NHCs. N-Heterocyclic Carbenes: Versatile Organocatalysts and Reagents. N-Heterocyclic Carbenes: Versatile Organocatalysts and Reagents

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1 -eterocyclic Carbenes: Versatile rganocatalysts and eagents Evans Group eminar -eterocyclic Carbenes: Versatile rganocatalysts and eagents cope of eminar polymerization 1,2-additions acylations and hydroacylations An Evans Group Afternoon eminar December 14, 2007 s s base s- history and mechanistic studies ring-opening reactions properties Cs transesterification utline 1. Benzoins and the eslow chanism 2. The Wanzlick Equilibrium 3. Properties of Cs 4. Preparation of Cs 5. The Benzoin Condensation 6. The tetter eaction 7. C-derived omoenolates 8. C-catalyzed Transesterification Problem of the Day p-- C 6 mol% s- 12 mol% DBU TF, rt, 8 h = p-- s preparation C s benzoin condensation tetter reaction homoenolate additions and condensations 78%, one diastereomer air JAC Literature General 1. "-eterocyclic Carbenes as rganocatalysts." Marion,.; Diez-Gonzalez,.; olan,.p. Angew. Chem. nt. Ed. 2007, 26, (general review) 2. "-eterocyclic Carbenes." Eastman, K.J. Baran Group eminar istory 3. "ucleophilic Carbenes: An ncredible enaissance." egitz, M. Angew. Chem. nt. Ed. Engl. 1996, 35, (discovery) 4. "Looking for table Carbenes: The Difficulty in tarting Anew." dugengo, A.J. Acc. Chem. es. 1999, 32, (discovery) Properties 5. "Formation and tability of -eterocyclic Carbenes in Water: The Carbon Acid pk a of midazolium Cations in Aqueous olution." Amyes, T.; Diver,.T.; ichard, J.P.; ivas, F.M.; Toth, K. J. Am. Chem. oc. 2004, 126, (pk a of Cs) 6. "table Carbenes." Bourissou, D.; Guerret,.; Gabbai, F.P.; Bertrand, G. Chem. ev. 2000, 100, (general review) 7. "When and ow Do Diaminocarbenes Dimerize?" Alder,.W.; Blake, M.E.; Chaker, L.; arvey, J..; Paolini, F.; chutz, J. ACE (general review) Preparation 8. "Convenient, calable, and Flexible thod for the Preparation of midazolium alts With Previously naccessible ubstitution Patterns." Chem. Commun. 2006, (synthesis of imidazolium salts) 9. "An Efficient ynthesis of Achiral and Chiral 1,2,4-Triazolium alts: Bench table Precursors for -eterocyclic Carbenes." Kerr, M..; de Alaniz, J..; ovis, T. J. rg. Chem. 2005, 70, (synthesis of triazolium salts) eactions 10. "Catalyzed eactions of Acyl Anion Chemistry." Johnson, J.. Angew. Chem. nt. Ed. 2004, 43, (benzoin, tetter) 11. "ucleophilic Carbenes in Asymmetric rganocatalysis." Enders, D.; Balensiefer, T. Acc. Chem. es. 2004, 37, (asymmetric benzoin, tetter) 12. "Extending chanistic outes in eterazolium Catalysis--Promising Concepts for Versatile ynthetic thods." Zeitler, K. Angew. Chem. nt. Ed. 2005, 44, (homoenolates)

