8 Organometalfic Chemistry The Transition Elements By G.R. STEPHENSON School of Chemical Sciences University of East Anglia Nurwich NR4 7TJ UK 1 Introduction Not every year produces results which point to new directions in organometallic chemistry. During 1993 however significant advances have been made in the use of supercritical fluids as solvents for preparative-scale organometallic synthesis. At Nottingham Bannister Howdle and Poliakoff ' have developed a flow reactor to perform photochemistry under supercritical conditions. In the Nottingham set-up an infrared flow cell is placed in series with the reactor vessel to allow on-line study of the reaction process (Figure 1). In this way the pentacarbonylchromium complex of ethene was isolated for the first time.This experiment used supercritical ethene as the solvent in the flow reactor. Figure 1 (Reproduced with permission from J. Chem. Soc. Chem. Cornmun. 1993 1814) At CIernson University in the USA supercritical water has been used as a reaction solvent. Dicarbon y1(cyclopen tadien yl )co balt-catal ysed cyclo trimerizat ion of a1k ynes was studied under these conditions. At 374 "Cgood yields of aromatic products were obtained with regioisorner distributions comparable to those observed in the organic solvents more customarily employed for this type of reaction. The temperature conditions were important. At 140°Ca diverse mixture of products was The cyclooligomerization and cooligomerization of alkynes has always been an J.A. Banister S. M.Howdle and M.PoIiakoff J. Chem. Soc. Chem. Commun. I993 1814. K.S. Jerome and E. J. Parsons Orgonometallics 1993,12 2991. 217 G. R . Stephenson 70% OTBDMS -OTBDMS Reagents i rPd(dba)J; ii TBDMSCI CO [RU~(CO)~J Scheme I important topic in organometallic chemistry. Alkynes are highly reactive starting materials and so participate readiIy in a great variety of reactions. During the year there has been particular progress with the development of the organometaiiic chemistry of alkynes for controlled carbonsarbon bond formation. Few of the reactions under study are new in type but looking back over the year it is clear that this continues to be an exciting and rapidly deveIoping area of organornetallic chemistry.In this year's Report we will look in detail at the most recent developments in this field.2 Alkynes in C-C Bond Formation DicarbonyIfcyclopentadieny1)cobalt is the most common reagent used for the cyclotrimerizationof alkynes. An alternative based on organopalladium chemistry is remarkable for its chemical selectivity (Scheme 1). Palladium catalysis produces a dimer from a bispropargyl ester of an alkyne-containing dicarboxyclic acid .3 Combination of two alkynes with two molecules of carbon monoxide can produce a 1,2-dioxygenated aromatic ring. Ru,(CO) and tricyclohexylphosphine are used to promote this cyclization rea~tion.~ When two alkynes are joined within a larger ring these can be dimerized using a (cydopentadieny1)cobalt system to form a superphane containing q4-cyclobutadiene CoCp complexes at each end.Yields are low (less than 1%) but this interesting product was characterized by X-ray ~rystallography.~ Enyne cyclizatim-When an alkene and an alkyne are combined by a palladium catalyst the typical product is a 1,3-diene. An example from the Trost group forms a six-membered ring in this way? When an extra alkyne is present in the starting material further carbon-carbon bond formation forms a triene which cyclizes C. Stephan and H.Torn Dieck J. Mot. Cotal. 1993 81 313. 'N. Chatani Y. Fukumoto,T. Ida and S. Murai J. Am. Chem. Soc. 1993 115 11614. R.Gleiter G. Pflasterer and B. Nuber J. Chem. Soc. Chem. Commun. 1993,454. B. M.Trost and 0.J. Gelling TetrahedronLert. 1993,34,8233. Organomtalk Chemistry I 4 Med Med 68% (11 0 0 63% Reagents i [Pd(OAc),] Py; ii Pd[(dba),] CH,CO,H,P(O-tol) scheme 2 thermally thus providing a cycIohexa-l,3-diene ~ynthesis.~ If the alkene is a vinylbrom- ide,' cocyclization with an additional alkyne affords an aromatic product.Enyne cyclization can be performed on elaborate substrates as evidenced by the formation of (1) (Scheme 2).9 Inclusion of acetic acid among the reagents allows the formation of an alkene [e-g. (211 rather than a diene. The product (2) was used as an intermediate in the total synthesis of chokol C." There are now many variants on the enyne cyclization. A combination of the cyclization reaction with a metathesis step is of particular note. Palladium-catalysed cycfization of (3) affords (4) in 85% yield.The CHMe unit originating in the alkene has been transferred to the atkyne-end of the carbon chain." In some cases a cyclobutene for example (3, can be isolated." Use of a palladium chloride catalyst in the presence of five equivalentsof copper(11) dichloride allows the introduction of two ' B.M. Trost and Y. Shi J. Am. Gem. Soc. 1993 115 12491. * E.-i. Negishi M. Ay and T.Sugihara Tetrahedron 1993 49 5471. F.-H. Wartenberg B. Hellendahi and S. Blechert SYNLETT,1993 539. lo 8.M. Trost and L.T. Phan Tetrahedron Lett. 1993 34,4735. 'I B. M. Trost and V.K. Chang Synthesis 1993 824. B.M. Trost M. Yanai and K. Hoogsteen J. Am. Chem. SOL 1993,115,5294. 220 G.R. Stephenson chlorine atoms one to the alkene and one to the a1k~ne.l~ The potential for further elaboration of the alkenyl and the alkyl chloride groups in such products will make them attractive as intermediates in organic synthesis.To gain access to a precursor of isohinokinin hydrogenation conditions were employed to remove both halides and the carbonsarbon doubIe bond.14 In a further variant P-ketoester and alkyne coreac- tants in an intermolecular process combine in a new synthesis of 2,3,4-trisubstituted furans.' Allylic alcohols acetates and chlorides have been examined as starting materials in intramolecular cyclizations with terminal alkynes. Lithium chloride is included as a coreactant. In the case of the allylic alcohol depending on the substitution at the CHOH centre either hydrogen or OH transfer to the metal is observed.Bulky substituents favour hydrogen transfer forming an enol ether and hence ultimately a ketone. With a methyl group the only product is that of oxygen transfer. In both cases a chlorine atom becomes attached forming an alkenyl ch1oride.l6 Allylic acetates show more general selectivity for leaving group displacement in this type of rea~ti0n.l~ Allylic chlorides have aIso been used as starting rnaterials.l8 In the presence of carbon monoxide the reaction takes a different course. This is a palladium-catalysed version of the Pauson-Khand reaction. The dienone (6) was formed in 43% yield.lg Progress continues to be made in the development of the organocobalt Pauson-Khand reaction. Dimethyl sulfoxide and other polar solvents have been shown to promote cyclopentenone formation from alkyne hexacarbonyldicobalt complexes.20The dry-state adsorption conditions developed by Smit and Caple have been employed in a version of the Pauson-Khand cyclization of N-protected ally1 propargyl amines which in the absence of oxygen give rise to saturated bicyclic cyclopentanone products rather than the usual cyclopentenones.2 The use of coordinating ligands has also been evaluated,2 and a 1-alkynylcycfopropanoI has been shownz3 to be an alternative starting material for this type ofcyclization.In this case a catalytic amount of octacarbonyldicobalt and triphenylphosphite was em-ployed. In the patent literature reports of catalytic versions of the Pauson-Khand cyclization have appeared. An intermolecular reaction between hept- 1-yne and ethene has been performed.Pentacarbonyliron may be used in combination with the dindear cobalt catalyst (Scheme 3). The reaction is described as regioselective and useful on an industrial scale. Another catalytic version of the reaction used dicyclopentadienyltitanium(trimethylphosphine)in place of the cobalt complex and an isocyanide in place ofcarbon monoxide.25 Since the recently reported first catalytic l3 S. Ma and X.Lu J. Org. Chem. 1993,58 1245. lo X. Eu and G. Zhu SYNLETT 1993 68. N. Greeves and J. S. Torode Synthesis 1993 1109. l6 S. Ma and X. Lu J. Organornet. Chem. 1993 447 305. l7 G. Zhu S. Ma and X. Lu J. Chem. Res. (S) 1993 366. la S. Ma G.Zhu and X.Lu,J. Org. Chern. 1993,58 3692. i9 N.C.IhIe and C. H. Heathcock J. Org. Chem. 1993,58 560. 2o Y.K. Chung B. Y. Lee N. Jeong M. Hudecek and P. L. Pauson Organometalks 1993,12 220. '' D. P.Becker and D. L. Flynn Tetrahedron Lett. 1993 34 2087. 22 M.E. Krafft I. L. Scott R. €3. Romero S. Feibelmann and C. E. Van Pelt J. Am. Chem. Soc. 1993,115 7199. 23 N. Iwasawa and T. Matsuo Chem. Lett. 1993 997. 24 W. Keim Potentschrift (Switz.),CH 681224 1993 (Chem. Abstr. 1993 119 95004). 25 S.C. Berk R. B. Grossman and S.L.Buckwald J. Am. Chem. Soc. 1993 115,4912. Organometaliic Chemistry 221 (6) 43% 0 51% Reagents i [Pd,(dba)J PPh,,LiCl,CO; ii ethene CO [Co,(CO),] (cat.) [Fe(CO),] Scheme 3 Me (7)91% 62% Reagents i [Co,(CO),];ii [Mo(CO),] DMSO toluene Scheme 4 version of a Pauson-Khand cyclization considerable progress has been made.Under stoichiometric conditions cyclizations of electron deficient alkynes have been examined. The enedione product (7) was obtained in excellent yieldsz6 (Scheme 4). With three equivalents of a simple propargylketone and (octacarbonyl)dicobalt a compound with a dinuclear ‘flyover bridge-type’ structure has been obtained and characterized by X-ray crystallography .” The use of other transition metal systems in cydopentenone formation continues to be developed. Both tungsten’ and moIyb- denum2’ complexeshave been used to effect the intramolecular cyclization of enynesto form cyclopentenones. In the tungsten case a pentacarbonyltungsten-THF complex was used. The hexacarbonylmolybdenum method on the other hand employed the recently developed DMSO promoter conditions.The second example shown in Scheme 4 includes a potential allylic leaving group but unlike the reaction leading to T. R. Hoye and I.A. Suriano J. Urg. Chem. 1993 58 1659, ’’ G. Gervasio E. Sappa and L. Marko J. Organomet. Chem. 1993,444 203. 28 T. R. Hoye and J.A. Suriano J. Am. Chem. SOC.,1993 115 1154. 29 N. Jeong S,J. Lee B.Y. Lee,and Y.K.Chung Tetrahedron Lett. 1993 34,4027. G.R. Stephenson (6) (Scheme 3) in this benzyl ether case the ether is retained in the product. Indenones can be prepared with palladium catalysts from alkynes and substituted benzal- dehydes. O There have been further developments with cyclopentadienone f~rmation.~ Cyclization of diynes with carbonyl insertion initially formed an q2-cornplex from which the metal can be removed by oxidation with trimethylamine N-oxide.The tetrasubstituted cycfopentadienone (8) can be prepared in 46% yield in this way from 1,7-bistrimethyIsi~ylhept-I$-diyne. Four equivalents of the amine oxide reagent are used. When a large excess of amine oxide is employed (9) is obtained in an improved yield of 67%. It has been shown that (8) is converted into (9) by the action of trimethylamine N-oxide. In the case of the thioether (lo),cyclopentadienone formation affords the q4-compIex in 76% yield. On metal removal bath double bonds muve to produce the substituted thiophene (1 1 ) (Scheme 5). I-SiMej s -2d-L smo dSiMe3 (10) (11) 22% Reagents i [Fe(CO),]; ii Me,NO Scheme 5 When the starting material is the tricarbonyliron complex of a vinylketene intermolecular reaction with an alkyne can under the correct conditions produce a 2,2-disubstituted cyclopent-4-ene-l,3-dione.Phenolic products are also obtained in this way particular€y when electron-rich alkynes are An example of phenol production is given in Scheme 6. This type of cyclization is related to the Dotz-WulR cyclizationof vinylcarbenes with alkynes which is also believed to involve coordinated ketene-type intermediates. In the case of (12) however the usual 1,4-oxygenation pattern on the aromatic ring is replaced by a 1,3-regiochemistry. The Dotz-Wulff cyclization has itself been undergoing further development. The direct preparation of differentially protected hydroquinone complexes has been demon~trated,~~ and the dry-state adsorption conditions discussed above for the 30 R.C.Larock M.J.Doty and S. Cacchi J. Org. Chem. 1993,58,4579. 31 H.-J. Knolker and J. Heber SYNLETT 1993 924. 32 K. E.Morns S. P.Saberi and S. E. Thomas J. Chem.SOC.,Chem. Comun. 1993,209; K.G.Moms,S. P. Saberi M.W.Salter S.E.Thomas and M. F.Ward Tetrahedron,1993,49 5637. 33 S. Chamberlin W. D. Wulff and B.Bax Tetrahedron 1993 49 5531. 223 Organornetallic Chemistry Reagents i EtOC-CH A Scheme 6 Reagents i Ceriumfrvf;ii PPh Scheme 7 Pauson-Khand reaction have been shown to be effective.34 In a variant under examination in the Herndon group a cyclopropylcarbene complex (13) is used (Scheme 7).Opening of the cyclopropyl ring forms a cydoheptadienone product (14).35 Fluorinated vinyfcarbene complexes afford fluorinated hydroq~inones.~~ 1,4-Dioxygenated 1,3-dienes can be obtained from molybdenum carbene complexes and alkyne~.~~ With aminocarbenes bearing a pendant alkyne tricyclic five-membered lactams are ~btained.~' 3 Palladiumcatalysed Cross Coupling There are many palladium-catalysed procedures to effect coupling reactions. Most involve aryI or vinyl halides (or equivalents)with alkenes or hetero-substituted vinyl compounds or arenes. Heck and Stille/Suzuki (organotin/organoboron) coupling reactions are among the most widely used. In the Heck procedure an alkene receives the incoming group. After carbon<arbon bond formation fl-elimination detaches the " J.P. A. Harrity W. J. Kerr and D. Middlemiss Tetrahedron 1993 49 5565. 35 J. W. Herndon and M. Zora SYNLETT 1993 363. 36 K.H. Dotz and J. GIanzer J. Chem. Soc. Chem. Commun. 1993 1036. 