Electrophilic Carbenes

The reaction of so-called stabilized diazo compounds with late transition metals produces a metal carbene intermediate that is electrophilic. The most common catalysts are Cu(I) triate and Rh(II) aceate and related complexes. Others include Pd(II) salts and Rh6(CO)16. These intermediates engage in very rich chemistry, often as part of cascade processes.
R1 EWG

cyclopropanation This resonance structure shows why these carbenes are electrophilic
R2 R2 O R R1 N2 EWG C R R1 O R EWG R

+ LnM N2

R1

EWG MLn

R1

EWG MLn RZ H R1 H EWG ZR

carbonyl ylide formation

no change in oxidation state

Z = C, O, N, S, Si
O R MLn R R R MLn

insertion reactions

O R N2 R

+ LnM N2

a new carbene for further reactions

Diazo Formation
While diazo alkanes are normally reactive and unstable, those that are conjugated to electron-withdrawing groups (typically carbonyls) are often quite stable. Several methods available for their production. Diazo transfer reactions sulfonyl azide RSO2N3 Et3N EWG = ketone, nitro ester, amide
O EWG N2 EWG Me N2 O OR O OR N2

EWG

EWG

K2CO3 MeOH

O R1 R2

LHMDS, THF CF3CO2CH2CF3 78 C

R1

O CF3 R2

MsN3, Et3N H2O, CH3CN

R1

O R2 N2

J. Org. Chem. 1990, 55, 1959.

O R Cl

CH2N2 CaO
R

O N2

a. EtO2CCl, Et3N b. CH2N2

R

O OH

Cyclopropanation
If formed in the presence of an olen, the carbene can form cyclopropanes. Both inter- and intramolecular reactions are possible. Because the carbenes are electrophilic, the react much faster with electron-rich olens. catalyst
N2 CO2Et X CO2Et

X = CH2Br, CH2Cl, OPh, Bu, OAc, OEt, OBu, i-Pr, t-Bu, CH2=CPh, CH2=CMe, CH2=Ct-Bu, CH=CHOMe, CH=CHCl, CH=CHPh, CH=CHMe catalyst = Rh2(OAc)4, CuClP(Oi-Pr)3, Rh6(CO)16, PdCl2(PhCN)2 Order of reactivity: electron-rich > "neutral" >> electron poor !-substitution on olen slows reactivity & cis > trans Alkene geometry is maintained, but little stereoselectivity for diazo-bearing carbon Other reactive groups: dienes, alkynes, aromatic rings, and heteroaromatic rings Asymmetric reactions are possible with chiral ligands on Rh and Cu catalysts. Intramolecular reactions usually prefer to form 5-membered rings. With polyenes, the regioselectivity is usually good, but can depend on catalyst choice.

Cyclopropanation
O O Ph

K2CO3 Bu4NBr BrCH2CH=CHR PhCH3, 40 C 82%

O Ph

pNBSA, DBU CH2Cl2, 0 C 83%

N2

a. KHMDS, THF RCHO, LiBr 78 C b. TBDPSCl DMAP, imidazole 38%

TBDPSO

O CO2Et N2 Me

1% Rh2(Oct)4 CH2Cl2, rt 70% 83:17 dr

O CO2Et TBDPSO Me H

thiophenol BF3OEt2 CH2Cl2 78 C 90%, 10:1 dr

TBDPSO H SPh

CO2Et

J. Org. Chem. 1997, 62, 194.

Cyclopropanation
O O Me N2 O H Me H
J. Am. Chem. Soc. 2001, 123 ,12432.

Rh2[5(S)-MEPY]4
O

MeO2C

N Rh

O Rh
4

CH2Cl2, 80%, 92% ee

Rh2[5(S)-MEPY]4

OH Me

a. CH3C(OEt)3 EtCO2H, ! 65% b. aq. NaOH 90%

Me

a. (COCl)2
OH Me Me Me O

Me Me Me Me N2 Me

b. CH2CHN2

Me

Me O

Me

Me O

CuSO4 52% (from acid)

Me Me Ph

Li NH3 81%
Me Me Ph

Me

Me

Me cyclohexane, !

