New route to 2-arylthieno[2,3-d]pyrimidin-4(3H)-ones and isolation of the unoxidized intermediates

Article abstract of DOI:10.1007/s00706-008-0032-3

A new route to the synthesis of 2-arylthieno[2,3-d]pyrimidin-4(3H)-ones has been developed through heterocyclization of 2-amino-4,5-dimethylthiophene-3- carboxamide with aromatic aldehydes in boiling glacial acetic acid followed by air oxidation. The unox

Full text of DOI:10.1007/s00706-008-0032-3

Monatsh Chem (2009) 140:355–358
DOI 10.1007/s00706-008-0032-3
ORIGINAL PAPER
New route to 2-arylthieno[2,3-d]pyrimidin-4(3H)-ones
and isolation of the unoxidized intermediates
Abolghasem Davoodnia Æ Mehdi Bakavoli Æ
Mehdi Soleimany Æ Niloofar Tavakoli-Hoseini
Received: 10 June 2008 / Accepted: 20 June 2008 / Published online: 17 September 2008
Ó Springer-Verlag 2008
Abstract A new route to the synthesis of 2-arylthieno[2,3-
d]pyrimidin-4(3H)-ones has been developed through
heterocyclization of 2-amino-4,5-dimethylthiophene-3-car-
boxamide with aromatic aldehydes in boiling glacial acetic
acid followed by air oxidation. The unoxidized intermedi-
ates, 2-aryl-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-ones,
are isolated when the reactions are carried out either at room
temperature or under a nitrogen atmosphere.
involves cyclocondensation of suitably functionalized
thiophenes with different electrophiles such as chloro-
formamidine [15], a-substituted acetonitriles [16], formic
acid [17], phosgene [18], ethyl chloroformate [18] and
guanidine [19]. To the best of our knowledge, heterocyc-
lization of 2-amino-4,5-dimethylthiophene-3-carboxamide
with aromatic aldehydes and isolation of the unoxidized
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 [20–27], as well as in continuation of our
works on the synthesis of thieno[2,3-d]pyrimidine deriva-
tives [28–30], we report herein a new route to the synthesis of
2-aryl-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-ones 3a–
3d through the heterocyclization of 2-amino-4,5-dimethyl-
thiophene-3-carboxamide 1 with aromatic aldehydes in
boiling glacial acetic acid followed by air oxidation. At room
temperature or under a nitrogen atmosphere, the unoxidized
intermediates, 2-aryl-2,3-dihydrothieno[2,3-d]pyrimidin-
4(1H)-ones 2a–2d, were isolated.
Keywords 2-Arylthieno[2,3-d]pyrimidin-4(3H)-ones Á
2-Aryl-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-ones Á
2-Amino-4,5-dimethylthiophene-3-carboxamide Á
Aromatic aldehydes Á Heterocyclization
Introduction
Thieno[2,3-d]pyrimidines are a large group of heterocycles
with diverse and interesting biological activities. These
compounds are reported to possess significant analgesic
[1, 2], fungicidal [3, 4], antiviral [5] and antiinflammatory
[6, 7, 9, 10] activities. Also, some thieno[2,3-d]pyrimidines
show the ability to depress the CNS [8] and are useful as
muscle relaxants [9, 10], sedatives [9, 10], diuretics
[11, 12], pesticides and herbicides [13, 14].
Results and discussion
Treatment of 2-amino-4,5-dimethylthiophene-3-carboxam-
ide 1 [31] with aromatic aldehydes in refluxing glacial acetic
acid gave products identified as 2-aryl-5,6-dimethylthieno
[2,3-d]pyrimidin-4(3H)-ones 3a–3d. Under these conditions,
attempts to isolate the intermediates 2-aryl-5,6-dimethyl-2,
3-dihydrothieno[2,3-d]pyrimidin-4(1H)-ones 2a–2d failed
when we carefully monitored the reaction, but these inter-
mediates were isolated when the reaction mixture was stirred
at room temperature (Scheme 1).
Various methods have already been proposed for the
synthesis of these compounds, and the most general ones
A. Davoodnia (&) Á M. Bakavoli Á M. Soleimany Á
N. Tavakoli-Hoseini
Department of Chemistry, School of Sciences,
Islamic Azad University, Mashhad Branch,
Mashhad 91735-413, Iran
The formation of the products 3a–3d was assumed to
proceed via the air oxidation of the intermediates 2a–2d,
e-mail: adavoodnia@yahoo.com
123