37 D.F. Harvey and D.A. Neil Tetrahedron 1993,49 2145. '' E. Chelain A. Parlier M. Audouin H. Rudler J.-C. Daran J. Vaissermann J. Am. Chem. SOC.,1993,115 10568. G.R. Stephenson cc__) Ar-X f i Reagents 1 Palladium(o) L 65 "C Scheme 8 metal and replaces the unsaturation in the product. In the Stille/Suzuki cross- couplings the alkene is substituted with a heteroatom (tin in the Stille case boron in the Suzuki case) to allow oxidative addition to transfer an alkenyl substituent to the metal. In this case carbon-carbon bond formation occurs by reductive elimination.When the substrate is a simple vinylboronate ester it is an open question whether reaction with an aryl halide will proceed by a Heck or a Suzuki process (Scheme 8). A study of the selectivity of this reaction3g has shown that the nature of the aryl halide exerts a considerabIe influence. With iodobenzene the ratio of (15) (16) was greater than 95 :5. With 4-iodoanisoie on the other hand reaction was slower and selectivity was reversed (10 :90) to favour product (16). Acrylic esters are commonly used substrates for the Heck coupling. Bates and Gabel have applied this reaction to good effect in a short synthesis of phcatin B (17) (Scheme 9).40Styrenes are also typical receiving groups. The effect of chelating ligands in Heck coupling to styrenes has been studied in detail under base-free c~nditions.~' A recent trend is to apply Heck coupling in heterocyclic synthesis.4-Vinylpyridine has been combined with 4-brornoiodobenzene urfdet the normal palladium acetate triethylamine conditions?* Indoles have been coupled to a~rylates.~~ Oxidative addition to an iodopyridine by a triphenylphosphine complex formed from palladium acetate begins a short total synthesisof (+_)-epibatidine.Coupling to the alkene (18) is followed by a reductive procedure using formic acid to complete the substituted ring system in 35% yield (Scheme 10).Deprotection at nitrogen completed the synthesis of epibatidine (19) (R = 39 A. R. Hunt S. K. Stewart and A. Whiting Tetmhedron Lett. 1993,34,3599.*O R. W. Bates and C. J. Gabel Tetrahedron Lett. 1993 34 3547. 41 M. Portnoy Y. Ben-David and D. Milstein Organametallics 1993 12 4734. *' J. Burdeniuk and D.Milstein J. Organornet. Chem. 1993,451 213. 43 Y. Yokoyama M. Takashima C. Higaki K. Shidori S. Moriguchi C. Ando and Y. Murakami Heterocycles 1993 36 1739. 44 S.C. Clayton and A.C. Reagan Tetrahedron Lett. 1993 34 7493. Organometallic Chemistry Reagents i methyl acrylate [PdfOAc),] PR, NEt,; ii K,CO, MeOH Scheme 9 Reagents i [Pd(OAcj,(PPh )J,piperidine formic acid 2-chloro-5-iodopyridine Scheme 10 (20) -72% Reagents i [Pd(OAc),] AgJO, PPh, DMF Scheme 11 Attention is currently turning to more unusuai substitution on the alkene. Examples involving vinylphosphine and enamine~~~ illustrate this trend.The alkene linkage in a 1,3-dioxep-5-ene is also suitabIe (Scheme 13).47 In this case silver carbonate was used as the base in place of the more norma1 triethylamine. The product (20) was employed in a synthesis of 4-arylbutyrolactones. 45 K. M. Petrusiewicz M. Kuznikowski. and M. Koprowski Tetrahedron:Asymmetry 1993,4 2143. 46 C. A. Busacca R. E. Johnson and J. Swestock J. Org. Chem. 1993 58 3299. 4’ T. Sakamoto Y. Kondo and H. Yamanaka Heterocycles 1993 36 2437. G.R. Stephenson (21)98% RNm OBn lii t)Bn (24) 60% Reagents i [Pd(OAc),] NEt, CH,CN; ii [Pd(OAcf,] PPh, KOAc; iii [Pd(OTf),(PPh,),] toluene Scheme 12 Intramolecular Heck reactions work well (Scheme 12). Tndoles can be made by cyclization of N-aIlyl-2-iodoanaline derivatives.The #?-elimination step completes the methylene substituent at C-3. The reaction has been used in the synthesis of the CC- 1065/duocarrnycin pharmacophore?8 Cyclization of an N-arylenamine also works. The highly efficient formation of (21) illustrates that ester substituents on the receiving alkene are not restricted to the far end of the double bond.49 Polycyclic indoIe derivatives are accessibk by use of the C-2 C-3 double bond as the receiving unit.50 Acrylic amides obtained from iodoanilines offer similar coupling possibihties. Larger rings [e.g. (23)] can be formed by attachment of the allylamine portion via a spacer unit as in (22).52More elaborate po~ycyclic structures are obtained in a similar way.53 The example leading to (24) empIoys the relatively unusual palladium trifluoroacetate catalyst.The alkene links in the products (23) and (24)illustrate the importance of the b-elimination step at the conclusion of the coupling process. A highly functionalized substrate has been used in an intramolecular Heck arylation to give rapid access to 48 T. Sakamoto Y. Kondo M. Uchiyarna and H. Yamanaka J. Chem. Soc. Perkin Truns.1,1993 1941. 49 J. P. Michael S.-F. Chang and C. Wilson Tetrahedron Lett. 1993 34 8365. ’* P.Melnyk J. Gasche and C. ThaI Tetruhedron Lett. 1993 34 5449. 5* A. Arcadi S. Cacchi F. Marinelli and P. Pace SYNLETT 1993 734. 52 L. F. Tietze and R. Schimpf Synthesis 1993 876. ’’ C.Y. Hong N,Kado and L. E. Overman J. Am. Chem. Soc. 1993,115 11028.Organometallic Chemistry 227 congeners of FR900482.54An allylic leaving group an N-0 bond and an aziridine were all present as structural features in the substrate in this case yet side reactions did not prevent the effective application of the process. Regiocontrol has been studied. Depending on the reaction conditions coupling to vinyl ethers can occur at either end but pendant amines in the alkyl group of the enol ether promote far-end attack by chelation control.55 The regiocontrol of the b-elimination step in the Heck coupling of allylamines has been st~died.'~ When a vinyl epoxide is the receiving group carbon-oxygen bond cleavage replaces #3-elimin- ation at the metal-removal step5' A reductive base-free version of the Heck reaction has been reported.Half an equivalent of zinc is included in the reaction mixt~re.~' The reaction conditions shown in Schemes 9-11 are typical of those currently employed in Heck coupling reactions. Normally palladium acetate and triethyIamine are used in polar aprotic solvents such as DMF or acetonitrik. Common variants on the base include other alkylamines silver carbonate or an acetate. The palladium complex need not be the diacetate. Other palladium(i~) and fo) complexes are also employed. The use of aryl triflates in place of aryl halides is common. An example with an en01 ether again employs a coordinating group in the alkyl side chain of the receiving unit. In this case an alkyldiphenylphosphine was used. The enoI ether couples with the triflate of €-naphthol.59 An intramolecular coupling involving an aryI triAate has been used to build benzofluoranthenes." Turning to cross-coupling similar trends are clear.Aryl bromides are again typical building blocks but are now combined with tin- or boron-containing aIkenes. Scheme 13 shows a typical Bromobenzene couples with the vinyltin reagent (25)to afford (26) in 95% yield. The reaction has been applied to the preparation of seven-membered azaheterocydes e.g. (27) using bromobenzaldehydes. The pallad- ium@) catalyst [Pd(PPh,),] is typical for this type of coupling. Product (26) is formed efficiently in the presence of the free amine but a version of the reaction using a bistrimethylsilyl-protected amine has also been reported.62 An advantage of the cross-couplingis that regiocontrol in the coupling step can be dictated by the location of the carbon-tin bond.Coupling 4-iodonitrobenzene with an a-stannyl acrylate affords a branched product in 76% yield.63 The reaction has been applied to 2-bromo-6-methoxynaphthalene, again to afford a branched coupling product. This requiresonly reduction and ester hydrolysis to complete a short synthesis of naproxen a commercially important inhibitor of cyclooxygenase. An intramolecular version of vinyltin coupling has been reported.64 This type of coupling reaction is useful in heterocyclic synthesis. 2,6-Dibromoaniline couples with a tributyltin derivative of an " K. F. McClure and S. J. Danishefsky J. Am. Chem. Soc. 1993 115 6094. 55 M. Larhed C.-M. Anderson and A.Hallberg Acta Chem. Scad. 1993,47 212. s6 L. Filippini M. Gusrneroli and R. Eva Tetrahedron Len. 1993 34 1643. '' R.C. Larock and S. Ding J. Org. Chem. 1993,58 804. '* M. Portnoy,Y. Ben-David and D. Milstein OrganornetaNics,1993 12 4734. 59 D. Badone and U. Guzzi Tetrahedron Left. 1993 34 3603. 6o J.E. Rice and 2.-W. Cai J. Org. Chem. 1993,58 1415. R.J. P.Corriu B.Geng and 1.J. E.Moreau J. Org. Chem. 1993,58 1443. 62 R.J. P. Corriu G. BoIin and J. J.E. Moreau Bull. SOC.Chim. Fr. 1993 273. 63 J. I. Levin Tetrahedron Left. 1993 34 6211. H. Finch N.A. Pegg and 3. Evans Terrahedron Lett. 1993 34 8353. G.R. Stephenson i X=H / (26) 95% oBr X i X=CHO c (27) 89% Reagents i (25),[Pd(PPh,)J Scheme 13 OprlI BnO BnoYY"'Bu3 78% Reagents i [Pd(OAc),J AsPh Scheme 14 enol ether providing bromoindoles for use in a short synthesis of hi~padine.'~ With tetramethyltin alkyl groups are transferred.Methylation of an iodo derivative of a purine nucleoside has been effected in this way.66 Cross-coupling reactions can be performed on highly elaborate intermediates. The combination of (28) with the tin-substituted chiral. dihydrofuran derivative (29)provides a good example (Scheme 14).67The catalysts in these cases were palladiumfxt)complexes. Stannylquinones can 65 T. Sakamoto. A. Yasuhara Y.Kondo and H. Yamanaka Heterocycles 1993 36,2597. 66 A. A. Van Aerschot P. Marnos N.J. Weyns S. Ikeda E. De Clerq and P.A. Herdewijn,J. Med. Chem. 1993 36,2938. 67 H.-C.Zhang M. Brakta and G.D. Daves Jr. Tetrahedron Lett. 1993 34,1571. Organometallic Chemistry 86% &B(O&)2 (31) n= 1 78%; n=2 30% Reagents i [PdCl,(PPh,)] NaOEt; ii [Pd(PPh,),] NaCO Scheme 15 be coupled with aryl iodides,68 and heteroaryltin derivatives couple similarly.69 Tin derivatives of BOC-protected anilines couple with bromochlorobenzenes in the first step of a new carbazole synthesis. The bromine in the haloarene takes part in the coupling step and the chlorine is eliminated with strong base to complete the carbazole by a benzyne rnechani~m.~~ The use of carbon-boron bonds in cross-coupling is now common (Scheme 15). A trifluoromethyl-substituted dime (30) has been linked to 4-iodonitrobenzene in this way.71In this case a boronate ester was used though often it is a simpIe boronic acid that is employed.An azacarbazole synthesis is based on this approach using iodoff uoropyridines in combination with N-protected boronic acid derivatives of aniline.72 The reaction has been employed in a synthesis of the antimicrobial arene sponge pigment fa~caplysin.~~ A bisboronic acid can be used to produce symmetrical 68 L.S. Liebeskind and S. W. Riesinger i.Org. Chem. 1993 58 408. 69 S. Gronwitz P. Bjork J. Malm and A.-B. Hornfeldt J. Orgonomer. Chem. 1993 460,127. ’O M.Iwao H. Takehara S. Furukawa and M. Watanabe Heterocycles 1993 36 1483. ” F. Jin Y. Xu and B. Jiang J. Fluorine Chem. 1993 65 11I. 72 P. Rocca F. Marsais A. Godard and G. Queguiner Tetrahedron 1993 49,49. 73 P.Rocca F. Marsak A. Gadard and G. Queguiner Tetrahedron Lett. 1993 34 7917. G.R. Stephenson (32) (33) 80% Reagents i [Pd(OAc),] K,CO,; ii [PdfOAc),] K,CO, DMF Scheme 16 doubly-extended structures such as the tetrapyridine-substituted triphenyl derivative (31)(n = l).74Aryl triflates have been employed in the same way as aryl halides. The reaction can couple a porphyrin-substituted aryl triflate with 2,4-dimethoxyphenyl- boronic acid providing an alternative access to elaborated quinone~.~~ Couptingwith Vinyl Halides and Triflates.-Vinyl halides work well in Heck couplings (Scheme16).The reaction proceeds in the presence of unprotected OH groups even in allylic alcohols and has been performed without racemization on optically active ally1 alcoholin an enantioselective direct synthesis of dien~ls.’~ Palladium acetate and silver acetate or carbonate were used in this coupling.In a simiIar reaction (using palladium acetate and potassium carbonate) intramolecular cyclization of (32) to form the taxoI intermediate (33) proceeded with concomitant oxidation of the allylic alcohol in the produ~t.~’ Another intramolecular Heck coupling7’ is notable because of the inversion of geometry in the exocyclic alkene in the product (34). Vinyl halides are useful in cross-coupling. Combination with vinyl tin coupling partners provides an attractive route to conjugated polyenes (Scheme 17).The tetraene building block for calyculins has been prepared in this way.79 Intramolecular coupling of the same type closes the macrocyclic ring in (35).80 A still more ambitious 74 M.Beley S.Chodorowski,I.-P. Collin and J.-P. Sauvage Tetrahedron Lett. 1993,34,2933. 75 C.-S. Chan C. C. Mak and K. S. Chan Tetrahedron Lett. 1993,34 5125. 76 T. JefFery TetrahedronLert. 1993,34 1133. 77 1.J. Masters D. K. lung,W. G.30rnmann S. J. Danishefsky and S.de Gala Tetrahedron Lett. 1993,34 7253. 78 V.H. Rawal and C. Michoud J. Org. Chem. 1993,58,5583. 79 F. Yokokawa Y. Hamada and T. Shioiri Tetrahedron Lett. 1993 34,6559. 80 G. Pattenden and S. M. Thorn SYNLETT 1993,215. Organometallic Chemistry 231 SnBu3 88% Ncpf (35) 37% Reagents 1 [PdCl,(CH ,CN),] DMF ; ii [Pd(AsPh )J ; iii trans-1,Z-bis( tributyIstanny1 fethyne [PdCl,tCH,CN),j DMF-THF Scheme 17 cross-coupling constitutes the key step in a total synthesis of raparnycin (36).Here 1,2-di(tributylstannyl)etheneis coupled with a pair of vinyl iodide end-groups to complete a triene and close the macrocycle in the target Palladium dichloride or triphenylphosphine complexes are generally used in these reactions though in the case of the formation of (35)triphenylphosphine proved ineffective and the triphenylarsine analogue of the catalyst was required. Enantiomerically pure *’K. C.Nicolaou T. K. Chakraborty,A. D. Piscopio N. Minowa and P. Bertinato J. Am.Cltern. Soc. 1993 115 1 IS,4419. 232 G R . Stephenson dienylsulfoxides can be obtained by coupling tributylvinyltin with a sulfoxide-substituted vinyl bromide.’’ An unusual coupling of distannylethene was used to link two bromocyclooctatetraenes.83Boronic acids are often used in coupling with vinyl halides.In a synthesis of belamcandaquinones a substituted arylboronic acid is coupled with a bromoquinone derivative by [Pd(PPh,),J catalysis and sodium carbonate.84 This reaction is the converse of the quinone elaboration illustrated in the preceding section. Vinyl triflates are used in coupling reactions with vinyltin reagents.85 This type of coupling has been applied to polyene synthesiss6 and the elaboration of aromatic rings87 by organotin reagents. Vinyltriflates couple with alkyl- alkenyl- and aryl- boronic acid derivatives and other organoboron compounds.88 3-Indoleboronic acids have been used in similar couplings to form 3-substituted indoles.89 Carbapenems have been obtained by Suzuki cross-coupling between boronic acid derivatives and vinyltriflate functionality in the carbapenem unit.90 Nucleophilic Reagents in PalIadiurn-catalysed Cross-coupling.-NucleophiIic species are commonly used in cross-coupling reactions.One of the most general procedures employs acetylide reagents. TypicaI conditions involve besides the palladium catalyst the presence of copper([) iodide and an amine base in the reaction mixture. Coupling with aryl halidesg1 and with heterocyclic derivativesg2 illustrate this reaction. Considerable attention has been paid to the elaboration of uracils and pyridines. Protected uracil derivatives couple with propargyl alcohols and ketones under the typical copper iodide condition^.^^ This type of coupling can be performed with en01 triflate derivatives of pyrimidinucle~sides.~~ Propargyl alcohols couple with aryl haIides in a reaction that has been used in the early stages of the synthesis of water-soluble phthalocyanine derivatives destined for use in the photosensitized inactivation of cancer cells and vir~ses.’~ Chiral propargyl alcohoIs (37) have been employed,96 and retain their stereointegrity during the coupling process (Scheme 18).The product was taken on in another palladium-cataiysed alkyne addition step to complete a synthesis of lipoxin B,. The use of a coupling step to circumvent the need for protecting groups on the alcohols in this synthesis of (38) (of which only reduction is required to complete the tetraene heart oflipoxin B4)is an important advantage.The synthesis of polyenynes in a fashion similar to that illustrated in Scheme 17 is a typical application of this type of 82 R. S. PaIey and A. de Dios Tetrahedron Lett. 1993,34 2429. 83 D.A. Siesel and S. W. Staley Tetrahedron Lett. 1993,34 3679. 84 Y. Fukuyama Y. Kiriyama and M. Kodama Tetrahedron Lett. 1993,34 7637. 85 I.N. Houpis L. DiMicheIe and A. Molina SYNLETT 1993 365. 86 B.H. Lipshutz and M. Alami Tetrahedron Lett. 1993,34 1433. ” V. Farina B. Krishnan D. R. Marshall and G.P. Roth J. Org. Chem. 1993,58 5434. ” T.Oh-e N. Miyaura and A. Suzuki .I. Org. Chem. 1993,58 2201. R9 Q.Zheng Y. Yang and A. R. Martin Tetrahedron Lett. 1993,34 2235. yo N.Yasuda L. Xavier D. L. Rieger Y.Li A. E. Decamp and U.-ff. Dolling Tetrahedron Lett. 1993,34 3211. 91 B.V. Nguyen 2.-Y. Yang and D. J. Burton J. Urg. Chem. 1993 58 7358. 92 G.GaIarnbos C. Szintay J. Tarnas and C. Szantay Heterocycles 1993,36 2241. 93 N.G.Kundu and S. K. Dasgupta J. Chem. Soc. Perkin Trans. 1 1993,21,2657. ’‘ G.T. Crisp and B. L. Flynn J. Urg. Chern. 1993 58 6614. y5 R. W. Boyle and J.E. van Lier SYNLETT 1993 351. 96 M. AIarni B. Cronsse G. LinstrumeIle L. Mambu and M. LarchevEque SYNLETT 1993 217. Organometallic Chemistry OH (37) SiMe SiMe, I Reagents i [PdCI,(PhCN),] CuI piperidine; ii [Pd(PPh,),] CuI piperidine Scheme 18 reaction. The procedures to form dienediyne system^^',^^ are effective and provide the starting point98 for work related to the neocarzinostatin series of natural products.Tribenzocyclotriynesg9 and higher polybenzopolydehydroannulenes have been pre- pared by sequences of coupling reactions (Scheme 19)between arylalkynes and aryI halides. The formation"' of (39) (n= 5) provides another fine example of large ring closure using palladium-catalysed coupling methods. In these reactions it has always been thought that the combination of organic base and copper salt produced traces of copper acetylides as the active nucleophile. In a route to building blocks for functionalized butenolides coupIing at the alkyne was performed in the presence of a 1,3-dicarbonyl compound that could also be easiIy deprotonated."' Coupling of alkynes with aryl halides however can be efficient in the presence of a typical amine base such as pyrrolidine without the presence of a copper salt.lo2 In a synthesis of aryl-and alkynyI-linked pyridine systems a key coupling between a functionalized alkyne and a similarly functionalized aryl halide was found to proceed efficiently (71-79% yield) in the presence of n-propylamine.When copper salts were used side reactions were observed.' O3 97 J. Suffert A. Eggers S. W. Scheuplein and R. Bruckner Tetrahedron Lett. 1993,34 4177. 98 K. Nakatani K. Arai and S. Terashima Tetrahedron 1993 49 1901. 99 J. D. Kinder C.A. Tessier and W. J. Youngs SYNLETT 1993 149. "O K. P.BaIdwin J.D. Bradshaw C.A. Tessier and W.J. Youngs SYNLETT 1993 853. "' A. Arcadi S. Cacchi G. Fabrizi and F. Marinelli SYNLETT 1993 55. ID' M.Alami F. Ferri and G. LinstrnrnelIe Tetrahedron Lett. 1993 34 6403. G.R. Stephenson + (39) n=5 Reagents i [Pd(PPh,),] CuI NEt Scheme 19 Not all aryl halides participate in coupling with alkynes. Efficient homocoupling of the acetylide (to form a diyne) has been reported in the presence of the iodoarene portion of 2-nitro-3-hydroxy-4-iodophenol~104 Coupling of acetylides to a second alkyne carrying a propargylic leaving group has proved to be an efficient route to 1,2-dien-$-ynes. O5 Two examples have appeared where silylalkynes participate in coupling with 2-iodoanilines (and related heterocyclic systems) to provide effective syntheses of heterocondensed pyrroles106 and substituted trypt~phans."~ In these '03 V. Grosshenny and R.ZiesseI J. Organonref. Chem. 1993 453 C19. Io4 N.G. Kundu M. Pal and C. Chowdhury J. Chem. Res. (S) 1993,432. S. Gueugnot and G. Linstrumelle TetrahedronLett. 1993 34 3853. D. Wensbo A. Eriksson T. Jeschke U. Annby S. Gronowitz and L. A. Cohen Tetrahedron Lett. 1993 34,2823. '13' T. Jeschke D. Wensbo U.Annby S. Gronowitz and L.A. Cohen Terruhedron Lett. 1993 34 6471. Organometailic Chemistry examples the silicon is retained during the coupiing step which involves palladium transfer to the alkyne and ring closure with the nitrogen atom. Frequently more potent nucleophiles are used in coupling reactions. In many cases a carbon-zinc bond initiates reaction with a palladium complex. This has been employed in the elaboration of serine-derived iodozinc derivatives of amino acids O8 and imidazole-derived organozinc lo9 and vinylzinc' lo*l reagents.Vinylzincs are often prepared in situ for example from a vinyl halide,'12 or vinyltin reagent.' Their use thus provides a direct alternative to the combination of the halides and tin compounds themselves in cross-coupling steps. Heterocyclic systems have been used. Deprotonation of N-protected indoles followed by addition of zinc chloride prepares the way for coupling with iodobenzene.' l4 In this reaction the protecting group is an electron-withdrawing group. Similar zinc chloride derivatives of indoles have been used in coupling with pyridines.' Grignard reagents have also been used even in the presence of alcohol functional groups. Boron is a Iess-common precursor for metallation but there are examples of the use of trivinylboron derivatives in transmetallation with diethylzinc prior to coupling under palladium-catalysed conditions.' 'Electrochemically prepared arylzinc halide derivatives have also been successfully employed.* Double Heteroatom Attachment.-The use of palladium-catalysed coupling conditions to form bonds to heteroatoms rather than to carbon is of growing importance (Scheme 20). Coupling of 2-brornotrifluoromethyIbenzene with hexarnethyldisilane affords (40) in 50% yield.' l9 Double silylation with concomitant dimerization of 1,3-dienes to form (41) has also been reported.'20 In the case of formation of (421 a dimethylsilyl group is introduced during the cyclodimerization of two alkynes.'" An intramolecular process adds an 0-tethered R2Si-SiR unit across an alkene.' 22 With a mixed trimethyltin-trimethylsilyl reagent tin and silicon add across n~rbornene.'~' Wexarnethyiditin can be used to replace an enol triflate by a trimethyltin unit.124 Thioboration of alkynes proceeds under palladium-catalysed conditions.12s Iodine can be introduced in place of an S02Ph group by the use of zinc iodide with [PdCl,(PhCN) J.25 The examples given in Scheme 20 indicate that all the typical lo* M. J. Dunn R. F. W. Jackson J. Pietruszka,N. Wishart D. Ellis,and M. J. Wythes S YNLETT 1993,499. '09 R. M. Turner S. V. Ley and S. D. Lindell SYNLETT 1993,748. 'Io T.L. GiIchrist and M. A. M. Healy Tetrahedron 1993 49,2543. ''I R. Rossi A. Carpita F.Bellina and P. Cossi J. Organornet. Chem.. 1993,451 33. '" E.4. Negishi M. Ay Y. V. Gulevich and Y. Noda Tetrahedron Lett. 1993,34 1437. B.H. Lipshutz M. Alami and R. B. Susfalk SYNLETT 1993,693. lL4 T. Sakamoto Y. Kondo N. Takazawa and H. Yamanaka Heterocycles 1993,36 1993. 'I5 M. Amat S.Hadida and J. Bosch Tetrahedron Lett. 1993 34 5005. R. W. Hoffman V. Giesen and M. Fuest Liebigs Ann. Chem. 1993.629. 'I7 K. A. Agrios and M. Srebnik 3. Organornet. Chem. 1993,444 15. S. SibiIle V.Ratovelamanana J. Y. NtdtIec and J. Pkrichon SYNLETT 1993,425. 'I9 P.Babin B. Bennetau M. Theurig and J. Dunoguts J. Organomet. Chem. 1993,446 135 ''O Y.Obora Y. Tsuji and T. Kawamura Organometallics 1993 12 2853. ''I K. Ikenaga K. Hiramatsu N. Nasaka and S. Matsumoto J. Org Chem.1993,58 5045. "'M. Murakami M. Suginome K. Fujimoto H. Nakamura P.G. Andersson and Y. €to,J. Am. Chem.SOC. 1993 115 6487. lZ3 Y. Obora Y. Tsuji M. Asayama and T. Kawamura Organometallics I993,12,4697. ''' T.A. Tius G.S.K. Kannangara M.A. Kerr and K. J.S. Grace Tetrahedron 1993,49,3291 T.Ishiyama K.-i. Nishijima N. Miyaura and A. Suzuki J. Am. Chem. Soc. 1993 115 7219. '" T.Satoh K. Itoh M. Miura and M. Nomura,Bull. Chem. Soc. Jpn. 1993,66,2121. T. Satoh K. Itoh M. Miura and M. Nomura Bull. Chem. Soc. Jpn. 1993 66,2121. G.R. Stephenson (40) 50% (41) 85% Reagents i Me,SiSiMe, [Pd(PPh,),J HMPT; ii Mc,SiSiMe, [Pd(dba),] DMF; iii HMc,SiSnBu, CPdCI,(PPh,)J Scheme 20 types of palladium(0) and palladium(I1) catalysts can be empIoyed Multi-step Coupling Reactions-A simple two-step process adds two coupling partners across an alkene.Norbornadiene couples with 4-methoxyiodobemzene and a tributyl- tin acetylide. Effectively this is a Heck coupling reaction intercepted by a Stille coupling. Pyrolysis of the product effects a retro Diels-Alder reaction to place a cis-alkene between the acetylene and the aromatic ring.127The second double bond in norbornadiene can also participate in coupIing. A new carbon+arbon bond is formed across the base of the norbornadiene framework and a second coupling reaction completes the process. A combinationof zinc zinc dichIoride and an alkyl iodide have been used in the final stage of this reaction.128 Reaction of norbornadiene with 3-iodocyclohexenone attached two enone units to the same alkene.In the presence of triethylamine these products then cycIizedin a normal aldol reaction. A vinylzinc reagent provides the starting point for an unusual double coupling (Scheme 21) to a diiodobiaryl coreactant with axial chirality and C symmetry. The product (43) arises from a sequence of metal-rnediated stepsending in p-elimination to pIace the alkene in the five-membered ring. Since a quaternary centre has been formed the alkene moves to the next place around the ring.130 An iodocinnamate ester couples with norbor- nadiene by a double Heck process. In this reaction too an aikene is put back into the 'I' M.Kosugi T.Kimura H.Oda and T. Migita Bull. Chem. SUC.Jpn. 1993,66,3522. ''13 c.s. Li,D.C. Jou and C.H. Chcng Organometdlics 1993 12 3945. 'I9 C.-S. Li D.-C. Jou C.-H. Cheng F.-L. Liso and S.-L. Wang OrganornetaNics 1993,12 3553. lJoT.J. Katz A.M. Gilbert,M.E.Huttenloch G. Min-Min and H.H. Brintzinger TetrahedronLett. E993 34,3551. Organometallic Chemistry Q-"" (43) 66% Reagents i [Pd(PPh,),] THF Scheme 21 OMe Reagents i HCEX.,H,OH EPdCl,(PPh,),] CuI NEt Scheme 22 product by #%eIirninati~n.'~' Heteroatoms can participate in the final bond formation. Coupling of a monosubstituted alkyne with 3-bromoacrylic acid under the copper iodide-triethylamine conditions affordsbutenolides by a sequence of carbonxarbon and carbon-oxygen bond formations. I 32 2-Iodobenzoic acid couples with alkynes in a similar fa~hi0n.I~~ The quinolinofuren (44)can be prepared by attachment of an acetylide to a vinylhalide and trapping of the oxygen atom after tautomerization of the amide (Scheme 22).Benzofurans can also be obtained.134 1,3-Dicarbonyl compounds are precursors to furan ring systems in a tandem coupling pracess in which tautomerization to the enol form completes the product structure.13s In all these reactions an intermolecular initial coupling is followed by an intramolecular process. With a l-en-6-yne a sequence of three carbonxarbon bond formations is possible to effect a [2 + 2 -k 21 cycIoaddition.'36 An alternative way to combine inter- and intramolecular steps is to place both the initial site of reaction and the first receiving carbon-arbon multiple bond within the 13' R.Grigg P. Kennewell A. J. Teasdale and V. Sridharan Tetrahedron Lett. 1993 34 153. 