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N-Heterocyclic carbenes : A powerful tool in organic synthesis Thomas BUYCK PhD Student in Prof. Zhu Group, LSPN, EPFL Frontiers in Chemical Synthesis June 6 th , 2011
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N-Heterocyclic carbenes :A powerful tool in organic synthesis
Thomas BUYCKPhD Student in Prof. Zhu Group,
LSPN, EPFL
Frontiers in Chemical Synthesis
June 6th, 2011
2
Questions
I. Why is this type of catalysis important ?
II. What is the name of the reactive specie in all the presented reactions ?
3
Plan
Introduction
I. Benzoin condensation and Stetter reaction
II. Homoenolate reactivity
III. Miscellanous reactions
4
Introduction
N-Heterocyclic carbenes
Alternative to metal catalysed reactions
Cheaper and more environment friendly
New field in organic chemistry
NNR R' NNR R' NN
NR R'NS R'
Imidazolylidene Imidazolinylidene Triazolylidene Thiazolylidene
5
Introduction
1960 1970 1980 1990 2000 2010 20200
100
200
300
400
500
600
700
800
Publications containing "NHC"
Explosion in this field during the last decade
6
Introduction
NN
NPh
Ph
PhNN
NPh
Ph
PhNN
NPh
Ph
Ph
OMeClO4
NaOMe
MeOH, RT70%
80°C0.01 mbar
Quant.
Multigram scale synthesis of carben by Enders
Commercially available from Acros® 195 CHF/g
D. Enders, Synthesis, 2003, 1292-1295
7
Benzoin Condensation
R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719-3726
Autocondensation of benzaldehyde
F. Wöhler, J. Liebig, Ann. Pharm., 1832, 3, 249-282 ; T. Ukai, J. Pham Soc. Jpn, 1943, 63, 296-300
O
Ph H
SN
N
N
H2N
OH
Cl
Thiamin 1
B H
Thiamin
Thiamin
Ph
H
HO
Thiamin
HO Ph
Thiamin
HO
O
Ph
Ph
Thiamin
O
OH
Ph
Ph
Ph
O
Ph
OH
O
Ph H
B Breslow Intermediate
Ph
O
Ph
OH
O
Ph H2
8
Benzoin Condensation
Ph
O
Ph
OH3
O
Ph H2
2
Creation of a stereogenic center
D. Enders, T. Balensiefer, Acc. Chem. Res., 2004, 37, 534-541
How to control the selectivity of this reaction to obtain a single enantiomer ?
9
Benzoin CondensationEnantiomeric version
Ph
OON S
Cl
Cat =H
O
O
OH
Cat (10 mol %)Et3N (10 mol %)
MeOH RT
50%, 2% ee
First example in 1966 by Sheehan
Ar H
O
Ar
O
OH
ArCat (10 mol %)
t-BuOK (10 mol %)
THF
8-100%, 80-95% ee
NN
N
Ph
Cat = O
BF4
Enders published in 2002 a more efficient method
D. Enders, Angew. Chem. Int. Ed., 2002, 41, 11743-1745
J. Sheehan, J. Am. Chem. Soc., 1966, 88, 3666-3667
10
Benzoin Condensation
D. Enders, Angew. Chem. Int. Ed., 2006, 45, 1463-1467 ; K. Suzuki, Angew. Chem. Int. Ed., 2006, 45, 3492-3494
Enantiomeric version OH
O RO
ROH
4 - 7 (10-20 mol %)
THF or TolueneBase, RT
NN N
NN N
NN N
RO
4a, R = TBS 4b, R = TIPS
5
BF4 BF4
ON
N N
O
ClCl
6 7a, R = OMe7b, R = H
Enders et al. Suzuki et al.
O
OOHO
OH
OH
O
OH93%, 94% ee90%, 63% ee 4b43%, 93% ee 5
68%, 67% ee 95%, 74% ee
OOH
OOH
O
OH
O
OOH
70%, 96% ee 44%, 96% ee
74%, 85% ee 56%, 88% ee
11
Stetter reaction
R1 H
O
R2 X
O
R2CN
X
O
CN
R2
R1
O
R1
O
R2
X = R, OR
Catalyst,Base
H. Stetter, Angew. Chem. Int. Ed., 1973, 12, 81 ; H. Stetter, Angew. Chem. Int. Ed., 1976, 15, 639-712
In the early 70’s Stetter described a new reaction usefull to create 1,4 dicarbonyl
Catalyst : CN- (1973) Thiazolium salt (1976)
12
Stetter reaction
First example in 1996 by Enders
OO
N
NPhNHO
O
CO2R2
Re-face shielded by Phenyl group
Model explaining the facial selectivity
D. Enders, Helv. Chim. Acta., 1996, 79, 1899-1902
Enantiomeric version
CHO
O CO2R2
R1
Cat. (20 mol %)K2CO3, THF
44 - 73% O
CO2R2
O
R1
41 - 74% ee
Cat. =
NN
N
Ph
O O
Ph
ClO4
13
Stetter reaction
Enantiomeric version
The second example is published only in 2002 by Rovis
CHO
O CO2Et
NN N
OBF4
OMe
Cat. (20 mol %)KHMDS (20 mol %)
Xylenes, 25°C, 24h94%, 94% ee
O
CO2Et
O
Cat. =
T. Rovis, J. Am. Chem. Soc., 2002, 124, 10298-10299 ; T. Rovis, J. Am. Chem. Soc., 2005, 127, 6284-6289
14
Stetter reactionExtension of the scope
Merck published in 2001 an Aldehyde-Imine Cross-Coupling
Enantiomeric version is described by the group of Miller in 2005
J. A. Murry, D. E. Franz, J. Am. Chem. Soc., 2001, 123, 9696-9697
S. J. Miller, J. Am. Chem. Soc., 2005, 127, 1654-1655
Cat. =R1 H
O
R2 NH
SO2
R3
OTol
SNR4
OH
Cl
Et3N, CH2Cl2, 35°C58 to 98%
HNR2 R3
OOR1
Cat. (10 mol %)
NH
Me
OHN
O
NHBoc
Me OBn
SN Me I
75-87% ee
15
Stetter reactionExtension of the scope
Sila-Stetter reaction
Ph SiMe3
O
R1 R2
O 1) Cat. (30 mol %), DBU i-PrOH, THF
2) H2O R1 R2
OPh O
Cat. =
NS
HO
H Br
Addition of acylsilanes to Imines
K. A. Scheidt, J. Am. Chem. Soc., 2004, 126, 2314-2315
K. A. Scheidt, Org. Lett., 2004, 6, 4363-4366
Ph SiMe3
O 1) Cat. (30 mol %), DBU i-PrOH, CHCl3
2) H2O
NP
Ph
O
Ph
Ph
HN
O
R1
PPh
O
Ph
Cat. =NS
H I
1) HCl, THF
2) Boc2O, NaHCO3
Ph
NHBoc
O
R1
BH3.SMe2, THF
R1 = Ph, 70%, 15:1 dr Ph
HN
OH
R1
PPh
O
Ph
16
Stetter reactionExtension of the scope
NS R2
R1
O
SiMe3R1
O
O
O
HOR1
N
S
R2
R3Si
O
R1N
S
R2
O O
R1
OSiR3
N
S
R2R1
OH
N
S
R2
CO2
R'OH
R'OSiR3
Generation of acyl anion equivalent
Keto carboxylate as acyl anion precursor
K. A. Scheidt, J. Am. Chem. Soc., 2005, 127, 14675-14676
R
O
N
NO
O
ONa
Cat. (20 mol %)pH 7.2 buffer
70°C, MeOH R
O
N
N
O
N
S
OH
PhCl
Cat. =
71 to 95%
17
O
O
RR1
R1
O
HR H
O NHC
O
O
R
R1
O
R1
OHR
O
OH
R
R
O
OH
R1
R1
O
OH
R
R1
O
R
CHO
O
R CHO
R
R
Homobenzoin products
Crossbenzoin products
Stetter products
Homoenolates
F. Glorius, Angew. Chem. Int. Ed., 2004, 43, 6205-6208 ; J. Bode, J. Am. Chem. Soc., 2004, 126, 14370-14371
In 2004, Glorius and Bode reported independently a new reaction
18
Homoenolates
R H
ONNAr Ar
R
O
N
NAr
Ar
R
OH
N
NAr
Ar
R
OH
N
NAr
Ar
F. Glorius, Angew. Chem. Int. Ed., 2004, 43, 6205-6208 ; J. Bode, J. Am. Chem. Soc., 2004, 126, 14370-14371
Homoenolate formation
O
O
RR1
R1
O
HR H
O NHC
19
OO
R
R1
R1
O
H
R H
ONNAr Ar
R
OH
N
NAr
Ar
R
O
N
NAr
Ar
R1 O
Homoenolates
Enantiomeric version but with only 25% ee
Mechanism for the lactone formation
F. Glorius, Angew. Chem. Int. Ed., 2004, 43, 6205-6208 ; J. Bode, J. Am. Chem. Soc., 2004, 126, 14370-14371
NN NN
NN NN
O O
TfO
IMes IPr unselective
ICy unreactive Enantiomeric version
20
HomoenolatesElectrophile diversification
• N-Sulfonylimines
• Proton trapping followed by addition of a Nucleophile
J. Bode, Org. Lett, 2005, 7, 3131-3134
K. A. Scheidt, Org. Lett, 2005, 7, 905-908
Ar
O
H
H R
NS
O O
MeO
N
RAr
O
SO2Ar
Cat. (15 mol %)DBU (10 mol %)
0.1M t-BuOH, 60°C, 15h61-75%
Cat. =N
N
Mes
Mes
Cl
R H
O
R2
R1 Cat. (5 mol %)DBU
PhOH, HNuToluene56-90%
R1
H
RNu
O
R2Cat. =
N
N H
I
21
HomoenolatesElectrophile diversification
• Azadiene Diels-Alder reaction
J. Bode, J. Am. Chem. Soc., 2006, 128, 8418-8420
R2 H
NSO2Ar
R1
O
H
O Cat. (10 mol %)DIPEA (10 mol %)
10:1 Toluene/THF, RT51-90%
Cat. =NNN
O
Cl
N
R2
O
ArO2S R1
O
>50:1 dr97-99% ee
22
HomoenolatesElectrophile diversification
• Azadiene Diels-Alder reaction
J. Bode, J. Am. Chem. Soc., 2006, 128, 8418-8420
NNN
O
Mes
NN
N
O
MesHO
EtO2C
NN
N
O
MesHO
EtO2C
NN
N
O
MesO
EtO2C
H
N
R2
OArO2S R1
O
N
NNMes
N
R2
O
ArO2S R1
O
R2 H
NSO2Ar
R1
O
H
O
Proton transfert
Diels-Alder
Nucleophilic addition
23
Homoenolates
• Azadiene Diels-Alder reaction
J. Bode, J. Am. Chem. Soc., 2006, 128, 8418-8420
NR2
ArO2S
O
H
NNN
ArO
R'
Model explaining the selectivity
R2 H
NSO2Ar
R1
O
H
O Cat. (10 mol %)DIPEA (10 mol %)
10:1 Toluene/THF, RT51-90%
Cat. =NNN
O
Cl
N
R2
O
ArO2S R1
O
>50:1 dr97-99% ee
Electrophile diversification
24
Homoenolates
• 1,2-Dicarbonyl Compounds
V. Nair, Org. Lett, 2006, 8, 507-509
O
O
RCHO N
N
Mes
Mes
Cl
Cat. (6 mol %)DBU (12 mol %)
THF, 12h
O
OO
NR2
O
O
or
NR2
O
O
O
Ph
NR2
O
O
O
Ph
or
60-78%
1:185-98%
Cat. =
Electrophile diversification
25
Homoenolates
N
N
Mes
Mes
ClCat. =R2 R3
OR3
R1R2
R1 H
O
R1R2
OO
R3
Cat. (6 mol %)
DBU (12 mol %)THF, RT, 8h
• ,a b unsaturated ketone
V. Nair, J. Am. Chem. Soc., 2006, 128, 8736-8737
Electrophile diversification
26
Homoenolates
V. Nair, J. Am. Chem. Soc., 2006, 128, 8736-8737
Mechanism to form the cyclopentene
N
N
Mes
Mes
N
N
Mes
Mes
OH
R1
R1 H
O
N
N
R
R
OR1
R2R3
O
N
N
R
R
O
O
R3
R1
R2
N
N
R
R
O
O
R3
R1
R2
R3
R1
R2
O
OR3
R1R2
R2 R3
O
CO2
N
N
R
R
OR1
R2R3
O
O O
R3
R1 R2
27
Homoenolates
Br
EWG
NN
N
MeO OMeClO4
(10 mol %)
K2PO4 (2.5 equiv.)Glyme, 80°C
EWG
n n
CO2Et CNO
NOMe
n
n = 1, 48%n = 2, 94%n = 3, 81%
68% 71%
Intramolecular alkylation of a b unsaturated ester
G. C. Fu, J. Am. Chem. Soc., 2006, 128, 1472-1473
28
HomoenolatesHomoenolates obtention via a b unsaturated ester
G. C. Fu, J. Am. Chem. Soc., 2006, 128, 1472-1473
O
ORX
nNHC
O
ORX
n
O
OR
NHCNHC
H
n
O
OR
Base
Base-H
n
O
ORX
nNHC
