Dithiocarbamate as an efficient intermediate for the synthesis of 2-amino-1,3,4-thiadiazoles in water Fezzeh Aryanasab a , Azim Ziyaei Halimehjani b, * , Mohammad R. Saidi a, * a Department of Chemistry, Sharif University of Technology, PO Box 11465-9516, Tehran, Iran b Faculty of Chemistry, Tarbiat Moallem University, 49 Mofateh St., Tehran, Iran article info Article history: Received 7 June 2009 Revised 20 October 2009 Accepted 24 November 2009 Available online 27 November 2009 abstract A new and facile protocol for the synthesis of 2-amino-1,3,4-thiadiazoles in water is described. Reaction of acid hydrazides with easily prepared dithiocarbamates gives the corresponding thiadiazoles in moder- ate to excellent yields. 2-Amino-1,3,4-oxadiazoles were not observed as side products using this procedure. Ó 2009 Elsevier Ltd. All rights reserved. The synthesis of organic molecules via green, mild, and simple procedures is currently receiving considerable attention. Also, reducing or eliminating the use and generation of hazardous sub- stances is a goal of green chemistry. In this context, water is the preferred choice as a solvent. Reactions in aqueous media are gen- erally environmentally safe, devoid of any carcinogenic effects, are simple to handle, cheaper to operate, and are especially important in industry. 1 The development of efficient methods for the synthesis of 1,3,4- thiadiazoles has attracted significant interest. Substituted 1,3,4- thiadiazoles have become very useful compounds in medicine, agriculture, and in many fields of technology such as dyes, 2 lubri- cating compositions, 3 optically active liquid crystals, 4 photo- graphic materials 5 , and many others. Also, applications of 1,3,4- thiadiazoles in agriculture as herbicides, 6 fungicides 7 , and bacte- riocides 8 have been patented. Acetazolamide (acetazol), a carbonic anhydrase inhibitor launched in 1954, is a well-known drug based on the 1,3,4-thiadiazole ring. 9 Also, 1,3,4-thiadiazole derivatives have shown anti-inflammatory activity. 10 A variety of synthetic methods for the preparation of 1,3,4-thi- adiazoles have been reported. One of the most common procedures involves the cyclization of a 1,2-diacylhydrazine or its thia analog in the presence of a coupling agent such as SOCl 2 or POCl 3 , and a strong mineral acid. 11 Several recent publications have reported milder cyclization methods using (PhO) 2 P(O)Cl, Ph 3 P, TMSCl, and Lawesson’s reagent for the synthesis of 1,3,4-thiadiazoles. 12 There are many reports on the multi-step synthesis of thiadiazoles, 13 however, one-pot or one-step syntheses are rare. Varma and co- workers reported the first one-pot, one-step, solvent-free proce- dure for the synthesis of substituted 1,3,4-thiadiazoles using acid hydrazides and triethylorthoalkanoates in the presence of P 4 S 10 / Al 2 O 3 under microwave irradiation. 14 Solid-phase synthesis of 2- amino-1,3,4-thiadiazole derivatives via selective, reagent-based cyclization of acyldithiocarbazate resins was reported by Gong. 12a Also, Lau and co-workers reported the synthesis of 2-amino- 1,3,4-thiadiazole derivatives via reaction of a thiosemicarbazide bound to a resin and an aldehyde, followed by cyclization of the resulting thiosemicarbazone with a solution of iron(III) chloride in dichloromethane/methanol. 15 We recently reported several green, one-pot, and simple methods for the synthesis of dithiocarbamates from amines, CS 2 , and different nucleophile acceptors, such as alkyl halides, activated olefins, and epoxides, under solvent-free and aqueous conditions. 16 In continua- tion of our interest in the synthesis of novel dithiocarbamates and the use of these intermediates in organic transformations, 17 we have focused our attention on the reaction of dithiocarbamate 1 with acid hydrazide 2 (Scheme 1). We found that compound 3 was the only product and no cyclization product was observed. Also, on refluxing the reaction mixture in high boiling point solvents such as benzene, toluene, and DMF, acyclic product 3 was formed. Surprisingly, we found that the reaction of the dithiocarbamate and acid hydrazide in the presence of triethylamine or pyridine in water and under reflux, afforded the substituted 2-amino-1,3,4-thiadiazole 4 in 0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2009.11.100 * Corresponding authors. E-mail addresses: azimkzn@yahoo.com (A.Z. Halimehjani), saidi@sharif.edu (M.R. Saidi). N H R S S R N H H 2 N O R N H R S N H H N R O S N N R N H R 1 2 3 3 + solvent-free Et 3 N, 60 o C Et 3 N, H 2 O reflux 1 3 1 1 2 3 4 Scheme 1. Reaction of dithiocarbamate 1 with acid hydrazide 2 in water and under solvent-free conditions. Tetrahedron Letters 51 (2010) 790–792 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet