Synthesis and crystal and molecular structure of the anti-somer of 5-methyl-2-(β-chloropropionyl)aminobenzophenone β-chloropropionyloxyimine

Full text of DOI:10.1023/A:1017902424210

Journal of Structural Chemistry, Vol. 42, No. 5, pp. 871-876, 2001
Original Russian Text Copyright © 2001 by S. A. Andronati, V. I. Pavlovskii, O. V. Kulikov, Yu. A. Simonov, and M. Gdanets
SYNTHESIS AND CRYSTAL AND MOLECULAR
STRUCTURE OF THE ANTI-ISOMER OF 5-METHYL-
2-(β-CHLOROPROPIONYL)AMINOBENZOPHENONE
β-CHLOROPROPIONYLOXYIMINE
S. A. Andronati, V. I. Pavlovskii, O. V. Kulikov,
Yu. A. Simonov, and M. Gdanets
UDC 615.213+615.214+547.891
2
-Aminobenzophenones and their oximes, hydrazones, and semicarbazones are convenient synthons for syntheses
of various heterocyclic compounds: 1,4-benzodiazepin-2-ones, 1,3,4-benzotriazepin-2-ones, quinazolines, etc. [1-3], and also
of some dimer heterocycles [4-6]. Both cyclic and acyclic derivatives of 2-aminobenzophenone possess useful pharmacological
properties (antithrombotic and psychotropic activity, etc.) [3, 7].
Previously, it was shown [4] that under the Schotten–Bauman reaction conditions the 5-chloro-2-aminobenzophenone
oxime syn-isomer (1) reacts with chloroacetyl chloride to form the 2-chloroacetamido-5-chlorobenzophenone oxime syn-isomer
(
2). The latter may be converted in the presence of an alkali into the 16-membered dibenzodioxatetraaza macroheterocycle 3:
In order to obtain the intermediates for the synthesis of 18-membered cyclo-homologs of compound 3, we investigated
the acylation of the 5-methyl-2-aminobenzophenone oxime syn-isomer (4) by β-chloropropionyl chloride. Acylation of
compound 4 by the above reagent in 1,4-dioxane forms a mixture of syn- and anti-isomers of 5-methyl-2-(β-
chloropropionyl)aminobenzophenone β-chloropropionyloxyimine (6 and 7). The acylating agent may be taken in excess, or
the substrate and reagent may be taken in equimolar amounts:
The reaction of the 5-methyl-2-aminobenzophenone oxime anti-isomer (5) with β-chloropropionyl chloride also
leads to a mixture of isomers 6 and 7.
The structure of the products was studied by IR, UV, and mass spectroscopy (and by X-ray diffraction analysis
for compound 7).
Institute of Applied Physics, Academy of Sciences of Moldova Republic, Kishinev. A. V. Bogatskii Physicochemical
Institute, National Academy of Sciences of Ukraine, Odessa. I. I. Mechnikov Odessa State University. A. Mickiewicz
University, Poznan, Poland. Translated from Zhurnal Strukturnoi Khimii, Vol. 42, No. 5, pp. 1035-1041, September-October,
2
001. Original article submitted September 25, 2000.
0
022-4766/01/4205-0871$25.00 ©2001 Plenum Publishing Corporation
871

Fig. 1. IR spectrum (CCl ) of 5-methyl-2-(β-chloropropionyl)aminobenzophenone
4
β-chloropropionyloxyimine syn- (6) and anti- (7) isomers.
