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2 Acc. Chem. Res. 1995,28, 2-7

A R T I C L E SRecent Developments and New Perspectives in theHeck Reaction

WALTER CABRI" A N D ILARIA CANDIANIPha rma cia, Process Research, via G iovan ni xx111,23 20014-Nerviano, Milan, I taly

R e c ei v ed N o v e m b e r 29,1993

More than tw o decades ago, Mizorokil and Heck2independently discovered the palladium-catalyzedarylation and vinylation of olefins. This methodology,known worldwide as the Heck reaction (Scheme 1),3is attractive from a synthetic point of view becausehigh chemoselectivity and mild reaction conditions areassociated with low toxicity and cost of the reagent^.^During the past few years, the experience obtainedin several palladium-based reactions helped in under-standing the rules which govern the coordination-insertion of unsaturated systems on palladium(I1)complexes. In fact, this process has a central role indetermining the reaction rate, stereoselectivity, andregioselectivity of intra- and intermolecular Heckreactions, hydrosilylations,oligomerizationsof olefins,and olefin-CO copolymerization^.^The purpose of this account is t o review and criti-cally evaluate the results on the Heck reaction re-cently obtained by several research groups. Theseresults can be explained on the basis of a commonmechanistic hypothesis fo r the coordination-insertionprocess of unsaturated systems on palladium(I1) com-plexes (Scheme 2, step b).Heck Reaction Mechanism

Oxidative Addition (Scheme 2, Step a). Exceptfo r the case of aryl iodides, the presence of ligands isnecessary in order t o effect oxidative addition of RXto the palladium(0) complex at a reasonable tempera-ture (Scheme 2, step a).6 The catalytically activespecies is a 14-electroncomplex, LzP ~( O) ,~nd effectiveligands in the Heck reaction are monodentate3 andbidentate phosphines8 and 1 lo-phenanthroline de-r iva t ive~ .~Coordination-Insertion (Scheme 2, Step b).The geometry of the complex is a central point, and

Waiter Cabri was born in Milan, Italy, in 1959. He received a degree in chemistryfrom the University of Milan in 1985, where he worked for one year as postdoctoralfellow with Protessor C. Scolast ico. He then joined the Enzymatic Catalysis Groupof the lstituto Guido Done ani and in 1987 moved to Farmitalia Carlo Erba (nowPharmacia), where he wo rk in the Process Research Group. He was ResearchAssociate at the University of Montreal with Prof. S. Hanessian, n 1989-1990: Hisresearch interests focus on the synthesis of drugs by environmentally friendlymethodologies, biomimetic reactions, and enzymatic and organometallic catalysis.He was a reci ient of the Federchimica Pnze for his work in the field of anthracyclinechemistry, Itat (1993)llaria Candiani was born in Siena, Italy, in 1962. She received a degree inchemistry from the University of Milan in 1987. She then joined the Organic ChemistryDepaltment of the lstituto Guido Donegani and in 1989 moved to Farmitalia CarloErba (now Pharmacia), where she works in the Process Research Group. She wasResearch Associate at the Univers ity of Basel, Switzerland, with Professor B. Giesein 1992-1993. Her research interests are in synthetic organic chemistry, organo-metallic catalysis, and radical reactions.0001-4842/95/0128-0002$09.00/0

Scheme la"Pd(0)'>-(* + R X ___* >R + H X

a R = aryl, vinyl; X = I, Br, COC1, OTf, etc.Scheme 2. The Heck Reaction: General Mechanism

. -i L

R H' 'Y

several theoretical studies aimed at the identificationof the reactive species in the coordination-insertionof unsaturated systems on Pd(I1) and Pt(I1)complexeshave appeared in the literature. The orbital studieson the insertion of ethylene into a Pt-H bond carriedout by Thorn and Hoffmann'O gave two importantpieces of information: (1) The insertion process re-quires a coplanar assembly of the metal, ethylene, andthe hydride. Therefore, the insertion process is ste-reoselective and occurs in a syn manner. This is inagreement with experimental observations by Heck.ll(2 ) The energy barrier for the generation of the

(1)Mizoroki,T.; Mori, K.; Ozaki, A. Bul l . C h e m . S O C . p n . 1971,44,(2) Heck, R. F.; Nolley, J. P., Jr . J. Org. Chem . 1972,37, 320.(3) (a) Heck,R. F.PaEZadium Reagents in O rganic Synthesis; AcademicPress: London, 1985. (b) Heck, R.F. Org. React. (N.Y.) 982,27, 45.(4) Cabri, W. Ch im. In d . (M i la n )1993,75,314nd references therein.(5) Colman,J. P.;Hegedus, L. S.; Norton, J. R.; Finke, R. G .Principlesand Applications of Organotransition Metal Chemistry, 2nd ed .; Uni-versity Science Books: Mill Valley, CA, 1987.(6) ther leaving groups have been described in the literature, buttheir applications are limited. Sulfinates: (a) Garves,K. J . Org. Ch em.1970,35, 273. Sulfonyl chlorides: (b) Kasahara , A.; Izumi,T. ;Azami,H.; Yamamoto, S. Ch em. In d . (Lo n d o n ) 1988, 1. Iodonium salt s: (c )Moriarty, R. M.; Epa, W. R.; Awasthi, A. K. J . A m . C h e m . SO C . 991,113, 6315. Diazonium salts: (d) Kikukawa, K.; Naritomi, M.; He, G. -H.; Wada, F.; Matsuda, T. J . O r g. Chem. 1986, 0, 99 and referencestherein.

581.

0 1995 American Chemical Society

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New Perspectives in the Heck ReactionScheme 3. The Coordination-Insertion Process

L . L .1 l a - .,

ACC.Chem. Res., Vol.28, N o. 1, 1995 3out without ligands in the case of aryl iodides or inthe presence of monodentate phosphines [i.e.,PPh3 orP(o-Tol)sl with the other compound^.^ Under thesereaction conditions a square planar palladium(11)oxidative addition complex with a weak Pd-PR3 bond(or Pd-solvent bond when phosphine ligands are notpresent) and a strong Pd-I(Br,Cl) bond16 is generated.Therefore, the coordinationof the unsaturated systemtakes place via dissociation of one of the neutralligands, and a neutral palladium(I1) omplex is formed(Scheme 3, path A).13 In this context, the Heckobservation, Chelating diphosphines.. in general donot produce useful catalysts,17was valid because onlyaryl halides were used. In fact, with bidentate ligandsa decrease of the reaction rates or sometimes acomplete suppression of the reaction is observed.14J5The approach of the olefin is hampered by the com-petitive coordination of the ligand, the equilibrium 1Z= 2 being shifted to the left.14bThe introduction of triflates as leaving groups gavea completely different scenario owing t o the labilityof the Pd-OTfbondl* present in the oxidative additioncomplex 1. In 1991 we14c and O~ aw a-H ay ash il~ ~independently proposed the formation of cationicpalladium(I1) omplexes in the coordination-insertionprocess of the Heck reaction. In fact, combiningtriflate as leaving group and bidentate phosphorousor nitrogen ligands, the coordination of the unsatur-ated system takes place via dissociation of the coun-terion (Scheme 3, path B), affording the cationicpalladium(I1)complex6. The complex 6 can give highasymmetric induction when the diphosphine is chiralwhile complex 3 cannot.14d Furthermore, the reactiv-ity of complexes2 and 5 depends on the charge densityof the unsaturated Competitive experi-ments showed that the neutral complex2 reacts fasterwith electron poor olefins (good n-acceptors and poora-donors). In contrast, the cationic complex 5 reactsfaster with electron rich olefins (poor n-acceptors andgood a-don~rs) .~~The Heck reaction is a flexible methodology. In fact,it is easy to switch from one mechanism to the other.14bComplex 3 can be generated using halides as leavinggroup or by simple addition of halide anions to thereaction of aryl and vinyl triflates. The labile Pd-OSOzR bond is substituted with the strong Pd-I(Br,-C1) bond.lg On the other hand, complex 6 can begenerated using triflate as leaving group o r by addi-tion of sequestrating agents of halide anions, such asAgV0 or TlY21 sal ts (Y = nitrate, carbonate, phos-phate, acetate, triflate, etc.), t o the reaction of aryl andvinyl halides. The strong Pd-I(Br,Cl) is substitutedwith a labile Pd-Y bond.P-Hydride Elimination-Dissociation (Scheme2, Step c). The ,&hydride elimination is stereoselec-

(16) enry, P. M. Palladium Catalyzed Oxidation of Hydrocarbons;D. Riedel Dordrecht: Holland, 1980; p 11-15.(17) eck, R. F. cc . Ch em. Res . 1979, 2, 146.(18) he lability ofthe Pd-OTfand Pt-OTfbonds is well documented.See: (a) Dekker, G. P. C. M.; Elsevier, C. J. ;Vrieze, K.; van Leeuwen,P. W. N. M. Organometallics 1992,11,1598.b) Stang, P. J. ;Kowalsky,M. H.; Schiavelli, M.D.; Longford, D. J .A m . C h em .SOC. 989,111,3347.(19) chavarren, A. M.; Stille,J. K.J . A m . C h em .SOC. 987,109,5478.(20) eading references: (a) Larock, R. C.; Gong, W. H.; Baker, E.Tetrahedron Lett. 1989,30,2603.b)Abelman, M. M.; Oh, T.; Overman,L. E. J . Org . Ch em. 1987, 2, 130. (c) Karabelas, K.; Westerlund, C.;Hallberg, A. J . Org. Chem . 1985, 0, 3896.(21) eading references: (a )Reference 14b. b) Cabri, W.; Candiani,I.; Bedeschi, A.; Santi, R. Tetrahedron Lett. 1991, 2,1753. (c) Grigg,R.; Loganathan, V.; Santhakumar, V.; Sridharan, V.; Teasdale, A.Tetrahedron Lett. 1991, 2, 87.

Pd -42 x - 3, - -* I

X4L L

P i/R

/PathB R 5reactive configuration in a tetracoordinated complexis low with respect t o a pentacoordinated one. There-fore, pentacoordinated species are possibly not in-volved in the coordination process. These results arealso supported by experimental work on the chemistryof in-plane coordinated double bonds12 and by kineticstudies.13Results of catalytic as well as stoichiometric studieson the coordination-insertion process of an olefin ona palladium(I1) complex in the Heck reaction14 and inolefin-CO cop~lymerizationl~upport a mechanismbased on two reaction pathways (Scheme 3): path Ainvolves coordination of the olefin via dissociation ofone neutral ligand; path B involves coordination of theolefin via dissociation of the anionic ligand. Twocoordination sites of the square planar complexes 3and 6 are occupied by the olefin and the fragment Rthat has t o migrate onto the x-system. Therefore, thecontrol exerted by the catalyst depends on the remain-ing two ligands, which are one neutral and one anionicin the neutra l complex 3 (path A) o r both neutral inthe cationic complex 6 (path B).Historically, the Heck reaction was the functional-ization of olefins by aryl iodides, aryl bromides, aroylchlorides, o r the corresponding vinyl halides, carried

