Cyclization, 5-ethyl-2-methylpyridine

Seidel28 cyclized compounds (32) derived from the amides (31) with dimethylformamide dimethyl acetal to the 3-substituted 2-oxo-2H-pyrido-[l,2- ]pyrimidines (33) by heating in acetic anhydride. On this basis he corrected the conclusion of Antaki,29 who had assumed that by reacting 2-amino-4-methylpyridine and ethyl ethoxymethylenecyanoacetate, the 2-oxo-2//-pyrido[l,2-a]pyrimidine (33 R = 8-Me, R1 = OEt) was produced. The product was in fact the 4-oxo isomer (36 R = 8-Me, R1 = H, R2 = COOEt). 

Shur and Israelstam41 applied polyphosphoric acid to cause ring closure. Although the crotonates (39) and the crotonic amides (40) cyclized almost quantitatively to 4-oxo-4H-pyrido[l,2- ] pyrimidines (41), cyclization of the 2-acetylacetamidopyridines (38) could only be achieved in less than 50% yield. When one additional equivalent of 2-aminopyridine was included in the reaction mixture of 38, the yield of 41 increased to over 80%. When the ring closure was carried out from crotonic amides (40) containing different 2-aminopyridine moieties, the resulting 4-oxo-4//-pyrido[l,2-a]pyrimidines bore the substituent of the pyridine of the enamine part of the crotonic amide. The authors proposed that the 4-oxo-4H-pyrido[l,2-a]pyrimidines (41) may arise from 2-aminopyridines and ethyl acetoacetate in polyphosphoric acid via two pathways (see Scheme 1). 2-Amino-3-methylpyridine and 2-amino-3,5-dibromopyridine react via pathway A and 2-aminopyridine, 2-amino-4-, -5-, and -6-methylpyridines react via pathway B, whereas 2-amino-5-chloro- and 5-bromopyridines may react via both pathways. 

Diethoxycarbonylvinylamino)-6-fluoro-7-methylpyridine (23) gave ethyl 6-fluoro-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (24) (Dowtherm, heat 80%) 1091 such a cyclization has also been done under... 

An entry into the 6-mcthylpyrido[3.4-(i]pyrimidine systems, directed towards the syntheses of folate and pteroate analogs, is provided by ethyl 5-amino-2-methylpyridine-4-carboxylate.369 Its reaction with benzoyl isothiocyanate to give the corresponding benzoylthiourea followed by cyclization in alkaline medium furnishes 6-methyl-2-sulfanylpyrido[3,4-d]pyrimidin-4(3/f)-one (3). 

A methyl group at one of the amino substituents of pyridine-3,4-diamine influences the regiochemistry of the cyclization. Thus, the reaction of A -methylpyridine-S,4-diamine and ethyl pyruvate yields 49% of l,3-dimethylpyrido[3,4-6]pyrazin-2(l//)-one (14), whereas N3-methylpyridine-3,4-diamine gives the same yield of 2,4-dimethylpyrido[3,4-/j]pyrazin-3(4f/)-one (15).97... 

In the synthesis of ( )-D-homoestrone (Scheme 7), Michael addition of the monoketal 42 of the Wieland-Miescher enedione to 6-vinyl-2-methylpyridine 41 led to tricyclic adduct 43 in good yield. Reduction to the 17a-P-alcohol, double bond hydrogenation, and ketalization produced 44 with the requisite 8 J,14a-stereochemistry in 58% yield. However, modification of the hydrogenation conditions from ethyl acetate-triethylamine to ethanol-perchloric acid raised the yield to 82%.Birch reduction, hydrolysis, cyclization, and ketal reversal... 

Anary-Abbasinejad and coworkers reported an interesting three-component type ace cyclization leading to substituted 3-pyrrolin-2-ones that combined an amidation ( a bond), Michael addition ( e bond), and intramolecular Wittig reaction ( e bond) (Scheme 103 2010SC1350). Treatment of 2-amino-4-methylpyridine 391, DMAD (303), and ethyl chlorooxoace-tate (392) with triphenylphosphine gives the 3-pyrrolin-2-one 394 via the ylide intermediate 393. 

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