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

Article abstract of DOI:10.1002/chem.201102254

CO and CO again: A new double carbonylation methodology for the synthesis of 2-arylbenzoxazinones has been developed (see scheme). Copyright

Full text of DOI:10.1002/chem.201102254

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
E-mail: matthias.beller@catalysis.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102254.
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Chem. Eur. J. 2011, 17, 12246 – 12249

COMMUNICATION
Table 1. Palladium-catalyzed carbonylative coupling of 2-bromoaniline
and bromobenzene.[a]
acyl complex, which reacts immediately with the amino
group of 2-bromoaniline to give N-(2-bromophenyl)benza-
mide. After this initial amino-carbonylation of bromoben-
zene, another oxidative addition of the active Pd0 species to
N-(2-bromophenyl)benzamide takes place, followed by CO
insertion and intramolecular cyclization. Notably, the initial
oxidative addition is highly chemoselective for bromoben-
zene due to the reactivity difference to the electron-rich 2-
bromoaniline.
Next, other substrates were tested under the optimized re-
action conditions. As shown in Table 2, para-, meta-, and
ortho-bromotoluene as well as 2-bromonaphthalene did not
differ significantly in reactivity and gave good yields of the
corresponding products (Table 2, entries 2–5). tert-Butyl-, di-
methylamino-, and methoxy-substituted electron-rich bro-
moarenes reacted smoothly with 2-bromoaniline under our
standard conditions and resulted in 71–83% isolated yield
(Table 2, entries 6–11). Besides, bromoarenes with electron-
withdrawing substituents led to the corresponding 2-arylben-
zoxazinones in 70–91% yield (Table 2, entries 12–14). Inter-
estingly, N- and S-heterocyclic bromides gave the desired
Entry
Ligand
Solvent
Base
T
Conv.
[%][b]
Ratio
[oC]
1/2[b,c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17[d]
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
PPh3
CH3CN
dioxane
DMF
NMP
NMP
DMAc
DMSO
NMP
NMP
NMP
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NEt3
100
100
100
100
110
110
110
110
110
110
110
110
110
110
110
110
110
66
59
80
33:67
37:63
29:71
21:79
0:100 (69)
25:75
15:85
8:92
26:74
0:100 (63)
0:100 (55)
0:100 (75)
18:82
0:100 (79)
0:100 (86)
0:100 (81)
24:76
87
100
100
100
100
36
100
100
100
68
100
100
100
89
P
A
P
A
NMP
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
toluene
dioxane
toluene
toluene
toluene
toluene
DiPEA
TMEDA
DiPEA
Table 2. Palladium-catalyzed carbonylative coupling of 2-bromoanilines
and aryl bromides.[a]
[a] PdACHTUNGTRENNUNG(OAc)2 (6 mol%), ligand (12 mol%), solvent (2 mL), base
(4 mmol), 2-bromoaniline (1.2 mmol), bromobenzene (1 mmol), CO
(5 bar), 20 h (reaction time is not optimized). [b] Conversion and ratio of
1 and 2 were determined by GC using hexadecane as internal standard.
[c] The data in parentheses shows isolated yields. [d] Use PdACTHNUTRGNEUNG(OAc)2
(3 mol%), BuPAd2 (6 mol%). DiPEA: N,N-diisopropylethylamine;
TMEDA: N,N,N’,N’-tetramethylethylenediamine.
Entry
1
Aryl bromide
Product
Yield [%][b]
86
2
3
4
5
6
89
69
74
82
79
Scheme 2. Palladium-catalyzed carbonylation of N-(2-bromophenyl)benz-
amide.
7
76
Scheme 3. Proposed mechanism for the carbonylative synthesis of 2-phe-
nylbenzoxazinone.
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12247

M. Beller et al.
products in good yields as well (Table 2, entries 15 and 16).
Furthermore, three substituted 2-bromoanilines were used
in this domino-transformation to also demonstrate the varia-
bility of this substrate (Table 2, entries 17–19). Unfortunate-
ly, using electron-deficient heterocyclic bromides and alken-
yl bromides led to low selectivity and yields of the desired
products (5–10%). In addition, we performed the reaction
of phenyl triflate with 2-bromoaniline. In this case, under
our standard conditions, decomposition of phenyl triflate oc-
curred and carbonylative homocoupling of 2-bromoaniline
Table 2. (Continued)
Entry
Aryl bromide
Product
Yield [%][b]
8
83
9
71
71
to form dibenzo
observed.
ACHTUNGTNER[UNGN b,f]ACHTUNRTGENN[GUN 1,5]diazocine-6,12ACHTNUGTRNE(NUGN 5H,11H)-dione was
Finally, we demonstrated that our methodology can be
easily extended to a one-pot synthesis of 2-arylquinazoli-
nones (Scheme 4). It has been shown that arylquinazolines
can be used as intermediates for the synthesis of other inter-
esting heterocycles.[11] Indeed, completing our double car-
bonylation process and directly adding anilines under air
gave 2-arylquinazolinones in good isolated yields after heat-
ing the reaction mixture for another 16 h at 1008C (63–
86%).
10
11
76
In conclusion, a new domino synthesis of 2-arylbenzoxazi-
nones has been developed. Starting from commercially
available 2-bromoanilines and (hetero)aryl bromides 19 dif-
ferent benzoxazinones were produced in good yields (65–
91%). Key step of this transformation is the chemoselective
carbonylation of the aryl bromide. Moreover, a one-pot syn-
thesis of 2,3-diarylquinazolinones was demonstrated exem-
plarily.
12
13
14
91
78
70
15
65
16
17
18
87
81
78
68
Scheme 4. A new one-pot synthesis of 2, 3-diarylquinazolinones.
Experimental Section
General procedure for the carbonylative synthesis of 2-arylbenzoxazi-
nones: PdACHTNUGRTNEUNG(OAc)2 (6 mol%) and BuPAd2 (12 mol%) were transferred
into a vial (12 mL reaction volume) equipped with a septum, a small can-
nula and a stirring bar. After the vial was purged with argon, bromoben-
zene (1 mmol), 2-bromoaniline (1.2 mmol), toluene (2 mL), DiPEA
(4 mmol), and hexadecane (0.1 mL, internal GC standard) were injected
into the vial by syringe. Then, the vial was placed in an alloy plate, which
was transferred into a 300 mL autoclave of the 4560 series from Parr In-
struments under argon atmosphere. After flushing the autoclave three
times with CO, a pressure of 5 bar was adjusted and the reaction was per-
formed for 20 h at 1108C. After the reaction, the autoclave was cooled
down to room temperature and the pressure was released carefully.
Water (6 mL) was then added to the reaction mixture and the resulting
solution was extracted with ethyl acetate 3–5ꢃ2–3 mL). The extracts
19
[a] PdACHTUNGTRENNUNG(OAc)2 (6 mol%), BuPAd2 (12 mol%), toluene (2 mL), DiPEA
(4 mmol), 2-bromoanilines (1.2 mmol), aryl bromides (1 mmol), CO
(5 bar), 1108C, 20 h (reaction time is not optimized). [b] Isolated yield.
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Palladium-Catalyzed Carbonylative Coupling
COMMUNICATION
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Acknowledgements
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.
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Keywords: aryl bromides · benzoxazinone · carbonylation ·
heterocycles · palladium
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Received: July 22, 2011
Published online: September 28, 2011
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ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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