2 -eterocyclic Carbenes: The Benzoin Condensation Evans Group eminar The Benzoin Condensation the original reaction ac Et, 90-92% Lapworth chanism C C - incomplete condensation observed for aliphatic aldehydes - electron deficient benzaldehydes are subject to side reactions Wohler/Liebig Ann. arm Adams rg. yn. Coll. Vol C 3 eslow chanism 3 -C 2 3 "[Mizuhara and coworkers] proposed an unusual and rather unlikely mechanism...we are thus forced to look elsewhere in the molecule for a site of potential reactivity..." - carbon acidity of thiazolium compounds was known: decarboxylated much faster than to benzoin condensation eslow JAC 1958, 80, 3719 chenkel elv. Chim. Acta. 1948, 31, 924 C - intermediate cyanohydrins were isolated as crystalline K salts C Thiamine-Catalyzed eactions known in 1954: pyruvic acid pig heart carboxylase -C 2 acetoin Lapworth J. Chem. oc known that these reactions were possible in proteinfree systems if thiamine was present - reaction is optimal at p addition of doubly 14 C labelled acetaldehyde gives doubly labelled acetoin originally proposed mechanism: 2 thiamine (vitamin B 1 ) - 2 "pseudobase" = 3 Mizuhara JAC neutral D 2 several hours base -heterocyclic carbene - D - could this be analogous to the Lapworth mechanism? thiamine is regenerated acetoin

3 -eterocyclic Carbenes: The Benzoin Condensation Evans Group eminar evidence for mechanism: - independent generation of proposed intermediate gives product: unstable - various analogs of thiamine have varying efficacy: competent - an illuminating comparison: competent - consider parent thiazolium first: ineffective (cannot form C) ineffective ineffective (steric hindrance) pseudobase C - both exchange with D 2 - why is the thiazolium inactive? eslow JAC 1958, 80, another prediction: Compounds in which - aromaticity: aromatic C will be ineffective catalysts. aromatic - comparison with imidazoliums: C not aromatic could ring-open to is especially stable compared to C still aromatic - the disruption of aromaticity is less significant here C but C C C will not be formed. catalytically inactive and non-aromatic - prediction: at high p, benzoin condensation should be supressed - this has been found: Mizuhara Proc. Japan Acad

4 -eterocyclic Carbenes: Wanzlick Equilibrium Evans Group eminar solation of a table Carbene Ad Ad a TF Ad Ad - stable if not exposed to moisture or 2 - crystalline (mp= C) ppm the first isolated stable carbene duengo JAC X-ray structure - a wide variety of stable carbenes have now been isolated (see ermann ACE ) Carbene Dimerization? proposed by Wanzlick C() 3 - based on molecular weight measurements Ad 102 Ad - the hypothesized mechanism of the formation of tetraaminoethylenes C 3 Wanzlick ACE no ordinary olefins 4 smg TF colorless - incredibly electron rich, these dimers oxidize very easily reactivity C 130 C C C rt C C C C Wanzlick ACE what is the reactive species? Wanzlick Proposal: There is an equilibrium, and is the active species. Lemal Proposal: There is no equilibrium, and is the active species. Lemal JAC air deep violet Lemal JAC % 100% C C 70%

5 Crossover Experiements = o-tol - 2 h reflux in xylene: no crossover product observed an electrophilic addition mechanism E E? 2 E Lemal JAC E - alternate mechanism proposed - requires: rate(dimerization) << rate (carbene electrophile) - further crossover experiments with alkyl and aryl tetraaminoethylenes confirmed the lack of crossover: Wiberg JAC a reinvestigation ' ' ' ', ' = /Et; Et/iPr; ipr/; /ptol - statistical mixture (1:2:1) obtained? -eterocyclic Carbenes: Wanzlick Equilibrium 2 ' ' ' ' Denk TL alternate possibility: contamination bridged carbenes C 2 n C 2n K DM n=3,4 - n=3: no dissociation even at 100 C - n=4: dimer at -33 C, carbenes at rt C 2 n C 2n Evans Group eminar - to investigate the possibility that a contaminant catalyzes crossover, the experiements were repeated: = p-tol as drawn: 19% crossover after 6 h with K: no crossover product C 6 D C - after 22 h at 140 C with K, still no crossover product - implies G > 35 kcal/mol Lemal TL potential explanation: in the original 1964 work, substrates were prepared using tripheynlcarbinol oxide, rather than heating the diamines with triethyl orthoformate as was done in the more recent studies - confirmation: addition of acid catalyzed equilibrium (u Mol ysics ) 2 Chen ACEE X-ray structure Do these findings prove the Wanzlick Equilibrium exists? o. egative Crossover = Definitely no equilibrium Positive Crossover = Might be an equilibrium alternate possiblity: cycloaddition-cycloreversion - C=C bond length is normal, despite being extremely weak! (a few kj/mol) Å A B A B A B A B A B A B

6 -eterocyclic Carbenes: The Benzoin Condensation evisited Evans Group eminar less aromatic carbenes 2 = alkyl - equilibrium is observed (M) - bulky favors carbene (=ipr, neopentyl) - for =Et, = 13.7±0.6 kcal/mol, = 30.4 ± 1.7 cal mol -1 K -1 - at 25 C, this corresponds to G = 5 kcal/mol - aromatic carbenes do not dimerize as easily Lemal JAC ahn ACE ummary: errmann ACE Further eading "When and ow Do Diaminocarbenes Dimerize?" Alder,.W.; Blake, M.E.; Chaker, L.; arvey, J..; Paolini, F.; chutz, J. ACE The chanism of Benzoin Condensation: A Controversy a dimeric mechanism? option 1 E and Z benzoin condensation, further dimerization evidence for dimer involvement (1) crossover is observed - unclear how this implicates dimer C 4 acyloins (2) dimers give higher yields than thiazolium salt base (3) behavior when C is generated via decarboxylation Et C 2 - dimers prepared by passing solution of salt in methanol through basic ion exchange resin 10 mol% monomer, 10 mol% Et3 or - argument: this should generate C is much higher concentrations - however, same loadings of carboxylate are needed to effect reaction 5 mol% dimer Et monomer: 6% dimer: 21% Castells J eterocyclic Chem (4) behavior when C is generated via desilylation Tf TM af no benzoin condensation - reaction performed in dioxane at 100 C - solubility of af under these conditions? option 2 - is this anion significantly stabilized? Castells JC

7 -eterocyclic Carbenes: The Benzoin Condensation Evans Group eminar (5) bridged thiazolium salts C 2 n 2 yields in the benzoin condensation parent salt n=3 n=4 n=5 n=6 "this very clear dependency between yields and length of the polymethylene bridge supports our views on the relevant protagonism of bis(thiazolin-2-ylidenes)s as the catalytic species..." - conditions: 10 mol% salt, 30 mol% DPEA, dioxane, 100 C, 24 h eslow's eply - study the kinetics (UV, M) of the benzoin condensation: - A B Et 3 proposed rds 69% 59% 14% 40% 44% Castells TL C rate law: order in benzaldehyde - B is formed rapidly before much benzoin is produced - in the early part of the reaction, A and B are in semi-equilibrium - as C is consumed, B/A ratio decreases - if B to C is the rds, then the order in C depends on the state of the thiazolium ion: first order if in form B but second order if in form A - indeed, the order in C is between first and second order, depending on the initial concentrations rate law: order in thiazolium ion - M shows no trace of dimer - rate law is first order in total thiazolium ion - this excludes option 2 reaction with ferricyanide present - option 1 is not excluded, because it generates B - what if the process is changed to make the formation of B rate determining? A Et 3 proposed rds - K 3 Fe(C) 6 rapid oxidation B = p rate law is first order in aldehyde, first order in A, and zero-order in ferricyanide "The thiazolium catalyzed benzoin condensation with mild base does not involve a 'dimer' intermediate." further confusion eslow TL contradictory reports appeared that the reaction might actually be second-order in both aldehyde and thiazolium ion Lopez-Calahorra Tet "Contrary to recent reports, the catalysis of the benzoin condensation is firstorder in thiazolium ion, even based on the results recently reported by others. Thus there is no need to propose an unusual anion intermediate in the reaction." eslow TL first order second order Jordan JC eslow TL

