754 Microwave Assisted Synthesis of Dibenzoxazepines Vol 50 Mohammad Ghafarzadeh, * Ebrahim Saeedian Moghadam, and Fereshteh Faraji Chemistry and Chemical Engineering Research center of Iran (CCERCI), PO Box14335-186 Tehran, Iran *E-mail: mghaffarzadeh@ccerci.ac.ir Received October 6, 2011 DOI 10.1002/jhet.1548 Published online 24 June 2013 in Wiley Online Library (wileyonlinelibrary.com). Dibenzo[b,f][1,4]oxazepine derivatives were synthesized in good yields and short reaction times by the reaction of 2-chlorobenzaldehydes and 2-aminophenoles in basic conditions under microwave irradiation. J. Heterocyclic Chem., 50, 754 (2013). INTRODUCTION During the last decades microwave (MW) irradiation has became an increasingly valuable tool in organic chemistry, because it offers a versatile and facile pathway in a large variety of syntheses [1–3]. Thus, a large number of organic reactions can be carried out under MW irradiation in higher yields, shorter reaction time, and milder conditions. In this context, dibenzoxazepines show interesting features that make them attractive for use in MW synthesis. Benzoxazepine derivatives are important scaffolds in medicinal chemistry with various biological activities [4–7], and attractive compounds of growing pharmaceutical interest as documented by many publications. Among the benzoxazepines, the dibenzo[b,f][1,4]oxazepine derivatives are found in many physiologically active compounds [8–11]. Compound I acts as a non-nucleoside inhibitor of HIV-1 reverse transcriptase with an IC 50 value of 20 nM [12]. Other N-substituted dibenz[b,f][1,4]oxazepin-11(10H)-ones have been reported to exhibit antidepressant [13] and calcium antagonist activities [14]. Numerous derivatives II have been prepared and evaluated for PGE 2 antagonist and analgesic activities (Figure 1) [15–17]. Because of the wide range of pharmacological activity of dibenzo[b,f][1,4]oxazepines, there are different methods for the preparation of these compounds [18–24]. Reaction of 1-chloro-2-nitrobenzene and salicylaldehyde for the synthesis of dibenzo[b,f][1,4]oxazepine by a two-step method [18] (etherification and reductive cyclization) or by a three-step method (etherification, ketalization, and reductive cyclization) [19] was reported. Generally, these compounds are synthesized by intramolecular nucleophilic displacement of nitro, fluoro, or chloro groups in high boiling polar aprotic solvents at high temperature and long reaction times [25–29]. Because of these disadvantages, we sought to develop a facile, fast, and versatile method for the synthesis of dibenzo[b,f][1,4]oxazepines. RESULTS AND DISCUSSION Initially, the reaction of 2-chlorobenzaldehyde 1a and 2- aminophenol 2a as a simple model substrate in the presence of various bases in DMF was investigated under MW irradiation at 100  C (Table 1). As can be seen in Table 1, the best result was obtained with KOH as an inexpensive and available base under MW irradiation (entry 1). When this reaction was carried out without any base, the yield of the expected product was trace (Table 1, entry 5). Moreover, to further optimize the reaction temperature, the model reaction was carried out at the temperatures ranging from 80 to 140  C in DMF in the presence of KOH. As can be seen from Table 1, when the temperature was increased from 90 to 120  C in the same reaction time of 6 min, the yield of product 3a improved from 74 to 87% (Table 1, entries 6–8). Further increase of the temperature to 140  C caused a reduction in the yield (entries 9 and 10) and the formation of side products, presumably because of the breakup of the dibenzo[b,f][1,4]oxazepines. Therefore, 120  C was chosen as the most suitable reaction temperature for all further MW-assisted reactions. To delineate the role of MW irradiation, we performed the synthesis of 3a under classical heating conditions at 120  C. The product 3a was obtained in < 30% yield after 5 h (Scheme 1). However, under MW irradiation, the Cl CHO + HO H 2 N KOH/ DMF MW, 5 min. N O X Y X Y © 2013 HeteroCorporation