DOI: 10.1002/chem.201102254
A Convenient and General Palladium-Catalyzed Carbonylative Coupling for
the Synthesis of 2-Arylbenzoxazinones
Xiao-Feng Wu, Johannes Schranck, Helfried Neumann, and Matthias Beller*[a]
Benzoxazinones represent a class of annulated nitrogen
heterocycles that are of interest to organic synthesis owing
to their various biological activities.[1] Among the different
methodologies developed for their preparation,[2] cyclization
of anthranilic acid, N-acylanthranilic acid, or isotonic anhy-
dride are most accepted.[3] Although alternative methodolo-
gies are known,[4] 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 inex-
pensive carbon monoxide.[5] Combining such carbonylative
processes with subsequent intramolecular cyclization reac-
tions permits an efficient access to different heterocycles.[6]
In this respect, also few palladium-catalyzed carbonylative
syntheses of benzoxazinones are known (Scheme 1).[7]
of 2-iodoanilines with acid chlorides were developed by
Alper and Petricci and their co-workers.[7c,d] More recently,
À
interesting palladium-catalyzed carbonylative C H activa-
tion of benzanilides and aryl urea derivatives were inde-
pendently disclosed by Yu and co-workers,[7f] as well as
Lloyd-Jones and Booker-Milburn and their co-workers.[7e]
Despite these elegant achievements, it is still desirable to
extend known protocols for benzoxazinone synthesis. Based
on our ongoing interest in palladium-catalyzed carbonyla-
tion reactions,[8] we wish to present a new double carbonyla-
tion procedure, which allows for a general synthesis of 2-
(hetero)arylbenzoxazinones starting from easy available 2-
bromoanilines and (hetero)aryl bromides.
Initial experiments were carried out using the carbonyla-
tion of 2-bromoaniline and bromobenzene as a model reac-
tion. Some years ago, we introduced Pd/diadamantylalkyl-
phosphine catalysts for coupling reactions.[9] Recently, we
have shown that the Pd/BuPAd2 catalyst system is well
suited for different carbonylations.[10] Hence, we tested this
catalyst system in a model reaction at 1008C 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 in-
termediate 1 were observed as a side product. By simply in-
creasing the temperature to 1108C in NMP full conversion
of bromobenzene and 69% yield of product 2 was achieved
(Table 1, entry 5). Notably, other polar solvents at this tem-
perature still gave a mixture of 1 and 2 (Table 1, entries 6
and 7). Variation of ligands showed that other phosphine li-
The first example consisting of a stoichiometric thallation
and subsequent carbonylation of N-acetylaniline was report-
ed by Larock and Fellows.[7a] Later on, Cacchi and co-work-
ers published a general method for the carbonylative cou-
pling of 2-iodoanilines with unsaturated halides or trifla-
tes.[7b,g] In addition, similar carbonylative coupling reactions
gands such as PCy3 and PACHTUNTRGNEUNG(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 ap-
plying toluene in the presence of organic amines as base
gave the best yields (79–86%; Table 1, entries 14–16). How-
ever, at lower catalyst loading again a mixture of starting
materials and 1 and 2 was formed (Table 1, entry 17). Appa-
rently, the key intermediate of this carbonylative sequence
towards 2-phenylbenzoxazinone is N-(2-bromophenyl)ben-
zamide (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 Pd0 species to bromoben-
zene to give the ligated phenylpalladium(II)bromide com-
plex. Insertion of carbon monoxide leads to the respective
Scheme 1. Synthesis of benzoxazinones by means of Pd-catalyzed carbon-
ylation sequences.
[a] X.-F. Wu, J. Schranck, Dr. H. Neumann, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Fax : (+49)381-1281-5000
Supporting information for this article is available on the WWW
12246
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Chem. Eur. J. 2011, 17, 12246 – 12249