Palladium-Catalyzed Carbonylative Synthesis of N-Acetyl Benzoxazinones

Article abstract of DOI:10.1002/cctc.201800532

A palladium-catalyzed intramolecular carbonylation reaction for the synthesis of N-acetyl benzoxazinones has been achieved for the first time. To avoid the using of toxic and flammable CO gas, formic acid was utilized as the CO source here. This carbonylative process is conducted under mild reaction conditions with high reaction efficiency. A variety of the desired N-acetyl benzoxazinone products were obtained in moderate to excellent yields with very good functional group compatibility. The presents of acid anhydride holds two roles here: formic acid activator and acyl source.

Full text of DOI:10.1002/cctc.201800532

Accepted Article
Title: Palladium-Catalyzed Carbonylative Synthesis of N-Acetyl
Benzoxazinones
Authors: Xiao-Feng Wu, xinxin qi, rui li, hao-peng li, Jin-Bao Peng, and
jun ying
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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To be cited as: ChemCatChem 10.1002/cctc.201800532
Link to VoR: http://dx.doi.org/10.1002/cctc.201800532
A Journal of
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ChemCatChem
10.1002/cctc.201800532
COMMUNICATION
Palladium-Catalyzed Carbonylative Synthesis of N-Acetyl
Benzoxazinones
[a]
[a]
[a]
[a]
[a]
[a,b]
Xinxin Qi, Rui Li, Hao-Peng Li, Jin-Bao Peng, Jun Ying, and Xiao-Feng Wu*
Abstract:
A
palladium-catalyzed intramolecular carbonylation
palladium-catalyzed intramolecular carbonylative reaction for N-
acetyl benzoxazinones synthesis with N-(benzylidene)-2-
iodoanilines as the starting materials and formic acid as the
liquid CO source.
reaction for the synthesis of N-acetyl benzoxazinones has been
achieved for the first time. To avoid the using of toxic and flammable
CO gas, formic acid was utilized as the CO source here. This
carbonylative process is conducted under mild reaction conditions
with high reaction efficiency. A variety of the desired N-acetyl
benzoxazinone products were obtained in moderate to excellent
yields with very good functional group compatibility. The presents of
acid anhydride holds two roles here: formic acid activator and acyl
source.
Initially, N-(benzylidene)-2-iodoaniline was selected as the
model substrate to establish the reaction system. The first
o
reaction was carried out in THF at 100 C with Pd(OAc)
2
as the
3
N as the base and
catalyst and DAPP as the ligand using Et
formic acid as the CO surrogate. To our delight, 72% yield of the
desired product was observed (Tabel 1, entry 1). Screening of
catalyst loading shown that the product yield can be improved to
Benzoxazinone is a class of important N-heterocycles with
2
89% with 1 mol% of Pd(OAc) (Table 1, entry 2). Subsequently,
1
significant biological activities,
and present widely in
solvents such as DMSO, toluene, 1,4-dioxane were examined
(Table 1, entries 3-5). Toluene provides the same yield as THF
(Table 1, entry 4). Considering the reaction temperature, we
chosen toluene as the solvent to continue the condition
optimizations. Furthermore, several ligands were studied (Table
2
pharmaceutical compounds and natural products. Additionally,
they have been commonly employed as the key intermediate in
the synthesis of a variety of heterocycles as well. In view of their
broad applications, synthetic methods have been developed for
3
their preparation. However, compared with the parent
1, entries 6-10). PPh
yield (Table 1, entry 6), while the other monodentate ligands
such as PCy , P(p-anis) didn’t work well (Table 1, entries 7-8).
Bidentate ligands, including Xantphos and DPPP afford a little
bit lower yields compare to PPh (Table 1, entries 9-10).
Moreover, the screening of bases showed that Et N was the
3
resulted the target product in very high
benzoxazinones, the synthetic methodology for N-substituted
benzoxazinones is rather limited. The very few reported
examples are all based on the reaction between anthranilic
3
3
4
acids and aldehydes. Besides the disadvantages such as harsh
3
reaction condition and low efficiency, the availability of the
starting materials is problematic as well. Thus, new procedures
with higher efficiency and using readily available substrates for
N-substituted benzoxazinones synthesis are highly desirable.
