Click reaction of epoxides with anthranilic acids using neat grinding to access benzoxazepines

Article abstract of DOI:10.1055/s-0031-1290988

An atom-economic, efficient, rapid (5 min), and highly regioselective one-pot click reaction has been developed for the synthesis of benzo[e][1,4]oxazepin-5-ones in excellent yields (78-92%). The method involves epoxide ring-opening-ring-closing cascade with anthranilic acids using neat grinding at room temperature in the presence of lithium bromide as a mild catalyst. In this procedure, pure products are obtained simply by washing the reaction mixture with warm water, thus hazardous solvents, tedious workup processes, and purification steps, such as column chromatography and recrystallization, are avoided. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290988

PAPER
▌2353
paper
Click Reaction of Epoxides with Anthranilic Acids Using Neat Grinding To
Access Benzoxazepines
Click Synthesis of Benzoxazepines Using Grinding Technique
Atul K. Singh, Ruchi Chawla, Lal Dhar S. Yadav*
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
Fax +91(532)2460533; E-mail: ldsyadav@hotmail.com
Received: 05.03.2012; Accepted after revision: 13.06.2012
tions,12 and others.13 Most of these reactions are carried
Abstract: An atom-economic, efficient, rapid (5 min), and highly
out at room temperature under neat conditions using only
regioselective one-pot click reaction has been developed for the
a pestle and mortar.
synthesis of benzo[e][1,4]oxazepin-5-ones in excellent yields (78–
92%). The method involves epoxide ring-opening–ring-closing cas-
cade with anthranilic acids using neat grinding at room temperature
in the presence of lithium bromide as a mild catalyst. In this proce-
have been used for the synthesis of medium-sized rings
dure, pure products are obtained simply by washing the reaction
mixture with warm water, thus hazardous solvents, tedious workup
In recent years, annulation reactions involving three-
membered heterocycles, namely epoxides and aziridines,
via the ring-opening–ring-closing cascade.14 We have
also very recently reported a rapid synthesis of benzodiaz-
epines by an annulation reaction of aziridines with anthra-
nilic acids.14a
processes, and purification steps, such as column chromatography
and recrystallization, are avoided.
Key words: epoxides, anthranilic acids, click reaction, solvent-
free, grinding, 4,1-benzoxazepines, cascade reactions
Considering the above points and in continuation of our
ongoing efforts to develop new cyclization processes,15
we herein report the first efficient one-pot regioselective
protocol for the synthesis of benzo[e][1,4]oxazepin-5-
ones employing the click reaction of epoxides with an-
thranilic acids using simple grinding with a pestle and
mortar under neat conditions at room temperature.
Devising a new synthetic method for a class of com-
pounds that are not easily accessible by existing methods
is an important objective in organic chemistry. In general,
the chemistry of seven-membered heterocycles has been
far less extensively studied than that of five- and six-
membered heterocycles and the inherently strained small
ring heterocycles. The synthesis of heterocycles with sev-
en-to-eleven-membered rings is difficult for enthalpic and
entropic reasons. In recent decades, the design and synthe-
sis of seven-membered heterocycles has received much
attention owing to their wide variety of applications, such
as biologically active natural products,1 drug candidates,2
materials,3 and catalysts.4 Among seven-membered nitro-
gen heterocycles, nitrogen-containing lactones with two
heteroatoms in the 1,4-positions, benzo[e][1,4]oxaze-
pines, have rarely been explored. Recently, Dong and co-
workers reported a nitrogen-directed ketone hydroacyla-
tion strategy for the enantioselective synthesis of this class
of compounds.5 On the other hand, numerous reports on
the synthesis6a–q and medicinal activity6r–v of structural an-
alogues of benzo[e][1,4]oxazepinones are available in the
literature. Thus, the development of an efficient method
for the synthesis of the 4,1-benzo[e][1,4]oxazepinone ring
system appears to be an interesting target of investigation.
