Direct oxidative cascade cyclisation of 2-aminobenzoic acid and arylaldehydes to aryl 4H-3,1-benzoxazin-4-ones with oxone

Article abstract of DOI:10.1016/j.tetlet.2016.12.072

This paper presents a methodology of oxidative cascade cyclisation of 2-aminobenzoic acids and arylaldehyde using I₂as a catalyst and an environmentally benign oxidant oxone. This method displays facile access to a diverse range of substituted aryl 4H-3,1-benzoxazin-4-ones. This synthetic methodology has many advantages such as: (1) easy availability of starting material, (2) transition metal-free condition (3) use of an environmentally benign oxidant.

Full text of DOI:10.1016/j.tetlet.2016.12.072

Accepted Manuscript
Direct oxidative cascade cyclisation of 2-aminobenzoic acid and arylaldehydes
to aryl 4H-3,1-benzoxazin-4-ones with oxone
Sathishkumar Munusamy, Vivek Panyam Muralidharan, Sathiyanarayanan
Kulathu Iyer
PII:
S0040-4039(16)31728-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.072
TETL 48484
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 September 2016
21 December 2016
23 December 2016
Please cite this article as: Munusamy, S., Panyam Muralidharan, V., Kulathu Iyer, S., Direct oxidative cascade
cyclisation of 2-aminobenzoic acid and arylaldehydes to aryl 4H-3,1-benzoxazin-4-ones with oxone, Tetrahedron
Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.072
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Graphical Abstract
Direct oxidative cascade cyclisation of 2-aminobenzoic Leave this area blank for abstract info.
acid and arylaldehydes to aryl 4H-3,1-benzoxazin-4-ones
with oxone
Sathishkumar Munusamy, Vivek Panyam Muralidharan and Sathiyanarayanan Kulathu Iyer*

1
Tetrahedron Letters
Direct oxidative cascade cyclisation of 2-aminobenzoic acid and arylaldehydes to aryl
4H-3,1-benzoxazin-4-ones with oxone
Sathishkumar Munusamy, Vivek Panyam Muralidharan, and Sathiyanarayanan Kulathu Iyer*
*Chemistry Division, School of Advanced Sciences, VIT University, Vellore-632014, Tamil Nadu, India
E-mail: sathiya_kuna@hotmail.com
Fax: +914162243092
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
This paper presents a methodology of oxidative cascade cyclisation of 2-aminobenzoic acids
and arylaldehyde using I2 as a catalyst and an environmentally benign oxidant oxone. This
method displays facile access to a diverse range of substituted aryl 4H-3,1-benzoxazin-4-ones.
This synthetic methodology has many advantages such as: (1) easy availability of starting
material, (2) transition metal- free condition (3) use of an environmentally benign oxidant.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Oxidative cascade cyclisation
Oxone
Iodine
2-aminobenzoic acid
Arylaldehye
1. Introduction
isocyanobenzoates with N,N-dialkyliminium iodides7. In the last
few years research for the synthesis of benzoxazinones has
Synthesis of fused heterocycles is of particular interest to
organic chemists because of its potential biological activity.
Among them, 4H-3,1-benzoxazin-4-one derivatives are important
skeletons due to their proven pharmaceutical activity1. For
example, some of the drugs which contain 4H-3,1-benzoxazin-4-
one as the core structure act as HSV-1 protease inhibitors1a,
human leukocyteelastase inhibitors1b, chymotrypsin inactivator1c,
involved carbonyl insertion method using carbon monoxide (CO)
using either carbon monoxide gas or in situ release of CO to
avoid handling the gas. Palladium catalyzed carbonyl insertion
method with CO gas with different starting materials was a
highly reported method in the last decade8. In the case of
carbonyl insertion using in situ prepared CO for the synthesis of
benzoxazinones, Wu et al. have reported the synthesis of
benzoxazinones from N-(o-bromoaryl)amides by palladium-
catalyzed carbonylation with paraformaldehyde as the carbonyl
source9. Manabe et al. have developed palladium catalyzed
carbonylative synthesis form haloarenes with phenyl formate as
the carbonyl source10. Recently, Ulven et al. have reported an
interesting synthetic method for the synthesis of benzoxazinones
from 2-iodobenzamide with oxalyl chloride as the carbonyl
source11. Though the successful synthesis of benzoxazinones
from these methods is possible, the method which is highly
desirable and compatible under all conditions is one that utilizes
a simple starting material and proceeds under mild reaction
condition. In continuation of our research on the synthesis of
benzoxazinones12, we report a simple, efficient and economical
synthesis of 2-arylbenzoxazinones from anthranilic acid and
benzaldehyde with oxone as the sole oxidizing agent.
cathepsin
G
inhibitor1d, serine protease inhibitor1e and
humanchymase inhibitor1f. Moreover, some of the 4H-3,1-
benzoxazin-4-one derivatives have been reported to have the
ability to lower the plasma cholesterol. 4H-3,1-benzoxazin-4-
ones also act as successful precursors for the biologically much
important derivatives, such as quinazolin-4(3H)-ones and
quinolin-2(1H)-ones2. Hence, it is no surprise that the synthesis
of benzoxazinones has received intensive attention over the past
decade.
The most common methods for the synthesis of
benzoxazinones are cyclisation of anthranilic acid with benzoyl
chloride, cyclisation of N-acylanthranilic acid, ring
transformation of isatoic anhydride and cyclisation of N-
acylanthranilic acid under the influence of cyclization agent,
cyanuric chloride3. In the last decade, other notable methods have
been developed for the synthesis of benzoxazinones in order to
improve the yield and reduce the cost of the reaction. These
methods include copper(I) catalyzed cyclisation of N-acyl-2-
iodobenzamide4, oxidation of 2-arylindoles using oxone as the
sole oxidizing agnent5, intramolecular C−N coupling and
rearrangement of N-acyl-2-halobenzamides using CuI as a
catalyst6, Ugi-type reaction of 1,1-dimethylethyl 2-
2. Results and Discussion
We began the study of the synthesis of 2-arylbenzoxazinones
reaction utilizing 2-aminobenzoic acid (1a) and benzaldehyde
(2a) to optimize the reaction condition such as oxidants, catalysts
and solvents. When the reaction was carried out in DMF solvent

2
Tetrahedron
in the presence of 20 mol% of iodine (catalyst) and one
many functional groups such as C-Cl bond, C-Br bond, NO2
equivalent of oxone (oxidant) for 4 h at reflux condition, the
group in aryl aldehydes. We have tried the same reaction in alkyl
aldehyde but we could not get the desired product.
Table 1 Optimization of reaction conditionsa
Scheme 1 Previous reported strategies for the synthesis of 2-
arylbenzoxazinones.
O
X
O
N
R
Heavy metal, Base
Heavy metal catalyst
(a)
H
O
N
NH2
X
O
(b)
direct CO gas or
in situ release of CO
R
entry
Catalyst
Oxidant
Solvent
Yield
(%)a,b
83
1
2
I2
AlCl3
FeCl3
SnCl2
ZnCl2
I2
Oxone
Oxone
Oxone
Oxone
Oxone
O2
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
DMSO
DMF
(c)
Oxone
N
54
H
3
62
4
---
This work
5
---
6
17
O
N
CHO
COOH
NH2
(d)
20 mol % I2, 1 equiv oxone
R2
7
I2
H2O2
27
O
8
I2
DDQ
32
Toluene, reflux
R1
R1
R2
9
I2
CrO3
---
1
2
10
11
12
13
14
15
16
17
I2
mCPBA
Na2S2O8
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
12
3
I2
---
desired product 2-phenyl-4H-benzo[d][1,3]oxazin-4-one was
obtained in 30 % yield (Table 1, entry 13). With this initial
achievement, various solvents have been examined for this
cascade reaction in order to improve the yield. Toluene was
found to be the most suitable solvent for this reaction to give 3a
with 83 % yield (Table 1, entry 1). We obtained only inferior
results when we used other solvents such as polar protic solvents
and nonpolar solvents (Table 1, entries 12-17). Solvent
optimization was carried out under the reflux condition of the
reaction. The effect of various oxidants for this cascade reaction
was examined. A study of the screening of oxidants such as O2,
H2O2, DDQ, CrO3, m-CPBA, Na2S2O8 and oxone revealed that
the best choice of oxidant is oxone (Table 1, entry 1).
Subsequently, the effect of Lewis acid for this cascade reaction
was carried out. Among the tested Lewis acids such as I2, AlCl3,
FeCl3, SnCl2, and ZnCl2, I2 afforded the 3a in the highest yield
(Table 1, entries 1-5) when used in 10 mol% catalyst load.
Moderate yield was obtained in the presence of AlCl3 and FeCl3
while in other cases the reaction did not proceed at all. Other
Bronsted acids such as acetic acid and p-toluenesulfonic acid did
not yield the product at all. When I2 load was increased to 30 mol
%, no positive result was observed and the yield was the same as
that of 20 mol%. Using 10 mol% of I2 eventually decreased the
product yield. Further increase in the catalyst did not give any
improvement in the yield. On the basis of reaction condition
optimization results, 20 mol% I2 and one equivalent oxone in
toluene solvent at reflux condition was used for further
investigation.
I2
72
I2
30
I2
Acetonitrile
THF
26
I2
21
I2
ETOH
16
I2
H2O
---
aUnless otherwise noted, the reactions were carried out with 2 mmol of 1a and
2 mmol of 2a, 0.4 mmol of catalyst, and 2 mmol of oxidant in solvents under
reflux condition.
bIsolated yield.
O
N
O
N
O
N
O
N
O
Cl
O
O
O
Cl
Cl
3b 77%
3c 78%
3d 80%
3a 83%
O
O
N
O
O
O
N
O
O
O
F
Cl
Cl
N
N
Cl
Cl
3h 82%
3g 73%
3e 82%
O
3f 76%
O
N
O
O2N
O2N
O
O
O
Cl
N
N
OCH3
Cl
3k 76%
3i 65%
3j 78%
O
N
O
N
O
O
N
O2N
O2N
O2N
O
O
With optimized reaction condition in hand, the substrate scope
of this oxidative cascade reaction was investigated. As shown in
the table 2, a series of aromatic aldehydes 2 was allowed to react
with 2-aminobenzoic acid under the reaction condition
developed. Arylaldehyde derivatives with both electron donating
(4-ethyl, 4-Br), neutral and electron withdrawing (4-F) groups on
the aromatic ring participated in this reaction smoothly with
average to good yield of 3. In addition to this, 2-
chlorobenzaldehyde gave the corresponding product with the
yield of 77 % (Table 2, 3b), which indicates that steric effects
had little influence on this reaction since 2-chlorobenzaldehyde
gave comparable yield as that of 4-chlorobenzaldehyde (Table 2,
3d). This I2 catalysed, oxidative cascade reaction could tolerate
F
Br
NO2
3l 73%
3n 74%
3m 69%
Table 2 Scope of arylaldehydesa
aReaction conditions: Unless otherwise noted, the reactions were carried out
with 2 mmol of 1 and 2 mmol of 2, 0.4 mmol of catalyst, and 2 mmol of
oxone with toluene solvent under reflux condition. The samples were
characterized by comparison of their spectroscopic and physical data with
authentic samples synthesized by reported methods.
Considering the phenomenon, the following mechanism for
the oxidative cascade reaction for the synthesis of 2-
arylbenzoxazinones using 2-aminobenzoic acid and

3
purified by column chromatography (hexane(80)/ ethyl acetate
benzaldehyde is proposed as example (Scheme 2). The first
step is the formation of imine from reaction between 2-
(20)) on silica gel to afford 2-phenyl-4H-benzo[d][1,3]oxazine-
4-one.
4
aminobenzoic acid and benzaldehyde catalyzed by iodine.
The second step involves the activation of imine group to
iminium salt (5) by the active constituent KHSO5 of oxone
6. References and notes
(2KHSO5·KHSO4·K2SO4)13.
Subsequent
cyclisation3i
1.
(a) Jarvest, R. L.; Parratt, M. J.; Debouck, C. M.; Gorniak, J.
G.; JohnJennings, L.; Serafinowska, H. T.; Strickler, J. E.
Bioorg. Med. Chem. Lett. 1996, 6, 2463-24; (b) Krantz, A.;
Spencer, R. W.; Tam, T. F.; Liak, T. J.; Copp, L. J.; Thomas, E.
M.; Rafferty, S. P. J. Med. Chem. 1990, 33, 464-479; (c)
Hedstrom, L.; Moorman, A. R.; Dobbs, J.; Abeles, R. H.
Biochemistry, 1984, 23, 1753-1759; (d) Gutschow, M.;
Neumann, U. Bioorg. Med. Chem. 1997, 5, 1935-1942; (f)
Hays, S. J.; Caprathe, B. W.; Gilmore, J. L.; Amin, N.;
Emmerling, M. R.; Michael, W.; Nadimpali, R.; Nath, R.;
Raser, K. J.; Stafford, D.;Watson, D.; Wang, K.; Jaen, J. C. J.
Med. Chem. 1998, 41, 1060-1067.
followed by oxidation leads to 2-arylbenzoxazinones.
Scheme 2 Proposed reaction mechanism
2.
(a) El-Hashash, M. A.; El-Bardy, Y. A. Helv. Chim. Acta.
2011, 94, 389-396; (b) Abd-Elhakeem, M. A.; Elsayed, A. M.
J. Chem. Pharm. Res. 2013, 5, 275-279; (c) Holland, J. P.;
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Chem. 2013, 21, 496-507; (d) Zhang, Z.; Liang, X.; Li, X.;
Song, T.; Chen, Q.; Sheng, H. Eur. J. Med. Chem. 2013, 69,
711-718; (e) Kamal, A.; Tamboli, J. R.; Ramaiah, M. J.; Adil,
S. F.; Pushpavalli, S. N.; Ganesh, R.; Sarma, P.; Bhadra, U.;
Pal-Bhadra, M. Bioorg. Med. Chem. 2013, 21, 6414-6426.
(a) Beck, J. R.; Yahner, J. A. J. Org. Chem. 1973, 38, 2450-
2452; (b) Zentmyer, D. T.; Wagner, E. C. J. Org. Chem. 1949,
14, 967-981; (c) Papadopoulos, E. P.; Torres, C. D.
Heterocycles. 1982, 19, 1039-1042; d) Ulrich, R. J. Heterocycl.
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Helliwell, M. Org. Biomol. Chem. 2006, 4, 2106-2108; (f)
Nayak, M. K.; Kim, B. H.; Kwon, J. E.; Park, S.; Seo, J.;
Chung, J.W.; Park, S. Y. Chem. Eur. J. 2010, 16, 7437-7447;
(g) Manivannan, E.; Chaturvedi, S. C. Bioorg. Med. Chem.
2011, 19, 4520-4528; (i) Shariat, M.; Abdullah, S. Molecules,
2004, 9, 705-712.
3.
3. Conclusion
4.
5.
6.
7.
8.
Ge, Z. Y.; Xu, Q. M.; Fei, X. D.; Tang, T.; Zhu, Y. M.; Ji, S. J.
J. Org. Chem. 2013, 78, 4524−4529.
Lian, X. L.; Lei, H.; Quan, X. J.; Ren, Z. H.; Wang, Y. Y.;
Guan, Z. H. Chem. Commun. 2013, 49, 8196-8198.
Ge, Z. Y.; Xu, Q. M.; Fei, X. D.; Tang, T.; Zhu, Y. M.; Ji, S. J.
J. Org. Chem. 2013, 78, 4524−4529.
Kobayashi, K.; Hashimoto, H.; Matsumoto, M.; Inouchi, H.
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686–693. (f) Houlden, C. E.; Hutchby, M.; Bailey, C. D.; Ford,
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In summary, we have developed I2 catalysed oxidative
cyclisation method for the synthesis of 2-arylbenzoxazinones
using 2-aminobenzoic acid and arylaldehyde with oxone as
oxidant. Such a novel, transition-metal-free simple reaction
condition using inexpensive and readily available reagents,
provides a convenient and highly efficient access to 2-
arylbenzoxazinones. This synthetic protocol can tolerate a broad
range of functional groups. In addition to this, precursor
preparation from starting materials was not required in this
reaction, which avoided multiple reaction steps.
4. Acknowledgment
Sathishkumar Munusamy thanks CSIR for providing Senior
Research Fellowship. The DST-FIST NMR facility at VIT
University and VIT management are duly acknowledged.
Authors would like to thank Dr. R. Srinivasan, SSL, and VIT
University for English language editing.
9.
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Tetrahedron Lett. 2015, 56, 203–205.
5. Experimental data
13. Armstrong, A. Angew. Chemie Int. Ed., 2004, 43, 1460–1462.
General procedure for the synthesis of 2-phenyl-4H-
benzo[d][1,3]oxazine-4-one:
An oven dried three neck RB was loaded with 2-aminobenzoic
acid (1) (2 mmol), benzaldehyde (2) (2 mmol), I2 (0.4 mmol,
catalyst) and oxone (1 equivalent, oxidant) in toluene (5 ml).
Then, the reaction mixture was allowed to reflux for 4h. The
completion of the reaction was monitored by TLC. After being
cooled at room temperature the reaction mixture was poured in
the saturated solution of sodium thiosulfate in order to remove
iodine and extracted with ethylacetate. The combined organic
layer was washed with brine and then dried over anhydrous
Na2SO4. The solvent was evaporated and the crude product was

4
Tetrahedron
Highlights
 Cascade cyclisation of 2-aminobenzoic acids and arylaldehyde using I2 and oxone.
 Easy availability of starting material
 As many aromatic aldehydes are available reagents, the versatility of the product can
be increased.
 Transition metal- free condition.
 Use of an environmentally benign oxidant.