemacatalticoytamizmolecularde4(Esquema2.26).33
37
Captulo2
Esquema2.26.Sntesisenantioselectivadetrescomponentesdepropargilaminas.
La alquinilacin requiri tiempos de reaccin largos (16 das), pero las

propargilaminas se obtuvieron con rendimientos altos y enantioselectividades de
moderadas a excelentes empleando tanto alquinos aromticos como alifticos.
Asimismo, la reaccin permiti modificaciones en la sustitucin de la amina y el
aldehdo. Sin embargo, la presencia de sustituyentes en orto al grupo carbonilo del
aldehdoproporcionlosproductosconresultadosinsatisfactorios.
Knochelycolaboradorespropusieronunmecanismo(Esquema2.27)enelque
el complejo dimrico de cobre quiral, despus de coordinarse con el alquino, se
coordina con el aminal intermedio (formado por la reaccin entre la amina y el
aldehdo).LadesprotonacindelalquinocoordinadoylaeliminacindeH2Odalugar
al complejo de cobre coordinado con el acetiluro y con un ion iminio. La adicin del
acetiluroalasaldeiminiosituadoenlaesferadecoordinacindelcomplejoquiralde
Cu(I)conducealapropargilaminaquiralyalaregeneracindelcatalizador.
38
Captulo2
Esquema2.27.Propuestamecansticaparalasntesisdetrescomponentesde
propargilaminas.
Losautorestambinestudiaronlaadicindetrimetilsililacetilenoenlareaccin
de tres componentes obteniendo los productos sililados con rendimientos altos y
enantioselectividades elevadas.3436 Las enantioselectividades observadas eran
menores para las reacciones con aldehdos aromticos que para las reacciones con
aldehdosalifticos,tantoramificadoscomolineales.Comounamuestradelautilidad
de esta reaccin se llev a cabo la sntesis de (S)(+)coniina, un alcaloide altamente
txico(Figura2.6).
Figura2.6.(S)(+)Coniina.
Uno de los mayores problemas que plantean los grupos unidos al tomo de
nitrgenoessudificultaddeeliminacin.KnochelyGommermman37observaronque
se obtenan mayores enantioselectividades con dibencilaminas (98%) que con
dialilaminas (90% ee). Sin embargo, los protocolos de desproteccin del grupo
benclico no fueron compatibles con el triple enlace de las aminas proparglicas. Por
39
Captulo2
ello, desarrollaron la reaccin con bis(fenilalil)aminas. Estas proporcionaron el

producto deseado con valores de exceso enantiomrico superiores que las
dialilaminas. Adems, se podan desproteger eficientemente utilizando una reaccin
desustitucinallicacatalizadaporPd(0)concidodimetilbarbitrico(Esquema2.28).
Esquema2.28.ReaccindedesproteccindeN,Nbis(fenilalil)propargilaminas.
El sistema cataltico formado por CuBrQUINAP tambin se ha aplicado a la

adicindealquinosterminalesaionesiminioderivadosdelaisoquinolena.Schreibery
Taylor38realizaronestareaccinconvariosalquinosobteniendorendimientosaltosy
enantioselectividades de buenas a excelentes (Esquema 2.29). Por otra parte, los
autoresaplicaronestametodologaareaccionesenfaseslidauniendolossustratosa
unas macroesferas de resina de poliestireno, aunque las enantioselectividades
alcanzadasfueroninferiores.
N
PPh2
R1
N
MeO
R2
Br
R3
R4
Ligando (5,5 mol %)

CuBr (5 mol %)
H
Et3N (1 equiv)
CH2Cl2, -55 oC
R1
N
MeO
R3
R4
67-95%
83-99% ee
Esquema2.29.Adicinenantioselectivadealquinosterminalesasalesdealquilisoquinolinio
catalizadaporCuBr/QUINAP.
40
Captulo2
Estesistemacatalticoseutilizenalasntesisde(S)()homolaudanosina,un
producto natural con actividad neurolgica, y en la preparacin de una molcula
inhibidoradecrecimientodelevaduras(Figura2.7).
Figura2.7.(a)(S)Homolaudanosina.(b)Molculainhibidoradelcrecimientodelevaduras.
ApesardelxitoobtenidoconlossistemasdetipoCuBrQUINAP,esteligando
presentaciertosinconvenientesdebidotantoasucostosasntesisyresolucindelos
enantimeros,comoasuelevadopreciocuandoseadquierecomercialmente.Porello,
Carreira y colaboradores desarrollaron en 2004 una serie de nuevos ligandos P,N
(PINAP)preparadosencuatropasossencillos(Figura2.8).39Lapresenciadeungrupo
quiral, (R)feniletilo, unido covalentemente a la unidad de biarilo quiral facilitaba la
separacindelosdiastereoismerosporcristalizacinocromatografaenslicagel.
Figura2.8.DiastereoismerosdelligandoPINAP.
EstosautoresemplearonelnuevoligandoPINAPparalamismareaccindetres
componentes previamente realizada por Knochel con CuBrQUINAP. La
enantioselectividadobservadaconelcomplejoCu(I)PINAPessuperioralalogradacon
elQUINAP(Esquema2.30).
41
Captulo2
Esquema2.30.Sntesisenantioselectivadetrescomponentesdepropargilaminascatalizada
porCu/PINAP.
Posteriormente, estos autores llevaron a cabo la misma reaccin utilizando

clorhidrato de 4piperidona en lugar de dibencilamina (Esquema 2.31).40 El
benzaldehdonocondujoaresultadossatisfactorios.Sinembargo,aldehdosalifticos
linealesyramificados,ascomo2furaldehdo,participaronenlareaccinconbuenos
rendimientos y enantioselectividades elevadas. Las piperidonas Nsustituidas
resultantessetransformaronenaminasprimariasconfacilidad.
Esquema2.31.Reaccindeacoplamientodetrescomponentescon4piperidonaHCly
desproteccindelasaminasproparglicasresultantes.
En 2009, Ardnsten y colaboradores41 examinaron la adicin de alquinos a

iminas utilizando como fuente de quiralidad diferentes derivados de amino cidos
capacesdeformarenlacesdehidrgenoconelnitrgenoazometnico(Esquema2.32),
aumentando as la electrofilia del doble enlace C=N. La utilizacin conjunta de P(o
tolil)3conNBocprolinacondujoalosmejoresresultados.
42
Captulo2
Esquema2.32.AlquinilacinenantioselectivadeiminaspromovidaporP(otolil)3,NBoc
prolinayCuPF6(MeCN)2.
Recientemente,elgrupodeShibasaki42hadesarrolladounprocedimientopara
la alquinilacin asimtrica cataltica de cetoiminas no cclicas basado en la activacin
simultneadelalquinoydelaiminamediantecondicionesdetransferenciadeprotn
(Esquema2.33).Elsistemacatalticoutilizadoestformadoporunligandoquiraltipo
bifosfina,(S,S)PhBPEymesitilcobre.Losproductosdealquinilacinseobtuvieroncon
buenosrendimientosyenantioselectividadesmoderadas.
Esquema2.33.Alquinilacinenantioselectivadecetiminascatalizadapor(S,S)PhBPEy
mesitilcobre
2.1.2.2.Adicionesenantioselectivascatalizadasporotrosmetales
Loscompuestosdedialquilzinchansidoampliamenteutilizadosenreaccinde
alquinilacin de iminas.43 Sin embargo, no es tan comn encontrar mtodos de
alquinilacin de iminas empleando reactivos de dialquinilzinc o alquilalquinilzinc. A
continuacinsepresentanlosmsdestacados.
En2003,elgrupodeHoveyda44describilaadicincatalticaenantioselectiva
dereactivosmixtosdealquinilzincaoanisidilbenzaldiminaspromovidaporelligando
43
Captulo2
quiral de tipo aminocido que se muestra en el Esquema 2.34 y en presencia de

Zr(OiPr)4HOiPr.
Esquema2.34.Adicinenantioselectivadereactivosdealquinilzincaiminascatalizadapor
Zr(IV).
Esteligandosepuedeprepararfcilmenteapartirdeaminocidoscomerciales
y 5metoxisalicilaldehdo. Se examinaron diferentes oanisidilbenzaldiminas con
sustituyentes de diversa naturaleza electrnica obtenindose enantioselectividades
entre81y90%eeyrendimientossuperioresa69%.Lapresenciadesustituyentesen
ortocondujoaundescensodelaenantioselectividad(69%ee).Elestudiosecentren
reactivos del tipo trimetilsililacetileno que proporcionaron aminas proparglicas
terminalestraslaeliminacindelgrupoTMS.Tambinseemplearonenestareaccin
otros reactivos de alquinilzinc alifticos y aromticos. Se pudo disminuir la carga de
catalizador hasta 2,5% de ligando y 10% de Zr(OiPr)4HOiPr, obtenindose buenos
resultados(90%rendimiento,86%ee).
Las aminas proparglicas sintetizadas se pudieron desproteger oxidativamente
paradarlacorrespondienteaminalibre(Esquema2.35).
44
Captulo2
Esquema2.35.Desproteccinoxidativadelgrupooanisidilo.
Estos mismos autores desarrollaron la sntesis de aminas proparglicas

mediante la reaccin de tres componentes entre aldehdos proparglicos, una amina
primariaaromticayunreactivodealquilzinc(Esquema2.36).45
Esquema2.36.Sntesisenantioselectivadetrescomponentesdepropargilaminasutilizando
reactivosdedialquilzinc.
Posteriormente, Jiang y Si46 describieron la aplicacin del aminoalcohol

indicado en el Esquema 2.37 como ligando estequiomtrico quiral para la adicinde
alquinosaiminascclicasactivadasporelgrupotrifluorometilo,enpresenciadetriflato
dezincytrietilamina.Estareaccinsupusoelpasoclaveenlasntesisdelcompuesto
conocido como DPC961, un anlogo del frmaco contra el VIH, Efavirenz (Sustiva,
BristoMyersSquibb) (Esquema 2.37). Adems, se ensayaron otros acetilenos
aromticos, allicos y sililsustituidos alcanzando resultados excelentes (rendimientos
superioresal63%,hasta99,5%ee).
45
Captulo2
Esquema2.37.Adicinenantioselectivadeciclopropilacetilenoatrifluorometiliminacclica.
Recientemente,elgrupodeMa47hallevadoacabolaadicindediinosaNacil
trifluorometiliminascclicasutilizandounligandoquiraldetipoaminoalcoholyMe2Zn
(Esquema 2.38). La reaccin tolera sustituyentes electrndadores y electrn
aceptoresenelanilloaromticodelaimina,ascomolaadicindediinosaromticos,
alicclicosyalifticosconrendimientosyenantioselectividadeselevados.
Esquema2.38.AdicindediinosaNaciliminascatalizadaporunligandodetipoaminoalcohol
yMe2Zn.
Los autores tambin sintetizaron los enantimeros opuestos de los productos

de diinilacin empleando el enantimero del ligando amino alcohol mostrado en el
Esquema 2.38. La eliminacin del grupo pmetoxibencilo y la reduccin parcial del
tripleenlaceprocedesinprdidadelapurezaptica.
En2006,elgrupodeBolmdescribielprimerejemplodeadicindeacetilenos
terminalesaNariliminaspromovidaporMe2Zn,enausenciadeligando.48Pocotiempo
despus, desarrollaron la sntesis de tres componentes de aminas proparglicas
46
Captulo2
mediadaporMe2Znutilizandovariosaldehdosyometoxianilina.49Laeficienciadela
reaccinconfenilacetilenopudomejorarsetrabajandobajocondicionesconcentradas
empleandocomonicodisolventeeltoluenodeladisolucindeMe2Znutilizada(2M).
A continuacin, desarrollaron la versin enantioselectiva aplicando esta
metodologa en presencia de un derivado de (1R,2S)norepinefrina como inductor
quiral (Esquema 2.39). Se utilizaron aldehdos aromticos, heteroaromticos y
alifticos sustituidos, ometoxianilina y fenilacetileno obtenindose rendimientos
entremoderadosyaltosyenantioselectividadescomprendidasentre68y97%ee.Sin
embargo, otros alquinos alifticos y trimetilsililacetileno dieron lugar a
enantioselectividadesinferiores(1353%ee).
Esquema2.39.Sntesisenantioselectivadetrescomponentesdeaminasproparglicas
utilizandounaminoalcoholyMe2Zn.
Teniendo en cuenta que la presencia de grupos electrnaceptores en el

nitrgeno azometnico aumenta la electrofilia del enlace C=N, nuestro grupo de
investigacinhadescritolaprimeraalquinilacinenantioselectivadeNsulfoniliminas
promovida por Me2Zn en presencia de ligandos de tipo BINOL (Esquema 2.40).50 En
esta reaccin, la reduccin del volumen de disolvente al 50% supuso una mejora
adicional de la enantioselectividad (de 96 a 98% ee), lo cual coincida con las
observacionesdeBolm.48,49
47
Captulo2
Esquema2.40.AdicinenantioselectivadealquinosaNtosiliminaspromovidaporMe2Zny
ligandostipoBINOL.
Se obtuvieron enantioselectividades elevadas (87>99% ee) con diferentes N

tosilbenzaldiminas independientemente de la naturaleza electrnica de los
sustituyentes del anillo bencnico. Ntosiliminas derivadas de aldehdos
heteroaromticos dieron la correspondiente sulfonilamida proparglica con buenos
rendimientos y valores de ee (6491% ee). Sin embargo, iminas alifticas mostraron
enantioselectividadesinferiores(1838%ee).Tambinseevalulareaccinutilizando
alquinos alifticos como 4fenil1butino y 1hexino con los que se alcanzaron ee
comprendidos entre 87100% y 7693%, respectivamente. La fcil eliminacin del
grupo tosilo en aminas proparglicas derivadas de alquinos alifticos con SmI2 hace
estemtodotilenelreadequmicafina.
Recientemente,elgrupodeMahaaplicadoestemismosistemacatalticoenla
adicin de diinos a Ntosiliminas.51 La adicin de 4fenil1,3butadiino a iminas
aromticas con grupos electrndadores y electrnaceptores en las posiciones orto,
metayparadelanillotranscurriconrendimientosyenantioselectividadeselevados.
Sin embargo, la utilizacin de iminas alifticas condujo a peores resultados. Este
protocolo tambin pudo extenderse con xito al uso de diversos diinos aromticos y
alifticos.
48
Captulo2
LareduccintotaldelostriplesenlacessellevacaboconPd/Cylareduccin
parcialdeunodelostripesenlacesserealizconLiAlH4.Ambosprocesosprocedensin
prdidadelaenantiopureza.Ladesproteccindelgrupoaminosellevacabosobreel
productodereduccintotalutilizandoSmI2.
Esquema2.41.AdicinenantioselectivadediinosaNtosiliminascatalizadaporBINOLZn.
El sistema cataltico formado por BINOLZn tambin fue utilizado por Zhang y
colaboradores52 en la alquinilacin enantioselectiva de alquinos a
trifluorometilcetoimino steres (Esquema 2.42). Se examinaron alquinos de diversa
naturaleza, aril, alquil y sililsustituidos. En todos los casos proporcionaron los
productosdeadicinconenantioselectividadesexcelentes.
49
Captulo2
Esquema2.42.Alquinilacinenantioselectivadetrifluorometilcetoiminosterescatalizada
porBINOLZn.
En 2008, el grupo de Wang53 public la alquinilacin enantioselectiva de N

(difenilfosfinoil)benzaldiminaspromovidaporEt2Znyligandosdetipoaminoalcohol.
Los resultados alcanzados con cantidades subestequiomtricas de ligando no fueron
satisfactorios(68%ee),porloquefuenecesarioaumentarlacargadepromotorquiral
hasta 100 mol % con lo que consiguieron un 78% rendimiento y una
enantioselectividaddel95%ee.Pocodespus,estosautoresemplearonelmismotipo
de iminas en la reaccin de adicin de trimetilsililacetileno (Esquema 2.43).54 Como
precursoresquirales,sintetizaronyensayarondiferentesaminoalcoholesconsimetra
C2 y C3. Examinaron aril, heteroaril y alquil iminas con buenos rendimientos y
enantioselectividades entre moderadas y altas (7295% ee). Tambin examinaron
varias N(dietoxifosfinoil)iminas obteniendo buenos resultados. La ventaja de estas
iminasesqueenlosproductosformadosresultafcilladesproteccinconHCl/MeOH
yladesililacinconBu4NF.
50
Captulo2
Esquema2.43.AdicinenantioselectivadetrimetilsililacetilenoaN(difenilfosfinoil)iminas
promovidaporEt2Znyligandosdetipoaminoalcohol.
En 2010, este mismo grupo dise y sintetiz un conjunto de ligandos

tridentados de tipo amino alcohol derivados de la prolina.55 Estos ligandos fueron
evaluados en la reaccin de adicin enantioselectiva de fenilacetileno, 2tienil y 3
tienilacetilenoaN(difenilfosfinoil)benzaldiminasaromticasenpresenciadedietilzinc,
proporcionandoloscorrespondientesproductosdeadicinconbuenosrendimientosy
enantioselectividadeselevadas(Esquema2.44).Sinembargo,laobtencindeaminas
proparglicas alifticas se consigui con enantioselectividades moderadas y
nicamente utilizando amido sulfonas como precursores de las N
(difenilfosfinoil)benzaldiminas.
Esquema2.44.AdicinenantioselectivadealquinosaN(difenilfosfinoil)iminas.
51
Captulo2
2.2.OBJETIVOS
La finalidad de este primer captulo es el diseo de un sistema cataltico que
permita llevar a cabo la sntesis enantioselectiva de aminas proparglicas quirales
mediantelareaccindeadicindealquinosterminalesaN(difenilfosfinoil)aldiminas
conbuenosrendimientosyexcesosenantiomricos.
Paraello,sevaallevaracaboelestudiodelossiguientesaspectos:
1. Identificacin de las condiciones ptimas de reaccin: Influencia de la
estructura de diversos ligandos de tipo (R)BINOL (L1L7) sobre el
rendimiento y la enantioselectividad de la reaccin de adicin de
fenilacetilenoaN(difenilfosfinoil)benzaldimina.

temperatura,eldisolventeyelreactivodedialquilzincutilizado.
53
Captulo2
3. Alcance y limitaciones de la reaccin: Evaluacin de diversas N

(difenilfosfinoil)aldiminas aromticas y alifticas con diferente naturaleza
electrnicayestricaenlareaccindeadicindefenilacetileno.
4. Alcance y limitaciones de la reaccin: Evaluacin de distintos alquinos

aromticosyalifticoscondiferentenaturalezaelectrnicayestricaenla
reaccinconN(difenilfosfinoil)aldiminas.
5. Desproteccin del grupo amino en los productos de alquinilacin para

obtenerlasaminasproparglicaslibres.
6. Determinacin de la configuracin absoluta del centro estereognico

presenteenlasaminasproparglicasquiralesobtenidas.
54
Captulo2
2.3.RESULTADOSYDISCUSIN
2.3.1.SntesisdeN(difenilfosfinoil)iminas
LasN(difenilfosfinoil)iminas1seprepararondeacuerdoconelprocedimiento
experimental descrito en la bibliografa.56 Este consisti en la reaccin de P,P
difenilfosfinamida con el aldehdo correspondiente en presencia de tetracloruro de
titanioytrietilaminautilizandodiclorometanocomodisolventea0C(Tabla2.1).
Lapurificacindelasiminassintetizadasserealizmediantecromatografade
columna sin que se observara descomposicin por hidrlisis de las mismas. No
obstante,todaslasiminasseobtuvieronconrendimientosbajosomoderados.
Tabla2.1.SntesisdeN(difenilfosfinoil)iminas1.
Entrada
R(%)
5a
Ph
1a
52
5b
4MeC6H4
1b
64
5c
4MeOC6H4
1c
61
5d
4FC6H4
1d
38
5e
4ClC6H4
1e
45
5g
3MeC6H4
1g
63
5h
2MeC6H4
1h
51
5i
2MeOC6H4
1i
60
5k
2naftil
1k
52
10
5m
2furanil
1m
16
11
5n
2tienil
1n
53
12
5o
3furanil
1o
43
La numeracin de los aldehdos se corresponde con la indicada en el
Anexo II. b Rendimiento de producto aislado por cromatografa de

columna.
55
Captulo2
Todos los intentos de sintetizar la N(difenilfosfinoil)imina derivada del

dihidrocinamaldehdo mediante el procedimiento anteriormente descrito o
modificacionesdeestefueroninsatisfactorios.Porello,estaiminasepreparinsitua
partir de la amido sulfona correspondiente en las condiciones de la reaccin de
alquinilacin.
La preparacin de la amido sulfona se realiz mediantela reaccinentre la
P,Pdifenilfosfinamida y dihidrocinamaldehdo en presencia de cido sulfnico
utilizandodietilteranhidrocomodisolventeatemperaturaambiente(Esquema2.45).
Tras15hdereaccin,seobtuvoelproductodeseadocomoprecipitadoblanco,quese
purificporfiltracinylavadocondietilter.
Esquema2.45.SntesisdeN{1[(4metilfenil)sulfonil]3fenilpropil}P,Pdifenilfosfinamida7.
2.3.2.Optimizacindelascondicionesdereaccin
Para llevar a cabo el proceso de optimizacin de la reaccin de alquinilacin
enantioselectivadeNfosfoniliminas,seeligilareaccindeadicindefenilacetileno
(2a)aN(difenilfosfinoil)benzaldimina(1a).Inicialmente,setomaroncomoreferencia
las condiciones optimizadas para la alquinilacin enantioselectiva de Ntosiliminas
publicadaanteriormentepornuestrogrupo.50As,seaadiunadisolucindeMe2Zn
2Mentoluenosobrefenilacetileno.Tras1horadeagitacin,seaadiunadisolucin
deBINOL(L1)entoluenoy,transcurridos15min,seadicionlaimina(Procedimiento
A, Figura 2.9). Sin embargo, despus de sucesivos intentos de optimizacin, no
encontramos resultados satisfactorios, por lo que decidimos modificar el
procedimientoexperimental.Dichamodificacinsebasenvariarelordendeadicin
de los reactivos implicados en la formacin de la especie cataltica. El nuevo
procedimientoconsistiendisolverelfenilacetilenoyBINOL(L1)entolueno,aadirla
disolucindeMe2Zn2Mentoluenoy,trasformarlaespeciecatalticadurante1hora,
adicionarlaimina(ProcedimientoB,Figura2.9).
56
Captulo2
PROCEDIMIENTOAPROCEDIMIENTOB
+R Zn
2
+(R)BINOL
1h
(R)BINOL
R2Zn
15min
imina
5min
1h
imina
Figura2.9.ProcedimientosexperimentalesAyB.
Debido a que la aplicacin de este nuevo procedimiento (Procedimiento B,

Figura 2.9), condujo a resultados esperanzadores, comenzamos el proceso de
optimizacin ensayando una serie de ligandos de tipo BINOL en presencia de 6
equivalentes de Me2Zn (2 M en tolueno), utilizando tolueno como disolvente a 0 C
(Tabla 2.2). Los resultados revelaron que el tamao de los sustituyentes en las
posiciones 3,3 del BINOL utilizado como ligando tiene un efecto esencial sobre el
rendimientoylaenantioselectividaddelareaccin.
Figura2.10.LigandosdetipoBINOL.
El ligando L1, que soporta el sustituyente de menor tamao (X1 = H),

proporcionlaenantioselectividadmsbajayunrendimientomoderado(Tabla2.2),
mientrasqueel3,3dibromobinol(L3)(X1=Br)dioelmejorresultado(84%eey81%
derendimiento).Sinembargo,unmayorincrementodelimpedimentoestricodelos
57
Captulo2
sustituyentesenlasposiciones3,3condujoamenoresenantioselectividades.As,con
elligandoL6(X1=3,5diCF3C6H3),seobtuvounaenantioselectividaddel36%eeycon
elligandoL7(X1=2,4,6triiPrC6H2)del22%ee.
Tabla 2.2. Adicin enantioselectiva de fenilacetileno (2a) a N(difenilfosfinoil)imina 1a
utilizandoMe2Zn.Screeningdeligandos,temperaturasydisolventes.a
Entrada
Disolvente
T(C)
t(h)
R(%)
ee(%)d
L1
Tolueno
20
68
L2
Tolueno
48
66
37
L3
Tolueno
30
81
84
L4
Tolueno
24
57
12
L5
Tolueno
30
75
72
L6
Tolueno
24
63
36
L7
Tolueno
35
68
22
L3
Tolueno
ta
20
84
24
L3
Tolueno
20
48
63
65
10
L3
Hexano
20
70
11
L3
CH2Cl2
30
61
57
12
L3
THF
48
73
20
13e
L3
Tolueno
30
75
73
14f
L3
Tolueno
48
66
73
1a(0,125mmol),2a(0,900mmol),Me2Zn2Mentolueno(0,750mmol),L(0,025mmol).b0,2
mLconLy0,4mLconlaimina. cRendimientodeproductoaislado. d DeterminadoporHPLC

usandofasesestacionariasquirales.eEt2ZnenlugardeMe2Zn.fMe2Zn(0,500mmol).
Una vez identificado el ligando L3 como el que proporcionaba los mejores

resultados entre los BINOLES ensayados, la optimizacin de las condiciones de
reaccin continu ensayando la reaccin a distintas temperaturas, con varios
58
Captulo2
disolventes y reactivos de dialquilzinc (Tabla 2.2, Entradas 814). Tanto una

disminucin de la temperatura a 20 C, como un incremento hasta temperatura
ambiente(ta),tuvieronunefectonegativosobrelaenantioselectividad.Asimismo,la
utilizacindeotrosdisolventes(hexano,diclorometanoytetrahidrofurano)resulten
un detrimento del rendimiento y la enantioselectividad. Finalmente, la utilizacin de
Et2Zn en lugar de Me2Zn, tambin proporcion peores valores de exceso
enantiomrico. Por tanto, los mejores resultados en trminos de rendimiento y
enantioselectividadseobtuvieroncuandosellevacabolareaccinconelligandoL3,
dimetilzincytoluenoa0C(Tabla2.2,Entrada3).
2.3.3.Alcanceylimitacionesdelareaccin
Acontinuacin,seexaminlareaccindeadicindefenilacetileno(2a)avarias
N(difenilfosfinoil)iminas1bajolascondicionesoptimizadas(Tabla2.3).
Las diferentes benzaldiminas ensayadas proporcionaron los productos de
alquinilacin
con
enantioselectividades
entre
buenas
muy
buenas,
independientementedelanaturalezaelectrnicaoestricadelossustituyentesenel
anilloaromticodelaimina(Tabla2.3,Entrada18).Tantolossustituyenteselectrn
dadores (Me, MeO), como los electrnaceptores (F, Cl), as como la sustitucin en
orto, meta y para fueron bien toleradas. Es destacable que las arilaldiminas con un
sustituyente en la posicin orto proporcionaron el producto de alquinilacin con
rendimientomoderadoybuenaenantioselectividad(Tabla2.3,Entradas78).Resulta
particularmenteinteresantelareaccindefenilacetileno(2a)conN(difenilfosfinoil)2
metilbenzaldimina(1h),lacualdio,connuestrosistemacataltico,elproducto3hacon
un 71% de rendimiento y una enantioselectividad del 86% ee, frente a un 72% de
rendimientoy33%eeconelsistemacatalticodescritoporWang.53
La N(difenilfosfinoil)imina 1k voluminosa derivada de 2naftilcarbaldehdo
proporcion la correspondiente amida proparglica 3ka con un buen valor de exceso
enantiomrico(76%)(Tabla2.3,Entrada9).
59
Captulo2
Tabla2.3.Adicinenantioselectivadefenilacetileno(2a)aN(difenilfosfinoil)iminas1.a
t(h)
R(%)
ee(%)c
Ph
30
3aa
81
84
1b
4MeC6H4
24
3ba
60
85
1c
4MeOC6H4
30
3ca
54
96
1d
4FC6H4
42
3da
67
76
1e
4ClC6H4
24
3ea
61
65
1g
3MeC6H4
48
3ga
59
68
1h
2MeC6H4
30
3ha
71
86
1i
2MeOC6H4
42
3ia
56
77
1k
2naftil
48
3ka
62
76
10
1m
2furanil
24
3ma
68
91
11
1n
2tienil
30
3na
68
78
12
1o
3furanil
30
3oa
46
83
13d
1q
PhCH2CH2
30
3qa
37
16
Entrada
1a
1(0,125mmol),2a(0,900mmol),2MMe2Znentolueno(0,750mmol),L3(0,025mmol).b
Rendimientotraslacromatografadecolumna.cDeterminadomedianteHPLCusandofases
estacionariasquirales.dEstaalquiliminafuepreparadainsituapartirdelacorrespondiente
amidosulfona.
TambinseevaluaronunconjuntodeN(difenilfosfinoil)arilaldiminasderivadas
de aldehdos heteroaromticos (Tabla 2.3, Entradas 1012). Todas ellas dieron los
productosdealquinilacinconbuenosexcesosenantiomricos(7891%).Sinembargo,
laadicindefenilacetilenoalaiminaalquilsustituidageneradainsituapartirdela
amidosulfonacorrespondientetranscurriconbajorendimientoyenantioselectividad
(Tabla2.3,Entrada13).
60
Captulo2
Por otra parte, se estudi la aplicabilidad de la reaccin utilizando otros

alquinos.LosresultadossemuestranenlaTabla2.4.
Tabla2.4.Adicinenantioselectivadealquinos2aN(difenilfosfinoil)iminas1aand1h.a
t(h) 3
R(%) ee(%)d
2b 4MeOC6H4
20
3ab
69
85
Ph
2d 4FC6H4
30
3ad
69
91
1a
Ph
2e 4ClC6H4
24
3ae
79
92
1a
Ph
2g
3,5(MeO)2C6H3 20
3ag
64
90
1a
Ph
2j
3tienil
50
3aj
70
76
1a
Ph
2l
nbutil
72
3al
22
14
1a
Ph
2p ciclopropil
48
3ap
38
72
1h
2MeC6H4
2b 4MeOC6H4
48
3hb
93
90
1h
2MeC6H4
2d 4FC6H4
24
3hd
77
93
10
1h
2MeC6H4
2e 4ClC6H4
48
3he
81
73
11
1h
2MeC6H4
2g
3,5(MeO)2C6H3 48
3hg
67
85
12
1h
2MeC6H4
2j
3tienil
3hj
90
83
Entrada 1
1a
Ph
1a
2b
48
1(0,125mmol),2(0,900mmol),2MMe2Znentolueno(0,750mmol),L3(0,025mmol). b
LanumeracindelosalquinossecorrespondeconlaindicadaenelAnexoI. cRendimiento
tras purificacin por cromatografa de columna. d Determinado por HPLC utilizando fases
estacionariasquirales.
Las reacciones con 4metoxifenilacetileno (2b), 4fluorofenilacetileno (2d), 4

clorofenilacetileno
(2e)
3,5dimetoxifenilacetileno
(2g)
con
(difenilfosfinoil)benzaldimina (1a) condujeron a los correspondientes productos con

buenas enantioselectividades (8993%), por lo que podemos concluir que el sistema
tolerabiensustituyentesdedistintanaturalezaelectrnicaenelanilloaromticodel
alquino(Tabla2.4,Entradas14).
61
Captulo2
La reaccin con alquinos heteroaromticos como 3tienilacetileno (2j)

transcurri con enantioselectividad moderada, 76% ee (Tabla 2.4, Entrada 5). La
adicin de alquinos alifticos como el 1hexino o el ciclopropilacetileno a N
(difenilfosfinoil)benzaldimina (1a) tuvo lugar con rendimientos bajos (Tabla 2.4,
Entradas 67). No obstante, el producto de alquinilacin 3ap se obtuvo con
enantioselectividadmoderada.
Una de las principales ventajas que presenta el sistema cataltico que hemos
identificado para la alquinilacin enantioselectiva de iminas, frente a los descritos
previamenteesqueescompatibleconlautilizacindesustratoscuyoanilloaromtico
seencuentrasustituidoenlaposicinorto.Porello,seexaminlareaccindeadicin
de diversos alquinos aromticos a la imina orto sustituida 1h, obtenindose los
correspondientes productos de alquinilacin con enantioselectividades entre
moderadasybuenas(7393%)(Tabla2.4,Entradas812).
2.3.4.DesproteccindelaagrupacinN(difenilfosfinoil)amina
La desproteccin del grupo amino en las N(difenilfosfinoil)propargilaminas
sintetizadas puede llevarse a cabo fcilmente mediante un tratamiento con cido
clorhdricoenmetanol.Estareaccinproporcionlaaminalibre4conunrendimiento
de92%(Esquema2.46).
Esquema2.46.Desproteccindelgrupoamino.
2.3.5.Determinacindelaestereoqumicaabsoluta
El compuesto 4 obtenido por desproteccin del grupo amino nos permiti
establecerlaestereoqumicaabsolutadelcentroestereognicoformadoenlareaccin
de alquinilacin, por comparacin de su poder rotatorio con el descrito para este
mismo compuesto en la bibliografa53 (Figura 2.11). La amina proparglica 4 presenta
62
Captulo2
unaconfiguracin(S).LaestereoqumicadelrestodelasN(difenilfosfinoil)aminasse
asignporanaloga.
Figura2.11.Determinacindelaestereoqumicaabsolutadelaaminaproparglica4.
2.3.6. Propuesta mecanstica para la alquinilacin de N

(difenilfosfinoil)iminas
A continuacin, se propone un posible ciclo cataltico para la reaccin de
alquinilacin de N(difenilfosfinoil)iminas con (R)BINOL y Me2Zn (Figura 2.12).
InicialmenteseproduceladesprotonacindelligandoBINOLydelacetilenoporparte
deldimetilzincparadarlugarauncomplejocatalticoBINOLzincatometilalquinilzincI.
Este complejo se coordinara con la N(difenilfosfinoil)imina para dar lugar al
intermedio II. A continuacin tendra lugar la transferencia del alquiniluro desde el
metilalquinilzincalaimina,queliberaraelproductodereaccinyelBINOLzincatoIII.
Estesecoordinaraconotramolculademetilalquinilzinc,regenerandoaselcomplejo
catalticoyreiniciandoelciclo.
63
Captulo2
Figura2.12.CiclocatalticosimplificadoparalaalquinilacindeN(difenilfosfinoil)iminasen
presenciadecomplejosdeBINOLZn.
La molcula de alquinilmetilzinc coordinada a un oxgeno del BINOL en el

intermedioII,secoordinatambinaltomodeoxgenodelafosfinoilamidaatravs
deunanillodeseismiembros.Estacoordinacinasistelatransferenciadelalquiniluro
delzincalaiminaproporcionandolaamidaproparglicaconlaconfiguracin(S).
Figura2.13.ModeloestereoqumicoparalaalquinilacindeN(difenilfosfinoil)iminasen
presenciadecomplejosBINOLZn(unodelossustituyentesenelC(3)delligandohasido
omitidoporclaridad).
64
Captulo2
2.4.CONCLUSIONES
Sehadiseadounmtodoenantioselectivodeadicindealquinosterminalesa
N(difenifosfinoil)iminas catalizada por un sistema formado por un ligando de tipo
BINOLyMe2Zna0Centolueno.
Eltamaodelossustituyentesenlasposiciones3,3delBINOLtieneunagran
influenciasobreelrendimientoylaenantioselectividaddelareaccin.Elligando(R)
(+)3,3dibromo1,1binaphtol(L3)proporcionlosmejoresresultados.
SehanensayadotreceN(difenifosfinoil)iminasaromticasyheteroaromticas
con sustituyentes de diversa naturaleza electrnica y estrica en la reaccin de
alquinilacin con fenilacetileno. Los correspondientes productos de alquinilacin se
hanobtenidoconrendimientosentremoderadosybuenosyconenantioselectividades
de moderadas a elevadas. La utilizacin de una N(difenifosfinoil)imina aliftica
condujoarendimientoyenantioselectividadbajos.
Sehanutilizadocincoalquinosaromticosdediversanaturalezaelectrnicay
estricaenlaadicinalasN(difenifosfinoil)iminasderivadasdelbenzaldehdoydelo
tolualdehdo, proporcionando las correspondientes amidas proparglicas con buenos
rendimientos y enantioselectividades elevadas. Se obtuvieron resultados moderados
con la utilizacin de un alquino heteroaromtico. Alquinos alifticos condujeron a
resultadosvariables.
Se ha llevado a cabo la desproteccin de la agrupacin N(difenilfosfinoil)
amina,locualhapermitidoestablecerlaestereoqumicaabsolutadelosproductosde
alquinilacin.
Se ha realizado una propuesta mecanstica que explica la obtencin de las
amidasproparglicasconconfiguracin(S).
65
Captulo2
2.5.SECCINEXPERIMENTAL
2.5.1.Tcnicasgenerales
2.5.1.1.Tcnicasfsicasyespectroscpicas
Puntodefusin
Los puntos de fusin de los productos slidos se han determinado en tubos
capilares en un aparato Bchi Punto de Fusin M560 y en ningn caso han sido
corregidos.
Poderrotatorio
La determinacin de los valores de rotacin ptica se han medido en un
polarmetro PerkinElmer utilizando una lmpara de sodio (lnea D, 589 nm) y una
celdade1dmdelongitud.Lasconcentraciones(c)seexpresaneng/100mL.
ResonanciaMagnticaNuclear(RMN)
La mayora de los espectros de RMN se han registrado en un espectrmetro
BrukerAvance300DPX(300,13MHzparaRMN 1Hy75,48MHzpara 13C).Enalgunos
casos,sehautilizadounespectrmetroBrukerAvance400.
Se ha empleado CDCl3 como disolvente, tomando el residuo de disolvente no
deuteradocomoreferencia(7,26ppmpara 1Hy77,00ppmpara 13C).Los valoresde
desplazamiento qumico estn expresados en unidades (ppm) y las constantes de
acoplamiento (J) en hertzios (Hz). La multiplicidad del carbono se ha determinado
medianteexperimentosDEPT.(Abreviaturas:doblete(d),multiplete(m),cuadruplete
(q),singulete(s),triplete(t)).
EspectrometradeMasas
Losespectrosdemasasporionizacinporelectrospray(ESI)seregistraronen
un espectrmetro de masas Waters QTOF premier equipado con una fuente de
electrosprayconunvoltajecapilarde3,3kV.
67
Captulo2
2.5.1.2.Tcnicascromatogrficas
Cromatografadecapafina(CCF)
Para llevar a cabo la cromatografa de capa fina se han utilizado placas
cromatogrficas de Slica Gel Merck 60 F254 (ref 5554 Merck) de 0,2 mm de grosor
sobre soporte de aluminio. Una vez eluidas, se han observado a la luz UV y se han
revelado qumicamente con una disolucin de 10 g de Ce(SO4)2, 25 g de cido
fosfomolbdico y 80 mL de H2SO4 (conc.) en un litro de agua. Seguidamente, se han
calentadohastaobservarlacoloracinadecuada.
Cromatografadecolumnaflash
EnlacromatografadecolumnasehautilizadoSlicaGelMerck60,0,0400,063
mm de tamao de partcula (ref 109385 Merck). La fase mvil se ha especificado en
cadacaso.
Cromatografalquidadealtapresin(HPLC)
Los anlisis HPLC sobre fase estacionaria quiral se han desarrollado en un
instrumento Agilent 1100 Series o en un instrumento Hitachi Elite Lachrom, ambos
equipadosconundetectorL4500HitachiUVdiodoarray.Sehanutilizadocolumnas
CHIRALPAKADH(4,6x250mm),CHIRALCELODH(4,6x250mm)yCHIRALPAKIC(4,6
x250mm),fabricadasporDaicel.Lasmuestrassehaninyectadoenunbuclede20L
y se han eluido con una mezcla de hexano: isopropanol en proporciones adecuadas
con un flujo de 1 mL/minuto. Los tiempos de retencin (tr) estn expresados en
minutos.
2.5.1.3.Disolventes
Los disolventes utilizados para extracciones y eluciones en cromatografa de
capa fina y columna son de grado tcnico, convenientemente destilados. Para la
cromatografa de HPLC,se han utilizado disolventes de calidad HPLC. Los disolventes
utilizadosenlasreaccionessehansecadoypurificadosiemprequehasidonecesario.
ElCH2Cl2yeltoluenosehansecadosobreCaH2ydestiladoenatmsferadenitrgeno.
68
Captulo2
ElTHFyEt2OsehandestiladosobreNa/benzofenonabajoatmsferadenitrgeno.El
hexanosesecaysedestilasobreCaH2.
2.5.1.4.Reactivos
Todoslosreactivosadquiridoscomercialmentesehanutilizadosinpurificacin
previa.
2.5.1.5.Reacciones
Lasreaccionessellevaronacabobajoatmsferadenitrgenoenmatracesde
fondoredondosecadosenestufadurantetodalanochea120C.
2.5.2. Procedimientos generales de sntesis y caracterizacin de

nuevosproductos
2.5.2.1.SntesisycaracterizacindeN(difenilfosfinoil)iminas1
Seaadidifenilfosfinamida(1,00g,4,6mmol)ydiclorometano(50mL)enun
matrazdefondoredondode250mLyseenfria0Cbajoatmsferadenitrgeno.A
continuacin,seaaditrietilamina(1,93mL,4,6mmol),tetraclorurodetitanio(0,30
mL, 2,8 mmol) y aldehdo (4,6 mmol). Se dej que la mezcla de reaccin alcanzara
temperaturaambientey,tras1,5hdeagitacin,sefiltragravedadparaeliminarel
xidodetitanio.Elfiltradoserecogiyeldisolventeseeliminapresinreducidaen
elrotavapor.Elresiduosetratcondietilter(40mL)areflujoysefiltrparaeliminar
el cloruro de trietilamonio. El filtrado de este proceso se recogi y el disolvente se
elimin a presin reducida en el rotavapor. El residuo slido resultante se purific
mediante cromatografa de columna flash sobre slica gel empleando como eluyente
una mezcla de hexano:AcOEt, 4:6 para dar el producto 1. Debido a que las N
(difenilfosfinoil)iminas 1 haban sido descritas con anterioridad,56 solo se
caracterizaronmediante1HRMN.
69
Captulo2
(E)N(difenilfosfinoil)benzaldimina(1a)
Slidoblanco;1HRMN(300MHz,CDCl3)9.33(d,J=32.0Hz,
1H),8.037.91(m,6H),7.617.55(m,1H),7.537.41(m,8H).
1a
(E)N(difenilfosfinoil)ptolilaldimina(1b)
Slidoamarilloplido;1HRMN(300MHz,CDCl3)9.28(d,J=
32.2Hz,1H),7.977.89(m,6H),7.507.41(m,6H),7.31(d,J=
8.0Hz,2H),2.44(s,3H).
1b
(E)N(difenilfosfinoil)4metoxifenilaldimina(1c)
Slidoamarillo;1HRMN(300MHz,CDCl3)9.22(d,J=32.1
Hz, 1H), 7.987.89 (m, 6H), 7.497.40 (m, 6H), 6.98 (d, J =
8.8Hz,2H),3.87(s,3H).
1c
(E)N(difenilfosfinoil)4fluorofenilaldimina(1d)
1H), 8.067.99 (m, 2H), 7.977.89 (m, 4H), 7.547.42 (m, 6H),
7.19(t,J=8.6Hz,2H).
1d
70
Captulo2
(E)N(difenilfosfinoil)4clorofenilaldimina(1e)
1H),7.967.89(m,6H),7.547.42(m,8H).
1e
(E)N(difenilfosfinoil)mtolilaldimina(1g)
1H),7.987.91(m,4H),7.83(sa,1H),7.79(td,J=4.5,1.4Hz,
1H),7.537.41(m,6H),7.39(da,J=5.1Hz,2H),2.43(s,3H).
1g
(E)N(difenilfosfinoil)otolilaldimina(1h)
1H),8.15(dd,J=7.7,1.4Hz,1H),7.997.92(m,4H),7.527.40
(m, 7H), 7.32 (t a, J = 7.4 Hz, 1H), 7.24 (d a, J = 7.3 Hz, 1H),
2.67(s,3H).
1h
(E)N(difenilfosfinoil)naftalen2ilaldimina(1k)
1H),8.33(sa,1H),8.22(dd,J=8.6,1.7Hz,1H),8.027.88(m,
7H),7.637.54(m,2H),7.517.43(m,6H).
1k
71
Captulo2
(E)N(difenilfosfinoil)furan2ilaldimina(1m)
Slidomarrn; 1HRMN(300MHz,CDCl3)9.47(dd,J=32.8,
0.6 Hz, 1H), 7.957.88 (m, 4H), 7.717.70 (m, 1H), 7.527.40
(m,6H),7.19(d,J=3.5Hz,1H),6.60(dd,J=3.6,1.7Hz,1H).
1m
(E)N(difenilfosfinoil)tien2ilaldimina(1n)
Slidomarrn; 1HRMN(300MHz,CDCl3)9.33(dd,J=30.9,
0.7 Hz, 1H), 7.957.88 (m, 4H), 7.67 (d, J = 4.1 Hz, 2H), 7.53
7.41(m,6H),7.197.16(m,1H).
1n
(E)N(difenilfosfinoil)furan3ilaldimina(1o)
Slidomarrn; 1HRMN(300MHz,CDCl3)9.24(dt,J=31.8,
0.6 Hz, 1H), 8.007.99 (m, 1H), 7.947.86 (m, 4H), 7.527.41
(m,7H),6.97(dt,J=1.9,0.6Hz,1H).
1o
2.5.2.2.SntesisycaracterizacindelprecursordeN(difenilfosfinoil)2
feniletilaldimina(7)57
Sobre una suspensin de P,Pdifenilfosfinamida (1,00 g,
4,6mmol)ycidosulfnico(1,08g,6,9mmol)endietil
ter anhidro (40 mL) se aadi dihidrocinamaldehdo
(6,9 mmol, 6,9 mmol) a temperatura ambiente. La

mezcla se agit durante 15 h, durante las cuales se fue
formando un precipitando blanco. Cuando la reaccin se complet, la mezcla de

reaccinsefiltryelslidoblancoselavcondietilteranhidro(15mL)yseseca
vacoparaobtenerelproducto7.
1
HRMN(300MHz,DMSOd6)7.827.76(m,2H),7.567.43(m,10H),7.28(d,J=8.2
Hz,2H),7.217.18(m,3H),7.00(d,J=6.9Hz,2H),6.45(t,J=11.6Hz,1H),4.39(tdd,J=
72
Captulo2
21.2,21.2,2.1Hz,1H),2.692.64(m,1H),2.532.46(m,1H),2.35(s,3H),2.312.24(m,
1H),1.961.89(m,1H).
13
CRMN(75.5MHz,DMSOd6)145.3(C),141.4(C),136.0(C),134.3(CH),133.4(CH),
132.6(d,J=2.4Hz,C),132.4(d,J=2.4Hz,C),132.3(CH),132.1(CH),132.0(CH),130.5
(CH),129.4(CH),129.3(CH),129.2(CH),129.0(CH),128.9(CH),127.0(CH),72.9(CH),
31.9(CH2),31.7(CH2),22.0(CH3).
2.5.2.3.
Sntesis
caracterizacin
de
P,Pdifenilfosfinamidas
proparglicas3
Procedimiento general para la alquinilacin enantioselectiva de N
(difenilfosfinoil)iminas1
Se aadi gota a gota una disolucin de Me2Zn en tolueno (0,375 mL, 0,750
mmol) sobre una disolucin de ligando L3 (11,2 mg, 0,025 mmol) y alquino 2 (0,900
mmol)entolueno(0,2mL)atemperaturaambientebajoatmsferadenitrgeno.Tras
agitardurante1h,lamezcladereaccinseenfria0C.Tras15min,unadisolucin
deimina1(0,125mmol)entolueno(0,4mL)seaadivajeringuilla.Ladisolucinse
agithastaquelareaccinsecomplet(CCF).Lamezcladereaccinsehidrolizcon
HCl1M(15mL),seextrajoconCH2Cl2(315mL),sesecsobreMgSO4yseconcentr
avaco.Elproductosepurificmediantecromatografaflashencolumnadeslicagel
empleandocomoeluyenteunamezcladehexano:AcOEtparadar3.
LaalquinilacindeN(difenilfosfinoil)iminasracmicasellevacabosiguiendo
elmismoprocedimientoenpresenciadeligandoracmico()L1.
(S)N(1,3difenilprop2inil)P,Pdifenilfosfinamida(3aa)
El exceso enantiomrico (84%) se determin mediante
HPLC quiral (Chiralpak ADH), hexanoiPrOH 85:15, 1
mL/min, enantimero mayoritario tr = 13.9 min,
enantimerominoritariotr=12.5min.
3aa
Mp173175C;[]D2063.1(c0.90,CHCl3,84%ee).
73
Captulo2
1
H RMN (300 MHz, CDCl3) 8.138.06 (m, 2H), 7.907.83 (m, 2H), 7.717.69 (m, 2H),
7.547.46(m,4H),7.447.37(m,5H),7.357.30(m,5H),5.40(t,J=9.6Hz,1H),3.55(t,J
=9.3Hz,1H).
13
CRMN(75.5MHz,CDCl3)140.4(d,JCP=4.5Hz,C),133.4(CH),132.8(d,JCP=9.8
Hz,CH),132.1(d,JCP=6.8Hz,CH),131.7(CH),131.5(CH),129.0(CH),128.7(d,JCP=6
Hz,CH),128.4(d,JCP=12Hz,CH),128.0(CH),127.4(CH),122.8(C),89.0(d,JCP=6Hz,
C),85.6(C),47.2(CH).
HRMS(ESI)m/z:430.1336[M+Na]+,C27H22NNaOPrequiere430.1337.
(S)N(3fenil1ptolilprop2inil)P,Pdifenilfosfinamida(3ba)
El exceso enantiomrico (85%) se determin
medianteHPLCquiral(ChiralpakADH),hexanoiPrOH
85:15, 1 mL/min, enantimero mayoritario tr = 16.7
min,enantimerominoritariotr=15.0min.
Mp183185C;[]D2060.4(c0.79,CHCl3,85%ee).
3ba
1
7.527.42(m,4H),7.427.34(m,4H),7.327.26(m,3H),7.15(d,J=7.9Hz,2H),5.34(d,
J=9.31Hz,1H),3.64(sa,1H),2.32(s,3H).
13
CRMN(75.5MHz,CDCl3)137.7(C),137.4(d,JCP=4.6Hz,C),132.9(d,JCP=47.0
Hz,C),132.8(CH),132.7(CH),132.1(CH),132.00(CH),131.96(CH),131.8(CH)(d,JCP=
9.9 Hz, C), 131.6 (CH), 131.2 (d, J = 49.0 Hz, C), 129.3 (CH), 128.5 (CH), 128.4 (CH),
128.2(CH),127.2(CH),122.7(C),89.0(d,J=6.5Hz,C),85.4(C),46.9(CH),21.1(CH3).
(S)N(1(4metoxifenil)3fenilprop2inil)P,Pdifenilfosfinamida(3ca)
mediante HPLC quiral (Chiralpak ADH), hexano
3ca
74
Captulo2
PrOH 85:15, 1 mL/min, enantimero mayoritario tr = 19.9 min, enantimero
minoritariotr=15.7min.
Mp187189C;[]D2062.6(c1.06,CHCl3,96%ee).
1HRMN(300MHz,CDCl3)8.128.02(m,2H),7.897.79(m,2H),7.59(d,J=8.6Hz,
2H),7.527.42(m,4H),7.417.34(m,4H),7.337.26(m,3H),6.86(d, J=8.8Hz,2H),
5.34(t,J=9.7Hz,1H),3.78(s,3H),3.54(t,J=9.1Hz,1H).
13
CRMN(75.5MHz,CDCl3)159.2(C),133.4(C),132.8(CH),132.7(CH),132.5(d,JCP=
4.3Hz,C),132.0(d,J=2.9Hz,CH),131.9(d,J=2.8Hz,CH),131.8(d,JCP=9.8Hz,CH),
131.6 (CH), 128.6 (CH), 128.39 (CH), 128.37 (CH), 128.34 (CH), 128.2 (CH), 122.7 (C),
113.9(CH),89.0(d,JCP=6.2Hz,C),85.3(C),55.3(CH3),46.6(CH).
HRMS(ESI)m/z:438.1621[M+H]+,C28H25NO2Prequiere438.1617.
(S)N(1(4fluorofenil)3fenilprop2inil)P,Pdifenilfosfinamida(3da)
3da
Mp174175C;[]D2055.5(c1.04,CHCl3,76%ee).
7.557.28(m,11H),7.02(t,J=8.7Hz,2H),5.37(t,J=8.6Hz,1H),3.73(ta,J=8.1Hz,
1H).
13
CRMN(75.5MHz,CDCl3)162.3(d,JCF=246.5Hz,C),136.1(dd,JCP=JCF=3.6Hz,
C),133.1(C),132.8(CH),132.7(CH),132.1(d,JCP=2.8Hz,CH),132.0(d,JCP=2.7Hz,
CH), 131.8 (CH), 131.7 (CH), 131.6 (CH), 131.4 (C), 130.7 (C), 129.2 (CH), 129.1 (CH),
128.6 (d, J = 3.3 Hz, CH), 128.5 (CH), 128.4 (d, J = 3.2 Hz, CH), 128.3 (CH), 122.4 (C),
115.36(d,JCF=21.6Hz,C),88.5(d,JCP=6.7Hz,C),85.7(C),46.5(CH).
HRMS(ESI)m/z:426.1420[M+H]+,C27H21FNOPrequiere426.1418.
75
Captulo2
(S)N(1(4clorofenil)3fenilprop2inil)P,Pdifenilfosfinamida(3ea)
3ea
Mp193195C.[]D2046.4(c0.60,CHCl3,65%ee).
HRMN(300MHz,CDCl3)8.128.02(m,2H),7.887.79(m,2H),7.64(d,J=8.4Hz,
2H),7.597.44(m,4H),7.447.36(m,4H),7.367.28(m,5H),5.36(d, J=9.3Hz,1H),
3.933.55(sa,1H).
13
C RMN (75.5 MHz, CDCl3) 138.8 (d, JCP = 4.0 Hz, C), 133.8 (C), 132.8 (CH), 132.7
(CH), 122.4 (C), 132.2 (d, J = 2.7 Hz, CH), 132.1 (d, J = 2.7 Hz, CH), 131.8 (CH), 131.7
(CH),131.6(CH),128.8(CH),128.7(CH),128.7(CH),128.6(d,JCP=3.1Hz,CH),128.5
(d,J=2.7Hz,CH),128.3(CH),88.2(d,JCP=6.7Hz,C),85.9(C),46.6(CH).
HRMS(ESI)m/z:464.0945[M+Na]+,C27H21ClNNaOPrequiere464.0947.
(S)N(3fenil1mtolilprop2inil)P,Pdifenilfosfinamida(3ga)
3ga
Mp129131C;[]D2042.1(c1.45,CHCl3,68%ee).
H RMN (300 MHz, CDCl3) 8.098.02 (m, 2H), 7.877.80 (m, 2H), 7.24 (t, J = 7.6 Hz,
1H),7.09(d,J=7.6Hz,1H),5.34(t,J=9.3Hz,1H),3.59(t,J=8.2Hz,1H),2.34(s,3H).
13
CRMN(75.5MHz,CDCl3)140.3(d,JCP=4.7Hz,C),138.3(C),132.7(d,JCP=9.9Hz,
CH),131.8(d,JCP=9.9Hz,CH),131.6(CH),128.7(CH),128.6(CH),128.54(CH),128.51
(CH),128.4(CH),128.3(CH),128.3(CH),128.2(CH),128.0(CH),124.3(CH),122.7(C),
89.0(d,JCP=6.0Hz,C),85.4(C),47.1(CH),21.4(CH3).
76
Captulo2
(R)N(3fenil1otolilprop2inil)P,Pdifenilfosfinamida(3ha)
3ha
Mp184186C;[]D2057(c0.99,CHCl3,86%ee).
7.557.12(m,14H),5.52(t,J=8.8Hz,1H),3.52(ta,J=7.0Hz,1H),2.41(s,3H).
13
CRMN(75.5MHz,CDCl3) 1138.7(d,JCP=5.6Hz,C),135.6(C),132.5(d,JCP=9.9
Hz, CH), 131.9 (d, JCP = 4.6 Hz, CH), 131.9 (CH), 131.8 (CH), 131.6 (CH), 130.9 (CH),
128.5 (d, JCP = 2.5 Hz, CH), 128.3 (d, JCP = 2.4 Hz, CH), 128.2 (CH), 128.1 (CH), 127.0
(CH),126.4(CH),122.7(C),89.1(d,JCP=4.6Hz,C),85.0(C),44.4(CH),19.1(CH3).
HRMS(ESI)m/z:422.1683[M+H]+,C28H25NOPrequiere422.1668.
(R)N(1(2metoxifenil)3fenilprop2inil)P,Pdifenilfosfinamida(3ia).
Mp178180C;[]D2068.3(c0.65,CHCl3,77%ee).
HRMN(300MHz,CDCl3)7.997.91(m,2H),7.857.78(m,2H),7.487.23(m,13H),
6.92(td,J=7.5,1.1Hz,1H),6.86(dd,J=8.3,0.9Hz,1H),5.47(ta,J=9.4Hz,1H),4.03
(ta,J=8.8Hz,1H),3.78(s,3H).
13
CRMN(75.5MHz,CDCl3)156.6(C),133.4(C),132.3(d,JCP=9.8Hz,CH),132.2(d,
JCP=9.9Hz,CH),131.8(d,JCP=2.7Hz,CH),131.7(d,J=2.9Hz,CH),131.6(CH),129.3
(CH),129.1(d,JCP=5.0Hz,C),128.5(CH),128.3(d,JCP=3.1Hz,CH),128.2(d,JCP=4.4
Hz,CH),128.0(CH),123.0(C),120.8(CH),111.3(CH),89.4(d,JCP=6.1Hz,C),83.8(C),
55.5(CH3),43.7(CH).
77
Captulo2
(S)N(1(naftalen2il)3fenilprop2inil)P,Pdifenilfosfinamida(3ka)
Mp190192C;[]D2033.9(c1.33,CHCl3,76%ee).
3ka
1
HRMN(300MHz,CDCl3)8.128.05(m,2H),8.04(sa,1H),7.887.79(m,6H),7.51
7.30(m,13H),5.54(ta,J=9.5Hz,1H),3.72(ta,J=8.8Hz,1H).
13
CRMN(75.5MHz,CDCl3)137.6(d,JCP=4.5Hz,C),133.1(C),133.0(C),132.8(d,JC
P=9.9Hz,CH),132.1(d,JCP=2.8Hz,CH),132.0(d,JCP=2.7Hz,CH),131.9(CH),131.8
(CH),131.7(CH),128.7(CH),128.6(d,JCP=4.1Hz,CH),128.4(CH),128.3(CH),128.2
(CH),127.6(CH),126.2(CH),125.9(CH),125.5(CH),122.7(C),88.8(d,JCP=6.0Hz,C),
85.8(C),47.3(CH).
(R)N(1(furan2il)3fenilprop2inil)P,Pdifenilfosfinamida(3ma)
3ma
Mp133136C;[]D2044.7(c1.03,CHCl3,91%ee).
H RMN (300 MHz, CDCl3) 8.017.85 (m, 4H), 7.507.36
(m,9H),7.307.26(m,3H),6.37(dt,J=3.2,0.8Hz,1H),6.29(dd,J=3.3,1.9Hz,1H),
5.38(ta,J=9.2Hz,1H),3.69(ta,J=8.4Hz,1H).
13
C RMN (75.5 MHz, CDCl3) 152.1 (d, JCP = 5.8 Hz, C), 142.7 (CH), 132.7 (C), 132.5
(CH),132.3(CH),132.2(CH),132.1(d,JCP=6.5Hz,CH),131.8(CH),131.0(C),128.6(d,
78
Captulo2
JCP=3.0Hz,CH),128.5(CH),128.4(d,JCP=2.9Hz,CH),128.2(CH),122.3(C),110.4
(CH),107.5(CH),86.5(d,JCP=5.6Hz,C),84.4(C),41.4(CH).
(R)N(3fenil1(tien2il)prop2inil)P,Pdifenilfosfinamida(3na)
3na
Mp131133C;[]D2058.4(c0.91,CHCl3,78%ee)
1
H RMN (300 MHz, CDCl3) 8.078.00 (m, 2H), 7.937.85
(m,2H),7.527.38(m,8H),7.307.23(m,5H),6.93(dd,J=5.0,3.7Hz,1H),5.55(ta,J=
9.5Hz,1H),3.78(dd,J=9.9,8.1Hz,1H).
13
CRMN(75.5MHz,CDCl3)144.8(d,JCP=6.1Hz,C),132.8(C),132.5(d,JCP=10.0
Hz,CH),132.1(d,JCP=2.3Hz,CH),131.9(d,JCP=10.0Hz,CH),131.7(CH),131.0(d,JC
P=16.2Hz,C),128.6(d,JCP=1.1Hz,CH),128.5(CH),128.4(d,JCP=0.8Hz,CH),128.2
(CH),126.9 (CH),125.9 (CH),125.5 (CH),122.3 (C),88.3(d,JCP=5.4Hz,C),84.7(C),