J. Chem. Soc., Perkin Trans 1 2000, 2583

Cyclopropanation
With appropriate substitution patterns, cascade reactions are possible
MeO2C N2 OTBS MeO2C H OTBS TBSO MeO2C H H Me H O

+
Me O

Rh2(OAc)4 CH2Cl2, ! 94%

Me O

J. Org. Chem. 1991, 56, 723.

Boc OTBS N Boc Me

+
N2

CO2Me

1% Rh2(S-PTAD)4 2,2-dimethylbutane 50 C 69%, 96% ee

N CO2Me OTBS

Me

J. Am. Chem. Soc. 2007, 129, 10312.

Me

O CO2Me N2 Me

Rh2(OAc)4 CH2Cl2 50%

TBDPSO CHO

O CO2Me

TBDPSO O

Org. Lett. 2003, 5, 4113.

Ylide Formation
The electrophilic nature of the carbenes means they are also capable of reacting with Lewis basic groups such as carbonyls, ethers, and suldes. This will form an ylide structure. If appropriate functionality is present, other reactions will take place (cycloadditions, rearrangements). Intramolecular formation of ylides are most common.
EWG

cat.
X

EWG

N2

[2,3]-rearrangements
Me O O OTBDPS N2
Org. Lett. 2004, 6, 1773.

ylide
OTBDPS O

Cu(acac)2 THF, ! 75%

O O Me Me H O H OTBDPS

oxonium ylide
O TBDPSO

>95:5

"
H Me O + " H

Ylide Formation
O MeO O N2 SPh CO2Me Rh (OAc) 2 4 MeO O H MeO2C O CO2Me SPh S Ph H O

C6H6, ! 77%

J. Chem. Soc., Perkin Trans. 1 1995, 2989.

N2

OH

+
Ph CO2Me R

1% Rh2(S-DOSP)4 pentane, 0 C 5070% yield 9298% ee

Ph

R HO CO2Me

racemic
J. Am. Chem. Soc. 2010, 132, 396.

Stevens-type rearrangement
Ph S N2 N O CO2Et Ph S CO2Et PhS CO2Et

Rh2(OAc)4 C6H6, ! 55%

N O O N

Chem. Commun. 1986, 651.

Ylide Formation
Dipolar Cycloadditions Addition of carbonyls will for a carbonyl ylide. These are 1,3-dipoles that can undergo cycloaddition reactions with electron decient olens/alkynes.
O O N N Me O N2 CO2Et O OPMP N Et O N Me OPMP H O CO2Et

Rh2(OAc)4
Et O
J. Org. Chem. 1998, 63, 556.

C6H6, 50 C 95%

one diastereomer

OTBDPS N2 O

Rh2(OAc)4
O

PhCF3, 100 C 73%

H O

O H

O OTBDPS

Angew. Chem. Int. Ed. 2006, 45, 6532.

O N2 t-BuO2C TMSO O OMOM OTBDPS CO2t-Bu O

Ac

OMOM

Rh2(OAc)4 C6H6, ! 72%

t-BuO2C t-BuO2C

O O OTMS OTBDPS

Angew. Chem. Int. Ed. 2003, 42, 5351.

Insertion Reactions
Rh(II) catalysts promote the insertion of diazoalkanes into CH, OH, NH, SH, and SiH bonds. Likely involves a three-center transition state. Chiral ligands can be used for enantioselective reactions. Intramolecular reactions generally favor 5-membered ring formation. Fluorinated carboxylate ligands on the metal promote insertion into aromatic CH bonds. General order of reactivity for CH bonds: 2 > 1 ! 3, but is catalyst dependent Electron-withdawing groups deactivate CH bonds, electron-donating groups activate Proposed transition state: J. Am. Chem. Soc. 1993, 115, 958.
R C R R H MLn R C EWG R R H C EWG MLn R R C R C EWG H

This mechanism implies that the insertion reaction is stereospecic Rh2(NHCOC3F7)4 CH2Cl2, rt then Et3N, TIPSOTf 91% MeO
CO2Et

N2 MeO N Ph

CO2Et O

With Rh2(OAc)4 a mixture was obtained OTIPS with benxylix CH insertion.

Ph

Insertion Reactions
N2 O O

Rh2(4(S)-MACIM)4 cis:trans = 99:1 9697% ee

O
n

Ac O O

N N

CO2Me

6275%
J. Am. Chem. Soc. 1994, 116, 450.

4(S)-MACIM

+ 5 equiv

Rh2(S-PTAD)4
N2 P(O)(OMe)2

2,2-di-Me-butane, ! 83%, 92% ee

Org. Lett. 2006, 8, 3437.

Ph

P(O)(OMe)2

Br MeO

CO2Me

Rh2(S-DOSP)4
N2 CO2Me

2,2-di-Me-butane 50 C 56%, 94% ee

J. Org. Chem. 2002, 67, 4165.

MeO

Br

Insertion Reactions
NH insertions
H HO NH O O H Me N2 CO2

Rh2(Oct)4 EtOAc/hexane !

H HO

Me O CO2

N O

J. Org. Chem. 1991, 56, 3183.

OH insertions
OH OH Me H P(O)(OEt)2

1. Rh2(OAc)4 C6H6, 80 C OH 96% 2. H2CrO4 Et2O, rt

EtO2C O O Me O H O

CO2Et O Me H

NaH THF, rt 86% (2 steps)

Tetrahedron Lett. 1995, 36, 8347.

SiH insertions
N2 CO2Me

Rh2(OAc)4 PhMe2SiH CH2Cl2, rt 75%

PhMe2Si CO2Me

Z/E = 96:4

Z/E = 95:5

Tetrahedron Lett. 1994, 35, 9549.

Metathesis with Alkynes

Once formed, Rh carbenoids can undergo "metathesis"-type chemistry with alkynes. This generates a new Rh carbene that can undergo other processes, such as those we have already discussed.
O RhLn R R O Me N2 R O RhLn O RhLn

Rh2(OAc)4 CH2Cl2, rt 95%

Me

Tetrahedron Lett. 1991, 32, 4103.

Me

Me

O Me N2

Rh2(OAc)4 CH2Cl2, rt 97%

O
Tetrahedron Lett. 1993, 34, 7853.

Me O

Nitrenoid Intermediates
Much like metal-catalzyed decomposition of diazo compounds produces carbenoid intermediates, it is also possible to generate nitrenoid intermediates. This typically involves the in situ oxidation of a non-basic primary nitrogen atom (sulfonamide, amide, carbamate, urea, etc.).
O H2N O CO2t-Bu O

5% Rh2(OAc)4 PhI(OAc)2, MgO CH2Cl2, 40 C 82% 5% Rh2(OAc)4 PhI(OAc)2, MgO CH2Cl2, 40 C

O

HN O CO2t-Bu

O HN O Me Me

Me Me O NH2

carbonyl groups prefer 5 membered rings, sulfonyls prefer 6 membered rings.

one enantiomer

one enantiomer intermolecular are possible: J. Am. Chem. Soc. 2007, 129, 562.

Angew. Chem. Int. Ed. 2001, 40, 598.

O H2N Me S

O O

5% Rh2(esp)2 PhI(OAc)2, MgO CH2Cl2, 40 C 90%

Me

O HN S

O O
Me HO2C

Me

Me

Me CO2H

J. Am. Chem. Soc. 2004, 126, 15378.

esp

Nitrenoid Intermediates
O H2N MeO S O O O O S O O O S HN O

Rh2(OAc)4 PhI(OAc)2 MgO CH2Cl2 quant.

HN MeO

BF3OEt2 CH2Cl2 68%

TBSO

OTBS

TBSO

OTBS
Org. Lett. 2007, 9, 5465.

OH

Other types of reactions are possible besides CH insertions

NTces H2N NH OTBDPS TcesN

Rh2(esp)2 PhI(OAc)2 MgO CH2Cl2, 40 C 61%

NH HN N AcO N O NH

OTBDPS

N N

NH CCl3 O

CCl3

J. Am. Chem. Soc. 2008, 130, 12630.