The IR spectrum (CCl ) of the 5-methyl-2-(β-chloropropionyl)aminobenzophenone β-chloropropionyloxyimine
4
−1
syn-isomer (6) contains the absorption bands of stretching vibrations at 3390 cm (NH bond of the free amide group),
330 cm (associated group), 1688 cm (amide carbonyl group), 1748 (ether carbonyl group), 1575 cm−1 (azomethine
−1
−1
3
bond). The IR spectrum of the anti-isomer (7) contains the absorption bands of stretching vibrations at 3225 and
−
1
−1
−1
3
1
265 cm (amide group NH bond), 1680 cm (amide carbonyl group), 1753 cm (ether carbonyl group), and
−1
590 cm (azomethine bond) (Fig. 1). The anti-isomer 7 has an intramolecular hydrogen bond between the hydrogen atom
of the amide group and the nitrogen atom of the azomethine bond, analogous to the one described in [3]. This bond is
reflected in a shift of the absorption band of the N–H group to the long-wave region relative to the absorption band of the
−1
free NH group of syn-isomer 6. The intensity of the absorption band at 3245 cm does not change when the concentration
−
2
−3
of the solution decreases from 3.7×10 to 1.15×10 M. In the case of syn-isomer 6, after dilution the absorption band at
3
−1
−1
330 cm gradually decreased in intensity compared to the band at 3390 cm corresponding to the free NH group, and
then completely vanished. This may be explained by the formation of the intermolecular associates of syn-isomer 6 due to
the hydrogen bonds between the NH and CO groups.
According to XRD data, the molecule of anti-isomer 7 is claw-like in shape and is stabilized by the intramolecular
hydrogen bond N(2)–H...N(1); the amide group has E-configuration (Fig. 2). Previously, the intramolecular hydrogen bonds
forming a six-membered cycle linked to the benzo group were recorded in 5-nitro-2-aminobenzophenone (N–H...O type)
[
8], 2-bromoacetamido-5-bromobenzophenone 2,4-dinitrophenylhydrazone anti-isomer (N–H...N type) [9], and 2-amino-5-
nitrobenzophenone p-nitrophenylhydrazone [10]. In all of these compounds, the N–H...N bonds have similar parameters. In
compound 7, the bonds are N(2)...N(1) 2.630, H...N(1) 1.95 Å; the angle at H is 141°. This interaction provides the
coplanarity of the p-toluidine fragment and the azomethine bond. The coplanarity is additionally fixed by the C(9)–H...O(1)
interaction with parameters C(9)...O(1) 3.735(3) Å, H...O(1) 2.75(2) Å; the angle at H equals 149°. The dihedral angle
between the p-toluidine fragment and phenyl at the C(1) atom equals 85.1°. This value is close to the values found in
1
,4-benzodiazepines [11]. As a rule, it varies from 73 to 85°. The geometrical parameters of the molecule (Table 1) are
close to those found in other structures of this type [10]. Note that the conjugation to the p-toluidine fragment involves
substituents at the C(2) and C(3) atoms. The corresponding distances are shorter than the standard ones. Thus C(3)–N(2)
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72

Fig. 2. Structure of molecule 7 with numbering of nonhydrogen atoms.
1
.408 Å, N(2)–C(8) 1.365 Å, and C(8)–O(2) 1.222 Å. In the second substituent, the conjugation to the p-toluidine fragment
involves a linear chain C(2)–C(1)–N(1)–O(3)–C(18)–O(1). The distances in the chain are listed in Table 1. Figure 3 presents
molecular packing in crystal. One can note the C–H...O type hydrogen bond between the molecules related by the n reflection
plane in the crystal. Its parameters are C(14)–H...O(1) 3.308 Å, H...O(1) 2.51 Å, and the angle at H equals 139°. The other
contacts are van der Waals contacts. The coordinates of the basic nonhydrogen atoms and the equivalent isotropic thermal
parameters Ueq for 7 are presented in Table 2.
