Reactions of Methyl Ketones and (Hetero)arylcarboxamides with N,N-Dimethylacetamide Dimethyl Acetal. A Simple Metal-Free Synthesis of 2,4,6-Trisubstituted Pyridines

Abstract

Two metal-free syntheses of 2,4,6-trisubstituted pyridines 10a-m and 16a-j are described. N, N, pyridin-2-amines 10 were prepared from aryl or heteroaryl methyl ketones which were transformed with N,Ndimethylacetamide dimethyl acetal (DMADMA) into enaminones 4a-m, followed by treatment with ammonium acetate to give (Z)-3-amino-1-(substituted)but-2-en-1-ones 5a-m. These were treated with DMADMA under microwave irradiation in a closed vessel at 1308C, to give via intermediates 7-9 the final products 10a-m. N 2 ,N 2 ,N 4 ,N 4 -Tetramethyl-6-(substituted) pyridine-2,4-diamines 16a-j were prepared in a one-pot synthesis from the corresponding carboxamides 11a-j by treatment with an excess of DMADMA in a closed vessel under microwave irradiation to give via intermediates 12a-j to 15a-j the final products 16a-j. X-Ray single crystal diffractometry studies of the enaminones 5c, 5g, 5i, 5j, and 5m and 2,4,6-trisubstituted pyridines 16a, 16b, 16g, 16i, and 16j were consistent with the expected structures.

Enaminone, Enaminoesters, and Related Compounds in the Metal‐Free Synthesis of Pyridines and Fused Pyridines

“…In this manner a series of 2-methyl-6-(N,Ndimethylamino)-4-(het)aryl-substituted pyridines 53 were prepared. [67] (Scheme 7).…”

“…Under influence of base the intermediate 57 is formed, followed by elimination of water affording the final 6-(het)aryl-2,4-bis(N,N-dimethylamino)pyridines 58. [67] (Scheme 8). In the reaction of malononitrile (59) with dialkyl acetone-1,3dicarbocylates (60) alkyl (3-cyano-6-alkoxy-2-oxo-1,2-dihydropyridin-4-yl) acetates 62 are formed in contrast to an earlier report [68] according to which diethyl 3-(dicyanomethylene)glutarate (61, R = Et) was produced in the reaction of 59 and 60 (R = Et).…”

“…[98] In all cases, the orientations around the double bonds are (2E, 3E), based on the arguments reported earlier for polysubstituted butadienes. [67,[89][90][91][92]94] (Scheme 31).…”

“…We have reported on another application of the enaminone system in the synthesis of heterocyclic compounds by expanding the DMADMA methodology on aryl‐ and (hetero)aryl‐enaminone systems, as well as on aromatic and heteroaromatic carboxamides, to prepare N , N ,6‐trimethyl‐4‐(substituted)pyridin‐2‐amines and N 2 , N 2 , N 4 , N 4 ‐tetramethyl‐6‐(substituted) pyridine‐2,4‐diamines as the final products …”

Dedication to Desmond Joseph Brown

“…The first starts with methyl ketones and N,N-dimethylacetamide dimethyl acetal (DMADMA) to provide 2-dimethylamino-6-methyl-4substituted pyridines; the second starts with substituted amides and DMADMA to yield 2,4-bis(N,N-dimethylamino)-6-(substituted) pyridines. [56] Lucjan Strekowski was a former Research Fellow who worked with Des (1981Des ( -1983 and published four papers with him. He is now Emeritus Professor of Organic Chemistry at Georgia State University, Atlanta.…”