Improved etherification procedure for the preparation of dibenz[b,f][1,4]oxazepine

Article abstract of DOI:10.1002/jhet.5570450535

(Chemical Equation Presented) The effect of temperature and catalyst on the yield and rate of the etherification reaction between 1 and 2 was investigated and alternative methods for separation of 3 and 4 from the reaction mixture have been described.

Full text of DOI:10.1002/jhet.5570450535

Sep-Oct 2008
1469
Improved Etherification Procedure for the Preparation of
Dibenz[b,f][1,4]oxazepine
H. Fakhraian*, Y. Nafary, A. Yarahmadi and H. Hadj-Ghanbary
Department of Chemistry, Imam Hossein University, Tehran, IRAN
E-mail: fakhraian@yahoo.com
Received July 23, 2007
NO2
O
ONa
Cl
O
+
CHO O2N
CHO
N
1
2
3
4
The effect of temperature and catalyst on the yield and rate of the etherification reaction between 1 and 2
was investigated and alternative methods for separation of 3 and 4 from the reaction mixture have been
described.
J. Heterocyclic Chem., 45, 1469 (2008).
INTRODUCTION
etherification of 1 with 2 in equimolar amount was
performed in DMSO at different temperatures (T> 200°C)
in a pressure glass autoclave and the yield was determined
by weighting the crude product after washing the reaction
mixture with water and extraction into diethyl ether
(Table 1, experiments 1-6). The use of DMSO (bp 189°C)
favored completion of the reaction at temperature higher
than 200°C using a pressure glass autoclave.
Dibenz[b,f][1,4]oxazepine (4) is an incapacitating and a
lachrymatory agent [1-6]. It is chemically related to
loxapine (antipsychotic), amoxapine (antidepressant) [7]
and others substituted dibenzoxazepine compounds that
are analgesic or useful for the treatment of various
diseases [8-10]. There are different methods for the
preparation of this compound [11-19]. Tambute et al.
described the use of 1-chloro-2-nitrobenzene and
salicylaldehyde as starting materials for the preparation of
4 by a two-step reaction [11] (etherification and reductive
cyclization) or by a three-step reaction (etherification,
ketalization and reductive cyclization) [12].
We observed a strong temperature dependence of the
etherification reaction rate between
1 and 2. At
temperatures higher than 100°C, a resinous component
was formed, the amount of which increased with reaction
time. A temperature between 200 and 300°C was
favorable for the rapid etherification with high yields. At
temperatures lower than 200°C, the reaction rate was very
slow and at temperatures higher than 300°C, the reaction
mixture decomposed to undesirable components and low
yields of 3 was obtained.
Aryl etherifications require long periods of heating and
several procedures under different conditions [phase-
transfer-catalyst, ionic liquid, copper salt catalyst
(Ullmann synthesis), etc.] have been studied [20-22].
Other etherification attempts were studied using CuCl
or CuO as catalyst and the yield of 3 was determined by
GC (Table 1, Experiments 6-9). CuCl seems to be an
adequate catalyst in a reasonable time at 120°C and at
reflux temperature with a minor amount of resinous
component in the reaction mixture. Compound 1 was
thermally unstable and decomposed to a black solid in
contact with air moisture and thus should be used freshly
prepared and in excess amount in the etherification
reaction with 2 at high temperatures.
RESULTS AND DISCUSSION
We have preliminary performed the etherification step
by refluxing the mixture of salicylaldehyde with 2 (200
mol %) in the presence of K2CO3 in DMF (the procedure
of Tambute et al. [11]) for 6 h and obtained 2-(2-
nitrophenoxy)benzaldehyde (3) in 15% yield. Even the
use of benzyltriethylammonium chloride in conjunction
with NaOH in a two-phase solvent system (H2O/CH2Cl2)
was unsuccessful for the preparation of 3. The two-step
reaction of sodium salt of salicylaldehyde (1) with 1-
chloro-2-nitrobenzene (2) (etherification and reductive
cyclization) for the preparation of 4 was investigated.
Special attention was paid to determine optimized
conditions (temperature, time of reaction and catalyst) for
the etherification step and formation of 3. The sodium salt
Separation of 3 from the reaction mixture was achieved
either by washing the reaction mixture with water and
extraction of 3 from the residue with ether or by addition
of the reaction mixture to a large amount of water (10 fold
of volume of DMSO used) followed by adjustment of the
pH to 9 by addition of 1 mg solid NaOH and separation of
the precipitate formed.
of salicyladehyde (1) was prepared as
a yellow
Reductive cyclization of 3 (second step) was performed
by the classical method proposed by Tambute et al. [11]
fluorescent solid by the addition of salicylaldehyde to a
saturated methanolic solution of sodium methoxide. The

