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

•Enantiotopic differentiation of dinitrile to all-carbon quaternary centers•Atom economic synthesis of enantioenriched densely substituted pyridines•Zinc-promoted hetero-cyclometallation of nickel with alkyne and nitrile•Broad scope, good enantioselectivity, and excellent regioselectivity Pyridines are among the most significant heterocycles not only prevalently found in pharmaceuticals, natural products, and materials, but also widely applied as ligands or catalysts in organic synthesis. State-of-the-art methods to access enantioenriched and densely functionalized pyridines are rather limited due to great challenges to selectively install devise substitution patterns. In this article, we report a zinc-promoted nickel-catalyzed enantioselective [2 + 2 + 2] cycloaddition of alkynes with alkyne-tethered malononitriles for the construction of densely substituted pyridines from chemical feedstocks. The nitrile-containing all-carbon quaternary stereocenter is efficiently introduced by desymmetrization of dinitrile in good yield, regioselectivity, and enantioselectivity. We believe that the established strategy and its underlying mechanism will provide new opportunities in asymmetric catalysis and organic synthesis and find applications in broad research fields. Efficient strategies to assemble enantioenriched pyridine derivatives are highly important, given their significance in both synthetic and medicinal chemistry. Here, we report an enantioselective nickel-catalyzed intermolecular [2 + 2 + 2] cycloaddition of alkyne-tethered malononitriles with alkynes for the synthesis of densely substituted pyridines. The α-all-carbon quaternary center adjacent to pyridine is introduced by desymmetrizing the two cyano groups of disubstituted malononitriles. Notably, terminal alkynes are also tolerated with good regioselectivity to afford tetrasubstituted pyridines. Zinc halide is essential to enable the occurrence of the transformation by promoting the hetero-cyclometallation step. The reaction uses bio-renewable 2-MeTHF as the solvent and features mild reaction conditions, good functional group compatibilities, and enantioselectivities. This study offers a straightforward approach to the valuable enantioenriched heteroarenes from feedstock chemicals by forming three bonds and one quaternary stereocenter simultaneously in a single reaction step. Efficient strategies to assemble enantioenriched pyridine derivatives are highly important, given their significance in both synthetic and medicinal chemistry. Here, we report an enantioselective nickel-catalyzed intermolecular [2 + 2 + 2] cycloaddition of alkyne-tethered malononitriles with alkynes for the synthesis of densely substituted pyridines. The α-all-carbon quaternary center adjacent to pyridine is introduced by desymmetrizing the two cyano groups of disubstituted malononitriles. Notably, terminal alkynes are also tolerated with good regioselectivity to afford tetrasubstituted pyridines. Zinc halide is essential to enable the occurrence of the transformation by promoting the hetero-cyclometallation step. The reaction uses bio-renewable 2-MeTHF as the solvent and features mild reaction conditions, good functional group compatibilities, and enantioselectivities. This study offers a straightforward approach to the valuable enantioenriched heteroarenes from feedstock chemicals by forming three bonds and one quaternary stereocenter simultaneously in a single reaction step. The incorporation of stereogenic centers to enhance the three-dimensional complexity of privileged molecules is of great importance in drug discovery.1Lovering F. Bikker J. Humblet C. Escape from flatland: increasing saturation as an approach to improving clinical success.J. Med. Chem. 2009; 52: 6752-6756Crossref PubMed Scopus (1807) Google Scholar,2Liu Y. Han S.J. Liu W.B. Stoltz B.M. 