Regioselective Syntheses of Substituted Pyridines and 2,2′-Bipyridines by Cobalt-Catalyzed [2+2+2] Cycloaddition of α,ω-Diynes with Nitriles

Abstract

In the presence of a 1,2-bis(diphenylphosphino)ethanecobalt(II) chloride-zinc catalyst in 1-methylpyrrolidin-2-one at room temperature to 50°C, a,w-diynes reacted with nitriles by a [2+2+2] cycloaddition pathway to give annulated pyridines or 2,2¢-bipyridines. The regioselectivity of the reaction is controlled by a combination of steric and electronic effects. The reaction of diynes with a terminal trimethylsilyl group gave the corresponding 3-(trimethylsilyl)pyridines exclusively; these products could be proto-or halodesilylated to give the corresponding protonated or halogenated pyridines or 2,2¢-bipyridines.The catalytic cycloaddition of alkynes and nitriles in a [2+2+2] fashion provides a straightforward method for preparing substituted pyridines. 1,2 The regiochemistry of the reaction and its control are important in relation to utilizing the method in synthesis. Successful regiocontrol in a fully intermolecular reaction is possible but challenging, 3,4 whereas the regiochemistry of fully intramolecular reactions can be more readily controlled by altering the positions of the alkyne and nitrile groups or by the strain in the intermediates or products. Pyridines with unique tricyclic or spiro skeletons have been prepared by this method. 5 In contrast, comprehensive data on the regioselectivity of partially intramolecular reactions, 6 such as the cycloadditions of a,w-diynes to nitriles or of w-cyanoalkynes with alkynes, are not available.The synthesis of pyridines by the cycloaddition of nonsymmetrical a,w-diynes 1 to nitriles 2 gives two regioisomers 3 and 4 (Scheme 1). We assumed that the regioselectivity of this reaction might be controlled by steric or electronic effects or by the balance of the two. The reactions of 6-substituted (1-unsubstituted) 1,6-diynes catalyzed by CpCo(CO) 2 7a (Cp = h 5 -cyclopentadienyl) or Cp*RuCl(cod) 3b,5b,8 (Cp* = h 5 -pentamethylcyclopentadienyl; cod = cyclooctadienyl) gave the corresponding 2,6-substituted pyridines predominantly rather than the 2,3-substituted pyridines. The selectivity of this reaction has been rationalized by considering the steric repulsion between the metallacyclopentadiene intermediate and the nitrile. Several examples that might be explained in terms of the electronic nature of the diyne substrate (and that of the corresponding metallacycle intermediates) have been reported by Schreiber and coworkers, 9 Tanaka et al., 3c,10 Louie and co-workers, 11 and our research group 12 for reactions catalyzed by CpCo(CO) 2 , cationic diphosphine-rhodium, N-heterocyclic carbene (NHC)-nickel, or diphosphine-cobalt systems, respectively. Here we report a regioselective [2+2+2] cycloaddition of diynes with nitriles catalyzed by a 1,2-bis(diphenylphosphino)ethane-cobalt(II) chloride hexahydrate-zinc [(dppe)CoCl 2 ·6H 2 O-Zn] reagent, 12 and we discuss the relationship between the selectivity and the substrate structure. Scheme 1During the course of our previous studies on alkyne cycloaddition, 12,13 we found that a CoCl 2 ·6H 2 O/Zn reagent catalyzed the cycloaddit...

Transition‐Metal‐Mediated/Catalyzed Synthesis of Pyridines, Pyrimidines, and Triazines by [2+2+2] Cycloaddition Reactions

“…In 2011, Sugiyama and Okamoto reported Co-catalyzed [2 + 2 + 2] cycloaddition of α,ω -diyne 25 with nitrile 26. [12] The dppe (1,2-bis(diphenylphosphino)ethane), CoCl 2 • 6H 2 O and Zn system was found to be an effective catalyst for pyridine 27 synthesis in excellent yields at room temperature to 50°C in NMP (Nmethylpyrrolidone) (Scheme 11).…”