Construction of C(sp2)-C(sp3) bonds is relatively difficult in comparison to C(sp2)-C(sp2) bonds. Recently, photoredox catalytic and other photochemical methodologies, together with technological achievements expanded the scope of C(sp2)-C(sp3) bond constructions. In particular, the Minisci reaction allows the introduction of an alkyl group to nitrogen heterocycles without the need for prefunctionalization. Traditional procedures require harsh reaction conditions and often provide low yields, however, photoredox Minisci reactions can be performed under mild conditions with good selectivity and improved yields. Alcázar et al. developed a continuous flow procedure for the synthesis of organozinc reagents, which were then employed in the Negishi reaction. The same group showed that the efficiency of nickel- and palladium-catalyzed Negishi reactions can be enhanced by irradiation with blue light. Herein, we show how the stepwise combination of the flow Negishi reaction, photochemical benzylic bromination and photoredox Minisci reaction allows access to mono-, di, and trisubstituted 5-membered ring heteroarenes (e.g. thiazoles, pyrazoles) in a highly modular manner. These compounds typically feature multiple C(sp2)-C(sp3) connection points and display high fsp3 character.

Diversity oriented synthesis of highly substituted heteroarenes using photochemistry and flow technology

2019 Fall National Meeting

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