A simple, convenient, and efficient synthetic route for the preparation of (Z)-3,5-Dichloro-N-(3-(4-substitutedphenyl)-4-phenylthiazole-2(3H)-ylide) benzamide heterocyclic compounds from aroyl thiourea derivatives via s-cyclization mechanism

Article abstract of DOI:10.1002/jhet.820

A series of variously substituted 1,3-thiazole heterocyclic compounds (3a-3d) were prepared by base-catalyzed S-cyclization of corresponding 2,4-dichloro-N-{[(4-substitutedphenyl)amino]carbonothioyl}benzamide (2a-2d) with acetophenone in the presence of bromine. The structure of all compounds was established by IR, ¹H-NMR, ¹³C-NMR, elemental analysis, and X-ray crystallographic analysis.

Full text of DOI:10.1002/jhet.820

580
A Simple, Convenient, and Efficient Synthetic Route for The
Preparation of (Z)-3,5-Dichloro-N-(3-(4-substitutedphenyl)-4-
phenylthiazole-2(3H)-ylide)benzamide Heterocyclic Compounds
from Aroyl Thiourea Derivatives via S-cyclization Mechanism
Vol 49
a
b
*
Sohail Saeed and Wing-Tak Wong
aDepartment of Chemistry, Research Complex, Allama Iqbal Open University,
Islamabad 4400, Pakistan
bDepartment of Chemistry, The University of Hong Kong, Pokfulam Road, Pokfulam, Hong Kong
SAR, People’s Republic of China
*
E-mail: sohail262001@yahoo.com
Received November 24, 2010
DOI 10.1002/jhet.820
View this article online at wileyonlinelibrary.com.
A series of variously substituted 1,3-thiazole heterocyclic compounds (3a–3d) were prepared by base-cat-
alyzed S-cyclization of corresponding 2,4-dichloro-N-{[(4-substitutedphenyl)amino]carbonothioyl}benza-
mide (2a–2d) with acetophenone in the presence of bromine. The structure of all compounds was
1
established by IR, H-NMR, 13C-NMR, elemental analysis, and X-ray crystallographic analysis.
J. Heterocyclic Chem., 49, 580 (2012).
INTRODUCTION
and HIV infections [13]. 2-Thiazolylimino-5-arylidene-
4-thiazolidinones show marked antimicrobial activity
against bacteria, yeasts, and molds [14]. Some cyclic
chiral oligothiazolines, having a wheel-like architecture
containing a linear array of thiazoline rings, are well-
known supramolecules [15]. 2-(Tetrahydronaphthalen-1-yl)
iminothiazolidine exhibits pronounced antidepressant
activity [16], and b-(hydrooxyethyl)thiazolidines are effec-
tive antihypertensives [17]. 3-Substituted 2-(cyanoimino)
thiazolidines can be used in agriculture due to their neonico-
tinoid insecticidal activity [18]. 3-Substituted thiazolidines
show radioprotective properties against γ-radiations [19].
2-Imino-1,3-thiazolines derivatives have shown antifungal
activity against the rice blast fungus Pyricularia oryzae
[20] and thus can be used fungicides. 2-Imino-1,3-thiazoline
derivatives significantly inhibit melanin production in a
dose-dependant manner, thus acting as a skin whitening
agent [21], and pifithrin-a is a reversible inhibitor of
p53-mediated apoptosis and p53-dependant gene transcrip-
tion [22].
