Reactions of 2,3-dihydro-1 H-1,5-benzodiazepines and chloroacetyl chlorides: Synthesis of 2a,3,4,5-tetrahydro-azeto [1,2-a][1,5] benzodiazepin-1 (2H)-ones

Article abstract of DOI:10.1002/hc.1097

2a, 4-Disubstituted 5-benzoyl-2-chloro/-2,2-dichloro-2a,3,4,5-tetrahydro-azeto[1, 2-a] [1,5]benzodiazepin-1 (2H)-ones (3a-h) were synthesized by cycloaddition reactions of 2,4-disubstituted 1-benzoyl-2,3-dihydr o-1H-1,5-benzodiazepines(2a-h) and ketenes, generated from chloroacetyl chloride or dichloroacetyl chloride in the presence of triethylamine, in anhydrous benzene. In some cases, ring contraction of benzodiazepines has also been observed.

Full text of DOI:10.1002/hc.1097

Heteroatom Chemistry
Volume 12, Number 7, 2001
Reactions of 2,3-Dihydro-1H-1,5-benzo-
diazepines and Chloroacetyl Chlorides:
Synthesis of 2a,3,4,5-Tetrahydro-azeto
[1,2-a][1,5] benzodiazepin-1(2H)-ones
Jiaxi Xu,1 Gang Zuo,1 and Wing Lai Chan2
1College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. China
2Open Laboratory of Chirotechnology, The Hong Kong Polytechnic University, Hong Kong,
P. R. China
Received 13 June 2000; revised 5 January 2001
moiety incorporated into the tricyclic ring system
ABSTRACT: 2a,4-Disubstituted 5-benzoyl-2-chloro/
is highly possibly biologically active. For this rea-
2,2-dichloro-2a,3,4,5-tetrahydro-azeto[1,2-a] [1,5]be-
son and also as a continuation of our previous work
nzodiazepin-1 (2H)-ones (3a–h) were synthesized by
in the study of benzodiazepine and benzothiazepine
cycloaddition reactions of 2,4-disubstituted 1-benzo-
tricyclic derivatives [3–9], we here report in this pa-
yl-2,3-dihydr o-1H-1,5-benzodiazepines(2a–h) and
per the synthesis of new tricyclic benzodiazepine of
ketenes, generated from chloroacetyl chloride or dich-
␤-lactam derivatives.
loroacetyl chloride in the presence of triethylamine, in
anhydrous benzene. In some cases, ring contraction of
C
benzodiazepines has also been observed. 2001 John
Wiley & Sons, Inc. Heteroatom Chem 12:636–640, 2001
RESULTS AND DISCUSSION
The cycloaddition reaction of 2,4-disubstituted 1-
benzoyl-2,3-dihydro-1H-1,5-benzodiazepines 2a–h
was conducted by treating 2a–h with an appropri-
ate acetyl chloride in the presence of triethylamine
(Scheme 1).
Compounds 1a–h were N-benzoylated to give
2a–h [5]. Compounds 2a–f were heated with mono-
chloroketene, and generated in situ from chloro-
acetyl chloride and triethylamine in anhydrous ben-
zene to yield 3a–f. In a similar manner, compounds
3g–h were prepared by the reaction of 2g–h with
dichloroketene in anhydrous benzene at room
temperature.
INTRODUCTION
In recent years, numerous benzodiazepine tricyclic
derivatives have been synthesized, and their stereo-
structures have been studied because of their bio-
logical and pharmaceutical importance [1–10]. Until
now, only a few examples of the ␤-lactam derivatives
of benzoxazepines, benzothiazepines, and benzodi-
azepines have been published [11–13]. Since some
␤-lactam derivatives, such as penicillin, show life-
saving antibacterial activity [11] and act as inhibitors
of human leukocytase elastase [14], it is believed
that the tricyclic benzodiazepine with a ␤-lactam
The proposed structures for 3a–h are based on
1H NMR, IR, and mass spectral and elemental analy-
sis data. In 1H NMR spectra of 3a–f, ␤-lactam benzo-
diazepine derivatives showed a characteristic singlet
of the azetidinone ring proton at 4.94–5.07 ppm, and
Correspondence to: Jiaxi Xu; e-mail: jxxu@chem.pku.edu.cn.
2001 John Wiley & Sons, Inc.
c
636

