SYNTHESIS AND RESOLUTION OF 2-ARYLALKYL-2-(TETRAZOL-5-YL)-N-ARYLALKYL-CARBOXAMIDES. A NEW CLASS OF CHIRAL STERICALLY HINDERED TETRAZOLE DERIVATIVES

Chiral, racemic 2-arylalkyl-2-(tetrazol-5-yl)-N-arylalkylcarboxamides 3 were conveniently prepared from ethyl cyanoacetate in four steps. The synthetic methodology developed is a facile way of introducing bulky substituents into a peptide-like framework, affording intermediate α-arylalkyl-α-amidonitriles. These nitriles were sufficiently activated to give, upon treatment with ammonium azide in dimethylformamide at 145° for twenty-four to thirty hours, the corresponding tetrazoles in good yields. It has been determined that an optically pure α-arylalkyl-α-amidonitrile epimerized to give diastereomeric products under the above conditions. A procedure for the fractional crystallization of the (S)-(-)-α-methylbenzylamine salts 4 of the tetrazoles to give the optically enriched tetrazoles 5 was also developed.