4.7- Dihydrothieno pyridines

Similar transformations were also found on heating of 2-(but-3-ynylthio)pyrimidine (X = S) and 2-(but-3-ynylsulfonyl)pyrimidine (X = S02), 2,3-dihydrothieno[2,3-h]pyridine and l,l-dioxo-2,3-dihy-drothieno[2,3-h]pyridine, respectively being obtained (Scheme 35). 

Whereas in all previously mentioned inverse cycloaddition reactions [h]-fused pyrido annelated systems are formed, some reactions are described which lead to [c]-pyridine annelated bicyclic systems. 5-(Butynylthio)pyrimidines (R = Ph, NHCOCH3) give on heating at 180°C in nitrobenzene 5-R-2,3-dihydrothieno[2,3-c]pyridines (89T803). 5-Propynyloxymethylpyrimidines also readily undergo cycloaddition into l,3-dihydrofuro[3,4-c]pyridines (89T5151) (Scheme 39). Considerable rate enhancements were observed with quaternized pyrimidinium salts. Whereas... 

Klemm and coworkers18a prepared some isomeric chlorinated 2,3-dihydrothieno-[2,3-b]pyridine 1-oxides and reported their El mass spectra at 70 eV. Only one isomer (30) was isolated in the case of the 5-ethyl derivative the mass spectrum of which... 

CN (5 )-.a-(2-Chlorophenyi)-6,7-dihydrothieno[3,2-c]pyridine-5(4//)-acetic acid methyl ester sulfate (1 1)... 

Table 2 Dipole moments of dihydrothieno[2,3-b]-pyridines, 27 <1997JHC931>...

Related compound (A) has the systematic name (+)-(S)-(o-chlorophe-nyl)-6,7-dihydrothieno[3,2-c]pyridine-5-(4H)-acetic acid [2], and is a hydrolysis product of the ester group of clopidogrel. This impurity is formed as a result of the combined effects of moisture and temperature [2, 6, 7],... 

Related compound (B) has the systematic name methyl-( )-(o-chloro-phenyl)-4,5-dihydrothieno[2,3-c]pyridine-6-(7H)-acetate, hydrogen sulfate salt [2], and is a racemic residue formed during the manufacturing process. This compound may appear as a racemic mixture in samples of bulk drug substance as impurities (la) and (lb) [6, 7]. 

Related compound (D) has been reported to result from an oxidation process, and has the systematic name 5-[l-(2-chlorophenyl)-2-methoxy-2-oxoethyl]-6,7-dihydrothieno[3,2-c]pyridine-5-ium [8]. 

Method Cis based on intramolecular cyclization of 2-aminothiophenes containing a substituent with the electrophilic y-carbon atom at position 3. This class of compounds, for example, amines 50, can be prepared by multicomponent cascade heterocyclization of phenyl isothiocyanate, CH-acids, and alkylating agents (1991SL229, 1992G147, 1992M341, 2001PS215). Cyclization of compounds 50 affords 6-oxo(imino)-6,7-dihydrothieno[2,3-Z>]pyridines 51 as the final products. 

Method U (pyridine ring construction through N(5)-C(4) and C(6)-C(7) bond formation) can be exemplified by the synthesis of 6,7-dihydrothieno[3,2-c]pyridines... 

It has been reported that the intramolecular transformation of 5-phenyl-3-(3-butynylthio)-l,2,4-triazine (143) into 6-phenyI-2,3-dihydrothieno[2,3-b] pyridine (145) requires heating in refluxing dioxane (100°C) for 24 hr (Scheme 83) (87JOC4280). Our own experiments show that the same result can also be reached under considerably milder conditions if the tria-zinium salt 146 is used as the starting material (88H(ip)). The salt 146, easily obtained by treatment of triazine 143 with triethyloxonium te-trafluoroborate at room temperature in dichloromethane solution, gives on heating in acetone (60°C) for 7 hr the borate salt 147 in nearly quantitative yield (Scheme 83) (88H(ip)). 

Benzamido-3-cyano-4,5-dihydrothiophenes (321) cyclize at 120°C with cyclohexylamine, morpholine, piperidine, and pyrrolidine to the corresponding 4-amino-2-phenyl-5,6-dihydrothieno [2,3-d ] pyrimidines (322).181 However, when 321 and 2 equivalents of dimethylamine hydrochloride in pyridine were refluxed for 5 hr, the 4-oxothieno [2,3-d] pyrimidine 323 was formed nearly quantitatively181 (Scheme 92). Ethyl iV-(3-cyano-4,5-dihydro-2-thienyl)oxamates (324) give, with cyanomethylene compounds in the presence of triethylamine, thieno[2,3-d]pyrimidines (325).182... 

A complex sequence of pericyclic reactions, intramolecular and intermolecular cycloadditions and cycloreversions, was studied in an attempt to readily achieve bicyclic five-membered heterocycles, the methyl 4,6-dihydrothieno- and methyl-4, 6-dihydrofuro[3,4-b]-furan-3-carboxylates 146 and 147. The results give further evidence of the potential of intramolecular Diels-Alder based multiple processes [129], 2-Substituted furans and thiophenes 148 and 149, heated in the presence of 3,6-di(pyridin-2 -yl)-,y-tetrazine, underwent intramolecular and intermolecular cycloadditions. The cycloadducts underwent double cycloreversion reactions with the loss of a nitrogen and dipyridyldiazine as illustrated in Scheme 2.55. The electron-deficient dipyridyltetrazine reacts with the isolated, electron-rich olefinic bond rather than with the bond conjugated with the methylcarboxylate. 

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