Synthesis of some new 2-arylthieno[2,3-d]pyrimidin-4(3H)-one derivatives

Article abstract of DOI:10.3184/030823408X283685

Some new derivatives of 2-arylthieno[2,3-d]pyrimidin-4(3H)-ones have been prepared through a condensation reaction of 2-amino-4,5-dimethylthiophene-3- carboxamide with aroyl halides in boiling pyridine followed by cyclisation with 10% NaOH.

Full text of DOI:10.3184/030823408X283685

JOURNAL OF CHEMICAL RESEARCH 2008
JANUARY, 1–2
RESEARCH PAPER
1
Synthesis of some new 2-arylthieno[2,3-d]pyrimidin-4(3h)-one derivatives
Abolghasem Davoodnia*, Hossein Eshghi, Akram Salavaty and Niloofar Tavakoli-Hoseini
Department of Chemistry, School of Sciences, Islamic Azad University, Mashhad Branch, Mashhad 91735-413, Iran
Some new derivatives of 2-arylthieno[2,3-d]pyrimidin-4(3H)-ones have been prepared through a condensation
reaction of 2-amino-4,5-dimethylthiophene-3-carboxamide with aroyl halides in boiling pyridine followed by
cyclisation with 10% NaOH.
Keywords: 2-amino-4,5-dimethylthiophene-3-carboxamide, aroyl halides, condensation, cyclisation, thieno[2,3-d]pyrimidin-
4(3H)-ones
Thieno[2,3-d]pyrimidines are a class of fused heterocycles
some of which have interesting biological activities.
These compounds are reported to possess significant
analgesic,1,2 antiviral,3 fungicidal4 and antiinflammatory5,6,9
activities. Furthermore, a number of these compounds were
found to exhibit CNS depressing7 and DHFR inhibitory
activities8 and are useful as muscle relaxants,9 sedatives,9
diuretics,10 pesticides and herbicides.11
2-substitutedbenzamido-4,5-dimethylthiophene-3-carboxamides
2a–e as the result of a nucleophilic attack of the amino
group in 2-position of thiophene at the carbonyl group of
aroyl halides. Since the IR spectra have not shown the imido
group for compounds 4a–e at around 1700 cm-1 and the fact
that the amino group is more reactive than the amido group
as nucleophile, we believe that the compounds 4a–e have not
been formed (Scheme 1).
Various methods for the synthesis of these compounds
have been reported in the literature that mainly involve
cyclocondensation of suitably functionalised thiophenes
with different electrophiles such as chloroformamidine,8
α-substituted acetonitriles,12 formic acid,13 phosgen,14 ethyl
chloroformate,14 guanidine15 and nitriles.16 To the best of our
knowledge, reaction of 2-amino-4,5-dimethylthiophene-3-
carboxamide 1 with aroyl halides and isolation of intermediates
has not been reported in the literature.
Prompted by these findings and due to our interest in the
synthesis of new heterocyclic compounds with potential
biological activities,17-22 and in continuation of our work on
the synthesis of new thieno[2,3-d]pyrimidine derivatives,23,24
we report here a convenient synthesis of some new 2-aryl-5,6-
dimethylthieno[2,3-d]pyrimidin-4(3H)-ones 3a–e that might
be of pharmacological importance.
When compounds 2a–e were heated under reflux for 7 hours
with 10% NaOH, cyclisation reaction occurred and the cyclic
products 3a–e were obtained. The structural assignment of all
compounds 2–3 was based upon spectral and microanalytical
data (see Experimental). For example, the 1H NMR spectrum
of 3a was devoid of the NH2 and NH signals of the precursor
2a at d 7.50 and 12.73 ppm respectively, but instead showed a
broad 1H signal at d 12.96 ppm for NH proton as well as the
characteristic signals for aromatic protons at δ 7.2–8.4 ppm.
The IR spectrum did not show the stretching vibration bands
at 3416, 3323, and 3203 cm-1 for NH and NH2 absorptions of
the precursor, but instead showed a new absorption band at
3097 cm-1 for NH group. The MS of 3a showed a molecular
ion peak at m/z 256 (M+) corresponding to the molecular
formula C14H12N2OS.
In conclusion, condensation of 2-amino-4,5-dimethyl-
thiophene-3-carboxamide 1 with aroyl halides in refluxing
pyridine gave the corresponding 2-substitutedbenzamido-4,5-
dimethylthiophene-3-carboxamides 2a–e that subsequently
were cyclised with 10% NaOH under reflux to give the cyclic
products 3a–e.
Results and discussion
When 2-amino-4,5-dimethylthiophene-3-carboxamide 125
was allowed to interact with aroyl halides in refluxing
pyridine, condensation reaction occurred giving the
O
O
Me
Me
NH2
NH
10% NaOH
Ar
N
Me
NH
Me
S
S
O
Ar
Me
NH2
O
ArCOCl
Pyridine
2a-e
3a-e
Me
NH2
S
O
O
Ar
1
Me
NH
Me
NH2
a, Ar = Ph
S
b, Ar = 2-ClC6H4
c, Ar = 4-ClC6H4
d, Ar = 4-MeC6H4
e, Ar = 4-BrC6H4
4a-e
Scheme 1
* Correspondent. E-mail: adavoodnia@yahoo.com
PAPER: 07/4954

2
JOURNAL OF CHEMICAL RESEARCH 2008
2-(2-Chlorophenyl)-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-
one (3b): White crystals (0.22 g, 76%), m.p. 300–303°С. FT IR (KBr,
Experimental
Melting points were recorded on an electrothermal type 9100
melting point apparatus. The IR spectra were obtained on a 4300
Shimadzu spectrophotometer as KBr disks. The 1H NMR (100 MHz)
spectra were recorded on a Bruker AC 100 spectrometer. The mass
spectra were determined on a Shimadzu GCMS 17A instrument.
Elemental analysis was performed on a Thermo Finnigan Flash EA
microanalyser.
1
υmax/cm-1): 3065 (NH), 1665 (C=O). H NMR ([2H6]DMSO, TMS):
d 2.37 (s, 3H, Me), 2.42 (s, 3H, Me), 7.4–7.7 (m, 4H, aromatic ring
H), 12.62 (br s, 1H, NH). MS: m/z 292 (M+ + 2, 26), 290 (M+, 76),
277 (17), 275 (50), 153 (19), 138 (37), 102 (50), 59 (41), 44 (24),
28 (100). Found: C, 57.97; H, 3.62; N, 9.44; S, 11.21. Calc. for
C14H11ClN2OS (290.77): C, 57.83; H, 3.81; N, 9.63; S, 11.03%.
2-(4-Chlorophenyl)-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-
one (3c): White crystals (0.25 g, 84%), m.p. 338–340°С. FT IR (KBr,
General procedure for the synthesis of 2-substitutedbenzamido-4,5-
dimethylthiophene-3-carboxamides (2a–e)
1
υmax/cm-1): 3060 (NH), 1661 (C=O). H NMR ([2H6]DMSO, TMS):
d 2.34 (s, 3H, Me), 2.40 (s, 3H, Me), 7.2–8.1 (dd, 4H, aromatic ring
H), 12.75 (broad, 1H, NH). MS: m/z 292 (M+ + 2, 34), 290 (M+,
100), 277 (27), 275 (79), 154 (31), 138 (42), 101 (48), 58 (46), 44
(37), 28 (89). Found: C, 58.05; H, 3.95; N, 9.49; S, 11.16. Calc. for
C14H11ClN2OS (290.77): C, 57.83; H, 3.81; N, 9.63; S, 11.03%.
