Baran Lab N - H e t e r o c y c l i c C a r b e n e s ( N H C s ) K. J. Eastman
An Introduction to N-heterocyclic Carbenes: How viable is resonance contributer B?
Prior to 1960, a school of thought that carbenes were too reactive to be smaller isolated thwarted widespread efforts to investigate carbene chemistry. base ! N N N N R R R R Perhaps true for the majority of carbenes, this proved to be an inaccurate X- assessment of the N-heterocyclic carbenes. H longer Kirmse, W. Angerw. Chem. Int. Ed. 2004, 43, 1767-1769 In the early 1960's Wanzlick (Angew. Chem. Int. Ed. 1962, 1, 75-80) first investigated the reactivity and stability of N-heterocyclic carbenes. Attractive Features of NHCs as Ligands for transition metal catalysts: Shortly thereafter, Wanzlick (Angew. Chem. Int. Ed. 1968, 7, 141-142) NHCs are electron-rich, neutral "#donor ligands (evidenced by IR frequency of reported the first application of NHCs as ligands for metal complexes. CO/metal/NHC complexes).
Surprisingly, the field of of NHCs as ligands in transition metal chemistry Electron donating ability of NHCs span a very narrow range when compared to remained dormant for 23 years. phosphine ligands
In 1991, a report by Arduengo and co-workers (J. Am. Chem. Soc. 1991, Electronics can be altered by changing the nature of the azole ring: 113, 361-363) on the extraodinary stability, isolation and storablility of benzimidazole
Different from traditional carbenes, NHCs are electron rich: (resonance) MLn (robust) (sensitive)
R R R N N N PR3 PR3 + MLn N N N MLn R R R A B C
1 Baran Lab N - H e t e r o c y c l i c C a r b e n e s ( N H C s ) K. J. Eastman
NHCs are most frequently prepared via deprotonation of the corresponding c) unsymmetrical synthesis of imidazolidinium salts: 1 2 azolium salts (imidazolium, triazolium, tetrazolium, pyrazolium, benz- Ar NH2, Et3N, Ar NH2, O O THF, 0 oC O O toluene, 120 oC O O imidazolium, oxazolium, thiazolium salts - pKa - 21-24).
Cl OEt Ar1HN OEt Ar1HN NHAr2 Imidazolium syhthesis: 1) BH -THF, reflux 3 HC(OEt) 1) Existing imidazoles can be alkylated with appropriate electrophiles. 2) conc. HCl 3 - 1 2 X Ar H2N NH2Ar N N 120 oC Ar1 Ar2 2 Cl- 2) The imidazolium ring can be built: d) unsymmetrical synthesis of imidazolium salts: 4 a) symmetric synthesis: R O OEt
O O O HX, -H O 5 2 Cl- HO R Br A OEt R NH2 N N R R 1 H H R NH2, H H R1NH , cat. HCl, 2 nBuLi, toluene, then A reflux R N N R Cl OEt R4 O OEt
H H O 1 5 1 , (AgOTf) R NH R R NH OEt Cl O tBu 1) HCOOH, Ac O MeC(O)OC(O)H 2 b) unsymmetrical synthesis: 2) HCOOH
4 5 R O R OAc O O O O 2 - 4 HX, -H2O R X X Ac O, HX R Ac O, HX 1 N N 2 2 R NH2 + NH3 1 N N R1 R2 R R1 N R5 X- O R1 N H H H H H N O O
H 2 H base R NH2 N N R1 X H 1 R = alkyl 5 R5 R OH 4 R4 R HX - 2 Furstner et al. Chem. X- N R2 X N R Commun. 2006, 2176-2178 N N 1 R1 R
2 Baran Lab N - H e t e r o c y c l i c C a r b e n e s ( N H C s ) K. J. Eastman
Different Monodentate NHC Ligand Classes:
4-membered NHC - stable benzannulated imidazolin-2-ylidene N N 2 R - R1 steric influence is in very close proximity to metal iPr NiPr iPr R1 P - Grubbs N N - bulk required for stability - less reactive/! donating H base iPr iPr N N 2 N N 2 5-membered NHC R R (R1)H X- (R1)H X- R(H) R(H) N N N N R1, R2 R1 R2 R1 R2 - most abuntantly blocked or substituted "abnormal carbene" used as ligands 2,4,6-(Me)3C6H2 IMes SIMes 2,6-(iPr)2C6H3 IPr SIPr 6 and 7-membered NHC cyclohexyl ICy tert-butyl ItBu 2 2 1-adamantyl IAd R R
N N N N N N O O - electron richness comparable to tBuP R1 R1 iPr iPr Ad-2 2-Ad - flexibility in steric bulk on rigid tricyclic backbone R1 N N R2 - sterics can be modified w/out affecting electronics - rarely seen outside of initial preparation and testing R2 R1 (rare for monodentate ligands) - only complexes of 7-member ring carbene isolable 1 2 R , R = (CH2)4 : IBiox 5 1 2 R , R = (CH2)5 : IBiox 6 NHC as ligands for high-oxidation-state metal complexes and oxidation 1 2 R , R = (CH2)6 : IBiox 7 catalysts: 1 2 R , R = (CH2)7 : IBiox 8 1 2 R , R = (CH2)11 : IBiox 12 Points to consider:
R R 1) Phosphines are not used as ancillary ligands in oxidation chemistry. Why? - R = H - very electron rich, but also unstable - R = tBu - very electron rich and stable 2) Are free NHC subject to the same fate as free phosphines? N N 3) Promise held by NHC for oxidation chemistry. R = H R = tBu
3 Baran Lab N - H e t e r o c y c l i c C a r b e n e s ( N H C s ) K. J. Eastman
NHC as a ligand for the stabilization of high-oxidation-state metals: Recent independent studies by Stahl and Kawashima show NHCs playing a role as stabilizing ligands in palladium oxidation reactions (J. Am. Chem. Soc. 2001, 123, 7188-7189, J. Am. Chem. Soc. 2004, - stable complex below -20 oC CH3 N N 126, 10212-10213 and J. Am. Chem. Soc. 2005, 127, 7294-7295.) - NHC NOT oxidized at -60 oC Re N X O (NHC)2Re(CH3)O3 II O THF, -60 oC - phosphines are rapidly HOOH Pd SH O N X 2 oxidized with MTO MTO Herrmann et al. J. Organomet. Chem. 1994, 480:C7 2HX Sox + 2 HX N O N A number of additional high-valent metal complexes have been PdII Pd0 stabilized with NHCs: N O N Cl-
N N MesN NMes N N N N O2 O Cl Cl O O Cl O Cl W N U Mo N N Mo N Ar O Cl N N N Cl Cl Ar Ar O O O N MesN NMes N N N ArN + O O Pd 2 Pd ArN O Ar Ar N N - first cationic Mo(VI) N complex Ar - stability of these metal-complexed NHCs relative to phosphines will permit further analysis of these fundmental reactions Ph N Cl PMe Ph Mes Cl 2 N Ph N N Re Cl NHCs have been found to be useful with cobalt and nickel as stabilizing Cl PMe Ph V U O 2 N Re N N N Cl ligands for oxidation (allylic oxidations). N O N N N Mes Cl N Ph NPh N However, sterically hindered bis-carbene complexes of Cu(I) undergo Ph Ph Ph Ph rapid oxidation: - first examples of NHC-coordinated metal-oxo complexes characterized R R R by X-ray crystallography N N N O2 Cu1 2 O N N CH2Cl2 N R R R R = ethyl, allyl, benzyl NHCs are not yet universally applicable to metal-mediated oxidation
4 Baran Lab N - H e t e r o c y c l i c C a r b e n e s ( N H C s ) K. J. Eastman
Oxidation Reactions Catalyzed by NHC-Coordinated Metal Complexes Oxidative Cleavage of Alkenes: (Crabtree and PersisOrganometallics 2003, Opppenauer-Type Alcohol Oxidation:(Yamaguchi et al. Organometallics 22, 1110-1114) 2004, 23, 1490-1492) N N N R Br N Ir OTf N N Ru OTf nBu Br nBu O N CO OH O R O OH
NaIO4 Ph Ph O O - smaller R-substituents promoted catalytic activity " - R = Me - cat. loading = 0.025 mol % w/ 3200 turnovers - Analogs with PPh3 or PnBu3 ligands were not active " Palladium-Catalyzed Aerobic Alcohol Oxidation: (Sigman et al. J. Org. Chem. O 2005, 70, 3343-3352)
