A Click Chemistry Approach to Tetrazoles by Huisgen 1,3-Dipolar Cycloaddition: Synthesis of 5-Acyltetrazoles from Azides and Acyl Cyanides We thank the National Institute of General Medical Sciences, National Institutes of Health (GM-28384), the National Science Foundation (CHE-9985553), the Skaggs Institute for Chemical Biology for a Predoctoral Fellowship (Z.D.), and the W. M. Keck Foundation for financial support.

Abstract

The preceding communication [1] describes the facile [23] cycloaddition of azides and p-toluenesulfonyl cyanide to form 5-sulfonyl tetrazoles, interesting compounds in their Together with the known substitutions of the resulting sulfonyl tetrazoles, the two-step sequence is formally equivalent to regioselective cycloadditions of azides with a wide variety of nitriles. Further studies on the scope of this chemistry will be reported. [20] Experimental Section Note: Many low-molecular-weight azides are known to be explosive. In this lab, no problems have been encountered, but great caution should be exercised when heating compounds of this type, especially neat. The reactions described here were run on only a few grams; an increase in the scale of these reactions will decrease the efficiency of heat dissipation and explosions may result.A vial was charged with a stir bar, p-toluenesulfonyl cyanide (905 mg, 5.0 mmol), and azide (5.0 mmol), and tightly capped. The reagents were stirred neat in an oil bath set to 80 8C, for 16 h. If the reaction was not complete at this time, stirring was continued, in some cases with the temperature reset to 100 8C. In the cases of unhindered azides, the crude product, a light yellow solid, was analytically pure. To remove color, the product can be dissolved in a mixture of ethyl acetate (30 %) and hexanes (70 %), and run down a short plug of silica gel to yield a white solid. If excess toluenesulfonyl cyanide was present, the product was crushed and placed under vacuum at 80 8C for four hours. In the case of hindered azides, the product was purified by column chromatography, by eluting with ethyl acetate (10 %) and hexanes (90 %), to give the product as a white or lighttan solid. In some cases (9, 14) the product was sufficiently insoluble that trituration with ethyl acetate (10 %) and hexanes (90 %) was sufficient to purify the compound.

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

“…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 °C 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” approach4, 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 °C 4a. From the more reactive p ‐toluenesulfonyl cyanide, excellent yields of 1,5‐disubstituted tetrazoles were similarly obtained at 80–100 °C 4b…”

“…[d] Anhydrous and pentahydrate, with identical results. Addition of sodium ascorbate (aqueous solution or in t BuOH/H 2 O)4a, b, 5e is not recommended, as partial hydrolysis of EtOCO‐CN (EWG‐CN) takes place.…”

“…[b] Overall yield of tetrazoles. [c] This nitrile decomposes under the reaction conditions, so that 1.5 equiv were added 4a. [d] Heating is not recommended (compare with entry 7).…”

Unexpected Zirconium‐Mediated Multicomponent Reactions of Conjugated 1,3‐Butadiynes and Monoynes with Acyl Cyanide Derivatives

“…The proximity of the CO and CN groups in acyl cyanides enhances the electrophilicity of both functionalities. Although the reactions usually occur at the carbonyl group,19 attack at the CN moiety by soft nucleophiles such as H 2 S20 and azides21 are known. Here we found that the zirconium‐mediated reaction of TBS‐substituted butadiyne 1 a with PhCOCN provided azazirconacyclopentene 16 a in 29 % yield (Table 2, entry 1).…”

Combining the Ugi-azide multicomponent reaction and rhodium(III)-catalyzed annulation for the synthesis of tetrazole-isoquinolone/pyridone hybrids

“…Among the most versatile methods for obtaining tetrazoles are the Ugi-azide four-component reaction (Ugi-azide-4CR) [14–16] and the 1,3-dipolar cycloaddition of azides with (acyl)cyanides [17–18]. The Ugi-azide-4CR enables the incorporation of three different diversity-generating sites (Scheme 1), a feature that has been exploited for the construction of libraries of tetrazole-based compounds with potential bioactivity [9–12 19].…”