Transition metal-catalyzed synthesis and direct functionalization of N-fused heterocycles

An exceptionally mild, practical, and efficient method for synthesis of N-fused heterocycles via the transition metal-catalyzed cycloisomerization of heterocyles possessing a propagyl group has been developed. It has been demonstrated that 1-monosubstituted and 1,3-disubstituted indolizines, pyrroloquinoxalines, and pyrrolothiazoles can be synthesized from readily available precursors in good to excellent yields.;An approach to 1,2-disubstituted N-fused heterocycles through the Au-catalyzed cascade migration/cycloisomerization of heterocycles possessing a non-conjugated propargylic moiety has been developed. The key step of this transformation is the alkyne-vinylidene isomerization with concomitant 1,2-migration of silyl-, stannyl-, and germyl groups. This mild and simple method allows for selective and highly efficient synthesis of indolizines, pyrroloisoquinolines, pyrroloquinoxalines, pyrrolo-pyrazines, and pyrrolothiazoles, not available via existing cycloisomerization methodologies.;An efficient and regioselective protocol for the direct C-H arylation of indolizines has been developed. It has been demonstrated that a variety of substituents at both the indolizine and the aryl halide are tolerated. This approach provides rapid access to C-3 substituted indolizines in good to very high yields. For the first time, a systematic studies on the mechanism of a direct Pd-catalyzed arylation of heterocycles has been performed. Electrophilic substitution mechanism has been proposed for arylation of indolizines, which was strongly supported by a combination of experimental and computational data.;A new method for the direct palladium-catalyzed C-H alkynylation of electron-rich heterocycles has been developed. Generality of the protocol has been demonstrated by the employment of various N-fused heterocycles, including indolizine, pyrroloquinoline, pyrroloisoquinoline, pyrrolooxazole, and bis-pyrrolopyrimidine. This conceptually new method for sp2-sp carbon-carbon bond-formation in heterocycles was proposed to proceed via electrophilic substitution motif.