Synthesis and single crystal x-ray structure of bis[4-oxo-3-(2- ethoxycarbonylphenyl)-3,4-dihydroquinazolin-2-yl]disulfide

Article abstract of DOI:10.1515/znb-2009-0912

Diethyl 2,2'-thiocarbonyl-bis(azanediyl)dibenzoate was synthesized from the reaction of ethyl anthranilate with thiophosgene. Its treatment with sodium ethoxide in ethanol at room temperature gave ethyl 2-(4-oxo-2-thioxo-1,2- dihydroquinazolin-3(4H)-yl) b

Full text of DOI:10.1515/znb-2009-0912

Synthesis and Single Crystal X-Ray Structure of Bis[4-oxo-3-
(2-ethoxycarbonylphenyl)-3,4-dihydroquinazolin-2-yl]disulfide
a
a
a
b
b
´
Mehdi Rimaz , Jabbar Khalafy , Khadijeh Tavana , Katarzyna Slepokura , Tadeusz Lis ,
Ali Souldozic, Amir Tofangchi Mahyarid, Nahid Shajarid, and Ali Ramazanid
a Chemistry Department, Urmia University, Urmia 57154, Urmia, Iran
b Faculty of Chemistry, University of Wrocław, 14 Joliot-Curie St., 50-383 Wrocław, Poland
c Chemistry Department, Islamic Azad University-Urmia Branch, P. O. Box 969, Urmia, Iran
d Chemistry Department, Zanjan University, P. O. Box 45195-313, Zanjan, Iran
Reprint requests to Dr. Ali Ramazani. Fax: +98 241 5283100. E-mail: aliramazani@gmail.com
Z. Naturforsch. 2009, 64b, 1065 – 1069; received May 22, 2009
Diethyl 2,2ꢀ-thiocarbonyl-bis(azanediyl)dibenzoate was synthesized from the reaction of ethyl an-
thranilate with thiophosgene. Its treatment with sodium ethoxide in ethanol at room temperature gave
ethyl 2-(4-oxo-2-thioxo-1,2-dihydroquinazolin-3(4H)-yl) benzoate, whereas in the presence of ethyl
nitroacetate and under the same reaction conditions, the corresponding bis(quinazolin)disulfide was
1
formed. Its structure was confirmed by IR, H and 13C NMR spectroscopy elemental analysis and
single crystal X-ray structure determination.
Key words: Thiophosgene, Ethyl Anthranilate, Ethyl Nitroacetate, Disulfide, Single Crystal X-Ray
Structure
Introduction
The reaction of o-substituted arylamines with thio-
phosgene to form isothiocyanates is well known [1, 2].
However, the direct generation of N,Nꢀ-disubstituted
thioureas by using this reaction is not so well- Scheme 1.
known. Herein, we report the preparation of diethyl
2,2ꢀ-thiocarbonyl-bis(azanediyl)dibenzoate (2) and its
treatment with sodium ethoxide in ethanol at r. t. lead-
ing to ethyl 2-(4-oxo-2-thioxo-1,2-dihydroquinazol-
in-3(4H)-yl) benzoate (3), which may possess bio-
logical activity and provide an incentive for further
exploration of this class of compounds as poten-
Scheme 2.
tial drug precursors [3 – 9]. Finally, we treated the
N,Nꢀ-disubstituted thiourea 2 with ethyl nitroacetate
We observed that treatment of the thiourea 2 with
in the presence of sodium ethoxide in ethanol at r. t.
to form bis[4-oxo-3-(2-ethoxycarbonylphenyl)-3,4-di-
hydroquinazolin-2-yl]disulfide (4).
ethyl nitroacetate and sodium ethoxide in ethanol un-
der the same reaction conditions gave, surprisingly,
the corresponding disulfide 4 in moderate yield (46 %,
Scheme 3).
Results and Discussion
The structure of compound 4 was confirmed by IR,
1H and 13C NMR spectroscopy, elemental analysis and
X-ray single crystal structure determination.
The N,Nꢀ-disubstituted thiourea 2 was prepared
from the reaction of ethyl anthranilate (1) with thio-
phosgene [1, 2] (Scheme 1).
