2-substituted 4H-[1,3]thiazolo[3,2-a][1,3,5]triazine-4-thiones: Synthesis, crystal structure, and antifungal activity

Article abstract of DOI:10.1002/jhet.439

2-(4-Substituted aryl)-4H-[1,3]thiazolo[3,2-a][1,3,5]triazine-4-thiones (3a-3b) and 2-(2-thiophene)-4H-[1,3]thiazolo[3,2-a][1,3,5]triazine-4-thione (3d) were synthesized by the reaction of arylisothiocyanates/thiophene-2- isothiocyanate with 2-aminothiazo

Full text of DOI:10.1002/jhet.439

908
2-Substituted 4H-[1,3]thiazolo[3,2-a][1,3,5]triazine-4-thiones:
Synthesis, Crystal Structure, and Antifungal Activity
Vol 47
Sohail Saeed,a* Naghmana Rashid,a Peter G. Jones,b and Uzma Yunasa
aDepartment of Chemistry, Research Complex, Allama Iqbal Open University, Islamabad, Pakistan
bInstitut fu¨r Anorganische und Analytische Chemie, Technische Universita¨t Braunschweig,
Postfach 3329, 38023 Braunschweig, Germany
*E-mail: sohail262001@yahoo.com
Received November 14, 2009
DOI 10.1002/jhet.439
Published online 17 June 2010 in Wiley InterScience (www.interscience.wiley.com).
2-(4-Substituted aryl)-4H-[1,3]thiazolo[3,2-a][1,3,5]triazine-4-thiones (3a-3b) and 2-(2-thiophene)-4H-
[1,3]thiazolo[3,2-a][1,3,5]triazine-4-thione (3d) were synthesized by the reaction of arylisothiocyanates/
thiophene-2-isothiocyanate with 2-aminothiazole in the presence of tetrabutylammonium bromide as
phase transfer catalyst. Compound 3c was synthesized by the catalytic reduction (10% Pd-C) of 3a.
1
Compounds 3a–d were characterized by IR, H NMR, 13C NMR, and elemental analysis. All the com-
pounds were tested in vitro against Fusarium solani, A.fumigatus, and Aspergillus flavus using standard
drugs. The crystal structure of 3a was determined from single crystal X-ray diffraction data.
J. Heterocyclic Chem., 47, 908 (2010).
INTRODUCTION
We became interested in the synthesis of fused heter-
ocyclic 1,3,5-triazine compounds containing aryl and
thiophene moieties and in the systematic study of their
biological activity. All the structures of these novel tar-
get compounds were characterized by spectroscopic
techniques. We have also confirmed the structure of one
representative by X-ray crystallography.
Heterocyclic compounds containing nitrogen and sul-
phur possess potential pharmacological activities [1–4].
Recent years have seen a dramatic increase in fungal
infections, mostly caused by Candida albicans; these
infections are often spread through the use of broad-
spectrum antibiotics, immunosuppressive agents, anti-
cancer, and anti-AIDS drugs [5]. The main problem in
the treatment of fungal infections is the increasing prev-
alence of drug resistance, especially in patient’s chroni-
cally subjected to antimycotic therapy such as persons
infected with HIV [6]. For these reasons, serious atten-
tion has recently been directed toward the discovery and
development of new antifungal drugs.
RESULTS AND DISCUSSION
A series of new fused heterocyclic 1,3,5-triazines 3a–d
with thiophene and aroyl substituents (Scheme 1) were
prepared by slight modification of published procedures
[12,13]. The use of phase transfer catalysts (PTCs) as a
method of agitating a heterogeneous reaction system is
gaining recognition [14,15]. In search of improved meth-
ods to prepare the target fused heterocyclic 1,3,5-triazines
by reacting isothiocyanates with nucleophiles, we have
found the use of tetrabutylammonium bromide (TBAB)
as PTC, which can afford thiophenoyl and aroyl isothio-
cyanates in good yield, as reported here.
Fused heterocyclic 1,3,5-triazines possess a wide
array of biological activities such as herbicidal and fun-
gicidal activity [7], antitumor activity [8], and inhibitory
activity against the enzymes phosphodiesterase (PED)
[9,10], which is expected to be the target for the treat-
ment of diseases such as asthma, diabetes mellitus, and
thrombosis. They are also able to block dihydrofolate
reductase, the inhibition of which leads to cell death
[11]. The title compounds are examples of such fused
heterocyclic 1,3,5-triazines.
All the structures of newly synthesized compounds
were assigned on the basis of their elemental analysis
and spectroscopic data, IR, and 1H NMR. All the
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July 2010
2-Substituted 4H-[1,3]thiazolo[3,2-a][1,3,5]triazine-4-thiones: Synthesis,
Crystal Structure, and Antifungal Activity
909
Scheme 1. Preparation of compounds (3a–d).
compounds were soluble in DMF, DMSO, ethanol, and
ethyl acetate.
Single crystals of 3a suitable for X-ray diffraction
studies were obtained by evaporation from dichlorome-
thane/ethanol. The molecular structure is shown in
Figure 1. Molecular dimensions may be regarded as nor-
mal. The bicyclic thiazolotriazine system is planar
Surprisingly, to the best of our knowledge, 2-(4-sub-
stituted phenyl)-4H-[1,3]thiazolo [3,2-a][1,3,5]triazine-4-
thiones (3a–c) and 2-(2-thiophene)-4H-[1,3]thiazolo
[3,2-a][1,3,5]triazine-4-thione (3d) have never been
described in the literature. The formation of 3a–d would
be explained through the formation of an unstable inter-
mediate form containing thiazole, alcoholic, and isothio-
cyanate functional groups as shown in Scheme 2.
The yield of the target products was very sensitive to
the reaction conditions. Two types of products were
obtained during the reaction of arylisothiocyanate with
2-aminothiazole. The major product, using a molar ratio
of 1:1 between arylisothiocyanate and 2-aminothiazole,
was a fused heterocyclic 1,3,5-triazine with about 75%
yield and the minor product was a thiourea derivative
with about 20% yield. Initially, the experiments were
performed three times and these yields remained. How-
ever, the yield of fused heterocyclic 1,3,5-triazine prod-
ucts increased to above 90% when the molar concentra-
tion of 2-aminothiazole was doubled and refluxed time
increased to 4.5 h.
˚
(mean deviation 0.01 A) and subtends an interplanar
angle of 11.9ꢁ to the phenyl ring. The molecular pack-
˚
ing (Fig. 2) displays two contacts, H16ꢂꢂꢂO2 2.36 A and
˚
S1ꢂꢂꢂO1 3.01 A, which combine to form ribbons parallel
to the vector [100] and to the plane (012). These ribbons
˚
are connected by N1ꢂꢂꢂO2 3.03 A (not shown).
Primary bioassay screening provides the first indica-
tion of bioactivities and helps in the selection of lead
compounds for secondary screening for detailed pharma-
cological evaluation. The synthesized fused heterocyclic
1,3,5-triazines 3a–d were checked for their antifungal
activity against three fungal strains: Fusarium solani,
A.fumigatus, and Aspergillus flavus. The antifungal ac-
tivity was carried out in DMSO using the agar tube dilu-
tion method [16]. Growth in the media was determined
by measuring linear growth (mm) and growth inhibition
was calculated with reference to the negative control.
No significant activity against yeast was detected. All
the compounds in the series showed weak antimicrobial
activity against Fusarium solani, A.fumigatus, and
Aspergillus flavus with 30–40% inhibition, which shows
low activity. However, the compound 2-(2-thiophene)-
4H-[1,3]thiazolo [3,2-a][1,3,5]triazine-4-thione (3d)
showed 40% inhibition.
The cyclization of 2a–d to fused heterocyclic 1,3,5-tria-
zines 3a–d was monitored by the IR spectra, where the car-
bonyl chloride peak disappeared on the expense of the
appearance of thioamide (C¼¼S) peak in the region of
1445–1440 cmꢀ1. The thioamide group was also confirmed
by 13C NMR, with signals at d 182–179 ppm.
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DOI 10.1002/jhet

910
S. Saeed, N. Rashid, P. G. Jones, and U. Yunas
Vol 47
Scheme 2. Proposed reaction mechanism.
(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. Thin layer
chromatography (TLC) analysis were carried out on 5 ꢃ
20 cm plate coated with silica gel GF254 type 60 (25–250
mesh) using an ethyl acetate-petroleum ether mixture (1:2) as
solvent.
