Nickel-Catalyzed Site- and Stereoselective Reductive Alkylalkynylation of Alkynes

Abstract

Development of a catalytic multicomponent reaction by orthogonal activation of readily available substrates for the streamlined difunctionalization of alkynes is a compelling objective in organic chemistry. Alkyne carboalkynylation, in particular, offers a direct entry to valuable 1,3-enynes with different substitution patterns. Here, we show that the synthesis of stereodefined 1,3-enynes featuring a trisubstituted olefin is achieved by merging alkynes, alkynyl bromides and redox-active <i>N</i>-(acyloxy)phthalimides through nickel-catalyzed reductive alkylalkynylation. Products are generated in up to 89% yield as single regio- and <i>E</i> isomers. Transformations are tolerant of diverse functional groups and the resulting 1,3-enynes are amenable to further elaboration to synthetically useful building blocks. With olefin-tethered <i>N</i>-(acyloxy)phthalimides, a cascade radical addition/cyclization/alkynylation process can be implemented to obtain 1,5-enynes. The present study underscores the crucial role of redox-active esters as superior alkyl group donors compared to haloalkanes in reductive alkyne dicarbofunctionalizations.

Nickel-Catalyzed Reductive Cross-Couplings: New Opportunities for Carbon–Carbon Bond Formations through Photochemistry and Electrochemistry

“…166 The strategy of reductive cascade activation modes was also successfully expanded to reactions with alkynes, alkynyl bromides, and NHPI esters by Koh and coworkers. 167 In this case, the cascade sequence furnished the corresponding 1,3-enynes in moderate to good yields with good to excellent E/Z ratio, which presumably originated from the alkylnickelation intermediate (eq 2). 167…”

“…167 In this case, the cascade sequence furnished the corresponding 1,3-enynes in moderate to good yields with good to excellent E/Z ratio, which presumably originated from the alkylnickelation intermediate (eq 2). 167…”

Ligand-controlled stereodivergent alkenylation of alkynes to access functionalized trans- and cis-1,3-dienes

“…The highly stereoselective metalation step ensures the selective construction of syn-addition products, with a few exceptions of anti-selective examples that proceed via substrate-driving E/Z isomerization of alkenyl nickel species [27][28][29][30][31][32][33][34] . Recently, radical-involved catalytic 1,2-difunctionalization of alkynes has been disclosed to furnish trisubstituted alkenes with complementary anti-selectivity [35][36][37][38][39][40][41][42] . Particularly, utilizing dual nickel/ photoredox catalysis [43][44][45][46][47] has further exploited a number of selective difunctionalization of alkynes with diverse coupling partners under mild conditions [48][49][50][51][52][53][54][55][56] .…”

Ni-Catalyzed Reductive Arylalkenylation of Alkynes for the Selective Synthesis of Polysubstituted Naphthalenes

“…Recently, a sharper focus has been placed on the difficulty of reactivity and regioselectivity with untethered electrophiles (Scheme 1C). 6 In this context, Koh, 7 Shu, 8 and Chu 9 recently reported a nickel-catalyzed reductive difunctionalization of alkynes with two-carbon electrophiles. Despite the impressive progress in the work described above, the reductive difunctionalization of alkynes remains underexploited.…”