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REVIEW 1405

Transition-Metal-Catalyzed Site-Selective Cross-Coupling of Di- and Polyhalogenated CompoundsSite-Selective Cross-CouplingJia-Rui Wang, Kei Manabe*Manabe Initiative Research Unit, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako 351-0198, JapanFax +81(48)4624662; E-mail: [email protected] 26 January 2009; revised 16 February 2009

SYNTHESIS 2009, No. 9, pp 1405–1427xx.xx.2009Advanced online publication: 14.04.2009DOI: 10.1055/s-0029-1216632; Art ID: E23309SS© Georg Thieme Verlag Stuttgart · New York

Abstract: This review highlights transition-metal-catalyzed cross-coupling reactions in which one of the halogen atoms (or pseudo-halogen groups) of di- or polyhalogenated compounds is convertedsite-selectively into another group. The compounds are categorizedas halogenated alkenes, heteroarene derivatives, benzene deriva-tives, and alkanes. Enantioselective cross-coupling of substrateshaving two enantiotopic halo groups is also described.

1 Introduction2 Di- and Polyhalogenated Alkenes2.1 1,1-Dihalogenated Alkenes2.1.1 Grignard Reagents2.1.2 Organozinc Reagents2.1.3 Organostannanes and Others2.1.4 Boronic Acids and Derivatives2.1.5 Alkynes2.2 1,2-Dihalogenated Alkenes2.3 Trihalogenated Alkenes and Others3 Di- and Polyhalogenated Heteroarene Derivatives3.1 Five-Membered Heteroarene Derivatives3.2 Six-Membered Heteroarene Derivatives3.3 Other Heteroarene Derivatives3.4 Mechanism4 Di- and Polyhalogenated Benzene Derivatives4.1 Polyhalogenated Benzenes4.2 With Electron-Withdrawing Groups4.3 With Electron-Donating Groups4.4 Other Dihalogenated Benzenes5 Dihalogenated Alkanes6 Enantioselective Cross-Coupling Reactions7 Conclusions

Key words: cross-coupling, catalysis, halides, transition metals,site selectivity

1 Introduction

Cross-coupling of halogenated compounds with organo-metallic reagents constitutes one of the most importantand practical reactions among transition-metal-catalyzedtransformations.1 Not only carbon–carbon bonds but alsoother types of bonds, among them carbon–nitrogen,carbon–oxygen, carbon–phosphorus, and carbon–sulfurbonds, have been constructed by this method. Cross-cou-pling has been applied to the synthesis of a wide variety ofcompounds including natural products, drugs, and func-tional materials.

When the starting compounds contain several halogroups, selectivity between the groups can be an impor-tant issue in the cross-coupling. In general, halo groupsexhibit the reactivity order of I > Br > Cl > F, which canbe utilized to install a desired substituent at a desired po-sition (Scheme 1, a).2 This type of chemoselective cross-coupling reaction can also be realized with the aid of thereactivity difference between a halogen and a pseudo-halogen such as a trifluoromethanesulfonyloxy group (tri-flyloxy, TfO-).3 Because the remaining halo group in theproduct of the cross-coupling reaction can be further con-verted into another group through a subsequent syntheticprocedure, chemoselective cross-coupling has been a use-ful method in synthetic chemistry.

On the other hand, when the starting molecules have morethan one substituent of the same halogen atom, selectivecross-coupling at one of the halo groups is more difficultto realize than chemoselective cross-coupling. Neverthe-less, this type of site-selective4 cross-coupling (Scheme 1,b) offers more convenient and efficient methods for thepreparation of multiply substituted products, because thestarting di-(or poly-)halogenated compounds can often beprepared more easily than compounds with two differenthalo groups as needed in chemoselective cross-coupling.Therefore, it is of great value to develop such site-selec-tive cross-coupling reactions.

In fact, various examples of site-selective cross-couplingreactions have thus far been reported, and developing newmethods remains an area of ongoing interest. We, too,have been involved in this area of research and have de-

Scheme 1 Chemoselective cross-coupling and site-selective cross-coupling

R Mcatalyst

X2

X1

X1, X2 = halogen or pseudo-halogenreactivity order: X1 > X2 (e.g., X1 = I, X2 = Br)

R1

(a) chemoselective cross-coupling

(b) site-selective cross-coupling

X2

R

R1

R Mcatalyst

X1

X1

R1

X1

R

R1

1406 J.-R. Wang, K. Manabe REVIEW

Synthesis 2009, No. 9, 1405–1427 © Thieme Stuttgart · New York

veloped a catalyst-controlled system that is a unique ap-proach in site-selective cross-coupling. In this Review, wesummarize the reported examples of site-selective cross-coupling of di- and polyhalogenated compounds. The ex-amples are categorized based on the structures of the ha-logenated starting materials – alkenes, heteroarenederivatives,5 benzene derivatives, and alkanes (Scheme2). We focused on examples in which similar types of halogroups are differentiated in selective reactions and omit-ted those examples based on differentiation between dif-ferent types of halo groups; for example, between Csp3–Xand Csp2–X, or Carene–X and Calkene–X.6 We also omittedexamples of site-selective reduction to form a carbon–hydrogen bond.7

Scheme 2 Site-selective cross-coupling of dihalogenated alkenes,heteroarene derivatives, benzene derivatives, and alkanes

2 Di- and Polyhalogenated Alkenes

2.1 1,1-Dihalogenated Alkenes

1,1-Dihaloalkenes are easily prepared from aldehydes viathe Wittig-type reaction or by carbometalation of metalat-ed alkynes. They have been widely used for the synthesisof trisubstituted alkenes of defined stereochemistry bytransition-metal-catalyzed site-selective monoarylationand monoalkylation reactions. 1,1-Dihaloalkenes aremore reactive toward metal (such as palladium and nickel)catalysts than the corresponding monohaloalkenes, there-by making their cross-coupling facile. Owing to the dif-ference of the reaction rate and the steric effects, the cross-coupling reaction of 1,1-dihaloalkenes with organometal-lic reagents can be stopped at the monosubstituted stage,giving the trans-configured main products. The term ‘site-selectivity’ for this type of substrate has the same meaningas ‘stereoselectivity’.

Here we discuss individual reactions, classified accordingto the nucleophilic reagents used. In addition, these kindsof reactions have wide application in the total synthesis ofnatural products, and these are also briefly described.

2.1.1 Grignard Reagents

In 1987, Minato and co-workers reported the first success-ful site-selective monoalkylation and -arylation of 1,1-dichloroalk-1-enes with Grignard reagents in the presenceof PdCl2(dppb), as a catalyst to produce 1-substituted (Z)-1-chloroalk-1-enes (Scheme 3).8 Using PdCl2(PPh3)2 in-stead of PdCl2(dppb) as the catalyst resulted mainly in theformation of disubstituted products.

Jia-Rui Wang was born inHenan, China. She receivedher Ph.D. in 2007 in chemis-try from the University ofScience and Technology ofChina. Then, she joined

RIKEN, where she is cur-rently a unit researcher inManabe Initiative ResearchUnit, RIKEN AdvancedScience Institute. Her re-search interests are the de-

velopment of new catalyticcross-coupling and C–Hbond-activation reactionsfor organic synthesis.

Kei Manabe was born inKanagawa, Japan. He com-pleted his doctoral work in1993 at the Graduate Schoolof Pharmaceutical Sciences,University of Tokyo underthe direction of ProfessorKenji Koga. After workingas a postdoctoral fellow at

Columbia University in thegroup of Professor GilbertStork, he moved back to theUniversity of Tokyo andworked as an Assistant Pro-fessor, Lecturer, and Asso-ciate Professor in the groupsof Professor Koga and Pro-fessor Shu Kobayashi. In

2005, he joined RIKEN,where he is currently an Ini-tiative Research Scientist inRIKEN Advanced ScienceInstitute. His research inter-ests include the develop-ment of functionalmolecules and new reac-tions for organic synthesis.

Biographical Sketches

X

XR2

R1 R

XR2

R1

Y X

nY = heteroatomn = 0, 1

X R Mcatalyst

Y R

n

X

X X

X R

R1 R1

R1

XX

R1

RX

REVIEW Site-Selective Cross-Coupling 1407


Scheme 3 Site-selective coupling of 1,1-dichloroalk-1-enes withGrignard reagents. R1 = Ph, 4-MeOC6H4, 2-thienyl, Me; R2 = Ph, 4-ClC6H4, 2-thienyl.

Okamoto and co-workers found that the reactions of 1,1-dihalo-2-phenylalk-1-enes with phenylmagnesium bro-mide in the presence of NiCl2(dppp) in tetrahydrofuranaccompanied by partial reduction gave (E)-1,2-diphenyl-alk-1-enes as the major products (Scheme 4).9 Use of alarge excess of Grignard reagents increased the yields ofmonoalkylated products.

Scheme 4 NiCl2(dppp)-catalyzed site-selective coupling of 1,1-di-halo-2-phenylalk-1-enes with phenylmagnesium bromide. R = Me,Et, i-Pr; X = Cl, Br.

Neidlein and Friedrich reported the synthesis of diynyl-substituted 1,6-methano[10]annulene derivatives using asite-selective palladium-catalyzed coupling of an acety-lene with geminal dibromo-substituted alkenes to yieldenynes followed by dehydrohalogenation.10 The couplingoccurred selectively at the trans-position (Scheme 5).

Scheme 5 Site-selective coupling reaction in the synthesis of di-ynyl-substituted 1,6-methano[10]annulene derivatives. R = Ph, t-Bu,TMS.

Braun and co-workers utilized a palladium-catalyzed site-selective cross-coupling of geminal dibromosubstitutedalkenes with hexynylmagnesium bromide in the synthesisof the novel antifungal butenolide fugomycin.11 The antic-ipated monocoupling occurred in 82% yield, and the iso-meric Z- and E-configured products were obtained in an80:20 ratio (Scheme 6).

Figadère and co-workers reported the coupling of 1,1-dichloroalk-1-enes with Grignard reagents in the presenceof an environmentally friendly iron(III) catalyst.12 The re-actions, however, proceeded with no selectivity and gavedicoupled compounds as the major products.

2.1.2 Organozinc Reagents

Minato and co-workers reported the first site-selectivecross-coupling of organozinc reagents with 1,1-dichloro-alk-1-enes in the presence of PdCl2(dppb).8 Both aryl- andalkylzinc reagents were successfully used in the reactionand gave the products site-selectively in high yields of94% and 81%, respectively (Scheme 7).

Scheme 7 Site-selective cross-coupling of 1,1-dichloroalkenes withorganozinc reagents. R = Ph (94% yield); R = n-Bu (81% yield).

Minato modified the synthesis of pyrethroids by site-selective monoarylation and heteroarylation of (2,2-di-haloethenyl)cyclopropanecarboxylates with organozincreagents.13 The coupling using 1–1.2 equivalents of orga-nozinc reagent and 2 mol% of PdCl2(dppb) gave themonocoupled products, site-selectively, in 61–100%yields at room temperature after 5–8 hours (Scheme 8).

Scheme 8 Site-selective coupling reaction in the synthesis of pyre-throids. R1 = Me, Et; R2 = Ph, 4-ClC6H4, 3-ClC6H4, 4-FC6H4,C4H9C≡C, 2-thienyl, 2-furyl.

Panek and Hu described an efficient palladium-catalyzedcoupling reaction between complex subunits – an in situgenerated alkenylzinc intermediate and a chiral alkenylhalide.14 The coupling of a 1,1-dibromoalkenyl substrateproduced a single E,Z-isomer in 55% yield (Scheme 9).

Negishi and Shi reported the trans-selective coupling ofarylzinc bromides with 1,1-dibromo- and 1,1-dichloroalk-1-enes in the presence of PdCl2(dpephos).15 The reactionsproceeded at ambient temperature site-selectively to givemonoarylated products in high yields of 82–94%. Tet-rahydrofuran, toluene, and diethyl ether were all good sol-vents for the reactions (Scheme 10).

H

R1

Cl

Cl

PdCl2(dppb) (1 mol%) H

R1

R2

ClEt2O, reflux

76–98%

+ R2MgBr

Ph

R

X

X

PhMgBr (12 equiv)NiCl2(dppp) (2 mol%)

THF, reflux, 28 h

Ph

R

Ph

H+

Ph

R

H

Ph

(Z) 8–16% (E) 20–59%

Br

Br

R MgBrPd(PPh3)4 (cat.)

