Heterocyclic Chemistry 5th Edition 2010

All Answers to Exercises

Chapter 8

OEt f. HNO3, c. H2SO4 OEt

100 °C
ch8 1(i) N N NO2 Electrophilic substitution ortho to EtO

Me Me CO2H
Br2, c. H2SO4 Br Br
oleum KMnO4, heat
Electrophilic !-
ch8 1(ii) N N N substitution
then side-chain oxidation

KHN(CH2)2NMe2
heat

ch8 2 N N NH(CH2)2NMe2 Chichibabin reaction (!-substitution)

N2H4
ch8 3(i)(a) N Cl N NHNH2 Nucleophilic displacement of an !-chlorine

H2O
ch8 3(i)(b) N Cl N OH N O
H
Nucleophilic displacement of an !-chlorine
then tautomerism to 2-pyridone

NO2 OH O

H2O, 60 °C

ch8 3(ii) N N N
H
Nucleophilic displacement of a !-nitro
then tautomerism to 4-pyridone
 Cl OMe OMe O

NaOMe MeI 185 °C

+
ch8 4 N N N – N
Me I Me
Nucleophilic displacement of a !-chlorine
then quaternisation at ring nitrogen
then de-O-methylation by iodide attack

Br NH2
NH2
NaNH2, NH3(liq) + NH3
+
– HBr
ch8 5 N N N N
3,4-pyridyne

Br OMe

NaOMe

N N Nucleophilic displacement of a !-bromine

i-Pr2N O i-Pr2N O i-Pr2N O

OH
Ph
Li
LDA Ph2CO Ph

ch8 6(i) N N N
ortho-lithiation O
O
Ph

acid, heat Ph

lactonisation N

Li I
LDA I2
ch8 6(ii) N Cl N Cl N Cl
ortho-lithiation
 OH
Me Me
Li
F F F
LDA Me2CO

ch8 6(iii) N N N
ortho-lithiation
selective for C-4

n-BuLi, –78 °C Me3SnCl

ch8 6(iv) N Br N Li N SnMe3
metal/halogen exchange
then Me3SnCl as an electrophile

O2N O O2N O 2N
+ NaHCO3
Br
Me +
ch8 7 N Me N Me Deprotonation of N
Ring nitrogen Br– acidified methyl
quaternisation O O

Me Me
O 2N O2N

+ – H+ N
N
– H 2O
OH
Me Me

n-Bu3SnH, AIBN
+ I I +
I +
ch8 8 N N Intramolecular N
Ring nitrogen
I– I–
quaternisation radical substitution

Me Me H
HO
O3 Me
h! then NaBH4 HO

ch8 9 N O N O HN
H H O
 Me Me Me
NaNO2, H2SO4
NaNH2 0 °C to rt H2O

Chichibabin + Very easy nucleophilic

ch8 10 N N NH2 Diazotisation N N2 displacement of nitrogen
substitution
then tautomerism

Me Me CO2Et

MeI, NaOMe (CO2Et)2, KOEt

O-Methylation of
N O N OMe N OMe
H pyridone anion
Deprotonation of !-methyl
then condensation with diethyl oxalate

NH2

do have
has no and activating amino
+ activating + +
ch8 11 NH3 N NH2 N substituent
substituent H H

OH OH O–
Br
+ base
+ +
ch8 12 N Quaternisation of N – H+ N
ring nitrogen Br –

Intramolecular O
1,3-dipolar cycloaddition
N

Final tautomerism
ch8 13 N – CO2 N N Me to aromatic product
H
H
O O
 AcHN CO2Et AcHN CO2Et AcHN CO2Et
–

+ H+

–
ch8 14 N N N

Me Me Me
n-BuLi PhS–SPh
SPh
ch8 15(i) N Me Selective N CH2Li N
deprotonation
of 2-methyl

Me CH2Br
NBS PhSH SPh

ch8 15(ii) N Me Selective N Me N Me

radical bromination
of 3-methyl

CN CN CN CN CN
K3Fe(CN)6, NaOH [O]
H H +
+ + 4:3
ch8 16 N – HO N N OH O N N O
Me I Me Me Me Me
Hydroxide !-adducts
trapped by oxidant

H
– –
+D + H+ H +D
H H
+ Enamine +
ch8 17 N N N D N D
n-Bu I
– n-Bu D !-protonation n-Bu D Bu

ClCO2Me
– h! Acylation of ring nitrogen
then NaBH4 +H
+ then hydride addition to C-2
ch8 18 N N N N then electrocyclisation
– CO2Me
Cl CO2Me CO2Me
 NO2 NO2 NO2 NH2
c. HNO3, c. H2SO4 H2, Pd/C
heat PCl3
+ +
ch8 19 N N N N
O– O– Nitration at C-4
assisted by electron release
by N-oxide
De-oxygenation of N-oxide
producing POCl3

O CH2Ph O O O O Me O
Me H
MeO H O OMe MeO OMe
NH3 MeO OMe
[O]
Hantzsch
ch8 20 Me O O Me Me N Me Me N Me synthesis
H

(CH2)2OH
H2NOH, HCl (CH2)2OH
+
No final oxidation
O
ch8 21 O O O required using H2NOH N
Hetero Diels–Alder O O
cycloaddition
Synthon for a 1,5-dialdehyde

Et Et
CN CN
O
+ Oxidation level of ester
ch8 22(a)(i) EtO O H 2N O HO N O leads to oxy-pyridine
H
 CN

