Catalytic bond formation Heck reaction

Carbon-carbon bond formation reactions and the CH activation of methane are another example where NHC complexes have been used successfully in catalytic applications. Palladium-catalysed reactions include Heck-type reactions, especially the Mizoroki-Heck reaction itself [171-175], and various cross-coupling reactions [176-182]. They have also been found useful for related reactions like the Sonogashira coupling [183-185] or the Buchwald-Hartwig amination [186-189]. The reactions are similar concerning the first step of the catalytic cycle, the oxidative addition of aryl halides to palladium(O) species. This is facilitated by electron-donating substituents and therefore the development of highly active catalysts has focussed on NHC complexes. 

The Heck reaction has proven to be an extremely useful method for the formation of C-C bond at a vinyl carbon centre. There are numerous reported examples of enantioselctive Pd catalyzed C-C bond forming reactions.10"13 Surprisingly, reports of Heck transformations using amino acid based phosphine, phosphinite ligands are rare. Recently Gilbertson reported a proline derived phosphine-oxozoline ligand in a catalytic asymmetric Heck reaction.5 In this paper we present some novel amino acids derived ligands as part of a catalytic system for use in asymmetric Heck reactions. 

Reaction of organic halides with alkenes catalyzed by palladium compounds (Heck-type reaction) is known to be a useful method for carbon-carbon bond formation at unsubstituted vinyl positions. The first report on the application of microwave methodology to this type of reaction was published by Hallberg et al. in 1996 [86], Recently, the palladium catalyzed Heck coupling reaction induced by microwave irradiation was reported under solventless liquid-liquid phase-transfer catalytic conditions in the presence of potassium carbonate and a small amount of [Pd(PPh3)2Cl2]-TBAB as a catalyst [87]. The arylation of alkenes with aryl iodides proceeded smoothly to afford exclusively trans product in high yields (86-93%) (Eq. 61). 

The formation of carbon-carbon bonds by palladium-promoted reactions has been widely used in organic synthesis [114-116]. A major advantage is that most of these coupling reactions can be performed with catalytic amounts of palladium. Palladium(II)-catalyzed reactions, e.g., the Wacker process, are distinguished from palladium(O)-catalyzed reactions, e.g., the Heck reaction, since they require oxidative regeneration of the catalytically active palladium(II) species in a separate step [117]. Several groups have applied palladium-mediated and -catalyzed coupling reactions to the construction of the carbazole framework. 

If the initial organopalladium complex is formed in the presence of an alkene, transfer of the organyl group to the alkene can occur (Heck reaction, Scheme 8.7) [5, 78], Electron-deficient and electron-rich alkenes and even some arenes [79] can be used. In the last step of this process a Pd-hydrido complex is formed by /3-hydride elimination, leading to the formation of the C-C double bond. In the presence of bases the hydrido complex eliminates HX, regenerating the catalytically active Pd(0) complex (Scheme 8.7). 

The reaction sequence in the vinylation of aromatic halides and vinyl halides, i.e. the Heck reaction, is oxidative addition of the alkyl halide to a zerovalent palladium complex, then insertion of an alkene and completed by /3-hydride elimination and HX elimination. Initially though, C-H activation of a C-H alkene bond had also been taken into consideration. Although the Heck reaction reduces the formation of salt by-products by half compared with cross-coupling reactions, salts are still formed in stoichiometric amounts. Further reduction of salt production by a proper choice of aryl precursors has been reported (Chapter III.2.1) [1]. In these examples aromatic carboxylic anhydrides were used instead of halides and the co-produced acid can be recycled and one molecule of carbon monoxide is sacrificed. Catalytic activation of aromatic C-H bonds and subsequent insertion of alkenes leads to new C-C bond formation without production of halide salt byproducts, as shown in Scheme 1. When the hydroarylation reaction is performed with alkynes one obtains arylalkenes, the products of the Heck reaction, which now are synthesized without the co-production of salts. No reoxidation of the metal is required, because palladium(II) is regenerated. 