132 X. Lu X. Huang and S. Ma Tetrahedron Lett. 1993 34 5963. 13' N.G. Kundu and M. Pal 1.Chem. Soc. Chem. Commun. 1993 86. 134 J. Reisch P. Nordhaus and T. Pfiug J. Heterocydic Chem. 1993,30,1161; I. Candiani S. Dekrnardinis W. Cabri M. Marchi A. kdeschi and S. Penco SYNLETT 1993 269. A. Arcadi S. Cacchi R.C. Larock and F. Marinelli Tetrohedron Lett. 1993 34 2813. 13' S.&Own. S. Clarksan R. Grigg and V. Sridharan Tetrahedron Lett. 1993 34 157. G.R.Stephenson (45) 50% Reagents i Bu,SnC=CCH,OTBDMS [Pd(PPh,),j THF; ii [PdCI,(PPh,),],CuI,Et,NH HC=CCH(OEt) Scheme 23 same molecule. Reaction in the presence of an external coreactant traps the final organometallic intermediate.A dienediyne motif has been obtained in this way from a 1,l-diiodoalkene equipped with a terminal alkyne group (Scheme 23). These two unsaturated portions become the 1,3-diene moiety in the dieneldiyne. The acetylides became attached in different ways. One by direct coupling with the vinyl iodide and the other in the trapping step following the closure to the pendent alkyne to complete (45).13'The control of stereochemistry at the exocyclic alkene in this reaction is an important feature and is determined by the syn stereochemistry of metal-mediated doubIe addition to the alkyne. In a variant of the reaction a 1,1-dibromoalkene was used with palladium acetate and triphenyIphosphine as the catalyst system. One equivalentof a tributyltin derivative of a protected propargyl alcohol was employed to complete the coupIing reaction.The intermediate obtained in this way contained one remaining vinylbromide unit and was coupled with a second propargyl alcohol derivative using the copper iodide method.138 The final trapping can also use a copper-mediated acetylide addition. An example that starts through transmetallation to produce an aIkyizinc reagent from an alkyl iodide proceeds by intramolecular cyclization to a pendent alkene. This produces an intermediate that couples to a propargyIic ester.139 A similar strategy but in a different ring size and with the vinyl halide at an internal position (Scheme 241 gives access to an exocyclic 1,3-diene which can couple to a vinyltin derivative.In this way a route to the diene portion of vitamin D can be achieved.14' In a similar cyclization an exocyclic vinylbromide derived from a steroidal CD fragment has been used to terminate the coupling pro~ess.'~' Since the metal moves through the molecule with each successive carbon-carbon bond formation an extensive series of new bonds can be made in a single reaction. This forms the basis of the palIadium zipper polycyclization process (Scheme 25).142Three new carbon<arbon bonds and three rings are formed in the cyclization leading to (46). In the route to (47),reaction is initiated at the vinyl halide with cyclization occurring in J. M. Nuss R.A. Rennels and B. M. Levine J. Am. Chem. SOC. 1993 115,6991. 136 S. Torii H.Okumoto T. Tadokoro A. Nishimura and M.A. Rashid Tetrahedron tett. 1993,34,2139. 13' H. Stadtmiiller C.E. Tucker A. Vzupel and P. Knochei Tetrahedron Lett. 1993,34,791 I. J. M. Nuss M. M. Murphy R. A. Rennels B. H. Heravi and B. J. Mohr Tetrahedron Lett. 1993,34,3079. B. M. Trost and J. Dumas Tetrahedron Left. 1993 34 19. B.M.Trost and Y. Shi J. Am. Chem. Soc. 1993 115 9421. Organometallic Chemistry TBDMSO TBDMSO 72% Reagents i [Pd(PPh,),] THF Scheme 24 89% majordiastemisomer (4) turn at each of the two alkene links in the right-hand portion of the substrate.143 This type of cyclization has been used in the first total synthesis of ( f)-scopadukic acid B. 144 In this case oxidative addition to an aryl halide initiated the reaction sequence. Heteroatom groups can become involved in the termination of tandem palladium coupling reactions.Intramolecular Heck cyclization of a vinyl bromide to an alkene has been combined with carbon-nitrogen bond formation to a terminal NHTs '43 D.3. Kucera S.J. O'Connor and L.E. Overman 3. Org. Chem. 1993 58 5304. 144 L. E. Overman D. J. Ricca and V. D Tran 3. Am. Chem. SOL 1993 115 2042. 14' G. D. Harris Jr. R.J. Herr and S. M. Weinreb J. Org. Chem. 1993,58 5452. G.R. Stephenson Q- N I SO2Ph R (49) 73-8296 Reagents i Pd(OAc), PPh, CH,CN CO(latm) TIOAc; ii PdCI, CuCI, LiC1 CH,CN Scheme 26 Carbanion centres can also terminate coupling reactions (Scheme 26). Car-bon-carbon bond formation by cyanide ion capture provides a good e~amp1e.l~~ In another case carbonylation is combined with Heck coupfing and anion capture to form spirocyclic derivatives of indole (49).'47 Capture by halide ions is also possible.An unusual example employing copper(I1) chloride and lithium chloride in the presence of a catalytic amount of palladium(I1) chloride couples an alkyne and two terminal alkenes with the introduction of two halide ions to form (49). Under different conditions a monocyclic product predominates indicating that halide trapping had occurred at an earlier stage in the reaction sequence.148 Unusual Coupling Processes.-In the previous sections developments over the year in the most common types of coupling reactions have been surveyed. Clear trends are emerging for the pairing of coupling partners.The same patterns apply with the more unusual coupling processes.For example a diazonium salt takes the place of the iodide or triflate in a Heck coupling process performed using palladium acetate in aqueous media.14' Vinyltin reagents have ken coupled with acid chlorides,150 and with dienes with concomitant silylation by a hexaalkyldisilane.' "Coupling of acid chlorides and Several investigations have examined cyclobutane- 1,2-diones and their haloketone analogues. Both vinyItin-acid chloride coupling with a palladium(n) catalyst in the 146 R.Grigg V.Santhakumar and V.Sridharan TetrahedronLett, 1993,34 3153 147 R.Grigg and V,Sridharan Tetrahedron Lett. 1993,34,7471. 14' J. Ji and X.Lu,SYNLETT 1993 745. lr9 S. Sengupta rtnd S.Bhattacharya J. Chem.SOC.,Perkin Trans I 1993 17 1943. IJ0J.-L. Parrain I. Beaudet A. DuchEne S. Watrelot and J. P. Quintard Tetrahedron Lett. 1993,34,5445. lJ1Y. Obora Y. Tsvji and T.Kawarnura J. Am. Chem. Soc. 1993 115 10414. W. Shihua Y. Shenggang H. Xinquan and G. Hefu Huaxue Xuebao 1993,51 393. '2 aromatic halides with heterocyclic tributyltin reagents has been examined.' Organornsta2lic Chemistry 241 Me3Si SiMe (51) 83% Me Me. Reagents i Me,SnC=CCzCSnMe,; ii Me,SiCECSiMe, [Pd,(dba),] AsPh, DMF; iii MeCECSnMe Scheme 27 presence of copper iodide” and the reverse reaction with a chlorocyclobutenone combined with a tin derivative of a quinone154 succeed. A tin-siIicon disubstituted furan has been combined with a chlorocyclobutenone in a new synthesis of benzofurans.Benzothiophenes are also accessible. 5s Hydrosilylation and pallad- ium-catalysed cross-coupling have been combined in a one-pot reaction sequence. 56 During 1993there have been a series of investigationsof palladium-catalysed coupling to heteroatom-substituted x-bound ligands (Scheme 27). The bimetallic product (50)15’and the tetrayne (51)15’ were prepared by coupling reactions of iodocyc-lobutadiene complexes. Similar coupling with a (pentaiodocyclopentadieny1)manga-nese complex leadsto (52).15’ Products (50)and (51)have been characterizedby X-ray L.S.Liebeskind M. S. Yu and R. W. Fen& 3. Org. Chem. 1993,58,3543. Is* J. P.Edwards D. J. Krysan and L.S.Licbeskind J. Am. Chem. Suc. 1993,115,9868. Is’ L.S. Liebeskind and J. Wang 3.Org. Chem. 1993 58 3550. K. Takahashi T. Minami Y. Ohara and T. Hiyama Tetrahedron Lett. 1993,34 8263. ’’’ J. E. C,Wiegelrnann and U. H. F. Bunz Orgmumetallics 1993,12 3792. ’” U.H.F. Bunz and V. Enkelmann Angew. Chem. Int. Ed. Engl. 1993,32,1653. 159 LJ.H. F. Bunz V. Enkelmann and J. Rader Organornetaliics,1993,12,4745. G.R. Stephenson (53) 45% yield 74% e-e. Me (54) 70% yield 80% e.e --OH OR (55) 76% yield 86%e.e. Reagents:i [Pd,(dba),] (R,S) -BPPFOH,CaCO, AgPO,; ii Pd(OAc), (S)-BINAP Bu,NOAc DMSO; iii [Pd,(dba),] (RFBINAP Bu'OH QCH,CH,C1 Scheme 28 crystallography. Cross-coupling to tricarbonylchromium arene compIexes is welt precedented. An asymmetric version has been reported in which the symmetrical tricarbonylchromium complex of 1,Zdichlorobenzene is coupled in the presence of a chiral auxiliary to introduce a vinyl group in place ofone of the chlorines.The resdting metal complex is chiral and is formed in 44% enantiomeric excess.16o Asymmetric Palladium-catalysedCross-coupling reactiona-At the end of the preced- ing section an example of palladium-catalysed cross-coupling induced asymmetry to form a product with planar chirality The asymmetric modification of pallad-ium-catalysed cross-coupling has been a topic of growing importance. Most work in this area concentrates on the induction of asymmetry at chiral centres at carbon. Further examples of enantiofacial differentiation in coupling with dihydrofurans have appeared.'61.162 In both cases BINAP was used as the chiral auxiliary.An I6O M. Uernura H. Nishimura and T. Hayashi Tetrahedron Lett. 1993,34,107. 16' S. Hillers and 0.Reiser Tetrahedron Lett. 1993 34 5265. F. Ozawa Y. Kobatake and T. Hayashi Tetrahedron Lett. 1993,34 2505. Organometaltic Chemistry 243 intermediate in an efficient synthesis of (-)-eptazocine also relied on BINAP to differentiate the enantiofaces ofa silyl-protected allylic alcohol. After the /&elimination step a silylenol ether was produced. Enantioselectivity in the coupling step was 91 A simiIar strategy employing a pendant ally1 alcohol and BINAP was used in an enantioseIective synthesis of physostigmine. The en01 ether product was hydrolysed to position an aldehyde correctly for a condensation reaction with methylamine in the foHowing step.64 Enantiofacial differentiation leading to the asymmetric formation of (53)(Scheme 27) has been studied in detail. Variation of the chirat auxiIiary and the use of silver additives produced a pronounced variation in the efficiency of asymmetric induction. Enantiomeric excesses ranged from 5-86% and the chemicaI yields from 444%. An additional complication was the possibility of formation of mixtures of or,/% and #?,y-unsaturated lactams. In the first example illustrated in Scheme 28 complete selectivity fur (53)was achieved.'65 Enantiotopic group differentiation holds the key to the asymmetric synthesis of (54);'66 the same strategy afforded (55),'67 which was required as a key intermediate fur a synthetic route to vernolepin.'68 An example of enantioselective Grignard cross-coupling employs a chiraI ferrocenylaminophosphine Iigand to effect an asymmetric transformation during the coupling of a chiral Grignard reagent with a vinyl bromide.'69 4 Use of Other Metals in Couphg Reactions Zirconium complexes are effective at forming carbonxarbon bonds between alkenes and alkynes.Because of the stoichiometric nature of these reactions functional groups can be introduced by exploiting the carbon-metal bonds in the final metallocyclic intermediate. Protonation can simply repIace the metal by a hydrogen. The use of iodine produces vinyl halides.' 70 The chemoselectivity of functionalization of zirconacyclopentenes has been exam- ined.I7l When a pendent alkyl halide is included in the alkene cyclization to form cyclopropanes can Two alkenes can also be coupled using dicyclopenta- dienylzirconiurn dichloride.A study with an unsymmetrical dialkene has demonstrated that the cycIization step is reversible at 75 "C. An initial kinetic product (dimerization) is converted into an intramolecular cycloaddition product over a period of time.' 73 Non-conjugated dimes have been converted into conjugated dienezirconocenes. '74 Organornetallic nucleophiles can be combined with alkynes by the reaction of dicyclopentadienylzirconiumdichloride. Carboahmination can be effected even in the presence of water.'75 163 T. Takernoto M. Sodeoka H. Sasai and M. Shibasaki J. Am. Chem. Soc. 1993 115 8477. A. Ashirnori T. Matsuura L.E. Overmann and D.J.Poon J. Org. Chem. 1993 58 6949. S. Nukui M. Sodeoka and M. Shibasaki Tetrahedron LRtt. 1993,34,4965. K Kagechika T. Ohshima. and M.Shibasaki Tetrahedron,1993,49 1773. 16' K. Kondo M. Sodeoka M.Mori and M. Shibasaki Synthesis 1993 920. K. Kondo M. Sodeoka M. Mori and M. Shibasaki Tetrahedron Lett. 1993,34 4219. 169 €3. Jedicka C. Kratky W. Weissensteiner and M. WidhaIm J. Chem. Soc. Chem. Commun. 1993 1329. 17' T. Takahashi N. Suzuki,M. Kageyarna D. Y.Kondakov and R.Hara Tetrahedron Lett. 1993,34,4811. "' T. Takahashi K. Aoyagi R. Hara and N.Suzuki J. Chem. Soc. Chem. CO~~UR., 1993 1042. 17' T. Takahashi D. Y. Kondakov and N. Suzuki Tetrahedron Lett.. 1993 34,6571. 173 D. F. Taber J. P. Louey and J. A. Lim Tetrohedron Lett. 1993 34 2243. 174 1.P.Maye and E.-i. Negishi Tetrahedron Lett. 1993,34 3359. 17' P. Wipf and S. Lim Angew. Chem. Int. Ed. Engi. 1993,32 1068. 16' G.R. Stephenson Reagents i CpJrMeC1; ii hept-1-ene; iii CO Scheme 29 Catalytic amounts of dicyclopentadienylzirconiurn dichloride have been used to promote the addition of alkyl Grignard reagents to alkyne~.'~~ Oxygenated vinyl- lithium reagents cart also be linked to alkynes. The resulting metallocycies are cIeaved to dienes in protic solvents or can be carbonylated in a cyclojmtenone synthesis. The bicyclic product (56) was obtained in this way (Scheme 29).'" Dimethyltitanocene reacts with alkynes to form metallocyclobutenes. Subsequent addition to a ketone provides a route to homoallylic alcohols.17* Organic nitriles can replace the alkyne in this reaction sequence.There has been a structural study of a titanium ester homoenolate derivative. 