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Studies on the palladium-catalysed direct alkenylation of 1,2-azolesBen Chappell,Nathan Dedman,Simon Wheeler ⇑Worldwide Medicinal Chemistry,Pfizer,Ramsgate Road,Sandwich,Kent CT139ND,UKa r t i c l e i n f o Article history:Received 8February 2011Revised 15March 2011Accepted 12April 2011Available online 18April 2011a b s t r a c tElectron-rich isoxazoles,isothiazoles and pyrazoles undergo palladium-catalysed direct alkenylation in moderate yields.Ó2011Elsevier Ltd.All rights reserved.Despite many recent advances C–H activation chemistry fre-quently requires a directing group.However,it is possible instead to exploit the intrinsic reactivity of aromatic heterocycles and this tactic enables the synthetic chemist to join substructures to a pre-viously unfunctionalised heteroaromatic ring.Most commonly these substructures are other aromatic rings,1but other moieties have also been successfully appended.Reports of such methods include the rhodium-catalysed chemistry of Bergman and co-workers,2and nickel-mediated alkenylations (starting from al-kynes)published by Nakao et al.3Alkynes have also been attached to aromatic heterocycles.4Alkylations catalysed by either nickel or palladium have been reported.5Very recently,acylations and re-lated reactions have been developed.6However,perhaps the most attractive approach is what has become known as the Fujiwara–Moritani reaction where C–H activation is combined with a Heck reaction.Thus,under the influence of a Pd(II)salt a heterocycle and an alkene are coupled with the formation of a new C–C bond.Whilst the original report 7was mostly restricted to furan and thi-ophene,and required stoichiometric amounts of palladium,a cata-lytic version,using Cu(OAc)2as the stoichiometric oxidant,was then developed and also applied to benzofuran and benzothio-phene.8Subsequently the reaction has been applied to indoles 9(including a version allowing regioselective vinylation at C-2or C-3),10pyrroles,11pyridones,12enaminones,13indolizines 14and 1,2,3-triazoles.15Miura has disclosed conditions [catalytic Pd(OAc)2and stoichiometric AgOAc in propionic acid as solvent]which allow for the alkenylation of oxazoles and thiazoles.16The mechanism is traditionally assumed to involve an electrophilic pal-ladation.17The het-Pd(II)-X species thereby generated can react with alkenes according to the usual Heck reaction mechanism to give the organic product and Pd(0).Oxidation of the palladium to Pd(II)by a stoichiometric oxidant completes the catalytic cycle.This mechanism,exemplified for thiophene,is shown in Scheme 1.It should be noted that neither the heterocycle nor the alkene requires prior functionalisation.We successfully applied Miura’s conditions 16to the alkenyla-tion of isoxazoles.Moreover,we were able to demonstrate that air could be used as the stoichiometric oxidant without significant loss of yield (Scheme 2).However,under these conditions,yields were often low and the reaction times long so we attempted to refine the reaction param-eters.A brief survey of solvents and oxidants demonstrated that bubbling air through the reaction gave a messy profile and the0040-4039/$-see front matter Ó2011Elsevier Ltd.All rights reserved.doi:10.1016/j.tetlet.2011.04.051Corresponding author.Tel.:+441304649173;fax:+441304651817.E-mail address:simon.wheeler@pfi (S.Wheeler).reaction could not be driven to completion.Running the reaction under neutral conditions was more effective than using acid sol-vents,and indeed,the addition of 0.3equiv of pivalic acid was of no benefit in any of the cases examined.Thus,from the conditions examined,dimethylacetamide (DMA)appeared to be the optimum solvent and Cu(OAc)2an efficient oxidant.We were able to apply our preferred conditions to a small set of commercially available 1,2-azoles and our results are shown in Table 1.The E-isomer was formed in all cases.We believe that the S E Ar mechanism shown in Scheme 1is a reasonable working