Oxidative cyclization tandem nucleophilic

An intramolecular palladium-catalyzed tandem cyclization of dienamides 67 in which the amide nucleophile adds twice has been developed (equation 29)60. This reaction constitutes a formal [4+1] cycloaddition and provides a new route to pyrrolizidine and indolizidine alkaloids. Reaction of dienamides 67 in the presence of catalytic amounts of Pd(OAc)2 and CUCI2/O2 as the oxidant afforded bicyclic compounds 68 in good yields. The pyrrolizidine derivative 68 (R = Me, n = 1) was transformed to the alkaloid ( )-heliotridane. 

A further variation of these functionalizations of cyanoarenes is the NOCAS process [14, 15]. As shown in Scheme 14.2, path g, this involves the addition of a nucleophile (which is often the solvent) to the donor radical cation. The thus-formed neutral radical adds to the acceptor radical anion, while rearomatization by the loss of an anion leads again to an overall ipso-substitution. AUenes could be used as the donors in these reactions, as shown recently by Arnold [50]. Accordingly, the irradiation of TCB in the presence of tetramethylaUene (15) in a 3 1 MeCN/MeOH mixture afforded 1 1 1 arene-allene-methanol adduct 16 in 48% yield (Scheme 14.9, central part). Interestingly, the addition of methanol took place exclusively at the central allene carbon, while aromatic substitution occurred through the terminal carbons. co-Alkenols, in which an O-nucleophile and an easily oxidized moiety are both present, could also be used. In the latter case, the initial ET was followed by a cyclization, yielding aryl-substituted tetra-hydrofurans or tetrahydropyrans as the final products via a tandem Ar—C, C—O bond formation [51]. 

A further extension of the Pd-catalyzed intramolecular 1,4-oxidation was the use of amide, whose amino functionality had the ability of making a twofold nucleophilic attack. The use of nitrogen as nucleophile led to pyrrolizidine and indolizidine derivatives. This strategy was applied for the synthesis of another alkaloid, ( )-heliotridanef (Scheme 36). Pd-catalyzed reaction of dieneamide, obtained from the known ester 167, in THF employing CUCI2/O2 as the oxidant afforded the azabicyclic product 168 in 85% yield. The mechanism of this tandem cyclization involved a TT-allylpalladium... 

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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