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A. Davoodnia et al.
Scheme 1
O
O
O
Me
Me
Me
NH2
NH
NH
Ar CHO
Air oxidation
Ar
Ar
N
N
Me
Me
NH2
Me
S
S
S
H
3a-3d
1
2a-2d
a: Ar = 4-MeC6H4
b: Ar = 4-ClC6H4
c: Ar = 4-BrC6H4
d: Ar = 4-HOC6H4
because when the same reaction mixture was refluxed
under a nitrogen atmosphere, the reaction did not proceed
to form compounds 3a–3d and the intermediates 2a–2d
were isolated. Finally, when these intermediates were
heated under reflux in glacial acetic acid, air oxidation
occurred and the products 3a–3d were obtained. It is
important to mention that if the glacial acetic acid is
replaced with another solvent system, such as ethanol
containing a few drops of sulfuric acid, similar results are
obtained.
4(3H)-ones 3a–3d via heterocyclization of 2-amino-
4,5-dimethylthiophene-3-carboxamide 1 with aromatic
aldehydes in boiling glacial acetic acid followed by air
oxidation. The intermediates, 2-aryl-5,6-dimethyl-2,3-
dihydrothieno[2,3-d]pyrimidin-4(1H)-ones 2a–2d, were
isolated when the reactions were carried out either at room
temperature or under a nitrogen atmosphere.
Experimental
The structures of the new products (2a–2d and 3d) were
established from their spectral and microanalytical data and
for known compounds (3a–3c) by comparison with
authentic samples. For example, the IR spectrum of com-
pound 2a was devoid of the two NH2 absorption bands at
t = 3363, 3305, 3250 and 3152 cm-1 of the precursor, but
instead showed new absorption bands at t = 3412 and
Melting points were recorded on an Electrothermal
(Rochford, UK) type 9100 melting point apparatus. The IR
spectra were obtained on a 4300 Shimadzu (Kyoto, Japan)
spectrophotometer as KBr disks. The 1H NMR (100 MHz)
spectra were recorded on a Bruker (Rheinstetten, Germany)
AC 100 spectrometer. The mass spectra were determined
on a Shimadzu GCMS 17A instrument. Elemental analysis
was performed on a Thermo Finnigan (San Jose, CA, USA)
Flash EA microanalyzer, and the results were found to
agree satisfactorily with the calculated values (Table 2).
1
3291 cm-1 for two NH groups. The H NMR spectrum in
DMSO-d6 showed three singlets at d = 2.15, 2.30 and
2.36 ppm for methyl groups, a singlet at d = 8.44 ppm
belonging to the CH proton of the pyrimidine ring, two
single broad bands at d = 7.42 and 7.93 ppm for two NH
groups, along with two doublets for four aromatic protons
at d = 7.22 and 7.82 ppm. The MS of 2a showed a
molecular ion peak at m/z = 272 (M?) corresponding to
the molecular formula C15H16N2OS (Table 1).
General procedure for the synthesis of 2-aryl-5,
6-dimethylthieno[2,3-d]pyrimidin-4(3H)-ones 3a–3d
Method A. 4 mmol of the appropriate aromatic aldehyde
was added to a solution of 3 mmol 2-amino-4,5-dimeth-
ylthiophene-3-carboxamide 1 in 30 cm3 boiling glacial
In conclusion, we have described a new route to the
synthesis of 2-aryl-5,6-dimethylthieno[2,3-d]pyrimidin-
Table 1 Times, yields and melting points for the synthesized compounds 2a–2d and 3a–3d
Entry
Product
Ar
Method A
Method B
mp (°C)
Time (min)
Yield (%)
Time (min)
Yield (%)
Found
Reported [30]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
3a
3b
3c
3d
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-HOC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-HOC6H4
50
35
85
90
87
94
83
90
85
90
40
30
87
92
85
92
90
92
88
96
179–180
192–193
189–190
247–249
314–316
339–340
341–343
363–365
–
–
45
40
–
30
30
–
200
120
180
100
170
100
140
70
314–316
338–340
342–344
–
123

