IntroductionThe palladium(I) dimer, di-μ-bromobis(tri-tert-

butylphosphine)dipalladium(I), [Pd(μ-Br)( tBu3P)]2,was synthesised and fully characterised by Mingos(1, 2). However, its potential as a unique C–C andC–N coupling catalyst (3) was first explored byHartwig (6). It has emerged as one of the bestthird-generation coupling catalysts for cross-cou-pling reactions, including C–heteroatom couplingand α-arylations. In this review, the physical andchemical characteristics of the Pd(I) dimer as a cat-alyst material are discussed from a practicalviewpoint, and up to date information on its appli-cations in coupling catalysis is provided.

Characteristics and HandlingThe Pd(I) dimer is a dark greenish-blue

crystalline material, which gives a single peak in the31P NMR spectrum at (δ) 87.0 ppm. The 1H NMRspectrum gives a peak at (δ) 1.33 ppm (singlet; onexpansion it appears as a distorted triplet) in deuter-ated benzene (1, 2). The compound decomposes in

chlorinated solvents, especially in deuterated chlo-roform. The X-ray crystal structure is reported inthe literature as a dimer with Pd–Pd bonding, stabilised by bromine atoms via bridge formation(1, 2). It can be handled in air as a solid for a shortperiod of time, allowing the user to place it into areactor in the absence of a solvent, degas and thencarry out catalysis under inert conditions. However,this compound is highly sensitive to air and mois-ture in the solution phase. It can also decompose inthe solid phase if not stored under strictly inert conditions. The solid state decomposition patternover time was monitored in our laboratory at 0, 48and 112 hours (Figure 1) (4). Its sensitivity towardsoxygen is well understood, and is based on the formation of an oxygen-inserted product with theelimination of hydrogen (Scheme I) (5). Figure 2shows the oxygen sensitivity of the Pd(I) dimer ona proton-decoupled 31P NMR spectrum recordedusing a solvent which was not degassed. The peakat 107 ppm indicates the presence of the oxygen-inserted decomposition product.

183Platinum Metals Rev., 2009, 53, (4), 183–188

A Highly Active Palladium(I) Dimer forPharmaceutical Applications[Pd(µ-Br)(tBu3P)]2 AS A PRACTICAL CROSS-COUPLING CATALYST

By Thomas J. ColacotJohnson Matthey, Catalysis and Chiral Technologies, West Deptford, New Jersey 08066, U.S.A.; E-mail: colactj@jmusa.com

The Pd(I) dimer [Pd(μ-Br)( tBu3P)]2 is one of the best third-generation cross-coupling catalystsfor carbon–carbon and carbon–heteroatom coupling reactions. Information on itscharacterisation and handling are presented, including its decomposition mechanism in thepresence of oxygen. The catalytic activity of [Pd(μ-Br)( tBu3P)]2 is higher than either( tBu3P)Pd(0) or the in situ generated catalyst system based on Pd2(dba)3 with tBu3P. Examplesof suitable reactions for which the Pd(I) dimer offers superior performance are given.

DOI: 10.1595/147106709X472147

0 h 48 h 112 h

Fig. 1 The solid stateoxygen sensitivity of purePd(I) dimer, [Pd(μ-Br)( tBu3P)]2, withtime (4)

Applications in Coupling CatalysisThe high catalytic activity of the Pd(I) dimer

[Pd(μ-Br)(tBu3P)]2 is due to its ease of activation,presumably to a highly active, coordinatively unsat-urated and kinetically favoured ‘12-electron’catalyst species, (tBu3P)Pd(0) (Scheme II). Thisrenders the Pd(I) dimer more active than either theknown ‘14-electron Pd(0)’ catalyst, (tBu3P)2Pd(0),or the Pd(0) catalyst generated in situ by mixingPd2(dba)3 with two molar equivalents of tBu3P. Theapplications of the Pd(I) dimer in organic synthesisare described below.

Carbon–Heteroatom CouplingHartwig identified the potential of the Pd(I)

dimer as a highly active catalyst for C–N coupling

using aryl chlorides as substrates with variousamines at room temperature. A few examples areshown in Scheme III (6). Typically, aryl chloridecoupling requires higher temperatures and longerreaction times when using the in situ generatedPd(0) catalyst, or even the (tBu3P)2Pd(0) complex(7). Around the same time, Prashad and cowork-ers at Novartis reported an amination reactionusing [Pd(μ-Br)(tBu3P)]2 with challenging sub-strates such as hindered anilines (8). Scheme IVshows the coupling of N-cyclohexylaniline withbromobenzene, comparing the performance ofthe Pd(I) dimer with those of in situ generated cat-alysts derived from Pd(OAc)2 with tBu3P, BINAP,Xantphos or DPEphos. The performance of[Pd(μ-Br)(tBu3P)]2 is superior in each case.

