asymmetric organocatalysis with n-heterocyclic carbenes · pdf filen nch3 nnh2 s h3c ho cl...
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N
N CH3
NH2N
S
H3C
HO
Cl
Asymmetric Organocatalysis with N-Heterocyclic CarbenesHistory and Recent Developments
Adam NobleMacMillan Group Meeting
January 29th 2014
Early DevelopmentsThe Benzoin Condensation
! 1832: First report of bezoin condensation by Wöhler and Liebig
Ph H
OPh
OPh
OH
! 1903: Mechanism proposed by Lapworth
CN–
CN–
Ph H
O
Ph
HO H
N
Ph •N
OH
Ph
ON
Ph
OH
Ph
OPh
OH
+ H2O
OH
Ph H
O
HHO
H2O Wöhler, F.; Liebig, J. Ann. Pharm. 1832, 3, 249.Lapworth, A.; J. Chem. Soc. 1903, 83, 995.
benzoin
Thiamine (Vitamin B1 )Enzymatic Acyl Anion Generation
! Thiamine is responsible for the genaration of acyl anion equivalents in a number of biochemical reactions
Cl
NN
N
NH2
Me
S
Me
Kluger, R.; Tittmann, K. Chem. Rev. 2008, 108 , 1797.
OH
thiamine
NN
N
NH2
Me
S
Me
OPO
OPO
OHO O
thiamine diphosphate (TDP)
! Most commonly found as the co-enzyme thiamine diphosphate (TDP)
R
O
O
OR
O+ CO2
! Pyruvate oxidase! Pyruvate dehydrogenase
! Pyruvate decarboxylase
! Transketolase
Early DevelopmentsThiamine-Catalyzed Benzoin Condensation
Ph H
OPh
OPh
OH
! 1943: Ugai discovered that thiazolium salts could replace cyanide in benzoin condensations
Cl
N
N
N
NH2
MeS
HOMe
NaOH, MeOH
A variety of other thiazolium compounds were also demonstrated to be effective catalysts
Cl
N Ar
SR
MeHO Ph
expected formed
Ugai, T.; Tanaka, R.; Dokawa, T. J. Pharm. Soc. Jpn. 1943, 63, 296.
BrN
S
Me
BrN
S
PhMe/H
BrN
S
MeMe
Br
N
S
MePh
OHMe/HI
N
N
MeMe
Me
Early DevelopmentsThiamine-Catalyzed Benzoin Condensation
! 1954: Mizuhara demonstrated that thiamine could catalyze a number of reactions that had also been observed in biological systems
Me
O
Me
OMe
OH
Me
SNCHO
N
N
NH2
Me
OH
2
O
RMe
O
H
no reaction with:
Cl
N
N
N
NH2
MeS
HOMe
Mizuhara, S.; Handler, P. J. Am. Chem. Soc. 1954, 76, 571.
! Showed that the thiazolium moiety of thiamine was responsible for the catalytically activity
R = Me or OH
acyloin
+ AcOH (R = Me) or CO2 (R = OH)
Early DevelopmentsMechanism of the Thiamine-Catalyzed Benzoin Condensation?
! Reactions such as pyruvate decarboxylation and benzoin-type condensations catalyzed bythiamine (vitamin B1) dependent enzymes were considered some of the most "mysterious" transformations
! 1958: Breslow demonstrated that the C-2 proton of thiazoliums exchanges rapidly with deuterium
N
N
N
NH2
MeS
HOMe
N
S
Me MeBr
D2OCl
N
N
N
NH2
MeS
HOMe
H
N
S
Me MeBr
D
H
Cl
N
N
N
ND2
MeS
DOMe
D
the origin of reactivity was unknownuntil the work of Breslow
??
?
Breslow, R. J. Am. Chem. Soc.. 1958, 80, 3719.
D2O
Early DevelopmentsBreslows Proposed Mechanism
S
NR1
R3 H
R2– H+
S
NR1
R3
R2
S
NR1
R3
R2
O-
Ph
S
NR1
R3
R2
S
NR1
R3
R2
OH
Ph
O PhPh
OH
Ph
OPh
OH
! 1958: Breslow proposed his mechanism for the thiazolium catalyzed benzoin condensation
Breslowintermediate
S
NR1
R3
R2
S
NR1
R3
R2
Ph H
O
Ph H
O
Breslow, R. J. Am. Chem. Soc.. 1958, 80, 3719.
Rovis, T, Nolan, S. P. Synlett 2013, 1188.