O +
CN
ch8 22(a)(ii) H2N O
Me O
Me N O
H

CN CN

EtO +
Oxidation level of ester
ch8 22(a)(iii) H2N O HO N O leads to oxy-pyridine
O H
Synthon for
1,3-aldehydo-ester

CO2Et CO2Et

Me +
ch8 22(b)(i) O Me N Me
H2N Me
Synthon for
1,3-keto-aldehyde

OEt
CO2Et EtO2C CO2Et
EtO2C
+
ch8 22(b)(ii) H2N Me Me N Me
Me O
Synthon for
1,3-keto-aldehyde

ONa O O

Me Me
+
ch8 23 Me O H2N Me N

Chapter 9

+
NO2

ch9 1(i) N N

Substituent benzene ring

much more reactive than the
NO2 isoquinoline benzene ring
 NO2 NO2
MeO + MeO
NO2
ortho to the activating group
ch9 1(ii) N N and at C-5 rather than C-7

+
NO2
ortho to the activating group
ch9 1(iii) MeO N N
MeO and at C-8 rather than C-7
NO2 NO2

H Br H Br
Br
Br2
+ Br– Br2 H
ch9 2 + +
N N N enamine N
–
Br Br Br !-bromination Br

Br Br
–
Br
– HBr + – Br2
N N
Br

Cl Cl
NaCH(CO2Et)2
ch9 3 N N

Cl CH(CO2Et)2
Of the two !-type positions
the isoquinoline 1-position is much more reactive

Li Li
3n-BuLi O

ch9 4 N NHCOt-Bu N N t-Bu

ortho-Lithiation

SMe
MeS–SMe

N NHCO-t-Bu
 H H

NaBH4 +
+ –
ch9 5 NMe I NMe enamine NMe
!-protonation
H H H H

NaBH4
NMe

OH
OH

ch9 6 NH N N
N
O OH

O O
H
+ Me OMe CO2Me DMF, POCl3
ch9 7 – H2O enamine
NH2 N
H !-formylation
Me
(Vilsmeier reaction)
H H
O Cl CO2Me
CO2Me CO2Me
– HCl
+
N N N Me
H Me probable intermediate H Me
for electrophilic ring closure

O
CO2Me
H
+ CO2Me
ch9 8(i) – MeOH
NH2 N N CO2Me
CO2Me H CO2Me H
MeO MeO MeO
Addition of the aniline to activated alkyne
is an alternative to condensation with 1,3-dicarbonyl compond
 EtO2C CO2Et EtO2C
+ CO2Me 250 °C
ch9 8(ii)Cl Cl – EtOH
NH2 H OEt N
H CO2Me
O O
O
C CO2Me CO2H
CO2Me aq. NaOH

Cl N Cl N Cl N
CO2Me H H
probable intermediate
for electrocyclic ring closure

O CO2Na CO2H

NaOH O Me
O +
ch9 9(i) N NH2 O Ph N Ph
H
Pfitzinger variation
of Friedländer synthesis

O CO2K
Cl
KOH O
O +
ch9 9(ii) N NH2 O CO2H
H

CO2H CO2H
OH OH

– CO2
N CO2H N
Like decarboxylation
of a !-keto-acid

NaO2C CO2H
O
O
NaOH
O Me
ch9 9(iii) N N O
Ac N
H O H
 H O O

O NH NH
+
ch9 10(i) NH2 O N O N N O
H H
Friedländer synthesis
many variations are possible

H H
CO2Me
O O O
O
+ CO2Me
ch9 10(ii) O NH2 O
CO2Me N
Friedländer synthesis H CO2Me
many variations are possible Addition of the aniline to activated alkyne
produces likely intermediate

O CO2Me

O N CO2Me

Me Me

O Me
+
ch9 10(iii) S S
NH2 O N

Friedländer synthesis
many variations are possible

Ph O O

O
+ Me Me
ch9 10(iv) O N
NH2 Me Me
Friedländer synthesis
many variations are possible

H
SO2Ph SO2Ph
O + Friedländer synthesis
ch9 10(v) many variations are possible
N NH2 O Me N N Me
 H

N O + N
ch9 10(vi) O
N NH2 N N

Friedländer synthesis
many variations are possible

Chapter 11

Me Me Me Me

PhNH2
Me HO
+
ch11 1 Me O Me Me O Me O HN Me Me N Me
NHPh Ph Ph
Me

+ H+ Nucleophilic addition at C-2

– H 2O then electrocyclic ring opening
+ and ring closure
Me N Me
Ph

Ph
Ph Ph

Ph3P=CH2
Ph
+ Ph Ph
ch11 2 Ph O Ph Ph O + O
CH2PPh3 Electrocyclic
ring opening Ph3P+

Ph

Ph3P=CH2
– H+
Ph Ph
Wittig reaction to close

O OMe OMe
–
HO HO O
MeOTf
– + +
ch11 3 O Me TfO O Me O Me
Powerful alkylating agent
reacts at carbonyl oxygen
OMe
O
CN
O
1,3-Dipolar Me
cycloaddition
CN
 O O O O O
+ H
H
PhNH2 H
– H2O
ch11 4 O O HN HO N N
O NHPh
Ph Ph Ph

MeO2C MeO2C MeO2C

PhCH2NH2
H O – H2O
O O O NH N O
Bn
Bn
Amine attack at carbonyl carbon
ring opening and reclosure

t-Bu
t-Bu t-Bu
t-Bu
O H
– Ph3C+ ClO4–
Me CH3
ch11 5(i) +
t-Bu t-Bu t-Bu O t-Bu
t-Bu O t-Bu O O t-Bu O O
Aldol Michael Oxidation required at end
to achieve aromatic oxidaiton level

