Cu₂(OTf)₂‐Catalyzed and Microwave‐Controlled Preparation of Tetrazoles from Nitriles and Organic Azides under Mild, Safe Conditions

Abstract

In connection with a project aimed at preparing new series of diketotetrazoles (see compound 1 in Scheme 1, for which two representative tautomers are shown) and pharmacophorrelated quinolinocarbonyltetrazoles, as further candidates for HIV-1 integrase inhibitors, [1] we sought a rapid entry into the synthesis of tetrazole esters 2 and/or 5-acetyltetrazoles 3 (Scheme 1). Formation of tetrazole rings by cycloaddition between nitriles and organic azides is in principle the most direct method, [2] but it usually requires very harsh conditions. Moreover, since N-unsubstituted tetrazole rings are wellrecognized bioisosters of the carboxyl groups, [2a] the development of any safe approach to tetrazoles of type 2 and 3, as well as to derivatives of general formula 4 (Scheme 1), would be of great use in the pharmaceutical industry.Most recent studies on the subject rely on a classical paper in which benzyl azide derivatives and alkyl cyanoformates (ROCO-CN) were heated without solvent at 130 8C in a sealed tube;[3] tetrazoles of type 2 can be achieved in roughly 60-70 % yields, at best. To reduce the hazards inherent to heating these polynitrogenated starting materials and products, Demko and Sharpless investigated a "click chemistry" approach [4,5] by using mainly acyl cyanides (RCO-CN) and organic azides, which allowed them to obtain compounds of type 3 (1,5-disubstituted) under solvent-free conditions, without catalysts, at 120 8C.[4a] From the more reactive p-toluenesulfonyl cyanide, excellent yields of 1,5-disubstituted tetrazoles were similarly obtained at 80-100 8C.[4b]These outstanding results encouraged us to investigate a series of potential catalysts for these [3+2]-cycloaddition reactions, aimed at achieving even safer conditions. The copper(I) complexes Cu 2 (OTf) 2 ·tol and Cu 2 (OTf) 2 ·C 6 H 6 (OTf = O 3 SCF 3 , tol = toluene) allow one to carry out most of the above reactions at room temperature, with or without solvent. This catalytic activity was not observed for other Cu I

Microwave‐Assisted 1,3‐Dipolar Cycloaddition: an Eco‐Friendly Approach to Five‐Membered Heterocycles

“…For the reluctant secondary azide 188, an AZT derivative, however, it was found that heating at 80°C under microwave irradiation conditions for a few hours was able to force the reaction to proceed. [127] Scheme 68.…”

Advances in synthesis of tetrazoles coordinated to metal ions

“…[71][72][73][74][75][76][77][78][79][80] The range of metal salts applied to the preparation of the tetrazole-containing coordination compounds constantly grows. However their efficiency is variable.…”

Methyl Cyanoformate (Mander’s Reagent)

“…(B) The title reagent was used to prepare an acetylenic ester that served as an early stage intermediate in the first asymmetric total synthesis of (-)-platensimycin reported by Nicolaou and co-workers. 6 (D) Nájera and co-workers reported the one-step synthesis of various chiral cyanocarbonates from a range of aldehydes using the title reagent in the presence of chiral bifunctional catalysts such as (R)-or (S)-BINOLAM-AlCl. 12,13 It is believed that the catalytic cycle involves enantioselective hydrocyanation promoted by BINOLAMAlCl, followed by the turnover-limiting O-alkoxycarbonylation step.…”