Organocatalysis with N-Heterocyclic

Frontiers of Chemistry

Robert B. Lettan II March 28th, 2009

Key References: Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606-5655. Marion, N.; Díez-González, S.; Nolan, S. P. Angew. Chem. Int. Ed. 2007, 46, 2988-3000. Johnson, J. S. Curr. Opinion Drug. Discov. Develop. 2007, 10, 691-703.

Rob Lettan @ Wipf Page 1 of 34 3/30/2009 -Dependent Enzymes

NH 2 Me N OR Thiamine: R = H N 3— TPP: R = P2O6 S Me N H

Thiamine diphosphate (TPP) is required by a number of enzymes that catalyze the cleavage and formation of bonds to the carbon atom of a carbonyl group.

Mechanism of pyruvate decarboxylase (PDC) Me Me N Me N OR HO N N pyruvate Me S —CO2 Me NH2 S Me H O O N N HO S H S Me N Me Me Me H N OR N N O H S NH H Me S Me H All 3 on aminopyridine ring OH involved in binding to enzyme. Jordan, F. Nat. Prod. Rep. 2003, 20, 184-201.

Rob Lettan @ Wipf Group Page 2 of 34 3/30/2009 Thiamine-Dependent Enzymes

Rob Lettan @ Wipf Group Page 3 of 34 3/30/2009 Thiamine-Dependent Enzymes

Mechanism of pyruvate dehydrogenase (E1) Me Me N Me pyruvate N N N HO —CO2 S NH2 S E1 Me carbene ylide

S S H N E2 O SH H O FADH2 NAD N lipoamide Me S E2 O E3

SH H FAD NADH CoASH N E2 HS E2 O

O Krebs cycle How can nature’s method cellular Me SCoA of bond-formation be applied to synthesis? respiration Acetyl-CoA Leeper, F. J. et al. Biochem. Soc. Trans. 2005, 33, 772.

Rob Lettan @ Wipf Group Page 4 of 34 3/30/2009

A "stable" carbene that is a reactive intermediate. 1943: Ugai Recognized that thiamine can be used as a catalyst for the .

1957: Breslow

Br H Br D D2O, 28 °C Me Me Me N S N S N S t1/2 ~ 20 min Me Me Me Me Me Me

1960: Wanzlick 1964: Lemal Lemal ruled out dimerization H CCl through cross-over exp. Ph Ph 3 150 °C N N HCl Ph Ph Ph Ph N N N N X N N —HCCl3 Ph Ph

H X Ph Ph X H HCl N N Ph Ph N N 1970: Wanzlick N N Ph Ph

H Ph Ph ClO4 N N NPh Ph Ph tBuOK PhNCS N N N N S Ugai, T. et al. J. Pharm. Soc. Jpn. 1943, 63, 296. Ph Ph Breslow, R. J. Am. Chem. Soc. 1957, 79, 1762. Wanzlick, H. W. Angew. Chem. Int. Ed. Engl. 1962, 1, 75. increased Lemal, D. M. et al. J. Am. Chem. Soc. 1964, 86, 2518. stabilization Wanzlick, H. W. et al. Liebigs Ann. Chem. 1970, 731, 176.

Rob Lettan @ Wipf Group Page 5 of 34 3/30/2009 Isolated Carbenes

1991: Arduengo

H NaH, THF, cat. DMSO, RT N N 2 isolated crystal structure 3N N1 4 5 Cl

Bond angles: N1-C2-N3 = 102.2 ° (imid = 109 °). In agreement with theoretical studies on singlet (1A') carbenes bearing !"donor substituents. Change in !-delocalization supported by upfield shift of ring (7.92 6.91). 13 C NMR of C2: # = 211 ppm No dimerization. Some other isolated N-heterocyclic carbenes by Arduengo Me Me Me Me Me Me 1997 N N Me Me Me Me N N !C = 220 ppm N N Me Me N-C-N angle = 102 ° Cl Cl Me Me Air Stable Me Me 1992 1995 !C = 214 ppm !C = 245 ppm i-Pr N-C-N angle = 102 ° N-C-N angle = 105 ° 1997 ! = 254 ppm Less hindered cyclic diamino carbene N S C tetramethyl-imidazol-2-ylidene dimesityl N-C-N angle = 104 ° i-Pr Me Me thiazolium carbene No dimerization suggests this is also stable due to electronic stabilization. Arduengo, A. J., et al. J. Am. Chem. Soc. 1991, 113, 361.

Rob Lettan @ Wipf Group Page 6 of 34 3/30/2009 Carbene Stability

Carbene Stability ! Singlet Character ! Electron Donation into ca. –87 kcal/mol Vacant p-Orbital of Carbene H H

R R ca. –6 kcal/mol N N R R ca. –20 kcal/mol R R N N Electron donating groups promote more stable singlet carbene R R Ph Ph N N N N N Ph Further stabilized by aromatization. Does not dimerize.

NaH, N H N DMSO N N Electron lone pairs in close proximity. Repulsive electrostatic interactions would have a N H N N N significant destabilzing effect.

Herrmann, W. A.; Kocher, C. Angew. Chem. Ind. Ed., Engl. 1997, 36, 2162.

Rob Lettan @ Wipf Group Page 7 of 34 3/30/2009 Preparation of Stable Carbenes

Deprotonation W X Y Z a R2 N CR3 CR4 H

Base b — S CR2 CR4 R1 W R1 W N X N X c R2 N N CR3 Y Z Y Z 2 d R N CH2 CH2

2 e R N CH2 C2H4

H NHC formation caveats: pKa = 24 (DMSO) i-Pr i-Pr — strongly basic N N — react with — their imidazole precursor's are susceptible to nucleophilic attack — sometimes difficult to isolate free carbene from metal ions used to prepare Me Me

Bases: Metal hydrides: Work, but often sluggish due to relative insolubilitiy in suitable solvents (THF) Catalysts (DMSO, t-BuOH) improve solubility and reactivity, but ineffective for non-imidazolium adducts due to nucleophilicity. Must avoid , especially with non-aromatic salts. KOt-Bu: Has been shown to be effective. Alkyllithiums: Unreliable. n-BuLi and PhLi can act as nucelophiles, t-BuLi can act as a hydride donor. Amides: LDA and LiTMP work well, if not too much LiOH in n-BuLi during preparation. Metal hexamethyldisilazides: Works very well for the most part.

Alder, R. W., et al. J. Chem. Soc., Chem. Commun., 1995, 1267.

Rob Lettan @ Wipf Group Page 8 of 34 3/30/2009 Preparation of Stable Carbenes Some Other Methods

AgCl2 R R N N 40 - 100 °C R N Ag N R N N R R

H X R 40 - 100 °C R N N N R N R

X = C6F5, CF3, CCl3

H 80 °C, 0.1 mbar; Ph OMe Ph N toluene, ! N N Ph N Ph Ph N quant. Ph N

X = N, CH2; R' =

Me Me N K, THF, Me ! N S N Me N Me Me Me Me Nolan, S. P. N-Heterocyclic Carbenes in Synthesis, Wiley -VCH & Co., 2006.

Rob Lettan @ Wipf Group Page 9 of 34 3/30/2009 NHC/Umpolung Reactivity

O OH O OH O O aldol Me Me Me Me Me H Me Normal Polarity O O O O O O Michael Me Me Me Me Me Me

O O OH O O Me benzoin Me Me Me Me H H Me (+ catalyst) Inverted OH Polarity O O O O O Me Stetter Me Me Me Me H Me O (+ catalyst) NHC Catalyzed Umpolung Reactions Additional NHC Catalyzed Reactions benzoin condensation Stetter reaction transesterification hydroacylations - oxidation acylation of aryl flourides - polymerization nucleophilic substitution ring-opening reactions homoenolate reactivity 1,2-additions - cross condensations - Diels-Alder reaction Seebach, D. Angew. Chem. Int. Ed., Engl. 1979, 18, 239. - Heck-type cyclizations Johnson, J. S. Curr. Opin. Drug Disc. Dev. 2007, 10, 691.

Rob Lettan @ Wipf Group Page 10 of 34 3/30/2009 Benzoin Condensation

Breslow Mechanism

O

Me N Me Ph H Me N N N Me S NH S 2 H OH N thiamine carbene H thiamine S O Ph HO Ph Me Ph Me O HO N benzoin N S Ph HO O S Ph Me Ph

O N O

Ph S Ph H HO Ph

Ugai, T. et al. J. Pharm. Soc. Jpn. 1943, 63, 296. Breslow, R. J. Am. Chem. Soc. 1957, 79, 1762.