! This was the case until 1968, when seminal work by the groups of Wanzlick and Öfeledemonstrated that NHCs could be isolated in their metal-ligated forms
From 'Laboratory Curiosities' to Catalysis MainstaysSynthesis of Stable N-Heterocyclic Carbenes
! Since the mechanistic work by Breslow, NHCs were only considered as highly reactiveintermediates.
! Their high reactivty made the isolation of such species seemingly impossible, with dimerizationbeing a major reaction pathway.
N
NPh
Ph
CCl3N
NPh
PhN
NPh
PhN
NPh
Ph
X– CHCl3
∆
Wanzlick, H.-W. Angew. Chem. Int. Ed. 1962, 1 , 75.
Hans-Werner Wanzlick Karl Öfele
Wanzlick and Öfele1968: First isolation of ligated NHCs
! Wanzlick et al isolated a mercury complexed NHC
– 2 AcOH
Hg(OAc)2, !
N
NPh
Ph
HgN
NPh
Ph
2 [ClO4]–
EtO
OEtN
S
HN
Ph
Phconc. HCl
N
NPh
Ph
S
66%
1) HNO3
94%
N
N+
Ph
Ph
H [ClO4]–
quant.
Wanzlick, H.-W.; Schönherr, H.-J. Angew. Che. Int. Ed. 1968, 7, 141.
! Isolated as colourless plates! Structure confirmed by 1H NMR
2) NaClO4
Wanzlick and Öfele1968: First isolation of ligated NHCs
N
N+
Me
Me
H [HCr(CO)5]–– H2
120 ºC
N
NMe
Me
Cr(CO)5
80%
! Öfele isolated a chromium NHC complex while trying to generatedehydro-complexes from heterocyclic salts
Öfele, K. J. Organomet. Chem. 1968, 12 , 42.
! Despite these advances, the field remained relatively inactive for 23 years until a breakthroughdiscovery by the group of Arduengo
! Light yellow crystalline solid
[HCr(CO)5]–– 2 CON
MeNMe
Cr(CO)3!
! Structure confirmed by 1H NMR
Arduengo1991: First isolation of a stable crystalline NHC
Arduengo, III, A. J.; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991, 113 , 361.
N+
NH
NaH, THF
cat. DMSO anion N
N
96%
! The synthesis of isolable NHCs was instrumental in causing the explosion in interest instable carbene chemistry
! Isolated the free carbene by deprotonation of a bis-adamantyl imidazolium chloride
Cl
! The structure was unequivocally established by single-crystal X-ray analysis
! Thermally stable in the absense of oxygen and moisture
Isolable NHCsExplosion in the Number of Reported Isolations
! After the first report from Arduengo in 1991, many other groups reported successfulsyntheses of a variety of new NHCs
N
N
Alkyl
Alkyl
N
N
N
Ph
Ph
Ph
Enders et al1995
(first commerciallyavailable carbene)
N N
Herrmann et al1996
MeMe
Bourissou, D.; Guerret, O.; Gabbai, F. P.; Bertrand, G. Chem. Rev. 2000, 100 , 39.
Herrmann et al1996
N
N
Alkyl
Alkyl
Arduengo et al1992
Me
MeS
N
Arduengo et al1997
Me
Me
i-Pr
i-Pr
N
N
Mes
Mes
Arduengo et al1992
N
N
Mes
Mes
Arduengo et al1995
Isolable NHCsStability
! Original reports suggested that isolation was due to sterics preventing dimerization
N
N
N
N
XN
N
N
N
! The isolation of the carbene from 1,3,4,5-tetramethylimidazolium chloride suggestedthat electronic factors may have greater impact on the stability of carbenes than sterics.
N
N
Me
MeMe
MeN
N+
Me
MeMe
Me
HNaH
KOtBu, THF
Bourissou, D.; Guerret, O.; Gabbai, F. P.; Bertrand, G. Chem. Rev. 2000, 100 , 39.
Isolable NHCsStability
N
N
R1
R1R
R
! Electronic factors operating in both the ! and " frameworks result in a "push-pull" synergisticeffect to stabilize the carbene.
!-electrondonation
"-electronwithdrawal
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.
! ! donation into the carbene from theout-of-plane ! orbital stabilizes
electrophilic reactivity
! " withdrawal by electronegative atomsstabilizes 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
Isolable NHCsReactivity: Why are they so useful?
! NHCs are exceptionally good ! donors so form strong metal–carbon bonds:
! Singlet carbenes of NHCs are distinct Lewis bases that show both ! basicity and " acidity:
N N
Me
Me
Me
Me
Me
Me
RuPh
PCy3Cl
Cl
N NMe Me
Pd
! Compared to phosphines, NHCs form complexes that:
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.