New route to 2-arylthieno[2,3-d]pyrimidin-4(3H)-ones and isolation of the unoxidized intermediates
357
Table 2 Microanalytical data for the new synthesized compounds 2a–2d and 3d
Entry
Formula
Calculated
C (%)
Found
C (%)
H (%)
N (%)
S (%)
H (%)
N (%)
S (%)
2a
2b
2c
2d
3d
C15H16N2OS
66.15
57.43
49.86
61.29
61.75
5.92
4.48
3.89
5.14
4.44
10.29
9.57
11.77
10.95
9.51
66.32
57.69
49.57
61.44
61.53
6.11
4.27
4.02
5.27
4.63
10.07
9.31
11.54
11.14
9.68
C
C
C
C
14H13ClN2OS
14H13BrN2OS
14H14N2O2S
14H12N2O2S
8.31
8.09
10.21
10.29
11.69
11.77
9.94
11.43
11.58
10.08
acetic acid. The reaction mixture was heated under reflux
for the indicated time. After the completion of the reaction
(monitored by TLC, CHCl3:MeOH, 93:7), the mixture was
cooled to room temperature and subsequently neutralized
by 10% NaOH solution. The crude product was collected
and recrystallized from EtOH/DMF to give compounds 3a–
3d in high yields (Table 1).
aromatic aldehyde in 30 cm3 glacial acetic acid was stirred at
room temperature for the indicated time. After the comple-
tion of the reaction (monitored by TLC, CHCl3:MeOH,
95:5), the mixture was neutralized by 10% NaOH solution.
The crude product was collected and recrystallized from
ethanol to give compounds 2a–2d in high yields (Table 1).
Method B. A mixture of 2 mmol 2-amino-4,5-dim-
ethylthiophene-3-carboxamide 1 and 3 mmol of the app-
ropriate aromatic aldehyde in 20 cm3 glacial acetic acid
was refluxed under a nitrogen atmosphere for the indicated
time. After the completion of the reaction (monitored by
TLC, CHCl3:MeOH, 95:5), the mixture was cooled to room
temperature and subsequently neutralized by 10% NaOH
solution. The crude product was collected and recrystal-
lized from ethanol to give compounds 2a–2d in high yields
(Table 1).
Method B. A mixture of 1 mmol 2-aryl-5,6-dimethyl-
2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-ones 2a–2d and
20 cm3 glacial acetic acid was heated under reflux for the
indicated time. After the completion of the reaction
(monitored by TLC, CHCl3:MeOH, 93:7), the mixture was
neutralized by 10% NaOH solution. The crude product was
collected and recrystallized from EtOH/DMF to give
compounds 3a–3d in high yields (Table 1).
5,6-Dimethyl-2-(4-methylphenyl)thieno[2,3-d]pyrimidin-
4(3H)-one (3a)
5,6-Dimethyl-2-(4-methylphenyl)-2,3-dihydrothieno
[2,3-d]pyrimidin-4(1H)-one (2a, C15H16N2OS)
Mp 314–316 °C ([30] 314–316 °C)
Mp 179–180 °C; 1H NMR (100 MHz, DMSO-d6):
d = 2.15 (s, CH3), 2.30 (s, CH3), 2.36 (s, CH3), 7.22–
7.82 (dd, 4H-aromatic ring H), 7.42 (br s, NH), 7.93 (br s,
NH), 8.44 (s, 1H, CH-2) ppm; IR (KBr): t 1645 (CO),
3291, 3412 (two NH) cm-1; MS: m/z (%) = 272 [M?]
