An efficient asymmetric synthesis of 1-acyl-2-alkyl-1,2-dihydropyridines

Abstract

Two efficient chiral auxiliary mediated asymmetric syntheses of synthetically useful l-acyl-2-alkyl-1,2-dihydropyridines are described.For many years there has been considerable interest in the synthesis, synthetic utility, and biological activity of various dihydropyridines.1 The ability of an iV-acyl substituent to stabilize2 the dihydropyridine system has encouraged the use and study of 1-acyldihydropyridines as synthetic intermediates. Several 2-unsubstituted 1-(alkoxycarbonyl)-l,2-dihydropyridines 1 have proven to be useful dienes for the Diels-Alder reaction and have been Supplementary Material Available: Experimental details for the preparation of 7a and 21a and physical data for 7,15, and 21a,b (13 pages). This material is contained in many libraries on microfiche, immediately follows this article in the microfilm version of the journal, and can be ordered from the ACS; see any current masthead page for ordering information.

One-pot synthesis of highly functionalized 1,2-dihydropyridines from primary alkylamines, alkyl isocyanides, and acetylenic esters

“…When the ethyl and methyl substituents of the alkynes are reversed, two different products (5m and 5p) were obtained. Although compounds 5 are well set up to undergo a [1,5]sigmatropic shift, we conclude that no [1,5]-sigmatropic shift is taking place under the reaction conditions employed.…”

“…As a part of our current studies on the development of new routes in heterocyclic synthesis, 12e15 we report the results of our studies involving the reaction of the zwitterionic intermediates derived from alkyl isocyanides 1 and acetylenic esters 2 with dialkyl 2-(alkyl(aryl)amino)but-2-enedioates [generated in situ from primary alkyl(aryl)amines and acetylenic esters 4], which constitutes a synthesis of highly functionalized 1,2-dihydropyridines (5) in good yields (Scheme 1).…”

“…The majority of synthetic approaches to 1,2-dihydropyridines has relied on nucleophilic addition to N-alkyl or N-acylpyridinium salts. 4,5 However, regioisomeric mixtures of addition products are often obtained if unsymmetrically substituted pyridinium salts are employed. 6 More recently, other strategies for the synthesis of 1,2-dihydropyridines have emerged that address some of these limitations.…”

Synthesis, utility and medicinal importance of 1,2- & 1,4-dihydropyridines

“…Comins, et al 8 have reported the asymmetric synthesis of 2-substituted-1,2-dihydropyridines 25 & 26 from N-acyl pyridinium salt 24, which was synthesized via the addition of 3-(triisopropylstannyl)pyridine 22 to an enantiopure chloroformate 23a-b derived from (À)-8-(4-phenoxyphenyl)menthol or (À)-8-phenyl-menthol. The reaction of Nacyl pyridinium salt 24 with different Grignard reagents followed by treatment of the reaction mixture with silica gel containing oxalic acid provided chiral 1,2-dihydropyridines 25 and 26 (Scheme 6, Table 1).…”

4-Methoxy-1-[(1R,4S,5R)-8-phenylmenthoxycarbonyl]pyridinium hexachloroantimonate, C23H30NO3+.SbCl6−

“…This is the first non-racemic N-acylpyridinium salt prepared in crystalline form. Chiral salts of this type have been prepared in situ and reacted with Grignard reagents to give synthetically useful l-acyl-2-alkyl-2,3-dihydro-4(1H)-pyridinones (Comins, Goehring, Joseph & O'Connor, 1990;Comins & Dehghani, 1991;Comins, Hong & Salvador, 1991;Comins & LaMunyon, 1992;Comins & Killpack, 1993).…”