5,6-Dimethyl-2-(4-methylphenyl)thieno[2,3-d]pyrimidin-4(3H)-
one (3d): White crystals (0.22 g, 82%), m.p. 314–316°С. FT IR (KBr,
To a solution of 2-amino-4,5-dimethylthiophene-3-carboxamide 1
(3 mmol) in boiling pyridine (30 ml), the appropriate aroyl halid
(3 mmol) was added. The reaction mixture was heated under reflux
for 8 hours. After the completion of the reaction (monitored by TLC,
CHCl3:MeOH, 93:7), the solvent was evaporated in vacuo. The residue
was recrystallised from ethanol/water to give compounds 2a–e.
2-Benzamido-4,5-dimethylthiophene-3-carboxamide (2a): White
crystals (0.66 g, 80%), m.p. 216–218°С. FT IR (KBr, υmax/cm-1):
3416, 3323, and 3203 (NH and NH2), 1651 (two C=O stretching
and NH2 bending). 1H NMR ([2H6]DMSO, TMS): d 2.23 (s, 6H,
2Me), 7.50 (br s, 2H, NH2), 7.6-8.0 (m, 5H, phenyl), 12.73 (s, 1H,
NH). MS: m/z 274 (M+, 40), 257 (48), 155 (43), 105 (100), 77 (98),
44 (52), 28 (96). Found: C, 61.07; H, 5.31; N, 10.03; S, 11.56. Calc.
for C14H14N2O2S (274): C, 61.29; H, 5.14; N, 10.21; S, 11.69%.
2-(2-Chlorobenzamido)-4,5-dimethylthiophene-3-carboxamide
(2b): Brown crystals (0.63 g, 68%), m.p. 221–223°С. FT IR
(KBr, υmax/cm-1): 3427, 3309, and 3205 (NH and NH2), 1657
(two C=O stretching and NH2 bending). 1H NMR ([2H6]DMSO,
TMS): d 2.31 (s, 6H, 2Me), 7.4–7.9 (m, 6H, aromatic ring H and
NH2), 12.68 (s, 1H, NH). MS: m/z 310 (M+ + 2, 12), 308 (M+, 36),
293 (17), 291 (51), 155 (52), 141 (33), 139 (100), 113 (30), 111 (90),
44 (38), 28 (86). Found: C, 54.24; H, 4.09; N, 9.28; S, 10.55. Calc.
for C14H13ClN2O2S (308.78): C, 54.46; H, 4.24; N, 9.07; S, 10.38%.
2-(4-Chlorobenzamido)-4,5-dimethylthiophene-3-carboxamide
(2c): Brown crystals (0.65 g, 70%), m.p. 235–238°С. FT IR (KBr,
υmax/cm-1): 3476, 3316, and 3171 (NH and NH2), 1640 (two C=O
1
υmax/cm-1): 3060 (NH), 1655 (C=O). H NMR ([2H6]DMSO, TMS):
d 2.33 (s, 6H, 2Me), 2.38 (s, 3H, Me), 7.2-8.15 (dd, 4H, aromatic
ring H), 12.40 (br s, 1H, NH). MS: m/z 270 (M+, 64), 255 (100), 154
(31), 138 (55), 102 (57), 91 (96), 57 (37), 44 (41), 28 (73).Found:
C, 66.47; H, 5.39; N, 10.58; S, 11.74. Calc. for C15H14N2OS (270):
C, 66.64; H, 5.22; N, 10.36; S, 11.86%.
2-(4-Bromophenyl)-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-
one (3e): White crystals (0.26 g, 78%), m.p. 342–344°С. FT IR (KBr,
1
υmax/cm-1): 3063 (NH), 1656 (C=O). H NMR ([2H6]DMSO, TMS):
d 2.40 (s, 6H, 2Me), 7.6–8.2 (dd, 4H, aromatic ring H), 12.55 (br s,
1H, NH). MS: m/z 336 (M+ + 2, 75), 334 (M+, 76), 321 (98), 319
(100), 153 (21), 138 (35), 102 (49), 59 (51), 44 (38), 28 (72). Found:
C, 50.03; H, 3.19; N, 8.17; S, 9.76. Calc. for C14H11BrN2OS (335):
C, 50.16; H, 3.31; N, 8.36; S, 9.57%.