2-(4-Nitrophenyl)-4H-[1,3]thiazolo[3,2-a][1,3,5]triazine-4-
thione (3a). A solution of 4-nitrobenzoyl chloride (1.85 g,
0.01 mol) in anhydrous acetone (80 mL) and 3% TBAB in
acetone was added dropwise to a suspension of ammonium thi-
ocyanate (0.76 g, 0.01 mol) in acetone (50 mL), and the reac-
tion mixture was refluxed for 45 min. After cooling to room
temperature, a solution of 2-aminothiazole (1.0 g, 0.01 mol) in
acetone (25 mL) was added and the resulting mixture refluxed
for 4.5 h. The reaction mixture was poured into five times its
volume of cold water, to precipitate the product, which was
recrystallized from ethanol: dichloromethane (1:2) as intensely
yellow crystals. Yield: 1.50 g (93%), m.p. 196ꢁC; IR (KBr pel-
let) in cmꢀ1: 1529 (benzene ring), 1512 (NO2), 1401 (CAN
1
stretching), 1140 (C¼¼S); H NMR (300 MHz, DMSO-d6) in d
(ppm) and J (Hz): 8.10(2H, d, J ¼ 8.41), 7.34 (2H, d, J ¼ 8.7
Hz); 13C NMR (300 MHz, DMSO-d6) in d (ppm): 179.2
(C¼¼S), 165.5 (C), 162.0 (C), 150.4 (C), 145.6 (C), 141.3 (C),
135.1 (C), 128.4 (C) .Anal.Calcd. for C11H6N4O2S2 (290.32):
C, 45.51; H, 2.08; N, 19.30; S, 22.09. Found: C, 45.50; H,
2.09; N, 19.30; S, 22.07.
2-(4-Methylphenyl)-4H-[1,3]thiazolo[3,2-a][1,3,5]triazine-
4-thione (3b). A solution of 4-methylbenzoyl chloride (1.54 g,
0.01 mol) in anhydrous acetone (80 mL) and 3% TBAB in ac-
etone was added dropwise to a suspension of ammonium thio-
cyanate (0.76 g, 0.01 mol) in acetone (50 mL), and the reac-
tion mixture was refluxed for 45 min. After cooling to room
temperature, a solution of 2-aminothiazole (1.0 g, 0.01 mol) in
acetone (25 mL) was added and the resulting mixture refluxed
for 4.5 h. The reaction mixture was poured into five times its
volume of cold water to precipitate the product, which was
recrystallized from ethanol as a pale yellow power. Yield: 1.50
g (90%), m.p. 175ꢁC; IR (KBr pellet) in cmꢀ1: 1531 (benzene
ring), 1403 (CAN stretching), 1143 (C¼¼S); 1H NMR (300
MHz, DMSO-d6) in d (ppm) and J (Hz): 8.04(2H, d, J ¼
8.33), 7.24 (2H, d, J ¼ 8.5 Hz), 2.46 (3H,s, ACH3); 13C NMR
(300 MHz, DMSO-d6) in d (ppm) : 180.1 (C¼¼S), 165.0 (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 C12H9N3S2 (259.35): C, 55.57; H,
3.50; N, 16.20; S, 24.73.Found: C, 55.59; H, 3.52; N, 16.18;
S, 24.72.
2-(4-Aminophenyl)-4H-[1,3]thiazolo[3,2-a][1,3,5]triazine-4-
thione (3c). Compound 3a (2.60 g, 0.01 mol), 5 mL hydrazine
monohydrate, 70 mL ethanol and 0.03 gm of 10% PdAC was
transferred into 250-mL two-necked round-bottom flask and
refluxed for 18 h. The reaction was monitored by TLC. After
completion, the reaction mixture was allowed to stand for 1
day and then filtered. The solvent was removed by rotary
evaporation. The crude product was recrystallized from ethyl
acetate. Yield: 1.50 g (85%), m.p. 165ꢁC; IR (KBr pellet) in
cmꢀ1: 1529 (benzene ring), 1405 (CAN stretching), 1140
(C¼¼S); 1H NMR (300 MHz, DMSO-d6) in d (ppm) and J
(Hz): 8.10(2H, d, J ¼ 8.41), 7.34 (2H, d, J ¼ 8.7 Hz),
4.01(2H, br s, NH2); 13C NMR (300 MHz, DMSO-d6) in
EXPERIMENTAL
Melting points were recorded on Electrothermal IA9000 se-
ries 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 s (broad singlet), d (doublet), dd
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2010
2-Substituted 4H-[1,3]thiazolo[3,2-a][1,3,5]triazine-4-thiones: Synthesis,
Crystal Structure, and Antifungal Activity
911
Figure 1. The structure of 2-(4-nitrophenyl)-4H-[1,3]thiazolo[3,2-a][1,3,5]triazine-4-thione (3a) with displacement ellipsoids plotted at 50% proba-
bility level.
