Asymmetric Organocatalysis with N-Heterocyclic Carbenes
History and Recent Developments
N
CH3
N
H 3C
N
NH 2
S
Cl
HO
Adam Noble
MacMillan Group Meeting
January 29th 2014
Early Developments
The Benzoin Condensation
! 1832: First report of bezoin condensation by Wöhler and Liebig
Ph
O
CN –
O
H
OH
benzoin
! 1903: Mechanism proposed by Lapworth
O
CN –
Ph
Ph
Ph
Ph
O
+
Ph
OH
H 2O
H
N
HO
H
HO
O
OH
Ph
Ph
H
Ph
N
OH
O
Ph
OH
H
Ph
•
H 2O
N
Wöhler, F.; Liebig, J. Ann. Pharm. 1832, 3, 249.
Lapworth, A.; J. Chem. Soc. 1903, 83, 995.
Thiamine (Vitamin B1 )
Enzymatic Acyl Anion Generation
! Thiamine is responsible for the genaration of acyl anion equivalents in a number of
biochemical reactions
NH 2
O
R
Cl
N
O
O
Me
CO2
R
N
O
+
thiamine
N
Me
OH
S
! Most commonly found as the co-enzyme thiamine diphosphate (TDP)
NH 2
N
Me
Me
O
N
N
O
S
!
!
!
!
P
O
thiamine diphosphate (TDP)
O
O
P
O
OH
Pyruvate decarboxylase
Pyruvate oxidase
Pyruvate dehydrogenase
Transketolase
Kluger, R.; Tittmann, K. Chem. Rev. 2008, 108 , 1797.
Early Developments
Thiamine-Catalyzed Benzoin Condensation
! 1943: Ugai discovered that thiazolium salts could replace cyanide in benzoin condensations
Me
NH 2
Cl
HO
N
N
S
N
O
Ph
H
Me
HO
Ph
N
Ar
O
Me
R
NaOH, MeOH
S
Ph
Ph
OH
Cl
expected
formed
A variety of other thiazolium compounds were also demonstrated to be effective catalysts
Me/H
Me
Me/H
Ph
N
N
Br
S
Me
Me
N
Br
S
OH
N
Me
N
Br
S
Me
Me
S
Ph
Br
I
N
Me
Ugai, T.; Tanaka, R.; Dokawa, T. J. Pharm. Soc. Jpn. 1943, 63, 296.
Early Developments
Thiamine-Catalyzed Benzoin Condensation
! 1954: Mizuhara demonstrated that thiamine could catalyze a number of reactions that had also
been observed in biological systems
Me
HO
O
O
Me
H
N
N
O
S
R
Me
NH 2
Cl
N
Me
Me
Me
O
acyloin
OH
R = Me or OH
+ AcOH (R = Me) or CO2 (R = OH)
! Showed that the thiazolium moiety of thiamine was responsible for the catalytically activity
NH 2
no reaction with:
N
Me
OH
Me
N
N
CHO S
2
Mizuhara, S.; Handler, P. J. Am. Chem. Soc. 1954, 76, 571.
Early Developments
Mechanism of the Thiamine-Catalyzed Benzoin Condensation?
! Reactions such as pyruvate decarboxylation and benzoin-type condensations catalyzed by
thiamine (vitamin B1 ) dependent enzymes were considered some of the most "mysterious"
transformations
?
?
NH 2
Me
HO
N
N
S
N
Me
the origin of reactivity was unknown
until the work of Breslow
?
! 1958: Breslow demonstrated that the C-2 proton of thiazoliums exchanges rapidly with deuterium
Me
Me
N
Br
HO
N
S
N
S
NH 2
Cl
D 2O
N
H
N
Me
Me
Me
H
S
Me
D 2O
Br
D
Me
ND 2
Cl
DO
N
S
N
D
N
Me
Breslow, R. J. Am. Chem. Soc.. 1958, 80, 3719.
Early Developments
Breslows Proposed Mechanism
! 1958: Breslow proposed his mechanism for the thiazolium catalyzed benzoin condensation
R2
R1
N
R3
R2
– H+
R3
N
R3
OH
Ph
S
R2
OH
O
R3
Ph
R1
OS
Ph
R2
R1
N
O
Ph
H
N
Ph
S
S
O
R1
N
R3
R3
R1
Ph
R2
R1
N
S
R2
O
Ph
R2
N
H
S
R1
H
R3
OH
S
Ph
Breslow
intermediate
Breslow, R. J. Am. Chem. Soc.. 1958, 80, 3719.
From 'Laboratory Curiosities' to Catalysis Mainstays
Synthesis of Stable N-Heterocyclic Carbenes
! Since the mechanistic work by Breslow, NHCs were only considered as highly reactive
intermediates.
! Their high reactivty made the isolation of such species seemingly impossible, with dimerization
being a major reaction pathway.
Ph
Ph Ph
N
Ph
∆
N
N
– CHCl3
N
N
CCl3
N
Ph
X
Ph Ph
N
N
Ph
! This was the case until 1968, when seminal work by the groups of Wanzlick and Öfele
demonstrated that NHCs could be isolated in their metal-ligated forms
Hans-Werner Wanzlick
Karl Öfele
Wanzlick, H.-W. Angew. Chem. Int. Ed. 1962, 1 , 75.