A general catalytic cycle proposed for Heck reaction is shown in Fig. 7.17. While all the steps in the catalytic cycle have precedents, the proposed reaction mechanism lacks direct evidence. The basic assumption is that under the reaction conditions, the precatalyst is converted to 7.64, a coordinatively unsaturated species with palladium in the zero oxidation state. Oxidative addition of ArX, followed by alkene coordination, leads to the formation of 7.65 and 7.66, respectively. Alkene insertion into the Pd-C bond followed by /3-H abstraction gives 7.67 and 7.68, respectively. Reductive elimination of HX, facilitated by the presence of base B, regenerates 7.64 and completes the catalytic cycle. The C-C coupled product is formed in the 7.67 to 7.68 conversion step. 

Another catalytic methodology that is widely used for C-C bond formation is the Heck and related coupling reactions [86, 87]. The Heck reaction [88] involves the palladium-catalysed arylation of olefinic double bonds (Fig. 1.31) and provides an alternative to Friedel-Crafts alkylations or acylations for attaching carbon fragments to aromatic rings. The reaction has broad scope and is currently being widely applied in the pharmaceutical and fine chemical industries. For example, Albemarle has developed a new process for the synthesis of the anti-in-... 

In a similar approach, naproxen is prepared from an olefin, the product of a Heck reaction (see Section 5.3.2.1). As described above, the reaction proceeds in the presence of water and HC1, additionally copper(n)chloride is added, possibly to prevent the formation of palladium black (Scheme 5.39). Addition of HC1 to the double bond and subsequent oxidative addition reaction of the benzylic chloride with the active Pd° species initiates the catalytic cycle, which proceeds similarly to the ibuprofen synthesis [70-73]. 

The Murai reaction (Scheme 4), the replacement of an ortho-CH on an aromatic ketone by an alkyl group derived from a substrate olefin, is catalyzed by a variety of Ru complexes. This C bond formation occurs via chelate directed C-H bond activation (cyclometalation) in the first step, followed by alkene insertion into RuH and reductive elimination of the alkylated ketone. In a recent example of the use of a related cyclometalation in complex organic synthesis, Samos reports catalytic arylation (Suzuki reaction) and alkenylation (Heck reaction) of alkyl segments of a synthetic intermediate mediated by Pd(II). 

The basic mechanism of the Heck reaction (as shown below) of aryl or alkenyl halides or triflates involves initial oxidative addition of a pal-ladium(O) species to afford a a-arylpalladium(II) complex III. The order of reactivity for the oxidative addition step is I > OTf > Br > Cl. Coordination of an alkene IV and subsequent carbon-carbon bond formation by syn addition provide a a-alkylpalladium(II) intermediate VI, which readily undergoes 3-hydride elimination to release the product VIII. A base is required for conversion of the hydridopalla-dium(II) complex IX to the active palladium(O) catalyst I to complete the catalytic cycle. 

Related to the Heck reaction is the Larock annulation of internal alkynes, which is a general route to heterocyclic and carbocyclic systems. Especially attractive is the construction of the pharmaceutically important indole ring system via palladium-catalyzed coupling of 2-iodo-aniline and the corresponding V-methyl, acetyl, and tosyl derivatives with a wide variety of internal alkynes. The catalytic process appears to involve arylpalladium formation, regioselective addition to the carbon-carbon triple bond, and subsequent intramolecular palladium displacement.- ... 

The term Heck reaction summarizes catalytic C-C-coupling processes, such that a vinylic hydrogen is replaced by a vinyl, aryl, or benzyl group, with the latter being introduced from a halide or related precursor compound (cf. eq. (3)) [9 a, 14-16]. Therefore, the final step of product formation is the elimination of a hydrogen halide, and a base is thus required to bind the acid. The olefinic (vinylic) double bond is retained throughout the Heck reaction. Palladium is practically the only catalyst metal used, in the form of certain Pd and Pd" salts or complexes normally 1-5 mol % of catalyst is administered. 

The Mizoroki-Heck reaction, a palladium-catalyzed coupling of olefins with aryl or vinyl halides/triflates, is a powerful method for carbon-carbon bond formation. " " High efficiency is usually obtained only by starting from expensive aryl iodide (or bromide) or by using a fairly large amount of catalyst. Improvement of the catalytic activity as well as recovery and recycling of the catalyst is needed. 

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