Regiospecific Reduction of the C=N Bond in 5,6-Dialkyl-2-Chloropyridine-3,4-Dicarbonitriles

Dihydropyridines are an important group of heterocyclic compounds and they can show different forms of biological activity [1], e.g., antihypertensive [2], antiarrhythmic [3], bioprotective [4], and hepatoprotective [5]. Amongst this group, 1,2(1,6)-dihydropyridines are very poorly represented, that is linked to the small number of methods for preparing them. With the aim of developing novel methods for the synthesis of 1,2(1,6)-dihydropyridines we have studied the reduction process of polyfunctional 5,6-dialkyl-2-chloropyridine-3,4-dicarbonitriles 1. These compounds were prepared according to a three-component method developed by us from tetracyanoethylene, ketones, and concentrated hydrochloric acid [6]. A special feature of the pyridines 1 is the presence of several reactive centers which can undergo a reduction, viz. two cyano groups, the C–Cl bond, and the pyridine ring. This fact complicates the problem of a targeted reduction of the C=N bond in the pyridine ring. It should be noted that, up to the time of our study, the literature has reported reduction processes of structural analogs of pyridines 1, viz compounds containing a 2-halopyridine-3-carbonitrile fragment including other heterocycles in composition. Hence there has been reported a selective reduction of a C–Cl bond by hydrogenolysis in the presence of Pd/C [7], by the action of zinc dust in acidic medium [8], and by the action of a solution of hydriodic acid, iodine, and red phosphorus [9]. In the hydrogenolysis of 2,6-dibromopyridine3,5-dicarbonitrile in the presence of Pd/CaCO3 a simultaneous reduction of the C–Br and C=N bonds of the pyridine ring occurs [10]. The process of reduction of pyrido[2,3-d]pyrimidines has also been reported using NaBH4 in which the pyridine ring was reduced with retention of the halogen to yield 1,4-dihydropyridine derivatives [11]. A selective reduction of the cyano group to an aminomethyl has been reported for 2-chloropyridine-3-carbo-nitrile reaction with NaBH4 in the presence of CoCl2 or with hydrogen using Raney nickel [12]. We have developed a method for the selective reduction of the C(6)=N bond in the pyridines 1a-d which is achieved via their reaction with sodium borohydride in methanol at 20oC for 30 min. The result of this reaction is the formation of the 5,6-dialkyl-2-chloro-1,6-dihydropyridine-3,4-dicarbonitriles 2a-d in 74-91% yields. _______ *To whom correspondence should be addressed, e-mail: oleg.ershov@mail.ru.