Special features of the alkylation of 7-bromo-5-(2-chlorophenyl)- 3-hydroxy-1,2-dihydro-3h-1,4-benzo- diazepin-2-one with alkyl tosylates

Article abstract of DOI:10.1007/s10593-010-0436-y

On interacting 7-bromo-5-(2-chlorophenyl)-3-hydroxy-1,2-dihydro-3H-1,4- benzodiazepin-2-one with methyl, hexyl, dodecyl, and cetyl tosylates, 1-alkyl-7-bromo-5-(2-chlorophenyl)-1,2,4,5-tetrahydro-3H-1,4-benzodiazepin-2, 3-diones, and 1-alkyl-7-bromo-5-(2-

Full text of DOI:10.1007/s10593-010-0436-y

Chemistry of Heterocyclic Compounds, Vol. 45, No. 11, 2009
SPECIAL FEATURES OF THE ALKYLA-
TION OF 7-BROMO-5-(2-CHLOROPHENYL)-
3-HYDROXY-1,2-DIHYDRO-3H-1,4-BENZO-
DIAZEPIN-2-ONE WITH ALKYL TOSYLATES
V. I. Pavlovsky1*, E. A. Semenishina1, S. A. Andronati1, I. G. Filippova2,
Yu. A. Simonov2, M. Gdaniec3, and J. Lipkowski4
On interacting 7-bromo-5-(2-chlorophenyl)-3-hydroxy-1,2-dihydro-3H-1,4-benzodiazepin-2-one with
methyl, hexyl, dodecyl, and cetyl tosylates, 1-alkyl-7-bromo-5-(2-chlorophenyl)-1,2,4,5-tetrahydro-
3H-1,4-benzodiazepin-2,3-diones, and 1-alkyl-7-bromo-5-(2-chlorophenyl)-3-hydroxy-1,2-dihydro-
3H-1,4-benzodiazepin- 2-ones were obtained. Only the dione was formed in the case of hexyl tosylate.
On alkylating with methyl tosylate only the 3-hydroxy derivative was formed. It was shown that at pH 14
the 1-cetyl and 1-dodecyl-3-hydroxy derivatives were completely converted into the corresponding
diones. The molecular and crystal structures of the compounds were established by X-ray structural
analysis.
Keywords: 1,4-benzodiazepine, molecular and crystal structure, prototropic migration, synthesis.
Derivatives of 1,2-dihydro-3H-1,4-benzodiazepine possess valuable pharmacological properties. Among
them such preparations as diazepam, lorazepam, nitrazepam, phenazepam, and hydazepam, etc. are widely known
[1-3]. The effect of substituents in position 1 on the geometric parameters and antispasmodic properties of
1,2-dihydro-3H-1,4-benzodiazepin-2-ones was shown by us previously in [4].
In investigations of the link of structure and properties of 1-substituted 1,2-dihydro-3H-1,4-benzo-
diazepin-2-ones, we have in the present work studied the alkylation of 7-bromo-5-(2-chlorophenyl)-3-hydroxy-
1,2-dihydro-3H-1,4-benzodiazepin-2-one (1) with methyl, hexyl, dodecyl, and cetyl tosylates in anhydrous
dioxane. On alkylating compound 1 with methyl tosylate 7-bromo-5-(2-chlorophenyl)-3-hydroxy-1-methyl-
1,2-dihydro-3H-1,4-benzodiazepin-2-one (4a) was obtained, and in the case of hexyl tosylate 7-bromo-5-(2-
_______
*To whom correspondence should be addressed, e-mail: medchem_department@ukr.net, victor_pavlovsky@ukr.net.
1A.V. Bogatsky of Physico-Chemical Institute, National Academy of Sciences of Ukraine, Odessa 65080,
Ukraine.
2Institute of Applied Physics, Academy of Sciences of Moldova, Kishinev MD-2028, Republic of Moldova; e-mail:
simonov@phys.asm.md.
3Department of Chemistry, A. Mickiewicz University, 60-780 Poznan, Poland.
4Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw 01-224, Poland.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1714-1724, November, 2009.
Original article submitted September 19, 2008; revision submitted April 21, 2009.
