Microwave assisted synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from substituted amidoximes and benzoyl cyanides Shivaji Kandre a , Pundlik Rambhau Bhagat b , Rajiv Sharma a , Amol Gupte a,⇑ a Department of Medicinal Chemistry, Piramal Enterprises Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon (East), Mumbai 400 063, Maharashtra, India b VIT University, Vellore 632 014, Tamil Nadu, India article info Article history: Received 12 February 2013 Revised 22 April 2013 Accepted 25 April 2013 Available online 3 May 2013 Keywords: Microwave-assisted synthesis 3,5-Disubstituted 1,2,4-oxadiazoles Amidoximes Benzoyl cyanides abstract We report herein the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from amidoximes and substituted or unsubstituted benzoyl cyanides under microwave irradiation. Substituted or unsubstituted O-carboxy- phenyl amidoxime is a key intermediate of this alternative method developed for the synthesis of these heterocycles. These reactions employ simple synthetic protocols devoid of lengthy purification proce- dures and proceed with good yield. Ó 2013 Elsevier Ltd. All rights reserved. The heterocycle, 1,2,4-oxadiazole is frequently observed in a number of biologically relevant molecules. 1a–e The importance of a 1,2,4-oxadiazole motif in medicinal chemistry has increased due to its application as a stable bioisostere in place of an amide, ester, or urea functionality. 2a–c Within literature, the 1,2,4-oxadiaz- ole ring system appears as a part of several compounds that may potentially act as serotonergic (5-HT3) antagonists, 3 tyrosine kinase inhibitors, 4 monoamine oxidase inhibitors, 5 aldose reduc- tase inhibitors, 6 metabotropic glutamate subtype 5 (mGlu5) recep- tor antagonists, 7 muscarinic agonists, 8 and S1P1 agonists. 9 The application of 5-benzyloxy-1,2,4-oxadiazole as a precursor and protecting group for amidines has also been documented. 10 As a re- sult of such a wide spread application of the 1,2,4-oxadiazole ring system, there has been an immense interest in developing conve- nient methodologies for the synthesis of this heterocycle. An approach commonly reported for 1,2,4-oxadiazole synthesis undertakes O-acylation of an amidoxime by an activated carbox- ylic acid derivative in the first step followed by a second step of cyclodehydration. 11 Activated carboxylic acid derivatives used for the O-acylation step include esters, 12 orthoesters, 13 acid chlo- rides, 14 and anhydrides. 15 The use of carbodiimides such as EDC, 16a–c CDI, 17 and DCC 18a,b for in situ activation of carboxylic acids has been previously published. Cyclization of the O-acyl amidox- ime intermediate can be subsequently achieved following the use of bases such as sodium hydride or sodium ethoxide at room temperature, or in pyridine on heating. Effective cyclization of the O-acyl amidoxime intermediate generally warrants the use of elevated temperature coupled with varying reaction times. 19 Another commonly used method for the synthesis of 1,2,4-oxadi- azoles involves a 1,3-dipolar cycloaddition of nitriles to nitrile oxi- des. 20 Microwave assisted organic synthesis of 1,2,4-oxadiazoles involving a one pot three-component reaction between organic nitriles, hydroxylamine, and aldehydes has also been reported. 21 This reaction requires conditions that involve heating under micro- wave irradiation at 150 °C with an organic nitrile and exhibits excellent yields of 3,5-disubstituted 1,2,4-oxadiazoles. The use of PTSA-ZnCl 2 provides a milder alternative for the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from amidoximes and organic nitriles. 22 Tetrabutylammonium fluoride (TBAF) has also been developed as a mild catalyst for the synthesis of 1,2,4-oxadiazoles from amidoximes. 23 A one pot palladium mediated coupling of amidoximes with aryliodides under one atmosphere carbon mon- oxide for the synthesis of 1,2,4-oxadiazoles has also been pub- lished. 24 A simple catalyst-free synthesis of 1,2,4-oxadiazoles from amidoximes and anhydrides in water with moderate yields is also possible. 25 With a variety of challenges involved in organic synthesis and the advent of newer technologies, methodologies providing for ease of synthesis from readily available chemical reagents, purifi- cation, and convenient isolation of the products prove valuable additions to existing scientific literature. The use of microwave irradiation for shortening reaction time and improving yield has increased dramatically in recent years. In this letter, we have eval- uated the feasibility of synthesizing 1,2,4-oxadiazoles from ami- doximes and commercially available benzoyl cyanides. Our 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.04.101 ⇑ Corresponding author. Tel.: +91 22 30818312; fax: +91 22 30818036. E-mail address: amol.gupte@piramal.com (A. Gupte). Tetrahedron Letters 54 (2013) 3526–3529 Contents lists available at SciVerse ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet