Copper catalyzed C-N bond formation/C-H activation: Synthesis of aryl 4H-3,1-benzoxazin-4-ones

Article abstract of DOI:10.1016/j.tetlet.2014.11.070

We have developed a practical and efficient synthesis of 2-phenyl-4H-benzo[d][1,3]oxazine-4-one derivatives through copper catalyzed tandem reaction of 2-iodobenzoic acid with arylmethanamines under aerobic conditions. Compared to the literature methods toward the synthesis of 2-phenyl-4H-benzo[d][1,3]oxazine-4-one, the synthetic method reported in this Letter has broad substrate scope, mild reaction condition, and uses an inexpensive catalyst.

Full text of DOI:10.1016/j.tetlet.2014.11.070

Accepted Manuscript
Copper catalyzed C-N bond formation / C-H activation: Synthesis of aryl
4H-3,1-benzoxazin-4-ones
Sathishkumar Munusamy, Sathesh Venkatesan, Kulathu Iyer Sathiyanarayanan
PII:
S0040-4039(14)01963-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.11.070
TETL 45454
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 August 2014
13 November 2014
14 November 2014
Please cite this article as: Munusamy, S., Venkatesan, S., Sathiyanarayanan, K.I., Copper catalyzed C-N bond
formation / C-H activation: Synthesis of aryl 4H-3,1-benzoxazin-4-ones, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.11.070
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Graphical Abstract
Copper catalyzed C-N bond formation / C-H
activation: Synthesis of aryl 4H-3, 1-
benzoxazin-4-ones
Leave this area blank for abstract info.
Sathishkumar Munusamy, Sathesh Venkatesan and Kulathu Iyer Sathiyanarayanan*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Copper catalyzed C-N bond formation / C-H activation: Synthesis of aryl 4H-3,1-benzoxazin-4-ones
Sathishkumar Munusamy, Sathesh Venkatesan and Kulathu Iyer Sathiyanarayanan*
aChemistry 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
We have developed a practical and efficient synthesis of 2-phenyl-4H-benzo[d][1,3]oxazine-4-
one derivatives through copper catalyzed tandem reaction of 2-iodobenzoic acid with
arylmethanamines under aerobic conditions. Compared to the literature methods towards the
synthesis of 2-phenyl-4H-benzo[d][1,3]oxazine-4-one, the synthetic method reported in this
paper has broad substrate scope, mild reaction condition and uses an inexpensive catalyst.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
heterogeneous catalysis
C-N bond formation
aerobic oxidation
domino reaction
heterocycle
The development of simple synthetic methods for the rapid access to
N-heterocycles with complexity and diversity has broad applications
in chemistry, biology and material sciences. This has attracted
considerable attention in synthetic organic chemistry.1 In this
respect, benzoxazinones are among the most important N-
heterocycles in many biological compounds and pharmaceutical
drugs (Fig. 1).2 They exhibit a variety of bioactivities such as
antibacterial, antifungal, HSV-1 protease inhibition, serine proteases
inhibition, and others.3 Along similar lines, the key pharmacophore
in cetilisate, which showed promising market prospect as an
antiobesity remedy, contains benzoxazinone unit.4
silica-sulphuric acid (SSA)10 and a solid phase traceless synthesis.11
Recently, Rajendar Reddy and co-workers reported the synthesis of
benzoxazinones through benzylic oxidation and oxidative
dehydrogenation using potassium iodide-tert-butylhydroperoxide(KI-
TBHP).12 Zheng-Hui Guan and coworkers have reported the
synthesis of 2-arylbenzoxazinones from the oxidation of 2-
arylindoles using oxone as the sole oxidizing agent.13 Another
notable method has been developed by Liu and coworkers. This
method involves palladium catalyzed C≡C triple bond cleavage of 2-
azidoalkynylbenzenes for the synthesis of benzoxazinones.14
However, in terms of substrate scope, yields and reaction conditions,
these methods suffer from one or more drawbacks. These methods
use carbon monoxide gas or heavy metals or rely on the involvement
of multi-step process for the synthesis of substrate. Herein, we report
a simple, efficient and economical copper catalyzed strategy for the
synthesis of benzoxazinones derivatives through cascade reaction of
2-iodobenzoic acid and (aryl) methanamines with air as the sole
oxidizing agent without the addition of any ligand. Oxidation
reactions that utilize environmentally benign oxidizing agents such
as peroxides or O2 are preferable according to the principles of green
chemistry.15
Figure 1
Structure of some of the bioactive 4H-3,1-benzoxazin-4-one derivatives
O
O
O
O
O
O
O
H
N
O
N
N
O
N
I
CF3
O
II
III
R
Cl
N
O
N
O
N
O
O
H
S
N
O
N
O
O
N
O
H
O
O(CH3)15CH3
NH
O
N
N
Cetilistat
IV
VI
V
Initial experiments were carried out with 2-iodobenzoic acid and
benzylamine as the model substrates to optimize the reaction
conditions including catalaysts, bases and reaction temperature under
air (1atm). Various copper catalysts were tested (0.2 equivalents)
with 2 equivof K2CO3 (with respect to 2-Iodobenzoic acid) as a base
and DMSO as a solvent at 90 °C. Among the various copper
catalysts used, CuI provided the expected product with high yield
(Table 1, entry). During optimization of the catalyst, it was noted
that this CuI catalyzed tandem reaction could be realized without the
addition of any ligand. Effects of bases, including organic and
Considering the importance of these heterocyclic compounds,
many synthetic routes have been developed for the synthesis of
benzoxazinone derivatives.5 Conventional methods for the synthesis
of benzoxazinones are the cyclization of anthranilic acid or N-
acylanthranilic acid6 and palladium catalyzed carbonylation reactions
of o-iodoanilines with unsaturated halides,7 triflates8 and acid
chlorides9 which have been developed by many groups recently.
Other notable synthetic methods include solvent-free synthesis from
isatoic anhydride5 and orthoester with primary amine employing