8 modern data - primary kinetic isotope effect when CD used: inverse solvent isotope effect when CD 3 D used: all rate constants have now been determined, confirming eslow's position - under many conditions, there is no single rate-determining step -eterocyclic Carbenes: The Benzoin Condensation ummary of eactivity dimerization potential do not dimerize dimerize reversibly Evans Group eminar dimerize irreversibly singlet-triplet gap (kj/mol) dimer C=C bond strength (kj/mol) Further eading C thiazolium catalyzed cyanide catalyzed "Kinetics of the Thiazolium on-catalyzed Benzoin Condensation." White, M.J.; Leeper, F.J. J. rg. Chem. 2001, 66, B general reactivity coordinatively unsaturated s s s s X-ray structure - nucleophiles - complex rapidly with most metals - moisture sensitive - do not react with triplet oxygen Tf TF s s Tf s s colorless solid (mp = 200 C)

9 -eterocyclic Carbenes: Acidity Evans Group eminar s s Tf s s 175 ppm (average of C and salt) Facile Deuterium Exchange the seminal report Ts D 2 pd 13 D 2 pd 9 D 2 pd 9 - bridging C- bond length = 1.16 Å - -C- bond angle = (typical C: 102 ) - counterions form hydrogen-bonded bridges between imidazole C- bonds - a bridging iodine complex is also known - rate varies by less than a factor of 2 for various buffer concentrations and types D D D duengo JAC t 1/2 = 14 min t 1/2 = 5 min t 1/2 = 6 min lofson JAC acidity in water: methods - rate of /D exchange measured in buffered D 2 with 1 M - this allows exchange at acidic C to be distinguished from exchange at - rate in 2 extrapolated from known kinetic isotope effect k D /k = 2.4 (Jencks JAC ) - reverse rate, protonation of carbene, extrapolated from flash photolysis: k = s -1 - pk a = pk w log(k /k ), where K w = and k is the rate of deprotonation ichard JAC acidity in water: results rate of deprot. (M -1 s -1 ) / relative rate - determined by relating rate of /D exchange to solvent kinetic isotope effect - kinetic and thermodynamic acidity are correlated Eisen mechanism 1.54 x 10 1 (1) pk a = x 10 2 (7) pk a = x 10 3 (150) pk a = 21.6 C C encounter complex: aligned for deprotonation work is done to bring reactants together - small primary KEs are observed for imidazolium ion deprotonation estimated barrier for azolium ions: 5 kcal/mol C 6.17 x 10 3 (400) pk a = x 10 5 (8 400) pk a = x 10 7 ( ) pk a = 16.9 ichard JAC C reorganization rate depends on "intrinsic Marcus barrier" energy: protonation of: isobutylene aryl ring ethyl vinyl ether barrier (kcal/mol): carbonyl compounds 6 phenol, acetic acid 2 2 Eisen ACEE Kresge Acc Chem es

10 -eterocyclic Carbenes: Acidity Evans Group eminar Acid-Base Behavior in rganic olvents DM ipr tbu ipr ipr completely deprotonates partially deprotonates indene pk a = carbene preparation (1. K/TF 2. filtration 3. evaporation) - deprotonation monitored by M TF - a less polar solvent which disfavors the formation of ions ipr ipr almost completely deprotonates and 9-phenylxanthene pk a = 27.7 from which an apparent pk a of 24 can be derived (corrected only for the number of protons). but fails to deprotonate - spectra show only slight broadening: rapid proton transfer on M timescale Basicity vs. ucleophilicity ipr ipr DM highly nucleophilic elimination 20% - cf. elimination/substitution ratios for DB (91%) and DBU (21%) (Fritz Chem. Ber ) - one of the strongest known neutral bases C substitution 80% Alder JC Chem Commun Compiled pk a Values (DM) - primarily determined from titrations with indicators - little dependence on counterion (not shown) imidazolium core thiazolium and related cores other 19.7 tbu tbu 23.2 ~9* Et ~ ** Bz 21.6 ipr ipr =, Et, nbu, nct references * complicated by dimerization 1. Jencks JAC ** estimated by computations (ref. 5) 2. Cheung JC Alder JC Chem Commun Bordwell JAC refs. therein 5. Yates JAC ** 27.9** 16.5