0009-3122/09/4511-1379©2009 Springer Science+Business Media, Inc.
1379

chlorophenyl)-1,2,4,5-tetrahydro-3H-1,4-benzodiazepine-2,3-dione (3b). Alkylation of compound 1 with
dodecyl and cetyl tosylates led to the formation of a mixture of 7-bromo-1-dodecyl- and 7-bromo-1-cetyl-5-(2-
chlorophenyl)-1,2,4,5-tetrahydro-3H-1,4-benzodiazepine-2,3-diones 3c,d and 7-bromo-5-(2-chlorophenyl)-
1-dodecyl- and 7-bromo-1-cetyl-5-(2-chlorophenyl)-3-hydroxy-1,2-dihydro-3H-1,4-benzodiazepin-2-ones 4c,d.
It is known that 3-hydroxy derivatives of 1,4-benzodiazepin-2-one undergo a prototropic migration with
conversion into the corresponding 1,2,4,5-tetrahydro-1,4-benzodiazepin-2,3-diones [5-7].
O
H
N
K2CO3
OH
TsO(CH2)nMe
+
2
N
Br
Me
N
Cl
O
1
OH
Br
Me
n =
N
Br
(CH2)5
N
O
Cl
O
4a
N
n = 5
Cl
3b
Me
Me
(CH2)n
(CH2)n
n = 11, 15
O
O
N
N
OH
O
+
N
Cl
Br
N
Br
H
Cl
3c,d
3, 4 c n = 11, d n = 15
4c,d
We have studied the possibility of prototropic migration in the case of compounds 4c,d under the conditions
of carrying out the reaction. However even on extended heating no formation of products 3c,d was observed.
The formation of compounds 3c,d was observed when using aqueous alcoholic solutions of bases (NaOH).
If the solution pH is 10 then conversion of 4c,d to 3c,d occurs by 10% after 7 days at 20-25oC, but at pH 14
prototropic migration occurs to 100% after 2.5 h. Conversion of 3c,d into 4c,d was not observed on varying the pH
value within the limits 1-14.
pH 14
95%
3c,d
4c,d
pH 1–14
Monocrystals of 3c and 4c were grown from hexane and their molecular and crystal structures were
established by X-ray analysis.
1380

The molecular structures of compounds 3c and 4c are shown in Fig. 1. Analysis of the molecular structure
showed that these compounds are structural isomers. Redistribution of the hydrogen atoms in the framework of the
molecule leads to a different character of intermolecular hydrogen bonds in the crystals of compounds 3c and 4c. In
both cases dimeric associates are formed (Fig. 2). It is known that in the absence of a substituent at position 1
(fenazepam [8], nitrazepam [9]) dimerization occurs as a result of the formation of hydrogen bonds between the
amide groups. In this way a dimeric associate of dimension R28 is formed [10].
....
....
N(1)
C(2)
H
O
O
H
C(2)
N(1)
A substituent in position 1 makes dimerization similar to this impossible. Dimeric associates of different
sizes are formed in the crystals of compounds 3c and 4c, R28 in 3c and R210 in 4c.
....
....
N(4)
C(3)
C(3)
N(4)
O
H
H
O
3c
4c
....
O
O
C(3)
C(2)
H
O
O
C(2)
C(3)
....
H
The parameters of the hydrogen bonds are given in Table 1, and the redistribution of the bond character in
compounds 3c and 4c in Table 2.
The geometric parameters of the heterocycles 3c and 4c are different. The bond lengths of N(1)–C(2) and
C(2)–C(3) are close to those found in 7-bromo-3-hydroxy-1-methyl-5-phenyl- and 7-bromo-5-(2-chlorophenyl)-
3-hydroxy-1-methyl-1,2-dihydro-3H-1,4-benzodiazepin-2-ones [11], where they are on average equal to 1.372 and
1.534 Å respectively. The C(3)–N(4) distances differ significantly at 1.341(3) in compound 3c and 1.468(4) Å in
compound 4c. These values correspond to a single bond and are close to those found in [11] in the range
1.454-1.460 Å. The N(4)–C(5) bond in compound 3c is single [1.469(3) Å], but in compound 4c is double [1.280(4)
Å]. The remaining distances in the 3c and 4c molecules are analogous to the corresponding distances in other
compounds of this class [8, 11, 12].
