Facile synthesis of novel fluorinated thieno[2,3-d]pyrimidine derivatives containing 1,3,4-thiadiazole

Article abstract of DOI:10.1016/j.cclet.2012.02.007

A series of novel fluorinated thieno[2,3-d]pyrimidine derivatives incorporating 1,3,4-thiadiazole were synthesized by a facile microwave-assisted procedure, including the cyclization of 2-aminothiophene-3-carbonitrile with trifluoroacetic acid, chlorinati

Full text of DOI:10.1016/j.cclet.2012.02.007

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 549–552
www.elsevier.com/locate/cclet
Facile synthesis of novel fluorinated thieno[2,3-d]pyrimidine
derivatives containing 1,3,4-thiadiazole
a
a
b
Xin Jian Song a, , Zheng Chao Duan , Yu Shao , Xing Gao Dong
*
a Key Laboratory of Biological Resources Protection and Utilization of Hubei Province, Hubei University for Nationalities, Enshi 445000, China
b Medical School, Hubei University for Nationalities, Enshi 445000, China
Received 8 December 2011
Available online 29 March 2012
Abstract
A series of novel fluorinated thieno[2,3-d]pyrimidine derivatives incorporating 1,3,4-thiadiazole were synthesized by a facile
microwave-assisted procedure, including the cyclization of 2-aminothiophene-3-carbonitrile with trifluoroacetic acid, chlorination
and nucleophilic substitution reaction. This protocol offered such advantages as mild reaction conditions, short reaction time,
simple purification and good yields. The structures of the products were characterized by 1H NMR, MS, elemental analysis and X-
ray diffraction.
# 2012 Xin Jian Song. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Thieno[2,3-d]pyrimidine; 1,3,4-Thiadiazole; Trifluoromethyl; Microwave-assisted synthesis
Thieno[2,3-d]pyrimidines have attracted great attention from both synthetic and medicinal chemists due to a
multitude of interesting pharmacological properties [1–4] such as antibacterial, antitumor and anti-inflammatory
activities. 1,3,4-Thiadiazoles and their derivatives represent an important class of compounds possessing broad
biological activities [5–7], especially anticancer properties [8–10]. In general, strategically positioned fluorine
substituents, the trifluoromethyl group in particular, in heterocyclic compounds play a fundamental role in medicine
and agrochemicals because of their enhanced activities and decreased toxicities [11,12]. In addition, microwave (MW)
irradiation technique is well known to present the advantages of being efficient, rapid and eco-friendly compared with
the traditional heating methods [13]. These observations prompted us to pursue the synthesis of some novel
trifluoromethylthieno[2,3-d]pyrimidine derivatives incorporating 1,3,4-thiadiazole moiety under MW irradiation for
evaluating their antitumor activity. The title compounds 5a–j were prepared using the synthetic strategy outlined in
Scheme 1.
Thesynthesisbeganbyreactingaccessible2,5-dihydroxy-1,4-dithianewithmalonitriletodeliver2-aminothio-phene-
3-carbonitrile 1 according to the modified Gewald procedures [14]. The aminothiophene 1 was then refluxed with
trifluoroacetic acid (TFA) in the presence of phosphorus oxychloride to provide the key intermediate 2 under microwave
heating. It is worth mentioning that 2-trifluoromethyl-3H-thieno[2,3-d]-pyrimidin-4-one 2 was obtained efficiently by a
facile microwave-assisted one-pot procedure. However, the traditional conversion to 2-substituted-3H-thieno
* Corresponding author.
E-mail address: whxjsong@yahoo.com.cn (X.J. Song).
1001-8417/$ – see front matter # 2012 Xin Jian Song. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2012.02.007

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X.J. Song et al. / Chinese Chemical Letters 23 (2012) 549–552
O
Cl
CN
TFA, POCl3
POCl3
NH
CF3
N
MW, 70°C, 25 min
MW, 90°C, 18 min
NH2
S
S
S
CF3
N
N
2
3
1
N
N
Cl
S
Ar
S
N
N
N
CH3CN, NEt3
MW, 70°C, 5 min
N
+
Ar
SH
S
S
CF3
N
S
CF3
N
3
4 a-j
Scheme 1. Synthetic route of the title compounds 5a–j.
5 a-j
[2,3-d]pyrimidin-4-ones usually utilize multi-step procedures [15–17] which suffer from such disadvantages as rigorous
conditions, long reaction time, complex handling and poor total yields. Compound 2 was transformed by the action of
phosphorus oxychloride into 4-chlorothieno[2,3-d]pyrimidine 3 that was readily reacted with 1,3,4-thiadiazole-2-thiols
4a–j [18] underMWirradiation toafford the desiredproducts5a–j in good isolated yields(82–91%), as shownin Table 1.
The overall three-step synthesis including cyclization, chlorination and nucleophilic substitution reaction involved MW
irradiation which made the procedure rapid and efficient.
The structures of the newly synthesized compounds 5a–j [19] were confirmed by 1H NMR, mass spectroscopy and
elemental analysis. The 1H NMR spectra of 5 showed the thienyl protons emerged normally as a pair of doublets, each
appearing near d 8.42 and 7.90 with J = 6.0 Hz. However, their signals from one of the two protons in some products
were indecipherable because they overlapped with aryl hydrogens. The EI mass spectra gave the anticipated molecular
ion peaks and main fragmentation peaks, which were in accordance with the title structures. The structure of product
5g was further proved by the X-ray diffraction.
A colorless single crystal of compound 5g with dimensions of 0.34 mm  0.28 mm  0.23 mm was put on a
˚
BRUKER SMART APEX-CCD diffractometer equipped with a graphite-monochromated Mo Ka (l = 0.71073 A)
radiation at 293(2) K. The non-hydrogen atoms were refined anisotropically, and the hydrogen atoms were added
according to theoretical models. The structure was refined by full-matrix least-squares method on F2 with SHELXL-
97. The molecular structure of compound 5g is depicted in Fig. 1. The X-ray analysis revealed that the molecule of the
title compound 5g essentially assumes a planar conformation except for the F atoms and methyl H atoms. The
pharmacological evaluation and structure–activity relationships of the title compounds are underway.
Table 1
Physical and MS data for the title compounds 5a–j.
Entry
Compd.
Ar
Formula
m.p./8C
Yield/%
Appearance
EI-MS (m/z, M+)
1
2
5a
5b
5c
5d
5e
5f
C6H5
C15H7F3N4S3
C15H6F4N4S3
C15H6F4N4S3
C15H6F4N4S3
C16H9F3N4S3
C16H9F3N4S3
C16H9F3N4S3
C15H6F3N5O2S3
C15H6F3N5O2S3
C15H6F3N5O2S3
196–197
206–207
198–199
209–210
161–162
204–205
218–219
183–184
224–225
219–220
87
84
86
91
83
84
88
82
83
85
White crystal
White crystal
White crystal
White crystal
White crystal
White crystal
White crystal
Yellowish crystal
Yellowish crystal
Yellowish crystal
396
414
414
414
410
410
410
441
441
441
2-FC6H4
3
3-FC6H4
4
4-FC6H4
5
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
6
7
5g
5h
5i
8
9
10
5j