+Et2O–benzene

r.t., 3–24 h28–59% Br

R

Scheme 6 Site-selective coupling of dibromoalkene and hexynyl-magnesium bromide

OO

Br

Br

n-Bu MgBr+Pd(PPh3)4 (2.5 mol%)

Et2O–benzene0 °C to reflux, 12 h

OO

Br

n-Bu

OO

Br

n-Bu

+

(Z) (E)

82%(80:20)

RZnCl+PdCl2(dppb) (1 mol%)

Et2O, reflux

Cl

ClPh

H R

ClPh

H

Cl

Cl

H

CO2R1r.t., 5–8 h61–100%

R2ZnCl (1–1.2 equiv)PdCl2(dppb) (2 mol%)

Cl

R2

H

CO2R1



Negishi’s research group also reported the trans-selectivemonoalkylation of unactivated 1,1-dichloroalk-1-eneswith alkylzinc reagents (Scheme 11).16 It was found thatthe use of one mole equivalent of N-methylimidazole(NMI) relative to the alkylzinc reagent further improvedthe yields in some cases.

Scheme 11 trans-Selective monoalkylation of 1,1-dichloroalkenes.R1 = n-Hex, TBSOCH2CHMe, TBDPSO(CH2)2, TBSOCH(Me)CH2,TBSO(CH2)3, Ph, TMSC≡C, TMSC≡C–CH=CH; R2ZnX = Me2Zn,Me2Zn-NMI, Et2Zn, n-OctZnBr, n-OctCH(Me)CH2ZnBr.

Wnuk and Andrei investigated the palladium-catalyzedcoupling of b,b-dihalostyrenes with an alkylzinc bromidebearing an ester group.17 It was found that b,b-dichlo-rostyrene reacted with BrZn(CH2)3CO2Et to give thetrans-monoalkylated product in 65% yield, together with22% yield of a monocoupled/reduced byproduct. Similarcoupling with more active b,b-dibromostyrenes producedmainly dialkylated product (Scheme 12).

Scheme 12 Site-selective monocoupling of b,b-dichlorostyrenewith an alkylzinc reagent bearing an ester group

Hayashi and co-workers described a p-allylpalladium-mediated catalytic method for the synthesis of multiplyfunctionalized allenes. The substrates, (Z)-2-bromobuta-1,3-dienes, were synthesized by palladium-catalyzed site-selective cross-coupling of 1,1-dibromoalk-1-enes withvarious alkenylzinc reagents in 63–90% yields (Scheme13).18 The use of the organozinc reagent is important forthis step and the less reactive vinyltin reagent, or more ba-sic Grignard reagents, either resulted in very low yields orafforded more byproducts.

Scheme 13 The synthesis of (Z)-2-bromobuta-1,3-dienes. R1 = Ph,Bn, (E)-PhCH=CH, i-Pr, n-heptyl, H; R2 = H, Me, Ph; R3 = H, Me.

Negishi and co-workers synthesized a variety of 2-bromo-1,3-dienes by palladium-catalyzed trans-selective cross-coupling of 1,1-dibromoalk-1-enes with alkenylzinc re-agents (Scheme 14).19 These products were used for sub-sequent palladium-catalyzed coupling reactions withother organozinc reagents. Interestingly, it was found thatin this coupling of 2-bromo-1,3-dienes with organozincreagents, the configuration of the products could be finelycontrolled by the use of different palladium–phosphinecatalysts. With PdCl2(dpephos), PdCl2(PPh3)2,PdCl2(dppf), or PdCl2(tfp) [TFP = tris(2-furyl)phosphine]as catalyst, the stereo-inversion at the bromine-bearingcarbon–carbon double bond was complete and the reac-tion gave high yields and high stereoselectivity of the con-jugated Z,E-dienes.19a However, using Pd(t-Bu3P)2 or acombination of Pd2(dba)3 and an N-heterocyclic carbeneas catalyst, the stereo-inversion was suppressed and theproducts were the E,E-dienes.19b

Hayashi and co-workers reported a palladium-catalyzedsynthesis of functionalized butatrienes from 2-bromobut-1-en-3-yne derivatives.20 The substrates were easily pre-pared by a two-step reaction sequence involving palladi-

Scheme 9 One-pot site-selective coupling reaction

1) Cp2Zr(H)Cl

2) ZnCl2

ZnCl

H

OBnOBn

Br

Br

Bn

OMe

Pd(PPh3)4 (5 mol%)THF, 50 °C

(E,Z)-diene 55%

H

OBnOBn

Br

Bn

OMe

BnOOBn

Scheme 10 PdCl2(dpephos)-catalyzed trans-selective arylation of1,1-dihaloalk-1-enes. R = n-Hex, (S)-Et(Me)CH, Ph, Me3Si; X = Clor Br; Ar = Ph, 2-thienyl, 2-thiazolyl.

HX

X

RPdCl2(dpephos) (5 mol%)

23 °C, 1–24 h, 82–94%ArZnBr H

X

Ar

R

+

O

PPh2 PPh2

DPEphos

R1

Cl

ClH

R1

R2

ClH

PdCl2(dpephos) (5 mol%)

DMF, 23–70 °C, 5–24 h50–90%

R2ZnX+

(1.2 equiv)

Cl

Cl

BrZn(CH2)3CO2Et (2.5 equiv)

PdCl2(dppf) (10 mol%)

THF, 65 °C, 65% Cl

CO2Et3

R1Br

Br

R2

ClZnR3

R1

Br

R2

R3+

Pd(PPh3)4 (1.5 mol%)

THF, r.t., 1 h63–90%

Scheme 14 The synthesis of 2-bromo-1,3-dienes. R1 = OTBS,OTBDPS, Me; R2 = H, Et; R3 = H, Et, n-Bu, n-Hex, Ph, C≡CSiMe3;R4 = H, n-Bu; R5 = n-Hex, Ph, C≡CSiMe3, R6 = n-Bu, CH2OTBS,C≡CSiMe3.

H

Br

BrR1

R2

R4

R3BrZn

+H

Br

R1

R3

R4

R2

Pd(PPh3)4 (5 mol%)

THF, 45 °C, 3 h64–91%

H

Br

BrR5

H

H

R6BrZn+

Pd(PPh3)4 (5 mol%)

THF, 45 °C, 3 h76–90%

H

Br

R6

H

H

R5



um-catalyzed coupling of 1,1-dibromoalkenes withtrimethylsilylethynylzinc chloride, followed by removalof the trimethylsilyl group. The first coupling stage pro-ceeded with high selectivity to give the trans-products ex-clusively, in moderate yields of 41–66% (Scheme 15).

Scheme 15 The site-selective coupling of 1,1-dibromoalkenes withtrimethylsilylethynylzinc chloride. R = Ph, 1-naphthyl, 4-F3CC6H4,4-MeOC6H4, Bn, PhCH2CH2.

Negishi and co-workers developed a palladium-catalyzedtrans-selective monoalkynylation of 1,1-dihaloalk-1-eneswith ethynylzinc reagents (Scheme 16).21 It was foundthat when both R1 and R2 were alkyl groups,PdCl2(dpephos) showed a much higher activity thanPdCl2(tfp)2, PdCl2(dppf), or Pd(PPh3)4. On the other hand,when both R1 and R2 were phenyl groups, Pd(PPh3)4 gavethe best result.

Scheme 16 Trans-selective monoalkynylation of 1,1-dihaloalk-1-enes with ethynylzinc reagents. X, Y = Cl or Br; R1 = n-nonyl, n-Hex,n-Pr, TBSOCH2CH2, Me3SiC≡C, Ph; R2 = Me, i-Pr, Ph.

2.1.3 Organostannanes and Others

Shen and Wang synthesized 3-substituted isocoumarins ingood to excellent yields via palladium-catalyzed couplingof 2-(2,2-dibromovinyl)benzoates with organostannanes(Scheme 17).22 The process involved a trans-selectiveStille coupling and a subsequent annulation reaction.

Scheme 17 The synthesis of 3-substituted isocoumarins. R1 = H,5-CO2Me, 4-CO2Me, 5-MeO, 4-MeO; R2 = Ph, 2-furyl, 3-furyl,2-thienyl, vinyl; R3 = Me, Bu.

They reported later the palladium-catalyzed Stille cou-pling of 1,1-dibromoalk-1-enes with aryl- and vinylstan-nanes. It was found that the reactions gave (Z)-bromoalkenes in good to excellent yields when the reac-tions were conducted in toluene or 1,4-dioxane with TFPas ligand (Scheme 18).23 However, 2-aryl-1,1-dibro-moalk-1-enes having electron-donating methoxy groupsin the para- or ortho-positions resulted in poor yields.When the coupling was conducted in a highly polar sol-vent (DMF), monobromides and/or internal alkynes werethe main products.

Scheme 18 Stille coupling of 1,1-dibromoalk-1-enes with aryl- andvinylstannane reagents. R1 = H, 2-NO2, 4-CO2Me, 4-CN, 3-CN, 2-CN, 4-MeO, 3-MeO; R2 = Ph, 2-furyl, 3-furyl, 2-thienyl, vinyl;R3 = Me, Bu; R4 = Ph, vinyl.

Brückner and co-workers found that the palladium-cata-lyzed Stille coupling of g-(dibromomethylene)butenolidewith phenyl- or styryltributylstannane give monobro-mobutenolides in high yields and excellent site-selectivi-ties (Scheme 19).24 A second Stille coupling or areduction with zinc dust led to bromine-free g-alky-lidenebutenolides as the single stereoisomers.

Scheme 19 Stille coupling of g-(dibromomethylene)butenolidewith phenyl- or styryltributylstannane. Reagents and conditions: (a)PhSnBu3 (1.11 equiv), Pd(dba)2 (0.05 equiv), Ph3As (0.20 equiv),THF, 65 °C, 8 h. (b) PhSnBu3 (1.17 equiv), Pd(dba)2 (0.06 equiv),Ph3As (0.20 equiv), THF, 65 °C, 7 h.

Negishi and Xu reported the first trans-selective cross-coupling of alkenylzirconium with 1,1-dibromoalkene inthe synthesis of lissoclinolide (Scheme 20).25 The reactionresulted in a satisfactory yield and selectivity in the pres-ence of palladium catalyst. It was found that use of alke-nylzinc reagents instead of alkenylzirconium reagents didnot afford the desired coupling product at all.

Recently, Sestelo, Sarandeses, and co-workers reportedthe site-selective palladium-catalyzed cross-coupling oforganoindiums with 1,1-dihaloalkenes.26 The reaction

RBr

Br

Me3SiC CZnCl+ R

Br

SiMe3Pd(PPh3)4 (2 mol%)

THF, 50 °C, 2 h41–66%

R1X

X

R23SiC CZnY

R1

X

SiR23

PdCl2(dpephos) (5 mol%)

THF, 0 °C, 1 h, 65–99%

CO2MeBr

Br

R1

O

R2

R1

O

R2SnR33 (1.05 equiv)

Pd2(dba)3 (2.5 mol%)TFP (15 mol%)

toluene, 100 °C, 20 h30–92%

Br

Br

R1

R2SnR33

(or R4SnR33)

Pd2(dba)3 (2.5 mol%)TFP (15 mol%)

toluene, 100 °C, 20 hBr

BrO

O

Br

BrEtO2C

Br

PhO

O

Br

R2

R1

Br

R4

EtO2C

63–97%

72%

63–64%

Br

Br O O

Ph

Br O O Br O O

Ph

(a) (b)

84% 67%

Scheme 20 Cross-coupling of 1,1-dibromoalkene with alkenylzir-conium

TBSOBr

Br

ClCp2Zr OTBS+

TBSOBr

OTBSPdCl2(PPh3)2 (5 mol%)DIBAL-H (10 mol%)

OHHO

OO

THF, 50 °C, 5 h91% (98% stereoselection)

lissoclinolide



with 40 mol% triaryl-, vinyl- or alkynylindium derivativesgave monosubstitution products with trans-selectivity inmoderate to good yields (Scheme 21).

Scheme 21 Cross-coupling of organoindiums with 1,1-dihalo-alkenes. R1 = n-heptyl, Ph; R2 = Ph, Me3SiC≡C, PhC≡C, CH2=CH.

2.1.4 Boronic Acids and Derivatives

Roush and co-workers first utilized a highly site-selectiveSuzuki coupling in the synthesis of the octahydronaphtha-lene subunit. The reaction in the presence of Pd(PPh3)4

and thallium(I) hydroxide resulted in a yield of 85%(Scheme 22).27

Scheme 22 The site-selective Suzuki coupling reaction in the syn-thesis of the octahydronaphthalene subunit

In 1990, Roush and co-workers reported the Suzuki cou-pling of 1,1-dibromoolefins and alkenylboronic acids(Scheme 23).28 This provided a convenient approach tothe synthesis of (Z,E)-2-bromo-1,3-dienes with excellentstereoselectivity, and a wide range of potentially base-sensitive functionalities were tolerated under the reactionconditions. It was observed that the reaction was most ef-ficient for the coupling of 1,1-dibromoolefins possessingan allylic alkoxy substituent.

Scheme 23 Site-selective Suzuki coupling of 1,1-dibromoolefinswith vinylboronic acids

They reported later the application of a palladium-cata-lyzed site-selective cross-coupling of dibromoolefin withalkenylboronic acid in the synthesis of spirotetronates

corresponding to the top half of chlorothricolide (Scheme24).29

Baldwin and co-workers utilized a Suzuki coupling in thesynthesis of himgravine.30 The coupling could beachieved by refluxing overnight in the presence ofPd(PPh3)4 and potassium carbonate in tetrahydrofuran–methanol–water. Furthermore, use of barium hydroxide inplace of potassium carbonate gave rise to a dramatic rateacceleration, with the reaction reaching completion in justone hour at 20 °C with a yield of 58% (Scheme 25).

Scheme 25 The site-selective Suzuki coupling reaction in the syn-thesis of himgravine

Roush and co-workers described an application of theSuzuki coupling in the synthesis of nargenicin A1.

31 Thereaction of 1,1-dibromoalkene and alkenylboronic acid inthe presence of Pd2(dba)3 and thallium(I) hydroxide pro-vided the seco ester in 74% yield (Scheme 26).

They also reported a similar application in the synthesis ofthe bottom-half fragment of (+)-tetronolide (Scheme27).32 The dibromoolefin underwent cross-coupling withalkenylboronic acid under Kishi’s modified Suzuki cou-pling conditions, providing the tetraenoate after protec-tion of the primary hydroxy as a tert-butyldimethylsilylether. The yield of the two steps was up to 85%.

Br

Br

R1 R23In

R2

Br

R1+Pd2(dba)3/TFP (1:1, 2 mol%)

THF, 8–10 h, 55–77%

MeO2CBr

BrOAc OBn

MeO2C

BrOAc OBn

OH

OH(HO)2B

(1.4 equiv)

Pd(PPh3)4 (0.2 equiv)TlOH (1.4 equiv)THF, 5 min, 85%

OAc

OBnBr

octahydronaphthalene subunit

O OMeOH

BrHO B(OH)2

R

Br

RHO33

Pd(PPh3)4 (10 mol%)TlOH, THF

23 °C, 43–87%

Br

Scheme 24 The site-selective Suzuki coupling reaction in the syn-thesis of spirotetronates

Br Br

OTBDPS

Br

OTBDPS

(HO)2B

Pd(PPh3)4 (cat.)TlOH, 72%

spirotetronates

(Z/E = 4–5:1)

OTBDPS

TBSO5

O

MOMO

OBn

O

OH

HO

5

5

Br Br

OMEMOH

B(OH)24

OH

4 Br

OMEM

+

Pd(PPh3)4 (0.25 equiv)Ba(OH)2 (3.0 equiv)

THF–MeOH–H2O20 °C, 1 h, 58%

O

N

H

H H

H

H

Me

O

himgravine



Roush and co-workers improved the Suzuki coupling re-action by utilizing thallium(I) ethoxide.33 This reagent of-fers distinct advantages over thallium(I) hydroxide interms of commercial availability, stability, and ease ofuse. 1,1-Dibromoolefin is an excellent coupling partnerand many potentially sensitive functional groups such asmethyl esters, geminally alkylated malonate systems, silylethers, and enones, are fully compatible with these reac-tion conditions (Scheme 28).

Brückner and Hanisch described a versatile strategy forthe stereocontrolled synthesis of polyunsaturated buteno-

lides (a-alkenyl-g-alkylidenebutenolide) by sequentialSuzuki coupling reactions with a dibromoiododiene.34

The second Suzuki coupling, site-selective coupling of1,1-dibromoolefin with alkenylboronic acid, gave the de-sired Z-configured monobromoolefin in 79% yield to-gether with a very small amount of its E-isomer (Scheme29).

Scheme 29 The site-selective Suzuki coupling reaction in the ste-reocontrolled synthesis of a-alkenyl-g-alkylidenebutenolide

Shen modified the Suzuki coupling of 1,1-dibromoalk-1-enes utilizing TFP as the ligand on palladium.35 The cou-pling gave the best results when a combination of 1,4-di-oxane and aqueous sodium carbonate was used (Scheme30). It is noteworthy that the reaction avoids the use of thehighly toxic thallium(I) hydroxide, and both alkenyl- andarylboronic acids can be used as substrates.

Scheme 30 The site-selective Suzuki coupling of 1,1-dibromoalk-1-enes using TFP as ligand. R1 = H, 4-CO2Me, 4-MeO, 3-MeO, 2-MeO; R2 = Ph, PhCH=CH.

Scheme 26 The site-selective Suzuki coupling reaction in the syn-thesis of nargenicin A1

TESO

TBDPSO

O

Br

O

O

TESO

TBDPSO

O

Br

O

O

BnO2C

CO2Bn

BHO OH

+

Pd2(dba)3 (15 mol%)

PPh3 (1.7 equiv)

TlOH, THF, 74%

O

O

O

HO

MeOO

HOH

O

N

H

nargenicin A1

H

Br

Scheme 27 The site-selective Suzuki coupling reaction in the syn-thesis of the bottom-half fragment of (+)-tetronolide

EtO2CBr

Br

TBSO

CO2Et

OMOMBr

HO

B(OH)2

+

1) Pd(PPh3)4 (7 mol%) TlOH, THF

2) TBSCl, DMF, imidazole up to 85%

OTBSO

H

H OMOM

bottom-half fragmentof (+)-tetronolide

MOMO

Scheme 28 The site-selective Suzuki coupling reaction using thal-lium(I) ethoxide as additive

BrBr

CO2Me

OTBS

O

OO

Me

OMeOMe

BrR

CO2Me

OTBS

O

OO

Me

OMeOMe

RB(OH)2 (5 equiv)

Pd(PPh3)4 (10 mol%)TlOEt (1.8 equiv)THF–H2O (3:1)

(HO)2B OH(HO)2B

OH81% 77%

+Br

Br

O

O

Br

O

O

(HO)2B

Pd(PPh3)4 (3 mol%)aq NaOH (1.9 equiv)

toluene, 70 °C, 4 h79%

OO

α-alkenyl-γ-alkylidenebutenolide

Br

Br

R2B(OH)2 (1.05 equiv)Pd2(dba)3 (2.5 mol%)

TFP (15 mol%)

Na2CO3 (1.0 M in H2O)1,4-dioxane, 65 °C, 4 h

40–89%

R1

R2

BrR1



Sherburn and co-workers developed a short and modularapproach to didehydro analogues of biologically impor-tant Galbulimima alkaloids.36 The synthesis began with aSuzuki coupling between (S)-lactic acid derived dibro-moalkene and cyclohexene-1-boronic acid, in line withearlier observations by Roush, giving the Z-configuredbromodiene in high yield (Scheme 31).

Scheme 31 The site-selective Suzuki coupling reaction in the syn-thesis of didehydro analogues of Galbulimima alkaloids

Yokoyama and Molander described a sequential, site-selective disubstitution of 1,1-dibromoalkenes using avariety of alkenyltrifluoroborates followed by alkyl-trifluoroborates in the presence of Pd(PPh3)4.

37 The syn-thesis proceeded smoothly in one pot under mild reactionconditions to provide the corresponding trisubstituted,conjugated dienes in excellent yields (Scheme 32).

Scheme 32 The site-selective Suzuki coupling of 1,1-dibromoal-kenes with alkenyltrifluoroborates. R1 = c-Hex, n-heptyl, Ph(CH2)2,etc.; R2 = NC(CH2)3, Cl(CH2)3, Ph(CH2)2, C8H17, MeOOC(CH2)3;R3 = PivO(CH2)4, MeCO(CH2)4, BzO(CH2)4, NC(CH2)4, PhS(CH2)3,Me, Et, H2C=CH(CH2)3.

Roulland and co-workers addressed an unexplored appli-cation of the Suzuki protocol in the cross-coupling of 1,1-dichloroalk-1-enes with 9-alkyl-9-BBNs (Scheme 33).The coupling required the use of a large-bite-angle bis-phosphine ligand (such as Xantphos) to realize an effi-cient preparation of chlorinated internal alkenes of Z-configuration. This could result from a faster decomposi-tion rate of the unusually persistent palladium(0)-chloro-olefin complex due to the geometrical constraints im-posed by the large bite angle and rigid bisphosphineligand.38

Roulland also described the application of the Suzuki cou-pling in the total synthesis of (+)-oocydin A.39 Unfortu-nately, in the reaction of 1,1-dichloroalk-1-enes with 9-alkyl-9-BBN, using their previously described optimalconditions [Pd2(dba)3, Xantphos, KF, and K3PO4 in THFat reflux], the desired compound was produced in only34% yield along with degradation of the starting material.After reinvestigation of the method, they eventually foundthat the use of DPEphos in place of Xantphos in the ab-

sence of potassium fluoride led to an effective cross-cou-pling with a much improved yield of 87% (Scheme 34).

Hiyama and co-workers reported the three-fold cross-cou-pling reaction of 1,1-dibromo-3,3,3-trifluoro-2-tosyloxy-propene with arylboronic acids (Scheme 35), providing asimple and straightforward stereocontrolled approach tothe synthesis of trifluoromethyl-substituted triarylethenes.The presence of a trifluoromethyl group is essential forboth high chemical yields and high Z-selectivity in thefirst coupling reaction.40 It was assumed that a Pd···F in-teraction in the oxidative addition step may be operative.

Scheme 35 Site-selective Suzuki coupling of 1,1-dibromo-3,3,3-trifluoro-2-tosyloxypropene. Ar = Ph, 4-MeOC6H4, 4-MeC6H4, 4-F3CC6H4, 4-BrC6H4, 4-PhC6H4, 3-FC6H4, 2-naphthyl, 3-thienyl.

2.1.5 Alkynes

Myers and Goldberg utilized the palladium-catalyzedsite-selective coupling of dibromoolefin and diyne in thesynthesis of the kedarcidin core structure.41 The coupling

B(OH)2

Br

Br OTBS

Br

OTBS(1.8 equiv)

Pd(PPh3)4 (10 mol%)

THF–MeOH–H2O25 °C, 15 h, 70%

Br

Br

R1

R2BF3K

2) R3BF3K (1.1 equiv) Cs2CO3 (3.0 equiv) 80 °C, 1–5 h, 85–91%

(1.05 equiv)

Cs2CO3 (3.0 equiv)Pd(PPh3)4 (7 mol%) toluene–H2O, 60 °C

R3

R1R2

1)

Scheme 33 Cross-coupling of 1,1-dichloroalk-1-enes with 9-alkyl-9-BBNs. R1 = H, 4-MeO, 4-F, 2,4-(MeO)2; R

2 = Ph, BnO, n-Bu.

Cl

Cl

Cl

B

R2

O

PPh2 PPh2

Xantphos

Pd2(dba)3 (2.5 mol%)Xantphos (5 mol%)

KF–K3PO4 or CsF–Cs2CO3THF, reflux, 46–88%

R2

(1.2 equiv)

R1 R1

MeO2C

Cl

Cl MeO2C

Cl

R2

3

3

Cl

Cln-C5H11

Cl

n-C5H11 R23

Scheme 34 The site-selective Suzuki coupling reaction in the totalsynthesis of (+)-oocydin A

OTBS

ClCl

CO2Et

O

OBz

OMPM

OTBS

Cl

CO2Et

O

OBz

OMPM

+1) 9-BBN, THF

2) Pd2(dba)3 (6 mol%) DPEphos (13 mol%) K3PO4, THF, reflux 44 h, 87%

O

PPh2 PPh2

DPEphos

ArB(OH)2 (1.1 equiv)PdCl2(PPh3)2 (5 mol%)

P(m-tolyl)3 (5 mol%)

5 M aq Cs2CO3 (2.0 equiv)toluene, 80 °C, 24 h

73–96% (Z/E = 87:13–92:8)

Br

BrTsO

F3C Ar

BrTsO

F3C



proceeded optimally in the presence of Pd(PPh3)4, cop-per(I) iodide, and triethylamine, affording the Z-alkenylbromide exclusively in 61% yield (Scheme 36).

Uenishi and Matsui demonstrated a novel and efficientpreparation of geometrically pure branched enynes from1,1-dibromoalk-1-enes by palladium-catalyzed Sono-gashira coupling and subsequent Sonogashira, Suzuki,and Kumada coupling reactions.42 Sonogashira couplingof 1,1-dibromoalk-1-ene with (trimethylsilyl)acetylene inthe presence of PdCl2(dppf) catalyst, copper(I) iodide, anddiisopropylamine stereoselectively afforded the enyne ordienyne in 79–87% yields (Scheme 37).