Received 20 November 2007; accepted 16 January 2008
Paper 07/4954
doi: 10.3184/030823408X283685
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1
(s, 6H, 2Me), 7.52 (br s, 2H, NH2), 7.6–7.95 (dd, 4H, aromatic ring
H), 12.70 (s, 1H, NH). MS: m/z 310 (M+ + 2, 11), 308 (M+, 32), 294
(16), 292 (47), 155 (61), 141 (33), 139 (100), 113 (25), 111 (73), 44
(51), 28 (74). Found: C, 54.63; H, 4.43; N, 8.89; S, 10.49. Calc. for
C14H13ClN2O2S (308.78): C, 54.46; H, 4.24; N, 9.07; S, 10.38%.
4,5-Dimethyl-2-(4-methylbenzamido)thiophene-3-carboxamide
(2d): Brown crystals (0.63 g, 73%), m.p. 233–235°С. FT IR (KBr,
υmax/cm-1): 3459, 3305, and 3180 (NH and NH2), 1637 (two C=O
4
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1
6
7
(s, 6H, 2Me), 2.46 (s, 3H, Me), 7.3–7.9 (m, 6H, aromatic ring H and
NH2),12.75 (s, 1H, NH). MS: m/z 288 (M+, 38), 271 (41), 155 (36),
119 (94), 91 (100), 44 (61), 28 (78). Found: C, 62.31; H, 5.36; N,
9.92; S, 11.25. Calc. for C15H16N2O2S (288): C, 62.48; H, 5.59; N,
9.71; S, 11.12%.
8
9
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2-(4-Bromobenzamido)-4,5-dimethylthiophene-3-carboxamide
(2e): Brown crystals (0.82 g, 78%), m.p. 244–246°С. FT IR (KBr,
υmax/cm-1): 3479, 3316, and 3179 (NH and NH2), 1641 (two C=O
stretching and NH2 bending). H NMR ([2H6]DMSO, TMS): d 2.25
1
(s, 6H, 2Me), 7.48 (br s, 2H, NH2), 7.6–7.90 (dd, 4H, aromatic
ring H), 12.72 (s, 1H, NH). MS: m/z 354 (M+ + 2, 41), 352
(M+, 42), 338 (58), 336 (59), 185 (98), 183 (100), 157 (53), 155 (78),
44 (38), 28 (72). Found: C, 47.46; H, 3.89; N, 8.11; S, 8.91. Calc. for
C14H13BrN2O2S (353): C, 47.60; H, 3.71; N, 7.93; S, 9.08%.
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A
mixture of 2-substitutedbenzamido-4,5-dimethylthiophene-3-
carboxamides 2a–e (1 mmol) in 10% NaOH solution (20 ml) was
heated under reflux for 7 hours. After the completion of the reaction
(monitored by TLC, CHCl3:MeOH, 93:7), the mixture was cooled to
room temperature. The precipitate was collected and recrystallised
from ethanol to give compounds 3a–e.
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5,6-Dimethyl-2-phenylthieno[2,3-d]pyrimidin-4(3H)-one
(3a):
White crystals (0.22 g, 86%), m.p. 293–295°С(Lit25 290°С). FT IR
1
(KBr, υmax/cm-1): 3097 (NH), 1660 (C=O). H NMR ([2H6]DMSO,
TMS): d 2.26 (s, 3H, Me), 2.39 (s, 3H, Me), 7.2–8.4 (m, 5H, phenyl),
12.96 (broad, 1H, NH). MS: m/z 256 (M+, 84), 241 (100), 154 (23),
138 (47), 101 (41), 58 (33), 44 (54), 28 (85). Found: C, 65.42; H,
4.53; N, 11.09; S, 12.36. Calc. for C14H12N2OS (256): C, 65.60; H,
4.72; N, 10.93; S, 12.51%.
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PAPER: 07/4954