A simple synthesis of 4-substituted 2,3-benzoxazinones from C-2 arylated 1,3-indanediones

Article abstract of DOI:10.1016/j.tetlet.2011.04.076

A simple one-pot procedure for the conversion of 2-hydroxy-2-(2′- hydroxy-aryl)-1,3-indanediones to 4-substituted benzoxazinones has been developed. The process constitutes an interesting acid-catalyzed rearrangement followed by condensation with hydroxyl

Full text of DOI:10.1016/j.tetlet.2011.04.076

Tetrahedron Letters 52 (2011) 3243–3246
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A simple synthesis of 4-substituted 2,3-benzoxazinones from C-2 arylated
1,3-indanediones
Suven Das a,b, Pradyot Koley a, Animesh Pramanik a,
⇑
a Department of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata 700 009, India
b Rishi Bankim Chandra College for Women, Naihati, North 24-Parganas 743 165, India
a r t i c l e i n f o
a b s t r a c t
A simple one-pot procedure for the conversion of 2-hydroxy-2-(20-hydroxy-aryl)-1,3-indanediones to 4-
substituted benzoxazinones has been developed. The process constitutes an interesting acid-catalyzed
rearrangement followed by condensation with hydroxylamine.
Article history:
Received 10 March 2011
Revised 14 April 2011
Accepted 19 April 2011
Available online 27 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ninhydrin
Hydroxylamine
2,3-Benzoxazinones
Acid-catalyzed reaction
Benzoxazinones are an important class of naturally occurring
heterocycles with interesting biological properties. For example,
2-substituted 4H-3,1-benzoxazin-4-ones are found in nature as
phytoalexins avenalumin I1 and dianthalexin.2 Efavirenz (Trade
name Sustiva(R)) is a marketed human immunodeficiency virus
type
1
(HIV-1) specific non-nucleoside reverse transcriptase
O
R1
R4
OH
HO
R2
R3
R3
R2
R4
HO
R3
R2
HON
O
O
3a-f
NH2OH.HCl
Ninhydrin
R4
R1
N
O
HO
EtOH
Reflux, 3h
AcOH
Reflux
R1
1a-f
OH
R4
O
1, 2, 3 and 4
------------------------------------
a: R1 = R2 = R3 = R4 = H
4a-f
R3
b: R1 = R2 = R4 = H, R3 = CH3
c: R1 = R2 = R4 = H, R3 = OCH3
d: R1 = R2 = R4 = H, R3 = Cl
e: R1 = R4 = H, R2 = CH3, R3 = Cl
f : R1 = R2 = R4 = H, R3 = Br
O
HO
R2
2a-f
R1
Scheme 1. Synthesis of 4-substituted 2,3-benzoxazinones 4a–f.
⇑
Corresponding author. Tel.: +91 33 2484 1647; fax: +91 33 2351 9755.
E-mail address: animesh_in2001@yahoo.co.in (A. Pramanik).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.076

3244
S. Das et al. / Tetrahedron Letters 52 (2011) 3243–3246
Table 1
Preparation of 4-substituted 2,3-benzoxazinones 4a–f from 2a–f
Entry
Phenols
Substrates
Products
HO
Time (h)
Yielda (%)
Mpb (°C)
O
OH
OH
HON
1
3.0
45
189–190
O
N
O
2a HO
O
4a
OH
O
HO
OH
CH3
OCH3
Cl
HON
CH3
OCH3
Cl
2
2.5
50
193–194
N
O
O
CH3
OH
2b HO
O
4b
O
HO
OH
HON
3
4
5
3.0
3.5
3.0
52
48
46
186–187
173–174
183–185
N
O
O
OCH3
OH
2c
HO
O
4c
O
HO
OH
HON
N
O
O
Cl
2d HO
O
HO
4d
OH
O
CH3
Cl
OH
Cl
HON
CH3
CH3
N
O
O
Cl
HO
2e
2f
O
4e
4f
OH
O
HO
OH
Br
HON
Br
6
3.5
42
193–194
N
O
O
Br
HO
O
a
Yields are for isolated products.
Mps are uncorrected.
b
inhibitor (NNRTI) that contains benzoxazinone moiety.3 Some
derivatives of 3,1-benzoxazinones act as competitive inhibitors4
or potent inactivators5 of chymotrypsin and other serine proteases,
or are inhibitors of human leukocyte elastase (HLE),6 neutrophil
elastase,7 herpes simplex virus type 1 (HSV-1) protease,8 and C1r
serine protease.9 Bioactivity and ecological role of 1,4-benzoxazi-
none systems has recently been explored.10,11 Although there are
several methods for the synthesis of substituted 3,1- and 1,4-ben-
zoxazinones, very few methods are available for the synthesis of
2,3-benzoxazinone skeletons.12 Herein we report an efficient and
novel procedure for the synthesis of 4-substituted 2,3-benzoxazi-
nones from easily available starting materials.
the preparation of various heterocyclic skeletons14 from ninhydrin,
we thought that 2-hydroxy-2-(20-hydroxy-aryl)-1,3-indanediones
2 could be a flexible precursor for the synthesis of heterocycles con-
taining both nitrogen and oxygen. To achieve this, hydroxylamine
was chosen as nucleophile for the reaction. Interestingly we found
that upon refluxing 2-hydroxy-2-(20-hydroxy-aryl)-1,3-indanedi-
ones 2a–f with hydroxylamine hydrochloride in ethanol, 4-substi-
tuted 2,3-benzoxazinones 4a–f are formed in moderate yields
through sequence of reactions within 3 h (Scheme 1, Table 1). The
current one-pot protocol possesses a simple work-up and purifica-
tion procedure, requiring only filtration followed by crystallization
from acetone.15 All the compounds were characterized by 1H and
13C NMR specta.16 In the 1H NMR spectra of compound 4c, for exam-
ple, phenolic proton comes to resonate at d = 9.56 ppm and the
oxime proton appears at d = 12.23 ppm as a singlet. The 13C NMR
spectrum of compound 4c shows lactone carbonyl signal at
When ninhydrin is refluxed in a mixture of phenols 1 and acetic
acid, 2-hydroxy-2-(20-hydroxy-aryl)-1,3-indanediones 2 are forme-
d.13,14a The adducts so formed preferentially remain in the cyclic
hemiketal form 3.13a–c On the basis of our previous experience in

S. Das et al. / Tetrahedron Letters 52 (2011) 3243–3246
3245
d = 163.0 ppm. X-ray crystal structure of 4b is shown in Figure 1
which confirms the product formation.17 In the structure the intra-
molecular hydrogen bonding is indicated by a broken line.
nucleophilic attack of hydroxyl group of oxime on the lactone
carbonyl results in the formation of 2,3-benzoxazinone skeleton
7. Under the reaction conditions 7 spontaneously is oxidized to ke-
tone 8 which finally condenses with hydroxylamine to furnish
compound 4. It was not possible to isolate any of the intermediates
5–8 under the reaction conditions.
The formation of 4 can be explained from the proposed mecha-
nism depicted in Scheme 2 and in accordance with our previous re-
sults.14a In the acidic condition, protonation of the carbonyl group
of the bicyclo[3.3.0]octano system 3 initiates the breaking of the
central C–C bond to afford an eight-membered lactone intermedi-
ate 5 which undergoes the tautomeric keto form. Then the ketonic
carbonyl preferentially condenses with hydroxylamine to furnish
the oxime intermediate 6. Subsequently the intramolecular
In summary, we have developed
a simple and efficient
procedure for the synthesis of benzoxazinones from 2-hydroxy-
2-(20-hydroxy-aryl)-1,3-indanediones through an acid catalyzed
rearrangement followed by condensation with hydroxylamine.
The present method constitutes a one-pot reaction from easily pre-
pared starting materials and easy work-up procedure. To the best
of our knowledge, this is the first time the synthesis of benzoxaz-
inone skeleton from C2-arylated 1,3-indanediones has been
accomplished.
C6
O4
C7
C15
Acknowledgments
We gratefully acknowledge the financial assistance from the
University of Calcutta. S.D. is thankful to UGC for a Minor Research
Project [No. F.PSW-123/10-11 (ERO)].
C5
C4
C16
Supplementary data
C14
C3
Supplementary data (IR, 1H, 13C data of compounds 4a, 4d, and
4f and crystallographic data for 4b) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2011.04.076.
N2
C9
C2
O3
N1
O2
References and notes
C10
C8
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Figure 1. ORTEP diagram of 4b with atom numbering scheme. Thermal ellipsoids
are shown at the 50% probability. Intramolecular hydrogen bond is shown as dotted
line. Color code: red, oxygen; blue, nitrogen; gray, carbon; light gray, hydrogen.
O
+OH
OH
OH
O
OH
H+
OH
HO
HO
HO
O
O
O
O
R
R
3
5
O
R
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NH2OH
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Scheme 2. Proposed mechanism for the formation of 2,3-benzoxazinone derivatives 4.

3246
S. Das et al. / Tetrahedron Letters 52 (2011) 3243–3246
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appropriate substrate 2a–f (1.4 mmol) was added to ethanol (15 ml)
followed by the addition of hydroxylamine hydrochloride (650 mg,
9.4 mmol). The reaction mixture was refluxed for about 3 h. The cold
reaction mixture was then poured into 50–60 ml ice cold water. The solid
product separated was filtered and washed with water. The resulting solids
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16. 4-((2-Hydroxy-5-methylphenyl)(hydroxyimino)methyl)-1H-benzo[d][1,2]
oxazin-1-one 4b: IR (KBr): 3322, 3214, 1710 cmꢀ1
;
1H NMR (DMSO-d6,
300 MHz) d 12.20 (1H, s), 9.91 (1H, s), 8.29 (1H, dd, J = 7.6, 1.2 Hz), 8.04–7.93
(2H, m), 7.53 (1H, dd, J = 7.3, 1.0 Hz), 7.28 (1H, d, J = 1.5 Hz), 7.06 (1H, dd,
J = 8.3, 1.8 Hz), 6.71 (1H, d, J = 8.4 Hz), 2.16 (3H, s); 13C NMR (DMSO-d6,
75 MHz) d 163.0, 154.0, 153.9, 148.2, 136.3, 134.5, 132.0, 128.9, 128.2, 127.8,
127.2, 126.0, 121.5, 119.4, 116.4, 20.0; Anal Calcd for C16H12N2O4: C, 64.86; H,
4.08; N, 9.45. Found: C, 64.80; H, 4.02; N, 9.37. 4-((2-Hydroxy-5-
methoxyphenyl)(hydroxyimino)methyl)-1H-benzo[d][1,2]oxazin-1-one 4c: IR
11. (a) Macías, F. A.; Marín, D.; Oliveros-Bastidas, A.; Molinillo, J. M. G.
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2053.
(KBr): 3345, 3224, 1708 cmꢀ1 1H NMR (DMSO-d6, 300 MHz) d 12.23 (1H, s),
;
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9.56 (1H, s), 8.28 (1H, d, J = 7.2 Hz), 8.04–7.93 (2H, m), 7.54 (1H, d, J = 7.5 Hz),
7.06 (1H, d, J = 3.0 Hz), 6.88 (1H, dd, J = 8.7, 3.0 Hz), 6.70 (1H, d, J = 9.0 Hz), 3.66
(3H, s); 13C NMR (DMSO-d6, 75 MHz) d 163.0, 154.4, 152.2, 149.9, 147.4, 136.2,
134.4, 127.7, 127.3, 126.2, 121.3, 120.5, 117.6, 117.4, 112.9, 55.6. Anal Calcd for
C
16H12N2O5: C, 61.54; H, 3.87; N, 8.97. Found: C, 61.49; H, 3.82; N, 8.93. 4-((5-
Chloro-2-hydroxy-4-methylphenyl)(hydroxyimino)methyl)-1H-benzo[d][1,2]
oxazin-1-one 4e: IR (KBr): 3222, 1707 cmꢀ1 1H NMR (DMSO-d6, 300 MHz) d
;
12.37 (1H, s), 10.28 (1H, s), 8.39 (1H, d, J = 8.4 Hz), 8.03–7.93 (2H, m), 7.62–7.50
(2H, m), 6.76 (1H, s), 2.21 (3H, s); 13C NMR (DMSO-d6, 75 MHz) d 162.9, 154.7,
153.9, 146.6, 138.8, 136.2, 134.5, 128.1, 127.8, 127.2, 126.0, 123.6, 121.5, 119.5,
118.9, 19.7. Anal Calcd for C16H11ClN2O4: C, 58.11; H, 3.35; N, 8.47. Found: C,
58.04; H, 3.30; N, 8.42.
17. Crystallographic data for the structure 4b in this Letter have been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication No. CCDC 809903. Copies of the data can be obtained, free of
charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax:
+44 01223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
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