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Investigations of the reaction conditions were carried out using 2-benzyl-2-phenylbutynyl-malononitrile 1a and 6-dodecyne as the model substrates, as highlighted in Figure 1 (see Tables S1–S5 for details). Previous remarkable observations by Liu et al. revealed that the addition of Lewis acids could promote the cycloaddition of nitriles with alkynes.60You X. Xie X. Wang G. Xiong M. Sun R. Chen H. et al.Nickel-catalyzed [2+2+2] cycloaddition of alkyne-nitriles with alkynes assisted by Lewis acids: efficient synthesis of fused pyridines.Chem. Eur. J. 2016; 22: 16765-16769Crossref PubMed Scopus (20) Google Scholar,61Wang G. You X. Gan Y. Liu Y. Synthesis of δ- and α-carbolines via nickel-catalyzed [2+2+2] cycloaddition of functionalized alkyne-nitriles with alkynes.Org. Lett. 2017; 19: 110-113Crossref PubMed Scopus (50) Google Scholar Inspired by this, we first examined the effect of ligands using ZnCl2 as an additive. Bisphosphine ligands with a biaryl backbone showed moderate reactivity and selectivity in general (Table S1). For instance, BINAP (L1) and TolBINAP (L2) delivered the desired product 2a with moderate enantioselectivity (75:25 er, entries 1 and 2), while XylBINAP (L3) resulted in an increased er (83:17, entry 3). By screening solvents, we were delighted to find that the reaction in bio-renewable 2-MeTHF provided a better yield and enantioselectivity (entries 3–5 and Table S2), which is probably due to its weak coordination ability to transition metals and high solubility of zinc halides.62Aycock D.F. Solvent applications of 2-methyltetrahydrofuran in organometallic and biphasic reactions.Org. Process Res. Dev. 2007; 11: 156-159Crossref Scopus (325) Google Scholar The addition of 4 Å molecular sieves (MS) slightly improved the yield and er (entry 6 and Table S3). Lowering the temperature diminished the yield but enhanced the enantioselectivity, and an increased yield was obtained at a higher concentration of 1a with 3 equivalents of 6-dodecyne (entry 7 and Table S4). Our further evaluation of the additives led to a better balance of yield and enantioselectivity (97:3 er) by using 1 equivalent of ZnBr2 (entry 8 and Table S5). The zinc halide plays a substantial role in this cycloaddition process (vide infra) and virtually no desired product was observed in the control experiment without its presence (entry 9). We also conducted the reaction using a rhodium/BINAP catalyst,39Tanaka K. Suzuki N. Nishida G. Cationic rhodium(I)/modified-BINAP catalyzed [2+2+2] cycloaddition of alkynes with nitriles.Eur. J. Org. Chem. 2006; 2006: 3917-3922Crossref Scopus (125) Google Scholar but resulted in no product formation (Scheme S1). With optimal reaction conditions established, we turned our attention to elucidate the scope of the substrates (Scheme 2). Substituents on the aryl group of the tethered alkyne moiety were first examined (Scheme 2A). Substrates with electron-donating substituents, including 4-methyl (2b), 4-methoxy (2c), and 3-methoxy (2j), delivered the corresponding products in 53%–79% yields with 95:5–97:3 er. Substrates bearing halides and electron-withdrawing groups generally provided the desired pyridines (2d–2h, 2k–2m) in increased yields (67%–90%) with a slightly lower er (92:8–95:5). It is notable that valuable functional groups, including aldehyde, ketone, and ester, were compatible with the cycloaddition reaction. Importantly, 2-thienyl alkyne-tethered malononitrile afforded the corresponding pyridine (2i) with good enantioselectivity (97:3 er), albeit in moderate yield. A 2-naphthyl-substituted substrate was also tested, resulting in 75% yield with 95:5 er (2n). Next, malononitriles with a range of substituents (R2) attached to the α-prochiral center were explored (Scheme 2B). Substituents with varying electronic nature on the benzylic moiety, such as methyl (2o, 2p), methoxy (2q), and trifluoromethyl (2r), delivered acceptable yields (70%–75%) and