Intrigued by the inherent ring strain associated with epox-
ides and their synthetically important ring-opening reac-
tions with various nucleophiles,16 we hypothesized the
synthesis of benzo[e][1,4]oxazepin-5-ones 3 from termi-
nal epoxides 1 and anthranilic acids 2 via ring-opening–
ring-closing cascade which could be achieved in the pres-
ence of 10 mol% of lithium bromide under neat conditions
at room temperature as depicted in Scheme 1.
O
O
R2
O
LiBr (10 mol%)
HO
H2N
O
+
neat, r.t.
grinding
R1
R2
N
H
R1
1
2
3
Scheme 1 Ring expansion of epoxides to benzo[e][1,4]oxazepin-5-
ones
Lewis acids have been recorded as mild and efficient cat-
alysts for epoxide activation towards nucleophilic at-
tack.17 Moreover, an increase in the concentration of the
reactants generally enhances synthetic efficiency. Thus,
to realize our hypothesis, we relied on the reaction under
neat conditions using a Lewis acid, which would efficient-
ly catalyze both the steps of epoxide ring-opening–ring-
closing cascade with an anthranilic acid. We focused our
initial effort on the screening of a range of Lewis acid cat-
alysts for the synthesis of benzo[e][1,4]oxazepin-5-one 3a
using epoxide 1a and anthranilic acid (2a) as model sub-
strates under neat conditions (Table 1). Among the cata-
Recently, mechanochemical (MC) synthesis using the
grinding method has received great interest and proved to
be a useful laboratory technique for performing various
organic reactions, for example, aldol condensations,7
Grignard reactions,8 Reformatsky reactions,9 Dieckmann
condensations,10 Knoevenagel condensations,11 reduc-
SYNTHESIS 2012, 44, 2353–2358
Advanced online publication: 04.07.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1290988; Art ID: SS-2012-N0236-OP
© Georg Thieme Verlag Stuttgart · New York

2354
A. K. Singh et al.
PAPER
lysts tested, lithium bromide was found to be the best for
the epoxide ring expansion to afford 3a (entry 2). No ap-
preciable amount of product 3a was formed from 1a and
anthranilic acid (2a) in the absence of lithium bromide af-
ter grinding for 5 minutes at room temperature, demon-
strating its catalytic efficiency. This is in accordance with
the strong oxophilicity of Li+ in the activation of oxygen-
containing electrophiles to nucleophilic attack.17a,c
Table 2 Comparison of Solvents in the Synthesis of Ben-
zo[e][1,4]oxazepin-5-one 3aa
O
O
O
LiBr (10 mol%), solvent
stirring, r.t., 8–17 h
HO
O
+
H2N
Ph
N
H
Ph
2a
1a
3a
Entry
Solvent
Time (h)
Yieldb (%)
Table 1 Optimization of the Catalyst in the Synthesis of Ben-
zo[e][1,4]oxazepin-5-one 3aa
1
2
3
4
5
6
7
H2O
8
14
15
11
11
11
17
83
75
77
73
78
74
67
O
O
THF
O
catalyst, neat
HO
O
1,4-dioxane
EtOH
+
r.t., grinding, 5 min
H2N
Ph
N
H
Ph
1a
2a
3a
CH2Cl2
CHCl3
toluene
Entry
Catalyst
mol%
Yieldb (%)
1
2
LiCl
10
10
5
69
87
78
87
65c
24
30
60
62
53
57
35
39
LiBr
a Reaction conditions: epoxide 1a (1 mmol), anthranilic acid (2a, 1
mmol), LiBr (10 mol%), solvent (1 mL), r.t.
b Isolated yield of purified product 3a.
3
LiBr
4
LiBr
15
10
10
10
10
10
10
10
10
10
5
LiI
found that the regioisomer 3 was formed exclusively. This
is in conformity with the earlier observations that in the
case of aryl epoxides, the ring opening occurs at the 2-po-
sition.17c,d The reaction is straightforward and works well
for various epoxides bearing both electron-donating and
electron-withdrawing groups (Table 3). Anthranilic acids
2 bearing an electron-withdrawing group give slightly
lower yields (entries 5–8) than those bearing electron-
donating groups (entries 9–12).
