Heck reaction electron-rich alkene arylation

Representative examples of Heck reactions are depicted in Scheme 8.8. Terminal alkenes react faster than internal alkenes, and the formation of mixtures of products resulting from further arylation or vinylation of the initial product is therefore only observed when a large excess of halide and long reaction times are employed. Electron-poor alkenes usually react more rapidly than electron-rich alkenes, and the new C-C bond is usually formed at the most electron-deficient carbon atom. 

In 1990, Cabri el al. [40a] reported that the precursor Pd(OAc>2 associated with a biden-tate P P ligand as dppp (1,3-bis-diphenylphosphinopropane) appeared to be more efficient than PPhs in Mizoroki-Heck reactions performed from aryl Inflates and enol ethers (electron-rich alkenes) moreover, the regioselectivity in favour of the a-arylated alkenes was improved to 100%. Since that time, dppp associated with Pd(OAc)2 has been used extensively to catalyse Mizoroki-Heck reactions and to investigate the factors that control the regioselectivity [Ig, 40]. The chiral bidentate (7 )-Binap (2,2 -bis(diphenylphosphino)-1,1-binaphthyl) associated with Pd(OAc)2 has also been used by Shibasaki and coworkers [2b,d,41a] and Overman andPoon [41b] in intramolecular enantioselective Mizoroki-Heck reactions (also, see Link [2f] for an authorative review on the Overman-Shibasaki chemistry), as well as by Hayashi and coworkers [2a, 41c,d] to control the regioselectivity and enantioselectivity of intermolecular Mizoroki-Heck reactions performed from cyclic alkenes (see Schemes 1.3 and 1.2 (Z = O) respectively). 

Regioselectivity is one of the major problems of Mizoroki-Heck reactions. It is supposed to be affected by the type of mechanism ionic versus neutral, when the palladium is ligated by bidentate P P ligands. The ligand dppp has been taken as a model for the investigation of the regioselectivity. Cabri and Candiani [Ig] have reported that a mixture of branched and linear products is formed in Pd°(P P)-catalysed Mizoroki-Heck reactions performed from electron-rich alkenes and aryl halides (Scheme 1.26a) or aryl ttiflates in the presence of halide ions (Scheme 1.26b). This was rationalized by the so-called neutral mechanism (Scheme 1.27). The neutral complex ArPdX(P P) is formed in the oxidative addition of Pd°(pAp) yj Qj. Q aj.yj triflates in the presence of halides. The carbopalladation... 

In more recent studies by Xiao and coworkers [40m,n], Mizoroki-Heck reactions catalysed by Pd(OAc)2 associated with dppp and performed from the eleclron-rich alkene ( -butylvinyl ether) and aryl halides (without any halide scavenger, i.e. under the conditions of the textbook neutral mechanism of Scheme 1.27 proposed by Cabri and Candiani [Ig]) give a mixture of branched and linear products in DMF, whereas the branched product is exclusively produced in ionic liquids (in the absence of halide scavengers) in a faster reaction. Whatever the medium, the cationic complex ArPd5(dppp)+ is always the sole reactive complex with electron-rich alkene (Scheme 1.33) [53]. Consequently, the regioselectivity should not vary with the experimental conditions. 

Favoring the jS-regioselectivity of the Heck reaction with electron-rich alkenes is not so simple. In 1988, Andersson and Hallberg observed that the type of halide coordinating to the metal center had a profound influence on the regioselectivity, chloride favoring the formation of the )S-alkene when using vinyl ethers [214,215]. Scheme 4.65 shows the most relevant results in the hterature toward the p-reg-ioselective arylation of vinyl ethers. 

Blaser and Spencer used aroyl halides in place of aryl halides, with aroyl chlorides being of specific interest as ubiquitous, relatively cheap compounds ( Blaser reaction ) [24], This latter reaction is normally conducted in aromatic solvents phosphines are not used here as catalyst ligands since they fully inhibit the reaction. In the same way, benzoic acid anhydrides can be used as the aryl source in combination with PdCl2 and catalytic amounts of NaBr [79]. In this reaction, one of the arenes is used in the coupling reaction by elimination of CO, whereas the other benzoate serves as the base. The benzoic acid thus formed can easily be recycled into the anhydride. The use of aryl and vinyl triflates according to Cacchi [25] and Stille [26] extends the scope of the Heck coupling to carbonyl compounds phenol derivatives act via triflate functionalization as synthetic equivalents of the aryl halides. The arylation of cyclic alkenes [27], electron-rich vinyl ethers [28], and allylic alcohols [29] is accessible through Heck reactions. Allylic alcohols yield C-C-saturated carbonyl compounds (aldehydes) for mechanistic reasons (y9-H elimination), as exemplified in eq. (6). 

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. ... 

In contrast to facile reactions of aryl halides with alkenes and alkynes, reactions of aromatic compounds with aryl halides have received less attention. Only intramolecular arylation of benzene derivatives, except phenols, is known [1]. On the other hand, electron-rich heterocycles such as ffirans, thiophenes, pyrroles, oxa-zoles, imidazoles, and thiazoles undergo facile inter- and intramolecular arylation with aryl halides. These are called heteroaryl Heck reactions [2]. 

Carbopalladation is the reaction of a cr-bonded organopalladium complex I with an unsaturated molecule (such as an alkene 2) to yield the migratory insertion product 3 (Scheme 1). The reaction is tremendously flexible, allowing for a wide variety of structural types for both reactants 1 and 2. The precursors of palladium complexes 1 are commonly alkenyl or aryl halides or triflates (8 and 9, respectively), the reaction of which is more commonly termed the Heck reaction. Allylic systems 10, which react to provide -Tr-allylpalladium complexes, can participate in the reaction as can benzylic precursors 11. Acylpalladium complexes 12 also react and are commonly generated in the same reaction vessel by Pd-catalyzed carbonylation. Their unsaturated reaction partners include alkenes 2, alkynes 4, dienes 6, allenes, and arenes, all of which can be electron rich or poor. Carbopalladation occurs in a syn fashion allowing the installation of stereocenters (2- 3) or control of alkene geometry (4- 5). 

The Mizoroki-Heck reaction is a subtle and complex reaction which involves a great variety of intermediate palladium complexes. The four main steps proposed by Heck (oxidative addition, alkene insertion, )3-hydride elimination and reductive elimination) have been confirmed. However, they involved a considerable number of different Pd(0) and Pd(Il) intermediates whose structure and reactivity depend on the experimental conditions, namely the catalytic precursor (Pd(0) complexes, Pd(OAc)2, palladacycles), the Ugand (mono- or bis-phosphines, carbenes, bulky monophosphines), the additives (hahdes, acetates), the aryl derivatives (ArX, ArOTf), the alkenes (electron-rich versus electron-deficient ones), which may also be ligands for Pd(0) complexes, and at least the base, which can play a... 

Quite recently, the arsenal of methods for aryl chlorides in the Mizoroki-Heck reaction was broadened by using the cheaper complex (Cy3P)2PdCl2 with CS2CO3 as the base in 1,4-dioxane at 120 °C [134]. The reported scope of substrates is broad, involving several nonstandard alkenes and many aryl chlorides electron-rich aryl chlorides, except for 4-chlorotoluene and sterically hindered couphng partners, were excluded in this study. 

In general, the Mizoroki-Heck coupling of aryl halides with both electron-rich and electron-poor terminal alkenes affords monoarylated products. With electron-deficient alkenes under selected reaction conditions, such as with excess of the aryl halide, with special catalysts at high temperatures or under high pressure, a twofold terminal arylation to give 1,1-diarylalkene derivatives may occur (Figure 3.41) [103]. Triple arylations... 

At present, due to extensive research by the groups of Cabri, Hallberg, and Larhed, the a-regioselectivity of the Heck reaction with electron-rich olefins can be controlled. Therefore, the a-arylated alkene is favored by the correct choice of the ligand and the leaving group of aryl substrate. For example, using ... 

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