Ac2O, HClO4
ch11 5(ii)
– H 2O
Me
+
Me O Me O Me
Me
O O

Alkene acylations
'Aliphatic Friedel–Crafts reactions'

H
Ac2O
Me O HClO4 + H+
ch11 5(iii)
– H2O +
O Ph Me O O Ph Me O Ph
Me O Aldol

O O O O
CO2H
Me
c. HCl, heat
ch11 6 Me O OH Me Me – CO2 Me O Me
O O – H2O
 Me
Me OH Me OH
EtO2C EtO2C EtO2C
O
ch11 7 CO2Et CO2Et CO2Et
Me OH Me O Me OH
Me
EtO2C

– EtOH – H2O
Me O O

Ph
Ph
Me Enolate addition to
+ CO2Et
NaOEt activated alkyne
ch11 8(i) Ph O Ph O O then lactonisation

O
Et CO2H Et
Et Et
+ CO2H
PPA, 200 °C
CO2H HO2C
ch11 8(ii) n-Pr n-Pr – CO2 n-Pr O n-Pr

O
HO2C COn-Bu
COn-Bu First step probably
+ CDI activation of acid by CDI
ch11 8(iii) n-Bu O CO2H n-Bu O OH then C-acylation

O O

Me NaH First step probably

+ Claisen condensaation
ch11 8(iv) MeO2C
Ph O C6H4-p-Cl Ph O C6H4-p-Cl

O O
First step probably
Cl Me
KOt-Bu acylation by acid chloride
+ Note enol ether
ch11 8(v) Ph O OMe Ph O synthon for aldehyde
Chapter 12

H
Me Me
O
+
ch12 1 + +
O Me HO O
Cl – Selective condensation Cl –
at !-methyl HO

Me
pyridine

O
O

O
O O O
Me
CO2Me NaOH Ac
then HCl
O
– MeOH
ch12 2 O OH
O Me OH OMe
–
O
CO2Me

Me
O
OH
Initial addition at C-2

H
OMe OMe PhMgBr OMe
O Ac2O, heat then HCl
+
ch12 3 CO2Na +
OH Perkin condensation O O O Ph
then lactonisation Cl –
 Ph Ph

O HCl, AcOH
+
ch12 4(i) HO +
OH O Me HO O Me
Cl –
O O
Ph Ph

– H2O
HO O OH HO O
Me Me
Probable first intermediates

O
O
MeO
MeO2C
H2SO4
+
ch12 4(ii) HO OH HO O HO
O O
Probably via

Chapter 14

O Cl OMe OPOCl2
POCl3 NaOMe
+
NH N Nucleophilic N NH
ch14 1(i) N N N N
Attack at amide-type displacement
carbonyl oxygen of !-chlorine Nucleophilic displacement
of !-dichlorophosphate by chloride

N N
BuNH2, 120 °C Nucleophilic
displacement
ch14 1(ii) N Cl N NHBu of !-chlorine

SMe SMe Cl Cl
MeI MeI
N + N N + N
ch14 2(i) N N Me N Me N
Me I
– Me I –
Regioselectivity of quaternisation
of nitrogen in diazines is not easy to predict
 N N Li N CHO
LiTMP HCO2Et

ch14 2(ii) Cl N Cl Cl N Cl Cl N Cl
ortho-Lithiation

Ph
N LiTMP N I N
then I2 HC!CPh, Pd(0)

ch14 2(iii) MeO N OMe MeO N OMe MeO N OMe

ortho-Lithiation Sonogashira coupling

N N N
HNO2, –5 °C Me2NH
+
ch14 3(i) N NH2 N N2 N NMe2

Easy nucleophilic displacement

of nitrogen at !-position

Me Ph
PhCHO, Ac2O, heat
N N Condensation with
ch14 3(ii) Ph N Ph N methyl at an !-position

CO2H
O
O O AlCl O
O 3 N2H4
+ NH
14 4(i) Cl Cl Ar N
Friedel–Crafts
O
Br2, AcOH
– HBr NH
Ar N

Br2, MeOH Me Me aq. acid

Me Me
14 4(ii) O MeO O OMe
1,4-Addition to furan O O

Me
N2H4
N
– 2H2O Me N
 Me
Me
NH2 N
O +
+ –
14 5(i) CH(OMe)2 H 2N NH2 HCO3 N NH2
Synthon for
1,3-keto-aldehyde

OEt O
NH2 NaOEt
O + NH Nitrile leads to amino-heterocycle
HN NH2 Ester leads to oxy-heterocycle
14 5(ii) H2N N NH2
N

O
OEt
NH2 NaOEt NH
O +
Nitrile leads to amino-heterocycle
H2N O H2N N O Ester leads to oxy-heterocycle
H
14 5(iii) N

CH(OEt)2 NH2 N
NaOEt 1,1,3,3-Tetraethoxypropane
+
synthon for malondialdehyde
14 5(iv) CH(OEt)2 H2N O N O
H

MeO MeO MeO

NH2 N
HCO2Et, Na O +
14 6(i)
Me O Claisen Me O H 2N S Me N S
condensation H
MeO
H2, Ni N

Me N
Hydrogenolysis of sulfur
with Raney nickel
 Ph Ph

NH2 N
O +
14 6(ii)
CO2Me HN Et O N Et
H

H
O NH2 O Ph O N Ph
+
14 6(iii)
Me NH2 O Me N

Chapter 16

NO2

HNO3, Ac2O + !-Position preferred

Me O 2N Me 6:1 Me
ch16 1 N N N for electrophilic substitution
H H H Even mild electrophiles react well.