11 -eterocyclic Carbenes: Preparation Evans Group eminar midazolium alts diamine precursor s C(Et) 3 X 1. B 3 ; / 2. C(Et) 3 45% s via oxazolium intermediate 1. 2,, Dean-tark 2. Ac formic acetic anhydride: rg yn Coll. Vol this method: Fürstner Chem. Commun C Ac 2, 4 Ac - does not aromatize 1. 2, nbuli 2. C, Ac Et Et diamine precursor: variation Et ethyl chlorooxoacetate above: oveyda JAC another example: elmchen ynlett , Et 3 2. ' 2,, or ' 2,, 2 4, rt or a; ' 2, DCC, Bt 1. B 3 TF, 2 2. conc. 3 2 ' sequential lithiations 1. nbuli 2. C 2 Li a/k rt C(Et) 3, ' ' above: Grubbs rgmet further examples: Gilbertson L Maudit JMC sbuli δ(c 2 )=240 ppm Li Li ahn ACE ,'-substituted thione synthesis: Ahlbrecht ynthesis Ac 2, sterically hindered amines are tolerated X-ray structure

12 -eterocyclic Carbenes: Preparation Evans Group eminar Benzoimidazolium alts via oxazolidinone 1. Pd(0), 2 Diver L Pd(0), ' C(Et) 3, X Buchwald-artwig Amination: Pd 2 dba 3, BAP, atbu X tbu Buchwald JAC artwig JAC optimization was required to supress epimerization of chiral primary amines Triazolium alts via phenylhydrazone release of carbene , a C 2, Ac Enders ynthesis C 0.01 mbar Enders ACEE base is also effective: Ad KtBu ppm Ad - amides are also useful: aminoindanol-derived - from amino acids: Boc phenylalanine ab 4 Ac Boc tbu C(Et) 3 ldrum's acid DCC DMAP tbu ; C() 3 tbu Enders ACE presumably via: Boc Leeper JC PT ovis JC Boc mreina Tet reaction with acetonitrile: Ad a C Ad above 100 C C Ad C 2 C C 2. TFA C(Et) 3 4 Cowley JC

13 -eterocyclic Carbenes: Asymmetric Benzoin Condensation Evans Group eminar a first attempt C = 10 mol% C 10 mol% Et 3 1:2 / 2 30 C, 24 h an improved system C = an efficient system C = tbu mol% C K 2 C 3 TF, rt, 60 h 78%, 8% ee 4 10 mol% C 10 mol% KtBu TF, rt, 16 h heehan JAC %, 20-86% ee Enders elv Chim Acta %, 80-95% Enders ACE crossed-benzoin condensations C = = C = '=alkyl ' F 3 C CF 3 10 mol% C 9 mol% KMD TF, rt, h 7.5 mol% C 7.5 mol% Et 3, rt, 12 h 24-93%, 71-99% ee Enders ACE Enders ynlett %, 95% ee ()-sappanone B 3 steps Ac Ac uzuki ACE uzuki L

14 acyloin macrocyclization C = - imidazolium salts are inactive - low yields: product is unstable 1 equiv C 2 equiv DBU C 2 2, rt, 90 min F 5 -eterocyclic Carbenes: Benzoin thodology 21% 3 steps - proposed mechanism: 2 C 2 C cross-benzoin (reversible) s aldol 2 C 2 C Evans Group eminar s oxy-cope (irrev.) s trans-resorcylide acyl addition tandem benzoin-oxy-cope-aldol sequence 10 mol% C 15 mol% DBU Miller JC C - proposed mechanism: -C 2 2 C 2 C C = 1,2-DCE, 0 to rt 40 h s 2 C 78%, 99% ee 11:1 dr Bode JAC evidence for oxy-cope: TM Et 10 mol% C 15 mol% DBU 1,2-DCE/Et, rt, 24 h C TM Bode JAC