Platinum Metals Rev., 2009, 53, (4) 184

180 140160 120 100 80 60 40 20 0 ppm

Fig. 2 The oxygensensitivity of Pd(I)dimer, [Pd(μ-Br)( tBu3P)]2, as observed in the 31P NMR (ppm)spectrum recordedusing non-degassedC6D6

P P

B r

P d

B r

P d O 2

- 2 H

O

P d

O

P d

C H 2

C H 2

P

B r P

B r

3 1 P N M R : 8 7 P P M 3 1 P N M R : 1 0 7 P P M

P d ( I ) d i m e r 31

P NMR: 107 ppm

–2H

P P

Br

Pd

Br

Pd P Pd

Highly active 12-electron species

Scheme I Theoxygen sensitivityof Pd(I) dimer,[Pd(μ-Br)( tBu3P)]2,with the formationof an inactive Pd-Ospecies (5)

Scheme II The activationof Pd(I) dimer to a 12-electron catalystspecies during couplingcatalysis

Pd(I) dimer

31P NMR: 87 ppm

Hartwig’s group subsequently conducted adetailed study to understand the activity and scopeof [Pd(μ-Br)(tBu3P)]2 in the amination of five-membered heterocyclic halides. Variouscombinations of Pd precursors with tBu3P werestudied for a model system, the reaction of N-methylaniline with 3-bromothiophene. Thefastest reaction occurred with the Pd(I) dimer (9).

More recently, Eichman and Stambuli reporteda very interesting zinc-mediated Pd(I) dimer-catalysed C–S coupling, which should generatemuch interest in the area of C–S coupling(Scheme V) (10). For the reactions of alkyl thiolswith aryl bromides and iodides, potassium hydridewas the best base, as illustrated in Scheme V. Forthe Pd-catalysed cross-coupling reactions of aryl

bromides and benzenethiol using zinc chloride incatalytic amounts, with sodium tert-butoxide asthe base, most of the reactions were sluggish andgave low yields. However, the addition of stoi-chiometric amounts of lithium iodide increasedthe rate of the reaction significantly, which isspeculated to be due to the anionic effects pro-posed by Amatore and Jutand (11).

Carbon–Carbon Bond FormationHartwig’s group also studied the Suzuki cou-

pling of sterically hindered tri-substituted arylbromides. A Pd(I) dimer loading of 0.5 mol%, inthe presence of alkali metal hydroxide base, gavegood yields at room temperature within minutes(Scheme VI) (6).

Platinum Metals Rev., 2009, 53, (4) 185

0.5 mol% Pd(I) dimer

NaOtBu, RT

15 min–1 h

R = Bu, Ph

or R2NH = morpholine

R

Yield 88–99%

Cl

R

R

NH +

R

N

Scheme III Arylchloride coupling atroom temperature (6)

Pd catalysts

NaOtBu, Toluene, 110°C

Catalyst loading Yield

[Pd(μ-Br)(tBu3P)]2 0.25 mol% 93%

Pd(OAc)2 + tBu3P 0.5 mol% 86%

Pd(OAc)2 + BINAP 0.5 mol% 27%

Pd(OAc)2 + Xantphos 0.5 mol% 27%

Pd(OAc)2 + DPEphos 0.5 mol% none

Br

+

HN N

Scheme IV Pd(I) dimer-catalysed C–N coupling of N-cyclohexylaniline (8)

0.5–2.0 mol% Pd(I) dimer

THF

ZnCl2 (catalyst)

KH (1.1 equiv.)

X = Br, I

Ar-X + RSH Ar-S-R

Yield 46–99%

R = tBu,

nBu, PhCH2

Scheme V Zinc-mediatedPd(I) dimer-catalysed C–Scoupling (10)

Research work from Ryberg at Astra Zeneca(12) demonstrated a very practical, clean methodfor C–CN coupling using the Pd(I) dimer [Pd(μ-Br)(tBu3P)]2 to produce 3 kg to 7 kg ofproduct routinely (Scheme VII). During the initialin situ studies, Pd2(dba)3 in combination withcommercial ligands such as Q-Phos, tBu2P-biphenyl or Cy2P-biphenyl gave poor results,although with proper process tweaking improve-ments were made. The conventional ligands, suchas Ph3P and dppf, were not useful. However, theP(o-tol)3/Pd2(dba)3 system behaved somewhatwell with the formation of some byproducts. The

Pd loading was as high as 5 mol% (12).For the α-arylation (13) of fairly challenging

carbonyl compounds, Hartwig identified thePd(I) dimer [Pd(μ-Br)(tBu3P)]2 as one of the bestcatalysts, especially for amides and esters. Thework from Hartwig’s group provided generalconditions for α-arylations of esters and amides(14–16). The coupling reactions of aryl halideswith esters are summarised in Scheme VIII (17).For aryl bromides, lithium dicyclohexylamide(LiNCy2) was the best base, while sodium hexa-methyldisilazide (NaHMDS) was required for arylchloride substrates. Intermolecular α-arylation of

Platinum Metals Rev., 2009, 53, (4) 186

Yield 84–95%

0.5 mol% Pd(I) dimer

KOH, THF

15 min, RT

Ph

R1R

2

R3

PhB(OH)2

X

R1R

2

R3

+

Scheme VI Roomtemperature Suzukicoupling of stericallybulky aryl bromides (6)

Pd(I) dimer, Zn(CN)2

Zn, DMF

50ºC, 1–3 hN

HN

Br

OH

N

O

N

HN

NC

OH

N

O

Yield 71–88%R

1, R

2= Me, H; R = Me,

tBu

X = Br, Cl; R3

= Me, MeO, F

(i) LiNCy2 (X = Br) or

NaHMDS (X = Cl)

Toluene, RT, 10 min

(ii) Pd(I) dimer

RT–100ºC, 4 h

R2

R1

R3

O

OR

+

X

R3

O

R1

OR

R2

Scheme VIII α-Arylation of esters under milder conditions using the Pd(I) dimer catalyst (17)

Scheme VIIThe Pd(I)dimer-catalysedcyanationreaction, whichmay be carriedout on akilogram scale(12)

X = Br;

R1

= H, CN, CF3, OCH3 or CH3; R2, R

3= H or CH3

in situ generated zinc enolates of amides was alsoreported in excellent yield under Reformatskyconditions using the Pd(I) dimer, (Scheme IX)(18). The appropriate choice of base for the sub-strate is critical for this reaction.

The α-vinylation of carbonyl compounds hasbeen reported recently by Huang and coworkersat Amgen, catalysed by the Pd(I) dimer in con-junction with lithium hexamethyldisilazide(LiHMDS) base (Scheme X) (19). The same cat-alytic system can be extended to the α-vinylation

of ketones and esters. The combination ofPd2(dba)3 with Buchwald ligands such as X-Phosand S-Phos gave inferior results, as did in situcatalysis with ligands such as Xantphos, (S)-MOP,BINAP and IPr-HCl (carbene) in the presence ofPd2(dba)3. Amgen researchers also reported astereoselective α-arylation of 4-substituted cyclo-hexyl esters using the Pd(I) dimer at roomtemperature, with lithium diisopropylamide(LDA) as the base. Diastereomeric ratios, dr, ofup to 37:1 were achieved (Scheme XI) (20).

Platinum Metals Rev., 2009, 53, (4) 187

Glossary

Ligand Full name

BINAP 2,2' -bis(diphenylphosphino)-1,1' -binaphthyltBu2P-biphenyl 2-(di-tert-butylphosphino)biphenyltBu3 tri-tert-butylphosphine

Cy2P-biphenyl 2-(dicyclohexylphosphino)biphenyl

dba dibenzylideneacetone

DPEphos bis(2-diphenylphosphinophenyl)ether

dppf 1,1' -bis(diphenylphosphino)ferrocene

IPr-HCl (carbene) 1,3-bis-(2,6-diisopropylphenyl)imidazolium chloride

(S)-MOP 2-(diphenylphosphino)-2' -methoxy-1,1' -binaphthyl

OAc acetate

P(o-tol)3 tri(o-tolyl)phosphine

Ph3P triphenylphosphine

Q-Phos 1,2,3,4,5-pentaphenyl-1' -(di-tert-butylphosphino)ferrocene

S-Phos 2-dicyclohexylphosphanyl-2' ,6' -dimethoxybiphenyl

Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

X-Phos 2-dicyclohexylphosphino-2' ,4' ,6' -triisopropylbiphenyl

(i) 1.5 equiv. Zn*

THF, RT, 30 min

(ii) 2.5 mol% Pd(I) dimer

Yield

94%

O

X

NMe2

Br

N

O

NMe2

N

Yield 48–95%

Toluene, 80ºC, 24 h

Pd(I) dimer, LiHMDS

X = Br, OTf, OTs

R1

R3

X

R2

R'''R''R'

OR

1

R2

R3

R'''

R''R'

O

+

Scheme IX α-Arylation ofamides underReformatskyconditions (18);Zn* = activatedzinc species

Scheme X α-Vinylationreaction usingPd(I) dimercatalyst (19);OTf =trifluoromethanesulfonate; OTs = tosylate

ConclusionsThe Pd(I) dimer [Pd(μ-Br)(tBu3P)]2 stands out

as unique among the third generation catalysts forcross-coupling. It has a higher activity than othercatalysts, a fact which can be attributed to its abili-ty to form a 12-electron ‘ligand-Pd(0)’ speciesduring the activation step in the catalytic cycle. Itsapplication to a wide variety of C–C, C–N and C–S

cross-coupling reactions will enable higher yieldsand better product selectivities under relativelymild conditions.

AcknowledgementsFred Hancock and Gerard Compagnoni of

Johnson Matthey’s Catalysis and Chiral Technologiesare acknowledged for their support of this work.

Platinum Metals Rev., 2009, 53, (4) 188

The AuthorDr Thomas J. Colacot is a Research and DevelopmentManager in Homogeneous Catalysis (Global) ofJohnson Matthey’s Catalysis and Chiral Technologiesbusiness unit. Since 2003 his responsibilities includedeveloping and managing a new catalyst developmentprogramme, catalytic organic chemistry processes,scale up, customer presentations and technologytransfers of processes globally.

1 R. Vilar, D. M. P. Mingos and C. J. Cardin, J. Chem.Soc., Dalton Trans., 1996, (23), 4313

2 V. Durà-Vilà, D. M. P. Mingos, R. Vilar, A. J. P. Whiteand D. J. Williams, J. Organomet. Chem., 2000, 600, (1–2),198

3 T. J. Colacot, ‘Di-μ-bromobis(tri-tert-butylphos-phine)dipalladium(I)’, to be included in 2009 in“e-EROS Encyclopedia of Reagents for OrganicSynthesis” , eds. L. A. Paquette, D. Crich, P. L.Fuchs and G. Molander, John Wiley & Sons Ltd.,published online at: www.mrw.interscience.wiley.com/eros (Accessed on 30th July 2009)

4 Johnson Matthey Catalysts, ‘Coupling CatalysisApplication Table’, West Deptford, New Jersey, U.S.A.:http://www.jmcatalysts.com/pharma/pdfs-uploaded/Coupling%20%20Apps%20Table.pdf(Accessed on 30th July 2009)

5 V. Durà-Vilà, D. M. P. Mingos, R. Vilar, A. J. P. Whiteand D. J. Williams, Chem. Commun., 2000, (16), 1525

6 J. P. Stambuli, R. Kuwano and J. F. Hartwig, Angew.Chem. Int. Ed., 2002, 41, (24), 4746

7 R. Kuwano, M. Utsunomiya and J. F. Hartwig, J. Org.Chem., 2002, 67, (18), 6479

8 M. Prashad, X. Y. Mak, Y. Liu and O. Repic, J. Org.Chem., 2003, 68, (3), 1163

9 M. W. Hooper, M. Utsunomiya and J. F. Hartwig, J.Org. Chem., 2003, 68, (7), 2861

10 C. C. Eichman and J. P. Stambuli, J. Org. Chem., 2009,74, (10), 4005

11 C. Amatore and A. Jutand, Acc. Chem. Res., 2000, 33,(5), 314

12 P. Ryberg, Org. Process Res. Dev., 2008, 12, (3), 54013 C. C. C. Johansson and T. J. Colacot, Angew. Chem.,

2009, in press14 T. Hama and J. F. Hartwig, Org. Lett., 2008, 10, (8),

154915 T. Hama and J. F. Hartwig, Org. Lett., 2008, 10, (8),

154516 T. Hama, X. Liu, D. A. Culkin and J. F. Hartwig, J.

Am. Chem. Soc., 2003, 125, (37), 1117617 T. Hama and J. F. Hartwig, Synfacts, 2008, (7), 075018 T. Hama, D. A. Culkin and J. F. Hartwig, J. Am. Chem.

Soc., 2006, 128, (15), 497619 J. Huang, E. Bunel and M. M. Faul, Org. Lett., 2007,

9, (21), 434320 E. A. Bercot, S. Caille, T. M. Bostick, K. Ranganathan,

R. Jensen and M. F. Faul, Org. Lett., 2008, 10, (22),5251

Pd(I) dimer, LDA

Toluene, RT, 3–24 h

Yield 37–85%

Up to 37:1 dr

R1 R

1

CO2Et

R–X+

CO2Et

R

Scheme XI Roomtemperaturediasteroselectiveα-arylation of 4-substitutedcyclohexyl estersusing Pd(I) dimer(20)

References