Rovis, T, Nolan, S. P. Synlett 2013, 1188.
Wanzlick and Öfele
1968: First isolation of ligated NHCs
! Wanzlick et al isolated a mercury complexed NHC
OEt
EtO
Ph
Ph
Ph
H
N
N
N
conc. HCl
S
Ph
N
S
Ph
66%
Ph
N+
2) NaClO 4
N
H
[ClO 4]–
Ph
94%
Ph
N
N
2
Hg
N
Ph
1) HNO 3
[ClO 4]–
N
Hg(OAc) 2, !
– 2 AcOH
Ph
quant.
! Isolated as colourless plates
! Structure confirmed by 1H NMR
Wanzlick, H.-W.; Schönherr, H.-J. Angew. Che. Int. Ed. 1968, 7, 141.
Wanzlick and Öfele
1968: First isolation of ligated NHCs
! Öfele isolated a chromium NHC complex while trying to generate
dehydro-complexes from heterocyclic salts
[HCr(CO) 5]–
N
!
– 2 CO
Me
Me
N+
H
Me
N
Me
Me
N
Cr(CO)3
[HCr(CO) 5]–
120 ºC
– H2
80%
N
Cr(CO)5
N
Me
! Light yellow crystalline solid
! Structure confirmed by 1H NMR
! Despite these advances, the field remained relatively inactive for 23 years until a breakthrough
discovery by the group of Arduengo
Öfele, K. J. Organomet. Chem. 1968, 12 , 42.
Arduengo
1991: First isolation of a stable crystalline NHC
! Isolated the free carbene by deprotonation of a bis-adamantyl imidazolium chloride
NaH, THF
N
N
H
N+
Cl
cat. DMSO anion
N
96%
! The structure was unequivocally established by single-crystal X-ray analysis
! Thermally stable in the absense of oxygen and moisture
! The synthesis of isolable NHCs was instrumental in causing the explosion in interest in
stable carbene chemistry
Arduengo, III, A. J.; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991, 113 , 361.
Isolable NHCs
Explosion in the Number of Reported Isolations
! After the first report from Arduengo in 1991, many other groups reported successful
syntheses of a variety of new NHCs
Alkyl
Me
Alkyl
Ph
N
N
i-Pr
N
N
Me
Me
N
Ph
Alkyl
N
N
Alkyl
Ph
Arduengo et al
1992
Mes
Enders et al
1995
(first commercially
available carbene)
N
N
N
Arduengo et al
1992
Herrmann et al
1996
i-Pr
S
Arduengo et al
1997
Mes
N
Mes
Me
N
N
Me
N
Me
Mes
Arduengo et al
1995
Herrmann et al
1996
Bourissou, D.; Guerret, O.; Gabbai, F. P.; Bertrand, G. Chem. Rev. 2000, 100 , 39.
Isolable NHCs
Stability
! Original reports suggested that isolation was due to sterics preventing dimerization
N
N
N
N
X
N
N
N
N
! The isolation of the carbene from 1,3,4,5-tetramethylimidazolium chloride suggested
that electronic factors may have greater impact on the stability of carbenes than sterics.
Me
Me
Me
N+
NaH
Me
KOtBu, THF
Me
N
H
Me
N
Me
N
Me
Bourissou, D.; Guerret, O.; Gabbai, F. P.; Bertrand, G. Chem. Rev. 2000, 100 , 39.
Isolable NHCs
Stability
! Electronic factors operating in both the ! and " frameworks result in a "push-pull" synergistic
effect to stabilize the carbene.
!-electron
donation
N
R
R
R1
N
R1
"-electron
withdrawal
! ! donation into the carbene from the
out-of-plane ! orbital stabilizes
electrophilic reactivity
! " withdrawal by electronegative atoms
stabilizes nucleophilic reactivity
! The combined effect is to increase the singlet-triplet gap and stabilize the
singlet-state carbene over the more reactive triplet-state carbene
Phillips, E. M.; Chan, A.; Scheidt, K. A. Aldrichimica Act. 2009, 42, 55.
Bourissou, D.; Guerret, O.; Gabbai, F. P.; Bertrand, G. Chem. Rev. 2000, 100 , 39.
Isolable NHCs
Reactivity: Why are they so useful?
! NHCs are exceptionally good ! donors so form strong metal–carbon bonds:
! Compared to phosphines, NHCs form complexes that:
! are more straightforward to prepare (due to in situ NHC formation)
! show greater air and thermal stability
! often have catalytic activities 100 to 1000 times greater
Ph
Me
Ph
Ph
Me
N
Me
Ph
N
Me
Cl Me
Me
Ru
Cl
PCy 3
Ph
N
Me
Ph
Ph
N
Pd
Cl
Me
Ph
Ph
Ph
! Singlet carbenes of NHCs are distinct Lewis bases that show both ! basicity and " acidity:
! Allows for the generation of a second nucleophile during a reaction (e.g. Breslow intermediate)
! This unique "doubly" nucleophilic aspect allows NHCs to react as powerful organocatalysts
Rovis, T, Nolan, S. P. Synlett 2013, 1188.
Arnold, P. L.; Pearson, S. Coord. Chem. Rev. 2007, 251, 596.
Phillips, E. M.; Chan, A.; Scheidt, K. A. Aldrichimica Act. 2009, 42, 55.
Isolable NHCs
Reactivity: Why are they so useful?
! These factors have resulted in a huge increase in interest in NHCs over the past 70 years
Number of Publications on NHC Catalysis!
700 600 400 300 200 100 Year!
2013 2008 2003 1998 1993 1988 1983 1978 1973 1968 1963 1958 1953 1948 0 1943 Number of!
Publications!
500 N-Heterocyclic Carbenes In Enantioselective Organocatalysis
Modes of Reactivity
Acyl Anions
R
O
N
N
OH
R
R
R
O
N
R
H
R
N
R
Homoenolates
R
O
N
N
OH
R
R
R
O
N
R
H
R
N
R
Azolium Enolates / Acyl Azoliums
O
X
O
•
H
R
O
R
R
N
N
O
O
R
R
N
R
R
R
OR
R
O
N
N
R
R
N
R
N-Heterocyclic Carbenes In Enantioselective Organocatalysis
Modes of Reactivity
Acyl Anions
R
O
N
N
OH
R
R
R
H
N
R
! Benzoin Condensations
! Stetter Reactions
! Hydroacylations
O
N
R
R
The Use of NHCs for the Generation of Acyl Anion Equivalents
Early Developments
! 1943: Ugai discovered the thiazolium-catalyzed benzoin condensation
R3
R2
N
X
R1
O
Ph
H
O
S
Ph
Ph
NaOH, MeOH
OH
Ugai, T.; Tanaka, R.; Dokawa, T. J. Pharm. Soc. Jpn. 1943, 63, 296.
The Use of NHCs for the Generation of Acyl Anion Equivalents
The First Asymmetric Examples
! 1966: Sheehan described the first asymmetric benzoin condensations catalyzed by chiral
thiazolium salts
Me
Ph
S
*
N
O
O
Br
Ph
O
(10 mol%)
O
Ph
Ph
H
Et3N (10 mol%)
MeOH
OH
Precipitate: 50%, 0.8% ee
Filtrate: 9% yield, 22% ee
! 1974: Sheehan reported slight improvements to enantioselectivity but still low yield
Me
S
Br
O
Ph
N
H
Me
O
(10 mol%)
Ph
Ph
Et3N (10 mol%)
MeOH
OH
6% yield, 52% ee
Sheehan, J. C.; Hunneman, D. H. J. Am. Chem. Soc. 1966, 88, 3666.
Sheehan, J. C.; Hara, T. J. Org. Chem 1974, 39, 1196.
The Use of NHCs for the Generation of Acyl Anion Equivalents
The First Asymmetric Examples
! Following the work of Sheehan, a number of other groups reported the use of similar NHCs to
catalyze benzoin condensations
Ph
Me
N
Cl
S
N
Me
ClO4
N
S
Me
Me
I
N
Br
I
N
Me
S
Me
N
Ph
N
S
O
Me
47-57%, 20-30% ee
Zhao et al, 1988
20%, 35% ee
Takagi et al, 1980
21%, 26% ee
López-Calahora et al, 1993
Ph
O
Me
66%, 75% ee
Enders et al, 1996
O
TBSO
N
N
Cl
TfO
S
N
N
Bicyclic triazoliums are key!
Ph
50%, 21% ee
Leeper et al, 1997
45%, 80% ee
Leeper et al, 1998
Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534.
The Use of NHCs for the Generation of Acyl Anion Equivalents
The First Asymmetric Examples
! The initial development of N-aryl-bicyclic triazoliums led the way to improved catalyst efficiency
Tunable sterics
catalytic activity
asymmetric
induction
Tunable electronics
X
N
n
R1
N
N
catalytic activity
R2
basicity
Rovisr, T. Chem. Lett. 2008, 37, 534.
The Use of NHCs for the Generation of Acyl Anion Equivalents
Bicyclic Triazolium Salts Give High Enantioselectivities
! Modification of Leepers bicyclic triazoliums allowed Enders to develop a highly efficient NHC
catalysts
Me
Me
Me
O
N
(10 mol%)
BF 4
O
N
Ph
O
Ph
N
H
KOt-Bu (10 mol%)
THF
favored
Ph
Ph
disfavored
OH
83% yield, 90% ee
favored
Dudding, T.; Houk, K. N. Proc. Nat. Acad. Sci. 2004, 101 , 5770.
Enders, D.; Kallfass, U. Angew. Chem. Int. Ed. 2002, 41, 1743.
The Use of NHCs for the Generation of Acyl Anion Equivalents
Bicyclic Triazolium Salts Give High Enantioselectivities
! Connon et al demonstrated the NHCs bearing alcohol directing groups can give exceptional
levels of enantioinduction
O
N
Ph
Ph
OH
BF 4
N
F
F
F
(4 mol%)
O
Ph
N
H
F
O
F
Ph
Ph
Rb 2CO3 (4 mol%)
THF
OH
90% yield, >99% ee
Baragwanath, L.; Rose, C. A.; Zeitler, K.; Connon, S. J. J. Org. Chem. 2009, 74, 9214.
The Use of NHCs for the Generation of Acyl Anion Equivalents
Early Developments
! 1943: Ugai discovered the thiazolium-catalyzed benzoin condensation
R3
R2
N
X
R1
O
Ph
O
S
Ph
Ph
H
NaOH, MeOH
OH
! 1974: Stetter reported the 1,4-addition variant = The Stetter Reaction
R
Me
N
X
HO
O
R1
R2
H
O
S
R1
EWG
Et 3N, MeOH
EWG
R2
EWG = COR, CO2R, CN
Ugai, T.; Tanaka, R.; Dokawa, T. J. Pharm. Soc. Jpn. 1943, 63, 296.
Stetter, H.; Kuhlmann, H. Angew. Chem. Int. Ed. Engl. 1974, 13 , 539.
The Use of NHCs for the Generation of Acyl Anion Equivalents
Intramolecular Stetter Reactions
! In 1996 Enders et al. reported the first asymmetric Stetter Reaction
Ph
N
N
ClO4
N
Ph
O
O
Me
O
(20 mol%)
O
CO2R 2
Me
H
R1
O
CO2R 2
K 2CO3 (20 mol%)
THF
R1
O
22-73% yield, 41-74% ee
Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. Helv. Chim. Act. 1996, 79, 1899.
The Use of NHCs for the Generation of Acyl Anion Equivalents
Intramolecular Stetter Reactions
! Following the original report by Enders, Rovis et al. developed the first highly enantioselective
intramolecular Stetter reactions
O
N
N
N
BF 4
O
OMe
O
CO2Et
(20 mol%)
H
O
KHMDS (20 mol%)
CO2Et
O
xylene
94% yield, 94% ee
N
N
Bn
N
BF 4
O
(20 mol%)
H
CO2Et
KHMDS (20 mol%)
O
CO2Et
xylene
81% yield, 95% ee
Kerr, M. S.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2002, 124 , 10298.
The Use of NHCs for the Generation of Acyl Anion Equivalents
Intermolecular Stetter Reactions
! Development of asymmetric intermolecular Stetter reactions still remains a formidable challenge
! This is due to the diminished reactivity of Michael acceptors containing a !-substituent
! Enders et al. developed a high yielding protocol taking advantage of the higher reactivity of
chalcones, although the enantioselectivities were only moderate
N
N
N
Ph
TBDPSO
BF 4
O
Ar3
Ar1
O
(10 mol%)
O
H
Ar2
Cs2CO3 (10 mol%)
Ar3
Ar1
Ar2
O
THF
49-98% yield, 58-78% ee
Enders, D.; Han, J.; Henseler, A. Chem. Commun. 2008, 3989.
The Use of NHCs for the Generation of Acyl Anion Equivalents
Intermolecular Stetter Reactions
! In the same year Rovis et al. reported a highly enantioselective intermolecular Stetter reaction
of glyoxamides a number of Michael acceptors
R
CO2t-Bu
O
CO2t-Bu
N
N
N
Bn
H
N
O
O
CO2t-Bu
N
O
C6F 5
BF 4
O
R
O
CO2t-Bu
51-97% yield, 80-91% ee
(20 mol%)
R1
O
iPr 2NEt (100 mol%), MgSO 4
NMe 2
CCl4
R1
O
O
O
R2
N
O
! A limitation was the need for highly activated alkylidene dicarbonyls
NMe 2
O
O
R2
44-95% yield, 81-98% ee
4:1-19:1 dr
A general strategy for asymmetric intermolecular Stetter reactions has not yet been developed!
Liu, Q.; Rovis, T. Org. Lett. 2009, 11 , 2856.
Liu, Q.; Perreault, S.; Rovis, T. J. Am. Chem. Soc. 2008, 130 , 14066.
The Use of NHCs for the Generation of Acyl Anion Equivalents
Hydroacylation of Unactivated Double Bonds
! In 2008, She et al. reported the intramolecular hydroacylation of enol ethers
HO
Me
O
N
S
H
O
I
Me
(25 mol%)
DBU (70 mol%)
R
Ph
O
O
Ph R
xylene, reflux
66-99%
! In 2011, Glorius et al. reported a highly asymmetric variant
O
N
N
Bn
O
Me
N
Cl
Me
Me
O
(10 mol%)
H
Me
Ar
DBU (10 mol%)
O
Ar
dioxane, 80 ºC
O
28-99% yield, 96-99% ee
Piel, I.; Steinmetz, M.; Hirano, K.; Fröhlich, R.; Grimme, S.; Glorius, F. Angew. Chem. Int. Ed. 2011, 50, 4983.
He, J.; Tang, S.; Liu, J.; Su, Y.; Pan, X.; She, X. Tetrahedron 2008, 64, 8797.
The Use of NHCs for the Generation of Acyl Anion Equivalents
Hydroacylation of Unactivated Double Bonds
! The mechanism was investigated by Glorius and Grimme and found to likely proceed via
a concerted but highly asynchronous transition state.
N
O
R
H
N
N
O
O
Mes
!+
H
O
‡
N
R
N
N
DBU
N
Mes
R
N
N
H
R
N
N
Mes
Cl
O
O
or
N
Me
N Mes
N
O
R
Me
O
O
R 2N
(Conia)-Ene
Mes
reverse-Cope
elimination
vs.
H
1 st
2nd
O
‡
H
!-
O
N
!+
‡
O
‡
H
1 st
R 2N
NR 2 2nd R
concerted but
asynchronous
O
Hirano, K.; Biju, A. T.; Piel, K.; Grimme, S.; Glorius, F. J. Am. Chem. Soc. 2009, 131 , 14190.
