NHC Organocatalysis

Home , Organocatalysis

Asymmetric Organocatalysis with N-Heterocyclic Carbenes History and Recent Developments

N CH3

N NH2 H3C

S Cl

Adam Noble MacMillan Group Meeting January 29th 2014 Early Developments The Benzoin Condensation

! 1832: First report of bezoin condensation by Wöhler and Liebig

O O CN– Ph Ph Ph H OH benzoin ! 1903: Mechanism proposed by Lapworth

O CN– O Ph + H O Ph 2 Ph H OH

N H O HO H HO Ph OH Ph Ph N OH

O OH

Ph H Ph • N H O 2 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

NH2 O N Cl O O Me thiamine + CO2 R Me N N R O S OH

! Most commonly found as the co-enzyme thiamine diphosphate (TDP)

NH2

N Me Me N O O thiamine diphosphate (TDP) N P P S O O OH O O

! 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 Cl NH2 HO N N HO Ph S N Me O O Me Ph N Ar Ph Ph H R NaOH, MeOH OH S Cl

expected formed

A variety of other thiazolium compounds were also demonstrated to be effective catalysts

OH Me Me Me/H Me/H Me Me Me Ph Me N N N N N I Br Br Br Ph N S S S Br S 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 Cl NH2 HO N N O O O S N Me R Me Me Me acyloin Me H O 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

OH NH2 Me

no reaction with: N N CHO S Me N 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 ? ?

Me NH2 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 Me Me D O N Br 2 N Br

H D S S

Me Cl NH2 Me Cl ND2 D O HO 2 DO N N N N

S H N Me S 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 R2 R1 R2 R1 – H+ N N N

R3 S H R3 S R3 S

O R2 R1 N O Ph Ph R3 S Ph H OH

R2 R1 R2 R1 N OH N - R3 S Ph O R3 S O Ph Ph

R2 R1 O N OH Ph H R3 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 Ph N ∆ N N N CCl3 X N N N N – CHCl3 Ph Ph Ph 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

Ph Ph OEt Ph N N+ H conc. HCl 1) HNO3 N N – EtO Ph S H [ClO4] N 2) NaClO N S 4 Ph Ph 66% 94%

Ph Ph

N N Hg(OAc)2, ! – Hg 2 [ClO4] N N – 2 AcOH Ph 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

! Cr(CO) – 3 [HCr(CO)5] N – 2 CO N Me Me

Me Me + N 120 ºC N H – [HCr(CO)5] Cr(CO)5 N – H2 N Me Me 80%

! 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

N NaH, THF N H N+ N Cl cat. DMSO anion

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 Ph Alkyl Me i-Pr N N N N Me i-Pr N N N Me Ph N Alkyl Ph Alkyl S Me Arduengo et al Enders et al Herrmann et al Arduengo et al 1992 1995 1996 1997 (first commercially available carbene)

Mes Mes N N N N N N Me Me Mes Mes Arduengo et al Arduengo et al Herrmann et al 1992 1995 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 N H N N Me KOtBu, THF Me Me 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 ! ! donation into the carbene from the out-of-plane ! orbital stabilizes R1 electrophilic reactivity R N

R N R1 "-electron ! " withdrawal by electronegative atoms withdrawal 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 Ph Ph Ph Me Me Me N N Me Me N N Me Me ClMe Ph Pd Ph Ru Ph Ph Cl Ph Cl PCy3

! 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

500

400

Number! of 300 ! Publications

200

100

0 1943 1948 1953 1958 1963 1968 1973 1978 1983 1988 1993 1998 2003 2008 2013 Year! N-Heterocyclic Carbenes In Enantioselective Organocatalysis Modes of Reactivity

Acyl Anions

N N OH R R R O N O R R H N R R

Homoenolates

N N OH R R R O O N R R H N R R

Azolium Enolates / Acyl Azoliums

O O O O O R R N N O R R R X • N N H OR R R N N R R R R R N-Heterocyclic Carbenes In Enantioselective Organocatalysis Modes of Reactivity

Acyl Anions

N N OH R R R O N O R R H N R R

! Benzoin Condensations

! Stetter Reactions

! Hydroacylations The Use of NHCs for the Generation of Acyl Anion Equivalents Early Developments

! 1943: Ugai discovered the thiazolium-catalyzed benzoin condensation

R2 R3 N X 1 O O R S Ph Ph Ph H 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 O S N * O Br O O (10 mol%) Ph Ph Ph H Et N (10 mol%) 3 OH MeOH Precipitate: 50%, 0.8% ee Filtrate: 9% yield, 22% ee ! 1974: Sheehan reported slight improvements to enantioselectivity but still low yield

S N O O Br Me (10 mol%) Ph Ph Ph H Et N (10 mol%) 3 OH MeOH 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 N Me Cl ClO4 N S N I I S N N N Ph Me Me Br Me S S O O Me Me Me

20%, 35% ee 47-57%, 20-30% ee 21%, 26% ee 66%, 75% ee Takagi et al, 1980 Zhao et al, 1988 López-Calahora et al, 1993 Enders et al, 1996

Ph O TBSO N N TfO Cl N N S Bicyclic triazoliums are key! Ph 50%, 21% ee 45%, 80% ee Leeper et al, 1997 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 Tunable electronics X N catalytic activity catalytic activity n N N R2 asymmetric R1 basicity induction

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%) BF4 N N O O Ph Ph Ph Ph H KOt-Bu (10 mol%) OH THF 83% yield, 90% ee

favored disfavored 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 F Ph N N F Ph OH BF4 F F O O (4 mol%) F Ph Ph Ph H Rb CO (4 mol%) 2 3 OH THF 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

R2 R3 N X 1 O O R S Ph Ph Ph H NaOH, MeOH OH

! 1974: Stetter reported the 1,4-addition variant = The Stetter Reaction

Me R N X O O HO S R2 EWG R1 EWG R1 H Et3N, MeOH 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 O 2 (20 mol%) O CO2R Me Me H R1 1 K CO (20 mol%) R 2 2 3 O CO2R O THF

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

BF4 OMe O O CO2Et (20 mol%) H KHMDS (20 mol%) O CO2Et O xylene 94% yield, 94% ee

N N N Bn BF4 O O (20 mol%) H CO Et KHMDS (20 mol%) 2 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 O 4 O O (10 mol%) 3 3 Ar Ar Ar1 Ar1 H Cs2CO3 (10 mol%) 2 Ar2 Ar 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 R CO2t-Bu CO2t-Bu N N N N O O CO t-Bu C F 2 Bn 6 5 O BF4 (20 mol%) 51-97% yield, 80-91% ee H N R1 O O O iPr2NEt (100 mol%), MgSO4 NMe CCl 2 4 O R1 O O R2

N NMe2 O O O R2

44-95% yield, 81-98% ee 4:1-19:1 dr ! A limitation was the need for highly activated alkylidene dicarbonyls

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 I S N O H Me (25 mol%)

O DBU (70 mol%) O Ph R R Ph xylene, reflux 66-99% ! In 2011, Glorius et al. reported a highly asymmetric variant

O N Me N N

Bn O Cl Me Me O Me H (10 mol%) Ar

O DBU (10 mol%) O Ar dioxane, 80 ºC 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 N N R Mes H H !+ ‡ !+ ‡ O H H O O or O O !- R2N

(Conia)-Ene reverse-Cope N ‡ elimination N DBU N N N N N R Mes vs. R Mes N N R Mes H Cl O O 1st ‡ H 2nd O 1st R N O N 2 N Mes Me nd R N O NR2 2 R Me concerted but O asynchronous

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

N N OH R R R O N O R R H N R R

Homoenolates

N N OH R R R O O N R R H N R R

Azolium Enolates / Acyl Azoliums

O O O O O R R N N O R R R X • N N H OR R R N N R R R R R N-Heterocyclic Carbenes In Enantioselective Organocatalysis Modes of Reactivity

Homoenolates

N N OH R R R O O N R R H N R R

! Cyclopentene Synthesis

! Spiroannulations

! Lactam/Lactone Synthesis

! Conversion of Enals to Saturated Esters 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

Cl O N N O O Mes Mes (8 mol%) Bode: O Ar1 H Ar2 H DBU (7 mol%) 1 2 THF/t-BuOH Ar Ar

41-87%, 3:1-7:1 cis:trans

Cl O N N O O Mes Mes (5 mol%) Glorius: O Ar1 H Ar2 H KOt-Bu (10 mol%) 1 2 THF Ar Ar

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 Mes OH Mes N N Ph Ph N N O Mes Mes

Ph H

OH Mes N N N Ph Mes Mes N Mes homoenolate O

O O O Ar O O Mes OH Mes H Ar Ph Ar N N Ph Ph N N Mes Mes 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 Cl O N N Mes R1 H (10 mol%)

SO2Ar SO2Ar O N N O O OH 3 R H Ph Ph Me Me 2 2 2 R R2 R2 R R

O SO2Ar O O O N O OH Ph Me SO2Ar H Ph H R1 O R1 N Me R1 R1 R1 2 3 2 R R R R2 R2 R2 >20:1 dr >50:1 dr >10:1 dr 2:1 dr 4->20:1 dr 99% ee 97-99% ee 87-99% ee 99% ee 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

O O OH H Me Me R1

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 Cl N N Mes R3 O R1 (20 mol%) O H O O R2 3 1 R R H DBU (30 mol%) O O THF 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 R2 product 5

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

N N OH R R R O O N R R H N R R

R1 OH R R1 O R ROH RO– 1 N N R O R2 R2 2 N N (-NHC) R OR R R

"Redox Relay" 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 BF N N 4 Mes OH O OH (30 mol%) O Ph H OH proton sponge K2CO3, 18-crown-6 Ph O CH2Cl2 58%, 80% ee

O Ph N BF4 Ph N N Mes Bn Me O (30 mol%) Me O Me OH Ph H proton sponge Ph O Me K2CO3, 18-crown-6 58%, 55% ee CH2Cl2

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 N N O Me Me Me H O O base Me N Ph N Ph Ph OAr (– ArO–) N Me N N Me N

OH Me OH Me N N Ph Ph N N Me N Me 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 BF Me N N 4 O Me Ph

Me Ar CF3 O NO2 (20 mol%) O up to 61% yield O DBU (150 mol%) 88% ee, 2:1 dr R O 4 Å MS, MeCN Ar F C 3 R BzHN N O H CO2Et BzHN N up to 76% yield 94% ee, 7:1 dr EtO2C 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

N N OH R R R O N O R R H N R R

Homoenolates

N N OH R R R O O N R R H N R R

Azolium Enolates / Acyl Azoliums

O O O O O R R N N O R R R X • N N H OR R R N N R R R R R N-Heterocyclic Carbenes In Enantioselective Organocatalysis Modes of Reactivity

Azolium Enolates / Acyl Azoliums

O O O O O R R N N O R R R R • N N H OR R R N N X R R R R

! [2+2] Cycloadditions

! [4+2] Cycloadditions

! [3+2] cycloadditions

! Enolate Chemistry 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 BF N N 4 Ph Ph Ph OTBS O Boc O Boc (10 mol%) N • N 1 2 Cs2CO3 (10 mol%) Ar 1 Ar H Ar2 Ar R THF R

53-78% yield, 91-99% ee 2.5-99:1 dr O N BF N N 4 Ph

O Ts O Ts (10 mol%) N • N KHMDS (9 mol%) Ph Ar1 H 1 Ph Ph Ph Ar Et2O 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 O N N N • Ph Ar1 TBSO Ar2 1 R Ph Ph Ar R

N N N N Ph TBSO N N R TBSO Ph Ph Ph O Ar1 azolium Ph Ph R enolate acyl Ar2 O N azolium H Ar1 Boc

Boc N

Ar2 H

! Since 2008, Ye et al. have reported numerous other enantioselective [2+2] cycloadditions

O O 2 2 O CO2Et O Ar O Ar O O 1 R N N N Ar R 2 N O S Ar O Ar R R Ar1 CO Et R 2 1 1 O O N Ar Ar 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 BF N N 4 1 Ar2 Ar 2 O Cl O Ar OTBS O NTs Cl (10 mol%) • NTs R O Cs2CO3 (10 mol%) Ar Ar1 R toluene (+/–) up to 78% yield, up to 95% ee 8-15:1 dr

N N N N Ar R N N NTs R1 Ar R O Ar1 R1 Ar2 O TsN O O 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 BF N N 4 Ph Ph

O Ph OTMS O CO2Et EtO2C N (10 mol%) N • N N Ar CO Et Cs2CO3 (10 mol%) Ar1 R 2 CO2Et THF R

52-95% yield, 33-91% ee

N BF N N 4 Ph Ph Ph OTMS O O Ph O Bz N (10 mol%) • Ar N N N Cs2CO3 (10 mol%) R Ar1 R Bz THF 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

Ts O O Ph O O Ar2 O N Ar2 Ar N Ar1 N Ar1 R R 1 Bz CO2Et R R2

50-92% yield >80% yield >80% yield >90% ee 57-93% ee 83-93% ee >15:1 dr >10:1 dr

EtO2C R Ar1 O O O

Ar1 O O O N R PMP Bz 88-99% yield 30-96% yield 69-90% ee 51-99% ee 3-10:1 dr 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 O O O O R R N N O R R R R • N N H OR R R N N X R R R R

! [2+2] Cycloadditions

! [4+2] Cycloadditions

! [3+2] cycloadditions

! Enolate Chemistry N-Heterocyclic Carbenes As Enantioselective Organocatalysts Modes of Reactivity

Azolium Enolates / Acyl Azoliums

O R O R O O O N N R R R R • N N H OR R R N N X R R R R

! Enolate chemistry of !-functionalized aldehydes

N N OH R O R O R R – HX R R R N N H X N N X R 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 Br Br N BF N N 4 C6F5

Me O O (10 mol%) (120 mol%) Ar OH R OAr R H KH (100 mol%), 18-crown-6 Cl Cl Cl toluene

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 Me N BF4 Me N N C6F5 Bn O Ts (10 mol%) Ts O N NH O H Ar 4-NO2-C6H4ONa (200 mol%) Ar NHBn O2N THF-CH2Cl2 then BnNH 2 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

N N OH R R R O N O R R H N R R

Homoenolates

N N OH R R R O O N R R H N R R

Azolium Enolates / Acyl Azoliums

O O O O O R R N N O R R R X • N N H OR R R N N R R R R R Oxidative NHC Catalysis Oxidative Functionalization of Aldehydes

! In 2007 and 2008, Scheidt et al. demonstrated NHCs could catalyze the MnO2-promoted oxidation of benzylic and vinylic alcohols to esters, and unactivated aldehydes to esters

R1 OH N activated alcohol I N N Me Me (10 mol%) O

O 2 1 2 R OH, MnO2, DBU R OR

R1 H 64-99% yield unactivated aldehyde

OH Me O Me N [O] N R1 R1

N N N N Me Me

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 BF N N 4 Mes O (10 mol%) O O O O

Ar H R1 R2 oxidant Ar R2 Cs CO (50 mol%), THF 2 3 R1 O

53-98% yield, 70-94% ee

O t-Bu t-Bu OH Me O Me O Me N [O] N [O] N oxidant:

N N N N N N Ar Me Ar Me Ar Me t-Bu 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 BF N N 4 Mes O O (10 mol%) O H O 2 R1 R2 oxidant R Me R1 X X Cs2CO3 (50 mol%), THF

61-89% yield, 84-99% ee

O t-Bu t-Bu O O O O O O oxidant: CF3 CF3 Ph NH N Et O S O t-Bu t-Bu Boc 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

61-89% yield, 84-99% ee

O R OH R O R [O] N base N N X RN N RN X N CH2 X RN N Me base 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 Br N N

Br Br

O (5 mol%) N N Ph Ph Ph H Ru(bpy)3Cl2 (1 mol%) m-dinitrobenzene (120 mol%) O Ph

CH2Cl2, blue LEDS 91% yield, 92% ee

via: X– N Ph

DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2012, 134, 8094.