Rob Lettan @ Wipf Group Page 11 of 34 3/30/2009 Asymmetric Benzoin Enders BF4 N N N O Me

Me Me O (10 mol%) Ar ArCHO Ar KOt-Bu, THF OH 0 or 18 °C 8-83% yield 80-95% ee

J. You O 1 mol% A or B Ph A: 27%, 88% ee 2 PhCHO Ph KOt-Bu, B: 95%, 95% ee THF, 23 °C OH

Cl Cl N N N N N N

O N O N N O

DFT calculations show B has a larger conjugation interaction over mono-triazolyldine A.

A Enders, D.; Kallfass, U. Ang. Chem. Int. Ed. 2002, 41, 1743. B You, J. et al. Adv. Synth. Catal. 2008, 350, 2645.

Rob Lettan @ Wipf Group Page 12 of 34 3/30/2009 Crossed Benzoin Et Inoue N

S O O O (10 mol%) OH 64-100% selectivity R R H H H R = Me, Et, n-Pr, i-Pr, Cy, Ph, 2-furyl

Müller: enzymatic BAL, ThDP, Mg2+, KPi buffer, O O O 2 1 DMSO, 30 °C Ar must be a better electron acceptor that Ar . Ar2 1 conversion, selectivity, ee up to > 99% Ar1 H Ar2 H Ar OH BAL = benzaldehyde lyase ThDP = thiamine diphosphate

Johnson: metallophosphite catalyzed Ar = 2-FPh Ar Ar CHO OMe O O O 5 mol% A, O Me O n-BuLi (20 mol%) P 87% yield Me H Ph SiEt Ph 91% ee O O 3 THF, 30 min Ar Ar OSiEt3 A OMe

via a Brook rearrangement pathway Inoue, S. et al. J. Org. Chem. 1985, 50, 603. Müller, M. et al. J. Am. Chem. Soc. 2002, 124, 12084. Johnson, J.S. et al. J. Am. Chem. Soc. 2004, 126, 3070.

Rob Lettan @ Wipf Group Page 13 of 34 3/30/2009 Azabenzoin

Me OBn Murray/Frantz & Miller O Cl H Bn N catalyst, Me Me N NHBoc O R2 O R2 O A N H conditions O R1 1 Ts N R N R S I R H 3 3 HO S B H H N O Me Murray/Frantz: 58-98% yield 10 mol% A, NEt3, DCM, 35-60 °C, 0.5-24 h

Miller: 57-100% yield 15 mol% B, PEMP, DCM, 23 °C, 2 h 75-87% ee

Scheidt I Me Me O N Me Me O P 30 mol% Me Me 2 O N Ph Me S N OSiZ3 N OH R Ph R1 Ph 1 2 R SiZ3 R H S R1 S R1 HN Ph DBU, CHCl3, Me Me P i-PrOH O Breslow Intermediate 51-94% yield

Murray, J. A.; Frantz, D. E. et al. J. Am. Chem. Soc. 2001, 123, 9696. Miller, S. J. et al. J. Am. Chem. Soc. 2005, 127, 1654. Mattson, A. E.; Scheidt, K. A. Org. Lett. 2004, 6, 4363.

Rob Lettan @ Wipf Group Page 14 of 34 3/30/2009 Intramolecular Crossed Benzoin

Complex Anthraquinone Precursors

Br Et Me MeO N O N OMe O N 20 mol% HO S 79% yield dr = 20:1 DBU, t-BuOH, Me Me O CHO 40 °C, 0.5 h OH EtO2C O CO2Et

Enantioselective Synthesis of the Eucomol Core

O OH O CHO 15 mol% OH OH Rovis' catalyst Ph

O Ph NEt3, THF, rt, 25h O HO O OMe O Ph (S)-eucomol N N

N BF4 O

Suzuki, K. et al. Adv. Synth. Catal. 2004, 346, 1097. Rovis' Catalyst Suzuki, K. et al. Angew. Chem. Int. Ed. 2006, 45, 3492. Rovis, T. et al. J. Org. Chem. 2005, 70, 5725.

