Key References: Bourissou, D; Guerret, O.; Gabbai, F.; Bertrand, G. Chem. Rev. 2002, 100, 39-91.Enders, D.; Balensifer, T. Acc. Chem. Res. 2004, 37, 534-541.Nair, V.; Bindu, S.; Sreekumar, V. Angew. Chem. Int. Ed. 2004, 43, 5130-5135.

Recent Catalysis with N-Heterocyclic Carbenes

1. Stable Carbenes

•Reasons for Stability•Isolated Carbenes

2. Reactivity of N-Heterocyclic Carbenes

•Ligands•Reactants•Catalysts

3. N-Heterocyclic Carbenes as Catalysts

•Brief History•Recent Catalysis•Asymmetric Catalysis

Outline

Stable Carbenes

N

N

N

N

N N

N

N

S

cyclicdiaminocarbenes

imidazol-2-ylidenes

1,2,4-triazole-3-ylidenes

1,3-thiazol-2-ylidenes

NN NO NS

acyclicdiaminocarbenes

acyclicaminooxycarbenes

acyclicaminothiocarbenes

BB BB

cyclicdiborylcarbenes

acyclicdiborylcarbenes

PSi PP SCF

F

F

FS

F

F

F

FF F FF

FS

F

phosphinosilyl-carbenes

phosphinophosphino-carbenes

sulfenyl-trifluoromethylcarbene

sulfenyl-pentafluorothiocarbene

Stable Carbenes

N

N

N

N

N N

N

N

S

cyclicdiaminocarbenes

imidazol-2-ylidenes

1,2,4-triazole-3-ylidenes

1,3-thiazol-2-ylidenes

NN NO NS

acyclicdiaminocarbenes

acyclicaminooxycarbenes

acyclicaminothiocarbenes

BB BB

cyclicdiborylcarbenes

acyclicdiborylcarbenes

PSi PP SCF

F

F

FS

F

F

F

FF F FF

FS

F

phosphinosilyl-carbenes

phosphinophosphino-carbenes

sulfenyl-trifluoromethylcarbene

sulfenyl-pentafluorothiocarbene

N-Heterocyclic Carbenes (NHC)

Stability of N-Heterocyclic Carbenes

Electronic Stabilization:1. π-Donation: There is electron donation into the carbene out-of-plane p-orbital by the electron-rich system (N-C=C-X).

π-Donation moderates typical electrophilic reactivity of carbenes

2. σ-Withdrawal: Additional stability of the carbene is offered by σ-electron-withdrawal effect of the carbene center by more electronegative atoms (in this case, two nitrogens).

σ-Effect moderates typical nucleophilic reactivity of carbenes

Arduengo, A.; Harlow, R.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361-363.

R2N

X

Resonance Forms:

N X N X N X N X

Best Resonance Structurefor monoaminocarbenes

Best Resonance Structurefor diaminocarbenes

N

X

R

Carbene

Stability of N-Heterocyclic Carbenes

Electronic Stabilization:1. π-Donation: There is electron donation into the carbene out-of-plane p-orbital by the electron-rich system (N-C=C-X).

π-Donation moderates typical electrophilic reactivity of carbenes

2. σ-Withdrawal: Additional stability of the carbene is offered by σ-electron-withdrawal effect of the carbene center by more electronegative atoms (in this case, two nitrogens).

σ-Effect moderates typical nucleophilic reactivity of carbenes

Arduengo, A.; Harlow, R.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361-363.

R2N

X

Resonance Forms:

N X N X N X N X

Best Resonance Structurefor monoaminocarbenes

Best Resonance Structurefor diaminocarbenes

N

X

R

Carbene

Stability of N-Heterocyclic Carbenes

Stability Due to Steric Hindrance: Adamantyl substituents contribute to kinetic stability.

Arduengo, A.; Harlow, R.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361-363.

First isolated crystalline carbene!

Bulky substituents clearly kinetically stabilize all types of carbenes

An Example:

NN AdAd

•Steric hindrance can help stablize carbenes, however, it is not necessary.

•Electronic stabilization is necessary.