(7) a)Negishi, EA.; Takahashi , T.; Akiyoshi, K. J.C h e m .SOC., h em.C o m m u n . 1986, 1336. Amatore and Jutand showed that LzPdX- (X=C1 or Br) can be involved in the oxidative addition of aryl halides tozerovalent palladium complexes carried out in the presence of halideanions. See: (b) Amatore, C.; Jut and, A.; Suarez, A.J . A m . C h e m .SOC.1993,115, 531.(8) (a) Chen,Q.-Y.;Yang, Z.-Y. Tetrahedron Le tt . 1986,27,171. (b)Cabri, W.; Candiani, I.; Bedeschi, A.; Santi, R. J . Org. Chem . 1990,55,3654.(9) a) Cabri, W.; Candiani, I.; Bedeschi, A.; Santi, R. J . Org . Ch em.1993,58,7421.b) Cabri,W.; andiani,I.; Bedeschi, A.; Santi, R.Synlett1992, 71.(10) horn, D. L.; Hoffmann, R. J . A m . C h e m. SOC. 978,100,2079.(11)Heck, R. F. J . A m . C h em . SOC.969,91, 707.(12) a) Rakowsky, M. H.; Woolcock,J. C.; Rettig, M. F.; Wing, R.M.Organometallics 1988, 7, 2149. (b) Miki, K.; Kai, Y.; Kasai, Y.; Kuro-sawa, H. J . Am. C h e m . S O C .1983,105, 482.(13) amsel, E. G.; Norton,J. R. J . Am. C h e m .SOC. 984,106,5505.(14)Catalytic studies: (a) See ref 9a. (b) Cabri, W.; Candiani, I.;Bedeschi, A,; Penco, S.;Santi, R. J . Org. Chem. 1992,57, 481. (c) Cabri,W.; Candiani, I.; DeBernardinis, S.;Francalanci, F.; Penco, S.;Santi, R.J . Org. Chem. 1991,56, 796. (d) Ozawa, F.; ubo, A.; Hayashi, T. J .A m . C h em .SOC. 991,113,1417. toichiometric studies: (e)Yamamoto,A,; Kawataka, F.; Kayaki, Y.; Shimizu, I. 7th IUPAC Symposium onOrgano-Metallic Chemistry directed towards Organic Synthesis, Kobe,September 1993,Abstr. No. 137A.(15) a) Dekker, G. P. C. M.; Elsevier, C. J. ;Vrieze, K.; van Leeuwen,P. W. N. M.; Roobeek, C. F. J . Organomet. Chem . 1992, 30, 57. (b)Markies, B. A.; Rietveld,M. H. P.; Boersma, J. ; Spek, A. L.; van Koten,G. J . Organomet. Chem. 1992, 424, C12. (c) Ozawa, F.;Hayashi, T.;Koide, H.; Yamamoto, A. J . Ch em. SOC., h em. Co mmu n . 1991, 469.(d) Brumbaugh, J.S.;Whittle, R. R.; Parvez, M.; Sen, A. Organometallics1990,9, 735.

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4 Ace. Chem . Res., Vol. 28, N o. 1, 1995Scheme 4

Cabri and CandianiScheme 6. Heck Reaction Regioselectivity.Coordination-Insertion Process via Path B

+dissociation +dissociationScheme 5. Heck Reaction Regioselectivity.Coordination-Insertion Process u i a Path A

Y Ph

10 0 100 60 40Y- C W R , CONH? CN

O-n-Bu-pH t t mixture of isomers90 10t100OAc4

mixture of products80 80-85tive and occurs in a syn manner;" its efficiency isrelated t o the dissociation of the olefin from thepalladium(I1)-hydride complex. The 8-hydride elimi-nation is a reversible process, and a slower dissociationof the olefin can determine the formation of severalproducts because of the isomerization of the doublebond (Scheme 4). This disadvantage can be elimi-nated, in reactions between cyclic olefins and arylhalides, by adding Ag(I)20a*br Tl(1) salts.21cRecycling of the L2Pd(O) (Scheme 2, Step d).The presence of a base is necessary in order t otransform the L2Pd(H)X into the starting L2Pd(O)complex and close the catalytic cycle. Typical basesare trialkylamines (EtsN, 'PrzNEt, etc.) or inorganicsalts (AcONa,%COS, etc.); however, good results weresometimes obtained with either Proton Spongeor TUI)or Ag(1) salts.Regioselectivity

Aryl Derivatives. Intermolecular Heck Reac-tion. The regioselectivities of the arylation of severalclasses of olefins usually reported in books and re-v i e ~ s ~ ~ ~ J ~ l ~ ~re described in Scheme 5 . All theseresults have been obtained using procedures that favorthe coordination-insertion process via dissociation ofthe ligand (Scheme 3, path A). Our results on theintermolecular arylation of olefins modified substan-tially this scheme allowing the extension of thesynthetic usefulness of the Heck reaction (cf. Schemes5 and 6). The protocol, centered on the use of aryl(22) (a) Trost, B. M. ; Verhoeven, T. . In Comprehensive Orgunom-tallic Chemistry; Wilkinson, G., Stone, F. G . A,, Abel, E. W ., Eds.;Pergamon Press: Oxford, 1982; Vol. 8,p 799. For the arylation ofheteroatom-substituted olefins, see: (b) Davis, G . D., Jr.; Hallberg, A.C h e m . Reu. 1989,89, 1433.

100 60 40 100 100Y- C W R , CONHc CN

100 5 95 100 100

9" OAcOHt

20-25 10 5 95triflates8b*9J4b,c,23ar aryl ha l i de ~ / ( T l ( I ) l ~ ~ > ~ l~nd thegeneration i n situ of the palladium(0) catalyst fromPd(0Ac)z and bidentate phosphorous ligands (i.e.,DPPP, DPPF),24 allows the coordination-insertionprocess to follow path B. Preferential formation of thebranched products in the arylation of heterosubsti-tuted olefins (enol ethers, enol amides, and vinylacetate), allyl alcohols, and homoallyl alcohols wasobserved independentlyof the substituents on the aryltriflate, the reaction temperature, and the solvent(Scheme 6 ) . Similar results were obtained in thereaction between aryl triflates and enol ethers or enolamides carried out in the presence of bidentatenitrogen ligands (i.e., 1,lO-phenanthroline deriva-t i v e ~ ) . ~he best selectivities and yields were obtainedusing neo~uproine~~s palladium ligand.The selected examples of Table 1 show that theregioselectivity is related only t o the coordination-insertion pathway. Steric factors always favor themigration of the R group in complexes 3 and 6 to theless substituted carbon with formation of the linearproducts. However, when the reaction proceeds viadissociation of the counterion (path B), electronicfactors predominate. In fact, the coordination of thez-system in a cationic complex 6 determines anincrease of the polarization, and selective migrationof the aryl moiety (formally as anion) onto the carbonwith the lower charge density is observed.The flat nature of 1,lO-phenanthroline derivativesallows the Heck reaction t o be carried out at lowertemperature than that required in the case of thecorresponding bidentate phosphorous ligands becauseof a decreased steric hindrance above and below thecoordination plane (Table 1). Unfortunately, withbidentate nitrogen ligands the substitutions on thearyl triflate affect the reaction course. In fact, lowregioselectivities and conversions were observed withelectron-withdrawing and electron-donating groups,

(23) (a) C abri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R. J.Org. Chem. 1992 ,57 , 3558. For a review on synthetic transformationsof aryl and vinyl triflates, see: (b) Ritter, K. Synthesis 1993, 735.(24) DPPP = 1,3-bis(diphenylphosphino)propane; DPPF = 1,l'-bis-(dipheny1phosphino)femocene;eocuproine - 2,9-dimethyl-l,lO-phenan-throline; (R)-BIN@ = (R)-2,2'-bis(diphenylphosphino)-l l'-binaphthyl;Proton Sponge = l&bis(dimethylamino)naphthalene; PMP = 1,2,2 ,6 ,6-pentamethylpiperidine.

