共老我白发phenylalanine Scheme
16.
Scheme
17.
Scheme18.
F.Alonso et al./Tetrahedron61(2005)11771–1183511783
derivatives with high stereocontrol.Unfortunately,the authors did not give any information about the isolated yields of the ?nal products,making it dif?cult to evaluate the ef?ciency of the whole process.
Portnoy et al.synthesised various poly(aryl benzyl ether)dendrimers on a solid support,based on the initial immobilisation of commercially available 5-hydroxy-isophthalate onto the Wang resin,followed by ester reduction.Repetitive Mitsunobu coupling and ester reduction led to the formation of a second and third-generation of dendrimers.94The three resins were subjected to Mitsunobu reaction with p -iodophenol,followed by Heck coupling with methyl acrylate,with complete conversions being achieved for every resin.Only moderate yields and fair purities were,however,obtained for any of the resins tested upon TFA-induced cleavage (Scheme 19).In fact,this methodology has no advantage with respect to that developed by Hanessian et al.95in which the aryl iodide was directly attached to the Wang resin.In this case,the free cinnamic ester was obtained in 90%overall yield under the same reaction conditions,but minimising the number of steps and consequently,the generation of waste,making the process more economic and time saving.
In a study on indole synthesis,Kondo et al.described the palladium-catalysed intramolecular cyclisation of enamino-esters in the solution phase and on solid supports.96In the solution phase,the expected ethyl 3-phenyl-2-indole-carboxylate was obtained in 56%yield after treatment with a catalytic amount of Pd 2(dba)3,(o -Tol)3P and Et 3N in DMF at 1208C for 2h (Scheme 20).The polymer-supported version of this reaction involved the attachment of the substrate to a hydroxymethyl-polystyrene resin,treatment with the same catalytic system at 1108C for 12h,and ?nal transesteri?cation of the resulting polymer-bound indole carboxylate using NaOMe in MeOH–THF.In this case,the product was obtained in 48%yield after further puri?cation by column chromatography.It seems clear that the solution-phase reaction is advantageous,since it reduces the reaction time in the intramolecular coupling,less steps are used,and the yield is slightly improved.Similar solid-phase indole synthetic strategies have been published recently by the same research group.97
It is clear that the main reason for immobilising a molecule on a solid support for the Heck or any other reaction relies on the simple separation of the intermediates and,?nally,of the products from the reagents and soluble by-products.This fact,which represents a major advantage,compared to the solution-phase chemistry,may hide some inherent incon-veniences and limitations that can curtail the whole ef?ciency of the process,for example,(a)reactions can be driven to completion in most cases,but only in return for consuming an excess of reagent,(b)suitable,robust and versatile linkers are required,which have to be cleaved selectively under mild reaction conditions without destroy-ing the product,(c)a second functionality in the starting material is normally necessary for attachment to the support,as exempli?ed by the intermolecular Heck reaction,in which the polymer-bound aryl iodides must bear an additional group (carboxy,hydroxy,amino,etc.)that remains at the end in the product,whereas most of the polymer-bound alkenes studied are derived from a ,b -unsaturated carboxylic acid derivatives,(d)the selection of usable solvents and the temperature range can be quite restricted (1008C is at the upper limit),(e)the chemistry involving heterogeneous catalysts such as palladium on charcoal is incompatible with solid-phase synthesis methods,(f)the dif?culty of analysing the outcome of a given reaction makes it necessary for the cleavage of the products from the support to be analysed by normal methods and (g)in the case of solid-phase combinatorial chemistry,additional investment is essential for laboratory automation,robotics and mechanical and tag-reading/sorting devices enabling the simultaneous performance of multiple tasks.In short,there is a need for more solid-phase methodology,including the development of traceless
linkers.
Scheme
19.
Scheme 20.
F.Alonso et al./Tetrahedron 61(2005)11771–11835
11784
5.Catalytic systems
The selection of a proper catalytic system is fundamental for achieving the best ef?ciency in a given Heck reaction.In order to design such an ef?cient catalytic system,however, we have to focus not only on its catalytic activity or selectivity,but also on other important topical issues,such as the possibility of recovery of the components,or their toxicity and environmental impact,especially for appli-cation to an industrial scale.In fact,industrial applications
are rare,because the cheap aryl chlorides or many readily available bromides do not react with suf?ciently high yields, turnover numbers and selectivities,even in the presence of the traditional phosphane catalysts.98Signi?cant efforts have been made in recent years to develop more ef?cient catalytic systems,trying to simplify these reactions as much as possible.
5.1.Ligands:ligand-free catalytic systems
Tertiary phosphane ligands have traditionally been used to ensure catalyst stability,in spite of the fact that they can have some detrimental effect on the rate of the inpidual steps of the coupling reaction.The use of phosphorus ligands in?ne-chemical and industrial processes,however, is less desirable.They are usually toxic,unrecoverable and frequently hamper the isolation and puri?cation of the desired product,as well as the performance of consecutive catalytic steps of the total synthesis.In spite of the fact that numerous phosphane-free ligand systems have been developed,including palladacycles,nucleophilic carbene ligands and others,99these catalytic systems suffer from some drawbacks.The high ligand sensitivity to air and moisture,their tedious multistep synthesis,the high cost of the ligands and the use of various additives curtails their applications.On the other hand,the ligand-free Heck catalytic systems have very recently emerged as more advantageous at all levels,operationally,economically and environmentally.100
We have described in Section4.1a series of methodologies involving the use of alternative arylating agents to aryl halides in the Heck reaction,most of which have a common and advantageous feature,that is,no ligand was added to the reaction mixture.The ligandless approach to carbon–carbon coupling was,however,pioneered independently by Beletskaya101and Jeffery.102The latter author reported,in 1984,the palladium-catalysed vinylation of organic iodides under solid–liquid phase-transfer conditions at,or near, room temperature,using TBAC as the phase-transfer agent and sodium hydrogen carbonate as a base in the absence of any ligand.102a The reactions proceeded with excellent yields(85–98%)and with high regio-and stereoselectivity. Aryl iodides furnished the(E)-products exclusively (Scheme21),whereas(E)-1-iodohexen-1-ene gave a1:15 diastereomeric mixture in favour of the(E,E)-product.The mild conditions allowed this type of reaction to be generalised to thermally unstable vinylic substrates such as methyl vinyl ketone or acrolein.Fortunately,the vinylation of vinylic iodides was greatly accelerated (1–5h)by using potassium carbonate instead of sodium hydrogen carbonate as the inorganic base,with a parallel improvement of the stereoselectivity.102b More recently,a slightly modi?ed catalytic system was applied by Crisp et al.to the Heck coupling of the chiral non-activated alkenes,2-aminobut-3-en-1-ols,with cyclo-hexenyl tri?ate.103In this case,tetra-n-butylammonium tri?ate was used instead of TBAC under mild reaction conditions,the produced dienes being isolated in moderate to good yields and with little or no racemisation (Scheme22).The high reactivity observed with tetra-n-butylammonium tri?ate was attributed to the high rate of dissociation of the tri?ate anion from the neutral palladium(II) intermediate and the formation of a very reactive cationic palladium species.Some bene?cial in?uence was observed when a small amount of water(5equiv)was added to the reaction mixture.Little can be said about the scope of this reaction,since cyclohexenyl tri?ate was the only tri?ate tested.
A very simple catalytic system was used by Gundersen et al. in the coupling of vinylpurine with a variety of aryl iodides (Scheme23).104Better results were obtained when Pd(OAc)2alone was employed as the catalyst compared with catalysts containing phosphane ligands such as triphenylphosphane.All the couplings were highly stereo-selective,including the coupling of vinylpurine with(E)-methyl
3-iodo-2-methylacrylate.
Scheme
21.
Scheme
22.
Scheme23.
F.Alonso et al./Tetrahedron61(2005)11771–1183511785
Buchwald et al.introduced the bulky amine base,methyl(dicyclohexyl)amine,into a phosphane-free catalytic system that found application in the coupling of aryl iodides and bromides with 1,1-and 1,2-disubstituted ole?ns to give trisubstituted ole?ns (Scheme 24).105The method was applicable to the coupling of both electron-de?cient and electron-rich substrates and displayed good stereoselectivity and a high degree of functional-group compatibility.A combination of the bulky amine and tetraethylammonium chloride (TEAC)made the reaction faster and increased the E /Z selectivity,in comparison with other amines.
Reetz et al.discovered that Pd(OAc)2in the presence of the additive,N ,N -dimethylglycine (DMG),is a simple,reactive and selective catalytic system for the Heck reaction of aryl bromides with ole?ns.106The reaction of bromobenzene and styrene in NMP took place with O 95%trans-selectivity with only traces of side products in the presence of a 20:1DMG/Pd ratio (Scheme 25).It had been interesting to know the isolated yields instead of the conversions,as well as the experimental procedure for the product puri?cation,above all taking into account the presence of the additive DMG and the high boiling point solvent NMP.