PhPh
PhPh
PhPh
PhPh
Cl
Ph
! often have catalytic activities 100 to 1000 times greater! show greater air and thermal stability! are more straightforward to prepare (due to in situ NHC formation)
! 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
0
100
200
300
400
500
600
700
1943
1948
1953
1958
1963
1968
1973
1978
1983
1988
1993
1998
2003
2008
2013
Num
ber o
f!Pu
blic
atio
ns!
Year!
Number of Publications on NHC Catalysis!
Isolable NHCsReactivity: Why are they so useful?
! These factors have resulted in a huge increase in interest in NHCs over the past 70 years
N-Heterocyclic Carbenes In Enantioselective OrganocatalysisModes of Reactivity
R
O
H
Acyl Anions
O
H
Homoenolates
R
O
H
O
Azolium Enolates / Acyl Azoliums
XO•
N
NR
R
R
OH
N
NR
R
OR
O O
N
NR
R
R
ONNR R
OH
N
NR
R
ONNR R
RR
NNR R OR
R R
R
R R
N-Heterocyclic Carbenes In Enantioselective OrganocatalysisModes of Reactivity
R
O
H
Acyl Anions
R
OH
N
NR
RR
ONNR R
! Benzoin Condensations
! Stetter Reactions
! Hydroacylations
The Use of NHCs for the Generation of Acyl Anion EquivalentsEarly Developments
Ph H
OPh
OPh
OH
! 1943: Ugai discovered the thiazolium-catalyzed benzoin condensation
NaOH, MeOH
XN
S
R3R2
R1
Ugai, T.; Tanaka, R.; Dokawa, T. J. Pharm. Soc. Jpn. 1943, 63, 296.
The Use of NHCs for the Generation of Acyl Anion EquivalentsThe First Asymmetric Examples
! 1966: Sheehan described the first asymmetric benzoin condensations catalyzed by chiralthiazolium salts
Sheehan, J. C.; Hunneman, D. H. J. Am. Chem. Soc. 1966, 88, 3666.
S N
Me
Br
Ph
O
O
S N
Me
Br Me
Ph H
OPh
OPh
OHEt3N (10 mol%)MeOH
(10 mol%)
*
Precipitate: 50%, 0.8% eeFiltrate: 9% yield, 22% ee
! 1974: Sheehan reported slight improvements to enantioselectivity but still low yield
Ph H
OPh
OPh
OHEt3N (10 mol%)MeOH
(10 mol%)
6% yield, 52% ee
Sheehan, J. C.; Hara, T. J. Org. Chem 1974, 39, 1196.
The Use of NHCs for the Generation of Acyl Anion EquivalentsThe First Asymmetric Examples
! Following the work of Sheehan, a number of other groups reported the use of similar NHCs tocatalyze benzoin condensations
Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534.
S N
Me
Cl
MeMe
MeS
NI
N
S
I
NN
NClO4
O O
Ph
Me Me
Ph
20%, 35% eeTakagi et al, 1980
47-57%, 20-30% eeZhao et al, 1988
S N
Me
Br Me
21%, 26% eeLópez-Calahora et al, 1993
66%, 75% eeEnders et al, 1996
50%, 21% eeLeeper et al, 1997
N
STfO
TBSO
45%, 80% eeLeeper et al, 1998
NN
NCl
OPh
Bicyclic triazoliums are key!Ph
The Use of NHCs for the Generation of Acyl Anion EquivalentsThe First Asymmetric Examples
! The initial development of N-aryl-bicyclic triazoliums led the way to improved catalyst efficiency
Rovisr, T. Chem. Lett. 2008, 37, 534.
NN N
X
R1
nR2
Tunable electronics
catalytic activity
basicity
Tunable sterics
catalytic activity
asymmetricinduction
The Use of NHCs for the Generation of Acyl Anion EquivalentsBicyclic Triazolium Salts Give High Enantioselectivities
! Modification of Leepers bicyclic triazoliums allowed Enders to develop a highly efficient NHCcatalysts
Enders, D.; Kallfass, U. Angew. Chem. Int. Ed. 2002, 41, 1743.
NN
NBF4
O
Me
MeMe
Ph H
OPh
OPh
OHKOt-Bu (10 mol%)THF
(10 mol%)
83% yield, 90% ee
favored disfavored favored
Dudding, T.; Houk, K. N. Proc. Nat. Acad. Sci. 2004, 101 , 5770.
