共老我白发Another simple catalytic system recently developed by Schmidt et al.was found to catalyse the reaction of bromoarenes with styrene in air in the absence of any ligands.107Conversions of around 95%were achieved by the use of 0.04–1.6mol%PdCl 2,18%HCO 2Na and 112%NaOAc in DMF after 10min at 1408C or 180min at 1008C (Scheme 26).The presence of sodium formate as a reducing agent accelerated the reaction,although it had no effect on the yield of stilbene.It was corroborated that colloidal palladium particles formed in the course of the reaction are the main reservoir of catalytically active homogeneous Pd(0)complexes.The low catalyst loading,the availability and the low prices of the components of the catalytic system,together with the absence of an inert atmosphere,
makes this methodology attractive to be applied at a larger scale.The 6-fold excess of bromoarene required is,however,an important limitation,above all taking into account that bromoarenes are rather expensive and that an additional recycling strategy should be developed for better process ef?ciency.In our opinion,this work demands further study on the applicability to some other aryl bromides and alkenes,as well as a study on the compatibility of different functional groups attached to the substrates with the reaction conditions.
In this context,Pd(OAc)2in combination with K 3PO 4in DMA exhibited a high catalytic activity for the Heck reaction of both activated and deactivated aryl bromides in the absence of any stabilising ligands or additives.108Styrenes and vinylcyclohexene led to the expected coupling products with good to excellent isolated yields (63–98%)when the reaction was performed at 1408C for about 20h (Scheme 27).It is,however,surprising that the more activated terminal ole?ns such as n -butyl acrylate gave low yields.
The group of de Vries has recently concentrated much effort in developing ligand-free palladium catalytic systems for Heck reactions,for example,they reported a practical and cost-effective coupling methodology based on the recovery and re-use of the palladium catalyst,109with different Heck reaction mixtures being separated from precipitated palladium on Celite by ?ltration.The addition of 2equiv of iodine or bromine in NMP dissolved the recovered palladium and allowed the performance of eight successive runs without signi?cant loss of activity.This re-activated palladium catalyst,which is homogenous in character,was suggested to exist as a mononuclear anionic species,although the presence of nanoparticles was not excluded.The same research group proved that the catalytic system reported by Reetz et al.106(see Scheme 25)could work nicely in the absence of the additive DMG and with a lower catalyst loading.A broad range of aryl bromides was reacted with both electron-de?cient and electron-rich ole?ns in the presence of 0.05mol%Pd(OAc)2,and 2.4mmol of NaOAc in NMP at 1358C for 1–15h,affording the products in 80–100%conversion.110The fact that this method was scaled up to a few Kg,together with the low cost of the
catalytic
Scheme
24.
Scheme
25.
Scheme
26.
Scheme 27.
F.Alonso et al./Tetrahedron 61(2005)11771–11835
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system,the relatively low solvent volume used and the easy workup procedure,makes it very attractive for large-scale production.
As an example of a speci?c application,a ligand-free palladium-catalysed Heck reaction of methyl2-acetamido-acrylate and aryl bromides was used by de Vries et al.as the key step in the synthesis of enantiopure substituted phenylalanines.111All reactions were performed in NMP at1258C in the presence of Pd(OAc)2,BnNEt3Br and Pr2i NEt or NaOAc as base.A variety of aryl bromides with different electronic character was tested,giving rise to the corresponding products,puri?ed by simple crystallisation, in moderate yields(Scheme28).It is noteworthy that one of the reactions took place in55%yield,even in the absence of the tetraalkylammonium salt,simplifying the catalytic system even more.
The absence of any ligand in the reaction medium, especially phosphane ligands,is very desirable.This absence,however,normally implies the presence of other additives to stabilise the in situ generated palladium species, which nonetheless can be removed more easily.At any rate, more efforts are needed for the ligand-free Heck reaction in order to decrease the reaction temperature,above all in the coupling of aryl bromides.
5.2.Catalysts:supported catalysts
Although the Heck reaction is also very attractive also for industrial applications,the homogeneous Heck reaction has no practical application in industry.112The loss of catalyst, which usually cannot be recovered and the need for aryl bromides or iodides as the starting materials are the major drawbacks that have prevented a more extensive exploita-tion of this reaction at an industrial level.The loss of catalyst could perhaps be tolerated if the cheaper and much more readily available aryl chlorides could be employed as the starting materials.
In principle,heterogeneous catalysts or heterogenised homogeneous catalysts can be used to solve some of the above-mentioned technical applications in the Heck reaction.113Among the heterogeneous catalysts we should mention the supported metal catalysts,zeolite-encapsulated catalysts,colloid-nanoparticles and intercalated metal compounds.The homogeneous metal complexes catalysts can be heterogenised using modi?ed silica catalysts,polymer-supported catalysts,biphasic catalysts,supported liquid-phase catalysts,non-ionic liquid solvents,per?uori-nated solvents and re-usable homogeneous complexes.All these types of catalysts can be easily recovered from the reaction mixture and recycled,if they do not deactivate too quickly under duty.In addition,the palladium in hetero-geneous catalysts would already be present as metal crystallites dispersed onto the solid support,so that precipitation of palladium black should not occur.In general,the heterogeneous catalysts have a major drawback of lower selectivity towards Heck coupling and metal leaching,whereas the heterogenised metal complexes operate under milder reaction conditions.
Since an important part of this topic has been tackled in perse reviews,we are going to deal mainly with some selected examples of the most recent literature covering the study of catalysts supported on carbon,metal oxides, molecular sieves,clays,zeolites,polymeric and dendrimeric materials,among others.
5.2.1.Carbon.Palladium on carbon proved to be active for Heck coupling under several different conditions and is one of the most frequently investigated catalysts.113In general, carbon-supported catalysts do not seem to differ signi?-cantly in activity from their homogeneous counterparts, since the proportion of the metal to the limiting reagent, reaction temperatures,times and yields are comparable to those observed for homogeneous catalysts.Palladium supported on carbon,however,often causes unwanted hydrodehalogenation of the haloaromatic compounds and suffers from substantial palladium leaching.114Palladium leaching is also relevant to the mechanism of Pd/ C-catalysed Heck couplings.In fact,it is still the subject of debate as to whether the reaction takes place on the solid palladium surface or the true catalyst is the dissolved palladium that has been leached from Pd/C,which acts simply as a palladium reservoir.
It is worth mentioning the publication by Beller et al.which described the?rst Heck reaction of aryldiazonium salts using heterogeneous catalysts.115Palladium on carbon was shown to be a very effective catalyst in this reaction under very mild conditions(40–608C)(Scheme29).There was no need to add stoichiometric amounts of base or stabilising ligands such as phosphanes and these are major advantages. Unfortunately,the catalyst exhibited an important reduction in activity after its?rst use.The lack of commercial availability of the starting anilines and the additional step of conversion into the corresponding aryldiazonium
salts Scheme
28.
Scheme29.
F.Alonso et al./Tetrahedron61(2005)11771–1183511787
would be the only possible disadvantages of this methodology.
A very interesting and detailed study was reported by Ko
¨hler et al.concerning the Heck reaction of aryl bromides with ole?ns in the presence of a variety of Pd/C catalysts.116The activity of the catalysts was shown to be strongly dependent upon the palladium dispersion,palladium oxidation state in the fresh catalyst,the water content and the conditions of catalyst preparation.A high palladium dispersion,low degree of palladium reduction,high water content and uniform palladium impregnation led to the most active catalyst.The fact that uniformly impregnated Pd/C catalysts showed higher activities than eggshell catalysts supported the hypothesis that leached palladium is the active species,for which the solid Pd/C acts as a reservoir that delivers catalytically active palladium species into solution.In fact,Arai et al.have demonstrated that palladium exists on the support,in solution and in the form of free colloidal particles during and after the Heck reaction,which can be redeposited on the support.117The optimised Pd/C catalyst exceeded by at least one order of magnitude the activity of any heterogeneous palladium catalyst reported in the literature in the reaction of bromoarenes with ole?ns (Scheme 30).In general,all the catalysts studied exhibited a high activity and selectivity,without the exclusion of air and moisture,extremely low palladium concentrations,easy and complete separation from the product mixture,easy and quantitative recovery of palladium and commercial availability.Although the TONs were still lower than those of the most active homogeneous catalytic systems for the activation of aryl bromides,the TOFs were higher,the activity at the beginning of the reaction being extremely high before deactivation of the catalyst occurred.In contrast to the results of Arai et al.,118who observed up to 80%hydrodehalogenation,no hydrodehalogenation of bromoarenes was observed in any experiment.
