Microwave-Assisted One-Pot Tandem Reactions for Direct Conversion of Primary Alcohols and Aldehydes to Triazines and Tetrazoles in Aqueous Media Jiun-Jie Shie and Jim-Min Fang* Department of Chemistry, National Taiwan UniVersity, Taipei 106, Taiwan, and The Genomics Research Center, Academia Sinica, Taipei 115, Taiwan jmfang@ntu.edu.tw ReceiVed December 12, 2006 A series of primary alcohols and aldehydes were treated with iodine in ammonia water under microwave irradiation to give the intermediate nitriles, which without isolation underwent [2 + 3] cycloadditions with dicyandiamide and sodium azide to afford high yields of the corresponding triazines and tetrazoles, including the R-amino- and dipeptidyl tetrazoles in high optical purity. Using water as a safe medium for various organic reactions has been reviewed. 1 We have previously shown that a variety of aldehydes are converted to their corresponding nitriles using iodine as an appropriate oxidant in ammonia water. 2 In comparison with similar reactions using liquid ammonia or ammonia gas saturated in alcohol solvents, 3 operation in ammonia water is simpler and more efficient, giving the nitriles in high yields at room temperature within a short reaction time (<1 h). Nitrile compounds are viable precursors for preparation of nitrogen-containing functional compounds. 4 We have previ- ously demonstrated the tandem reactions of various aldehydes in aqueous media to furnish the corresponding amides, triazines, and tetrazoles via the intermediate nitriles by additions of H 2 O 2 , dicyandiamide/KOH, and NaN 3 /ZnBr 2 in one-pot procedures. 5 Though the reaction of the intermediate nitriles with H 2 O 2 was carried out smoothly at room temperature, the formation of triazines and tetrazoles still required refluxing (e.g., g100 °C) for a prolonged period (12-48 h). In order to improve these preparation protocols, we considered using microwave irradia- tion, which has become a powerful technique to accelerate thermally driven chemical reactions. 6 It has been shown that aryl halides are converted to the aryl nitriles and further to the aryl tetrazoles in a tandem reaction with sodium azide under microwave irradiation in DMF solution or on solid support. 7 We anticipated that the similar cycloaddition reactions of nitriles would be enhanced by microwave irradiation, especially in the above-mentioned salt-containing aqueous media that may take microwave energy effectively. Our study began with the direct conversion of an aldehyde with iodine in ammonia water to a nitrile intermediate, which without isolation was heated with dicyandiamide, using a focused microwave reactor (power of 80-100 W), to furnish the [2 + 3] cycloaddition product 2,6-diamino-1,3,5-triazine in a one-pot operation (Scheme 1 and Table 1). The 1,3-dipolar cycloaddition of nitrile compounds 2a-e (generated in situ from aldehydes 1a-e) with dicyandiamide proceeded smoothly at 80 °C under microwave irradiation. 8 The reaction time was shortened to 15-30 min, even without using KOH as an external base, which is often utilized as a promoter in conventional heating methods. 5,9 Diamino-1,3,5-triazines such as 3a-e are a class of compounds possessing diverse bioactivities 10 and widely used in material design via assembly of the multiple hydrogen-bonded complexes. 11 * To whom correspondence should be addressed. Tel: (886-2)-33661663. Fax: (886-2)-23637812. (1) (a) Reichardt, C. In SolVents and SolVent Effects in Organic Chemistry; VCH: Weinheim, Germany, 2003. (b) Li, C. J. Chem. ReV. 1993, 93, 2023-2035. (c) Li, C. J. In Organic Reactions in Aqueous Media; Wiley: New York, 1997. (d) Lindstro ¨m, U. M. Chem. ReV. 2002, 102, 2751-2772. (e) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275-3279. (2) Talukdar, S.; Hsu, J.-L.; Chou, T.-K.; Fang, J.-M. Tetrahedron Lett. 2001, 42, 1103-1105. (3) Misono, A.; Osa, T.; Koda, S. Bull. Chem. Soc. Jpn. 1967, 40, 2875- 2884. (4) (a) Mowry, D. T. Chem. ReV. 1948, 42, 189-283. (b) Friedrich, K.; Wallensfels, K. In The Chemistry of Cyano Group; Rappoport, Z., Ed.; Wiley-Interscience: New York, 1970. (c) North, M. In ComprehensiVe Organic Functional Group Transformations; Katritzky, A. R., Meth-Conn, O., Rees, C. W., Eds.; Pergamon: Oxford 1995; pp 617-618. (5) (a) Shie, J.-J.; Fang, J.-M. J. Org. Chem. 2003, 68, 1158-1160. (b) Taber, D. F. Org. Chem. Highlights: Best Synthetic Methods; March 8, 2004; www.organic-chemistry.org. (6) (a) Mingos, D. M. P.; Baghurst, D. R. MicrowaVe-Enhanced Chemistry: Fundamentals, Sample Preparation, and Applications; Kingston, H. M., Haswell, S. J., Eds.; American Chemical Society: Washington, DC, 1997. (b) Hayes, B. L. MicrowaVe Syntheses: Chemistry at the Speed of Light; CEM Publishing: Mattews, NC, 2002. (c) De la Hoz, A.; Diaz- Ortiz, A.; Langa, F. MicrowaVes Org. Syn. 2002, 295-343. (d) Nuechter, M.; Ondruschka, B.; Bonrath, W.; Gum, A. Green Chem. 2004, 6, 128- 141. (e) Kuznetsov, D. V.; Raev, V. A.; Kuranov, G. L.; Arapov, O. V.; Kostikov, R. R. Russ. J. Org. Chem. 2005, 41, 1719-1749. (f) Wolkenberg, S. E.; Shipe, W. D.; Lindsley, C. W.; Guare, J. P.; Pawluczyk, J. M. Curr. Opin. Drug DiscoVery DeV. 2005, 8, 701-708. (g) Westman, J. MicrowaVe Assisted Org. Synth. 2005, 102-132. (h) Leadbeater, N. E. Chem. Commun. 2005, 23, 2881-2902. (i) Kaval, N.; Ermolat’ev, D.; Appukkuttan, P.; Dehaen, W.; Kappe, C. O.; Van der Eycken, E. J. Comb. Chem. 2005, 7, 490-502. (7) Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984-7989. (8) The cycloadditions of nitriles with dicyandiamide are usually conducted by heating methods; however, an example using microwave irradiation in ionic liquid has been reported. See: Peng, Y.; Song, G. Tetrahedron Lett. 2004, 45, 5313-5316. 10.1021/jo0625352 CCC: $37.00 © 2007 American Chemical Society J. Org. Chem. 2007, 72, 3141-3144 3141 Published on Web 03/16/2007