Ph
! Connon et al demonstrated the NHCs bearing alcohol directing groups can give exceptionallevels of enantioinduction
Baragwanath, L.; Rose, C. A.; Zeitler, K.; Connon, S. J. J. Org. Chem. 2009, 74, 9214.
NN N
BF4
O
Ph H
OPh
OPh
OHRb2CO3 (4 mol%)THF
(4 mol%)
90% yield, >99% ee
OH
PhPh
F
F
FF
F
The Use of NHCs for the Generation of Acyl Anion EquivalentsBicyclic Triazolium Salts Give High Enantioselectivities
The Use of NHCs for the Generation of Acyl Anion EquivalentsEarly Developments
Ph H
OPh
OPh
OH
! 1943: Ugai discovered the thiazolium-catalyzed benzoin condensation
NaOH, MeOH
Stetter, H.; Kuhlmann, H. Angew. Chem. Int. Ed. Engl. 1974, 13 , 539.
XN
S
R3R2
R1
R1 H
OR1
O
R2
! 1974: Stetter reported the 1,4-addition variant = The Stetter Reaction
Et3N, MeOH
XN
S
RMe
Ugai, T.; Tanaka, R.; Dokawa, T. J. Pharm. Soc. Jpn. 1943, 63, 296.
HO
EWGR2
EWG
EWG = COR, CO2R, CN
The Use of NHCs for the Generation of Acyl Anion EquivalentsIntramolecular Stetter Reactions
! In 1996 Enders et al. reported the first asymmetric Stetter Reaction
Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. Helv. Chim. Act. 1996, 79, 1899.
H
O
K2CO3 (20 mol%)THF
(20 mol%)
22-73% yield, 41-74% ee
O CO2R2 O
O CO2R2
NN
NClO4
O O
Ph
Me Me
Ph
R1 R1
The Use of NHCs for the Generation of Acyl Anion EquivalentsIntramolecular Stetter Reactions
! Following the original report by Enders, Rovis et al. developed the first highly enantioselectiveintramolecular Stetter reactions
Kerr, M. S.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2002, 124 , 10298.
NN N
BF4
H
O
KHMDS (20 mol%)xylene
(20 mol%)
94% yield, 94% ee
OMe
O
O CO2Et O
O CO2Et
O
CO2Et
O
HCO2Et
NN N
BF4
KHMDS (20 mol%)xylene
(20 mol%)
Bn
81% yield, 95% ee
The Use of NHCs for the Generation of Acyl Anion EquivalentsIntermolecular Stetter Reactions
! Development of asymmetric intermolecular Stetter reactions still remains a formidable challenge
Enders, D.; Han, J.; Henseler, A. Chem. Commun. 2008, 3989.
! Enders et al. developed a high yielding protocol taking advantage of the higher reactivity ofchalcones, although the enantioselectivities were only moderate
NN N
BF4
Cs2CO3 (10 mol%)THF
(10 mol%)
Ph
49-98% yield, 58-78% ee
TBDPSO
Ar1 H
O
Ar2
O
Ar3 Ar1
O
Ar2
Ar3
O
! This is due to the diminished reactivity of Michael acceptors containing a !-substituent
The Use of NHCs for the Generation of Acyl Anion EquivalentsIntermolecular Stetter Reactions
! In the same year Rovis et al. reported a highly enantioselective intermolecular Stetter reactionof glyoxamides a number of Michael acceptors
Liu, Q.; Perreault, S.; Rovis, T. J. Am. Chem. Soc. 2008, 130 , 14066.
NN N
BF4
iPr2NEt (100 mol%), MgSO4CCl4
(20 mol%)
C6F5Bn
44-95% yield, 81-98% ee4:1-19:1 dr
H
O
! A limitation was the need for highly activated alkylidene dicarbonyls
N
O
O
ON
O
O
RCO2t-Bu
CO2t-Bu
RCO2t-Bu
CO2t-Bu
R1
R2O
ON
O
O
R1
O R2
51-97% yield, 80-91% ee
A general strategy for asymmetric intermolecular Stetter reactions has not yet been developed!
Liu, Q.; Rovis, T. Org. Lett. 2009, 11 , 2856.
NMe2
O
NMe2
O
The Use of NHCs for the Generation of Acyl Anion EquivalentsHydroacylation of Unactivated Double Bonds
! In 2008, She et al. reported the intramolecular hydroacylation of enol ethers
He, J.; Tang, S.; Liu, J.; Su, Y.; Pan, X.; She, X. Tetrahedron 2008, 64, 8797.