Rob Lettan @ Wipf Group Page 15 of 34 3/30/2009 Stetter Reaction X R Stetter, 1976 Me N

O O O 10 mol% A HO S n-Pr n-Pr H OMe NEt , EtOH, OMe A: R = Bn, X = Cl 3 B: R = Et, X = Br 78 °C O 95% yield A for aliphatic B for aromatic O R n-Pr H Me N OH O

S n-Pr OMe HO Breslow Intermediate

R R O Me Me N OH NEt3 N A OMe S S n-Pr HO HO

R O Me N O

O OMe S n-Pr n-Pr HO OMe O Stetter, H. Angew. Chem. Int. Ed., Engl. 1976, 15, 639. Yates, B. F.; Hawkes, K. J. Eur. J. Org. Chem. 2008, 5563.

Rob Lettan @ Wipf Group Page 16 of 34 3/30/2009 Asymmetric Intramolecular Stetter Reaction

— Ciganek was the first to report and intramolecular Stetter reaction (1995). — Enders was the first to report an asymmetric intramolecular Stetter reaction (1996, 41-74% ee). — Significant progress has been more recently acheived by Rovis (2004-present).

Rovis air and water stable, crystalline solid

O O BF4 O 20 mol% A or B, base N R N toluene or xylenes R N EWG Ar X 24 h, 25 °C X EWG

X = O, S, NR, CH2 82-99% ee if R = H: catalyst A, Ar = 4-OMePh R = H, alkyl, aryl base = 20 mol% KHMDS if R = alkyl/aryl: catalyst B, Ar = C6F5 base = 2 equiv. NEt3

Desymmetrization

O O 10 mol% A, 10 mol% KHMDS, 60-94% yield R' R' H 82-99% ee toluene, 23 °C O >95:5 dr R R O CHO O

Ciganek, E. Synthesis 1995, 1311. Ender, D. et al. Helv. Chim. Acta. 1996, 79, 1899. Rovis, T. et al. J. Am. Chem. Soc. 2004, 126, 8876. Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2552.

Rob Lettan @ Wipf Group Page 17 of 34 3/30/2009 Asymmetric Intermolecular Stetter Reaction

Enders BF4 N N N Bn PhCHO OTBS O (10 mol%) Ph Ph O 10 mol% Cs2CO3, THF, 0 °C, 6 h Ph O Ph Ph 65% yield, 66% ee

Rovis BF4 N F N N F 1. Super-hydride O F F O Et O Et THF, —100 °C F CO H (20 mol%) 95%, 8:1 dr O 2 H CO2t-Bu CO2t-Bu N N i-Pr2NEt, CCl4, 2. HCO2H, 23 °C O Et O O CO2t-Bu O O CO2t-Bu MgSO4, —10 °C, quant. N 12 h, 84% yield, 90% ee O

Enders, D.; Han, J. Synthesis 2008, 3864. Rovis T. et al. J. Am. Chem. Soc. 2008, 130, 14066.

Rob Lettan @ Wipf Group Page 18 of 34 3/30/2009 X Special Intermolecular Stetter Reactions R Me N One-Pot Synthesis of Pyrrols and Furans (Stetter-Paal-Knorr) HO S A: R = Me, X = I Müller 1. (Ph P) PdCl , R3 B: R = Et, X = Br 3 2 2 3 OH R NH2, TsOH, CuI, NEt3, ! R1 N Ph R2Br 53-82% yield 4Å Sieves, ! Ph 2. R1CHO, R1 O 20 mol% A O R2

Scheidt R2 Ph O O 20 mol% B, HOAc, ! R1 O Ph

1 42-84% yield R SiMe3 R2 Ph DBU, i-PrOH, THF, 70 °C R2

Polymer-Supported Stetter Reactions

Ph Can easily recover polymer and use up to n 4 times without loss of reactivity. S

Me 1 N I R O O O O Me 68-99% yield R1 H R2 R4 R2 R4 66->95% purity DMF, NEt3, 80 °C R3 R3

Müller, T. J. J. et al. Org. Lett. 2001, 3, 3297. Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465. Barrett, A. G. M. et al. Org. Lett. 2004, 6, 3377.