Isolation of N-Heterocyclic Carbenes

N

NPh

Ph

HCCl3 -HCCl3

N

NPh

Ph

N

NPh

PhN

N

Ph

Ph

Wanzlick, H. W.; Kleiner, H.J. Angew. Chem. 1961, 73, 493.

First carbene isolationattempt.

N

NAd

Ad

H

H

H

Cl

NaH

THF, cat. DMSO N

NAd

Ad

H

HRT, quantitative

Arduengo, A.; Harlow, R.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361-363.

Stable in the absence of oxygen and moisture.

N

NMe

Me

Me

Me

H

Cl

NaH

THF, cat. KOtBu N

NMe

Me

Me

MeRT, quantitative

Arduengo, A.; Dias, H.; Harlow, R.; Kline, M. J. Am. Chem. Soc. 1992, 114, 5530-5534.

Electronic stabilization more importantthat steric hindrance.

Isolation of N-Heterocyclic Carbenes

Commercially available fromEburon Organics Product List

N

N N

Ph

Ph

PhH

OMe

0.1 mbar, 80 °C N

N N

Ph

Ph

Ph

Ender, D.; Bruer, K.l Raabe, G.; Runsink, J.; Teles, J. H.; Melder, J.; Ebel, K.; Brode, S. Angew. Chem., Int. Ed. Engl. 1995, 34, 1021.

N

NMe

Me

Me

Me

H

Cl

NaH

N

NMe

Me

Me

Me

A more general, rapid approach found to access carbenes.liq. NH3

Herrmann, W. A.; Elison, M.; Fischer, J.; Kocher C., Artus, G. Chem. Eur. J. 1996, 2, 772.

N

NS

R

RMe

Me

K

THF, 80 °C N

N

R

RMe

Me

Kuhn, N.; Kratz, T. Synthesis 1993, 561.

Versatile approach to alkyl-substitutedN-heterocyclic carbenes.

Isolated N-Heterocyclic Carbenes

NN

N

N

N

N

N N

N

S

N

N N

N O

N SMe

Me

Me

MeMe Me

Me

Me

MeMe

Me

Me

Me

Me

Me

Me

Me

Me

MeMe

Me

Me

Me

Me

Me

Me

Me

Me

Me Me

Me MeMe

Me

MeMe

MeMeMe

Me

MeMe

Chem. Rev. 2000, 100, 39-91.

Examples of carbenes that have been isolated

Reactivity of N-Heterocyclic Carbenes

NX

R

RR

Ligands Reactants

Catalysts

NHCs have been foundto be excellent ligandsfor many transition metals.

NHCs can be employed in several types of reactions, includingmulticomponent couplings andcycloadditions, as reactants.

NHCs are able to catalyze a variety of reactions, mainly various acyl anion additions.

N-Heterocyclic Carbenes as Ligands

-In the early 90's NHC were found to have bonding properties similar to trialklyphosphanes and alkylphosphinates.

-compatible with both high and low oxidation state metals

-examples

WCO

OC COCOOC

NN MeMe

VCl

ClNHCCHNNHCCHN Ti

ClClClCl

ReMe

OO

NN

N N

MeMe

Me Me

O

N N MeMe

-reaction employing NHC's as ligands:

Heck and Suzuki CouplingsAryl AminationAmide α-ArylationHydrosiylationOlefin MetathesisMetathesis Cross-CouplingSonogashira CouplingEthylene/Carbon Monoxide Copolymerization

Kumada CouplingStille CouplingC-H ActivationHydrogenation, HydroformylationFuran Syntheis and Alkyne CouplingOlefin CyclopropanationArylation and Alkenylation of AldehydesReduction of Aryl HalidesAtom-Transfer Radical PolymerizationAsymmetric Catalysis

Herrmann, W. Angew. Chem. Int. Ed. 2002, 41, 1290-1309.

