Recent Developments in Transition-Metal Catalyzed Direct C–H Alkenylation, Alkylation, and Alkynylation of Azoles

Abstract

The transition metal-catalyzed C–H bond functionalization of azoles has emerged as one of the most important strategies to decorate these biologically important scaffolds. Despite significant progress in the C–H functionalization of various heteroarenes, the regioselective alkylation and alkenylation of azoles are still arduous transformations in many cases. This review covers recent advances in the direct C–H alkenylation, alkylation and alkynylation of azoles utilizing transition metal-catalysis. Moreover, the limitations of different strategies, chemoselectivity and regioselectivity issues will be discussed in this review.

Lewis acid mediated, mild C–H aminoalkylation of azoles via three component coupling

“…Overall, this manuscript outlines a new strategy to diversify azoles via Lewis-acid mediated C–H functionalization under much milder conditions than those typically employed with transition metal catalysts. 3–5 Moreover, the protocol employs both acidic and basic components, which is another distinguishing feature from more common, base-promoted azole C–H functionalization approaches. 17 Importantly, this leads to broad functional group tolerance, which is typically inaccessible through other direct azole functionalizations approaches proceeding through catalytic or stoichiometric metalation.…”

“… 17 Importantly, this leads to broad functional group tolerance, which is typically inaccessible through other direct azole functionalizations approaches proceeding through catalytic or stoichiometric metalation. 3–6 …”

“…In fact, most azole C–H alkylation methods are promoted by transition metals and require forcing conditions, such as high temperatures, stoichiometric amounts of strong bases, and high catalyst loadings. 3–5 Although various metal-free azole C–H alkylations are reported in the literature, 2 b ,3,6 no examples of direct C–H aminoalkylations of azoles under mild reaction conditions have been described.…”

Unactivated Alkyl Halides in Transition-Metal-Catalyzed C–H Bond Alkylation

“…Azoles are essential structural motifs found in a wide range of molecules with diverse applications in pharmaceuticals and natural products. Regioselective C–H functionalization of azoles leading to arylation, alkenylation, benzylation, and alkylation has been well documented . Various precious and less expensive transition metal catalysts have been used to realize these transformations.…”

Nickel‐Catalyzed C−H Bond Functionalization of Azoles and Indoles

“…However, the poor selectivity, low functional group tolerability and low atom economy are the major concerns with the traditional approaches. Transition‐metal‐catalyzed direct C−H bond functionalization of azoles has proven beneficial to access bioactive azoles more selectively with high atom economy and with diminished waste formation [3d,6e] . Since last one‐decade substantial progress has been achieved in the regioselective C−H functionalization of azoles by the employing diverse transition metal catalysts.…”