TABLE 1. Hydrogen bonds and DHA angles in compounds 3c and 4c
Com-
pound
d, Å
DHA
D–H⋅⋅⋅A*
angle, deg
D–H
H...A
D...A
3c
N(4)–H(4)···O(3)*2
O(3)–H(3A) ···O(2)*3
0.88
0.84
2.32
2.07
2.956(3)
2.824(3)
129
148
4c
_______
*Transformations of symmetry of equivalent atoms.
*2 −x + 1, −y + 2, −z + 2.
*3 −x + 2, −y, −z + 1.
1381

3c
4c
Fig. 1. Molecular structure of compounds 3c and 4c (the second position for the disordered fragment of 4c is
not shown).
Table 2. Selected Bonds (d) in the Seven-membered Heterocycles of
Compounds 3c and 4c
d, Å
d, Å
Bond
Bond
3c
4c
3c
4c
N(1)–C(2)
C(2)–C(3)
C(2)–O(2)
C(3)–N(4)
C(3)–O(3)
1.370(3)
1.538(3)
1.218(3)
1.341(3)
1.224(3)
1.358(4)
1.533(4)
1.235(4)
1.468(4)
1.395(4)
N(4)–C(5)
1.469(3)
1.520(3)
1.394(3)
1.430(3)
1.280(4)
1.488(4)
1.403(4)
1.435(4)
C(5)–C(11)
C(11)–C(10)
N(1)–C(10)
TABLE 3. Selected Valence Angles (ω) in the Seven-membered
Heterocycles of Compounds 3c and 4c
ω, deg
Angle
3c
4c
C(2)–N(1)–C(10)
N(1)–C(2)–C(3)
O(2)–C(2)–N(1)
O(2)–C(2)–C(3)
N(4)–C(3)–C(2)
O(3)–C(3)–C(2)
O(3)–C(3)–N(4)
C(3)–N(4)–C(5)
N(4)–C(5)–C(11)
C(10)–C(11)–C(5)
C(11)–C(10)–N(1)
124.0(2)
119.0(2)
123.3(2)
117.7(2)
117.0(2)
119.1(2)
123.7(2)
120.0(2)
106.7(2)
118.0(2)
120.8(2)
122.6(3)
115.8(3)
123.3(3)
120.8(3)
106.5(2)
111.6(3)
110.9(3)
117.2(3)
124.3(3)
123.1(3)
121.1(3)
1382

3c
4c
Fig. 2. Dimerization of the 3c and 4c molecules in the crystal through hydrogen bonds (hydrogen atoms
are omitted from the aliphatic chains).
TABLE 4. Torsion Angles (θ) in the Heterocycles of Compounds 3c and 4c
θ, deg
Angle
3c
4c
N(4)C(3)C(2)N(1)
C(3)C(2)N(1)C(10)
C(2)N(1)C(10)C(11)
N(1)C(10)C(11)C(5)
C(10)C(11)C(5)N(4)
C(11)C(5)N(4)C(3)
C(5)N(4)C(3)C(2)
61.1(3)
-8.1(3)
-44.4(3)
4.5(3)
75.5(3)
0.9(4)
-47.5(4)
7.4(5)
70.4(3)
-65.3(3)
-14.4(3)
41.2(5)
-1.7(5)
-72.5(3)
1383

The valence angles also undergo some changes. The total angle at the N(1) atoms are 359.6(2) in 3c and
360.1o in 4c, which indicates the low pyramidicity of the nitrogen atom. The angles at atoms C(3) of 117.0(2)o (3c),
106.5(2)o (4c) and at atom C(5) at 106.7(2)o (3c), and 124.3(3)o (4c) are subject to a larger change (Tables 3 and 4).
This indicates once again the change in character of the hybridization of the C(3) and C(5) atoms.