CCl3COCl CCl3 Br2 CCl3

ch16 2(i) N N
H !-Position preferred H
for electrophilic substitution
Br
N
tendency for !-position H
O O
substitution dominant

NaOMe OMe
Br
N
H O

Ac

DMF, POCl3 AcCl, AlCl3

ch16 2(ii) CHO CHO
N N N
H !-Position preferred H H
for Vilsmeier substitution
Deactivated pyrrole requires
Lewis acid catalyst for reaction.
meta-Directing group
controls regiochemistry
 DMF, POCl3 LiAlH4
Cl OHC Cl Me Cl
ch16 2(iii) N N N
H !-Position preferred H
for Vilsmeier substitution H

via HO – H 2O –
Cl H Cl
N N
H

PhCONMe2, POCl3
Ph
ch16 3(i) N N Vilsmeier !-substitution
H H
O

+ Me2N POCl3
Vilsmeier !-substitution
ch16 3(ii) N N N N
H O H H H
O

+ POCl3
Cyclic nature of this Vilsmeier intermediate
ch16 3(iii) N O N
N H ensures that it does not hydrolyse to ketone
H H N

H+ H
HCl
Me Me Me H
ch16 4 N N N
H H HN H +
HN
Me Me
ketone-like iminium ion not
sufficiently reactive
to attack a third pyrrole
+ Me
–H N
H N
Me

Zn, HCl +
Me Me Me Me Me Me
ch16 5 N N N
H H H
H
Reduction involves
Me + protonated pyrrole
NH Me
 CO2Me
N MeO2C CO2Me

160 °C CO2Me
+ MeO2C CO2Me
ch16 6(i) N – H H N
CO2Me CO2Me CO2Me
Diels–Alder addition and then reverse Diels–Alder loss of ethyne

NCO2Me NCO2Me

1O N O
2
O Me
ch16 6(ii) SnCl2
N N N via
O
CO2Me O CO2Me Me
Diels–Alder addition of singlet oxygen

CH2O, Me2NH
ch16 7 AcOH +
NMe2 MeI NMe3
N Mannich substitution N N
H at pyrrole !"position H H
Me
+ C5H11N
electrophile = N N
Me N
H

via
N HN
H+

H H n-PrNH2, H+
ch16 8(i) MeO O OMe N
Synthon for n-Pr
succindialdehyde

H H NH2
S
ch16 8(ii) MeO O OMe N
Synthon for
succindialdehyde S

H H PhSO2NH2
ch16 8(iii) MeO O OMe N
Synthon for O S O
succindialdehyde
Ph
 O
Me O Me Me
O O
16 9 HNO2 Zn, AcOH Me
+
EtO2C EtO2C NOH EtO2C NH2 O Me

hydrolyse, Me Et
Me Ac then – CO2,
then N2H4, EtONa

EtO2C Me H Me
N N
H H

Me Me CO2Et
O CO2Et
16 10(i) +
– + CO2Et
Cl NH2 O CO2Et N
H

Me CO2Et
Me O CO2Et
Na2S2O4
+ Reduction of oxime to
16 10(ii)
Me NOH O Me Me Me amino in situ
N
H

H 2N CO2Et
CO2Et
CN Nitrile instead of carbonyl
16 10(iii) + leads to amino-substituted
NH2 O Me Me heterocycle
N
H

Me Me Me Me
Me
Me
O O NaOEt
16 10(iv) Me +
Enamine Aldol Me CO2Et
O H2N CO2Et Me N CO2Et N
formation H H
Chapter 17

O2N O2N

ClSO3H f. HNO3 H2O, heat

SO3H SO3H H
ch17 1 S S S S
!-Position preferred meta-Directing group
for electrophilic substitution dominates
AcONO2
O2N
S S

NO2
HNO3, AcOH
>
–20 °C
OMe O2N OMe OMe
ch17 2 S S S
!-Selectivity dominates

(EtCO)2O, H3PO4 Et Strong benzene-type

conditions can be used
ch17 3(i) S S with thiophenes
O

t-Bu t-Bu

PhN(Me)CHO, POCl3
Selectivity for the less-hindered
OHC of two !-positions
ch17 3(ii) S S

Tl(O2CCF3)2 aq. KI
TlO2CCF3 I
ch17 3(iii) S S S

OMe OMe

n-BuLi n-BuLi
OMe Li OMe Li
ch17 4 S S S S
Selectivity for !-position Selectivity for that !-position
in lithiation dominates over ortho-directivity which is also ortho to methoxyl

Br Br Br Br Br Br

Mg then H2O Mg then H2O

Br Br Br H H H
ch17 5 S Grignard formation S S
preferred at an !-position
 n-BuLi CO2 S P4O10
Li CO2H
ch17 6 S S S S S
Lithiation selective Friedel–Crafts type O
for an !-position conditions usable with thiophenes

NC CN NC CN
H2S
ch17 7(i) NC CN Nitrile cyclisations
H2N NH2 lead to amino-substituted heterocycles
S