1470
H. Fakhraian, Y. Nafary, A. Yarahmadi, H. Hadj-Ghanbary
Vol 45
Table 1
Temperature and Catalytic Effect on the Etherification Reaction Between 1 and 2.
Catalyst
Temperature
Expta
Reaction time (hr.)
Yieldb (%)
(mol%)
(°C)
1
2
3
4
5
6
7
8
9
--
--
--
--
--
200
250
300
350
400
reflux
120
120
120
10
5
3
7
1
91
74
86
30
41
74
86
50
35
CuCl, 10
CuCl, 10
CuO, 10
--
3
16
24
24
a) Equimolar amounts of 1 and 2 (in 0.01 molar scale) with 5 mL of DMSO as solvent were used in all experiments. b) In experiments
1-6, Reaction was performed in a pressure glass autoclave and the yields were expressed as the crude product weighted after washing the
reaction mixture with water, extracting 3 with diethyl ether and evaporation of solvent. In experiments 6-9 the yields were expressed as
the proportional surface area of 3 after GC analysis of the reaction mixture.
(Experimental Section). Performing the separation of 4 from
the reaction mixture, without neutralization of the reaction
mixture as suggested by some authors [11], afforded a purer
product. Surprisingly, the solvent of choice that caused
separation of pure 4 (mp 68°C) was carbon tetrachloride
where 3 and resinous residues have low solubility. This
property can also be used to obtain purer 3, free of 2 (which
is very soluble in CCl4), by washing the product obtained in
the first step with CCl4. It is to be noted that the previous
reports [11,13] suggested the purification of 4 by distillation
[11] (bp 125 °C/0.2 mmHg) or by chromatography on silica
gel column using benzene as eluent [13].
The 1H NMR spectra of 3 and 4 are presented in Figure
1. The chemical shift of the aldehyde proton in 3 (at ꢀ
10.5) and the imine proton in 4 (at ꢀ 8.5) are characteristic
of these two compounds. We observed distinct signals for
the aryl protons of 3, but the same protons in 4 showed a
complex signal between ꢀ 7.13-7.45 in agreement with
those reported in literatures [12,13,23].
Figure 1. 1H NMR Spectra (in CDCl3) of 3 (a) and 4 (b).
In summary, the effect of temperature and catalyst on
the yield and rate of the etherification reaction between 1
and 2 was investigated and alternative methods for
separation of 3 and 4 from the reaction mixture have been
described. A temperature between 200 and 300°C was
favorable for the rapid and high yield etherification
between 1 and 2 using DMSO as solvent in a pressure
autoclave. CuCl seem to be an adequate catalyst for the
etherification reaction between 1 and 2 in a reasonable
time at 120°C and at reflux temperature. Carbon
tetrachloride is an appropriate solvent to obtain pure 4 and
3 without need of purification procedures (distillation,
crystallization or column chromatography).
solvent; chemical shifts are reported in ꢀ (ppm) from TMS.
Electronic ionization GC-ms spectra were recorded on a Varian
(SATURN 4D) spectrometer with capillary column (DB-5MS,
0.1 micron, 30 m x 0.250 mm). Only m/z values having
intensities of more than 10% are given and retention times are
reported using temperature programming (100-250°C,
10°C/min) with He flow rate of 10 mL/min. Melting points were
obtained on a Mettler FP61 apparatus.
Preparation of 2-(2-nitrophenoxy)benzaldehyde (3). The
freshly prepared sodium salt of salicylaldehyde (79 g, 0.55 mol),
1-chloro-2-nitrobenzene (78.5 g, 0.50 mol) and DMSO (200
mL) were placed in a 1000-mL, one-necked flask equipped with
a two-inch magnetic stir bar. The mixture was stirred at 120°C
for 72 h. After cooling, it was added to 2 L of water and the pH
was adjusted to 9 by addition 1 mg solid NaOH. The
precipitated brown solid crude product (90.9 g, 75%) was
collected and air-dried. Crystallization of the precipitate from n-
heptane afforded very pure yellow-orange needled solid of 3, mp
80-81°C, lit. [12] mp 77-78°C . 1H nmr (CDCl3): ꢀ 6.88 (d, 3JH-H
EXPERIMENTAL
Nmr spectra were obtained on a Bruker DPX-250 instrument
(250 MHz for 1H and 62.5 MHz for 13C), and CDCl3 was used as

Sep-Oct 2008
Improved Etherification Procedure for the Preparation of Dibenz[b,f][1,4]oxazepine
1471
= 8.2 Hz, 1H, CH), 7.12 (d, 3JH-H = 8.2 Hz, 1H, CH), 7.27 (t, 3JH-
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3
= 7.5 Hz, 1H, CH), 7.33 (t, JH-H = 7.5 Hz, 1H, CH), 7.55 (t,
241.
H
3
3JH-H = 7.5 Hz, 1H, CH), 7.61 (t, JH-H = 7.5 Hz, 1H, CH), 7.96
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3
3
(d, JH-H = 7.5 Hz, 1H, CH), 8.35 (d, JH-H = 7.5 Hz, 1H, CH),
10.49 (s, 1H, CHO). 13C nmr (CDCl3): ꢀ 118, 121.7, 124.5,
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188.6. GC-ms: retention time: 14.3 min; m/z (intensity (%)): 50
(14), 51 (26), 63 (32), 65 (11), 92 (30), 115 (31), 120 (10), 139
(45), 168 (46), 182 (27), 196 (16), 197 (31), 198 (100), 199 (15),
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Preparation of Dibenz[b,f][1,4]oxazepine (4). Sulfuric acid
(25%, 100 mL) was added dropwise to a mixture of 3 (10.23 g,
0.07 mol), iron powder (23.1 g, 0.42 mol), methanol (35 mL)
and H2O (35 mL) in a 250-mL, two-necked flask equipped with
an addition funnel and a mechanical stirrer. The mixture was
stirred at reflux temperature for 6 h and then was extracted by
CHCl3 (200 mL). The crude viscous product obtained after
vacuum stripping was extracted into CCl4 (2 x 50 mL) and, after
evaporation of solvent, pure 4, mp 68-69°C was obtained, lit.
[13-15] mp 71-72°C, lit. [11] mp 68-74°C). 1H nmr (CDCl3): ꢀ
7-7.5 (m, 8H, CH), 8.52 (s, 1H, CHN). 13C nmr (CDCl3): ꢀ
119.6, 120.3, 124, 124.6, 126.3, 127.7, 128.2, 129, 132.3, 139.5,
151.6, 159.4, 159.5, in agreement with literature [24]. GC-ms:
retention time : 10.2 min; m/z (intensity (%)): 50 (11), 51 (16),
63 (16), 139 (27), 140 (13), 166 (29), 167 (55), 195 (100), 196
(24) (lit.25 139 (25), 167 (52), 195 (100)).
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