Post on 23-Oct-2020
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.