EtO OEt HO OH MeO OMe

NaOEt aq. NaOH, MeI

ch17 7(ii) O O
EtO2C CO2Et HO2C CO2H
EtO2C S CO2Et S S

Double Claisen condensation

P4S10
ch17 7(iii) Me

O S Me
O

Chapter 18

+ H – OMe
+H + HO
OMe + OMe O
ch18 1 O ! protonation H O O O H – MeOH O
H H+
+ H – H
+H + HO CO2Me
OMe + OMe H O OMe H
O " protonation O O O

DMF, POCl3
then aq. NaOH
ch18 2(i) Ph OHC Ph
O O Furan ring far more reactive
than substituent phenyl ring
 !-Position preferred
Ac2O, SnCl4
CO2Et Ac CO2Et for electrophilic substitution
ch18 2(ii) O O Mild Lewis acids must be used

CN CN

HNO3, Ac2O Nitrile substitutent stabilises the system

O 2N and allows use of more vigorous reagents
ch18 2(iii) O O

Cl3CCHO
Cl3C CO2Me Cl3C
H2SO4 O
CO2Me CO2Et CO2Et
ch18 2(iv) O O via + O
– H2O
HO

!-Position preferred
for electrophilic substitution
MeO2C CO2Me
of furans O O
CCl3

[O] MeOH MeO OMe H2, catalyst MeO OMe

ch18 3 Me CH2OH
O Me O CH2OH Me O CH2OH
O 1,4-Diketone synthon

+ O
H3O
Me – H2O OH
O CH2OH
Aldol
Me

CO2Me CH2Cl Me
LiAlH4 Br2, MeOH
then SOCl2 LiAlH4
Me Me Me
ch18 4 O O O

Me Me Me
H2O, 60 °C NaBH4
MeO OMe
OHC HOH2C Me
Me
H O Me O HO H
1,4-Keto-aldehyde synthon
 c-C6H10O
ch18 5(i) Li
O O
HO
Lithiation selective
for an !"position

Br(CH2)7Cl Cl
ch18 5(ii) Li
O O
Lithiation selective
for an !"position

Me Me
DMF, POCl3
then aq. NaOH Vilsmeier substitution
OHC
ch18 6(i) O O at the less-hindered !-position

Br Br Br
n-BuLi
then H2O
ch18 6(ii)
Br Li H
O Metallation O O
selective for !-position

Br Br Br
LDA
then CH2O
ch18 6(iii) Li CH2OH
O O O
Lithiation at that !-position
which is also ortho to Br

n-BuLi
EtOH, H+ then B(OBu)3
ch18 6(iv) CHO CH(OEt)2 Li CH(OEt)2
O O O
Lithiation selective
for an !-position

+
H3O
(BuO)2B CHO (HO)2B CHO
O O
 O
Br Sn-n-Bu3 Me
n-BuLi, –78 °C
then n-Bu3SnCl MeCOCl, PdCl2
ch18 6(v) O O ipso substitution of tin O
allows formation of 3-acyl-furan

O CH OH
2
CN
CN
C Furans behave like 1,3-dienes and undergo
18 7(i) CH2OH
O Diels–Alder cycloadditions
CH2

O O
Me
Me
Ac Furans behave like 1,3-dienes and undergo
Diels–Alder cycloadditions
Me Me
18 7(ii) O Me

Cl O

Et3N, LiClO4 Furans behave like 1,3-dienes and undergo

+ cycloadditionsm with 1,3-dipoles
18 7(iii) O O
O

TMSCl
Et3N, ZnCl2 O-Silylation of butenolides
O OTMS
18 8(i) O O gives 2-trimethylsilyloxy-furans

Electrophilic substitution
ICH2CN, AgO2CCF3 of 2-trimethylsilyloxy-furans
OTMS NCCH2 O produces 5-substituted butenolides
18 8(ii) O O

n-BuLi PhCHO Ph
Ot-Bu Li Ot-Bu Ot-Bu
18 9 O O O
Lithiation of furans HO
selective for an !"position

TsOH Ph
– C4H8 O
O
HO
 O O
H CrO3
MgBr
m-CPBA pyridine
Et Et Et Et
18 10(i) O HO HO O
O
BF3
Et via Et
O HO

Me
ClMg Me Me Me + Me
HC(OEt)3 m-CPBA H3O O
18 10(ii) O
OHC OHC – H2O
OH
O via

Me Me Me
ClCH2CO2Me, NaOMe O
heat
18 10(iii) (MeO)2HC O Darzens reaction (MeO)2HC
CO2Me CO2Me
O

CO2Me MeHN
MeHN MeHN
MeNH2 LiAlH4 +
H
HOH2C CO2Me O
MeO2C CO2Me O
ch18 11 CO2Me Selective reduction – other
ester is a vinylogous amide
HO
+
H3O
O
O

Chapter 20

O
NHMe

POCl3
+
Electrophilic substitution of indoles
ch20 1 N O N Vilsmeier reaction N preferred at a !-position
H Me H
 Me
Me Me
Me
Cl
+
+
ch20 2 N HO N HO Me
H H
Me Electrophilic attach on an indole
Me preferred at a !-position

Me

O Me

N
H

ch20 3
NH indole, H +
NH2 + NH2
via

N N N N
H H H H

–
+ NC
NMe2 –
NMe3 I
CH2O, Me2NH
MeI
AcOH via
ch20 4 N N selective
N N
H Mannich reaction H quaternisation H
preferred at indole !"position of amine
KCN

CN CO2H
NH2 +
LiAlH4 H3O

N N N
H H H
I Ph
Br PhB(OH)2, Pd(PPh3)4 Br
aq. Na2CO3
ch20 5(i) N Suzuki coupling N
PhSO2 PhSO2

CO2Et
I
CO2Et
Br Br
Pd(OAc)2, Ph3P, Et3N

ch20 5(ii) N Heck reaction N

PhSO2 PhSO2
 +
H Ph3PCH=CH2 Br– H
NaH Wittig

ch20 6 N O N O N
H Deprotonation of indole N–hydrogen –
gives indolyl anion nucleophilic at nitrogen
Ph3P+

Et

Me
N
Et Et H
Me Me
1,2-Migration and
+ H+ then loss of proton
Me
+
ch20 7 N N
H
Et
N
H

N NaH N
PhSO2Cl

ch20 8 N N
H PhSO2
Deprotonation of indole N–hydrogen
gives indolyl anion nucleophilic at nitrogen
OH
Li
N O N
t-BuLi, –100 °C

N N
PhSO2 PhSO2
Lithiation with
ortho-assistance from pyridine N

OH

+
N N
aq. NaOH HBr
–
N N Br
H H

I I I
n-BuLi LDA LDA
then I2 then PhSO2Cl then I2
I
ch20 9 N N N N
H Indolyl anion can react H Indolyl anion can react PhSO2 Lithiation at PhSO2
on N or C on N or C preferred !-position
 CH2OH HO
CH2
starting
+ indole
heat, H
– H2O + +
ch20 10 N N N N
H H H H

– CH2O
N N
H H

OH
OH

Fischer
+ synthesis
H H
+
ch20 11 O N
NHNH2 N N H
Synthon H
for 4-hydroxybutanal

N Me N CO2Et N
(CO2Et)2, NaOEt H2, Pd/C
CO2Et
O
ch20 12 NO2 Easy deprotonation NO2 N
of pyridine 2-methyl H
also ortho to nitro gorup Reduction of nitro to amino
then condensation with loss of water

Me CO2Et
(CO2Et)2, NaOEt H2, Pd/C
CO2Et
N N O N
NO2 Easy deprotonation NO2 N
of pyridine 4-methyl H
also ortho to nitro gorup Reduction of nitro to amino
then condensation with loss of water

MeO Me Deprotonation of methyl

– + ortho to nitro
DMFDMA MeO + N
then reaction with MeO(H)C=NMe2
H Me then loss of MeOH
NO2 NO2 NH2
Me NMe2
DMFDMA, heat TiCl3
ch20 13(i) N
NO2 NO2
H
Reduction of nitro
!-protonation of enamine, cyclisation
and loss of Me2NH
 MeO Me Deprotonation of methyl
– + ortho to nitro
DMFDMA MeO + N
then reaction with MeO(H)C=NMe2
H Me then loss of MeOH BnO
BnO BnO
Me NMe2
DMFDMA, heat H2, Pt

ch20 13(ii) NO2 N

NO2 H

Reduction of nitro
!-protonation of enamine, cyclisation
and loss of Me2NH

Deprotonation of methyl
MeO Me ortho to nitro
– +
DMFDMA MeO + N then reaction with MeO(H)C=NMe2
H Me then loss of MeOH
Me NMe2
DMFDMA, heat H2, Pd

ch20 13(iii) MeO N

NO2 MeO NO2 MeO H
Reduction of nitro
!-protonation of enamine, cyclisation
and loss of Me2NH

Deprotonation of methyl
MeO Me ortho to nitro
– +
DMFDMA MeO + N then reaction with MeO(H)C=NMe2
H Me then loss of MeOH
Me NMe2
DMFDMA, heat H2, Pd
ch20 13(iv) NO2 N
Me NO2
H
NO2 NO2 NH
Me2N
Reduction of nitro
!-protonation of enamine, cyclisation
and loss of Me2NH
Chapter 21
CO2Et
O
CO2Et PPA, heat
EtO2CCH2COCH2Cl
ch21 1 – H2O
SH S S

CONH2 NH
NH2
NH3 LIAlH4 HCO2H, heat H
O
S S S

N
POCl3, heat Intramolecular Vilsmeier
S

O
Me Me Me
Me Me
Me Me O Me Me
Me
Cl c. H2SO4 Me
ch21 2(i) O Me O
OH
Me Me
Me

Br
K2CO3 heat
ch21 2(ii) O O OH O O O O O OH
MeO MeO Claisen rearrangement MeO

H
O3 H+
O – H2O
O O OH O O O
MeO MeO

F3C LDA F3C CHO F 3C

then DMF HSCH2CO2Me
CO2Me
ch21 2(iii) F ortho lithiation F S

O2N O2N Me Me O2N

–
Me2C=NO Na+ c. HCl
Me
N – NH3
ch21 2(iv) F O O
 O
Cl PCl3 Cl O Cl Cl
then AlCl3
ch21 3 S S
S CO2H
Friedel–Crafts
H
H
N N N
PhNHNH2 Cl Cl
AcOH, heat Fischer indole synthesis
S S

Chapter 22

O O
CH2Br
t-Bu H2NCH2C!CH t-Bu N
ch22 1 CH2Br
H H
O

O NPh O O

500 °C t-Bu O t-Bu

NH NH NPh

Typical Diels–Alder reactivity of isoindoles O

H OSO3H H CN
CHO NaHSO3
then MeNH2 2KCN
NMe NMe
ch22 2(i) CHO
H OSO3H H CN

CN

NMe
– HCN
 NEt2 NEt2 O
n-BuLi
O then PhCHO O H+
O
ortho Lithiation OH
ch22 2(ii)
Ph
Ph H
Ph Ph
PhMgBr
O
then H+
1O
2 O
O
O Cycloaddition of singlet oxygen

Ph Ph

O O
CHO O O
(CH2OH)2, CuSO4 NaBH4
ch22 3 OH
CHO CHO

TsOH CO2Me
MeO2CC!CCO2Me
O O
CO2Me

Typical Diels–Alder reactivity

of isobenzofurans

O O

S + O S O
ch22 4
O Typical Diels–Alder reactivity O
of benzo[c]thiophenes

NaOH, heat CO2H

then H +

CO2H

Chapter 24

Cl
N N
NaOCl
Electrophilic substitution
ch24 1(i) N Cl N preferred at C-4(5)
H H
 Br Br
N N EtMgBr N
Br2, AcOH then H2O
Br Br Br MgBr
N N N
ch24 1(ii) Me Me Me
Sective Grignard
formation at C-2

Br Li MeO2C
n-BuLi
N N N
then (MeO)2CO
Br H Sective metal/halogen Br N Br
N exchange at C-4 N
Me Me Me

Ph Ac
O
N O
heat N Ac
+ H
ch24 2(i) O Me – PhCN O
Oxazoles (like furans) Ph Retro Diels–Alder
take part in Diels–Alder cycloadditions loss of benzonitrile

O
N CO2Me
heat N
+ MeO2CH2 CO2Me
EtO
ch24 2(ii) O Oxazoles (like furans) EtO
take part in Diels–Alder cycloadditions CO2Me

MeO2C CO2Me

– HCN OEt
Retro Diels–Alder O
loss of HCN

N (t-BuO)2NMe2 N
heat NMe2 Ac2O, heat
O 2N Me O2N
ch24 3i/ii N N
Me Me enamine !-acetylation

N
NMe2
O 2N
N
Me
O
Me
NH2
1,3-aldehydo-ketone
synthon
HN NH2 MeNHNH2

N N Me
N O 2N
O2N N
N Me NMe
Me NH2
N N
Me
 N n-BuLi N N n-BuLi
then TMSCl then TMSCl
Li SiMe3 Selective lithiation
ch24 4 N Selective lithiation N N
Me at C-2 Me Me at C-5 if C-2 blocked

N N N
MeOH
Li Me3Si SiMe3 Me3Si H
SiMe3 N Selective N
N Me Me
Me ipso protonolysis

Br Li OHC
N n-BuLi, –78 °C N N
then DMF
ch24 5 N N N
Me Me Me

Br Li
N
N n-BuLi, –78 °C ! 0 °C N N
then DMF CHO
Li N
N N N Me
Me Me equilibration to Me
more stable lithium compond

+ –
NH NH Br N
Br(CH2)3Br
S
S
S-Alkylation S
S(CH2)3Br – H+ S(CH2)3Br
ch24 6 S

Br– +
N

S
S

Et
Et O NH2 N
+
S NH2 NH2
ch24 7(i) Cl S

H O NH2 N
+
S Ph Ph
ch24 7(ii) Cl S
 HO
EtO2C O NH2 N
+ ester oxidation level
S H leads to oxy-heterocycle
ch24 7(iii) Br S

Ph
Ph O heat
+ N
NH4 HCO2– AcOH2C CH2OAc

ch24 8 Br O

O AcOCH2 CH2OAc

N CH2OAc Diels–Alder
– PhCN then retro-Diels–Alder
Ph O
CH2OAc

N
n-BuLi PhCN
ch24 9(i) Me N C LiH2C N C Ph
N
H

NH2 Ph
Ph O
N
ch24 9(ii) +
N Ph NH2 Use of nitrile in cyclisation
Ph NH2 N leads to amino-heterocycle
H

Chapter 25

O2N

c. HNO3, c. H2SO4
N N via attack on salt +
ch25 1(i) NH
N N (but positively charged heterocycle
Ph Ph N
still more reactive than the phenyl group) Ph

HNO3, Ac2O
N N via attack on the neutral pyrazole
ch25 1(ii) O2N
N N
Ph Ph

Me Me Me

NaNH2 n-PrBr n-Pr

Me N N N
ch25 2(i) NaH2C
O O O
Selective deprotonation
of 5-methyl
 Me Me Me

NaNH2 CO2 HO2C

Me N N N
NaH2C
ch25 2(ii) O O O
Selective deprotonation
of 5-methyl

Me Me Me
O
NaNH2 PhCO2Me
N N Ph N
Me NaH2C
ch25 2(iii) O O O
Selective deprotonation
of 5-methyl

Cl
Cl CN
SO2Cl2 aq. NaOH
Me N Me N
ch25 3 O O Me O
Selective electrophilic
substitution at C-4 –
HO
Cl H

via
Me N
O

CO2Me CO2Me Me

O BnNHNH2 +
Me N N
MeO2C
ch25 4 N N
Me O Bn Bn

n-BuLi
Me2NSO2Cl, Et3N then TMSCl
N N Li N
ch25 5 N N N
H SO2NMe2 SO2NMe2
Removal of acidic N-hydrogen Selective
only requires weak base lithiation at C-5

Ph
PhCHO, CsF N
Me3Si N
N
N HO SO2NMe2
SO2NMe2
 Ph
Ph
O
H2NOH
+ N
N Ph
ch25 6 H O O O

2n-BuLi
then DMF Li OHC
N N N N
ch25 7(i) – H 2O
HO O O O
Li Li

Br Me3Si Li MeOH, K2CO3

ch25 7(ii) S S SiMe3
NOH N O

via
S SiMe3
NOH

Me Me Me Me Me Me

(EtO)2P(O)CH2SEt, n-BuLi via N SEt

N O N – HSEt
ch25 7(iii) NHPh N NHPh
Ph

H2NOH Me3SiCH2 N
ch25 8 Me3Si SiMe3 O
Chapter 27

OP(O)Cl2
+
O HN Cl Cl
via
N N N
HN N t-BuONO, CH2I2 N
POCl3
ch27 1(i) H 2N N N H2N N N via the diazonium salt I N N
AcO O AcO O AcO O

AcO OAc AcO OAc AcO OAc

NH2
NH2
PhB(OH)2 N
N N
N Pd(PPh3)4, Na2CO3
NH3, MeOH N
N Suzuki coupling Ph N
I N
HO O
HO O
Selective nucleophilic
displacement of 6-chlorine
HO OH
HO OH

O O
H2N H2N H2N
N PhCO2Et Ph N Ph N
NaOEt Ac2O
H2N N N
ch27 1(ii) N O H N O H N
HO O HO O AcO O

HO OH HO OH AcO OAc

O Cl NH2

N N N
POCl3 HN N NH3 N
via
N Ph N N Ph N N
Ph N
AcO O AcO O HO O

AcO OAc AcO OAc HO OH

NH2 NH2 NH2

N Br2 N PhB(OH)2 N
N AcOH N Pd(0) N
Br Ph
ch27 2 N N N N Suzuki coupling N N
HO O HO O HO O
Selective
bromination
at C-8
HO OH HO OH HO OH
 NH2 NH NH

N N N
N Me2SO4 MeN aq. HCl MeN

ch27 3 N N N N N N
H
HO O HO O
N-1-quaternisation Hydrolytic removal
then N-deprotonation of sugar
HO OH HO OH
H+
NHMe NH NMe

N N N – H 2O
N MeN H2N
aq. NH3 via Dimroth
process H
N O N O N N
N N H
H H H H

NH2 NH2
NH2 N
N HCONH2, heat N

ch27 4(i) N N
N NH2 H

O O
NH2 quinoline N
HN HCS2– Na+ HN
heat SH
ch27 4(ii) Me N NH2 Me N N
H

Chapter 28

+ LiAlH4 H2, Pd
N N N N n-Bu
Electrocyclic
ch28 1 Br – ring opening
 LDA
then EtO(CH2)2CH=O HI, heat
Side-chain
ch28 2 N Me lithiation N CH2Li N
H
EtO OH

Ac2O, heat Pd/C, heat

+ – H 2O + +
N N N Dehydrogenation
H to aromatic molecule
I– I– I–
OH

Me

N Me O
NaHCO3
+ Br
Me N
ch28 3(i)(a)
Quaternisation of
nitrogen
Me Me

O O
Br
– N+ Me N
via

O
N Me NaHCO3
+ Br Me
H N
ch28 3(i)(b)
Quaternisation of Me
nitrogen
H H
Me Me
O O
Br
– N+ Me N
via
 Me
O N
N NH2
NaHCO3
+ Br
Me N
ch28 3(ii)
Quaternisation of
ring nitrogen
Me Me

O O
Br
– N+ NH2 N NH
via

O N
N NH2 NaHCO3
+ Br Me
H N

Quaternisation of Me
ring nitrogen
H H
Me Me
O O
Br
– N+ NH2 N NH
via

HON H H 2N N
Me

N KNH2, i-AmONO N Zn, AcOH HCO2Me, PPE N

N
ch28 4 Side-chain lihtiation

OMe OMe OMe OMe

H+ O
O HO
NO N H N
N N HN
H HN
HNO2
N N H O N
N
ch28 5
Electrophilic nitrosation O
of five-membered ring N
N
– H2O

N
 HNO2 ON
N N
Electrophilic nitrosation
of five-membered ring

N
N N N N + N
HNO2 N
N via
NHNH2 N
ch28 6(i) S S S H

Ph

O Ph + –
N N N Br
O
+ Br N via
NH2 Ph NH2
ch28 6(ii) S S S

Chapter 29

N N
N N N – HCN
+ via
N – pyrrolidine
ch29 1(i)(a) N N
N N

N
N
N via – N2
+ – pyrrolidine
N N N
ch29 1(i)(b) N N N

EtO EtO OEt

N Ph EtO Ph Ph
OEt via – N2
N
+ N N – EtOH
N N
ch29 1(ii) N N N N

Cl N N N N HN N
NaN3 MeNH2
Cl N MeHN N MeN N
ch29 2 Cl S S S S
 NH2 N NMe2 N
DMFDMA N2H4
Ph N
ch29 3(a) Ph O Ph O N
H

MeO Me
– +
DMFDMA MeO + N
H Me
attacks the NH2

NH2 N NMe2 N
DMFDMA H2NOH
Ph N
ch29 3(b) Ph O Ph O O

MeO Me
– +
DMFDMA MeO + N
H Me
attacks the NH2

N N N NH2 N N NH2
+ H 2N H
NH2
ch29 4(i) N NH2 N N N
H H

N N NH2 N NH H
H NH
N
NH2 N
N N N N NH2 NH2
N
H H H HN N

CO2Et
N N N N N N N
+ CH2(CO2Et)2 H
OEt
ch29 4(ii) N N CO2Et N CO2Et N O
H H2
CO2Et CO2Et
NH2
CO2Et CO2Et
N N
+
N O N O
H
NH2