The conformation of the 7-membered ring is a pseudoboat with angles θ1 (angle between the aromatic
rings), θ2 (angle between N(1)C(2)N(4)C(5) and N(1)C(10)N(11)C(5)) and θ3 (N(1)C(2)N(4)C(5) and
C(10)C(3)N(4)), given in Table 5. Compound 4c is close in its conformational parameters (Table 6) to phenazepam
[8]. The parameters of compound 3c are significantly different. In compound 3c the torsion angles at
TABLE 5. Some Geometric Characteristics of 7-Membered Heterocycles
θ, deg
θ2
Compound
θ1
θ3
3c
86.1
85.3
75.4
52.9
36.6
33.8
149.8
118.3
59.8
4c
Phenazepam
TABLE 6. Crystallographic Data and Parameters of X-ray Structural
Experiments
3c
4c
Empirical formula
Molecular mass
Т, К
C27H34BrClN2O2
533.92
C27H34BrClN2O2
533.92
100(2)
100(2)
Wavelength, Å
System
Space group
а, Å
0.71073
0.71073
Triclinic
P-1
Triclinic
P-1
8.5262(5)
10.7145(7)
14.2342(9)
85.567(5)
84.041(5)
89.785(5)
1289.44(14)
2
8.4950(2)
10.8270(4)
14.2250(5)
96.187(1)
102.417(2)
92.140(2)
1267.83(7)
2
b, Å
c, Å
α, deg
β, deg
γ, deg
V, Å3
Z
ρ
calc g/cm3
1.375
1.399
µ, mm–1
1.724
1.753
F(000)
556
556
Crystal parameters, mm
Range of θ for data selected, deg
Range of indices
0.4×0.4×0.05
4.14-26.37
-10 ≤ h ≤ 10
-13 ≤ k ≤ 11
-17 ≤ l ≤ 17
0.3×0.3×0.1
2.46-27.53
-11 ≤ h ≤9
-14 ≤ k ≤ 14
-18 ≤ l ≤ 18
Number of reflections
measured
17 686
10 023
independent
5255 [Rint = 0.0363]
5552 [Rint = 0.0310]
Number of parameters refined
GOOF
298
293
1.054
1.005
R factor (I>2σ(I))
R1 = 0.0401
wR2 = 0.1029
R1 = 0.0507
wR2 = 0.1286
R factor (for the whole mass)
R1 = 0.0471
R1 = 0.0610
wR2 = 0.1086
wR2 = 0.1345
∆ρmax, eÅ–3
∆ρmin, eÅ–3
0.827
-0.713
1.208
-0.550
1384

the C–C bond in the aliphatic chain are close to 180o (trans conformation). In compound 4c a portion of the angles
turn into a gauche conformation. Analysis of the packing in compound 3c showed that adjoining dimers are joined in
bands as a result of π-π interactions, effected between the bromo-substituted aromatic rings with a distance between
centers of 3.34 Å. Adjacent bands interact through hydrogen bonds C-H···O, in which a CH2 group of the aliphatic
chain and the carbonyl oxygen atom in position 2 of the 7-membered ring of the heterocycle participate. In
compound 4c adjacent dimers are linked with one another basically by van der Waals forces.
EXPERIMENTAL
1
The IR spectra were recorded on a Specord IR 75 in chloroform solution, and the H NMR spectra on a
Varian WXP 300 instrument (299 MHz) in CDCl3, internal standard was TMS, at 25 oC. Mass spectra were recorded
by electron impact on a MX 1321 mass spectrometer (ionizing voltage 70 eV, temperature of ionization chamber
200oC). The purity of compounds was checked by HPLC, Shimadzu chromatograph LC 8A, analytical column
Zorbax C 18, mobile phase, methanol + 2% TFA : water + 2% TFA, 9:1. The progress of reactions was checked by
TLC. Thin layer chromatography was carried out on Silufol UV 254 plates in acetonitrile–chloroform––hexane,
1:1:3, visualization was with UV light at λ 254 nm.
X-ray Structural Investigation. The main parameters of the experiment and the interpretation of structures
are given in Table 6. Monocrystals of compound 3c were colorless plates. The experimental material was obtained on
a KUMA CCD-4 diffractometer with monochromatized (graphite monochromator) MoKα radiation at 100 K.