N-Heterocyclic Carbenes as Reagents

N N

N

Ph

PhPh Toluene

Heat

R

R

+N N

N

Ph

PhPh R

RN N

N

Ph

PhPh R

R N N

N

Ph

PhPh

R

R

68% R=CO2MeEnders, D.; Breuer, J. Raabe, J.; Runsink, J.; Teles, J.; Melder, S. Angew. Chem. , Int. Ed., 1995, 34, 1021.

N N

N

Ph

PhPh

+NCO

Ph

THF

RT N N

N

Ph

PhPh

NH

O Ph-NCO

N N

N

Ph

PhPh

N

N

O

O

Ph

Ph

Kuhn, N.; Weyers, G.; Henkel, G. Chem. Commun., 1997, 627. 90%

[3+2]

N

NPh

Ph

CCl3H N

N NN

Ph

Ph

Toluene

Heat+ N

N N

NPh

Ph

Ph

Ph[4+1]

Mohrle, H.; Dwuletzki, H. Chem.-Ztg. 1987, 111, 9.

N

NMes

Mes

ClCO2Me

CO2Me

CHO

Cl

NaH

THF, Ar, RT30 min, 80% N

N

O

CO2Me

H

CO2Me

Cl

Mes

Mes

+ +

Nair, V.; Bindu, S.; Sreekumar, V.; Rath, N. Org. Lett. 2003, 5, 665.

98%

Ph

N-Heterocyclic Carbenes as Catalysts

- 1958, Breslow was first to recognize the role of N-heterocyclic carbenes as catalysts.

N

S

HO

Me

N

NNH2

Me

Cl

Thiamine

- catalyzes decarboxylation of pyruvic acid- catalyzes the benzoin condensation

- using NHC's as catalysts, both aryl and alkyl aldehydes can condense

H

O

+

NH

S O

Ph

R

R

NH

S OH

Ph

R

R

NH

S OPh

R

R OHPh

O

OH

S

NR

R

R

Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719.

N-Heterocyclic Carbenes as Catalysts:The Stetter Reaction

N

N

Me

MeCl Base

CH2O N

N

Me

MeOH

H

O

Me

MeMe

MeO

Me

Me

MeMe

O

H

R R

O

α,β-Unsaturated Ketones

Mannich Bases

NMe

Me

Vinyl Ketones

R

O

α,β-Unsaturated Nitriles

RCN

R OR

O

Carboxylic Esters

Possible Electrophiles

R

Stetter, H. Angew. Chem. Int. Ed. 1976, 15, 639-712.

60-95% 30-91%

29-68%10-61%

34-91%

N-Heterocyclic Carbenes as Catalysts:Addition of Aldehydes to Acylimines

Murry, J.; Frantz, D.; Soheili, A.; Tillyer, R.; Grabowski, E; Reider, P. J. Am. Chem. Soc. 2001, 123, 9696-9697.

R1

O

H R2

SO2

NH

O

R3

Tol N

S

R4Me

OHX

Et3N, CH2Cl235 °C

R2HN R3

OR1 O

+

4-PyridylPh2-Br-Ph3-OMe-Ph4-CN-Ph2-Furyl3-PyridylCH3BnOCH2PhCH=CH4-Pyridyl4-Pyridyl

PhPhPhPhPhPhPhPhPhPhc-C6H11H

HOtBuOtBuOtBuOtBuOtBuOtBuOtBuOtBuc-C6H11PhPh

86758668807393627580

N-Heterocyclic Carbenes as Catalysts:Synthesis of Substituted Imidazoles

Frantz, D.; Morency, L.; Soheili, A.; Murry, J.; Grabowski, E.; Tillyer, R. Org. Lett. 2004, 6, 843-846.

R5

O

H R4

SO2

NH

O

R2

Tol N

S

R4Me

OHI

Et3N, CH2Cl235-60 °C

R4HN R3

OR5 O

+R1NH2

AcOH N

NR2

R1R5

R4(5-20 mol%)

NH

N 68%

NH

N

F

NH

N

N

N

N

HO2C

Ph

82%

78%

73%>98% ee

N

N

BnO

N

22%

N

N

N

OH

75%

N-Heterocyclic Carbenes as Catalysts:Nucleophilic Aromatic Substitution Reactions

F

H

O

+N

NMe

Me

I

NaH, DMF, 46-77%

O Ar

Suzuki, Y.; Toyota, T.; Imada, F.; Sato, M. Miyashita, A. Chem. Commun. 2003, 1314.

