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

Gold(III) Complexes Catalyze Deoximations/Transoximations at Neutral pH

“…Except for AuX 3 , none of these salts was a suitable initiator or catalyst at pH 4-8; [8] in fact, in most cases when the solutions were neutralized, the corresponding hydroxides or oxide hydrates precipitated out of solution, as expected. Despite their lack of solubility in water, we also examined a platinum(II) salt (entry 8), copper(I) salts (entries 10-14), [9] and a gold(I) salt (entry 17), because of their success as catalysts in other contexts, but no effect was observed. Among all these common transition-metal cations, only the gold(III) species worked at neutral pH.…”

Iron (III)‐porphyrin Complex FeTSPP as an efficient catalyst for synthesis of tetrazole derivatives via [2 + 3]cycloaddition reaction in aqueous medium

“…The resulting product, although evident as a single compound by TLC, was purified by simple recrystallization from aqueous ethanol giving pure tetrazoles 3 a‐af . Products for 3 a to 3 r reported . All products were pure enough for IR and NMR spectroscopic analyses.…”

“…Earlier repоrted methods for the synthesis of 5‐sustituted 1 H ‐tetrazole suffered from drаwbacks such as the use of strong Lewis acids or expensive and toxic metals. In order to overcome these difficulties, severаl new mild methods recently described, among them the use of TMSN 3 –TBAF, FeCl 3 – SiO 2, Zn/Al‐hydrocаlcite, Fe 2 O 3, Zn hydroxyapatite, Sb 2 O 3, NaHSO 4 .SiO 2 or I 2, mesoporous ZnS nanospheres, tungstаtes as novel heterogeneous catalysts,25a CuFe 2 O 4 25b and β‐Cyclodextrin . However, some of these methоds still require long reaction times to achieve reasonable yields, environmentally hazardous catalysts, and tedious purification of the products.…”

Azide Chemistry – An Inorganic Perspective, Part II[‡][3+2]‐Cycloaddition Reactions of Metal Azides and Related Systems

“…[170] The exceedingly simple protocol for and the generally high yield of this transformation more or less comply with the tenets of “click‐chemistry” whose ideal has been defined through the solvent‐free fusion of organic azides with acyl or sulfonyl cyanides to give 5‐substituted tetrazoles, [4a, c] or the copper‐catalyzed [3+2]‐cycloadditions of organic azides with terminal alkynes to give 1, 4‐disubstituted 1, 2,3‐triazoles (CuAAC), respectively (see chapter 3) 1–3. Many variations and even improvements of these pioneering “click reactions” have been published ever since, such as the copper(I) triflate‐catalyzed and microwave‐controlled preparation of tetrazoles from nitriles and organic azides representing the safest procedure to date 4b…”