Piel, I.; Steinmetz, M.; Hirano, K.; Fröhlich, R.; Grimme, S.; Glorius, F. Angew. Chem. Int. Ed. 2011, 50, 4983.
N-Heterocyclic Carbenes In Enantioselective Organocatalysis
Modes of Reactivity
Acyl Anions
R
O
N
N
OH
R
R
R
O
N
R
H
R
N
R
Homoenolates
R
O
N
N
OH
R
R
R
O
N
R
H
R
N
R
Azolium Enolates / Acyl Azoliums
O
X
O
•
H
R
O
R
R
N
N
O
O
R
R
N
R
R
R
OR
R
O
N
N
R
R
N
R
N-Heterocyclic Carbenes In Enantioselective Organocatalysis
Modes of Reactivity
Homoenolates
R
O
N
N
OH
R
R
R
O
N
R
H
N
R
! Cyclopentene Synthesis
! Spiroannulations
! Lactam/Lactone Synthesis
! Conversion of Enals to Saturated Esters
R
The Use of NHCs for the Generation of Homoenolates
The First Examples
! In 2004, the groups of Bode and Glorius reported the use of NHC-catalyzed homoenolate
formation for the synthesis of !-butyrolactones
O
O
Mes
N
N
Cl
Mes
O
(8 mol%)
Bode:
O
Ar1
H
Ar2
H
DBU (7 mol%)
THF/t-BuOH
Ar1
Ar2
41-87%, 3:1-7:1 cis:trans
O
O
Mes
N
N
Cl
Mes
O
(5 mol%)
Glorius:
O
Ar1
H
Ar2
H
KOt-Bu (10 mol%)
THF
Ar1
Ar2
33-70%, up to 4:1 cis:trans
Burstein, C.; Glorius, F. Angew. Chem. Int. Ed. 2004, 116 , 6331.
Sohn, S. S.; Rosen, E. L.; Bode, J. J. Am. Chem. Soc. 2004, 126 , 14370.
The Use of NHCs for the Generation of Homoenolates
The First Examples
! Proposed mechanism for the NHC-catalyzed formation !-butyrolactones
O
N
Ph
O
Ph
Mes
OH
Mes
Mes
N
Ph
N
Mes
N
H
OH
Mes
N
N
Mes
N
Ph
Mes
Mes
N
homoenolate
O
O
Ph
Ar
O
Ar
O
Mes
N
Ph
Mes
N
O
O
OH
Mes
H
Ar
N
Ph
Mes
N
activated carboxylate
Burstein, C.; Glorius, F. Angew. Chem. Int. Ed. 2004, 116 , 6331.
Sohn, S. S.; Rosen, E. L.; Bode, J. J. Am. Chem. Soc. 2004, 126 , 14370.
The Use of NHCs for the Generation of Homoenolates
Many Asymmetric Examples Followed
! Bode et al. demonstrated a variety of highly enantioselective transformations of homoenolates
O
N
O
R1
N
N
Cl
Mes
H
(10 mol%)
O
N
SO2Ar
N
SO2Ar
O
O
OH
R3
H
Me
R2
R2
O
R1
O
R1
O
SO2Ar
R3
O
N
SO2Ar
H
O
Ph
H
Me
R2
>50:1 dr
97-99% ee
>10:1 dr
87-99% ee
Ph
OH
Me
R1
R2
>20:1 dr
99% ee
R2
N
R1
R2
Me
R2
R2
O
Ph
Ph
R2
2:1 dr
99% ee
R1
R2
4->20:1 dr
96-99% ee
He, M.; Bode, J. W. J. Am. Chem. Soc. 2008, 130 , 418.
Kaeobamrung, J.; Bode, J. W. Org. Lett. 2009, 11 , 677.
He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128 , 8418.
Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem. Soc. 2007, 129 , 3520.
Kaeobamrung, J.; Kozlowski, M. C.; Bode, J. W. Proc. Nat. Acad. Sci. 2010, 107 , 20661.
The Use of NHCs for the Generation of Homoenolates
Many Asymmetric Examples Followed
! Bode et al. demonstrated a variety of highly enantioselective transformations of homoenolates
O
SO2Ar
N
H
Ph
R1
R2
O
O
H
OH
Me
Me
R1
R2
Ph
R1
R2
He, M.; Bode, J. W. J. Am. Chem. Soc. 2008, 130 , 418.
Kaeobamrung, J.; Bode, J. W. Org. Lett. 2009, 11 , 677.
Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem. Soc. 2007, 129 , 3520.
The Use of NHCs for the Generation of Homoenolates
Many Asymmetric Examples Followed
! Recently, Chi et al. demonstrated a homoenolate coupling with benzodi(enone)s for the synthesis
of complex tricyclic structures
O
N
N
N
Cl
Mes
O
O
R1
R1
R2
R3
H
O
R3
(20 mol%)
DBU (30 mol%)
THF
O
H
O
O
H
R3
53-84% yield
96-99% ee
10-20:1 dr
Fang, X.; Jiang, K.; Xing, C.; Hao, L.; Chi, Y. R. Angew. Chem. Int. Ed. 2011, 50, 1910.
