New Optically Active Bis-Heterocycles Derived from (S)-Proline

Abstract

Enantiomerically pure bis-heterocycles containing a (S)-proline moiety have been prepared starting from (S)-N-benzylprolinehydrazide (2b). The reactions with isothiocyanates or butyl isocyanate in refluxing MeOH led to the corresponding thiosemicarbazide 5 and semicarbazide 9 with a N-benzylprolinoyl residue. The structure of the tert-butyl derivative 5d was established by X-ray crystallography. Base-catalyzed cyclization of 5 and 9 led to (S)-3-(pyrrolidin-2-yl)-1H-1,2,4-triazole-5(4H)-thiones 6 and the corresponding 5(4H)-one 8, respectively, whereas, in concentrated H2SO4, compounds 5 undergo cyclization to give (S)-5-amino-2-(pyrrolidin-2-yl)-1,3,4-thiadiazoles 7. Furthermore, 2b reacted with hexane-2,5-dione in boiling iPrOH to yield the (S)-N-(2,5-dimethylpyrrol-1-yl) prolinamide 10. In the case of the bis-heterocycle 8, treatment with HCOONH4 and Pd/C in MeOH gave the debenzylated product 12.