3
optimal base for this transformation (Table 1, entries 11-15).
a
Table 1. Optimization of the reaction conditions.
5
O
On the other hand, since the first report in 1974, palladium-
N
I
N
O
[
Pd]
catalyzed carbonylation reaction has experienced impressive
2H
Ac O
2
HCO
6
O
progresses during the past decades. Many interesting
applications both in academic and industrial fields were realized.
However, gaseous carbon monoxide is needed as the carbonyl
source in most of the developed procedures. Due to the high
toxicity, high flammable and odorless properties of CO gas, its
related carbonylation procedures are difficult to handle. Thus, a
variety of CO precursors have been explored and CO-free
b
Entry Ligand
Base
Solvent
THF
Yield (%)
c
1
2
3
4
5
6
7
8
9
1
1
1
DAPP
DAPP
DAPP
DAPP
DAPP
Et
Et
Et
Et
Et
Et
3
N
3
N
3
N
3
N
3
N
3
N
72
THF
89
51
89
DMSO
toluene
7
carbonylation procedures have been estabilished. Our group
1,4-dioxane 67
has been interested in this area as well and has disclosed a
series of carbonylation reactions with formic acid as the CO
PPh
3
toluene
toluene
toluene
toluene
toluene
toluene
97
n.r.
trace
89
93
11
0
8
precursor. As our continuous work on CO surrogates research
PCy3
3
Et N
and carbonylative heterocycles synthesis, we describe here a
P(p-anis)
3
Et
Et
Et
3
N
3
N
3
N
Xantphos
DPPP
0
1
2
[
a]
b]
Dr. X. Qi, R. Li, H.-P. Li, Dr. J.-B. Peng, Dr. J. Ying, Prof. Dr. X.-F.
Wu
Department of Chemistry, Zhejiang Sci-Tech University, Xiasha
Campus, Hangzhou 310018, People’s Republic of China
E-mail: xiao-feng.wu@catalysis.de
PPh
PPh
PPh
PPh
PPh
3
3
3
3
3
DBU
DABCO toluene
13
NaOH
CO
KOAc
toluene
toluene
toluene
n.r
n.r
n.r
[
Prof. Dr. X.-F. Wu
14
K
2
3
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-
Einstein-Straße 29a, 18059 Rostock, Germany
15
a
Reaction conditions: N-(benzylidene)-2-iodoaniline (0.5 mmol),
Pd(OAc) (1 mol%), ligand (2 mol% for monodentate ligand; 1 mol%
for bidentate ligand), base (4 mmol), HCOOH (2 mmol), Ac O (3
Supporting information for this article is given via a link at the end of
the document.
2
2
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ChemCatChem
10.1002/cctc.201800532
COMMUNICATION
o
a
mmol), solvent (1 mL), 100
C,
3
h; DAPP
P(p-anis)
methoxyphenyl)phosphine. Isolated yield. Pd(OAc) (5 mol%).
=
4-
Table 2. Reaction scope on benzylidene ring.
(
dimethylamino)phenyldiphenylphosphine.
3
:
tris(4-
O
b
c
(1
mol%)
Pd(OAc)
PPh3 (2 mol%)
2
2
N
I
Ar
N
O
Ar
HCO
2
H
Ac O
2
°
NEt3, toluene, 100 C, 3 h
O
With the best reaction condition in hand, we went on our
studies on substrates scope screening. We first studied the
variation of substrate on benzylidene ring, and the results were
summarized in Table 2. Those substrates with electron-donating
groups, including methyl, ethyl, t-butyl, methoxy provided the
corresponding products in good to excellent yields (2b-g). Those
bearing methyl group at ortho position resulted in higher yield
than at meta or para positions (2b vs 2c-d). This phenomenon
can be explained by the favoured reductive elimination step due
to the steric hindrance of the ortho substitution. Substrates with
halogen substitutions, including fluoro, chloro, and bromo groups,
the desired products were obtained in moderate to good yield
O
O
O
N
O
O
N
N
N
O
O
O
O
O
O
O
O
2a, 97%
2b, 93%
2c, 63%
2d, 67%
Et
O
N
O
O
N
N
O
O
O
O
O
2
e, 78%
2f, 80%
2g, 65%
O
O
F
O
Cl
O
Br
O
CN
N
O
N
O
N
O
N
(
2h-j). We also tested other electron-withdrawing groups, and
O
O
O
O
high yields were obtained with substrates containing cyano or
trifluoro substituent (2k-l). It was noted that heteroaryl groups
such as 2-furan and 2-thiophene can still worked very well to
afford the corresponding products in 77% and 67% yields (2m-
n). Furthermore, 1-naphthalene substrate was examined, and
the target product was isolated in 69% yield (2o).
O
2h, 73%
2i, 64%
2j, 50%
2k, 81%
O
CF
3
O
O
N
O
S
O
N
O
N
O
N
O
O
O
O
O
2l, 80%
2m, 77%
O
2n, 67%
2o, 69%
We next turn our attention to substrate scope on 2-
iodoaniline ring; the outcomes were shown in Table 3.
Substrates with halogen groups involving fluoro, chloro, and
bromo groups at the meta position to the iodo moiety provided
the corresponding products in good yields (2p-r). The target
product was obtained in a high yield with meta-methyl group (2s).
The meta-trifluoro substitution resulted in 56% yield (2t).
Furthermore, para-substitution such as fluoro, chloro, and ester
groups were also tolerated well to afford the desired products in
moderated yield (2u-w).
a
Reaction conditions: N-(benzylidene)-2-iodoanilines (0.5 mmol),
Pd(OAc) (1 mol%), PPh (2 mol%), Et N (4 mmol), HCOOH (2
mmol), Ac
2
3
3
o
2
O (3 mmol), toluene (1 mL), 100 C, 3 h, isolated yield.
a
Table 3. Reaction scope on 2-iodoaniline ring.
O
Pd(OAc)
2
(1 mol%)
N
I
Ph
PPh3 (2 mol%)
N
O
Ph
HCO
2
H
Ac O
2
°
NEt3, toluene, 100 C, 3 h
O
R2
R2
O
O
O
O
Additionally, when using propionic anhydride as the activator
of formic acid, the corresponding N-propionyl product 2x were
isolated in 88% yield (eq. 1).
N
O
Ph
N
O
O
Ph
N
O
Ph
N
O
Ph
O
O
O
F
Cl
Br
2s, 84%
2
p, 82%
2q, 71%
2r, 72%
(1)
O
Et
O
Et
N
I
Ph
O
O
O
O
Pd(OAc)
2
, PPh
3
, Et
3
N
N
O
Ph
HCO
2
H
O
°
toluene, 100 C, 3 h
N
O
Ph
F
Cl
Ph
N
Ph
O
O
O
Et
O
O
N
Ph
F
C
N
3
O
2
x, 88%
O
O
O
2t, 56%
2u, 64%
O
2v, 55%
2w, 63%
O
Furthermore, a large scale reaction of our model reaction
was carried out as well (eq. 2). To our surprise, only very low
loading of Pd(OAc) (0.2 mol%) was necessary here, and gave
the final product in 83% isolated yield.
a
Reaction conditions: N-(benzylidene)-2-iodoanilines (0.5 mmol),
Pd(OAc) (1 mol%), PPh (2 mol%), Et N (4 mmol), HCOOH (2
mmol), Ac O (3 mmol), toluene (1 mL), 100 C, 3 h, isolated yield.
2
3
3
2
o
2
4
,8
Base on the above results and literature,
a possible
(
2)
O
reaction mechanism was proposed in Scheme 1. Firstly,
oxidative addition of N-(benzylidene)-2-iodoaniline with Pd Ln to
give complex A, followed by the insertion of CO, which was
generated in-situ from formic acid and acetic anhydride, afford
acylpalladium intermediate B. Afterwards, a ligand exchange of
iodide with formic acid to form acylpalladium formic acid
Pd(OAc)
2
(0.2 mol%)
N
I
Ph
0
O
O
PPh3 (0.4 mol%), Et N (8 equiv)
N
O
Ph
3
HCO
2
H
O
°
toluene (5 mL), 100 C, 6 h
O
2
.5 mmol
(4 equiv) (8 equiv)
2
a, 83%
3
complex C. The formed HI will be neutralized by NEt . Anhydride
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ChemCatChem
10.1002/cctc.201800532
COMMUNICATION
product D was then obtained by reductive elimination, and
mmol, 4.0 equiv.) instead of acetic anhydride and propionic formic
anhydride (2 mmol, 4.0 equiv.) instead of acetic formic anhydride.
0
regenerated L
n
Pd species for the next catalytic cycle. Moreover,
anhydride D decomposed to afford acid product E, which
subsequently underwent cyclization to produce the final N-acetyl
benzoxazinone products in the presence of acetic anhydride Acknowledgements
through an intermediate F.
The authors thank the financial supports from NSFC (21602201,
1472174, 21772177) and Zhejiang Natural Science Fund for
Distin-guished Young Scholars (LR16B020002). X.-F Wu
appreciates the general support from Professors Matthias Beller
and Armin Börner in LIKAT.
2
Scheme 1. Proposed mechanism
HCOOH
Ac
2
O
O
N
O
O
I
Pd
HCOOH
H
O
Keywords: Palladium catalyst • Carbonylation • N-Acetyl
L
n
NEt
3
.
Benzoxazinones • Heterocycle synthesis • Domino reaction
B
CO
Ph
NEt HI
3
I
O
N
O
[1]
a) R. Alazard, J. Bechet, A. Dupaix, J. You, Biochim. Biophys. Acta.
973, 309, 379-396; b) L. Hedstrom, A. R. Moorman, J. Dobbs, R. H.
Pd
1
L
n
PdO
H
H
L
n
Abeles, Biochemistry 1984, 23, 1753-1759; c) A. Krantz, R. W. Spencer,
T. F. Tam, T. J. Liak, L. J. Copp, E. M. Thomas, S. P. Rafferty, J. Med.
Chem. 1990, 33, 464-479; d) R. L. Jarvest, M. J. Parratt, C. M.
Debouck, J. G. Gorniak, L. J. Jennings, H. T. Serafinowska, J. E.
Strickler, Bioorg. Med. Chem. Lett. 1996, 6, 2463-2466.
N
Ph
C
A
Ph
O
O
I
Pd0L
n
O
[
2]
3]
G. M. Coppola, J. Heterocycl. Chem. 1999, 36, 563-588.
N
Ph
N
Ph
[
Selected examples on benzoxazinone synthesis, see: a) J. L. Gilmore,
S. J. Hays, B. W. Caprathe, C. Lee, M. R. Emmerling, W. Michael, J. C.
Jaen, Bioorg. Med. Chem. Lett. 1996, 6, 679-682; b) M. Alajarin, A.
Vidal, M. M. Ortin, D. Bautista, Synthesis 2005, 14, 2426-2432; c) H.
Yoshida, H. Fukushima, J. Ohshita, A. Kunai, J. Am. Chem. Soc. 2006,
128, 11040-11041; d) N. Zhang, R. Cheng, D. Zhang-Negrerie, Y. Du,
K. Zhao, J. Org. Chem. 2014, 79, 10581-10587.
D
CO
-
OAc
O
N
H
O
O
N
O
O
N
O
OH
Ph
Ph
Ph
O
E
F
O
O
[4]
a) L. Legrand, N. Lozach, Bull. Soc. Chem. Fr. 1967, 2067-2074; b) N.
J. Herib, J. G. Jurcut, D. E. Bergna, K. L. Burgher, H. B. Hartman, S.
Kafca, L. L. Kerman, S. Kongsamut, J. E. Roehr, M. R. Szewczak, A. T.
Woods-Kettelberger, R. Corbett, J. Med. Chem. 1996, 39, 4044-4057; c)
P. Wiklund, I. Romero, J. Bergman, Org. Biomol. Chem, 2003, 1, 367-
O
In summary, we have developed a palladium-catalyzed
intramolecular carbonylation reaction for N-acetyl
372; d) P. Wiklund, J. Bergman, Tetrahedron Lett. 2004, 45, 969-972; e)
F. Nikpour, D. Sheikh, M. Saraji, Chem. Lett. 2007, 36, 1074-1075; f) D.
Azarifar, D. Sheikh, Heteroatom Chem. 2011, 22, 106-113; g) D.
