Triethylamine-catalyzed synthesis of oxazepine from maleamic acids

Article abstract of DOI:10.1002/jhet.2114

2-Thioxo-1,3-oxazepine-4,7-dione compounds were obtained via triethylamine-catalyzed condensation of maleamic acids with thiophosgene under anhydrous conditions. This method features relatively a simple methodology, use of inexpensive reagents, convenient operating conditions and high yields.

Full text of DOI:10.1002/jhet.2114

Month 2014
Triethylamine-Catalyzed Synthesis of Oxazepine from Maleamic Acids
Rahul Badru* and Baldev Singh
Department of Chemistry, Punjabi University, Patiala 147002, Punjab, India
*
E-mail: rahulbadru@gmail.com
Received June 11, 2013
DOI 10.1002/jhet.2114
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
2
-Thioxo-1,3-oxazepine-4,7-dione compounds were obtained via triethylamine-catalyzed condensation of
maleamic acids with thiophosgene under anhydrous conditions. This method features relatively a simple
methodology, use of inexpensive reagents, convenient operating conditions and high yields.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
of α-methoxyisoindolones [33], from imines by their
acylation and further cyclization [34], and one-pot multicom-
ponent reaction of 2-aminophenols, Meldrum’s acid and
isocyanides [35]. The use of microwave irradiation has also
been employed [36].
However, above-reported methods suffer from draw-
backs like prolonged reaction times and complex meth-
odology and frequently have low yields. Thus, despite
the great success in the synthesis of oxazepine deriva-
tives, a convenient and efficient way to form the
oxazepine ring is still preferred owing to its utmost
importance as pharmaceutical drugs and active sub-
stances in biological systems.
Seven-membered ring systems containing two hetero-
atoms oxazepines (N and O) and their aryl-annelated
benzoxazepines) and structural analogues diazepines (N
and N) and thiazepines (N and S) occupy an important
place in the realm of synthetic organic chemistry, as they
account for a significant portion of widely prescribed
azepine-based drugs possessing/showing manifold biologi-
cal activities like antidepressant [1], anticonvulsant [2],
antiviral [3], antimicrobial [4], antifungal [5], anticancer
(
[
6], antithrombotic [7], antihistamines [8], nonnarcotic
analgesic [9], sedatives, and hypnotics [10]. They are also
active in the treatment of Alzheimer’s disease and type 2
diabetes [11]. They act as inhibitors of several enzymes like
glycosidase [12], kinase [13] and nitric oxide synthases [14],
angiotensin-converting enzyme [15], HIV-1 integrase [16],
and HIV-1 reverse transcriptase [17] and also inhibit several
targets such as cannabinoid-1 receptor [18], squalene
synthase [19], 5-HT1A receptor [20], progesterone receptor
RESULTS AND DISCUSSION
In the present study, 2-thioxo-1,3-oxazepine-4,7-diones
have been efficiently synthesized by the triethylamine-
catalyzed condensation of maleamic acids with thiophos-
gene under anhydrous conditions. The nucleophilic attack
of O and N of maleamic acid moiety onto thiophosgene,
followed by elimination, leads to 2-thioxo-1,3-oxazepine-
4,7-dione as the cyclized product. This method relatively
features a low catalyst loading, use of inexpensive reagents,
convenient operating conditions and high yields.
In the first step, the maleamic acids were obtained by
adopting a procedure similar to that reported in litera-
ture [37]. For this purpose, a variety of amines 1a–h
(1 mmol) was treated with maleic anhydride 2 (1 mmol)
in sodium-dried toluene (5 mL) at room temperature
(Scheme 1) to afford the corresponding maleamic acids
3a–h (Table 1).
[
21], histamine H , and gastrin receptor [22]. They are active
constituents of a series of new potent bradykinin agonists
23]. Some of these compounds have also shown activity
2
[
as endogenous natriuretic factors [24] and also induce
apoptosis in MCF-7 cells [25] and myeloma cells [26].
Because of a wide range of physiological properties, syn-
thetic manipulations on these molecules have been an area
of current interest.