79 Dicyclopentadienyltitaniurn derivatives of arenes also react well with alkynes. After protonation substituted styrenes such as (57) are obtained (Scheme 30). This reaction sequence proceeds through a titanium aryne intermediate (58) and the metallocycle (59).' 8o Nickel catalysts couple aryl triflates to form biaryls in the presence of zinc or potassium iodides. *' A combination of nickel dichloride and chromium dichloride has been used to convert vinyl triflates into nucleophilic species for reaction with carbonyl groups in work that completes the tricyclic framework needed for the taxane ring system.'82 The dimerization of alkynes using a rhodium catalyst can proceed in two different fashions.Under acidic conditions followed by exposure to carbon monoxide enynes are produced. On the other hand if reaction with carbon monoxide occurs prior to acidification a disubstituted butatriene is obtained.'83 A dicationic benzene(ethy1- tetramethylcyclopentadieny1)rhodiumcomplex promotes oxidative coupling of phen-ol~.'~~ (PentamethyIcyclopentadieny1)rutheniumcomplexes are used to codimerize conjugated dienes with 1,5-dienes. Intermediate complexes can be obtained or catalytic conditions afford direct access to the free pulyenes.l8' A mechanistic study has been made of reactions between cyclopentadienyl- and (pentamethylcyclopenta- dieny1)ruthenium cations and conjugated dienes and ethyne.IB6 ''' T.Takahashi K. Aoyagi V. Denisov N. Suzuki,D. Choueiry and E.-i. Negishi Tetrahedron Lett. 1993 34,8301. M.C. J. Harris R. J. Whitby and J. BIagg SYNLETT 1993 705. 178 N.A. Petasis and D.-K. Fu Organometallics 1993 12 3776. P. G. Coui T. Carofiglio and C. Floriani Organometallics 1993 12 2845. J. Campora and S. L. Buchwald Organomerallics 1993 12 4182. A. Jutand and A. Mosleh SYNLETT 1993 568. M.H. Kress R. RueI W. H. Miller and Y. Kishi Tetrahedron Lett. 1993 34 6003. i83 M. Schafer N. Mahr J. Wolf and H. Werner Angew. Chem. Int. Ed. Engl. 1993 32 1315. 184 A.G. M. Barrett T. Itoh and E. M. Wallace Tetrahedron Lett. 1993 34 2233. K. Masuda H. Ohkita S. Kurumatani and K. Itoh J. Organornet. Chem. 1993,454 C13. K.Masuda H. Ohkita S. Kurumatani and K. Itoh Urgonometallics I993 12 2221. 245 Organometallic Chemistry Reagents i hex-3-yne; ii MeOH Scheme 30 Unusual I ,1-dizinc carbenoid organometallics have been under investigation in Paris."' These species can be combined with Grignard reagents and after copper modification propargylic esters to produce coupling products. Full details have appeared of homologations of copper reagents using (iodomethy1)zinc iodide.' '* Boron-zinc transmetallation has also been investigated. 89 Zinc/copper chemistry gives rise to new a-amino acid y-amine equivalents and so to direct methods for the synthesis of enantiomerically pure protected amino acids.lgO 5 The Nicholas Reaction The chemistry of dicobalt-stabilized propargyl cations continues to deveIop.The main stepforward comesfrom the laboratory of Nicholas himself where chid metal clusters [(HC~CR)CoL(CO),Co(Co,llhave been used in stereoselective propargyl addition rea~tions.'~' ChiraI allylboron reagents have also been empIoyed with propargyl aldehyde complexes."' Diastereoselectivity is good in Lewis-acid promoted aldol reactions between trimethylsilylenol ethers and dicobalt complexes of pr~pyna1s.'~~ Stereoselectivity is also good in the addition of boron enolates to (propargyl ether)dicobalt c~mplexes.'~~ This reaction (Scheme 31)has been employed in a formal total synthesis of thienarny~in.'~~ After the enolate addition step oxidative removal of 18' F. Chemla 1. Marek J.-F. Normant SYNLETT 1993 445.188 A. Sidduri M.J. Rozema and P. Knochel J. Org. Chem. 1993,58 2694. 18' F. Langer J. Was and P. Knochel Tetrahedron Lett. 1993,34 5261. 19' R.F. W. Jackson N. Wishart and M.J.Wythes SYNLETT 1993 219. 19' A.J. M. Caffyn and K.M. Nicholas J. Am. Chem. SOL 1993 115,6438. lg2 P. Ganesh and K. M. Nicholas J. Org. Chem. 1993 58 5587. C. Mukai 0.Kataoka and M. Hanoaka J. Chem. SOC.,Perkin Trans. 1 1993 563. P.A. Jacobi and W. Zheng Tetrahedron Lett. i993 34 2581. 19' P. A. Jacobi and W. Zheng Tetrahedron Lett. 1993 34 2585. G.R. Stephenson t ii I OSi$uPr (60)79% Reagents I Bu,BOTf; ii ceriurn(1v) scheme 31 the metal with ceric ammonium nitrate afforded the key building block (60). Intramolecular reactions between silyl end ethers and propargyl cations have been Arnine~’~’ and indoles’98 react well with propargyI cations.A crystal structure study of metal-cluster-stabiIized propargyl cations has been performed. 99 AIkynyl derivatives of pyranoses easily invert their stereochemistry when converted into hexacarbonyIdicobaIt complexes.”* Carbon-oxygen bond cleavage under acidic conditions must be combined with the interconversion of stereoisomeric propargyl cation complexes to account for this observation. The effect of modification of the alkyne portion of estradiol on the binding of organometallic units in the estradiol receptor provides evidence fur the irreversible covalent attachment of the metal- labelled steroid to its specific receptor.’*’ The Pauson-Khand reaction was discussed in Section 2.A format total synthesis of loganinehas made use first of stabilization of positive charge CL to the cobalt complexed alkyne and second a Pauson-Khand step to complete a bicyclic cyclopentenoneZo2 196 E. Tyrrell P. Heshmati and L. Sarrazin SYNLETT 1993 769. 19’ K.-D. Roth and U. Muller Tetrahedron Lett. 1993 34 2919. 198 K.-D. Roth SYNLETT 1993 529. IP9M. GruselIe H.EI Hafa M. Nikolski G. Jaouen J. Vaissermann L. Li and M.J. McGlinchey Organometallics 1993 12 4917. S. Tanaka T. Tsukiyama and M. Isobe Tetrahedron Lett. 1993 34 5757. D. Osella G. Dutto G. Jaouen A. Vessieres P. R. Raithby L. De Benedetto and M. J. McGlinchey Organometallics 1993 12 4545. ’” N. Jeong B.Y. Lee S.M.Lee Y.K. Chung and S.-G. Lee Tetrahedron Lett.i993,34,4023. Urganometallic Chemistry 77% Reagents i NaCH(C0,Et)(C02Bu') NEt, [PdCl,(CH,CN,)]; ii CO;iii Me,SnCH=CMe scheme 32 6 Transition Metal Alkeue and Arene z-Cornplexes q2-Cornplexes-Pa11adium-catalysed nucleophilic addition to alkenes and pallad- ium-catalysed coupling reactions are closely related by the similarity of their reaction products though mechanistically the reactions are distinct. Intramolecular versions are popular. An example leading to 2-alkenyltetrahydrofurans uses one double bond link of an alIene as the metal-bound electrophilic centre.203 Combining nucleophile addition with a subsequent cross-coupling step provides a good use for the metakarbon a-bond that is formed when a 7t-bound alkene acts as an electrophile.Intramolecular closure of a pendent amine to an allene has been combined with coupling to an aIkyl halide.204 A similar procedure again using an allene but in the presenceof carbon monoxide and methanol combines nucleophilic attack by a NHTs group with carbonyl insertion to place an ester at the end of the double bond to promote the site of nucleophile addition.20s Unlike the preceding examples which used palladium@) catalysts and a base (typical conditions for coupling reactions) this carbonyl insertion example employs palladium dichloride with copper(i1) chloride as an oxidant. These are typical conditions for a Wacker oxidation modified for carbonylation. Intermolecular nucleophilic addition to an enone carrying a cyclic chiral auxiliary at nitrogen is followed by carbonyl insertion in the early steps of an enantioselective total synthesis of ( + )-negamycin (Scheme 3Q206 An intramolecular closure to a 1,3-diene combined with chlorination by the action of lithium chloride under palladium acetate catalysis illustrates further extensions of the methods for 1,6difunctionaIization of dienes under investigation in Backvall's Hexacarbonylmolybdenum-TMNO has been reported to affect cyclization of pendent OH groups to alkynes to afford substituted dihydrofuran compIexes.208 '03 R.D.Walkup L. Guan M. D. Mosher S.W. Kim and Y. S. Kim SYNLETT 1993,88. M. Kimura N. Saeki S. Uchida,H. Harayama,S. Tanaka K. Fugami and Y. Tamaru TetruhedronLert. '*' I. W. Davies D.I.C. Scopes and T. Gallagher SYNLETT 1993,85.1993,34 7511. '06 J.J. Masters and L. S. Hegedns 3. Org. Chem. 1993,58 4547. '07 J. E. Bickvall K. L. Cranberg P.G.Andersson R. Gatti and A. GogolI J. Org. Chem. L993,58,5445. '** F.E. McDonald C. B. ConnoIly M. M. Gkason T. B.Towne and K. D. Treiber,J.Org. Chem. 1993,SS. 6952. G.R. Stephenson (COhF:'Yp '-BF3 I (61) 45% Reagents i KOBu' CH,CI,; ii cerium(rv) CO MeOH Scheme 33 In stoichiometric examples development of the chemistry of cationic dicar- bonyl(cyc1opentadien y1)iron-alkene complexes continues. Again intramolecular nuc- leophile attack has been the focus of attention (Scheme 33). Suitable electrophiles can be obtained by the reaction ofketones with allyliron complexes in the presence of BF,. Treatment of the resuiting q'-complex with base effects cyclization which under oxidative carbonylation conditions can ultimately replace the iron atom by an ester group.In this way (61) can be obtained.209 Cyclopentadienylruthenium-nitrosyl-phosphine complexes of 1,3-dienes and enynes provide interesting q2-cornplexes that undergo linkage isomerism.' ' Work continues on q2-styrene complexes" and side-on aldehyde q2-Enone complexes have also been investigated." Following work on tricarbonyliron complexes of enones the Thomas group has now extended this investigation to B,y-unsaturated esters and amide~.~'~ New examples of cyclic alkyne complexes have employed the dicarbonyl(cyclopentadieny1)manganese group to form an q2-adduct which rearranges to a 1,2-~yclooctadiene complex.' ' q3-Complexes.-The regioselectivity of nucleophilic addition to q3-transition metal complexes is a topical issue.Further results with cationic iridium complexes from the Stryker group illustrate the generality of reaction pathways for nucleophilic addition at the centre ofthe q3-unit.'l6 Examples with neutral q3-palladium chloride dimers have now also been Both examples use ketone enolates as the nucleophile though in the palladium case the presence of TMEDA is important and the use of a carbon monoxide atmosphere improves yields which can be as high as 70%. With an ally1 bromide as the starting material central attack has been observed in a '09 S. Jiang and E. Turos Organometallics 1993 12 4280. 'Io T.-S. Peng Y. Wang A.M.Arif and J.A. Gladysz Organometallics 1993 12 4535. M. A. Dewey Y&Zhou Y.Liu and J. A. Gladysz Urganametallics 1993 12 3924. 'I2 D. P. Klein,N. Q. Mendez,J. W. Seyler,A. M. Arif,and J. A. Gladysz J. Organornet. Chem. 1993,450,157. Y.Wang F.Agbossou D. M. Dalton Y. Liu A.M. Arif and J.A. Gladysz Organometallics 1993 12 2699. C.Alt S. L. Griffiths C. F. Marcos M. M. Salter A.M. Z. Slawin S.E.Thomas and D.J. Williams J. Chem. Soc. Chem Comun. 1993 201. *I5 S. M. Coughlan and G.K. Yang J. Organornet. Chem. 1993,450 151. '16 K. E. Schwiebprt and J. M. Stryker Organometallics 1993 12 600. 'I7 A. Wilde A. R. Otte and H. M. R. Hoffmann J. Chem. SOC.,Chem. Curnun. 1993 615. Organometallic Chemistry aO”-im 249 I (62) 70% Reagents i Pd(OAc), PPh, NaHCO Scheme 34 palladium-catalysed process; selectivity to favour central attack can be as high as 97 :3 under the correct conditions though in other cases exclusive terminal attack was observed.The nucleophile was a trimethylsilylketene acetal and the reactions were performed in the presence of thallium acetate.218 The centre of an q3-dienyl complex corresponds to the vinyl-substituted end of the q3 unit. Stabilized-enolate addition under palladium acetate catalysis can be manipulated to favour central attack by the presence of trib~tylphosphine.~”The position of the acetate leaving group in the starting material has also been found to influence regiochemistry showing that the approach of the nucleophile can be influenced by the nature of the ion pair after departure of the leaving group.22* Manipulation of synlanti ratios continues to receive attention.There has been a detailed investigation of dynamic processes in q3-paIladium complexes,22 and molecular mechanics parameters fur the n-ally1 palladium moiety have been re-ported.z22 As with q2-chemistry so too with q3-examples; Combination of z-ally1 chemistry with coupling reactions is an important progression (Scheme 34). Silylation of an allylic acetate with hexamethyldisilane can be achieved with a palladium catalyst.223 In another example coupling to an alkene followed by a hydrogen shift forms a y3-allyl complex which is picked up by an internal nucleophile. In this way the cyclic ether products (62) can be obtained.224 Allylic acetates and alcohols can be cyclized to pendent alkenes.In the first case,225 the reaction is a metallo-ene process and was combined with coupling to a vinyltin species. In the second example the tether between the alIyl moiety and the alkene was short and a substituted cyclopentadiene was Ring opening of viny10xetanes~~~ and #3-lactams228 has been combined with palladium-catalysed coupling reactions. AlIylic displacement can be accompanied by 218 M. Formica A. Musco and R. PonteIlini J. Mol. Card. 1993 84 239. ’I9 Y.I. M. Nilsson P. G. Andersson and J. E. BiickvaIl 1.Am. Chem. SOC.,1993 115 6609. ’” B.M. Trost and R.C. Bunt Tetrahedron Lett. 1993 34 7513. ’” S. Hansson P.-0.Norrby M. P.T. Sjogren and 3.Akermark M. E. Cucciolito F. Giordano and A. Vitagliano Organometullics 1993 12 4940.12’ P.-0. Norrby B. Akermark F. Haeffner S. Hansson and M. Blomberg J. Am. Chem. SOC. 1993 115 4859. 223 Y. Tsuji S. Kajita S. Isobe and M. Futano J. Org. Chem. 1993 58 3607. 224 R.C. Larock N.G. Berrios-Pefia C. A. Fried E. K. Yum C. Tu and W. Leong J. Org. Chem. 1993,!58 4509. 225 W. Oppolzer and J. Ruiz-Montes Helu. Chim. Am 1993 76 1266. 