N N O Ar Ar " O Pd O R R O O OH O " O H H O O /air Ph 2 Ph O - A single NHC ligand can withstand the aerobic oxidation conditions O - small reaction scope - electron-deficient alkenes appear - Suggesting, despite numerous cycling between PdII and Pd0, the to react slower than electron-rich alkenes ligand does not dissociate from the palladium center - evidence supports the NHC-Ru complex remaining in tact Wacker-Type Oxidation: (Muniz, K. Adv. Synth. Catal. 2004, 346, 1425 –1428) during the reaction Oxidation of Methane: (Herrmann and Strassner Angew. Chem. Int. Ed. 2002, 41, 1745-1747) N N IMesPd(TFA)2
toluene, O , 80 oC N Pd N OH 2 O X X - Nitrogen-containing heterocycles have been prepared similarly CH4 + CF3COOH CF3COOCH3 - seven membered NHC ligands have been successfully employed K2S2O8 2 KHSO4 80 oC - Chelating nitrogen ligands did not work under comparable conditions - Yield is only 2-3 times higher than with Pd(OAc)2 without ligands
5 Baran Lab N - H e t e r o c y c l i c C a r b e n e s ( N H C s ) K. J. Eastman
Palladium Catalyzed Reactions (Other than Oxidations) Using NHCs !-"rylation of Malonitrile: (Huang et al. Chem. Commun. 2003,1444–1445)
2.3-3.5 mol % Allylic Alkylation: (Mori et al. Org. Lett. 2003, 5, 31-33)
N N
. Pd2(dba) CHCl3 (2.5 mol %) MeO C CO Me Cl- OAc 2 2 CO2Me IPr.HCl R CN Pd (dba) (1-1.5 mol %) R CN Ph Ph Cs CO (2.1 equiv) 2 3 CO2Me 2 3 Ph Ph X THF, 50 oC, 10 h o 100 % CN NaH, py, 85 C CN - no conversion in the absence of the NHC ligand 45-94 % - asymmetric version has been reported (Organometallics 2003, 22, 4187-4189) - aryl chlorides were low yielding - rxn can be run in THF when using aryl iodides
Heck reaction: (Herrmann et al. Angw. Chem. Int. Ed. 1995, 34, 2371-2374)
Borylation of Aryl Chlorides: (Furstner et al. Org. Lett. 2002, 4, 541-543) Pd(OAc) (2 mol %) 2 COOtBu R1 COOtBu IMes.HCl (4 mol %) R1 Pd(OAc)2 (3-6 mol %) Cl O O . O Cs2CO3 (2 eqiv) IPr HCl (6 mol %) o R Cl B B R B DMAc, 120 C 91-100 % st O O KOAc (2.5 eqiv) O - 1 catalytic application of Pd-NHC complexes THF, heating - considered a standard for new palladium systems - first general NHC/palladium cat. coupling of ArX with pinacolborane (for reactivity and stability - long rxn times/harsh conditions) - more mild conditions can be used with aryl-diazonium salts (r.t./no base) - mixed-carbene phosphine ligands have been developed
- r.t. and short reaction times with diazonium salts !-Arylation of Carbonyl Compounds: (Nolan et al. Tetrahedron 2005, 61, 9716-9722) Hiyama Reaction: (Nolan et al. Organic Letters 2000, 2, 2053-2055) O (IPr)Pd(acac)Cl O R1 (1 mol %) R1 Cl 3 Pd (dba) (3 mol %) R R3 2 3 NaOtBu (1.5 equiv) IPr.HCl (3 mol %) 2 o 2 R Toluene, 60 C R R X (MeO)3Si R 70-97 % TBAF (2 equiv) o - short reaction times of 1-3 h with one exception (10 h) THF, 1,4-dioxane, 80 C quant. when R = EWG or H - moderate temperature - has been extended to esters (J. Am. Chem. Soc. 2001, 123, 8410- 8411) and amides (J. Org. Chem. 2001, 66, 3402-3415) by Hartwig
6 Baran Lab N - H e t e r o c y c l i c C a r b e n e s ( N H C s ) K. J. Eastman
Kumada-Tamao-Corriu Reaction: (Nolan et al. J. Am. Chem. Soc. Stilli Reaction: (Herrmann et al. J. Organomet. Chem. 1999, 585, 348-352) 1999, 121, 9889-9890) (1 mol %) Pd2(dba)3 (1 mol %) R1 R2 . 2 Ph Ph IPr HCl (4 mol %) R1 R N N Cl BrMg THF/p-dioxane 80 oC I Pd I - first successful coupling between unactivated aryl chloride with ArMgBr PPh3 R Br Bu3Sn R - NHCs are also efficient ligands for the palladium-catalyzed coupling of Toluene, 110 oC primary alkyl halides with ArMgBr (J. Organomet. Chem. 2003, 687, 403-9) R = H, ketone or ether 82-91 % Negishi Reaction: (Organ et al. Org. Lett. 2005, 7, 3805-3807) - this transformation remains largely unexplored with NHC ligands
Pd2(dba)3 (2 mol %) Suzuki-Miyaura Reaction: (Buchwald et al. Angew. Chem. Int. Ed. 2004, . Br IPr HCl (8 mol %) 43, 1871-1876) (nBu)ZnBr 5 THF/NMP (2:1) Pd(OAC)2 (3 mol %) 77 % IBiox12 (3.6 mol %) - one noteworthy point is the good functional group tolerance: esters Cl (HO)2B nitriles, amides, alkynes, and acetals! K3PO4 (3 equiv) Toluene, 110 oC Sonogashira Reaction: (Batey et al. Org. Lett. 2002, 4, 1411-1414) 96 % - greater than 15 papers on this transformation with NHCs Pd(OAc)2 (3 mol %) - first report of tetra-ortho-substituted biaryl coupling from . IMes HCl 6 mol %) aryl chlorides R CuI (2 mol %) R Br H Cs2CO3 (2 equiv) Buchwald-Hartwig Reaction: (Nolan et al. Org. Lett. 2003, 5, 1479-1482) DMAc, 80 oC R = Me or OMe = 86-93 % Ar - there is currently no efficient application of carbene ligands to the Cl N coupling of aryl chlorides! Pd - a method for cross-coupling of unactivated, !-hydrogen containing N NMe2 alkyl electrophiles using NHCs has been described (J. Am. Chem. Soc. Ar 2003, 125, 13642-13643) 2 1 2 R1 R (1 mol %) R R - bulky ligands work best, phosphine ligands don't work! Cl H N N R3 NaOtBu (1.1 equiv) R3 1,4-dioxane, r.t. - reaction can be carried out in 2 h at room temperature with ArCl
7 Baran Lab N - H e t e r o c y c l i c C a r b e n e s ( N H C s ) K. J. Eastman
Tandem Coupling Reaction: (Ackermann, L. Org. Lett. 2005, 7, 439-442) Routes to NHC Complexes
Insertion of a Metal into the C=C Bond of Bis(imidazolidin-2-ylidene) Olefins R2 Pd(OAc) (5 mol %) 2 R1 R1 IPr.HCl (5 mol %) R R 3 2 N N R H2N R R R N H -HCCl N ML N N KOtBu (3 equiv) N 3 n R R o Cl Toluene, 105 C R3 " R R x 66 - 98 % N CCl3 N N N MLn-x - reaction proceeds via amination with short reaction times - 2 h R R x = 1-4 - Wanzlick's attempt at obtaining NHC - postulated equilibrium Dehalogenation Reactions: (Nolan et al. Organometallics 2001, - basis for preparation of NHC complexes from electron rich alkenes 20, 3607-3612) - all NHC obtained this way are saturated Use of Carbene Adducts or "Protected" Forms of Free NHCs Pd(II) + NHC.HCl
base + MLn N N ArH ArX R R N N (NHC)Pd - HY, -L R R Y H MLn-1 Y = OR' of CCl3 Ar Ar LnPd LnPd - readily eliminate alcohol or chloroform to give carbene H X - it is not clear whether the so formed NHC reacts with the metal or if the adduct first dimerizes and subsequently complexes with aldehyde Ar RO- or LnPd the metal. OR - ketone X
X- . LiBEt3H - SIMes HCl works well for bromides and chlorides at high temperature N N N N Mo(CO)6 N N R R R R R R - the use of a base containing a !-hydrogen is essential THF, -78 oC "/Toluene - aryl chlorides have been removed with (IPr)Pd(allyl)Cl at low catalyst H BEt3 Mo(CO)5 loading (0.5-0.025 mol %) and moderate temperature (60 oC) Yamaguchi et al. Chem. Commun 2004, 2160-2161 (J. Org. Chem. 2004, 69, 3173-3180) - the NHC-borane adduct can be used as a versatile stable synthon for the preparation of NHC complexes.