d (ppm): 180.2 (C¼¼S), 163.3 (C), 162.1 (C), 150.8 (C), 144.6
(C), 140.3 (C), 134.9 (C), 128.7 (C). Anal. Calcd. for
C11H8N4S2 (260.34): C, 50.75; H, 3.10; N, 21.52; S, 24.63.
Found: C, 50.78; H, 3.12; N, 21.52; S, 24.64.
Hz, Thiophene CH); 13C NMR (300 MHz, DMSO-d6) in d
(ppm): 179.2 (C¼¼S), 165.5 (C), 162.0 (C), 150.4 (C) , 145.6
(C), 141.3 (C), 135.1 (C), 128.4 (C) . Anal. Calcd. for C9H5N3S3
(251.35): C, 43.01; H, 2.01; N, 16.72; S, 38.27. Found: C, 43.01;
H, 2.01; N, 16.72; S, 38.27.
2-(2-Thiophene)-4H-[1,3]thiazolo[3,2-a][1,3,5]triazine-4-
thione (3d). A solution of thiophene-2-carbonyl chloride (1.46
g, 0.01 mol) in anhydrous acetone (80 mL) and 3% TBAB in
acetone was added dropwise to a suspension of ammonium thio-
cyanate (0.76 g, 0.01 mol) in acetone (50 mL), and the reaction
mixture was refluxed for 45 min. After cooling to room tempera-
ture, a solution of 2-aminothiazole (1.0 g, 0.01 mol) in acetone
(25 mL) was added and the resulting mixture refluxed for 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. Yield: 1.50 g (93%),
m.p. 184ꢁC; IR (KBr pellet) in cmꢀ1: 1402 (CAN stretching),
Single crystal X-ray diffraction analysis of 3a. Crystal
data: C11H6N4O2S2, orthorhombic, space group Pbca, a ¼
˚
12.4958(6), b ¼ 8.9836(5), c ¼ 20.5812(12) A, V ¼ 2310.4ꢀ(23)
3
˚
A , T ¼ 100 K, Z ¼ 8, F (000) ¼ 1184, Dx ¼ 1.669 g cm
,
l ¼ 4.236 mmꢀ1. Single crystals suitable for X-ray diffraction
studies were obtained by evaporation from dichloromethane/
ethanol. A yellow plate 0.08 ꢃ 0.04 ꢃ 0.015 mm3 was
mounted on a glass fiber in inert oil. Measurements were per-
formed at 100 K on an Oxford Diffraction Xcalibur Nova dif-
fractometer with mirror-focused Cu-Ka radiation to 2ymax
152ꢁ (99.4% complete to 145ꢁ). The data were corrected for
absorption using the multiscan method. Of 26,206 intensities,
2367 were independent (Rint 0.071). The structure was refined
anisotropically using SHELXL-97 [17]. Hydrogen atoms were
1
1144 (C¼¼S); H NMR (300 MHz, DMSO-d6) in d (ppm) and J
(Hz): 8.10 (1H, d, J ¼ 7.2 Hz, Thiophene CH), 7.91 (1H, dd, J1
¼ 7.5 Hz, J2 ¼ 8.2 Hz, Thiophene CH), 7.80 (1H, d, J ¼ 6.7
Figure 2. Packing diagram of compound 3a.
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S. Saeed, N. Rashid, P. G. Jones, and U. Yunas
Vol 47
included using a riding model. The final wR2 was 0.124, with
a conventional R1 of 0.046, for 172 parameters; S ¼ 0.94;
Acknowledgment. The authors thank the National Engineering &
Scientific Commission, Islamabad for providing the facility of elemental
analyses and chemicals free of cost.
ꢀ3
˚
max. Dq 0.39 e A
.
CCDC 754654 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.
com.ac.uk/deposit.
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DOI 10.1002/jhet