R R

R1

R R1 Yield (%)

4-CN

4-C6H5CO

2-F-4-NO2

2-F-4-NO2

2-F-4-NO2

Ph

Ph

Ph

3-ClC6H5

3-MeOC6H5

37

32

75

56

60

N-Heterocyclic Carbenes as Catalysts:Transesterification

R' OR''

OROH

NHC

4A M.S., RT, THF+

R' OR

OR''OH+

Grasa, G.; Kissling, R.; Nolan, S. Org. Lett. 2002, 4, 3583-3586.

Ester Alcohol Product Yield(%)

O

O

O

OMe

OMe

OMeO

OMe

O2N

OMe

O

OH OAc 96

OH OAc

OH O

OOMe

OMe

OH

O2N

OBn

O

95

95

96

N-Heterocyclic Carbenes as Catalysts:Living Polymerization

N-Heterocyclic Carbenes can be employed as ring-opening polymerization catalysts.

O

O

Me

NN MeMeI 1.2 eq

1 eq KOt-butoxideMe

O

O

N

N

Me

O

O

N

N

Me

O

O

N

N

O

O

Me n

Comparison of Carbenes: (ROP of lactide)Catalyst Time Conv. (%) M/I

N

S

MeMe

OMe

O I

NS

Me

MeI

NN

NNMe MeCl

MeMe

Me

Me

Me

Me Cl

48 83 60

72 83 120

0.25 99 200

0.25 97 200

Nyce, G.; Glauser, T.; Connor, E.; Mock, A.; Waymouth, R.; Hedrick, J. J. Am. Chem. Soc. 2003, 125, 3046-3056.

N-Heterocyclic Carbenes as Catalysts:Synthesis of β-Hydroxyesters

R1 H

OO

R2

+ R3OH

NS

Me Me

Bn

10 mol %

8 mol % DIPEA30 °C, 3-15h

R1 OR3

O

R2

OH R1

O

S

N

Me

Me

BnOH

R2

Activated Carboxylate

Chow, K.; Bode, J. J. Am. Chem. Soc. 2004, 126, 8126-8127.

Ph OBn

O

Me

OH

Ph OCD3

O

Me

OH

Ph OEt

OOH

OMe

O

Me

OH

OEt

OMe

89

81

84

82

85

10:1

9:1

7:1

D(H)

HO

Me

Me

Product Yield dr Product Yield dr

S

N

Me

Me

Bn

R2R1 H

OO

R2R1

OO

S

NMe

Me

BnH

R2R1

OHO

S

NMe

Me

Bn

R2R1

OH

S

NMe

Me

BnO

R2R1

O

S

NMe

Me

BnOH

R2R1

O

S

NMe

Me

BnOH

R1 OR3

OOH

R2

R3OH

Catalytic Cycle for β-Hydroxyester Synthesis

N-Heterocyclic Carbenes as Catalysts:Internal Redox Reaction

Reynolds, N.; Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2004. ASAP

H

O

Br

20 mol % Catalyst1 equiv BnOH

1 equiv Et3Ntoluene, 25 °C, 4h

OBn

O

N

S

Ph

HO

Me

Cl

Catalyst:

77%

N N

N

Ph

Cl80%

N

N

Me

Me

Me

Me

Me

Me

Cl trace

BrH

O

Ph H

O

Br

Ph H

O

Cl

H

OBr

Aldehyde

60%

80%

65%

99%

Alcohols

MeOH

PhOH

OH

OH

NH2

HOOEt

O

Me

78%

73%

66%

55%

91%

56%

N-Heterocyclic Carbenes as Catalysts:Internal Redox Reaction

Reynolds, N.; Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2004. ASAP

H

O

Br

20 mol % Catalyst1 equiv BnOH

1 equiv Et3Ntoluene, 25 °C, 4h

OBn

O

N

S

Ph

HO

Me

Cl

Catalyst:

