1383720-89-5

Upstream product

• 955-40-8 N-benzyl-L-proline ethyl ester 
• 31795-93-4 N-benzyl-L-proline 
• 911429-36-2 (2S)-1-benzylpyrrolidine-2-carbohydrazide 
• 592-82-5 butyl isothiocyanate 

Downstream Products

• 1383720-92-0 5-[(2S)-1-benzylpyrrolidin-2-yl]-4-butyl-2,4-dihydro-3H-1,2,4-triazole-3-thione 
• 1383720-93-1 5-[(2S)-1-benzylpyrrolidin-2-yl]-N-butyl-1,3,4-thiadiazol-2-amine 

Relevant academic research and scientific papers

Synthesis of enantiopure bis-heterocycles derived from (S)- prolinehydrazides

A convenient synthesis of new enantiomerically pure bis-heterocycles containing a (S)-proline moiety starting from (S)-N-benzylprolinehydrazide (1) is described. The reactions of 1b with isothiocyanates in refluxing MeOH led to the thiosemicarbazide 3 with a N-benzylprolinoyl residue. Thiosemicarbazide 3 underwent cyclization reactions under basic (NaOH) and acidic (H2SO4) conditions to yield (S)-prolinyl-substituted 1,2,4-triazole-3-thione 4 and 1,3,4-thiadiazole-2-amine 5, respectively.

Studies on the synthesis and some reactions of (S)-proline hydrazides

A convenient synthesis of (S)-proline hydrazide 2a via the reaction of ethyl (S)-N-benzylprolinate with hydrazine hydrate and subsequent deprotection of (S)-N-benzyl proline hydrazide 5 is described. The latter, in methanolic solution, reacted with aromatic aldehydes as well as with cycloaliphatic ketones at room temperature to give the corresponding hydrazones of type 7 in good yields. The structure of the product with furan-2-carbaldehyde 7b, proving the (E)-configuration of the hydrazone, was established by X-ray crystallography. In the case of the unprotected (S)-proline hydrazide 2a, the analogous reaction with aromatic aldehydes led either to the expected hydrazones 7 or the 1H-pyrrolo[1,2-c]imidazol-1-one derivatives 8, depending on the reaction conditions. The latter were formed via a secondary cyclocondensation of the initially formed 7 with a second molecule of the aldehyde. Whereas the reaction of (S)-N-benzyl proline hydrazide 5 with butyl isocyanate and isothiocyanate gave the corresponding semicarbazide and thiosemicarbazide, respectively, of type 9, the unprotected (S)-proline hydrazide 2a yielded the 1:2 adducts 10. Thiosemicarbazide 9b underwent cyclization reactions under basic (NaOH) and acidic (H2SO4) conditions to yield (S)-prolinyl- substituted 1,2,4-triazole-3-thione 11 and 1,3,4-thiadiazole-2-amine 12, respectively.

New optically active bis-heterocycles derived from (S)-proline

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.