Asymmetric Organocatalysis with N-Heterocyclic NCH3 NNH2 S H3C HO Cl Asymmetric Organocatalysis with N-Heterocyclic Carbenes History and Recent Developments ... Rovis, T, Nolan, S

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


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


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.


! 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 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


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


R

O

H

Acyl Anions

O

H

Homoenolates

R

O

H

O


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


! 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.


! 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.


! 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.


! 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 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 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


R

O

H

Acyl Anions

O

H

Homoenolates

R

O

H

O


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


! [2+2] Cycloadditions


! [3+2] cycloadditions

! Enolate Chemistry

O

H

O


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.


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


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



! Ye et al. also demonstrated a number [4+2] cycloaddition reactions


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



! Ye et al. reported the use of a variety of other 'dienes' in [4+2] cycloaddition reactions


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



! [3+2] cycloadditions

! Enolate Chemistry

O

H

O


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


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


R

O

H

Acyl Anions

O

H

Homoenolates

R

O

H

O


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.


! 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.



NN N BF4

Mes

(10 mol%)

oxidant

61-89% yield, 84-99% ee


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.



NN N BF4

Mes

(10 mol%)

oxidant

61-89% yield, 84-99% ee


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–

Documents

Asymmetric Organocatalysis with N-Heterocyclic NCH3 NNH2 S H3C HO Cl Asymmetric Organocatalysis with N-Heterocyclic Carbenes History and Recent Developments ... Rovis, T, Nolan, S