The Use of NHCs for the Generation of Homoenolates
Many Asymmetric Examples Followed
! Recently, Chi et al. demonstrated a homoenolate coupling with benzodi(enone)s for the synthesis
of complex tricyclic structures
R1
R
O
H
O
O
H
product
5
R2
Fang, X.; Jiang, K.; Xing, C.; Hao, L.; Chi, Y. R. Angew. Chem. Int. Ed. 2011, 50, 1910.
N-Heterocyclic Carbenes As Enantioselective Organocatalysts
Alternative Applications of Homoenolates
Homoenolates
R
O
N
N
OH
R
R
R
O
N
R
H
R
N
R
R1
OH
R
N
R2
R1
O
N
R2
N
R
R
ROH
N
R
"Redox Relay"
RO –
(-NHC)
R1
R2
O
OR
The Use of NHCs for the Generation of Homoenolates
Alternative Applications of Homoenolates
! Using this ester formation reaction they could perform desymmetrizations of meso diols
and enantioselective protonations of !,!-disubstituted enals
O
N
N
N
BF 4
Mes
OH
OH
O
Ph
H
(30 mol%)
O
proton sponge
K 2CO3, 18-crown-6
CH2Cl2
OH
O
O
58%, 80% ee
N
Ph
N
Ph
Ph
N
BF 4
Mes
Bn
Me
O
Me
Ph
Me
(30 mol%)
H
OH
proton sponge
K 2CO3, 18-crown-6
CH2Cl2
Ph
O
O
Me
58%, 55% ee
Maki, B.; Chan, A.; Phillips, E. M.; Scheidt, K. A. Org. Lett. 2007, 9, 371.
Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905.
The Use of NHCs for the Generation of Homoenolates
Alternative Applications of Homoenolates
! The group of Chi has reported the reversed process for the generation of homoenolates
from saturated esters, allowing for direct !-substitution.
N
Me
O
N
N
O
Me
Me
N
Ph
Ph
OAr
(– ArO–)
OH
Me
N
Me
N
N
O
Me
N
Ph
N
N
Me
OH
Me
Ph
H
base
N
N
Me
N
Ph
Me
N
N
homoenolate
Fu, Z.; Xu, X.; Zhu, X.; Leong, W. W. Y.; Chi, Y. R. Nat. Chem. 2013, 5, 835.
The Use of NHCs for the Generation of Homoenolates
Alternative Applications of Homoenolates
! The group of Chi has reported the reversed process for the generation of homoenolates
from saturated esters, allowing for direct !-substitution.
O
R2
R1
R2
up to 81% yield
94% ee, 20:1 dr
R1
R
N
Me
Me
NO 2
O
R
O
Me
N
N
BF 4
Ph
O
Ar
CF3
(20 mol%)
O
up to 61% yield
88% ee, 2:1 dr
O
DBU (150 mol%)
4 Å MS, MeCN
Ar
F 3C
BzHN
H
R
N
CO2Et
O
BzHN
N
up to 76% yield
94% ee, 7:1 dr
EtO 2C
R
Fu, Z.; Xu, X.; Zhu, X.; Leong, W. W. Y.; Chi, Y. R. Nat. Chem. 2013, 5, 835.
N-Heterocyclic Carbenes In Enantioselective Organocatalysis
Modes of Reactivity
Acyl Anions
R
O
N
N
OH
R
R
R
O
N
R
H
R
N
R
Homoenolates
R
O
N
N
OH
R
R
R
O
N
R
H
R
N
R
Azolium Enolates / Acyl Azoliums
O
X
O
•
H
R
O
R
R
N
N
O
O
R
R
N
R
R
R
OR
R
O
N
N
R
R
N
R
N-Heterocyclic Carbenes In Enantioselective Organocatalysis
Modes of Reactivity
Azolium Enolates / Acyl Azoliums
O
R
O
•
H
X
O
R
R
N
N
O
O
R
R
N
R
R
R
OR
R
O
N
N
R
R
! [2+2] Cycloadditions
! [4+2] Cycloadditions
! [3+2] cycloadditions
! Enolate Chemistry
N
R
The Use of NHCs for the Generation of Azolium Enolates
The First Examples
! The groups of Ye and Smith independently developed formal [2+2] cycloadditions promoted by
the addition of NHCs to ketenes
N
N
N
Ph
Ph
O
N
•
Ar1
R
Ar2
Boc
H
BF 4
Ph
OTBS
O
Boc
(10 mol%)
N
Cs2CO3 (10 mol%)
THF
Ar1
Ar2
R
53-78% yield, 91-99% ee
2.5-99:1 dr
O
N
N
O
N
•
Ph
Ph
Ar1
Ts
H
N
BF 4
Ph
O
(10 mol%)
KHMDS (9 mol%)
Et 2O
Ts
N
Ph
Ph
Ar1
79-96% yield, up to 75% ee
(>99% ee after recryst.)
Zhang, Y.-R.; He, L.; Wu, X.; Shao, P.-L.; Ye, S.; Org. Lett. 2008, 10 , 277.
Duguet, N.; Campbell, C. D.; Slawin, A. M. Z.; Smith, A. C. Org. Biomol. Chem. 2008, 6, 1108.
