The Other Side of NHCs: NHCs in TransitionMetal Catalysis

Long Lit 2-23-09John Roberts

Outline of Long Lit.

•History of NHCs/Physical Properties

•Formation of Metal Complexes/Comparisonto Phosphines

•Cross Couplings/Oxidation/Reduction

•Metathesis/Conj. Addn./ApplicationsTowards Clavirolide C

Timeline of NHCs in Synthesis

1943 1957 1962 1968 1991 1995

Ugai Breslow Wanzlick Wanzlick Arduengo Herrmann Olefe

1st reactionusing NHCs

1st proposalof NHC

1st NHCsynthesis

1st NHC MetalComplexsynthesis

1st NHC isolation

1stNHC—Metal

Complexcatalyzedreaction

Types of Transition Metal Carbene Complexes•Historically, there have been two types of transition metal carbenecomplexes: Fischer and Schrock.

•NHC—Metal complexes represent a new class of complexes.

•Due to the NHCs poor π-backbonding capabilities a metal—NHCbond is usually represented as a single bond.

R

RM

Fischer Carbene

Carbene = ElectrophilicLow Ox. Metal

!—Acceptor Ligands

R

RM

Schrock Carbene

Carbene = NucleophilicHigh Ox. Metal

non !—Acceptor Ligands

Types of N—Heterocyclic Carbenes

•There are many types of NHC precursors, but thiazolium,triazolium, and imidazolium salts are the most important tocatalysis.

•Imidazoles, saturated and unsaturated, are the most widelyused NHCs as ligands.

•Four, six, and seven—membered NHCs also exist, but are notas widely used.

N SR1

R2 R3

X

N NR1

R2 R3

X

R4N

N

NR1

R2

X

R3

Thiazolium Imidazolium Triazolium

Routes to N—Heterocyclic Carbenes• Imidazolium and triazolium salts are the most prevalent ligands.

•Synthesis usually involves cyclizing a linear NHC precursor oralkylating the intact NHC core.

•Unsymmetrical/chiral NHCs involve more complex synthesis

Y

N N RR

R = Alkyl,Y = N, CH

X

N NR

X

X

HN N

R = Aryl,Y = N

R = Aryl,Y = CH

N

HN RNHR

Z

LG

NR

Z = Alkyl, Aryl

+ RNHNH2

N N RR O ORX + +RNH2

Arduengoʼs Breakthrough•Synthesized an adamantyl substituted imidazolium salt and rigorouslycharacterized it.

•They were able to deprotonate and grow a crystal of the free carbene.

•NMR, Mass Spec., X-ray, and IR data unequivoqually show the freecarbene has been formed.

Arduengo, A.J.; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361-363.

NC

N

Cl

KOtBu

THF, 96%

NC

N

H

C—N = 1.32 Å

C—N—C = 108.5° to 109.7°

C—N = 1.367 Å

C—N—C = 102.2°

Physical Characteristics of Carbenes

•NHCs are are singlet carbenes, with a filled σ orbital and an empty πorbital.

•The pKa of the C2 carbon is 24 (DMSO), making NHCs strongly basic.

•NHCs are nucleophilic, but they can also undergo cycloadditions andinsertions like other carbenes.

Alder, R. W.; Allen, P. A.; Williams, S. J.; Chem. Comm. 1995, 1267-1268.Enders, D.; Breuer, K.; Teles, J. H; Ebel, K. J. Prakt. Chem. 1997, 339, 397-399.

N

N

R

R

N

C2

NRR

H

Cl N NPhPh

Ph

N NPhPh

Ph

RO H

HORN N

PhPh

Ph

N

N N

N

Ph

Ph

N N

Ph Ph

Bonding Characteristics to Metals•NHCs are electron rich and strong σ donors. Their π back-bondingability is the source of debate.

•Substitution on the NHC, the metal complex, and the specific metal allaffect the π back-bonding ability.

•All NHCs have relatively similar donating ability, where as phosphinesvary widely.

Yin, l.; Liebeskind, L. S. J. Am. Chem. Soc. 1999, 121, 5811-5812.

2056.1Ni(CO)3(PtBu3)PtBu3

2056.4Ni(CO)3(PCy3)PCy3

2068.9Ni(CO)3(PPh3)PPh3

2049.6Ni(CO)3(ICy)ICy

2052.2Ni(CO)3(SIPr)SIPr

2051.5Ni(CO)3(IPr)IPr

2051.5Ni(CO)3(SImes)SIMes

2050.7Ni(CO)3(Imes)IMes

νCO(A1)ComplexLigand

Stability/Shape of NHC Ligands

• NHC ligands, in general, form more stable bonds with metals.Saturated NHCs bind more weakly than their unsaturatedcounterparts.

•The metal—NHC bond is not inert. Migratory insertion and reductiveelimination are degradation pathways.

•NHC ligands have a different profile than phosphine ligands.

NNRR

X

< NNRR

X

NNRR

X

<M

P

R

RR

M

C

NNRR

Metals NHCs can Bind to•NHCs can form complexes with 52 elements, including every transitionmetal except Sc, Tc, and Cd.• Most prevalent complexes are Group 6—9 transition metals.• Strategies for forming NHC—metal complexes include transmetallation,oxidative addition, and deprotonation.

Herrmann, W. A. Köcher, C. Angew. Chem. Int. Ed. Engl. 1997, 36, 2162-2187

Insertion of Metal into NHC Dimer•There is an equilibrium between the free carbene and its dimer, known asthe Wanzlick equilibrium.

• The free carbenes from the dimer can add to a metal or displace otherligands with heating.

• Dimers are synthesized by deprotonating the corresponding azoliumsalts.

N NRR

or

N NRR

H CCl3

HXN N

NN

RR

RR

!

-CHCl3

N NR R

NaH

- NaX, H2

MLnNN

RR

MLn-x

Lappert, M. F. J. Organomet. Chem. 1988, 358, 185-214.

ʻProtectedʼ NHCs•When forming air sensitive metal complexes, protecting the freecarbene with an alcohol or chloroform proves useful.

•Not all azolium salts can be protected in thismanner—unsaturated NHCs are deprotonated.

•Coordination to metal may involve carbene dimer and Wanzlickequilibrium.

N N RR

HX

KOtBu

-KX

N N RR

HX

KOtBu

-KX, KOtBu

N N RR

H OtBu

N N RR

Ru

PCy3

PCy3

Cl

Cl Ph

For R = Mes!, THF

Ru

PCy3

Cl

Cl Ph

NNMesMes

Trnka, T. M.; Morgan, J. P.; Sanford, M. S.; Wilhelm, T. M.; Scholl, M,; Choi, T. L.; Ding, s.;Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 2546-2558

Preformed Carbenes/in situ Deprotonation•Exposing a metal complex to preformed carbenes or formingthe carbene in situ with an irreversible base is the most straightforward process.

•The free carbene must be relatively stable.

•The base can be added to the reaction mixture or be part of themetal complex.

N NRR

HX

KOtBu

-KX, KOtBu

N NRR

MLn

-L

NNR R

MLn-1

N N

N N

Me MeI I Pd(OAc)2

N NMe

N

N

Me

Pd

I

I

O Me

O

Pd

I

I

N

N

NN

Me

Me

Weskamp, T; Bohn, V. P. W.; Herrmann, W. A. J. Organomet. Chem. 2000, 600, 12.

Transmetallation from NHC-AgComplexes/Oxidative Addition

•The lability of the Ag-NHC bond allows Ag-NHC complexes to be carbenetransfer agents.

•NHCs can undergo oxidative addition at the C2 carbon when exposed tometal complexes.

•Oxidative addition works with Y = H, X, but low valent metals can onlyundergo it with hydrogen.

N N RR

YX

NNR R

Ag

Ag2O

X

MLn

NNR R

MLn

AgX

+

Y = H, Halogen

MLnNNR R

MLn

N N RR

X

Wang, H. M. J.; Lin, I. J. B. Organometallics, 1998, 17, 972-975.

Cross-Coupling Reactions : Suzuki Coupling

•Employing NHCs as ligands for palladium in the Suzuki-Miyaura couplingreactions has several benefits.

•The electron donating properties of NHCs aids oxidative addition.

•NHC-palladium complexes can catalyzed the coupling of unactivated arylchlorides and or sterically encumbered coupling partners.

•Catalyst systems can be used with common solvents and mild reactionconditions.

Cl

R

R = deactivating, ortho substitution

+

B(OH)2

RR R

NHC-Pd

Cross-Coupling Reactions : Suzuki Coupling•Glorius has used electron rich NHCs as ligands to perform thesedifficult couplings.

•Nolan uses a NHC-palladium complex to perform couplings at roomtemp. using isopropanol in minutes.

Cl

+

B(OH)2 3 mol % Pd(OAc)2MeMe

Me Me

Me

Me

Me

Me

3.6 mol% NHC3 eq K3PO4

Toluene, 110°C18 hrs

75%

NHC

N N

OO

OTf

n = 8

n n

Navarro ,O.; Kelly, R. A. II;, Nolan, S. P. J. Am. Chem. Soc. 2003, 125,16194-16195

Pd

N

MeMe

Cl

N

N

R

R

R = Mes

Cl

+

B(OH)2 2 mol % NHC-PdMeMe Me Me

Me

MeMe

0.6 mmol NaOtBu

1 ml IPA

23°C

88%, 75 min

0.5 mmol 0.7 mmol

NHC-Pd =

Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F. J. Am. Chem. Soc. 2004, 126, 15195-15196

Cross-Coupling Reactions : Suzuki Coupling•The palladacycle Nolan uses is only the precatalyst.

•Palladium (0) must be generated for the coupling.

•Drawbacks are harsh conditions for forming palladacycle andmanditory slow additionn of aryl chloride.

Pd

N

MeMe

Cl

IMes

OiPr

Cl

Pd

N

MeMe

O

IMes H!-Hydride Elim. Pd

N

MeMe

IMes

H

Red. Elim.

N

Me

Me

+IMesPd(0)

Cross Coupling: Kumada Coupling• Using NHCs as ligands once again allows for the use ofunactivated aryl or alkyl chlorides.

•The mild reaction conditions and fast reaction times allow forgreater functional group tolerance.

•Ortho substituents are also tolerated.

Frisch, A. C.; Rataboul, F.; Zapf, A.; Beller, M. J. Organomet. Chem. 2003, 687, 403-409

Cl

+

MgBr

Pd2(dba)3, 1 mol %Me Me

Me

Me

IPrHCl, 4 mol %THF/Dioxane, 80 °C

95%, 3 hrs

OMe Me

OMeMe

IPrHCl

N N

Cl

MgBr

+NHC-Pd, 2 mol %

NMP, 23 °C

70%, 1 hr

NHC-Pd

Cl

1.5 eq

O

O

O

O

Pd IMesPdMesI

Huang, J.; Nolan, S. P. J. Am. Chem. Soc. 1999, 121, 9889-9890

Cross Coupling: Sonogashira• NHC-Pd complexes cannot catalyze this reaction for aryl chlorides.

•NHC-Pd complexes catalyze the coupling of β hydrogen-containingalkyl electrophiles while phosphine-Pd complexes are ineffective.

•Coupling with aryl iodides can be accomplished at room temp.

Me

Ligand % YieldPPh3 < 5%

PCy3 < 5%

IPr·HCl 67%

IAd·HCl 80%

Br

7+ Me

3

Ligand

[(!"allyl)PdCl]2, 2.5 mol%CuI, 7.5 mol%, Cs2CO3, 1.4 eq

1:2 DMF/Et2O, 45 °C, 16 hr

n-Hexn-Non

Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642-13643.

I

Me

O

Ph+

Me

O

Ph

1 mol% NHC-Pd, 1mol% PPh3

2 mol% CuI, 1.2 eq NEt3DMF, 23° C, 2-24 hr

NHC-Pd =

N N Me

N

OPd

NI

I

N

MeBatey, R. A.; Shen, M.; Lough, A. J. Org. Lett. 2002, 4, 1411-1414.

Cross Coupling: Heck•First report of transtion metal catalysis using NHC ligand(Herrmann, 1995).•The coupling of aryl chlorides can be carried out in ionic liquids.•Mild reaction conditions can only be accessed when usingdiazonium salts

Andrus, M. B.; Song, C.; Zhang, J. Org. Lett. 2002, 4, 2079-2082.

Selvakumar, K.; Zapf, A.; Beller, M. Org. Lett. 2002, 4, 3031-3033.

NN

BF4

+

SIPr·HCl, Pd(OAc)2, 2 mol % ea.

THF, 23 °C, 77%

SIPr·HCl =

N N

Cl

Cl

O

Me +

O

O

Bu

Et

NHC-Pd, 0.5 mol %

Bu4NBr, NaOAc140 °C, 24 hr, 99%

O

Me

O

O

Bu

Et

Cross Coupling: Heck•A NHC-Pd complex was employed in a recent cost effectivesynthesis of resveratrol.

•Other Heck couplings and an optimized HWE gave either longerroutes or poor yields.

•There is speculation whether resveratrol is in part responsiblefor the ʻFrench Paradoxʼ.

HO

OH

CO2H

~ $25/ 100g

Ac2O, Pyr.

90%

AcO

OAc

CO2H SOCl2

91%

AcO

OAc

O

Cl+

OAc

Pd(OAc)2,SIPr·HCl (1 mol% ea.)N-Ethyl Morpholine, xylenes,

120 °C, 73%

AcO

OAc

OAc

THF, NaOH

88%

HO

OH

OH

resveratrol

53% overall yieldAndrus, M. B.; Liu, J. Meredith, E. L.; Nartey, E. Tetrahedron Lett. 2003, 44, 4819-4822.

Cross Coupling: Buchwald-Hartwig Amination•As with the Suzuki-Miyaura reaction, NHCs help catalyze the amination ofunactivated aryl chlorides.

•Steric bulk on the NHC or around the palladium helps to generate the activecatalyst more efficiently.

•NHC-Pd complexes can catalyze this reaction with very low catalyst loadingsor mild reaction conditions.

Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M. Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101-4111.

For theactivity of thecomplex, R =H < Me < Ph

NHC Pd

Cl

R

NHC Pd

Cl

R

KOtBu

KCl

NHC Pd

O

R

Me

Me

Me

O Me

MeMe

R

NHC-Pd (0)

KCl

KOtBuNHC = SIPr

Cross Coupling: Buchwald-Hartwig Amination•As with the Suzuki-Miyaura reaction, NHCs help catalyze the amination ofunactivated aryl chlorides.

•Steric bulk on the NHC or around the palladium helps to generate the activecatalyst more efficiently.

•NHC-Pd complexes can catalyze this reaction with very low catalyst loadingsor mild reaction conditions.

Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M. Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101-4111.

Me

Cl O NH+

NHC-Pd ,1 mol %

KOtBu, DCE, 23 °C

Me

N O

92 %, 2 Min!

Me

Br O NH+

NHC-Pd ,0.001 mol %

KOtBu, DCE, 80 °C

Me

N O

97 %, 30 hr

Me

Me

Cross Coupling: Buchwald-Hartwig Amination•NHC-Pd complexes can even catalyze the reaction in technical gradesolvents under aerobic conditions.

•NHC-Pd complexes can also catalyze the related indole synthesis.

Me

Br O NH+NHC-Palladacycle ,1 mol %

KOtBu, DCE, air, 80 °C

Me

N O

78 %, 3 hr

Me

Me

Technical grade

Viciu, M. S.; Kissling, R. M.; Stevens, E. D.; Nolan, S. P. Org. Lett. 2002, 4, 2229-2231.

I

Cl

CuI, 10 mol%, HCCPh (1.5 eq)

Pd(OAc)2, IPr ·HCl, 5 mol % ea.Cs2CO3, toluene, 105 °C, 1 hr

Cl

Ph

NH2

Me

1.2 eq

18 hr N

Ph

p-tol

64%

Altermann, L. Org. Lett. 2004, 7, 439-442.

Olefin Metathesis•Olefin metathesis is a very powerful tool, both in natural productrelated synthesis and in polymer chemistry.•The incorporation of a NHC ligand onto Grubbsʼ Ru based catalystallowed for more widespread applications.•Hoveydaʼs internal chelate modification allows for greater stability andrecycling via chromatography.•Ru based metathesis catalysts are generally more ʻuser-friendlyʼ thanSchockʼs Mo-alkylidine catalysts.

Ru

PCy3Cl

ClPCy3

Ph

RuCl

ClPCy3

Ph

NNMesMes

Grubbs I Grubbs II Hoveyda-Grubbs II

RuCl

Cl

NNMesMes

O

Me

Me

MoO

O N

CF3F3C Ph

CF3

F3C

Schrock's catalyst

N-Heterocyclic Carbenes in Synthesis. Ed: Nolan, S. P. 2006, Wiley-VCH. Weinheim, Germany.

Olefin Metathesis: Mechanistic Insights•Grubbs I has more functional group tolerance and is less air sensitivethan Schrockʼs catalyst.•Low thermal stability, C—P bond degredation, and reduced activity allproblems.•Mechanism states phosphine dissociation and low reassociationessential for high turnover.•Steric bulk and electron donating ability important factors for ligand.

Ru

LCl

ClPCy3

R + PCy3

- PCy3

Ru

LCl

Cl

R

+

-

R'

R'

Ru

LCl

Cl

R

R'

Ru

LClCl

R'

R

R

R'

Dias, E. L.; Nguyen, S. T.; Grubbs, R. H.; J. Am. Chem. Soc. 1997, 119, 3887-3897.

Olefin Metathesis: Incorporation of NHCs•NHCs are perfect candidates as ligands for Ru based metathesis.•Strong σ donation and weak π acceptor character leads to strong NHC-Ru bonds (5 kcal/mol greater!)•These factors, along with greater steric bulk, result in increased activity,more robust reaction conditions, and decreased reaction times.

E E

E E Me

E E MeMe

E EMe

Me

E E

E E

E E

MeMe

Me

E E

Me

Me

52900

93310

Quant.Quant.20

Quant.Quant.Quant.

SchrockGrubbs 2Grubbs 1

N-Heterocyclic Carbenes in Synthesis. Ed: Nolan, S. P. 2006, Wiley-VCH. Weinheim, Germany.

Olefin Metathesis: Phosphine-Free andChiral Catalysts

•Phosphine-free catalysts prepared by Hoveyda and Blechert groupsindependently.•These catalysts improve cross metathesis and work with electrondeficient olefins.•Chiral metathesis catalysts carry out AROM/CM catalysis

OOO

10 mol% A

Cy

OOO

Cy

RuCl

O

N NMes

O

Me

Me

A =

60%, > 98% ee, 98:2 Cis/Trans

Van Veldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 4954-4955.

O O

CO2Me

CN

Hoveyda Grubbs II

O O

CO2Me

NC

83%, Z:E = 9:1

Randl, S.; Gessler, S.; Wakamatsu, H.; Blechert, S. Synlett 2001, 430-432.

Olefin Metathesis: Applications to Synthesis• Aside from many applications in the polymer science field, RCM,cross-methasis, and enyne metathesis have found many applicationsin the total synthesis of natrual products.

NBoc

HO

Et

NBoc

HO

Et

RuCl

Cl

NNMesMes

O

Me

Me

NO2

1 mol %CH2Cl2

80%

NBoc

O

H

NBoc

O

H

10 mol %CH2Cl2

69%

N

O

O

H

N

O

O

H

(—)-Securinine (+)-viroallosecurinine

Honda, T.; Namiki, H.; Kaneda, K.; Mizutani, H. Org. Lett.2004, 6, 87-89.

Honda, T.; Namiki, H.; wantanabe, M.; Mizutani, H.Tetrahedron. Lett. 2004, 45, 5211-5213.

Olefin Metathesis: Applications to Synthesis• Aside from many applications in the polymer science field, RCM,cross-methasis, and enyne metathesis have found many applicationsin the total synthesis of natrual products.

Geng, X.; Danishefsky, S. J. Org. Lett. 2004, 6, 413-416.

O

TBSO

O

O

MeO

(OC)3Co

(OC)3Co

O

TBSO

O

O

MeO

(OC)3Co

(OC)3Co25 mol% Grubbs II

CH2Cl2, 80%

O

MeO

OH

OH

OH

HO

Aigialomycin

Asymmetric Additions with NHC-Metal Complexes •Chiral phosphine ligands are successful ligands for manyasymmetric transition metal—mediated reactions.

•Could NHCs be successful ligands with their unique features?

•The profile of chiral NHC ligands differs significantly from chiralphosphine complexes. NHCs do not have an ʻedge-to-faceʼorientation of their aryl groups like phosphines.

PPh2

PPh2 Fe PPh2PCy2

P

P

R

R

RR

BINAP Josiphos DuPhos

Asymmetric Additions with NHC-Metal Complexes:Conjugate Arylation

•First investigated by Miyaura and Hayashi in 1998 using aRh/BINAP complex.

•A system developed by Ardus using a NHC-paracyclophaneligand gives comparable yields and selectivity with more mildconditions.

•Bulky NHC ligands are essential, which was first shown byFürstner.

O

+ ArB(OH)2

1.5 eq

O

ArS

Rh(acac)(C2H4)2, 2 mol%

NHC (3 mol %)10:1 THF/H2O

60 °C

N H

ArAr

BF4

Ma, Y.; Song, C.; Ma, C.; Sun, Z.; Chai, Q.; Andrus, M. B. Angew. Chem. Int. Ed. 2003, 42, 5871-5874

Asymmetric Additions with NHC-Metal Complexes:Asymmetric α-arylation

•Reaction reported in 1997 by Buchwald and Hartwig. Muratakeand Natsume reported intramolecular version at the same time.

•Best ligand for the asymmetric intramolecular version is a NHC.

•This ligand better than workhorse phosphine ligands.Unfortunately, only modest selectivity is achievable at presenttime.

N

O

Me

1-Np

Me

Br

N

Me

O

Me1-Np

Pd(OAc)2, 5 mol%

Ligand, NaOtBu

Dioxane

NHC 1 NHC 2

N N

BF4

N N

BF4

767510NHC2

678825NHC 1

6170100DuPhos

272100Josiphos

4649100(R)-BINAP

ee (%)Yield (%)Temp.(°C)

Ligand

Lee, S.; Hartwig, J. F. J. Org. Chem. 2002, 66, 3402-3415.