Regioselective synthesis of 6-benzylthiazolo- [3,2-b]1,2,4-triazoles during Sonogashira coupling Majid M. Heravi, a, * Ali Kivanloo, b Mohammad Rahimzadeh, b Mehdi Bakavoli, b Mitra Ghassemzadeh c and Bernhard Neumu ¨ller d a Department of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran 1993891167, Iran b Department of Chemistry, School of Sciences, Ferdowsi University of Mashhad, Mashhad 1331418, Iran c Chemistry & Chemical Engineering Research Center of Iran, Tehran 14335186, Iran d Fachbereich Chemie der Universita ¨t, Marburg 35043, Germany Received 29 September 2004; revised 9 January 2005; accepted 19 January 2005 Available online 1 February 2005 Abstract—The reaction of 3-mercaptopropargyl-1,2,4-triazoles with various iodobenzenes catalyzed by Pd–Cu leads to the regio- selective formation of 6-benzylthiazolo[3,2-b]1,2,4-triazoles 4. The structure of 4d was confirmed by X-ray analysis. Ó 2005 Elsevier Ltd. All rights reserved. 1. Introduction The azole antifungals appear to offer scope for provid- ing truly effective drugs. 1 Imidazole antifungals such as clotrimazole, miconazole and ketoconazole show good activity, but are only of limited value for systemic administration. 2 Triazole derivatives possess a broad spectrum of antifungal activity and reduced toxicity compared with the imidazole antifungals. 2 Although several methods have been reported for the synthesis of thiazolo[3,2-b]1,2,4-triazoles, 3 those which use 3-mercapto-1,2,4-triazoles 1 as the starting materials have the disadvantage of also giving regioisomeric thiaz- olo[2,3-c]1,2,4-triazoles. 4 Pd-catalyzed annulation has been utilized successfully for the synthesis of carboxylic 5 and heterocyclic com- pounds. 6 In continuation of our recent studies 7 on Pd- catalyzed reactions of acetylenes leading to heterocyclic compounds of biological significance, we became interested in developing a regioselective synthesis of substituted thiazolo-1,2,4-triazoles. 3-Mercapto-1,2,4-triazoles 1 (R = CH 3 and Ph) 8 were reacted with propargyl bromide in refluxing ethanol to yield the corresponding 3-propargylmercapto-1,2,4- triazoles 2. 8 When 2 (R = Ph) was treated with 4-nitro- 1-iodobenzene 3d and triethylamine in the presence of bis(triphenylphosphine)palladium chloride and copper iodide, a single compound was obtained as detected by TLC. The 1 H NMR spectrum of the product showed one aromatic proton at d 6.52 ppm, characteristic of a fused thiazole ring, as well as benzylic protons at d 6.52 ppm. The mass spectrum showed an M + at m/z 336. Mechanistically, either thiazolo-1,2,4-triazines 4d or 5d were possible products as illustrated in Scheme 1. Prob- ably a two-step process had occured: a standard Sono- gashira coupling 9 followed by a Pd(II)-catalyzed intermolecular cyclization of either nitrogen 2 or nitro- gen 4 onto the triple bond followed by base-induced aromatization. 10 However, other mechanisms for this reaction are also plausible, for example, cyclization via initial generation of the exocyclic olefin followed by an intermolecular Heck reaction, which would provide a facile pathway for migration of the double bond into the endocyclic po- sition 11 or alternatively a 5-exo dig. cyclization may be simply triggered by the formation an Ar–Pd(II) species followed by reduction, elimination–isomerization. This type of cyclization has been observed for acetylenic lactams. 12 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.01.091 Keywords: Sonogashira coupling; Thiazoles; Triazoles; Pd-catalyzed reaction; Thiazolotriazoles. * Corresponding author. Tel.: +98 21 804 13 47; fax: +98 21 804 78 61; e-mail: mmh1331@yahoo.com Tetrahedron Letters 46 (2005) 1607–1610 Tetrahedron Letters