29
Homoenolates
R
OH
N
NAr
Ar
H R3
NPG
R1
O
H R2
N
H
SO2Ar
R
O
H
Nu HO
O
R4 R5
O
NO
ON
OO
O
R2
R
SO2Ar
O
R
R
R Nu
O
O
H
R5
RR4
R3
R
O
O
R
R1
PG
R
Protonation / Diels-Alder
Cross-condensationenal-aldehyde
Cross-condensationenal-imine
Cross-condensationenal-1,2 dione
Cross-condensation enal-enone/decarboxylation
Protonation / Nu- trapping
Homo-condensation
Homoenolate
30
Trans-esterification
M. Movassaghi, Org. Lett., 2005, 7, 2453-2456
Amide formation
Proposed mechanism
R1 OMe
OR2 N
H
OH IMes (5 mol %)
THF, RTR1 N
O
R2
OH MeOH
N
NMes
Mes
HNHR2
OR1 OMe
O
O
NHR2
H
OR1
OMeN
NMes
Mes
O
Me
H
OR1
ON
NMes
MesNHR2
HN
NMes
Mes
OMe
NHR2HO
R1 N
O
R2
OH
R1 O
O
NHR2
O N acyl transfert
MeOH
31
Trans-esterification
H
O
R
OH
OR
R
orOMe
O
N N I
(20 mol %)
KOtBu, 4A MSTHF, RT
OR
RO
O
H. Zhai, Org. Lett., 2005, 7, 3769-3771
g-butyrolactone formation
OH
OR
R
O
OR
R
OR
R
O
OH
O OMe OR
RO
O
Michael addition
Transeterification
Lactonisation
Michael addition
2 possibles pathways
32
Acylation reaction
Kinetic resolution with chiral NHCs
Need to have a hindered acylating agent
K. Maruoka, Org. Lett., 2005, 7, 1347-1349
R
OHO
OPh
Ph
N NAr ArCat. (5 mol %)
THF, -20 to -78°CCat. =
Ar = Ph, -naphthyl
R
OH
R
O
O
Ph
Ph
27-39%87-96% ee
33
1,2-Addition reactions
Reaction with E-NuO
HRE-Nu
NHC
Nu
O
H
E
Possible activation by NHC
O
HR R NHC
O
TMS CF3
H
TMS CN
(EtO)2P CNO
H
R CF3H
R
OTMS
CNH
R
OH
CNH
R
OP(OEt)2
CNH
OH
O
NHCO
HR Nu SiR3
NHC
34
1,2-Addition reactions
Asymetric version was tried by Suzuki and Sato with a poor ee 22%
D. H. Song, Synth. Commun., 2004, 34, 2973-2980 ; Y. Suzuki, M. Sato, Tetrahedron, 2006, 62, 4227-4231 ; K. Maruoka, Tetrahedron Lett., 2006, 47, 4615-4618
Ketone Enal Imine a-ester
O
R R' TMS CN
NHC
R
OTMS
CNR'
R
OH
CNR'
or
Song et al. Suzuki, Sato et al. Maruoka et al.
OTMS
CN
OOEt
OTMSCN
OTMS
CNBr
OTMS
CNH
CN
OH
H
CN
OH
H
OTMS
CN
OEtOCN
OTMS
OTBSCN
NHTs
CNH
79% 79%
86% 86%
77%
75%
89% 93%
98% 92%
35
1,2-Addition reactions
K. Kondo, T. Aoyama, Chem. Pharm. Bull., 2006, 54, 397-398
PhCHO
CHO CHO
CHO CHO
Cl
CHO
91% 94% 98%
94% 92% 90%
Cyanophosphorylation of aldehyde
Reaction time less than 5 min
NN
Cl
Cat =R
O
HR
OP(OEt)2
CN
O
H
Cat (5 mol %)t-BuOK (4 mol %)
THF 0°CNCP(OEt)2
O
Conclusion
NHC as an organocatalyst allows access to a wide diversity of molecules
EWG
OR
OH
R5
RR4
R
O
O
Ph
Ph
R1 N
O
R2
OH
O
CO2R2
O
R1
N
R3
R
O
PG
OO
R
R1
R
OP(OEt)2
CNH
O
NO
R2
R
SO2Ar
R
OH
CNH
OR
RO
O
OO
R
R
R Nu
OH
R
OTMS
CNH
R
OH
CF3H
OO
O
R
R
O
N
N
O
Still a lot of reactions to develop Enantiomeric version of homoenolate reaction to upgrade
36
NHTs
CNH
Conclusion
37
Questions
Reviews :
N-Heterocyclic carbenes as organocatalysts N. Marion, S. Díez-González*, and S. P. Nolan*, Angew. Chem. Int. Ed., 2007, 46, 2988-3000
Nucleophilic cabenes in asymetric organocatalysisD. Enders*, T. Balensiefer, Acc. Chem. Res., 2004, 37, 534-541