Experimental. The IR spectra were recorded on a Specord-75 IR spectrophotometer in CCl . The UV spectra
4
were measured on an SF-56 spectrophotometer in a 3×10−5 M ethanol solution (layer thickness 10 mm). The mass spectra
TABLE 1. Selected Bond Lengths d (Å) and Angles ω (deg) for Compound 7
Bond
1
d
Angle
3
ω
2
4
Cl(1)–C(20)
Cl(2)–C(10)
O(1)–C(18)
O(2)–C(8)
O(3)–C(18)
O(3)–N(1)
N(1)–C(1)
N(2)–C(8)
N(2)–C(3)
C(1)–C(2)
C(1)–C(11)
C(2)–C(3)
C(6)–C(17)
C(8)–C(9)
C(9)–C(10)
C(18)–C(19)
C(19)–C(20)
1.794(2)
1.794(2)
1.196(2)
1.222(2)
1.355(2)
1.429(2)
1.286(2)
1.365(2)
1.408(2)
1.490(2)
1.491(2)
1.426(2)
1.503(2)
1.511(2)
1.504(3)
1.500(2)
1.506(2)
C(18)–O(3)–N(1)
C(1)–N(1)–O(3)
C(8)–N(2)–C(3)
N(1)–C(1)–C(2)
N(1)–C(1)–C(11)
C(2)–C(1)–C(11)
C(7)–C(2)–C(3)
C(7)–C(2)–C(1)
C(3)–C(2)–C(1)
C(4)–C(3)–N(2)
C(4)–C(3)–C(2)
N(2)–C(3)–C(2)
C(5)–C(4)–C(3)
C(4)–C(5)–C(6)
C(7)–C(6)–C(5)
C(7)–C(6)–C(17)
C(5)–C(6)–C(17)
C(6)–C(7)–C(2)
O(2)–C(8)–N(2)
111.17(11)
110.99(12)
129.71(14)
116.47(14)
122.99(14)
120.48(13)
118.34(14)
117.34(14)
124.29(13)
121.92(14)
118.48(14)
119.59(13)
121.0(2)
122.0(2)
116.9(2)
121.6(2)
121.5(2)
123.2(2)
124.4(2)
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TABLE 1 (Continued)
1
2
3
4
O(2)–C(8)–C(9)
N(2)–C(8)–C(9)
122.1(2)
113.43(14)
113.6(2)
111.50(13)
124.7(2)
126.44(14)
108.90(13)
111.06(13)
109.23(11)
C(10)–C(9)–C(8)
C(9)–C(10)–Cl(2)
O(1)–C(18)–O(3)
O(1)–C(18)–C(19)
O(3)–C(18)–C(19)
C(18)–C(19)–C(20)
C(19)–C(20)–Cl(1)
4
TABLE 2. Coordinates of Basic Nonhydrogen Atoms (×10 ) and Equivalent Isotropic Thermal
2
3
Parameters Ueq (Å ×10 ) for 7
Atom
x
y
z
Ueq
Atom
x
y
z
Ueq
Cl(1)
Cl(2)
O(1)
O(2)
O(3)
N(1)
N(2)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
6495(1)
2102(1)
5406(1)
4596(1)
6459(1)
6107(1)
5340(1)
6754(1)
6512(1)
5863(1)
5785(2)
6289(2)
6883(1)
507(1)
1163(1)
2916(1)
1888(1)
3591(1)
659(1)
932(1)
2274(1)
632(1)
45(1)
74(1)
45(1)
44(1)
33(1)
32(1)
30(1)
26(1)
26(1)
28(1)
35(1)
37(1)
34(1)
C(7)
C(8)
C(9)
6990(1)
4799(1)
4513(2)
3421(2)
7739(1)
7522(2)
8448(2)
9574(2)
9796(2)
8880(2)
7399(2)
5996(1)
6348(1)
5959(2)
–5866(1)
–4844(1)
–3957(1)
–3972(1)
–4051(1)
361(1)
3162(1)
3617(2)
4071(2)
84(1)
31(1)
33(1)
41(1)
45(1)
26(1)
46(1)
47(1)
45(1)
86(1)
68(1)
46(1)
29(1)
32(1)
35(1)
–4087(1)
–2298(1)
–5544(1)
–2792(1)
–3657(1)
–4775(1)
–4258(1)
–5191(1)
–5437(1)
–6334(1)
–6975(1)
–6761(1)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
C(17)
C(18)
C(19)
C(20)
–3847(1) –1083(2)
–3625(1) –1567(2)
–3604(1)
–3806(2)
–4027(2)
–7465(1)
–2157(1)
–1264(1)
–536(1)
–910(2)
254(2)
743(2)
–29(2)
1219(1)
861(1)
1547(1)
914(1)
1733(1)
1988(2)
1432(2)
590(2)
Fig. 3. Fragment of packing of molecules 7 in crystal.