Scheme 37 Preparation of geometrically pure branched enynes bysite-selective Sonogashira coupling of 1,1-dibromoalk-1-ene

Kim and co-workers reported the Sonogashira couplingreactions of 1,1-dibromoethenes with alk-1-ynes.43 It wasfound that both the solvent polarity and the nature of theamines used as reaction solvents had a significant impacton the selectivity. The selectivity for monoalkynylationwas not high, and significant amounts of the correspond-ing dialkynylated product and the diyne byproduct wereobtained. In the best case of the mono-selective alkynyla-tion, the coupling only resulted in a moderate yield of50% (Scheme 38).

Uenishi and co-workers described the stereoselective So-nogashira coupling of 1,1-dibromoalk-1-enes with acety-lenes using PdCl2(dppf) as a catalyst in benzene. Thereactions selectively gave the (Z)-bromoenyne along with

small amounts of the enediynes (Scheme 39).44 The acet-ylene substituent (R2) played a key role in the selectivity,and effective couplings were limited to those of trialkyl-silylacetylenes.

Scheme 39 Stereoselective Sonogashira coupling of 1,1-dibromo-alk-1-enes with acetylenes. R1 = Bn, TBDPSO; R2 = SiMe3, SiEt3, t-Bu,n-Bu, Ph.

Negishi and co-workers successfully achieved the site-selective Sonogashira coupling of 1,1-dihaloalkenes withtrimethylsilylethyne. The coupling with 1,1-dichloroalk-enes resulted in slightly lower yields than the coupling of1,1-dibromoalkenes.21a When PdCl2(dpephos) was usedas catalyst, the coupling of 1,1-dihaloalkenes gave the de-sired mono-coupled products in 26–92% yields (Scheme40).

Scheme 40 PdCl2(dpephos)-catalyzed selective Sonogashira cou-pling of 1,1-dihaloalkenes. X, Y = Cl or Br; R = n-nonyl, n-Hex,TBSOCH2CH2, Me3SiC≡C, Ph.

2.2 1,2-Dihalogenated Alkenes

Rossi and co-workers reported a highly site-selective pal-ladium-catalyzed synthesis of stereoisomerically pure(Z)- and (E)-alkyl-2-bromo-3-(hetero)arylpropenoatesfrom easily available (Z)- and (E)-alkyl-2,3-dibromopro-penoates.45 The coupling with (hetero)arylzinc halides oc-curred at the 3-position and gave the coupling products in52–85% yields (Scheme 41).

They further found that alkylzinc reagents were also suit-able in the reaction when PdCl2(dppf) was used as a cata-lyst precursor.46 Coupling with butyl- and isobutylzincchloride gave stereoisomerically pure (Z)-3-alkyl-2-bro-mopropenoates in 63% and 79% yields, respectively(Scheme 42).

Sulikowski and co-workers reported an application of pal-ladium-catalyzed site-selective Suzuki coupling in the in-vestigation into a biomimetic approach toward CP-225,917 and CP-263,114.47 The reaction of a mucobromicacid derivative with alkenylboronate gave a dienoate, and

Scheme 36 Site-selective coupling of dibromoolefin and diyne inthe synthesis of the kedarcidin core structure

N

O

Br

Br

Cl

TBS

HO

OOH

TBS

OTBS

OO

TBS

OTBSBr

TBS

O

N

HO

Cl

+

Pd(PPh3)4 (10 mol%)CuI (0.3 equiv)Et3N (2.0 equiv)

Et2O, 23 °C, 61%

PhBr

Brn

OTBSBr

Ph

Brn

SiMe3

OTBS

Me3Si

PdCl2(dppf)(5 mol%)

CuI, i-Pr2NHbenzene, r.t.

n = 0 or 1

SiMe379–87%

81%

BrBr

Scheme 38 The site-selective Sonogashira coupling of 1,1-dibro-moethene with an alk-1-yne

Br

BrAr

Br

Ar

(CH2)2OHPdCl2(PPh3)2 (10 mol%)

Ph3P (20 mol%), CuI (20 mol%)Et3N (4 equiv), toluene, 5 h, r.t.

50%

(CH2)2OH (2.2 equiv)

Br

BrR1

Br

R1

R2R2 (1.5 equiv)PdCl2(dppf) (5 mol%)

CuI (4 mol%), i-Pr2NH (3 equiv)

benzene, 10–60 min, r.t.15–87%

RX

XR

X

SiMe3PdCl2(dpephos) (5 mol%)CuI (5 mol%), i-Pr2NH (2 equiv)

benzene, 0–60 °C, 1–24 h26–92%

SiMe3



subsequent cross-coupling with a silyl ketene acetal gavethe disubstituted product in 59% yield (Scheme 43).

Bellina, Rossi and co-workers found that 4-aryl-3-bromo-2(5H)-furanones were synthesized from easily available3,4-dibromo-2(5H)-furanone.48 Coupling with arylboronicacids or with aryl(trialkyl)stannanes selectively gave thedesired products in satisfactory yields (Scheme 44).

Scheme 44 The site-selective arylation of 3,4-dibromo-2(5H)-fura-none. Ar1 = Ph, 3-Cl-4-MeOC6H3, 4-ClC6H4; Ar2 = Ph, 4-MeSC6H4,4-MeOC6H4, 3-FC6H4, 4-MeC6H4, 3-Cl-4-MeOC6H3; R = Bu, Me.

Bellina and co-workers found that 3,4-dibromo-2(5H)-furanone also underwent a site-selective cross-couplingreaction with alkylboronic acids in the presence of catalyt-ic amounts of PdCl2(MeCN)2 and a large molar excess ofsilver(I) oxide to provide the corresponding 4-alkyl-3-bromo-2(5H)-furanones in satisfactory yields (Scheme45).49

Scheme 45 The site-selective alkylation of 3,4-dibromo-2(5H)-furanone. R = n-octyl, n-Bu, t-BuO(CH2)6, t-BuOCH(Me)(CH2)5.

2.3 Trihalogenated Alkenes and Others

Compared with 1,1- or 1,2-dihaloalkenes, the coupling re-actions of 1,1,2-trihaloalkenes with nucleophilic reagentsare more complicated and the selectivity varies under dif-ferent reaction conditions. Only a few examples that arewithin the scope of this review have been reported.

Linstrumelle and Ratovelomanana found that alkyl Grig-nard reagents reacted easily with trichloroethylene in thepresence of palladium or nickel catalysts at room temper-ature, and selectively led to 1,1-dichloroolefins in goodyields (Scheme 46).50

Scheme 46 Site-selective alkylation of trichloroethylene. R = n-oc-tyl, n-Hex, i-Bu, i-Pr, c-Hex.

Interestingly, Minato and co-workers found that the cou-pling reactions of trichloroethylene with aryl Grignard re-agents selectively gave 1,2-dichloroolefins as the mainproducts (Scheme 47).8

Scheme 47 Site-selective arylation of trichloroethylene. R = Ph, 4-ClC6H4, 2-thienyl.

Roulland and co-workers reported a Suzuki coupling oftrichloroethylene catalyzed by Pd2(dba)3–Xantphos. De-pending on the reaction conditions, the coupling tookplace at either the bischlorinated or the monochlorinatedcarbon. Under their reaction conditions, two productswere observed, the 1,2-dichloroalk-1-ene and themonochloroolefin, in 29% and 21% yields, respectively(Scheme 48).38

Chelucci and Baldino reported stereoselective tandemarylation–arylation of 1,1-dihaloalk-1-enes having a bro-mopyridyl group to give trisubstituted alkenes under

Scheme 41 Site-selective coupling of (Z)- and (E)- alkyl-2,3-dibro-mopropenoates with arylzinc reagents. R1 = Me, Et; Ar1 = Ph, 2-thie-nyl, 4-FC6H4, 3,4-(methylenedioxy)phenyl; Ar2 = Ph, 4-MeOC6H4,4-EtO2CC6H4.

COOR1

Br

H

Br

Ar1ZnCl (1.2 equiv)Pd(PPh3)4 (5 mol%)

THF, 20 °C, 16–25 h77–85%

COOR1

Br

H

Ar1

COOEt

Br

Br

HCOOEt

Br

Ar2

H

Ar2ZnCl (1.2 equiv)Pd(PPh3)4 (5 mol%)

THF, 20 °C, 2–6 h52–79%

(Z)

(E) (E)

(Z)

Scheme 42 Site-selective coupling of (Z)-alkyl-2,3-dibromoprope-noates with alkylzinc reagents. R = n-Bu, i-Bu.

COOMe

Br

H

Br

RZnCl (1.2 equiv)PdCl2(dppf) (5 mol%)

THF, 20 °C, 24 h63–79%

COOMe

Br

H

R

(Z) (Z)

Scheme 43 The site-selective Suzuki coupling of mucobromic acidderivative with alkenylboronate

O

OBr

Br

OTBS

OB

O

O

OBr

OTBS

PdCl2(PPh3)2 (cat.), aq KOAcbenzene, reflux

O

O

OTBS

t-BuO2C

(2 equiv)

PdCl2(o-Tol3P)2 (3 mol%)KOAc

THF, reflux, 59% (2 steps)

OTBS

Ot-Bu

OO

BrBr

OO

Ar1BrAr1B(OH)2 (1.1 equiv)

PdCl2(MeCN)2 (5 mol%)AsPh3 (20 mol%), Ag2O (3 equiv)

THF, 65 °C, 18–26 h, 61–79%

OO

BrBr

OO

Ar2BrAr2SnR3 (1.1 equiv), AsPh3 (10 mol%)

Pd2(dba)3 (2.5 mol%) or PdCl2(PhCN)2 (5 mol%)

NMP, 20 °C, 22–250 h, 59–76%

OO

BrBr RB(OH)2 (1.1 equiv)

PdCl2(MeCN)2 (5 mol%)Ph3As (20 mol%), Ag2O (3 equiv)

THF, reflux, 18–23 h, 69–79% OO

RBr

Pd(PPh3)4 or Ni(PPh3)4 (5 mol%)

Et2O–benzene, 20 °C6 h, 52–81%

+ RMgBr

Cl

Cl

Cl R

Cl

Cl

Cl

Cl

ClRMgBr (1.2 equiv)

PdCl2(PPh3)2 (1 mol%)

Et2O, reflux, 3 h55–90%

Cl

R

Cl



Suzuki coupling conditions.51 It is noteworthy that in thesequential cross-coupling processes, the palladium inser-tion occurred selectively on the carbon–bromine bond onthe alkene moiety, notwithstanding the high electrophilic-ity of the bromine–pyridine bond (Scheme 49).

Scheme 49 Suzuki coupling reactions selectively occur on the car-bon–bromine bond of the alkene moiety. Ar = Ph, 4-O2NC6H4, 3-ClC6H4, 3-Me-4-MeOC6H3, 3-pyridyl, 5-Me-2-thienyl.

Li and Fang developed the copper-catalyzed intramolecu-lar coupling of alkenyl bromides with alcohols and de-scribed the first examples of transition-metal-catalyzedreactions to predominantly provide 4-exo cyclization.52

The results revealed that the 4-exo ring closure was funda-mentally preferred over 5-exo, 6-exo and 6-endo modes(Scheme 50). However, the analogous palladium-cata-lyzed reaction preferred to undergo 5-exo cyclization.

Scheme 50 Site-selective O-alkenylation of alcohols. R1 = H, Bn;R2 = H, Me, Et; R3, R4 = H, Me.

They further found that the copper(I)-catalyzed intramo-lecular carbon–nitrogen coupling of amides with alkenylbromides also occurred and preferred the 4-exo ring clo-sure to form b-lactams (Scheme 51).53

Scheme 51 Preference of 4-exo ring closure. R = Ph, Bn; n = 1, 2.

Triflate is also a very popular leaving group used in tran-sition-metal-catalyzed cross-coupling reactions. It wasemployed instead of halogens to achieve higher yields orspecial selectivity in some cases. Suffert and co-workersutilized site-selective cross-coupling of alkynes with ditri-flate compounds under palladium(0) catalysis in the syn-thesis of highly unsaturated polycyclic rings and achievedyields of 66–79%.54 Interestingly, site-preference depend-ed on the ring size of the ditriflates (Scheme 52).