Description of the crystal structure of 4
Treatment of the N,Nꢀ-disubstituted thiourea 2 with
sodium ethoxide in ethanol at r. t. afforded the cor-
responding quinazoline derivative 3 in 89 % yield
(Scheme 2).
The crystals of 4 are built up from molecules,
the geometry of which reveals a pseudo (non-cryst-
allographic) two-fold axis running through the center
c
0932–0776 / 09 / 0900–1065 $ 06.00 ꢀ 2009 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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1066
M. Rimaz et al. · Bis[4-oxo-3-(2-ethoxycarbonylphenyl)-3,4-dihydroquinazolin-2-yl]disulfide
Scheme 3.
˚
Table 2. Selected interatomic distances (A), valence and tor-
Table 1. Crystal data and structure refinement details for 4.
sion angles (deg) in 4.
Empirical formula
C34H26N4O6S2
650.71
Formula weight, g mol−1
Crystal system, space group
S(1)–S(2)
2.023(2)
1.798(4)
1.790(4)
1.375(5)
1.446(5)
1.410(5)
1.390(5)
1.455(5)
N(12)–C(92)
N(21)–C(11)
N(21)–C(31)
N(22)–C(12)
N(22)–C(32)
C(81)–C(91)
C(82)–C(92)
1.414(5)
1.286(5)
1.411(5)
1.280(5)
1.398(5)
1.458(5)
1.460(6)
monoclinic, P21/n
12.483(4)
18.819(5)
13.853(4)
110.77(3)
3042.8(15)
4
1.420
0.229
1352
S(1)–C(11)
S(2)–C(12)
N(11)–C(11)
N(11)–C(13)
N(11)–C(91)
N(12)–C(12)
N(12)–C(14)
˚
a, A
˚
b, A
˚
c, A
β, deg
3
˚
V, A
Z
Dcalc, g cm−3
C(11)–S(1)–S(2)
101.4(2)
C(12)–S(2)–S(1)
100.9(2)
µ, mm−1
C(11)–S(1)–S(2)–C(12)
91.9(2)
11.5(4)
2.1(3)
9.9(4)
5.3(3)
90.3(4)
170.7(4)
98.9(4)
F(000), e
C(13)–N(11)–C(11)–S(1)
S(2)–S(1)–C(11)–N(21)
C(14)–N(12)–C(12)–S(2)
S(1)–S(2)–C(12)–N(22)
C(91)–N(11)–C(13)–C(23)
C(83)–O(23)–C(73)–C(63)
C(92)–N(12)–C(14)–C(24)
C(84)–O(24)–C(74)–C(64)
C(53)–C(63)–C(73)–O(13)
C(73)–O(23)–C(83)–C(93)
C(54)–C(64)–C(74)–O(14)
C(74)–O(24)–C(84)–C(94)
Crystal size, mm
Crystal color and form
Data collection method
Radiation type; wavelength λ, A
T, K
0.24×0.13×0.08
colorless block
ω scans
MoKα ; 0.71073
100(2)
˚
θ range, deg
2.68 – 25.50
−15 ≤ h ≤ 15, −20 ≤ k ≤ 22,
−16 ≤ l ≤ 14
24906 / 5655
3251
h, k, l ranges
−179.8(4)
18.7(6)
Measured / independent refl.
Observed refl. [I > 2σ(I)]
Refinement on
−158.8(8)
15.6(6)
−166.7(5)
F2
Data / parameters
5655 / 429
0.069 / 0.157
0.118 / 0.189
0.0980 / 0.0
1.017
2
R1 / wR2 [Fo ≥ 2σ(Fo2)]a
R1 / wR2 (all data)a
Weighting parameter a / b
GoF = Sb
−3
˚
∆ρmax / ∆ρmin, e A
0.64 / −0.36
a
2
R1 = ΣꢁFo| − |Fcꢁ/Σ|Fo|, wR2 = [Σw(Fo − Fc2)2/Σw (Fo2)2]1/2
,
w = [σ2(Fo2) + (aP)2 + bP]−1, where P = (Max(Fo2, 0) + 2Fc2)/3;
b
2
GoF = [Σw(Fo −Fc2)2/(nobs −nparam)]1/2
.
of the S–S bond (Fig. 1). The S–S bond length of
˚
2.023(2) A is close to the average value observed in or-
ganic disulfides [10]. The summary of the experimen-
tal details is given in Table 1.
The value of the torsion angle C(11)–S(1)–S(2)–
C(12) amounts to 91.9(2)◦, which is very close to the
average found in compounds of similar structure [10].
The values of the torsion angles S–S–C–N (Table 2)
indicate that the S–S bond lies in the plane of the re-
spective quinazolin-4-one ring. Thus, according to the
Fig. 1. The molecular structure of compound 4 showing the
atom numbering scheme. Only one position (with higher oc-
cupation factor) for each of the disordered methyl groups is
Shefter classification [11], molecule 4 exists in a so- shown. The intramolecular C–H···O contacts forming two
S(13) motifs are shown with dashed lines. Displacement el-
lipsoids are drawn at the 30 % probability level.
called equatorial conformation. At the same time, the
two quinazolin-4-one moieties are almost perpendicu-
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M. Rimaz et al. · Bis[4-oxo-3-(2-ethoxycarbonylphenyl)-3,4-dihydroquinazolin-2-yl]disulfide
1067
Table 3. Geometry of proposed hydrogen
˚
˚
˚
D–H···A
D−H (A)
H···A (A)
D···A (A)
D−H···A (deg)
˚
bonds for 4 (A, deg).
C(41)–H(41)··· O(14)
C(51)–H(51)··· O(11)i
C(42)–H(42)··· O(13)
C(33)–H(33)··· O(12)ii
C(83)–H(83B)···O(14)iii
0.95
0.95
0.95
0.95
0.99
2.63
2.53
2.66
2.63
2.71
3.552(6)
3.281(5)
3.540(5)
3.462(5)
3.501(7)
164
136
154
146
137
Symmetry codes: (i) x−1/2, −y+3/2, z−1/2;
(ii) x, y, z+1; (iii) x+1/2, −y+3/2, z+1/2.
Fig. 2. The arrangement of the molecules
in the crystal lattice of 4 (viewed down
the a axis). Intermolecular C–H···O
and C=O···π contacts are shown with
dashed lines. Symmetry codes are given
in Table 3.
lar to each other, with the dihedral angle between the in the planes of the quinazolin-4-one rings, but with
least-squares planes defined by the condensed rings almost perpendicular mutual orientation of these two
amounting to 87.5(1)◦. The quinazolin-4-one rings are ring planes.
also almost perpendicular to the respective, directly
bonded, phenyl rings.
Experimental Section
The overall conformation of the molecule 4 is sta-
bilized by two intramolecular C–H···O contacts (Ta-
ble 3) linking the two halves of the molecule and re-
sulting in two S(13) motifs, as shown in Fig. 1. Atom
O(14) is additionally involved in a weak intermolecular
C–H···O interaction, as well as in a close centrosym-
metric C=O···π contact [C(74)=O(14)···Cg(1)iv;
symmetry code (iv): −x, −y + 1, −z; Cg(1) is the
centroid of the phenyl C(14)– C(64) ring; geomet-
General procedures
Freshly distilled solvents were used throughout, and an-
hydrous solvents were dried according to Perrin and Ar-
marego [12]. 1H (300 MHz) and 13C (75.5 MHz) NMR mea-
surements were carried out on a Bruker 300 spectrometer in
CDCl3 with tetramethylsilane as internal standard. Infrared
spectra were recorded on a Thermonicolet (Nexus 670) FT-
infrared spectrometer, using sodium chloride cells, measured
as Nujol mulls or films. Melting points were determined on
a Philip Harris C4954718 apparatus and are uncorrected. El-
emental analysis was performed on a Carlo Erba 1106 C, H,
N analyzer.
˚
rical parameters: O···Cg 3.784(4) A, perpendicular
˚
˚
O···Cg 3.698 A, C···Cg 3.865(4) A, C=O···Cg an-
gle 84.7(2)◦]. Two other carbonyl oxygen atoms, O(11)
and O(12), act as acceptors of yet another set of inter-
molecular hydrogen contacts (Table 3). All that gives
rise to a three-dimensional architecture of the crystal
lattice of compound 4, shown in Fig. 2.
Diethyl 2,2ꢀ-thiocarbonyl-bis(azanediyl)dibenzoate (2)
In a 250 mL round-bottomed flask were placed water
(50 mL) and thiophosgene (2.53 g, 1.75 mL, 22 mmol).
To the vigorously stirred reaction mixture was added slowly
ethyl anthranilate (1) (3.63 g, 22 mmol, diluted in ethyl ac-
etate), during about half an hour. The dark-brown oil was
separated, washed with 10 % hydrochloric acid (2 mL), and
placed in a two-necked flask for steam distillation. Product
2 passed over with water as a pale-yellow oil. The prod-
Conclusions
In summary, we have synthesized a new derivative
of 4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline 3 and
the related bis(quinazoline)-disulfide 4 under two con-
venient reaction conditions. The single crystal X-ray
analysis of compound 4 reveals that the S–S bond lies uct was extracted with dichloromethane (30 mL) and dried
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1068
M. Rimaz et al. · Bis[4-oxo-3-(2-ethoxycarbonylphenyl)-3,4-dihydroquinazolin-2-yl]disulfide
over sodium sulfate. Removal of the solvent gave a yel- and dried over sodium sulfate. Removal of the solvent gave
low oil which was recrystallized from n-hexane to give 2 as 4 as pale-yellow needles. Yield: 0.41 g, (46 %); m. p. 189 –
pale-yellow crystals (not suitable for an X-ray experiment). 192 ◦C. – 1H NMR (CDCl3): δ (ppm) = 1.14 (t, J = 6.9 Hz,
Yield: 1.23 g (30 %); m. p. 86 – 87 ◦C. – 1H NMR (CDCl3):
δ (ppm) = 1.39 (t, J = 7.2 Hz, 6H), 4.36 (q, J = 6.9 Hz, 4H),
7.18 (td, J1 = 8.7 Hz, J2 = 1.5 Hz, 2H, Ar), 7.57 (td, J1 =
6H), 4.18 (q, J = 6.9 Hz, 2H), 4.20 (q, J = 6.9 Hz, 2H), 7.18
(d, J = 8.1 Hz, 2H, Ar), 7.32 (d, J = 7.8 Hz, 2H, Ar), 7.35
(t, J = 6.9 Hz, 2H, Ar), 7.61 (td, J1 = 7.5 Hz, J2 = 0.9 Hz,
2H, Ar), 7.64 (td, J1 = 9.6 Hz, J2 = 1.5 Hz, 2H, Ar), 7.75
(td, J1 = 7.8 Hz, J2 = 1.2 Hz, 2H, Ar), 8.18 (dd, J1 = 7.8 Hz,
J2 = 1.2 Hz, 2H, Ar), 8.28 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz, 2H,
Ar). – 13C NMR (CDCl3): δ (ppm) = 13.85, 61.29, 115.07,
116.45, 125.07, 127.83, 128.68, 129.34, 130.34, 132.19,
133.77, 135.69, 138.97, 139.00, 160.35, 164.32, 176.38. –
FT IR: ν = 3218, 3173, 3072, 3035, 2976, 1719, 1663, 1620,
1525, 1487, 1451, 1406, 1365, 1199, 1127, 1078, 1039, 988,
890, 800, 756, 715 cm−1. – Anal. for C34H26N4O6S2: calcd.
C 62.76, H 4.03, N 8.61; found C 62.84, H 4.11, N 8.50.
8.7 Hz, J2 = 1.5 Hz, 2H, Ar), 8.05 (dd, J1 = 7.8 Hz, J2
=
1.5 Hz, 2H, Ar), 8.50 (bd, J = 8.4 Hz, 2H, Ar), 11.05 (s, ex-
changed by D2O addition, 2H, NH). – 13C NMR (CDCl3):
δ (ppm) = 14.17, 61.59, 118.64, 123.10, 123.73, 131.08,
133.30, 140.51, 167.49, 178.82. – FT IR: ν = 3236, 2976,
1685, 1605, 1580, 1509, 1447, 1364, 1301, 1251, 1168,
1089, 1004, 927, 765, 730 cm−1. – Anal. for C19H20N2O4S:
calcd. C 62.27, H 5.41, N 7.52; found C 62.38, H 5.50,
N 7.45.