A considerable number of methods toward the forma-
tion of oxazepine ring have been reported in recent years
via the Baylis–Hillman reaction [27], by the cyclization of
propenamides with 2-aminophenol [28], by the reaction
of nitrosonaphthol with TNT [29], a phosphine-
mediated tandem reaction of ynones with 2-azido
alcohols [30], intermolecular amidoalkylation reaction
In the performed reaction, the desired products usually
precipitated from the reaction mixtures after the reaction
mixture was cooled to below the room temperature. The
obtained precipitates were recrystallized out of ethanol,
[
31], using the benzotriazole methodology [32],
scandium- or copper-triflate-catalyzed acylaminoalkylation
©
2014 HeteroCorporation

R. Badru and B. Singh
Vol 000
Scheme 1
The maleamic acids thus synthesized were initially air-
dried and then well-dried in a vacuum desiccator for
2
–3 days under anhydrous calcium chloride and phospho-
rus pentachloride mixture before using them for the next
step. In the next step, the ice-cold solution of well-dried
maleamic acid of aniline 1 mmol (Table 1, entry 1) in
5
mL dry toluene was topped with 1 equiv triethylamine,
followed by dropwise addition of solution of thiophosgene
1 mmol thiophosgene in 5 mL dry toluene) with constant
stirring for 15 min. Stirring was continued for a further
h. After that, the cooling bath was removed, and the
(
3
and the physical data (mp, IR, NMR) of the known
compounds were found to be identical with those reported
in literature [37,38].
reaction mixture was kept overnight at room temperature.
The reaction mixture was separated using diethyl ether
and washed with aqueous sodium hydrogen carbonate
Table 1
Synthesis of maleamic acids.
a
b
Entry
1
Amine
Product
Yield (%)
94
2
3
92
90
92
88
4
5
6
7
8
94
96
90
a
Reaction conditions: amine (1 mmol), maleic anhydride (1 mmol), sodium-dried toluene (5 mL), room temperature.
Isolated yields after recrystallization.
b
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Triethylamine-Catalyzed Synthesis of Oxazepine from Maleamic Acids
Table 3
solution to neutralize any residual thiophosgene and to
wash out the triethylamine hydrochloride salt that formed
during the reaction. Further workup and purification by
column chromatography afforded the cyclized product 2-
thioxo-1,3-oxazepine-4,7-diones in low yields of 41%
Thiocarbonylation of maleamic acid of aniline (Table 1, entry 1) with
a
thiophosgene in different solvents.
b
Yield of
Entry
Solvent
Toluene
Catalyst (equiv)
4a (%)
(Scheme 2).
1
2
3
4
2.2
2.2
2.2
2.2
72
67
70
59
In an effort to improve the yield, the quantities of
Dichloromethane
Chloroform
triethylamine catalyst were varied, and results are summa-
rized in Table 2. Use of 2.2 equiv of catalyst per equivalent
of reactant afforded the product in 72% yield. This may be
attributed to 2 equiv of catalyst required to remove two
proton equivalents from N–H and O–H of the maleamic
acid. Further increase did not show much improvement in
the yield.
Tetrahydrofuran
a
Reaction conditions: maleamic acid of aniline 3a (1 mmol), triethylamine
(2.2 equiv), thiophosgene solution (1 mmol in 5 mL solvent).
b
Isolated yield.
observed for cis protons C –H and C –H with coupling
5
6
After screening the reaction for catalyst loading, the
reaction was performed in different solvents to further
study the effect of a solvent and improve the yield
constants J = 7.28Hz for each proton. Aromatic protons
appeared as two doublets at δ 7.16 and δ 7.54 as per para
substitution pattern with coupling constants J = 8.56Hz for
each proton. In the C-NMR spectrum, carbonyl carbons
of lactam and lactone moiety appeared at δ 166.96 and δ
171.37, respectively. A signal at δ 178.03 was assigned to
C═S carbon. Rest of the carbons appeared in the aromatic
region at δ 126.98–136.17.
13
(
Table 3). Maximum yields were obtained in either toluene
or chloroform as a solvent.
After establishing the optimized conditions, the various
synthesized maleamic acid precursors were used to synthesize
a variety of 2-thioxo-1,3-oxazepine-4,7-diones (Table 4).
1
13
The products were identified by IR, H-NMR, C-NMR,
and mass spectral techniques. Absence of O–H and N–H
stretch in their IR spectra and peaks corresponding to acidic
protons (COOH and NH) in their NMR spectra confirmed
the formation of cyclized product from corresponding
maleamic acid. Their mass spectra results further supported
this fact (Table 4).
This method holds good to a broad range of aromatic
amines bearing electron donating as well as electron-with-
drawing groups, including cyclohexylamine and phenylhy-
drazine even (Table 4, entry 7 and 8). The phenylhydrazine
afforded the corresponding product but with a somewhat
low yield (Table 4, entry 8); however, in the case of cyclo-
hexylamine, the yield was comparable with that of other
aromatic amines (Table 4, entry 7).
1
In the H-NMR spectrum of 2,3-dihydro-3-(4-
chlorophenyl)-2-thioxo-1,3-oxazepine-4,7-dione (Table 4,
entry 2), two doublets at δ 6.30 and δ 6.61, respectively, were
In summary, we have synthesized a number of oxazepine
derivatives by the condensation of maleamic acids with
thiophosgene under base catalytic conditions. This method
is effective with a variety of amines. The attractive features
of this protocol are simplicity of the experimental procedure,
use of inexpensive reagents, convenient operating condi-
tions, and high yields. Further studies to replace thiophos-
gene with environment-friendly dialkyl carbonates are
being investigated and will be discussed in the near future.
Scheme 2
EXPERIMENTAL
Table 2
Effect of catalyst loading for thiocarbonylation of maleamic acid of
General.
Melting points reported are uncorrected.
H-NMR spectra were recorded on a 400-MHz spectrometer
Bruker, Fallanden, Switzerland) in CDCl3 solution, and the
a
aniline 3a (Table 1, entry 1) with thiophosgene.
1
(
Catalyst equiv per
b
chemical shifts are reported in parts per million (δ) relative to
internal standard TMS (0ppm). The coupling constants (J) are
reported in Hertz (Hz). C-NMR spectra were obtained at
100 MHz and referenced to the internal solvent signals (central
Entry
equiv of 3a
Solvent
Yield of 4a (%)
13
1
2
3
4
5
—
1
2
2.2
2.5
Toluene
Toluene
Toluene
Toluene
Toluene
22
41
63
72
74
peak is 77.00 CDCl ). Mass spectra were recorded on a Thermo
3
Scientific LTQ-XL LCMS (Waltham, MA). IR spectra were
recorded on a Perkin Elmer RX I FTIR Spectrophotometer
(Buckinghamshire, England). TLC plates were coated with silica
gel G suspended in methanol–chloroform. Elemental analysis was
carried out using an Elementar vario MICRO cube CHNS
a
Reaction conditions: maleamic acid of aniline 3a (1 mmol), dry toluene
5 mL), thiophosgene solution (1 mmol in 5 mL dry toluene).
Isolated yield.
(
b
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Badru and B. Singh
Vol 000
Table 4
a
Synthesis of 2-thioxo-1,3-oxazepine-4,7-diones.
b
Entry
1
Maleamic acid
Product
Yield (%)
m/z
72
67
70
68
63
233
267, 269
247
c
2
3
4
5
263
278
6
7
74
66
247
239
8
56
248
a
Reaction conditions: maleamic acid (1 mmol), dry toluene (5 mL), triethylamine (2.2 equiv), thiophosgene solution (1 mmol in 5 mL dry toluene).
Isolated yield.
b
c
Molecular ion peaks M and M+2.
analyzer. All reactions were carried out under an inert nitrogen
atmosphere in oven-dried glassware. Purification of compounds
was done with column chromatography over silica gel using
hexane-ethyl acetate mixture as the eluent.
General
procedure
for
the
synthesis
A flask surrounded
of
2-thioxo-1,3-oxazepine-4,7-diones.
by ice-water bath was charged with 1 mmol well-dried maleamic
acid of aniline (Table 1, entry 1), followed by 5 mL dry toluene
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Triethylamine-Catalyzed Synthesis of Oxazepine from Maleamic Acids
+
and 2.2equiv triethylamine. The solution became clear. A solution
of thiophosgene (1mmol) in dry toluene (5mL) was added to it
slowly with constant stirring for 15 min. There was a little
foaming. The stirring was continued for a further 3 h. After that,
the cooling bath was removed, and the reaction mixture was kept
overnight at room temperature. On the next day, the reaction
mixture was separated using diethyl ether and washed with
aqueous sodium hydrogen carbonate solution to neutralize any
residual thiophosgene and to wash out the triethylamine
hydrochloride salt that formed during the reaction. The ether
layer was dried over sodium sulfate, filtered, and reduced on a
rotary evaporator. Further purification by column chromatography
provided the cyclized product 2-thioxo-1,3-oxazepine-4,7-diones
in good to excellent yields.
(C═O of lactone), 1157 (C═S); MS: m/z: 278 [M] . Anal.
Calcd for C11 S: C, 47.48; H, 2.17; N, 10.07; S,
11.52. Found: C, 47.81; H, 2.11; N, 9.97; S, 11.56.
H N O
6 2 5
3-Benzyl-2,3-dihydro-2-thioxo-1,3-oxazepine-4,7-dione
H-NMR (DMSO-d , 400MHz, ppm):
6
δ = 4.31 (s, 2H); 6.32 (d, 1H, J = 7.72 Hz), 6.42 (d, 1H,
J = 7.72 Hz), 7.03–7.16 (m, 5H); C-NMR (DMSO-d , 125MHz,
ppm): δ = 44.60, 127.82, 128.55, 129.28, 131.88, 133.71,
1
(Table 4, entry 6).
13
6
À1
135.08, 166.93, 170.85, (C═O), 178.35 (C═S); IR (υ cm
CHCl
(C═S); MS: m/z: 247 [M] . Anal. Calcd for C12
,
): 1717 (C═O of lactam), 1680 (C═O of lactone), 1153
3
+
H
NO
S: C,
9
3
58.29; H, 3.67; N, 5.66; S, 12.97. Found: C, 58.41; H, 3.72; N,
5.75; S, 13.02.
3-Cyclohexyl-2,3-dihydro-2-thioxo-1,3-oxazepine-4,7-dione
1
(
Table 4, entry 7).
H-NMR (DMSO-d , 400 MHz, ppm):
The Spectral data for all products are provided as follows:
6
2
,3-Dihydro-3-phenyl-2-thioxo-1,3-oxazepine-4,7-dione
δ = 0.79–1.08 (m, 5H), 1.50–1.68 (m, 5H), 3.51 (m, 1H), 6.32
1
13
(
Table 4, entry 1).
6
H-NMR (DMSO-d , 400 MHz, ppm):
(d, 1H, J = 7.16 Hz), 6.49 (d, 1H, J = 7.16 Hz); C-NMR
δ = 6.31 (d, 1H, J = 7.36 Hz), 6.61 (d, 1H, J = 7.36 Hz), 7.04
(DMSO-d , 125 MHz, ppm): δ = 22.90, 27.06, 33.81, 51.22,
6
1
3
(m, 1H), 7.21 (m, 2H), 7.64 (m, 2H); C-NMR (DMSO-d6,
127.35, 130.68, 166.27, 169.33, (C═O), 178.33 (C═S); IR
À1
1
1
25 MHz, ppm): δ = 127.11, 128.74, 131.56, 132.32, 133.91,
(υ cm , CHCl ): 1706 (C═O of lactam), 1672 (C═O of lactone),
3
À1
+
35.53, 166.78, 171.24, (C═O), 177.83 (C═S); IR (υ cm
,
1160 (C═S); MS: m/z: 239 [M] . Anal. Calcd for C H NO S:
11
13
3
CHCl ): 1715 (C═O of lactam), 1678 (C═O of lactone), 1155
C, 55.21; H, 5.48; N, 5.85; S, 13.40. Found: C, 55.07; H, 5.40; N,
5.90; S, 13.48.