Scheme 52 Site-selective cross-coupling of ditriflates

3 Di- and Polyhalogenated Heteroarene Deriv-atives

Heterocycles and their derivatives are widespread in na-ture. They can be found in materials as well as in pharma-ceuticals. Transition-metal-catalyzed site-selective cross-coupling of di- or polyhalogenated heteroarene deriva-tives with various nucleophiles is becoming an efficientmethod to synthesize multiply substituted heterocycles. In

Scheme 48 Site-selective Suzuki coupling of trichloroethylene

Ph 9-BBN+Cl

Cl

Cl

Cl

Cl Ph

Cl

PhPh

+

29% 21%

Pd2(dba)3 (2.5 mol%)Xantphos (5 mol%)

KF–K3PO4, THF, reflux

N BrBr

Br

N BrBr

Ar

N NBrBr

Ar

N Br

BO

O

arylboronic acid or ester (1.05 equiv)

Pd2(dba)3 (2.5 mol%), TFP (15 mol%)aq Cs2CO3 (2 equiv)

1,4-dioxane, 65 °C, 10–17 h, 65–87%

(1.05 equiv)

Pd2(dba)3 (5 mol%), TFP (30 mol%)aq Cs2CO3 (2 equiv)

1,4-dioxane, 65 °C, 30–40 h, 52–77%

Br OH

BrR1

Br

Br

OH

OH Br

Br

Br BrOH OBr

O Br

O Br

CuI (10 mol%)1,10-phenanthroline

(20 mol%)Cs2CO3 (2 equiv)

reflux, 4–24 h60–83%

R2

R3

R4

BrR1

R2

R3

R4

O

Br NHR

Br

O

n

Br NHR

O

Br

N

O

R

Br

n

N

Br

O

R

CuI (5 mol%)Me2NCH2CO2H⋅HCl

(10 mol%)K2CO3 (2 equiv)

reflux, 17–25 h96–99%

O O

SnBu3

OTf

OTf

O O

SnBu3

TfO

Pd(PPh3)4 (4 mol%)CuI (10 mol%)

benzene–i-Pr2NH (3:1)79% 79%

O O

SnBu3

Pd(PPh3)4 (4 mol%)CuI (10 mol%)

benzene–i-Pr2NH (3:1)72% (n = 1)66% (n = 2)

OTf

OTfn

TfO n



early 2005, an excellent comprehensive review was re-ported by Bach and co-workers, describing site-selectivecross-coupling reactions of multiply halogenated hetero-cycles.5a In 2007, Fairlamb summarized palladium-catalyzed site-selective reactions by highlighting the elec-tronic properties of the heterocycles.5b Here, we summa-rize the most recent works published in this area,including the original studies and their applications insynthesis.

3.1 Five-Membered Heteroarene Derivatives

Amb and Rasmussen developed site-selective cross-cou-pling reactions of 2,3,5-tribromothiophene with arylzincreagents (Scheme 53).55 Taking advantage of both elec-tronic differences between the 2- and 3-positions and ster-ic differences between the 2- and 5-positions of thethiophene ring, the cross-coupling reactions occurredpreferentially in the order: 5-position > 2-position > 3-po-sition.

Scheme 53 C5-Selective cross-coupling reaction of 2,3,5-tribro-mothiophene. R = 2-thienyl, 5-Me-2-thienyl, 3-C6H13O-2-thienyl, 4-MeOC6H4, Ph, 4-BrC6H4, 4-F3CC6H4.

Langer and co-workers reported site-selective Suzukicoupling reactions of tetrabromothiophene.56 The reactiontook place selectively at the two a-positions of thethiophene ring to give 2,5-diaryl-3,4-dibromothiophenesas the main products in the presence of 6 mol% Pd(PPh3)4

and 2.2 equivalents of boronic acid (Scheme 54). Increas-ing the catalyst loading to 10 mol% and using 5 equiva-lents of boronic acid resulted in no selectivity and led totetraarylthiophenes.

Scheme 54 Selective diarylation of tetrabromothiophene at the a-positions. Ar = Ph, 4-MeOC6H4, 2-MeOC6H4, 4-MeC6H4.

Further studies showed that N-methyltetrabromopyrroleunderwent a similar Suzuki coupling reaction to give N-methyl-5-aryl-2,3,4-tribromopyrroles in high yields. Sub-sequent coupling with another arylboronic acid selective-ly produced N-methyl-2,5-diaryl-3,4-dibromopyrrole asthe main product (Scheme 55). Further Suzuki couplingleading to N-methyltetrabromopyrrole was also feasibleby careful adjustment of the reaction conditions.57

Schröter and Bach reported the Suzuki coupling reactionof di- and tribrominated pyrroles. The results showed thatmonosubstitution at the 5-position was preferred with a

variety of boronic acids using Pd2(dba)3 and TFP as cata-lyst (Scheme 56). Further Suzuki coupling at the remain-ing bromo-substituted positions was also feasible atslightly elevated temperature.58

Scheme 56 Suzuki coupling of di- and tribrominated pyrroles.Ar1 = Ph, 4-MeC6H4, 4-t-BuC6H4, 4-MeOC6H4, 3-MeO-4-i-PrOC6H3, 4-ClC6H4, 3-thienyl; Ar2 = Ph, 2-MeC6H4, 4-MeC6H4, 4-t-BuC6H4, 4-MeOC6H4, 3-MeOC6H4, 3,4,5-(MeO)3C6H2, 4-BnOC6H4,4-ClC6H4.

De Lera and co-workers reported a successful utilizationof site-selective palladium-catalyzed cross-coupling of2,4-dibromo-5-hydroxymethylthiazole with organometal-lic derivatives in the synthesis of the potent PPARb/d ag-onist GW501516 and analogues.59 Both Stille and Suzukicouplings selectively gave 2-arylated thiazoles as themain products (Scheme 57).

Scheme 57 Site-selective reaction in the synthesis of the potentPPARb/d agonist GW501516 and analogues. Reagents and condi-tions: (1) M = SnBu3 (1.3 equiv), Pd2(dba)3/Ph3As (cat.), DMF,70 °C, 24 h, 68% yield; (2) M = B(OMe)2 (1.3 equiv), Pd(PPh3)4

(cat.), K2CO3, toluene, 100 °C, 87%.

SBr Br

Br

SR Br

BrRZnCl (1.2 equiv)PdCl2(dppf) (2.5 mol%)

Et2O, 11–63%

SAr Ar

BrBrArB(OH)2 (2.2 equiv)Pd(PPh3)4 (6 mol%)

K3PO4 (4 equiv)

1,4-dioxane or toluene–H2O (4:1)90 °C, 12–24 h, 32–77%SBr Br

BrBr

Scheme 55 Site-selective Suzuki coupling of N-methyltetrabromo-pyrrole. R1 = 3-PhC6H4, 3-ClC6H4, 4-EtC6H4, 2-MeOC6H4, 4-MeC6H4, 3,5-Me2C6H3; R

2 = 3-ClC6H4, 4-MeC6H4.

N

Me

Br Br

Br Br N

Me

Br Br

R1 Br

N

Me

Br Br

Br

R1B(OH)2 (1.1 equiv)Pd(PPh3)4 (6 mol%)

K3PO4 (4 equiv)

1,4-dioxane or toluene–H2O (4:1)90 °C, 12 h, 66–81%

R2B(OH)2 (1.1 equiv)Pd(PPh3)4 (10 mol%)

K3PO4 (4 equiv)

DMF–toluene–EtOH–H2O (4:1:1:1), reflux48 h, 45–51%

N

Me

Br Br

R2

mesitylene–EtOH–H2O (5:1:1)Cs2CO3, 80 °C, 6–24 h

34–86%

NH

Br

Br NO2 NH

Br

Ar2 NO2

Ar2B(OH)2

Pd2(dba)3 (cat.), TFP (cat.)

NH

Br

Br CO2Et5

Br

5

NH

Br

Ar1 CO2Et

Br

mesitylene–EtOH–H2O (5:1:1)Cs2CO3, 150 °C, 8–24 h

33–65%

Ar1B(OH)2

Pd2(dba)3 (cat.), TFP (cat.)

S

NBr

BrHO

S

NBr

HO

CF3

CF3M

S

N

S

CF3

O

HO2CGW501516



They also studied the mechanism of the site-selective se-quential cross-coupling reactions of dibromothiophenes/dibromothiazoles and arylboronic acids aided by 19F and31P NMR spectroscopy.60 It was found that the transmeta-lation was the rate-limiting step for both sequential substi-tution processes, and that the extremely facile oxidativeaddition at the carbon–bromine bond next to the sulfuratom of the heterocycle instead determined the positionalselectivity.

Greaney and co-workers found that the site-selectiveSuzuki coupling of 4-phenyl-2,5-diiodooxazole preferen-tially occurred at the 2-position (Scheme 58).61 With asubsequent Stille coupling reaction, the procedure easilyafforded trisoxazoles in high yield.

Scheme 58 C2-Selective Suzuki coupling of 4-phenyl-2,5-diio-dooxazole

3.2 Six-Membered Heteroarene Derivatives

Bach and co-workers reported the synthesis of the hetero-cyclic core of a thiazolyl peptide using site-selectiveNegishi cross-coupling. The site-selectivity was not per-fect, and the desired 6-substituted 2-bromopyridine wasaccompanied by the 2-substituted 6-bromopyridine with asite-selective ratio (s.r.) of 6.5:1 (Scheme 59).62

Scheme 59 Negishi cross-coupling in the synthesis of the hetero-cyclic core of a thiazolyl peptide

Majumdar and Mondal used the site-selective Sonoga-shira cross-coupling in the synthesis of pyrrolopy-ridines.63 It was found that the reaction occurredpreferentially at the position ortho to the amine group andno cyclized product (indole derivative) was detected in thereaction mixture (Scheme 60).

Braun and co-workers found that the reaction of penta-fluoropyridine with Pd[P(i-Pr)3]2 selectively affordedtrans-{PdF(4-C5NF4)[P(i-Pr)3]2}. This palladium com-plex served as a catalyst for the Stille cross-coupling reac-tion of pentafluoropyridine with tributyl(vinyl)stannane

to give 4-vinyltetrafluoropyridine with a turnover number(TON) of 6 (Scheme 61).64

They also reported the site-selective cross-coupling reac-tions of 5-chloro-2,4,6-trifluoropyrimidine with arylbo-ronic acids catalyzed by trans-[NiF(4-C4N2ClF2)(PPh3)2]which was prepared by oxidative addition of 5-chloro-2,4,6-trifluoropyrimidine to Ni(cod)2 in the presence oftriphenylphosphine (Scheme 62).65 The reaction gave the4,6-dicoupled products selectively in 37–88% yields.

Scheme 62 Site-selective diarylation of 5-chloro-2,4,6-trifluoropy-rimidine. R = Ph, 4-MeC6H4, 4-F3CC6H4.

Monteiro, Vors, Balme, and co-workers found that theSuzuki coupling reaction of 3,5-diiodo-4-oxypyridin-2(1H)-ones reacted selectively at the less-hindered 5-po-sition (Scheme 63).66 They assumed that steric factorsplayed a role in the relative rates of coupling.

O

NI

I PhO

NI

PhO

NPhPd2(dba)3 (5 mol%)PCy3 (10 mol%), K2CO3, DMF

microwave, 150 °C, 46%

O

NB

Ph O

O

N

Br

N S

BnHNOC

NS

COOMe

N

Br

Br

N S

BnHNOC

ZnCl

NS

COOMe

PdCl2(PPh3)2(cat.)

THF–DMA78% (s.r. = 6.5:1)

Scheme 60 Site-selective Sonogashira cross-coupling reaction inthe synthesis of pyrrolopyridines. R = H, OBn.

NBr Br

NH2

N

BrBr

NH2

NBr

NH2

R

N

Br

NH2

R

PdCl2(PPh3)2 (5 mol%)CuCl2 (10 mol%)

DMF–Et3N (5:2), 110 °C, 2 h72–75%

R

Scheme 61 Catalytic Stille cross-coupling reaction of pentafluoro-pyridine with Bu3SnCH=CH2

N

F

F

F

F

F N

F

F

F

F

N

Pd

F

F

F

F

F

(i-Pr)3P P(i-Pr)3

(10 mol%)

Bu3SnC2H3 (1 equiv)Cs2CO3, THF, 50 °C

48 h, TON = 6

N N

F

F F

Cl

N N

F

R R

Cl

N

N

F

F

Ni

Cl

F

PPh3

PPh3

(10 mol%)

RB(OH)2 (2 equiv)Cs2CO3, Ph3P, THF50 °C, 36 h, 37–88%

Scheme 63 The Suzuki coupling reaction of 3,5-diiodo-4-oxypyri-din-2(1H)-ones

N

Me

OMe

II

O N

Me

OMe

I

O

MeO

MeO B(OH)2

(1.4 equiv)

Pd(OAc)2 (5 mol%), TPPTS (15 mol%)i-Pr2NH, MeCN–H2O, 60 °C, 36 h, 72%



Alvarez-Builla and co-workers reported a site-selectiveSuzuki coupling reaction on 3¢,5¢-dibromopyridinium N-(2¢-azinyl)aminides. A series of 3¢-aryl (or heteroaryl)-5¢-bromopyridinium N-(2-pirazinyl)aminides were obtainedin good yields.67 The substitution occurred preferentiallyat the 3-position, vicinal to the aminide nitrogen, and thisobserved site-selectivity was ascribed to the increased sta-bility of the palladium intermediate (Scheme 64).

Scheme 64 Site-selective Suzuki coupling of 3¢,5¢-dibromopyridi-nium N-(2¢-azinyl)aminides. R = Ph, 4-MeOC6H4, 3,5-Me2C6H3, 4-AcC6H4, 3-thienyl, 3-benzothienyl, 3-pyridyl, 4-pyridyl, 5-pyridyl.

3.3 Other Heteroarene Derivatives

Herdewijn and co-workers synthesized a 5,7-dichloropy-rido[4,3-d]pyrimidine scaffold and studied its catalyticsite-selective Sonogashira, Suzuki, and Stille cross-cou-pling reactions.68 It was found that in all the mentioned re-actions, only a single 5-substituted isomer was isolated(Scheme 65).

Routier and co-workers developed a new efficient route todissymmetric 2,4-di(hetero)arylpyrido[3,2-d]pyrim-idines via site-selective Suzuki or Stille cross-coupling re-actions.69 When 2,4-dichloropyrido[3,2-d]pyrimidine wasallowed to react with near stoichiometric amounts of re-

agents, only 4-arylated compounds were observed bothfor Suzuki and Stille coupling reactions, indicating thelack of reactivity at the 2-Cl versus the 4-Cl position(Scheme 66).

3.4 Mechanism

Mechanistic studies on the site-selective cross-couplingof heterocycles bearing multiple halogens have concen-trated on finding and predicting the origin of the selectiv-ity. NMR spectroscopy and theoretical calculations arethe most commonly used methods.

Despite the intuitive role of steric and directing groups,the bond dissociation energy (BDE) of the respectivecarbon–halogen bond usually accounts for the observedselectivity. However, this is not always the case.

Merlic, Houk, and co-workers found that the selectivity inpalladium-catalyzed cross-coupling reactions of hetero-cycles bearing multiple identical halogens is determinedby both the strength of the carbon–halogen bond (relatedto BDE) and the LUMO of the heterocycles (related tofrontier molecular orbital interactions) (Figure 1).70

Figure 1 Molecular orbital interaction between HOMOPd andLUMOheteroarene in the oxidative addition process

4 Di- and Polyhalogenated Benzene Deriva-tives

Transition-metal-catalyzed cross-coupling reactions ofhalogenated benzene derivatives with nucleophilic re-agents such as organometallic reagents, alkenes, alkynes,amines, and alcohols are among the most useful reactionsin organic synthesis. Cross-coupling reactions of multiplyhalogenated benzene derivatives are also very useful syn-thetically, especially if one of the halogen atoms is site-selectively converted into another group. The selectivityof the reaction is affected both by the electronic propertiesand the steric circumstances, so the presence and proper-ties of other substituents have a great influence on the se-lectivity.

4.1 Polyhalogenated Benzenes

Fahey reported the oxidative addition of 1,2,4-trichlo-robenzene to nickel(0) complexes.71 Trichlorobenzenewas treated with (Et3P)2Ni(C2H4) and the crude mixturewas dissolved in diethyl ether saturated with hydrogenchloride. Oxidative addition occurred preferentially at the2-position (Scheme 67). Although this is not an exampleof catalytic cross-coupling, this provides important infor-mation about selectivity in the oxidative addition step.

N

N

N

N

BrBr

N

N

N

N

BrR

N

N

Y

N

Br

PdL

L Ar

RB(OH)2 (1.1 equiv)Pd(PPh3)4 (1–5 mol%)

K2CO3 (10 equiv)

toluene–EtOH (4:1)65–87%

Scheme 65 Reagents and conditions: R = 3-hydroxypropynyl,Sonogashira coupling, method A: propargyl alcohol, Et3N,Pd(OAc)2(PPh3)2 (cat.), dioxane, reflux, N2, 24 h; R = Ph, Stille cou-pling, method B: PhSnBu3, Pd(PPh3)4 (cat.), dioxane, reflux, N2, 1 h;R = 3,4-(MeO)2C6H3, Suzuki coupling, method C: 3,4-(MeO)2C6H3B(OH)2, K2CO3, Pd(PPh3)4 (cat.), dioxane–H2O, reflux,N2, 2 h.

N

N

N

OEt

Cl

Cl

N

N

N

OEt

Cl

R

Sonogashira, Suzuki, Stille

Scheme 66 Site-selective Suzuki and Stille cross-coupling of 2,4-dichloropyrido[3,2-d]pyrimidine. Ar = Ph, 2-naphthyl, 3-MeOC6H4,2-thienyl, 2-furyl, 3,4-(methylenedioxy)phenyl, 2-pyridyl, 2-N-SO2Ph-indole.

NN

N Cl

Cl

NN

N Cl

Ar

ArB(OH)2 (1.05 equiv) and K2CO3 (1.5 equiv) or ArSnBu3 (1.05 equiv)

and LiCl (2.8 equiv)Pd(PPh3)4 (0.05 equiv)

toluene, 100 °C, 50–89%

PH3H3P

dxy

π*

Pd



Scheme 67 Selectivity of the oxidative addition of 1,2,4-trichloro-benzene to (Et3P)2Ni(C2H4)

Nakamura and co-workers found that nickel-catalyzedarylation of 1,2,3-trichlorobenzene selectively gave the1,3-diphenylated compound in a high yield of 85%, prob-ably because of steric effects (Scheme 68).72

Scheme 68 Site-selective coupling of 1,2,3-trichlorobenzene.R = 4-MeC6H4.

Aryl fluorides were regarded as uncommon coupling part-ners for transition-metal-catalyzed cross-coupling reac-tions due to the strong carbon–fluorine bond and resultinglack of reactivity for oxidative addition. This belief has re-sulted in the relative lack of development of transition-metal-catalyzed site-selective cross-coupling reactions ofdi-, poly-, and perfluoroaromatic compounds.

Saeki and co-workers investigated the nickel- and palladi-um-catalyzed cross-coupling reactions of polyfluorinatedarenes and alkenes with Grignard reagents.73 The cou-pling of di- or trifluorobenzenes with 1.5 equivalents of p-tolylmagnesium bromide catalyzed by PdCl2(dppf) gavemonocoupled products selectively (Scheme 69). Howev-er, using NiCl2(dppp) as catalyst, the reactions were notselective and di- or triarylated compounds were the mainproducts.

Scheme 69 Palladium-catalyzed site-selective cross-coupling oftrifluorobenzenes and a Grignard reagent

Radius and co-workers reported the first example of anactive catalytic system for the Suzuki coupling reaction ofperfluorinated arenes.74 Using the N-heterocyclic carbene(NHC)-stabilized nickel complex [Ni2(i-Pr2Im)4(cod)] [i-Pr2Im = 1,3-di(isopropyl)imidazol-2-ylidene] as the cata-lyst, the coupling of perfluorotoluene with phenylboronicacids selectively gave para-arylated products in 44–66%yields. The reaction of perfluorinated biphenyl and phe-nylboronic acid gave the para-monoarylated product in66% isolated yield (Scheme 70).

Scheme 70 Site-selective Suzuki coupling of perfluorinated arenes.R = OMe, Me, Ph.

Takahashi and co-workers studied the early-transition-metal-catalyzed coupling reactions of fluoroarenes withphenethylmagnesium chloride.75 Cyclopentadienyltitani-um(IV) trichloride and tantalum(V) chloride showedmuch higher activity than the others. The reaction of2,3,4,5,6-pentafluorotoluene with phenethylmagnesiumchloride in the presence of tantalum(V) chloride selective-ly gave 4-(1-phenethyl)-2,3,5,6-tetrafluorotoluene as thesole product (Scheme 71).

Scheme 71 Tantalum(V) chloride catalyzed para-selective cou-pling of 2,3,4,5,6-pentafluorotoluene

SanMartin, Domínguez, and co-workers reported on thepalladium-catalyzed site-selective reactions of enolatesderived from aryl methyl ketones with dibromobenzenederivatives as shown in Scheme 72.76 They also used di-bromo heteroarenes. The products were converted intooxcarbazepine derivatives through carbon–nitrogen bondformation.

Scheme 72 Site-selective reaction of a methyl ketone with a dibro-mobenzene

Yamaguchi and co-workers reported the rhodium-cata-lyzed substitution reaction of aryl fluorides with disul-fides and found an interesting para-orientation in thepolyarylthiolation of polyfluorobenzenes (Scheme 73).77

The origin of this p-difluoride rule is an interesting sub-

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl1) (Et3P)2Ni(C2H4)

2) HCl, Et2O

87% 6%7%

+ +

Cl

ClCl

Cl

RR

RMgBr (3.5 equiv)Ni(acac)2 (5 mol%)

ligand (5 mol%)

Et2O, r.t., 24 h85%

OH PPh2

ligand

F

THF, reflux, 48 h, 69%

F4-MeC6H4MgBr (1.5 equiv)

PdCl2(dppf) (1 mol%)F

FF

CF3

F

F

F

F

F

CF3

F

F

F

F

R

F

F

F

F

F

F

F

F

F FF

F

F

F

F

F

F

F

F Ph

4-RC6H4B(OH)2 [Ni2(i-Pr2Im)4(cod)] (2 mol%)

Et3N (3 equiv)THF, 60 °C, 12 h, 44–66%

PhB(OH)2 [Ni2(i-Pr2Im)4(cod)]

(2 mol%)K2CO3 (3 equiv)

THF, 60 °C, 18 h 66%

F

F

F

F

F

F

F

F

F

Ph

PhCH2CH2MgCl (1.5 equiv)TaCl5 (5 mol%)

THF–DME, 50 °C, 24 h73%

Pd(OAc)2 (4.4 mol%)Xantphos (8.5 mol%)Cs2CO3 (1.4 equiv)

toluene–H2O, 120 °C94%

O

HN

Ts+

Br

Br

FF

O

HN

Ts

F F

Br

(2.4 equiv)



ject. An explanation for this is the minimization of the di-pole through formation of the p-difluoride structure.Alternatively, it could be due to an unusually high reactiv-ity of p-arylthiolated fluorobenzenes toward the rhodiumcatalyst.

Scheme 73 The p-difluoride products and their yields in rhodium-catalyzed polyarylthiolation of polyfluorobenzenes. Ar = 4-MeC6H4.DPPBZ = 1,2-bis(diphenylphosphino)benzene.

4.2 With Electron-Withdrawing Groups

Singh and Just reported the first site-selective cross-cou-pling of dibromobenzenes with alkynes.78 The reaction of1,2-dibromo-4-nitro- or 1,2-dibromo-3-nitrobenzeneswith hept-1-yne in triethylamine as solvent in the presenceof Pd(PPh3)4 and Cu2Br2 gave the para- or ortho-substi-tuted compounds as the only detectable products (Scheme74). These results indicate that the reaction occurred pref-erentially at the less electronically negative carbons.

Scheme 74 Site-selective cross-coupling of dibromobenzenes withalkynes

Blum and co-workers developed the palladium-catalyzedcross-methylation of aryl chlorides by stabilized dimeth-ylaluminum and -gallium reagents.79 The activation of thechlorine atom was affected by introducing strong elec-tron-withdrawing groups into the aromatic moiety. Themethylation of 1,2-dichloro-4-nitrobenzene catalyzed by

Pd(PPh3)4 gave 2-chloro-4-nitrotoluene as the sole prod-uct (Scheme 75). Only the chloride at the position para tothe nitro group reacted.

Tour and co-workers synthesized several oligo(phenyleneethynylene)s containing easily reducible nitro or quinonefunctionalities for incorporation into molecular electronicdevices.80 The palladium-catalyzed site-selective Sono-gashira and Suzuki coupling reactions were effectivelyused in their synthesis, and all the couplings occurred se-lectively at the position ortho to the nitro group (Scheme76).

Scheme 76 Site-selective Sonogashira and Suzuki coupling of di-bromobenzene derivatives. R1 = H, NH2, NHAc; R2 = Ph, 4-H2NC6H4; 4-pyridyl. R3 = H, TMS (K2CO3 and MeOH were added).

