Experimental and theoretical push-pull Chemo- and regioselectivity in 1,3-Dipolar cycloaddition reactions: The case of benzotriazepin-5-one with mesitylnitrile oxide Saida Azzouzi, 1 Rachid Jalal, 2 Malika El Messaoudi, 1 Luis R. Domingo, 3 M’hamed Esseffar 1 * and M. Jose ´ Aurell 3 1 Universite ´ Cadi Ayyad, Faculte ´ des Sciences-Semlalia, De ´ partement de Chimie, BP 2390, Marrakesh, Morocco 2 Universite ´ Cadi Ayyad, Faculte ´ des Sciences et Techniques, De ´ partement des Sciences Chimique, BP 549, Marrakesh, Morocco 3 Instituto de Ciencia Molecular, Departamento de Quimica Organica, Universidad de Valencia, Dr. Moliner 50, E-46100 Burjassot, Valencia, Spain Received 13 June 2006; revised 20 July 2006; accepted 31 July 2006 ABSTRACT: A novel heterocyclic compound 3-mesityl-5-methyl-4,5,11,11a-tetrahydro-6H-[1,2,4]oxadiazolo [5,4-b][1,3,4]benzotriaze ´pin-6-one 4 has been synthesised by a 1,3 dipolar cycloaddition (13DC) reaction of 1,3,4-benzotriazepin-5-one 1 with mesitylnitrile oxide 3. The reaction, beside its synthetic interest, has shown to be completely chemo- and regioselective. The structure of the compound was determined by X-ray crystallography and analysed by spectral methods (NMR and mass spectrometry). The molecular mechanism for the reaction has been studied using quantum mechanical calculations at the B3LYP/6-31G  theory level. Two mechanisms are possible for the formation of the cycloadduct 4. The first one involves a 13DC reaction between 1, as dipolarophile and 3, as dipole. Analysis of the results indicates that it takes place along asynchronous concerted bond-formation process with a very low polar character. The regioselectivity obtained from the calculations are in complete agreement with the unique formation of the cycloadduct 4. The second mechanism is initiated by the nucleophilic attack of the N3 nitrogen of the tautomer form of 2, to the C5 carbon of the nitrile oxide 3 to yield an amidoxime. However, the large energy involved in this addition prevents this mechanism. The large energy difference between the tautomers 1 and 2, makes that only the C — —N site of benzotriazepin-5-one 1 could act as a dipolarophile site. This fact makes the 13DC reaction to be chemoselective. The analysis of global electrophilicity of the reagents allows explaining the low polar character of these 13DC reactions. Copyright # 2007 John Wiley & Sons, Ltd. Supplementary electronic material for this paper is available in Wiley InterScience at http://www.mrw.interscience. wiley.com/suppmat/0894-3230/suppmat/v20.html KEYWORDS: 1,3-dipolar cycloaddition; Benzotriazepines; chemo- and regioselectivity; synthesis; quantum mechanical calculations INTRODUCTION The 1,3-dipolar cycloaddition (13DC) reaction constitu- tes one of the most important way used, in organic reaction, for the synthesis of a variety of five-membered heterocyclic systems. 1–10 13DC reactions were long been drawing the attention of both experimental and theoretical chemists since their introduction by Huisgen in the early 1960s. 11 In view of such a myriad of possibilities, much effort has been devoted towards the development of synthetic methods using heteroatomic systems. 12 Among them, 2-isoxazolines, obtained by reaction of nitrile oxides with alkene dipolarophiles, have been extensively studied due to their usefulness in medicine and agriculture, as well as their synthetic versatility. 13 Isoxazoline systems are often used in total synthesis as latent synthons, such as masked new heterocyclic or aromatic rings. Owing to their well-established role as psychother- apeutics, 14 benzodiazepines have been the object of intense investigation in medicinal chemistry. The area of biological interest of this family of compounds has been extended recently to various diseases such as cancer, 15 viral infections (HIV) 16 and cardiovascular disorders. 17 Such a versatile biological activity of the benzodiazepine pharmacophore has prompted investigations into their JOURNAL OF PHYSICAL ORGANIC CHEMISTRY J. Phys. Org. Chem. 2007; 20: 245–254 Published online in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/poc.1145 *Correspondence to: M. Esseffar, Universite ´ Cadi Ayyad, Faculte ´ des Sciences-Semlalia, De ´partement de Chimie, BP 2390, Marrakesh, Morocco. E-mail: esseffar@ucam.ac.ma Copyright # 2007 John Wiley & Sons, Ltd. J. Phys. Org. Chem. 2007; 20: 245–254