TBAF-Catalyzed Synthesis of 5-Substituted 1H-Tetrazoles under Solventless Conditions David Amantini,* Romina Beleggia, Francesco Fringuelli, Ferdinando Pizzo,* and Luigi Vaccaro Dipartimento di Chimica, Laboratorio di Chimica Organica, Universita ` di Perugia, CEMIN (Centro di Eccellenza Materiali Innovativi per applicazioni chimiche, fisiche e biomediche), via Elce di Sotto 8, I-06123 Perugia, Italy pizzo@unipg.it Received January 8, 2004 Abstract: Tetrabutylammonium fluoride (TBAF) is an efficient catalyst in the [3 + 2] cycloaddition reaction of organic nitriles 1 with trimethylsilyl azide (TMSN 3 ) in solventless conditions. The corresponding 5-substituted 1H- tetrazoles 2 were obtained under mild conditions and in 80- 97% yields. Tetrazoles are a class of heterocycles with a wide range of applications that is receiving considerable attention. 1 This functionality has been frequently used as a meta- bolically stable surrogate for a carboxylic acid group, 2 and tetrazoles have shown valuable properties as precursors of a variety of nitrogen-containing heterocycles 3 and have found use in various material sciences, including pho- tography, information recording systems, and explosives. 4 5-Substituted 1H-tetrazoles 2 are usually obtained by the addition of azide ion to organic nitriles 1, and many methods are reported in the literature. 5 Unfortunately, each of those protocols suffers from some disadvan- tages: the use of both toxic metals and expensive reagents, drastic reaction conditions, water sensitivity, and the presence of dangerous hydrazoic acid. Recently, Sharpless and co-workers have reported an innovative and safe procedure for the preparation of 2 starting from the corresponding nitriles 1, by using NaN 3 and stoichiometric amounts of Zn(II) salts in water. 6 This procedure has shown a good level of generality but in the case of sterically hindered aromatic or alkyl inactivated nitriles high temperatures (140-170 °C) are usually required. Our research group devoted particular attention to the development of environmentally friendly and efficient protocols by using water as the reaction medium 7 or by working under solventless conditions. 8 To improve the ecocompatibility of organic processes we are also focusing our attention on the development of nonmetallic catalysts, and recently, we reported that by using TMSN 3 in the presence of catalytic tetrabuty- lammonium bromide (TBABr) a variety of alcohols and phenols are readily converted into the corresponding OTMS derivatives in high yields and selectivities under solventless conditions. 8a Our aim is to extend this re- search to other important organic transformations such as addition and cycloaddition reactions. We inquired into the use of TMSN 3 as azide source in the conversion of nitriles 1 to 2 by using the anionic activation of silicon-nitrogen bond strategy. 9 TMSN 3 has been already used in such transformations in the pres- ence of either an equimolar amount of a strong Lewis acid such as AlMe 3 5b or by using a catalytic amount of toxic dialkyltin oxide. 5c We hypothesized that fluoride anion could be an efficacious basic activator for the cycloaddition of TMSN 3 to organic nitriles and tetrabutylammonium fluoride (TBAF) a good candidate as fluoride ion source. To establish the feasibility of our approach, the conversion (1) Butler, R. N. In Comprehensive Heterocyclic Chemistry; Katritz- ky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, U.K., 1996; Vol. 4. (2) Singh, H.; Chawla, A. S.; Kapoor, V. K.; Paul, D.; Malhotra, R. K. Prog. Med. Chem. 1980, 17, 151-183. (3) Huisgen, R.; Sauer, J.; Sturm, H. J.; Markgraf, J. H. Chem. Ber. 1960, 93, 2106-2124. (b) Moderhack, D. 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(7) For more recent papers, see: (a) Fringuelli, F.; Pizzo, F.; Vaccaro L. Synthesis 2000, 646-650. (b) Amantini, D.; Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. Green Chem. 2001, 3, 229-232. (c) Fringuelli, F.; Matteucci, M.; Piermatti, O.; Pizzo, F.; Burla M. C. J. Org. Chem. 2001, 66, 4661-4666. (d) Fioroni, G.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. Green Chem. 2003, 5, 425-428. (e) Fringuelli, F.; Pizzo, F.; Rucci, M.; Vaccaro, L. J. Org. Chem. 2003, 68, 7041-7045. (f) Fringuelli, F.; Pizzo, F.; Tortoioli, S.; Vaccaro, L. J. Org. Chem. 2003, 68, 8248-8251. (g) Fringuelli, F.; Piermatti, O.; Pizzo, F. Synthesis 2003, 2331-2334. (h) Amantini, D.; Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. J. Org. Chem. 2003, 68, 9263-9268. (8) Amantini, D.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. J. Org. Chem. 2001, 66, 6734-6737. (b) Amantini, D.; Fringuelli, F.; Pizzo, F. J. Org. Chem. 2002, 67, 7238-7243. (c) Fringuelli, F.; Pizzo, F.; Tortoioli, S.; Vaccaro, L. Tetrahedron Lett 2003, 44, 6785-6787. (9) Corriu, R. J. P.; Perz, R.; Reye, C. Tetrahedron 1983, 39, 999- 1009. TABLE 1. TBAF-Catalyzed Reaction of Benzonitrile (1a) with TMSN3 under Solventless Conditions entry TMSN3 (equiv) TBAF (equiv) T (°C) C a (%) 1 1.0 85 2 1.0 0.1 85 35 3 1.5 0.1 85 40 4 1.5 0.1 120 78 5 1.5 0.3 85 89 6 1.5 0.5 85 >99 a Determined by 1 H NMR analysis. 2896 J. Org. Chem. 2004, 69, 2896-2898 10.1021/jo0499468 CCC: $27.50 © 2004 American Chemical Society Published on Web 03/20/2004