Wolf and co-workers developed a site-selective copper-catalyzed cross-coupling reaction for effective aminationof 2-chlorobenzoic acids with aniline derivatives.81 Thereaction tolerated a variety of functional groups, and re-sulted in high to excellent yields with both electron-defi-cient and electron-rich reagents. The reaction of 2,4-dichlorobenzoic acid with 4-methoxyaniline gave the 2-aminated product selectively in 86% yield (Scheme 77). Itmust be mentioned that the amination of 5-bromo-2-chlo-robenzoic acid also gave the 2-aminated product in 85%yield.

Scheme 77 Site-selective amination of 2,4-dichlorobenzoic acid

SAr

F

F

F

F

SAr

F

F

F

F

F

F

RhH(PPh3)4 (2 mol%)DPPBZ (4 mol%)PPh3 (0.5 equiv)

ArSSAr

chlorobenzene80 °C, 95%

SAr

F

F

F

F

76%

SAr

SAr

F

F

74%

F

SArArS

40%F

F

SAr

87%F

ArS

F

SAr

74%F

Br

Br

O2N

Br

BrO2N

Br

O2N C5H11

Br

O2N

C5H11

Pd(PPh3)4 (2 mol%)Cu2Br2 (3 mol%)Et3N, r.t., 10 min

92%

hept-1-yne (1 equiv)

Pd(PPh3)4 (2 mol%)Cu2Br2 (3 mol%)

Et3N, r.t., 5 h82%


Scheme 75 Cross-methylation of 1,2-dichloro-4-nitrobenzene by astabilized dimethylaluminum reagent

Cl

Cl

NO2

Cl

NO2

Al

Me

OOAl

Me

O O

Me

MeMeMe

Pd(PPh3)4 (2 mol%)

benzene, 90 °C, 15 min58%

(1 equiv)

Br Br

O2N

NHAc

Br

O2N

NHAcPhB(OH)2 (1.2 equiv)

PdCl2(PPh3)2 (5 mol%)PPh3 (10 mol%)

Cs2CO3 (1.5 equiv)

toluene, 60 °C, 2 d64%

Br Br

O2N

R1

Br

O2N

R1

R2

R2 R3

PdCl2(PPh3)2 (1–5 mol%)or Pd(dba)2 (5 mol%)

CuI (1–5 mol%)

THF, r.t. or 60 °C39–88%

NH2

MeO (1.05 equiv)

Cu (9 mol%), Cu2O (4 mol%)K2CO3 (1 equiv), EtOCH2CH2OH

130 °C, 24 h, 86%

COOH

Cl

Cl

COOHHN

Cl

OMe



It was further found that these optimized reaction condi-tions could also be used in the site-selective amination ofbromobenzoic acids.82 The coupling of 2,5-dibromoben-zoic acid with aniline gave the 2-aminated product in 84%yield (Scheme 78).

Scheme 78 Site-selective amination of 2,4-dibromobenzoic acid

Ackermann and Althammer reported a novel palladium-catalyzed domino synthesis of annulated heterocycles thatconsisted of an amination and direct carbon–hydrogenbond arylation of 1,2-dihalo(hetero)arenes with readilyavailable anilines.83 It was found that the amination of 4-CO2Et and 4-COPh substituted 1,2-dichlorobenzenesoccurred selectively at the para-position. However, theamination of 4-morpholinocarbonyl-substituted 1,2-dichlorobenzene happened at the position meta to the sub-stituent (Scheme 79).

Scheme 79 Palladium-catalyzed domino synthesis of annulated he-terocycles. R1 = OEt, Ph; R2 = H, Me.

Houpis and co-workers reported the palladium-catalyzedKumada coupling of an acetaldehyde enolate synthonwith bromobenzoic acid derivatives.84 With the directingeffect of the carboxylate functionality, the coupling oflithium 2,5-dibromobenzoate selectively gave ortho-sub-stituted products in 78% yield. Sodium tert-butoxide wasfound to be the most effective additive for this substrate inthe presence of one equivalent of tert-butyl alcohol(Scheme 80).

Recently, the same research group reported highly selec-tive carboxyl-directed cross-coupling reactions of 2,4-di-bromobenzoic acid with arylboronic acids.85 The couplingcatalyzed by Pd2(dba)3 selectively gave ortho-substitutedderivatives in 50–80% yields (Scheme 81). Interestingly,when a combination of palladium(II) acetate and

DPEphos was used as catalyst, the opposite selectivitywas observed.

Zlotin and co-workers described an ortho-preference inthe cross-coupling of polychlorophenyl ketones with phe-nylboronic acid, although the selectivity was not veryhigh (Scheme 82).86

Scheme 82 Cross-coupling of dichloroacetophenone with phenyl-boronic acid

Murai and co-workers reported rhodium-catalyzed fluo-rine–silicon exchange reactions between fluorobenzenesand a disilane.87 The reaction of 2,3,4,5,6-pentafluoroace-tophenone with hexamethyldisilane in toluene at 130 °Cin the presence of [Rh(cod)2]BF4 for 20 hours gave2,3,4,5-tetrafluoro-6-(trimethylsilyl)acetophenone in79% yield (Scheme 83). The replacement of fluoro by tri-methylsilyl took place site-selectively at the ortho posi-tion.

Knochel and co-workers showed that the Co(acac)2-cata-lyzed cross-coupling reactions of various aryl fluoridesand tosylates with functionalized arylcopper compoundsled to polyfunctional biphenyls in the presence of the pro-moters, 4-fluorostyrene and tetra-n-butylammonium io-

NH2

MeO (1.05 equiv)

Cu (9 mol%), Cu2O (4 mol%)K2CO3 (1 equiv), EtOCH2CH2OH

130 °C, 24 h, 84%

Br

COOH

Br

NH

Br

COOH

MeO

Cl

Cl

COR1

Cl

ClN

O

O

Ph

N

COR1R2

Ph

N

R2

N

O

PhNH2 (1.2 equiv)Pd(OAc)2 (5 mol%)

PCy3 (10 mol%)K3PO4 (2.2–3.0 equiv)

NMP, 130 °C, 18 h

57–77%

71%

O

Scheme 80 ortho-Selective Kumada coupling of lithium 2,5-dibro-mobenzoate

Br

Br

COOLiOO

BrMg

Br

COOH

O

O

+

Pd2(dba)3 (3 mol%)t-BuONa (1 equiv)t-BuOH (1 equiv)

THF–dioxane (7:3)65 °C, 78%

Scheme 81 ortho-Selective coupling of 2,4-dibromobenzoic acid.R = H, 4-Me, 3-MeO, 4-F, 4-CF3.

CO2H

Br

Br

CO2H

Br

R

B(OH)2

R

+

Pd2(dba)3–CHCl3 (0.5 mol%)

LiOH (2.2 equiv)

NMP–H2O (1:1)65 °C, 16–42 h

55–80%

PhB(OH)2 (1.1 equiv)Pd(OAc)2 (8 mol%)

1,3-bis(tetrazol-1-yl)benzene (8 mol%)

18-crown-6 (12 mol%)K3PO4 (4 equiv)

DMF, 95 °C

10%

Cl

Cl

O

Cl

Ph

O

Ph

Cl

O

75%

+

Scheme 83 Rhodium-catalyzed ortho-selective Si–F exchange re-action

O

F

F

F

F

F

O

F

F

SiMe3

F

F

Me3SiSiMe3 (10 equiv)[Rh(cod)2]BF4 (10 mol%)

toluene, 130 °C, 20 h79%



dide.88 The reactions of pentafluorinated benzophenonewith arylcopper proceeded smoothly at room temperaturewithin 30 minutes and gave the di-ortho-coupled ketonesselectively in acceptable yields of 39–50% (Scheme 84).

Scheme 84 ortho-Selective coupling of pentafluorinated benzo-phenone with arylcopper. R = 3,4-Cl2C6H3, 3-NCC6H4.

Love and co-workers demonstrated the first examples ofplatinum-catalyzed methylation of polyfluoroarylimines.89 A series of polyfluoroaryl imines reacted withdimethylzinc to generate monomethylated fluoroarenesselectively (Scheme 85). The reaction was selective forortho-carbon–fluorine activation even in the presence ofweaker aryl carbon–bromine bonds.

Scheme 85 Platinum-catalyzed ortho-selective methylation of po-lyfluoroaryl imines. R1 = Bn, Ph, 4-BrC6H4CH2; R2 = 4-F, 4-Br, 4-CN, 3-F, 3,5-F2, 3,4,5-F3.

4.3 With Electron-Donating Groups

Multiply halogenated benzene derivatives bearing elec-tron-donating groups usually have low reactivity in tran-sition-metal-catalyzed cross-coupling reactions withnucleophilic reagents because of their electronically deac-tivated nature. If the carbons are at more sterically hin-dered positions, the reactions are even more difficult toachieve.

Singh and Just found that the ethynylation of 4-amino-and 4-acetamido-1,2-dibromobenzene in boiling triethyl-amine in the presence of Pd(PPh3)4 and Cu2Br2 providedmeta-substituted products in 70–78% yields. A similar re-action with 3-amino-1,2-dibromobenzene also gave themeta-substituted product in 72% yield (Scheme 86). Thereactions of those amino-substituted dibromobenzeneswere much slower than the analogous nitro-substituted di-bromobenzenes and longer reaction times were needed toachieve good yields.78

In studying a triply convergent approach to the taxane sys-tem, Wender and Glass found that the coupling of 1,2-di-iodoanisole with an alkenylzinc reagent selectively gavethe 1-alkenylated compound in 72% yield (Scheme 87).90

Recently, our group developed a series of hydroxylatedoligoarene-type phosphines (HOP) for palladium-cata-lyzed site-selective cross-coupling reactions.91 The hy-droxy group of HOP was introduced during the synthesisof the oligoaryl moiety, while it was expected to function

as an assisting group in a catalytic reaction in which HOPis used as a metal ligand. For example, the metal oxidogroup (M2-O in Figure 2), formed from the hydroxygroup, would bind a substrate through a functional group(Y). This binding would place the reactive group (X) closeto the catalytic metal (M1) coordinated by the phosphinogroup, leading to acceleration of the catalytic reaction.Optimizing the linker length and substitution pattern(ortho-, meta-, para-) of the HOPs would give reaction-specific HOPs and thereby lead to high substrate specific-ity and reaction selectivity.

Figure 2 (a) General structure of a HOP; (b) proposed intermediateof the reaction using an oligoarene-type metal complex as catalyst

It was found that HOP 1 (purified and handled as its HBF4

salt) and HOP 2 dramatically accelerated the ortho-selec-tive cross-coupling of dibromophenols and dibromoa-nilines with Grignard reagents in the presence of apalladium catalyst (Scheme 88).92 On the other hand,when DPPF was used as the ligand instead of HOP 1 and2, the selectivity was opposite (meta- or para-selective).

Highly ortho-selective cross-couplings of dichloroben-zene derivatives with Grignard reagents have also beenachieved by our group.93 The combination of palladi-um(0) and tricyclohexylphosphine resulted in high selec-tivity for substrates with directing groups such as OH,

F

F

F

F

F

O

Ph

R

F

F

F

R

O

Ph

RCu(CN)MgCl (6 equiv)Co(acac)2 (15 mol%)

Bu4NI (1 equiv)4-fluorostyrene (40 mol%)

DME–THF–DMPU (3:2:1)r.t., 0.5 h, 39–50%

NR1

F

FR2

NR1

F

MeR2

Pt2Me4(SMe2)2 (5 mol%)Me2Zn (0.6 equiv)

60 °C or 80 °C, 2–24 h70–95%

Scheme 86 Site-selective ethynylation of 4-amino- and 4-acetami-do-1,2-dibromobenzene. R = H, Ac.

Pd(PPh3)4 (2 mol%)Cu2Br2 (3 mol%)Et3N, reflux, 6 h

70–78%


Br

BrH2N BrH2N

C5H11

Br

Br

RHN BrRHN

C5H11

Pd(PPh3)4 (2 mol%)Cu2Br2 (3 mol%)Et3N, reflux, 3 d

72%


Scheme 87 Mono-selective coupling of 1,2-diiodoanisole with analkenylzinc reagent

ZnCl

O

O

I

OMe

Pd(PPh3)4 (10 mol%)THF–DME (9:1)

r.t., 72%II

OMe

PR2OH

nP O

n

linker

R

RM1

M2Y

X(a) (b)

X



CH2OH, NH2, NHAc, and NHBoc. Furthermore, HOP 1and 2 were more effective than tricyclohexylphosphinefor the coupling of dichlorophenol and dichloroaniline.For the reactions using tricyclohexylphosphine, transitionstate A was proposed. For the reaction using HOP, on theother hand, transition state B, in which the magnesiumbridge between the oxido group of the HOP and the sub-strate places the ortho-carbon–chlorine bond of the sub-strate close to the palladium atom, was proposed toexplain the acceleration effect (Scheme 89), although thereal mechanism of selectivity remains unknown.

Scheme 89 ortho-Selective cross-coupling of dichlorobenzene de-rivatives with Grignard reagents. YH = OH, CH2OH, NH2, NHAc,NHBoc; R = 4-MeOC6H4, 4-ClC6H4, Ph, 2-thienyl, Me2C=CH.

It was further found that fluorobenzenes with directinggroups such as hydroxy, hydroxymethyl, and aminogroups underwent highly ortho-selective cross-couplingwith Grignard reagents in the presence of PdCl2(PCy3)2.

94

Fluoro and chloro groups at positions other than ortho tothe directing groups survived under the reaction condi-tions (Scheme 90).

The results mentioned above clearly show that electron-donating groups such as hydroxy and amino groups,which are rapidly deprotonated in the presence of a

Grignard reagent, can serve as good directing groups inthe cross-coupling of halogenated benzene derivativeswith Grignard reagents. High yields and high reactionrates can be realized through the proper choice of catalystsand ligands.95

The methodologies described above were efficient foraryl, alkenyl, and benzyl Grignard reagents. For alkylGrignard reagents that possess b-hydrogens, however, thereaction resulted in only reduction of the starting haloben-zenes, without formation of the desired cross-coupledproduct. To overcome this problem, we studied the reac-tions utilizing nickel, instead of palladium, catalysts.It was found that the catalytic systems involvingNiCl2(dppbz) or NiCl2(dippbz) were highly efficient forthe cross-coupling of dihalophenols with alkyl Grignardreagents.96 Reactions of 2,4-dihalophenols, with variouscombinations of F, Cl, and Br, were shown to affordortho-cross-coupled products selectively at room temper-ature (Scheme 91).

Scheme 91 ortho-Selective cross-coupling of dihalobenzene deri-vatives with alkyl Grignard reagents. X1, X2 = F, Cl, Br; R1 = Me, Et,n-Bu, i-Bu, n-dodecyl; R2 = H: NiCl2(dppbz), i-Pr: NiCl2(dippbz).

4.4 Other Dihalogenated Benzenes

The examples mentioned above indicate that the proper-ties of the substituents have a great influence on the selec-tivity of the reactions. In some cases, however, thesubstituent served only as a blocking group, and its prop-erties had much less significant effect on the selectivity ofthe coupling reaction. For example, Reddy and Tam foundthat substituted dichloroarenes reacted with ethylGrignard reagent in the presence of a catalytic amountof [NiCl(triphos)]PF6 [triphos = bis(2-(diphenylphosphi-no)ethyl)phenylphosphine] to give mainly monoalkylatedproducts.97 The coupling preferentially occurred at thecarbon–chlorine bonds drawn in bold in Figure 3under the reaction conditions: EtMgBr (1 equiv),[NiCl(triphos)]PF6 (0.5 mol%), Et2O, 0 °C, overnight. Noobvious explanation can be found for the selectivity, butsteric effects may be one of the influences.

Yamamoto and Hattori reported the palladium-catalyzedsite-selective Sonogashira coupling of substituted diiodo-benzenes with phenylacetylene in the synthesis of multi-ply functionalized benzenes.98 The two carbon–iodinebonds were strictly distinguished one from the other be-

Scheme 88 ortho-Selective cross-coupling of dibromobenzene de-rivatives with Grignard reagents. YH = OH, NH2; R = 4-MeOC6H4,3-MeOC6H4, 2-MeOC6H4, Bn, 2-thienyl.

YH

Br

Br

YH

R1

Br

Pd2(dba)3 (1 mol%)HOP 1 or 2 (2.4 mol%)

THF, 25 °C, 2–72 h63–89%

+ R1MgBr(4 equiv)

PR2 HOHOP 1 (R = Cy)HOP 2 (R = Ph)

YH

Cl

Cl

YH

R

Cl

Pd2(dba)3 (1 mol%)PCy3, HOP 1, or

HOP 2 (2.4 mol%)

THF, 50 °C, 4–24 h55–99%

+ RMgBr(3 equiv)

Y

Cl

Mg

Pd

O

P

R R

= terphenyl

proposed transition states

Y

Cl

MgX

Pd⋅PCy3

A BCl Cl

Scheme 90 ortho-Selective cross-coupling of fluorobenzene deri-vatives with Grignard reagents. X = F, Cl; YH = OH, CH2OH, NH2;R = Ph, 4-MeC6H4, 4-MeOC6H4, Me2C=CH.

YH

F

X

YH

R

X

PdCl2(PCy3)2 (2 mol%)

THF, 50 °C or 70 °C,24 h, 49–85%

+ RMgBr(3 equiv)

OH

X1

X2

+ R1MgBrcatalyst (5 mol%)

toluene, r.t., 22 h33–76%

OH

R1

X2

P PNi

Cl Cl

R2R2

22

catalyst

(3 equiv)



cause of the difference in their steric environments im-posed by the substituent. The coupling selectively gavemonosubstituted products in 43–94% yields (Scheme 92).

5 Dihalogenated Alkanes

The catalytic cross-coupling of alkyl halides withGrignard reagents has become one of the most straight-forward methods for constructing methylene chains.Terao, Kambe, and co-workers reported copper-catalyzedcross-coupling reactions of Grignard reagents with prima-ry alkyl halides.99 The high selectivity for primary alkylhalides allows for the successful synthesis of 2-chlorooc-tane in high yield from 1,3-dichlorobutane and n-butyl-magnesium chloride (Scheme 93).

Scheme 93 Copper-catalyzed primary alkyl chloride selectivecross-coupling reaction with Grignard reagent

A similar selectivity for primary alkyl halides was ob-served in the nickel-catalyzed cross-coupling of alkyl bro-mides with Grignard reagents.100 No reaction took placewith secondary alkyl bromides, thereby allowing the suc-cessful synthesis of 2-bromooctane in high yield from thecoupling of 1,4-dibromopentane with n-propyl Grignardreagent (Scheme 94).

Scheme 94 Nickel-catalyzed selective cross-coupling reaction witha Grignard reagent

6 Enantioselective Cross-Coupling Reactions

There are a few examples of enantioselective cross-cou-pling reactions in which two enantiotopic halo (or pseudo-halo) groups of an achiral substrate are differentiated bychiral catalysts. For example, Uemura and co-workersfound that asymmetric cross-coupling of tricarbonyl(o-dichlorobenzene)chromium with alkenyl metals in thepresence of a chiral palladium catalyst gave the monocou-pled products with up to 44% ee (Scheme 95).101

Scheme 95 Asymmetric cross-coupling of tricarbonyl(o-dichloro-benzene)chromium

It was further found by the same research group that a sim-ilar coupling between tricarbonyl(o-dichloroben-zene)chromium and arylboronic acids selectively gave themonocoupled products with up to 69% ee (Scheme 96).102

Scheme 96 Asymmetric arylation of tricarbonyl(o-dichloroben-zene)chromium. R = H, Me.

Hayashi and co-workers reported a palladium-catalyzedenantioselective cross-coupling of phenylmagnesium re-agents with biaryl ditriflates.103 Their protocol provides anew catalytic method for the synthesis of axially chiral bi-aryls. PdCl2[(S)-Phephos] was found to be the best palla-dium complex for the coupling (Scheme 97).

They also found that for the coupling of biaryl ditriflateswith ethynylmagnesium reagents, PdCl2[(S)-Alaphos]and PdCl2[(S)-Valphos] showed a much higher activitythan other palladium complexes (Scheme 98).104 The inor-

Figure 3 Site-selective coupling of substituted dichloroarenes withethylmagnesium bromide

Cl

Cl

Cl

CF3

Cl

Cl

OMe

Cl

Cl

Cl

Cl

Cl

Scheme 92 Site-selective Sonogashira coupling of substituted diio-dobenzenes. R = boronate, n-Bu, Ph, n-C8H17O, CO2Me.

O

II

R

O

I

R

Ph

Ph (1.5 equiv)PdCl2(PPh3)2 (5 mol%)CuI (10 mol%), i-Pr2NH (1.5 equiv or as solvent)

t-BuOMe, r.t. or 0 °C, 2–12 h43–94%

Cl

Cl Cl

n-BuMgCl (1.5 equiv)CuCl2 (2 mol%)

MePh (10 mol%)

THF, reflux, 6 h, 89%

BrBr

n-PrMgCl (1.15 equiv)NiCl2 (8 mol%)

buta-1,3-diene (30 mol%)

THF, –20 °C, 25 min94% (GC yield)

Brn-Pr

Cl

Cl(OC)3Cr

Cl

(OC)3Cr

H2C=CMeB(OH)2 (3 equiv)[PdCl(π-C3H5)]2 (10 mol%)

(S)-(R)-PPFA (12 mol%)

TIOH, THF, 27 °C, 48 h61%, 44% ee (1S,2R)

Fe

PPh2NMe2

MeH

(S)-(R)-PPFA

(OC)3Cr(OC)3Cr

Cl

Cl

Cl

TIOH, THF–H2O, 10 °C18–40 h, 40–51%

55–69% ee (1S,2R)

R-C6H4B(OH)2 (3 equiv)[PdCl(π-C3H5)]2 (5 mol%)(S)-(R)-PPFA (12 mol%)

R

Scheme 97 Enantioselective arylation of biaryl ditriflates. R = Ph,3-MeC6H4.

OTfTfO OTfR

RMgBr (2.1 equiv)LiBr (1.0 equiv)

PdCl2[(S)-Phephos] (5 mol%)

toluene–Et2O, 48 h83–87%, 90–93% ee (S)

PPd

N Cl

ClPh Ph

MeMeBn

PdCl2[(S)-Phephos]



ganic salt lithium bromide greatly enhanced the coupling.In the absence of lithium bromide, the cross-coupling re-action was very slow.

Bräse found that the palladium-catalyzed intramolecularMizoroki–Heck reaction of bis(enol nonaflate) proceededwith low enantioselectivity in the presence of BINAP.The reaction was followed by an intermolecular Mizoro-ki–Heck reaction with tert-butyl acrylate (Scheme 99).105

Scheme 99 Enantioselective Mizoroki–Heck reaction

Willis and co-workers reported enantioselective Suzukicoupling of ditriflates (Scheme 100).106 Use of MeO-MOP as the chiral ligand is a key for the good selectivi-ties.

Scheme 100 Enantioselective Suzuki coupling of a ditriflate.Ar = 4-AcC6H4, 3-AcC6H4, 4-OHCC6H4, 3-OHCC6H4, 2-OHCC6H4,4-HOC6H4, 3-furyl, 3-N-Bs-indolyl.

7 Conclusions

In truly ideal synthetic chemistry, complex moleculesshould be synthesized from simple starting materials inone step, or at most several steps, with high atom-efficien-

cy. Undoubtedly, transition-metal-catalyzed site-selectivecross-coupling of di- and polyhalogenated compoundsprovides an efficient approach to the installation of sub-stituents at specific positions of alkenes, heterocycles,benzene, and alkane derivatives. The ready availability ofthe starting materials and versatility of the methodologymake it practical and useful in the total synthesis of natu-ral compounds and pharmaceuticals.

It has been clearly demonstrated, by the many examplesmentioned in the text and shown in the schemes, that theorigin of the selectivity in cross-coupling processes isdominated by electronic and steric effects. Directinggroups (such as carboxyl, imides, amines, and hydroxygroups) at sites neighboring the reactive position also playa significant role in the selectivity.

In terms of methodology, application of classical couplingto site-selective coupling is very practical, and the devel-opment of catalysts that enable both highly selective andhighly efficient transformations is also very attractive. Weare very happy to see that great progress has been made inthese areas, and we anticipate many more in this excitingfield.

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Scheme 98 Enantioselective ethynylation of biaryl ditriflates.R1 = Ph3Si, Ph, n-C5H11.

OTfTfO OTf

R1

R1C CMgBr (2.1 equiv)

toluene–Et2O (1:1)79–88%, 64–92% ee (S)

LiBr (1.0 equiv)PdCl2[(S)-Alaphos] or

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PPd

N Cl

ClPh Ph

MeMeRPdCl2[(S)-Alaphos] (R = Me)

PdCl2[(S)-Valphos] (R = (Me)2CH)

Ph

ONfNfO

Ph

t-BuO

O

O

t-BuO

Pd(OAc)2 (cat.)BINAP(cat.), Et3N

DMF, 80 °C, 12 h37%, 28% ee

ArB(OH)2 (2 equiv)Pd(OAc)2 (10 mol%)

(S)-MeO-MOP (11 mol%)CsF (2 equiv)

dioxane, r.t.41–66%, 72–86% ee

OTfTfO

Ph

ArTfO

Ph

OMe

PPh2

(S)-MeO-MOP



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