15 -eterocyclic Carbenes: The tetter eaction Evans Group eminar benzoin acyl anion tetter ' acyl anion aldehyde ' Michael acceptor ' α-hydroxy ketones 1,4-dicarbonyl compounds - essentially a vinylogous tetter reaction - removes problem of self vs. crossed additions - the C-catalyzed process is a useful alternative to the radical process the original reaction tetter ACEE Christmann ACE Et ac DMF, rt 1-4 h - thiazolium salts were soon found to be useful as well asymmetric tetter reactions the original report C C 2 ' - =,, ; ' =, Et - key advance: triazolium salts are more active Enders elv Chim Acta mol% C K 2 C 3 TF, rt, 24 h C = ' useful reviews 33% Et tetter ACE % 56-74% ee 4 C 2 ' ovis variant C C 2 ' 20 mol% C 20 mol% KMD xylenes, rt, 24 h - significantly improved yields and ee's - Z enoates do not react - α,β-unsaturated aldehydes, carboxamides, and nitro compounds are inactive - α,β-unsaturated ketones react more rapidly than corresponding esters - extended substrate scope: C C 2 Et " 81%, 95% ee C 2 Et - six-membered variant: no reaction - an unsolved problem: high catalyst loadings formation of quaternary stereocenters 20 mol% C C 2 Et 2 equiv Et 3, rt, 24 h C = 20 mol% C 20 mol% KMD xylenes, rt, 24 h F5 C = 63-94% 82-97% ee C 2 ' ovis JAC ovis ynlett %, 99% ee 90%, 84% ee C 2 Et C ovis JAC some kinetic resolution can also be obtained with racemic g-substituted substrates ovis Tet

16 -eterocyclic Carbenes: The tetter eaction Evans Group eminar diastereo- and enantioselective variant C 2 Et ovis JAC mechanism of reaction? C 2 C 2 C 2 C 2 - proposed model for selectivity 20 mol% C 20 mol% KMD, rt, 24 h C = 20 mol% C 20 mol% KMD, rt, 24 h 20 mol% C 20 mol% KMD, rt, 24 h C 2 Et 94%, 95% ee, dr 30:1 A(1,3) min. CF 3 C 2 C 2 80%, 93% ee, dr 42:1 C 2 C 2 70%, 38% ee, dr 6:1 - evidently, intramolecular protonation is faster than intermolecular protonation - Z acceptor: tetter addition from the same face, but protonation from the opposite face enantioselective desymmetrization C = sila-tetter reactions C 10 mol% C 10 mol% KMD, rt, 5 min - acylsilanes are competent nucleophiles i 3 C = Et - an analogue of thiamine diphosphate 86%, >99% ee one diastereomer ovis JAC ovis rg Proc &D mol% C DBU ipr, TF 70 C, 2-12 h cheidt JAC Et

17 -eterocyclic Carbenes: The tetter eaction Evans Group eminar - ook rearrangement: i 3 ipr Et Et TM Et Et Et TM Et Et cheidt JC acylimidazoles Pr a 20 mol% C p 7.2 buffer 70 C, Pr 92% m C = cheidt JAC decarboxylative addition: a -C 2 m Et m

