Crystals Crystals 2073-4352 Molecular Diversity Preservation International (MDPI) 10.3390/cryst1030171 crystals-01-00171 Communication Synthesis and Crystal Structure of 3-(4-Methoxyphenyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one SaeedAamer1* MahmoodShams ul1 IshidaH.2 Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan Department of Chemistry, Faculty of Science, Okayama University, Okayama, 700-8530, Japan Author to whom correspondence should be addressed; E-Mail: aamersaeed@yahoo.com; Tel.: +92-51-9064-2128; Fax: +92-51-9064-2241. 2011 29 08 2011 1 3 171 177 13 07 2011 19 09 2011 24 08 2011 © 2011 by the authors, licensee MDPI, Basel, Switzerland. 2011

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).

Synthesis of the title compound from 4-methoxyaniline was accomplished in three steps. The structure was supported by spectroscopic data and unambiguously confirmed by single crystal X-ray diffraction data. It crystallizes in the monoclinic space group P21 with unit cell dimensions a = 9.9349(8), b = 6.3377(5), c = 10.5783(10) Å, β = 97.752(3)°, V = 659.97(10) Å3, Z = 2.

 quinazolinone 3-aryl-2-thioxo-2,3-dihydroquinazolin-4(1H)-ones synthesis Introduction

Quinazolinone is the building unit of approximately 150 naturally occurring alkaloids isolated from microorganisms, plants and animals [1]. It is a very important heterocycle exhibiting excellent pharmacological activities such as antimicrobial [2], antifungal [3], antitumor [4], anticancer [5], antiinflammatory [6], antidepressant [7], and anticonvulsant [8] activities. 3-Aryl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one are derivatives of quinazolinones have a wide range of pharmacological and biological activities such as anticonvulsant and antitumor [9]. Altanserin (3-(2-(4-(4-fluorobenzoyl)-l-piperidinyl)-ethyl)-2,3-dihydro-2-thioxo-1H-quinazolin-4-one) and nitro altanserin are used as drugs for 5-HT2A receptor antagonists [10].

 Results and Discussion

The title compound was synthesized by slight modification of a reported method [11] according to the route depicted in Figure 1. 4-Methoxyaniline in DMSO was treated with carbon disulfide and aqueous sodium hydroxide to afford sodium 4-methoxyphenylcarbamodithioate (1) followed by reaction with dimethyl sulfate to furnish the methyl 4-methoxyphenylcarbamodithioate (2). A solution of (2) in ethanol (20 mL) was treated with methyl anthranilate in presence of anhydrous potassium carbonate to provide the methyl 2-(3-(4-methoxyphenyl)thioureido)benzoate as intermediate (3), which on basic hydrolysis yielded the title compound (4) which was recrystallized from ethanol as colorless crystals.

Formation of (4) was confirmed by IR which showed peaks at 3187.6 cm−1 for NH, 1706.6 cm−1 for C=O and 1224.9 cm−1 for C=S, respectively. In the 1H-NMR spectrum a singlet at δ 3.88 ppm due to OCH3 group, a multiplet at δ 7–8.1 ppm for aromatic (8H) protons and a singlet at d 10.36 ppm indicated the presence of NH.

The molecular structure of (4) is shown in Figure 2. The dihydroquinazoline N1/C1/N2/C2-C8 ring system essentially planar with an r.m.s. deviation of 0.052(1) Å. The molecule is twisted around the C9-N2 bond with a dihedral angle of 79.84(4)° between the dihydroquinazoline ring system and the substituted phenyl C9-C14 ring. The C1=S1 and C2=O1 bond lengths are 1.6799(10) and 1. 2119(14) Å, respectively, which are comparable with the reported double bond lengths [12]. Packing diagrams of (4) are shown in Figures 3 and 4. The molecules are linked by an N-H… S hydrogen bond (N1-H1…S1i N1-H1 = 0.796(17) Å, H1…S1 = 2.656(18) Å, N1…S1 = 3.4181(10) Å, <H1-N1…S1 = 160.9(16)°; symmetry code: (i) 1−x, −1/2+y, −z) forming a zig-zag chain structure along the b axis (Figure 3). The molecular chains are further connected by a C-H… O hydrogen bond (C11-H11…O1ii C11-H11 = 0.95 Å, H11…O1 = 2.36 Å, C11…O1 = 3.2543(15) Å, C11-H11…O1 = 157°; symmetry code: (ii) 1−x, −1/2+y, 1−z), forming a layer parallel to the bc plane (Figure 4).

Crystal Structure Determination

Data were collected at 180(1) K on a Rigaku RAPID II IP diffractometer using MoKα radiation. The numerical absorption correction with NUMABS were employed [13]. The structure was solved by direct methods [14], and refined by full-matrix least-squares refinement [14] on F2 with 185 parameters for 3719 unique intensities. All atoms except H were refined anisotropically. H atoms were found in a difference Fourier map and the N-bound H atom was refined freely. Other H atoms were refined on idealized positions (C-H = 0.95 or 0.98 Å) with Uiso(H) = 1.2 Ueq(C) or 1.5Ueq(Cmethyl). Experimental data are listed in Table 1.

 Experimental Section

Melting points were recorded using a digital Gallenkamp (SANYO) model MPD BM 3.5 apparatus and are uncorrected. The FTIR spectra were recorded on FTS 3000 MX, Bio-Rad Merlin (Excalibur Model) spectrophotometer. 1H NMR spectra were determined as CDCl3 solutions at 300 MHz using a Bruker Mass Spectra (EI, 70 eV) on a GC-MS instrument. All compounds were purified by thick layer chromatography using silica gel from Merck.

Synthesis of 3-(4-Methoxyphenyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (4)

To a solution of 4-methoxyaniline (0.02 mol) in DMSO (10 mL), carbon disulfide (1.6 mL, 0.026 mol) was added followed by an aqueous solution of sodium hydroxide (1.2 mL, 20 M) dropwise with stirring to afford salt (1) as an intermediate. After two hours, dimethyl sulfate (0.02 mol) was added gradually while the reaction mixture was kept stirring in a freezing mixture for five hours. After the completion, the reaction mixture was poured into ice water. The solid obtained was filtered, washed and re-crystallized from ethanol to obtain methyl 4-methoxyphenylcarbamodithioate (2). To the solution of (2) (0.01 mol) in ethanol (20 mL), methyl anthranilate (0.01 mol), anhydrous potassium carbonate (100 mg) was added and the solution was refluxed for 25 hours. The reaction mixture was poured onto cold water. Solid methyl 2-(3-(4-methoxyphenyl)thioureido)benzoate (3) obtained, was filtered and refluxed in 10% alcoholic sodium hydroxide solution for two hours. After cooling at room temperature, it was re-precipitated by treatment with dilute hydrochloric acid. The solid obtained was washed with water and recrystallized from ethanol to afford (4) as colourless crystals. (80%): m.p. 280 °C; Rf: 0.15 (petroleum ether: ethyl acetate,4:1); IR (KBr) υ cm−1: 3187 (N-H),1704 (C=O), 1585 (Ar-C=C), 1196 (C=S); 1H NMR (DMSO, 300 MHz) δ: 13.02 (s, 1H, NH), 7.9 (d, 1H, Ar-H), 7.7 (Pseudo t, 1H, Ar-H), 7.4 (d,1H, Ar-H), 7.3 (pseudo t, 1H, Ar-H), 7.1 (d, 2H, Ar-H), 7.0 (d, 2H, Ar-H), 3.8 (s, 3H, OCH3); 13C NMR (75.4 MHz) δ: 176.8 (C=S), 160.4 (C=O), 159.19 (C-N), 139.9 (Ar), 136.0 (Ar), 132.4 (Ar), 130.4 (Ar), 127 (Ar), 124.7 (Ar), 116.6 (Ar), 116.1 (Ar), 114.5 (Ar), 55.7 (MeO); Anal. Calcd. For C15H12N2O2S: C, 63.36; H, 4.25; N, 9.85; S, 11.28; Found: C, 63.35; H, 4.24; N, 9.84; S, 11.27; GC-MS m/z: 284.06 (M·+, 100).

 Conclusions

Synthesis and molecular structure of a medicinally important compound is described. The dihydroquniazoline ring system is essentially planar; the molecule is twisted around the C9-N2 bond between the dihydroquinazoline ring system and the substituted phenyl C9-C14 ring. The molecules are linked by an N-H…S hydrogen bond forming a zig-zag chain structure along the b axis.

 Figures and Table

Synthetic route to 3-(4-methoxyphenyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one.

The molecular structure of (4). Anisotropic displacement ellipsoids are drawn at the 50% probability level.

A packing diagram of (4), showing a zig-zag chain structure running along the b axis. N-H…S hydrogen bonds are indicated by dashed lines. H atoms not involved in the hydrogen bonds have been omitted.

A packing diagram of (4) viewed along the b axis, showing a layer structure formed by N-H..S and C-H…O hydrogen bonds. The hydrogen bonds are indicated by dashed lines. H atoms not involved in the interactions have been omitted.

Crystal data and structure refinement for (4).

Empirical formula C15H12N2O2S
Formula weight 284.33
Temperature 180(1)K
Wavelength 0.71075 Å
Crystal system Monoclinic
Space group P21
Unit cell dimensions a = 9.9349(8) Å α = 90°
b = 6.3377(5) Å β = 97.752(3)°
c = 10.5783(10) Å γ = 90°
Volume 659.97(10) Å3
Z 2
Density (calculated) 1.431 mg/m3
Absorption coefficient 0.247 mm−1
F(000) 296
Crystal size 0.13 × 0.36 × 0.38 mm3
Theta range for data collection 3.0 to 30.0°.
Index ranges −13 ≤ h ≤ 13, −8 ≤ k ≤ 8, −14 ≤ l ≤ 14
Reflections collected 12985
Independent reflections 3719 [R(int) = 0.014]
Completeness to theta = 29.97° 99.8%
Absorption correction Numerical
Max. and min. transmission 0.968 and 0.915
Refinement method Full-matrix least-squares on F2
Data/restraints/parameters 3719/1/185
Goodness-of-fit on F2 1.07
Final R indices [I > 2σ(I0)] R1 = 0.0271, wR2 = 0.0704
R indices (all data) R1 = 0.0266, wR2 = 0.0702
Extinction coefficient none
Largest diff. peak and hole 0.347 and −0.150 eÅ−3
Flack parameter 0.00(4)
CCDC No. 831309

The author gratefully acknowledges a research grant from the Higher Education Commission of Pakistan under project No. 4-279/PAK-US/HEC 2010-917.

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