Fused 5.6-dihydropyridines, synthesis

In addition to procedures for pyridine ring closure based on the use of 3-amino-thiophene derivatives, there are alternative methods for the construction of thieno [3,2-Z>]pyridines. One approach made use of cyclic (3-keto sulfones, which proved to be convenient synthons for the modified Hantzsch synthesis of fused pyridines (1986KGS1563, 1990JHC1453, 2000MI1, 2002USP6191140). For example, the reactions of benzothiophene 1,1-dioxide 168 with enamines 169 or methylene-active compounds 170 in the presence of NH4OAc produced fused dihydropyridines 171 (1990JHC1453). 

The Hantzsch pyridine synthesis gives initially a dihydropyridine from the cyclization reaction. Adaptation of this reaction to the use of a 2-methylenethiazolidine yields the fused tetrahydro derivative (502) (77LA1888). Perhydro derivatives are simply prepared from 2-substituted thiazolidines by cycloalkylation as for (503) (80S387). The thiazolidine may also be generated in situ as in the reaction between y-benzoylbutyric acid and 2-mercaptoethylamines under azeotropic conditions to yield (504) (65JOC1506). 

Meyer and co-workers were one of the first groups to use preformed enamines to synthesize 1,4-dihydropyridines in their synthesis of unsymmetrical fiased nifedipine analogs. Michael addition of alkylidene acetoacetic esters substituted with various aryl groups 188 and enaminocarbonyls 189 (where = 1 or 2) in the presence of refluxing ethanol led to the corresponding fused systems 190 in good yield. 

M. Nikpassand, M. Mamaghani, K. Tabatabaeian, Molecules 2009, 14, 1468-1474. An efficient one-pot three-component synthesis of fused 1,4-dihydropyridines using HY-zeolite. 

Catalytic Synthesis of Fused 1,4-dihydropyridines and 1,4-dihydropyridine Derivatives Using Preyssler Heteropolyacids Catalyst... 

An efficient and convenient method for the synthesis of 1,4-dihydropyridines (1,4-DHPs) from P-dicarbonyl componnds, aldehydes, and ammonium acetate and the synthesis of fused 1,4-DHPs from dimedone in the presence of Preyssler HPA catalyst is reported under reflux conditions with good to excellent yields. Preyssler HPAs catalyst is easily prepared, stable (up to 300 °C), reusable, efficient, green, and inexpensive (Scheme 3.17) [57]. 

Scheme3.17 Synthesis of fused 1,4-dihydropyridines and 1,4-dihydropyridines using green method...

GharibA, Jahangir M, Roshani M, Seheeren JHW (2012) Catalytic synthesis of fused 1,4-di-hydropyridines and 1,4-dihydropyridine derivatives using preyssler heteropolyacids catalyst. Synth Comun 42 3311-3320... 

Oxo-4,7-dihydrothieno[2,3- ]pyridine-5-carbonitriles such as compoimd 53 are important intermediates in the synthesis of thieno[2,3-Z)]pyridine-5-carbonitrile kinase inhibitors [130, 131]. A facile three step synthesis of 4-oxo-4,7-dihydrothieno[2,3-i]pyridine-5-carbonitriles 53 from substituted 2-aminothiophene-3-carboxylate esters 7 was developed [132]. The key step of the synthesis is a thermally promoted elimination/decarboxylation followed by nucleophilic cyclization of 52 to give fused thieno-dihydropyridines 53 (Scheme 20) in good yields (Table 10). 

Table 10. Yields of synthesis of the acrylates 52 and fused thieno-dihydropyridines 53...

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