Ethyl 2-(4-oxo-2-thioxo-1,2-dihydroquinazolin-3(4H)-yl)
benzoate (3)
Crystal structure determination of 4
The crystallographic measurement for crystal 4 was per-
formed on a κ-geometry Kuma KM4CCD automated four-
circle diffractometer with graphite-monochromatized MoKα
radiation. The data were collected at 100(2) K using the
Oxford Cryosystems cooler. The data were corrected for
Lorentz and polarization effects. A summary of the condi-
tions for the data collection and the structure refinement pa-
rameters are given in Table 1. Data collection, cell refine-
ment, and data reduction and analysis were carried out with
the KM4CCD software CRYSALIS CCD and CRYSALIS
RED, respectively [13]. The structure was solved by Di-
rect Methods using SHELXS-97 [14] and refined by full-
matrix least-squares techniques using SHELXL-97 [14] with
anisotropic displacement parameters for non-H atoms, ex-
cept for disordered low-occupied methyl C930 and C940
atoms. Both ethyl groups are disordered and were refined
with methylene C atoms in the same positions and with the
same anisotropic displacement parameters (constrains were
applied with EXYZ and EADP instructions). Methyl C atoms
were refined in two distinct positions. The ethyl groups were
refined with s. o. f. = 0.76(3)/0.24(3) for C83/C830–C93/
C930 and 0.71(2)/0.29(2) for C84/C840–C94/C940. Most of
the H atoms were found in difference Fourier maps, and in
the final refinement cycles all hydrogens were treated as rid-
In a 25 mL round-bottomed flask, absolute ethanol
(10 mL) was reacted with sodium (0.015 g, 0.65 mmol),
and after cooling to r. t. compound 2 (0.12 g, 0.322 mmol)
was added. The reaction mixture was stirred at r. t. for
15 min. Then the mixture was acidified with 10 % acetic
acid (2 mL), and the white precipitate was collected by vac-
uum filtration. The white solid was recrystallized from ab-
solute ethanol to give the desired product 3 as white nee-
◦
dles. Yield: 93 mg (89 %); m. p. 183 – 185 C. – 1H NMR
(CDCl3): δ (ppm) = 1.14 (t, J = 6.9 Hz, 3H), 4.19 (q, J =
6.9 Hz, 2H), 7.15 (d, 8.1 Hz, 1H), 7.34 (d, J = 9.3 Hz,
2H), 7.60 (td, J1 = 7.5 Hz, J2 = 1.2 Hz, 1H), 7.64 (td,
J1 = 7.5 Hz, J2 = 1.2 Hz, 1H), 7.74 (td, J1 = 7.5 Hz, J2 =
1.2 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 7.8 Hz,
1H), 10.89 (s, exchanged by D2O addition, 1H, NH). – 13C
NMR (CDCl3): δ (ppm) = 13.85, 61.26, 114.94, 116.45,
125.05, 127.78, 128.72, 129.32, 130.29, 132.17, 133.75,
135.69, 138.91, 138.97, 160.26, 164.29, 176.44. – FT IR:
ν = 3245, 3136, 2976, 1717, 1665, 1620, 1529, 1487, 1406,
1263, 1199, 757 cm−1. – Anal. for C17H14N2O3S: calcd.
C 62.56, H 4.32, N 8.58; found C 62.67, H 4.40, N 8.45.
Bis[4-oxo-3-(2-ethoxycarbonylphenyl)-3,4-dihydro-
quinazolin-2-yl]disulfide (4)
˚
ing atoms, with C–H distances of 0.95 – 0.99 A, and with
Uiso values of 1.5 Ueq(C) for CH3 groups, and 1.2 Ueq(C) for
CH2 and CH groups. All figures were made using the pro-
gram XP [15].
CCDC 731854 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data request/cif.
In a 25 mL round-bottomed flask, absolute ethanol (3 mL)
was reacted with sodium (0.092 g, 4 mmol), and after cooling
to r. t. ethyl nitroacetate (0.665 g, 5 mmol) was added. The
reaction mixture was stirred at r. t. for 15 min. Compound 2
(1.86 g, 5 mmol) was added, and the stirring was continued
for further 24 h, during which a yellowish-white precipitate
was formed. The precipitate was extracted with chloroform
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M. Rimaz et al. · Bis[4-oxo-3-(2-ethoxycarbonylphenyl)-3,4-dihydroquinazolin-2-yl]disulfide
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