Indolizines, metal catalyzed

Two different research groups independently reported metal-catalyzed cycloisomerizations of alkynyl-substituted pyridines leading to indolizines. Specifically, treatment of pyridine 7 with silver tetrafluoroborate gave indolizine 8 in excellent yield <07OL3433>. This reaction could also be mediated by copper(I) iodide <07JOC7783>. 

Until very recently, no examples of a transition metal-catalyzed cycloisomerization of allenylpyridines into indolizines had been reported. A well-known instability of these seemingly versatile precursors prevented any significant use in the construction of the indolizine nucleus. The only precedent of this transformation was documented by Gevorgyan and coworkers. Thus, 1,3-disubstituted alkyl- and aryl-indohzines 316 were synthesized via the Cu(I)-catalyzed 5-endo-trigcydLzaiion of the corresponding disubstituted allenylpyridines 315, whereas the cycloisomerization of gem-disubstituted allene failed to produce the expected monosubstituted indolizine (Scheme 9.109) [290]. 

Aiming for the development of transition metal-catalyzed protocols, which would allow a regioselective synthesis of C2-substituted indolizine cores, Gevorgyan reported a highly efficient Au(III)-catalyzed cascade cycloisomerization of skipped propargylpyridines 346 into indolizines 347 (Scheme 9.119) [299,300]. This cascade transformation involved a facile 1,2-migration of silyl-, stannyl-, and even germyl... 

A regiodivergent transition metal-catalyzed synthesis of differently substituted indolizines vas recently elaborated on by Gevorgyan and co vorkers. Thus, pyridyl-substituted cyclopropenes 356 vere smoothly cycloisomerized in the presence of... 

Base-catalyzed d exchange of (20) with NaOD in MeOD took place only at the 5-position <87KGS1285>. Regioselective metallation of 2-phenylindolizine occurred at C(5). Subsequent reaction with electrophiles led to 5-substituted indolizines (21) in 90-96% yields <92TL4433>. 

The same group demonstrated that a variety of mono- and disubstituted 1-oxyindolizine derivatives 3S2 could be readily synthesized via a facile Ag-catalyzed cydoisomerization of skipped propargylpyridines 3S1 (Scheme 9.121) [300, 301]. It was suggested that this Au-catalyzed reaction involved a 5 -endo-d cyclization of the alkyne 351 activated by a jt-philic metal. Formation of the indolizine product 352 was accomplished via a subsequent proton transfer in cyclic vinylmetal zwitterion 354 (Scheme 9.122). It should be noted that a variety of transition metals, such as Au(I), Au(III), Cu(I), Pt(II), and Pd(II), were shown to catalyze this transformation with variable degrees of efficiency. 

A highly related method showed that pyrrole ring formation from 50 to produce indolizines 52 is promoted efficiently by various transition-metal catalysts, such as platinum(II) [17], indium(lll) [17], copper(I) [18,19], gold(I) [18], and silver(I) [18] (Scheme 19.11). It should be noted that these reactions were reported independently by the three research groups at nearly the same time [17-19]. The palladium-catalyzed two-component reaction of alkynylpyridines 53 with aryl halides is a convenient strategy for the synthesis of highly substituted fused pyrroles 55 [20]. 

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