SYNTHESIS OF NEW CHIRAL α-AMINO ACID DERIVED 3,5-DISUBSTITUTED 1,2,4-TRIAZOLES
Keywords:
azines, triazole, microwave irradiation, amide isomerism, computational study.Abstract
An enantio pure pyrazine-linked 3,5-disubstituted 1,2,4-triazoles, an amide bond isosteres, were synthesized by ring closure of acylated with L-α-amino acid residues N-acylamidrazone precursors. Pyrrolidine ring opening of methyl esters of (2S)-2-(imino-oxo-dihydro-6H-pyrrolo[3,4-b] (hetero)aryl)alkanoic acid bearing amino acid moiety at endo-N atom of pyrrolidine ring with Boc-protected L-Phe amino acid hydrazide was firstly shown to provide a new convenient method for preparing pyridine or pyrazine derived N-acylamidrazone intermediates in good yields. No cyclic pyrrolopyridines(pyrazines) derivatives as a result of exo-imine group substitution were found as final compounds. Pyrazine-linked 1,2,4-triazoles were successfully synthesized by thermal cyclization of N-acylamidrazone derivatives using microwave-assisted irradiation. However, pyridine-containing 1,2,4-triazoles of this type are not available from corresponding N-acylamidrazones probably due to their high thermo and solvent sensibility. Under reaction conditions they underwent decomposition followed by intramolecular cyclization giving rise starting pyrrolopyridines. (Z)/(E) isomerism of N-acylamidrazone intermediates was studied by means of NMR spectroscopy and quantum chemical calculations. It was found to be dependent on the heterocycle type. A NOE experiment for phenylalanine substituted pyridine-based N-acylamidrazone demonstrated the occurrence of Z and E rotamers due to amide-type isomerism. Theoretical calculations (B3LYP DFT with the standard 6-31G(d,p) basis set) on N-acylamidrazone isomers indicated amide bond isomerism for pyridine-linked N-acylamidrazones and C=N bond isomerism for pyrazine-linked analogues.
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