18 -eterocyclic Carbenes: omoenolates Evans Group eminar chanistic ationale if aldehyde is α,β-unsaturated: = E E ntial eports: γ-butyrolactone Formation representative examples: Bode TP C - potential for: (a) benzoin/tetter (a 1 to d 1 ) (b) homoenolate (a 1 to d 3 ) reactivity patterns - selectivity for dimerization vs. cross-addition? - moderate cis selectivity is observed - simultaneously reported by Bode and Glorius groups - steric bulk of C catalyst is important C p-- p-c 2 - TP p-- 79% dr 4:1 41% dr 3:1 p-c 2 - Bode JAC dimerization also possible: TP C conditions: - 8 mol% s-, 7 mol% DBU - 2 equiv electrophilic aldehyde - rt, 15 h, 10:1 TF/tBu s- = s s - aliphatic aldehydes are not effective - slow addition of enal increases yields - performing the reaction with cis-p-anisaldehyde still leads to the cis adduct - if reaction is performed with tbud, D is incorporated exclusively at the α-position (no quenching of homoenolate by solvent) representative examples: Glorius C p-- - ketones are competent electrophiles: C CF 3 conditions: - 5 mol% s-, 10 mol% KtBu - 1 equiv electrophilic aldehyde - 16 h, rt, TF TP Extending the cope of the Electrophile γ-lactams from -sulfonylimines aph Bode L C p-tol PG = 2, = p-- - choice of PG is important PG TP 15 mol% s- 10 mol% DBU, 60 C, tbu, 14 h 83% dr 5:1 p-- CF 3 70% dr 4:1 84% dr 2:1 Glorius ACE % dr 4:1 PG p-tol

19 -eterocyclic Carbenes: omoenolates Evans Group eminar edox Esterification u C = - a representative example: u C 5 equiv - kinetic resolution is possible: C 5 mol% C 5 mol% DBU 82% u - primary and secondary alcohols are tolerated - nitrogen nucleophiles are not useful: sulfonamides, amides azides, and anilines give other products - β,β-disubstitution of the enal gives no reaction (±) 5 mol% C conv. cheidt L s = proposed stereochemical model: cheidt L C = 2 equiv 110 C, TF, 2-6 h C = - selectivity between mechanistic pathways is dependent on the choice of base: C s protonation pathway (slow) preferred for DPEA - α-branched enals are unsuccessful due to A(1,3) strain: reactive for protonation, but suffers A(1,3) unreactive for protonation, out of conjugation expoxyaldehydes and epoxyaziridines are also useful Ts Et 10 mol% C 8 mol% DPEA 30 C, C 2 2, 15 h C-C bond formation (fast) preferred for tbuk Bode L mol% C 8 mol% DPEA Ts 30 C, C 2 2, 15 h 89%, dr >10:1 Et - an improved system: C 3 equiv 5 mol% C 10 mol% DPEA 60 C, TF, 24 h 89% Bode L C = Bode JAC % - acyloin dimers, C-C bond formation are supressed

20 -eterocyclic Carbenes: omoenolates Evans Group eminar - proposed mechanism: - if reaction is run in the presence of CD 3 D, recovered epoxide contains no deuterium - implies concerted process or rate-determining deprotonation - product has deuterium at the alpha position; no Favorskii or hydride-shift mechanism Bode JAC presumably via: - α,α-dihaloaldehydes: A = 1 equiv 10 equiv 20 mol% C, 1 equiv Et 3, 25 C, 4 h 10 mol% C, 1 equiv K, 1.2 equiv A 50 mol% 18-cr-6, rt, 19 h C = 78% product ovis JAC %, 93% ee - 18-cr-6 required for solubility of K in - A acts to reduce background epimerization by acting as the "base reservoir" - enantioselective protonation leads to product - products are useful in further transformations: Li 85% LiAl 4 95% Mg() 2 93% use of formylcyclopropanes C 2 C 2 C = F F F F - transformations preserve ee F ovis JAC mol% C, 20 mol% DBU TF, 23 C, 15 h 5 equiv 90%, 89% ee Bode ACE range of aromatic, unsaturated, and aliphatic substrates are useful - water and thiols are also useful nucleophiles - if CD 3 D used: - recovered starting material: - indicates reversibility in intitial addition of C D D /D 100% D 40% D C = s - potential hydride shift mechanism: s s - however, reaction with an enantioenriched substrate gives racemic product; actual mechanism remains unknown - substrates are available using Macmillan protocol: 20 mol% cat. C 2 MacMillan JAC