Since the initial isolation of the polypyrrole netropsin in
1951 and distamycin in 1964, the interest in this class of
compounds has been increased [1].These natural antibio-
tics showed anticancer and antiviral activities by DNA
binding [2]. Bleomycins, a group of anticancer antibiotics,
also have a dithiazole moiety along with the imidazole and
pyrimidine ring systems [3]. Thiazole heterocycle is a
commonly occurring substructure in organic chemistry,
found in a variety of structurally and biologically interest-
ing natural products such as mirabazoles, thiangazole, and
tantazoles, which display selective cytotoxicity against
murine solid tumors and are potent and selective inhibi-
tors of HIV-1 [4,5]. Synthetic thiazoline derivatives are
useful medicaments showing antifungal [6,7], anti-tumor
[8], anti-allergic [9], anti-inflammatory [10], anti-hyper-
tension [11], analgesic, anti-bacterials, anti-rheumatic,
anti-pyretic, and anti-HIV [12] activities. Some fused
thiazolines find applications in the treatment of allergies,
hypertension, inflammation, schizophrenia, and bacterial
© 2012 HeteroCorporation

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A Simple, Convenient, and Efficient Synthetic Route for the Preparation of (Z)-3,5-
581
N-(3-(4-substitutedphenyl)-4-phenylthiazole-2(3H)-ylide)benzamide Heterocyclic Compounds
Scheme 1. Synthetic route of compounds 3a–3d: R=OCH3 (a), CH3 (b),
Cl (c), and NO2 (d).
In search of improved methods to prepare the 2,4-
dichloro-N-{[(4-substitutedphenyl)amino]carbonothioyl}
benzamides by reacting isothiocyanates with nucleophiles,
we have found the use of tetrabutylammonium bromide
(TBAB) as a phase transfer catalyst (PTC) can afford aroyl
isothiocyanates in good yield, as reported here. The com-
pounds (2a–2d) showed absorptions at 3351 and 3200
cmꢀ1 for free and associated NH, at ꢁ1660 for carbonyl,
and at 1230–1226 cmꢀ1 for thiocarbonyl groups in IR
spectra and singlets at d 9.39–9.32 and 12.02–11.95
(ppm) for NH (1) and NH (3) and peaks at 166–164 and
180.0–175.1 (ppm) for carbonyl and thiocarbonyl were
1
observed in H- and 13C-NMR spectra, respectively. The
cyclocondensation of 2,4-dichloro-N-{[(4-substitutedphe-
nyl)amino]carbonothioyl}benzamide with acetophenone
was achieved in the presence of bromine and base. Thus,
triethyl amine was added to a solution of 2,4-dichloro-N-
{[(4-substitutedphenyl)amino]carbonothioyl}benzamide in
anhydrous dichloromethane, followed by the treatment
with a mixture of acetophenone and bromine under an inert
atmosphere to afford heterocyclic (Z)-3,5-dichloro-N-(3-
(4-substitutedphenyl)-4-phenylthiazole-2(3H)-ylide)ben-
zamide derivatives. The absence of N—H peaks at 3200–
3400 cmꢀ1, slight shifting of C¼O absorptions to 1630–
1650 cmꢀ1, and appearance of characteristic C¼N at
1
1450–1495 cmꢀ1 were observed in the IR spectra. H-
NMR spectra showed the disappearance of N—H peaks
1
and emergence of a H characteristic singlet at d 6.85–
6.75 due to C¼C—H of the thiazole ring. In 13C-NMR,
the characteristic peak for olefinic carbon at d 107.5–
107.8 (ppm) confirmed the formation of (Z)-3,5-dichloro-
N-(3-(4-substitutedphenyl)-4-phenylthiazole-2(3H)-ylide)
benzamide derivatives (3a–3d).
Although the same mesomeric anionic thiourea interme-
diate may furnish either imino-1,3-thiazoles (S-cyclization
products) or isomeric imidazole-2-thiones (N-cyclization
products), it has already equally demonstrated [29] that
under these conditions the thermodynamically stable
Taking into consideration the aforementioned biological
and synthetic significance of 2-imino-1,3-thiazolines, we
designed the synthesis of some new 1,3-thiazolines having
three points of structural diversity for systematic evaluation
of biological activities and establishment of structure activ-
ity relationship (SAR) in depth. Herein, the synthesis of
some 1,3-thiazoline derivatives is described.
RESULTS AND DISCUSSION
2,4-Dichloro-N-{[(4-substitutedphenyl)amino]carbono-
thioyl}benzamide (2a–2d) were prepared according to the
published procedure involving treatment of aroyl chloride
with ammonium thiocyanate in anhydrous acetone
followed by reaction with suitably substituted anilines
[23–26] as shown in Scheme 1. The use of phase transfer
catalysts as a method of agitating a heterogeneous reaction
system is gaining recognition [27,28].