2z6 T. Zair C. Santelli-Rouvier and M. Santelli Tetrahedron 1993 49 3313. ’” R.C. Larock S. Ding and C. Tu SYNLETT 1993 145. ”* R. C. Larock and S. Ding Tetrahedron Lett. 1993 34 979. G.R. Stephenson OH Reagents i [PdCI2(C,H,),] EtOH CO Pr’,NEt NaBr rnaleic anhydride Scheme 35 carbonylation as illustrated for the opening of the vinyl epoxide (53)(Scheme 35).229 In this case palladium catalysis was used but alIylic carbonylation (with a phosphate Ieaving group) employing catalysis by a rhodium carbonyl duster has also been reported.230 Work continues to extend the range of nucleophiles that can be employed in palladium-catalysed allylic displacement.Trirnethylsilyl~yanide,~~ triphenyisilanol (as a water and an ahminate formed in situ froman aluminium acetylide and dimethyl ethylidenemal~nate,~~~ have a11 been used. Interest in bisphosphonates as enzyme inhibitors has revived work on their use as nucleophiIes in pallad-ium-catalysed aIlylic di~pIacernent.~ 34 N-protected amines carrying two Boc groups have been employed as nudeophiles in a reaction that forms intermediates which afford esters of N-protected amino acids after ozonolysis of the alkene formed by aIlylic substitution.235 This approach has aIso been used in a synthesis of (+)-N6-hy-dro~ylysine.’~~ By the use of BPh, an oxyborane leaving group has been brought into play to provide a new way to use allylic alcohols directly in palladium-catalysed aIlylic substitution.237 Less-common substitution patterns have been introduced on stoichiornetric q3-ligands in palladium chIoride dimers.Trialkyl~ilyI~~~ and formyl and acetal substituent~~~~ have been examined. Synthetic applications this year (Scheme 36) have featured some of the less cummun types of nucIeophiles. Palladium-catalysed allyiic rearrangement of propenyI-3-py- rimidinyl carbonatesz4’ have been used in the preparation of pyrimidine nucleoside analogues I The Boc-protected hydroxylamines (referred to earlier) have been used in a synthesis of ( + )-laminine.242 In syntheses of buspirone (65)and gepirone a 1,4-disubstituted but-Zene is used to introduce a simple C,H strap by a sequenceof two palladium-catalysed allyIic displacements followed by hydrogenation to remove 229 I.Shimizu T. Maruyama T. Makuta and A. Yamamoto Tetrahedron tett. 1993,34 2135. 230 Y. Imada 0.Shibata and S.4. Murahashi J. Orgonomet. Chem. 1993 451 183. 231 Y. Tsuji N. Yamada and S. Tanaka J-Urg. Chem. 1993,sS 16. 232 B.M,Trost N. Ito and P. D. Greenspan Tetrahedron Lett. 1993 34 1421. 233 B. M. Trost and C.-J. Li Tetrahedron Lett. 1993 34 2271. 234 R. Sulsky and D. R. Magnin SYNLETT 1993 12 933. ”’ R.lumnah J. M.J.Williams and A. C. Williams Tetrahedron Lett. 1993 34 6619. ”15 J. P. Genet S. Thorimbert and A.4. Touzin Terrohedron Lett. 1993 34 1159. 237 I. Starj I.G. Stari and P. KoEovlky Tetmhedron Lett. 1993 34 179. S. Ogoshi W. Yoshida K.Ohe and S. Murai Organometallics 1993 12 578. 239 S. Ogoshi K. Hirako J. Nakanishi X.Ohe and S. Murai J. Orgonomet. Chem. 1993 445. C13. 240 M. L. Falck-Pedersen T. knneche and K. Undheim Acto Chem. Scad. 1993 47 63. ’*’ M. L.Falck-Pedersen T. Benneche and K. Undheim Acto Chem. Scond. 1993 47 72. ’‘’ J. P. Genet S. Thorimbert S. Mallart and N. Kardos Synthesis 1993 321. OrganometaHic Chemistry 25 1 (64) 95% 80% (65) 70% Reagents:i [PdCl,(PhCN),],THFor DMF; ii 4-chiorobut-2-enyl acetate [Pd(PPh,)J; iii [Pd(PPh,),]; iv H,,Pd EtOH Scheme 36 An intramolecular N-alkylati~n'~~ the central alkex~e.~~~ has made use of the selectivity between halide and oxygen leaving groups at the two ends of an alkene.An example (Scheme 37) that illustrates the use of q3-complexes to prepare optically active silylallylamines makes use of the trimethylsilyl directing group in a catalytic process.245 Similar silicon-directed displacements of (EtO) PO from chiral allyl-phosphates with methyImagnesium bromide proceed in a highly regiocontrolled manner.246In another example with optically active allylic acetates manipulation of leaving-group selectivity gives access to both R and S products from a biologically derived monoester of a rnes0-2-ene-l,4-diol.~~' Since biotechnology is used to gain 243 D.L.Kuo Heterocycles 1993 36,1463. 244 K. Tadano K. Takao Y. Nigawara E. Nishino I. Takagi K. Maeda and S. Ogawa SYNLETT 1993 565. *" H.Inarni T. 110 H.Urabe F. Sam Tetrahedron Lett. 1993 34,5919. *" H. Urabe H. Inarni and F. Sato J. Chem. Soc. Chem. Comun. 1993 1595. 247 J.-E. Backvall R. Gatti and H.E. Schink Synthesis 1993 343. G.R. Stephenson Me$i 1 NHBn OKoMe 0 99%(< 98%e.e.> Reagents i,BnNH, [Pd,(dba),] PBu Scheme 37 entry to the optically active allylic acetate the stereodivergence of the two routes is an important feature. Further advances have been made in reactions employing trimethylenemethane complexes. Cycloaddition to N-to~ylimines,~~’ and to sugar-derived to ynone~,’~~ acrylates’ are developments this year.The chemistry of (oxodi-methy1enemethane)paMadium and -platinum complexes has been reported. * The complexes form metallacyclobutanones. A mild and selective method for palladium-catalysed dealIylation has been Allyloxycarbonyl protecting groups have been removed by pallad- ium-catalysed reactions253 and the procedure (performed in aqueous media) has been applied to liberation of N-protected amino acid derivative^.^'^ EnantioselectivePalhdium-catalysed AllyIic Displacement.-The use of chiral auxili- ary Iigands to direct palladium-catalysed allylic displacement is a major growth area. A range of chefating phosphine auxiliaries have been applied to the differentiation of enantiotopic allylic leaving groups.By use of a 1,Zarninoalcohol as the nucleophile the asymmetric construction of chiral morpholines and piperazines has been achieved.255A more common substrate is a 1,3-diphenyI substituted allylic alcohol which becomes prochiraI once the leaving group has been displaced. A range (66bf74) of heteroatom-functionalized chiral bisphosphine ligands has now been employed in this reaction.256 The best optical yieId was obtained with (66)(BHMP-COOH) which proved much more effective (49% e.e.1 than the corresponding t-butyl ester. This indicates a role for the pendent carboxylic acid group. The 1,2-diamine derivative (57) with a C,-symmetric pyrrolidine at each end has also proved effective with an e.e as high as 91%.2s7A more unusual nitrogen-containing chelating Iigand (68) has been prepared from menthone.Asymmetric aflylic substitution proceeded in 84% e.e.258 248 B. M. Trost and C. M. Marrs J. Am. Chem. SOC.,1993 115 6635. 249 B. M. Trost S. Sharma and T. Schmidt Tetrahedron Lett. 1993 34 7183. 250 M. Janson I. Kvarnstrom S. C.T. Svensson B. Classon and 3.Samueisson Synthesis 1993 129. 251 A. Ohsuka T. Fujirnori,T. Hirao H. Kurosawa and I. Ikeda J. Chem.SOC. Chem.Commun. 1993 i039. 252 F. Garro-Helion A. Merzouk and F. GuiM J. Org. Chem. 1993 58 6109. 253 J. P.Genet E. Blart M. Savignac,S. Lerneune S. Lernaire-Audoire and J. M. Bernard SYNLETT 1993 680. 254 J. P. GenEt E. Hart M.Savignac S. Lemeune and J.-M. Paris Tetrahedron Lett. i943 34 4189. 255 Y. Uozumi A. Tanahashi and T. Hayashi J. Org. Chem.1993 58 6826. 256 A. Yamazaki T. Morirnoto and K. Achiwa Tetrnhedron Asymmetry 1993,4 2287. ”’ H. Kubota M. Nakajirna and K. Koga Tetrahedron Lett. 1993 34 8135. M.Bovens A. Togni and L. M. Venanzi J. Organomer. Chern. 1993 451 C28. Organumetallic Chemistry 253 Reiser2" has been using the ligand (69) which combines two nitrogen atoms with a pair of pendent oxygen donors. i$.vN4 Me Me Me Me I %> PPhz N OSiMq'Bu OSiMQ'Bu R TBDMSO (69) 00) (71) Work continues on ligands in which phosphorus and nitrogen donors are combined with a view to distorting the coordination sphere of palladium metal. The groups of Helmchen260and Williams2" have evaluated (70) while Pfaltz262 has afso worked with (71). Optical yields greater than 37% enantiomeric excess are now obtained in these reactions.Sulfur and nitrogen centres are combined in the thiophene derivative (72)263and in the thiophenol derivative (73) (X = SMe)254 and the corresponding phenol (X = OH)265and diarylthioether (73) (X = SPh).266 In (74) the spacing between the sulfur and nitrogen atoms is varied.266 The range of chiral auxiliaries illustrated is a clear indicator of how important this aspect of asymmetric synthesis has become. Stoichiornetric iron carbonyl complexes have also been used as cationic electrophiles 259 0. Reiser Angew. Chern. Int. Ed. Engl. 1993 32 547. J. Sprinz and G. Helmchen Tetrahedron Lett. 1993 34 1769. 260 261 G.J. Dawson C.G. Frost J. M. J. Williams and S. J. Coote Tetrahedron Lett.1993 34 3149. 262 P. von Matt and A. Pfaltz Angew. Chem. Int. Ed. Engl. 1993 32 566. 263 C.G. Frost and J. M. J. Williams Tetrahedron Lett. 1993 34,2015. 264 C. G. Frost and J. M. J. Williams Tetrahedron Asymmetry 1993 4 1785. 265 B. Yang M. A. Khan and K. M. Nicholas Organometallics 1993 12 3485. 266 G. J. Dawson C.G. Frost C.J. Martin J. M. J. Williams and S. J. Coote Tetrahedron hit. 1993 34 7793. 254 G.R. Stephenson in the q3-series. Acy€ directing groups direct enol ether nucleophiles to the far end of the allyl system.267 Optically active acrylates268 and pyrrolin-2-0nes~~~ have been employed in enantioselective aIlylic functionalization steps. Amines and allylsilanes respectively were used as nucleophiles and products had enantiomeric excesses greater than 95%.q3-Ally~(dicarbonyl)cyclopentadienylmolybdenumcomplexes have been prepared from allylicdiphenylph~sphinates;'~' ruthenium complexes have been examined as catalysts for allylic di~piacement;~~' rhodium complexes to carbonylate aIlyl phosphate and an q3-propargyl complex of platinum has been studied.273The bent geometry of the q3-1-ene-2-yne unit corresponds to that of the cationic rhenium example discussed last year. Anionic $-complexes have also received attention. Functional and crystaIlographic studies have been made of the tricarbonyl(cyc1oheptatrienyl)iron complex,274 and with a new twist to palladium allyl chemistry an q3 intermediate has heen converted (by use of a dialkylzinc reagent) into an allylzinc nucleophile effectively providing the iimpolung of the electrophilic ally1 complex.275 A neutral cyclopentadienylmolyb- denum complex with an q3-ligand and chirality at the metal atom has been resolved.276 This neutral reagent serves as a nucleophile in a stereocontrolled reaction with benzaldehyde.In another organomolybdenum example a pendent enone was used in a stereoselective MichaeI reaction.277 Enolates next to dicarbonyl(q3-cyclopen-tadienyl)molybdenum complexes have been used in aldol reactions. Subsequent CO replacement by NO' prepares for a cyclization forming isoxazoles and conjugated die none^.^ q'-Complexes-New structural studies of a well-known organometallic complex is a rare event. Tricarbonyl(butadiene)iron was one of the earliest of the n-complexes to be studied; in 1993 microwave spectroscopy has provided an exceptionally detailed structural characterization of this material.279 A new heterocyclic tricarbonyliron complex containing a silacyclopentadiene ligand has been prepared.280 Ruthenium dicarbonylphosphine complexes of q4-enune ligands can be made by photolysis of tet racarbon ylru theniumphosp hine complexes.*' When nucleophiles are added to q4-ligands cationic molybdenum complexes are often used to promote electrophilicity. Indenyl(dicarbony1)molybdenurn complexes help functionalize spirocyclopentadiene by reaction with dimethyl cuprateZs2 26' T. Zhou and J. R.Green TetrahedronLett. 1993 34,4497. 268 D. Enders and M. Finkam SYNLETT 1993,401. 269 W.-J. Koot H.Hiemstra and W.N.Speckamp J. Chem. Soc. Chem. Cotnmun. 1993 156. 270 J. S. McCallurn J. T. Sterbenz and L. S. Liebeskind Organomerallics 1993 12 927. 271 S.-W. Zhand ".-a. Mitsudo T. Kondo and Y. Watanabe J. Urgnnonter. Chem.. 1993 450 197. 272 Y. Imada 0.Shibata and %-I. Murahashi J. Urganomer. Chem. 1993 451 183. 273 P. W. Blosser D.G. Schimpff J.C.GaIlucci and A. Wojcicki OrganometaMics 1993 12 1993. 274 M. AiroIdi G. Deganello G. Gennaro M. Moret and A. Sironi Organometdlics 1993 12 3964. 275 K.Yasui,Y. Goto,T. Yajima Y.Taniseki,K. Fugami,A. Tanaka,and Y.Tarnaru Tetrahedron Lett. 1993 34,7619. 276 J. W. Faller J.T. Nguyen W. Ellis M. R. Mazzieri Organometallics 1993 12 1434. 277 S.-H. Lin W.J. Cheng Y.-L. Liao S,-L. Wang,C.-H. Lee,S.-M. Peng,and R.S. Liu,J. Chem. SOC.,Chem. COMK~. 1993 1391. 278 S.-H. Lin G.-H. Lee,S.-M. Peng and R.4. Liu Organometallics 1993 12 2591. 279 S. G. Kukolich M. A. Roehrig D. W. Wallace and G. L. Henderson J. Am. Chem. Soc. 1993,115,2021. 280 M. Kako S. Oba and Y. Nakadaira J. Organometni. Chem. 1993 461 173. 281 A. Marcuzzi A. Linden and W. Von Philipsborn Helv. Chim. Acta 1993,76 976. 282 D.J. Norris J. F. Corrigan Y. Sun N. J. Taylor and S. Collins Can.J. Chem. 1993 71 1029. Organometailic Chemistry (75) 55% OR (COhFe Reagents i LDA CO; ii CF,CO,H; iii ArLi Et,O -50°C; iv Et,OBF,; v PPh,; vi [HBEtJ-; Vii SnMe,C1 Scheme 38 Neutral tricarbonyliron complexes can also react with nucleophiles (Scheme 38).An intramolecular example invoIving enolate addition to an inner position on the diene afforded the bicyclic product (75).Carbonyl insertion followed by protonation at iron and reductive elimination completes the cyclopentenone ring.283With aryllithium reagents nucleophile addition occurs at a carbonyl group.The product can be trapped with Meerwein’s reagent to form a carbene which in the presence of an incoming ligand adds to the q4-ligand to produce (76).284 Hydride addition to neutral q4-tricarbonyliron compIexes affords q3-anionintermediates and can be trapped with trimethyltin chloride.285 The anti,syn product (77) interconverts into the preferred syn,syn structure (78). Examples of highly stereoselective nucleophiIe addition at ketone groups adjacent to neutral q4-tricarbonylirondiene complexes have been reported.286 Methyllithium and triethylaluminium gave complimentary stereoselectivity .Similar reactions at imines have also been de~cribed.’