Ni-catalyzed enantioselective [2 + 2 + 2] cycloaddition of malononitriles with alkynes

•Enantiotopic differentiation of dinitrile to all-carbon quaternary centers•Atom economic synthesis enantioenriched densely substituted pyridines•Zinc-promoted hetero-cyclometallation nickel with alkyne and nitrile•Broad scope, good enantioselectivity, excellent regioselectivity Pyridines are among the most significant heterocycles not only prevalently found in pharmaceuticals, natural products, materials, but also widely applied as ligands or catalysts organic synthesis. State-of-the-art methods access functionalized pyridines rather limited due great challenges selectively install devise substitution patterns. In this article, we report a zinc-promoted nickel-catalyzed enantioselective [2 + 2 2] cycloaddition alkynes alkyne-tethered malononitriles for construction from chemical feedstocks. The nitrile-containing stereocenter is efficiently introduced by desymmetrization yield, regioselectivity, enantioselectivity. We believe that established strategy its underlying mechanism will provide new opportunities asymmetric catalysis find applications broad research fields. Efficient strategies assemble pyridine derivatives highly important, given their significance both synthetic medicinal chemistry. Here, an intermolecular pyridines. ?-all-carbon center adjacent desymmetrizing two cyano groups disubstituted malononitriles. Notably, terminal tolerated afford tetrasubstituted Zinc halide essential enable occurrence transformation promoting step. reaction uses bio-renewable 2-MeTHF solvent features mild conditions, functional group compatibilities, enantioselectivities. This study offers straightforward approach valuable heteroarenes feedstock chemicals forming three bonds one simultaneously single incorporation stereogenic centers enhance three-dimensional complexity privileged molecules importance drug discovery.1Lovering F. Bikker J. Humblet C. 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Bisphosphine biaryl backbone showed moderate reactivity selectivity general (Table S1). For instance, BINAP (L1) TolBINAP (L2) delivered desired product 2a (75:25 er, entries 2), XylBINAP (L3) resulted increased (83:17, entry 3). screening solvents, delighted better yield (entries 3–5 Table S2), probably weak coordination ability metals high solubility zinc halides.62Aycock D.F. Solvent organometallic biphasic reactions.Org. Process Dev. 11: 156-159Crossref 4 Å molecular sieves (MS) slightly improved (entry 6 S3). Lowering temperature diminished enhanced obtained at higher concentration 3 equivalents 7 S4). Our further additives led balance (97:3 er) equivalent ZnBr2 8 S5). substantial (vide infra) virtually no observed experiment without presence 9). rhodium/BINAP catalyst,39Tanaka With optimal established, turned attention elucidate scope 2). Substituents tethered 2A). Substrates electron-donating substituents, including 4-methyl (2b), 4-methoxy (2c), 3-methoxy (2j), corresponding 53%–79% yields 95:5–97:3 er. electron-withdrawing (2d–2h, 2k–2m) (67%–90%) lower (92:8–95:5). It notable groups, aldehyde, ketone, ester, compatible reaction. Importantly, 2-thienyl afforded (2i) er), yield. 2-naphthyl-substituted substrate tested, resulting 75% 95:5 (2n). Next, range (R2) attached ?-prochiral 2B). electronic nature moiety, methyl (2o, 2p), methoxy (2q), trifluoromethyl (2r), acceptable (70%–75%) 1-naphthyl 2s 69% Remarkably, heterocycle-containing malononitriles, 2-furyl (2t), (2u), 3-indolyl (2v), all tolerated, giving 61%–76% 93.5:6.5–94:6 noted decreases smaller size R2 substituents. cyclohexylmethyl (2w) 97:3 methyl-substituted (2x) 86:14 allyl out, leading 76% decreased (2y). array alkynes, internal terminal, partner investigated 2C). Besides 2-butyne Scheme 2A, other aliphatic 3-hexyne, 4-octyne, 5-decyne, 2z–2ab (54%–57%) enantioselectivities (95:5 er). When diaryl acetylenes employed, (63%–73%) (92:8–94:6 (2ac–2ae). absolute configuration enantiopure 2ac (>99.5:0.5 determined X-ray analysis. unsymmetrical 1-phenyl-1-propyne, 3.4:1 91:9 major isomer 2af. accessed substrates. 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(e.g., cyclopropyl, 2aw; methyl, 2ax) compatible, providing Specific limitations chemistry terms unsuccessful tried S2. No occurred propynyl chloride, amine, benzoate. Ethynyl borate proven unreactive. tether has profound influence reactivity, either lo