共老我白发Together with boronic acids,arylsilanols78and arylstan-nanes78c,79have been used as arylating agents in the Heck reaction with electron-de?cient ole?ns.There are,however, some evident disadvantages of these materials,when compared with the carboxylic acid derivatives.Firstly, these starting materials are not so readily available,their preparation involving less common and more expensive reagents,with the corresponding generation of waste. Secondly,boric acid,silanols and stannanes are formed as by-products in the Heck reactions,which can make the puri?cation of the products dif?cult with a low possibility of recycling.Thirdly,the presence of large amounts of Cu(II) salts as re-oxidants,phosphanes and organic bases is required for a maximum ef?ciency.
Uemura et al.found that diphenyltellurium(IV)dichloride reacted with a variety of ole?ns in the presence of a catalytic amount of PdCl2,together with NaOAc in HOAc to afford the corresponding arylated(E)-ole?ns in variable yields (3–98%)(Scheme12).80A suitable oxidant such as tert-butyl hydroperoxide or copper(I)or copper(II)chloride had to be added for the reaction to proceed catalytically on palladium.The stereoselectivity was very high,except for acrylonitrile(Z/E26:74).Transmetallation of tellurium with palladium was suggested as the key step of the reaction. Alternatively,diaryltellurides could be used as arylating agents for a variety of ole?ns in the presence of Et3N as base and AgOAc as oxidant(40–99%product yield).81
As an alternative to the above reagents,Kamigata et 5a98184be45c3b3567ec8bfced aryldimethyltellurium iodides for the palladium-catalysed Heck-type reaction with electron-de?cient ole?ns and styrene,in the presence of a stoichiometric amount of silver(I)acetate.82For the telluronium salt partner,the best results were obtained when the aryl moiety bore electron-donating substituents at the para position,those at the ortho position retarding the reaction(Scheme13).The yields are good to excellent,although a3-fold excess(with respect to the ole?n)of the expensive silver acetate is needed for the anion exchange and oxidation steps in the catalytic cycle.In contrast with the reactions with organic tellurides,for which the crude mixtures must be puri?ed to remove the excess reagent,in the reactions with the telluronium salts the pure products were obtained by simple?ltration using silica gel to remove the solids in the reaction mixture. Unfortunately,the organic tellurides and tellurium salts are not commercially available.Diaryltellurium(IV)dihalides are normally prepared from TeCl4with activated arenes, arylmercury chlorides or arenediazonium
salts. Scheme
11.
Scheme
12.
Scheme13.
F.Alonso et al./Tetrahedron61(2005)11771–1183511781
Symmetrical diaryltellurides can be prepared from alkali tellurides and non-activated aryl halides,sodium telluride or potassium tellurocyanate and arenediazonium?uoro-borates,tellurium(IV)halides and arylmagnesium halides, or elemental tellurium and diarylmercury compounds.Alkyl aryl tellurides are the precursors of the corresponding telluronium salts and are generally prepared by sequential arylation–alkylation of sodium telluride or from organyl tellurolates,generated by tellurium insertion into organo-magnesium or organolithium reagents.83In short,the
preparation of these arylating agents represents a major disadvantage that adds to the toxic and mutagenic properties of the starting materials,tellurium and TeCl4,respectively, and to the possible toxicity of the organotellurium compounds.84
A variety of organoantimony compounds have also found application in the arylation of ole?ns with different catalytic systems,including:(a)triphenylstibine with AgOAc and catalytic Pd(OAc)2,85(b)diphenyl-and phenylantimony chloride with catalytic Pd(OAc)2under air,86(c)triaryl-antimony diacetates under PdCl2(MeCN)2catalysis87 and(d)triarylstibines88or tetraphenylantimony(V) carboxylates89in the presence of equimolecular amounts of a peroxide and catalytic amounts of Li2PdCl4or PdCl2 (see some selected examples in Scheme14).In spite of the fact that these antimony compounds cannot be considered as usual reagents,all of them have an interesting feature in common,namely that the coupling reactions can be carried out under very mild reaction conditions,normally at room temperature or508C.
Less common is the use of organolead(IV)compounds as arylating agents for ole?ns.Kang et al.described in1998for the?rst time that aryllead triacetates could be coupled with a variety of electronically different ole?ns under mild reaction conditions and palladium catalysis(see one example in Scheme15).90Most of the reactions proceeded at room temperature with moderate to good yields,although the homocoupling reaction competed in some of the experiments reported.It was presumed that the oxidative addition step was facilitated by the formation of the organolead trimethoxide,ArPb(OMe)3,to give a polar reactive intermediate,ArPdPb(OMe)3,which allowed the coupling under mild conditions.On the other hand,the aryllead triacetates are not commercially available and are rather toxic reagents.
