Cinnamates Heck coupling

Again, good results were obtained, but nothing was said about the recycling protocol of the IL support. The use of a complex linker does not seem to be a limiting addition, unlike the former system. These acryhc esters have also been used as partners in several other reactions such as 1-4 additions of nucleophiles such as pyrrohdine or thiophenol in the presence of EtjN, Heck coupling and chhydroxylation of the obtained cinnamic esters. Methyl esters could be isolated in... 

Mizoroki-Heck couplings of bromo- and chloroarenes were successfully achieved by using the electron-rich benzimidazolylidene palladium complex 2 (Figure 15.1), generated in situ in tetrabutylammonium bromide as solvent [29]. The coupling of 4-chloroacetophenone with butyl acrylate in the presence of 1 mol% 2 yields 93% 4-acetyl-(El-cinnamic ester in 6 h reaction time. Butyl acrylate was also coupled with 2 equiv of bromobenzene leading to the trisubstituted olefin 3,3-diphenylpropenoic acid butyl ester in 91% yield. 

Metal-catalyzed cross-couplings are key transformations for carbon-carbon bond formation. The applicability of continuous-flow systems to this important reaction type has been shown by a Heck reaction carried out in a stainless steel microreactor system (Snyder et al. 2005). A solution of phenyliodide 5 and ethyl acrylate 6 was passed through a solid-phase cartridge reactor loaded with 10% palladium on charcoal (Scheme 2). The process was conducted with a residence time of 30 min at 130°C, giving the desired ethyl cinnamate 7 in 95% isolated yield. The batch process resulted in 100% conversion after 30 min at 140°C using a preconditioned catalyst. 

The Heck reaction is a C-C coupling reaction where an unsaturated hydrocarbon or arene halide/triflate/sulfonate reacts with an alkene in presence of a base and Pd(0) catalyst so as to form a substituted alkene. Kaufmann et al. showed that the Heck reaction carried out in presence of ILs such as tetra-alkyl ammonium and phosphonium salts without the phosphine ligands, resulted in high yields of product. They attributed the activity to the stabilizing effect of ammonium and phosphonium salts on Pd(0) species. Carmichael et al. used ionic liquids containing either A,A -dialkylimidazolium and A-alkylpyridinium cations with anions such as halide, hexafluorophosphate or tetrafiuoroborate to carry out reactions of aryl halide and benzoic anhydride with ethyl and butyl acrylates in presence of Pd catalyst. An example of iodobenzene reacting with ethyl acrylate to give trans-et vy cinnamate is shown in Scheme 14. 

Most recently, the test has been applied to examination of the mechanism of a heterogeneous Heck reaction, promoted by Pd on alumina [25]. In the presence of the solid catalyst, 4-iodobenzamide coupled efficiently with butyl acrylate yielding the cinnamate, and it was suspected that the catalytic agent was a soluble form of palladium released from and then recaptured by the alumina support. To test this, the amide was attached to a commercially available resin with suitable functionality, and the supported amide (15 in Scheme 9.10) was allowed to react with the acrylate and Pd on alumina. The same product, identified after release from the polymer by TFA treatment, was formed, and further experiments were able to narrow down the form of the soluble catalysing palladium species. 

The first palladium catalyzed reaction reported in an ionic liquid, by Kaufmann in 1996, was a Heck reaction.15 A series of aryl bromides were efficiently coupled with n-butyl acrylate in tributylhexadecylphosphonium bromide ([Ci6PBu3]Br) and tetrabutylammonium bromide ([NBu4]Br) to afford the trans-cinnamates in yields of over 90% in some cases (Scheme 1). Product isolation was achieved by distillation from the ionic liquid or by solvent extraction. 

Heck reaction in the presence of the aminoethylimidazolium salt 1 requires no additional base. Using the l,l -bis(di-t-butylphosphino)ferrocene ligand Heck reaction is accomplished at room temperature in water to prepare styrenes and cinnamate esters. The same conditions are conducive to performing Suzuki coupling. ... 

One of the most important transformations catalysed by palladium is the Heck reaction. Oxidative addition of palladium(O) into an unsaturated halide (or tri-flate), followed by reaction with an alkene, leads to overall substitution of a vinylic (or allylic) hydrogen atom with the unsaturated group. For example, formation of cinnamic acid derivatives from aromatic halides and acrylic acid or acrylate esters is possible (1.209). Unsaturated iodides react faster than the corresponding bromides and do not require a phosphine ligand. With an aryl bromide, the ligand tri-o-tolylphosphine is effective (1.210). The addition of a metal halide or tetra-alkylammonium halide can promote the Heck reaction. Acceleration of the coupling can also be achieved in the presence of silver(I) or thallium(I) salts, or by using electron-rich phosphines such as tri-tert-butylphosphine. ... 

Polyurea-encapsulated palladium catalysts promote the phosphine-free Mizoroki-Heck reaction, which results in a high yield of cinnamates 46 (Scheme 86). The catalyst, which is easily recovered by filtration, is also applicable to the Suzuki-Miyaura and Stifle coupling reactions. 

Supported catalysts involving palladium on carbon and dendrimer-encapsulated palladium and a polymer-supported phosphine palladium catalyst have facilitated C-C coupling reactions in SCCO2. Polymer-tethered substrates or amine bases have also been successfully used for the Mizoroki-Heck and Suzuki-Miyaura reactions in SCCO2. For example, REM resin underwent a Mizoroki-Heck reaction with iodobenzene to yield, after cleavage, ( )-methyl cinnamate 48 (74%) (Scheme 88). It is assumed that SCCO2 acts as a good solvent that swells the polymers and exposes reactive sites. 

Frequently, a considerable amount of side products, derived from facile aryl-aryl exchange in the oxidative addition complex, is formed in a Heck reaction executed in the presence of phosphine hgandsJ t This process is particularly significant at higher reaction temperatures and with electron-rich aryl halides. Thus, a reaction of 4-bromoanisole with butyl acrylate with Pd(OAc)2/PPh3 as the catalyst system and sodium acetate furnish butyl E-cinnamate in addition to the expected coupling product (Schente... 

Other examples for which homogeneously catalyzed Heck reactions have been exploited toward an industrial production include the preparation of the fragrance Lihal developed by Givaudan, the synthesis of the nonsteroidal anti-inflammatory drug Nabumeton by Hoechst-Celanese, ° and the synthesis of the sunscreen agent 2-ethylhexyl p-methoxy-cinnamate (EHMC) by Hoechst AG and other companies (Scheme 6). Noteworthy, Nabumeton is obtained in one step via coupling and domino isomerization reaction of 2-bromo-6-methoxynaphthalene with 3-buten-2-ol. ° ... 

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