Synthesis of aryl-hydrazones via ultrasound irradiation in aqueous medium Ana Cristina Lima Leite * , Diogo Rodrigo de M. Moreira, Lucas Cunha Duarte Coelho, Frederico Duarte de Menezes, Dalci Jose ´ Brondani * LabSINFA—Laboratory for the Planning, Synthesis and Evaluation of Pharmaceutical Products, Department of Pharmaceutical Science, Centre for Health Science, Federal University of Pernambuco, 50740-520 Recife, PE, Brazil Received 11 November 2007; revised 15 December 2007; accepted 18 December 2007 Abstract The synthesis of aryl-hydrazones from aromatic aldehydes/ketones and hydrazides (semicarbazide, thiosemicarbazide and amino- guanidine) is described using aqueous medium (acid conditions) under ultrasound irradiation with short reaction times (20–30 min), the reactions occurring at room temperature and giving rise to good to excellent yields of the products, along with the diastereoselectivities. The procedure is also simple and clean. Ó 2007 Published by Elsevier Ltd. Keywords: Hydrazones; Aqueous medium; Ultrasound irradiation; Condensation Aryl-hydrazones, such as semicarbazones, thiosemicar- bazones and guanyl hydrazones, are important compounds for drug design, 1 as possible ligands for metal complexes, 2 organocatalysis 3 and also for the preparation of hetero- cyclic rings. 4 At present a broad range of methods for synthesizing imines 5 in the presence of catalysts are available: ZnCl 2 , 6 TiCl 2 , 7 K-10, 8 MgSO 4 -PPTL, 9 Mg(ClO 4 ) 2 10 and also SiO 2 –NaHSO 4 (under MW irradiation condition). 11 More recently, ultrasound irradiation has been used to give rise to the formation of a series of Schiff bases (aryl–aryl and aryl–alkyl), under solvent-free conditions 12 or using SiO 2 as a catalyst in ethanol, 13 with short reaction times (10– 20 min) and high yields. For aryl-hydrazones, most reaction methods described to date involve the use of methanol as a solvent without catalysts at reflux, although ethanol and acid catalysis (or p-toluenesulfonic acid in dried toluene) are required if the carbonyl compounds bear a strong electron-withdrawing group. 14 Improvements in yields of the aryl-hydrazones synthesis have been achieved when MW-irradiation at sol- vent-free conditions were used. 15 In some cases, a mixture of isomers (Z and E) is reported, mainly for reaction pro- cedures that are only possible at high temperatures or for prolonged reaction periods. 16 At the same time, many addition/condensation reactions have been demonstrated to occur in aqueous media (such as: Barbier and Mannich-type reactions, Diels–Alder cyclo- addition, and Knoevenagel condensation). 17 Water is the cheapest and safest solvent available, and in the presence of reactive functional groups, protection and deprotec- tion processes are often unnecessary. In fact, total solubility is required for efficient reaction in water, and thus, either organic co-solvents or heating are almost always employed. 18 Although Schiff and colleagues have reported that the presence of water is a disadvantage in imine synthe- sis, three works have shown that such reactions can be effective in completely aqueous media under mild condi- tions. 19 More recently, a protocol for the synthesis of aryl- and heterocyclic-hydrazones from aryl-hydrazine 0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd. doi:10.1016/j.tetlet.2007.12.103 * Corresponding authors. Tel./fax: +55 81 2126 8511 (A.C.L.L.). E-mail addresses: ana.leite@pq.cnpq.br (A. C. L. Leite), dalci@ufpe.br (D. J. Brondani). Available online at www.sciencedirect.com Tetrahedron Letters 49 (2008) 1538–1541