6
NaCl
NaBr
AlCl3
AlBr3
FeCl3
FeBr3
CuCl2
CuBr2
7
8
9
10
11
12
13
On the basis of the above experimental results, a plausible
mechanism for the formation of benzo[e][1,4]oxazepin-5-
ones 3 is depicted in Scheme 2. Anthranilic acid 2 con-
tains two nucleophilic centers, the amino group and the
carboxy group. Under neutral conditions the nucleophilic
properties of the amino group dominate.18 Lithium bro-
mide activates the epoxide ring through coordinating with
its oxygen, which facilitates regioselective nucleophilic
epoxide opening with the amino group of anthranilic acid
2 to form intermediate 4. Intramolecular dehydrative cy-
clization of 4 affords benzo[e][1,4]oxazepin-5-ones 3 and
liberates lithium bromide to complete the catalytic cycle
(Scheme 2).
a Reaction conditions: epoxide 1a (1 mmol), anthranilic acid (2a, 1
mmol), Lewis acid (5–15 mol%), grinding, r.t., 5 min.
b Isolated yield of purified product 3a.
c In addition to 3a (65%), 2-iodo-2-phenyl-N-tosylethylamine was
also isolated in 26% yield.
For comparison purposes, the reaction was also performed
in different solvents using lithium bromide as the catalyst,
but significantly lower yields of 3a were obtained with
relatively longer reaction times of 8–17 hours (Table 2).
Of the solvents tested, the best solvent in terms of yield
and reaction time was water (entry 1). With the optimal
conditions established, the grinding method permits us to
introduce great molecular diversity, including substitution
and scaffold diversity, under mild reaction conditions.
In a pilot work on the one-pot synthesis of ben-
zo[e][1,4]oxazepin-5-one 3A (Scheme 3), a mixture of
(R)-epoxide 1A (1 mmol), anthranilic acid (2a, 1 mmol),
and lithium bromide (10 mol%) was subjected to grinding
in a mortar with a pestle at room temperature for five min-
utes to afford (S)-benzo[e][1,4]oxazepin-5-one 3A in 91%
yield with >98% ee as determined by chiral HPLC [chiral
Eurocel column (250 × 4.6 mm, 5μ), λ = 225 nm, i-PrOH–
hexane, 10:90, 1 mL/min): tR = 3.8 (major), 5.7 min (mi-
A large number of benzo[e][1,4]oxazepin-5-ones 3 were
synthesized rapidly and in excellent yields with complete
regioselectivity; the results are summarized in Table 3.
The regioselectivity of the reaction was ascertained by re-
cording the 1H NMR spectra of the crude sample, and we
20
nor)]; specific rotation [α]D –135 (c 0.90, THF). This
shows that the ring opening of optically active (R)-epox-
Synthesis 2012, 44, 2353–2358
© Georg Thieme Verlag Stuttgart · New York

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Click Synthesis of Benzoxazepines Using Grinding Technique
2355
Table 3 Synthesis of Benzo[e][1,4]oxazepin-5-ones 3a
2
ide 1A with anthranilic acid 2a proceeds via an SN -type
pathway.
O
O
R2
O
LiBr, neat
HO
O
O
+
O
R1
r.t., grinding, 5 min
H2N
R2
N
H
R1
R2
3
1
2
O
N
H
R1
R1
Entry Epoxide 1
R2
Product 3
Yieldb,c
(%)
3
1
LiBr
– H2O
O
O
O
Li
Br
OH2
O
1
H
H
H
87
90
91
OLi
O
Ph
N
H
Ph
R1
H2N
HO
R2
3a
3b
N
R1
H
O
R1
H
R2
N
O
O
R2
OH
2
O
2
4-MeC6H4
N
H
OH
C6H4Me-4
O
4
Li
Br
O
Scheme 2 A plausible mechanism and catalytic cycle of ring expan-
sion of epoxides
O
O
3
4-ClC6H4
O
N
H
O
C6H4Cl-4
O
LiBr (10 mol%)
HO
H2N
O
3c
+
neat, r.t.
grinding
O
Ph
N
H
Ph
O
1A
2a
3A
ee >98%
O
4
H
82
85
89
N
H
Scheme 3 Synthesis of (S)-2-phenyl-2,3-dihydrobenzo[e][1,4]oxa-
zepin-5(1H)-one (3A)
3d
O
In summary, we have demonstrated a highly efficient one-
pot click reaction of epoxides with anthranilic acids for
the synthesis of relatively less explored benzo[e][1,4]ox-
azepin-5-one derivatives. This rapid (5 min) synthesis is
performed at room temperature under neat conditions us-
ing simple grinding. The pure products are obtained sim-
ply by washing the reaction mixture with warm water.
Thus tedious workup and purification steps, such as col-
umn chromatography and recrystallization, are avoided.
Moreover, atom-economy, economic viability of the cata-
lyst, high yield, and formation of water as the sole byprod-
uct are additional advantages of the present methodology,
which make it one of the most convenient, efficient, and
inexpensive methodologies for the synthesis of this class
of compounds.
Cl
O
O
5
5-Cl
5-Cl
Ph
N
H
Ph
3e
O
Cl
O
O
6
4-MeC6H4
N
H
C6H4Me-4
3f
O
Cl
O
O
7
5-Cl
88
4-ClC6H4
N
H
C6H4Cl-4
3g
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2353–2358

2356
A. K. Singh et al.
PAPER
Table 3 Synthesis of Benzo[e][1,4]oxazepin-5-ones 3a (continued)
Benzo[e][1,4]oxazepin-5-ones 3 by One-Pot Synthesis Using
Neat Grinding; General Procedure
O
O
Epoxide 1 (1 mmol), anthranilic acid 2 (1 mmol), and LiBr (10
mol%) were thoroughly ground in a mortar with a pestle for 5 min
at r.t. After completion of the reaction (TLC monitoring, EtOAc–
hexane, 2:3), the mixture was washed with warm H2O to afford an
analytically pure sample of benzo[e][1,4]oxazepin-5-one 3 (Table
3).
R2
O
LiBr, neat
HO
O
+
R1
r.t., grinding, 5 min
H2N
R2
N
H
R1
3
1
2
2-Phenyl-2,3-dihydrobenzo[e][1,4]oxazepin-5-one (3a): One-
Pot Synthesis in the Solution Phase; General Procedure
A mixture of epoxide 1a (1 mmol), anthranilic acid (2a, 1 mmol),
and LiBr (10 mol%) in solvent (1 mL) was stirred at r.t. for the time
indicated in Table 2. After completion of the reaction (TLC moni-
toring, EtOAc–hexane, 2:3), the crude product was filtered and
washed with warm H2O to afford an analytically pure sample of 4,1-
benzoxazepin-5-one 3a.
Entry Epoxide 1
R2
Product 3
Yieldb,c
(%)
O
Cl
O
O
8
5-Cl
78
86
N
H
2-Phenyl-2,3-dihydrobenzo[e][1,4]oxazepin-5(1H)-one (3a)
Yellow solid; yield: 207 mg (87%); mp 172–175 °C.
IR (KBr): 695, 745, 1582, 1602, 1720, 3325 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 3.63 (dd, J = 10.8, 7.1 Hz, 1
H), 3.78 (dd, J = 10.8, 5.6 Hz, 1 H), 4.52 (dd, J = 7.1, 5.6 Hz, 1 H),
5.01 (br, 1 H, NH, exchanged with D2O), 6.41 (dd, J = 8.4, 1.4 Hz,
1 H), 6.50 (m, 1 H), 7.10–7.35 (m, 5 H), 7.82 (m, 1 H), 8.57 (dd, J =
8.4, 1.4 Hz, 1 H).
