Baran Lab N-Heterocyclic Carbenes (NHCs) 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<imidazole<imidazoline (order of electron donating power).
crystalline NHC IAd.
NHC-metal complex stability:
NaH, DMSO,
MeOH
N N N N + H2 + NaCl NHCs form very strong bonds with the majority of metals (stronger than
Cl- phosphines!)
H
IAd
N-heterocyclic carbenes are electronically (orbital overlap) and sterically
(Me vs. Ad) stablilized. N N N N + MLn
R R R R

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

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 Baran Lab N-Heterocyclic Carbenes (NHCs) K. J. Eastman

NHCs are most frequently prepared via deprotonation of the corresponding c) unsymmetrical synthesis of imidazolidinium salts:
azolium salts (imidazolium, triazolium, tetrazolium, pyrazolium, benz- Ar1NH2, Et3N, Ar2NH2,
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) BH3-THF, reflux
HC(OEt)3
1) Existing imidazoles can be alkylated with appropriate electrophiles. 2) conc. HCl X-
Ar1H2N NH2Ar2 N N
120 oC Ar1 Ar2
2 Cl-
2) The imidazolium ring can be built:
d) unsymmetrical synthesis of imidazolium salts:
R4 O OEt
a) symmetric synthesis:
O O O HX, -H2O
Cl- HO R5 Br A OEt
R NH2 N N
R R R1NH
H H H H 2,
R1NH2,
cat. HCl,
nBuLi,
toluene,
then A
reflux
R N N R Cl OEt R4 O OEt

H H O
, (AgOTf) R1 NH R5 R1 NH OEt
Cl O tBu
1) HCOOH, Ac2O
MeC(O)OC(O)H
2) HCOOH
b) unsymmetrical synthesis:

R4 O R5 OAc O
O O O HX, -H2O R2 X X- R4
N N Ac2O, HX Ac2O, HX
R1 NH2 + NH3 N N R1 R2
R1 R1 N R5 X- O R1 N H
H H H H N
O O
H H
base R2NH 2
N N R1 X
H
R1 = alkyl
R5 OH R5
R4 R4
HX
Furstner et al. Chem. X- N R2 X- N R2
Commun. 2006, 2176-2178 N N
R1 R1

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 Baran Lab N-Heterocyclic Carbenes (NHCs) K. J. Eastman

Different Monodentate NHC Ligand Classes:

4-membered NHC - stable benzannulated imidazolin-2-ylidene

N N R2 - R1 steric influence is in very close proximity to metal
iPr NiPr iPr R1
P - Grubbs
N N - bulk required for stability
H
- less reactive/! donating
base
iPr iPr
N N R2 N N R2
5-membered NHC
(R1)H X- (R1)H X-
R(H) R(H)
R1, R2 R1
N N
R2 R1
N N
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
1-adamantyl IAd R2 R2

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
R1, R2 = (CH2)4 : IBiox 5
R1, R2 = (CH2)5 : IBiox 6 NHC as ligands for high-oxidation-state metal complexes and oxidation
R1, R2 = (CH2)6 : IBiox 7 catalysts:
R1, R2 = (CH2)7 : IBiox 8
R1, R2 = (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-Heterocyclic Carbenes (NHCs) 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 (NHC)2Re(CH3)O3 N X
O O - phosphines are rapidly HOOH PdII
O THF, -60 oC SH2
N X
MTO
oxidized with 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
Cl O Cl Cl N N N
Ar Ar
O O O
N MesN NMes N N N ArN O
Pd + O2
Pd
ArN O
Ar Ar
- first cationic Mo(VI) N N
N
complex Ar

- stability of these metal-complexed NHCs relative to phosphines

will permit further analysis of these fundmental reactions
Ph N
Mes Cl Cl PMe2Ph N Ph
N Cl N Re Cl NHCs have been found to be useful with cobalt and nickel as stabilizing
U O PMe2Ph Re N
V
N N Cl N ligands for oxidation (allylic oxidations).
N O N N N
Mes Cl N Ph N
NPh
Ph Ph
However, sterically hindered bis-carbene complexes of Cu(I) undergo
Ph Ph rapid oxidation:
- first examples of NHC-coordinated
metal-oxo complexes characterized R R R
by X-ray crystallography N N O2 N
Cu1 2 O
N N CH2Cl2 N
R R R
R = ethyl, allyl, benzyl
NHCs are not yet universally applicable to metal-mediated oxidation

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 Baran Lab N-Heterocyclic Carbenes (NHCs) 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
N Br N
N Ir OTf
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 H O "
H O
O2/air O
Ph Ph
- 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, O2, 80 oC N Pd N
OH 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-Heterocyclic Carbenes (NHCs) 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).CHCl 3 (2.5 mol %) MeO2C CO2Me Cl-
OAc CO2Me IPr.HCl
R CN Pd2(dba)3 (1-1.5 mol %) R CN
Ph Ph CO2Me Cs2CO3 (2.1 equiv) Ph Ph X
THF, 50 oC, 10 h 100 % NaH, py, 85 oC
CN CN
45-94 %
- no conversion in the absence of the NHC ligand
- 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 (2 mol %)
COOtBu
R1 COOtBu IMes.HCl (4 mol %)
Pd(OAc)2 (3-6 mol %) Cl R1
O O O Cs2CO3 (2 eqiv)
IPr.HCl (6 mol %)
R Cl B B R B DMAc, 120 oC 91-100 %
O O KOAc (2.5 eqiv) O - 1st 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 R3 Pd2(dba)3 (3 mol %)
NaOtBu (1.5 equiv) R3
IPr.HCl (3 mol %)
R2 Toluene, 60 oC R2 R X (MeO)3Si R
70-97 % TBAF (2 equiv)
- short reaction times of 1-3 h with one exception (10 h) THF, 1,4-dioxane, 80 oC 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-Heterocyclic Carbenes (NHCs) 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 IPr.HCl (4 mol %) R1 R2 Ph Ph
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 NMe2 N
alkyl electrophiles using NHCs has been described (J. Am. Chem. Soc. Ar
2003, 125, 13642-13643) R1 R2 (1 mol %) R1 R2
- 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-Heterocyclic Carbenes (NHCs) 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)2 (5 mol %)
R1
R1 IPr.HCl (5 mol %) R R
R3H2N R2 N N
N H N R R MLn N N
KOtBu (3 equiv) -HCCl3 R R
N
Cl Toluene, 105 oC 3 x
66 - 98 % R N CCl3 "
N
R
N N
R MLn-x
R R x = 1-4
- reaction proceeds via amination with short reaction times - 2 h
- 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
ArH ArX N N N N
R R R R
(NHC)Pd - HY, -L
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 X-
ketone

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-Heterocyclic Carbenes (NHCs) 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)2 O- N
isolate and use H
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- 2+ 2X- N N
R R
N N N
1) nBuLi + X- Ag
N 2) PdI2 N N
H X XMLn
Pd N N N N
H - nBuH, - LiI R R or R R
N N N

N N N H MLn
+ Ag2O N N
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
other (than C-2) acidic or electrophilic center R
N N
R

+ 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
+ MLn-1 atmosphere and complicated workups
H + Et3N [Et3NH]+ - complexes with Au, Cu, Ni, Pd, Pt, Rh, Ir or Ru - lability of NHC-Ag
high yields!
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-Heterocyclic Carbenes (NHCs) 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-) 3) NHC ligands containing an element of axial chirality
Ph3P N
Ph Pt 4) NHC ligands containing an element of planar chirality
I PPh3 5) NHC ligands incorporating oxazoline units
Cy Cy
(BF4 -)
N N P
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)]2 N N
N N
P I
Cl- Rh Cl
Cy Cy
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 nBuLi N MXLn N R-Cl N - newer catalysts work very well for Michael additions (>90 % ee)
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)
KOtBu, CO2 [RhCl(cod)]2
N N R R
Mes Mes R R R R HC(OEt)3
+ X- MeCN, ArBr
Mes Mes
75 oC N NH4BF4
N O O H 2N NH2 Pd(OAc)2 Ar NH HN Ar Ar
N
Ar
N binap
H BF4 -
NaOtBu
[RhCl(cod)]2, Rh Cl Mes
N
1) NaH, MeCN N N
K2CO3 - more bulk at R(s) forces Ar onto reactive center for better ee's
Mes Mes Mes
2) isobutyl-
- ortho-monosubstituted N-aryl substituents in the carbene ligands lead
MeCN,
chloroformate to greater selectivity than more symmetrically substituted derivatives
80 oC
O O - ee's are very good overall

10
 Baran Lab N-Heterocyclic Carbenes (NHCs) 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
N C 1) EtOH,
Cl C N N
Br N N N NaOEt (1 mol %)
1) imidazole, NaH N N
N N N
2) H2N OH
2) MeI R 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
85, 2518-2522) 2) NaBARF, O
O Ar O CH2Cl2, H2O
O- I
SiMe3 O- SiMe3 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 SiMe3 Fe N N Ar = 2,6-(iPr)2C6H3 CHPh2 25 12
A N N
Ph Ph tBu 50 81
Ph H2 (50 bar) Ph 1-Ad 98 99

SiMe3 SiMe3 SiMe3

NaH,
tBuOK CH3I
- inspired by the chiral bidentate phosphine-oxazoline ligands (Phox)
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-Heterocyclic Carbenes (NHCs) K. J. Eastman

NHC-Ruthenium Complexes in Olefin Metathesis: - greater stability (to air) better activity than Grubbs I
F3C - reactivity in some cases surpasses Schrock's catalyst
Ph
F3C PCy3 - useful for tri- and tetrasubstituted olefins
Cl - good E/Z selectivity depending on catalyst (E or Z)
PCy3 Ru
Mo
Cl
Cl - Grubbs II most active - saturated = more basic = more reactive
Ru
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
- Grubbs I is less active than Schrock's catalyst Mes
N N
Mes Cl
Ru
- Grubbs I has greater functional group tolerance Cl Cl
- Grubbs I has relatively low thermal stability Ru CuCl, CH2Cl2,
Cl Ph O
- How to make it better??? - mechanism? PCy3 reflux

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
N N R R
- works, but no improved
PCy3 R R
Cl Cl catalytic activity vs Grubbs I
Ru CF3 CN
Ru O O O O NC O O
Cl Ph Cl Ph - perhaps a combo of NHC A, 5 mol % A, 5 mol %
PCy3 R
N N
R and phosphine is the key
F3 C trifluorotoluene, CH2Cl2,
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 - Chiral Grubbs II
R R Ru Mes Mes
Cl Cl Ph Cl - Chiral phosphine free Grubbs II
Ru Cl Ru
Cl - 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-Heterocyclic Carbenes (NHCs) 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
OH N Br- (5-20 mol %) O N OMe
O
DBU (10-70 mol %)
N
Cl-
H tBuOH, 40 oC
S
N N R1 O 79-96 % R1
OH
thiamin O R2 O
O O R2
NH2
B
* Ph BH+ - the benzoin condensation can be catalyzed by a large number of NHCs
Ph Ph H
ranging from chiral complexes to simple ionic liquids
OH thiamin:
B Stetter Reaction:
O- - simply extending the benzoin condensation to Michael acceptors
H OH
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
O- Ph CN
R2 X R2
Ph R2
R2 O
O
R1 R1 CN
X
Ph H
O O

13
 Baran Lab N-Heterocyclic Carbenes (NHCs) K. J. Eastman

Generation of Homoenolates:
[PdCl2(PPh3)2] (2 mol %)
OH O
CuI (1 mol %)
Ar1 Br
Et3N, heat Ar1 Ar2 N N O- Ar
Ar2 O Ar Ar
H
N
R
R H
OH R N
N S Ar
RNH2 N
Ar2 O Ar3 Ar2
I- (20 mol %) O AcOH, !
OH Ar OH Ar
O N N
Ar1 Ar3 Ar1 R
R
Ar3 H 40-59 %
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-
R1 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
CO2 R2 R'OSiR3 R2
TfO-

ICy - not reactive enantioselective = (25 % ee)

- employ carbonyl anion precursors such as "-keto carboxylates or
acylsilanes

14
 Baran Lab N-Heterocyclic Carbenes (NHCs) K. J. Eastman

SO2Ar
R1 R2 N
O
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
R O
PG R1 H R2 H
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
R5 H O
(w/ DIPEA)
R4 R5
mechanism? O O R Nu
R O
Bode et al. Org. Lett. 2005, 7, 3873-3876
R4 N
Ph Scheidt et al. Org. Lett. 2005, 7, 905-908
N
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-Heterocyclic Carbenes (NHCs) 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 R1 OMe N
O
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
O- N N R1
O
H Me #+ H O O
EtO2C Nu+ OEt N N OMe
Mes Mes
Nu+ O-N
R2 O
acyl transfer NHR2
X N R1 NHR2
O HO R1 O
O
X- OEt Ring Opening Reactions: Ring-opening polymerization:
Nu+
N N
O
X
O
O O- RO O H
- interestingly neither the imidazolium or thiazolium NHCs worked
- phosphines also proved ineffective - this is in sharp contrast to their O O n
ability to cat. alkylation of unsaturated ketones (!-position) O
O
Transesterification and Acylation reactions: O
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
O THF
esterification reactions
- 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) KOtBu
BF4-
KBF4

16
 Baran Lab N-Heterocyclic Carbenes (NHCs) 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 %)
EWG R EWG R
- In 2006, Wu established (Tet. Lett. 2006, 47, 4813-4816) that NHCs are 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)
(20 mol %) O
R1
R1 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
50 oC (iPr)2N
R2 NHTs R2 NHTs
R2 R3 R3 R3 H H
Mechanism? R R
H2
1,2-Addition reactions: N
Dipp Dipp N
R R
OH
H H
H2
R CF3 OTMS tBu N N 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)2N
OH (iPr)2N
O
O H NH2
(EtO)2P CN
P(OEt)2 R CN
O H R NH3 R

Dipp N N
R CN 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