(89), 255 (67), 226 (20), 212 (47), 194 (14), 181 (14), 168
(9), 153 (100), 138 (42), 120 (47), 105 (56), 91 (98), 77
(64), 65 (92), 59 (97), 43 (64).
2-(4-Chlorophenyl)-5,6-dimethylthieno[2,3-d]pyrimidin-
4(3H)-one (3b)
Mp 339–340 °C ([30] 338–340 °C)
2-(4-Bromophenyl)-5,6-dimethylthieno[2,3-d]pyrimidin-
4(3H)-one (3c)
Mp 341–343 °C ([30] 342–344 °C)
2-(4-Hydroxyphenyl)-5,6-dimethylthieno[2,3-d]pyrimidin-
4(3H)-one (3d, C14H12N2O2S)
2-(4-Chlorophenyl)-5,6-dimethyl-2,3-dihydrothieno
Mp 363–365 °C; 1H NMR (100 MHz, DMSO-d6):
d = 2.33 (s, CH3), 2.38 (s, CH3), 6.75–8.10 (dd, 4H-
aromatic ring H), 10.19 (br s, OH), 12.25 (br s, NH); IR
(KBr): t 1658 (CO), 2750–3250 (OH and NH) cm-1; MS:
m/z (%) = 272 [M?] (17), 255 (31), 225 (15), 168 (18),
153 (48), 138 (22), 120 (33), 104 (38), 82 (56), 63 (41), 43
(100).
[2,3-d]pyrimidin-4(1H)-one (2b, C14H13ClN2OS)
Mp 192–193 °C; 1H NMR (100 MHz, DMSO-d6):
d = 2.13 (s, CH3), 2.33 (s, CH3), 7.50 (br s, NH), 7.52–
8.00 (dd, 4H-aromatic ring H), 7.83 (br s, NH), 8.49 (s, 1H,
CH-2) ppm; IR (KBr): t 1643 (CO), 3327, 3413 (two
NH) cm-1; MS: m/s (%) = 294 [M? ? 2] (8), 292 [M?]
(23), 277 (9), 275 (26), 248 (4), 246 (11), 234 (5), 232 (14),
214 (7), 212 (20), 188 (7), 153 (45), 139 (46), 138 (49), 115
(33), 113 (11), 111 (32), 89 (60), 59 (90), 43 (100).
General procedure for the synthesis of 2-aryl-5,
6-dimethyl-2,3-dihydrothieno[2,3-d]pyrimidin-4
(1H)-ones 2a–2d
2-(4-Bromophenyl)-5,6-dimethyl-2,3-dihydrothieno
[2,3-d]pyrimidin-4(1H)-one (2c, C14H13BrN2OS)
Mp 189–190 °C; 1H NMR (100 MHz, DMSO-d6): d = 2.13
(s, CH3), 2.32 (s, CH3), 7.48 (br s, NH), 7.55-7.95
Method A. A mixture of 3 mmol 2-amino-4,5-dimethylthi-
ophene-3-carboxamide 1 and 4 mmol of the appropriate
123

358
A. Davoodnia et al.
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(5H-aromatic ring H and NH), 8.46 (s, 1H, CH-2) ppm; IR
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(%) = 338 [M? ? 2] (33), 336 [M?] (34), 321 (91), 319
(92), 294 (10), 292 (11), 278 (7), 276 (8), 258 (17), 256 (18),
232 (21), 183 (24), 157 (31), 155 (31), 153 (100), 138 (48),
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2-(4-Hydroxyphenyl)-5,6-dimethyl-2,3-dihydrothieno
[2,3-d]pyrimidin-4(1H)-one (2d, C14H14N2O2S)
Mp 247–249 °C; 1H NMR (100 MHz, DMSO-d6):
d = 2.17 (s, CH3), 2.30 (s, CH3), 6.75–7.85 (dd, 4H-
aromatic ring H), 7.40 (br s, NH), 8.03 (br s, NH), 8.39 (s,
1H, CH-2), 10.32 (br s, OH) ppm; IR (KBr): t 1651 (CO),
2800–3300, 3399 (OH and two NH) cm-1; MS: m/z
(%) = 274 [M?] (10), 272 (23), 257 (21), 255 (20), 228
(10), 170 (12), 153 (35), 138 (15), 121 (24), 105 (29), 97
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