3
+
(
C═S); MS: m/z: 233 [M] . Anal. Calcd for C H NO S: C,
11 7 3
5
6.64; H, 3.02; N, 6.01; S, 13.75. Found: C, 56.23; H, 2.98;
3-(Phenylamino)-2,3-dihydro-2-thioxo-1,3-oxazepine-4,7-
1
N, 5.95; S, 13.64.
,3-Dihydro-3-(4-chlorophenyl)-2-thioxo-1,3-oxazepine-4,7-
dione (Table 4, entry 2).
dione (Table 4, entry 8).
H-NMR (DMSO-d , 400 MHz,
6
2
ppm): δ = 4.02 (brs, 1H, NH), 6.30 (d, 1H, J = 7.24 Hz), 6.57
1
13
H-NMR (DMSO-d , 400 MHz,
(d, 1H, J = 7.24 Hz), 6.93–7.11 (m, 5H); C-NMR (DMSO-d6,
6
ppm): δ = 6.30 (d, 1H, J = 7.28 Hz), 6.61 (d, 1H, J = 7.28 Hz),
125 MHz, ppm): δ = 112.74, 117.28, 126.11, 128.27, 132.85,
13
À1
7
.16 (d, 2H, J = 8.56 Hz), 7.54 (d, 2H, J = 8.56 Hz); C-NMR
148.17, 166.08, 170.61, (C═O), 178.39. (C═S). IR (υ cm
,
(
DMSO-d 125 MHz, ppm): δ = 126.98, 128.19, 130.92,
6
,
CHCl ): 1710 (C═O of lactam), 1678 (C═O of lactone), 1158
3
+
1
32.86, 133.69, 136.17, 166.96, 171.37, (C═O), 178.03
(C═S); MS: m/z: 248 [M] . Anal. Calcd for C H N O S: C,
1
1 8 2 3
À1
(
C═S); IR (υ cm , CHCl ): 1717 (C═O of lactam), 1678
53.22; H, 3.25; N, 11.28; S, 12.92. Found: C, 52.99; H, 3.22; N,
11.35; S, 13.01.
3
+
(
C═O of lactone), 1153 (C═S); MS: m/z: 267 [M] , 269 [M
+
+
2] . Anal. Calcd for C11
H
6
ClNO
3
S: C, 49.36; H, 2.26; N,
5
.23; S, 11.98. Found: C, 49.43; H, 2.19; N, 5.31; S, 11.93.
,3-Dihydro-3-(4-methylphenyl)-2-thioxo-1,3-oxazepine-4,7-
2
1
Acknowledgments. The authors are thankful to the University Grant
Commission (UGC), New Delhi, for the financial assistance and to the
Sophisticated Analytical Instrumentation Facility (SAIF), Punjab
University, Chandigarh, for the spectral analysis. R. Badru is
thankful to UGC, New Delhi, for providing a research fellowship
[10-2(5)/2007(ii)-E.U.II].
dione (Table 4, entry 3).
H-NMR (DMSO-d , 400 MHz,
6
ppm): δ = 2.35 (s, 3H), 6.27 (d, 1H, J = 7.44 Hz), 6.48 (d, 1H,
J = 7.44 Hz), 6.88 (d, 2H, J = 8.88 Hz), 7.57 (d, 2H,
1
3
J = 8.88 Hz);
C-NMR (DMSO-d
6
,
125 MHz, ppm):
δ = 127.33, 129.51, 132.58, 132.46, 136.55, 144.62, 167.43,
À1
1
71.04, (C═O), 177.86 (C═S); IR (υ cm , CHCl ): 1715
3
(
C═O of lactam), 1677 (C═O of lactone), 1157 (C═S); MS:
+
m/z: 247 [M] . Anal. Calcd for C12
N, 5.66; S, 12.97. Found: C, 58.41; H, 3.78; N, 5.58; S, 13.06.
,3-Dihydro-3-(4-methoxyphenyl)-2-thioxo-1,3-oxazepine-
9 3
H NO S: C, 58.29; H, 3.67;
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,7-dione (Table 4, entry 4).
H-NMR (DMSO-d , 400 MHz,
6
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3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Badru and B. Singh
Vol 000
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet