A convenient palladium-catalyzed carbonylative synthesis of 2-aminbenzoxazinones from 2-bromoanilines and isocyanates

Article abstract of DOI:10.1002/chem.201300537

Mon ami(ne)! A general and convenient methodology for 2-aminobenzoxazinone synthesis has been developed (see scheme). Readily available 2-bromoanilines and isocyanates were used as substrates and various products have been prepared in good yields. Notably, [Mo(CO)₆] as a solid CO source was applied instead of gas. Copyright

Full text of DOI:10.1002/chem.201300537

DOI: 10.1002/chem.201300537
A Convenient Palladium-Catalyzed Carbonylative Synthesis of
2-Aminbenzoxazinones from 2-Bromoanilines and Isocyanates
Xiao-Feng Wu,*[a, b] Muhammad Sharif,[b, c] Khurram Shoaib,[c] Helfried Neumann,[b]
Anahit Pews-Davtyan,[b] Peter Langer,[b, d] and Matthias Beller*[b]
Benzoxazinones represent an important class of nitrogen
heterocycles with various biological activities. Among all the
substituted benzoxazinones, 2-amino substituted benzoxazi-
nones can be considered as the most valuable as numerous
biological activities have been reported for these com-
pounds; however, methodologies for their preparation are
still rare.[1,2]
zoxazinones.[5h,i] However, we didn’t succeed in the synthesis
of the biologically more important 2-amino-substituted ben-
zoxazinones (Scheme 1). As part of our continual interest in
Palladium-catalyzed carbonylation reactions allow for a
general synthesis of all kinds of benzoic acid derivatives by
starting from easily available (hetero)aryl halides and inex-
pensive carbon monoxide.[3] Combining such carbonylative
processes with subsequent intramolecular cyclization reac-
tions permits an efficient access to different heterocycles.[4]
Palladium-catalyzed carbonylative syntheses of benzoxazi-
nones have been developed for a long time, but the applica-
tion of carbonylation in the preparation of biologically im-
portant 2-amino-substituted benzoxazinones is rarely report-
ed.[5]
Even though carbon monoxide (CO) is known as one of
the cheapest C1 sources, the necessity of special equipment
(such as an autoclave) for its manipulation and its high tox-
icity have limited the synthetic applications of carbonylation
reactions that require CO gas. With these problems in mind,
over the last two decades, organic chemists have been look-
ing for alternative CO sources.[6] Among all of them,
[Mo(CO)6] is certainly an ideal candidate.[7]
Scheme 1. Synthetic strategies.
carbonylation reactions and also due to the importance of
these compounds, we wish to report for the first time a con-
venient palladium-catalyzed carbonylative synthesis of 2-
amino benzoxazinones. Notably, readily available 2-bromoa-
niline and isocyanates were applied as substrates and
[Mo(CO)6] was used as a solid CO source.
Based on our previous work and experience, the first re-
action was carried out with 2-bromoaniline (1 mmol), phe-
nylisocyanate (1 mmol), [Mo(CO)6] (1.5 mmol), PdACHTUNGTRENNUNG(OAc)2
Recently our group reported some interesting methodolo-
gies for the synthesis of 2-aryl and 2-alkyl-substituted ben-
(3 mol%), BuPAd2 (6 mol%), and K2CO3 (2 mmol) in tol-
uene (2 mL), at 1408C for 16 h. To our delight, 42% of the
desired product was formed. We then tested several organic
and inorganic bases (1,8-diazabicycloACTHNUTRGNEUNG[5.4.0]undec-7-ene
[a] Dr. X.-F. Wu
(DBU), K3PO4, NEt3, N,N-diisopropylethylamine (DIPEA),
Na2CO3) and K3PO4 was found to be the best base for this
reaction and gave 84% of the desired product. The reaction
temperature succeeded to be decreased to 1208C, but the
starting material could not be totally converted if we carried
out the reaction at 1008C. We then chose K3PO4 as the base
to test the generality of this new procedure at 1208C.
Regarding the reaction mechanism, the most possible one
has been proposed and is shown in Scheme 2. The first step
is the formation of the urea 1 from 2-bromoaniline and phe-
Department of Chemistry, Zhejiang Sci-Tech University
Xiasha Campus, Hangzhou, Zhejiang Province
310018 (P. R. China)
E-mail: xiao-feng.wu@catalysis.de
[b] Dr. X.-F. Wu, Dr. M. Sharif, Dr. H. Neumann, Dr. A. Pews-Davtyan,
Prof. P. Langer, Prof. M. Beller
Leibniz-Institut fꢀr Katalyse an der Universitꢁt Rostock e.V.
Albert-Einstein-Str. 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
[c] Dr. M. Sharif, K. Shoaib
Department of Chemistry, COMSATS Institute of Information
Technology, Abbottabad (Pakistan)
nylisocyanate, followed by oxidative addition of in situ gen-
[d] Prof. P. Langer
0
À
erated Pd to the C Br bond to form the complex 2. After
Institut fꢀr Chemie, Universitꢁt Rostock
Albert-Einstein-Str. 3a, 18059 Rostock (Germany)
coordination and insertion of [Mo(CO)6] released CO, the
key intermediate 3 is produced. Reductive elimination pro-
duces the final product, 2-amino benzoxazinone, and Pd0 for
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300537.
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Chem. Eur. J. 2013, 19, 6230 – 6233

COMMUNICATION
Table 1. Palladium-catalyzed carbonylative coupling of phenylisocyanate
with 2-bromoanilines.[a]
Entry
1
2-Bromoaniline
Product
Yield [%][b]
73
2
3
77
69
Scheme 2. Proposed reaction mechanism.
4
5
6
73
70
66
the next catalytic cycle. Notably, 3-phenylquinazoline-2,4-
ACHTUNGTRENNUNG(1H,3H)dione, one of the most plausible possible products,
was not detected in our system.[5j] We estimate that
[Mo(CO)6] may also play a crucial role in this reaction
system. Molybdenum salt might act as a Lewis acid and co-
ordinate with 3 to assistant in the formation of 2-amino-ben-
zoxazinones as our target product.
The generality and efficiency of this methodology has
been proved by the 22 examples provided in Tables 1 and 2.
For the first stage of discovering the reaction scope, we
choose phenylisocyanate to test different 2-bromoanilines
under our best reaction conditions ([Mo(CO)6] (1.5 mmol),
PdACHTUNGTRENNUNG(OAc)2 (3 mol%), BuPAd2 (6 mol%), K3PO4 (2 mmol),
toluene (2 mL), 1208C, 16 h). Both electron-donating and
-withdrawing substituents are tolerable under our conditions
7
8
75
63
68
À
À
À
(Table 1, entries 2–7). F , CF3 , and CF3O as important
substituents can be tolerated in this system and give the cor-
responding products in 66–75% yields (entries 4–7).[8] Re-
markably, 2-bromopyridin-3-amine and 3-bromopyridin-2-
amine are two examples of heterocycles that can also be ap-
plied as substrates and resulted in the desired products in
63–68% yields (Table 1, entries 8, 9).
9
[a] PdACTHUNGTRNEUNG(OAc)2 (3 mol%), BuPAd2 (6 mol%), toluene (2 mL), K3PO4
(2 mmol), 2-bromoanilines (1.0 mmol), phenylisocyanate (1 mmol),
[Mo(CO)6] (1.5 mmol), 1208C, 16 h. [b] Isolated yield.
We then used 2-bromoaniline as a model substrate to
check the generality of isocyanates (Table 2). Ethoxy, ethyl,
methylthio, and halogen-substituted aromatic isocyanates
were successfully applied and gave the desired products in
we expected, 70% of 2-(phenylamino)-4H-benzo[d]-
AHCTUNGTREG[NNUN 1,3]oxazin-4-one was isolated from the reaction of 2-bromo-
phenylisocyanate and aniline (Scheme 3). As anilines are
ready available and abundant chemicals, this can dramatical-
ly extend the scope of our methodology and increase the ap-
plication potential of our procedure.
In conclusion, a general and convenient methodology for
2-amino benzoxazinone synthesis has been developed.
Ready available 2-bromoanilines and isocyanates were used
as substrates and various products have been prepared in
good yields. Notably, [Mo(CO)6] as a solid CO source was
applied instead of gas, which increased the application po-
tential of this methodology. Additionally, we could also
extend our methodology to 2-bromophenylisocyanate and
anilines, which will definitely increase the substrates scope
À
À
À
good yields (Table 2, entries 1–7). CF3 , CF3O , CN , and
À
EtOOC as strong electron-withdrawing functional groups
are all tolerable and the designed products were isolated in
40–84% yields (entries 8–11). Additionally, 60% of 2-(naph-
thalen-1-ylamino)-4H-benzo[d]ACTHNUGTRNEUNG[1,3]oxazin-4-one was pre-
pared from the corresponding naphthylisocyanate under our
conditions (entry 12). To our delight, even alkyl isocyanate
succeeded to be applied and gave the desired product in a
90% yield (entry 13).
Additionally, we think it is also possible to generate the
needed urea from 2-bromophenylisocyanate and aniline. As
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X.-F. Wu, M. Beller et al.
Table 2. Palladium-catalyzed carbonylative coupling of 2-bromoaniline
with phenylisocyanates.[a]
Scheme 3. Synthesis of 2-(phenylamino)-4H-benzo[d]ACTHUNRTGNEUNG[1,3]oxazin-4-one
from 1-bromo-2-isocyanatobenzene and aniline.
Entry Isocyanate
1
Product
Yield [%][b]
47
Experimental Section
General procedure for the carbonylative synthesis of 2-amino-benzoxazi-
nones: After the pressure tube was purged three times with argon, phe-
nylisocyanate (1.0 mmol), 2-bromoaniline (1.0 mmol), and toluene
(3 mL) were added and the mixture was stirred for 1 h at room tempera-
2
80
82
80
75
71
64
61
84
78
40
ture under argon. PdACHTUNGTRENNUG(OAc)2 (3 mol%), BuPAd2 (6 mol%), K3PO4
(2.0 mmol), and [Mo(CO)6] (1.5 mmol) were transferred into the pressure
tube under an argon flow and the reaction was performed for 16 h at
1208C. The mixture was cooled to room temperature and diluted with
ethyl acetate. The organic layer was washed with water and dried over
MgSO4. After removal of the solvent in vacuum, the products were iso-
lated by column chromatography in hexane/ethyl acetate 9:1 as the
eluent.
3
4
5
Acknowledgements
6
The authors thank the state of Mecklenburg-Vorpommern and the Bun-
desministerium fꢀr Bildung und Forschung (BMBF) for financial support.
We also thank Mrs. K. Mevius, Drs. W. Baumann, C. Fischer, and Mrs. S.
Buchholz (LIKAT) for analytical support.
7
8
Keywords: benzoxazinones
· carbonylation · catalysis ·
nitrogen heterocycles · palladium
9
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Synthesis of 2-Amino-Benzoxazinones
COMMUNICATION
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Received: February 11, 2013
Published online: March 20, 2013
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