A convenient and general palladium-catalyzed carbonylative coupling for the synthesis of 2-arylbenzoxazinones.

Benzoxazinones represent a class of annulated nitrogen heterocycles that are of interest to organic synthesis owing to their various biological activities. Among the different methodologies developed for their preparation, cyclization of anthranilic acid, N-acylanthranilic acid, or isotonic anhydride are most accepted. Although alternative methodologies are known, the availability of substrates and required reaction conditions limited their application so far. Palladium-catalyzed carbonylation reactions allow for a general synthesis of all kinds of benzoic acid derivatives starting from easily available (hetero)aryl halides and inexpensive carbon monoxide. Combining such carbonylative processes with subsequent intramolecular cyclization reactions permits an efficient access to different heterocycles. In this respect, also few palladium-catalyzed carbonylative syntheses of benzoxazinones are known (Scheme 1). The first example consisting of a stoichiometric thallation and subsequent carbonylation of N-acetylaniline was reported by Larock and Fellows. Later on, Cacchi and co-workers published a general method for the carbonylative coupling of 2-iodoanilines with unsaturated halides or triflates. In addition, similar carbonylative coupling reactions of 2-iodoanilines with acid chlorides were developed by Alper and Petricci and their co-workers. More recently, interesting palladium-catalyzed carbonylative C H activation of benzanilides and aryl urea derivatives were independently disclosed by Yu and co-workers, as well as Lloyd-Jones and Booker-Milburn and their co-workers. Despite these elegant achievements, it is still desirable to extend known protocols for benzoxazinone synthesis. Based on our ongoing interest in palladium-catalyzed carbonylation reactions, we wish to present a new double carbonylation procedure, which allows for a general synthesis of 2(hetero)arylbenzoxazinones starting from easy available 2bromoanilines and (hetero)aryl bromides. Initial experiments were carried out using the carbonylation of 2-bromoaniline and bromobenzene as a model reaction. Some years ago, we introduced Pd/diadamantylalkylphosphine catalysts for coupling reactions. Recently, we have shown that the Pd/BuPAd2 catalyst system is well suited for different carbonylations. Hence, we tested this catalyst system in a model reaction at 100 8C in the presence of K2CO3 in various solvents (Table 1, entries 1–4). In all cases the desired 2-phenylbenzoxazinone (2) was formed; however, significant amounts of the aminocarbonylated intermediate 1 were observed as a side product. By simply increasing the temperature to 110 8C in NMP full conversion of bromobenzene and 69% yield of product 2 was achieved (Table 1, entry 5). Notably, other polar solvents at this temperature still gave a mixture of 1 and 2 (Table 1, entries 6 and 7). Variation of ligands showed that other phosphine ligands such as PCy3 and P ACHTUNGTRENNUNG(tBu)3 were also successful in this reaction, but BuPAd2 gave slightly better product yields (Table 1, entries 5 and 8–11). Finally, it was found that applying toluene in the presence of organic amines as base gave the best yields (79–86%; Table 1, entries 14–16). However, at lower catalyst loading again a mixture of starting materials and 1 and 2 was formed (Table 1, entry 17). Apparently, the key intermediate of this carbonylative sequence towards 2-phenylbenzoxazinone is N-(2-bromophenyl)benzamide (1). Indeed, further carbonylation of isolated 1 under the optimized conditions resulted in 92% yield of the desired product 2 (Scheme 2). Hence, the following mechanism is proposed for this new domino transformation (Scheme 3). The reaction starts with an initial oxidative addition of a Pd species to bromobenzene to give the ligated phenylpalladium(II)bromide complex. Insertion of carbon monoxide leads to the respective [a] X.-F. Wu, J. Schranck, Dr. H. Neumann, Prof. Dr. M. Beller Leibniz-Institut f r Katalyse e.V. an der Universit t Rostock Albert-Einstein-Strasse 29a, 18059 Rostock (Germany) Fax: (+49)381-1281-5000 E-mail : [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201102254. Scheme 1. Synthesis of benzoxazinones by means of Pd-catalyzed carbonylation sequences.