! In 2011, Glorius et al. reported a highly asymmetric variant
Piel, I.; Steinmetz, M.; Hirano, K.; Fröhlich, R.; Grimme, S.; Glorius, F. Angew. Chem. Int. Ed. 2011, 50, 4983.
O
H
O
PhR
O
O
RPh
S N I
DBU (70 mol%)xylene, reflux
(25 mol%)Me
66-99%
MeHO
NN N
Cl
DBU (10 mol%)dioxane, 80 ºC
(10 mol%)
Me
MeMe
O
BnO
H
OAr
O
O
ArMe
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.
The Use of NHCs for the Generation of Acyl Anion EquivalentsHydroacylation of Unactivated Double Bonds
! The mechanism was investigated by Glorius and Grimme and found to likely proceed viaa concerted but highly asynchronous transition state.
NN N
ClMes
O
H
O
O
O
Hirano, K.; Biju, A. T.; Piel, K.; Grimme, S.; Glorius, F. J. Am. Chem. Soc. 2009, 131 , 14190.
DBU NN N
Mes
O
O
NN
NMesR
R R
Me
O
NN
NMesR
H
H
O
MeO
NN
NMes
R
‡
O
OH
!-
!+ ‡
OR2N
H!+ ‡
or
(Conia)-Ene reverse-Copeelimination
vs.
O H
NR2
R2N
R
1st
1st
2nd
2nd‡
concerted butasynchronous
N-Heterocyclic Carbenes In Enantioselective OrganocatalysisModes of Reactivity
R
O
H
Acyl Anions
O
H
Homoenolates
R
O
H
O
Azolium Enolates / Acyl Azoliums
XO•
N
NR
R
R
OH
N
NR
R
OR
O O
N
NR
R
R
ONNR R
OH
N
NR
R
ONNR R
RR
NNR R OR
R R
R
R R
N-Heterocyclic Carbenes In Enantioselective OrganocatalysisModes of Reactivity
! Cyclopentene Synthesis
! Spiroannulations
! Lactam/Lactone Synthesis
O
H
Homoenolates
R
OH
N
NR
R
ONNR R
RR
! Conversion of Enals to Saturated Esters
Sohn, S. S.; Rosen, E. L.; Bode, J. J. Am. Chem. Soc. 2004, 126 , 14370.
The Use of NHCs for the Generation of HomoenolatesThe First Examples
! In 2004, the groups of Bode and Glorius reported the use of NHC-catalyzed homoenolateformation for the synthesis of !-butyrolactones
Burstein, C.; Glorius, F. Angew. Chem. Int. Ed. 2004, 116 , 6331.
O
Ar1 H Ar2
O
H
N N Cl
DBU (7 mol%)THF/t-BuOH
(8 mol%)MesMesO
O
Ar1 Ar2
41-87%, 3:1-7:1 cis:trans
Bode:
O
Ar1 H Ar2
O
H
N N Cl
KOt-Bu (10 mol%)THF
(5 mol%)MesMesO
O
Ar1 Ar2
33-70%, up to 4:1 cis:trans
Glorius:
Sohn, S. S.; Rosen, E. L.; Bode, J. J. Am. Chem. Soc. 2004, 126 , 14370.
The Use of NHCs for the Generation of HomoenolatesThe First Examples
! Proposed mechanism for the NHC-catalyzed formation !-butyrolactones
Burstein, C.; Glorius, F. Angew. Chem. Int. Ed. 2004, 116 , 6331.
N NMesMes
O
Ph H
OH
Ph N
NMes
MesO
Ph N
NMes
Mes
OH
Ph N
NMes
MesAr OO
Ph N
NMes
MesO
OH
Ph N
NMes
Mes
homoenolate
H Ar
O
activated carboxylate
O
O
Ph Ar
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 HomoenolatesMany Asymmetric Examples Followed
! Bode et al. demonstrated a variety of highly enantioselective transformations of homoenolates
O
R1 H
NN N Cl
Mes
O
O
(10 mol%)
R2
R3
N
R2
H
SO2ArN
R2
Ph
SO2Ar O
R2
OH
Me Me
O
R2
Ph
O
O
R1
R2 R3
N
O
R1
R2
SO2ArN
R2
R1
O SO2Ar
PhHO
R2
R1
O
HOH
Me
Me
R2
R1
Ph
4->20:1 dr96-99% ee
>50:1 dr97-99% ee
>10:1 dr87-99% ee
2:1 dr99% ee
>20:1 dr99% ee
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 HomoenolatesMany Asymmetric Examples Followed
! Bode et al. demonstrated a variety of highly enantioselective transformations of homoenolates
N
R2
R1
O SO2Ar
PhH
O
R2
R1
O
HOH
Me
Me
R2
R1
Ph
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 HomoenolatesMany Asymmetric Examples Followed
! Recently, Chi et al. demonstrated a homoenolate coupling with benzodi(enone)s for the synthesis of complex tricyclic structures
O
R1 H
NN N Cl
Mes
O
(20 mol%)
DBU (30 mol%)
53-84% yield
R2
O
R3
O THF
10-20:1 dr96-99% ee
O
O
R3
R1
O
R3
H
H
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 HomoenolatesMany Asymmetric Examples Followed
! Recently, Chi et al. demonstrated a homoenolate coupling with benzodi(enone)s for the synthesis of complex tricyclic structures
O
O
R2
RO
R1
H
H
product5
N-Heterocyclic Carbenes As Enantioselective OrganocatalystsAlternative Applications of Homoenolates
O
H
Homoenolates
R
OH
N
NR
R
ONNR R
RR
OH
N
NR
R
R2
O
N
NR
R
R2
R1R1ROH RO– O
ORR2
R1
(-NHC)
"Redox Relay"
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 HomoenolatesAlternative Applications of Homoenolates
! Using this ester formation reaction they could perform desymmetrizations of meso diolsand enantioselective protonations of !,!-disubstituted enals
O
Ph H
NN N BF4
Mes
O
(30 mol%)OH
OH proton spongeK2CO3, 18-crown-6
CH2Cl2
OH
O
OPh
58%, 80% ee
O
Ph H
NN N BF4
Mes
O
(30 mol%)
proton spongeK2CO3, 18-crown-6
CH2Cl2
O
Ph
58%, 55% ee
Me OHMe
O
MeBn
PhPh
Me
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 HomoenolatesAlternative Applications of Homoenolates
! The group of Chi has reported the reversed process for the generation of homoenolates from saturated esters, allowing for direct !-substitution.
NN N
MeMeO
Ph OAr
O
Ph
N
N
NMe
Me
OH
Ph
N
N
NMe
Me
homoenolate
O
Ph
N
N
NMe
MeHbase
OH
Ph
N
N
NMe
Me
(– ArO–)
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 HomoenolatesAlternative 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
R O
NN N BF4
Ph
(20 mol%)
DBU (150 mol%)4 Å MS, MeCN
Me
MeMe
NO2
R1
O
R2R2
R1R
Ar
O
CF3
O
O
ArF3C R
N
O
R
BzHN
NBzHN
CO2EtH
up to 81% yield94% ee, 20:1 dr
up to 61% yield88% ee, 2:1 dr
up to 76% yield94% ee, 7:1 drEtO2C
N-Heterocyclic Carbenes In Enantioselective OrganocatalysisModes of Reactivity
R
O
H
Acyl Anions
O
H
Homoenolates
R
O
H
O
Azolium Enolates / Acyl Azoliums
XO•
N
NR
R
R
OH
N
NR
R
OR
O O
N
NR
R
R
ONNR R
OH
N
NR
R
ONNR R
RR
NNR R OR
R R
R
R R
N-Heterocyclic Carbenes In Enantioselective OrganocatalysisModes of Reactivity
! [2+2] Cycloadditions
! [4+2] Cycloadditions
! [3+2] cycloadditions
! Enolate Chemistry
O
H
O
Azolium Enolates / Acyl Azoliums
RO•
N
NR
R
OR
O O
N
NR
R
NNR R OR
X R
R
R R
Duguet, N.; Campbell, C. D.; Slawin, A. M. Z.; Smith, A. C. Org. Biomol. Chem. 2008, 6, 1108.Zhang, Y.-R.; He, L.; Wu, X.; Shao, P.-L.; Ye, S.; Org. Lett. 2008, 10 , 277.
The Use of NHCs for the Generation of Azolium EnolatesThe First Examples
! The groups of Ye and Smith independently developed formal [2+2] cycloadditions promoted bythe addition of NHCs to ketenes
NN N BF4
Ph
(10 mol%)
Cs2CO3 (10 mol%)
PhOTBSPh
Ar1
•O
Ar2
NBoc
H
N
R
O Boc
Ar2Ar1
R
53-78% yield, 91-99% ee2.5-99:1 dr
NN N BF4
Ph
(10 mol%)
KHMDS (9 mol%)Ph
•O
Ar1
NTs
H
N
Ph
O Ts
Ar1Ph
Ph
79-96% yield, up to 75% ee(>99% ee after recryst.)
THF
Et2O
O
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 EnolatesThe First Examples
! The groups of Ye and Smith independently developed formal [2+2] cycloadditions promoted bythe addition of NHCs to ketenes
Zhang, Y.-R.; He, L.; Wu, X.; Shao, P.-L.; Ye, S.; Org. Lett. 2008, 10 , 277.
NN N
Ph
O
NN N
Ar1
R
Ar1
•O
Ar2
NBoc
H
N
R
O Boc
Ar2Ar1
R
O
NN N
Ar1R
N HAr2
Boc
TBSOPhPh
Ph
TBSOPh
Ph
TBSOPh
PhPh
azoliumenolateacyl
azolium
Douglas, J.; Churchill, G.; Smith, A. C. Synthesis 2012, 44, 2295.
The Use of NHCs for the Generation of Azolium EnolatesExpanding the Scope of [2+2] Cycloadditions
! Since 2008, Ye et al. have reported numerous other enantioselective [2+2] cycloadditions
OO
RAr1
2008
O
Ar2
O
O
R1
Ar
2010
NO
R2
NN
O
ArR
2010
CO2Et
CO2EtON
O
RAr1
2011
Ar2
SN
O
RAr1
2011
Ar2
O
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
Chen, X.-Y.; Ye, S. Synlett 2013, 1614.
NN N BF4
Ar1
(10 mol%)
Cs2CO3 (10 mol%)
Ar2
OTBSAr2
Ar1
•O
R
up to 78% yield, up to 95% ee8-15:1 dr
toluene
ClNTs
O
O
NTsO
ClRAr
(+/–)
NN N
ArR
OO
Ar1R1
Ar2
TsN
NN N
ArR
OAr1
R1 Ar2
NTs
O
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
Chen, X.-Y.; Ye, S. Synlett 2013, 1614.
NN N BF4
Ph
(10 mol%)
Cs2CO3 (10 mol%)
PhOTMSPh
Ar1
•O
R
52-95% yield, 33-91% ee
THF
NN
EtO2C
CO2EtNN
O
ArR
CO2Et
CO2Et
NN N BF4
Ph
(10 mol%)
Cs2CO3 (10 mol%)
PhOTMSPh
Ar1
•O
R
52-95% yield, 33-91% ee
THF
NN
Bz
BzN
N
O PhO
ArR
Bz
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
Chen, X.-Y.; Ye, S. Synlett 2013, 1614.
NN
O PhO
ArR
Bz
O Ar2O
Ar1
RCO2Et
N Ar2O
Ar1
R1R2
Ts
OO
Ar1REtO2C
NBz
O O
Ar1
RPMP
O
O
30-96% yield51-99% ee
2-9:1 dr
88-99% yield69-90% ee3-10:1 dr
50-92% yield>90% ee
>80% yield57-93% ee>15:1 dr
>80% yield83-93% ee>10:1 dr
N-Heterocyclic Carbenes As Enantioselective OrganocatalystsModes of Reactivity
! [2+2] Cycloadditions
! [4+2] Cycloadditions
! [3+2] cycloadditions
! Enolate Chemistry
O
H
O
Azolium Enolates / Acyl Azoliums
RO•
N
NR
R
OR
O O
N
NR
R
NNR R OR
X R
R
R R
N-Heterocyclic Carbenes As Enantioselective OrganocatalystsModes of Reactivity
! Enolate chemistry of !-functionalized aldehydes
O
H
O
Azolium Enolates / Acyl Azoliums
RO•
N
NR
R
OR
O O
N
NR
R
NNR RR
X R
R
R R
O
HR
X
NNR ROH
N
NR
RX
RO
N
NR
R
R– HX
Reynolds, N. T.; Rovis, T. J. Am. Chem. Soc. 2005, 128 , 2860.
The Use of NHCs for the Generation of Azolium EnolatesUtilizing ! Functionalized Aldehydes
! In 2005, Rovis et al. devloped a synthesis of !-chloro esters utilizing an enantioselectiveprotonation of an in situ generated !-chloro enolate
NN N BF4
C6F5
(10 mol%)
KH (100 mol%), 18-crown-6
O
65-79% yield, 84-93% ee
toluene
O
HRCl Cl
Ar OH
OHBrBr
Me
(120 mol%)O
OArRCl
Kawanaka, Y.; Phillips, E. M.; Scheidt, K. A. J. Am. Chem. Soc. 2009, 131 , 18028.
The Use of NHCs for the Generation of Azolium EnolatesUtilizing ! Functionalized Aldehydes
! In 2009, Scheidt et al. demonstrated that !-aryloxyacetaldehyde to be competent enolateequivalents in Mannich reactions, giving "-amino amide derivatives
NN N BF4
C6F5
(10 mol%)
4-NO2-C6H4ONa (200 mol%)
O
56-75% yield, >90% ee
THF-CH2Cl2
O
HO O
NHBnAr
MeMe
Bn
then BnNH2
NHTs
O2N
NTs
Ar
N-Heterocyclic Carbenes In Enantioselective OrganocatalysisModes of Reactivity
R
O
H
Acyl Anions
O
H
Homoenolates
R
O
H
O
Azolium Enolates / Acyl Azoliums
XO•
N
NR
R
R
OH
N
NR
R
OR
O O
N
NR
R
R
ONNR R
OH
N
NR
R
ONNR R
RR
NNR R OR
R R
R
R R
Maki, B. E.; Scheidt, K. A. Org. Lett. 2008, 10 , 4331.
Oxidative NHC CatalysisOxidative Functionalization of Aldehydes
! In 2007 and 2008, Scheidt et al. demonstrated NHCs could catalyze the MnO2-promotedoxidation of benzylic and vinylic alcohols to esters, and unactivated aldehydes to esters
NN N I
Me (10 mol%)
R2OH, MnO2, DBU
64-99% yield
OHR1
O
OR2R1
Maki, B. E.; Chan, A.; Phillips, E. M.; Scheidt, K. A. Org. Lett. 2007, 9, 371.
Meactivated alcohol
R1 H
O
unactivated aldehyde
R1
OH
N N
N
Me
Me[O]
R1
O
N N
N
Me
Me
Mo, J.; Shen, L.; Chi, Y. R. Angew. Chem. Int. Ed. 2013, 52, 8588.
Oxidative NHC CatalysisOxidative Functionalization of Aldehydes
! Since these reports, Chi et al. have demonstrated the use of oxidative NHC catalysis in a varietyof highly enantioselective reactions
NN N BF4
Mes
(10 mol%)
oxidant
O
53-98% yield, 70-94% ee
Cs2CO3 (50 mol%), THF
O
HAr
O
O
t-Bu t-Bu
t-Bu t-Bu
O O
R1 R2
O
O
OR1
R2Ar
oxidant:
OH
N N
N
Me
Me[O]
O
N N
N
Me
Me
Ar Ar
O
N N
N
Me
Me
Ar
[O]
Chen, X.; Yang, S.; Song, B.-A.; Chi, Y. R. Angew. Chem. Int. Ed. 2013, 52, 11134.
Oxidative NHC CatalysisOxidative Functionalization of Aldehydes
! Since these reports, Chi et al. have demonstrated the use of oxidative NHC catalysis in a varietyof highly enantioselective reactions
NN N BF4
Mes
(10 mol%)
oxidant
61-89% yield, 84-99% ee
Cs2CO3 (50 mol%), THF
O
O
O
t-Bu t-Bu
t-Bu t-Bu
O
R2R1
oxidant:
X Me
OH
X
O
O
R1R2
N
O
O
Ph
CF3
S
O
O
Et
CF3
BocO
O
O
NHO
Chen, X.; Yang, S.; Song, B.-A.; Chi, Y. R. Angew. Chem. Int. Ed. 2013, 52, 11134.
Oxidative NHC CatalysisOxidative Functionalization of Aldehydes
! Since these reports, Chi et al. have demonstrated the use of oxidative NHC catalysis in a varietyof highly enantioselective reactions
NN N BF4
Mes
(10 mol%)
oxidant
61-89% yield, 84-99% ee
Cs2CO3 (50 mol%), THF
O
O
R2R1
X Me
OH
X
O
O
R1R2
OH
RN N
NR
[O]
XMe
O
RN N
NR
XCH2
H
increased acidity of benzylic position
base
O
RN N
NR
X
base
DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2012, 134 , 8094.
Oxidative NHC CatalysisAn Enantioselective Oxidative Aza-Acyloin Reaction
! In 2012, Rovis et al. reported the merger of photoredox and NHC catalysis for theenantioselective !-acyaltion of tertiary amines
NN N
(5 mol%)
Ru(bpy)3Cl2 (1 mol%)
91% yield, 92% eem-dinitrobenzene (120 mol%)
O
O
HNPh
CH2Cl2, blue LEDS
Br
Br
Br
NPh
OPh
Ph
NPh
via: X–