Azarifar, D. Sheikh, Helv. Chim. Acta 2012, 95, 1217-1225.
benzoxazinones synthesis with formic acid as the CO surrogate.
A variety of substrates with a wide range of functional groups
were smoothly reacted under our reaction conditions, affording
the corresponding N-acetyl benzoxazinone compounds in
moderate to excellent yields with high efficiency. The presents of
acid anhydride holds two roles here: formic acid activator and
acyl source.
[5]
[6]
A. Schoenberg, R. F. Heck, J. Am. Chem. Soc. 1974, 96, 7761-7764.
For selected reviews, see: a) X.-F. Wu, H. Neumann, M. Beller, Chem.
Soc. Rev. 2011, 40, 4986-5009; b) X.-F. Wu, H. Neumann,
ChemCatChem 2012, 4, 447-458; c) B. Gabriele, R. Mancuso, G.
Salerno, Eur. J. Org. Chem. 2012, 6825-6839; d) X. F. Wu, H.
Neumann, M. Beller, Chem. Rev. 2013, 113, 1-35; e) S. Sumino, A.
Fusano, T. Fukuyama, I. Ryu, Acc. Chem. Res. 2014, 47, 1563-1574; f)
S. D. Friis, A. T. Lindhardt, T. Skrydstrup, Acc. Chem. Res. 2016, 49,
594-605; g) J.-B. Peng, X. Qi, X.-F. Wu, Synlett 2017, 28, 175-194; h)
X.-F. Wu, RSC Adv. 2016, 6, 83831-83837; i) J.-B. Peng, X. Qi, X.-F.
Wu, ChemSusChem 2016, 9, 2279-2283; j) Y. Bai, D. C. Davis, M. Dai,
J. Org. Chem. 2017, 82, 2319-2328; k) L. Kollár, in Modern
Carbonylation Methods, Wiley-VCH, Weinheim, 2008.
Experimental Section
Toluene (1 mL), Et
mmol, 2 equiv.) was poured into a flask containing N-(2-iodophenyl)-1-
phenylmethanimine (0.5 mmol, 1.0 equiv.), Pd(OAc) (0.0011 g, 0.005
mmol, 1 mol%). PPh (0.0026 g, 0.01 mmol, 2 mol%). Then 2 mmol (4
3 2
N (0.56 ml, 4 mmol, 8 equiv.) and Ac O (95 μl, 1
[7]
For selected examples, see: a) T. Morimoto, K. Fuji, K. Tsutsumi, K.
Kakiuchi, J. Am. Chem. Soc. 2002, 124, 3806-3807; b) T. Shibata, N.
Toshida, K. Takagi, Org. Lett. 2002, 4, 1619-1621; c) T. Morimoto, K.
Yamasaki, A. Hirano, K. Tsutsumi, N. Kagawa, K. Kakiuchi, Y. Harada,
Y. Fukumoto, N. Chatani, T. Nishioka, Org. Lett. 2009, 11, 1777-1780;
d) W. Li, X.-F. Wu, J. Org. Chem. 2014, 79, 10410-10416; e) S. Ko, H.
Han, S. Chang, Org. Lett. 2003, 5, 2687-2690; f) K. Hosoi, K. Nozaki, T.
Hiyama, Org. Lett. 2002, 4, 2849-2851; g) T. Ueda, H. Konishi, K.
Manabe, Angew. Chem. Int. Ed. 2013, 52, 8611-8615; (h) T. Ueda, H.
Konishi, K. Manabe, Org. Lett. 2012, 14, 5370-5373; i) S. Ko, C. Lee,
M.-G. Choi, Y. Na, S. Chang, J. Org. Chem. 2003, 68, 1607-1610; j) Y.
2
3
equiv.) of the in-situ prepared acetic formic anhydride was added to the
flask and the flask was sealed rapidly. The acetic formic anhydride was
prepared by mixing formic acid (2.0 mmol) and acetic anhydride (2.0
mmol) and stirred at 30°C for 1.5 h. The mixture was stirred for 3 h in an
o
oil bath at 100 C. After the reaction was completed, the crude reaction
mixture was concentrated and purified by silica gel column
chromatography (PE/EtOAc=10/1~5/1) to provide the desired products.
It’s same to the preparation of 2x except using propionic anhydride (2
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ChemCatChem
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COMMUNICATION
Katafuchi, T. Fujihara, T. Iwai, J. Terao, Y. Tsuji, Adv. Synth. Catal.
Wu, Chem. Eur. J. 2016, 22, 5835-5838; g) X. Qi, R. Li, X.-F. Wu, RSC
Adv. 2016, 6, 62810-62813; h) L.-B. Jiang, X. Qi, X.-F. Wu,
Tetrahedron Lett. 2016, 57, 3368-3370; i) H.-P. Li, H.-J. Ai, X. Qi, J.-B.
Peng, X.-F. Wu, Org. Biomol. Chem. 2017, 15, 1343-1345; j) F.-P. Wu,
J.-B. Peng, L.-S. Meng, X. Qi, X.-F. Wu, ChemCatChem 2017, 9, 3121-
3124; k) F.-P. Wu, J.-B. Peng, X. Qi, X.-F. Wu, Catal. Sci. Technol.
2017, 7, 4924-4928; l) J.-B. Peng, F.-P. Wu, C.-L. Li, X. Qi, X.-F. Wu,
Eur. J. Org. Chem. 2017, 1434-1437; m) F.-P. Wu, J.-B. Peng, X. Qi,
X.-F. Wu, J. Org. Chem. 2017, 82, 9710-9714; n) F.-P. Wu, J.-B. Peng,
L.-Y. Fu, X. Qi, X.-F. Wu, Org. Lett. 2017, 19, 5474-5477.
2011, 353, 475-482; k) T. Fujihara, T. Hosoki, Y. Katafuchi, T. Iwai, J.
Terao, Y. Tsuji, Chem. Commun. 2012, 48, 8012-8014; l) L. R. Odell, F.
Russo, M. Larhed, Synlett 2012, 685-698; m) J. Wannberg, M. Larhed,
J. Org. Chem. 2003, 68, 5750-5753; n) P. Gautam, B. M. Bhanage,
Catal. Sci. Technol. 2015, 5, 4663-4702.
[8]
a) X. Qi, L.-B. Jiang, C.-L. Li, R. Li, X.-F. Wu, Chem. Asian J. 2015, 10,
1870-1873; b) X. Qi, L.-B. Jiang, H.-P. Li, X.-F. Wu, Chem. Eur. J. 2015,
21, 17650-17656; c) X. Qi, H.-P. Li, X.-F. Wu, Chem. Asian J. 2016, 11,
2453-2457; d) X. Qi, C.-L. Li, L.-B. Jiang, W.-Q. Zhang, X.-F. Wu, Catal.
Sci. Technol. 2016, 6, 3099-3107; e) L.-B. Jiang, R. Li, H.-P. Li, X. Qi,
X.-F. Wu, ChemCatChem 2016, 8, 1788-1791; f) X. Qi, C.-L. Li, X.-F.
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ChemCatChem
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COMMUNICATION
COMMUNICATION
O
R
O
Xinxin Qi, Rui Li, Hao-Peng Li, Jin-Bao
Peng, Jun Ying, and Xiao-Feng Wu*
N
I
Ar
Pd(OAc)
2
, PPh
3
N
O
Ar
HCO H
2O
2
(RCO)
°
24 examples
to 97%
NEt3, 100 C, toluene, 3 h
R'
Up
yield
Page No. – Page No.
R'
Palladium-Catalyzed Carbonylative
Synthesis of N-Acetyl
Benzoxazinones
A palladium-catalyzed intramolecular carbonylation reaction for the synthesis of N-
acetyl benzoxazinones has been achieved for the first time. Formic acid was
utilized as the CO source here. A variety of the desired N-acetyl benzoxazinone
products were obtained in moderate to excellent yields with very good functional
group compatibility.
This article is protected by copyright. All rights reserved.