Accepted Article Direct C-H Bond Activation of Benzoxazole and Benzothiazole with Aryl Bromides Catalyzed by Palladium(II)-N-Heterocyclic Carbene Complexes Murat Kaloğlu, a,b Nazan Kaloğlu a,b and İsmail Özdemir* a,b a Department of Chemistry, Faculty of Science and Arts, İnönü University, 44280 Malatya, Turkey b Catalysis Research and Application Center, İnönü University, 44280 Malatya, Turkey *E-mail: ismail.ozdemir@inonu.edu.tr; Tel. and fax number: +90-422-341-0212. Herein we report, a series of novel palladium(II)-NHC complexes (NHC = N-heterocyclic carbene) were synthesized. The structures of all novel complexes were characterized by 1 H NMR, 13 C NMR, FT-IR spectroscopy and elemental analysis techniques. These palladium(II)-NHC complexes were tested as efficient catalysts in the direct C-H bond activation of benzoxazole and benzothiazole with aryl bromides in presence of 1 mol% catalyst loading at 150 °C for 4 h. Under the given conditions, various aryl bromides were successfully applied as the arylating reagents to achieve the 2-arylbenzoxazoles and 2-arylbenzothiazoles in acceptable to high yields. Keywords benzimidazolium bromide, benzoazoles, direct C-H bond activation, N-heterocyclic carbene, palladium Introduction 2-Arylsubstituted benzoazoles are an important class of heterocyclic compounds that are widely found in bioactive molecules, [1,2] pharmaceuticals [3,4] and natural products, [5] due to their diverse biological and pharmacological properties. In addition, these compounds have become essential building blocks for the synthesis of conjugated functional materials, such as industrial dyes and plant growth regulators. [6] For example, benzothiazole derivatives are the pharmacophore of zopolrestat, which has been used for the treatment of diabetes. [7,8] Benzoxazoles are also well known for their biological activities, e.g. as an antiinflammatory agent and antibacterial agent. [9] Biologically active some benzoazoles are exemplified in Figure 1. Figure 1 Examples of biologically active benzoazole derivatives Given the importance of benzoazoles, many methods have been developed for the preparation of these benzofused heterocyclic structures in recent years. Specifically, benzoxazole and benzothiazole derivatives have attracted the attention of many research groups and biological activities have made them popular synthetic targets. [10-12] The conventional methods for the synthesis of 2-arylsubstituted benzoxazoles and benzothiazoles typically involve three main strategies: (i) Intermolecular cyclization of 2-amino(thio)phenol with amines (Scheme 1a), [13] (ii) Intramolecular cyclization of halobenzanilides (Scheme 1b), [14] and (iii) Ring-opening-coupling-recyclization of benzoxazole or benzothiazole with aromatic aldehydes or benzoyl chloride (Scheme 1c). [15] These protocols require high temperatures, which limits the substrate scope with temperature-sensitive heterocyclic aryl halides. Furthermore, in many cases these reactions were performed in high boiling solvents, such as DMSO, DMF, and NMP, which complicate product isolation. Alternatively, 2-aryl-substituted benzoxazoles and benzothiazoles can be prepared by direct arylation of heterocycles through metal-catalyzed direct C-H bond activation (Scheme 1d). [16-20] Since the direct arylation has many advantages such as step-economy, atom-economy, high efficiency, simple operation, and mild reaction conditions, it represent an environmentally, economically and potentially more attractive strategy. Hence, the direct C-H bond arylation of such compounds is receiving growing attention in the context of organic synthesis. A variety of electrophilic reagents including aryl halides [21-24] , aryl organometallic reagents [25] , unactivated simple arenes [26] , and phenol derivatives such as triflates [19,27-28] , mesylates [29] , sulfamates [30] and acids [31] have been employed for the transformation. Similarly, arene sulfonyl chlorides [32] and arene diazonium salts [33] are inexpensive and readily available arylating reagents. Among these arylating reagents, especially aryl halides have been employed as the most widely used arylating reagents owing to their commercial availability and substituted diversity. This article is protected by copyright. All rights reserved. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/cjoc.201800166