~’ Stereoselective synthesis of diols from alkenes adjacent to the tricarbonyliron diene unit is now well known but an unusual epimerization at the 283 M.-C. P. Yeh B.-A. Sheu H.-W. Fu S.4. Tau and L.-W. Chuang. J. Am.Chem. Suc. 1993,115 5941. ’”J. Chen Y. Yu L. Hu and Z. Jin J. Organmet. Chem. 1993,447 113. S. Chang P.S.White and M.Brookhart Organometallics 1993 12 3636. 286 Y. Takernoto J. Takeuchi and C. Iwata Tetrahedron Lett. 1993 34 6067. ’” Y. Takemoto J. Takeuchi and C. Iwata Tetruhedron Lett. 1993,34,6069. G. R. Stephenson ii-tv e Reagents:i 2-methylpropafia1 BF,.OEt,; ii dimethyl malonate enolate; iii NO+;iv NaCO %hem&39 a-carbon has been reported through the action of tetrabutylammonium fluoride at -20 0C.288Friedel-Crafts acylation of 1,3-diene tricarbonyliron complexes has been extended to alkoxyalkylation using EtOCH,Cl with aluminium tri~hloride.~~~ In cycloheptadienone chemistry enolates developed towards an allylic position between the ketone group and the alkene can be alkylated stereoselectively with methyl iodide.290 Nitrile oxides and nitrile imides have been used in the synthesis of bicyclic derivatives of cycloheptadiene by dipolar cycloaddition reactions with tricarbonyl(q'- cyc10heptatriene)iron.~~'Cationic q4-diene cornpiexes are obtained by the reaction of electrophiles (formed from aldehydes and boron trifluoride etherate) with (q3-cy- clohexadienyl)dicarbonyl(cyclopentadieny~)molybdenum complexes.The q4 products can be taken on in reactions with nucfeophiles foIlowing a linear sequence of steps to form the bicyclic product (79)with efficient stereocontrot (Scheme 39).'" The product from the initial Lewis-acid-catalysed reaction with the aldehyde is an q4-diene complex formed with complete stereoselectivity. q5-Complexes.-Tricarbonyl(pentadienyl)iron complexes often show different proper- ties to their cyclic counterparts. In particular since they are nut locked in a ring switching between cisojd and transoid products complicates work in the acylic series. A series of disubstituted examples have now been studied in detail (Scheme 40).In the case of and (81) (X = Me293and O~bfe~~'), additiotl of triphenylphusphine affords products which retain their cisoid geometry. Carbon+arbon bond formation from (81) (X= OMe) with allyltrimethylsilane affords a transoid product with a stereodefined methyl substituent originating from the methyl group at the terminus of the dienyl system. Triphenylphosphine addition to the indenyl tricarbonyliron complex (82) however proceeds with displacement of a carbonyl group from the 288 J.-P.Lellouche A. Gibou-Barbedette and R. Grke J. Orgonomet. Chem. 1993 461 167. M. Frank-Neumann P.Bissinger and P.Geoffroy Tetrahedron Lett. 1993 34 4643. A.J. Parson and K. Chang J. Urg. Chem. 1993 58 1228. 29' A. Gambe R. Gandolfi and P. Grunanger Gnzz. Chim. Itat. 1993 123 209.Wang Y.-C. Cheng G.-H. Lee S.-M. 292 S.-H. Peng and R.3. Liu Organornetallics 1993 12 3282. "'W.A. Donaldson M.J. h,and P.T. Bell Organometaflics 1993 12 1174. 294 W. A. Donaldson and M.-J.Jin Bull. SOC.Chim. Belg. 1993 102 297. 295 D.A. Brown N.1. Fitzpatrick W.K. Glass H.A. Ahmed D. Cunningham and P. McArdle J. Organornet. Chem. 1993,455 157. 257 Orgunometaliic Chemistry MeYm7 In hde’ Me’ X = Me OMe + Reagents i PPh Scheme 40 Substituted cyclohexadienylones react with hydroxide (sodium carbonate in water) to introduce an OH group at the far end of the q5unit. Oxidation affords a diene4one complex. Substituents include methyl phenyl and a chlorine atom the last of which provides a rare example of a 1-chloro substituted dienyl complex of tricarbonylir~n.~~~ Double functionalization of cyclooctadienyl systems extends methods developed in the heptadienyl series.297 The two nucleophile addition steps foilow an iterative sequence alternating between cationic dienyl cornpIexes and neutral q4-addition products.With smaller ring sizes the reformation of the dienyl complex following nucleophilic addition is bIocked. A strategy for reactivation that overcomes this disadvantage has been reported.298 Protonation of a side-chain alkene followed by a hydrogen shift reforms the dienyl salt. A kinetic study of the electrophiIicity of cationic y’-tricarbonyliron complexes has been published.299 Several natural product syntheses starting from tricarbonyliron4ienyf complexes have been described during the year (Scheme 40).Knolker has utilized in addition the substituted aniline (83) in a short synthesis of carbazomycins A and B.300A variety of oxidative cyclizations of this type have been rep~rted.~” The Donaldson group has completed an enantioselective lipoxygenase-inhibitor synthesis in which the dkylation ofa pentadienyliron complex provides a key step.302 296 N. Morita S. Ito and T. Asao 3. Organomet. Chem. 1993,460 67. 297 A. J. Pearson S. Balasubramanian and K. Srinivasan Tetrahedron,1993 49 5663. 298 I. J. Alexander N. J. Hales and G. R. Stephenson 1.Organornet. Chem. 1993 453 11 1. 299 H. Mayr K.-H. Muller and D. Rau Angew. Ckem. Int. Ed. Engl. 1993 32,1630. 300 H.-J. Knolker and M. Bauermeister Helu. Chirn. Am 1993 76,2500.301 H.-J. Knolker M. 3auermeister and J. B. Pannek Tetrahedron 1993 49 841. ’02 C. Tao and W.A. Donaldson 3. Org. Chem. 1993,58 2134. G.R.Stephenson ?Me OMe 0 (84) Reagents i MeCN; ii MnO,; iii 4-methoxyphenylithium; iv; HPF,; v (84) Scheme 41 The sequence oftwo nucleophile additions to a cyclohexadienyl complex completes a synthesis of ( +_ )-0-methyljoubertiamine (85). Again an iterative reaction sequence was used. In this case the reactivation step employed a leaving group in place of hydrogen abstraction. 30 Tricarbonyl(cyclohexadieny1)iron compIexes have been used as selective labels in reactions with peptides and even with the protein ly~ozyrne,~~~ and as a recoverable protecting group in peptide synthesis.305 New exampies of spirolactone formation based on cyanide addition to q5-tricarbonyliron complexes empIoy trimethyIsily1 cyanide to introduce the nitrile.3*6 303 G.R. Stephenson H. Finch D.A. Owen and S. Swanson Tetrahedron 1993 49 5649. 304 J.A. Carver B. Fates and L. A. P. Kane-Maguire J. Chem. Soc. Chern. Conrmun. 1993 928. '05 S. Fu J. A. Carver and L.A.P. Kane-Maguire J. Organornet. Chem. 1993 454 C11. '06 C.W. Ong and C.J. Chien Organometallics 1993 12 241. Organumetallic Chemistry Reagents i MeLi; ii Ph,CHLi; iii 0,; iv. Me,CfCO,Ef)Li; v 0 Scheme 42 Progress with nucleophilic addition to neutral q 5-tricarbonylmanganese complexes has opened the way for a linear double functionalization leading to 5,S-disubstituted cyclohexadienes.A range of nuckophilic additions to the q5 intermediates have been examined. When the starting material for the reaction sequence is a cationic q6-arene complex a sequence of two nucleophilic additions (first to form a neutral q5 intermediate and then to an anionic q4 adduct with two substituents) can provide a successful synthetic route if the final anionic intermediate is oxidized in sit^.^'^ Two examples are illustrated in Scheme 42. Thisreaction sequence represents a considerable step forward since previous attempts to promote electrophilicity for the second nucleophile addition by replacement of carbon monoxide by NO ,while affording cationic q5 intermediates had not proved successful in the identification of general nucleophik addition reactions to introduce the second substituent.Among the unusual q5-complexes reported this year two heterocyclic examples tricarbonyl(pentamethylpyrrole)chromium308 and pentacarbonyl(2,5-dimethylbis-rnoIyl)mangane~e,~~~ are notable. q'-Complexes.-By attachment of a transition metal to an aromatic ring methods are now well established to manipulate the reactivity not only of the metal-bound ring itself but also at positions more remote from the site of metal attachment. Some of the developments highlighted in the preceding sections with small metal complexes advance these methodologies in this direction but it is in the chemistry of t]6-tricarbonylchromium complexes in particular that the most highly developed general methods that utilize the metal in a variety of ways have become established as procedures for organic synthesis.Natural product syntheses reported during 1993 ihstrate the power of the methodology. The Schmalz group have completed a total synthesis of (1S,4S)-7,8-dihydoxycalamenene(Scheme 43).310 The ability of tricar-bonyIchromium complexes to facilitate metallation of the arene and to stabilize benzylanions and benzyl cations are all brought into play in this synthesis. The optical 307 B.C. Roell Jr. K.F. McDaniel W. S. Vaughan and T.S. Macy Urganornetallics 1993 12 224. 308 N. Kuhn J. Kreutzberg E.-M.Larnpe D. Blaser and R Boese,J. Organornet. Chem. 1993 458 125. 309 A. J. Asbe 111 J. W. Kampf and D.B. Puranik J. Organornet. Chem. 1993 447 197. 310 H.-G. Schmalz J. Hollander M. Arnold and G.Diirner Tetrahedron Lett. 1993 34 6259. G. R . Stephenson OMe i ii iii iv (COhCr SiMe OMe -P % 99%e.e. (86) 99% 95% Reagents:i BuLi; ii SiMe,Cl; iii BuLi THF HMPA; iv MeI; v Bu*Li,THF;vi €‘?I HMPA; vii,TBAF; viii BuLi; ix Mel; x I,; xi BBr Scheme 43 purity of the final product was checked at the metal-free diether stage and was found to be greater than 99%. The key to the synthesis is the control of sites of metallation. First a silyl group was introduced on the aromatic ring to block the most acidic site. The product (86)was then elaborated through a sequence of two bemyl anion complexes with complete regio- and stereocontrol. Very high yields are reported for this route to (87). The trimethyIsily1 blocking group was then removed (TBAF),and a repeat of the initial metallation foilowed by reaction with methyi iodide completes the substitution pattern on the aromatic ring.All that remains is removal ofthe chromium with iodine and ether cleavage to complete the target molecule (88). Enantioselective modification of this route employed a dimethoxytetralone as a prochiral starting material. Enantioselective oxazaborolidine-catalysedboron hydride reduction was followed by diastereoselective complexation. It is here that the benzyl cation complexes come into play. The unnecessary OH group was removed by silane reduction (HSiEt,) in trifluroacetic acid. In this step protonation of the OH group foIIowed by loss of water created a chromium-stabilized benzyl cation which was reduced by the silane.This enantioselective synthesis of (88) uses established bond-forming methods in an elegant and efficient way and provides an excellent demonstration of the superb control of diastereoselectivity available from the use of the tricarbonylchrumium group. Planar chirality of tricarbonylchromiurn complexes is exploited in an initial aldol reaction to control stereocentres 01 and p to the metal-bound ring at the start of a synthesis of (+)-goniofufurone (91).311In this synthetic route (Scheme 44),the silyl 311 C. Mukai I.J. Kim and M. Hanaoka Tetrahedron Lett. 1993 34,6081. Organornetallic Chemistry 26 1 (co),cr I Reagents i desilylation; ii metal removal; iii steps; iv 2-(trimethyIsilyloxy)furan Scheme 44 group on the aromatic ring of (89) is necessary to introduce chirality.The later steps after removal of the chromium utilize conventional chemistry to elaborate a further chiral centre and complete the carbon chain in (90).The relative stereochemistry in the intermediate (901 obtained in a racemic series of experiments was proved by X-ray crystallography. Organochromium routes towards (-)-indolactarn V312 and teleocidin A313 have been investigated. 4-Fluoroindole complexes react with amines replacing the fluorine atom but extension of this procedure to the ester amino acids for a route to indolactam V was unsuccessful. The target molecule however was completed by an alternative route. The preparation of the fluoroindole complex used an interesting trick. The ethylzinc adduct (at nitrogen) of the fluoroindole was formed prior to complexation adding electron density to the ring.Only ethylzinc was suitable for this purpose. Copper sodium magnesium and even zinc bromide were unsuccessful. Nonetheless the yield of the indole complex was low. In the case of teleocidin (93) an 3'z M.P. Sernrnelhack and H. Rhee Tefrahedron Lett. 1993,34 1395. 313 M. F. SemmeIhack and H. Rhee Tetrahedron Lett. 1993,34 1399. G.R. Stephenson Me Reagents i 2-methyl-6-cyanohept-2-en-6-yllithium; ii I,; iii steps Scheme 45 organochromium-based route (Scheme 45) was successful. The tricarbonylchromium group was needed to promote eIectrophiIicity on the indole ring. Nucleophilic addition followed by oxidation of the resulting metal anion afforded (92) which was elaborated to complete a formal total synthesis of the target molecule.Without a nitrogen substituent at C4 of the indole nucleophiIic addition occurs preferentially there. This has been used (Scheme 46) in a synthesis of (94),a key intermediate in a route to cIavicipitic acid. l4 An unusual cycloaddition reaction has been reported involving an aniline-derived imine a pendent alkene and one carbon-carbon double bond of a chromium-bound aromatic ring. Lewis acids are employed to promote this hetero cycloaddition process and the final product is a tricyclic chromium arene complex.315 Electrocyclic addition at pendent groups on tricarbonylchromium complexes are more common. Stereoselec- tive nitrile oxide addition3I6 and the reverse process,317 in which a metal-free alkene is combined with a nitrile oxide unit attached to a tricarbonylchromium complex illustrate new developments.Under photolytic conditions isocyanate adds to the 3'4 M,F. SemrneIhack P. Knochel and T. Singieton Tetrahedron Lett. 1993,34,5051. 3'5 S. Laschat R. Noe,M. Riedel and C. Kriiger Organometallics 1993,12,3738. 316 C.BaIdoli P. Del Buttero S. Maiorana G. Zecchi and M. Moret Tetrahedron Lett. 1993,34,2529. 317 C. Mukai 1.J. Kim W.J. Cho M. Kido and M. Hanaoka J. Chem. Soc. Perkin Trans. I 1993,2495. Organometallic Chemistry Reagents i Bu,NH Scheme 46 tricarbonylchromium complex of cycl~heptatrienes.~’’Activated alkene dienophiles aIso react in a 16 + 2) cycloadditionto complexesof seven-memberedring triene~.~” An intramofecular version has been reported.In this case no electron withdrawing end-group was present on the dienophile and photochemical conditions were employed A [6 + 41 cycloaddition is also described. This reaction involves a pendent There are examples of electrocyclic ring openings involving tricarbnyl(o- quinodimethane)chromi~rn~~~ obtained from an alkoxybenzocyclobutane complex and related reactions employing dihydroxybenzo~yclobutanes.~~~ Stereocontrolled nucleophile addition adjacent to a chromium arene complex continues to be developed in work on acetylide addition,323 and also in carbanion addition to aldehydes and irnine~.’~~ A more unusual reaction involves cydopropanation in the presence of the tricarbonylchromium complex .32 An asymmetric oxidation of a chromium-bound aryh hioet her affords a sulfin yl substituted complex with high diastereoselectivit y .326 In another oxidation a 1,Zdione replaces the carbonxarbon double bond in a bis(tricarbony€)chromiumcomplex of a trimeth~xystilbene.~~~ Conformational studies of the Cr(CO) tripod units in phenanthrene complexes have been made.32B ConformationaI preferences in fluorobiphenyl complexes contain- ing tricarbonylchromiurn units have been studied by I3C and ‘’F NMR spectros-Restricted rotation in polysubstituted aromatic complexes has been inves- 318 J.H. Rigby G. Ahmed and M. D. Ferguson Tetrahedron Lett. 1993,34 5397. 319 J.H. Rigby H.S. Ateeq N.R. Charles J.A. Henshlwood K.M.Short and P.M. Sugathapala Tetrahedron 1993,49 5495.320 f. H. Rigby and V. P. Sandanayaka Tetrahedron Lett. 1993,34,935. 321 E. P. Kiindig and J. Leresche Tetrahedron 1993 49 5599. 322 M. Brands R. Goddard H.G. Wey and H. Butenschon Angew. Chem. Int. Ed. Engf. 1993,32 267. 323 C. Baldoli P.Del Buttero E. Licandro S. Maiorana,A. Papagni and M.Torchio TetrahedronLett. 1993 34,7943. 324 E.P.Kiindig L. H. Xu P.Romanens and G. Bernardinelli Tetrahedron Lett. 1993,34,7049. 325 S. Ganesh K.M. Sathe M. Nandi P. Chakrabarti and A. Sarkar,J. Chem. Soc. Chem. Comun. 1993 224. 326 A. Perez-Encabo S.Perrio A. M.Z. Slawin S.E. Thomas A.T. Wierzchleyski and D.J. Williams J. Chem. Soc. Chem. Commun. 1993 1059. 327 Z.V.Todres and E. A. Ionina 1.Orgonomet. Chem. 1993,453 193. 32% D.J. Peitz R.T. Palmer L. J. Radonovich and N.F. Woolsey Organometallics 1993 12 4580. 329 P. Szczecinski and J. Zachara J. Organomet. Chem. 1993 447 24i. G.R. Stephenson tigated by variable temperature NMR spectroscopy.330 FTIR spectroscopy is usefuI for the trace measurement of the presence of organometalcarbonyl tags on biologicalIy active substances. A new contribution to this area which previously had been almost the excIusive preserve of the Jaouen group in Paris has involved the preparation of tricarbonylchromium and dicarbonyl- chromiumphosphite derivatives of aminoglycoside antibiotics such as (95). The compIexes will be used as metallotracers for immunoassay work.331 (CO)& /OH fl OH OH Access methods to optically pure tricarbonylchromium units include the use of a microorganism to effect an asymmetric reduction of an a~etophenone,~~~ and direct metallation of a prochiral chromium-bound aromatic ring in the presence of a chirat auxiliary that promotes orth~metallation.~~~ Organochromium-based auxiliaries are effective as asymmetric catalysts for the addition of an ethyl group from diethylzinc to aldehydes.Examples include chiral auxiliaries with two chiral centres in a side chain attached to an achiral tricarbonyl(arene)chromium complex,334and a case where the two coordinating groups that bind the zinc are in separate substituents in a chromium complex of a 1,2-disubstituted benzene ring.335 In this latter case planar chirality is present on the aromatic ring.From the point of view of asymmetric synthesis the main thrust this year has been the use of tricarbonylchrornium units as chiral auxiliaries for example in a catalytic enantioselective synthesis of (R)-(+)-lasi~diplodin,~~~ and asymmetric DieIs-Alder reactions.337 The chemistry of other metal complexes of aromatic rings develops in a similar way. Cyclopentadienyliron cations promote nucleophilic replacement of halides from aryI halide compIexes from mono-and dichloroarene~.~~~,~~~ Nucleophile addition to tricarbonylmanganese complexes of indoles has been examined,340 as has the regiocontrol of nucleophilic addition to silyl-substituted manganese-bound aromatic 330 J. A. S. HowelI M.G. Palin P. McArdIe D. Cunningham Z. Goldschmidt H.E. Gottlieb and D.Hezront-Eangerman,Organometa!lics 1993 12 1694. 331 J. Szymoniak B. El Mouatassim J. Besanqon C. Mdise and P. Brossier Tetrahedron 1993 49 3109. 332 Y. Yamazaki and H. Kobayashi Terrahedron Asymmetry 1993 4 1287. 333 Y. Kondo J.R. Green and J. Ho J. Org. Chem. 1993 58 6182. 334 G. B. Jones and S. B. Heaton Terruhedron Asymmetry 1993 4 261. 335 M. Uemura R. Miyake K. Nakayama M. Shiro and Y. Hayashi J. Org. Chem. 1993 58 1238. 336 G. B. Jones and R.S.Huber SYNLETT 1993 367. 33' M. Uemura Y. Hayashi and Y.Hayashi Tetrahedron Asymmetry 1993 4 2291. 338 A.S. Abd-El-Aziz and C. R. de Denus J. Chem. SOC. Perkin Trans. 1 1993 293. 339 S. Motallebi and P. Muller Organometollics 1993 12 4658. 34a W.J. Ryan P. E. Peterson Y. Cao P.G. Williard D.A. Sweigart C.D.Baer C. F. Thompson Y. K. Chung and T. M. Chung Inorg. Chim. Acta 1993 211. Organometaliic Chemistry CpFe CGFe Reagents i paIladium(o)(cat.) SnPhBu,; ii palladium(o) (1 eq.);iii SnPhBu Scheme 47 rings,341 the use of Wittig reagents as nucleophiles with manganese arene com- ~lexes,~~’ and electrochemical reduction in the presence of phosphines (which converts tricarbonyl(arene)manganesecomplexes into the dicarbonylphosphine adducts but does not proceed with the corresponding rhenium complexes).343 The formation of ruthenium arene complexes by demethylation of steroids344 has received further attention and bimetallic cyclopentadienylruthenium complexes of dibenzo-p-quinodimethane Iigands have been prepared.345 Two unusual reports conclude this section.Trifluorophosphine is often used in place of carbonyl groups because of its roughly comparable electron-withdrawing effect. Hydride reduction of tris(trifluorophosphine)chromium complexes has produced an intermediate with agostic hydrogens shared between the aromatic ligand and the metal,346 In the cyclopentadienyliron complexes an unusual coupling reaction has been performed. Palladium-catalysed cross-coupling (Scheme 47) replaced a chlorine atom from the cationic chlorobenzene complex with a substituent transferred from a tributyltin reagent. When one equivalent of a palladium complex was used a stoichiometric bimetallic product could be isolated in 65% yield. This is the cyclopentadienyliron complex of a palladated aromatic ring.This intermediate reacts with tributyltin reagents to afford the same product as those arising from the cross-coupling reaction.347 7 Other Aspects Not all areas of organometallic chemistry can be covered in detail every year in an 3L’ S. S. Lee J.-S. Lee and Y. K. Chung Organometallics 1993 12 4540. 342 S. Lee Y. K. Chung T.3. Yoon and W. Shin Organometallics 1993 12 2873. 343 C.C. Neta C.D. Baer Y.K. Chung and D.A. Sweigart J. Chem. Soc. Chem. Comrnun. 1993 816. 344 F. Urbanos M.A. HaIcrow J. Fernandez-Baeza F. Dahan D. Labroue,and B. Chaudret J. Am. Chem. SOC., 1993 115 3484; M.A. Halcrow F. Urbanos and B. Chaudret Organornetallics 1993 12 955. 345 D. T. Glatzhofer Y. Eiang and M. A. Khan Organometallics 1993 12 624. 346 E. P. Kiindig D. Amurrio G.Bernardinelli and R. Chowdhury Orgonornerallics 1993 12 4275. 347 N. Jevnaker T. Benneche and K. Undheim Acta Chem. Scand. 1993,47 406. 265 G.R. Stephenson Annual Report.The main theme this year has been a discussion of alkyne chemistry and coupling reactions. Nonetheless in each year there are developments in all aspects of organometallic Chemistry. During 1993 there has been considerable progress with organometallic dendrimers containing iron348.349 and ruthenium.349 In one case iron complexes have been placed at the centre and the periphery of the tentacled structures. In the fiefd of ferrocene chemistry much synthetic work has been performed. The most notable products are designed for special purposes such as thermotropic crystals;35 53 as end groups on a structure along which a cyclophane moiety as polydecker pentalene complexes linked in stacks at opposite faces of the back-to-back five-membered rings,355 or even larger stacked structures (formed by palladium-cataIysed cross-coupIing to ferrocenylzinc derivatives to produce a range of ferrocene units linked by naphthalenes356 or by binaphth~l~~~ units) or dimeric metallocenes connected by a (dicyclopentadieny1)-methyleneunit.358 Ferrocenes span rnacrocy~les~~~*~~~ and in a smaller ring system the iron participates as a fourth ligand in an interaction with a palladium acetonitrile complex.36 Tetrathi~fulvalene,~~~ f~lgides,~~~ systems have been prepared.Boronic acid and tetrazole hydra~one~~~ substituents on ferrocene units can participate in cross-coupling in the presence of the metal attached to the cyclopentadienyl liga~~d,~~’ but in (arene)tricarbonylchromium complexes coupling is prevented by the presence of the Chiral centre^^^'*^^' including an example at sulfur,349 have been formed and in one case asymmetry was induced by microbial reduction.370 Ferrocene-based chiral auxiliaries are usefuI in and Grignard37 cross-coupling reactions.Work on acyliron complexes has continued with their utility being illustrated by 348 F.MouIines L. Djakovitch R. Boese,B. Gioaguen W. Thiel J.-L. Fillaut M.-H. Delville and D. Astruc Angew. Chem. Int. Ed. Engl. 1993 32 1075. 349 Y.-H.Liao and J. R. Moss J. Chem. SOC.,Chem. Commun.,1993 1774. 350 J.-L. Fillaut and D. Astruc J.Chem. SOC.,Chem. Commun. 1993 1320. 35 I R. Deschenaux M. Rarna and J. Santiago Tetrahedron Lett. 1993 34 3293. 352 C. Loubser C. Imrie and P. H. Van Rooyen Ado. Mater. 1993 545. 353 R. Deschenaux and J. Santiago J. Mater. Chem. 1993 3 219. 354 A. C. Benniston and A. Harrirnan Angew. Chem. Int. Ed. Engl. 1993 32 1459. 355 B. Oelckers I. Chavez J-M. Manriquez and E. Romin Organometallics 1993 12 3396. 356 H. M. Nugent and M.Rosenblurn J. Am. Chern. SOC. 1993,115 3848. 357 B. M.Foxman M. Rosenblum V. Sokolov and N. Rhrushchova Organomerollics 1993 12 4805. 358 M. Watanabe S. Iwamoto S. Nakashima H. Sakai 1. Motoyarna and H. Sano,J. Orgonomet. Chem. 1993,448 167. 359 P.D. Beer Z. Chen M.G.B. Drew J. Kingston M. Ogden and P. Spencer,J. Chem. Soc.Chem. Commun. 1993 13 1046. 360 R.A. Holwerda J.S. Kim,T. W. Robison R. A. Bartsch,and R. P.Czech J.Organornet.Chem. 1993,443 123. 361 M. Sato H. Asano and S. Akabori J. Organomet. Chem. 1993,452 105. 362 A. J. Moore P. J. Skabara M. R. Bryce A. S. Batsanov J. A. K.Howard and S.T.A.K. Daley J. Chem. SOC.,Chem. Commm. 1993 417. 363 R. W. McCabe D. E. Parry and S. P. Saberi J. Chem. SOC. Perkin Trans. 1 1993 1023 364 W. Shaozu L. Benyan Z. Yulan and L. Zenglu Synth React. lnorg. Met. Org. Chem. 1993 23 1139. 365 R. Knapp and M. Rehahn J. Org. Chem. 1993,452 235. 366 M.A. Beckett R. J. Gilmore and K. Idrees J. Organomet. Chem. 1993,455,47. 367 H. Wally,C. Kratky W. Weissensteiner M.Widhalm,and K. Schogl J. Organornet.Chem. 1993,450,185. 368 0.Riant 0.Samuel and H.B.Kagan J. Am. Chem. Soc. 1993,115 5835. 369 F. Rebikre 0.Rian! L. Ricard and H. B. Kagan Angew.Chem. Int. Ed. Engl. 1993,32 568. 370 Y. Yarnazaki A. Maruyama K. Hosono T. Higashihara H. Kobayashi Z. Noturforsch. BioSci. 1993,48 451. 371 B. Jedicka C. Kratky W. Weissensteiner and M.Widhalm J. Chem. Soc. Chem. Commun. 1993 1329. 372 Z.-X.Wang and Z.-Y. Cheng Youji Huaxue 1993,13,496. Organometalfic Chemistry their role as intermediates in syntheses of (-)-actin~nin,~~~ (S)-(-)-methyl tr~pinate,~~~ and a precursor for erap pa mil.^'^ The triphenylphosphine(cyc1open-tadieny1)iron complex has been used as a chiral auxiliary to induce stereoselective reactions in dihydronicotinoyl systems.376 Two resohtion procedures for this iron-based auxiliary have been reported,37 and pentarnethylcy~lopentadienyl~~~ and diphenylalkylph~sphine~~~ anaiogues have been studied.Acknowkdgement. I am grateful to Professor S. Maiorana and his coworkers and to the Library of the Dipartimento di Chimica Urganica e Industriale for assistance with bibliographic work during my visit to the Universita degli Studi di Milano in 1993. 373 G. Bashiardes G.J. Bodwell and S. G.Davies J. Chem. Soc. Perkin Trans. 1 1993 459. 374 T. M. Baker G. J. Bodwell S.G.Davies A.J. Edwards,and M.R. Metzlev Terrahedron 1993,49,5535. 37s H. Brunner S. Forster and B. Nuber Organomeruliics 1993 12 3819. 376 R. P. Beckett V. A. Burgess S.G. Davies and M.Whittaker Tetrahedron Lett. 1993 34 3617. 377 R.W.Baker and S.G. Davies Tetrahedron Asymmetry 1993,4 1479; S.C.Case-Green J. F. Costello S.G.Davies N. Heaton C. J. R. Hedgecock and J. C. Prime J. Chem. Soc. Chem. Commun. 1993,1621. 378 J.-P. Barras S.G. Davies M.R.Metzler A. J. Edwards V. M. Humphreys and K. Prout J. Organomel. Chem. 1993,461 157. 379 H.Stepowska and A. Zamojski J. Organornet. Chem. 1993,456 221.