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New Perspectives in the Heck ReactionTable 1. Palladium-CatalyzedReaction between ArylDerivatives 8a-c and Butyl Vinyl Ether 9 in DMFg414b

ArCOCH312

OnBu H+ORBU WOAc)p I L

DMF, base On-Bu8a-cAr

11

Acc. Chem. Res., Vol. 28, N o. 1, 1995 5Stereoselectivity

Over the years several chiral ligands for asymmetriccatalysis have been synthesized and studied.27How-ever, the best enantiomeric purities in the Heckreaction have been obtained using a bidentate phos-phine ligand, chiral BINLW.~~Intermolecular Asymmetric Heck Reaction.Generally, the Heck reaction has been used t o incor-porate aryl, vinyl, or benzyl moieties on sp2 carbons(Scheme 1). However, several examples of allyliccross-coupling with cyclic alkenes have been re p ~ r t e d .~It is worth noting tha t with cyclic olefins the hydrogenpresent on the functionalized carbon cannot be in-volved in the ,&hydride elimination process, being antiwith respect to the carbon-palladium(I1) bond; there-fore, the R group is incorporated on an sp3 carbon.In this context, Hayashi and Ozawa have reportedsignificant results on the stereoselective intermolecu-lar Heck reactions using aryl triflates and the catalystgenerated in situ from Pd(0Ac)z and (R)-BINAP.14dt28The selected examples reported in Table 3 werecarried out under analogous conditions (benzene,30-60 "C).When the mechanism follows path B, thechiral ligand is strongly attached to the metal withboth phosphorus atoms throughout the coordination-insertion process, determining an effective transfer ofthe chiral information from the catalyst to the sub-strate. The breakthrough was the combinationof (R)-BINAP as ligand (other chiral ligands gave badresults) and triflate as leaving group (entries 1 and2). However, the stereoselectivity was dependent onthe added base; in fact,with simple trialkylamines theenantiomeric purity of the major product rangedbetween 63% and 93%. In contrast, with ProtonSponge24 he enantiomeric purity ranged between 87%and '96% irrespective of the aryl substitution (entries2 vs 3 and 4 vs 5). As previously observed, if thedissociation of the olefin from the palladium(I1)-Hspecies is not sufficiently fast, the migration of thedouble bond cannot be avoided (Scheme 4). In thiscase, Ozawa and Hayashi proposed that a kineticresolution process, via selective isomerization of theminor enantiomer, allowed an increase in the stereo-selectivityof the reaction with a concomitant decreasein the yield. In fact, using Proton Sponge as addedbase, the ee increased, but low 25/26 ratios wereobtained (entries 3 and 5).The steric influence of (R)-BINAP determines thehigh enantioselectivityof the reaction. Unfortunately,only electron-rich systems like 2,3-dihydrofuran andN-substituted 2-pyrrolines are sufficiently reactive.29As pointed out above, electronic factors affect thecoordination process and cationic complexes like 5react faster with electron rich o l e f i n ~ . ~ ~ J ~ ~The palladium-catalyzed asymmetric alkenylationcarried out using [Pd((R)-BINAP}2] s precatalyst didnot suffer from the drawbacks of the corresponding

12,A r X a ligand base conditns 10111 %yield pathS a DPPP Et3N lOO"C, 1 8 h 67/33 63 ASb DPPP Et3N 100C, 1 8 h 61/39 54 ASC PPh3 Et3N 100C, 1. 5h 63/37 55 ASc DPPP Et3N 60 C ,0 .5 h 29911 97 BSc neocuproine Et3N 40 "C, 2.5 h '9911 95 B

Sa DPPP TlOAc 80 "C, 1h >99/1 92 BSb DPPP TlOAc 80 C ,0 .7 h >99/1 97 B

a Sa, l-na phth yl iodide; Sb, -naph thyl bromide; Sc,l-naphthyltriflate.Table 2. Palladium-CatalyzedArylation of p-Aminozsand /3-PhosphorusZ6unctionalized Vinyl Ethers 17

ArX + fro) - [ P d R 4 :) $0neutral orPd(0AC)p s o ationic A,R 2 Ar R2

Y L 'YR2

13-16 17 18 19 2020,ArXu (CH3)zN ligand conditns 19/20 %yi el d

13 (CHdzN 80 "C, 16 h 3/97 8214 (CH3)zN PPh3 80"C, 1 6 h 4/96 5216 PhzP 80 "C, 0.5 h

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6 Ace. Chem. Res., Vol.28, No. 1, 1995 Cabri and CandianiTable 3. Intermolecular Asymmetric Heck Reaction28.soPd(OAO)y(R)- BINAP- J+penzene,bese R,\\"RX +

13,21-23 24 25 26% ee (% yield)

entry R P Y base 25/26 25 26 path1 13 0 EtsN 92/8 (23) (2) A2 21 0 'PrzNEt3 21 0 Proton Sponge4 22 N(CO0Me) Et3N5 22 N(CO0Me) Proton Sponge6 23 0 Proton Sponge7 23 N(CO0Me) Proton Sponge

a 21,PhOTf; 22, -ClCsH40TE 23, -cyclohexenyl triflate.Table 4. Intramolecular Asymmetric Heck Reactionfor the Stereoselective Synthesis of &-DecalinDerivativess2e

COOMe COOMePd(0AC) 2/(R)- BINAP&-olvent, base

H27 2828,% eeentry X base conditns (%yie ld) path

1 I Et3N NMP 0.4 A2 I AgC03 NMP,6O0C,210h 58(65) B3 I Ag3P04 NMP, 60" C, 18 8h 69(48) B4 OTf &co3 toluene, 60C,55 h 91 (54) Ba r y l a t i ~ n . ~ ~n fact, compound 26 was the only reac-tion product (entries 6 and 7). Using this methodol-ogy, the stereoselective alkenylationof cis-2-cycloalkene-1,4-diolshas been recently reported by P r a ~ i t . ~ ~hecorresponding arylation failed.Intramolecular Asymmetric Heck Reaction.Highly stereoselective palladium-catalyzed cycliza-tions have been reported by S h i b a ~ a k i ~ ~nd Over-man.33 It is worth noting that the best results interms of stereoselectivity, reaction rate, and yield havebeen obtained using BINAP as ligand and the halide/Ag(1) system or triflate as leaving group.Among the several examples reported by Shibasakifor the stereoselective synthesis of ~is-decalins,~~"h y d r i n d a n ~ , ~ ~ ~nd indo l i z id in e ~ ,~ ~ ~t is possible toappreciate the increase in enantiomeric purity movingfrom path A to path B in the cis-decalin series (Table4). The addition of Ag(1) salts as sequestrating halideagents t o the reaction of the vinyl iodide derivativeallowed isolation of the cyclized product in good yieldsand enantiomeric purities (entries 1-3). However, asin the case of the intermolecular stereoselective Heckreaction, the best results have been obtained using the

(30) Ozawa,F.; Kobatake,Y.; Hayashi, T. Tetrahedron Lett. 1993,34,2505.(31)Prasit, P.; Chua, P.; Roy, P. 7th IUPAC Symposium on Organo-Metallic Chemistry directed towards Organic Synthesis, Kobe, Septem-ber 1993, Abstr. No. S 18.(32) (a) Shibasaki, M.; Sato, Y.; Kagechika, K. Yuki &sei KugukuKyokuishi 1992,50,826and references therein. (b) Nukui, S.; Sodeoka,M.; Shibasaki, M. Tetrahedron Lett . 1993, 34, 4965. (c) Takemoto, T.;Sodeoka, M.; Sasai, H.; Shibasaki, M.J .Am. Ch em.SOC. 993,115,8477.(33)(a)Ashimori, A.; Overman, L. E. J . Org. Chem. 1992,57, 4571.This methodology was used for the stereoselective synthesis of (-1-physostigmine; see: (b) Ashimori, A,; Matsuura, T.; Overman, L. E.;Poon,D. J. J . Org . Ch em. 1993,58, 6949.

89111 93 (71) 67 (7) B71/29 ~ 9 646) 17 (24) B86/14 66 (74) 11(12) B56/44 83/19 4 (15) B0/100 87 (58) BOh00 96 (45) B

Scheme 7

OTf K z C 0 3 THF , 70%. 87hOTBDPS

(R)-(E).3Q,70%yidd. 3Q%ee(R)-(Z)-30,19%yield, 3 2 % ~

(E)-=

OTBDPS

3% Pdz(dba)3/8% R)-BINAPOTf K2C03 THF, 5OoC, 336hO f sDPS

(S)-(E)-SO,97%yldd. 91%eew-=Scheme 8

0

(5)-(+)-32,l%yidd, 7 1 % ~

(R)-(-)-32, 77%yidd, 66% W

Ag (-)-33,63%ee A9 (+)-34,64%w Ag (+)-35,496596 eePMP(+)-a,5% ee PMP 8% PMP (-)-35,-7%ee

corresponding triflate derivative (entry 4). Anotherimportant result was the synthesis of tetralin deriva-tives having a benzylic quaternary carbon center viaasymmetric intramolecular Heck reaction using tri-flate as leaving In this case the enantiose-lectivity of the reaction was related t o the geometryof the olefin present in the start ing material (Scheme7) .Overman reported the stereoselective synthesis ofquaternary carbon via asymmetric intramolecularHeck reaction (Scheme 8).33The enantiomeric purityof the reactions carried out at 80 "C in N,N-dimethyl-acetamide with (R)-BINAF' and the aryl iodide/Ag(I)system ranged between 49% and 71%. However, when

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New Perspectives in the Heck ReactionPMPZ4was used as base in the absence of the Ag(1)salt, long reaction times but still good stereoselectivi-ties of the opposite enantiomers were obtained. Theseresults seem to be in contrast with the mechanism ofthe coordination-insertion process described in Scheme3. In fact, in the absenceof Ag(1) the reaction followspath A and the transfer of the chiral informationshould be difficult. However, when the double bondis not in a cyclic ring (33),the ee drops to 25%, andwith more flexible substrates the products (34 and 35were almost racemic. Therefore, even though (R)-BINAP was coordinated only by one of the phosphorusatoms, with rigid substrates like 31 an effectivetransfer of the chiral information was observed viapath A.

Polycyclizations. The palladium-catalyzed poly-ene cyclization is an attractive synthetic methodol-however, there is only one example of thecorresponding stereoselective version using chiralligands (Scheme 9). Overman reported in 1989 thatthe cyclization of a trienyl trifalte 36 carried out inthe presence of (R,R)- or (S,S)-DIOP afforded thetarget product 37 with an enantiomeric excess of(34) a) Overman,L. .; Abelman,M. M.; Kucera, D. J.;Tran,V. D.;Ricca,D. J. Pure Appl . Chem. 1992, 64, 1813. Very interesting resultshave been reported by Grigg on palladium-catalyzed tandem-cyclization-anion capture processes. See, for example: (b) Burns, B.;Grigg, R.;Santhakumar,V.; Sridharan,V.; Stevenson,P.;Worakun, T. Tetrahedron1992 ,48 , 7297.

ACC.Chem. Res., Vol.28, No. 1, 1995 7Scheme 9

10% Pd(OAc)$(R,R)-DIOP\ CH$N,rt,2h

0 036 37,>Wh yield, 45% w

45%.35 Possible applications of this approach,via pathB, t o polycyclic compounds are unexplored.Concluding Remarks

From a mechanistic point of view, the coordination-insertion process described in Scheme 3 explains theeffects that several factors (leaving groups, neutralligands, additives, and olefin substituents) have on thereaction course. This mechanistic model is a usefultool fo r a better understanding of the scope and limi-tations of the Heck reaction.Taking into consideration the high level of regio- andstereoselectivity control obtained during the last fiveyears and the flexibilityof the methodology, the Heckreaction offers excellent opportunities in the synthesisof polyfunctional compounds.AR930075Q1989 ,54 , 5846.(35) arpenter,N. .;Kucera,D. J.; Overman, L. E. J.Org. Chem.