Most of the alternative arylating agents presented in this report have the main advantage of minimising by-product formation,therefore facilitating the work-up.Except in the case of the carboxylic acids,however,the rest of the reagents are not commercially available and the generation of waste in their preparation is inevitable.In addition,rather high temperatures are needed for the coupling reactions in order to achieve reasonable conversions.
4.2.Supported substrates
Intermolecular Heck reactions on solid supports have been extensively used in synthetic organic and combinatorial chemistry,due to the easy accessibility of the starting halo-alkenes or-arenes and alkenes.The reactions involve immobilised aryl halides,mostly iodides,or iodonium salts with soluble alkenes,or immobilised alkenes with soluble aryl halides.When performed on the same type of resin and with the same catalytic system,the immobilisation of aryl iodides appears to be more bene?cial than that of alkenes. Two main protocols have been applied:(a)the standard Heck conditions[Pd(OAc)2,Ph3P or(o-Tol)3P,DMF,80–1008C],2–24h]and(b)the Jeffery conditions[Pd(OAc)2, Ph3P,TBAC,K2CO3,DMF,20–808C].The intramolecular Heck reaction on solid supports has found application in the preparation of macrocycles and heteroatom-containing ?ve-,six-and seven-membered rings,as well as in the construction of indoles,benzofurans,dihydroisoquinolines and benzazepines.The pseudo dilution effect exhibited by the starting material in the intramolecular version has led to an increased yield.Both inter-and intramolecular Heck reactions on a solid support have been recently reviewed17 and,therefore,it is not our objective to repeat all of this information here.Instead,we will deal with the more recent and representative examples and present a general con-clusion at the end of this section.
Morphy et al.observed that the use of low solvent volumes in solid-phase Heck reactions resulted in large increases in yield,compared with the standard dilution conditions.91 3-Iodobenzoyl chloride was reacted with Wang resin,the resulting aryl halide being coupled with ethyl acrylate under palladium catalysis,followed by resin cleavage with
TFA. Scheme
14.
Scheme15.
F.Alonso et al./Tetrahedron61(2005)11771–11835
11782
After reaction at608C for2h at standard dilution(1ml),a conversion of40%was observed,compared to80%when only0.05ml of solvent was used.The reaction was complete after18h for a low solvent volume with only 54%conversion under standard dilution conditions (Scheme16).The optimal amount of solvent represented %2m L/mg of resin,signi?cantly less than that required to totally swell the resin used and lead to a separate solvent phase.This methodology is certainly advantageous,since it minimises the use of solvent and provides high conversions under mild reaction conditions.Unfortunately,all reactions were performed on a very small scale(0.05mmol of resin-bound3-iodobenzoic acid)with excess of ethyl acrylate (2equiv)and Et3N(5equiv)and,therefore,the behaviour of this catalytic system on a larger scale remains uncertain.
A small library of cinnamate esters was prepared by Gene?t et al.,based on the use of a new stable silylated polystyrene, PS-SiMe2CH2Cl.92This chloromethyl resin was esteri?ed with various iodobenzoic acids(o-,m-and p-derivatives),followed by a cross-coupling reaction with ethyl acrylate in DMF in the presence of Pd(OAc)2-PPh3as the catalytic system,the latter transformation taking place with complete conversion.The expected esters were released from the resin by treatment with TBAF in THF(Scheme17).Owing to the dif?culties of eliminating the excess of TBAF, however,further treatment with Amberlyst A-15and its calcium salt as scavengers was needed to purify the reaction mixture.Despite the?nal products being obtained in good yields and the mild resin-cleavage step,this methodology does not seem to introduce any advantage with respect to the use of the more conventional resins.Firstly,the silylated resin is not commercially available and had to be prepared from a1%pinylbenzene–styrene copolymer by lithiation and trapping with chloro(chloromethyl)dimethylsilane,a relatively expensive electrophile.Secondly,the cesium carboxylate had also to be prepared to increase its nucleophilicity in the S N2reaction to attach the resin. Thirdly,a special resin-cleavage protocol was needed, leading to more waste(additional to the excess of reagents) and to the generation of a new silylated resin with no chance of being recycled.
Takahashi et al.recently described the stereoselective synthesis of36peptides containing unnatural amino acids, utilising the Pd(0)-catalysed Mirozoki–Heck reaction of dehydroalanine derivatives in combination with an asym-metric hydrogenation on polymer support.93In this case, the alkene partner was supported on Synphase Rink-amino PS-Crowns e,whereas the aryl iodides were in solution.It was found that4mM Pd(dba)2in MeCN at808C for3h in the presence of TBAC and Et3N were the optimal reaction conditions.Products were obtained with a high purity, except for aryl iodides bearing electron-withdrawing substituents,where a low purity(45–60%,p-AcC6H4I)or no reaction(p-NO2C6H4I)was observed(Scheme18). Asymmetric hydrogenation and?nal cleavage with TFA–CH2Cl2furnished the corresponding