X.J. Song et al. / Chinese Chemical Letters 23 (2012) 549–552
551
Fig. 1. Molecular structure of 5g with the atomic labeling.
Acknowledgments
We are grateful for the Natural Science Foundation of Hubei Province (No. 2011CDB087), Scientific Research
Fund of Hubei Provincial Education Department (No. D20111904) and Open Fund of Key Laboratory of Biological
Resources Protection and Utilization of Hubei Province (No. PKLHB1102) for generous financial support.
References
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[19] General procedure for the synthesis of the title compounds (5a–j): a mixture of 2-aminothiophene-3-carbonitrile 1 (10 mmol), trifluoroacetic
acid (28 mL) and phosphorus oxychloride (2 mL) was irradiated at 70 8C for 25 min by microwave. The reaction mixture was allowed to cool to
room temperature, and then poured into ice water. The resulting precipitate was filtered, washed with cold water, and dried to give 2-
trifluoromethyl-3H-thieno[2,3-d]pyrimidin-4-one 2 in 81% yield. A mixture of 2 (10 mmol) and phosphorus oxychloride (8 mL) was irradiated
with microwave at 90 8C for 18 min. Thereafter, POCl3 was removed under vacuum and the residue obtained was poured onto ice-cold water
and neutralized with sodium bicarbonate. The solid was filtrated and recrystallized from n-hexane to afford 4-chloro-2-trifluoro-
methylthieno[2,3-d]-pyrimidine 3 in 73% yield as yellowish solid. m.p. 77–78 8C; 1H NMR (600 MHz, DMSO-d6): d 8.41 (d, 1H,
J = 6.0 Hz, Thienyl H), 7.77 (d, 1H, J = 6.0 Hz, Thienyl H); EI-MS (%): m/z 238 (M+, 100), 203 (68.3), 134 (25.0), 69 (66.8). A solution
of 3 (5 mmol) and the appropriate 1,3,4-thiadiazole-2-thiol 4 (5 mmol), triethylamine (0.5 mL) in dried acetonitrile (15 mL) was submitted to
microwave irradiation for 5 min at 70 8C. The reaction mixture was concentrated under reduced pressure and the solid was filtered off, washed

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X.J. Song et al. / Chinese Chemical Letters 23 (2012) 549–552
with water and recrystallized from ethanol-DMF to give compounds 5a–j. Analytical data of the representative compounds: 5a: 1H NMR
(600 MHz, DMSO-d6): d 8.42 (d, 1H, J = 6.0 Hz, Thienyl H), 7.90 (d, 1H, J = 6.0 Hz, Thienyl H), 8.02–7.62 (m, 5H, Ar-H); 13C NMR
(150 MHz, DMSO-d6): d 171.64, 166.96, 159.13, 155.98, 149.05, 148.77, 134.47, 132.35, 130.16, 129.43, 129.03, 128.06, 119.49; Anal. Calcd.
for C15H7F3N4S3: C 45.45, H 1.78, N 14.13; found: C 45.23, H 1.90, N 14.29. 5b: 1H NMR (600 MHz, DMSO-d6): d 8.42 (d, 1H, J = 6.0 Hz,
Thienyl H), 7.92 (d, 1H, J = 6.0 Hz, Thienyl H), 8.36–7.47 (m, 4H, Ar-H); Anal. Calcd. for C15H6F4N4S3: C 43.47, H 1.46, N 13.52; found: C
43.58, H 1.32, N 13.37. 5f: 1H NMR (600 MHz, DMSO-d6): d 8.42 (d, 1H, J = 6.0 Hz, Thienyl H), 7.91 (d, 1H, J = 6.0 Hz, Thienyl H), 7.86–
7.45 (m, 4H, Ar-H), 2.44 (s, 3H, CH3); Anal. Calcd. for C16H9F3N4S3: C 46.82, H 2.21, N 13.65; found: C 47.03, H 2.09, N 13.53. 5g: 1H NMR
(600 MHz, DMSO-d6): d 8.42 (d, 1H, J = 6.0 Hz, Thienyl H), 7.93–7.43 (m, 5H, Ar-H and Thienyl H), 2.41 (s, 3H, CH3); 13C NMR (150 MHz,
DMSO-d6): d 171.88, 167.01, 159.56, 155.47, 149.15, 148.80, 142.61, 134.49, 130.71, 129.08, 128.04, 126.73, 119.53, 21.54; Anal. Calcd. for
C16H9F3N4S3: C 46.82, H 2.21, N 13.65; found: C 46.94, H 2.07, N 13.82.