Rob Lettan @ Wipf Group Page 19 of 34 3/30/2009 Natural Product Synthesis using the Stetter Reaction Me Tius Bn N O O Cl O OH HN S 4 1. Me BzO 2. H , Pd/C (30 mol %) BzO 2 O HN Me 6-hexenal 3. (NH4)2CO3, Me Me Me Cl NEt3, dioxane, propionic , O Me 70 °C, 18 h, 60% Me 140 °C Me OMe 8 steps from NH 5-hexenal (±)-roseophilin Nicolaou BF O O 4 OH N C F O N 6 5 Me O N H Br O HO2C N O Br H NEt , CH Cl , OH 3 2 2 O H 45 °C, 64% Me 8 steps from single (±)-platensimycin dihydroresorcinol diastereoisomer Rovis O BF4 N HO OMe N O O O N O Ph C6F5 Me O N PMB (20 mol%) N PMB N PMB O Me O O 20 mol% KHMDS, O O O 0 °C, toluene O 88% yield, 99% ee FD-838 4 steps from Harrington, P. E.; Tius, M. A. Org. Lett. 1999, 1, 649. N-PMB maleimide Nicolaou, K. C. et al. Chem. Commun. 2007, 1922. Orellana, A., Rovis, T. Chem. Commun. 2008, 730.

Rob Lettan @ Wipf Group Page 20 of 34 3/30/2009 Homoenolates Can also access γ-lactams if imines Me Me Cl are used as the electrophile. Me Me N N O O 5 mol% Me Me O CHO 41-87% yield R1 H R2 cis/trans ! 4:1 KOt-Bu/THF or DBU/t-BuOH/THF R2 R1 OH Mes CHO R1 N R1 N Mes

Me Me OH Mes Me Me N 1 N N R N Me Me Mes

R2 O O Mes N O R1 O O N Mes H R R2 1 R Burstein, C.; Glorius, F. Angew. Chem. Int. Ed. 2004, 43, 6205. Bode, J. W. et al. J. Am. Chem. Soc. 2004, 126, 14370. Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7, 3873.

Rob Lettan @ Wipf Group Page 21 of 34 3/30/2009 β-Lactones

Me Me Cl Me Me

N N F3C Ph O 5 mol% Me Me O 48% yield Me CHO 3:2 dr Ph CF 3 NEt3, toluene, 60 °C O Me Me Me

OH Mes CHO OH Mes R1 N R1 N R1 N N Mes Mes

Me Me Me Me O Mes

N N N R1 Me Me N Mes

O O Mes 3 R 3 N 2 R R O R2 O N 1 R Mes O R3 R2 R1 Glorius, F. et al. Synthesis 2006, 2418.

Rob Lettan @ Wipf Group Page 22 of 34 3/30/2009 Azadiene Diels-Alder Reaction

O N N N O Mes ArO2S ArO2S N 10 mol% BF4 N CO Et CHO 2 90% yield EtO C 2 DIPEA, 23 h >99% ee H Ph Ph 0.05 M toluene/THF (10:1)

CHO EtO2C OH OH N N EtO C EtO2C 2 N N N N Mes Mes

O O N N N N EtO C Mes 2 N N Mes

Ph CO2Et

O ArO S N 2 N N CO2Et ArO2S O N ArO2S N N Ph Mes H Ph

Bode, J. W. et al. J. Am. Chem. Soc. 2006, 128, 8418.

Rob Lettan @ Wipf Group Page 23 of 34 3/30/2009 1,3,4-Trisubstituted Cyclopentenes

Me Me Cl Me Me 3 N N R O 6 mol% Me Me CHO 1 2 3 55-88% yield R R R 12 mol% DBU, THF, rt, 8h R1 R2 O O R3 CHO R2 R3 R1 O OH Mes R2 O Mes O N —NHC R1 N R1 3 N R1 R 2 Mes N R O Mes Me Me Mes Me Me R3 N N N R2 N Me Me 1 R O Mes OMe

3 R Mes N 3 O CHO O R 2 4-OMePh O R N S O R1 O Mes R3 S H R1 R2 43% CO2 R1 R2 Bode, J. W. et al. J. Am. Chem. Soc. 2006, 128, 8418.

Rob Lettan @ Wipf Group Page 24 of 34 3/30/2009 Enantioselective Cyclopentane Synthesis

O O OH 99% ee Me Me R1

CO2Et Cl

N N Mes 10 mol% N O DBU, toluene, rt, 15 h

O CHO OH 1 R EtO2C Me Me

ClO4

N N Mes 10 mol% O DBU, toluene, rt, 15 h

Me O O Me OH 99% ee R1

CO2Et Kaeobamrung, J.; Bode, J. W. Org. Lett. 2009, 11, 677.

Rob Lettan @ Wipf Group Page 25 of 34 3/30/2009 Annulation with Aryl Nitroso Compounds

Me Cl Me O N N NO Me Me O 20 mol% CHO 45-81% yield 1 R Ar Me 20 mol% DBU, THF, —5 °C N Me H

CHO OH i-Pr R1 NO N R1 N Me i-Pr

Me Me Ar' O N N N O i-Pr Me Me N Ar N i-Pr

O O Ar N O O O N O Ar Ar N Me H Bamberger-Type Me Rearrangement Me Zhong, G. J. Org. Chem. 2009, 74, 1744.

Rob Lettan @ Wipf Group Page 26 of 34 3/30/2009 NHC-Catalyzed Redox Processes Rovis

Cl N OH O O 20 mol% N N Ph CHO N N Ph Ph Ph Ph OBn NEt3, BnOH, Br Br N N N N 80% yield toluene, 25°C, 4 h Ph Ph Bode Bn Me N Cl OH O O 10 mol% S CHO Me Ph Ph OEt i-Pr2NEt, EtOH, Me Me CH2Cl2, 30°C, 15 h 89% yield, 13:1 dr

Scheidt Me I N

N O 5 mol% Me CHO Ph Ph OBn DBU, BnOH, PhOH, Zeitler Mes toluene, 100 °C, 2 h 82% yield Cl N

N O CHO 5 mol% Mes Ph OEt Rovis, T. et al. J. Am. Chem. Soc. 2004, 126, 9518. DMAP, EtOH, Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126. Ph toluene, 60 °C, 2h 65% yield Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 3873. Zeitler, K. Org. Lett., 2006, 8, 637.

Rob Lettan @ Wipf Group Page 27 of 34 3/30/2009 NHC-Catalyzed Azidation of Epoxy-Aldehydes

Cl O N OTMS O 20 mol% N N Ph H O CHO N N3 NH Ph Ph or 16 mol% NEt , Ph Me 3 Me O Me TMSN3/NaN3, (EtOH) toluene, 25°C, 4 h TMSN3/NaN3 TMSN3/NaN3/EtOH (2.5:1) (1:1:1)

O CHO OH O Ph N Me Ph Me N N Ph EtOH creates equilibrium, which leads to intramolecular oxazolidinone formation.

N OH O O H N N N Ph 1 O R NH N3 Me N Ph Ph Me w/ EtOH

Curtius OTMS OH O Rearrangement OH NuH H Nu N N 1 1 Ph R N3 R C O Me O Me Me Rovis, T. et al. J. Org. Chem. 2008, 73, 9727.

Rob Lettan @ Wipf Group Page 28 of 34 3/30/2009 O- to C-Acyl Transfer

BF4 CO R1 N O 2 O 2 1 R 1 mol% N N Ph R O2C R2 67-84% yield O O N 0.9 mol% KHMDS, N THF, rt, 5 min Ar Ar

N

N N 1 1 O Ph O CO2R R O2C R2 R2 O O N N

Ar Ar

O R2 N N N O Ph N

1 CO2R Ar Crossover experiment supports mechanism:

2 different starting materials (R1/R2 and R1'/R2') give 4 different products.

Rovis, T. et al. J. Org. Chem. 2008, 73, 9727.

Rob Lettan @ Wipf Group Page 29 of 34 3/30/2009 Trans-Esterification

Nolan Cl N N O 0.5-5 mol% Cy Cy O O R3OH MeOH 1 2 1 3 or R OR 4Å MS, THF, < 3 h R OR Me H R1 = alkyl, aryl R2 = Me, vinyl 90-99% yield R3 = 1° and 2° alkyl Equilibrium process that favors product under reaction conditions. Movassaghi Cl 3 N N 3 O R 0.5-5 mol%Mes Mes O R OH OH R2OH 1 2 1 R OR H2N R N 4Å MS, THF, < 3 h H R1 = alkyl, aryl 66-99% yield R2 = 1° alkyl

Competitive experiment with H2NBn gives only the desired product. Alcohol is necessary.

Mes O Mes HO N N R1 R1 OMe HO !+ H O OMe N N Mes Mes NH2 NH2

Mes Mes HO N N R1 Theoretical studies by Hu support this mechanism. HO + H O O Me ! N N NH Nolan, S. P. et al. Org. Lett. 2002, 4, 3583. Me 2 Hedrick, J. L. et al. Org. Lett. 2002, 4, 3587. Mes product Mes Movassaghi, M.; Schmidt, M. A. Org. Lett. 2005, 7, 2453. (after acyl transfer) Hu, C.-H. Tetrahedron Lett. 2005, 46, 6265.

Rob Lettan @ Wipf Group Page 30 of 34 3/30/2009 NHC-Catalyzed 1,2-Additions

Cl N N O 0.5-5 mol% R R OTMS OTMS or R1 H TMSCF3/DMF or TMSCN/THF R CF3 R CN R1 = aromatic, aliphatic, R = adamantyl, Mes 79-99% yield branched aliphatic O R Maruoka R1 H N O TMSNuc O NTs or H Ph Me Ph H N R1 R Cl N N R R R (1 mol%)

N O SiMe3 N N R R TMSCN/THF H N R1 Nuc R OH NHTs OTMS or Ph Me Ph H R1 Nuc CN OR CN 99% 92% O R N N R R Lewis-base mechanism N Me R1 H —NHC OTMS more plausible. Si O SiMe3 Me Nuc 1 Song, J. J. et al. Org. Lett. 2005, 7, 2193. N Me R Nuc 1 Suzuki, Y.; Sato, M. et al. Tetrahedron, 2006, 62, 4227. R R Nuc Maruoka, K. et al. Tetrahedron Lett. 2006, 47, 4615.

Rob Lettan @ Wipf Group Page 31 of 34 3/30/2009 Aziridine Ring-opening

Chen

O 20 mol% O R1 Cl R1 H N N Mes Mes R2 O R2 40-95% K CO , 18-crown-6 NTs 2 3 R3 NTs 50 °C, air, 24 h R3

Wu

5 mol% Lewis base-catalyzed pathway proposed. Cl N N R2 Mes Mes R2 NTs NTs 90-99% yield N N TMSX, THF, Mes Mes R1 R1 X TsN 23 °C, 0.3-24 h Me R1 X = N , Cl, I N3 Si 3 R2 Me Me Rate: I > Cl >> N3 R1 = alkyl, aryl, H 2 R = alkyl, aryl Chen, Y.-C. et al. Org. Lett. 2006, 8, 1521. Wu, J. et al. Tetrahedron Lett. 2006, 47, 4813.

Rob Lettan @ Wipf Group Page 32 of 34 3/30/2009 NHC-/Initiation of Silyl Enol Ethers Song LB OH SiMe3 Cl O N N CHO 0.5 mol% Ad Ad CO2Me Me OMe Me Me Me THF, 23 °C, 3 h; then HCl Me Me What is the Lewis base? 83% yield

Scheidt i-Pr i-Pr can be isolated N N

OSiMe2Ph O OH SiMe2Ph 5 mol% n-BuLi 5 mol% i-Pr i-Pr HO Et H Et Ph Et THF, 0 °C · PhCHO, —78 °C n-Bu n-Bu n-Bu 80% 20:1 Z:E

Song, J. J. et al. Org. Lett. 2007, 9, 1013. Scheidt, K. A. et al. Org. Lett. 2007, 9, 2581.

Rob Lettan @ Wipf Group Page 33 of 34 3/30/2009 In Conclusion

— N-Heterocyclic carbenes are powerful reagents for the synthesis that have seen a remarkable growth in application over recent years. — NHC organocatalysis has given chemists the ability to access unusual reactivity patterns (Umpolung) along with other reactions (1,2-additions, redox, opening of small rings). — New synthetic opportunities are just beginning to be explored, along with improvements in enantioselective NHC catalysis. — Although not covered in this discussion, it is worth mentioning that NHC's have also proven as valuable compounds for ring-opening polymerizations and have been utilized effectively as in metal catalysis.

Rob Lettan @ Wipf Group Page 34 of 34 3/30/2009