8 Baran Lab N - H e t e r o c y c l i c C a r b e n e s ( N H C s ) K. J. Eastman
Preformed, Isolated Free Carbene: Deprotonation with Metal Complex Containing Basic Ligand:
+ - Cl- NaH or KOtBu 2 2X N N N N N R R R R N N N N !, -HOAc H !, -HOAc H N + Pd(OAc) O- N isolate and use H 2 N I Pd I H - Arduengo's work shattered the idea that NHC were too unstable N Pd O Me N I - Initially thought to be stable due to STERICS, but now it is assumed N N I ELECTRONICS play a more important role (unsaturated more stable) - Advantage - can be used directly to replace labile ligands - convenient method - many metal complexes with acetate, hydride, or acetylacetonate ligands are $ or easy to make In Situ Deprotonation of Azolium Salt with a Base Transmetallation from a Silver-NHC Complex: Deprotonation with an External Base: (Fehlhammer et al. J. Organomet. Chem. 1995, 490, 149-153) 2+ 2X- + - N N 2 2X R R N N N 1) nBuLi + - Ag N N N X 2) PdI2 H X XMLn Pd N N N N H - nBuH, - LiI R R or R R N N N ML N N N H + Ag O N N n 2 R R + AgX - mono, bi and tridentate NHC ligands have been prepared this way - 1/2 Ag (AgX2) - use of strong base is convenient BUT can't use in presence of R R other (than C-2) acidic or electrophilic center N N + X- MLn N N N N N N - weak NHC-Ag bond makes this reagent a good transfer reagent R R R R R R -L - overcomes the difficulty associated with strong bases, inert + H MLn-1 atmosphere and complicated workups + Et3N [Et NH]+ 3 high yields! - complexes with Au, Cu, Ni, Pd, Pt, Rh, Ir or Ru - lability of NHC-Ag bond and insolubility of the silver halide are driving forces for reaction - pKa values 25.6 - 39.1 (most basic phosphine pKa = 10) - saturated NHCs are relatively inactive in this process - thermodynamics ??? this equilibrium needs to be studied
9 Baran Lab N - H e t e r o c y c l i c C a r b e n e s ( N H C s ) K. J. Eastman
Oxidative Addition Via Activation of the C2-X Bond (X = Me, Halogen or H): Chiral NHCs as Stereodirecting Ligands in Asymmetric Catalysis: (Yates et al. J. Am. Chem. Soc. 2001, 123, 8317-8328) Five Major Families of Chiral NHC Ligands: 1) NHC ligands with N-substitutents containing centers of chirality Pt(PPh3)4 N 2) NHC ligands containing chiral elements within the N-heterocycle - (BF4 ) Ph P 3) NHC ligands containing an element of axial chirality 3 N 4) NHC ligands containing an element of planar chirality Ph Pt I PPh3 5) NHC ligands incorporating oxazoline units Cy Cy (BF -) 4 P N N O 1) NHC Ligands with N-Substitutents Containing Centers of Chirality: Pd (Herrmann et al. Angew. Chem. Int. Ed. 1996, 35, 2805-2807) I P Ph Cy N Cy - (BF4 ) Cy Cy P N 1) NaH/NH3 R R pd R R 2) [RhCl(cod)] N N N N 2 P I - Rh Cl Cy Cy Cl Less Utilized Methods of Complex Formation: R = Ph or !-napht
Transmetallation of Lithiated Heterocycles: - initially these types of ligands showed good activity but poor R stereoselectivity - free rotation about C-N axis? N N N N - newer catalysts work very well for Michael additions (>90 % ee) nBuLi MXLn R-Cl Li MLn MLn - bidentate ligands improve enantioselectivity N N N N - some derived from amino acids
R = H or alkyl 2) NHC Ligands Containing Chiral Elements Within the N-Heterocycle: Via the C2 Carboxylate or Ester: (Crabtree et al. J. Am. Chem. Soc. 2005, (Grubbs et al. Org. Lett. 2001, 3, 3225-3228) 127, 17624-1765) [RhCl(cod)] KOtBu, CO2 2 N N R R Mes Mes R R R R HC(OEt) + X- ArBr 3 MeCN, Mes Mes o 75 C N NH BF O O H N NH Pd(OAc)2 Ar NH HN Ar 4 4 N N 2 2 binap Ar Ar N - H NaOtBu BF4 [RhCl(cod)] , N 2 Rh Cl Mes K CO 1) NaH, MeCN N N 2 3 - more bulk at R(s) forces Ar onto reactive center for better ee's Mes Mes Mes - ortho-monosubstituted N-aryl substituents in the carbene ligands lead 2) isobutyl- MeCN, to greater selectivity than more symmetrically substituted derivatives chloroformate 80 oC O O - ee's are very good overall
10 Baran Lab N - H e t e r o c y c l i c C a r b e n e s ( N H C s ) K. J. Eastman
3) NHC Ligands Containing an Element of Axial Chirality: (RajanBabu et al. 5) NHC Ligands Incorporating Oxazoline Units: (Herrmann et al. Org. Lett. 2000, 2, 1125-1128) Organometallics 1998, 17, 2162-8) 2+ 2 X- - Cl- Cl O 1) EtOH, N Cl C N C N Br N N N NaOEt (1 mol %) 1) imidazole, NaH N N N N N 2) H N OH 2) MeI R 2 R' Br N R R N R , HCl (cat.) - this ligand has been coordinated to rhodium (I) and palladium (II) - first example of an axially chiral NHC complex - can be complexed with Pd by refluxing in DMSO - good illustration, but no activity - too much flexibility in 11-mem. ring - direct functionalization on BINAP gives better results (bidentate) Ar I- N N - N N 1) [IrCl(cod)]2, BARF 4) NHC Ligands Containing an Element of Planar Chirality: (Bolm et al. DMF LiOtBu, THF N Organometallics 2002, 21, 707-710) (A: Togni et al. Helv. Chim. Acta. 2002, N N Ar Ir N 2) NaBARF, O 85, 2518-2522) Ar I O O CH2Cl2, H2O O- SiMe O- SiMe 3 3 N R R B S+ S+ 1) LiN(iPr)2 1) tBuLi R Fe Fe Fe OH Burgess et al. J. Am. Chem. Soc. 2001, 123, 8878-8879 2) Me3SiCl 2) DMF 3) NaBH4
Me3Si R ee (%) yield (%) N N O B (0.6 mol %) Ph 13 25 Fe SiMe Fe N N Ar = 2,6-(iPr) C H 3 N N 2 6 3 CHPh2 25 12 A Ph Ph tBu 50 81 Ph H2 (50 bar) Ph 1-Ad 98 99
SiMe3 SiMe3 SiMe3 NaH, - inspired by the chiral bidentate phosphine-oxazoline ligands (Phox) tBuOK CH3I Fe N Fe N Fe N - this design allows for facile and rapid access to a large library of ligands through variation at C-2 (oxazoline) and N-atom of NHC N N I- N - this ligand has been successfully employed in the cat. hydrogenation - first example of an NHC complex containing planar chirality of dienes (Burgess et al. Chem. Commun. 2005, 672-674) - again, good illustrations, but no reported activity yet - directly linked ferrocene derivatives wok well - paracyclophanes show promising results
11 Baran Lab N - H e t e r o c y c l i c C a r b e n e s ( N H C s ) K. J. Eastman
NHC-Ruthenium Complexes in Olefin Metathesis: - greater stability (to air) better activity than Grubbs I - reactivity in some cases surpasses Schrock's catalyst F3C Ph - useful for tri- and tetrasubstituted olefins F3C PCy3 Cl - good E/Z selectivity depending on catalyst (E or Z) PCy3 Ru Cl - Grubbs II most active - saturated = more basic = more reactive Mo Ru Cl N Cl Ph O PCy3 Viable phosphine-free catalysts: (Hoveyda et al. J. Am. Chem. Soc. 2000, F3C 122, 8168-8179)(Blechert et al. Tet. Lett. 2000, 41, 9973-9976) F3C
Schrock's catalyst Grubbs I Hoveyda-Grubbs N N O Mes Mes N N - Grubbs I is less active than Schrock's catalyst Mes Mes Cl - Grubbs I has greater functional group tolerance Ru Cl Cl Ru - Grubbs I has relatively low thermal stability CuCl, CH2Cl2, Cl Ph reflux O - How to make it better??? - mechanism? PCy3 First attempt at NHC ligated cat. for RCM: (Herrmann et al. Angew. Chem. Grubbs II A Int. Ed. 1998, 37, 2490-2494) - now one of the most widely used catalysts for metathesis - works in CM for electron-deficient olefins (high yield, selectivity) N N R R PCy N N - works, but no improved 3 R R Cl Cl catalytic activity vs Grubbs I CN Ru CF3 O O O O Ru - perhaps a combo of NHC O O NC Cl Ph Cl Ph A, 5 mol % A, 5 mol % PCy R R 3 N N and phosphine is the key CH Cl , F3C trifluorotoluene, 2 2 45 oC 45 oC Combination catalysts for RCM: CO2Me CO2Me CO2Me Blechert et al. Chem. Commun. 2001, 1692-1693 Blechert et al. Synlett 2001, 430-432 N N Cy Cy Additional Variations: N N Cl N N R R Ru Mes Mes - Chiral Grubbs II Cl Cl Ph Cl - Chiral phosphine free Grubbs II Ru Cl Cl Ru - Solid supported NHC-Ru complexes Cl Ph Ru Cl Ph PCy3 PCy3 - Immobilization via the NHC Ligand Grubbs II - Attachment through the anionic ligand - Homogenous catalysts Nolan et al. J. Am. Chem. Herrmann et al. Angew. Chem. Grubbs et al. Org. Lett. Soc. 1999, 121, 2674-2678 Int. Ed. 1999, 38, 2416-2419 1999, 1, 953-956 - Ionic liquids Furstner with Hermann Tet. Lett 1999, 40, 4787-4790
12 Baran Lab N - H e t e r o c y c l i c C a r b e n e s ( N H C s ) K. J. Eastman
N-Heterocyclic Carbenes as Organocatalysts: - a great deal of effort has gone into preparing asymmetric versions of the thiazolium salts with marked success in inducing chirality: (Sheehan Benzoin Condensation: et al. J. Am. Chem. Soc. 1966, 88, 3666-3667; Sheehan et al. J. Org. Chem. Soc. 1966, 39, 1196-1199; Takagi et al. Bull. Chem. Soc. Jpn. It's been known that cyanide anions catalyze the benzoin condensation 1980, 478-480; Marti et al. Tet. Lett. 199, 521-524; Leeper et al. Tet. Lett. since 1832: (Wohler, F. Liebig. J. Ann. Pharm. 1832, 3, 249-282) 1997, 3611-3614; Leeper et al. Tet. Lett. 1997, 3615-3618; Rawal et al. 1998, 2925-2928; Leeper et al. J. Chem. Soc. Perkin Trans. I, 1998, 1891- The mechanism was elucidated in 1903: (Lapworth, A. J. J. Chem. Soc. 1893) 1903, 83, 995-1005) - surprisingly it was only recently (2003) that an intramolecular version of the NHC catalyzed acyloin condensation appeared: (Suzuki et al. J. Am. The first report on carbene organocatalysis appeared in 1943: (van den Chem. Soc. 2003, 125, 8432-8433) Berg, H. J. J. Mol. Cat. 1943, 51, 1-12) OH Despite a good deal of debate, Breslow's 1958 description of the mechanism N S is still generally accepted: (Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-26) MeO Br- (5-20 mol %) OH O N O N OMe DBU (10-70 mol %) N Cl- H tBuOH, 40 oC S 1 N N R1 O 79-96 % R OH O 2 thiamin O R2 R O O NH2 B Ph BH+ - the benzoin condensation can be catalyzed by a large number of NHCs * Ph H Ph ranging from chiral complexes to simple ionic liquids OH thiamin: B Stetter Reaction:
O- H OH - simply extending the benzoin condensation to Michael acceptors thiamin+ Ph - well known for the formation of 1,4-diketones, but also works for the OH thiamin+ Ph preparation of 4-ketoesters and 4-ketonitriles Ph O proton transfer OH OH R1 H + thiamin+ Ph thiamin BH O cat., base - CN O Ph 2 R2 X R Ph 2 R2 O R O R1 R1 CN X Ph H O O
13 Baran Lab N - H e t e r o c y c l i c C a r b e n e s ( N H C s ) K. J. Eastman
Generation of Homoenolates: [PdCl (PPh ) ] (2 mol %) OH 2 3 2 O CuI (1 mol %) Ar1 Br - 2 Et N, heat 1 2 N N O Ar 3 Ar Ar O Ar Ar Ar H N R R H OH R N N S Ar RNH N Ar2 O 2 Ar3 Ar2 I- (20 mol %) O AcOH, ! OH Ar OH Ar O Ar1 Ar3 1 N N Ar R R 3 40-59 % Ar H N N Muller et al. Org. Lett. 2001, 3, 3297-3300 Ar Ar - the Stetter reaction is commonly employed in the synthesis of cyclopentanone homoenolate derivatives and heterocycles - above is an example of a one-pot four-step procedure to a pyrrole derivative - Glorius (Angew. Chem. Int. Ed. 2004, 43, 6205 –6208) and Bode (J. Avoiding homocondensation: Am. Chem. Soc. 2004, 126, 14370-14371) have both shown that it is S N necessary to carefully adjust the steric bulk of the NHC R2 O - O O O - O - R1 O 1 R SiR3 S O S HO R3Si R1 R1 N N N N N N R2 R2
IMes - works well IPr = unselective R'OH OH OSiR3 S S O O R1 R1 N N N N N N R2 R'OSiR R2 CO2 3 TfO-
ICy - not reactive enantioselective = (25 % ee) - employ carbonyl anion precursors such as "-keto carboxylates or acylsilanes
14 Baran Lab N - H e t e r o c y c l i c C a r b e n e s ( N H C s ) K. J. Eastman
SO2Ar 2 1 R R O N O O R Glorius et al. Angew. Chem. Int. Ed. 2004, 43, 6205 –6208 R Bode et al. J. Am. Chem. Soc. 2004, 126, 14370-14371 Bode et al. Org. Lett. 2005, 7, 3131-3134
SO2Ar O N O 1 R PG R H R2 H O N R O (w/ KOtBu) PG O R3 N R Bode et al. Org. Lett. 2005, 7, 3873-3876 R H H R3 OH Ar Bode et al. J. Am. Chem. Soc. 2006, 128, 8418-8420 N R obtained as a function N of reaction conditions Ar homoenolate Nu H O 5 R H O (w/ DIPEA) R4 R5 mechanism? O O R Nu O R Bode et al. Org. Lett. 2005, 7, 3873-3876 R4 N Ph N Scheidt et al. Org. Lett. 2005, 7, 905-908 Nair et al. J. Am. Chem. Soc. 2006, 128, 8736-8737
H R1 O O O O O N N R R Ph R1 Glorius et al. Angew. Chem. Int. Ed. 2004, 43, 6205 –6208 (ketones don't work) Scheidt et al. J. Am. Chem. Soc. 2007, 129, 5334-5335 Nair et al. Org. Lett. 2006, 8, 507-509 (vicinal diketones do work)
15 Baran Lab N - H e t e r o c y c l i c C a r b e n e s ( N H C s ) K. J. Eastman
Fu's extension to !, "-unsaturated esters: (J. Am. Chem. Soc. 2006, 128, Movassaghi's amidation of unactivated esters with amino alcohols: (Org. Lett. 1472-1473) 2005, 7, 2453-2456) Ar O Mes Mes #$ O N R1 N N 1 N O R OMe O H NHR2 #+ H O OMe CO2Et N Ph N N Ar OEt Mes Mes base+-H NHR2 MeOH Nu: HO base X NHR2
Mes Mes $ # O 1 O- N N R O H Me #+ H O O EtO C Nu+ OEt 2 N N OMe
+ Mes Mes Nu 2 O - N R O 2 acyl transfer NHR 1 X N R NHR2 O HO R1 O O X- OEt Ring Opening Reactions: Ring-opening polymerization:
Nu+ N N O X O O O- - interestingly neither the imidazolium or thiazolium NHCs worked RO O H - phosphines also proved ineffective - this is in sharp contrast to their O O n ability to cat. alkylation of unsaturated ketones (!-position) O O O Transesterification and Acylation reactions: O O - Nolan (Org. Lett. 2002, 4, 3583-3586) and independently Hendrick (Org. O N N RO O H Lett. 2002, 4, 3587-3590) showed NHCs effectively catalyzed trans- O n+1 esterification reactions O THF - Functional group tolerance, selectivity, and low catalyst loading are ionic liquid advantages of this approach - this reaction has been extended to secondary alcohols (Nolan et al. J. tBuOH N N + - Org. Chem. 2004, 69, 209-212) BF4 KBF4 KOtBu
16 Baran Lab N - H e t e r o c y c l i c C a r b e n e s ( N H C s ) K. J. Eastman
Ring-Opening Reactions of Three-Membered Rings: Nucleophilic benzoacylation: (Suzuki et al. Chem. Commun. 2003, 1314-1315)
- In 2001, Nguyen reported (Org. Lett. 2001, 3, 2229-2231) that O N N O NHCs can promote the ring opening of epoxides by trialkylaluminum F I- complexes H (25 mol %) - In 2006, Wu established (Tet. Lett. 2006, 47, 4813-4816) that NHCs are EWG R EWG R NaH, DMF efficient catalysts for the ring opening of aziridines by silylated nucleophiles. 36-60 % - Chen and co-workers have made a very interesting observation regarding the reaction of aziridines and aldehydes in the presence of an NHC cat. - moderate yields, but this cannot be accomplished via classic and oxygen (Org. Lett. 2006, 8, 1521-1524) Friedel-Crafts reaction - chloroarenes are inert under the reaction conditions
N N Facile splitting of hydrogen and ammonia: (Bertrand et al. Science 2007, 316, Cl- 439-441) O 1 (20 mol %) R 1 R O R R1 - typically the realm of transition metals K2CO3, 18-crown-6 R N Ts + RCHO + 1/2 O2 not H2 O (iPr)2N o (iPr)2N 50 C R2 NHTs 2 R2 R3 3 R NHTs R R3 H H
Mechanism? R R H2 1,2-Addition reactions: N N Dipp R Dipp R OH H H H2 N N R CF3 OTMS tBu tBu no rxn - H TMS CF3 H+ R CN H2 H (iPr)2N N(iPr)2 no rxn O O- NHC: TMS-CN + R H R NHC H+ NH3 (iPr) N (iPr) N 2 O OH 2 O H NH2 (EtO)2P CN P(OEt) R CN 2 H R R O NH3 N N R CN Dipp R Dipp R H H NH2
17 Additional References:
1) Nolan et al. Angew. Chem. Int. Ed. 2007, 46, 2988-3000
2) Nolan, S. P. N-Heterocyclic Carbenes in Synthesis; Wiley-VCH; Weinheim, 2006, pp 1-304
3) Glorius, F. N-Heterocyclic Carbenes in Transition Metal Catalysis; Topics in Organometallic Chemistry; Springer-Verlag: Berlin Heidelberg, 2006, Vol. 21, pp 1-218