hypothesis to explain most of the reactivity differences apparent in Table 1.Thus while dimethylisoxazole re-acts rapidly (entries 1–4),its 5-phenyl analogue requires a much longer time to react completely (entries 5and 6).Moreover the iso-thiazole example (entry 7)is less reactive still;presumably the poorer overlap of the sulfur orbitals renders the molecule less nucleophilic.It is also noteworthy that the compounds shown in Figure 1are almost entirely unreactive under the conditions dis-closed,whereas their more electron-rich counterparts (entries 5,6and 9)are productive.Further support is lent to the S E Ar hypothesis by the observa-tion that 1-methylpyrazole reacts principally at the 4-position (en-try 9),the preferred site for electrophilic reactions of this heterocycle.It should also be noted that in our screen of reaction conditions,no improvement was found when PivOH/K 2CO 3was added to the reaction mixture.This reagent combination is known to promote the arylation of heterocycles that proceeds via a con-certed metallation deprotonation mechanism.1cHowever,the much lower reactivity of pyrazoles (compare en-tries 2and 8)is less easy to explain by appealing to an electrophilic palladation.Preliminary spectroscopic and computational investi-Table 1Alkenylation reactions of 1,2-azoles.General reaction conditions:100mg of azole,2equiv of alkene,10mol %Pd(OAc)2,2equiv of Cu(OAc)2in 2ml of DMA EntryHeterocycleAlkeneTemperature (°C)Time (h)Product Isolated yield (%)1NOCO 2nBu1201NOCO 2n Bu632NOCO 2t Bu1201NOCO 2t Bu503NOPh1201NOPh684NONMe 2O1201NONMe 2O565NOPhCO 2n Bu1208NOPhCO 2n Bu556NOPhNMe 2O1208NOPh NMe 2O587aNSPhCO 2n Bu12018NSPhCO 2n Bu15b8NNCO 2t Bu1503NNCO 2t Bu249NNCO 2t Bu1504NNCO 2t Bu22ca The preparation of the starting isothiazole has been described in Ref.20.b Starting isothiazole (52%)was also recovered.cApproximately 30%yield of a 4:1mixture of 4,5-and 3,4-dialkenylated products was also recovered.3224 B.Chappell et al./Tetrahedron Letters 52(2011)3223–3225gations have so far not succeeded in elucidating the underlying reasons for this surprising lack of reactivity.Ourfindings in this re-spect are in line with previous work suggesting that these hetero-cycles are difficult substrates for C–H activation chemistry.18 In conclusion we have demonstrated a method for the direct alkenylation of1,2-azoles.19Regrettably,it has not so far been pos-sible to extend the reaction scope beyond ring systems bearing simple substituents.Furthermore,extension to less usual Heck substrates(alkenes bearing sulfonyl,phosphonyl or phthalimido substituents)has likewise been unsuccessful.While the electro-philic palladation mechanism can be seen as a useful tool to under-stand the reaction,further investigations are warranted to discover if this pathway is genuinely operative in this case,and in the Fujiw-ara–Moritani reaction more generally.It is to be hoped that such mechanistic understanding will lead to better catalyst systems that operate under milder conditions and across a broader range of substrates.AcknowledgementsWe thank Alexander Alex,Mark Andrews,David Blakemore, Manuel Perez and Guy Lloyd-Jones(University of Bristol)for useful discussions.References and notes1.For a review see:(a)Alberico,D.;Scott,M.E.;Lautens,M.Chem.Rev.2007,107,174–238;Selected more recent developments:(b)Do,H.-Q.;Kashif Khan,R.M.;Daugulis,O.J.Am.Chem.Soc.2008,130,15185–15192;(c)Liégault,B.;Lapointe,D.;Caron,L.;Vlassova,A.;Fagnou,.Chem.2009,74,1826–1834;(d)Canivet,J.;Yamaguchi,J.;Ban,I.;Itami,.Lett.2009,11,1733–1736;(e)Jarfarpour,F.;Rahiminejadan,S.;Hazrati,.Chem.2010,75, 3109–3112;(f)Strotman,N.A.;Chobanian,H.R.;Guo,Y.;He,J.;Wilson,J.E.Org.Lett.2010,12,3578–3581;(g)Roy,D.;Mom,S.;Beaupérin,M.;Doucet,H.;Hierso,J.-C.Angew.Chem.,Int.Ed.2010,49,6650–6654.2.(a)Tan,K.L.;Bergman,R.G.;Ellman,J.A.J.Am.Chem.Soc.2001,123,2685–2686;(b)Tan,K.L.;Bergman,R.G.;Ellman,J.A.J.Am.Chem.Soc.2002,124, 13964–13965;(c)Tan,K.L.;Park,S.;Bergman,R.G.;Ellman,.Chem.2004,69,7329–7335.3.