43.1(CH).
HRMS(ESI)m/z:414.1074[M+H]+,C25H21NOPSrequiere414.1076.
(R)N(1(furan3il)3fenilprop2inil)P,Pdifenilfosfinamida(3oa)
3oa
Oil;[]D2049.0(c1.21,CHCl3,83%ee).
6.70(d,J=0.9Hz,1H),5.26(ta,J=9.6Hz,1H),3.51(ta,J=9.3Hz,1H).
79
Captulo2
13
CRMN(75.5MHz,CDCl3)143.6(C),140.4(CH),132.8(d,JCP=9.8Hz,CH),132.1
(C),131.8(CH),131.7(CH),128.7(d,JCP=4.5Hz,CH),128.5(d,JCP=3.8Hz,CH),128.3
(CH),126.5(CH),122.5(C),110.1(CH),88.3(C),83.6(C),39.8(CH).
(S)N(1,5difenilpent1in3il)P,Pdifenilfosfinamida(3qa)
3qa
Mp127129C;[]D209.7(c1.20,CHCl3,16%ee).
7.327.27(m,3H),7.257.11(m,5H),4.214.09(m,1H),3.27(dd,J=10.2,8.1Hz,1H),
2.942.75(m,2H),2.272.07(m,2H).
13
CRMN(75.5MHz,CDCl3)141.0(C),133.5(C),132.6(d,JCP=9.9Hz),132.0(d,JCP=
2.7Hz,CH),131.7(d,JCP=9.9Hz,CH),131.7(CH),130.8(C),128.6(CH),128.5(CH),
128.42(CH),128.39(CH),128.3(CH),128.4(CH),125.9(CH),122.8(C),89.7(d,JCP=
7.4Hz,C),84.2(C),43.8(CH),40.3(d,JCP=3.7Hz,CH2),32.0(CH2).
HRMS(ESI)m/z:458.1651[M+Na]+,C29H26NOPNarequiere458.1650.
(S)N(3(4metoxifenil)1fenilprop2inil)P,Pdifenilfosfinamida(3ab)
Mp173175C;[]D2067.9(c1.02,CHCl3,85%ee).
3ab
1
7.377.27(m,11H),6.82(d,J=8.9Hz,2H),5.36(t,J=9.6Hz,1H),3.79(s,3H),3.57(t,J
=9.0Hz,1H).
80
Captulo2
13
CRMN(75.5MHz,CDCl3)159.7(C),140.5(d,JCP=4.5Hz,C),133.1(CH),132.8(d,
JCP=9.8Hz,CH),132.0(CH),131.97(CH),131.93(CH),131.89(CH),131.8(CH),128.6
(CH),128.5(d,JCP=12.6Hz,CH),127.9(CH),126.5(CH),126.3(CH),114.8(C),113.8
(CH),87.4(d,JCP=6.1Hz,C),85.5(C),55.3(CH3),47.2(CH).
HRMS(ESI)m/z:460.1448[M+Na]+,C28H24NNaO2Prequiere460.1442.
(S)N(3(4fluorofenil)1fenilprop2inil)P,Pdifenilfosfinamida(3ad)
3ad
Oil;[]D2047.3(c1.42,CHCl3,91%ee).
7.517.28(m,11H),6.97(t,J=8.8Hz,2H),5.30(t,J=9.0Hz,1H),3.55(t,J=7.8Hz,
1H).
13
CRMN(75.5MHz,CDCl3)162.5(d,JCF= 249.6Hz,C),140.2(d,JCP=4.9Hz,C),
133.5(d,JCP=8.3Hz,CH),132.7(d,JCP=9.7Hz,CH),132.0(d,JCP=2.2Hz,CH),131.9
(d,JCP=9.9Hz,CH),128.7(CH),128.5(d,JCP=12.7Hz,CH),128.0(CH),127.2(CH),
118.7(d,JCF=3.6Hz,C),115.5(d,JCF=22.0Hz,CH),88.5(d,JCP=4.5Hz,CH),84.5(C),
47.1(CH).
HRMS(ESI)m/z:448.1247[M+Na]+,C27H21FNNaOPrequiere448.1242.
(S)N(3(4clorofenil)1fenilprop2inil)P,Pdifenilfosfinamida(3ae)
3ae
Mp165167;[]D2072.5(c0.32,CHCl3,92%ee).
81
Captulo2
7.517.24(m,13H),5.30(t,J=9.1Hz,1H),3.53(t,J=7.9Hz,1H).
13
CRMN(75.5MHz,CDCl3)140.1(d,JCP =5.2Hz,C),134.4(C),132.9(CH),132.7(d,
JCP =9.8Hz,CH),132.0(d,JCP=2.3Hz,2CH),131.8(d,JCP=9.8Hz,CH),128.7(CH),
128.6(CH),128.5(CH),128.4(CH),128.1(CH),127.2(CH),121.0(C),89.8(d,JCP =6.0
Hz,C),84.5(C),47.1(CH).
(S)N(3(3,5dimetoxifenil)1fenilprop2inil)P,Pdifenilfosfinamida(3ag)
i
PrOH85:15,1mL/min,enantimeromayoritariotr=
20.7min,enantimerominoritariotr=16.9min.
Mp169171C;[]D2063.4(c0.69,CHCl3,90%ee).
3ag
HRMN(300MHz,CDCl3)8.098.02(m,2H),7.86
7.79(m,2H),7.677.64(m,2H),7.517.27(m,10H),6.54(d,J=2.3Hz,2H),6.43(t,J=
2.3Hz,1H),5.37(t,J=9.3Hz,1H),3.76(s,6H).
13
CRMN(75.5MHz,CDCl3)160.4(C),140.3(d,JCP=4.6Hz,C),132.8(d,JCP=9.9Hz,
CH),132.1(CH),132.02(CH),131.99(CH),131.8(d,JCP=9.8Hz,CH),128.5(d,JCP=
12.6Hz,CH),128.0(CH),127.3(CH),123.9(C),109.5(CH),101.7(CH),88.4(d,JCP=5.9
Hz,C),85.5(C),55.4(CH3),47.1(CH).
HRMS(ESI)m/z:490.1557[M+Na]+,C29H26NO3PNarequiere490.1548.
(S)N(1fenil3(tien3il)prop2inil)P,Pdifenilfosfinamida(3aj)
3aj
82
Captulo2
Mp163165C;[]D2051.3(c0.85,CHCl3,76%ee).
7.537.24(m,11H),7.07(dd,J=5.1,1.2Hz,1H),5.37(t,J=9.9Hz,1H),3.61(ta,J=
9.3Hz,1H).
C RMN (75.5 MHz, CDCl3) 140.2 (d, JCP = 5.2 Hz, C), 132.7 (d, JCP = 9.8 Hz, CH),
13
132.05 (d, JCP = 2.3 Hz, CH), 132.02 (d, JCP= 2.3 Hz, CH), 131.8 (d, JCP= 9.8 Hz, CH),
129.8 (CH), 128.7 (CH), 128.6 (CH), 128.4 (CH), 128.0 (CH), 127.3 (CH), 125.2 (CH),
121.6(C),88.3(d,JCP=6.0Hz,C),80.7(C),47.1(CH).
(S)N(1fenilhept2in1il)P,Pdifenilfosfinamida(3al)
3al
Mp114116C;[]D205.2(c0.70,CHCl3,14%ee).
7.527.26(m,9H),5.12(t,J=9.8Hz,1H),3.38(t,J=9.0Hz,1H),2.20(td,J=6.9,2.1
Hz,2H),1.531.33(m,4H),0.90(t,J=7.1Hz,3H).
13
CRMN(75.5MHz,CDCl3)141.0(d,JCP=4.6Hz,C),132.7(d,JCP=9.8Hz,CH),132.0
(CH), 131.93 (CH), 131.89 (CH), 131.8 (CH), 128.5 (CH), 128.3 (CH), 127.7 (CH), 127.2
(CH),86.3(C),79.7(d,JCP=6.2Hz,C),46.8(CH),30.7(CH2),22.0(CH2),18.4(CH2),13.6
(CH3).
83
Captulo2
(S)N(3ciclopropil1fenilprop2inil)P,Pdifenilfosfinamida(3ap)
3ap
Mp148150C;[]D2019.5(c2.15,CHCl3,72%ee).
7.517.17(m,10H),5.03(t,J=8.2Hz,1H),3.38(sa,1H),1.221.13(m,1H),0.710.61
(m,2H),0.600.51(m,2H).
13
CRMN(75.5MHz,CDCl3)140.9(d,JCP=4.8Hz,C),133.1(d,JCP=37.2Hz,C),132.7
(d,JCP =8.9Hz,CH),131.9(d,JCP =2.9Hz,CH),131.8(CH),131.7(CH),131.4(d,JCP=

39.1Hz,C),128.4(CH),128.5(d,JCP=12.8Hz,CH),128.3(CH),127.7(CH),127.2(CH),
89.2(C),74.8(d,JCP=6.1Hz,C),46.8(CH),8.1(CH2),0.47(CH).
(R)N(3(4metoxifenil)1otolilprop2inil)P,Pdifenilfosfinamida(3hb)
mediante HPLC quiral (Chiralpak IC), hexanoiPrOH
3hb
Mp167169C;[]D2055.5(c1.94,CHCl3,90%ee).
1
HRMN(300MHz,CDCl3)8.078.00(m,2H),7.81
7.75 (m, 2H), 7.687.65 (m, 1H), 7.517.42 (m, 4H), 7.377.32 (m, 2H), 7.267.11 (m,
5H),6.78(d,J=8.9Hz,1H),5.51(ta,J=9.0Hz,1H),3.78(s,3H),3.54(t,J=8.0Hz,1H),
2.40(s,3H).
13
CRMN(75.5MHz,CDCl3)159.5(C),138.9(d,JCP=5.6Hz,C),135.5(C),133.0(CH),
132.5(d,JCP=9.8Hz,CH),131.9(CH),131.8(d,JCP=7.0Hz,CH),130.8(CH),128.4(d,
84
Captulo2
JCP=2.5Hz,CH),128.2(d,JCP=2.4Hz,CH),127.0(CH),126.3(CH),114.8(C),113.7
(CH),87.7(d,JCP=4.6Hz,C),84.8(C),55.2(CH3),44.4(CH),19.1(CH3).
(R)N(3(4fluorofenil)1otolilprop2inil)P,Pdifenilfosfinamida(3hd)
Elexcesoenantiomrico(93%)sedeterminmediante
3hd
Mp196198C;[]D2057.5(c1.595,CHCl3,93%ee).
7.537.43(m,4H),7.407.34(m,2H),7.297.22(m,4H),7.2014(m,1H),6.96(t,J=8.8
Hz,2H),5.53(t,J=8.9Hz,1H),3.53(t,J=8.1Hz,1H),2.41(s,3H).
13
CRMN(75.5MHz,CDCl3)162.4(d,JCF= 249.4Hz,C),138.6(d,JCP=6.0Hz,C),
135.5(C),133.5(d,JCP=8.3Hz,CH),133.0(d,JCP=11.2Hz,CH),132.5(d,JCP=9.9Hz,
CH),132.0(CH),131.94(CH),131.91(CH),131.8(d,JCP=10.0Hz,CH),131.3(d,JCP=
11.6 Hz, CH), 130.9 (CH), 128.5 (CH), 128.3 (CH), 128.1 (CH), 127.0 (CH), 126.4 (CH),
118.7(d,JCF=3.6Hz,C),115.3(d,JCF=22.0Hz,CH),88.8(d,JCP=5.5Hz,C),84.0(C),
44.3(CH),19.1(CH3).
HRMS(ESI)m/z:462.1401[M+Na]+,C28H23FNOPNarequiere462.1399.
(R)N(3(4clorofenil)1otolilprop2inil)P,Pdifenilfosfinamida(3he)
HPLC quiral (Chiralpak IC), hexanoiPrOH 85:15, 1
3he
Mp203205C;[]D2049.7(c0.5,CHCl3,73%ee).
85
Captulo2
1
HRMN(300MHz,CDCl3)8.067.98(m,2H),7.817.44(m,2H),7.64(m,1H),7.54
7.33(m,6H),7.267.13(m,7H),5.52(t,J=8.7Hz,1H),3.48(ta,J=8.0Hz,1H),2.40(s,
3H).
13
CRMN(75.5MHz,CDCl3)138.4(d,JCP =5.9Hz,C),135.6(C),134.2(C),132.8(CH),
132.5 (d, JCP = 9.8 Hz, CH), 132.03 (d, JCP = 2.3 Hz, CH), 132.00 (d, JCP = 2.3 Hz, CH),
131.8(d,JCP =9.8Hz,CH),130.9(CH),128.5(CH),128.4(CH),128.3(CH),128.2(CH),
127.0 (CH), 126.5 (CH), 121.1 (C), 90.0 (d, JCP = 4.4 Hz, C), 84.0 (C), 44.3 (CH), 19.1
(CH3).
(R)N(3(3,5dimetoxifenil)1otolilprop2inil)P,Pdifenilfosfinamida(3hg)
i
Mp165167C;[]D2050.1(c1.67,CHCl3,85%ee).
3hg
HRMN(300MHz,CDCl3)7.997.91(m,2H),7.72
7.65 (m, 2H), 7.597.56 (m, 1H), 7.437.33 (m, 4H), 7.297.23 (m, 2H), 7.177.10 (m,
2H),7.077.03(s,1H),6.36(d,J=2.3Hz,2H),6.32(t,J=2.3Hz,1H),5.44(t,J=9.1Hz,
1H)3.65(s,6H),3.46(t,J=8.3Hz,1H),2.32(s,3H).
13
CRMN(75.5MHz,CDCl3)160.3(C),138.6(d,JCP=5.5Hz,C),135.5(CH),133.0(d,
JCP = 24.3 Hz, C), 132.5 (d, JCP = 9.9 Hz, CH), 131.91 (CH), 131.88 (CH), 131.84 (CH),
131.7(CH),131.3(d,JCP=24.5Hz,C),130.8(CH),128.4(d,JCP=2.6Hz,CH),128.3(d,
JCP=2.4Hz,CH),128.1(CH),127.0(CH),126.4(CH),124.0(C),109.3(CH),101.7(CH),
88.7(d,JCP=4.7Hz,C),84.8(C),55.3(CH3),44.3(CH),19.1(CH3).
86
Captulo2
(R)N(3(tien3il)1otolilprop2inil)P,Pdifenilfosfinamida(3hj)
3hj
Mp181183C;[]D2053.8(c1.13,CHCl3,83%ee).
HRMN(300MHz,CDCl3)8.057.98(m,2H),7.817.74(m,2H),7.65(dd,J=6.3,2.7
Hz,2H),7.547.12(m,10H),6.96(dd,J=5.1,1.2Hz,1H),5.50(t,J=9.0Hz,1H),3.54(t
a,J=7.8Hz,1H),2.34(s,3H).
13
CRMN(75.5MHz,CDCl3)138.6(d,JCP=5.5Hz,C),135.5(C)132.5(d,JCP=9.8Hz,
CH), 131.9 (d, JCP= 2.7 Hz, 2CH), 131.8 (d, JCP= 9.8 Hz, CH), 130.8 (CH), 129.8 (CH),
128.8 (CH), 128.5 (CH), 128.30 (CH), 127.29 (CH), 127.0 (CH), 126.4 (CH), 125.0 (CH),
121.7(C),88.6(d,JCP=4.5Hz,C),80.2(C),44.4(CH),19.1(CH3).
2.5.2.4.Sntesisycaracterizacinde(S)1,3difenilprop2in1amina(4)
cido clorhdrico concentrado (1 mL) se aadi a una
disolucindelcompuesto3aa(55mg,0,12mmol,84%ee)
en MeOH (15 mL). Tras 2 h, la mezcla de reaccin se
concentravaco,elresiduosedisolvienHCl1M(6mL)
4
y el precipitado se elimin por filtracin. El filtrado se
basificconNaOH2M(10mL)yseextrajoconCH2Cl2(320mL).Lafaseorgnicase
secsobreNa2SO4,sefiltryseconcentravaco.Cromatografaflashdecolumnaen
slicageleluyendoconhexane:EtOAc(1:9)dioelcompuesto4.
[]D2021.7(c0.90,CHCl3,84%ee),bibliografa53[]D2027(c0.6,CHCl3,99%ee)para
elenantimero(S).
1
HRMN(300MHz,CDCl3)7.10(d,J=7.2Hz,2H),7.487.45(m,2H),7.39(t,J=7.2
Hz,2H),7.337.30(m,4H),5.03(s,2H),2.31(t,J=7.5Hz,1H).
87
Captulo2
13
CRMN(75.5MHz,CDCl3)142.2(C),128.7(CH),128.3(CH),128.2(CH),127.9(CH),
127.7(CH),126.8(CH),123.0(C),91.3(C),84.2(C),48.1(CH).
HRMS(ESI)m/z:208.1129[M+H]+,C15H13Nrequiere208.1121.
88
Captulo2
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91
CH2Cl2
CAPTULO 3
Adicin enantioselectiva de alquinos

terminales a -amido sulfonas
O
HN
Ph
Ph
EtOH
CF3
Ph
Ph
F3C
O
HN
O
SO2Tol
Ph
CH2Cl2
SO2Tol
Ph Me HN
O
OMe
HN
NH
Cl
Et2Zn
Me
N
Me
F3C
HO
HO
Captulo3
3.1.ANTECEDENTES
LaadicinnucleoflicaaldobleenlaceC=Ndelasiminasesunodelosmtodos
mspracticadosenqumicaorgnicaparalasntesisdecompuestosnitrogenados.Sin
embargo, la baja electrofilia del carbono azometnico comparada con la del grupo
carbonilo,convierteestasadicionesenundesafosinttico.
3.1.1.Amidosulfonascomoprecursoresdeiminas
Conelobjetivodesuperaresteobstculo,sehandesarrolladodosestrategias
para llevar a cabo una adicin nucleoflica eficiente. La primera consiste en la
utilizacin de sistemas nuclefilos con elevada reactividad y baja basicidad, como
reactivos organocricos, alquilcupratos, boranos, estannanos o reactivos de
dialquilzinc. La segunda pretende aumentar la electrofilia del carbono azometnico.
Esto puede conseguirse mediante la coordinacin de un cido de Lewis al par de
electrones del nitrgeno o mediante la unin de un grupo electrnaceptor sobre el
nitrgeno (Figura 3.1), tal y como sucede en las nitronas (a), iones iminio (b), N
sulfiniliminas(c),Nsulfoniliminas(d),Nfosfinoiliminas(e)oNaciliminas(f).
Figura3.1.Iminaseiminoderivados.
LasnitronasoNxidosdeiminasylosionesiminiosonmsreactivosquelas
iminas,perosuestabilidaddependedelanaturalezadelossustituyentesqueforman
partedesuestructura.LaprincipalventajadelasNsulfiniliminasessuposibilidadde
inducirestereocontrolsobrelasreaccionesdeadicinaunqueimplicanelempleode
cantidadesestequiomtricasdematerialquiral.LasNsulfoniliminasyenconcretolas
Ntosiliminasderivadasdealdehdosaromticossonsustratosestables,mientrasque
95
Captulo3
aquellas derivadas de aldehdos alifticos deben utilizarse inmediatamente tras su

preparacin. Este problema tambin lo presentan las Nfosfinoiliminas, as como N
aciliminas.
Todas las iminas e iones iminio anteriores han demostrado su utilidad en
reaccionesdeadicin.Sinembargo,cuandosetrabajaconsustratosalifticosocurren
con frecuencia procesos adversos como su enolizacin. Esta reaccin compite con la
reaccindeadicinnucleoflicaalcarbonoazometnicoy,adems,puedeproducirla
isomerizacindeldobleenlaceC=N(Esquema3.1).Lautilizacindelosmencionados
nuclefilos menos bsicos disminuye la susceptibilidad a la enolizacin, pero no
siempreseconsigueeliminaresteproceso.
Esquema3.1.EnolizacindeiminaseisomerizacindelenlaceC=N.
Parasoslayaresteproblema,ascomolosderivadosdelasntesis,purificaciny
almacenamientodelasiminas,sepuedellevaracabolaformacininsitudeestasa
partirdeamidasogruposfuncionalesrelacionadosquetenganunbuengruposaliente
enquepuedaserfcilmenteeliminadoenlascondicionesadecuadas,tantobsicas
comocidas(Esquema3.2).1Deestemodo,sepuedenobteneriminasempleandouna
baseconunafuerzaapropiadaparaasegurarlairreversibilidaddelproceso.Porotra
parte,cuandoseutilizauncidodeLewisseproducedeformareversiblelaformacin
del ion iminio cuya posicin del equilibrio depende del cido de Lewis y de la
naturaleza del grupo acilo sobre el tomo de nitrgeno. La estabilidad del catin es
mayor cuando el grupo protector es de tipo acilo. En particular, un carbamato
estabiliza mejor al catin que una amida, debido, probablemente, a la mayor
disponibilidaddelparsolitariodelnitrgenodelcarbamato.
96
Captulo3
Esquema3.2.FormacindeionesNaciliminioyNaciliminasapartirdeamidasycompuestos
relacionadosconunbuengruposalienteen.
Sehanutilizadodiferentesamidasdeestetipoendiversasreacciones.1,2Las
haloamidas3(X=Cl,Br)sehanempleadoocasionalmentecomosustratoselectroflicos
debidoasuescasaestabilidad.Losamidoalquilbenzotriazoles4(X=benzotriazolilo)
han participado en numerosos procesos de alquilacin. Las bisamidas5 (X = NHCOR)
hansidoampliamenteutilizadasenreaccionesdecicloadicin.
Lasamidasoxigenadas(X=OR4,OCOR4)sonlosprecursoresmsexplotados
por su estabilidad y su fcil preparacin. El grupo de Konakahara6 ha utilizado estos
sustratos en la reaccin de adicin de alquinos terminales para obtener las
correspondientes aminas proparglicas (Esquema 3.3). Inicialmente, estos autores
estudiaron la alquinilacin de aldehdos en presencia de tribromuro de indio y
trietilamina. Las condiciones optimizadas para esta reaccin se aplicaron a la
alquinilacindeaminasprotegidasquepresentabanungrupometoxiloen.Tambin
seevalulareaccincuandoelsustratopresentabaungrupofeniltioenalaamina.
La adicin de fenilacetileno condujo a rendimientos mayores que cuando se
emplearonalquinosalifticos.Eltrimetilsililacetilenoproporcionlascorrespondientes
aminas proparglicas con rendimientos entre moderados y buenos. La reaccin
tambinsellevacaboconlaaminaNsililprotegidaderivadadelformaldehdocon
rendimientosmoderados.
Esquema3.3.Alquinilacindeaminasprotegidasconunbuengruposalienteen.
97
Captulo3
En 2009, Pyne y colaboradores7 llevaron a cabo la alquinilacin

diastereoselectiva de hidroxi aminas y amidas cclicas oxigenadas (Esquema 3.4).
Los correspondientes productos de alquinilacin se transformaron despus en
furo[3,2b]pirrolesyfuro[3,2b]piridinasvaunareaccindecicloisomerizacin.
OH
n
N
R2
OR1
1. R3
BF3Et2O
2. LiOH
OH
OH
BF3K
N
R2
N
R2
R3
31-89%
Esquema3.4.Alquinilacindiastereoselectivadehidroxiaminasyamidascclicas
oxigenadas.
El grupo de Zhang8 ha descrito un mtodo para la doble alquinilacin de los

dialquil acetales de la N,Ndimetilformamida en presencia de CuBr y 1,2
bis(difenilfosfino)propano(dppp)paradarlugara3amino1,4diinos(Esquema3.5).La
utilizacin de tamiz molecular de 3 mejor el rendimiento de la reaccin,
probablementedebidoaqueesteabsorbeelMeOHproducidoenlaformacindela
saldeiminiointermedia.Los1,4diinosresultantespuedenemplearsecomodadores
de Michael en la adicin a triples enlaces deficientes en electrones en presencia de
NaHCO3.
Esquema3.5.AlquinilacindedialquilacetalesdeN,Ndimetilformamida.
98
Captulo3
Porltimo,lautilizacindeamidosulfonas(X=SO2R)comoprecursoresde
iminashasidoampliamenteestudiada,yaquelahabilidaddelgrupoRSO2paraactuar
como buen grupo saliente es bien conocida.9 Adems, estos sustratos son slidos
altamente estables, que no necesitan ser utilizados inmediatamente despus de su
preparacinypurificacin.
Se han desarrollado varios mtodos para la preparacin de amido sulfonas.
En1964,EngbertsyStrating10describieronunodelosprocedimientosmsempleados
desde entonces que consiste en el acoplamiento de tres componentes, aldehdo,
carbamato y sulfinato de sodio en medio cido (Esquema 3.6). Este procedimiento
tambinsehaaplicadoutilizandootrosnuclefilosnitrogenados,comoamidas,ureas,
tioureas,tiocarbamatos,tionocarbamatosoditiocarbamatos.Sinembargo,cuandose
utilizadifenilfosfinamidacomonuclefilonitrogenado,sedebeutilizarcidosulfnico
enlugardesulfinatodesodioydietiltercomodisolvente.
Esquema3.6.Sntesisdeamidosulfonasmediantereaccindeacoplamientoentrealdehdo,
carbamatoysulfinatodesodio.
Un mtodo alternativo de sntesis de amido sulfonas es la oxidacin de los

correspondientes sulfuros empleando MCPBA o perxido de hidrgeno (Esquema
3.7).11
Esquema3.7.Sntesisdeamidosulfonasporoxidacindeamidosulfuros.
En 1978, Matthies12 describi un procedimiento de sntesis de este tipo de

sustratos consistente en la sustitucin del anin cloruro de las Nacilcloroglicinas
conionessulfinato(Esquema3.8).
99
Captulo3
Esquema3.8.SntesisdeamidosulfonasapartirdeNacilcloroglicinas.
Debido a las ventajas que ofrece la sntesis de las amido sulfonas y a su

enormeestabilidad,sehadescritosuutilizacinennumerosasreaccionesdeadicin
como FriedelCrafts,13 reacciones de Mannich, azaHenry, reacciones de Strecker,
alquilacinohidrofosfonilacin,entreotras.2
No obstante, son escasos los ejemplos de alquinilacin descritos en la
bibliografa. En 2002, Li y Zhang publicaron la adicin no enantioselectiva de
fenilacetilenoaamidosulfonasenpresenciadeCuBrenagua(Esquema3.9).14
Esquema3.9.Adicindefenilacetilenoaiminasgeneradasinsituapartirdeamidosulfonas.
Posteriormente, Denis y colaboradores15 emplearon NBocNhidroxiaminas

conungruposulfonaencomoprecursoresdenitronasenlareaccindeadicinno
enantioselectivadealquinilurosdelitio(Esquema3.10).Eltratamientoenmediocido
de las Nhidroxiaminas proparglicas obtenidas produjo la eliminacin del grupo
protector Boc, conduciendo a Nhidroxiaminas proparglicas. Por otra parte, la
reduccin del grupo NO, que se llev a cabo con SmI2, condujo a NBoc aminas
proparglicas.
100
Captulo3
Esquema3.10.AlquinilacindeNBocnitronasgeneradasinsituapartirdelas
correspondientessulfonas.
En 2010, el grupo de Wang16 realiz la alquinilacin enantioselectiva de N

(difenilfosfinoil)iminas aromticas catalizada por un ligando tridentado y Et2Zn
(Esquema 2.44, p. 51). Sin embargo, la alquinilacin de las iminas derivadas de
aldehdosalifticossellevacabogenerandoestasinsituapartirdeamidosulfonas
(Esquema 3.11). Las correspondientes Ndifenilfosfinoil aminas proparglicas se
obtuvieronconrendimientoselevadosyexcesosenantiomricosmoderados.
Esquema3.11.AdicinenantioselectivadealquinosaN(difenilfosfinoil)amidosulfonas.
3.1.2. Utilizacin de ciclopropilacetileno en reacciones de

alquinilacindeiminas
Durantelosltimosaos,lapresenciadelgrupociclopropiloenloscompuestos
orgnicos ha suscitado una enorme atencin debido a que presenta propiedades
excepcionalesdetipoestrico,electrnicoyconformacionalcomoconsecuenciadesu
estructura tensionada. Asimismo, existe un creciente inters por este anillo de
ciclopropano desde el punto de vista de la qumica mdica y biolgica, ya que se
encuentraenunagranvariedaddecompuestosnaturalescomoterpenos,antibiticos,
feromonasocidosgrasos(Figura3.2).Enmuchosprocesos,esteelementoestructural
101
Captulo3
esunaentidadestablepresenteendistintosmetabolitossecundarios,mientrasqueen
otrossetratasimplementedeunintermedioenlasrutasmetablicas.17
Figura3.2.(a)Ambruticino,antibiticoantifngicopresenteenelmediodefermentacinde
Polyangiumcellulosumvar.fulvumy(b)petrosterol,metabolitodetectadoenlaesponja
marinaPetrosiaficiformis.
Lapresenciadelgrupociclopropiloenlanaturalezahaconducidoalabsqueda
denuevoscompuestosbiolgicamenteactivosqueincorporaranesteanillo.As,sehan
desarrollado compuestos con actividad antitumoral,18 antiinflamatoria19 o
antimalrica,20 entre otras. Uno de los frmacos que contiene la agrupacin
ciclopropiloesPrasugrel(Efient,DaiichiSankyoCo.).Setratadeuninhibidorselectivo
delaagregacinplaquetariaatravsdelauninirreversibledesumetabolitoactivoa
los receptores adenosindifosfato de las plaquetas. Este ha demostrado ser ms
seguro,rpidoyefectivoquesusanlogosticlopidinayclopidogrel(Figura3.3).21,22
Figura3.3.Estructurasde(a)prasugrel,(b)ticlopidinay(c)clopidogrel.
Otrosfrmacosquetambincontienenlaagrupacinciclopropilacetilenoensu
estructurasonEfavirenz23(Sustiva,BristoMyersSquibb)yNeviparina24(Viramune,
Boehringer Ingelheim). Se trata de inhibidores no nuclesidos de la transcriptasa
inversaindicadoseneltratamientoantiviraldelvirusdelainmunodeficienciahumana
(VIH)(Figura3.4).
102
Captulo3
Figura3.4.Estructurasde(a)Efavirenzy(b)Neviparina.
En 2004, Jiang y Si25 describieron la reaccin de adicin enantioselectiva de

ciclopropilacetilenoaNacilcetiminascclicasutilizandounligandoquiralderivadodel
cloranfenicol y triflato de zinc en presencia de 2,5 equivalentes de trietilamina. Este
procedimiento les permiti la sntesis de DPC961, un inhibidor no nuclesido de la
transcriptasa inversa del VIH de segunda generacin, anlogo al Efavirenz (Esquema
3.12).
Esquema3.12.SntesisdeDPC961medianteadicinenantioselectivadeciclopropilacetilenoa
Nacilcetiminascclicas.
103
Captulo3
3.2.OBJETIVOS
Lasamidosulfonashandemostradopresentarenormesventajasendiversas
reacciones de adicin nucleoflica enantioselectiva. Sin embargo, la reaccin de
alquinilacin con este tipo de sustratos se encuentra poco explotada. Por ello, el
objetivo de este captulo se basa en el desarrollo de un mtodo cataltico y
enantioselectivodeadicindealquinosaamidosulfonasquetranscurraconbuenos
rendimientosyexcesosenantiomricos.
Enconcretosellevaracabounestudiodetalladodelareaccindeadicinde
alquinos terminales a aciliminas, generadas in situ a partir de amido sulfonas,
utilizandounsistemacatalticoformadoporligandosdetipo(R)BINOLyreactivosde
dialquilzinc.
Enesteestudioseconsiderarnlossiguientesaspectos:
estructuradediversosligandosdetipo(R)BINOL(L1L8),delatemperatura
ydeldisolventesobreelrendimientoylaenantioselectividaddelareaccin
de adicin de fenilacetileno a Nbenciloxicarbonilaminoptoluenosulfona
derivadadelbenzaldehdo.
105
Captulo3

naturalezadelreactivodedialquilzincutilizado(Me2ZnyEt2Zn).
3. Identificacin de las condiciones ptimas de reaccin: Influencia de

diferentesgruposprotectores,fcilmenteeliminablesycompatiblesconlos
grupos funcionales presentes en los productos de alquinilacin, sobre el
rendimientoylaenantioselectividaddelareaccin.
4. Alcance y limitaciones de la reaccin: Evaluacin de diversas amido

sulfonas aromticas y alifticas con diferente naturaleza electrnica y
estricaenlareaccindealquinilacinconfenilacetileno.
5. Alcance y limitaciones de la reaccin: Evaluacin de diversos alquinos con

diferente naturaleza electrnica y estrica en la reaccin con la amido
sulfonaderivadadelbenzaldehdo.
106
Captulo3

sulfonas aromticas con diferente naturaleza electrnica y estrica en la
reaccinconalquinosaromticosconelevadadensidadelectrnica.

sulfonas con diferente naturaleza electrnica y estrica en la reaccin de
adicindeciclopropilacetileno.
8. Utilidad sinttica: Evaluacin de distintas transformaciones basadas en la

reactividad del triple enlace y el grupo protector de los productos de
alquinilacinenantioselectiva.
107
Captulo3
3.3.RESULTADOSYDISCUSIN
3.3.1. Sntesisdeamidosulfonas
Para llevar a cabo la reaccin de adicin de alquinos terminales a iminas, se
utilizaron diversas amido sulfonas como precursores in situ de aciliminas. Las
amido sulfonas se prepararon siguiendo el procedimiento descrito por Engberts y
Strating en 1964.10 Este mtodo consiste en la reaccin de acoplamiento de tres
componentes entre un aldehdo, un carbamato y sulfinato de sodio en condiciones
cidas.
Las amido sulfonas obtenidas son slidos blancos o marrones estables que
precipitandelamezcladereaccinysepurificanfcilmenteporfiltracinylavadocon
aguaydietilter.
Todas ellas se prepararon con rendimientos entre moderados y buenos (31
80%)ysecaracterizaronporresonanciamagnticanuclear(1HRMN,13CRMN).
109
Captulo3
Tabla3.1.Sntesisdeamidosulfonasmedianteunareaccindetrescomponentes.
GP
Ar
Amidosulfona R(%)
5a
Ph
14
Cbz
17a Tol
8aa
80
5b
4MeC6H4
14
Cbz
17a Tol
8ba
78
5c
4MeOC6H4
14
Cbz
17a Tol
8ca
73
5d
4FC6H4
14
Cbz
17a Tol
8da
71
5e
4ClC6H4
14
Cbz
17a Tol
8ea
63
5f
4BrC6H4
14
Cbz
17a Tol
8fa
60
5g
3MeC6H4
14
Cbz
17a Tol
8ga
72
5h
2MeC6H4
14
Cbz
17a Tol
8ha
56
5j
2ClC6H4
14
Cbz
17a Tol
8ja
66
10
5k
2naftil
14
Cbz
17a Tol
8ka
36
11
5l
1naftil
14
Cbz
17a Tol
8la
47
12
5m 2furanil
14
Cbz
17a Tol
8ma
35
13
5n
2tienil
14
Cbz
17a Tol
8na
31
14
5o
3furanil
14
Cbz
17a Tol
8oa
41
15
5p
3tienil
14
Cbz
17a Tol
8pa
76
16
5q
C6H5CH2CH2
14
Cbz
17a Tol
8qa
66
17
5r
nbutil
14
Cbz
17a Tol
8ra
62
18
5s
ciclohexil
14
Cbz
17a Tol
8sa
85
19
5a
Ph
15
Boc
17a Tol
9aa
73
20
5a
Ph
16
COOEt 17a Tol
10aa
70
21
5a
Ph
14
Cbz
17b Ph
8ab
78
22
5a
Ph
14
Cbz
17c 4ClC6H4 8ac
75
23
5b
4MeC6H4
14
Cbz
17b Ph
8bb
69
24
5b
4MeC6H4
14
Cbz
17c 4ClC6H4 8bc
70
110
Captulo3
3.3.2.Optimizacindelascondicionesdereaccin
Para abordar el proceso de optimizacin de lareaccin de alquinilacin de
amido sulfonas, se escogi la reaccin entre la Nbenciloxicarbonilaminop
toluenosulfonaderivadadelbenzaldehdo8aayfenilacetileno(2a)yseevalutantoel
rendimiento como la enantioselectividad en funcin del ligando, la temperatura, el
disolvente, el dialquilzinc utilizado, el grupo protector y la sustitucin del grupo
sulfona.
Esquema3.13.Reaccindeadicindefenilacetileno(2a)aNbenciloxicarbonilaminop
toluenosulfona8aacatalizadapor(R)BINOLydialquilzinc.
Influenciadelaestructuradelligando,latemperaturayeldisolvente
Inicialmente, siguiendo el mismo patrn de trabajo que para la reaccin de
alquinilacindeN(difenilfosfinoil)iminas,seestudilareaccinutilizandocondiciones
similares a las descritas por nuestro grupo de investigacin26 para la alquinilacin
enantioselectivadeNsulfonilaldiminas.Enestetrabajosegenerelacetilurodezinca
partir de fenilacetileno y Me2Zn. Transcurrida 1 h, se adicion (R)BINOL disuelto en
toluenoyfinalmente,seaadilaNsulfoniliminadisueltaentolueno(Procedimiento
A,Figura2.9,p.57).
111
Captulo3
Figura3.5.LigandosdetipoBINOL.
Enprimerlugar,seanalizlainfluenciadelaestructuradelligando(20mol%)
utilizando distintos derivados de (R)BINOL con grupos electrnaceptores en las
posiciones3,3y6,6,ascomoconanillostetrahidrogenados(Figura3.5).
La reaccin se llev a cabo con 6 equivalentes de Me2Zn 2 M en tolueno.
Asimismo,seensayarondisolventesdediversanaturaleza.Losresultadosserecogen
enlaTabla3.2.
Los resultados sugieren que la presencia de grupos voluminosos en las
posiciones 3,3 del ligando favorece la enantioselectividad de la reaccin (Tabla 3.2,
Entradas3,57).Esteresultadoestdeacuerdoconloobservadopornuestrogrupo
de investigacin en un trabajo anterior,26 as como por Wu y Chong,27 quienes
describieronquelasustitucinenlasposiciones3,3deunBINOLalquinilboronatoera
esencial para obtener enantioselectividades elevadas. No obstante, un impedimento
estricoexcesivoimpidequelaadicintranscurraselectivamente(Tabla3.2,Entrada
8). El ligando L6 proporcion una enantioselectividad superior al resto de ligandos.
Utilizando tolueno como disolvente y llevando a cabo la reaccin a temperatura
ambiente, se obtuvo el producto de reaccin 11aa con un 81% ee aunque con un
rendimientobajo(35%)(Tabla3.2,Entrada6).
Se logr aumentar el rendimiento hasta el 50% manteniendo la
enantioselectividad llevando a cabo la reaccin a 0 C, mientras que se redujo
drsticamentea25C(Tabla2,Entradas9y10,respectivamente).
112
Captulo3
Tabla 3.2. Adicin enantioselectiva de fenilacetileno (2a) a Nbenciloxicarbonilaminop

toluenosulfona 8aa utilizando Me2Zn. Screening de ligandos, temperaturas y disolventes
siguiendoelProcedimientoA.a
Entrada
Disolventeb
T(C)
t(h)
R(%)c
ee(%)d
L1
Tolueno
ta
35
11
L2
Tolueno
ta
64
13
L3
Tolueno
ta
64
33
L4
Tolueno
ta
26
18
L5
Tolueno
ta
32
43
L6
Tolueno
ta
35
81
L7
Tolueno
ta
21
24
51
L8
Tolueno
ta
18
L6
Tolueno
50
83
10
L6
Tolueno
25
24
11
L6
Hexano
20
81
12
L6
CH2Cl2
52
84
13
L6
ClCH2CH2Cl
45
83
14
L6
CHCl3
24
80
15
L6
THF
17
16
8aa(0,125mmol),2a(0,900mmol),Me2Zn2Mentolueno(0,375mL,0,750mmol),L(0,025
mmol). b 0,2 mL de disolvente excepto cuando se utiliza hexano (0,4 mL). c Rendimiento de
productoaislado.dDeterminadoporHPLCusandofasesestacionariasquirales.
En cuanto a la utilizacin de diferentes disolventes, el hexano no aport

ningunamejoraenlosresultados(Tabla3.2,Entrada11).Porsuparte,lautilizacinde
disolventes clorados condujo a buenos ee y rendimientos moderados (Tabla 3.2,
Entradas1214),mientrasqueundisolventecoordinantecomoelTHFproporcionel
producto de alquinilacin deseado 11aa con bajo rendimiento y enantioselectividad
113
Captulo3
(Tabla3.2,Entrada15).Aspues,elmejorresultadoseobtuvoutilizandoCH2Cl2como
disolvente(52%derendimiento,83%ee)(Tabla3.2,Entrada12).
Influenciadelanaturalezadelreactivodedialquilzinc
Teniendoencuentaquenoconsiderbamossatisfactorioelrendimientodela
reaccin,decidimos,tomandocomoreferenciauntrabajopublicadoporWangparala
reaccin de alquinilacin de fosfinoiliminas,28 utilizar Et2Zn en lugar de Me2Zn (Tabla
3.3,Entrada1).
Sinembargo,losresultadosdelareaccinfueronesencialmenteidnticos,por
lo que decidimos determinar la estructura de un producto secundario que
observbamos por cromatografa de capa fina. El anlisis por resonancia magntica
nuclear de este concluy que no se trataba de un nico producto. La mezcla se
consigui separar con una posterior cromatografa de columna tras la que se
obtuvieron los dos productos secundarios, a los que denominamos 18 y 19, cuyas
estructurasseelucidaronmedianteRMNyespectrometrademasas.
ApartirdelacomparacindelRMNdelproductodealquinilacin11aaconlos
espectros de RMN de los dos productos secundarios obtenidos, se extrajeron las
siguientesconclusiones:
Ambos productos secundarios conservaban el grupo protector Cbz, ya que los

espectrosmostrabanunasealaaproximadamente5,2ppmquecorrespondeal
metilenodelgrupobencilo.
Enambosproductossehabaincorporadounnuclefilodistintoalalquinoyno
estabapresenteelgruposulfona.
Adems,encuantoalproducto18:
114
Captulo3
5.117
5.177
5.162
5 217
5.217
5.356
5.334
5.975
5.947
7 260
7.260
7.335
7.329
7.318
7.312
7.391
7.364
7.593
7.570
7.482
7.476
7.464
7.451
11aa
6.00
5.50
1.825
1.802
1 788
1.788
1.779
1.756
1.733
0.923
0.898
0.874
5.024
5.016
4.645
4.622
4 599
4.599
4.577
5.065
5
5.00
4.50
4.0
00
3.50
3.00
0
2.50
2.00
3.3
6.50
20
2.0
7.00
0.9
7.50
1.7
10
1.0
9.8
9
8
8.00
5.097
5.138
7.282
7.260
7.236
7.361
7.337
7 314
7.314
1.1
1
1
1.0
0.7
0.8
11.6
2.0
2.0
8.50
0
ppm
18
1.50
1.00
0.50
Figura3.6.EspectrossdeRMN1Hdelosprod
H
uctos11aayy18.
Lasealaa1,8ppm, pertenecieenteaunCH
H2delnucle
efiloadicioonado,acoplaba
conelpro
otnunidoalCestereoognico.
Lasealaa0,9ppm,p
perteneciennteaunCH3,acoplabaconelmettilenoanterior.
Tantolassintegraciones(3Hy22H)comolo
osdesplazamientos(0,,9y1,8ppm
m)de
los protones corre
espondienttes al nucclefilo, ass como llos argumentos
anteriorees, nos perm
mitieron cooncluir que el productto 18 es ell derivado de la
adicin del
d grupo ettilo a la aamido sulfo
ona. El anlisis por es pectrometrra de
masasconfirmestaahiptesis.
Figura3.7.Espectrodeemasasdelproducto18.[M+Na] =2292.2.
115
Captulo3
Encuantoalproducto19:
La seal a 6,5 ppm corresponde al protn del C estereognico y se encuentra

desplazada a campo bajo respecto a la seal equivalente en el producto de
alquinilacin11aa(5,9ppm).
La seal a 4,1 ppm perteneciente a un CH2 del nuclefilo adicionado, no

acoplabaconelprotndelCestereognico.
Laseala1,21ppm,pertenecienteaunCH3,acoplabaconelmetilenoanterior.
Lasintensidadesdelassealescorrespondientesalosprotonesdelnuclefiloy
sus desplazamientos indican que se trata de un grupo etilo unido a
heterotomo.
La espectrometra de masas fue determinante para la elucidacin de la

estructuradelcompuesto19.Elionmolecular([M+Na]+324,1),32umasuperior
al del producto 18 ([M+Na]+ 292,2), nos indica que el compuesto 19 es el
productodeadicindeperxidodeetiloalaamidosulfona8aa.
11aa
5.117
5.177
5.162
7.260
5.975
5.947
5.356
5.334
5.217
7.391
7.364
7.335
7.329
7.318
7.312
7.593
7.570
7.482
7.476
7.464
7.451
1.236
1.213
1.190
4.155
4.133
4.111
4.093
5.191
6.541
6.508
7.260
7.445
7.433
7.410
7.384
7.377
7.366
7.341
7.321
5.618
5.591
5.50
5.00
4.50
4.00
3.0
6.00
2.0
6.50
2.0
7.00
0.7
7.50
0.9
10.1
8.00
1.1
1.0
0.7
0.8
11.6
2.0
2.0
8.50
ppm
19
3.50
3.00
2.50
2.00
1.50
Figura3.8.EspectrosdeRMN1Hdelosproductos11aay19.
116
1.00
0.50
Captulo3
Figura3.9
9.Espectrod emasasdelproducto19
9.[M+Na]+= 324,1.
Portanto,elproducto18resuultadelaad
dicindelg
grupoetilo delEt2Znala
amid
dosulfonad
departida,299mientrasqqueelprod
ducto19deb
beformarseeporadici
ndel
radiccalperxido
ogeneradoapartirdel Et2Znyoxgenodirrad
dical.30,31
NHCbz
SO 2Tol
Ph
L6 , Et2Zn
NHC
Cbz
NHCbz
NHCb
bz
O
Ph
8aa
2a
11aa
a
18
19
Esqu
uema3.14.Formacinde
elosproducttossecundarrios18y19e
enlareaccinndealquinilacin
de
amidosulfo
onas.
Con el objetivo
o
de
e eliminar l a formaci
n de este ltimo, se extremaro
on las
cond
diciones de purga y se
s redujeroon posibless entradas de O2 en el montajje de
reacccin.Porottraparte,de
ecidimosm
modificarelp
procedimientoexperim
mental,yaq
quela
preseenciadelproductodealquilacinnparecain
ndicarunafformacini ncompleta dela
especieactiva(eelacetilurometlico). Dichamod
dificacinse
ebasenvaariarelorde
ende
adicin de los reactivos
r
im
mplicados een la formacin de la especie
e
cattaltica. El nuevo
n
proceedimientocconsistaen
ndisolverfeenilacetilenoyBINOLe
en0,4mLddeCH2Cl2,aaadir
eldieetilzinc(1M
Menhexano
o)y,trasla formacindelaespecciecatalticaa,adicionarrla
amid
dosulfona((Figura3.10
0,Procedim
mientoB).D
Deestemod
do,elproduuctodeseadose
obtuvo con reendimiento (60%) y eenantiosele
ectividad (8
84% ee) suuperiores a los
ProcedimienntoA(Tabla3.3,Entra
ada2),yaqquedisminu
uyla
conseguidossigguiendoelP
form
macindelo
osproductosssecundari os.
117
Captulo3
PROCEDIMIENTOAPROCEDIMIENTOB
+R Zn
2
+(R)BINOL
1h
(R)BINOL
R2Zn
15min
amidosulfona
5min
1h
amidosulfona
Figura3.10.ProcedimientosexperimentalesAyB.
Debido a que todava se observaba la aparicin de una pequea cantidad de

productodealquilacin,seincrementeltiempodeformacindelaespeciecataltica
de1a1,5horas.Deestemodoselogrreducirlaformacindelproductonodeseado
yseaumentelrendimientohasta69%,conservndoselaenantioselectividad(Tabla
3.3, Entrada 3). Sin embargo, un incremento del tiempo de formacin del complejo
activo a 2 h condujo a un descenso tanto del rendimiento como del ee (Tabla 3.3,
Entrada4).
Por tanto, los mejores resultados se alcanzaron cuando se utiliz Et2Zn
siguiendoelProcedimientoBcon1,5hdetiempodeformacindelaespeciecataltica.
118
Captulo3

toluenosulfona8aautilizandoEt2Zn.a
Disolvente
T(C)
tf(h)b
Et2Zn(1M)
CH2Cl2
0,25
54
85
Et2Zn(1M)
CH2Cl2
60
84
Et2Zn(1M)
CH2Cl2
1,5
69
85
Et2Zn(1M)
CH2Cl2
53
82
Proc.
R2Zn(M)
t(h) R(%)c ee(%)d
8aa(0,125mmol),2a(0,900mmol),Et2Zn1Menhexano(0,750mL,0,750mmol),L6(0,025
mmol). bTiemposdeformacindelaespeciecataltica. cRendimientodeproductoaislado. d