Synthesis of 2a,3,4,5-Tetrahydro-azeto [1,2-a][1,5] benzodiazepin-1(2H)-ones 637
it was inverted [16]. Based on the literature reports
[17,18], the nitrogen atom of the C N bond in
benzodiazepines 2 attacks the carbonyl group of
the ketene to yield a zwitterionic intermediate A.
The attack should occur from the less hindered side
of the ketene; for monochloroketene it is from the
small H group (path a), and for dichloroketene, the
approach from either side of the molecule (paths
a or b) is virtually the same. The conrotatory ring
closure can only occur via counterclockwise rotation
of the bonds involved, as shown in A, viewed from
the right side of the molecule. Since closure in the
other direction would necessitate ring constriction
in the diazepine ring, this was forbidden. Only one
enantiomer was obtained as the product in the
cycloaddition reaction. The result is well consistent
with their sulfur analogues, 2a,4-disubstituted
2-chloro-2,2a,3,4-tetrahydro-1H-azeto[2,1-d][1,5]
benzothiazepin-1-ones [8].
SCHEME
1 Synthesis of 2a,4-disubstituted 5-benzoyl-2-
chloro/2,2-dichloro-2a,3,4,5-tetrahydro-azeto[1,2-a] [1,5]ben-
zodiazepin-1(2H)-ones 3a – h.
Physical and spectral data are presented in
Table 1, and elemental analysis data are presented
in Table 2. The yields of most cycloadducts were
moderate except for the preparations of 3b and 3d;
these compounds were obtained in low yields, 6
and 16%, respectively. Low yields were ascribed to
the formation of 1-phenyl-3-aryl-propenones, 20%
in the case of 3b and 60% in the case of 3d, and
to the formation of 2-phenylbenzimidazole [19]. It
was reported that some 1,5-benzodiazepines could
undergo the ring contraction rearrangement reac-
tion to yield benzimidazole derivatives in the pres-
ence of acid [20,21] or by heating [20,22]. In or-
der to avoid this ring contraction, reactions were
carried out under basic conditions. Compounds 2b
and 2d were refluxed separately in the presence of
triethylamine hydrochloride in anhydrous benzene
for 24 h, and, in both reactions, no change was
observed.
SCHEME 2 Stereospecificity in cycloaddition reaction.
The cycloadduct 3b or 3d was obtained and
was increased slightly when chloroacetyl chloride
was added dropwise to the solution of the 1,5-
benzodiazepines(2b) or 2d in the presence of tri-
ethylamine in anhydrous benzene. Unreacted start-
ing materials 2b and 2d were recovered in both
reactions. A ring contraction reaction also happened
in the reaction of 2b, in which 3-(2-chlorophenyl)-1-
phenylpropanone was obtained in 25% yield.
signals of the diazepine CHCH2 protons, in most
cases, were of the ABX coupling system and shifted
upfield. In the case of 3g–h, signals of the C4-proton
and the C4-methyl protons were all shifted downfield.
One of the C3-methylene protons was shifted down-
field and the other was shifted upfield.
1
According to their H NMR spectra, only one
pair of enantiomers was found in the cycloaddition
reaction. The formation of the compound could
be rationalized by the reaction mechanisms as de-
picted in Scheme 2 (only one enantiomer is drawn).
It has been well known that 2,4-disubstituted
2,3-dihydro-1H-1,5-benzodiazepine adopts a boat-
like conformation [15]. After it was benzolyated,
N-benzoyl-2,3-dihydro-1H-1,5-benzodiazepine un-
derwent a conformation transformation, in which
EXPERIMENTAL
Melting points were obtained on a Yanaco melting
point apparatus and were uncorrected. Elemental
analyses were carried out on an Elementar Vario
1
EL elemental analyzer. The H NMR spectra were
recorded on a Varian Mercury 200 spectrometer with

638 Xu, Zuo, and Chan
TABLE 1 Physical and Spectral Data
Yield
R 3 (%) m.p. ( C)
1H NMR (CDCl3/TMS)
(ppm), J (Hz)
IR(KBr)
MS
m/z (M +
)
1
Compound
R1
R2
(cm
)
3a
Me
p-Meph
H
67
224–225 1.24 (3H, d, J = 6.4, Me), 2.22 (1H, dd,
J = 10.8, 14.8), 2.23 (3H, s, MeAr), 2.24
(1H, dd, J = 7.6, 14.8), 4.94 (1H, s,
CHCl), 5.25 (1H, dd, J = 6.4, 7.6, 10.8),
6.40 (1H, d, J = 7.8, aromatic), 6.72
(1H, t, J = 7.6, aromatic), 7.04–7.26
(9H, m, aromatic), 7.80 (1H, m,
1780.9
1644.5
430
aromatic), 8.42 (1H, d, J = 8.2,
aromatic)
3b
3c
3d
3e
o-CIPh
m-CIPh
p-CIPh
m-BrPh
Ph
Ph
Ph
Ph
H
H
H
H
6
210–211 2.64 (1H, dd, J = 6.8, 14.9), 3.48 (1H,
dd, J = 11.9, 14.9), 5.01 (1H, s, CHCI),
6.39 (1H, dd, J = 6.8, 11.9), 6.55 (1H, d,
J = 7.6, aromatic), 6.76 (1H, t, J = 7.8,
aromatic),7.02–7.56 (14H, m,
1755.9
1664.5
512
512
512
556
18a
aromatic), 7.79 (1H, m, aromatic), 8.53
(1H, d, J = 8.2, aromatic)
40
235–236 2.87 (1H, dd, J = 7.8, 15.1), 3.41 (1H,
dd, J = 11.8, 15.1), 5.07 (1H, s, CHCl),
6.18 (1H, dd,J = 7.8, 11.8), 6.11 (1H, d,
J = 8.2, aromatic), 6.67 (1H, t, J = 7.8,
aromatic),7.02–7.54 (14H, m,
1776.4
1642.7
aromatic), 7.81 (1H, m, aromatic), 8.49
(1H, d,J =9.6, aromatic)
16
237–238 2.87 (1H, dd, J = 7.8, 14.8), 3.39 (1H,
dd, J = 11.8, 14.8), 5.06 (1H, s, CHCI),
6.20 (1H, dd, J = 7.8, 11.8), 6.04, (1H, d,
J = 7.8, aromatic), 6.65 (1H, t, J = 7.6,
aromatic), 7.01–7.48 (14H, m,
1776.5
1639.0
32a
aromatic), 7.80 (1H, m, aromatic), 8.48
(1H, d, J = 8.2, aromatic)
53
30
65
227–239 2.86 (1H, dd, J = 7.6, 14.8), 3.41 (1H,
dd, J = 11.8, 14.8), 5.07 (1H, s, CHCl),
6.17 (1H, dd, J = 7.6, 11.8), 6.12 (1H, d,
J = 8.2, aromatic), 6.68 (1H, t, J = 7.6,
aromatic), 7.02–7.54 (14H, m,
1777.8
1647.2
aromatic), 7.82 (1H, d, J = 4.2,
aromatic), 8.50 (1H, d, J = 8.2,
aromatic)
3f
Ph
p-CIPh
H
251–252 2.93 (1H, dd, J = 7.6, 15.0), 3.37 (1H,
dd, J = 11.8, 15.0), 5.05 (1H, s, CHCI),
6.20 (1H, dd, J = 7.6, 11.8), 6.08 (1H, d,
J = 8.2, aromatic), 6.47 (1H, d, J = 2.6,
aromatic), 6.97–7.52 (14H, m,
1771.9
1631.6
512
450
aromatic), 7.78 (1H, d, J = 0.8,
aromatic), 8.46 (1H, d, J = 8.2,
aromatic)
3g
Me
Ph
Cl
185–187 1.25 (3H, d, J = 6.0, Me), 2.35 (1H, dd,
J = 11.0, 15.4), 3.25 (1H, dd, J = 7.6,
15.4), 5.10 (1H, ddq, J = 6.0, 7.6, 11.0),
6.43 (1H, d, J = 7.4, aromatic), 6.79
(1H, t, J = 7.6, aromatic), 7.06–7.46
(10H, m, aromatic), 7.74 (1H, d, J = 7.6,
aromatic), 8.47 (1H, d, J = 8.4,
1775.8
1638.2
aromatic)
(Continued)

Synthesis of 2a,3,4,5-Tetrahydro-azeto [1,2-a][1,5] benzodiazepin-1(2H)-ones 639
TABLE 1 Continued
Yield
(%)
1H NMR (CDCl3/TMS)
(ppm), J (Hz)
IR(KBr)
MS
m/z (M +
)
1
Compound R1
R2
R 3
m.p. ( C)
(cm
)
3h
Me p-MeOPh
Cl
71
201–202 1.27 (3H, d, J = 6.2, Me), 2.34 (1H, dd,
J = 11.4, 15.2), 3.21 (1H, dd, J = 7.4,
15.2), 3.69 (3H, s, MeO), 5.12 (1H, ddq,
J = 6.2, 7.4, 11.4), 6.43 (1H, d, J = 8.0,
aromatic), 6.68–6.81 (2H, m, aromatic),
6.99–7.36 (8H, m, aromatic), 7.63 (1H,
d, J = 8.4, aromatic), 8.45 (1H d, J =
8.2, aromatic)
1775.5
1639.5
480
aYield based on the converted 1,5-benzodiazepine in method B.
TABLE 2 Elemental Analysis Data
Cacd.
H
Found
Compound
Molecular Formula
Molecular Weight
C
N
C
H
N
3a
3b
3c
3d
3e
3f
C26H23N2ClO2
430.93
513.42
513.42
513.42
557.87
513.42
451.35
481.38
72.47
70.18
70.18
70.18
64.59
70.18
66.53
64.87
5.38
4.32
4.32
4.32
3.97
4.32
4.47
4.61
6.50
5.46
5.46
5.46
5.02
5.46
6.21
5.82
72.06
70.00
69.97
70.31
64.83
70.29
66.61
64.62
5.49
4.54
4.31
4.31
4.05
4.41
4.50
4.50
6.47
5.22
5.70
5.67
4.99
5.70
6.10
5.99
C30H22N2Cl2O2
C30H22N2Cl2O2
C30H22N2Cl2O2
C30H22N2BrCIO2
C30H22N2Cl2O2
C25H20N2Cl2O2
C26H22N2Cl2O3
3g
3h
tetramethylsilane (TMS) as an internal standard in
CDCl3. The IR spectra were taken on a Brucker Vec-
tor 22 FT-IR spectrophotometer in KBr. Mass spectra
were obtained on a VG ZAB-HS mass spectrometer.
Thin-layer chromatography (TLC) separations were
performed on silica gel G plates with petroleum ether
(60–90 C)/ethyl acetate (5:1), and the plates were vi-
sualized with UV light and/or iodine vapor.
was removed by filtration. The benzene solution was
washed with water, saturated aqueous NaHCO3, and
then brine. The separated benzene layer was dried
over Na2SO4. The benzene was removed, and the
residue collected was crystallized from ethanol to
yield the product as colorless crystals (3a, 3c, 3e,
3g, and 3h). For 3f, the residue obtained was sepa-
rated on a silica gel column with petroleum ether
(60–90 C)/ethyl acetate (5:1) as the eluent and af-
forded 3f as colorless crystals.
Synthesis of 2a, 4-Disubstituted-5-benzoyl-
2-chloro/-2,2-di-chloro-2a,3,4,5-tetrahydro-
azeto[1,2-a][1,5] benzodiazepin-1
(2H)-ones(3a–h)
In the preparation of 3b and 3d, after the re-
moval of benzene, the residue remaining was then
crystallized from ethanol to yield yellowish crystals
of 2- or 4-chloro-chalcone: 20% yield (m.p. 49–51 C)
in the 3b preparation and 60% (114–116 C) in the
3d case. Both of them have a molecular ion peak at
m/z of 242 (electron ionization–mass spectrometry
[EI-MS]). The mother liquid was concentrated, and
the residue was separated on a silica gel column with
petroleum ether (60–90 C)/ethyl acetate (5:1) as the
eluent to give colorless crystals of the product (3b or
3d).
General Procedure: Method A. 1,5-Benzodiaze-
pine (2) (1 mmol) and the appropriate chloroacetyl
chloride (2 mmol) were gently refluxed in anhydrous
benzene (20 ml). Dried triethylamine (0.202 g, 2
mmol) in anhydrous benzene (10 ml) was added
dropwise into the refluxing solution over a period
of 20 min, and the mixture was stirred (for dichlo-
racetyl chloride in the preparation of 3g–h, reflux-
ing was not required, and it was conducted at room
temperature). After the addition was completed, the
mixture was refluxed for a further 2 h and cooled (for
3g–h, it was stirred at room temperature for 4 h).
The crystalline triethylamine hydrochloride formed
General Procedure: Method B. A mixture of the
appropriate 1,5-benzodiazepine (2b) or 2d, (0.437 g,
1 mmol) and dried triethylamine (0.202 g, 2 mmol)
was gently refluxed in anhydrous benzene (20 ml).

640 Xu, Zuo, and Chan
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Chloroacetyl chloride (0.226 g, 2 mmol) in anhy-
drous benzene (10 ml) was added dropwise into
the aforementioned refluxing solution over a period
of 20 min with stirring. After addition was com-
pleted, the mixture was refluxed for a further 2 h
and then cooled. The crystalline triethylamine hy-
drochloride formed was removed by filtration. The
benzene solution was washed with water, saturated
aqueous NaHCO3, and then brine. The separated
benzene layer was dried over Na2SO4. The benzene
was removed, and the residue collected was sepa-
rated on a silica gel column with petroleum ether
(60–90 C)/ethyl acetate (5:1) as the eluent. The prod-
uct, as colorless crystals (3b and 3d), and a small
amount of unreacted starting material (2b or 2d)
was also recovered. In addition, in the reaction of
2b, 3-(2-chlorophenyl)-1-phenylpropanone was also
obtained in 25% yield.
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ACKNOWLEDGMENT
We wish to thank Professor Sheng Jin for his sugges-
tions and discussions.
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