(a)Nakao,Y.;Kanyiva,K.S.;Oda,S.;Hiyama,T.J.Am.Chem.Soc.2006,128,8146–8147;(b)Kanyiva,K.S.;Nakao,Y.;Hiyama,T.Heterocycles2007,72,677–680;(c)Nakao,Y.;Kanyiva,K.S.;Hiyama,T.J.Am.Chem.Soc.2008,130,2448–2449;(d)Kanyiva,K.S.;Löbermann,F.;Nakao,Y.;Hiyama,T.Tetrahedron Lett.2009,50,3463–3466;(e)Nakao,Y.;Idei,H.;Kanyiva,K.S.;Hiyama,T.J.Am.Chem.Soc.2009,131,15996–15997;For a cobalt-catalysed version,see:(f) Ding,Z.;Yoshikai,.Lett.2010,12,4180–4183.4.Dudnik,A.S.;Gevorgyan,V.Angew.Chem.,Int.Ed.2010,49,2096–2098.andreferences therein..5.A recent review is provided,see:(a)Ackermann,mun.2010,46,4866–4877;(b)Nakao,Y.;Kashahira,N.;Kanyiva,K.S.;Hiyama,T.Angew.Chem.,Int.Ed.2010,49,4451–4454;(c)Yao,T.;Hirano,K.;Satoh,T.;Miura,M.Chem.Eur.J.2010,16,12307–12311.6.Leading references for each metal are:For copper:(a)Boogaerts,I.I. F.;Fortman,G.C.;Furst,M.R.L.;Cazin,C.S.J.;Nolan,S.P.Angew.Chem.,Int.Ed.2010,49,8674–8677;For gold:(b)Boogaerts,I.I.F.;Nolan,S.P.J.Am.Chem.Soc.2010,132,8858–8859;For palladium:(c)Wu,X.-F.;Anbarasan,P.;Neumann,H.;Beller,M.Angew.Chem.,Int.Ed.2010,49,7316–7319;Without metal catalyst:(d)Vechorkin,O.;Hirt,N.;Hu,.Lett.2010,12,3567–3569.7.(a)Asano,R.;Moritani,I.;Fujiwara,Y.;Teranashi,S.Bull.Chem.Soc.Jpn.1973,45,663–664;(b)Jia,C.;Kitamura,T.;Fujiwara,Y.Acc.Chem.Res.2001,34,633–639;Included in the review article:(c)Rossi,R.;Bellina,F.;Lessi,M.Synthesis 2010,4131–4153.8.(a)Fujiwara,Y.;Maruyama,O.;Yoshidomi,M.;Taniguchi,.Chem.1981,46,851–855;For more recent catalytic work on thiophenes,see:(b)Maehara,A.;Satoh,T.;Miura,M.Tetrahedron2008,64,5982–5986.9.Jia,C.;Lu,W.;Kitamura,T.;Fujiwara,.Lett.1999,1,2097–2100.10.Grimster,N.P.;Gauntlett,C.;Godfrey,C.R.A.;Gaunt,M.J.Angew.Chem.,Int.Ed.2005,44,3125–3129.11.Beck,E.M.;Grimster,N.P.;Hatley,R.;Gaunt,M.J.J.Am.Chem.Soc.2006,128,2528–2529.12.(a)Itahara,T.;Ouesto,F.Synthesis1984,488–490;(b)Cheng,D.;Gallagher,T.C.Org.Lett.2009,11,2639–2641.13.As part of an aromatic system:(a)Li,M.;Li,L.;Ge,H.Adv.Synth.Catal.2010,352,2445–2449;Nonaromatic:(b)Ge,H.;Niphakis,M.J.;Georg,G.I.J.Am.Chem.Soc.2008,130,3708–3709.14.Yang,Y.;Cheng,K.;Zhang,.Lett.2009,11,5606–5609.15.Jiang,H.;Feng,Z.;Wang,A.;Liu,X.;Chen,.Chem.2010,1227–1230.16.Miyasaka,M.;Hirano,K.;Satoh,T.;Miura,.Chem.2010,75,5421–5424.17.See especially Refs.10,11.18.Arylation of1,3,5-trimethylpyrazole has been reported by(a)Fall,Y.;Doucet,H.;Santelli,M.Synthesis2010,127–135;But it is noteworthy that the reactionrequires more forcing conditions than those reported by the same group for the arylation of3,5-dimethylisoxazole,for which see:(b)Fall,Y.;Reynaud,C.;Doucet,H.;Santelli,.Chem.2009,4041–4050;Pyrazoles have successfully been arylated by exploiting the SEM group to enhance reactivity:(c)Goikhman,R.;Jacques,T.L.;Sames,D.J.Am.Chem.Soc.2009,131,3042–3048;To our knowledge the only other report of arylation of C-H pyrazoles is intramolecular:(d)Blaszykowski,C.;Aktoudianakis,E.;Alberico,D.;Bressy,C.;Hulcoop,D.G.;Jafarpour,F.;Joushaghani,A.;Laleu,B.;Lautens,.Chem.2008,73,1888–1897.19.Representative experimental procedure:To3-methyl-5-phenylisoxazole(100mg,0.63mmol)was added Pd(OAc)2(14mg,0.063mmol)followed by n-butyl acrylate(180l L,161mg,1.26mmol)and DMA(2ml).The mixture was stirred at120°C for8h.The cooled reaction mixture was then partitioned between dil.NH3(aq)/Et2O.The aqueous layer was re-extracted with Et2O.The combined organic layers were washed with brine,dried over MgSO4and evaporated.The resulting brown oil was columned over silica(15g)eluting with PhMe.Relevant fractions were combined and evaporated to give the product as a clear oil(99mg,0.35mmol,55%).1H NMR(400MHz,CDCl3)0.90 (3H,t,J=7.4Hz),1.36(2H,m),1.61(2H,m),2.43(3H,s),4.14(2H,t,J=6.8Hz),6.23(1H,d,J=16.3Hz),7.44–7.48(3H,m),7.60–7.63(2H,m),7.64(1H,d,J=16.3Hz).13C NMR(100MHz,CDCl3)12.6,14.0,19.4,31.0,64.9,111.3,120.2, 125.6,127.4,128.3,129.3,131.0,133.4,159.1,167.0,169.5.MS(ESI):m/z286 [M+1]+.20.Lin,Y.-I.;Lang,S.A.,.Chem.1980,45,4857–4860.B.Chappell et al./Tetrahedron Letters52(2011)3223–32253225。