2
Tetrahedron Letters
Table 2
inorganic bases, was screened, and K2CO3 showed the best activity.
Then the effects of solvent on this tandem reaction were also
investigated using CuI as the catalyst, and the highest yield was
observed in the case of DMSO as the reaction medium. When we
carried out the reaction in nitrogen atmosphere (exclusion of air), an
Ullmann type N-arylated product, 2-(benzylamino) benzoic acid was
observed.
Copper catalyzed domino condensation for the synthesis of 4H-3,1-
benzoxazin-4-onesa
O
CuI, K2CO3, DMSO
90°C, air
COOH
I
O
H2N
N
R1
R2
R1
1a
2a
R2
3a
Table 1
Optimization of the reaction condition for the synthesis of 3aa
Entry[a]
3
Yield
[%][b]
Time
(h)
O
1
2
3
4
5
6
7
8
9
3a: R1 = H, R2= H
70
12
13
12
14
12
11
14
15
12
11
11
11
COOH
3b: R1 = H, R2= 2-Cl
65
68
72
73
63
58
55
68
60
62
65
Various Conditions
H2N
O
I
3c: R1 = H, R2= 3-Cl
3d: R1 = H, R2= 4-Cl
N
2a
1a
3e: R1 = H, R2= 4-Br
3a
3f: R1 = H, R2= 4-NO2
3g: R1 = H, R2= 3-CH2NH2
3h: R1 = H, R2 = 4-CH2CH3
Entry
1
Catalyst
CuI
Base
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Yield(%)b
70
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
TEA
Pyridine
K2CO3
K2CO3
K2CO3
3i: R1 = H, R2=3- picolylamine
3j: R1 = 4-Cl, R2= H
2
3
4
5
6
7
8
9
CuBr
CuCl
Cu(OAc)2
CuSO4
CuCl2
CuI
CuI
CuI
CuI
CuI
58
42
35
Trace
Trace
45
42
30
10
11
12
3h: R1 = 4-Cl, R2= 3-F
3i: R1 = 4-Cl, R2= 4-Cl
aUnless otherwise noted, the reactions were carried out with 2 mmol of 1a
and 4 mmol of 2a, 0.4 mmol of catalyst and 4 mmol of base under aerobic
condition. The samples are characterized by comparison of their
spectroscopic and physical data with authentic samples synthesized by
reported methods. bIsolated yield.
10
11
12c
40
33
---
Acetonitrile
Solvent free
CuI
Scheme 1.
aUnless otherwise noted, the reactions were carried out with 2 mmol of 1a
and 4 mmol of 2a, 0.4 mmol of catalyst and 4mmol of base under aerobic
condition. bIsolated yield creaction was carried out under solvent-free
condition.
(A) Reaction between 1a and 2a under nitrogen atmosphere affords Ullmann
product (B) Aerobic oxidation of isolated Ullmann product under air
atmosphere
COOH
I
COOH
H
Unaffected
R2
CuI, K2CO3, DMSO
90°C, N2, 6h
H2N
(A)
R2
R1
R1
N
H
With the optimized reaction condition in hand, the scope and
the generality of this CuI catalyzed tandem reaction leading to 2-
arylbenzoxazinones were investigated. First, it was observed that
aryl- and heteroaryl- substituted benzyl amines were compatible
with the reaction conditions to provide the desired product in
moderate to good yields (Table 2).
2a
1a
4
O
O
N
COOH
CuI, K2CO3, DMSO
90°C, air, 6h
(B)
N
H
R1
R2
R1
R2
4
3a
It was also found that various aryl substituted benzylamines
underwent this tandem reaction smoothly irrespective of the
substituents present in the aromatic ring. In addition to this, we
tried the same reaction in alkyl methanamines but the results
were negative. This copper catalyzed domino reaction could
tolerate many functional groups such as C-Cl bond, a C-Br bond,
a nitro group and heterocycles containing nitrogen in aryl
methanamines.
Scheme 2.
Possible mechanism for the Copper catalyzed domino synthesis of 2-
arylbenzoxazinanes
COOH
COOH
I
CuI, K2CO3
DMSO
H2N
R2
N
H
R1
In order to explore the reaction mechanism, we carried out the
reaction in nitrogen atmosphere (exclusion of air) to avoid the
oxidation process. As expected, we got the Ullmann coupled
product without cyclization, and we got only trace amount of 2-
arylbenzoxazinones. The isolated Ullmann product was again
treated with our standard reaction condition (Scheme 1) under
air, and we got the 2-arylbenzoxazinones in good yield. A
possible mechanism has been proposed based on the results
derived from the experiments carried out. In the first step, copper
catalyzed Ullmann coupling afforded 2-(benzylamino) benzoic
acid (4). Subsequent aerobic oxidation of 4 afforded intermediate
I containing C=N bond and nucleophilic addition of carboxylic
acid group to the C=N bond in I gave II. Intermediate 4 was
isolated and characterized (see supporting information). Further
aerobic oxidation of II affords the target product (3).
R1
R2
4
isolated
O
O
COOH
CuI, K2CO3
Aerobic oxidation
DMSO
R1
N
I
R1
N
H
R2
R2
isolated
II
O
CuI, K2CO3
O
Aerobic oxidation
DMSO
N
R1
R2
3a

3
7. Cacchi, S.; Fabrizi, G.; Marinelli. F. Synlett. 1996, 997.
8. Larock, R. C.; Fellows, C. A. J. Org. Chem. 1980, 45, 363.
9. Larksarp, C.; Alper, H. Org. Lett. 1999, 1, 1619.
In summary, we report that we have developed a simple and
efficient copper catalyzed domino synthesis of 2-
arylbenzoxazinones using 2-iodobenzoic acid and substituted
benzylamine under air.16 This synthetic methodology has many
advantages such as 1) easily available starting material 2) use of
air as an oxidizing agent 3) ligand-free condition.
10. Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Baghbanzadeh. Tetrahedron Lett.
2005, 46, 7051.
11. O’Mahony, D. J. R.; Krchnak, V. Tetrahedron Lett. 2002, 43, 939.
12. Arun Kumar, R.; Uma Maheswari, C.; Ghantasala, S.; Jyothi, C.;
Rajendar Reddy, K. Adv. Synth. Catal. 2011, 353, 401.
13. Lian, X. L.; Lei, H.; Quan, X. J.; Ren, Z. H.; Wang, Y, Y.; Guan, Z. H.
Chem. Commun. 2013, 49, 8196.
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Catalytic. Wiley- VCH, Weinheim, Germany, 2007.
Acknowledgment
S. M and S. V thank VIT University, Tamil Nadu, India, for
providing Research Associateship. The DST-FIST NMR facility
at VIT University is greatly acknowledged.
16. General procedure for the synthesis of 2-phenyl-4H-
benzo[d][1,3]oxazine-4-one: To an oven dried three necked RB
flask containing 2-iodobenzoic acid (1) (2 mmol), benzyl amine
(2) (4 mmol) and CuI (0.4 mmol) in DMSO (3ml) 0.55 g of
K2CO3 was added. Then, the reaction mixture was stirred at 90
°C under air atmosphere for 12h. The completion of the reaction
was monitored by TLC. After being cooled at room temperature
the reaction mixture was poured into ice cooled water and
extracted with ethyl acetate two times. The combined organic
layer was washed with brine and then dried over anhydrous
Na2SO4. The solvent was evaporated and the crude product was
purified by column chromatography (hexane(80) / ethyl acetate
(20)) on silica gel to afford 2-phenyl-4H-benzo[d][1,3]oxazine-
4-one.
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