good enantioselectivities. The reactions of a substrate with 1-naphthyl group led to product 2s in 69% yield with 95:5 er. Remarkably, heterocycle-containing malononitriles, for instance, 2-furyl (2t), 2-thienyl (2u), and 3-indolyl (2v), are all well tolerated, giving 61%–76% yields and 93.5:6.5–94:6 er. It is noted that the enantioselectivity decreases with a smaller size of R2 substituents. For instance, the reaction with cyclohexylmethyl substrate (2w) resulted in 97:3 er, while methyl-substituted substrate (2x) provided only 86:14 er. The reaction with an allyl substituted substrate was also carried out, leading to 76% yield and decreased enantioselectivity (2y). An array of alkynes, including internal and terminal, as a cycloaddition partner were also investigated (Scheme 2C). Besides the 6-dodecyne and 2-butyne demonstrated in Scheme 2A, the cycloaddition of 1a with other aliphatic alkynes, including 3-hexyne, 4-octyne, and 5-decyne, delivered the corresponding pyridines 2z–2ab in moderate yields (54%–57%) with good enantioselectivities (95:5 er). When diaryl acetylenes were employed, slightly increased yields (63%–73%) but diminished enantioselectivities (92:8–94:6 er) were obtained (2ac–2ae). The absolute configuration of the enantiopure product 2ac (>99.5:0.5 er) was determined by X-ray analysis. With unsymmetrical 1-phenyl-1-propyne, the reaction resulted in 3.4:1 of regioselectivity and 91:9 er for the major isomer 2af. Remarkably, tetrasubstituted pyridines were also accessed by employing terminal alkynes as the substrates. Alkyl and aryl-substituted terminal alkynes were converted into the corresponding 2,3,4,5-tetrasubstituted pyridines (2ag–2aj) with good enantioselectivities (95:5–96:4) and perfect regioselectivities (>20:1 for all except 2aj). Moreover, ethynylcyclopropane, enyne, trimethylsilylacetylene, and nitrile- and benzyloxy-containing acetylenes were subjected to the transformation to form pyridines 2ak–2ap in good yields, enantioselectivities, and regioselectivities. The regioselectivities using terminal alkynes are consistent with previous observations in the non-enantioselective nickel-catalyzed cycloadditions.61Wang G. You X. Gan Y. Liu Y. Synthesis of δ- and α-carbolines via nickel-catalyzed [2+2+2] cycloaddition of functionalized alkyne-nitriles with alkynes.Org. Lett. 2017; 19: 110-113Crossref PubMed Scopus (50) Google Scholar Additional examples demonstrated the compatibility of chloro- and bromo-substituted aryl groups (2aq and 2ar), and heteroaryl (2as and 2at) on the pendent alkyne of malononitriles. Our preliminary bioactivity assay showed that pyridines 2d and 2ap were able to inhibit glucagon activity in cultured primary hepatocytes.63For an example of using substituted pyridines for inhibition of the glucagon receptor, see: Schmidt, G., Angerbauer, R., Brandes, A., Muller-Gliemann, M., Bischoff, H., Schmidt, D., Wohfeil, S., Schoen, W.R., Ladouceur, G.H., Cook, J.H.II, et al. (1996). Substituted pyridines and biphenyls as anti-hypercholesterinemic, anti-hyperlipoproteinemic and anti-hyperglycemic agents. WO9804528, filed, 29 July 1997, and published, 5 February 1998.Google Scholar We further expanded the scope of R1 substituent beyond aromatics. The reactions with enyne-tethered malononitriles were examined resulting in good enantioselectivities, albeit in lower yields (2au and 2av). The pendent alkyne substituted by alkyl groups (e.g., cyclopropyl, 2aw; methyl, 2ax) were also compatible, providing the corresponding pyridines in moderate yields with slightly decreased er. Specific limitations of this chemistry in terms of unsuccessful substrates that we tried are included in Scheme S2. No reaction occurred with propynyl chloride, amine, and benzoate. Ethynyl borate was also proven unreactive. The tether between the alkyne and malononitrile has a profound influence on the reactivity, as no reaction was observed with either one carbon lo