21 - redox amidation is also possible (difficult with other methods) 5 mol% C, Et 2 C C 20 mol% DBU equiv imidazole TF, 40 C, 15 h 1.5 equiv 1.0 equiv - presence of imidazole supresses formation of undesired imine - believed imidazole forms a transient hemiaminal which acts to protect the aldehyde - range of primary, secondary, anilinic, and hydroxyl- amines are tolerated Diels-Alder Cycloadditions the idea homoenolate equivalent -eterocyclic Carbenes: omoenolates Et C = 90% s Bode JAC Z enolate poised for Diels-Alder chemistry - problem: with imidazolium-derived Cs, β-protonation is slow, even at elevated temperatures in protic solvents triazolium catalysts are successful C 2 Et 2 = p-- - exclusively endo dihydropyridinone products formed in high yields - cis selectivity rationalized by Z enolate - α-chloro aldehydes are also viable dienophiles - fumarates and other non-aldehyde dienophiles are not reactive, arguing against a Morita-Baylis- illman-type pathway 10 mol% C 10 mol% DPEA 10:1 /TF rt, h C = C 2 Et C p-- 90%, >99% ee, dr >50:1 mechanistic rationale s - if s is replaced by, reaction fails α,β-unsaturated Ketones a surprising result an example C = s- C a more complex example -C 2 not observed 6 mol% C 12 mol% DBU TF, rt, 8 h " Evans Group eminar actual product - typically, =aryl 78%, one diasteromer C - β-lactone observed by FT - diastereoselectivity unexplained Bode JAC air JAC

22 ntramolecular Michael Additions - C homoenolates can be β-quenched for use as nucleophiles in Michael additions the idea an intramolecular example C 10 mol% C 10 mol% DPEA C 2 2, rt then, 5 h -eterocyclic Carbenes: omoenolates C C 2 substrate product yield ee Et 2 C Et 2 C C C C C C E E C C 2 C C 2 C C α,β-unsaturated Esters - what if the C attacked the β-carbon of a Michael acceptor? EWG n X 10 mol% C 2.5 equiv K 3 P 4 glyme, 80 C EWG EWG = C 2, C, Weinreb amide, X = Ts,,, n=1,2 a representative example C 2 Allyl isotopic scrambling 90% D C 2 Allyl 10 mol% C 2.5 equiv K 3 P 4 glyme, 80 C 10 mol% C 2.5 equiv K 3 P 4 glyme, 80 C - with PBu 3 : <3% D at β-carbon proposed catalytic cycle 48% D n Evans Group eminar C 2 Allyl C 2 Allyl D 42% C = = p-- 8 h, 94% 12 h - primary or secondary amides are accessed if amines are used instead of C = s cheidt ACE Fu JAC

23 -eterocyclic Carbenes: Transesterification Catalysts Evans Group eminar Transesterification Catalysts - Cs allow catalytic transesterification under mild conditions primary alcohols 1 mol% s or Cy, 4A M '' ' TF, rt '' 15 min - 3 h ' ' =, Et, primary % vinyl - secondary alcohols are not viable nucleophiles - simultaneous report: Waymouth/edrick sieves may absorb liberated alcohols secondary alcohols Et Amidation of Esters substrate scope ' = alkyl, aryl, heterocyclic ' = or lactone 2 olan L olan JC mol% Cy 4A M TF, rt Et 1 h secondary 68-98% - enantiopurity unchanged - numerous examples: see paper mechanism of action 6.5 mol% s- 5 mol% tbuk TF, rt h - previously proposed: activated C2 imidazolium intermediates olan JC ' typical yields 90% Movassaghi L another possibility: activation of alcohol nucleophile s s s s ' 2 ' s ' s 2 to acyl transfer 2 - mixing an equimolar mixture of s and in C 6 D 6 immediately produces mes- complex (visible by M) - complex is isolable: X-ray structure '? ' - react and M show transient -acylethanolamine intermediate Movassaghi L