Figure 1. Molecular structure and crystallographic numbering scheme for
compound 2c. Selected bond lengths (Å): C11–C1 1.722(2); C12–C3
1.739(2); S1–C8 1.6718(18); O1–C7 1.215(2); N1–C7 1.369(2); N1–C8
1.388(2); N2–H2N 0.8594; C11–C12 1.371(3). Selected bond angles
(ꢂ): C7–N1–C8 129.13(15); C7–N1–H1N 113.1; C8–N1–H1N 117.8;
C8–N2–C9 124.97(15); C8–N2–H2N 118.7; O1–C7–N1 123.18(17);
O1–C7–C6 122.58(17); N2–C8–S1 125.55(14); N1–C8–S1 118.19(13).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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S. Saeed and W.-T. Wong
Vol 49
s (broad singlet), d (doublet), dd (doublet of doublets), t (triplet),
q (quartet), and m (multiplet). Infrared measurements were
recorded in the range 400–4000 cmꢀ1 on spectrum 2000 by
Perkin Elmer. Elemental analysis was carried out using Perkin
Elmer CHNS/O 2400. Obtained results were within 0.4% of the
theoretical values. A thin layer chromatography (TLC) analysis
were carried out on 5 ꢃ 20 cm2 plate coated with silica gel
GF254 type 60 (25–250 mesh) using an ethyl acetate-petroleum
ether mixture (1:2) as solvent.
General method for the preparation of 2,4-dichloro-N-{[(4-
substitutedphenyl)amino]carbonothioyl}benzamide (2a–2d).
In a 250-mL round-bottom flask, 80 mL of anhydrous acetone
and 1.46 g (0.01 mol) of 2,4-dichlorobenzoyl chloride were
placed. The mixture was allowed to stir until the solid
dissolved. Then,
a solution of 3% tetrabutylammonium
bromide (TBAB) and 0.76 g (0.01 mol) of ammonium
thiocyanate in dry acetone was added dropwise in the round-
bottom flask, and the reaction mixture was refluxed for 45
Figure 2. The packing diagram of the unit cell of the compound 2c was
projected down the a-axis and shown at 50% probability thermal
ellipsoids.
min. After cooling to room temperature,
a solution of
substituted aromatic primary amine (0.01 mol) in acetone
(25 mL) was added and the resulting mixture refluxed for 2.5
h. The reaction mixture was poured into five times its volume
of cold water to precipitate the product, which was
recrystallized from ethanol as an intense yellow powder.
imino-1,3-thiazoles are the exclusive products as reported
the previous papers [30,31].
2,4-Dichloro-N-{[(4-methoxyphenyl)amino]carbonothioyl}
benzamide (2a).
This compound was obtained as colorless
Single crystals of 2c suitable for X-ray diffraction stud-
ies were obtained by evaporation from dichloromethane/
ethanol. The molecular structure is shown in Figure 1.
The compound (2c), 2,4-dichloro-N-{[(4-chlorophenyl)
amino]carbonothioyl}benzamide, crystallizes in a triclinic
primitive space group, P ꢀ 1 (#2). Like its other analogue,
the molecule is not planar. The amido group is 63.52(7)°
from the 2,4-dichloro-benzyl ring plane of C1—C6/C11/
C12. The thiourea group is slightly twisted (13.11(11)°)
from the amido group. The 4-chloro-phenyl ring plane,
C9—C14/C13, makes a dihedral angle of 10.03(11)° with
the 2,4-dichloro-benzyl ring plane, C1—C6/C11/C12.
There are intermolecular N—H···O and N—H···S H-bond
interactions. The intermolecular N—H···O H-bond interac-
tions link the molecules to form dimers, whereas N—H···S
H-bond interactions link the molecules to form 1D chains
along the b-axis in the crystal lattice (Fig. 2). There are also
π···π interactions between neighboring benzene rings in the
crystal lattice.
powder, yield: 1.41 g (90%), m.p. 162–163°C; IR (KBr pellet)
in cmꢀ1: 1531 (benzene ring), 1403 (C—N stretching), 1143
1
(C¼S); H-NMR (300 MHz, DMSO-d6) in d (ppm) and J (Hz):
12.01 (1H, s, broad, NH), 9.32 (1H, s, broad, NH), 7.85 (2H, d,
J = 8.15), 7.21 (2H, d, J = 7.5), 3.46 (3H, s, —OCH3); 13C-
NMR (300 MHz, DMSO-d6) in d (ppm): 180.1 (C¼S), 165.0
(C), 162.7 (C), 150.4 (C), 145.5 (C), 140.7 (C), 135.3 (C),
127.8 (C), 55.0 (C). Anal. Calcd. for C15H12Cl2N2O2S (355.23):
C, 50.72; H, 3.40; N, 7.89; S, 9.03. Found: C, 50.72; H, 3.42;
N, 7.88; S, 9.01.
2,4-Dichloro-N-{[(4-methylphenyl)amino]carbonothioyl}
benzamide (2b).
This compound was obtained as colorless
powder, yield: 1.38 g (92%), m.p. 175–176°C; IR (KBr pellet)
in cmꢀ1: 1535 (benzene ring), 1403 (C—N stretching), 1141
1
(C¼S); H-NMR (300 MHz, DMSO-d6) in d (ppm) and J (Hz):
11.95 (1H, s, broad, NH), 9.41 (1H, s, broad, NH),7.80 (2H, d,
J = 8.09), 7.24 (2H, d, J = 7.2), 2.46 (3H, s, —CH3); 13C-NMR
(300 MHz, DMSO-d6) in d (ppm): 180.0 (C¼S), 166.0 (C), 162.7
(C), 150.4 (C), 145.5 (C), 140.7 (C), 135.3 (C), 127.8 (C), 25.0
(C). Anal. Calcd. for C15H12Cl2N2OS (339.23): C, 50.11; H, 3.57;
N, 8.26; S, 9.45. Found: C, 50.13; H, 3.59; N, 8.23; S, 9.45.
2,4-Dichloro-N-{[(4-chlorophenyl)amino]carbonothioyl}
benzamide (2c). This compound was obtained as colorless
block crystals (ethanol:dichloromethane 1:2), yield: 1.55 g
(92%), m.p. 165–166°C; IR (KBr pellet) in cmꢀ1: 1534
(benzene ring), 1403 (C—N stretching), 1140 (C¼S); 1H-
NMR (300 MHz, DMSO-d6) in d (ppm) and J (Hz): 12.03
(1H, s, broad, NH), 9.39 (1H, s, broad, NH), 7.65 (2H, d, J =
8.11), 7.24 (2H, d, J = 7.5); 13C-NMR (300 MHz, DMSO-d6)
in d (ppm): 175.1 (C¼S), 164.0 (C), 150.4 (C), 140.7 (C),
135.3 (C), 127.8 (C). Anal. Calcd. for C14H9Cl3N2OS
(359.65): C, 46.75; H, 2.52; N, 7.79; S, 8.92. Found: C,
46.74; H, 2.53; N, 7.78; S, 8.93.
EXPERIMENTAL
All reagents were used as received unless otherwise stated.
Reagent-grade dry acetone, ethanol, ethyl acetate, triethylamine,
acetophenone, tetrabutylammonium bromide (TBAB), and 2,4-
dichlorobenzoyl chloride were obtained from Merck Chemical
Co. Acetone and dichloromethane were dried according to stan-
dard procedures and distilled before use. Melting points were
recorded on Electrothermal IA9000 series digital melting point
apparatus. The proton NMR and 13C spectra were recorded in
DMSO-d6 solvent on Bruker 300 MHz spectrophotometer using
tetramethylsilane as an internal reference, respectively. The
apparent resonance multiplicity is described as s (singlet), br
2,4-Dichloro-N-{[(4-nitrophenyl)amino]carbonothioyl}
benzamide (2d).
This compound was obtained as light
yellow powder, yield: 1.62 g (89%), m.p. 196°C; IR (KBr
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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A Simple, Convenient, and Efficient Synthetic Route for the Preparation of (Z)-3,5-
583
N-(3-(4-substitutedphenyl)-4-phenylthiazole-2(3H)-ylide)benzamide Heterocyclic Compounds
pellet) in cmꢀ1: 1536 (benzene ring), 1406 (C—N stretching),
1143 (C¼S); 1H-NMR (300 MHz, DMSO-d6) in d (ppm)
and J (Hz): 12.02 (1H, s, broad, NH), 9.32 (1H, s, broad,
NH), 8.28 (2H, d, J = 8.31), 7.24 (2H, d, J = 8.5); 13C-
NMR (300 MHz, DMSO-d6) in d (ppm): 179.1 (C¼S),
165.0 (C), 162.7 (C), 150.4 (C), 145.5 (C), 140.7 (C),
135.3 (C), 127.8 (C). Anal. Calcd. for C14H9Cl2N3O3S
(370.21): C, 45.42; H, 2.45; N, 11.35; S, 8.66. Found: C,
45.44; H, 2.47; N, 11.35; S, 8.65.
General method for the preparation of (Z)-3,5-dichloro-
N-(3-(4-substitutedphenyl)-4-phenylthiazole-2(3H)-ylide)
benzamide (3a–3d). Triethylamine (0.01 mol) was added to a
stirred solution of 1-aroyl-3-arylthiourea (0.01 mol) in dry
dichloromethane (30 mL), followed by drop-wise addition of a
solution of bromine (0.01 mol) in acetophenone (0.01 mol)
under nitrogen. The reaction mixture was stirred for 1–2 h, and
progress of the reaction was monitored by thin layer
chromatography (hexane:ethyl acetate 4:1). After the reaction
was complete, the mixture was filtered; the filtrate was
concentrated to afford thiazole derivatives, which were purified
by recrystallization from ethanol.
(Z)-3,5-Dichloro-N-(3-(4-methoxyphenyl)-4-phenylthiazole-2
(3H)-ylide)benzamide (3a). Yield: 1.49 g (71%), m.p. 169–170°
C; IR (KBr pellet) in cmꢀ1: 1641 (C¼O), 1531 (benzene ring),
1452 (C¼N stretching), 1275 (C—S), 1155 (C—N); 1H-NMR
(300 MHz, DMSO-d6) in d (ppm): 8.36–7.15 (m, 12H, Ar—H),
6.85 (s, CH¼C), 3.66 (s, 3H, OCH3); 13C-NMR (300 MHz,
DMSO-d6) in d (ppm): 171.1, 165.0, 162.7, 139.4, 135.5, 132.7,
130.3, 129.8, 128.4, 128.0, 126.5, 107.2, 56.4. Anal. Calcd. for
C23H16Cl2N2O2S (455.35): C, 60.67; H, 3.54; N, 6.15; S, 7.04.
Found: C, 60.68; H, 3.57; N, 6.12; S, 7.02.
Single crystal X-ray diffraction analysis of 2c. A colorless
block crystal having dimensions of 0.07 ꢃ 0.26 ꢃ 0.49 mm3 was
mounted in glass capillary. All measurements were made on a Bruker
SMART 1000 CCD detector with graphite monochromated Mo-
Ka radiation. Indexing was performed from 60 images that were
exposed for 10 s for a preliminary unit cell determination. Of
which, 33 out of total of 56 reflections were successfully
indexed. The crystal-to-detector distance was 50.00 mm. Cell
constants and an orientation matrix for data collection
corresponded to a primitive triclinic cell with dimensions: a =
6.0436(4) Å, a = 93.208(1)°, b = 9.5906(7) Å, b = 98.912(1)°,
V = 788.29(10) Å3, c = 14.0673(10) Å, γ = 100.772(1)°. For
Z = 2 and F.W. = 359.64, the calculated density is 1.515 g/cm3.
The data were collected at a temperature of 33(1)°C to a
maximum 2θ value of 50.05°. A total of 1421 oscillation
images were collected in four runs. A sweep of data was done
using ω scans from 330.0° to 148.2° in ꢀ0.3° step, at χ = 54.7°
and φ = 0.0°. The exposure rate was 50.0 (s/°). The detector
swing angle was ꢀ30.00°. A second sweep was performed
using ω scans from 330.0° to 201.5° in ꢀ0.3° step, at χ = 54.7°
and φ = 90.0°. The detector swing angle was ꢀ30.00°. Another
sweep was performed using ω scans from 330.0° to 261° in
ꢀ0.3° step, at χ = 54.7° and φ = 180.0°. A final sweep was
performed using ω scans from 330.0° to 285° in ꢀ0.3° step, at
χ = 54.7° and φ = 270.0°. CCDC 795456 contains the
supplementary crystallographic data for this article. Copies of
this information may be obtained free of charge from the
Director, CCDC, 12 Union Road, Cambridge, CBZ IEZ, UK.
Facsimile (44)-01223-336-033, E-mail: deposit@ccdc.cam.ac.
uk (or) http://www.ccdc.cam.ac.uk/deposit.
(Z)-3,5-Dichloro-N-(3-(4-methylphenyl)-4-phenylthiazole-2
(3H)-ylide)benzamide (3b). Yield: 1.61 g (75%), m.p. 158–159°
C; IR (KBr pellet) in cmꢀ1: 1643 (C¼O), 1585 (benzene ring),
1450 (C¼N stretching), 1262 (C—S), 1151 (C—N); 1H-NMR
(300 MHz, DMSO-d6) in d (ppm): 8.14–7.13 (m, 12H, Ar—H),
6.84 (s, CH¼C), 2.51 (s, 3H, CH3); 13C-NMR (300 MHz,
DMSO-d6) in d (ppm): 170.1, 168.0, 142.2, 138.5, 137.3,
136.7, 133.1, 131.9, 130.2, 129.4, 128.4, 128.0, 122.2, 107.6,
21.4. Anal. Calcd. for C23H16Cl2N2OS (439.35): C, 62.88; H,
3.67; N, 6.38; S, 7.30. Found: C, 62.86; H, 3.42; N, 6.36; S,
7.28.
(Z)-3,5-Dichloro-N-(3-(4-chlorophenyl)-4-phenylthiazole-2
(3H)-ylide)benzamide (3c). Yield: 1.50 g (79%), m.p. 182–183°
C; IR (KBr pellet) in cmꢀ1: 1647 (C¼O), 1541 (benzene ring),
1452 (C¼N stretching), 1255 (C—S), 1150 (C—N); 1H-NMR
(300 MHz, DMSO-d6) in d (ppm): 8.37–7.65 (m, 12H, Ar—H),
6.77 (s, CH¼C); 13C-NMR (300 MHz, DMSO-d6) in d (ppm):
173.1, 170.4, 139.4, 137.1, 135.5, 132.7, 131.3, 129.8, 128.8,
128.0, 126.5, 107.6. Anal. Calcd. for C23H13Cl3N2OS (459.77):
C, 57.47; H, 2.85; N, 6.09; S, 6.97. Found: C, 57.47; H, 2.88; N,
6.11; S, 6.95.
(Z)-3,5-Dichloro-N-(3-(4-nitrophenyl)-4-phenylthiazole-2(3H)-
ylide)benzamide (3d). Yield: 69%, m.p. 203–204°C; IR (KBr
pellet) in cmꢀ1: 1638 (C¼O), 1562 (benzene ring), 1454 (C¼N
stretching), 1271 (C—S), 1157 (C—N); 1H-NMR (300 MHz,
DMSO-d6) in d (ppm): 8.21–7.11 (m, 12H, Ar—H), 6.75
(s, CH¼C); 13C-NMR (300 MHz, DMSO-d6) in d (ppm): 174.1,
169.0, 162.7, 139.4, 135.5, 132.7, 130.3, 129.8, 128.4, 128.0,
126.3, 107.0. Anal. Calcd. for C22H13Cl2N3O3S (470.32): C,
56.18; H, 2.79; N, 8.93; S, 6.82. Found: C, 56.20; H, 2.81; N,
8.90; S, 6.79.
Acknowledgments. The authors thank National Engineering and
Scientific Commission, Islamabad for providing the facility of
elemental analyses and spectroscopic techniques.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet