COMMUNICATION
DOI: 10.1002/chem.201202142
A General Palladium-Catalyzed Carbonylative Synthesis of
2-Alkylbenzoxazinones from 2-Bromoanilines and Acid Anhydrides
Xiao-Feng Wu,*[a, b] Helfried Neumann,[b] and Matthias Beller*[b]
Benzoxazinones represent a class of annulated nitrogen
heterocycles that are of interest in organic synthesis due to
their various biological activities.[1] Among the different
methodologies developed for their preparation,[2] the cycli-
zation of anthranilic acid, N-acylanthranilic acid or isotonic
anhydride are the most accepted.[3] Although alternative
methodologies are known,[4] the availability of substrates
and the required reaction conditions have limited their ap-
plication so far.
Palladium-catalyzed carbonylation reactions allow for a
general synthesis of many kinds of benzoic acid derivatives
from easily available starting materials, such as (hetero)aryl
halides and inexpensive carbon monoxide.[5] Combining this
carbonylative process with a subsequent intramolecular cyc-
lization reaction would allow efficient access to different
heterocycles;[6] however, in this respect, few palladium-cata-
lyzed carbonylative syntheses of benzoxazinones are
known.[7] The first example, which involves a stoichiometric
thallation and subsequent carbonylation of N-acetylaniline,
was reported by Larock and Fellows.[7a] Later, Cacchi and
co-workers published a general method for the carbonyla-
tive coupling of 2-iodoanilines with unsaturated halides or
triflates.[7b] In addition, similar carbonylative coupling reac-
tions of 2-iodoanilines with acid chlorides were developed
by Alper and Petricci and their co-workers.[7c,d] Recently, an
interesting method for the palladium-catalyzed carbonyla-
bonylation reactions,[8] we herein wish to present a new car-
bonylation procedure that allows for a general synthesis of
2-alkylbenzoxazinones starting from easy available 2-bro-
moanilines and acid anhydrides.
Initial experiments were carried out by using the carbony-
lation of 2-bromoaniline and Ac2O as a model reaction. We
have recently shown that the Pd/BuPAd2 catalyst system is
well suited for different carbonylations.[9] Hence, we initially
used this catalyst system at 1008C in the presence of NEt3
and various solvents for our investigations (Table 1, en-
tries 1–6). Toluene, as a non-polar solvent, gave better yields
than polar solvents, and 73% of the desired product was
produced when this solvent was used (Table 1, entry 1).
Thus we used toluene as the solvent to test the influence of
various ligands. The use of PPh3 resulted in a lower yield,
and no product was formed with PACHTNURGTNEUNG(tolyl)3 as the ligand
(Table 1, entries 7 and 8). The bidentate phosphine ligands
that were tested show comparable results to BuPAd2, and
gave 62–71% yield of the desired products (Table 1, en-
tries 9–12). The reactions were also carried out with differ-
ent bases; an improved yield was obtained by using DiPEA
as the base, but none of the desired product was formed
with the use of inorganic bases (Table 1, entries 13–18). The
effect of different palladium salts was also tested (Table 1,
entries 19–23). 2-Methylbenzoxazinone was produced in
84% yield by applying K2PdCl4 as the catalyst precursor
(Table 1, entry 23). By combining the most effective base
(DiPEA) and palladium salt (K2PdCl4), the yield of desired
product was further improved to 88% (Table 1, entry 24).
With the use of 1 mol% of the catalyst, the yield of our de-
sired product decreased to 47%, and N-(2-bromophenyl)a-
cetamide was formed as a byproduct in 50% yield (Table 1,
entry 25). To our delight, a 95% yield of 2-methylbenzoxazi-
none was obtained from the reaction with 1.5 equivalents of
Ac2O, which could even be carried out under 2 bar of CO
without a change in the yield (Table 1, entries 26 and 27).
With the best conditions in hand, we tested the generality
of this methodology. Methyl-, fluoro- and chloro-substituted
2-bromoanilines reacted successfully with Ac2O and gave
the desired products in isolated yields of 83–94% (Table 2,
entries 2–7). 7-Acetyl-2-methyl-4H-benzoxazin-4-one was
obtained in 84% yield from the corresponding 2-bromoani-
line derivative (Table 2, entry 8). Pyridine was used as a rep-
resentative example of a heterocycle, and its bromoamino
derivative was transformed into the corresponding benzoxa-
zinone in 89% yield (Table 2, entry 9).
À
tive C H activation of benzanilides and aryl urea deriva-
tives was developed independently by Yu et al.[7f] and Loyd-
Jones, Booker-Milburn et al.[7e] More recently, our group re-
ported an efficient palladium-catalyzed carbonylative cou-
pling of aryl bromides with 2-bromoanilines to 2-arylbenzox-
azinones in good yields;[7 h] however, we failed in the prepa-
ration of 2-alkyl substituted benzoxazinone derivatives.
Based on our ongoing interest in palladium-catalyzed car-
[a] Dr. X.-F. Wu
Department of Chemistry
Zhejiang Sci-Tech University, Xiasha Campus
Hangzhou, Zhejiang Province 310018 (P.R. China)
[b] Dr. X.-F. Wu, 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
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Wu, Xiao-Feng