DeterminadoporHPLCusandofasesestacionariasquirales.
Siguiendo con el proceso de optimizacin, a continuacin analizamos cmo

afectabalaconcentracindelamezcladereaccinalaenantioselectividad,yaqueen
sistemas similares se haba observado una dependencia de la selectividad con la
dilucin.26, 32Noobstante,ennuestrocasonoobservamosdichadependencia(Tabla
3.4, Entradas 17). Finalmente, se redujo la cantidad de dietilzinc hasta 3 y 2,5
equivalentes (Tabla 3.4, Entradas 8 y 9). Se obtuvo una mayor enantioselectividad
cuando la reaccin se llev a cabo con Et2Zn 1 M en hexano (0,375 mmol, 3
equivalentesrespectoaamidosulfona8aa),utilizandoelligandoL6enCH2Cl2a0C
(Tabla3.4,Entrada8).
119
Captulo3

toluenosulfona 8aa utilizando Et2Zn en CH2Cl2. Screening a distintas concentraciones y
volumendedisolvente.a
Entrada
Et2Zn(M)b
Disolvente(mL)
t(h)
R(%)c
ee(%)d
Et2Zn(1M)
CH2Cl2(0,2)
17
63
80
Et2Zn(1M)
CH2Cl2(0,4)
69
85
Et2Zn(1M)
CH2Cl2(0,8)
54
84
Et2Zn(1,1M)
CH2Cl2(0,2)
3,5
60
69
Et2Zn(1,1M)
CH2Cl2(0,37)
64
81
Et2Zn(1,5M)
CH2Cl2(0,27)
52
78
Et2Zn(1,5M)
CH2Cl2(0,65)
53
81
Et2Zn(1M)e
CH2Cl2(0,4)
70
87
Et2Zn(1M)f
CH2Cl2(0,4)
51
76
TodaslasreaccionesserealizaronsiguiendoelProcedimientoB.8aa(0,125mmol),2a(0,900
mmol),L6(0,025mmol). b Et2Znenhexano(0,750mmol). cRendimientodelproductoaislado.

d
Determinado por HPLC usando fases estacionarias quirales. e Et2Zn (0,375 mmol). f Et2Zn
(0,275mmol).
Influenciadelgrupoprotector
Finalizado el proceso de optimizacin para la reaccin de adicin de
fenilacetileno (2a) a Nbenciloxicarbonilaminoptoluenosulfona derivada del
benzaldehdo8aa,seexaminlainfluenciadelgrupoprotector(Tabla3.5).Paraello,
se ensayaron adems del grupo benciloxicarbonilo (Cbz), tbutiloxicarbonilo (Boc) y
etiloxicarbonilo(COOEt).Enbasealosantecedentesbibliogrficosenlosquesellevaa
cabolaeliminacindeestosgruposprotectores,elbenciloxicarbonilogeneralmentese
elimina por hidrogenolisis, el tbutiloxicarbonilo se puede eliminar enmedio cido y,
por ltimo, el etiloxicarbonilo se elimina en medio bsico.33 Debe tenerse en cuenta
que el triple enlace de la amina proparglica puede sufrir reduccin en la etapa de
120
Captulo3
hidrogenolisis,porloquepodrasernecesarialabsquedademtodosselectivosde
desproteccindelbenciloxicarbonilo.
Tabla3.5.Adicinenantioselectivadefenilacetileno(2a)aamidosulfonas8aa,9aay10aa.a
R(%)b
ee(%)c
Amidosulfona GrupoProtector t(h) Producto
8aa
Cbz
11aa
70
87
9aa
Boc
12aa
59
84
10aa
COOEt
13aa
amidosulfona(0,125mmol),2a(0,900mmol),L6(0,025mmol), Et2Zn(0,375mmol). b
Rendimiento del producto aislado. c Determinado por HPLC usando fases estacionarias
quirales.dMezclacompleja,rendimientonodeterminado.
Con ninguno de los dos nuevos grupos estudiados se obtuvieron mejores

resultadosrespectoalgrupoprotectorinicialmenteutilizado,Cbz.
Influenciadelasustitucindelgruposulfona
Se acepta generalmente que la eliminacin asistida por base de cido
bencenosulfnico a partir de las amido sulfonas 8 conduce a la formacin de N
aciliminas que reaccionan con reactivos nucleoflicos para dar los correspondientes
productosdeadicin.Elprocesoglobalpuedeconsiderarsecomounareaccintndem
deeliminacinadicinquepuedellevarseacabousandounreactivonucleoflicoque
sea suficientemente bsico para promover la etapa de eliminacin, y que a
continuacintuvieralugarlareaccindeadicinenantioselectiva.
No obstante, tambin se podra considerar que la reaccin tuviera lugar a
travs de la sustitucin directa del grupo sulfona por el reactivo nucleoflico, dando
lugaraunaresolucincinticadinmica.
121
Captulo3
Conelobjetodediferenciarentreambasposibilidades,seevalulainfluencia
sobreelrendimientoylaenantioselectividaddelasustitucinenelgrupoarilodela
amido sulfona. Se ensayaron tres tipos de sustratos distintos derivados del
benzaldehdo y del ptoluenaldehdo: Nbenciloxicarbonilaminoptoluenosulfona, N
benciloxicarbonilaminofenilsulfona y Nbenciloxicarbonilaminopclorofenilsulfona
(Tabla3.6).
Tabla3.6.Adicinenantioselectivadefenilacetileno(2a)aamidosulfonas8.a
Amidosulfona
Ar
t(h) 11
R(%)b ee(%)c
8aa
Ph
Tol
11aa
70
87
8ab
Ph
Ph
11aa
68
88
8ac
Ph
pClC6H4
11aa
67
88
8ba
pMeC6H4
Tol
11ba
49
87
8bb
pMeC6H4
Ph
11ba
50
87
8bc
pMeC6H4
pClC6H4
11ba
52
87
8 (0,125 mmol), 2a (0,900 mmol), L6 (0,025 mmol), Et2Zn (0,375 mmol). Rendimiento del
productoaislado.cDeterminadoporHPLCusandofasesestacionariasquirales.
Comopuedeobservarsetantolaenantioselectividadcomoelrendimientodela
reaccinsonindependientesdelasustitucindelgrupoariloenlaamidosulfona,lo
cualestdeacuerdoconunprocesotndemdeeliminacinadicin.
Esquema3.15.Alquinilacinenantioselectivadeiminasgeneradasinsituapartirdeamido
sulfonas.
122
Captulo3
3.3.3.Alcanceylimitacionesdelareaccin
En el estudio del alcance de la reaccin, se aplicaron las condiciones
optimizadas para la reaccin entre fenilacetileno (2a) y Nbenciloxicarbonilaminop
toluenosulfona8aaadistintascombinacionesamidosulfonayalquinoterminal.
Evaluacindedistintasamidosulfonas
Enprimerlugarseevalulareaccinentredistintasamidosulfonas(8aa8sa)
yfenilacetileno(2a).LosresultadosseencuentranenlaTabla3.7.
Amido sulfonas con grupos electrndadores y electrnaceptores dieron
lugar a los correspondientes productos de alquinilacin con buenos rendimientos y
enantioselectividadesentornoa90%ee(Tabla3.7,Entradas26),aexcepcindelflor
yelgrupometoxilo,conlosqueelexcesoenantiomricodisminuyhasta83%(Tabla
3.7,Entradas34).Estopuedeatribuirsealfuertecarcterelectrnicodelsustituyente,
ya sea electrnaceptor (F) o electrndador (MeO). La presencia de grupos en la
posicin orto del anillo aromtico condujo a elevados excesos enantiomricos
independientementedelanaturalezaelectrnicadelsustituyente(Tabla3.7,Entradas
89). La reaccin con el sustrato derivado de 2naftaldehdo transcurri con
rendimiento bajo, pero enantioselectividad elevada, mientras que con el sustrato
derivado del 1naftaldehdo el producto deseado se obtuvo prcticamente racmico
(Tabla3.7,Entradas1011).Laaplicabilidaddelareaccinpuedeextenderseaamido
sulfonas heteroaromticas, con las cuales se obtuvieron enantioselectividades
comprendidas entre 7488% ee (Tabla 3.7, Entradas 1215). Finalmente, se ensay la
reaccin con tres amido sulfonas alifticas. Con todas ellas se obtuvieron los
correspondientesproductosdealquinilacinconrendimientosyenantioselectividades
moderados(Tabla3.7,Entrada1618).
123
Captulo3
Tabla3.7.Adicinenantioselectivadefenilacetileno(2a)aamidosulfonas8.a
Entrada 8
t(h)
11
R(%)b
ee(%)c
8aa
Ph
11aa
70
87
8ba
4MeC6H4
11ba
61
87
8ca
4MeOC6H4
11ca
60
83d
8da
4FC6H4
11da
42
83
8ea
4ClC6H4
11ea
73
90
8fa
4BrC6H4
11fa
61
90
8ga
3MeC6H4
11ga
61
86
8ha
2MeC6H4
11ha
62
90
8ja
2ClC6H4
11ja
63
90
10
8ka
2naftil
11ka
33
87
11
8la
1naftil
11la
33
12
8ma
2furanil
11ma
63
88
13
8na
2tienil
11na
58
79
14
8oa
3furanil
11oa
41
78
15
8pa
3tienil
11pa
66
74
16
8qa
C6H5CH2CH2
11qa
52
60
17
8ra
nbutil
11ra
59
46
18
8sa
ciclohexil
11sa
72
55
8 (0,125 mmol), 2a (0,900 mmol), L6 (0,025 mmol), Et2Zn (0,375 mmol). b
Rendimiento del producto aislado. c Determinado por HPLC usando fases

d
estacionarias quirales. El valor de exceso enantiomrico se determin tras

obtenerelproductodederivatizacinsegnelEsquema3.16.
124
Captulo3
Evaluacindedistintosalquinosterminales
La aplicabilidad de esta reaccin se ensay tambin con distintos alquinos
proporcionando buenos rendimientos y elevados excesos enantiomricos. Los
resultadossemuestranenlaTabla3.8.
Se examinaron diferentes alquinos con sustituyentes electrndadores y
electrnaceptoresenelanilloaromticoenlaposicinpara(Tabla3.8,Entrada14).
Todosellosdieronlosproductosdealquinilacindeseadosconbuenosrendimientosy
enantioselectividades elevadas (8591% ee). Sin embargo, los rendimientos fueron
inferioresenelcasodelalquinopfluorofenilacetileno(2d)(Tabla3.8,Entrada3).Los
sustratos con anillos aromticos sustituidos en orto y meta dieron lugar a
enantioselectividadesvariablesyrendimientosinferiores(Tabla3.8,Entradas57).Se
ensayaronalquinosconanillosheteroaromticosconloscualesseobtuvieronbuenos
rendimientosyvaloresdeeeelevados(Tabla3.8,Entradas89).
Laaplicabilidaddelareaccinpuedeextendersealusodelosalquinosalifticos
2k y 2m (Tabla 3.8, Entradas 1011). Ambos proporcionaron los correspondientes
productos de alquinilacin con rendimientos moderados y enantioselectividades
elevadas (82 y 88% ee, respectivamente). Finalmente se evaluaron tres alquinos
alicclicos de seis, cinco y tres miembros (Tabla 3.8, Entradas 1214). La reaccin
transcurriconrendimientosmoderadosyenantioselectividadeselevadasenlasque
se observa un mayor valor de exceso enantiomrico a medida que disminuye el
tamaodelanillo.
125
Captulo3
Tabla 3.8. Adicin enantioselectiva de varios alquinos 2 a Nbenciloxicarbonilaminop

toluenosulfona8aa.a
t(h)
11
R(%)b ee(%)c
2b
4MeOC6H4
11ab
84
86
2c
4(N,NdiMe)C6H4
11ae
70
85
2d
4FC6H4
11ac
43
88
2e
4ClC6H4
11ad
76
91
2f
2MeOC6H4
11af
74
66
2g
3,5diMeOC6H3
11ag
41
90
2h
2Me4MeOC6H3
11ah
55
80
2i
2tienil
11ai
81
90
2j
3tienil
11aj
66
90
10
2k
C6H5CH2CH2
11ak
53
82
11
2m
tercbutil
11am
46
88
12
2n
ciclohexil
11an
59
78
13
2o
ciclopentil
11ao
66
83
14
2p
ciclopropil
11ap
72
86
b
8aa (0,125 mmol), 2 (0,900 mmol), L6 (0,025 mmol), Et2Zn (0,375 mmol). Rendimiento
delproductoaislado.cDeterminadoporHPLCusandofasesestacionariasquirales.
Evaluacindedistintasamidosulfonasyalquinosterminales
Para profundizar en el estudio del alcance y limitaciones de la reaccin, se
escogieron los cuatro alquinos que proporcionaron las aminas proparglicas NCbz
protegidasconmejoresresultadosglobales(Tabla3.8,Entradas1,3,89)yseestudi
suadicinacincoamidosulfonasdiferentementesustituidas.
126
Captulo3
Tabla 3.9. Adicin enantioselectiva de varios alquinos aromticos a diferentes amido

sulfonasaromticas.a
t(h) Producto R(%)b ee(%)c
8aa Ph
2b
4MeOC6H4
11ab
84
86
8ba 4MeC6H4
2b
4MeOC6H4
11bb
72
88
8ea 4ClC6H4
2b
4MeOC6H4
11eb
72
92
8ha 2MeC6H4
2b
4MeOC6H4
11hb
89
91
8na 2tienil
2b
4MeOC6H4
11nb
74
86
8aa Ph
2e
4ClC6H4
11ae
76
91
8ba 4MeC6H4
2e
4ClC6H4
11be
84
92
8ea 4ClC6H4
2e
4ClC6H4
11ee
62
91
8ha 2MeC6H4
2e
4ClC6H4
11he
60
95
10
8na 2tienil
2e
4ClC6H4
11ne
75
87
11
8aa Ph
2i
2tienil
11ai
81
90
12
8ba 4MeC6H4
2i
2tienil
11bi
83
90
13
8ea 4ClC6H4
2i
2tienil
11ei
72
94
14
8ha 2MeC6H4
2i
2tienil
11hi
74
92
15
8na 2tienil
2i
2tienil
11ni
94
88
16
8aa Ph
2j
3tienil
11aj
66
90
17
8ba 4MeC6H4
2j
3tienil
11bj
57
89
18
8ea 4ClC6H4
2j
3tienil
11ej
80
91
19
8ha 2MeC6H4
2j
3tienil
11hj
56
94
20
8na 2tienil
2j
3tienil
11nj
56
89
8a
8a (0,125 mmol), 2 (0,900 mmol), L6 (0,025 mmol), Et2Zn (0,375 mmol). Rendimiento del
productoaislado.cDeterminadoporHPLCusandofasesestacionariasquirales.
Las veinte reacciones de alquinilacin ensayadas proporcionaron las

correspondientes propargilamidas con excelentes enantioselectividades y buenos
rendimientos.
127
Captulo3
ee (%)
100
80
60
40
20
S
S
HN
Cbz
SO2Tol
Me
HN
Cbz
SO2Tol
Cl
HN
Cl
Cbz
SO2Tol
MeHN
Cbz
SO2Tol
HN
S
Cbz
MeO
SO2Tol
Figura3.11.Excesoenantiomrico(%)delareaccindealquinilacinentrecuatroalquinosy
cincoamidosulfonas.
Lareaccindeadicindeciclopropilacetileno(2p)aNbenciloxicarbonilamino
ptoluenosulfona derivada del benzaldehdo 8aa (Tabla 3.8, Entrada 14) condujo a la
formacindelcorrespondienteproductodealquinilacinconunrendimientodel72%
y86%ee.Esteresultadoyelenormeintersquehadespertadolapresenciadelanillo
de ciclopropilo en los compuestos orgnicos en el campo de la qumica mdica, nos
condujoaexaminarlareaccinentreestealquino2pydiversasamidosulfonas.
128
Captulo3
Tabla3.10.Adicinenantioselectivadeciclopropilacetileno(2p)adiferentes
amidosulfonas8.a
t(h)
11
R(%)b
ee(%)c
8aa
Ph
11ap
72
86
8ba
4MeC6H4
11bp
58
93
8da
4FC6H4
11dp
69
89
8ea
4ClC6H4
11ep
45
95
8fa
4BrC6H4
11fp
50
93
8ga
3MeC6H4
11gp
52
89
8ha
2MeC6H4
11hp
53
96
8ja
2ClC6H4
11jp
30
92
8ka
2naftil
11kp
46
91
10
8ma
2furanil
11mp
68
84
11
8na
2tienil
11np
64
84
12
8oa
3furanil
11op
52
64
13
8qa
C6H4CH2CH2 4
11qp
59
42
14
8ra
nbutil
11rp
50
43
15
8sa
ciclohexil
11sp
63
65
8aa(0,125mmol),2(0,900mmol),L6(0,025mmol), Et2Zn(0,375mmol). b
Rendimiento del producto aislado. c Determinado por HPLC usando fases

estacionariasquirales.
La reaccin transcurri con rendimientos moderados y enantioselectividades

elevadas cuando se utilizaron amido sulfonas con grupos tanto electrndadores
como electrnatractores en la posicin para de su anillo aromtico (Tabla 3.10,
Entradas 25). Tambin se alcanz un valor de ee elevado cuando se llev a cabo la
reaccinconungrupometiloenlaposicinmeta(Tabla3.10,Entrada6).
129
Captulo3
Del mismo modo que para la adicin de alquinos aromticos, la adicin de

ciclopropilacetileno a amido sulfonas sustituidas en orto dio lugar a los
correspondientes productos de adicin con enantioselectividades excelentes,
independientemente de la naturaleza electrnica del sustituyente (Tabla 3.10,
Entradas78).Noobstante,lareaccintuvolugarconrendimientosmoderados.
Lareaccinconlaamidosulfonaderivadadel2naftaldehdo8ka(Tabla3.10,
Entrada 9), as como las derivadas de 2furanocarbaldehdo 8ma y 2
tiofenocarbaldehdo 8na (Tabla 3.10, Entradas 1011) proporcionaron las
correspondientesaminasproparglicasNCbzprotegidasconrendimientosmoderados
yenantioselectividadeselevadas.Porelcontrario,lareaccinconlaamidosulfona
derivada del 3furanocarbaldehdo 8oa transcurri con ee moderado (Tabla 3.10,
Entrada12).
Por ltimo, la alquinilacin de amido sulfonas alifticas tuvo lugar con
rendimientosyenantioselectividadesmoderadas(Tabla3.10,Entradas1315).
3.3.4.Modificacionessintticas
Los productos obtenidos contienen dos grupos, Nbenciloxicarbonilamino y
tripleenlace, con posibilidad de sufrir transformaciones que amplenlas aplicaciones
sintticasdelosmismos.
En primer lugar, llevamos a cabo la ozonolisis del triple enlace de las aminas
proparglicas protegidas y la esterificacin del cido obtenido (Esquema 3.16). Esto
permite la obtencin de un aminocido no proteinognico, el cual se obtuvo con
rendimientodel47%(paralosdospasos).
Esquema3.16.Sntesisdeaminocidosporozonolisisdeaminasproparglicas.
130
Captulo3
Acontinuacin,abordamoslareduccindeltripleenlace.Paraellollevamosa
cabolahidrogenacincatalticaconPdsobreCactivoal10%enetanol,obtenindose
as la correspondiente amina aliftica (Esquema 3.17). Esta reaccin transcurri con
rendimiento cuantitativo manteniendo la integridad estereoqumica del centro
estereognico.
Esquema3.17.Reduccindeltripleenlaceydesproteccindelaamina.
La reduccin selectiva del triple enlace para dar lugar a la correspondiente

aminaalifticaprotegidaseconsiguiconlautilizacindeuncatalizadormenosactivo,
PdsobreCaCO3al5%,enetanol(Esquema3.18).
Esquema3.18.Reduccinselectivadeltripleenlace.
La utilizacin de un catalizador de Pd sobre CaCO3 al 5% envenenado con Pb

(catalizador de Lindlar) condujo a la formacin de la correspondiente amina allica
protegida con isomera cis (99% de rendimiento), mientras que el ismero trans se
pudoobtenerporreduccindelaaminaproparglicaprotegidaconLiAlH41MenTHF
(64%derendimiento).
Esquema3.19.Sntesisdeaminasallicasprotegidascis(23)ytrans(24).
131
Captulo3
3.3.5.Determinacindelaconfiguracinabsoluta
La obtencin de la amina 21 (Esquema 3.17) permiti determinar la
configuracinabsolutadelaaminaproparglica11aaporcomparacindelvalordesu
poderrotatorioconeldescritoenlabibligrafa.26Laamina21obtenidapornosotros
presenta una configuracin (R), por lo que la configuracin de la amina proparglica
protegida11aaes(S).Paraelrestodeproductos11seasignlaconfiguracinabsoluta
asumiendounmecanismoestereognicouniforme.
Esquema3.20.Determinacindelaconfiguracinabsolutadelaaminaproparglicaprotegida
11aa.
3.3.6. Propuesta mecanstica para la alquinilacin de iminas

generadasinsituapartirdeamidosulfonas
La Figura 3.12 muestra un ciclo cataltico plausible para la reaccin de
alquinilacin de amido sulfonas con (R)BINOL y Et2Zn. En primer lugar, la
desprotonacindelligandoBINOLydelacetilenoporpartedeldietilzincdaralugara
uncomplejocatalticoBINOLzincatoetilalquinilzincI.Porotraparte,lareaccinentre
la amido sulfona y otro equivalente de dietilzinc proporcionara la imina NCbz
protegida, que se coordinara con el catalizador I para dar lugar al intermedio II. La
transferenciadelalquinilurodesdeeletilalquinilzincalaiminaliberaraelproductode
reaccin y el BINOLzincato III. Este, tras la coordinacin con otra molcula de
etilalquinilzincregeneraraelcomplejocataltico,reiniciandoelciclo.
132
Captulo3
Figura3.12.Ciclocatalticosimplificadoparalaalquinilacindeamidosulfonasenpresencia
decomplejosdeBINOLZn.
Latransferenciadelalquinilurodesdelamolculadealquiniletilzinccoordinada
a un oxgeno del BINOL en el intermedio II estara asistida mediante la coordinacin
del tomo de oxgeno carbonlico del carbamato a travs de un anillo de seis
miembros,proporcionandolaaminaproparglicaNCbzprotegidaconlaconfiguracin
(S).
133
Captulo3
R2
Et
Zn
O
OBn
O Zn N
O
R1
Figura3.13.ModeloestereoqumicoparalaalquinilacindeiminasNCbzprotegidas
generadasinsituapartirdeamidosulfonasenpresenciadecomplejosBINOLZn(unodelos
sustituyentesenelC(3)delligandohasidoomitidoporclaridad).
134
Captulo3
3.4.CONCLUSIONES
Sehadiseadounmtodoenantioselectivodeadicindealquinosterminalesa
Naciliminasgeneradasinsituapartirdeamidosulfonascatalizadaporunsistema
formadoporunligandodetipoBINOLyEt2Zna0CenCH2Cl2.
Esnecesarialapresenciadesustituyentesenlasposiciones3,3delligandode
tipo BINOL para conseguir enantioselectividades elevadas. El ligando (R)(+)3,3
bis(3,5bis(trifluorometil)fenil)1,1bi2naftol
(L6)
proporcion
los
mejores
resultados.
Sehautilizadoelgrupobenciloxicarbonilo(Cbz)comoprotector,debidoaque
dio lugar a un mayor rendimiento y enantioselectividad que los grupos terc
butiloxicarboniloyetiloxicarbonilo.
Los sustituyentes sobre el anillo aromtico del grupo sulfona no afectan a la
enantioselectividad y rendimiento del proceso, lo cual confirma que la reaccin
transcurreatravsdeunareaccintndemdeeliminacinadicin.
Se han utilizado un conjunto de quince amido sulfonas aromticas y
heteroaromticas de distinta naturaleza electrnica y estrica en la reaccin de
alquinilacin con fenilacetileno, proporcionando las correspondientes aminas
proparglicasprotegidasconbuenosrendimientosyenantioselectividadesdebuenasa
elevadas. La presencia de sustituyentes en orto condujo a elevadas
enantioselectividades independientemente de la naturaleza electrnica del
sustituyente. Se han ensayado tres amido sulfonas alifticas con rendimientos y
enantioselectividadesmoderados.
Se han ensayado nueve alquinos aromticos con grupos electrndadores y
electrnaceptores
en
el
anillo
benciloxicarbonilaminofenilmetil
aromtico
ptoluenosulfona
en
la
con
reaccin
con
rendimientos
la
y
enantioselectividades elevados. La presencia de sustituyentes en la posicin orto del

anilloaromticodelalquinodisminuyedeformavariablelaenantioselectividad.Sehan
evaluado cinco alquinos alifticos proporcionando los productos de alquinilacin con
buenasenantioselectividades.
135
Captulo3
Se han ensayado cinco amido sulfonas aromticas con diferente naturaleza

electrnica y estrica con cuatro alquinos aromticos, proporcionando las
correspondientes
aminas
proparglicas
protegidas
con
rendimientos
enantioselectividadeselevados.
Sehanllevadoacabodiversastransformacionessintticasquehanpermitido
demostrar la utilidad sinttica delos productos de alquinilacin formados. Con estas
transformaciones se han obtenido aminocidos no proteinognicos, se ha podido
determinar la configuracin absoluta de los productos de alquinilacin y se han
sintetizadolascorrespondientesaminasalifticasyallicasprotegidas.
136
Captulo3
3.5.SECCINEXPERIMENTAL
3.5.1.Tcnicasgenerales
Verapartado2.5.1.
Resonancia Magntica Nuclear (RMN): Se ha utilizado DMSOd6 como
disolvente para el anlisis y caracterizacin de las amido sulfonas de partida,
utilizandoelresiduodedisolventenodeuteradocomoreferencia(2,50ppmpara 1Hy
39,51ppmpara13C).
3.5.2. Procedimientos generales de sntesis y caracterizacin de

nuevosproductos
3.5.2.1.Sntesisycaracterizacindeamidosulfonas8
En un matraz de fondo redondo de 250 mL se disuelven 18 mmol del
carbamato adecuado y 36 mmol de sulfinato de sodio en una mezcla de MeOH:H2O
(1:2)(18:36mL).Seaade36mmoldealdehdo,1,37mLdecidofrmicoyseagitaa
temperaturaambientedurante72horas.Lamezcladereaccinsefiltraavacoenun
embudoBchneryselavaconaguayterparadarlugaralaamidosulfonapura.
Benciloxicarbonilaminofenilmetilptoluenosulfona(8aa)
RMN 1H(300MHz,DMSOd6)9.13(d,J=10.8Hz,
1H),7.69(d,J=8.4Hz,2H),7.61(dd,J=7.3,2.0Hz,
2H),7.427.32(m,8H),7.22(dd,J=7.8,2.1Hz,2H),
8aa
6.04 (d, J = 10.8 Hz, 1H), 4.93 (d, J = 12.6 Hz, 1H),
4.86(d,J=12.6Hz,1H),2.40(s,3H).
RMN 13C (75.5 MHz, DMSOd6) 155.2 (C), 144.6 (C), 136.4 (C), 133.8 (C), 130.4 (C),
129.6 (CH), 129.5 (CH), 129.3 (CH), 129.1 (CH), 128.3 (CH), 128.1 (CH), 128.0 (CH),
127.6(CH),74.9(CH),66.0(CH2),21.2(CH3).
137
Captulo3
Benciloxicarbonilaminoptolilmetilptoluenosulfona(8ba)
RMN1H(300MHz,DMSOd6)9.07(d,J=10.7
Hz,1H),7.68(d,J=8.2Hz,2H),7.49(d,J=8.1
Hz, 2H), 7.387.33 (m, 5H), 7.22718 (m, 4H),
5.98 (d, J = 10.7 Hz, 1H), 4.92 (d, J = 12.6 Hz,
1H),4.85(d,J=12.6Hz,1H),2.40(s,3H),2.31
8ba
(s,3H).
129.5(CH),129.1(CH),128.7(CH),128.3(CH),127.9(CH),127.6(CH),127.4(C),74.7
(CH),66.0(CH),21.2(CH3),20.8(CH3).
Benciloxicarbonilaminopmetoxifenilmetilptoluenosulfona(8ca)
RMN 1H (300 MHz, DMSOd6) 9.05 (d, J =
10.7Hz,H),7.68(d,J=8.23Hz,2H),7.54(d,J
=8.8Hz,2H),7.387.33(m,5H),7.237.20(m,
2H),6.94(d,J=8.8Hz,2H),5.98(d,J=10.7
Hz,1H),4.92(d,J=12.6Hz,1H),4.85(d,J=
8ca
12.6Hz,1H),3.77(s,3H),2.40(s,3H).
RMN13C(75.5MHz,DMSOd6)160.0(C),155.2(C),144.4(C),136.4(C),133.9(C),
131.0(CH),129.5(CH),129.1(CH),128.3(CH),127.9(C),127.6(CH),122.2(C),113.6
(CH),74.5(CH),66.0(CH2),55.2(CH3),21.2(CH3).
Benciloxicarbonilaminopfluorofenilmetilptoluenosulfona(8da)
RMN 1H (300 MHz, DMSOd6) 9.20 (d, J =
10.2Hz,1H),7.747.72(m,4H),7.387.22(m,
9H),6.17(d,J=10.3Hz,1H),4.96(d,J=12.6
Hz,1H),4.88(d,J=12.5,1H),2.38(s,3H).
8da
138
RMN13C(75.5MHz,DMSOd6)162.8(d,J=
Captulo3
246.4Hz,C),155.3(C),144.7(C),136.4(C),133.7(C),132.0(d,J=8.5Hz,CH),129.6
(CH),129.2(CH),128.4(CH),128.0(CH),127.7(CH),126.8(d,J=2.8Hz,C),115.1(d,J
=21.6Hz,CH),74.1(CH),66.1(CH2),21.2(CH3).
Benciloxicarbonilaminopclorofenilmetilptoluenosulfona(8ea)
Hz,1H),7.737.67(m,4H),7.49(d,J=8.0Hz,
2H),7.407.33(m,5H),7.21(d,J=5.7Hz,2H),
6.15 (d, J = 10.3 Hz, 1H), 4.93 (d, J = 12.5 Hz,
8ea
1H),4.86(d,J=12.5Hz,1H),2.40(s,3H).
RMN 13C(75.5MHz,DMSOd6)155.2(C=O),144.8(C),136.3(C),134.4(C),133.6(C),
131.5(CH),129.6(CH),129.2(CH),128.3(CH),128.2(CH),128.0(CH),127.7(CH),74.1
(CH),66.1(CH2),21.2(CH3).
Benciloxicarbonilaminopbromofenilmetilptoluenosulfona(8fa)
O
HN
O
SO2
Hz,1H),7.84(d,J=1.5Hz,1H),7.70(d,J=8.2
Ph
Hz,2H),7.61(d,J=3.0Hz,3H),7.407.33(m,
CH3
Br
5H), 7.21 (dd, J = 7.6, 2.1 Hz, 2H), 6.10 (d, J =
8fa
10.5Hz,1H),4.92(d,J=12.6Hz,1H),4.85(d,J
=12.6Hz,1H),2.40(s,3H).
RMN 13C (75.5 MHz, DMSOd6) 155.2 (C=O), 144.8 (C), 136.3 (C), 133.5 (C), 132.3
74.2(CH),66.1(CH2),21.2(CH3).
Benciloxicarbonilaminomtolilmetilptoluenosulfona(8ga)
RMN 1H (300 MHz, DMSOd6) 9.09 (d, J =
10.7 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.42
7.20(m,11H),5.97(d,J=10.7Hz,1H),4.91
(d,J=12.6Hz,1H),4.84(d,J=12.6Hz,1H),
8ga
139
Captulo3
2.40(s,3H),2.30(s,3H).
RMN13C(75.5MHz,DMSOd6)155.3(C=O),144.6(C),137.4(C),136.4(C),133.9(C),
130.3(C),130.2(CH),130.0(CH),129.6(CH),129.2(CH),128.4(CH),128.1(CH),128.0
(CH),127.7(CH),126.8(CH),74.9(CH),66.0(CH2),21.2(CH3),21.0(CH3).
Benciloxicarbonilaminootolilmetilptoluenosulfona(8ha)
RMN 1H (300 MHz, DMSOd6) 9.15 (d, J = 10.5
Hz,1H),7.73(d,J=7.7Hz,1H),7.69(d,J=8.2Hz,
2H),7.417.20(m,10H),6.20(d,J=10.5Hz,1H),
8ha
4.93(d,J=12.6Hz,1H),4.83(d,12.6Hz,1H),2.41
(s,3H),2.35(s,3H).
130.3 (CH), 129.8 (CH), 129.54 (C), 129.50 (CH), 129.3 (CH), 129.0 (CH), 128.5 (CH),
128.1(CH),127.8(CH),126.2(CH),70.8(CH),66.2(CH2),21.3(CH3),19.3(CH3).
Benciloxicarbonilaminooclorofenilmetilptoluenosulfona(8ja)
RMN1H(300MHz,DMSOd6)9.28(d,J=10.5Hz,
1H),7.957.92(m,1H),7.65(d,J=8.0Hz,2H),7.51
7.44 (m, 3H), 7.417.34 (m, 5H), 7.24 (dd, J = 7.6,
1.9 Hz, 2H), 6.55 (d, J = 10.6 Hz, 1H), 4.97 (d, J =
8ja
12.5Hz,1H),4.89(d,J=12.5Hz,1H),2.40(s,3H).
131.3(CH),130.9(CH),129.8(CH),129.3(CH),128.9(C),128.9(CH),128.3(CH),128.0
(CH),127.8(CH),127.4(CH),70.8(CH),66.3(CH2),21.2(CH3).
Benciloxicarbonilamino(naft2il)metilptoluenosulfona(8ka)
RMN 1H(300MHz,DMSOd6)9.27(d,J=10.7
Hz,1H),7.94(d,J=8.3Hz,2H),7.91(d,J=6.7
Hz, 1H), 7.757.73 (m, 3H), 7.597.56 (m, 2H),
7.397.33 (m, 6H), 7.22 (d, J = 6.5 Hz, 2H), 6.23
8ka
140
Captulo3
(d,J=10.7Hz,1H),4.94(d,J=12.6Hz,1H),4.87(d,J=12.6Hz,1H),2.40(s,3H).
RMN 13C(75.5MHz,DMSOd6)155.3(C),144.7(C),136.4(C),135.9(C),134.6(CH),
133.8 (C), 133.1 (C), 132.3 (C), 129.6 (CH), 129.5 (CH), 129.2 (CH), 128.4 (CH), 128.0
(CH),127.9(CH),127.6(CH),127.0(C),126.7(CH),126.6(CH),122.3(CH),75.1(CH),
66.1(CH2),21.2(CH3).
Benciloxicarbonilamino(naft1il)metilptoluenosulfona(8la)
Hz, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.097.98 (m,
3H),7.84(d,J=8.2Hz,2H),7.677.55(m,3H),
8la
7.407.32(m,5H),7.227.20(m,2H),6.93(d,J=
10.5Hz,1H),4.95(d,J=12.6Hz,1H),4.86(d,J
=12.6Hz,1H),2.39(s,3H).
RMN 13C (100 MHz, DMSOd6) 155.5 (C), 144.8 (C), 136.3 (C), 134.0 (C), 133.0 (C),
131.4(C),130.1(CH),129.7(CH),129.1(CH),128.7(CH),128.3(CH),128.1(CH),127.9
(CH),127.7(CH),127.1(C),127.1(CH),126.0(CH),125.2(CH),123.2(CH),69.8(CH),
66.2(CH2),21.2(CH3).
Benciloxicarbonilamino(furan2il)metilptoluenosulfona(8ma)
1H),7.72(dd,J=1.8,0.8Hz,1H),7.63(d,J=8.2Hz,
2H),7.397.32(m,5H),7.26(dd,J=7.7,1.8Hz,2H),
8ma
6.73(d,J=3.3Hz,1H),6.51(dd,J=3.3,1.9Hz,1H),
6.05 (d, J = 10.3 Hz, 1H), 6.05 (d, J = 10.3 Hz, 1H),
4.98(d,J=12.5Hz,1H),4.92(d,J=12.6Hz,1H),2.40(s,3H).
RMN 13C(75.5MHz,DMSOd6)155.2(C),144.9(C),144.4(CH),144.3(C),136.3(C),
133.4(C),129.6(CH),129.0(CH),128.3(CH),127.9(CH),127.7(CH),112.1(CH),111.2
(CH),70.0(CH),66.2(CH2),21.2(CH3).
141
Captulo3
Benciloxicarbonilamino(tien2il)metilptoluenosulfona(8na)
1H),7.69(d,J=8.2Hz,2H),7.64(dd,J=5.1,1.2Hz,
1H),7.397.34(m,6H),7.247.21(m,2H),7.08(dd,J
8na
=5.1,3.6Hz,1H),6.25(d,J=10.5Hz,1H),4.94(d,J
=12.6Hz,1H),4.87(d,J=12.6Hz,1H),2.40(s,3H).
129.9 (CH), 129.6 (CH), 129.2 (CH), 128.5 (CH), 128.3 (CH), 127.9 (CH), 127.6 (CH),
127.0(CH),71.0(CH),66.1(CH2),21.2(CH3).
Benciloxicarbonilamino(furan3il)metilptoluenosulfona(8oa)
O
HN
O
SO2
1H), 7.84 (s, 1H), 7.677.64 (m, 3H), 7.397.33 (m,
Ph
5H),7.25(dd,J=7.5,1.5Hz,2H),6.72(s,1H),6.02
CH3
8oa
(d,J=10.3Hz,1H),4.95(d,J=12.5Hz,1H),4.88(d,
J=12.6Hz,1H),2.4(s,3H).
RMN13C(75.5MHz,DMSOd6)155.1(C),144.6(C),143.5(CH),143.4(CH),136.4(C),
133.4(C),129.5(CH),129.2(CH),128.4(CH),128.0(CH),127.8(CH),115.7(C),110.7
(CH),68.5(CH),66.1(CH2),21.2(CH3).
Benciloxicarbonilamino(tien3il)metilptoluenosulfona(8pa)
1H),7.76(d,J=2.4Hz,1H),7.63(d,J=8.2Hz,2H),
7.55 (dd, J = 5.0, 3.0 Hz, 1H), 7.387.34 (m, 6H),
7.24 (dd, J = 7.2, 2.0 Hz, 2H), 6.16 (d, J = 10.5 Hz,
8pa
1H),4.94(d,J=12.6Hz,1H),4.88 (d,J=12.6 Hz,
1H),2.39(s,3H).
129.5 (CH), 129.1 (CH), 128.3 (CH), 128.3 (CH), 127.9 (CH), 127.7 (CH), 127.3 (CH),
126.2(CH),71.4(CH),66.1(CH2),21.2(CH3).
142
Captulo3
Benciloxicarbonilamino2feniletilmetilptoluenosulfona(8qa)
Hz,1H),7.667.57(m,2H),7.417.33(m,5H),
7.297.19(m,5H),7.147.12(m,2H),4.94(d,J
=12.6Hz,1H),4.88(d,J=12.6Hz,1H),4.75
8qa
4.67(m,1H),2.682.79(m,1H),2.592.52(m,
1H),2.37(s,3H),2.302.16(m,1H),2.021.89(m,1H).
129.5 (CH), 128.9 (CH), 128.32 (CH), 128.25 (CH), 127.8 (CH), 127.5 (CH), 126.1 (CH),
71.3(CH),61.7(CH2),30.6(CH2),27.9(CH2),21.0(CH3).
Benciloxicarbonilaminonbutilmetilptoluenosulfona(8ra)
RMN 1H (300 MHz, DMSOd6) 8.38 (d, J = 9.6
Hz, 1H), 7.647.53 (m, 2H), 7.417.30 (m, 5H),
7.147.12(m,2H),4.93(d,J=12.0Hz,1H),4.87
(d, J = 12.2 Hz, 1H), 4.734.66 (m, 1H), 2.36 (s,
8ra
3H), 1.801.71 (m, 2H), 1.521.43 (m, 2H), 1.40
1.38(m,2H),0.92(t,J=7.5Hz,3H).
128.9(CH),128.32(CH),128.25(CH),127.8(CH),71.1(CH),61.4(CH2),27.1(CH2),24.9
(CH2),22.3(CH2),21.1(CH3),14.0(CH3).
Benciloxicarbonilaminociclohexilmetilptoluenosulfona(8sa)
1H),7.647.57(m,2H),7.267.18(m,5H),7.157.12
(m,2H),4.92(d,J=12.3Hz,1H),4.84(d,J=12.4
8sa
Hz,1H),4.53(dd,J=8.1,6.0Hz,1H),2.36(s,3H),
1.901.79(m,4H),1.731.66(m,2H),1.391.13(m,
5H).
143
Captulo3
128.9(CH),128.3(CH),127.8(CH),127.5(CH),69.8(CH),61.3(CH2),27.4(CH2),27.2
(CH2),27.1(CH2),26.0(CH2),25.7(CH2),25.6(CH2),21.0(CH3).
tercButiloxicarbonilaminofenilmetilptoluenosulfona(9aa)
O
HN
1H),7.74(d,J=8.2Hz,2H),7.64(dd,J=7.4,1.9Hz,
2H), 7.437.39 (m, 5H), 5.96 (d, J = 10.7 Hz, 1H),
SO2
CH3
9aa
2.38(s,3H),1.18(s,9H).
RMN13C(75.5MHz,DMSOd6)154.1(C=O),144.4
(C),134.0(C),130.4(C),129.9(CH),129.5(CH),129.25(CH),129.22(CH),128.1(CH),
79.3(C),74.4(CH),27.8(CH3),21.1(CH3).
Etiloxicarbonilaminofenilmetilptoluenosulfona(10aa)
O
HN
1H),7.70(d,J=8.2Hz,2H),7.627.60(m,2H),7.41
Et
7.38(m,5H),6.02(d,J=10.8Hz,1H),3.897.80(m,
SO2
CH3
10aa
2H),2.38(s,3H),1.01(t,J=7.1Hz,9H).
RMN 13C (75.5 MHz, DMSOd6) 155.3 (C), 144.6
(C),133.8(C),130.5(C),129.7(CH),129.5(CH),129.3(CH),129.2(CH),128.1(CH),75.0
(CH),60.7(CH2),21.2(CH3),14.4(CH3).
Benciloxicarbonilaminofenilmetilfenilsulfona(8ab)
RMN 1H(300MHz,DMSOd6)9.15(d,J=10.7Hz,1H),
7.83(d,J=7.2Hz,2H),7.74(t,J=7.5Hz,1H),7.647.56
(m,4H),7.417.31(m,6H),7.20(dd,J=7.6,1.7Hz,2H),
6.09(d,J=10.7Hz,1H),4.90(d,J=12.5Hz,1H),4.84(d,
8ab
J=12.7Hz,1H).
RMN 13C(75.5MHz,DMSOd6)155.2(C),136.7(C),136.3(C),134.1(CH),130.2(C),
129.6 (CH), 129.4 (CH), 129.1 (CH), 129.0 (CH), 128.4 (CH), 128.1 (CH), 127.9 (CH),
127.7(CH),74.9(CH),66.1(CH2).
144
Captulo3
Benciloxicarbonilaminofenilmetilpclorofenilsulfona(8ac)
1H),7.82(d,J=8.6Hz,2H),7.687.63(m,4H),7.44
7.32(m,6H),7.21(dd,J=7.7,1.9Hz,2H),6.16(d,J
=10.7Hz,1H),4.95(d,J=12.6Hz,1H),4.86(d,J=
8ac
12.6Hz,1H).
129.9(C),129.7(CH),129.5(CH),129.2(CH),128.3(CH),128.2(CH),128.0(CH),127.7
(CH),74.9(CH),66.1(CH2).
Benciloxicarbonilaminoptolilmetilfenilsulfona(8bb)
1H),7.83(d,J=7.3Hz,2H),7.74(t,J=7.5Hz,1H),
7.58(t,J=7.8Hz,2H),7.50(d,J=8.2Hz,2H),7.37
8bb
7.31(m,3H),7.217.18(m,4H),6.04(d,J=10.7Hz,
1H),4.88(d,J=12.6Hz,1H),4.83 (d,J=12.6Hz,
1H),2.32(s,3H).
129.6 (CH), 129.1 (CH), 129.0 (CH), 128.7 (CH), 128.4 (CH), 127.9 (CH), 127.7 (CH),
127.2(C),74.7(CH),66.0(CH2),20.8(CH3).
Benciloxicarbonilaminoptolilmetilpclorofenilsulfona(8bc)
Hz,1H),7.84(d,J=8.5Hz,2H),7.66(d,J= 8.5
Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 7.387.31 (m,
3H),7.237.21(m,4H),6.12(d,J=10.6Hz,1H),
8bc
4.95(d,J=12.6Hz,1H),4.86(d,J=12.6Hz,1H),
2.32(s,3H).
145
Captulo3
131.1 (CH), 129.6 (CH), 129.2 (CH), 128.8 (CH), 128.4 (CH), 128.0 (CH), 127.7 (CH),
126.9(C),74.8(CH),66.1(CH2),20.8(CH3).
3.5.2.2. Sntesis y caracterizacin de las Nbenciloxicarbonil aminas