77%

N N

N

Ph

Cl80%

N

N

Me

Me

Me

Me

Me

Me

Cl trace

Ph H

O

Br

NN

NPh

Bn

Cl

20 mol%

2 equiv rac-ethyl lactate1 equiv Et3N

toluene, 25 °C, 4h

Ph O

OOEt

O

Me

71% yield32% ee

H

OBr

PhPh

OH

OH

NN

NPh

Bn

Cl

10 mol%

1 equiv Et3Ntoluene, 25 °C, 12h

O

O

PhPh

OH75% yield83% ee

N-Heterocyclic Carbenes as Catalysts:Synthesis of Functionalized Preanthraquinones

O

O NOMOM

O

N

S

Et

HO

Me

Cl

10-70 mol% DBUtBuOH, 40 °C 0.5h

79-96%

OMOM

O

NO

OH

OMOM

O

NO

OH

Pd/C, H2, RTthen

air, 110 °C

toluene, 75%

OH NH OMOM

O

aq. H2SO4

MeOH, DioxaneRT

86%

OH O OH

O

Hachisu, Y.; Bode, J.; Suzuki, K. J. Am. Chem. Soc. 2003, 125, 8432-8433.

- Although the isoxazole functionality is not essential for reaction, it serves as a convenient masking group for the synthesis of anthraquinoid structures.

N-Heterocyclic Carbenes as Catalysts:Asymmetric Catalysis and the Benzoin Condensation

-The first research into the asymmetric benzoin condensation was carried out by Sheehan and coworkers in 1966.-Examples of chiral thiazolium salts tested:

N

S

Ph

O

O

Me *Br N

S

MeBr

Me

N

S

Me

Cl

Me

Me

MeN N

S S

II

2% ee 52% ee6% yield

35% ee20% yield

27% ee41% yield

O

HR

CatalystO

OH

*

Sheehan et. al. J. Am. Chem. Soc. 1966, 88, 3666-3667.

Sheehan et. al. J. Org. Chem. 1974, 39, 1196-1199.

Tagaki et. al. Bull. Chem. Soc. Jpn. 1980, 53, 478-480.

Calahorra et. al. Tetrahderon Lett. 1993, 34, 521-524.

Acc. Chem Res. 2004, 37, 534-541.

Synthesis of Chiral Thiazolium Salts

Me NH2H SK

S+

H2O

Me NH S

Me

OCl

Benzene26%

93%

Me NS

Me

Cl49% HBF4Me N

S

Me

BF4Me N

S

Me

Br

Sheehan, J.; Hara, T. J. Org. Chem. 1974, 39, 1196-1199.

N-Heterocyclic Carbenes as Catalysts:Asymmetric Catalysis and the Benzoin Condensation

-The first research into the asymmetric benzoin condensation was carried out by Sheehan and coworkers in 1966.-Examples of chiral thiazolium salts tested:

O

HR

CatalystO

OH

*

Acc. Chem Res. 2004, 37, 534-541.

N

S

OSiMe2tBu

21% ee50% yield

Leeper et. al. Tetrahedron Lett. 1997, 38, 3611-3614.

NS

N OOBr

Leeper et. al. Tetrahedron Lett.1997, 38, 3615-3618,

26% ee100% yield

TfO

Synthesis of Chiral Thiazolium Salts

N

S

Me

NBS, AIBN

Benzene70%

N

S

Br

O

OMeMe

OH

KOC(CH3)3N

S

O O

OMeMe

50%

10% HCl100%

N

S

O OH

OHTBDMSCl

N

S

O OTBDMS

OH50%

Triflic AnhydrideN

S

O

Knight, R.; Leeper, F. Tetrahedron Lett. 1997, 38, 3611-3614.

OTf

OTBDMS

Synthesis of Chiral Thiazolium Salts

Me3SiO NO

OR

+ Heat

Me3SiO N OO

R

NS

N OO

R

BuONO

TiCl4 ON O

O

R

HON

84%87%

ZnHCO2H

HgCl2(Cat.)78%

ON O

O

R

HNH

ODavy's

Reagent61%

NS

N OO

R

R

MeIPhCH2Br orPhCH2OTf

X

Gerhard, A.; Leeper, F. Tetrahedron Lett. 1997, 38, 3615-3618.

PS P

S

SS

Me

SS

MeDavy Reagent:

N-Heterocyclic Carbenes as Catalysts:Asymmetric Catalysis and the Benzoin Condensation

-The first research into the asymmetric benzoin condensation was carried out by Sheehan and coworkers in 1966.-Examples of chiral triazolium salts tested:

O

HR

CatalystO

OH

*

Acc. Chem Res. 2004, 37, 534-541.

R

R

N

N

NPh

OO

Ph

MeMe

Enders et. al. Helv. Chim. Acta. 1996, 79, 1217-1221.

75% ee66% yield

ClO4 N

N

N

O

Ph

Me

MeMe

BF4

80-95% ee8-100% yield

Enders et. al. Angew. Chem. Int. Ed. 2002, 41, 1743-1745.

N N

N

Ph

MeO

Cl

11-47% yield20-68% ee

Leeper et. al. J. Chem Soc., Perkin Trans. 11998, 1891-1892.

Synthesis of Chiral Triazolium Salts

NH

O

Ph

Me3OBF4

77% N

O

PhOMe

PhNHNH2 HCl

85% NH

O

PhNH

HNPh

Cl HC(OMe)3

100%N

NN

O

Ph

Ph

Cl

Knight, R.; Leeper, F. J. Chem. Soc., Perkin Trans. 1 1998, 1891-1893.

ONH

O

tBu

Me3OBF4

QuantitativeO

N

OMe

tBu

PhNHNH2

77%O

NH

tBu

NHN

Ph HBF4 in Et2O

HC(OMe)365%

N

N

N

O

Ph

tBu

BF4

Enders, D.; Kallfass, U. Angew. Chem. Int. Ed. 2002, 41, 1743-1745.

O

N-Heterocyclic Carbenes as Catalysts:Asymmetric Catalysis and the Stetter Reaction

Acc. Chem Res. 2004, 37, 534-541.

Me H

O

Ph Ph

O S

N

MePh

Me

Me

Cl

+K2CO3

CHCl3/H2O

Me

O

Ph

Ph

O

*

4% yield39% ee

Tiebes, J. Diploma Thesis., Technical University of Aachen, 1990.-Both chiral thiazolium and triazolium salts have found to be unsuccessful catalysts for intermoleculat stetter reactions.

H

O

O CO2R O

O

CO2RCatalyst (20 mol%)

K2CO3, THF22-73%

41-74% ee

N

N

NPh

OO

Ph

MeMe

Catalyst

Enders, D.; Breuer, K.; Runsink, J.; Teles, J. Helv. Chim. Acta 1996, 79, 1899-1902.

N-Heterocyclic Carbenes as Catalysts:Asymmetric Catalysis and the Stetter Reaction

Acc. Chem Res. 2004, 37, 534-541.

H

O

X CO2R X

O

CO2R

Catalyst (20 mol%)KHMDS, Xylenes, RT, 24 h

63-95%

82-97% ee

Catalyst

N

N

N

O

OMe

BF4

Kerr, M.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298-10299.

H

O

CO2Et

Catalyst (20 mol %)KHMDS, toluene

RT, 24h81%

OCO2Et

*

H

O

CO2Et

CO2Et

Catalyst (20 mol%)KHMDS, toluene

RT, 36h97%

O

CO2Et

CO2Et

*

95% ee

82% eeN

N

NPh

Bn

Cl

Catalyst

Kerr, M.; Rovis, T. Synlett 2003, 1934-1936.

Conclusions

• The stability of N-heterocyclic carbenes is mainly due to electronic effects.

• N-Heterocyclic carbenes can participate in a variety of reactions as either a ligand, substrate or catalyst.

• Asymmetric variants of reactions relying on a chiral carbenes are difficult to master.

• N-Heterocyclic carbenes are viable catalysts for a number of reactions.