Overall 17686 refections were recorded of which 5255 were used for determining and refining the structure. The data
obtained were processed with the aid of the Kuma Diffraction (Wroclaw, Poland) set of programs.
The structure was solved by the direct method and was refined by the full-matrix least-squares method in an
anisotropic approximation for the non-hydrogen atoms with the SHELX-97 set of programs [13]. The coordinates of
the H atoms were found objectively from Fourier difference syntheses and were refined in a rigid body model.
Crystals of compound 4c were close in appearance to crystals of compound 3c. The experimental material
was obtained on a Nonius Kappa diffractometer at 100K with monochromatized MoKα-radiation by φ-ω scanning.
Parameters of the unit cell were refined from the overall mass of experimental data. The framework was integrated
and Lorenz and polarization factors were introduced into the intensities with the DENZO program [14]. Scaling and
refining of the cell parameters was carried out with the SCALEPACK program [14]. No correction for absorption
was considered. The methods for solving the structure and refinement were similar to those given for compound 3c.
In the refinement process it was established that the alkyl radical was randomized at two positions with a population
probability of 3:1. The hydrogen atoms in the framework of the molecule were found objectively and were refined in
a rigid body model, in the randomized aliphatic chain they were not determined. The coordinates of the main atoms
were deposited in the Cambridge Crystallographic Data Collection, Nos. 630346 and 630347.
7-Bromo-5-(2-chlorophenyl)-1-dodecyl-1,2,4,5-tetrahydro-3H-1,4-benzodiazepine-2,3-dione (3c) and
7-Bromo-5-(2-chlorophenyl)-1-dodecyl-3-hydroxy-1,2-dihydro-3H-1,4-benzodiazepin-2-one (4c). Potassium
carbonate (0.52 g, 3.7 mmol) was added to a suspension of compound 1 (0.5 g, 1.38 mmol) and dodecyl tosylate 2c
(0.58 g, 1.8 mmol) in anhydrous dioxane (10 ml), and the mixture was stirred at 40-50oC for 10 h. Chloroform
(30 ml) was added to the reaction mixture, which was washed with water (4×20 ml). The solvent was evaporated on
a rotary evaporator at reduced pressure. The residue obtained was recrystallized from chloroform and colorless
crystals of compounds 3c and 4c were obtained by fractional crystallization.
Compound 3c. Yield 0.28 g (38%); mp 135-140oC, Rf 0.4. IR spectrum, ν, cm-1: 3360 (N–H free), 3180 (N–
1
H assoc.), 1675 (C=O). H NMR spectrum, δ, ppm (J, Hz): 7.72 (1H, d, J = 7.8, H-4); 6.64-7.24 (7H, m,
1385

H-6,8,9, H-3′,4′,5′, 6′); 6.16 (1H, d, J = 7.8, H-5); 4.6 (1H, m, CH2(CH2)10CH3); 3.6 (1H, m, CH2(CH2)10CH3); 1.24
(20H, m, CH2(CH2)10CH3); 0.88 (3H, t, J = 6.7, CH3). Mass spectrum, m/z (Irel, %): 532 (20) [M]+, 503 (6)
[M-CHO]+, 489 (32) [M-NH–C=O]+, 364 (100) [M-C12H24]+. Found, %: C 60.82; H 6.37; N 5.16. C27H34BrClN2O2.
Calculated, %: C 60.74; H 6.42; N 5.25.
Compound 4c. Yield 0.095 g (11%); mp 97-100oC, Rf 0.54. IR spectrum, ν, cm-1: 3440 (O–H), 1655 (C=O).
1H NMR spectrum, δ, ppm (J, Hz): 7.24-7.71 (7H, m, H-6,8,9, H-3′,4′,5′,6′); 4.96 (1H, d, J = 9.3, H-3); 4.81 (1H, d,
J = 9.3, OH); 4.32 (1H, m, CH2(CH2)10CH3); 3.75 (1H, m, CH2(CH2)10CH3); 1.24 (20H, m, CH2(CH2)10CH3); 0.88
(3H, t, J = 6.8, CH3). Mass spectrum, m/z (Irel, %): 532 (14) [M]+, 503 (100) [M-CHO]+, 335 (49) [M-CHO–C12H24]+.
Found, %: C 60.67; H 6.33; N 5.43. C27H34BrClN2O2. Calculated, %: C 60.74; H 6.42; N 5.25.
7-Bromo-1-cetyl-5-(2-chlorophenyl-1,2,4,5-tetrahydro-3H-1,4-benzodiazepine-2,3-dione (3d) and
7-Bromo-1-cetyl-5-(2-chlorophenyl)-3-hydroxy-1,2-dihydro-3H-1,4-benzodiazepin-2-one (4d) were obtained
analogously to compounds 3c and 4c from compound 1 (1 g, 2.76 mol) as colorless crystals.
Compound 3d. Yield 0.65 g (40%); mp 97-99oC, Rf 0.48. IR spectrum, ν, cm-1: 3340 (N–H free), 3175 (N–
1
H assoc.), 1685 (C=O). H NMR spectrum, δ, ppm (J, Hz): 7.83 (1H, d, J = 7.8, H-4); 6.64-7.23 (7H, m, H-6,8,9,
H-3′,4′,5′,6′); 6.15 (1H, d, J = 7.8, H-5); 4.57 (1H, m, CH2(CH2)14CH3); 3.58 (1H, m, CH2(CH2)14CH3); 1.24 (28H,
m, CH2(CH2)14CH3); 0.86 (3H, t, J = 6.7, CH3). Mass spectrum, m/z (Irel): 588 (35) [M]+, 559 (9) [M-CHO]+, 545 (38)
[M-NH–C=O]+, 364 (69) [M-C16H32]+. Found, %: C 62.93; H 7.26; N 5.02. C31H42BrClN2O2. Calculated, %:
C 63.10; H 7.17; N 4.75.
Compound 4d. Yield 0.25 g (14%); mp 87-89oC, Rf 0.63. IR spectrum, ν, cm-1: 3465 (O–H), 1665 (C=O).
1H NMR spectrum, δ, ppm (J, Hz): 7.21-7.70 (7H, m, H-6,8,9, H-3′,4′,5′,6′); 4.95 (1H, d, J = 9.4, H-3); 4.81 (1H, d,
J = 9.3, OH); 4.31 (1H, m, CH2(CH2)14CH3); 3.73 (1H, m, CH2(CH2)14CH3); 1.23 (28H, m, CH2(CH2)14CH3); 0.86
(3H, t, J = 6.7, CH3). Mass spectrum, m/z (Irel, %): 588 (23) [M]+, 559 (100) [M-CHO]+, 545 (8) [M-NH–C=O]+, 364
(28) [M-C16H32]+, 335 (80) [M-CHO-C16H32]+. Found, %: C 63.16; H 7.25; N 4.83. C31H42BrClN2O2. Calculated. %:
C 63.10; H 7.17; N 4.75.
7-Bromo-5-(2-chlorophenyl)-1-hexyl-1,2,4,5-tetrahydro-3H-1,4-benzodiazepine-2,3-dione (3b) was
obtained analogously to compound 3c from compound 1 (1 g, 2.76 mmol). After recrystallization from benzene the
product (0.47 g) was isolated as colorless crystals. Yield 38%; mp 196-199oC, Rf 0.3. IR spectrum, ν, cm-1: 3360 (N–
1
H free), 3186 (N–H assoc.), 1673 br (C=O). H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 7.32-7.68 (7H, m,
H-6,8,9, H-3′,4′,5′,6′); 6.45 (1H, s, H-5); 5.95 (1H, s, H-4); 4.37-4.47 (1H, m, CH2(CH2)4CH3); 4.69-4.75 (1H, m,
CH2(CH2)4CH3); 1.23-1.50 (8H, m, CH2(CH2)4CH3); 0.83 (3H, t, J = 7.0, CH3). Mass spectrum, m/z (Irel, %): 448
(34) [M]+, 405 (28) [M-NH-C=O]+, 377 (8) [M-C5H11]+, 364 (52) [M-C6H12]+. Found, %: C 55.32; H 4.56; N 6.51.
C20H19BrClN2O2. Calculated, %: C 55.26; H 4.41; N 6.44.
7-Bromo-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one (4a) was
obtained analogously to compound 4c from compound 1 (1 g, 2.76 mmol). Product (0.53 g) was isolated as colorless
crystals after recrystallization from benzene. Yield of compound 4a was 51%; mp 120-127oC, Rf 0.4. IR spectrum, ν,
cm-1: 3443 (O–H), 1700 br (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 7.21-7.45 (7H, m, H-6,8,9, H-3′,4′,5′,6′); 5.02
(1H, d, J = 9.34, OH); 4.47 (1H, d, J = 9.33, H-3); 3.52 (3H, s, CH3). Mass spectrum, m/z (Irel, %): 378 (10) [M]+, 349
(100) [M-CHO]+, 334 (7) [M-CO2]+. Found, %: C 50.56; H 3.24; N 7.25. C16H12BrClN2O2. Calculated, %: C 50.62;
H 3.19; N 7.38.
7-Bromo-5-(2-chlorophenyl)-1-dodecyl-1,2,4,5-tetrahydro-3H-1,4-benzodiazepine-2,3-dione (3c) from
7-Bromo-5-(2-chlorophenyl)-1-dodecyl-3-hydroxy-1,2-dihydro-3H-1,4-benzodiazepin-2-one (4c). A mixture of
compound 4c (0.1 g, 0.18 mmol), ethanol (6 ml), and 30% KOH solution (4 ml) was stirred at room temperature for
2.5 h. Chloroform (10 ml) was added to the reaction mixture, which was then washed with water (3×10 ml). The
chloroform was evaporated on a rotary evaporator at reduced pressure. The residue was recrystallized from
chloroform and colorless crystals of compound 3c were obtained. Yield 0.095 g (95%); mp 97-100oC, Rf 0.54.
Compound 3d was obtained analogously to compound 3c from compound 4d (0.1 g, 0.18 mmol) as
colorless crystals. Yield 0.095 g (95%); mp 87-89oC, Rf 0.63.
1386

REFERENCES
1.
A. V. Bogatsky, S. A. Andronati, and N. Ya. Golovenko, Tranquillizers. 1,4-Benzodiazepines and Related
Structures [in Russian], Naukova Dumka, Kiev (1980), 280 pp.
2.
3.
4.
A. V. Bogatsky (editor), Fenazepam [in Russian], Naukova Dumka, Kiev (1980), 288 pp.
S. A. Andronati (editor), Hidazepam [in Russian], Naukova Dumka, Kiev (1992), 200 pp.
S. A. Andronati, I. A. Prokopenko, A. S. Yavorsky, Yu. A. Simonov, A. A. Dvorkin, T. Sh. Gifeisman, and
V. M. Chepelev, Pharmazie, 43, 730 (1988).
5.
6.
7.
8.
R. Ian Fryer, J. Heterocycl. Chem., 9, 744 (1972).
S. C. Bell and S. J. Childress, J. Org. Chem., 27, 1691 (1962).
A. Stempel, I. Douvan, E. Reeder, and L. H. Sternbach, J. Org. Chem., 32, 2417 (1967).
A. A. Karapetyan, V. G. Andrianov, Yu. T. Struchkov, A. V. Bogatskii, S. A. Andronati, and
T. I. Korotenko, Bioorg. Khim., 5, 1684 (1979).
9.
10.
11.
12.
G. Gilli, V. Bertolasi, M. Sacerdoti, and P. A. Borea, Acta Crystallogr. B33, 2664 (1977).
M. C. Etter, Israel J. Chem., 25, 312 (1985).
J. Lipkovskiy, K. S. Andronati, Yu. A. Simonov, and V. Ch. Kravtsov, J. Struct. Chem., 46, 116 (2005).
J. Rambaud, A. Dubourg, J.-L. Delarbre, J. Roger, L. Maury, and J.-P. Declercq, Bull. Soc. Chim. Belg., 100,
521 (1991).
13.
14.
G. M. Sheldrick, SHELX-97. Release 97-2, Univ. of Gőttingen, Germany (1998).
Z. Otwinowski and W. Minor, in: C. W. Carter and R. M. Swert (editors), Methods in Enzymology, Acad.
Press, London, 1996, Vol. 276, p. 307.
1387