proparglicas11ydesusderivados
Procedimientogeneralparalaalquinilacinenantioselectivadelasamidosulfonas
8(ProcedimientoB)
UnadisolucindeEt2Zn1Menhexano(0,375mL,0,375mmol)seaadigota
a gota sobre una disolucin de ligando L6 (17,7 mg, 0,025 mmol) y alquino 2 (0,900
mmol)enCH2Cl2(0,4mL).Seagit1,5hatemperaturaambiente.Seenfrilareaccin
a0Cdurante15minyseaadiunadisolucindeamidosulfona8(0,125mmol)
enCH2Cl2 (1,0mL)mediantejeringuilla.Ladisolucinseagithastaquelareaccinse
complet(CCF).Lareaccinseparcon1,0mLdeagua.Lafaseacuosaseextrajocon
CH2Cl2 (3x15 mL). La fase orgnica se lav con salmuera (25 mL) y se sec sobre
MgSO4.Laevaporacindeldisolventeavacocondujoalcrudodelproducto,elcualse
purific por columna de cromatografa flash con una mezcla de eluyentes
hexano:AcOEt(97,5:2,5mL)paradarelcompuesto11.
Procedimientogeneralparalasntesisdelosproductosracmicos.
UnadisolucinMe2Znentolueno(0,09mL,0,188mmol)seaadigotaagota
sobre una disolucin de alquino 2 (0,188 mmol) en tolueno (1,2 mL). Tras agitar
durante30minatemperatureambiente,lamezcladereaccinsecalenta70Cyse
aadilaamidosulfona8(0,125mmol).Ladisolucinseagithastaquelareaccin
secomplet(CCF).Lareaccinseparcon1,0mLdeagua.Lafaseacuosaseextrajo
conCH2Cl2(3x15mL).Lafaseorgnicaselavconsalmuera(25mL)ysesecsobre
MgSO4.Laevaporacindeldisolventeavacocondujoalcrudodelproducto,elcualse
purificporcolumnadecromatografaflashempleandocomoeluyenteunamezclade
hexano:AcOEt(97,5:2,5mL)paradarelcompuestoracmico11.
146
Captulo3
(S)Nbenciloxicarbonil1,3difenilprop2in1amina(11aa)
HPLC quiral (Chiralcel ODH), hexanoiPrOH 90:10, 1
11aa
Mp99101C;[]D2017.4(c0.83,CHCl3,87%ee).
HRMN(300MHz,CDCl3)7.57(d,J=7.2Hz,2H),7.477.44(m,2H),7.407.24(m,
11H),5.95(d,J=8.7Hz,1H),5.36(d,J=6.8Hz,1H),5.18(d,J=12.0Hz,1H),5.12(d,J
=12.7Hz,1H).
13
C RMN (75.5 MHz, CDCl3) 155.4 (C), 139.0 (C), 136.2 (C), 131.8 (CH), 128.7 (CH),
128.54(CH),128.52(CH),128.3(CH),128.2(CH),128.1(CH),127.0(CH),122.4(C),87.0
(C),85.1(C),67.2(CH2),47.4(CH).
HRMS(ESI)m/z:364.1314[M+Na]+,C23H19NO2Narequiere364.1313.
(S)Nbenciloxicarbonil3fenil1ptolilprop2in1amina(11ba)
medianteHPLCquiral(ChiralcelADH),hexanoiPrOH
11ba
Mp123124C;[]D2016.50(c1.06,CHCl3,88%ee).
2H),5.89(d,J=8.2Hz,1H),5.30(d,J=7.3Hz,1H),5.17(d,J=12.0Hz,1H),5.11(d,J=
11.1Hz,1H),2.34(s,3H).
13
CRMN(75.5MHz,CDCl3)155.3(C),138.0(C),136.2(C),136.1(C),131.7(CH),129.4
(CH), 128.5 (CH), 128.4 (CH), 128.2 (CH), 128.1 (CH), 126.9 (CH), 122.5 (C), 87.2 (C),
84.9(C),67.1(CH2),47.2(CH),21.1(CH3).
147
Captulo3
(S)Nbenciloxicarbonil3fenil1(pmetoxifenil)prop2in1amina(11ca)
mediante la ozonolisis del producto 20 con HPLC
quiral (Chiralpak IC), hexanoiPrOH 97:3, 1 mL/min,
enantimeromayoritariotr=76.6min,enantimero
11ca
Mp5658C;[]D2011.6(c0.61,CHCl3,83%ee).
1
10.8Hz,1H),3.79(s,3H).
13
128.3(CH),128.17(CH),122.4(C),114.0(CH),87.2(C),84.9(C),67.1(CH2),55.3(CH3),
47.0(CH).
(S)Nbenciloxicarbonil3fenil1(pfluorofenil)prop2in1amina(11da)
HPLC quiral (Chiralcel ADH), hexanoiPrOH 90:10, 1
11da
Mp114116C;[]D206.1(c0.81,CHCl3,83%ee).
7.04(d,J=8.7Hz,2H),5.91(d,J=7.6Hz,1H),5.34(d,J=6.1Hz,1H),5.17(d,J=12.0
Hz,1H),5.12(d,J=12.2Hz,1H).
13
CRMN(100MHz,CDCl3)162.6(d,J=246.8Hz,C),155.4(C),136.1(C),135.0(C),
131.8 (CH), 128.8 (CH), 128.7 (d, J = 4.3 Hz, CH), 128.6 (CH), 128.4 (CH), 128.3 (CH),
128.2(CH),122.2(C),115.6(d,J=21.8Hz,CH),86.7(C),85.4(C),67.3(CH2),46.9(CH).
HRMS(ESI)m/z:382.1224[M+Na]+,C23H18FNO2Narequiere382.1219.
148
Captulo3
(S)Nbenciloxicarbonil1(pclorofenil)3fenilprop2in1amina(11ea)
Mp140142C;[]D2011.8(c1.23,CHCl3,90%ee).
11ea
1
10H),5.90(d,J=8.1Hz,1H),5.36(d,J=8.4Hz,1H),5.17(d,J=12.1Hz,1H),5.11(d,J
=12.7Hz,1H).
13
(CH), 128.7 (CH), 128.5 (CH), 128.4 (CH), 128.33 (CH), 128.26 (CH), 128.2 (CH), 122.1
(C),86.3(C),85.5(C),67.3(CH2),46.9(CH).
HRMS(ESI)m/z:398.0921[M+Na]+,C23H18ClNO2Narequiere398.0924.
(S)Nbenciloxicarbonil1(pbromofenil)3fenilprop2in1amina(11fa)
11fa
Mp153155C;[]D205.6(c0.76,CHCl3,91%ee).
1H),5.35(d,J=8.4Hz,1H),5.17(d,J=12.1Hz,1H),5.11(d,J=12.0Hz,1H).
13
128.73(CH),128.71(CH),128.6(CH),128.33(CH),128.28(CH),128.2(CH),122.2(C),
122.1(C),86.2(C),85.5(C),67.3(CH2),47.0(CH).
HRMS(ESI)m/z:442.0423[M+Na]+,C23H18BrNO2Narequiere442.0419.
149
Captulo3
(S)Nbenciloxicarbonil3fenil1mtolilprop2in1amina(11ga)
medianteHPLCquiral(ChiralcelODH),hexanoiPrOH
11ga
Mp118120C;[]D2016.1(c1.12,CHCl3,86%ee).
12.0Hz,1H),5.12(d,J=12.6Hz,1H),2.36(s,3H).
13
87.1(C),84.9(C),67.2(CH2),47.4(CH),21.4(CH3).
(S)Nbenciloxicarbonil3fenil1otolilprop2in1amina(11ha)
HPLC (Chiralcel ODH), hexanoiPrOH 80:20, 1 mL/min,
enantimero mayoritario tr = 17.5 min, enantimero
11ha
Mp126128C;[]D2026.3(c0.75,CHCl3,90%ee).
7.257.17(m,3H),6.02(d,J=8.4Hz,1H),5.29(d,J=7.2Hz,1H),5.16(d,J=11.8Hz,
1H),5.12(d,J=12.6Hz,1H),2.45(s,3H).
13
(CH), 128.5 (CH), 128.4 (CH), 128.3 (CH), 128.22 (CH), 128.16 (CH), 128.1 (CH), 127.0
(CH),126.4(CH),122.5(C),87.2(C),84.7(C),67.1(CH2),45.2(CH),19.1(CH3).
150
Captulo3
(S)Nbenciloxicarbonil1(pclorofenil)3fenil2in1amina(11ja)
HPLC (Chiralcel ADH), hexanoiPrOH 80:20, 1 mL/min,
11ja
Mp139141C;[]D2020.1(c0.81,CHCl3,90%ee).
6.15(d,J=8.1Hz,1H),5.51(s,1H),5.16(d,J=12.0Hz,1H),5.11(d,J=7.4Hz,1H).
13
CRMN(100MHz,CDCl3)155.0(C),136.3(C),136.1(C),133.3(C),131.8(CH),130.2
(CH), 129.6 (CH), 129.0 (CH), 128.6 (CH), 128.5 (CH), 128.23 (CH), 128.15 (CH), 128.1
(C),127.2(CH),122.3(CH),86.2(C),84.9(C),67.2(CH2),45.9(CH).
HRMS(ESI)m/z:398.0921[M+Na],C23H18ClNO2Narequiere398.0924.
(S)Nbenciloxicarbonil3fenil1(naft2il)prop2in1amina(11ka)
11ka
Mp140143C;[]D201.6(c1.06,CHCl3,88%ee)
H RMN (300 MHz, CDCl3) 8.03 (s, 1H), 7.877.82 (m, 3H), 7.64 (d, J = 7.4 Hz, 1H),
7.507.47(m,4H),7.357.31(m,8H),6.11(d,J=8.5Hz,1H),5.46(d,J=7.6Hz,1H),
5.19(d,J=12.0Hz,1H),5.14(d,J=13.6Hz,1H).
13
CRMN(75.5MHz,CDCl3)155.4(C),136.3(C),136.1(C),133.1(C),133.0(C),131.8
126.4(CH),126.3(CH),125.8(CH),124.8(CH),122.4(C),86.9(C),85.4(C),67.2(CH2),
47.6(CH).
151
Captulo3
(S)Nbenciloxicarbonil3fenil1(naft2il)prop2in1amina(11la)
11la
Mp133135C;[]D200.3(c0.36,CHCl3,2%ee).
4H),7.367.29(m,9H),6.60(d,J=9.1Hz,1H),5.37(d,J=6.0Hz,1H),5.17(s,2H).
13
CRMN(75.5MHz,CDCl3)155.2(C),136.2(C),134.1(C),131.8(CH),130.4(C),129.4
(CH),128.9(CH),128.6(C),128.5(CH),128.3(CH),128.2(CH),128.1(CH),127.0(CH),
126.8(CH),126.0(CH),125.4(CH),125.2(CH),123.4(CH),122.5(C),87.3(C),85.5(C),
67.2(CH2),45.3(CH).
(S)Nbenciloxicarbonil3fenil1(furan2il)prop2in1amina(11ma)
11ma
Mp6769C;[]D208.0(c0.64,CHCl3,88%ee).
6.43(d,J=3.0Hz,1H),6.34(dd,J=3.2,1.9Hz,1H),5.99(d,J=8.5Hz,1H),5.39(d,J=
7.2Hz,1H),5.18(d,J=11.9Hz,1H),5.13(d,J=13.3Hz,1H).
13
C RMN (75.5 MHz, CDCl3) 155.2 (C), 151.0 (C), 142.9 (CH), 136.1 (C), 131.8 (CH),
128.7(CH),128.5(CH),128.3(CH),128.2(CH),122.1(C),110.4(CH),107.6(CH),84.7
(C),84.0(C),67.3(CH2),41.7(CH).
152
Captulo3
(S)Nbenciloxicarbonil3fenil1(tien2il)prop2in1amina(11na)
Mp9799C;[]D2010.8(c0.85,CHCl3,78%ee).
11na
1
Hz,1H),7.22(d,J=2.9Hz,1H),7.0(dd,J=5.1,3.6Hz,1H),6.14(d,J=8.5Hz,1H),5.44
(d,J=7.6Hz,1H),5.19(d,J=11.9Hz,1H),5.13(d,J=14.3Hz,1H).
13
128.5 (CH), 128.3 (CH), 128.23 (CH), 128.15 (CH), 126.8 (CH), 125.8 (CH), 125.7 (CH),
122.1(C),86.4(C),84.4(C),67.3(CH2),43.3(CH).
HRMS(ESI)m/z:370.0872[M+Na]+,C21H17NO2SNarequiere370.0878.
(S)Nbenciloxicarbonil3fenil1(furan3il)prop2in1amina(11oa)
11oa
Mp103105C;[]D2018.5(c0.38,CHCl3,76%ee).
HRMN(300MHz,CDCl3)7.55(s,1H),7.457.41(m,2H),7.38(t,J=1.7Hz,1H),7.35
7.29(m,8H),6.47(s,1H),5.83(d,J=8.9Hz,1H),5.24(d,J=7.1Hz,1H),5.15(s,2H).
13
C RMN (75.5 MHz, CDCl3) 155.3 (C), 143.7 (CH), 140.4 (CH) 136.1 (C), 131.8 (CH),
128.6(CH),128.5(CH),128.3(CH),128.2(CH),128.1(CH),124.7(C),122.2(C),109.4
(CH),86.4(C),83.5(C),67.2(CH2),40.0(CH).
153
Captulo3
(S)Nbenciloxicarbonil3fenil1(tien3il)prop2in1amina(11pa)
11pa
Mp105107C;[]D204.0(c0.41,CHCl3,74%ee).
14.1Hz,1H).
13
128.5 (CH), 128.3 (CH), 128.2 (CH), 128.1 (CH), 126.7 (CH), 126.5 (CH), 122.8 (CH),
122.3(C),86.8(C),84.2(C),67.2(CH2),43.4(CH).
(S)Nbenciloxicarbonil3fenil1(2feniletil)prop2in1amina(11qa)
HPLC(ChiralcelODH),hexanoiPrOH90:10,1mL/min,
11qa
Mp106108C;[]D2010.2(c0.58,CHCl3,60%ee).
1
5.12(s,2H),5.01(d,J=7.7Hz,1H),4.73(q,J=6.9Hz,1H),2.82(t,J=7.8Hz,2H),2.02
2.00(m,2H).
13
CRMN(75.5MHz,CDCl3)155.3(C),140.9(C),136.2(C),131.7(CH),128.54(CH),
128.48(CH),128.4(CH),128.3(CH),128.2(CH),126.1(CH),122.5(C),88.0(C),83.8(C),
67.0(CH2),43.8(CH),37.9(CH2),29.7(CH2).
154
Captulo3
(S)Nbenciloxicarbonil1fenilhept1in3amina(11ra)
11ra
Mp5557C;[]D2026.9(c0.78,CHCl3,46%ee).
RMN 1H(300MHz,CDCl3)7.427.29(m,10H),5.14(s,2H),5.03(da,J=7.3Hz,1H),
4.73(q,J=6.9Hz,1H),1.811.72(m,2H),1.521.45(m,2H),1.431.34(m,2H),0.93(t,
J=7.2Hz,3H).
RMN 13C(75.5MHz,CDCl3)155.4(C),136.4(C),131.7(CH),128.5(CH),128.3(CH),
128.2(CH),128.1(CH),122.7(C),88.5(C),83.2(C),66.9(CH2),44.1(CH),36.1(CH2),
27.8(CH2),22.2(CH2),14.0(CH3).
(S)Nbenciloxicarbonil1ciclohexil3fenilprop2in1amina(11sa)
11sa
Mp107109C;[]D2033.0(c1.35,CHCl3,55%ee).
1H),4.59(dd,J=8.3,6.2Hz,1H),1.851.76(m,4H),1.691.65(m,2H),1.341.09(m,
5H).
13
CRMN(75.5MHz,CDCl3)155.6(C),136.3(C),131.7(CH),128.5(CH),128.2(CH),
128.1 (CH), 122.7 (C), 87.4 (C), 84.0 (C), 67.0 (CH2), 49.2 (CH), 29.2 (CH2), 28.4 (CH2),
26.2(CH2),25.9(CH2),25.8(CH2).
155
Captulo3
(S)Nbenciloxicarbonil1fenil3(pmetoxifenil)prop2in1amina(11ab)
Mp8688C;[]D2018.7(c1.59,CHCl3,88%ee).
11ab
1
HRMN(300MHz,CDCl3)7.56(d,J=7.2Hz,2H),7.407.28(m,10H),6.83(d,J=8.9
Hz,2H),5.93(d,J=8.2Hz,1H),5.38(d,J=6.7Hz,1H),5.17(d,J=12.0Hz,1H),5.12(d,
J=12.6Hz,1H),3.79(s,3H).
13
(CH),128.5(CH),128.15(CH),128.09(CH),127.0(CH),114.5(C),113.9(CH),85.6(C),
85.0(C),67.1(CH2),55.2(CH3),47.5(CH).
(S)Nbenciloxicarbonil1fenil3(4(N,Ndimetilamino)fenil)prop2in1amina
(11ac)
O
HN
mediante HPLC (Chiralcel ODH), hexanoiPrOH
Ph
90:10,1mL/min,enantimeromayoritariotr=19.9
CH3
N
CH3
Mp9799C;[]D2021.6(c0.97,CHCl3,85%ee).
11ac
RMN 1H(300MHz,CDCl3)7.56(d,J=7.0Hz,2H),
7.387.27(m,10H),6.60(d,J=8.9Hz,2H),5.92(d,J=8.3Hz,1H),5.33(d,J=7.4Hz,
1H),5.17(d,J=11.9Hz,1H),5.11(d,J=12.9Hz,1H),2.95(s,6H).
RMN13C(75.5MHz,CDCl3)155.4(C),150.3(C),139.7(C),136.3(C),132.8(CH),128.6
(CH), 128.5 (CH), 128.1 (CH), 128.0 (CH), 127.0 (CH), 111.7 (CH), 109.1 (C), 86.1 (C),
84.6(C),67.1(CH2),47.6(CH),40.2(CH3).
HRMS(ESI)m/z:407.1734[M+Na]+,C25H24N2O2Narequiere407.1735.
156
Captulo3
(S)Nbenciloxicarbonil1fenil3(pfluorofenil)prop2in1amina(11ad)
11ad
Mp105107C;[]D2022.0(c1.33,CHCl3,88%ee).
RMN 1H(300MHz,CDCl3)7.54(d,J=6.7Hz,2H),7.427.31(m,10H),6.99(t,J=8.8
J=12.4Hz,1H).
RMN 13C(75.5MHz,CDCl3)162.7(d,J=249Hz,C),155.4(C),138.9(C),136.1(C),
133.7 (d, J = 8 Hz, CH), 128.8 (CH), 128.5 (CH), 128.3 (CH), 128.23 (CH), 128.18 (CH),
126.9(CH),118.5(d,J=3Hz,C),115.6(d,J=22Hz,CH),86.7(C),84.0(C),67.2(CH2),
47.4(CH).
HRMS(ESI)m/z:382.1216[M+Na]+,C23H18FNO2Narequiere382.1219.
(S)Nbenciloxicarbonil3(4clorofenil)1fenilprop2in1amina(11ae)
11ae
Mp117119C;[]D2019.0(c1.00,CHCl3,91%ee).
HRMN(300MHz,CDCl3)7.56(d,J=7.0Hz,2H),7.427.28(m,12H),5.95(da,J=
8.4Hz,1H),5.36(da,J=7.7Hz,1H),5.19(d,J=11.9Hz,1H),5.14(d,J=12.8Hz,1H).
13
88.0(C),84.0(C),67.2(CH2),47.4(CH).
HRMS(ESI)m/z:398.0932[M+Na]+,C23H18ClNO2Narequiere398.0924;
157
Captulo3
(S)Nbenciloxicarbonil1fenil3(ometoxifenil)prop2in1amina(11af)
HPLC(ChiralcelODH),hexanoiPrOH90:10,1mL/min,
Mp124127C;[]D2014.6(c1.48,CHCl3,66%ee).
11af
RMN1H(300MHz,CDCl3)7.62(d,J=7.0Hz,2H),7.417.26(m,10H),6.89(td,J=7.4,
1.0Hz,1H),6.86(d,J=8.3Hz,1H),5.99(d,J=8.7Hz,1H),5.38(d,J=6.9Hz,1H),5.17
(d,J=12.0Hz,1H),5.11(d,J=12.7Hz,1H),3.86(s,3H).
110.6(CH),90.9(C),81.6(C),67.1(CH2),55.7(CH3),47.7(CH).
(S)Nbenciloxicarbonil1fenil3(3,5dimetoxifenil)prop2in1amina(11ag)
O
HN
mediante HPLC (Chiralcel ADH), hexanoiPrOH
Ph
OCH3
OCH3
Mp118120C;[]D2025.4(c0.20,CHCl3,90%ee).
11ag
RMN 1H(300MHz,CDCl3)7.55(d,J=7.2Hz,2H),7.397.31(m,8H),6.60(d,J=2.2
Hz,2H),6.44(t,J=2.3Hz,1H),5.93(d,J=8.6Hz,1H),5.36(d,J=7.8Hz,1H),5.17(d,J
=12.0Hz,1H),5.11(d,J=13.0Hz,1H),3.76(s,6H).
(CH),128.21(CH),128.15(CH),127.0(CH),123.6(C),109.5(CH),102.0(CH),86.5(C),
85.0(C),67.2(CH2),55.4(CH3),47.4(CH).
158
Captulo3
(S)Nbenciloxicarbonil1fenil3(2metil4metoxifenil)prop2in1amina(11ah)
Mp98100C;[]D2022.1(c0.90,CHCl3,80%ee).
11ah
RMN 1H(300MHz,CDCl3)7.57(d,J=7.1Hz,2H),7.397.30(m,9H),6.72(d,J=2.4
Hz,1H),6.66(dd,J=8.5,2.6Hz,1H),5.95(d,J=8.2Hz,1H),5.32(d,J=6.3Hz,1H),
5.17(d,J=12.0Hz,1H),5.11(d,J=12.6Hz,1H),3.78(s,3H),2.38(s,3H).
RMN 13C(75.5MHz,CDCl3)159.7(C),155.4(C),142.2(C),139.4(C),136.2(C),133.4
111.2(CH),89.3(C),84.1(C),67.1(CH2),55.2(CH3),47.7(CH),21.0(CH3).
(S)Nbenciloxicarbonil1fenil3(tien2il)prop2in1amina(11ai)
11ai
Mp121123C;[]D2021.0(c1.12,CHCl3,90%ee).
HRMN(300MHz,CDCl3)7.53(d,J=7.1Hz,2H),7.407.29(m,8H),7.25(dd,J=5.1,
1.1Hz,1H),7.22(d,J=3.6Hz,1H),6.96(dd,J=5.1,3.7Hz,1H),5.95(d,J=8.5Hz,1H),
5.33(d,J=7.4Hz,1H),5.17(d,J=11.9Hz,1H),5.12(d,J=12.8Hz,1H).
13
128.5(CH),128.3(CH),128.2(CH),128.1(CH),127.4(CH),126.9(CH),122.3(C),90.8
(C),78.4(C),67.2(CH2),47.6(CH).
159
Captulo3
(S)Nbenciloxicarbonil1fenil3(tien3il)prop2in1amina(11aj)
mL/min,enantimeromayoritariotr=23.9,enantimero
minoritariotr=13.3.
11aj
Mp115117C;[]D2017.3(c1.12,CHCl3,90%ee).
HRMN(400MHz,CDCl3)7.54(d,J=7.1Hz,2H),7.45(d,J=2.1Hz,1H),7.407.30
(m,8H),7.25(dd,J=5.0,3.0Hz,1H),7.11(dd,J=5.0,1.0Hz,1H),5.92(d,J=8.5Hz,
1H),5.31(d,J=7.5Hz,1H),5.17(d,J=12.0Hz,1H),5.11(d,J=12.7Hz,1H).
13
C RMN (100 MHz, CDCl3) 155.4 (C), 138.9 (C), 136.1 (C), 129.9 (CH), 129.2 (CH),
128.7(CH),128.5(CH),128.20(CH),128.16(CH),126.9(CH),125.3(CH),121.4(C),86.6
(C),80.3(C),67.2(CH2),47.5(CH).
HRMS(ESI):370.0873[M+Na]+,C21H17NO2SNarequiere370.0878.
(S)Nbenciloxicarbonil1,5difenilpent2in1amina(11ak)
HPLC quiral (Chiralcel ODH), hexaneiPrOH 90:10, 1
mL/min, major enantiomer tr = 19.4 min, minor
enantiomertr=17.9min.
11ak
Mp8587C;[]D2010.2(c0.56,CHCl3,82%ee).
HRMN(300MHz,CDCl3)7.417.27(m,12H),7.22(d,J=7.9Hz,3H),5.67(d,J=7.5
Hz,1H),5.175.10(m,3H),2.84(t,J=7.4Hz,2H),2.55(td,J=7.4,2.0Hz,1H).
13
78.8(C),67.1(CH2),47.1(CH),34.8(CH2),20.9(CH2).
160
Captulo3
(S)Nbenciloxicarbonil4,4dimetil1fenilpent2in1amina(11am)
Elexcesoenantiomrico(88%)sedeterminmedianteHPLC
O
HN
quiral(ChiralcelODH),hexaneiPrOH90:10,1mL/min,major
Ph
enantiomertr=8.3min,minorenantiomertr=5.2min.
11am
Mp5758C;[]D2023.8(c1.00,CHCl3,88%ee).
HRMN(300MHz,CDCl3)7.52(da,J=7.0Hz,2H),7.377.30(m,8H),5.72(da,J=
8.3Hz,1H),5.24(da,J=7.8Hz,1H),5.18(d,J=12.1Hz,1H),5.11(d,J=12.3Hz,1H),
1.26(s,9H).
13
128.1(CH),127.9(CH),126.9(CH),94.1(C),76.3(C),67.0(CH2),46.9(CH),30.9(CH3),
27.4(C).
(S)Nbenciloxicarbonil3ciclohexil1fenilprop2in1amina(11an)
11an
Mp8789C;[]D207.4(c1.01,CHCl3,78%ee).
1
H RMN (300 MHz, CDCl3) 7.16 (d, J = 7.2 Hz, 2H),
7.387.29(m,8H),5.71(d,J=8.1Hz,1H),5.225.15(m,2H),5.10(d,J=14.0Hz,1H),
2.472.39(m,1H),1.831.26(m,10H).
13
128.2(CH),127.9(CH),126.9(CH),90.0(C),77.8(C),67.0(CH2),47.1(CH),32.5(CH2),
29.0(CH),25.8(CH2),24.8(CH2).
HRMS(ESI)m/z:348.1966[M+H]+,C23H26NO2requiere348.1964.
161
Captulo3
(S)Nbenciloxicarbonil3ciclopentil1fenilprop2in1amina(11ao)
Mp8184C;[]D2010.2(c1.00,CHCl3,83%ee).
11ao
1
Hz,1H),5.23(d,J=7.1Hz,1H),5.17(d,J=12.1Hz,1H),5.11(d,J=12.4Hz,1H),2.72
2.62(m,1H),1.981.87(m,2H),1.751.55(m,6H).
13
128.1(CH),127.9(CH),126.9(CH),80.1(C),77.4(C),67.0(CH2),47.1(CH),33.7(CH2),
30.1(CH),24.9(CH2).
(S)Nbenciloxicarbonil3ciclopropil1fenilprop2in1amina(11ap)
11ap
Mp102104C;[]D203.1(c1.01,CHCl3,86%ee).
(m,1H),0.820.76(m,2H),0.740.68(m,2H).
13
128.1(CH),127.9(CH),126.9(CH),88.8(C),73.1(C),67.0(CH2),47.1(CH),8.2(CH2),
0.5(CH).
162
Captulo3
(S)Nbenciloxicarbonil3(pmetoxifenil)1(ptolil)prop2in1amina(11bb)
mediante HPLC quiral (Chiralcel ODH), hexano
i
PrOH85:15,1mL/min,enantimeromayoritario
tr = 11.9 min, enantimero minoritario tr = 10.6

min.
11bb
Mp102103C;[]D2018.4(c1.36,CHCl3,89%ee).
1
Hz,2H),6.82(d,J=8.9Hz,2H),5.88(d,J=8.3Hz,1H),5.33(d,J=6.4Hz,1H),5.17(d,J
=12.0Hz,1H),5.11(d,J=12.5Hz,1H),3.79(s,3H),3.34(s,3H).
13
(CH), 129.3 (CH), 128.5 (CH), 128.1 (CH), 126.9 (CH), 114.6 (C), 113.9 (CH), 85.8 (C),
84.8(C),67.1(CH2),55.2(CH3),47.2(CH),21.1(CH3).
(S)Nbenciloxicarbonil1(pclorofenil)3(pmetoxifenil)prop2in1amina(11eb)
i
PrOH85:15,1mL/min,enantimeromayoritariotr
=13.6min,enantimerominoritariotr=12.4min.
11eb
Mp 110112 C; []D20 15.4 (c 1.59, CHCl3, 92%
ee).
1
J=12.3Hz,1H),3.79(s,3H).
13
(CH),128.8(CH),128.5(CH),128.4(CH),128.2(CH),128.1(CH),114.1(C),113.9(CH),
85.4(C),84.9(C),67.2(CH2),55.3(CH3),46.9(CH).
163
Captulo3
(S)Nbenciloxicarbonil3(pmetoxifenil)1(otolil)prop2in1amina(11hb)
mediante HPLC quiral (Chiralcel ADH), hexano
i
Mp 115116 C; []D20 20.1 (c 1.06, CHCl3, 91%
11hb
ee).
6.81(d,J=8.9Hz,2H),5.99(d,J=8.3Hz,1H),5.28(d,J=4.9Hz,1H),5.14(s,2H),3.79
(s,3H),3.44(s,3H).
13
(CH), 130.9 (CH), 128.5 (CH), 128.2 (CH), 128.12 (CH), 128.08 (CH),126.9 (CH), 126.3
(CH), 114.6 (C), 113.9 (CH), 85.8 (C), 84.6 (C), 67.1 (CH2), 55.2 (CH3), 45.3 (CH), 19.1
(CH3).
(S)Nbenciloxicarbonil3(pmetoxifenil)1(tien2il)prop2in1amina(11nb)
i
11nb
Mp113114C;[]D2016.8(c1.45,CHCl3,86%ee).
1
HRMN(300MHz,CDCl3)7.417.30(m,7H),7.25
(dd,J=5.1,1.1Hz,1H),7.21(d,J=2.8Hz,1H),6.96(dd,J=5.1,3.6Hz,1H),6.83(d,J=
8.9Hz,2H),6.13(d,J=8.4Hz,1H),5.44(d,J=7.6Hz,1H),5.18(d,J=11.7Hz,1H),
5.13(d,J=12.3Hz,1H),3.80(s,3H).
164
Captulo3
13
(CH),128.2(CH),128.1(CH),126.8(CH),125.7(CH),125.5(CH),114.1(C),113.9(CH),
85.1(C),84.4(C),67.2(CH2),55.3(CH3),43.4(CH).
(S)Nbenciloxicarbonil3(4clorofenil)1(ptolil)prop2in1amina(11be)
mediante HPLC quiral (Chiralcel ADH), hexano
i
11be
Mp113116C;[]D2015.4(c1.00,CHCl3,92%ee).
1HRMN(300MHz,CDCl3)7.40(d,J=7.9Hz,2H),7.357.29(m,7H),7.267.22(m,
2H),7.15(d,J=8.0Hz,2H),5.86(da,J=8.1Hz,1H),5.31(da,J=7.5Hz,1H),5.15(d,J
=11.9Hz,1H),5.09(d,J=12.7Hz,1H),2.32(s,3H).
13
88.2(C),83.7(C),67.2(CH2),47.2(CH),21.1(CH3).
(S)Nbenciloxicarbonil1,3di(4clorofenil)prop2in1amina(11ee)
i
PrOH 90:10, 1 mL/min, enantimero mayoritario tr
11ee
Mp115117C;[]D2012.3(c1.00,CHCl3,91%ee).
HRMN(300MHz,CDCl3)7.48(d,J=8.3Hz,2H),7.397.28(m,11H),5.90(da,J=
8.4Hz,1H),5.33(da,J=8.0Hz,1H),5.18(d,J=12.0Hz,1H),5.13(d,J=12.4Hz,1H).
165
Captulo3
13
(CH), 128.9 (CH), 128.7 (CH), 128.6 (CH), 128.3 (CH), 128.2 (CH), 120.6 (C), 87.3 (C),
84.4(C),67.4(CH2),46.8(CH).
(S)Nbenciloxicarbonil3(4clorofenil)1(otolil)prop2in1amina(11he)
11he
Mp108112C;[]D2012.2(c1.00,CHCl3,95%ee).
6.01(da,J=8.3Hz,1H),5.26(d,J=7.9Hz,1H),5.15(s,2H),2.44(s,3H).
13
(CH), 131.0 128.8 (CH), 128.6 (CH), 128.52 (CH), 128.45 (CH), 128.2 (CH), 128.1 (CH),
126.9(CH),126.4(CH),121.0(C),88.3(C),83.6(C),67.2(CH2),45.2(CH),19.1(CH3);
(S)Nbenciloxicarbonil3(4clorofenil)1(tien2il)prop2in1amina(11ne)
11ne
Mp108109C;[]D2018.1(c1.00,CHCl3,87%ee).
HRMN(300MHz,CDCl3)7.417.27(m,10H),7.21(d,J=3.1Hz,1H),6.98(dd,J=
3.6,5.1Hz,1H),6.15(da,J=8.3Hz,1H),5.42(da,J=7.3Hz,1H),5.20(d,J=11.9Hz,
1H),5.15(d,J=13.0Hz,1H).
166
Captulo3
13
87.4(C),83.3(C),67.3(CH2),43.3(CH).
(S)Nbenciloxicarbonil3(tien2il)1(ptolil)prop2in1amina(11bi)
11bi
Mp133136C;[]D2022.1(c1.62,CHCl3,91%ee).
1
H RMN (300 MHz, CDCl3) 7.42 (d, J = 7.9 Hz, 2H),
7.367.30(m,5H),7.24(dd,J=5.2,1.1Hz,1H),7.22(d,J=3.6Hz,1H),7.18(d,J=8.0
5.17(d,J=11.9Hz,1H),5.11(d,J=11.7Hz,1H),2.35(s,3H).
13
(CH), 128.5 (CH), 128.2 (CH), 128.1 (CH), 127.3 (CH), 126.89 (CH), 126.86 (CH), 122.4
(C),91.0(C),78.2(C),67.2(CH2),47.4(CH),21.1(CH3).
(S)Nbenciloxicarbonil1(pclorofenil)3(tien2il)prop2in1amina(11ei)
11ei
Mp133135C;[]D2020.2(c1.45,CHCl3,92%ee);
HRMN(300MHz,CDCl3)7.46(d,J=8.3Hz,2H),7.357.31(m,7H),7.26(dd,J=5.2,
1.2Hz,1H),7.22(dd,J=3.6,1.0Hz,1H),6.96(dd,J=5.2,3.7Hz,1H),5.91(d,J=8.0
Hz,1H),5.34(d,J=6.8Hz,1H),5.16(d,J=12.1Hz,1H),5.11(d,J=12.3Hz,1H).
167
Captulo3
13
90.2(C),78.9(C),67.3(CH2),47.1(CH).
HRMS(ESI)m/z:404.0497[M+Na]+,C21H16ClNO2SNarequiere404.0488.
(S)Nbenciloxicarbonil3(tien2il)1(otolil)prop2in1amina(11hi)
mL/min,enantimeromayoritariotr=11.9,enantimero
minoritariotr=17.1.
Mp111113C;[]D2021.4(c0.95,CHCl3,95%ee).
11hi
H RMN (400 MHz, CDCl3) 7.607.57 (m, 1H), ), 7.34
7.28(m,5H),7.227.16(m,5H),6.94(dd,J=5.2,3.7Hz,1H),6.02(d,J=8.5Hz,1H),
5.24(d,J=7.3Hz,1H),5.13(s,2H),2.42(s,3H).
13
CRMN(100MHz,CDCl3)155.1(C),136.5(C),136.2(C),136.0(C),132.3(CH),131.0
126.4(CH),122.4(C),91.1(C),78.0(C),67.2(CH2),45.4(CH),19.1(CH3).
(S)Nbenciloxicarbonil1,3(ditien2il)prop2in1amina(11ni)
11ni
Mp8182C;[]D2021.5(c1.47,CHCl3,88%ee).
1
HRMN(300MHz,CDCl3)7.377.30(m,5H),7.277.23
(m,3H),7.19(d,J=3.4Hz,1H),6.986.94(m,2H),6.15(d,J=8.7Hz,1H),5.43(d,J=
7.9Hz,1H),5.18(d,J=11.9Hz,1H),5.13(d,J=12.6Hz,1H).
168
Captulo3
13
128.2 (CH), 128.1 (CH), 127.6 (CH), 127.0 (CH), 126.9 (CH), 125.9 (CH), 125.7 (CH),
121.9(C),90.2(C),77.9(C),67.3(CH2),43.5(CH).
HRMS(ESI)m/z:376.0445[M+Na]+,C19H15NO2S2Narequiere376.0442.
(S)Nbenciloxicarbonil3(tien3il)1(ptolil)prop2in1amina(11bj)
mL/min, enantimero mayoritario tr = 20.6,
enantimerominoritariotr=23.9.
11bj
Mp120122C;[]D2014.9(c1.07,CHCl3,89%ee).
Hz,1H),7.16(d,J=7.9Hz,2H),7.10(dd,J=5.0,1.0Hz,1H),5.89(d,J=8.3Hz,1H),
5.28(d,J=6.2Hz,1H),5.16(d,J=12.0Hz,1H),5.10(d,J=7.1Hz,1H),2.34(s,3H).
13
(CH), 129.1 (CH), 128.5 (CH), 128.2 (CH), 126.9 (CH), 125.3 (CH), 121.5 (C), 86.8 (C),
80.1(C),67.1(CH2),47.2(CH),21.1(CH3).
(S)Nbenciloxicarbonil1(pclorofenil)3(tien3il)prop2in1amina(11ej)
11ej
Mp130132C;[]D2013.3(c1.05,CHCl3,92%ee).
5.16(d,J=12.1Hz,1H),5.11(d,J=11.7Hz,1H).
169
Captulo3
13
86.0(C),80.7(C),67.3(CH2),46.9(CH).
HRMS(ESI)m/z:404.0492[M+Na]+,C21H16ClNO2SNarequiere404.0492.
(S)Nbenciloxicarbonil3(tien3il)1(otolil)prop2in1amina(11hj)
Mp119121C;[]D2017.2(c1.28,CHCl3,94%ee).
11hj
1
HRMN(300MHz,CDCl3)7.637.60(m,1H),7.43(d,J=2.5Hz,1H),7.337.31(m,
5H),7.257.16(m,4H),7.09(d,J=5.0Hz,1H),5.99(d,J=8.1Hz,1H),5.24(d,J=6.8
Hz,1H),5.13(s,2H),2.43(s,3H).
13
125.3(CH),121.5(C),86.9(C),79.9(C),67.1(CH2),45.2(CH),19.1(CH3).
(S)Nbenciloxicarbonil1(tien2il)3(tien3il)prop2in1amina(11nj)
11nj
Mp9697C;[]D2015.6(c0.98,CHCl3,89%ee).
1
HRMN(400MHz,CDCl3)7.47(d,J=2.1Hz,1H),7.37
7.33(m,5H),7.277.24(m,2H),7.20(d,J=1.6Hz,1H),7.12(dd,J=5.0,0.8Hz,1H),
6.96(dd,J=5.1,3.6Hz,1H),6.12(d,J=8.1Hz,1H),5.42(d,J=6.2Hz,1H),5.18(d,J=
11.9Hz,1H),5.13(d,J=12.6Hz,1H).
170
Captulo3
13
C RMN (100 MHz, CDCl3) 155.1 (C), 142.8 (C), 136.1 (C), 129.8 (CH), 129.5 (CH),
128.5 (CH), 128.2 (CH), 128.1 (CH), 126.8 (CH), 125.8 (CH), 125.7 (CH), 125.4 (CH),
121.1(C),86.1(C),79.7(C),67.3(CH2),43.3(CH).
HRMS(ESI)m/z:376.0441[M+Na]+,C19H15NO2S2Narequiere376.0442.
(S)Nbenciloxicarbonil3ciclopropil1(ptolil)prop2in1amina(11bp)
11bp
Mp104107C;[]D209.4(c1.00,CHCl3,93%ee).
HRMN(300MHz,CDCl3)7.377.29(m,7H),7.15(d,J=8.0Hz,2H),5.195.13(m,
2H),5.09(d,J=12.4Hz,1H),2.34(s,3H),1.331.24(m,1H),0.810.75(m,2H),0.73
0.67(m,2H).
13
(CH), 128.1 (CH), 126.8 (CH), 88.6 (C), 73.3 (C), 67.0 (CH2), 46.8 (CH), 21.1 (CH3), 8.2
(CH2),0.5(CH).
(S)Nbenciloxicarbonil3ciclopropil1(pfluorofenil)prop2in1amina(11dp)
11dp
Mp116117C;[]D2016.6(c1.02,CHCl3,89%ee).
1
H RMN (400 MHz, CDCl3) 7.477.42 (m, 2H), 7.35
7.31(m,5H),7.02(t,J=8.7Hz,2H),5.63(d,J=7.7Hz,1H),5.22(d,J=5.4Hz,1H),
5.15(d,J=12.1Hz,1H),5.09(d,J=12.1Hz,1H),1.331.24(m,1H),0.830.74(m,2H),
0.730.67(m,2H).
171
Captulo3
13
CRMN(100MHz,CDCl3)162.4(d,J=246.5Hz,C),155.3(C),136.2(C),135.6(d,J=
3.2Hz,C),128.7(d,J=8.3Hz,CH),128.5(CH),128.2(CH),128.1(CH),115.4(d,J=21.6
Hz,CH),89.1(C),72.9(C),67.1(CH2),46.5(CH),8.2(CH2),0.6(CH).
HRMS(ESI)m/z:324.1389[M+H]+,C20H19NO2Frequiere324.1394.
(S)Nbenciloxicarbonil3ciclopropil1(pclorofenil)prop2in1amina(11ep)
Mp116117C;[]D206.3(c1.05,CHCl3,95%ee).
11ep
1
HRMN(300MHz,CDCl3)7.427.29(m,9H),5.61(d,J
=7.9Hz,1H),5.20(d,J=6.5Hz,1H),5.15(d,J=12.1Hz,1H),5.09(d,J=12.8Hz,1H),
1.331.23(m,1H),0.320.74(m,2H),0.720.67(m,2H).
13
(CH), 128.3 (CH), 128.2 (CH), 128.1 (CH), 89.3 (C), 72.3 (C), 67.2 (CH2), 46.5 (CH), 8.2
(CH2),0.6(CH).
HRMS(ESI)m/z:340.1097[M+H]+,C20H19NO2Clrequiere340.1099.
(S)Nbenciloxicarbonil3ciclopropil1(pbromofenil)prop2in1amina(11fp)
HPLC quiral (Chiralcel ICH), hexanoiPrOH 98:2, 1
11fp
Mp131133C;[]D203.6(c1.06,CHCl3,93%ee).
Hz, 1H) 5.205.13 (m, 2H), 5.08 (d, J = 12.1 Hz, 1H), 1.321.23 (m, 1H), 0.820.74 (m,
2H),0.720.66(m,2H).
172
Captulo3
13
128.5(CH),128.2(CH),128.1(CH),121.9(C),89.3(C),72.5(C),67.2(CH2),46.6(CH),
8.2(CH2),0.6(CH).
HRMS (ESI) m/z: 384.0591/386.0571 [M+H]+ 100.0/97.5, C20H19NO2Br requiere
384.0594/386.0574.
(S)Nbenciloxicarbonil3ciclopropil1(mtolil)prop2in1amina(11gp)
Mp8183C;[]D2010.6(c1.01,CHCl3,89%ee).
11gp
1
HRMN(300MHz,CDCl3)7.367.31(m,5H),7.267.21
(m,3H),7.11(d,J=7.0Hz,1H),5.62(d,J=7.8Hz,1H),5.215.14(m,2H),5.10(d,J=
12.4Hz,1H),2.35(s,3H),1.341.24(m,1H),0.820.75(2H),0.740.68(2H).
13
(CH),128.1(CH),127.7(CH),123.9(CH),88.6(C),73.2(C),67.0(CH2),47.0(CH),21.4
(CH3),8.2(CH2),0.5(CH).
(S)Nbenciloxicarbonil3ciclopropil1(otolil)prop2in1amina(11hp)
11hp
Mp120122C;[]D2024.4(c0.98,CHCl3,96%ee).
1
HRMN(300MHz,CDCl3)7.547.51(m,1H),7.377.30
(m,5H),7.20(dd,J=3.5,5.6Hz,2H),7.187.13(m,1H),5.73(d,J=8.2Hz,1H),5.16
5.07(m,3H),2.38(s,3H),1.311.22(m,1H),0.800.73(m,2H),0.720.65(m,2H).
173
Captulo3
13
(CH), 128.12 (CH), 128.06 (CH), 126.7 (CH), 126.2 (CH), 88.3 (C), 73.3 (C), 67.0 (CH2),
44.8(CH),19.0(CH3),8.2(CH2),0.5(CH).
(S)Nbenciloxicarbonil3ciclopropil1(oclorofenil)prop2in1amina(11jp)
11jp
Mp110113C;[]D2020.0(c0.92,CHCl3,92%ee).
5.86(d,J=7.7Hz,1H),5.33(d,J=5.9Hz,1H),5.14(d,J=12.1Hz,1H),5.08(d,J=12.4
Hz,1H),1.301.21(m,1H),0.800.73(m,2H),0.720.65(m,2H).
13
(CH),128.8(CH),128.5(CH),128.1(CH),127.1(CH),88.7(C),72.2(C),67.0(CH2),45.4
(CH),8.2(CH2),0.5(CH).
HRMS(ESI)m/z:340.1085[M+H]+,C20H19NO2Clrequiere340.1099.
(S)Nbenciloxicarbonil3ciclopropil1(naftalen2il)prop2in1amina(11kp)
Mp106108C;[]D20+1.6(c0.87,CHCl3,91%ee).
11kp
1
HRMN(300MHz,CDCl3)7.93(sa,1H),7.847.81(m,
3H),7.56(d,J=8.5Hz,1H),7.507.47(m,2H),7.397.30(m,5H),5.82(d,J=8.5Hz,
1H),5.31(d,J=6.8Hz,1H),5.18(d,J=12.1Hz,1H),5.11(d,J=12.5Hz,1H),1.371.30
(m,1H),0.840.79(m,2H),0.780.71(m,2H).
174
Captulo3
13
89.1(C),73.1(C),67.1(CH2),47.3(CH),8.3(CH2),0.5(CH).
(S)Nbenciloxicarbonil3ciclopropil1(furan2il)prop2in1amina(11mp)
Aceitemarrn;[]D20+5.9(c1.12,CHCl3,84%ee).
11mp
HRMN(300MHz,CDCl3)7.377.33(m,6H),6.326.31
(m,2H),5.69(d,J=8.6Hz,1H),5.24(d,J=5.4Hz,1H),5.16(d,J=12.0Hz,1H),5.10
(d,J=12.5Hz,1H),1.311.22(m,1H),0.810.75(m,2H),0.730.67(m,2H).
13
C RMN (75.5 MHz, CDCl3) 155.1 (C), 151.6 (C), 142.6 (CH), 136.1 (C), 128.5 (CH),
128.2(CH),110.3(CH),107.2(CH),87.8(C),70.9(C),67.1(CH2),41.3(CH),8.2(CH2),
0.6(CH).
(S)Nbenciloxicarbonil3ciclopropil1(tien2il)prop2in1amina(11np)
11np
Mp9194C;[]D204.8(c1.04,CHCl3,84%ee).
1
HRMN(300MHz,CDCl3)7.377.33(m,5H),7.23(dd,
J=5.1,1.3Hz,1H),7.12(dd,J=2.7Hz,1H),6.94(dd,J=5.1,3.5Hz,1H),5.86(d,J=
1.341.24(m,1H),0.830.77(m,2H),0.760.70(m,2H).
175
Captulo3
13
128.1(CH),126.7(CH),125.5(CH),125.3(CH),88.3(C),72.7(C),67.1(CH2),42.9(CH),
8.19(CH2),8.17(CH2),0.6(CH).
HRMS(ESI)m/z:312.1054[M+H]+,C18H18NO2Srequiere312.1053.
(S)Nbenciloxicarbonil3ciclopropil1(furan3il)prop2in1amina(11op)
11op
Aceitenaranja;[]D2011.0(c1.00,CHCl3,64%ee);
1
HRMN(300MHz,CDCl3)7.37(s,1H),7.297.26(m,
6H), 6.33 (s, 1H), 5.47 (d, J = 7.7 Hz, 1H), 5.105.01 (m, 3H), 1.241.14 (m, 1H), 0.74
0.68(m,2H),0.630.58(m,2H).
13
CRMN(75.5MHz,CDCl3)155.3(C),143.5(CH),140.2(CH),136.2(C),128.5(CH),
128.2(CH),128.1(CH),125.3(C),109.3(CH),87.2(C),72.6(C),67.1(CH2),39.5(CH),
8.2(CH2),0.7(CH).
(S)Nbenciloxicarbonil1ciclopropil5fenilpent1in3amina(11qp)
Aceiteamarillo;[]D206.6(c0.99,CHCl3,42%ee).
11qp
1
HRMN(300MHz,CDCl3)7.377.26(m,7H),7.217.16
(m,3H),5.10(s,2H),4.89(d,J=7.7Hz,1H),4.46(q,J=7.7Hz,1H),2.762.70(m,2H),
2.041.87(m,2H),1.291.19(m,1H),0.800.74(m,2H),0.690.63(2H).
176
Captulo3
13
128.1(CH),126.0(CH),87.4(C),74.0(C),66.8(CH2),43.5(CH),38.1(CH2),31.9(CH2),
8.20(CH2),8.19(CH2),0.7(CH).
(S)Nbenciloxicarbonil1ciclopropilhept1in3amina(11rp)
HPLCquiral(ChiralcelIC),hexanoiPrOH95:5,1mL/min,
Aceiteblanco;[]D2015.6(c1.00,CHCl3,43%ee).
11rp
H RMN (300 MHz, CDCl3) 7.367.31 (m, 5H), 5.10 (s,
2H),5.84(d,J=5.7Hz,1H),4.40(q,J=10.5Hz,1H),1.661.55(m,2H),1.401.25(m,
4H),1.221.16(m,1H),0.90(t,J=13.9Hz,3H),0.770.71(m,2H),0.660.60(m,2H).
13
CRMN(75.5MHz,CDCl3)155.3(C),136.4(C),128.5(CH),128.1(CH),86.7(C),74.6
(C),66.8(CH2),43.7(CH),36.3(CH2),27.7(CH2),22.2(CH2),14.0(CH3),8.14(CH2),8.13
(CH2),0.7(CH).
(S)Nbenciloxicarbonil1ciclohexil3ciclopropilprop2in1amina(11sp)
HPLCquiral(ChiralcelIC),hexanoiPrOH98:2,1mL/min,
11sp
Mp101104C;[]D20 23.6(c0.90,CHCl3,65%ee); 1H
RMN(300MHz,CDCl3)7.377.34(m,5H),5.12(d,J=
1.761.63(m,5H),1.251.03(m,7H),0.770.69(m,2H),0.660.60(m,2H).
177
Captulo3
13
CRMN(75.5MHz,CDCl3)155.5(C),136.4(C),128.5(CH),128.1(CH),87.5(C),73.2
(C),66.8(CH2),48.8(CH),42.9(CH),29.2(CH2),28.3(CH2),26.2(CH2),25.9(CH),25.8
(CH),8.2(CH2),0.6(CH).
Nbenciloxicarbonil1fenilpropanamina(18)
RMN 1H(300MHz,CDCl3)7.327.22(m,10H),5.10(d,J
=12.3Hz,1H),5.03(d,J=12.2Hz,2H),4.59(q,J=6.8Hz,
1H),1.841.74(m,2H),0.88(t,J=7.4Hz,3H).
18
RMN 13C (75.5 MHz, CDCl3) 155.7 (C), 142.4 (C), 136.5
(C),128.6(CH),128.5(CH),128.1(CH),127.3(CH),126.4
(CH),66.7(CH2),56.9(CH),29.7(CH2),10.6(CH3).
Nbenciloxicarboniletilperoxibencilamina(19)
RMN 1H(300MHz,CDCl3)7.427.30(m,10H),6.51(d,J
=10.0Hz,1H),5.57(d,J=8.2Hz,1H),5.17(s,2H),4.10
(q,J=6.2Hz,2H),1.19(t,J=6.9Hz,3H).
19
RMN 13C (75.5 MHz, CDCl3) 155.5 (C), 136.1 (C), 136.5
(C), 129.1 (CH), 128.7 (CH), 128.5 (CH), 128.23 (CH),
128.15(CH),126.3(CH),85.3(CH),70.4(CH2),67.2(CH2),30.3(CH),13.3(CH3).
HRMS(ESI)m/z:324.1254.[M+Na]+,C17H19NO4Narequiere324.1212.
(S)2benciloxicarbonilamino2(pmetoxifenil)acetatodemetilo(20)
Oxgenoenriquecidoenozonoseburbujeatravsde
una disolucin de producto 11ca (18.6 mg, 0,050
mmol) en MeOH (15 mL) a 40 C durante 1 h. El
20
178
exceso de ozono se elimin mediante burbujeo de

nitrgeno durante 5 min. Se dej que la disolucin
Captulo3
resultantealcanzaratemperaturaambiente,seaadiBF3Et2O(0,19mL)ylamezcla
secalentatemperaturadereflujodurante3,5h.Trasenfriarata,seaadiNaHCO3
acuoso saturado (10 mL), el disolvente orgnico se elimin a vaco y la disolucin
acuosa resultante se extrajo con diclorometano (315 mL), se lav con salmuera (10
mL) y se sec sobre MgSO4. La eliminacin del disolvente bajo presin reducida
seguidadeunacolumnacromatogrficaflasheluyendoconhexanoAcOEt(8:2)dioel
producto20(47%).
El exceso enantiomrico (83%) se determin mediante HPLC quiral (Chiralpak IC),
hexanoiPrOH 97:3, 1 mL/min, enantimero mayoritario tr = 76.6 min, enantimero
Mp6668C;[]D20+45.1(c0.7,CHCl3,83%ee).
1
(s,3H),3.70(s,3H).
13
(CH),128.4(CH),128.20(C),128.16(CH),114.3(CH),67.1(CH2),57.3(CH),55.3(CH3),
52.8(CH3).
HRMS(ESI)m/z:352.1583(M+Na)+,C18H19NO5Narequiere352.1161.
(R)1,3difenilpropan1amina(21)
Una disolucin del compuesto 11aa (33.5 mg, 0.098 mmol)
en EtOH absoluto (9.0 mL) se agita bajo atmsfera de
21
hidrgeno (globo) en presencia de Pd/C (10%) (12.7 mg)

durante30min.Trasestetiempo,lamezclasefiltratravs
deslicagel,eluyendoconEtOAc,yseelimineldisolventebajopresinreducidapara
darelcompuesto21(99%).
RMN 1H (300 MHz, CDCl3) 7.327.22 (m, 7H), 7.177.10 (m, 3H), 3.85 (t, J = 6.9 Hz,
1H),2.632.45(m,2H),2.001.93(m,2H),1.79(s,2H).
179
Captulo3
RMN 13C(75.5MHz,CDCl3)141.8(C),128.6(CH),128.3(CH),127.2(CH),126.5(CH),
125.8(CH),55.8(CH),40.8(CH2),32.7(CH2).
HRMS(ESI)m/z:212.1441[M+H]+,C15H18Nrequiere212.1439.
(R)Nbenciloxicarbonil1,3difenilpropan1amine(22)
Una disolucin del compuesto 11aa (27.5 mg, 0.081 mmol)
O
HN
en EtOH absoluto (7.5 mL) se agita bajo atmsfera de
Ph
hidrgeno(globo)enpresenciadePd/CaCO3(5%)(10.5mg)
durante1h.Trasestetiempo,lamezclasefiltratravsde
slicagel,eluyendoconEtOAc,yseelimineldisolventebajo
22
presinreducidaparadarelcompuesto22(99%).
El exceso enantiomrico (87%) se determin mediante HPLC quiral (Chiralcel ODH),
Mp6567C;[]D20+18.1(c1.29,CHCl3,87%ee).
1
Hz,2H),5.110(s,1H),5.113(d,J=12.3Hz,1H),5.04(d,J=12.2Hz,1H),4.73(q,J=7.2
Hz,1H),2.702.52(m,2H),2.172.02(m,2H).
13
(CH),128.4(CH),128.3(CH),128.1(CH),127.5(CH),126.4(CH),126.0(CH),66.8(CH2),
55.2(CH2),38.3(CH),32.5(CH2).
(R,Z)Nbenciloxicarbonil1,3difenil2propen1amina(23)
Una disolucin de 11aa (0,056 mmol) en benceno (0,56 mL)
seagitenpresenciadelcatalizadordeLindlar(3,6mg)bajo
unaatmsferadehidrgenodurante1,5h.Trasestetiempo,
23
180
lamezclasefiltratravsdeCelite,eluyendoconEtOAc,y
Captulo3
seelimineldisolventebajopresinreducidaparadarelcompuesto23(99%).
Mp6769C;[]D20+13.8(c1.04,CHCl3,87%ee).
1
Hz,1H),5.785.75(m,2H),5.17(s,1H),5.09(s,2H).
13
126.6(CH),120.3(CH),66.8(CH2),42.5(CH).
HRMS(ESI)m/z:366.1920[M+Na]+,C23H21NO2Narequiere366,1470.
(R,E)Nbenciloxicarbonil1,3difenilprop2en1amine(24)
UnadisolucindeLiAlH41MenTHF(0,050mmol,50L)se
aadegotaagotaaunadisolucinde11aa(0,050mmol)en
THF (0,4 mL) a 0 C bajo nitrgeno. Se deja que la reaccin
24
alcance temperature ambiente. Tras 3 horas, se aade 1 mL

de agua. La fase acuosa se extrae con diclorometano (3x15
mL),selavaconsalmuera(10mL)ysesecasobreMgSO4.La
eliminacin del disolvente bajo presin reducida seguida de una columna

cromatogrficaflasheluyendoconhexanoAcOEt(9:1)dioelproducto24(64%).
Mp110111C;[]D20+29.4(c0.68,CHCl3,87%ee).
1
HRMN(300MHz,CDCl3)7.337.22(m,15H),6.54(d,J=16.6Hz,1H),6.31(dd,J=
15.9,6.0Hz,1H),5.52(s,1H),5.18(s,1H),5.14(d,J=12.2Hz,1H),5.10(q,J=12.2Hz,
1H).
181
Captulo3
13
C RMN (75.5 MHz, CDCl3) 155.5 (C), 144.8 (C), 136.34 (C), 136.30 (C), 131.2 (C),
129.0 (CH), 128.8 (CH), 128.6 (CH), 128.5 (CH), 128.2 (CH), 127.81 (CH), 127.76 (CH),
127.0(CH),126.5(CH),67.0(CH2),56.8(CH).
HRMS(ESI)m/z:366.1920[M+Na]+,C23H21NO2Narequiere366,1470.
182
Captulo3
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T.;Souala,F.;Besnier,J..;Raffi,F.HIVMed.2006,7,431436.
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184
CH2Cl2
CHAPTER 4
Addition of zinc alkyloxygenated

species to -amido sulfones
O
Bn
HN
NH
SO2Tol
O
Ph
Et
O
O
NH
O
ClCH2CH2Cl
HN
O
HN
Cl
Et2Zn
Cbz
O
O
OH
OH
Ph
O
Me
Cbz
O
Bu
Ph
NH
Ph
O
O
O
O
Et
i Pr
NH
O
Ph
2Z
Cl
Chapter4
4.1.ANTECEDENTS
The enantioselective addition of alkynes to amido sulfones described in
Chapter3iscarriedoutinthepresenceofdiakylzincreagents.Duringourstudies,we
observed the formation of a product derived from the addition of an oxygenated
dialkylzinc species to the amido sulfone. This prompted us to study the controlled
oxidationofdialkylzincreagentsandtheirsubsequentadditiontoamidosulfones.
4.1.1.Oxidationofdialkylzincreagents
It has been over 160 years since Franklands pioneering studies led to the
discovery of dialkylzinc reagents when he was investigating the reaction between
metallic zinc and ethyl iodide in the search for ethyl radical.1,2 He rapidly noted the
highreactivityofthosenovelspeciestowardmolecularoxygenandin1849postulated
thatcontrolledoxidationofEt2ZnaffordsthealkoxideZn(OEt)2.In1864Lissenko3and
Butlerov4independentlyreportedtheformationofpartlyoxygenatedspecies,RZnOR.
Some years later, in 1890, Demuth and Meyer5 argued for the formation of
alkylperoxide,EtZnOOEt,fromtheinsertionofanoxygenmoleculeintotheZnCbond.
However, all these interpretations have been subjected to debate and, since then,
interestinthereactionofdialkylzincwithO2havepersistedovertheyears.
For example, in 1960 Abraham6 questioned the formation of partially
oxygenatedspeciesashereportedthatbothZnCbondsinR2Znmoleculesareeasily
oxidized in some minutes after the start of the reaction. Thus, he suggested the
formation of Zn(OOR)2, ROZnOOR, Zn(OR)2, which was later supported by Davies
(Scheme4.1).7
Scheme4.1.Possiblespeciesformedinthereactionbetweendialkylzincandmolecular
oxygen.
On the other hand, there has also been extensive controversy regarding the
mechanism followed by this oxidation. Despite some authors attempts to
demonstrate that the reaction occurred via a polar pathway,6,8 a radicalchain
187
Chapter4
mechanism is generally admitted nowadays (Scheme 4.2). Indeed, this radicalchain

character, which would be initiated by an adventitious alkyl radical followed by a
cascade of fast reactions, has been considered to be responsible for the difficulty to
controltheoxidationofonlyoneZnCbond.Thisradicalchainmechanismissupported
by a recent EPR spectroscopy study using spintrapping techniques which gave
evidencefortheformationofalkyl,alkoxylandalkylperoxylradicals.9,10
Scheme4.2.PlausiblechainradicalmechanismofdialkylzincoxidationreactionwithO2.
Although some authors have accomplished the controlled oxygenation of

simple dialkylzinc compounds11 (Scheme 4.3), most studies have focused on the
oxygenation of these organometallic species in the presence of donor ligands, which
have demonstrated to have significant influence on the oxygenation process by
decreasingthereactivityoftheR2ZnLadductaswellasenhancingthestabilityofthe
resulting oxygenated products. In fact, recent studies by Lewinski on dialkylzinc
compounds have proved that R2Zn adducts with donor ligands have a marked
tendencytoundergooxidationofonlyonealkylgroupwithsubsequentformationof
RZnOORorRZnORspecies.
Scheme4.3.Controlledoxidationofdialkylzincreagents.
188
Chapter4
In 2003, Lewinskis group12 exposed a solution of the aggregate [EtZn(azol)]n

whereazolHis1aziridineethanol,toanexcessofdryO2toaffordawhitecrystalline
precipitate of [EtOOZn(azol)]2[EtZn(azol)]2. In spite of the generally assumed high
reactivity of zinc alkyls toward oxygen, this compound did not undergo further
oxygenationinthepresenceofO2at78C.
In a later work, the same research group advanced a plausible hypothesis
concerningthemechanismofoxygenactivationbyorganometalliccompoundswhich
wouldinvolvetheattackofO2onthemetalcenter,followedbyelectrontransferfrom
theZnCbondto O2to affordasolventcagedradicalpairwhichatlowtemperature
wouldrearrangetoanalkylperoxidespecies(Scheme4.4).13
Scheme4.4.ProposedmechanismfortheactivationoforganometalliccompoundsbyO2.
In the same publication, these authors conducted a study to determine the

effect of the strength of donor ligands on the oxygenation reactions. tBu2Zn was
treatedwithO2inthepresenceoftwodifferentdonorligands,tetrahydrofuran(THF)
and 4methylpyridine (pyMe) (Scheme 4.5). The former led to the selective
oxygenation of one ZnC and the formation of the alkoxide compound [{ZntBu(
OtBu)(THF)}2]. The stronger Ndonor ligand (pyMe) decreased the reactivity of the
adduct, higher temperatures were required, and enhanced the stability of the
oxygenated products giving the tertbutyl peroxide species that results from the
insertionofO2intoonZnCbond.
189
Chapter4
Scheme4.5.Oxidationofzinccomplexesbyvariationofdonorligand.
In a more recent investigation, Lewinskis group14 has reported the

unprecedentedswitchonthereactionoutcomeproducedbychangingthecharacterof
thezincbondedalkylgroup(Scheme4.6).Thus,theuseofEt2Znledtoatetranuclear
zincoxoencapsulatedcluster,whereastheanalogousreactionwith tBu2Zngenerated
thecorrespondingzincalkylperoxide.
Scheme4.6.Preparationofzincoxoencapsulatedclusterversuszincalkylperoxidecomplexby
modifyingthealkylgroupattachedtoZn.
Recently,Sadowsgroup15hasdescribedthesynthesisandfeaturesofaseries
of monomeric alkyperoxides of the type ToMZnOOR (ToM = tris(4,4dimethyl2
oxazolinyl)phenylborate) which are available from the reaction between ToMZnR and
O2inquantitativeyields.Thesecompoundsarereactiveasoxidants,sotheyreactwith
phosphines to afford OPPh3 and the corresponding alkoxide complex and can also
190
Chapter4
react with organosilanes giving a peroxygroup transfer from zinc to silicon (Scheme
4.7).
Scheme4.7.ReactionofToMZnOORwithorganosilanes.
Although preparation of alkylperoxyl clusters from Et2Zn and tBu2Zn is well

documented, the synthesis of methylperoxide species from Me2Zn remains almost
unattended.In2008,Lewinskisgroup16reportedtheselectiveoxygenationofMe2Zn
with tBuDAB, where DAB is 1,4diazabutadiene, to provide a novel zinc
oxo(methylperoxide)cubane(Figure4.1).
Figure4.1.Oxo(methylperoxide)cubane.
Inalaterwork,Molloyandcoworkers17disclosedthereactionofMe2Znwith
1,3bis(dimethylamino)propan2ol
(Hbdmap)
in
2:1
ratio
to
afford
[MeZn(bdmap)ZnMe2]2 which, after exposure to O2 gave the isolable peroxide

[MeZn(bdmap)]2MeZnOOMe (Scheme 4.8). This complex decomposes slowly to
provide [MeZn(bdmap)]2MeZnOH, probably arising from the homolysis of the OO
bond, (MeZn)5(bdmap)3O and (MeZn)4(bdmap)4ZnO. The formation of these species
couldbeassociatedtoaradicalmechanism.
191
Chapter4
Scheme4.8.Synthesisofperoxide[MeZn(bdmap)]2MeZnOOMe.
On the other hand, homolytic RZnOOR bond cleavage has been shown to be
responsiblefortheformationofoxoandmetalcarboxylatespecies(Figure4.2),which
couldfindfutureapplicationsinthefieldsofcatalysisorhydrogenstoring.1820
Figure4.2.a)Zincoxocarboxilatecluster.b)Zincacetatecomplex.
4.1.2. Application of dialkylzinc oxygenation reactions in organic

synthesis
In addition, dialkylzinc oxygenation reactions can be useful tools in organic
synthesis.However,thisapplicationremainsalmostunexplored.Inrecentyearsmost
oftheinteresthasbeenfocusedinradicaladditionsinitiatedbytheR2Zn/O2system.
Among the few examples, the dimethylzincair promoted Reformatsky reaction has
beendescribedindependentlybyCozziandFeringa.2125
Cozzis group22 has performed the Reformatsky reaction between ethyl
iodoacetate and aldehydes and ketones employing Me2Zn as a source of methyl
radicalsandZn,asdepictedinScheme4.9.Theauthorshavereportedtheadditionof
192
Chapter4
Ph3P=O to shorten reaction times as well as to permit the use of rather unreactive
ketones, obtaining the final addition products in good to excellent yields. An
enantioselective variant of this reaction was evaluated with chiral amino alcohols as
ligandswithpromisingresults.
Scheme4.9.ReformatskyreactionmediatedbyMe2Znairandproposedcatalyticcycle.
Concurrently, Feringa and coworkers23 developed the enantioselective

Reformatsky reaction with aldehydes and ethyl iodoacetate mediated by Me2Zn and
promoted by air, which was found to be crucial to initiate the radical mechanism
(Scheme4.10).ABINOLtypeligandwaschosentocarryoutthereaction.Theuseof
aromatic and heteroaromatic aldehydes led to moderate to high enantioselectivities
(4284% ee), whereas aliphatic substrates provided lower stereocontrol (750% ee).
Besides,thesamemethodologywasappliedtothereactionwithketonesyieldingthe
correspondingproductsinsimilarresults.24,25
193
Chapter4
Scheme4.10.EnantioselectiveReformatskyreactionofaldehydescatalyzedbyBINOLtype
ligandmediatedbyMe2Znair.
The Me2Znairpromoted homolytic cleavage of carboniodine bond has also

been reported by Tomiokas and Bertrands groups.2630 The former research group26
has disclosed the addition of alkyl radicals from alkyl, chloroalkyl and acetoxyalkyl
iodides to Ntosylimines in good to high yields (5795%). The reaction required
stoichiometricamountofborontrifluoridediethyletherateandacatalyticamountof
copper(II) triflate to accelerate the process. Later, they performed the reaction
betweeniodomethylpivalateandNtosylbenzaldimineinthepresenceofMe2Znand
airwitha66%yield.Surprisingly,theuseofEt2Znfurnishedtheethyladditionadduct
insteadoftheexpectedproduct(Scheme4.11).27
Scheme4.11.RadicaladditiontoNtosyliminespromotedbyMe2Znair.
Bertrand29 and coworkers have described a stereoselective radicalanionic

tandem reaction promoted by Me2Znair employing iodomethyl esters as radical
194
Chapter4
precursorsandethylfumarateasradicalacceptortoaffordlactonesinmoderateto
highyields(3698%).Thechemoselectivityoftheprocesswasmodifiedbyadditionof
Lewisacids(Scheme4.12).Inarecentwork,30thesameresearchgroupfoundevidence
oftheformationofthephtalamidomethylradicaluponreactionwithdialkylzincandair
byspintrappingexperiments.Theseradicalswereaddedtodiethylfumarateproviding
functionalizedpyrrolidinederivatives.
Scheme4.12.RadicalanionictandemreactionpromotedbyMe2Znairemployingiodomethyl
estersandethylfumarate.
On the other hand, Tomioka31 and coworkers have reported the use of
dimethylzincinconjunctionwithairasanefficientradicalinitiatortogeneratecarbon
centered radicals from CH bonds which were added to electrophilic substrates to
affordthecorrespondingadducts.Forexample,imineshavebeenfoundtobesuitable
electrophilicsubstratesfortheproductionoftheseadductsinthereactionwithcyclic
ethers3234orcycloalkanes.35TheplausiblemechanismforthisprocesswithTHFbegins
withthegenerationofmethylradicalbytheactionofoxygenondimethylzinc(Scheme
4.13).Then,theresultingmethylradicalabstractsanhydrogenfromTHFtoproduce
a tetrahydrofuran2yl radical which adds to the imine to give an aminyl radical. Its
subsequent reaction with dimethylzinc generates a methyl radical (as the reaction
chaincarrier)andazincamide,whichuponworkupaffordsthefinaladduct.33
195
Chapter4
Scheme4.13.ProposedmechanismfortheradicaladditionofTHFtoimine.
This methodology has also been applied in the stereoselective addition of

alkoxyalkyl radicals to Nsulfinylimines promoted by Me2Znair, followed by the
oxidation of the resulting products with dry MCPBA to afford sulfonamides
enantiomerically enriched (Scheme 4.14). Lewis acid activation of the Nsulfinylimine
substrates facilitated the radical addition and further investigations showed that
substitution of the ptolyl group at the stereogenic centre led to higher levels of
stereocontrol.36,37
Scheme4.14.DiastereoselectiveradicaladditionofcyclicetherstoNsulfiniliminesand
subsequentoxidationtoaffordNsulfonamides.
Additionally, the authors have extended this approach to the utilization of N

tosyl ,unsaturated imines with THF (Scheme 4.15). The reaction preferentially
proceeds in a 1,4addition manner to give 2(3aminoalkyl)tetrahydrofurans in good
yields.Theuseofdimethylzincratherthandiethylzincortriethylboranewasessential
fortheefficiencyoftheaddition.38
196
Chapter4
Scheme4.15.RadicaladditionofTHFtoNtosyl,unsaturatedimines.
Although,unsaturatediminesdemonstratedtobegoodMichaelacceptors,
the precursor of ether radical was limited to THF. On the contrary,
alkylidenemalonates have been found to be useful Michael acceptors toward the
radicaladditionofdiversecyclicethers(Scheme4.16).3941
Scheme4.16.RadicaladditionofTHFtoalkylidenemalonates.
More recently, these substrates were employed in the reaction with

iodomethylpivalateinthepresenceofMe2Zn,airandtertbutylhydroperoxide(TBHP)
(Scheme4.17).42Whenthereactionwasperformedunderair,,dualoxymethylation
products were obtained. However, pivaloyloxymethylation products were obtained
underargon.Thisradicalconjugateadditionwasapplicabletothepreparationofthe
bioactiveligninhinokinin.
Scheme4.17.Radicaladditionofiodomethylpivalatetoalkylidenemalonates.
197
Chapter4
Finally,someauthorshaveemployedR2Zn/O2systemasradicalinitiatorinthe
carbozincationofalkynes.TakingintoconsiderationpreviousstudiesbyKnochel43and
Cohen,44 Chemla and coworkers45,46 have disclosed a domino 1,4addition/alkyne
carbozincationsequencebasedonaradicalzincatomtransfer.Theyhavedeveloped
twomulticomponentapproachestopolysubstitutedalkylidenetetrahydrofuransfrom
(propargyloxy)enoates(Scheme4.18).Thefirstoneconsistsofthedirectadditionof
dialkylzinc compounds, whereas the second one involves the dimethylzincpromoted
addition of alkyl iodides. The procedure tolerates well a wide variety of substituted
alkynes.
Scheme4.18.Me2Znairpromotedsynthesisoftetrahydrofuransthrough5exodigcyclization
reaction.
Aplausiblemechanismforthecarbozincationreactionstartswiththeoxidation
ofthedialkylzincbytracesofoxygen.Thisprocessproducesaradicalthatundergoes
1,4addition into the ,unsaturated ester to afford an inoxy radical, which
experiencesa5exodigcyclizationreactiontogiveavinylradicalthatreactswithR2Zn
via homolytic substitution. A nucleophilic alkenyl zinc species suitable for further
reactionswithelectrophilesisformed(Scheme4.19).
198
Chapter4
Scheme4.19.Me2Znairpromotedsynthesisoftetrahydrofuransthrough5exodigcyclization
reaction.
Bertrandsgroup47hasaccomplishedthedialkylzinc/airpromotedsynthesisof
alkylidenelactamsthroughasimilarstrategy.Moreover,theyhaveemployedthe
same system to trigger the stereoselective anticarbozincation of diethyl
acetylenedicarboxylate to give diethylfumarate derivatives in good yields (Scheme
4.20). The stereochemical outcome of the process is explained by means of the
coordination of Zn(II) with the oxygen atom of the ester group and the subsequent
reactionofanelectrophile,whichoccursinpositioncisrelativetothecarboxylate.48
Scheme4.20.Anticarbozincationofdiethylacetylenedicarboxylatethroughalkylzincgroup
radicaltransfer.
199
Chapter4
With respect to the oxygenated species originated by the oxidation of

dialkylzinc with oxygen, their main synthetic applications have been limited to the
preparation of hydroperoxides or alcohols, and their use as epoxidizing reagents for
enones.
Forexample,HaradaandKutsuda49havegeneratedpropargylichydroperoxides
from the reaction between propargylic derivatives and lithium triorganozincates
(Scheme 4.21). The reaction proceeds via allenyl zinc species which react
regioselectivelyatthepositionwithmolecularoxygen.TheuseofZnCl2iscrucialto
obtain the hydroperoxide instead of the propargyl alcohol. Moreover, addition of
chlorotrimethylsilane is necessary to trap the resulting zinc hydroperoxide with the
concomitantformationoftrimethylsilylperoxideandallenicchlorozinc.
Scheme4.21.Synthesisofhydroperoxidesfrompropargylicderivativesandlithium
triorganozincatesinthepresenceofmolecularoxygen.
Theuseofoxygenateddialkylzincspeciesasepoxidizingreagentshasaroused
widespreadattentionamongscientists.In1989,Yamamoto50reportedtheoxidationof
Et2Znandtheadditionoftheresultingalkylperoxozincto,unsaturatedketonesto
form alkylperoxozinc species, which finally gave the epoxidation products (Scheme
4.22). The process occurred through an erythroselective attack (>99%) of the
nucleophilic reagent when iPr was used as substituent. Besides, the procedure is
chemoselectiveandisnotapplicabletotheepoxidationof,unsaturatedesters.
200
Chapter4
O
R1
R3
OR2
Bu2Zn, O2
Toluene
R1
R3
OR2
34-87%
Scheme4.22.Epoxidationof,unsaturatedketonesmediatedbynBu2Znandmolecular
oxygen.
Later, Enders group51 reported the enantioselective epoxidation of ,

unsaturated ketones with Et2Zn and O2 in the presence of (R,R)N
methylpseudoephedrine to obtain chiral (R,S),epoxyketones in excellent yields
(9499%), diastereoselectivities (>99% de) and high enantiomeric excesses (8292%).
Accordingtotheirobservations,theauthorspostulatedamechanismwhichstartswith
the formation of ethylzinc alkoxide from diethylzinc and the chiral alcohol. Then, O2
insertsintotheZnCbondfurnishingthechiralalkoxy(ethylperoxy)zinc.Thezincatom
coordinatestotheoxygenofthecarbonylgroupintheketoneandconcomitantattack
oftheethylperoxyanioninpositionoccurs.Thesubsequentcyclizationgivesthe,
epoxyketone(Scheme4.23).
Scheme4.23.Plausiblemechanismfortheenantioselectiveepoxidationof,unsaturated
ketoneswithEt2ZnandO2inthepresenceofachiralligand.
Lewinski and coworkers52 have designed a zinc alkylperoxide complex from

Et2Zn,
2[(2,6diisopropylphenyl)amino]4[2,6diisopropylphenyl)imino]pent2ene
(BDIH) and molecular oxygen which demonstrated to be efficient in the regio and
chemoselective epoxidation of ,unsaturated ketones bearing an unconjugated
alkene(Scheme4.24).
201
Chapter4
Scheme4.24.Chemoselectiveepoxidationof,unsaturatedketonesbyanzincalkylperoxide
complex.
Walsh and coworkers have demonstrated that acyclic epoxy alcohols

containing up to three stereogenic centres can be synthetized from ,unsaturated
ketonesusingdialkylzincandachiralligandinthepresenceofTi(OiPr)4orTi(OtBu)4and
molecularoxygen(Scheme4.25).Asimilarmethodologycanbeappliedstartingfrom
aldehydes and ethyl vinyl zinc species. Both approaches yield the corresponding
products with high enantio and diastereoselectivities for a wide range of
substituents.5355
Scheme4.25.Diastereoselectiveepoxidationof,unsaturatedketonesusingdialkylzincanda
chiralligand.
DespitethevarietyofprocessesdescribedinliteraturewhereR2Znspeciesand
imines participate in radical addition reactions, to the best of our knowledge, the
additionofalkylperoxidespeciesgeneratedbythereactionofoxygenanddialkylzinc
reagentswithimineshasnotbeendescribedsofar.Theresultingproducts,particularly
202
Chapter4
thosederivedfromtheadditionofalkylperoxide,wouldbeofspecialinterestsincea
wide variety of natural products contain a peroxide group and present antibacterial,
antimalarial or antitumor activities.56 For example, artemisinin has demonstrated to
possesshigheffectsasantimalarialdrug.57,58
Figure4.3.Artimisinin.
The alkoxidation and peroxidation of imines by means of nonradical

approacheshasbeenperfomedbyAntillaandcoworkers.59In2008,theyreportedthe
enantioselective addition of alcohols to Nacylimines catalyzed by chiral phosphoric
acids.TheutilizationofdifferentlysubstitutedNacylbenzaldiminesledtotheresulting
productsinhighyieldswithexcellentenantiomericexcesses(7699%,8195%ee).On
thecontrary,animinederivedfromanaliphaticaldehydeprovidedlowerresults(62%,
65%ee).
Scheme4.26.EnantioselectiveadditionofalcoholstoNacylimines.
In a more recent work (2010),60 the same authors extended this strategy for
enantioselectiveperoxidationofNacyliminescatalyzedbythesamechiralphosphoric
acid (Scheme 4.27). The utilization of aromatic imines and tertiary peroxides yielded
203
Chapter4
the corresponding amino peroxides with good yields (7592%) and excellent
enantioselectivities(8998%ee).
Scheme4.27.EnantioselectiveperoxidationofNacylimines.
204
Chapter4
4.2.OBJECTIVES
The main objective of this chapter is to perform the addition of zinc
alkylperoxidespeciesresultingfromthecontrolledoxygenationofdialkylzincreagents
toamidosulfones.Thisprocesswoulddirectlyprovideamidoalkylperoxidesina
three component protocol. In addition, we intend to modify the oxygenation
conditionstoobtainzincalkoxidespecieswhoseadditiontoamidosulfoneswould
affordamidoalkoxides.
Inordertodevelopthiswork,wewillstudythefollowingaspects:
Additionofzincalkylperoxidespeciestoamidosulfones
1. Identification of optimal conditions of the reaction: Influence of the
structure of diverse O,Odonor ligands and solvents on the yield of the

reaction.
205
Chapter4
2. Influenceofdifferentprotectinggroupsontheyieldofthereaction.
3. Scopeandlimitationsofthereaction:evaluationofaromaticandaliphatic
amidosulfoneswithdifferentelectronicandstericnatureinthereaction
withEt2Zn,nBu2Zn,iPr2ZnandMe2ZnandO2.
Additionofzincalkoxidespeciestoamidosulfones
1. Identification of optimal conditions of the reaction: Influence of the
structureofdiverseO,Odonorligands,solventsandtemperaturesonthe
yield.
2. Scopeandlimitationsofthereaction:evaluationofaromaticandaliphatic
amido sulfones with different electronic and steric nature with Et2Zn,
n
Bu2Zn,Me2ZnandO2.
HN
R2
Cbz
SO2Tol
HN
R2Zn
O2
30, R = Et
31, R = nBu
32, R = Me
206
R2
Cbz
Chapter4
4.3.RESULTSANDDISCUSSION
4.3.1.Additionofzincalkylperoxidestoamidosulfones
4.3.1.1.Optimizationofreactionconditions
The formation of amido alkylperoxides was initially discovered during our
studies about enantioselective alkynylation of amido sulfones using diethylzinc
(Chapter3,p.117).Forthisreason,wefirstinvestigatedtheadditionofdiethylzincin
thepresenceofdryoxygentoamidosulfone8aawithacatalyticamount(20mol%)
ofseveralO,Odonorligandsindichloromethaneat0C.
Figure4.4.O,Odonorligands.
1,1Bi2naphtol (()L1), 2,2biphenol (L9), cathecol (L10) and salicylic acid

(L11)wereevaluatedprovidingexclusivelyamidoalkylperoxidesinallcases.()L1,
L9andL10ledtogoodyields(7382%)(Table4.1,Entries13).However,salicylicacid
(L11)wasfoundtobethemosteffectiveligand(Table4.1,Entry4).Ontheotherhand,
changingsolventtotoluenedidnothaveanyeffectontheyield(Table4.1,Entry5).
Surprisingly, when the reaction was performed in the absence of ligand, the
desiredproductwasobtainedinquantitativeyield(Table4.1,Entry6).Thispermitted
ustoisolatepureproductsbyasimpleextractionofthereactionmixturewithwater.
Finally,anincreaseintemperatureledtoamidoalkylperoxidein74%(Table
4.1,Entry7).
So, we concluded that the best results were afforded when the
ethylperoxidation reaction of amido sulfones was carried out with diethylzinc/dry
oxygenindichloromethaneat0Candintheabsenceofligand.
207
Chapter4
Table 4.1. Three component addition of Et2Zn/O2 to amido sulfone 8aa.
Screeningofligandsandsolvent.a
Entry
Solvent
T(C)
t(h)
Yield(%)b
()L1
CH2Cl2
20
73
L9
CH2Cl2
20
80
L10
CH2Cl2
20
82
L11
CH2Cl2
20
97
L11
Toluene
20
93
CH2Cl2
20
97
CH2Cl2
rt
20
74
8aa (0.125 mmol), L (0.025 mmol), 1 M Et2Zn in hexanes (0.375 mmol),
solvent(1.6mL).bYieldofisolatedproduct.
Then, the influence of the protecting group was examined. The screening
showed that Cbz and Boc protected amido sulfones performed better than
ethyloxycarbonylprotectedones(Table4.2).
DuetotheslightlybetterresultprovidedbytheCbzprotectinggroupandthe
availability of a wide variety of NCbzprotected amido sulfones which had been
previously synthesized, these substrates were selected to study the scope of the
process.
208
Chapter4
Table 4.2. Screening of reaction conditions for the ethylperoxidation of amido

sulfones.a
Entry
amidosulfone PG
t(h)
Product
Yield(%)b
8aa
Cbz
20
19a
97
9aa
Boc
20
25a
93
10aa
COOEt
20
26a
72
Amidosulfones(0.125mmol),1MEt2Zninhexanes(0.375mmol),CH2Cl2(1.6mL). b
Yieldofisolatedproduct.
4.3.1.2.Scopeandlimitationsofthereaction
Under the optimized conditions, the reaction with Et2Zn/O2 was found to be
general for a number of NCbzprotected amido sulfones 8 derived from aromatic,
heteroaromaticandaliphaticaldehydes(Table4.3).
Both electronwithdrawing and electrondonating groups in the aromatic ring
of the amido sulfones were well tolerated and led to excellent results (Table 4.3,
Entries 18). Likewise, amido sulfones derived from 1naphthaldehyde and 2
thiophenecarbaldehydeprovidedthedesiredproductsinveryhighyields(95and98%)
(Table 4.3, Entries 910). Finally, the reaction was also successfully performed with
aliphatic substrates which gave the corresponding amido alkylperoxide with yields
between94and99%(Table4.3,Entries1113).
209
Chapter4
Table4.3.ThreecomponentadditionofEt2Zn/O2toamidosulfones8.a
Entry
t(h)
19
Yield(%)b
8aa
Ph
20
19a
97
8ba
4MeC6H4
20
19b
93
8ca
4MeOC6H4
20
19c
91
8ea
4ClC6H4
20
19e
93
8fa
4BrC6H4
20
19f
95
8ga
3MeC6H4
20
19g
92
8ha
2MeC6H4
20
19h
97
8ja
2ClC6H4
20
19j
94
8la
1naphthyl
20
19l
95
10
8na
2thienyl
20
19n
98
11
8qa
C6H5CH2CH2
20
19q
99
12
8ra
nbutyl
20
19r
94
13
8sa
cyclohexyl
20
19s
94
8aa(0.125mmol),1MEt2Zninhexanes(0.375mmol),CH2Cl2(1.6mL).bYield
ofisolatedproduct.
Thestructureoftheseamidoalkylperoxideswasestablishedbyspectroscopy
methodsandconfirmedbyXraydiffractionanalysisofproduct19f,whichshowedthe
peroxidegroup(Figure4.5).
210
Chapter4
O
HN
O
O
O
Br
Figure4.5..Xraystructtureof19f.
The reaction also performedd well with

h the large
er dialkylzi nc nBu2Zn. This
reageentisalsoccompatiblewithelectrronwithdraawingande
electrondoonatinggrou
upsin
differentpositio
onsintheaaromaticrinngoftheamidosulfo
one(Table44.4,Entriess13).
Heteeroaromaticc amido sulfone 8naa yielded the corresponding perroxide derivvative
quan
ntitatively (98%) (Table 4.4, Entryy 4). Finally, aliphaticc amido ssulfones de
erived
from
mdihydrocin
nnamaldehyydeandcycclohexylcarbaldehyde werealsossubjectedtothe
addittion of nBu2Zn and oxxygen and tthe corresp
ponding a
amido butyylperoxides were
isolattedin90an
nd91%yield,respectivvely(Table4
4.4,Entries56).
Table4.4
4.Threecomp
ponentadditioonofnBu2Zn/O
O2toamido
osulfones8.a
HN
R
Cbz
n Bu Zn
2 n
SO2 Tol
O2
0 C
CH
C 2 Cl2
HN
R
Cbz
O
nB
Bu
27
8aa
Entry
t(h)
t
27
Yieeld(%)b
8aa
Ph
20
27a
933
8ba
4MeC6H 4
20
27b
911
8ja
2ClC6H4
20
27j
988
8na
2thienyll
20
27n
988
8qa
C6H5CH2CCH2
20
27q
900
8sa
cyclohexxyl
20
27s
911
8aa (0.1
125 mmol), 1 M Bu2Zn in heptane (0.375 mmol), CH2Cl2 ( 1.6 mL). b
Yieldofissolatedproduct.
211
Chapter4
We also extended our studies to the utilization of the secondary dialkylzinc

i
Pr2Zn(Table4.5).
Table4.5.ThreecomponentadditionofiPr2Zn/O2toamidosulfones8.a
Entry
t(h)
28
Yield(%)b
1c
8aa
Ph
20
28a
92
8aa
Ph
20
28a
95
8ba
4MeC6H4
20
28b
94
8ja
2ClC6H4
20
28j
98
8na
2thienyl
20
28n
91
8qa
C6H5CH2CH2
20
28q
95
8ra
nbutyl
20
28r
96
8aa(0.125mmol),1MiPr2Znintoluene(0.375mmol),CH2Cl2(1.6mL).bYield
ofisolatedproduct.cThereactionwasperformedat0C.
This reaction could be carried out at room temperature instead of 0 C. As

showninTable4.5,alldesiredproductswereobtainedinexcellentyieldsabove90%,
regardless of the electronic and steric nature of the substituents in the amido
sulfone.
Finally, amido sulfone 8aa was subjected to the reaction with Me2Zn and
oxygen. Due to the high reactivity of this dialkylzinc toward oxygen, we decided to
slightly modify the experimental procedure. The reactions with Et2Zn, nBu2Zn and
i
Pr2Znwereallentirelyperformedunderoxygenatmosphere.However,inthecaseof
Me2Zn, the addition of the reagent to the reaction mixture was realized under a
nitrogenatmosphereand,then,nitrogenwasreplacedbyoxygen.
UnderthismodificationoftheoptimizedconditionsforthereactionwithEt2Zn,
Me2Zn provided a mixture of two products which could not be totally separated by
flashchromatography.The 1HNMRofthismixturerevealedthatoneofthemwasthe
212
Chapter4
desirred amid
do methylperoxide 299a. The oth
her (32a) showed
s
a ssimilar 1H NMR
specttrum wherre, apparen
ntly, CH, NH
H and CH3 protons were
w
shiftedd at higher field
3.473
3.909
5.191
5 170
5.170
5.308
5.603
5.340
5.633
5.881
5.914
6 522
6.522
7.380
7.370
7.363
7 350
7.350
7.343
7.337
7.324
7.260
6.554
7.429
7.406
(Figu
ure4.6).
*
o
5.00
4.50
4..00
3.0
2.2
3.8
5.50
0.9
6.00
6.50
0
0.6
0
6
7.00
0.9
7.50
0.7
00
8.0
18.8
ppm
3.50
3.00
2.50
0
Fiigure4.6.1HNMRspectrrumofthep roductsobtaainedinthereactionbetw
weenamido
sulfo
one8aa,Me2ZnandO2.*
*Signalscorrrespondingtto29a.Signalscorresp
pondingto32a.
The mollecular weight of 32a was deterrmined by mass specttrometry, which

w
indiccated a [M+H]+ = 272
2.17, 16 unnits less th
han amid
do methylpperoxide 29
9a, as
illusttratedinFiggure4.7.
272.17
2
Figure4
4.7.Masssp ectrumof32
2a.[M+H]+=272.17.
213
Chapter4
Thisfindingwascrucialtoelucidatethestructureofproduct32a,whichmust
correspondtotheadditionofmethoxidetoamidosulfone8aa(Scheme4.28)
HN
Cbz
SO2Tol
HN
Me2Zn
O2
Cbz
0 C
O
CH2Cl2
8aa
HN
Me
29a
Cbz
O
Me
32a
Scheme4.28.Additionofoxygenateddimethylzincspeciestoamidosulfone8aa.
Several reactions were performed in order to achieve exclusively amido

methylperoxide 29a. However, all attempts failed and a mixture of compounds 29a
and 32a was always obtained. These results prompted us to study the controlled
oxygenationofdialkylzincreagentstoaffordamidoalkoxides.
speciestoamidosulfonesintheabsenceofaligand
Aplausiblemechanismfortheadditionofdialkylzincoxygenatedspeciesto
amidosulfonesisdepictedinScheme4.29.Initially,R2ZnwouldreactwithO2togive
thealkylperoxidespeciesRZnOOR. Besidesthesealkylperoxidespecies,RZnOORmay
reactwithanotherequivalentofR2ZntoformthealkoxidespeciesRZnOR.
Ontheotherhand,reactionbetweenamidosulfoneandanotherequivalent
ofdialkylzincwouldaffordtheNCbzprotectedpropargylicimine.Subsequentaddition
of RZnOOR to this protected imine would provide the amido alkylperoxide after
hydrolysis(RouteA),whilsttheadditionofRZnORtotheNCbzprotectediminewould
affordtheamidoalkoxide(RouteB).
This proposed mechanism would explain the formation of both products, 29a
and32a,whendimethylzincisemployed(Scheme4.28).
214
Chapter4
Scheme4.29.Plausiblemechanismfortheadditionofdialkylzincoxygenatedspeciesto
amidosulfone8aa.
4.3.2.Additionofzincalkoxidestoamidosulfones
To carry out the addition of zinc alkoxide species to amido sulfones, we
decided to investigate the reaction with dibutylzinc/O2. The optimization process
consisted of changing the reaction conditions progressively starting from the
conditionsfortheformationofamidoalkylperoxide27a(Table4.4,Entry1).
Gratifyingly, a simple increase in temperature from 0 C to rt led to the
appearance of the desired product 31a (Table 4.6, Entry 2). A greater increase in
temperatureto40Cimprovedtheresultsconsiderably.Thetendencyindicatedthat
formation of amido alkoxide 31a required higher temperatures. For this reason, a
solventwithahigherboilingpointthandichloromethanewasevaluated.Thereaction
seemed to follow the same tendency in toluene (Table 4.6, Entries 45). However,
whenitwasperformedat80C,compound27awasnotobtained;instead,amixture
of unidentified products was observed (Tabla 4.6, Entry 6). The utilization of a
chlorinatedsolvent,1,2dichloroethane,ledtopromisingresults(Table4.6,Entries7
8), but eventually only the addition of an O,Odonor ligand allowed us to further
increasetheproportionofthealkoxideproduct.
215
Chapter4
SeveralO,Odonorligands(Figure4.4)wereexaminedinthereactionwith1,2
dichloroethane at 40 C (Table 4.6, Entries 912). All of them provided a higher
proportion of the desired product (31a) compared to the reaction in the absence of
ligand(Table4.6,Entry7).Cathecol(L10)ledtoproductsina0.3:1ratioat40Cand
couldfinallyleadtotheexclusiveformationof31aat60Cina61%yield.
Thus,weestablishedthatamidobutoxide31acouldbeisolatedastheonly
reactionproduct(61%yield)inthereactionbetweenamidosulfone8aa,nBu2Znand
molecularoxygenin1,2dichloroethaneat60Cinthepresenceofcatechol.
Table 4.6. Three component addition of nBu2Zn/O2 to amido sulfone 8aa to give
amidobutoxide31a.Screeningoftemperature,solventandligands.a
Entry
Solvent
T(C)
t(h)
27:31 (%yield)
CH2Cl2
20
1.0:0(93)
CH2Cl2
rt
20
1.2:1
CH2Cl2
40
20
0.6:1
Toluene
40
20
0.8:1
Toluene
60
20
0.4:1
Toluene
80
20
ClCH2CH2Cl
40
20
0.6:1
ClCH2CH2Cl
60
20
0.4:1
ClCH2CH2Cl
()L1
40
20
0.5:1
10
ClCH2CH2Cl
L9
40
20
0.5:1
11
ClCH2CH2Cl
L10
40
20
0.3:1
12
ClCH2CH2Cl
L11
40
20
0.4:1
13
ClCH2CH2Cl
L10
60
20
0.0:1(61)
8aa (0.125 mmol), L (0.025 mmol), 1 M nBu2Zn in heptane (0.375 mmol), solvent (1.6
mL). b Proportion of products determined by 1H NMR. c Yield of isolated product. d

Mixtureofunidentifiedproducts.
216
Chapter4
With the optimized conditions in hand, a variety of amido sulfones was
subjectedtothebutoxylationreactionconditions(Table4.7,Entries15).
The utilization of substrates derived from benzaldehyde afforded the desired
productsingoodyields(5967%)regardlessthesubstituentinthearomaticring(Meor
Cl)anditsparaororthoposition(Table4.7,Entries24).Amidosulfone8qaderived
from dihydrocinnamaldehyde yielded the corresponding amido butoxide in similar
results(61%)(Table4.7,Entry5).
Furthermore,thereactionwasalsoperformedinthepresenceofEt2Zn(Table
4.7, Entries 68). The desired product could be isolated in moderate yield (53%) for
aromaticamidosulfonebearinganelectronwithdrawingsubstituentinpara(Table
4.7,Entry7).Aloweryieldwasaffordedwiththeamidosulfonederivedfromotolyl
aldehyde(41%)(Table4.7,Entry8).
Table 4.7. Three component addition of R2Zn/O2 to amido sulfones 8 to give amido
alkoxides30and31.a
Entry
R2Zn
t(h)
Product Yield(%)b
8aa
Ph
20
31a
61
8ba
4MeC6H4
20
31b
67
8ja
4ClC6H4
20
31j
63
8na
2MeC6H4
20
31n
59
8qa
C6H5CH2CH2
20
31q
61
8aa
Ph
Et2Zn
20
30a
60
8ja
4ClC6H4
Et2Zn
20
30j
53
8na
2MeC6H4
Et2Zn
20
30n
41
Bu2Zn
Bu2Zn
Bu2Zn
Bu2Zn
Bu2Zn
8(0.125mmol),1M Bu2Zninheptaneor1MEt2Zninhexanes(0.375mmol),ClCH2CH2Cl
(1.6mL).bYieldofisolatedproduct.
217
Chapter4
Allattemptstoobtainamidoalkoxidesfrom iPr2Znresultedintheformation
oftheperoxidederivative.
Finally,thecontrolledoxygenationofMe2Znandthemethoxylationreactionof
amido sulfones were performed. This oxygenated species was easily afforded at
roomtemperature,sothereactionwascarriedoutindichloromethaneinsteadof1,2
dichloroethane(Table4.8).
Amido sulfone derived from benzaldehyde led to the reaction product in a
60%yield(Table4.8,Entry1).Electrondonating(Me)andelectronwithdrawing(Cl)
groups in the aromatic ring of the amido sulfone provided amido methoxides in
good yields in both para and ortho positions (Table 4.8, Entries 24). Besides, the
procedure tolerated well the utilization of an amido sulfone derived from an
aliphaticaldehyde(Table4.8,Entry5).
Table 4.8. Three component addition of Me2Zn/O2 to amido sulfones 8 to
giveamidomethoxide32.a
Entry
t(h)
Product Yield(%)b
8aa
Ph
20
32a
60
8ja
4ClC6H4
20
32j
71
8na
2MeC6H4
20
32n
68
8oa
2ClC6H4
20
32o
72
8ra
cyclohexyl
20
32r
60
8(0.125mmol),2MMe2Znintoluene(0.375mmol),CH2Cl2(1.6mL). bYieldof
isolatedproduct.
218
Chapter4
speciestoamidosulfonesinthepresenceofaligand
A plausible catalytic cycle is outlined in Scheme 4.30 for the peroxidation or
alkoxylationofamidosulfonesinthepresenceofaO,Odonorligand.Initially,the
RZnLcomplex,formedbythereactionbetweenR2Znandtheligand,wouldbeoxidized
byO2toazincalkylperoxideROOZnL.Thisspeciescouldfollowtwodifferentroutes,A
orB.InrouteA,theadditionofthisalkylperoxidespeciestotheiminegeneratedfrom
the amido sulfones in the basic medium would give an amido alkylperoxide
complexwhichafterLRexchangewithanothermoleculeofdialkylzincwouldgivethe
finalproductandregeneratetheactivespecies.
Ontheotherhand,ROOZnLcouldreactwithamoleculeofRZnLtoaffordthe
alkoxideROZnL(RouteB).Theadditionofthisalkoxidetotheiminewouldgivean
amidoalkoxidecomplexwhichafterLRexchangewithanothermoleculeofdialkylzinc
wouldgivethefinalproductandregeneratetheactivespecies.
Scheme4.30.Catalyticcyclefortheperoxidation(RouteA)oralkoxylation(RouteB)of
amidosulfonesinthepresenceofaligand.
219
Chapter4
The formation of amido alkoxide products (Route B) is favoured by the

increase of temperature, as observed in the reaction of amido sulfone 11aa with
n
Bu2Zn under different reaction conditions (Table 4.6). On the other hand, the alkyl
groupinthedialkylzincreagentplaysanimportantroleintheoutcomeofthereaction.
Thus,primarydialkylzincreagents(Me2Zn,Et2Znand nBu2Zn)formalkoxidespeciesin
thepresenceofaO,Odonorligandatappropriatetemperatures,whereas iPr2Znonly
providesalkylperoxidespecies.
220
Chapter4
4.4.CONCLUSIONS
Wehavedesignedamethodologyfortheadditiontoamidosulfonesofzinc
alkyloxygenated species resulting from the controlled oxygenation of dialkylzinc
reagentsofdifferentchainlengthinthepresenceofmolecularoxygen.
The reaction was evaluated in the presence of several O,Odonor ligands.
However,intheadditionofalkylperoxidespeciesthebestresultswereobtainedinthe
absenceofligand,usingdichloromethaneat0C.
Benzyloxycarbonyl group in the starting amido sulfones provided better
yieldsthantertbutyloxycarbonylandethyloxycarbonylprotectinggroups.
The reaction of Et2Zn and oxygen was performed with ten aromatic amido
sulfonesofdifferentelectronicandstericnature,providingthecorrespondingamido
alkylperoxides in excellent yields. The utilization of three aliphatic amido sulfones
hasalsoledtoexcellentresults.ThestructureoftheseproductswasconfirmedbyX
rayanalysis.
The utilization of nBu2Zn and oxygen with five aromatic and one aliphatic
amidosulfonesgavetheethylperoxidationproductsinexcellentyieldsregardlessthe
electronicandstericcharacteristicsofthesubstituents.
Thereactionof iPr2Znandoxygenwithdifferentamidosulfoneswascarried
outatroomtemperature.Thecorrespondingamidoalkylperoxideswereobtainedin
excellentyieldswithbotharomaticandaliphaticsubstrates.
ThereactionwithMe2Znandoxygenundertheseconditionsledtomixturesof
amido methylperoxide and amido methoxide. All attempts to exclusively obtain
theperoxidederivativewereunsuccessful.
We have also carried out the addition to amido sulfones of zinc alkoxides
species resulting from the controlled oxygenation of dialkylzinc reagents of different
chainlengthinthepresenceofmolecularoxygen.
221
Chapter4
ThisprocessrequireshighertemperaturesandthepresenceofanO,Odonor
ligandtoaffordamidoalkoxidesastheuniquereactionproducts.
Theutilizationof nBu2Znwithseveralaromaticamidosulfoneswithelectron
donating and electronwithdrawing groups in ortho and para position led to good
yields.Asimilarresultwasobtainedwithanaliphaticamidosulfone.Et2Znprovided
thecorrespondingamidoethoxidesinmoderateyields.
ThereactionofMe2Znandoxygenwithdifferentamidosulfonesproceeded
withgoodyieldsregardlesstheelectronicandstericnatureofthesubstituents.
Allattemptstoobtaintheisopropoxidederivativewereunfruitfulandonlythe
formationoftheperoxidederivativewasobserved.
222
Chapter4
4.5.EXPERIMENTALSECTION
4.5.1.Generaltechniques
SeeSection2.5.1.
Three component reactions were carried out under oxygen atmosphere in
roundbottomflasksovendriedovernightat120C.
Diethylzinc1Msolutioninhexanes,dimethylzinc2Msolutionintolueneand
diisopropylzinc1MintoluenewerepurchasedfromAldrich.Dibutylzinc1Msolution
inheptaneswaspurchasedfromFluka.Theywereusedwithoutfurtherpurification.
4.5.2. General synthetic procedures and characterization of new

products
4.5.2.1.Alkylperoxidationofamidosulfones8withEt2Zn
A1MsolutionofEt2Zninhexanes(0.375mL,0.375mmol)wasstirredinCH2Cl2
(0.6 mL) at room temperature under oxygen atmosphere. After 1 h, the reaction
mixture was stirred at 0 C for 15 min. Then, a solution of amido sulfone 8 (0.125
mmol)inCH2Cl2(1.0mL)wasadded.After20 h,thereactionmixturewasquenched
with water (1 mL), extracted with CH2Cl2 (3x15 mL), dried over MgSO4 and
concentratedunderreducedpressuretogivecompound19.
N(ethylperoxy(phenyl)methyl)benzylcarbamate(19a)
Whitesolid;mp5557C.
1
HNMR(300MHz,CDCl3)7.457.32(m,10H),6.53(d,J=
10.0Hz,1H),5.60(d,J=8.2Hz,1H),5.19(s,2H),4.164.08
(m,2H),1.21(t,J=6.9Hz,3H).
19a
13
C NMR (75.5 MHz, CDCl3) 155.5 (C), 136.09 (C), 136.05
(C),129.1(CH),128.7(CH),128.5(CH),128.24(CH),128.16(CH),126.3(CH),85.3(CH),
70.4(CH2),67.2(CH2),13.3(CH3).
223
Chapter4
HRMS(ESI)m/z:324.1254[M+Na]+,C17H19NO4Narequires324.1212.
N(ethylperoxy(phenyl)methyl)tertbutylcarbamate(25a)
Whitesolid;mp5759C.
1
HNMR(300MHz,CDCl3)7.457.34(m,5H),6.45(d,J=9.8
Hz,1H),5.38(d,J=9.2Hz,1H),4.174.09(m,2H),1.49(s,9H),
1.23(t,J=7.0Hz,3H).
25a
13
CNMR(75.5MHz,CDCl3)155.8(C),136.5(C),128.9(CH),
128.6(CH),126.4(CH),84.9(CH),80.3(C),70.3(CH2),28.3(CH3),13.3(CH3).
N(ethylperoxy(phenyl)methyl)ethylcarbamate(26a)
Whitesolid;mp4851C.
1
HNMR(300MHz,CDCl3)7.457.33(m,5H),6.49(d,J=9.9
Hz, 1H), 5.50 (d, J = 6.1 Hz, 1H), 4.244.10 (m, 4H), 1.311.21
26a
(m,6H).
13
CNMR(75.5MHz,CDCl3)155.7(C),136.2(C),129.0(CH),128.6(CH),126.3(CH),
85.3(CH),70.4(CH2),61.4(CH2),14.5(CH3),13.3(CH3).
N(ethylperoxy(4tolyl)methyl)benzylcarbamate(19b)
Whitesolid;mp7172C.
1
HNMR(300MHz,CDCl3)7.397.29(m,7H),7.18(d,
J=7.9Hz,2H),6.49(d,J=9.9Hz,1H),5.62(d,J=9.1
19b
Hz, 1H), 5.19 (s, 2H), 4.154.08 (m, 2H), 2.35 (s, 3H),
1.21(t,J=6.9Hz,3H).
224
Chapter4
13
CNMR(75.5MHz,CDCl3)155.5(C),139.0(C),136.1(C),133.1(C),129.3(CH),128.5
(CH),128.2(CH),128.1(CH),126.2(CH),85.3(CH),70.4(CH2),67.1(CH2),21.2(CH3),
13.3(CH3).
N(ethylperoxy(4methoxyphenyl)methyl)benzylcarbamate(19c)
Palebrownsolid;mp150152C.
1
HNMR(300MHz,CDCl3)7.387.32(m,7H),6.89(d,
J=8.8Hz,2H),6.48(d,J=9.9Hz,1H),5.66(d,J=9.4
19c
Hz, 1H), 5.18 (s, 2H), 4.144.08 (m, 2H), 3.80 (s, 3H),
1.21(t,J=6.8Hz,3H).
13
13.3(CH3).
N((4chlorophenyl)(ethylperoxy)methyl)benzylcarbamate(19e)
Whiteneedles;decomp.
1
HNMR(300MHz,CDCl3)7.397.34(m,9H),6.49(d,
J = 9.8 Hz, 1H), 5.62 (d, J = 8.1 Hz, 1H), 5.19 (s, 2H),
19e
4.144.07(m,2H),1.20(t,J=6.9Hz,3H).
13
CNMR(75.5MHz,CDCl3)155.5(C),135.9(C),134.9
(C), 134.7 (C), 128.8 (CH), 128.5 (CH), 128.3 (CH), 128.2 (CH), 127.8 (CH), 84.8 (CH),
70.5(CH2),67.3(CH2),13.2(CH3).
HRMS(ESI)m/z:358.0824[M+Na]+,C17H18ClNO4Narequires358.0822.
225
Chapter4
N((4bromophenyl)(ethylperoxy)methyl)benzylcarbamate(19f)
Whitesolid;mp6869C.
1
H NMR (300 MHz, CDCl3) 7.50 (d, J = 8.6 Hz, 2H),
7.367.28 (m, 7H), 6.47 (d, J = 9.9 Hz, 1H), 5.68 (d, J =
10.2Hz,1H),5.18(s,2H),4.134.07(m,2H),1.20(t,J=
19f
6.9Hz,3H).
13
C NMR (75.5 MHz, CDCl3) 155.5 (C), 135.9 (C), 135.2 (C), 131.7 (CH), 128.5 (CH),
128.3 (CH), 128.2 (CH), 128.1 (CH), 123.1 (C), 84.8 (CH), 70.5 (CH2), 67.3 (CH2), 13.2
(CH3).
HRMS(ESI)m/z:402.0322[M+Na]+,C17H18BrNO4Narequires402.0317.
N(ethylperoxy(3tolyl)methyl)benzylcarbamate(19g)
Colorlessoil.
1
HNMR(300MHz,CDCl3)7.407.19(m,8H),7.18(t,J
=6.8Hz,1H),6.49(d,J=10.0Hz,1H),5.65(d,J=8.6
19g
Hz, 1H), 5.19 (s, 2H), 4.174.10 (m, 2H), 2.37 (s, 3H),
1.22(t,J=6.8Hz,3H).
13
67.1(CH2),21.4(CH3),13.3(CH3).
N(ethylperoxy(2tolyl)methyl)benzylcarbamate(19h)
Brownsolid;mp7172C.
1
HNMR(300MHz,CDCl3)7.397.18(m,9H),6.67(d,J
19h
226
=9.9Hz,1H),5.57(d,J=8.6Hz,1H),5.18(s,2H),4.14
4.12(m,2H),2.42(s,3H),1.20(t,J=6.9Hz,3H).
Chapter4
13
128.5(CH),128.2(CH),128.1(CH),126.1(CH),125.2(CH),82.9(CH),70.3(CH2),67.1
(CH2),19.0(CH3),13.3(CH3).
N(ethylperoxy(2chlorophenyl)methyl)benzylcarbamate(19j)
Paleyellowsolid;mp4143C.
1
H NMR (300 MHz, CDCl3) 7.497.46 (m, 1H), 7.41
7.29(m,8H),6.77(d,J=9.8Hz,1H),5.69(d,J=8.7Hz,
1H),5.18(s,2H),4.174.15(m,2H),1.22(t,J=6.8Hz,
19j
3H).
13
67.2(CH2),13.2(CH3).
N(ethylperoxy(1naphthyl)methyl)benzylcarbamate(19l)
Palebrownsolid;mp111113C.
1
H NMR (300 MHz, CDCl3) 8.15 (d, J = 8.2 Hz, 1H),
19l
7.907.85(m,2H),7.657.36(m,9H),7.17(d,J=9.9Hz,
1H),5.79(d,J=9.7Hz,1H),5.22(s,2H),4.214.19(m,
2H),1.24(t,J=6.9Hz,3H).
13
CNMR(75.5MHz,CDCl3)155.4(C),136.0(C),133.8(C),131.8(C),130.3(C),129.8
123.9(CH),123.3(CH),83.4(CH),70.5(CH2),67.2(CH2),13.3(CH3).
227
Chapter4
N(ethylperoxy(2thienyl)methyl)benzylcarbamate(19n)
Orangeneedles;mp5759C.
1
HNMR(300MHz,CDCl3)7.417.35(m,5H),7.32(dd,J
19n
=5.1,1.2Hz,1H),7.11(dt,J=3.6,1.1Hz,1H),7.00(dd,J
=5.1,3.6Hz,1H),6.73(d,J=9.9Hz,1H),5.76(d,J=9.0
Hz,1H),5.19(s,2H),4.164.09(m,2H),1.22(t,J=6.8Hz,
3H).
13
128.2(CH),126.9(CH),126.4(CH),126.0(CH),82.5(CH),70.7(CH2),67.3(CH2),13.2
(CH3).
HRMS(ESI)m/z:330.0779[M+Na]+,C15H17NO4SNarequires330.0776.
N(ethylperoxy(3phenyl)propyl)benzylcarbamate(19q)
Colorlessoil.
1
HNMR(300MHz,CDCl3)7.387.17(m,10H),5.545.47
(m,1H),5.34(d,J=9.5Hz,1H),5.15(s,2H),4.094.02(m,
19q
2H),2.73(t,J=7.7Hz,2H),2.101.98(m,1H),1.941.82
(m,1H),1.19(t,J=6.8Hz,3H).
13
128.2 (CH), 128.1 (CH), 126.1 (CH), 84.3 (CH), 70.2 (CH2), 66.9 (CH2), 34.1 (CH2), 31.2
(CH2),13.2(CH3).
N(ethylperoxypentyl)benzylcarbamate(19r)
Colorlessoil.
1
HNMR(300MHz,CDCl3)7.377.32(m,5H),5.515.43
19r
228
(m,1H),5.26(d,J=9.9Hz,1H),5.13(s,2H),4.074.00(m,
Chapter4
2H), 1.721.64 (m, 1H), 1.591.47 (m, 1H), 1.391.30 (m, 4H), 1.17 (t, J = 6.8 Hz, 3H),
0.89(t,J=7.1Hz,3H).
13
84.8 (CH), 70.1 (CH2), 66.8 (CH2), 32.1 (CH2), 27.0 (CH2), 22.3 (CH2), 13.8 (CH3), 13.2
(CH3).
N(ethylperoxy(cyclohexyl)methyl)benzylcarbamate(19s)
Whitesolid;mp4445C.
1
HNMR(300MHz,CDCl3)7.377.33(m,5H),5.305.17
(m, 2H), 5.13 (s, 2H), 4.074.00 (m, 2H), 1.841.61 (m,
6H),1.201.02(m,8H).
19s
13
88.2 (CH), 69.9 (CH2), 66.8 (CH2), 40.3 (CH), 28.4 (CH2), 28.0 (CH2), 26.1 (CH2), 25.7
(CH2),25.6(CH2),13.3(CH3).
4.5.2.2.Alkylperoxidationofamidosulfones8withnBu2Zn
A 1 M solution of nBu2Zn in heptane (0.375 mL, 0.375 mmol) was stirred in
CH2Cl2(0.6mL)atroomtemperatureunderoxygenatmosphere.After1h,thereaction
mixture was stirred at 0 C for 15 min. Then, a solution of amido sulfone 8 (0.125
mmol)inCH2Cl2(1.0mL)wasadded.After20 h,thereactionmixturewasquenched
with water (1 mL), extracted with CH2Cl2 (3x15 mL), dried over MgSO4 and
concentratedunderreducedpressuretogivecompound27.
N(nbutylperoxy(phenyl)methyl)benzylcarbamate(27a)
Whiteoil.
1
=9.9Hz,1H),5.64(d,J=8.7Hz,1H),5.19(s,2H),4.07(t,
27a
229
Chapter4
J=6.1Hz,2H),1.63154(m,2H),1.421.29(m,2H),0.91(t,J=7.3Hz,3H).
13
128.5(CH),128.2(CH),128.1(CH),126.3(CH),85.3(CH),74.8(CH2),67.1(CH2),29.8
(CH2),19.2(CH2),13.8(CH3).
N(nbutylperoxy(4tolyl)methyl)benzylcarbamate(27b)
Whitesolid;mp3638C.
1
HNMR(300MHz,CDCl3)7.397.29(m,7H),7.18
(d,J=7.9Hz,2H),6.49(d,J=9.9Hz,1H),5.61(d,J=
27b
9.0Hz,1H),5.18(s,2H),4.06(t,J=6.3Hz,2H),2.35
(s,3H),1.60153(m,2H),1.421.31(m,2H),0.90(t,
J=7.3Hz,3H).
13
21.2(CH3),19.2(CH2),13.9(CH3).
N(nbutylperoxy(2chlorophenyl)methyl)benzylcarbamate(27j)
Whitesolid;mp3940C.
1
HNMR(300MHz,CDCl3)7.487.45(m,1H),7.417.28
(m,8H),6.77(d,J=6.8Hz,1H),5.66(d,J=8.8Hz,1H),
27j
5.18 (s, 2H), 4.10 (t, J = 5.5 Hz, 2H), 1.63153 (m, 2H),
1.411.29(m,2H),0.90(t,J=7.3Hz,3H).
13
67.2(CH2),29.7(CH2),19.1(CH2),13.8(CH3).
230
Chapter4
N(nbutylperoxy(2thienyl)benzylcarbamate(27n)
Orangeoil.
1
HNMR(300MHz,CDCl3)7.407.31(m,6H),7.11(dt,J
=3.6,1.1Hz,1H),7.00(dd,J=5.1,3.6Hz,1H),6.73(d,J
27n
=9.9Hz,1H),5.76(d,J=9.3Hz,1H),5.19(s,2H),4.08(t,
J=6.4Hz,2H),1.63154(m,2H),1.421.30(m,2H),0.91(t,J=7.3Hz,3H).
13
128.2(CH),126.9(CH),126.4(CH),126.0(CH),82.4(CH),75.0(CH2),67.2(CH2),29.8
(CH2),19.1(CH2),13.8(CH3).
N(nbutylperoxy(3phenyl)propyl)benzylcarbamate(27q)
Whitesolid;mp4143C.
1
HNMR(300MHz,CDCl3)7.367.16(m,10H),5.54
5.46 (m, 1H), 5.33 (d, J = 9.6 Hz, 1H), 5.14 (s, 2H),
3.99(t,J=6.4Hz,2H),2.72(t,J=7.7Hz,2H),2.09
27q
1.91 (m, 1H), 1.931.81 (m, 1H), 1.60151 (m, 2H),

1.411.29(m,2H),0.90(t,J=7.3Hz,3H).
13
128.2(CH),128.11(CH),128.06(CH),126.1(CH),84.3(CH),74.6(CH2),66.9(CH2),34.1
(CH2),31.2(CH2),29.8(CH2),19.2(CH2),13.8(CH3).
N(nbutylperoxy(cyclohexyl)methyl)benzylcarbamate(27s)
Whitesolid;mp3638C.
1
H NMR (300 MHz, CDCl3) 7.377.31 (m, 5H), 5.30
5.20(m,2H),5.13(s,2H),3.98(t,J=6.5Hz,2H),1.84
27s
1.71 (m, 6H), 1.571.50 (m, 3H), 1.411.31 (m, 2H),

231
Chapter4
1.201.02(m,4H),0.90(t,J=7.3Hz,3H).
13
88.1 (CH), 74.3 (CH2), 66.8 (CH2), 40.3 (CH), 29.8 (CH2), 28.4 (CH2), 28.0 (CH2), 26.1
(CH2),25.6(CH2),25.5(CH2),19.2(CH2),13.9(CH3).
4.5.2.3.Alkylperoxidationofamidosulfones8withiPr2Zn
A1Msolutionof iPr2Zn(0.375mL,0.375mmol)wasstirredinCH2Cl2(0.6mL)
at room temperature under oxygen atmosphere. After 1 h, a solution of amido
sulfone 8 (0.125 mmol) in CH2Cl2 (1.0 mL) was added and the reaction mixture was
stirred at rt. After 20 h, the reaction mixture was quenched with water (1 mL),
extractedwithCH2Cl2(3x15mL),driedoverMgSO4andconcentratedunderreduced
pressuretogivecompound28.
N(isopropylperoxy(phenyl)methyl)benzylcarbamate(28a)
Whitesolid;mp6768C.
1
=10.0Hz,1H),5.64(d,J=8.7Hz,1H),5.19(s,2H),4.40
4.32(m,1H),1.21118(m,6H).
28a
13
C NMR (75.5 MHz, CDCl3) 155.6 (C), 136.2 (C), 136.1
(C),129.0(CH),128.6(CH),128.5(CH),128.2(CH),128.1(CH),126.4(CH),85.4(CH),
76.2(CH),67.1(CH2),20.4(CH3),20.3(CH3).
N(isopropylperoxy(4tolyl)methyl)benzylcarbamate(28b)
Whitesolid;mp5961C.
1
HNMR(300MHz,CDCl3)7.397.29(m,7H),7.18(d,
J=7.9Hz,2H),6.47(d,J=9.9Hz,1H),5.58(d,J=8.1
28b
232
Chapter4
Hz,1H),5.18(s,2H),4.384.30(m,1H),2.35(s,3H),1.201.18(m,6H).
13
(CH), 128.2 (CH), 128.1 (CH), 126.3 (CH), 85.4 (CH), 76.2 (CH), 67.0 (CH2), 21.2 (CH3),
20.40(CH3),20.37(CH3).
N(isopropylperoxy(2chlorophenyl)methyl)benzylcarbamate(28j)
Whitesolid;mp7677C.
1
HNMR(300MHz,CDCl3)7.497.46(m,1H),7.417.28(m,
8H),6.75(d,J=9.8Hz,1H),5.67(d,J=8.9Hz,1H),5.18(s,
28j
2H),4.444.37(m,1H),1.1941.186(brm,6H).
13
CNMR(75.5MHz,CDCl3)155.1(C),136.0(C),134.0(C),
133.1(C),130.2(CH),130.1(CH),128.5(CH),128.2(CH),128.1(CH),127.8(CH),127.0
(CH),83.2(CH),76.3(CH),67.2(CH2),20.4(CH3),20.3(CH3).
N(isopropylperoxy(2thienyl)methyl)benzylcarbamate(28n)
Yellowsolid;mp125127C.
1
HNMR(300MHz,CDCl3)7.397.35(m,5H),7.31(dd,J=
5.1,1.2Hz,1H),7.11(dt,J=3.6,1.1Hz,1H),7.00(dd,J=
28n
5.1,3.6Hz,1H),6.71(d,J=10.1Hz,1H),5.73(d,J=9.6Hz,
1H),5.19(s,2H),4.414.29(m,1H),1.221.18(m,6H).
13
128.2 (CH), 128.1 (CH), 126.8 (CH), 126.0 (CH), 82.5 (CH), 76.5 (CH), 66.9 (CH2), 20.3
(CH3).
233
Chapter4
N(isopropylperoxy(3phenyl)propyl)benzylcarbamate(28q)
Paleyellowsolid;mp3436C.
1
HNMR(300MHz,CDCl3)7.387.27(m,7H),7.237.17
(m,3H),5.535.46(m,1H),5.32(d,J=9.7Hz,1H),5.15
(s,2H),4.324.20(m,1H),2.73(t,J=7.7Hz,2H),2.11
28q
1.99(m,1H),1.951.83(m,1H),1.181.15(m,6H).
13
128.1 (CH), 126.1 (CH), 84.4 (CH), 75.8 (CH), 66.8 (CH2), 34.1 (CH2), 31.2 (CH2), 20.4
(CH3),20.3(CH3).
N(isopropylperoxypentyl)benzylcarbamate(28r)
Whitesolid;mp3436C.
1
H NMR (300 MHz, CDCl3) 7.377.29 (m, 5H), 5.495.41
28r
(m,1H),5.23(d,J=9.4Hz,1H),5.13(s,2H),4.314.19(m,
1H), 1.731.64 (m, 1H), 1.591.48 (m, 1H), 1.391.30 (m,
4H),1.15(d,J=6.0Hz,6H),0.89(t,J=7.1Hz,3H).
13
C NMR (75.5 MHz, CDCl3) 155.7 (C), 136.3 (C), 128.5 (CH), 128.1 (CH), 84.9 (CH),
75.7 (CH), 66.8 (CH2), 32.1 (CH2), 27.0 (CH2), 22.3 (CH2), 20.4 (CH3), 20.3 (CH3), 13.8
(CH3).
4.5.2.4.Alkoxylationofamidosulfones8withEt2Zn
A 1 M solution of nBu2Zn in heptane (0.375 mL, 0.375 mmol) was added
dropwise to a solution of catechol (2.8 mg, 0.025 mmol) and ClCH2CH2Cl (0.6 mL) at
room temperature under oxygen atmosphere. After stirring for 1 h, a solution of
amido sulfone 8 (0.125 mmol) in ClCH2CH2Cl (1.0 mL) was added and the reaction
mixturewasstirredat60C.After20h,thereactionmixturewasquenchedwithwater
(1 mL), extracted with CH2Cl2 (3x15 mL), dried over MgSO4 and concentrated under
234
Chapter4
reduced pressure. Purification by flash chromatography on silica gel afforded

compound30.
Nbenzyl(ethoxy(phenyl)methyl)carbamate(30a)
Whitesolid;mp6365C.
1
9.7 Hz, 1H), 5.35 (d, J = 8.9 Hz, 1H), 5.16 (s, 2H), 3.833.73
(m,1H),3.673.57(m,1H),1.27(t,J=7.0Hz,3H).
30a
13
CNMR(75.5MHz,CDCl3)155.9(C),139.4(C),136.1(C),
128.6 (CH), 128.54 (CH), 128.47 (CH), 128.2 (CH), 128.1 (CH), 125.9 (CH), 82.4 (CH),
67.0(CH2),63.7(CH2),15.1(CH3).
Nbenzyl((4chlorophenyl)(ethoxy)methyl)carbamate(30e)
Whitesolid;mp9699C.
1
=9.8Hz,1H),5.29(d,J=8.8Hz,1H),5.16(s,2H),3.83
3.73(m,1H),3.663.56(m,1H),1.26(t,J=7.0Hz,3H).
30e
13
CNMR(75.5MHz,CDCl3)155.9(C),138.0(C),136.0
(C), 134.3 (C), 128.7 (CH), 128.6 (CH), 128.3 (CH), 128.1 (CH), 127.4 (CH), 81.8 (CH),
67.2(CH2),63.8(CH2),15.0(CH3).
Nbenzyl(ethoxy(otolyl)methyl)carbamate(30h)
Whitesolid;mp5557C.
1
HNMR(300MHz,CDCl3)7.537.51(m,1H),7.357.31(m,
5H), 7.247.15 (m, 3H),6.09 (d, J =9.7 Hz, 1H), 5.29 (d, J =
30h
10.0Hz,1H),5.18(d,J =12.0Hz,1H),5.12(d, J=12.2Hz,
235
Chapter4
1H),3.823.72(m,1H),3.643.54(m,1H),2.33(s,3H),1.27(t,J=7.0Hz,3H).
13
63.5(CH2),18.9(CH3),15.1(CH3).
4.5.2.5.Alkoxylationofamidosulfones8withnBu2Zn
A 1 M solution of nBu2Zn in heptane (0.375 mL, 0.375 mmol) was added
dropwise to a solution of catechol (2.8 mg, 0.025 mmol) and ClCH2CH2Cl (0.6 mL) at
room temperature under oxygen atmosphere. After stirring for 1 h, a solution of
amido sulfone 8 (0.125 mmol) in ClCH2CH2Cl (1.0 mL) was added and the reaction
mixturewasstirredat60C.After20h,thereactionmixturewasquenchedwithwater
(1 mL), extracted with CH2Cl2 (3x15 mL), dried over MgSO4 and concentrated under
reduced pressure. Purification by flash chromatography on silica gel afforded
compound31.
N(nbutoxy(phenyl)methyl)benzylcarbamate(31a)
Whitesolid;mp4951C.
1
9.7Hz,1H),5.34(d,J=10.2Hz,1H),5.16(s,2H),3.763.68
31a
(m,1H),3.593.52(m,1H),1.681.58(m,2H),1.481.35(m,
2H),0.93(t,J=7.3Hz,3H).
13
128.2 (CH), 128.1 (CH), 125.9 (CH), 82.6 (CH), 68.0 (CH2), 67.0 (CH2), 31.7 (CH2), 19.4
(CH2),13.9(CH3).
236
Chapter4
N(butoxy(ptolyl)methyl)benzylcarbamate(31b)
Whitesolid;mp9396C.
O
H
Ph
HNMR(300MHz,CDCl3)7.377.30(m,7H),7.16(d,
J=7.9Hz,2H),5.94(d,J=9.6Hz,1H),5.31(d,J=9.3
Me
31b
Hz, 1H), 5.15 (s, 2H), 3.733.66 (m, 1H), 3.573.49 (m,
1H),2.34(s,3H),1.661.54(m,2H),1.461.34(m,2H),
0.92(t,J=7.3Hz,3H).
13
21.1(CH3),19.4(CH2),13.9(CH3).
N(nbutoxy(4chlorophenyl)methyl)benzylcarbamate(31e)
Whitesolid;mp7879C.
1
=9.8Hz,1H),5.31(d,J=8.9Hz,1H),5.16(s,2H),3.75
3.68(m,1H),3.583.51(m,1H),1.661.57(m,2H),1.46
31e
1.34(m,2H),0.92(t,J=7.3Hz,3H).
13
C NMR (75.5 MHz, CDCl3) 155.9 (C), 138.1 (C), 136.0 (C), 134.2 (C), 128.63 (CH),
128.56(CH),128.3(CH),128.1(CH),127.4(CH),81.9(CH),68.1(CH2),67.1(CH2),31.6
(CH2),19.3(CH2),13.9(CH3).
N(nbutoxy(2tolyl)methyl)benzylcarbamate(31h)
Whitesolid;mp4749C.
1
H NMR (300 MHz, CDCl3) 7.547.51 (m, 1H), 7.357.31
31h
(m,5H),7.247.15(m,3H),6.07(d,J=9.7Hz,1H),5.28(d,J
=9.9Hz,1H),5.16(s,2H),3.743.66(m,1H),3.573.49(m,
237
Chapter4
1H),2.33(s,3H),1.671.58(m,2H),1.471.35(m,2H),0.92(t,J=7.3Hz,3H).
13
66.9(CH2),31.7(CH2),19.4(CH2),18.9(CH3),13.9(CH3).
N(nbutoxy(3phenyl)propyl)benzylcarbamate(31q)
Whitesolid;mp4244C.
1
HNMR(300MHz,CDCl3)7.367.25(m,7H),7.21
7.16(m,3H),5.12(s,2H),4.994.95(m,2H),3.653.58
31q
(m, 1H), 3.473.39 (m, 1H), 2.752.67 (m, 2H), 2.04

1.81 (m, 2H), 1.581.50 (m, 2H), 1.431.31 (m, 2H),
0.91(t,J=7.3Hz,3H).
13
CNMR(75.5MHz,CDCl3)155.9(C),141.2(C),136.2(C),128.6(CH),128.43(CH),
128.36(CH),128.2(CH),128.1(CH),126.0(CH),81.7(CH),67.9(CH2),66.8(CH2),37.5
(CH2),31.8(CH2),31.3(CH2),19.4(CH2),13.9(CH3).
4.5.2.6.Alkoxylationofamidosulfones8withMe2Zn
A 2 M solution of Me2Zn in toluene (0.188 mL, 0.375 mmol) was added
dropwisetoasolutionofcatechol(2.8mg,0.025mmol)andCH2Cl2(0.6mL)atroom
temperature under nitrogen atmosphere. Then, nitrogen was replaced by oxygen
atmosphere. After stirring for 1 h, a solution of amido sulfone 8 (0.125 mmol) in
CH2Cl2(1.0mL)wasaddedandthereactionmixturewasstirredatrt.After20h,the
reactionmixturewasquenchedwithwater(1mL),extractedwithCH2Cl2(3x15mL),
dried over MgSO4 and concentrated under reduced pressure. Purification by flash
chromatographyonsilicagelaffordedcompound32.
238
Chapter4
N(methoxy(phenyl)methyl)benzylcarbamate(32a)
Whitesolid;mp5052C.
1
9.8Hz,1H),5.35(d,J=9.0Hz,1H),5.17(s,2H),3.47(s,3H).
13
CNMR(75.5MHz,CDCl3)155.9(C),139.0(C),136.1(C),
32a
128.61 (CH), 128.58 (CH), 128.55 (CH), 128.3 (CH), 128.1

(CH),125.8(CH),84.0(CH),67.1(CH2),55.7(CH3).
N((4chlorophenyl)(methoxy)methyl)benzylcarbamate(32e)
Whitesolid;mp8587C.
1
=9.9Hz,1H),5.33(d,J=9.1Hz,1H),5.17(s,2H),3.46(s,
3H).
32e
13
CNMR(75.5MHz,CDCl3)155.9(C),137.6(C),136.0
(C), 134.4 (C), 128.7 (CH), 128.6 (CH), 128.3 (CH), 128.1 (CH), 127.3 (CH), 83.3 (CH),
67.2(CH2),55.8(CH3).
N(methoxy(otolyl)methyl)benzylcarbamate(32h)
Whitesolid;mp5556C.
1
HNMR(300MHz,CDCl3)7.517.48(m,1H),7.387.34(m,
5H), 7.247.15 (m, 3H),6.00 (d, J =9.6 Hz, 1H), 5.31 (d, J =
32h
9.6Hz,1H),5.16(s,2H),3.46(s,3H),2.33(s,3H).
13
55.6(CH3),18.8(CH3).
239
Chapter4
N((2chlorophenyl)(methoxy)methyl)benzylcarbamate(32j)
Whitesolid;mp7377C.
1
HNMR(300MHz,CDCl3)7.587.56(m,1H),7.397.26(m,
8H),6.13(d,J=9.6Hz,1H),5.38(d,J=8.2Hz,1H),5.17(s,
32j
2H),3.48(s,3H).
13
(CH),128.5(CH),128.2(CH),128.1(CH),127.0(CH),81.7(CH),67.1(CH2),55.8(CH3).
N(cyclohexyl(methoxy)methyl)benzylcarbamate(32s)
Whitesolid;mp6062C.
1
HNMR(300MHz,CDCl3)7.377.34(m,5H),5.13(s,2H),
5.01(d,J=10.0Hz,1H),4.64(dd,J=10.2,6.2Hz,1H),3.34
32s
(s, 3H), 1.821.67 (m, 5H), 1.531.43 (m, 1H), 1.260.95 (m,
5H).
13
87.2 (CH), 66.8 (CH2), 55.8 (CH3), 42.8 (CH), 28.2 (CH2), 27.7 (CH2), 26.3 (CH2), 25.74
(CH2),25.67(CH2).
240
Chapter4
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244
CH2Cl2
CHAPTER 5
Halogen- and chalcogen-mediated cyclization

of N-Cbz protected propargylic amines
O
HN
SO2Cl2
HN
HN
ClSe
O
Ph
Te
NH
Ph O
Cl2
Se
Ph
Ph
HN
NH Me
S
I
TeBr
O
Ph
Br
I2
Se
I
Chapter5
5.1.ANTECEDENTS
5.1.1.Activationofalkynestowardnucleophilicattack
The activation of a strong bond is the key step in most catalytic chemical
transformations.Thisactivation,andthereforesplittingofthestrongbond,isachieved
bytheperturbationofthepairbondingelectronsinawaysoastoformachemically
activespecies.
Activation of carboncarbon triple bonds toward nucleophilic attack has
typically been performed by the formation of a cationic metal complex in transition
metal catalyzed reactions. However, alkyne activation by electrophiles in halogen or
organochalcogen reagent mediated processes has gained strength during the last
years. This latter reaction proceeds through the formation of a halonium or
chalconium ion and allows the synthesis of halo and chalcoderivatives, which are
versatileprecursorsinmanysynthetictransformations.
When the nucleophile involved in these processes and the triple bond are in
proper relative positions, the reaction occurs through an intramolecular mechanism
whichleadstoheterocycleandcarbocyclederivatives.
Theseringscanbeformedviaendoorexocyclizationmodes,dependingonthe
chainlength,thesubstitutionpatternofthechainandthe electrophileemployed.In
1976, Sir Jack E. Baldwin1 formulated a qualitative set of guidelines for the rational
designofsuchcyclizationstep.Baldwindescribedhisrulesintermsofthreefeatures
ofthereaction:
a) Theringsizebeingformed(indicatedthroughanumericalindex).
b) Thenatureofthebreakingbond(exo,thebreakingbondisexternaltothe
newly formed ring, and endo, the breaking bond is within newly formed
ring).
c) The hybridized state of the carbon atom undergoing the ring closing
reaction(digonalforspcarbon;trigonalforsp2carbonandtetrahedralfor
sp3carbon).
247
Chapter5
Figure5.1.Baldwinsrulesinsixmemberedringformation.
With regard to the internal nucleophile, a wide range of nucleophilic groups

such as alcohols, ethers, thioethers, selenoethers, amines, oximes, azides, aldehydes
andketones,carboxylicacidsandderivatives,1,3dicarbonylcompoundsandaromatic
ringshasbeeninvestigated.
5.1.1.1.Activationofalkynesbytransitionmetals
The utilization of transition metals as alkyne activators has been widely
developed during the last 30 years. Among other metals, gold and silver have been
successfully applied in the synthesis of heterocycles and carbocycles through the
intramolecularadditionofnucleophilestotriplebonds.
Some of the most relevant and recent examples of these reactions using
oxygen,nitrogen,chalcogenorcarbonnucleophilesareexposedbelow.
Metalcatalyzedcyclizationsusingoxygennucleophile
As early as 1958, Pascuals group2 originally carried out the cyclization of
acetylenicacidscatalyzedbysilvernitratetoaffordfuranonesina5exodigcyclization
mode. Later on, Pale and coworkers3 studied this reaction in more detail. They
observed that the counterion was crucial for the regioselectivity of the reaction and
obtainedthebestresultswithsilvercarbonate(Scheme5.1).Itisworthnotingthatthe
reaction proceeds via a 6endodig cyclization mechanism in the presence of zinc
bromide.4
248
Chapter5
Scheme5.1.5exodigcyclizationofacetylenicacids.
More recently, Ji and coworkers5 have developed a goldcatalyzed tandem

three component process for the synthesis of butenolides, which involves the
nucleophilicattackofacarboxylategrouptoagoldactivatedtriplebond,asshownin
Scheme 5.2. The use of aliphatic alkynes afforded the cyclization products in good
yields,whereastheuseofaromaticalkynesrequiredatrappingiminiumiontoobtain
theproductsinhigheryields.
Scheme5.2.Synthesisofbutenolidesbyatandemthreecomponentreaction.
Ithasalsobeendemonstratedthatphosphoricacidsbehaveastheircarboxylic
analogues toward activated alkynes.6 Ding and Peng7 reported a cyclization of o
ethylylphenylphosphoric acid monoethyl esters catalyzed by copper iodide to afford
phosphaisocoumarins
(Scheme
5.3).
Their
analogues,
isocoumarin8
and
iminoisocoumarin9derivatives,havealsobeenpreparedfollowingsimilarapproaches
through a 6endodig cyclization of oalkynylbenzoic acid alkyl esters or o(1
alkynyl)benzamides,respectively.
249
Chapter5
Scheme5.3.Synthesisofphosphaisocoumarinsby6endodigcyclizationofo
ethylylphenylphosphoricacidmonoethylesters.
The6exoOcyclizationofNacyloalkynylanilineshasbeenreportedbySaito10
and coworkers using Pd(OAc)2 as catalyst to give Nalkylidene4H3,1benzoxazines
(Scheme5.4).Thisreactionoccuredinaregioandstereoselectivemanner.Avariety
of alkyl and aryl substituents were examined obtaining the cyclization products in
moderatetohighyields.Theadditionof100mol%AcOHacceleratestheformationof
thefinalproductandtheregenerationofthePd(OAc)2.
Scheme5.4.6endodigcyclizationofNacyloalkynylanilinescatalyzedbyPd(II).
OCyclization of propargylic amides has also demonstrated to be a useful

method for the synthesis of oxazole derivatives.1115 In an initial work, Hashmis
group12provedtheefficiencyofgold(III)forthisprocess.Thereactionwasmonitored
by 1HNMRspectroscopyshowingtheformationoftheintermediate5methylene4,5
dihydrooxazole, which results from a 5exocyclization reaction. Although a great
varietyoffunctionalgroupswaswelltolerated,onlyterminalalkynesunderwentthis
transformation in the presence of AuCl3. In a later research,13 they discovered that
higher yields were obtained using Ph3PAuNTf2 (Scheme 5.5) and internal alkynes
reactedtogivethecorrespondingalkylideneoxazolineswhenthereactionwascarried
outusing(IPr)AuClandAgOTs.Thereactionproduct,inthepresenceofair,delivered
inthehydroperoxideoxazolederivatives.
250
Chapter5
Scheme5.5.Synthesisofhydroperoxideoxazolederivativesby5exodigcyclizationof
propargylicamidesandfurtheroxidation.
Theutilizationofketonesandaldehydesasnucleophilespermitsthesynthesis
of heterocycles such as isochromenes16 or furans1720. Very recently, Liu and
coworkers21 have developed a goldcatalyzed threecomponent coupling reaction of
phenylglyoxal, secondary amines and terminal alkynes that undergoes a 5endodig
cyclization process to afford furan derivatives. Alkynes bearing an electron
withdrawing group were more suitable substrates than those with an electron
donating group. Meta and parasubstituted phenylglyoxal derivatives could be
employedtogivethecyclizationproductsinmoderatetogoodyields(Scheme5.6).
Scheme5.6.Threecomponentreactionofphenylglyoxal,secondaryaminesandterminal
alkynes,followedby5endodigcyclizationtoobtainfuranderivatives.
Metalcatalyzedcyclizationsusingnitrogennucleophile
Transition metal catalyzed intramolecular cyclization processes have been
successfullyemployedinthepreparationofnitrogencontainingheterocycles.
The synthesis of indole and quinoline derivatives employing 5endodig
cyclization reactions of oalkynylanilines and 6endodig cyclization reactions of o
(prop2yn1yl)anilines,respectively,hasbeenextensivelyreported(Scheme5.7).22,23
251
Chapter5
Scheme5.7.a)Synthesisofindolesby5endodigcyclization.b)Synthesisofquinolinesby6
endodigcyclizationreaction.
Asanexample,Arcadi24hasrecentlyreporteda5endodigcyclizationreaction
of unprotected oalkynylanilines and the electrophilic fluorination of the resulting
intermediates for the synthesis of mono and difluorinated indoles (Scheme 5.8). A
onepot procedure was carried out, using NaAuCl4H2O as catalyst and Selectfluor as
fluorinatingagent.
Scheme5.8.Synthesisofmonoanddifluorinatedindoles.
2alkynylbenzaldoximes,25,26 N(2alkynylbenzylidene)hydrazides27, 28 and 2(1

alkynyl)phenylaldimines29canalsoundergoa6endodigcyclizationprocesstoafford
isoquinoline or dihydroisoquinoline derivatives. Wu and coworkers25 have achieved
the silver triflate catalyzed cyclization of 2alkynylbenzaldoxime, followed by the
reaction with aryne to afford 2oxo6azabicyclo[3.2.2]nona6,8diene derivatives in
moderatetogoodyields(5084%)(Scheme5.9).Thereactionproceededthrougha6
endodigcyclizationtofurnishisoquinolineNoxide,asubsequent[3+2]cycloaddition
withtheinsituformedaryneandarearrangementtoobtainthefinalproducts.
252
Chapter5
Scheme5.9.Synthesisof2oxo6azabicyclo[3.2.2]nona6,8dienederivativesviaa6endodig
cyclizationof2alkynylbenzaldoximes.
Pyridine derivatives can also behave as nucleophiles toward metal activated

alkynes.30 Guchhaitandcoworkers31havedescribedathreecomponentreactionof
2aminopyridine, aldehyde and alkyne followed by a 5exodig Ncyclization and
prototropic shift to afford Nfused imidazoles (Scheme 5.10). The reaction was
catalyzed by a mixed Cu(I)Cu(II) system in situ generated from partial reduction of
CuSO4 with glucose in ethanol and the products were isolated with good yields (66
82%). Other poorly reactive heterocyclic amidines were explored giving the
correspondingcyclizationproductsinmoderateyields(4578%).
Scheme5.10.SynthesisofNfusedimidazolesbythreecomponentreactionof2
aminopyridine,aldehydeandalkyne,5exodigcyclizationandprototropicshift.
Eyckens group32 has also developed a methodology to synthesize imizadole

derivativesfrompropynylaminopyrazinonesvia aregioselectivegoldcatalyzed5exo
digNcyclizationreaction.
253
Chapter5
Other 5membered heterocycles have been successfully synthesized using

metalcatalyzed cyclization strategies with alkynes and nitrogen containing
nucleophiles.3335 Lius group36 has carried out a regioselective cyclization of
alkynylaziridines to afford Nphthyl pyrroles using (PPh3)AuCl and AgOTf as catalyst
(Scheme5.11).Theauthorsproposeamechanismwhichinvolvescoordinationofgold
to the triple bond, nucleophilic attack of the aziridine nitrogen followed by ring
opening to give a cationic intermediate which, after deprotonation and deauration
affordsNphthylpyrrole.
Scheme5.11.MechanismforthesynthesisofNphthpyrrolesfromNphthalkynylaziridines.
Very recently, Fusteros group has reported the synthesis of a tetracyclic

framework as a single diastereoisomer from propargylic amino esters.37 The process
beganwiththeactivationofthealkynebythegoldcatalystfollowedbytheattackof
theaminetogivea5endodigcyclizationproductwhichunderwentastereoselective
tandemhydroaminationformalazaDielsAlderreactionprovidingthetetracycleswith
fivestereocenters(Scheme5.12)
Scheme5.12.Synthesisofatetracyclicframeworkasasinglediastereoisomerfrompropargylic
aminoesters.
254
Chapter5
Metalcatalyzedcyclizationsusingchalcogennucleophiles
Chalcogenophene heterocycles and their derivatives present interesting
propertiesinthefieldsoforganicsynthesis,biochemistry38ormaterialchemistry.39For
thisreason,notonlytheuseoforganochalcogenderivativesaselectrophiles,butalso
their application as nucleophiles in the cyclization of alkynes has attracted the
attention of a few authors.40 One of the representativeexamples wascarried out by
Nakamura and coworkers.41 They performed the platinumcatalyzed 5endodig
cyclization of alkyl oalkynylphenyl selenides to furnish 2,3disubstituted
benzo[b]selenophenesinhightoexcelletyields(Scheme5.13).
Scheme5.13.Synthesisof2,3disubstitutedbenzo[b]selenophenesthrough5endodig
cyclizationofalkyloalkynylphenylselenides.
Metalcatalyzedcyclizationsusingcarbonnucleophiles
Transitionmetal activation of alkynes toward carbon nucleophiles has been
appliedtothepreparationofavarietyofcarboandheterocycles.Ingeneral,carbon
nucleophilescanbedividedintothreecategories:dicarbonyliccompounds,areneand
olefins.Someofthemostrecentrepresentativepublicationsareoutlinedbelow.
Someauthorshavetakenadvantageoftheacidityofdicarbonyliccompounds
to develop cyclization strategies.42,43 Yorimitsu and coworkers44 have performed 5
endodigcyclizationofhomopropargylsubstituteddicarbonylcompounds,followedby
CC bond forming reductive elimination to provide 1,2disubstituted cyclopentenes
(Scheme 5.14). The reaction was catalyzed by palladium with bulky biaryl phosphine
ligandsinthepresenceofabase. Substituentsofdiverse naturewerewelltolerated
providingthecyclizationproductsinhighyields.
255
Chapter5
Scheme5.14.PalladiumXPhoscatalyzedcyclizationofhomopropargylsubstituteddicarbonyl
compounds.
Furanyne systems have been employed in cyclization reactions for the

formation of compounds such as phenols, fluorenes, phenanthrenes or
benzofuranes.45 Mechanistically, one of the most studied transformations is the
synthesis of phenol derivatives catalyzed by gold (Scheme 5.15). Initially, gold
coordinatesthetriplebondandthecarbonatthepositionofthefuranringclosesby
a 5exodig cyclization. The new cationic species evolves leading to a cyclopropyl
carbenoid, which opens up to a vinyl carbenoid. Nucleophilic attack of the carbonyl
oxygenatomandeliminationofgoldthengivesanoxepineintermediateintautomeric
equilibriumwiththeareneoxide.Openingoftheoxiraneringandaromatizationleads
tothephenolderivative.
Scheme5.15.Mechanismforthe5exodigcyclizationoffuranynesystems.
Aromaticcarbocycleshavebeenpreparedusingcyclizationstrategies.Rheeand
Lim46 have carried out a metalcatalyzed cyclization of ophenylarylakynes to afford
selectively 9 or 10selenyl phenanthrenes depending on the catalyst (Scheme 5.16).
In(OTf)3catalystledtothe6endodigcyclizationproductinwhichtheseleniumgroup
isretainedinthesamecarbonatom,whilst,theutilizationofAuCl(IPr)/AgSbF6catalyst
256
Chapter5
systeminvolvedavinylidenegoldformationthatledtotheisomericproduct.Inboth
cases,thereactionsproceededselectivelyandwithhighyields.
Scheme5.16.Selectivesynthesisof9and10selenylphenanthrenes.
Not only carbocycles, but also heterocycles have been furnished by carbon
nucleophilicattacktometaltransitionactivatedalkynes.47,48Xiandcoworkers49have
recently developed an efficient strategy for the preparation of quinolines by a
palladiumcatalyzedtandemNvinylationandthe6exodigcyclizationofanilinesand
haloenynes(Scheme5.17).Gagoszsgroup50havealsoaccomplishedthesynthesisof
tetrahydroquinolinesanddihydroquinolinesusinga6exodigcyclizationreactionofN
aminophenylpropargylmalonates.
Scheme5.17.Synthesisofquinolinesby6exodigcyclizationofanilinesandhaloenynes.
On the other hand, enyne systems have demonstrated to be appropriate

substrates to undergo cyclization reactions.51 There are numerous examples in the
literature describing this transformation. One of the most recent examples was
reported by Hayashi.52 He described the asymmetric preparation of 3aza and 3
oxabicyclo[4.1.0]heptane derivatives from heteroatom bridged 1,6eneynamides
(Scheme5.18).Thereactionwascatalyzedbyarhodium/chiraldienecomplexthrough
6endodigpathwayaffordingthereactionproductwithhighenantioselectivities.The
1,6eneynamides substituted with 2oxazolidinone and 2azetidinone at the alkyne
moietywerefoundtodisplayhighreactivitytowardthecatalyst.
257
Chapter5
Scheme5.18.6endodigcyclizationof1,6eneynamides.
5.1.1.2.Activationofalkynesbyelectrophiles
Activation of alkynes by an electrophilic source toward a nucleophilic
intramolecularattackhasdemonstratedtobeanefficientmethodforthesynthesisof
highly functionalized carbo and heterocycles. Different electrophilic sources have
been employed to carry out these reactions. Molecular halogens (X2), halogenation
agents such as Nhalosuccinimides, trichloroisocyanuric acid, I(coll)2PF6/BF3OEt2 or
IPy2BF4/HBF4,IClandorganochalcogenreagentsaresomeofthemostwidelyused.53
Due to the enormous amount of publications regarding these reactions, only
the latest approaches where molecular halogens (X2) and organochalcogen reagents
(RYYRorRYX)areusedaselectrophilicsourceswillbeconsideredbelow.
Electrophiliccatalyzedcyclizationsusingoxygennucleophiles
The behaviour of COOH or COO groups as internal nucleophile toward
electrophilicallyactivatedalkynesiswellknownsincetheearlyreportonthesynthesis
ofhalolactonesbysuchacyclizationapproachin1981.54Subsequently,severalauthors
have deepened into the usefulness of these nucleophiles to prepare heterocycles
throughelectrophiliccyclization.
Larocks group55 subjected a series of acetylenic acids and esters to
electrophiliccyclizationconditionstogive2(3H)furanonesingoodtoexcellentyields
(Scheme 5.19). They found that the electrophiles I2, ICl and PhSeCl were suitable for
this reaction. In most cases, the use of I2 gave only 4iodo2(3H)furanones, whereas
for some substrates the utilization of ICl afforded mixtures of 4iodo and 4chloro
2(3H)furanones.
258
Chapter5
Scheme5.19.Electrophilic5endodigcyclizationofacetylenicacids.
Some authors have employed this type of cyclization reaction with esters
havinganinternalalkyneinthesynthesisofisocoumarinsandpyranonederivatives.
In2012,Palsgroup56designedalibraryofnovel7iodo4Hthieno[3,2c]pyran
4one derivatives by the regioselective 6endodig iodocyclization of previously
synthesized2alkynylthiopheneesterderivatives(Scheme5.20).Moleculariodinewas
usedaselectrophile.Theproductswereobtainedingoodtohighyields(5880%)and
were subjected to further CC bond forming reactions such as Sonogashira, Heck or
Suzukicouplingreactions.Inaddition,someofthethienopyranonederivativesshowed
promisingselectivegrowthinhibitionofcancercells.
Scheme5.20.Synthesisofpyranonederivativesby6endodigiodocyclization.
Very recently, Reddy and coworkers57 have used OMe and OMOM
(methoxymethyl ether) groups as efficient nucleophiles for the intramolecular
cyclizationofalkynols.Ononehand,theycarriedoutthe6endodigiodocyclizationof
3ethoxy1(2alkoxyphenyl)2ylols to afford various 4substituted 3iodocoumarins.
Theyalsodevelopedthe5endodigiodocyclizationof1alkoxy4ethoxy3yn1,2diols
to give 4,5disubstituted 3iodobutenolides (Scheme 5.21). The reactions were
performed under very mild conditions using I2. A great diversity of substituents was
welltoleratedobtainingthecyclizationproductsingoodtohighyields(5489%).
259
Chapter5
Scheme5.21.Iodocyclizationofalkynolstoprovide3iodocoumarinsand3iodobutenolides.
Various authors have employed oalkynylanisoles for the synthesis of

benzo[b]furans through electrophilic cyclization.58 In 2009, Zenis group59 described
the synthesis of 2halogen and chalcogen benzo[b]furans from 2chalcogen
alkynylanisoles using I2, ICl, Br2 or PhSeBr. More recently, Zhong60 and coworkers
synthesized 3chalcogen benzo[b]furans via the iodinemediated cyclization of 2
alkynylanisoleswithdisulfidesordiselenidesinthepresenceofI2(Scheme5.22).
Scheme5.22.5endodigcyclizationofoalkynylanisolestoprovidebenzo[b]furans.
Thesubstratesemployedforthesynthesisoffuransbyelectrophiliccyclization
of alkynes having an internal nucleophile are diverse. Alcohols, carbonyl compounds
andoxiraneshavedemonstratedtobeefficientnucleophilesinthistypeofreaction.61
63
In2011,Jiangandcoworkers62reportedthepreparationof2,5disubstituted3
iodofurans through the Sonogashira coupling of (Z)bromoenol acetates with

terminal alkynes, followed by intramolecular iodocyclization (Scheme 5.23). The
reactionoccurredthrougha5endodigcyclizationpathway.Thesubstituentsattached
tothetriplebondhadagreatimpactonthesuccessofthereaction.Theobtained3
260
Chapter5
iodofurans were subjected to Sonogashira reaction conditions, providing the desired

couplingproductsinexcellentyields.
Scheme5.23.SynthesisoffuranderivativesbySonogashiraandiodocyclizationreactions.
Isoxazoles can also be synthesized by electrophilic cyclization methodologies

usingalkynoneOmethyloximesassubstrates.64Zenisgroup65hasrecentlycarriedout
the synthesis of 4organoselenylisoxazoles via a 5endodig cyclization reaction
mediatedbyRSeSeR/FeCl3withgoodyields(5070%)(Scheme5.24).
Scheme5.24.Synthesisofisoxazolesviaa5endodigselenocyclization.
Theoxygenatomofanamidegroupcanactasaninternalnucleophiletoward
anactivatedalkyneinordertofurnishcyclicimidates.6668Larock68hasdevelopedthe
Ocyclization reaction of 2(1alkynyl)benzamides using I2 (Scheme 5.25). The
procedure was also extended to other electrophilic sources such as ICl, NBS, PhSeCl
and pNO2C6H4SCl. The reaction proceeded through a 5exodig cyclization mode.
However, the reaction was not totally regioselective and the 6endodig cyclization
productswerealsoobtained.Theutilityoftheproductswasdemonstratedinfurther
couplingreactions.
Scheme5.25.Iodocyclizationof2(1alkynyl)benzamides.
261
Chapter5
Electrophiliccatalyzedcyclizationsusingnitrogennucleophiles
The enormous potential of the indole scaffold in the synthesis of biologically
active species has encouraged many scientists to develop new strategies for its
preparation.69 Electrophilic cyclization of oalkynylanilines via a 5endodig pathway
hasproventobeanefficientapproachinthesynthesisofthisheterocycle.70Inthelast
years,severalauthorshavecarriedoutthiscyclizationreactioninthepreparationof3
chalcogenoindolesusingorganochalcogenreagents(Scheme5.26).71
R2
YR3
R3YCl or R3YYR3
N
R1
R1
Y = Se or S
R2
N
R1
Scheme5.26.Synthesisofindolesbyelectrophilic5endodigcyclizationofoalkynylanilines.
The utility of the electrophilic cyclization of oalkynylanilines has been

demonstrated in a formal synthesis of oxopropaline G. Wangs group72 has
accomplished the synthesis of this natural product in several steps (Scheme 5.27).
Firstly,aSonogashiracouplingreactiongaveaccesstotheappropriateoalkynylaniline
substrate. Afterwards, it was subjected to a 5endodig iodocyclization reaction,
followedbya6exotrigiodocyclization.FurtherdeprotectionoftheNtosylgroupand
oxidationprovidedtheoxopropalineGprecursor.
Scheme5.27.SynthesisofoxopropalineG.
262
Chapter5
Veryrecently,Flynnandcoworkers73havedisclosedthesynthesisofringfused
indoles or quinolines from N(2iodophenyl)imines through the attachment of an
alkyne, followed by cascade cyclization reactions (Scheme 5.28). The use of NIS as
iodonium source led to ringfused 3iodoindoles, whereas the use of I2 gave furano
and pyranofused quinolines. Only when diphenylimines were employed, both
electrophilicsourcesprovidedthesameringfused3iodoindoleproducts.Theauthors
extended this methodology to the synthesis of quinolones by performing acyl
substitutionofWeinrebamideandcyclizationwithNIS.
Scheme5.28.Synthesisofindoles,quinolinesandquinolonesbyiodocyclizationapproaches.
The preparation of isoquinolines through 6endodig cyclization reactions has

beenfulfilledbyvariousauthors.In2011,Wusgroupperformeddifferentcyclization
approaches for the synthesis of isoquinoline derivatives.74,75 Concurrently, Li and co
workers76 reported the PdI2/I2catalyzed 6endodig cyclization of 2alkynylbenzyl
azides with disulfides to afford 4sulfenylisoquinolines (Scheme 5.29). A variety of 2
alkynylbenzyl azides were reacted with numerous disulfides with moderate to high
yields(4686%).However,disulfideswithelectrondeficientarylgroupswereinert.
263
Chapter5
Scheme5.29.Synthesisof4sulfenylisoquinolinesviaaPdI2/I2catalyzed6endodigcyclization
of2alkynylbenzylazideswithdisulfides.
Isoindolinones
and
isoquinolinones
can
be
formed
from
o(1
alkynyl)benzamides through an electrophilic cyclization process. However, the

regioselectivityofthisreactionisnotalwayshigh.Liandcoworkers77havecarriedout
a5exodigiodocyclizationofnitronealkynestoafford1isoindolonesregioselectively.
They proposed a process with formal 1,2oxygen transfer from the nitrogen to the
carbon in the nitrone group which involved the activation of the triple bond by
electrophiliciodonium,followedbynucleophilicadditionoftheoxaziridinenitrogento
give a vinyl iodide species that undergoes scission of the strained oxaziridine ring in
ordertofurnishthefinalproduct(Scheme5.30).
Scheme5.30.Mechanismforthesynthesisof1isoindolones.
Pyridine derivatives are other kind of compounds frequently employed in

electrophiliccyclizationofalkynes.Forexample,Kimsgroup78hasdescribeda5endo
dig iodocyclization of pyridinyl propargylic alcohols and subsequent 1,2Cshift to
provide 2iodoindolizinones in excellent yields (Scheme 5.31). The potential of this
functionalizedheterocyclesasprecursorsforincreasingmolecularcomplexityhasbeen
evaluatedviapalladiumcatalyzedreactions.
264
Chapter5
Scheme5.31.Synthesisof2iodoindolizinonesby5endodigiodocyclizationand1,2shift.
Propargylichydrazonescanundergoelectrophiliccyclizationtoaffordpyrazoles
as reported by Zora and coworkers (Scheme 5.32).79 They have performed the
condensationofhydrazineswithpropargylaldehydesanda5endodigiodocyclization
reactionoftheresultingpropargylichydrazonesproviding4iodopyrazolesingoodto
excellentyields(4095%).ThepresenceofNaHCO3wasrequiredtoobtainthereaction
productinhighyields.
Scheme5.32.Synthesisofpyrazolesviaa5endodigiodocyclizationreactionofpropargylic
hidrazones.
The construction of highly functionalized imidazole derivatives has also been

accomplished using electrophilic cyclization strategies. Liu and coworkers80 have
developed the iodocyclization of benzo[d]imidazoles to provide pyrrole and
piperidine[1,2]benzimidazoles, as well as oxafused benzimidazoles in good to
excellentyields(5594%)(Scheme5.33).Thereactionoccurredviaanexodigpathway.
Theauthorshypothesizethattheadditionofsilvernitrateassiststhereactionbythe
removalofiodineioninthesolutionandpreventsitfromattackingtheactivatedtriple
bondandformingbisiodineproducts.
265
Chapter5
Scheme5.33.Iodocyclizationofbenzo[d]imidazoles.
Very recently, Eyckens group81 has reported a protocol for the formation of
imidazo[1,2]pyrazinone core. This approach is based on a 5exodig iodocyclization
of propynylaminopyrazinones and subsequent oxidation or amination (Scheme 5.34).
Further functionalization of the cyclization products could be afforded under Suzuki
couplingconditions.
Scheme5.34.Iodocyclizationofpropynylaminopyrazinonesandfurtheroxidationor
amination.
Electrophiliccatalyzedcyclizationusingchalcogennucleophiles
Thesynthesisofthiophenesandbenzo[b]thiophenesbyelectrophiliccyclization
hasbeenfulfilledbyLarockandcoworkers.82,83Ononehand,thiopheneshavebeen
furnished by a 5endodig iodocyclization of 1mercapto3yn2ols and dehydrative
aromatization(Scheme5.35).82Thecorresponding3iodothiopheneswereaffordedin
good yields (6588%) in the presence of I2 and NaHCO3. On the other hand, the
synthesis of benzo[b]thiophene derivatives has been performed by 5endodig
cyclizationofoalkynylthioanisolederivatives.83
266
Chapter5
Scheme5.35.Synthesisofthiophenesbya5endodigiodocyclization.
Very recently, Queirozs group84 has disclosed an approach for a threestep

synthesis
of
3halo2(hetero)arylthieno[2,3b]pyridines
and
3halo2
(hetero)arylthieno[3,2b]pyridines. The process started by an initial nucleophilic

aromatic substitution with NaSMe on 3bromo2chloropyridine or 2bromo3
fluoropyridine,followedbyasubsequentSonogashiracouplingreaction.Final5endo
dig cyclization with Br2 or I2 furnished the corresponding 3halo2
(hetero)arylthieno[2,3b]pyridines and 3halo2(hetero)arylthieno[3,2b]pyridines
(Scheme5.36).
Scheme5.36.Synthesisof3alkynyl2(methylthio)pyridinesandsubsequenthalocyclization.
2Alkynylbenzyl chalcogenide derivatives can also undergo electrophilic

cyclizationtoprovideisochalcogenochromenes.Zeniandcoworkers85havepresented
the synthesis of the former 2alkynylbenzyl selenide and sulfide derivatives by
Sonogashira crosscoupling reactions and their subsequent iodocyclization with I2 as
iodonium source (Scheme 5.37). The process occurred in a regioselective manner
througha6endodigcyclizationgiving4iodo3substituted1Hisoselenochromenesor
isothiochromenes,astheonlyreactionproducts.
Scheme5.37.6Endodigcyclizationof2alkynylbenzylselenideandsulfidederivatives.
267
Chapter5
In 2012, the same research group developed two different strategies for the
synthesisofselenophenes86andtetrahydroselenophenes.87Theformerwereprepared
by a 5endodig cyclization of (Z)enynes, employing diorganoyl dichalcogenide
derivatives as electrophilic sources in the presence of FeCl3 (Scheme 5.38). The
methodology was extended to the formation of tellurophenes with moderate yields.
Theantidepressantlikeactivityoftheresulting3organochalcogenchalcogenophenes
wasevaluatedandofferedpromisingresults.Tetrahydroselenophenederivativeswere
obtained from 1butylseleno4alkynes through 5exodig cyclization reactions using
iodinewithgoodtohighyieldsforawiderangeofsubstituents.
Scheme5.38.Synthesisofchalcogenophenesbya5endodigcyclizationof(Z)enynes.
More recently, the same authors described the selective synthesis of 3

iodoimidazochalcogenazoles from Nalkynyl2(organochalcogen)imidazoles via a 5
endodig pathway in the presence of iodine (Scheme 5.39).88 The main advantage of
this approach is the high regioselectivitity with regards to a possible competition as
nucleophilesbetweentheseleniumorsulfurandotheroxygenatomspresentintheR1
groupofthesubstrate,sinceonlythechalcogenheterocycleswerepursued.
Scheme5.39.Synthesisof3iodoimidazochalcogenazolesviaa5endodigcyclizationreaction.
Electrophiliccatalyzedcyclizationsusingcarbonnucleophiles
Halo and chalcocyclizations involving an initial CC bond formation are less
developedthanthosecyclizationsofheteroatomnucleophileswithtetheredalkynes.
As for metaltransition alkyne activation, malonates and related active methyne
268
Chapter5
compounds,arenes,andolefinscanbehaveasnucleophilesandtheearliestandmost
representativeexampleswillbesummarizedherein.
Despite the numerous publications reporting the use of dicarbonylic
compounds as carbonucleophiles, its application in molecular halogen or
organochalcogenmediatedcyclizationswithinternalalkynesisnotbroadlydescribed.
Barluengasgroup89 has carried out a 5endodig cyclization of alkynylketoesters
to provide iodocyclopentenes in good yields using molecular iodine as electrophile
(Scheme 5.40). The synthetic utility of the resulting products was demonstrated in
furtherpalladiumcatalyzedcrosscouplingreactions.
Scheme5.40.Synthesisofiodocyclopentenesthrougha5endodigcyclizationofalkynyl
ketoesters.
A wide variety of heterocycles can be furnished by electrophilic cyclization of

alkynescontainingneighboringarenes.Someauthorshaveemployedthisapproachin
thesynthesisofquinolinesstartingfrompropargylicanilines.Larockandcoworkers90
havereportedthesynthesisof3halogen,seleniumandsulfurcontainingquinolines
bya6endodigcyclizationofN(2alkynyl)anilinesusingICl,I2,Br2,PhSeBrandArSClas
electrophilic sources (Scheme 5.41). A wide range of functional groups were well
tolerated, obtaining the desired products in moderate to good yields. Iodoquinolines
were converted to functionallysubstituted quinolines through palladiumcoupling
reactions.
Scheme5.41.6endodigcyclizationofN(2alkynyl)anilinestoobtainfunctionalized
quinolines.
269
Chapter5
Later, Vermas group91 carried out the preparation of 5iodopyrrolo[1,2

]quinolines and indolo[1,2]quinolines via regioselective 6endodig cyclization
reactionsmediatedbyiodineinthepresenceofNaHCO3.Thistransformationallowed
the accommodation of various functional groups in the quinoline nucleus with
moderatetoexcellentyields.
Scheme5.42.6endodigcyclizationofindolo[1,2]quinolines.
More complex cyclic structures have also been achieved by electrophilic

cyclizations.Forexample,theformationofheterocycletetheredspirocompoundshas
been fulfilled by the iodinemediated ipsocyclization reaction of NalkylNaryl
phenylpropiolamides via a 5endodig mode (Scheme 5.43).92 This approach allowed
the synthesis of azaspiro compounds tethered with coumarin, quinolone and
pyrimidineheterocyclicmotifsinexcellentyields(8492%).
Scheme5.43.Synthesisofazaspirocompoundsby5endodigcyclizationreactions.
270
Chapter5
In 2012, Nagarajan and coworkers93 described the synthesis of

pyranocarbazole derivatives from Opropargylated carbazoles by an iodocyclization
reaction (Scheme 5.44). Although the reaction proceeded through a 6endodig
pathway, the utilization of 9ethyl1,4dimethyl3(3(4ptolylprop2ynyloxy)9H
carbazoleexclusivelyledtothecompeting5exodigcyclizationproduct,givingaccess
tofurocarbazolederivatives.
Scheme5.44.Synthesisofpyranocarbazolederivativesby6endodigcyclizations.
Morerecently,Kesharwanisgroup94hasaccomplishedthesynthesisofpyrrolo
[2,1j]quinolone derivatives from N(alkynoyl)6methoxytetrahydroquinoline in good
yields.Thereactionoccurredviaa5endodigmechanismasdepictedinScheme5.45.
Iodinewassuccessfullyemployedaselectrophilicsource,whereasNISpoorlyyielded
thedesiredproducts.ThecyclizationwithBr2andNBSfailedforunknownreasons.
Scheme5.45.Mechanismforthe5endodigiodocyclizationofN(alkynoyl)6
methoxytetrahydroquinoline.
Not only heterocyclic compounds have been synthesized by electrophilic

cyclization reactions using arenes as nucleophiles, but also carbocycles have been
successfully formed using this type of nucleophile, as reported by Zhang and co
workers.95 They have described the palladiumcatalyzed iodinemediated 6endodig
271
Chapter5
cyclization of 2(1alkynyl)biphenyls using disulfides as electrophiles. Iodine could

promote the formation of 9sulfenyl phenanthrenes without PdCl2. However, only
whenbothspecieswereemployedhighyieldswereafforded.Theauthorsencloseda
plausiblemechanismexplainingthisevidence(Scheme5.46).
Scheme5.46.Twoplausiblepathwaysforthe6endodigcyclizationof2(1alkynyl)biphenyls.
The utilization of olefins as internal carbon nucleophiles in halogen and

chalcogenmediated cyclization reactions is also a powerful tool in the synthesis of
functionalizedcarbocycles.Nevertheless,thisapproachisnotbroadlydeveloped.
In 2010, Kirschs group96 performed the iodocyclization of 1,5enynes to
provide sixmembered cyclic products such as benzenes, 1,4cyclohexadienes and 4
fluorocyclohexenes using NIS, I2 and IPy2BF4, respectively (Scheme 5.47). The
proceduretoleratesdiversefunctionalgroups.However,theintroductionofatethered
carboxylicacidintheenynestructureleadstotheiodolactonizationproduct.
272
Chapter5
Scheme5.47.Iodocyclizationof1,5enynesusingdifferentiodoniumsources.
Perumals group97 has achieved the synthesis of 9(1iodovinyl) acridin1(2H)

one by a cascade transformation of 2aminophenyl propynyl oxyenone. The reaction
involvesa6endodigiodocyclizationandintramolecularcondensationfollowedby3,3
sigmatropicrearrangementtogivethefinalproductsingoodyields(5068%)(Scheme
5.48). Iodine is employed as iodonium source. Br2, NBS or PhI(OAc)2 resulted
ineffective.
Scheme5.48.Mechanismforthesynthesisof9(1iodovinyl)acridin1(2H)onefrom2
aminophenylpropynyloxyenone.
273
Chapter5
5.1.2.Synthesisofcycliccarbamatesbyelectrophiliccyclizationof
alkynes
Carbamates represent an important class of compounds with interesting
properties and have found wide utility in several areas, such as pharmaceuticals or
agrochemicals.98 Cyclic carbamates, although less known, have been used as chiral
auxiliaries99andbesidespresentinterestingbiologicalactivity.100Thereareavarietyof
methods forthesynthesisofthiskindofcompoundsfromdifferentstartingmaterials,
suchasalkenylamidesandcarbamates,aminoalcoholderivativesoraziridines.101105
Howeverthedevelopmentofpracticalandefficientapproachesforthepreparationof
these cyclic carbamates, especially those densely functionalized, is still of great
interest.
Carbamates containing an alkynyl group in an appropriate position may also
undergoanelectrophiliccyclizationleadingtocycliccarbamates.Thisstrategyleadsto
5membered cyclic carbamates, known as oxazolidinones, or 6membered cyclic
carbamates,knownasoxazinonesdependingontheregioselectivityofthereaction.In
spite of the apparent easiness and advantages of this approach, it has been rarely
pursued.
In1991,Muraisgroup106describedthe5exodigregioselectivesynthesisof4
alkylideneoxazolidinones having an Ntosyl group in good yields starting from
propargylicalcohol and ptoluenesulfonyl isocyanatein the presenceof CuI and Et3N
(Scheme5.49).IntheabsenceofCuIascatalyst,onlysimpleadditionreactiontogive
an acyclic carbamate was observed. 3substituted propargyl alcohol derivatives (R1 =
Me)requiredhighertemperaturestoaffordthecycliccarbamates.
Scheme5.49.Synthesisof4alkylideneoxazolidinonesby5exodigcyclization.
274
Chapter5
Tamaru and coworkers107,108 have reported the 5exodig cyclization of 2

propynyl tosylcarbamates catalyzed by CuCl/Et3N or AgNCO/Et3N to furnish 4
methylene2oxazolidinones in good yields (Scheme 5.49). When they performedthe
cyclization of the Nacyl derivatives, AgNCO and tBuOK were most effective as
catalysts.Ontheotherhand,Ntosylderivativesof3butynylcarbamatesunderwenta
6exodig cyclization to give 4methylenetetrahydro1,3oxazin2ones using
AgNCO/Et3NorAgNCO/tBuOKascatalyst.
Scheme5.50.Synthesisofcycliccarbamatesbyexodigcyclizationapproaches.
In2000,LuandLei109developedtheregioselectivesynthesisofoxazolidinones
from Ntosyl carbamates and ,unsaturated carbonyl compounds catalyzed by
Pd(OAc)2(Scheme5.51).Thereactionoccuredthroughatandemintramolecular5exo
cyclization to afford an (E)vinylpalladium intermediate (aminopalladation), followed
byolefininsertionandprotonolysisofthecarbonpalladiumbond.Theprocedurewas
extensiveforthepreparationofimidazolidinonesandlactams.
Scheme5.51.Regioselectivesynthesisofoxazolidinones,imidazolidinonesandlactams.
In 2006, Schmalz110 accomplished the 5exodig cyclization of Opropargyl

carbamates to give differently substituted oxazolidinones in moderate to high yields
275
Chapter5
(Scheme5.52).AlkynewasactivatedbyAu(I)andthereactionprovedtobeeffectivein
thepresenceofabasesuchasEt3NortBuOK.
Scheme5.52.Synthesisofoxazolidinonesby5exodigcyclizationofOpropargylcarbamates.
Concurrently, Carretero111 accomplished the synthesis of alkylidene 2

oxazolidinonesand1,3oxazin2onesbytheAu(I)catalyzedcyclizationreactionofthe
NBocderivativeofpropargylaminesand3butyn1amines,respectively.Thereaction
proceededinaregioselectivemannerthrougha5exodigand6exodigpathway.This
procedure provided the corresponding cyclic carbamates with good to high yields
regardlessthesubstitutionatnitrogenandthealkynemoiety.
Scheme5.53.Synthesisofoxazolidinoneandoxazinonederivativesby5exodigand6exodig
cyclizations,respectively.
Cyclic carbamates can also be synthesized by the incorporation of CO2 to

amines followed by a cyclization process as reported by Yamada and coworkers
(Scheme 5.54).112 They have recently prepared benzoxazine2one derivatives by the
reaction of oalkynylanilines with CO2 catalyzed by silver salts in good to excellent
yields. The cyclization occurred through a 6exodig pathway and only Z exoolefins
wereobtained.
276
Chapter5
Scheme5.54.Synthesisofbenzoxazine2onederivativesbyincorporationofCO2too
alkynylanilinesand6exodigcyclizationreaction.
277
Chapter5
5.2.OBJECTIVES
On the basis of the early reported results on halo and chalcoderivatives of
heterocyclesbyelectrophiliccyclizationofalkynesconvenientlyfunctionalized,NCbz
protected propargylic amines must be suitable substrates for the synthesis of cyclic
carbamates such as 1,3oxazin2ones or oxazolidin2ones through an Ocyclization
process.
For this reason, the main objective of this chapter is to develop a convenient
approachfortheregioselectivesynthesisofhighlyfunctionalized1,3oxazin2onesby
electrophiliccyclizationofNCbzprotectedpropargylicamines.
Thefollowingaspectswillbeconsideredinthisstudy:
Regioselective halogenmediated cyclization of NCbzprotected propargylic
amines.Synthesisof5halo1,3oxazin2ones.
1. Identification of the optimal reaction conditions: Influence of the solvent,
baseandtemperatureontheyieldofthereaction.
2. Identification of the optimal reaction conditions: Influence of different
protectinggroupsontheyieldofthereaction.
3. Scope and limitations of the reaction: evaluation of NCbzprotected
propargylic amines derived from aromatic and aliphatic aldehydes and

alkynesinthecyclizationwithiodine,bromineandchlorine.
279
Chapter5
4. Structure elucidation of the halocyclization products by means of Xray
diffractionanalysisand13CNMRspectroscopicstudies.
5. Computational study of the regioselective halocyclization of Nprotected
propargylicamines.
Regioselective chalcogenmediated cyclization of NCbzprotected propargylic
amines.Synthesisof5phenylchalco1,3oxazin2ones.
6. Identificationoftheoptimalreactionconditions.
7. Scope and limitations of the reaction: evaluation of NCbzprotected
propargylic amines derived from aromatic and aliphatic aldehydes and

alkynesinthecyclization.
8. Structure elucidation of the cyclization products by means of Xray
diffractionanalysisand13CNMRspectroscopicstudies.
9. Computational study of the regioselective cyclization of Nprotected
propargylicamineswithphenylselenylchloride.
280
Chapter5
5.3.RESULTSANDDISCUSSION
5.3.1. Regioselective halogenmediated cyclization of NCbz
protectedpropargylicamines.Synthesisof5halo1,3oxazin2ones
The starting chiral NCbzprotected propargylic amines were readily available
bytheenantioselectivealkynylationofiminesgeneratedinsitufromamidosulfones
aspreviouslydescribedinChapter3.
Inordertodeterminethegeneralconditionsforthehalocyclizationreactionof
NCbz propargylic amines 11, NCbz1,3diphenylprop2yn1amine 11aa was
subjectedtoiodocyclizationconditionsinthepresenceofiodineaselectrophilicsource
and NaHCO3 in dichloromethane at rt, such as is described for the iodocyclization of
severalfunctionalizedalkynes.82,91
Table 5.1. Screening of reaction conditions for the iodocyclization of NCbzprotected
propargylicamines11aa.a
Entry
E(Equiv)
Solvent
Base
T(C)
t(h)
Yield(%)b
I2(2)
CH2Cl2
NaHCO3
rt
12
67
I2(2)
CH2Cl2
NaOH
rt
24
I2(2)
CH2Cl2
NaHCO3
16
75
I2(2)
CH2Cl2
15
74
I2(2)
CH3CN
18
82
I2(1.5)
CH3CN
20
71
NIS(2)
CH3CN
10
n.d.c
11aa(0.1mmol)in2.5mLofsolvent.bYieldofisolatedproduct.cNotdetermined.
281
Chapter5
Intheseconditionsweobtainedthecorrespondingiodinated1,3oxazin2one
(33aa)astheonlyisolatedproduct(67%yield)(Table5.1,Entry1).TheuseofNaOH
failed to afford the cyclization product and the starting material was recovered. We
then continued the optimization process with NaHCO3 at 0 C, obtaining the desired
productwithabetteryield(75%).Interestingly,wefoundthatthepresenceofabase
was not required to afford the cyclization product in our reaction as it reached
completion in 74% yield. With regard to the solvent, the utilization of acetonitrile
insteadofdichloromethaneledtoahigheryield(82%).Wealsostudiedtheinfluence
of the amount of the electrophilic source. It was observed that reducing the
equivalentsofiodinefrom2to1.5decreasedtheyieldsignificantly.Itisworthnoting
thatNiodosuccinimideasaniodoniumsourceresultedinefficientinthisreaction.
Thus, this brief optimization process revealed that the best result for the
iodocyclization of NCbz1,3diphenylprop2yn1amine (11aa) was obtained with
iodine(2equiv)inacetonitrileat0CandabsenceofNaHCO3(82%yield).
Finally, the influence of the protecting group was examined. NBoc and N
ethyloxycarbonylprotected propargylic amines were submitted to the optimized
conditions. However, not only did they require higher temperatures, but also longer
reactiontimes,providingthecyclizationproductsinmoderateyields.
Table 5.2. Screening of protecting groups for the iodocyclization of Nprotected
1,3diphenylprop2yn1amines.a
Entry
Amine
PG
T(C)
t(h)
Yield(%)b
11aa
Cbz
18
82
12aa
Boc
rt
96
56
13aa
COOEt
rt
96
49
0.1mmolofstartingmaterialin2.5mLofacetonitrile. Yieldofisolatedproduct.
282
Chapter5
IodocyclizationreactionofNCbzprotectedpropargylicamines
TheoptimizedconditionswereappliedtotheiodocyclizationofseveralNCbz
protected propargylic amines 11 derived from the addition of phenylacetylene to
imines of substituted benzaldehydes giving the corresponding 5iodo1,3oxazin2
ones33ingoodtoexcellentresults(Table5.3,Entries14).
Table 5.3. Electrophilic cyclization of NCbzprotected propargylic amines 11 to 5iodo1,3
oxazin2ones33.a
Entry
11
R1
R2
t(h)
Product Yield(%)b
11aa
Ph
Ph
18
33aa
82
11ba
4MeC6H4
Ph
24
33ba
94
11ea
4ClC6H4
Ph
30
33ea
76
11ha
2MeC6H4
Ph
24
33ha
94
11qa
C6H5CH2CH2
Ph
20
33qa
70
11ra
nbutyl
Ph
33ra
45
11sa
cyclohexyl
Ph
33sa
94
11ab
Ph
4MeOC6H4
33ab
91
11ad
Ph
4FC6H4
18
33ad
98
10
11af
Ph
2MeOC6H4
33af
93
11
11ag
Ph
3,5(MeO)2C6H3 52
33ag
97
12
11ai
Ph
2thienyl
33ai
98
13
11ak
Ph
C6H5CH2CH2
30
33ak
97
14
11am
Ph
tertbutyl
24
33am
65
11(0.1mmol),iodine(0.2mmol)in2.5mLofacetonitrile. Yieldofisolatedproduct.
283
Chapter5
Both electrondonating (Me) and electronwithdrawing (Cl) substituents in

ortho and para positions were well tolerated, with yields ranging from 76 to 94%
(Table 5.3, Entries 24). On the other hand, the iodocyclization of NCbzprotected
propargylic amines 11 derived from alkylsubstituted imines gave the corresponding
productsinvariableyields(Table5.3,entries57).Whereasthecyclohexylsubstituted
starting material 11sa afforded the iodocyclization product 33sa with excellent yield
(Table 5.3, Entry 7), 2phenylethylsubstituted 11qa and the nbutylsubstituted 11ra
gavemoderateyields(70and45%,respectively)(Table5.3,Entries56).
Then we examined the reactivity of various Cbzprotected propargylic amines
11 bearing different aromatic, heteroaromatic and aliphatic groups attached to the
alkyne moiety, affording the corresponding products 33 in excellent yields in most
cases (Table 5.3, Entries 814). The reaction is not sensitive to electronic and steric
effectsofthesubstituentsinthearomaticringtetheredtothealkyne,asobservedin
Entries 811. In addition, heteroaromatic substituent 2thienyl gave excellent yields
(Table 5.3, Entry 12). The NCbzprotected propargylic amine derived from the
aliphatic alkyne 4phenyl1butyne furnished the corresponding 5iodo1,3oxazin2
one33akinexcellentyield(97%)(Table5.3,Entry13),whereasthepropargylicamine
bearingatertbutylgroupattachedtothealkynegavethedesiredproduct33amina
moderateyield(65%)(Table5.3,Entry14).
Inordertoestablishthestructureofthecyclizationreactionproducts,33afand
33ai were submitted to an Xray diffraction analysis (Figure 5.2). They allowed us to
establish the structure of 1,3oxazin2one (6membered ring) instead of 1,3
oxazolidinone (5membered ring) and to confirm the absolute configuration of the
stereogeniccenterofbothproducts.
284
Chapter5
O
H
HN
OMe
O
I
33af
O
H
HN
I
33ai
FFigure5.2.a)Xraystructtureof33af.b)Xraystru
uctureof33aai.
Moreoveer, to ensure that all tthe iodocycclization reactions prooceeded viaa a 6

endo
odig cyclization pathway, we ccarried outt a compa
arative NM
MR spectrosscopy
analyysis of the characterisstic signals of the obttained 5iod
do1,3oxazzin2ones 33.
3 In
particular, we compared the 13C NM
MR signals of the fou
ur carbon aatoms in the 6
mem
mberedringcontainingthecyclicccarbamate((Table5.4).
oupresonattesat149
9150ppm((whenR1isaromatic)aand
So,theccarbonylgro
151152 ppm (w
when R1 is aliphatic); the quaterrnary olefin
nic =CO givves a signal at
148150ppm;thequaternaaryolefinic IC=appearsathighfieldat6972ppman
ndthe
CH aappears at
6065 ppm. This conncordance in the signa
als was an evidence of
o the
form
mation of 6membered
d ring 5ioddo1,3oxazin2ones by
b a 6endoodig cyclizzation
mech
hanisminallcases.
285
Chapter5
Table 5.4. 13C NMR signals of the four carbon atoms in the 6memberedring containing the
cycliccarbamate.
Entry
33
R1
R2
C=O
=CO
33aa Ph
Ph
149.56
149.02 71.33
65.05
33ba 4MeC6H4
Ph
149.43
148.89 71.72
64.85
33ea 4ClC6H4
Ph
149.60
149.20 70.70
64.50
33ha 2MeC6H4
Ph
149.34
149.16 71.10
61.59
33qa C6H5CH2CH2
Ph
151.52
150.05 70.31
65.14
33ra nbutyl
Ph
151.72
149.76 71.75
60.78
33sa cyclohexyl
Ph
150.92
149.75 70.81
59.91
33ab Ph
4MeOC6H4
149.61
148.79 70.35
65.12
33ad Ph
4FC6H4
149.29
148.13 71.58
65.08
10
33af Ph
2MeOC6H4
149.61
148.08 74.40
64.54
11
33ag Ph
3,5(MeO)2C6H3 149.30
148.83 71.34
65.13
12
33ai Ph
2thienyl
149.03
143.85 69.63
65.67
13
33ak Ph
C6H5CH2CH2
149.16
150.16 71.75
64.00
14
33am Ph
tertbutyl
149.66
155.33 a
66.00
Notobserved.
286
(ppm)
IC=
CH
Chapter5
BromocyclizationreactionofNCbzprotectedpropargylicamines
Once we had studied the scope of the cyclization of NCbzprotected
propargylic amines 11 with iodine as electrophilic source, we broadened our
investigationtotheuseofbromine.
When we applied the optimized conditions for the iodocyclization to the
reaction between NCbz1,3diphenylprop2yn1amine (11aa) and bromine in
acetonitrileat0C,ashorterreactiontimewasrequired,butbesidesto3,4dihydro5
bromo1,3oxazin2one 34aa corresponding to the cyclization process, a second
product39wasobserved,probablyresultingfromasimpleadditionofbrominetothe
triple bond (Scheme 5.55). However, to our delight, in the presence of only 1.2
equivalentsofbromine(insteadof2equiv)andusingamoredilutedreactionmixture
(1/5) this secondary addition reaction was completely avoided and the
bromocyclization product 34aa was obtained with good yield (93%) (Table 5.5, Entry
1).
Scheme5.55.ReactionbetweenNCbz1,3diphenylprop2yn1amine(11aa)andBr2under
theoptimizedconditionsfortheiodocyclizationreaction.
Thereactionscopewasthenexploredunderthenewoptimizedconditionsfor
thebromocyclization.Thereactionhasprovedtobeageneralroutetoavarietyof3,4
dihydro5bromo1,3oxazin2ones34(Table5.5,Entries28).Bothelectrondonating
(Me) and electronwithdrawing (Cl) substituents in ortho and para positions of the
aromaticringofthebenzaldehydedeliveredthecyclizationproductsinhighyields(79
82%)(Table5.5,Entries24).Cyclohexylsubstitutedpropargylicamine11sagavethe
corresponding5bromo1,3oxazin2one34sainexcellentyield(91%)(Table5.5,Entry
5).Finally,theutilizationofstartingmaterialswitharomaticaswellasaliphaticgroups
287
Chapter5
attached to the alkyne provided the cyclization products in high yields (Table 5.5,
Entries68).
Table 5.5. Electrophilic cyclization of NCbzprotected propargylic amines 11 to 5bromo
1,3oxazin2ones34.a
Entry
11
t(h)
Product Yield(%)b
1c
11aa Ph
Ph
0.3
34aa
72
11aa Ph
Ph
0.5
34aa
93
11ea 4ClC6H4
Ph
0.3
34ea
82
11ha 2MeC6H4
Ph
0.5
34ha
79
11sa cyclohexyl
Ph
34sa
91
11ad Ph
4FC6H4
0.5
34ad
80
11ae Ph
4ClC6H4
0.5
34ae
86
11ak Ph
C6H5CH2CH2
34ak
80
11(0.1mmol),bromine(0.12mmol)in12.5mLofacetonitrile. Yieldofisolatedproduct.
2.5mLinsteadof12.5mLofacetonitrile.
288
Chapter5
Thestructuralcharacterizationofproducts34wascarriedoutbyspectroscopic
methods. As in the iodinated products, the four carbon atoms in the brominated 6
memberedringcontainingcycliccarbamategivecharacteristicsignals(Table5.6).The
carbonylgroupresonatesat149151ppm;thequaternaryolefinic=COgivesasignal
at 145148 ppm; the quaternary olefinic BrC= appears at 9799 and the CH
appearsat5863ppm.
cycliccarbamate.
(ppm)
Entry
34
R1
R2
C=O
=CO
34aa
Ph
Ph
149.29
146.18 98.30
62.27
34ea
4ClC6H4
Ph
149.30
146.46 97.81
61.60
34ha
2MeC6H4
Ph
149.20
146.42 98.16
58.87
34sa
Cyclohexyl
Ph
151.04
147.16 97.74
62.68
34ad
Ph
4FC6H4
149.16
145.32 98.42
62.25
34ae
Ph
4ClC6H4
149.25
145.12 98.84
62.22
34ak
Ph
C6H5CH2CH2
149.47
148.33 98.72
61.77
IC=
CH
ChlorocyclizationreactionofNCbzprotectedpropargylicamines
Finally, the chlorocyclization reaction of several NCbzprotected propargylic
amines 11 was carried out with chlorine in acetonitrile (Table 5.7). Due to the
formationofthedichlorinatedproductat0C,thereactionwasperformedat20C.
Under these new conditions, the yield of the competing product was significantly
289
Chapter5
reduced and the chlorocyclization products 35 were obtained with moderate yields
(5060%),regardlesstheelectronicnatureofthesubstituents.
Table5.7.ChlorocyclizationofNCbzprotectedpropargylicamines11to5chloro1,3oxazin
2ones35.a
Entry
11
R1
R2
t(h)
Product Yield(%)b
11aa
Ph
Ph
0.15
35aa
62
11ba
4MeC6H4
Ph
0.15
35ba
50
11qa
C6H5CH2CH2
Ph
0.15
35qa
61
11ab
Ph
4MeOC6H4
0.15
35ab
59
11(0.1mmol)andchlorine(0.12mmol)12.5mLofacetonitrile.bYieldofisolatedproduct.
The structural characterization of products 35 was also carried out by

spectroscopic methods. As in the iodinated and brominated analogues, the four
carbon atoms in the chlorinated 6memberedring containing cyclic carbamate give
characteristicsignals.Thecarbonylgroupresonatesat149151ppm;thequaternary
olefinic=COgivesasignalat144146ppm;thequaternaryolefinicClC=appearsat
107109andtheCHresonatesat5661ppm.
290
Chapter5
cycliccarbamate.
(ppm)
Entry
35
R1
R2
C=O
=CO
35aa Ph
Ph
149.01
144.85 108.90
60.39
35ba 4MeC6H4
Ph
149.02
144.62 109.12
60.73
35qa C6H5CH2CH2
Ph
150.45
145.38 108.87
56.00
35ab Ph
4MeOC6H4
149.34
144.53 107.65
60.90
IC=
CH
5.3.1.3. Theoretical calculations of the bromo and chlorocyclization

reactionsofprotectedpropargylicamines
In order to understand the mechanism of the regioselective halocyclization
reactionsofprotectedpropargylicamines11toyieldthecorresponding6membered
5halo1,3oxazin2ones3335,acomputationalstudyusingdensityfunctionaltheory
(DFT) methods at the B3LYP/6311G* level was carried out (Scheme 5.56). In this
theoretical study, the R1 group and the benzyl one present in NCbzprotected
propargylicamines11weremodelledbymethylgroups.
291
Chapter5
Scheme5.56.Twopossibleregioisomericchannels,6endodigand5exodigpathway,forthe
halocyclizationof11tatoafford1,3oxazin2ones3435or1,3oxazolidin2ones4041.
Startingfromtheprotectedpropargylicamine11ta,ananalysisofthepotential
energysurfaceforthetitlereactionsindicatesthatthesehalogenpromotedcyclization
reactionstakeplacethroughatwostepmechanismwhichcanundergoviaa6endo
dig or 5exodig pathway. In the first step, the halogen molecule X2 electrophilically
attacksontheC1orC2carbonofthetriplebondofthesepropargylicaminestogive
the cationic intermediates IN1endoX or IN1exoX, via the corresponding transition
states TS1endoX or TS1exoX, respectively. In the second step, the methyl group
present in the carbamate substituent is eliminated in these cationic intermediates
assistedbythehalideanionXyieldingthefinal1,3oxazin2ones3435oroxazolidin
2ones4041(Scheme5.56).
ForthereactioninthepresenceofbromineBr2thetworegioisomericchannels
were studied, while for the reaction in the presence of chlorine Cl2 only the most
favourable channel, 6endodig pathway, yielding 6membered 1,3oxazin2one 35ta
wasconsidered.
Relativeenergiesingasphaseaswellasinacetonitrilewerecalculatedforeach
species.However,sincesomespeciesinvolvedinthereactionsarecharged,theenergy
discussionwillbedoneusingtherelativeenergiesinacetonitrile(Table5.9).
292
Chapter5
Table 5.9. Relative energies in acetonitrile (in kcal/mol, relative to

11ta plus halogen X2) of the stationary points involved in the
halocyclizationsof11ta.
Bromocyclizationof11ta
MC1Br
1.0
Chlorocyclizationof11ta
MC1Cl
TS1endoBr
0.5
TS1endoCl
TS1exoBr
8.4
IN1endoBr
20.0
IN1endoCl
IN1exoBr
19.4
TS2endoBr
7.3
TS2endoCl
TS2exoBr
8.5
34ta+MeBr
28.6
35ta+MeCl
40ta+MeBr
31.8
1.2
12.8
41.3
29.1
51.4
Cyclizationof11tainthepresenceofbromine
In an earlier step of the reaction, Br2 forms a weak molecular complex (MC)
withthesystemofthetriplebondofpropargylicamine11ta(Figure5.3).ThisMCis
located1.0kcal/mol(MC1Br)belowtheseparatedreagents.Theactivationenergies
associatedwiththeelectrophilicattacksofBr2ontheC2andC1carbonsofpropargylic
amine 11ta are 0.5 (TS1endoBr) and 8.4 kcal/mol (TS1exoBr). Formation of the
correspondingcationicintermediatesareexothermicby20.0(IN1endoBr)and19.4
kcal/mol (IN1exoBr). Elimination of the methyl group from these cationic
intermediates takes place through a bimolecular nucleophilic substitution in the
methyl group assisted by the bromide anion Br generated in the first step of the
reaction. From the corresponding intermediates, the activation energies associated
withtheextrusionofthemethylgroupare12.7(TS2endoBr)and10.9kcal/mol(TS2
exoBr). Formation of 34ta and 40ta plus MeBr is exothermic by 28.6 and 31.8
kcal/mol,respectively.
293
Chapter5
Fromtheseenergyresultssomerelevantconclusionscanbedrawn:
1. Theelectrophilicattackofbromineonthetriplebondofpropargylicamine
11taiscompletelyregioselective,TS1endoBrbeing7.9kcal/mollowerin
energythanTS1exoBr.
2. Thehighexothermiccharacterofthefirststepmakesthisstepirreversible.
3. The activation energy associated with the second step is higher than that
associatedwithfirststep;thus,theeliminationofthemethylsubstituentis
the ratedetermining step (RDS) of the reaction. Consequently, while the
electrophilic attack of bromine against propargylic amine 11ta is the
regioselectivitydeterminingstep,themethyleliminationistheRDSofthe
reaction.
E(kcal/mol)
20
15
Me
Me
Ph
Br
10
Br
6endodigbromocyclization
5exodigbromocyclization
Br
Me
8.4
O
H
0.5
0
O
H
10
1
Me
O
H
O
Me
Br
Br
Ph
Ph
Br
7.3
Ph
8.5
Me
15
Me
Br
Me
Me
Br
Br
Br
Ph
Me
19.4
Br
20
20 H
25
O
H
30
Me
Me
O
Me
35
Me
Br
Ph
Br
Ph
28.6
31.8
Br
40
45
50
55
11ta+Br2MCTS1IN1TS234at/40at+MeBr
0,5
1,5
2,5
3,5
4,5
5,5
6,5
Figure5.3.Relativeenergiesinacetonitrile(inkcal/mol,relativeto11taplushalogenBr2)of
thestationarypointsinvolvedinthebromocyclizationof11ta.
294
Chapter5
The geo
ometries of the TSs a nd INs invvolved in th
he regioisoomeric path
hways
assocciated with
h the bromocyclizationn of phenyl propargylic amine 111ta are givven in
Figurre5.4.
a)
TS1endo
oBr
IN1endoBrr
TS22endoBr
TS1exo
oBr
IN1exoBr
TS22exoBr
b)
Figu
ure5.4.Geo
ometriesofth
heTSsandIN
Nsinvolvediintheregioissomericchannnelsassocia
ated
withthebromineemediatedccyclizationoffprotectedp
propargylica
amine11ta.TThelengthso
ofthe
forminggandbreakinngbondsare
egiveninAng
gstroms.
At the TSs
T associatted with th e first step
p of the bro
omocyclizattion processs the
lengtths of the Br6C2(1) and O3C 1(2) formin
ng bonds are
a 2.180 and 2.8
867
respeectivelyatTTS1endoB
Brand2.2477and2.19
93respecctivelyatTSS1exoBr.A
Atthe
295
Chapter5
correspondingintermediatesIN1endoBrandIN1exoBrthelengthsoftheBr6C2(1)
and O3C1(2) bonds are 1.910 and 1.440 , and 1.931 and 1.431 , respectively.
These geometrical parameters indicate that at the most favourable TS1endoBr, the
Br6C2 bond formation is very advanced, while the O3C1 bond formation is rather
delayed. At the most unfavourable TS1exoBr, the O3C2 bond formation is more
advanced than the O3C1 bond at TS1endoBr, showing a more synchronous bond
formationprocess.IngasphasethelengthsofBr6C2(1)andO3C1(2)formingbonds
are2.156and1.806atTS1endoBrand2.214and1.760atTS1exoBr,indicating
thatbothbondformationprocessesarecoupled.Consequently,polarsolventeffects
changethemechanismofthefirststepofthemostfavourablereactivechannelfroma
synchronousBr6C2andO3C1bondformationingasphasetoahighlyasynchronous
process in acetonitrile. This change of mechanism can be understood as a strong
stabilizationofbothbromineanionBrandtheincipientbenzylcarbocationicC1centre
atTS1endoBrinpolarsolventacetonitrile.
AttheTSsassociatedwiththeeliminationofthemethylgroupinIN1endoBr
andIN1exoBr,thelengthsoftheO4C5breakingbondandtheC5Br7formingbond
are1.908and2.600respectivelyatTS2endoBrand1.887and2.624atTS2exo
Br, respectively. In these asynchronous TSs, the O4C5 breaking bonds are more
advancedthantheC5Br7formingbond.
Cyclizationof11tainthepresenceofchlorine
For the reaction of 11ta in presence of chlorine, Cl2 forms a weak molecular
complex(MC)withthesystemofthetriplebondofpropargylicamine11ta.ThisMC
is located 1.2 kcal/mol (MC1Cl) below the separated reagents. TS1endoCl
associated with the electrophilic attack of Cl2 on the C2 carbon of propargylic amine
11ta is located 12.8 kcal/mol below the separated reagents. Formation of the 1,3
oxazin intermediate IN1endoCl is strongly exothermic by 41.3 kcal/mol. The
activationenergyassociatedwiththeeliminationofthemethylgroupinintermediate
IN1endoClviaTS2endoClis12.2kcal/mol,theoverallprocessisexothermicby51.4
kcal/mol. The fact that TS1endoCl is located below the separated reagents is a
consequence of the strong solvation of chloride anion Cl, which develops along the
296
Chapter5
electrophilic attack. It is worth noting that in gas phase TS1endoCl is located 9.5
kcal/molabovethereagents.AcomparisonofrelativeenergiesoftheTSsassociated
withtheelectrophilicattacksofhalogensBr2orCl2onpropargylicamine11ta,ingas
phaseandinacetonitrile,indicatesthattheadditionofCl2tothesepropargylicamines
E(kcal/mol)
isfavouredovertheadditionofBr2.
20
6endodig bromocyclization
6endodig chlorocyclization
15
10
5
0
5
00
O
H
10
Me
1.2
O Cl
Cl
O
H
1 Ph
Me
Me
15
0.5
12.8
Cl
20
7.3
Me
Ph
O
Cl
H
25
Me
20
Me
30
Cl
29.1
Ph
28.6
Cl
Cl
Me
35
O
H
41.3
40
45
50
O
Ph
Me Me
Cl
O
Me
Cl
Ph
51.4
Cl
55
0,511ta +Cl2 1,5
MCTS1IN1TS235at
+MeCl 6,5
2,5
3,5
4,5
5,5
Figure5.5.Relativeenergiesinacetonitrile(inkcal/mol,relativeto11taplushalogenCl2)of
thestationarypointsinvolvedinthebromocyclizationof11ta.
ThegeometriesoftheTSsandINinvolvedintheregioisomericchannel,6endo
digcyclization,associatedwiththereactionpromotedbychlorinearegiveninFigure
5.6.
At the most favourable TS1endoCl, associated with the first step of the
chlorine promoted cyclization process, the lengths of the Cl6C2 and O3C1 forming
bonds are 1.771 and 2.752 . At TS1endoCl, the Cl6C2 bond formation is more
297
Chapter5
advanced than the Br6C

C2 bond fformation at
a TS1end
doBr. At tthe TS2en
ndoCl
assocciatedwiththeeliminaationoftheemethylgrroupinIN1endoCl,thhelengthso
ofthe
O4C
C5 breakingg bond an
nd the C5Cl7 formin
ng bond arre 1.913
and 2.44
42 ,
respeectively. In these asyn
nchronous TS, the O4
4C5 breakin
ng bond is more advaanced
thantheC5Cl7formingbo
ond.
TS1end
doCl
IN1endoCl
TS22endoCl
Figurre5.6.Geom
metriesofthe
eTSsandIN involvedinttheregioisom
mericchanneelassociated
dwith
thecchlorinemed
diatedcyclizationofprottectedpropaargylicamine
e11tayieldinngsixmemb
bered
1,3o
oxazin2onee35ta.Thele
engthsoftheeformingandbreakingb
bondsaregivveninAngstrroms.
Cyclizationof11tqinthepreseenceofbro
omine
Finally, we examin
ned the reggioselectivity of the reaction w
when the alkyne
moieety was attaached to an
n aliphatic group, insttead of to an
a aromaticc group. Fo
or this
reaso
on, the rolle of this substituentt in the prropargylic system
s
wass now anaalyzed
studyying the tw
wo regioisom
meric channnels associaated with the additionn of bromin
ne on
theC
C1andC2caarbonsofm
methylproppargylicamine11tq(Scheme5.57)).
298
Chapter5
bromocyclizationof11tq.
The activation energies associated with the formation of intermediates IN3

endoBr and IN3exoBr via TS3endoBr and TS3exoBr are 2.0 and 3.3 kcal/mol
respectively, and the formation of these intermediates is exothermic by 27.5 and
25.4kcal/mol,respectively(Table5.10).
Table 5.10. Relative energies in acetonitrile (in
kcal/mol,relativeto11tqplushalogenBr2)ofthe
stationarypointsinvolvedinthebromocyclization
of11tq.
Bromocyclizationof11tq
MC2Br
4.1
TS3endoBr
2.0
TS3exoBr
3.3
IN3endoBr
27.5
IN3exoBr
25.4
Consequently, the cyclization reaction with methyl propargylic amine 11aq

should present lower regioselectivity. In fact, when NCbz1phenylbut2yn1amine
was subjected to the bromocyclization reaction a 92:8 mixture of the two
regioisomericproducts(34aqand40aq)wasobtained(75%yield)(Scheme5.58).
299
Chapter5
Scheme5.58.BromocyclizationofNCbz1phenylbut2yn1amine(11aq).
Onthecontrary,thereactionwithphenylpropargylicamine11aaiscompletely
regioselective. Thus, the phenyl substituent induces a total regioselectivity in these
halogen promoted cyclizations of protected propargylic amines as a consequence of
the stabilization of the incipient carbocationic C1 centre generated along the
E(kcal/mol)
electrophilicattackontheconjugatedC2carbon.
20
O
H
Me
6endodig bromocyclization
5exodig bromocyclization
15
Me
10
Br
3.3
2.0
0
5
10
15
Me
Br
4.1
O
H
Me
Me
Br
20
Me
Me
O
Br
Me
Me
Me
Br
Br
Br
Me
Me
Br
25
25.4
27.5
30
35
40
Me
Me
Br
O
Me
Br
45
50
55
0,511tq +Br2 1,5
MCTS3IN3
2,5
3,5
4,5
5,5
6,5
Figure5.7.Relativeenergiesinacetonitrile(inkcal/mol,relativeto11tqplushalogenBr2)of
thestationarypointsinvolvedinthebromocyclizationof11tq.
300
Chapter5
Thegeom
metriesofttheTSsand INsinvolve
edinthefirststepofthheregioisomeric
chan
nnel associaated with the bromiine promoted cyclization of prrotected methyl
m
prop
pargylicamine11tqare
egiveninFiggure5.8.
a))
3.466
endoBr
TS3e
IN3end
doBr
b))
3.554
TS3exoBr
IN3exxoBr
FFigure5.8.GeometriesofftheTSsanddINsinvolve
edinthefirsttstepofthe regioisomerric
chaannelsassociatedwithth
hebrominem
mediatedcyclizationofp
protectedproopargylicam
mine
helengthsofftheforminggandbreakin
ngbondsare
egiveninAn gstroms.
11tq.Th
AttheTSSs,thelengthsoftheB
Br6C2(1)an
ndO3C1(2))formingboondsare2.2
204
and22.453resspectivelyatTS3endoBr,and2.2
208and2
2.251resppectivelyattTS3
exoB
Br.Atthem
mostfavourrableTS3enndoBr,the
eO3C1length(2.453
)indicatessthat
theO
O3C1bond
dformationatthisTSissmoreadvancedthanthatatTS11endoBr,2.867
301
Chapter5
. This behaviour accounts for the role of the phenyl substituent in TS1endoBr,
stabilizing the incipient carbocationic C1 centre along the electrophilic attack of
bromineontheC1carbon.
Reactivityoftheprotectedpropargylicamines
Finally, an analysis of the reactivity of the protected propargylic amines 11ta
and 11tq was performed using the reactivity indices defined within the conceptual
DFT. The global and local reactivity indices, named global electrophilicity , global
nucleophilicityN,nucleophilicParrfunctions Pk andthelocalnucleophilicityindicesNk
ofpropargylicamines11taand11tqaregiveninFigure5.9.
21
11ta
=1.24
N=2.78
N1=0.03
N2=0.84
2 1
11tq
=0.62
N=2.17
N1=0.45
N2=0.46
Figure5.9.Mapsoftheatomicspindensityofthecationradicalsofpropargylicamines11ta
and11tqandthenucleophilicParrfunctions Pk attheC1andC2carbons,andglobal
electrophilicity,globalnucleophilicityN,andthelocalnucleophilicityindicesNk,ineV,of
11taand11tq.
Propargylicamines11taand11tqhavelowelectrophilicityvalues,1.24(11ta)
and 0.62 eV (11tq), being classified as moderate and marginal electrophiles,
respectively. On the other hand, the corresponding nucleophilicity N indices, 2.78
(11ta)and2.17eV(11tq)indicatethattheywillbehaveasmoderatenucleophiles.The
highernucleophiliccharacterofphenylpropargylicamine11tathanmethylpropargylic
amine11tqaccountsfortheloweractivationenergyfoundforthebrominemediated
additionto11tathanto11tq.
302
Chapter5
Building upon recent studies devoted to the bonding changes in polar

reactions,113 Domingo has proposed two new electrophilic, Pk , and nucleophilic, Pk ,
Parr functions, based on the analysis of the atomic spin density (ASD) at the
corresponding anion and cation radicals, to study the regio and chemoselectivity in
polar reactions. Analysis of the nucleophilic Parr functions Pk in propargylic amines
11ta and 11tq indicates that phenyl propargylic amine 11ta presents a strong
nucleophilicactivationoftheC2carbon,0.30,whencomparedtotheC1carbon,0.01,
whilemethylpropargylicamine11tqshowsasimilarnucleophilicactivationatthetwo
acetylenic C1 and C2 carbons (Figure 5.9). As a consequence, analysis of the local
nucleophilicityindicesofphenylpropargylicamine11taindicatesthattheC2carbonis
themostnucleophiliccentreofthismolecule,N2=0.84eV,whilethecorresponding
values for methyl propargylic amine 11ta show that the C2 carbon, N2 = 0.46 eV is
slightly more nucleophilically activated than the C1 carbon, N2 = 0.45 eV. This local
analysisisinagreementwiththeentireregioselectivityfoundinthebrominemediated
cyclization of phenyl propargylic amines 11ta, and with the lower regioselectivity
foundinthereactionof11tq.
5.3.2. Regioselective chalcogenmediated cyclization of NCbz

protected propargylic amines. Synthesis of 5phenylchalco1,3oxazin2
ones
The optimized conditions for the iodocyclization reaction were successfully
employed in the chalcogenmediated cyclization of NCbz1,3diphenyl prop2yn1
amine11aawith1.5equivalentsofphenylselenylchlorideinacetonitrileat0Cgiving
the corresponding selenylated 1,3oxazin2one 36aa as the only reaction product
(99%yield)(Table5.11,Entry1).
303
Chapter5
CyclizationreactionofNCbzprotectedpropargylicamineswithphenylselenyl
chloride
The optimized conditions were applied to the chalcogenmediated cyclization
of several NCbzprotected propargylic amines 11 derived from the addition of
phenylacetylenetoiminesderivedfromaromaticandaliphaticaldehydes(Table5.11,
entries 24) yielding the corresponding 5phenylselanyl1,3oxazin2ones 36 in
excellent results (8899%), regardless the electronic and steric character of the
substituents.
Table 5.11. Electrophilic cyclization of NCbzprotected propargylic amines 11 to 5
phenylselanyl1,3oxazin2ones36.a
Entry
11
t(h)
Product
Yield(%)b
11aa
Ph
Ph
0.3
36aa
99
11ea
4ClC6H4
Ph
0.3
36ea
88
11ha
2MeC6H4
Ph
0.25
36ha
99
11ra
nbutyl
Ph
0.5
36ra
90
11ad
Ph
4FC6H4
0.3
36ad
99
11af
Ph
2MeOC6H4
0.25
36af
96
11ak
Ph
C6H5CH2CH2
0.5
36ak
71
11(0.1mmol)andphenylselenylchloride(0.15mmol)in2.5mLofacetonitrile. bYield
ofisolatedproduct.
Excellent yields were also obtained when using NCbzprotected propargylic

amines bearing aromatic groups attached to the alkyne moiety with both electron
donating and electronwithdrawing groups in ortho and para positions (Table 5.11,
304
Chapter5
Entries 56). Furthermore, the procedure tolerates the use of propargylic amines
derivedfromaliphaticalkynes(Table5.11,Entry7).
Cyclization reaction of NCbzprotected propargylic amines with
phenylsulfenylchloride
NCbzprotected propargylic amines 11 were submitted to the optimized
conditionsforthepreviouscyclizationinthepresenceof1.5equivalentsofafreshly
prepared0.4Msolutionofphenylsulfenylchloridein1,2dichloroethane.Thereaction
proceededwithgoodtoexcellentyields(Table5.12).Aromaticgroupswithelectron
withdrawing substituents in para positions provided the cyclization products in
excellent yields (Table 5.12, Entries 2 and 5), whereas the utilization of amines with
aromaticgroupshavinganelectrondonatinggroupinorthopositiongavethedesired
products in somewhat lower yields (Table 5.12, Entries 3 and 6). The cyclization
reactionofanaminederivedfromanaliphaticaldehydeoccurredinhighyield(Table
5.12,Entry4).
phenylthio1,3oxazin2ones37.a
Entry
11
t(h)
Product
Yield(%)b
11aa
Ph
Ph
0.5
37aa
92
11ea
4ClC6H4
Ph
37ea
93
11ha
2MeC6H4
Ph
0.5
37ha
78
11qa
C6H5CH2CH2
Ph
0.6
37qa
90
11ad
Ph
4FC6H4
37ad
99
11af
Ph
2MeOC6H4
0.3
37af
79
11(0.1mmol)andphenylsulfenylchloridein1,2dichloroethane(0.4M,0.15mmol)in2.5
mLofacetonitrile.bYieldofisolatedproduct.
305
Chapter5
Cyclization reaction of NCbzprotected propargylic amines with

phenyltellurylbromide
Finally,NCbzprotectedpropargylicamines11werereactedwithasolutionof
phenyltellurylbromide0.5Min1,2dichloroethane.Thiscyclizationreactionrequired
longer times and provided the 5phenyltellanyl1,3oxazin2ones 38 in moderate to
highyields(Table5.13).
phenyltellanyl1,3oxazin2ones38.a
Entry 11
t(h)
Product
Yield(%)b
11aa
Ph
Ph
38aa
75
11ba
4MeC6H4
Ph
38ba
87
11sa
cyclohexyl
Ph
20
38sa
58
11ae
Ph
4ClC6H4
38ae
65
11ai
Ph
2thienyl
38ai
75
11ak
Ph
C6H5CH2CH2
38ak
80
11(0.1mmol)andphenyltellanylbromidein1,2dichloroethane(0.5M,0.15mmol)in2.5
mLofacetonitrile.bYieldofisolatedproduct.
The cyclization of propargylic amines derived from benzaldehyde and p

tolylaldehyde yielded the corresponding products with good results (7587%) (Table
5.13, Entries 12). However, the utilization of the propargylic amine derived from
cyclohexylcarbaldehyde (11sa) provided the desired 1,3oxazin2one 38sa in
moderateyield(58%)(Table5.13,Entry3).
Aromatic and heteroaromatic groups attached to the alkyne moiety were
tolerated by this procedure (Table 5.13, Entries 45). In addition, 2phenylethyl
306
Chapter5
substtituted 11aak gave the

e corresponnding 1,3oxazin2one
e 38ak in 880% yield (Table
5.13,,Entry6).
5.3.2.3.Structureelucidatioonofthecyyclizationp
products
Thestructuralelucidationof1 ,3oxazin2ones3638
8wascarrieedoutbym
means
ofXraydiffracttionanalysissandspecttroscopicm
methods,followingasim
milarstrate
egyto
theo
oneforthehalocyclizattionproduccts.
d1,3
Duetothefailuretoobtainannappropriatemonocryystalofthe synthetized
oxazin2ones 36,
3 37 and 38, 5phe nylthio1,3oxazin2one 37aa w
was subjecte
ed to
oxidaativecondittionsyieldin
ngthecorreespondingssulfoxidede
erivative42 (Scheme5..59).
O
HN
O
H 2 O2 (2 equiv)
Ph
Phenol
(C
CF 3) 2CHOH
Ph
SPh
h
HN
Ph
Ph
O
37aa
a
Ph
42
4 (99%)
Sch
heme5.59.O
Oxidationof3
37aatoyield
d42.
AnXrayyanalysisoff42alloweedustoestablishthesstructureoffthiscomp
pound
and undeniablyy confirmed
d the existeence of the 6membe
ered ring, as illustrated in
Figurre5.10.
O
HN
42
Figure5.100.Xraystrucctureof42.
307
Chapter5
As for the halocyclization products, a 13C NMR spectroscopy analysis was

carriedouttoensurethatallchalcogenmediatedcyclizationreactionsproceededviaa
6endodigmechanism.Wecomparedthe13CNMRsignalsofthefourcarbonatomsin
the6memberedringcontainingthecycliccarbamate(Table5.14).Thecarbonylgroup
givesasignalat150151(whenR2isaromatic)and154(whenR2isaliphatic);the
quaternaryolefinic=COresonatesat149151;thequaternaryolefinicSeC=appears
athighfieldat103105andtheCHappearsat5560.
Table5.14.13CNMRsignalsofthefourcarbonatomsinthe6memberedringcontainingthe
cycliccarbamate.
R1
R2
C=O*
=CO*
SeC=
CH
36aa Ph
Ph
151.50
150.27
103.85
60.21
36ea 4ClC6H4
Ph
151.61
150.12
103.49
59.62
36ha 2MeC6H4
Ph
151.84
150.03
103.38
56.75
36ra nbutyl
Ph
151.74
151.65
104.23
55.75
36ad Ph
4FC6H4
150.61
150.11
104.01
60.35
36af Ph
2MeOC6H4
157.44
150.14
105.93
60.17
36ak Ph
C6H5CH2CH2
153.95
149.88
103.11
60.16
Entry 36
*Signalscouldbeexchanged
308
(ppm)
Chapter5
13
C NMR spectra of 5phenylthio1,3oxazin2ones were also analyzed. The
carbonylgroupgivesasignalat152153;thequaternaryolefinic=COresonatesat
149150ppm;thequaternaryolefinicSC=appearsathighfieldat106andtheCH
appearsat5360ppm.
cycliccarbamate.
R1
R2
C=O*
=CO*
SC=
CH
37aa Ph
Ph
152.93
150.06
106.79
58.78
37ea 4ClC6H4
Ph
153.03
149.94
106.48
58.13
37ha 2MeC6H4
Ph
153.31
149.89
106.32
55.22
37qa C6H5CH2CH2 Ph
153.42
151.01
106.68
53.93
37ad Ph
4FC6H4
151.99
149.80
106.83
58.88
37af Ph
2MeOC6H4
157.44
150.14
105.93
60.17
Entry 37
(ppm)
*Signalscouldbeexchanged.
309
Chapter5
Finally,the13CNMRstudyof5phenyltellanyl1,3oxazin2onesshowsthatthe
carbonylgroupgivesasignalat150151(whenR1andR2arearomatic)and152
154(whenR1orR2isaliphatic);thequaternaryolefinic=COresonatesat150152;
thequaternaryolefinicTeC=appearsathighfieldat8889andtheCHappearsat
6263.
cycliccarbamate.
R1
R2
C=O*
=CO*
TeC=
CH
38aa Ph
Ph
151.86
150.38
89.14
62.54
38ba 4MeC6H4
Ph
151.85
150.33
89.49
62.37
38sa Ciclohexilo Ph
152.19
152.19
88.53
62.50
38ae Ph
4ClC6H4
150.91
150.09
89.82
62.85
38ai Ph
2tienil
149.95
146.27
88.46
63.22
38ak Ph
C6H5CH2CH2
154.56
150.08
89.41
63.21
Entry 38
(ppm)
*Signalscouldbeexchanged.
5.3.2.4. Theoretical calculations on the selenocyclization reaction of

protectedpropargylicamines
The mechanism of the regioselective chalcogen mediated cyclization of NCbz
protected propargylic amine 11aa to yield the 6membered 5phenylselanyl1,3
oxazin2one 36aa was studied theoretically using density functional theory (DFT)
methods at the B3LYP/6311G* level in acetonitrile (Scheme 5.60). A study of the
potential energy surface for the title reactions indicates that this cyclization reaction
310
Chapter5
takesplacethroughatwostepmechanism.Inthefirststep,theseleniumatomofthe
chalcogenmoleculePhSeClelectrophilicallyattacksontheC1orC2carbonofthetriple
bond of these propargylic amines to provide the cationic intermediate IN1endo or
IN1exo,viathecorrespondingtransitionstatesTS1endoorTS1exo,respectively.In
thesecondstep,thebenzylgrouppresentinthecarbamatesubstituentiseliminated
in these cationic intermediates assisted by the halide anion Cl yielding the final 1,3
oxazin2ones36aaand43aa(Scheme5.60).Totalandrelativeenergiesinacetonitrile
aregiveninTable5.17.
cyclizationof11aatoafford1,3oxazin2ones36aaor1,3oxazolidin2ones43aa.
Inanearlierstepofthereaction,PhSeClformsaweakmolecularcomplex(MC)
with propargylic amine 11aa. This MC is located 0.8 kcal/mol below the separated
reagents.TheactivationenergiesassociatedwiththeelectrophilicattacksofPhSeClon
the C2 and C1 carbons of propargylic amine 11aa are 4.5 (TS1endo) 11.1 kcal/mol
(TS1exo) and the formation of the corresponding cationic intermediates are
exothermicby12.6(IN1endo)and12.5kcal/mol(IN1exo).Eliminationofthebenzyl
group from these cationic intermediates takes place through a nucleophilic
substitutioninthebenzylgroupassistedbythechlorideanionClgeneratedinthefirst
step of the reaction. From the corresponding intermediates, the activation energies
associatedwiththeextrusionofthebenzylgroupare:8.0(TS2endo)and7.4kcal/mol
(TS2exo). Formation of 1,3oxazin2ones 2endo and 2exo plus PhCH2Cl is
exothermicby22.6and24.4kcal/mol,respectively.
311
Chapter5
Table5.17.Relativeenergiesinacetonitrile
(inkcal/mol,relativeto11aaplusPhSeCl)of
the stationary points involved in the
cyclization11aawithPhSeCl.
Cyclizationof11aawithPhSeCl
11aa+PhSeCl
MC
TS1endo
0
0.8
4.5
TS1exo
11.1
IN1endo
12.6
IN1exo
12.5
TS2endo
4.6
TS2exo
5.1
36aa+PhCH2Cl
22.6
43aa+PhCH2Cl
24.4
Fromtheseenergyresultssomerelevantconclusionscanbedrawn:
1. The electrophilic attack of chalcogen PhSeCl on the triple bond of
propargylic amine 11aa is completely regioselective, TS1endo being 6.6

kcal/mollowerinenergythanTS1exo.
2. Thehighexothermiccharacterofthefirststepmakesthisstepirreversible.
3. The activation energy associated with the second step, 8.0 kcal/mol is
higher than that associated with first step, 4.5 kcal/mol; thus, the
eliminationofthebenzylsubstituentistheratedeterminingstep(RDS)of
the reaction. Consequently, while the electrophilic attack of chalcogen
PhSeCl against propargylic amine 11aa is the regioselectivity determining
step,thebenzyleliminationistheRDSofthereaction.
4. Thesekineticandthermodynamicresultsaresimilartothosefoundinthe
halogenmediatedcyclizationsofpropargylicamines.
312
Chapter5
E(kcal/mol)
20
6endodig cyclization
5exodig cyclization
15
10
Cl
Ph
O
H
11.1
Ph
1 Ph
4.5
PhSeCl
0.8
Ph
SePh
4.6
5.1
Ph
Ph
Se
Cl
Ph
10
Ph
Ph
Ph
O
H
Cl
12.5
Ph
12.6
15
20
Ph
Ph
22.6
24.4
PhSe
25
O
H
30
Ph
35
Ph
PhSe
PhCH2Cl
40
45
50
55
0,5
1,5
2,5
11aa+PhSeClMCTS1
3,5
4,5
5,5
6,5
IN1TS236aa/43aa
+PhCH2Cl
Figure5.7.Relativeenergiesinacetonitrile(inkcal/mol,relativeto11aaplusPhSeCl)ofthe
stationarypointsinvolvedinthecyclizationof11aawithPhSeCl.
The geometries of the TSs and INs involved in the regioisomeric channels
associated with the chalcogen mediated cyclization of propargylic amine 11aa are
given in Figure 5.11. At the TSs associated with the first step of the chalcogen
mediatedcyclizationprocessthelengthsoftheSe6C2(1)andO3C1(2)formingbonds
are2.020and2.204respectivelyatTS1endo,and2.093and2.154respectively
atTS1exo.AtthecorrespondingintermediatesIN1endoandIN1exo thelengthsof
the Se6C2(1) and O3C1(2) bonds are 1.931 and 1.439 , and 1.944 and 1.432 ,
313
Chapter5
respeectively.Th
hesegeome
etricalparam
metersindicatethatatTS1s,the
eSe6C2(1) bond
form
mationisverryadvanced
d,whiletheO3C2(1)b
bondformattionismoreedelayed.
a)
TS1end
do
IN1endo
TSS2endo
TS1exxo
IN1exo
TS
TS2exo
b)
Figu
ure5.11.Geo
ometriesofttheTSsandIINsinvolvedintheregioiisomericchaannelsassociated
wiiththechalcogenmediatedcyclizatioonofNCbzprotectedpropargylicam
mine11aa.T
The
ngthsofthefformingand breakingbo
ondsaregiveninAngstrooms.
len
314
Chapter5
AttheTSsassociatedwiththeeliminationofthebenzylgroupinIN1endoand
IN1exo, the lengths of the O4C5 breaking bond and the C5Cl7 forming bond are
2.015and2.775respectivelyatTS2endoand1.981and2.821atrespectivelyTS2
exo. In these asynchronous TSs, the O4C5 breaking bonds are more advanced than
theC5Cl7formingbond.
315
Chapter5
5.4.CONCLUSIONS
Wehavedevelopedthe6endodigregioselectiveelectrophiliccyclizationofN
Cbzprotectedpropargylicaminestogivehighlyfunctionalized1,3oxazin2onesusing
molecularhalogensandorganochalcogenreagentsaselectrophilicsources.
The 6endodig regioselective halocyclizations of propargylic amines were
performedinthepresenceofI2,Br2orCl2employingacetonitrileassolventat0Cor
20C.Theutilizationofabasedidnotprovidebetterresults.
NtertbutyloxycarbonylandNethyloxycarbonylprotectedpropargylicamines
yieldedthecorresponding1,3oxazin2onesinloweryieldsthanNbenzyloxycarbonyl
protectedpropargylicamine.
Iodocyclization of propargylic amines derived from aromatic aldehydes and
alkynes afforded the corresponding 5iodo1,3oxazin2ones in excellent yields
regardless the electronic and steric nature of the substituents. Aliphatic derived
propargylicaminesledtovariableresults.
Bromocyclizationreactionwascarriedoutreducingtheequivalentsofbromine
andusingdilutedconditionstoavoidtheformationofdibrominatedproducts.Under
these conditions, aromatic and aliphatic propargylic amines underwent the
bromocyclizationreactioninhighyields.
ChlorocyclizationofdiversearomaticNCbzprotectedpropargylicaminesgave
thecorresponding5chloro1,3oxazin2onesingoodyieldsat20C.
The 6endodig regioselective chalcogenmediated cyclizations of propargylic
amineswereperformedemployingphenylselenylchloride,phenylsulfenylchlorideand
phenyltellurylbromideinacetonitrileat0C.
Cyclizationofaromaticpropargylicamineswithphenylselenylchloridegavethe
corresponding 5phenylselanyl1,3oxazin2ones in excellent yields regardless the
characteristicsofthesubstituents.Propargylicaminesderivedfromaliphaticaldehyde
oralkyneledtoexcellentandgoodresults,respectively.
317
Chapter5
Cyclizationofseveralpropargylicamineswithphenylsulfenylchlorideafforded
thecyclizationproductsinexcellentyields.However,loweryieldswereobtainedwith
substituentswithsterichindrance.
Chalcogenmediatedcyclizationofdiversepropargylicaminesbearingaromatic,
heteroaromatic and aliphatic substituents with phenyltelluryl bromide gave the
corresponding5phenyltellanyl1,3oxazin2onesingoodyields.
The formation of a sixmembered ring was confirmed by Xray diffraction
analysis.Toensurethatallcyclizationreactionsproceededviaa6endodigcyclization
pathway,comparativeNMRspectroscopyanalysiswasrealized.
Computational studies using DFT methods at the B3LYP/6311G* level and
analysis of the nucleophilic Parr functions were carried out. These studies indicated
that these electrophilic cyclization reactions take place through a twostep
mechanism. The first step is the regioselectivity determining step and 6endodig
cyclization process is favored over the 5exodig cyclization reaction. The rate
determiningstepofthereactionistheeliminationofthebenzylgroup.
318
Chapter5
5.5.EXPERIMENTALSECTION
5.5.1.Generaltechniques
SeeSection2.5.1.
5.5.2. General synthetic procedures and characterization of new

products
5.5.2.1. Synthesis and characterization of Nbenzyloxycarbonyl1
phenylbut2yn1amine(11aq)
A 0.5 M solution of magnesium propynyl bromide in THF
(0.55 mL, 0.275 mmol) was added to a solution of amido
sulfone8aa(49.4mg,0.125mmol)indichloromethane(1.5
mL)at0Cundernitrogen.Thesolutionwasstirredat0C
11aq
untilthereactionwascomplete(TLC).Thereactionmixture
was quenched with water (1.0 mL), extracted with CH2Cl2
(3x15mL),driedoverMgSO4andconcentratedunderreducedpressure.Purificationby
flashchromatographyonsilicagelaffordedthecompound11aq.
Whitesolid;mp112115C.
1
HNMR(300MHz,CDCl3)7.50(brd,J=7.1Hz,2H),7.397.30(m,8H),5.67(brd,J=
6.9Hz,1H),5.24(brd,J=6.8Hz,1H),5.16(d,J=12.1Hz,1H),5.11(d,J=12.4Hz,1H),
1.88(d,J=2.4Hz,3H).
13
128.1(CH),128.0(CH),126.9(CH),81.3(C),77.1(C),67.0(CH2),47.1(CH),3.6(CH3).
319
Chapter5
5.5.2.2.Synthesisandcharacterizationof5iodo1,3oxazin2ones33
Asolutionofiodine(50.6mg,0.2mmol)inacetonitrile(1.0mL)wasaddedtoa
solutionofNCbzprotectedpropargylicamine11(0.1mmol)inacetonitrile(1.5mL)at
0 C. The solution was stirred until the reaction was complete (TLC). The reaction
mixture was quenched with sodium bisulfate aq. sat. (1.0 mL), extracted with CH2Cl2
(3x15mL),driedoverMgSO4andconcentratedunderreducedpressure.Purificationby
flashchromatographyonsilicagelaffordedcompound33.
(S)5iodo4,6diphenyl3,4dihydro2H1,3oxazin2one(33aa)
Enantiomericexcess(87%)wasdeterminedbychiralHPLC
(Chiralcel ODH), hexaneiPrOH 90:10, 1 mL/min, major
33aa
Mp6568C;[]D20+64.7(c1.00,CHCl3,87%ee).
1
H NMR (300 MHz, CDCl3) 7.657.61 (m, 2H), 7.427.39
(m,8H),6.49(brs,1H),5.19(d,J=2.1Hz,1H).
13
(CH),129.2(CH),129.1(CH),128.0(CH),127.5(CH),71.4(C),64.9(CH).
HRMS(ESI)m/z:377.9984[M+H]+,C16H13NO2Irequires377.9986.
(S)5iodo6phenyl4(ptolyl)3,4dihydro2H1,3oxazin2one(33ba)
Viscousoil;[]D20+42.7(c1.03,CHCl3,88%ee).
1
H NMR (300 MHz, CDCl3) 7.657.62 (m, 2H), 7.42
7.39(m,3H),7.297.21(m,4H),5.85(brs,1H),5.17(d,
J=2.0Hz,1H),2.38(s,3H).
33ba
13
CNMR(75.5MHz,CDCl3)149.4(C),148.9(C),139.2
(C),137.4(C),133.8(C),130.0(CH),129.8(CH),129.4(CH),128.1(CH),127.4(CH),71.7
(C),64.9(CH),21.3(CH3).
320
Chapter5
(S)4(4chlorophenyl)5iodo6phenyl3,4dihydro2H1,3oxazin2one(33ea)
Enantiomeric excess (91%) was determined by chiral
HPLC(ChiralcelODH),hexaneiPrOH90:10,1mL/min,
majorenantiomertr=15.1min,minorenantiomertr=
22.2min.
Mp7477C;[]D20+27.99(c0.70,CHCl3,90%ee).
33ea
H NMR (300 MHz, CDCl3) 7.647.61 (m, 2H), 7.43
7.38(m,5H),7.357.31(m,2H),6.07(brs,1H),5.20(d,J=2.1Hz,1H).
13
(CH),129.4(CH),129.3(CH),128.9(CH),128.1(CH),70.7(C),64.5(CH).
HRMS(ESI)m/z:411.9596[M+H]+,C16H12NO2ClIrequires411.9596;
(S)5iodo6phenyl4(otolyl)3,4dihydro2H1,3oxazin2one(33ha)
1
H NMR (300 MHz, CDCl3) 7.667.63 (m, 2H), 7.437.41
(m,3H),7.387.35(m,1H),7.307.27(m,2H),7.237.19(m,
33ha
1H),5.78(brs,1H),5.52(d,J=1.8Hz,1H),2.46(s,3H).
13
CNMR(75.5MHz,CDCl3)149.3(C),149.2(C),138.0(C),
135.9(C),133.8(C),131.3(CH),130.1(CH),129.3(CH),129.1(CH),128.3(CH),128.1
(CH),127.1(CH),71.1(C),61.6(CH),19.1(CH3).
(S)5iodo4phenethyl6phenyl3,4dihydro2H1,3oxazin2one(33qa)
Mp99100C;[]D20+4.7(c0.87,CHCl3,60%ee).
1
H NMR (300 MHz, CDCl3) 7.597.56 (m, 2H), 7.42
7.40(m,3H),7.347.28(m,2H),7.257.22(m,3H),6.40
(br d, J = 5.3 Hz, 1H), 4.314.27 (m, 1H), 2.902.70 (m,
33qa
321
2H),2.242.15(m,2H).
13
(CH),128.6(CH),128.4(CH),128.1(CH),126.3(CH),70.8(C),59.9(CH),37.3(CH2),29.8
(CH2).
HRMS(ESI)m/z:406.0306[M+H]+,C18H17INO2requires406.0303.
(S)4butyl5iodo6phenyl3,4dihydro2H1,3oxazin2one(33ra)
1
HNMR(300MHz,CDCl3)7.597.56(m,2H),7.427.26
(m,3H),6.31(brs,1H),4.254.21(m,1H),1.891.79(m,
2H)1.451.35(m,4H),0.95(t,J=7.1Hz,3H).
33ra
13
CNMR(75.5MHz,CDCl3)151.3(C),149.3(C),133.8
(C),129.9(CH),129.3(CH),128.1(CH),71.3(C),60.3(CH),35.4(CH2),25.4(CH2),22.3
(CH2),14.0(CH3).
(S)4cyclohexyl5iodo6phenyl3,4dihydro2H1,3oxazin2one(33sa)
Mp152156C;[]D20+1.33(c1.00,CHCl3,54%ee).
1
H NMR (300 MHz, CDCl3) 7.607.55 (m, 2H), 7.427.39
(m, 3H), 6.42 (br s, 1H), 4.04 (t, J = 2.7 Hz, 1H), 1.991.60
33sa
(m,6H),1.361.34(m,5H).
13
CNMR(75.5MHz,CDCl3)151.5(C),150.1(C),133.9(C),
129.9(CH),129.3(CH),128.0(CH),70.3(C),65.1(CH),42.0(CH),29.3(CH2),26.3(CH2),
26.0(CH2),25.9(CH2),24.8(CH2).
HRMS(ESI)m/z:384.0447[M+H]+,C16H19INO2requires384,0455.
322
Chapter5
(S)5iodo6(4methoxyphenyl)4phenyl3,4dihydro2H1,3oxazin2one(33ab)
Enantiomericexcess(88%)wasdeterminedbychiral
HPLC (Chiralcel ODH), hexaneiPrOH 90:10, 1
mL/min, major enantiomer tr = 20.1 min, minor
enantiomertr=29.5min.
Mp161163C;[]D20+41.9(c1.19,CHCl3,88%ee).
33ab
1
HNMR(300MHz,CDCl3)7.60(dt,J=8.9,2.5Hz,2H),7.447.36(m,5H),6.91(dt,J=
8.9,2.5Hz,2H),5.94(brs,1H),5.18(d,J=2.1Hz,1H),3.84(s,3H).
13
(CH),129.1(CH),127.5(CH),125.9(C),113.3(CH),70.4(C),65.1(CH),55.3(CH3).
(S)6(4fluorophenyl)5iodo4phenyl3,4dihydro2H1,3oxazin2one(33ad)
Mp6871C;[]D20+46.6(c1.03,CHCl3,83%ee).
1
HNMR(300MHz,CDCl3)7.667.61(m,2H),7.447.36
(m,5H),7.10(t,J=8.7Hz,2H),5.94(brs,1H),5.20(d,J=
2.1Hz,1H).
33ad
13
C NMR (75.5 MHz, CDCl3) 163.4 (d, J = 250.8 Hz, C),
149.3(C),148.1(C),140.1(C),131.6(d,J=8.7Hz,CH),129.8(d,J=3.5Hz,C),129.3
(CH),129.2(CH),127.5(CH),115.2(d,J=21.9Hz,CH),71.6(C),65.1(CH).
HRMS(ESI)m/z:395.9895[M+H]+,C16H12NO2FIrequires395.9891.
(S)5iodo6(2methoxyphenyl)4phenyl3,4dihydro2H1,3oxazin2one(33af)
Mp195198C;[]D20+18.1(c1.04,CHCl3,66%ee).
1
HNMR(300MHz,CDCl3)7.447.37(m,6H),7.32(dd,J=
7.5,1.6Hz,1H),6.99(td,J=7.5,0.8Hz,1H),6.94(d,J=8.4
Hz,1H),5.85(brs,1H),5.20(d,J=1.9Hz,1H),3.88(s,3H).
33af
323
Chapter5
13
(CH), 129.2 (CH), 129.1 (CH), 127.6 (CH), 123.7 (C), 120.3 (CH), 111.2 (CH), 74.4 (C),
64.5(CH),55.7(CH3).
(S)6(3,5dimethoxyphenyl)5iodo4phenyl3,4dihydro2H1,3oxazin2one
(33ag)
1
HNMR(300MHz,CDCl3)7.447.36(m,5H),6.76(d,
J=2.3Hz,2H),6.51(d,J=2.3Hz,1H),5.88(brs,1H),
5.19(d,J=2.0Hz,1H),3.81(s,6H).
13
33ag
C NMR (75.5 MHz, CDCl3) 160.3 (C), 149.3 (C),
148.8(C),140.3(C),135.3(C),129.3(CH),129.2(CH),
127.6(CH),107.4(CH),102.5(CH),71.3(C),65.1(CH),55.5(CH3).
(S)5iodo4phenyl6(thiophen2yl)3,4dihydro2H1,3oxazin2one(33ai)
Enantiomeric excess (89%) was determined by chiral HPLC
Mp168170C;[]D20+85.7(c1.05,CHCl3,90%ee).
33ai
1
H NMR (300 MHz, CDCl3) 7.85 (dd, J = 3.8, 1.2 Hz, 1H),
7.46(dd,J=5.0,1.2Hz,1H),7.417.33(m,5H),7.12(dd,J=3.8,5.0Hz,1H),6.01(brs,
1H),5.22(d,J=2.3Hz,1H).
13
(CH),129.1(CH),128.2(CH),127.6(CH),126.9(CH),69.6(C),65.7(CH).
HRMS(ESI)m/z:383.9556[M+H]+,C14H11NO2SIrequires383.9550.
324
Chapter5
(S)5iodo6phenethyl4phenyl3,4dihydro2H1,3oxazin2one(33ak)
Mp147149C;[]D20+2.8(c0.20,CHCl3,82%ee).
1
H NMR (300 MHz, CDCl3) 7.367.23 (m, 8H), 7.14
7.11(m,2H),5.55(brs,1H),4.99(brs,1H),2.992.78
(m,4H).
33ak
13
CNMR(75.5MHz,CDCl3)150.2(C),149.2(C),140.1
(C), 139.8 (C), 129.1 (CH), 129.0 (CH), 128.7 (CH), 128.5 (CH), 127.5 (CH), 126.4 (CH),
71.8(C),64.0(CH),36.9(CH2),32.3(CH2).
(S)6(tertbutyl)5iodo4phenyl3,4dihydro2H1,3oxazin2one(33am)
Mp128130C;[]D20+52.2(c0.70,CHCl3,88%ee).
1
H NMR (300 MHz, CDCl3) 7.397.36 (m, 3H), 7.297.25 (m,
2H),5.74(brs,1H),5.01(d,J=2.4Hz,1H),1.44(s,9H).
33am
13
C NMR (75.5 MHz, CDCl3) 155.3 (C), 149.7 (C), 140.6 (C),
129.1 (CH), 129.0 (CH), 127.4 (CH), 66.7 (CH), 37.4 (C), 29.0
(CH3).
325
Chapter5
5.5.2.3.Synthesisandcharacterizationof5bromo1,3oxazin2ones34
Bromine (6.1 L, 0.12 mmol) was added to a solution of NCbz protected
propargylic amine 11 (0.1 mmol) in acetonitrile (12.5 mL) at 0 C. The solution was
stirreduntilthereactionwascomplete(TLC).Thereactionmixturewasconcentrated
under reduced pressure. Purification by flash chromatography on silica gel afforded
compound34.
(S)5bromo4,6diphenyl3,4dihydro2H1,3oxazin2one(34aa)
Mp5254C;[]D20+62.7(c1.00,CHCl3,87%ee).
1
H NMR (300 MHz, CDCl3) 7.727.69 (m, 2H), 7.437.41
(m,8H),6.12(brs,1H),5.19(d,J=2.1Hz,1H).
13
CNMR(75.5MHz,CDCl3)149.3(C),146.2(C),139.6(C),
34aa
131.6 (C), 130.1 (CH), 129.3 (CH), 129.2 (CH), 128.9 (CH),
128.1(CH),127.4(CH),98.3(C),62.3(CH).
HRMS (ESI) m/z: 330.0110/332.0090 [M+H]+ 100/96.5, C16H13BrNO2 requires
330.0130/332.0109.
(S)5bromo4(4chlorophenyl)6phenyl3,4dihydro2H1,3oxazin2one(34da)
HPLC (Chiralcel ODH), hexaneiPrOH 90:10, 1 mL/min,
34da
20.1min.
Mp6365C;[]D20+73.9(c0.86,CHCl3,90%ee).
HNMR(300MHz,CDCl3)7.707.67(m,2H),7.437.31(m,7H),6.38(brs,1H),5.17
(d,J=2.2Hz,1H).
13
(CH),129.4(CH),128.9(CH),128.8(CH),128.1(CH),97.8(C),61.6(CH).
326
Chapter5
HRMS (ESI) m/z: 363.9732/365.9722 [M+H]+ 100/96.8, C16H12BrClNO2 requires

363.9740/365.9719.
(S)5bromo6phenyl4(otolyl)3,4dihydro2H1,3oxazin2one(34ha)
Mp5355C;[]D20+57.1(c0.87,CHCl3,90%ee).
1
HNMR(300MHz,CDCl3)7.737.70(m,2H),7.447.36(m,
4H),7.307.27(m,2H),7.227.19(m,1H),5.94(brs,1H),5.53
(d,J=1.9Hz,1H),2.47(s,3H).
34ha
13
CNMR(75.5MHz,CDCl3)149.2(C),146.4(C),137.4(C),
136.0(C),131.7(C),131.3(CH),130.0(CH),129.1(CH),128.9(CH),128.14(CH),128.10
(CH),127.1(CH),98.2(C),58.9(CH),19.1(CH3).
344.0286/346.0266.
(S)5bromo4cyclohexyl6phenyl3,4dihydro2H1,3oxazin2one(34sa)
Mp6063C;[]D203.90(c0.65,CHCl3,54%ee).
1
H NMR (300 MHz, CDCl3) 7.687.67 (m, 2H), 7.417.37
(m,3H),6.21(brs,1H),4.04(brs, 1H),1.941.75(m,5H),
1.321.18(m,6H).
34sa
13
CNMR(75.5MHz,CDCl3)151.0(C),147.2(C),131.8(C),
129.9(CH),128.9(CH),128.0(CH),97.7(C),62.7(CH),41.6(CH),29.1(CH2),26.3(CH2),
26.0(CH2),25.8(CH2),25.0(CH2).
336.0599/338.0579.
327
Chapter5
(S)5bromo6(4fluorophenyl)4phenyl3,4dihydro2H1,3oxazin2one(34ad)
Mp5861C;[]D20+82.7(c0.99,CHCl3,83%ee).
1
HNMR(300MHz,CDCl3)7.747.67(m,2H),7.447.37
(m,5H),7.10(t,J=8.8Hz,2H),6.14(brs,1H),5.18(d,J=
2.2Hz,1H).
34ad
13
149.2(C),145.3(C),139.5(C),131.1(d,J=8.6Hz,CH),129.3(CH),129.2(CH),127.7
(d,J=3.4Hz,C),127.4(CH),115.2(d,J=21.9Hz,CH),98.4(C),62.3(CH).
HRMS (ESI) m/z: 348.0039/350.020 [M+H]+ 100/97.2, C16H12BrFNO2 requires
348.0035/350.0015.
(S)5bromo6(4chlorophenyl)4phenyl3,4dihydro2H1,3oxazin2one(34ae)
Mp5456C;[]D20+81.4(c0.89,CHCl3,91%ee).
1
HNMR(300MHz,CDCl3)7.66(dt,J=8.6,2.2Hz,2H),
7.437.37(m,7H),6.33(brs,1H),5.18(d,J=2.1Hz,1H).
13
CNMR(75.5MHz,CDCl3)149.3(C),145.1(C),139.4
34ae
(C), 136.0 (C), 130.3 (CH), 129.9 (C), 129.3 (CH), 129.2
(CH),128.4(CH),127.4(CH),98.8(C),62.2(CH).
HRMS (ESI) m/z: 363.9742/365.9708 [M+H]+ 100/96.8, C16H12BrClNO2 requires
363.9740/365.9719.
(S)5bromo6phenethyl4phenyl3,4dihydro2H1,3oxazin2one(34ak)
Mp135138C;[]D20+46.0(c1.03,CHCl3,82%ee).
1
H NMR (300 MHz, CDCl3) 7.367.34 (m, 3H), 7.30
7.23(m,5H),7.157.12(m,2H),5.80(brs,1H),4.98(br
s,1H),2.992.94(m,2H),2.892.67(m,2H).
34ak
13
CNMR(75.5MHz,CDCl3)149.1(C),147.9(C),139.8
328
Chapter5
(C), 139.4 (C), 129.1 (CH), 129.0 (CH), 128.6 (CH), 128.5 (CH), 127.3 (CH), 126.4 (CH),
98.3(C),61.4(CH),33.4(CH2),31.9(CH2).
358.0443/360.0422.
5bromo6methyl4phenyl3,4dihydro2H1,3oxazin2one(34aq)
Mp180183C.
1
H NMR (300 MHz, CDCl3) 7.427.34 (m, 3H),7.337.28 (m,
2H),6.34(brs,1H),5.36(quint,J=1.4Hz,1H),2.11(d,J=1.5
Hz,3H).
34aq
13
C NMR (75.5 MHz, CDCl3) 149.4 (C), 145.7 (C), 139.6 (C),
129.1(CH),129.0(CH),127.3(CH),97.7(C),61.2(CH),18.1(CH3).
267.9973/269.9953.
(E)5(1bromoethylidene)4phenyloxazolidin2one(40aq)
Decomp.
1
HNMR(300Hz,CDCl3)7.407.34(m,5H),5.55(brs,1H),5.36
(q,J=1.6Hz,1H),2.32(d,J=1.7Hz,3H).
40aq
13
CNMR(75.5MHz,CDCl3)155.0(C),145.1(C),137.4(C),129.1
(CH),129.0(CH),127.6(CH),100.7(C),60.6(CH),21.3(CH3).

267.9973/269.9953.
329
Chapter5
5.5.2.4.Synthesisandcharacterizationof5chloro1,3oxazin2ones35
A0.19Msolutionofchlorine114(0.63mL,0.12mmol)inacetonitrilewasadded
toasolutionofNCbzprotectedpropargylicamine11(0.1mmol)inacetonitrile(12.5
mL) at 20 C. The solution was stirred until the reaction was complete (TLC). The
reaction mixture was concentrated under reduced pressure. Purification by flash
chromatographyonsilicagelaffordedcompound35.
(S)5chloro4,6diphenyl3,4dihydro2H1,3oxazin2one(35aa)
1
H NMR (300 MHz, CDCl3) 7.767.73 (m, 2H), 7.447.40
(m,8H),5.98(brs,1H),5.12(d,J=2.0Hz,1H).
13
CNMR(75.5MHz,CDCl3)149.0(C),144.9(C),139.2(C),
35aa
130.5 (C), 130.0 (CH), 129.4 (CH), 129.2 (CH), 128.6 (CH),
128.1(CH),127.3(CH),108.9(C),60.4(CH).
HRMS(ESI)m/z:286.0632[M+H]+,C16H13ClNO2requires286.0629.
(S)5chloro6phenyl4(ptolyl)3,4dihydro2H1,3oxazin2one(35ba)
HPLC (Chiralcel ODH), hexaneiPrOH 90:10, 1 mL/min,
35ba
19.2min.
Whiteoil;[]D20+47.8(c0.59,CHCl3,88%ee).
HNMR(300MHz,CDCl3)7.767.72(m,2H),7.437.40(m,3H),7.30(d,J=8.3Hz,
2H),7.24(d,J=8.0Hz,2H),5.78(brs,1H),5.09(d,J=2.0Hz,1H),2.38(s,3H).
13
C NMR (75.5 MHz, CDCl3) 149.3 (C), 144.6 (C), 139.4 (C), 136.2 (C), 130.09 (C),
129.97(CH),129.85(CH),128.5(CH),128.1(CH),127.2(CH),109.1(C),60.7(CH),21.2
(CH3).
330
Chapter5
(S)5chloro4phenethyl6phenyl3,4dihydro2H1,3oxazin2one(35qa)
Mp145146C;[]D20+5.8(c0.78,CHCl3,60%ee).
1
H NMR (300 MHz, CDCl3) 7.727.69 (m, 2H), 7.43
7.41(m,3H),7.337.28(m,2H),7.247.19(m,3H),5.85
(br s, 1H), 4.274.23 (m, 1H), 2.902.73 (m, 2H), 2.22
35qa
2.14(m,2H).
13
(CH), 128.5 (CH), 128.4 (CH), 128.1 (CH), 126.3 (CH), 108.9 (C), 56.0 (CH), 36.2 (CH2),
29.9(CH2).
(S)5chloro6(4methoxyphenyl)4phenyl3,4dihydro2H1,3oxazin2one(35ab)
Mp4749C;[]D20+62.2(c0.79,CHCl3,88%ee).
1
H NMR (300 MHz, CDCl3) 7.70 (dt, J = 9.1, 2.6 Hz,
2H), 7.427.38 (m, 5H), 6.93 (dt, J = 9.1, 2.6 Hz, 2H),
6.12(brs,1H),5.09(d,J=2.1Hz,1H),3.84(s,3H).
35ab
13
C NMR (75.5 MHz, CDCl3) 160.6 (C), 149.3 (C),
144.5 (C), 139.3 (C), 130.1 (CH), 129.2 (CH), 129.1 (CH), 127.3 (CH), 122.7 (C), 113.5
(CH),107.7(C),60.9(CH),55.3(CH3).
331
Chapter5
5.5.2.5. Synthesisand characterization of 5phenylselanyl1,3oxazin2

ones36
Phenylselenylchloride(101.4mg,0.15mmol)wasaddedtoasolutionofNCbz
protectedpropargylicamine11(0.10mmol)inacetonitrile(2mL)at0C.Thesolution
was stirred until the reaction was complete (TLC). The reaction mixture was
concentrated under reduced pressure. Purification by flash chromatography on silica
gelaffordedcompound36.
(S)4,6diphenyl5(phenylselanyl)3,4dihydro2H1,3oxazin2one(36aa)
Mp157160C;[]D20+157.1(c1.00,CHCl3,86%ee).
36aa
H NMR (300 MHz, CDCl3) 7.627.59 (m, 2H), 7.447.23
(m,13H),6.16(brd,J=1.9Hz,1H),4.86(d,J=2.4Hz,1H).
13
(CH), 129.5 (CH), 129.2 (CH), 128.94 (CH), 128.89 (C), 128.8 (CH), 127.9 (CH), 127.7
(CH),127.2(CH),103.9(C),60.1(CH).
HRMS (ESI) m/z: 408.0500/406.0507 [M+H]+ 100.0/51.2, C22H18NO2Se requires
408.0503/406.0511.
(S)4(4chlorophenyl)6phenyl5(phenylselanyl)3,4dihydro2H1,3oxazin2one
(36ea)
Mp138142C;[]D20+136.1(c1.02,CHCl3,90%ee).
1
H NMR (300 MHz, CDCl3) 7.617.58 (m, 2H), 7.43
7.36(m,3H),7.327.25(m,7H),7.16(dt,J=8.8,2.3Hz,
2H),6.20(brd,J=2.0Hz,1H),4.85(d,J=2.5Hz,1H).
36ea
332
13
CNMR(75.5MHz,CDCl3)151.6(C),150.1(C),139.3
Chapter5
(C), 134.7 (C), 132.4 (C), 132.1 (CH), 130.1 (CH), 129.6 (CH), 129.2 (CH), 129.1 (CH),
128.6(C),128.5(CH),128.0(CH),127.9(CH),103.5(C),59.6(CH).
HRMS (ESI) m/z: 442.0115/440.0121 [M+H]+ 100.0/50.7, C22H17ClNO2Se requires
442.0113/440.0121.
(S)6phenyl5(phenylselanyl)4(otolyl)3,4dihydro2H1,3oxazin2one(36ha)
Mp5759C;[]D20+173.7(c1.03,CHCl3,90%ee).
1
H NMR (300 MHz, CDCl3) 7.667.62 (m, 2H), 7.42
7.38(m,3H),7.337.30(m,1H),7.267.20(m,7H),7.11
7.08 (m, 1H), 5.96 (br s, 1H), 5.22 (d, J = 2.2 Hz, 1H),
2.14(s,3H).
36ha
13
CNMR(75.5MHz,CDCl3)151.8(C),150.0(C),138.6
(C), 135.8 (C), 132.7 (C), 131.9 (CH), 131.0 (CH), 130.0 (CH), 129.4 (CH), 129.2 (CH),
128.9(C),128.6(CH),127.93(CH),127.89(CH),127.6(CH),127.0(CH),103.4(C),59.8
(CH),18.9(CH3).
422,0659/420.0667.
(S)4butyl6phenyl5(phenylselanyl)3,4dihydro2H1,3oxazin2one(36ra)
Mp103105C;[]D20+142.8(c1.72,CHCl3,46%ee).
1
HNMR(300MHz,CDCl3)7.597.55(m,2H),7.407.38
(m, 5H), 7.287.26 (m, 3H), 6.34 (br d, J = 2.4 Hz, 1H),
3.863.82 (m, 1H), 1.851.78 (m, 2H), 1.421.26 (m, 4H),
36ra
0.90(t,J=7.0Hz,3H).
13
C NMR (75.5 MHz, CDCl3) 151.7 (C), 151.6 (C), 132.7
(C), 131.8 (CH), 129.8 (CH), 129.5 (CH), 129.1 (CH), 128.8 (C), 127.8 (CH), 127.7 (CH),
104.2(C),55.8(CH),35.6(CH2),25.9(CH2),22.3(CH2),13.9(CH3).
388.0816/386.0824.
333
Chapter5
(S)5((4fluorophenyl)selanyl)4,6diphenyl3,4dihydro2H1,3oxazin2one(36ad)
Mp5255C;[]D20+185.4(c1.03,CHCl3,88%ee).
1
H NMR (300 MHz, CDCl3) 7.627.58 (m, 2H), 7.35
7.30(m,3H),7.297.23(m,7H),7.07(t,J=8.7Hz,2H),
6.15(brd,J=1.9Hz,1H),4.87(d,J=2.4Hz,1H).
36ad
13
CNMR(75.5MHz,CDCl3)163.4(d,J=253.9Hz,C),
150.6(C),150.1(C),140.7(C),131.8(CH),131.3(d,J=
8.5Hz,CH),129.5(CH),129.0(CH),128.82(CH),128.78
(C),128.7(d,J=3.4Hz,C),127.8(CH),127.2(CH),115.0(d,J=21.9Hz,CH),104.0(C),
60.4(CH).
HRMS (ESI) m/z: 426.0404/424.0413 [M+H]+ 100.0/50.9, C22H17FNO2Se requires
426.0409/424.0416.
(S)6(2methoxyphenyl)4phenyl5(phenylselanyl)3,4dihydro2H1,3oxazin2one
(36af)
Mp170177C;[]D20+139.4(c0.99,CHCl3,66%ee).
1
H NMR (300 MHz, CDCl3) 7.417.29 (m, 9H), 7.26
7.21(m,3H),6.98(td,J=7.5,0.9Hz,1H),6.9(d,J=8.2
Hz,1H),5.91(brs,1H),4.87(d,J=2.3Hz,1H),3.82(s,
3H).
36af
13
CNMR(75.5MHz,CDCl3)157.4(C),150.1(C),140.9
(C), 132.2 (CH), 131.3 (CH), 130.9 (CH), 129.2 (CH),

129.1(C),128.9(CH),128.7(CH),127.40(CH),127.35(CH),122.4(C),120.2(CH),110.9
(CH),105.9(C),60.2(CH),55.5(CH3).
438.0608/436.0616.
334
Chapter5
(S)6phenethyl4phenyl5(phenylselanyl)3,4dihydro2H1,3oxazin2one(36ak)
Whiteoil;[]D20+41.6(c.084,CHCl3,82%ee).
1
H NMR (300 MHz, CDCl3) 7.287.19 (m, 11H), 7.15
7.12(m,2H),7.047.01(m,2H),5.63(brs,1H),4.71(d,
J=1.9Hz,1H),3.092.92(m,4H).
36ak
13
CNMR(75.5MHz,CDCl3)154.0(C),149.8(C),140.7
(C),140.0(C),131.0(CH),129.4(CH),129.1(C),128.77
(CH), 128.75 (CH), 128.6 (CH), 128.5 (CH), 127.2 (CH),
127.2(CH),126.3(CH),103.1(C),60.2(CH),34.2(CH2),32.6(CH2).
HRMS (ESI) m/z: 436.0818/434.0824 [M+H]+ 100/48.5, C24H22NO2Se requires
436.0816/434.0824.
5.5.2.6.Synthesisandcharacterizationof5phenylsulfenyl1,3oxazin2
ones37
Preparationofthephenylsulfenylchloridesolution:115Sulfurylchloride(80L,
1.0 mmol) was added to a solution of diphenyl sulfide (240.2 mg, 1.1 mmol) in 1,2
dichloroethane(3mL)atroomtemperature.Thesolutionwasstirredfor5minandthe
volumewascompletedto5mL.
A freshly prepared 0.4 M solution of phenylsulfenyl chloride in 1,2
dichloroethane (0.375 mL, 0.15 mmol) was added to a solution of NCbz protected
propargylic amine 11 (0.10 mmol) in acetonitrile (2 mL) at 0 C. The solution was
stirreduntilthereactionwascomplete(TLC).Thereactionmixturewasconcentrated
under reduced pressure. Purification by flash chromatography on silica gel afforded
compound37.
335
Chapter5
(S)4,6diphenyl5(phenylthio)3,4dihydro2H1,3oxazin2one(37aa)
(Chiralcel ADH), hexaneiPrOH 90:10, 1 mL/min, major
Mp158159C;[]D20+328.0(c1.00,CHCl3,87%ee).
37aa
H NMR (300 MHz, CDCl3) 7.727.68 (m, 2H), 7.417.22
(m,13H),6.10(brs,1H),4.87(d,J=2.3Hz,1H).
13
127.0(CH),106.8(C),58.8(CH).
HRMS (ESI) m/z: 360.1051/361.1083 [M+H]+ 100.0/25.3, C22H18NO2S requires
360.1058/361.1092.
(S)4(4chlorophenyl)6phenyl5(phenylthio)3,4dihydro2H1,3oxazin2one
(37ea)
Mp156159C;[]D20+269.4(c1.00,CHCl3,90%ee).
1
H NMR (300 MHz, CDCl3) 7.707.67 (m, 2H), 7.43
7.35 (m, 3H), 7.337.16 (m, 9H), 6.22 (br d, J = 1.9 Hz,
1H),4.86(d,J=2.5Hz,1H).
13
CNMR(75.5MHz,CDCl3)153.0(C),149.9(C),139.0
37ea
(C), 134.7 (C), 133.4 (C), 131.3 (C), 130.3 (CH), 129.5
(CH), 129.2 (CH), 129.0 (CH), 128.8 (CH), 128.4 (CH),
128.0(CH),127.1(CH),106.5(C),58.1(CH).
HRMS (ESI) m/z: 394.0662/396.0633 [M+H]+ 100.0/32.1, C22H17ClNO2S requires
394.0669/396.0639.
336
Chapter5
(S)6phenyl5(phenylthio)4(otolyl)3,4dihydro2H1,3oxazin2one(37ha)
Mp139142C;[]D20+295.8(c1.25,CHCl3,90%ee).
1
H NMR (300 MHz, CDCl3) 7.747.70 (m, 2H), 7.427.37
(m, 3H), 7.317.17 (m, 8H), 7.117.08 (m, 1H), 6.07 (br s,
1H),5.23(d,J=2.2Hz,1H),2.13(s,3H).
37ha
13
CNMR(75.5MHz,CDCl3)153.3(C),149.9(C),138.5(C),
135.9(C),133.9(C),131.6(C),130.0(CH),130.1(CH),129.3
(CH),129.0(CH),128.7(CH),128.4(CH),127.9(CH),127.7
(CH),127.0(CH),126.8(CH),106.3(C),55.2(CH),18.9(CH3).
374.1215/375.1248.
(S)6phenethyl4phenyl5(phenyltellanyl)3,4dihydro2H1,3oxazin2one(37qa)
Mp145149C;[]D20+145.4(c1.00,CHCl3,60%ee).
1
H NMR (300 MHz, CDCl3) 7.687.64 (m, 2H), 7.42
7.37(m,3H),7.317.16(m,10H),6.19(brd,J=2.6Hz,
1H),3.963.92(m,1H),2.862.65(m,2H),2.212.13(m,
37qa
2H).
13
CNMR(75.5MHz,CDCl3)153.4(C),151.0(C),140.4
(C), 133.5 (C), 131.6 (C), 130.0 (CH), 129.4 (CH), 129.0 (CH), 128.8 (CH), 128.6 (CH),
128.3 (CH), 127.9 (CH), 127.0 (CH), 126.2 (CH), 106.7 (C), 53.9 (CH), 37.0 (CH2), 30.3
(CH2).
HRMS (ESI) m/z: 388,1365/389.1397 [M+H]+ 100.0/26.0, C24H22NO2S requires
388,1371/389.1405.
337
Chapter5
(S)5((4fluorophenyl)selanyl)4,6diphenyl3,4dihydro2H1,3oxazin2one(37ad)
Mp111114C;[]D20+237.5(c1.00,CHCl3,88%ee).
1
HNMR(300MHz,CDCl3)7.747.67(m,2H),7.387.20
(m, 10H), 7.107.03 (m, 2H), 5.94 (br d, J = 1.6 Hz, 1H),
4.87(d,J=2.4Hz,1H).
37ad
13
152.0(C),149.8(C),140.5(C),133.5(C),131.2(d,J=8.6
Hz,CH),129.5(CH),129.0(CH),128.9(CH),128.6(CH),127.6(d,J=3.4Hz,C),127.1
(CH),127.0(CH),115.1(d,J=21.9Hz,CH),106.8(C),58.9(CH).
HRMS (ESI) m/z: 378.0960/379.0993 [M+H]+ 100.0/23.8, C22H17FNO2S requires
378.0964/379.0998.
(S)6(2methoxyphenyl)4phenyl5(phenylthio)3,4dihydro2H1,3oxazin2one
(37af)
Mp172179C;[]D20+165.8(c1.00,CHCl3,66%ee).
1
H NMR (300 MHz, CDCl3) 7.427.29 (m, 9H), 7.25
7.21(m,3H),6.98(td,J=7.5, 1.0 Hz,1H),6.92(d,J=

8.1Hz,1H),5.83(brd,J=1.2Hz,1H),4.87(d,J=2.3
Hz,1H),3.82(s,3H).
37af
13
CNMR(75.5MHz,CDCl3)157.4(C),150.1(C),141.0
(C), 132.2 (CH), 131.3 (CH), 130.9 (CH), 129.2 (CH),

129.1(C),128.9(CH),128.7(CH),127.40(CH),127.35(CH),122.4(C),120.2(CH),110.9
(CH),105.9(C),60.2(CH),55.5(CH3).
390.1164/391.1197.
338
Chapter5
5.5.2.7.Synthesisandcharacterizationof5phenyltellanyl1,3oxazin2
ones38
Preparation of the phenyltelluryl bromide solution:116 Bromine (10 L, 0.2
mmol)wasaddedtoaflaskcontainingdiphenylditelluride(81.9mg,0.2mmol)in1,2
dichloroethane (0.4 mL) at 0 C. The reaction mixture was stirred for 15 min at this
temperature.
A0.5Msolutionofphenyltellurylbromidein1,2dichloroethane(0.3mL,0.15
mmol)isaddedtoasolutionofNCbzprotectedpropargylicamine11(0.10mmol)in
acetonitrile (2 mL) at 0 C. The solution was stirred until the reaction was complete
(TLC).Thereactionmixturewasconcentratedunderreducedpressure.Purificationby
flashchromatographyonsilicagelaffordedcompound38.
(S)4,6diphenyl5(phenyltellanyl)3,4dihydro2H1,3oxazin2one(38aa)
Mp6163C;[]D20+50.8(c0.39,CHCl3,87%ee).
38aa
H NMR (300 MHz, CDCl3) 7.527.47 (m, 4H), 7.437.39
(m,3H),7.357.30(m,4H),7.237.16(m,4H),5.97(brd,J
=1.6Hz,1H),4.86(d,J=2.4Hz,1H).
13
CNMR(75.5MHz,CDCl3)151.9(C),150.4(C),140.9(C),138.7(CH),134.4(C),130.0
113.0(C),89.1(C),62.5(CH).
HRMS (ESI) m/z: 458.0395/456.0379 [M+H]+ 100.0/93.1, C22H18NO2Te requires
458.0400/456.0382.
339
Chapter5
(S)6phenyl5(phenyltellanyl)4(ptolyl)3,4dihydro2H1,3oxazin2one(38ba)
Mp5458C;[]D20+58.4(c1.00,CHCl3,88%ee).
1
H NMR (300 MHz, CDCl3) 7.527.46 (m, 4H), 7.43
7.38 (m, 3H), 7.32 (tt, J = 7.1, 1.5 Hz, 1H), 7.19 (t, J =
7.34 Hz, 2H), 7.157.08 (m, 4H), 5.79 (br d, J =1.9 Hz,
1H),4.83(d,J=2.4Hz,1H),2.35(s,3H).
13
38ba
CNMR(75.5MHz,CDCl3)151.9(C),150.3(C),138.6
(C), 138.6 (CH), 138.1 (C), 134.5 (C), 130.0 (CH), 129.6
(CH), 129.5 (CH), 129.2 (CH), 128.6 (CH), 128.0 (CH), 127.2 (CH), 113.1 (C), 89.5 (C),
62.4(CH),21.2(CH3).
HRMS (ESI) m/z: 472,0554/470.0536 [M+H]+ 100.0/92.9, C23H20NO2Te requires
472,0556/470.0539.
(S)4cyclohexyl6phenyl5(phenyltellanyl)3,4dihydro2H1,3oxazin2one(38sa)
Mp6366C;[]D20+73.8(c1.00,CHCl3,54%ee).
1
H NMR (300 MHz, CDCl3) 7.707.66 (m, 2H), 7.47
7.40(m,4H),7.397.31(m,2H),7.23(tt,J=7.2,1.3Hz,
2H),5.90(brd,J=2.7Hz,1H),3.60(brt,J=2.7Hz,1H),
38sa
1.961.65(m,1H),1.781.65(m,5),1.261.07(m,5H).
13
C NMR (75.5 MHz, CDCl3) 152.2 (C), 138.9 (CH),
134.6 (C), 129.9 (CH), 129.6 (CH), 128.9 (CH), 128.8

(CH),128.0(CH),112.6(C),88.5(C),62.5(CH),42.5(CH),29.5(CH2),26.4(CH2),26.1
(CH2),25.9(CH2),24.9(CH2).
HRMS (ESI) m/z: 464.0865/462.0847 [M+H]+ 100.0/92.8, C22H24NO2Te requires
464.0869/462.0852.
340
Chapter5
(S)6(4chlorophenyl)4phenyl5(phenyltellanyl)3,4dihydro2H1,3oxazin2one
(38ae)
Mp6266C;[]D20+121.4(c1.00,CHCl3,91%ee).
1
HNMR(300MHz,CDCl3)7.487.45(m,2H),7.42(dt,
J = 8.7, 2.1 Hz, 2H), 7.377.29 (m, 6H), 7.237.16 (m,

4H),5.88(brd,J=1.7Hz,1H),4.90(d,J=2.4Hz,1H).
13
CNMR(75.5MHz,CDCl3)150.9(C),150.1(C),140.7
(C), 138.5 (CH), 136.0 (C), 132.8 (C), 130.5 (CH), 129.6
38ae
(CH), 129.0 (CH), 128.9 (CH), 128.7 (CH), 128.3 (CH),

127.3(CH),112.9(C),89.8(C),62.9(CH).
HRMS (ESI) m/z: 492.0006/489.9989 [M+H]+ 100.0/93.0, C22H17ClNO2Te requires
492.0010/489.9992.
(S)4phenyl5(phenyltellanyl)6(thiophen2yl)3,4dihydro2H1,3oxazin2one
(38ai)
Orangeoil;[]D20+87.8(c0.98,CHCl3,90%ee).
1
HNMR(300MHz,CDCl3)7.587.54(m,2H),7.53(dd,J
=3.8,1.2Hz,1H),7.43(dd,J=5.1,1.3Hz,1H),7.367.29
(m,4H),7.231.17(m,4H),7.09(dd,J=3.8, 5.2Hz,1H),
5.90(brd,J=1.8Hz,1H),4.88(d,J=2.6Hz,1H).
38ai
13
C NMR (75.5 MHz, CDCl3) 150.0 (C), 146.3 (C), 140.8
(C), 138.2 (CH), 135.5 (C), 130.1 (CH), 129.7 (CH), 129.0
(CH),128.74(CH),128.68(CH),128.5(CH),127.3(CH),126.8(CH),113.4(C),88.5(C),
63.2(CH).
HRMS (ESI) m/z: 463.9960/461.9942 [M+H]+ 100.0/92.8, C20H16NO2STe requires
463.9964/461.9946.
341
Chapter5
(S)6phenethyl4phenyl5(phenyltellanyl)3,4dihydro2H1,3oxazin2one(38ak)
20
Yellowoil;[]D 12.1(c1.00,CHCl3,82%ee)
1
H NMR (300 MHz, CDCl3) 7.397.36 (m, 2H), 7.29
7.23(m,6H),7.217.13(m,5H),7.037.00(m,2H),5.64
(brd,J=1.0Hz,1H),4.84(brs,1H),3.143.05(m,2H),
38ak
2.972.91(m,2H).
13
CNMR(75.5MHz,CDCl3)154.6(C),150.1(C),141.0
(C), 139.9 (C), 137.0 (CH), 129.5 (CH), 128.82 (CH),

128.76(CH),128.6(CH),128.5(CH),128.1(CH),127.4(CH),126.3(CH),113.3(C),89.4
(C),63.2(CH),37.7(CH2),33.0(CH2).
HRMS (ESI) m/z: 486.0711/484.0692 [M+H]+ 100/92.7, C24H22NO2Te requires
486.0713/484.0695.
5.5.2.8. Synthesis and characterization of (S)4,6diphenyl5((S)

phenylsulfinyl)3,4dihydro2H1,3oxazin2one(42)117
To a solution of (S)4,6diphenyl5(phenylthio)3,4dihydro2H1,3oxazin2
one (37aa) (18.0 mg, 0.05 mmol) and phenol (54 L, 0.60 mmol) in 1,1,1,3,3,3
hexafluoro2propanol (0.4 mL) was added 30% H2O2 (10.2 L, 0.10 mmol). The
reaction mixture was stirred at room temperature until the disappearance of the
reactant monitored by TLC, the excess H2O2 was quenched with saturated aqueous
Na2SO3. Phenol was neutralized with 10% aqueous NaOH. The aqueous layer was
extracted with EtOAc (2 3 mL). The combined organic layers were dried over
anhydrousMgSO4andconcentratedundervacuumtoaffordthecrudeproduct,which
waspurifiedbyflashcolumnchromatographyonsilicagelusinghexane/ethylacetate
as the eluent to afford 42. Only the major diastereoisomer was characterized (99%
yield,1:2.5dr).
342
Chapter5
Mp159161C;[]D20+43.0(c0.70,CHCl3,87%ee)
1
H NMR (300 MHz, DMSOd6) 8.358.32 (m, 2H), 8.14
(br d, J = 2.3 Hz, 1H), 8.098.04 (m, 8H), 7.927.77 (m,

5H),5.21(brd,J=2.8Hz,1H).
42
13
C NMR (75.5 MHz, DMSOd6) 168.4 (C), 158.9 (C),
153.8 (C), 152.5 (C), 141.9 (CH), 141.6 (CH), 141.4 (C),
140.1 (CH), 140.0 (CH), 139.4 (CH), 139.2 (CH), 138.7 (CH), 137.3 (CH), 135.1 (CH),
130.1(C),63.6(CH).
HRMS (ESI) m/z: 375.9906/376.9911 [M+H]+ 100/24.4, C22H18NOsS requires
376.1002/377.1036.
343
Chapter5
5.5.3.Additionalcomputationaldata
Table 5.17. B3LYP/6311G* Total (E, in au) relative (E, in kcal/mol, relative to 11ta or 11tq
plus halogen X2) energies, in gas phase and in acetonitrile, of the TSs, intermediates and
productofthehalogenmediatedcyclizationofprotectedpropargylicamines11taand11tq.
Gasphase
Acetonitrile
11ta
670.422630
670.436638
Br2
5148.283942
5148.285454
MC1Br
5818.711928
3.4
5818.723724
1.0
TS1endoBr
5818.683616
14.4
5818.721217
0.5
TS1exoBr
5818.678737
17.5
5818.708764
8.4
IN1endoBr
5818.686248
12.8
5818.753998
20.0
IN1exoBr
5818.681583
15.7
5818.752981
19.4
TS2endoBr
5818.692105
9.1
5818.733748
7.3
TS2exoBr
5818.691176
9.7
5818.735663
8.5
34ta+MeBr
5818.754904
30.3
5818.767702
28.6
40ta+MeBr
5818.759735
33.4
5818.772849
31.8
Cl2
920.405676
920.406713
MC1Cl
1590.833574
3.3
1590.845281
1.2
TS1endoCl
1590.813192
9.5
1590.863822
12.8
IN1endoCl
1590.823147
3.2
1590.909108
41.3
TS2endoCl
1590.845367
10.7
1590.889659
29.1
35ta+MeCl
1590.912542
52.9
1590.925218
51.4
11aq
478.643497
478.653276
MC2Br
5626.935241
4.9
5626.945236
4.1
TS3endoBr
5626.909958
11.0
5626.935527
2.0
TS3exoBr
5626.903185
15.2
5626.933514
3.3
IN3endoBr
5626.914192
8.3
5626.982556
27.5
IN3exoBr
5626.905634
13.7
5626.979213
25.4
344
Chapter5
Table5.18.Totalaandrelativeenergiesinacetonitrile
(in kcal/mol, relative to 11aa plus PhSeCl) of the
stationarypointsinvolvedincyclizationof11aa.
11aa
1093.306676
MC
4186.786573
0.8
TS1endo
4186.778112
4.5
IN1endo
4186.805353
12.6
TS2endo
4186.792541
4.6
2endo
3455.569547
22.6
TS1exo
4186.767667
11.1
IN1exo
4186.805128
12.5
TS2exo
4186.793389
5.1
2exo
3455.572583
24.4
Total energies of PhSeCl 3093.478606 au and
PhCH2Cl731.2516743au.
345
Chapter5
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352
CH2Cl2
ANEXOS
O
Ph
P
N
Ph
O
i Pr
HN
Ph
Et2Zn
2Z
OH
MeO
Br
Me
Me HN
OH
O
Ph
HN
O
O
O
H
OH
OH
Se
CH2Cl2
Anexos
ANEXOI.Alquinos
355
Anexos
ANEXOII.Aldehdos
O
H
Me
5a
5b
5c
5f
Cl
5m
O
H
5n
5p
O
H
5r
5o
356
5l
5q
5k
O
O
H
5j
O
5h
5i
5g
Me
Br
OMe O
Me
5e
5d
O
Cl
MeO
5s
Anexos
ANEEXOIII.Reelacindepublicacioonesderivvadasdee
estatesis
357
Anexos
358
Anexos
359
Anexos
360
Anexos
361

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SO2Cl2

Alquinilacin enantioselectiva de iminas:

Alicia Monlen Ventura

Introduccin y objetivos generales

enantiomricamente puras se basaban en la utilizacin de fuentes naturales

En trminos generales, son cuatro los mtodos que permiten la sntesis de

En esta ltima aproximacin, se aprovecha la acidez del protn acetilnico

La utilizacin de complejos de metales de transicin y ligandos quirales como

Uno de los inconvenientes derivados de la utilizacin de iminas es su posible

Los reactivos de dialquilzinc reaccionan con oxgeno molecular dando lugar a

Las especies obtenidas tras la oxidacin controlada de los reactivos de

Por otra parte, las aminas proparglicas obtenidas en la reaccin de

Asimismo, la ciclacicin electroflica mediada por halgenos o calcgenos a

La regioselectividad de estas ciclaciones electroflicas no siempre se consigue

Adicin enantioselectiva de alquinos terminales aN(difenilfosfinoil)iminas

Ciclacin regioselectiva de aminas proparglicas NCbzprotegidas mediada

Adicin enantioselectiva de alquinos

Chan y colaboradores emplearon un sistema cataltico similar para la

Los autores propusieron un mecanismo (Esquema 2.7) que implica la

En 2009, estos mismos autores publicaron la primera adicin cataltica

Debido a la baja estabilidad que presentan los imino steres, Chan y

con rendimientos buenos (6180%) y enantioselectividades moderadas tanto con

Los autores tambin llevaron a cabo la alquinilacin enantioselectiva de sales

Con el objetivo de mejorar los resultados de las reacciones de alquinilacin

Los mejores resultados se alcanzaron con 5 mol % de CuPF6 y el ligando

En 2010, Boysen sintetiz un nuevo ligando quiral de tipo PyBOX en el que

Moberg y Levacher disearon un nuevo ligando PyBOX unido a polmero de

Los resultados fueron similares a los hallados en disolucin homognea. El

El grupo de Benaglia24,25 introdujo un nuevo tipo de catalizadores quirales

Los mejores resultados se consiguieron con la bisimina en la que el

rendimientos entre buenos y excelentes y enantioselectividades hasta 80% ee. La

Estos autores aplicaron el mismo sistema cataltico a una versin de tres

En 2007, Chan y Li29,30 disearon una nueva clase de ligandos quirales

Ligando (20 mol %)

Simultneamente al trabajo pionero desarrollado por Wei y Li,3,4 el grupo de

La enantioselectividad de la reaccin aument con el tamao de los grupos

cuenta este hecho, propusieron un mecanismo de reaccin (Esquema 2.25) segn el

Con el objetivo de evitar la preparacin de enaminas sensibles y extender la

La alquinilacin requiri tiempos de reaccin largos (16 das), pero las

ello, desarrollaron la reaccin con bis(fenilalil)aminas. Estas proporcionaron el

El sistema cataltico formado por CuBrQUINAP tambin se ha aplicado a la

Ligando (5,5 mol %)

Posteriormente, estos autores llevaron a cabo la misma reaccin utilizando

En 2009, Ardnsten y colaboradores41 examinaron la adicin de alquinos a

quiral de tipo aminocido que se muestra en el Esquema 2.34 y en presencia de

Estos mismos autores desarrollaron la sntesis de aminas proparglicas

Posteriormente, Jiang y Si46 describieron la aplicacin del aminoalcohol

Los autores tambin sintetizaron los enantimeros opuestos de los productos

Teniendo en cuenta que la presencia de grupos electrnaceptores en el

Se obtuvieron enantioselectividades elevadas (87>99% ee) con diferentes N

En 2008, el grupo de Wang53 public la alquinilacin enantioselectiva de N

En 2010, este mismo grupo dise y sintetiz un conjunto de ligandos

2. Identificacin de las condiciones ptimas de reaccin: Influencia de la

3. Alcance y limitaciones de la reaccin: Evaluacin de diversas N

4. Alcance y limitaciones de la reaccin: Evaluacin de distintos alquinos

5. Desproteccin del grupo amino en los productos de alquinilacin para

6. Determinacin de la configuracin absoluta del centro estereognico

La numeracin de los aldehdos se corresponde con la indicada en el

Anexo II. b Rendimiento de producto aislado por cromatografa de

Todos los intentos de sintetizar la N(difenilfosfinoil)imina derivada del

Debido a que la aplicacin de este nuevo procedimiento (Procedimiento B,

El ligando L1, que soporta el sustituyente de menor tamao (X1 = H),

mLconLy0,4mLconlaimina. cRendimientodeproductoaislado. d DeterminadoporHPLC