3h
3i
O
O
O
9
5-Me
Ph
N
H
Ph
13C NMR (100 MHz, DMSO-d6): δ = 60.1, 77.6, 109.1, 116.4,
O
117.8, 126.6, 127.4, 128.5, 130.2, 132.8, 139.1, 147.6, 168.2.
MS (EI): m/z = 239 (M+).
O
O
O
O
10
5-Me
92
Anal. Calcd for C15H13NO2: C, 75.30; H, 5.48; N, 5.85. Found: C,
75.62; H, 5.13; N, 5.68.
4-MeC6H4
N
H
C6H4Me-4
3j
2-(4-Methylphenyl)-2,3-dihydrobenzo[e][1,4]oxazepin-5(1H)-
one (3b)
Yellow solid; yield: 227 mg (90%); mp 146–147 °C.
IR (KBr): 825, 1578, 1598, 1724, 3332 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.34 (s, 3 H), 3.60 (dd, J =
10.6, 7.2 Hz, 1 H), 3.76 (dd, J = 10.6, 5.4 Hz, 1 H), 4.50 (dd, J = 7.2,
5.4 Hz, 1 H), 4.98 (br, 1 H, NH, exchanged with D2O), 6.39 (dd, J =
8.3, 1.3 Hz, 1 H), 6.50 (m, 1 H), 7.05–7.36 (m, 4 H), 7.80 (m, 1 H),
8.56 (dd, J = 8.3, 1.3 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 25.1, 60.3, 77.5, 109.4, 115.9,
118.2, 127.6, 128.1, 130.5, 132.2, 135.3, 138.1, 147.8, 168.5.
O
O
11
5-Me
5-Me
89
84
4-ClC6H4
N
H
C6H4Cl-4
3k
3l
O
O
12
MS (EI): m/z = 253 (M+).
N
H
Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C,
75.50; H, 6.20; N, 5.88.
a Reaction conditions: epoxide 1 (1 mmol), anthranilic acid 2a (1
mmol), LiBr (10 mol%), grinding, r.t., 5 min.
2-(4-Chlorophenyl)-2,3-dihydrobenzo[e][1,4]oxazepin-5(1H)-
one (3c)
White solid,; yield: 248 mg (91%); mp 191–193 °C.
IR (KBr): 830, 1576, 1603, 1718, 3328 cm–1.
b Isolated yield of purified product 3.
c All compounds are solid, gave C, H, and N analyses within ±0.36%,
and satisfactory spectral (IR, 1H NMR, 13C NMR, and EIMS) data.
1H NMR (400 MHz, DMSO-d6): δ = 3.65 (dd, J = 10.9, 7.3 Hz, 1
H), 3.79 (dd, J = 10.9, 5.5 Hz, 1 H), 4.55 (dd, J = 7.3, 5.5 Hz, 1 H),
5.06 (br, 1 H, NH, exchanged with D2O), 6.42 (dd, J = 8.4, 1.5 Hz,
1 H), 6.52 (m, 1 H), 7.64–7.68 (m, 2 H), 7.84 (m, 1 H), 8.10–8.16
(m, 2 H), 8.59 (dd, J = 8.4, 1.5 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 60.9, 77.2, 110.1, 116.2,
118.4, 127.8, 128.6, 130.5, 132.4, 133.3, 139.2, 147.7, 168.3.
Melting points were determined by open glass capillary method and
are uncorrected. IR spectra in KBr were recorded on a Perkin-Elmer
993 IR spectrophotometer. H NMR spectra were recorded on a
1
Bruker Avance II (400 MHz) FT spectrometer in DMSO-d6 using
TMS as internal reference. 13C NMR spectra were recorded on the
same instrument at 100 MHz in DMSO-d6 and TMS was used as in-
ternal reference. Mass (EI) spectra were recorded on Jeol D-300
mass spectrometer. Elemental analyses were carried out in a Cole-
man automatic C, H, and N analyzer. All chemicals used were re-
agent grade and were used as received without further purification.
Silica gel-G was used for TLC.
MS (EI): m/z = 273 (M+).
Anal. Calcd for C15H12ClNO2: C, 65.82; H, 4.42; N, 5.12. Found: C,
65.51; H, 4.61; N, 5.33.
5a,6,7,8,9,9a-Hexahydrodibenzo[b,e][1,4]oxazepin-11(5H)-one
(3d)
Yellow solid; yield: 177 mg (82%); mp 78–79 °C.
Synthesis 2012, 44, 2353–2358
© Georg Thieme Verlag Stuttgart · New York

PAPER
Click Synthesis of Benzoxazepines Using Grinding Technique
2357
IR (KBr): 1450, 1580, 1604, 1722, 2910, 3332 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 1.31–1.69 (m, 4 H), 1.82–1.88
(m, 1 H), 2.08–2.18 (m, 2 H), 2.23–2.30 (m, 1 H), 3.14–3.27 (ddd,
J = 11.6, 11.4, 3.5 Hz, 1 H), 3.87–3.89 (ddd, J = 11.4, 11.2, 3.2 Hz,
1 H), 5.04 (br, 1 H, NH, exchanged with D2O), 6.76 (dd, J = 8.4, 1.3
Hz, 1 H), 7.96 (m, 1 H), 8.67 (dd, J = 8.4, 1.3 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 21.5, 22.7, 27.2, 28.8, 56.5,
85.6, 108.2, 116.1, 122.5, 130.4, 133.1, 147.1, 168.3.
1H NMR (400 MHz, DMSO-d6): δ = 1.30–1.67 (m, 4 H), 1.79–1.84
(m, 1 H), 2.05–2.15 (m, 2 H), 2.19–2.27 (m, 1 H), 3.12–3.24 (ddd,
J = 11.5, 11.2, 3.1 Hz, 1 H), 3.86–3.88 (ddd, J = 11.3, 11.2, 3.1 Hz,
1 H), 5.01 (br, 1 H, NH, exchanged with D2O), 6.41 (dd, J = 8.4, 1.4
Hz, 1 H), 6.50 (m, 1 H), 7.81 (m, 1 H), 8.54 (dd, J = 8.4, 1.4 Hz, 1
H).
13C NMR (100 MHz, DMSO-d6): δ = 21.7, 22.9, 27.6, 28.5, 56.1,
MS (EI): m/z = 251 (M+).
85.8, 108.8, 115.9, 118.2, 130.1, 132.6, 147.6, 168.2.
MS (EI): m/z = 217 (M+).
Anal. Calcd for C13H14ClNO2: C, 62.03; H, 5.61; N, 5.56. Found: C,
62.19; H, 5.31; N, 5.34.
Anal. Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C,
71.72; H, 6.66; N, 6.73.
7-Methyl-2-phenyl-2,3-dihydrobenzo[e][1,4]oxazepin-5(1H)-
one (3i)
White solid; yield: 217 mg (86%); mp 164–165 °C.
7-Chloro-2-phenyl-2,3-dihydrobenzo[e][1,4]oxazepin-5(1H)-
one (3e)
Yellow solid; yield: 232 mg (85%); mp 181–182 °C.
IR (KBr): 692, 747, 1458, 1576, 1598, 1718, 3335 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 3.64 (dd, J = 10.9, 7.3 Hz, 1
H), 3.80 (dd, J = 10.9, 5.6 Hz, 1 H), 4.53 (dd, J = 7.3, 5.6 Hz, 1 H),
5.04 (br, 1 H, NH, exchanged with D2O), 6.76 (dd, J = 8.5, 1.3 Hz,
1 H), 7.12–7.36 (m, 5 H), 7.95 (m, 1 H), 8.69 (dd, J = 8.5, 1.3 Hz, 1
H).
IR (KBr): 705, 745, 1452, 1580, 1605, 1718, 3320 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.32 (s, 3 H), 3.60 (dd, J =
10.7, 7.2 Hz, 1 H), 3.76 (dd, J = 10.7, 5.6 Hz, 1 H), 4.50 (dd, J = 7.2,
5.6 Hz, 1 H), 5.00 (br, 1 H, NH, exchanged with D2O), 6.72 (dd, J =
8.4, 1.4 Hz, 1 H), 7.11–7.35 (m, 5 H), 7.89 (m, 1 H), 8.61 (dd, J =
8.4, 1.4 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 25.3, 60.3, 77.8, 109.3, 116.7,
126.2, 126.9, 127.7, 128.9, 130.8, 133.3, 139.4, 147.2, 168.5.
13C NMR (100 MHz, DMSO-d6): δ = 60.1, 77.5, 109.1, 115.4,
MS (EI): m/z = 253 (M+).
123.8, 126.8, 127.5, 128.7, 130.2, 133.1, 139.5, 147.4, 168.3.
MS (EI): m/z = 273 (M+).
Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C,
75.65; H, 6.18; N, 5.33.
Anal. Calcd for C15H12ClNO2: C, 65.82; H, 4.42; N, 5.12. Found: C,
65.70; H, 4.61; N, 5.44.
7-Methyl-2-(4-methylphenyl)-2,3-dihydrobenzo[e][1,4]oxaze-
pin-5(1H)-one (3j)
White solid; yield: 245 mg (92%); mp 132–133 °C.
7-Chloro-2-(4-methylphenyl)-2,3-dihydrobenzo[e][1,4]oxaze-
pin-5(1H)-one (3f)
Yellow solid; yield: 255 mg (89%); mp 153–155 °C.
IR (KBr): 840, 1454, 1582, 1596, 1720, 3328 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.33 (s, 3 H), 3.62 (dd, J =
10.8, 7.1 Hz, 1 H), 3.79 (dd, J = 10.8, 5.5 Hz, 1 H), 4.51 (dd, J = 7.1,
5.5 Hz, 1 H), 5.00 (br, 1 H, NH, exchanged with D2O), 6.72 (dd, J =
8.4, 1.4 Hz, 1 H), 7.03–7.31 (m, 4 H), 7.94 (m, 1 H), 8.66 (dd, J =
8.4, 1.4 Hz, 1 H).
IR (KBr): 1603, 815, 1582, 1721, 3342 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.33 (s, 3 H), 2.36 (s, 3 H), 3.61
(dd, J = 10.6, 7.2 Hz, 1 H), 3.75 (dd, J = 10.6, 5.7 Hz, 1 H), 4.52 (dd,
J = 7.2, 5.7 Hz, 1 H), 5.03 (br, 1 H, NH, exchanged with D2O), 6.70
(dd, J = 8.3, 1.4 Hz, 1 H), 7.05–7.34 (m, 4 H), 7.88 (m, 1 H), 8.59
(dd, J = 8.3, 1.4 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 25.3, 25.8, 60.5, 77.2, 109.1,
116.2, 126.2, 127.5, 128.8, 130.8, 132.4, 135.1, 138.3, 147.5, 168.2.
13C NMR (100 MHz, DMSO-d6): δ = 25.7, 60.4, 77.2, 109.3, 115.5,
MS (EI): m/z = 267 (M+).
123.5, 126.9, 128.7, 130.5, 133.4, 135.8, 139.2, 147.1, 168.
MS (EI): m/z = 287.07 (M+).
Anal. Calcd for C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C,
76.69; H, 6.24; N, 5.53.
Anal. Calcd for C16H14ClNO2: C, 66.79; H, 4.90; N, 4.87. Found: C,
66.95; H, 4.63; N, 5.12.
2-(4-Chlorophenyl)-7-methyl-2,3-dihydrobenzo[e][1,4]oxaze-
pin-5(1H)-one (3k)
Yellow solid; yield: 255 mg (89%); mp 183–185 °C.
7-Chloro-2-(4-chlorophenyl)-2,3-dihydrobenzo[e][1,4]oxaze-
pin-5(1H)-one (3g)
White solid; yield: 270 mg (88%); mp 206–208 °C.
IR (KBr): 846, 1452, 1577, 1598, 1722, 3326 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 3.67 (dd, J = 10.8, 7.2 Hz, 1
H), 3.81 (dd, J = 10.8, 5.7 Hz, 1 H), 4.55 (dd, J = 7.2, 5.7 Hz, 1 H),
5.08 (br, 1 H, NH, exchanged with D2O), 6.77 (dd, J = 8.5, 1.3 Hz,
1 H), 7.65–7.69 (m, 2 H), 7.96 (m, 1 H), 8.12–8.19 (m, 2 H), 8.67
(dd, J = 8.5, 1.3 Hz, 1 H).
IR (KBr): 850, 1442, 1582, 1602, 1718, 3332 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.34 (s, 3 H), 3.63 (dd, J =
10.6, 7.4 Hz, 1 H), 3.78 (dd, J = 10.6, 5.5 Hz, 1 H), 4.53 (dd, J = 7.4,
5.5 Hz, 1 H), 5.07 (br, 1 H, NH, exchanged with D2O), 6.71 (dd, J =
8.4, 1.4 Hz, 1 H), 7.67–7.70 (m, 2 H), 7.89 (m, 1 H), 8.13–8.21 (m,
2 H), 8.65 (dd, J = 8.4, 1.4 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 25.4, 60.7, 77.4, 109.7, 115.7,
126.4, 127.5, 128.3, 131.1, 132.2, 133.5, 139.6, 147.5, 168.1.
13C NMR (100 MHz, DMSO-d6): δ = 60.3, 77.5, 109.6, 115.2,
MS (EI): m/z = 287 (M+).
123.8, 126.7, 128.9, 130.2, 131.8, 133.2, 139.6, 147.4, 168.2.
MS (EI): m/z = 307 (M+).
Anal. Calcd for C16H14ClNO2: C, 66.79; H, 4.90; N, 4.87. Found: C,
67.09; H, 4.99; N, 4.54.
Anal. Calcd for C15H11Cl2NO2: C, 58.46; H, 3.60; N, 4.55. Found:
C, 58.23; H, 3.92; N, 4.67.
2-Methyl-5a,6,7,8,9,9a-hexahydrodibenzo[b,e][1,4]oxazepin-
11(5H)-one (3l)
Yellow solid; yield: 194 mg (84%); mp 83–84 °C.
2-Chloro-5a,6,7,8,9,9a-hexahydrodibenzo[b,e][1,4]oxazepin-
11(5H)-one (3h)
Yellow solid; yield: 195 mg (78%); mp 89–91 °C.
IR (KBr): 1452, 1455, 1582, 1605, 1724, 2908, 3332 cm–1.
IR (KBr): 1450, 1578, 1604, 1722, 2875, 3315 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 1.31–1.68 (m, 4 H), 1.80–1.85
(m, 1 H), 2.06–2.16 (m, 2 H), 2.21–2.29 (m, 1 H), 2.34 (s, 3 H),
3.12–3.26 (ddd, J = 11.5, 11.4, 3.6 Hz, 1 H), 3.85–3.87 (ddd, J =
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2353–2358

2358
A. K. Singh et al.
PAPER
11.4, 11.3, 3.3 Hz, 1 H), 5.02 (br, 1 H, NH, exchanged with D2O),
6.72 (dd, J = 8.4, 1.4 Hz, 1 H), 7.87 (m, 1 H), 8.65 (dd, J = 8.4, 1.3
Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 21.5, 22.8, 25.2, 27.8, 28.7,
56.3, 85.4, 108.5, 116.1, 126.1, 130.8, 133.4, 147.3, 168.4.
MS (EI): m/z = 231 (M+).
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Acknowledgement
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We sincerely thank SAIF, Punjab University, Chandigarh, for pro-
viding microanalysis and spectra.
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Synthesis 2012, 44, 2353–2358
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