Molecular modification of anpirtoline (2a) is described. Several methods of preparation of 4-[(3-chlorophenyl)sulfanyl]-1-methylpiperidine (3a) and its demethylation led to the deazaanpirtoline (3c). Nucleophilic substitution of piperidine-4-thiole with 2-chloro-4-nitropyridine, 2,4-dichloro-6-methylpyridine, and 3,6-dichloropyridazine led to 2-chloro-4-(piperidin-4-ylsulfanyl)pyridine (6), 4-chloro-6-methyl-2-(piperidin-4-ylsulfanyl)pyridine (7), and 3-chloro-6-(piperidin-4-ylsulfanyl)pyridazine (8), respectively. 2-Chloro-6-(pyridin-4-ylsulfanyl)pyridine (10) and 4-[(2-chloropyridin-6-yl)sulfanyl]quinoline (11) were obtained from sodium 2-chloropyridine-6-thiolate. Homoanpirtoline analogs with methylene group inserted between the pyridine moiety and the sulfur atom (compound 12b) as well as between the sulfur atom and the piperidine ring (compound 13b) were also prepared.
Reaction of 1,2-hydroxyketones 5 with (2,2-diethoxyvinylidene)triphenylphosphorane (2) or (2,2-diethoxyvinyl)triphenylphosphonium tetrafluoroborates 6 yields the 2,2-diethoxy- 2.5-dihydrofurans 9. Depending on the reaction conditions used, the orthoesters 9 can be hydrolized to give 2(5 H)furanones 10 and 2-ethoxyfurans 11, respectively. 4,5-Dimethyl- 5.6-dihydro-2-pyranone (20) and 8-methoxycoumarin (23) are prepared, starting from (2,2-diethoxyvinyl)triphenylphosphonium tetrafluoroborate (6 a) and 1-hydroxy-2-methyl- 3-butanone (16) or 2-hydroxy-3-methoxy-benzaldehyde (21). The 2-ethoxyfuranes 11 readily undergo Diels-Alder reactions with 2-chloracrylonitrile (24), maleic anhydride (26), N-phenyl-1,2,4-triazoline-3,5-dione (28) and dimethyl acetylenedicarboxylate (30) to give the corresponding Diels-Alder products 25, 27, 29 and 31, respectively. Contrary to 2-ethoxyfuran 11b , 11a reacts with two equivalents of acetylene 30, to yield barrelenone 34. The structure of 34 unequivocally is established by X-ray structure analysis.
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