The Use of NHCs for the Generation of Azolium Enolates
The First Examples
! The groups of Ye and Smith independently developed formal [2+2] cycloadditions promoted by
the addition of NHCs to ketenes
O
Boc
N
TBSO
Ar1
Ar2
R
O
N
N
Ph
N
•
Ph
Ar1
Ph
R
N
N
N
TBSO
Ph
acyl
azolium
Ph
N
Ph
R
Ar1
O
N
Ph
Ph
Ar2
N
N
TBSO
Ph
R
O
azolium
enolate
Ar1
H
Boc
N
Ar2
Boc
H
Zhang, Y.-R.; He, L.; Wu, X.; Shao, P.-L.; Ye, S.; Org. Lett. 2008, 10 , 277.
Duguet, N.; Campbell, C. D.; Slawin, A. M. Z.; Smith, A. C. Org. Biomol. Chem. 2008, 6, 1108.
The Use of NHCs for the Generation of Azolium Enolates
Expanding the Scope of [2+2] Cycloadditions
! Since 2008, Ye et al. have reported numerous other enantioselective [2+2] cycloadditions
O
O
O
O
R
R1
Ar
O
Ar2
Ar1
O
N
O
CO2Et
Ar2
O
N
N
N
Ar
CO2Et
R
Ar2
O
O
R
Ar1
N
S
R
Ar1
O
R2
2008
2010
2010
2011
2011
Chen, X.-Y.; Ye, S. Synlett 2013, 1614.
Douglas, J.; Churchill, G.; Smith, A. C. Synthesis 2012, 44, 2295.
The Use of NHCs for the Generation of Azolium Enolates
[3+2] Cycloadditions
! The same group also reported an analogous [3+2] cycloaddition using oxaziridines
N
N
BF 4
Ar1
N
Ar2
Cl
O
NTs
•
Ar1
O
Ar2 OTBS
O
NTs
(10 mol%)
R
Cs2CO3 (10 mol%)
toluene
R
Cl
Ar
O
(+/–)
up to 78% yield, up to 95% ee
8-15:1 dr
N
N
N
R
N
Ar
R1
Ar1
O
TsN
O
N
N
R
O
R1
O
NTs
Ar
Ar2
Ar1
Ar2
Chen, X.-Y.; Ye, S. Synlett 2013, 1614.
Douglas, J.; Churchill, G.; Smith, A. C. Synthesis 2012, 44, 2295.
The Use of NHCs for the Generation of Azolium Enolates
[4+2] Cycloadditions
! Ye et al. also demonstrated a number [4+2] cycloaddition reactions
N
N
N
Ph
O
EtO 2C
•
Ph
R
OTMS
O
(10 mol%)
N
N
Ar1
BF 4
Ph
Cs2CO3 (10 mol%)
THF
CO2Et
CO2Et
N
N
Ar
CO2Et
R
52-95% yield, 33-91% ee
N
N
N
Ph
O
Bz
•
Ar1
R
Ph
BF 4
Ph
O
OTMS
N
(10 mol%)
N
Cs2CO3 (10 mol%)
THF
Ar
Bz
R
O
N
Ph
N
Bz
52-95% yield, 33-91% ee
Chen, X.-Y.; Ye, S. Synlett 2013, 1614.
Douglas, J.; Churchill, G.; Smith, A. C. Synthesis 2012, 44, 2295.
The Use of NHCs for the Generation of Azolium Enolates
[4+2] Cycloadditions
! Ye et al. reported the use of a variety of other 'dienes' in [4+2] cycloaddition reactions
O
Ar
R
O
N
Ph
O
O
Ts
Ar2
O
Ar1
N
R1
CO2Et
50-92% yield
>90% ee
>80% yield
57-93% ee
>15:1 dr
EtO 2C
N
R2
>80% yield
83-93% ee
>10:1 dr
R
O
Ar2
Ar1
R
Bz
N
Ar1
O
O
O
O
O
Ar1
R
PMP
Bz
88-99% yield
69-90% ee
3-10:1 dr
30-96% yield
51-99% ee
2-9:1 dr
Chen, X.-Y.; Ye, S. Synlett 2013, 1614.
Douglas, J.; Churchill, G.; Smith, A. C. Synthesis 2012, 44, 2295.
N-Heterocyclic Carbenes As Enantioselective Organocatalysts
Modes of Reactivity
Azolium Enolates / Acyl Azoliums
O
R
O
•
H
X
O
R
R
N
N
O
O
R
R
N
R
R
R
OR
R
O
N
N
R
R
! [2+2] Cycloadditions
! [4+2] Cycloadditions
! [3+2] cycloadditions
! Enolate Chemistry
N
R
N-Heterocyclic Carbenes As Enantioselective Organocatalysts
Modes of Reactivity
Azolium Enolates / Acyl Azoliums
O
R
O
O
•
H
R
X
R
N
O
N
O
R
R
R
R
N
N
R
OR
N
R
R
N
R
R
! Enolate chemistry of !-functionalized aldehydes
O
R
R
N
N
R
OH
R
R
N
– HX
O
R
R
N
H
X
N
X
R
N
R
The Use of NHCs for the Generation of Azolium Enolates
Utilizing ! Functionalized Aldehydes
! In 2005, Rovis et al. devloped a synthesis of !-chloro esters utilizing an enantioselective
protonation of an in situ generated !-chloro enolate
OH
O
N
Cl
BF 4
C6F 5
(10 mol%)
H
Cl
N
Br
Me
O
R
Br
N
Ar
(120 mol%)
OH
KH (100 mol%), 18-crown-6
toluene
O
R
OAr
Cl
65-79% yield, 84-93% ee
Reynolds, N. T.; Rovis, T. J. Am. Chem. Soc. 2005, 128 , 2860.
The Use of NHCs for the Generation of Azolium Enolates
Utilizing ! Functionalized Aldehydes
! In 2009, Scheidt et al. demonstrated that !-aryloxyacetaldehyde to be competent enolate
equivalents in Mannich reactions, giving "-amino amide derivatives
O
N
Me
N
Me
O2N
BF 4
C6F 5
Bn
O
O
N
N
H
Ar
Ts
(10 mol%)
4-NO2-C6H 4ONa (200 mol%)
THF-CH2Cl2
then BnNH 2
Ts
Ar
NH
O
NHBn
56-75% yield, >90% ee
Kawanaka, Y.; Phillips, E. M.; Scheidt, K. A. J. Am. Chem. Soc. 2009, 131 , 18028.
N-Heterocyclic Carbenes In Enantioselective Organocatalysis
Modes of Reactivity
Acyl Anions
R
O
N
N
OH
R
R
R
O
N
R
H
R
N
R
Homoenolates
R
O
N
N
OH
R
R
R
O
N
R
H
R
N
R
Azolium Enolates / Acyl Azoliums
O
X
O
•
H
R
O
R
R
N
N
O
O
R
R
N
R
R
R
OR
R
O
N
N
R
R
N
R
Oxidative NHC Catalysis
Oxidative Functionalization of Aldehydes
! In 2007 and 2008, Scheidt et al. demonstrated NHCs could catalyze the MnO 2-promoted
oxidation of benzylic and vinylic alcohols to esters, and unactivated aldehydes to esters
R1
OH
N
activated alcohol
Me
O
R1
N
N
I
Me
(10 mol%)
O
R 2OH, MnO 2, DBU
R1
H
64-99% yield
unactivated aldehyde
OH
O
Me
N
R1
N
Me
OR2
N
Me
[O]
N
R1
N
Me
N
Maki, B. E.; Chan, A.; Phillips, E. M.; Scheidt, K. A. Org. Lett. 2007, 9, 371.
Maki, B. E.; Scheidt, K. A. Org. Lett. 2008, 10 , 4331.
Oxidative NHC Catalysis
Oxidative Functionalization of Aldehydes
! Since these reports, Chi et al. have demonstrated the use of oxidative NHC catalysis in a variety
of highly enantioselective reactions
O
N
N
O
Ar
O
R1
H
N
BF 4
Mes
O
(10 mol%)
O
R2
O
oxidant
Cs2CO3 (50 mol%), THF
R2
Ar
R1
O
53-98% yield, 70-94% ee
O
t-Bu
t-Bu
OH
N
oxidant:
Ar
t-Bu
N
Me
O
Me
N
[O]
N
Ar
N
Me
O
Me
N
Me
[O]
N
Ar
N
Me
N
t-Bu
O
Mo, J.; Shen, L.; Chi, Y. R. Angew. Chem. Int. Ed. 2013, 52, 8588.
Oxidative NHC Catalysis
Oxidative Functionalization of Aldehydes
! Since these reports, Chi et al. have demonstrated the use of oxidative NHC catalysis in a variety
of highly enantioselective reactions
O
N
N
O
R1
X
BF 4
Mes
O
(10 mol%)
O
H
N
O
R2
oxidant
Cs2CO3 (50 mol%), THF
Me
R2
R1
X
61-89% yield, 84-99% ee
O
t-Bu
t-Bu
O
O
N
t-Bu
t-Bu
Boc
O
O
CF3
oxidant:
O
O
CF3
Ph
S
Et
NH
O
O
O
Chen, X.; Yang, S.; Song, B.-A.; Chi, Y. R. Angew. Chem. Int. Ed. 2013, 52, 11134.
Oxidative NHC Catalysis
Oxidative Functionalization of Aldehydes
! Since these reports, Chi et al. have demonstrated the use of oxidative NHC catalysis in a variety
of highly enantioselective reactions
O
N
N
O
R1
O
O
R2
oxidant
Cs2CO3 (50 mol%), THF
Me
X
BF 4
Mes
(10 mol%)
O
H
N
R2
R1
X
61-89% yield, 84-99% ee
OH
O
R
N
X
RN
Me
N
R
N
[O]
X
base
RN
CH2
O
R
base
N
N
X
RN
N
H
increased acidity
of benzylic position
Chen, X.; Yang, S.; Song, B.-A.; Chi, Y. R. Angew. Chem. Int. Ed. 2013, 52, 11134.
Oxidative NHC Catalysis
An Enantioselective Oxidative Aza-Acyloin Reaction
! In 2012, Rovis et al. reported the merger of photoredox and NHC catalysis for the
enantioselective !-acyaltion of tertiary amines
O
N
N
Br
N
Br
(5 mol%)
O
N
Ph
Ph
Br
N
Ph
Ru(bpy) 3Cl2 (1 mol%)
H
m-dinitrobenzene (120 mol%)
CH2Cl2, blue LEDS
via:
N
O
Ph
91% yield, 92% ee
X–
Ph
DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2012, 134 , 8094.