Tandem Heck/reduction/cyclization

Oxindoles have been considered as useful heterocycles as they display a wide range of biological properties including antiarthritis [26], antitumor [27], and antiviral [28] activities. Recently, Felpin et al. have developed a methodology based on a tandem Heck/reduction/cyclization (HRC) sequence to synthesize a variety of oxindoles from 2-(2-nitrophenyl)acrylates and aryl diazonium salts catalyzed by palladium [29]. The strategy, outlined in Scheme 12,... 

Felpin et al. developed a palladium-catalyzed tandem Heck reaction-reduction-cyclization synthesis of oxindoles (n=0) and dihydroquinolones (n= 1) using different 2-(2-nitrophenyl)aaylates (n=0) or 2-(2-nitrobenzyl)aaylates (n=l) and aryldiazonium salts 36 in good yield [15] (Scheme 6.7). However, a complementary approach was developed by the same group using diazonium salts 40 and substituted acrylates 41 to access a larger substitution pattern on the C3 position (Scheme 6.8). It is noteworthy that a different solvent was required and the charcoal had to be added after the Heck reaction. C3-unsubstituted, arylated, and alkylated dihydroquinolones 42 can be obtained efficiently using this protocol. 

SCHEME 6.7 Tandem Heck reaction/reduction/cyclization. 

SCHEME 6.8 Synthesis of dihydroquinolones by tandem Heck reaction/reduction/ cyclization. 

The synthesis of indoles and benzofiirans by the palladium-catalysed cyclization of o-alkynyl anilines and phenols can also form part of tandem processes through interception of the -intermediate (Scheme 6.41). Inclusion of an alkene results in a Heck process, giving 3-vinylated indoles 6.129." As the 3-hydride elimination step causes reduction of the palladium(II) to palladium(O), an oxidizing agent, such as copper(n) must be included to maintain catalysis. The intermediate may also be intercepted by alkoxycarbonylation, giving an ester 6.130." Again an oxidant is needed. 

Another tandem possibility is to use oxidative addition to generate the palladium(II) species that initiates cyclization (Scheme 6.44). The result is formation of both a C-C bond and a bond between an alkene carbon and a heteroatom. The C-C bond is formed by reductive elimination that generates a palladium(O) species. This is then returned to the palladium(II) state by oxidative addition, hence no added oxidant is required. The reaction has often been used in an intramolecular fashion to ensure regioselectivity. If the nucleophilic attack is slow, a by-product may occur, which is the Heck product arising from alkene insertion. Alkynes may also be used as substrates. 

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