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74

TABLE 3. Crystal and Refinement Data for 7
C H Cl N O
2 2 3
Molecular formula
Molecular weight
Temperature, K
Wavelength, Å
Crystal system
Space group
20
20
407.28
293(2)
0.71073
Monoclinic
P2 /n
1
Unit cell parameters
a, Å
b, Å
c, Å
α, deg
β, deg
γ, deg
Volume, Å
Z
11.666(2)
15.083(3)
11.897(2)
90
104.66(3)
90
2025.2(6)
4
1.336
3
3
Density (calc.), mg/m
Absorption coefficient, mm−1
0.343
F(000)
848
Crystal size, mm
0.20×0.20×0.1
θ range for data collection, deg
Range of h, k, l
Reflections collected
Unique reflections
Refinement method
3.47 ≤ θ ≤ 29.49
−14 ≤ h ≤ 16, −19 ≤ k ≤ 20, −14 ≤ l ≤ 15
13326
5217 [Rint = 0.0264]
Full-matrix least-squares method on F 2
Goodness-of-fit on F 2
1.029
Final R indices I > 2σ(I)
R index (all data)
Maximal and minimal peaks on the difference map
R1 = 0.0440, wR2 = 0.1058
R1 = 0.0781, wR2 = 0.1155
0.301 and −0.338 e(Å )
3
were recorded on an MX-1321 mass spectrometer (the sample placed in the source of ions, ionizing electron energy 70 eV,
ionization chamber temperature 150°C).
The data were collected on a Kuma KM4CCD diffractometer (monochromated MoKα radiation, graphite
monochromator) for a colorless crystal with dimensions 0.2×0.2×0.1 mm at 293(2) K. In four series of measurements, the
intensities of 532 frames were recorded (0.75° wide, 30 second frames). No absorption corrections were applied on passing
from the intensities to the structural factors. The total number of data was 13,326; 5217 reflections with I ≥ 2σ were used
for structure solution and refinement. The structure was solved by direct methods. The full-matrix least-squares refinement
was performed anisotropically for the C, Cl, N, and O atoms and isotropically for hydrogen atoms. For calculations we
used the SHELX-97 program package [12]. Table 3 lists the main experimental information.
The single crystals of compound 7 were obtained by recrystallization from hexane.
5-Methyl-2-(β-chloropropionyl)aminobenzophenone β-Chloropropionyloxyimine
Syn-(6) and Anti-(7) Isomers
1
. From 5-methyl-2-aminobenzophenone oxime syn-isomer (4). β-Chloropropionyl chloride (1.5 ml, 0.0157 mol)
was added with stirring to a suspension of 5-methyl-2-aminobenzophenone oxime syn-isomer (4) (1 g, 0.0044 mol) in
dioxane (20 ml) in such a way that the temperature is kept below 5°C. The mixture was stirred for 2-2.5 h and then poured
into water. The precipitate was separated, washed with water, dried, and chromatographed on silica gel using benzene as
eluent. After recrystallization of 6 and 7 from hexane, the yield of oxyimine syn-isomer 6 was 1.079 g (60%), T
=
m
+
+
+
1
13-115°C, UV spectrum, λmax (log ε): 240 (4.29) nm. Mass spectrum (m/z): 406 [M] , 370 [M-HCl] , 316 [M-COCH CHCl] ,
2
8
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+
+
+
2
98 [M-COCH CHCl-H O] , 262 [M-COCH CHCl-H O-HCl] , 235 [M-COCH CHCl-H O-HCl-C H ] , 208 [M-COCHO-
2 2 2 2 2 2 2 3
+
CHCl-HCl-COCCH ] . Yield of the oxyimine anti-isomer 7 is 0.537 g (30%), T = 82-87°C; UV spectrum, λmax (log ε):
2
m
2
37 (4.52), 275 (4.02), and 322 (3.57) nm. The mass spectrum of oxyimine anti-isomer 7 is identical to the mass spectrum
of oxyimine syn-isomer 6.
2
. From 2-amino-5-methylbenzophenone oxime anti-isomer (5). Compounds 6 and 7 were prepared from 5 using
the procedure analogous to the one given above; yields 32 and 63%, respectively. The physicochemical properties of the
compounds are identical to those of the same compounds prepared as described above.
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