Isolation of intermediates in the synthesis of thieno[2,3-d]pyrimidine-2, 4(1H,3H)-diones using microwave irradiation

Article abstract of DOI:10.1080/10426500802048573

A simple and fast method for the isolation of intermediates in the synthesis of 3-arylthieno[2,3-d]pyrimidine-2,4(1H,3H)-diones has been developed by microwave-assisted condensation of ethyl 2-amino-4,5-dimethylthiophene-3- carboxylate with aryl isocyanat

Full text of DOI:10.1080/10426500802048573

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Isolation of Intermediates in
the Synthesis of Thieno[2,3-
d]pyrimidine-2,4(1H,3H)-
diones Using Microwave
Irradiation
A. Davoodnia a , A. Zare-Bidaki a & H. Eshghi b
a Department of Chemistry, School of Sciences ,
Islamic Azad University , Mashhad Branch, Mashhad,
Iran
b Department of Chemistry, School of Sciences ,
Ferdowsi University of Mashhad , Mashhad, Iran
Published online: 03 Nov 2008.
To cite this article: A. Davoodnia , A. Zare-Bidaki & H. Eshghi (2008) Isolation of
Intermediates in the Synthesis of Thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones Using
Microwave Irradiation, Phosphorus, Sulfur, and Silicon and the Related Elements,
183:12, 2968-2973, DOI: 10.1080/10426500802048573
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Phosphorus, Sulfur, and Silicon, 183:2968–2973, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802048573
Isolation of Intermediates in the Synthesis of
Thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones Using
Microwave Irradiation
A. Davoodnia,1 A. Zare-Bidaki,1 and H. Eshghi2
1Department of Chemistry, School of Sciences, Islamic Azad University,
Mashhad Branch, Mashhad, Iran
2Department of Chemistry, School of Sciences, Ferdowsi University of
Mashhad, Mashhad, Iran
A simple and fast method for the isolation of intermediates in the synthesis of 3-
arylthieno[2,3-d]pyrimidine-2,4(1H,3H)-diones has been developed by microwave-
assisted condensation of ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate with
aryl isocyanates. The intermediates, subsequently, underwent cyclization in t-
butanol in the presence of potassium t-butoxide on heating to reflux to give the
desired bicyclic products, 3-arylthieno[2,3-d]pyrimidine-2,4(1H,3H)-diones.
Keywords Aryl isocyanates; condensation; ethyl 2-amino-4,5-dimethyl thiophene-3-
carboxylate; microwave irradiation; thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones
INTRODUCTION
Our interest in thieno[2,3-d]pyrimidine synthesis emerges from the
numerous reports on their diverse biological activities.1−10 In connec-
tion with our interest in the synthesis of new heterocyclic compounds
with potential biological activities,11−18 we have recently reported a
convenient one-pot synthesis of new 3-arylthieno[2,3-d]pyrimidine-
2,4(1H,3H)-diones 3a–e via cyclocondensation of ethyl 2-amino-4,5-
dimethylthiophene-3-carboxylate 1 with aryl isocyanates in the pres-
ence of potassium t-butoxide in t-butanol under reflux.19 Attempts
to isolate the reaction intermediates 2a–e failed when we monitored
the reactions under careful observation. Due to our interest in the
utilization of microwave irradiation for the synthesis of heterocyclic
compounds,20−24 we tried to extend this non-conventional synthetic
Received 23 January 2008; accepted 12 March 2008.
Address correspondence to A. Davoodnia, Department of Chemistry, School of Sci-
ences, Islamic Azad University, Mashhad Branch, Mashhad 91735-413, Iran. E-mail:
adavoodnia@yahoo.com
2968

Isolation of Intermediates Using Microwave Irradiation
2969
O
Ar
H3C
H3C
CO2Et
CO2Et
H3C
t-BuOH
t-BuOK
N
ArNCO
MW
O
NH
O
NH2
N
H
H3C
H3C
H3C
S
S
S
NHAr
1
2a-e
3a-e
a: Ar= Ph
b: Ar= 4-MeC6H4
c: Ar= 3-MeC6H4
d: Ar= 3-ClC6H4
e: Ar= 3,4-Cl2C6H3
SCHEME 1
method for the synthesis of 3-arylthieno[2,3-d]pyrimidine-2,4(1H,3H)-
diones 3a–e.
RESULTS AND DISCUSSION
Ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate 125 was allowed to
interact with aryl isocyanates under microwave irradiation in solvent-
free conditions at 700 w. During monitoring of the reaction mixture
by TLC (CHCl3:MeOH, 95:5), surprisingly, we observed that unex-
pected products, with different Rf ’s of those expected for compounds
3a–e, were forming. During work up and identification, it was es-
tablished that a condensation and not a cyclocondensation reaction
had occurred and the intermediates ethyl 2-[(arylcarbamoyl)amino]-
4,5-dimethylthiophene-3-carboxylates 2a–e were isolated. The reaction
did not proceed to form cyclic products even after prolonged irradiation
(Scheme 1).
The structure of new compounds 2a–e were established from their
spectral and microanalytical data. For example, the1H NMR spectrum
of 2a showed the disappearance of a broad signal belonging to NH2 moi-
ety of the precursor 1 at δ 5.61 ppm and the appearance of two sharp
signals for NH groups at δ 10.04 and 10.50 ppm, which was removed
on deuteration, along with a multiplet at δ 6.90–7.50 ppm for phenyl
protons. The IR spectrum showed the absorption bands at 3336, 3274,
1701, and 1654 cm−1 for two NH and two carbonyl groups respectively.
The MS of 2a showed a molecular ion peak at m/z 318 (M+) correspond-
ing to the molecular formula C16H18N2O3S. Also this compound gave
satisfactory elemental analysis data (Experimental section).
When the intermediates 2a–e were heated under reflux for 1 h in
the presence of potassium t-butoxide in t-butanol, cyclization reaction

2970
A. Davoodnia et al.
occurred, and the cyclic products 3a–e were obtained (Scheme 1). The
structure of these compounds were established by comparison with
authentic samples.19
In conclusion, we have developed a facile method for isolation
of intermediates in the synthesis of 3-arylthieno[2,3-d]pyrimidine-
2,4(1H,3H)-diones using microwave assisted condensation of ethyl 2-
amino-4,5-dimethylthiophene-3-carboxylate with aryl isocyanates.
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 microanalyzer.
General Procedure for the Preparation of Ethyl 2-
[(Arylcarbamoyl) amino]-4,5-dimethylthiophene-3-
carboxylates 2a–e
A mixture of ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate 1 (3
mmol) and the appropriate aryl isocyanate (4 mmol) was subjected to
microwave irradiation at 700 w for 3 min. After this time, the crude
product was collected, washed with n-hexane and recrystallized from
ethanol to give compounds 2a–e in 80–92% yields.
Ethyl 4,5-Dimethyl-2-[(phenylcarbamoyl)amino]
thiophene-3-carboxylate (2a)
1
Yield 90%; M.p. 153–154◦C; H NMR (d6-DMSO): δ 1.25 (t, 3H, J =
7Hz, CH3), 2.10 (s, 6H, 2CH3), 4.22 (q, 2H, J = 7Hz, CH2), 6.90–7.50
(m, 5H, Phenyl), 10.04 (s, 1H, NH), 10.50 (s, 1H, NH); FTIR (KBr disk):
ν 3336, 3274 (two NH), 1701, 1654 cm−1 (two C=O); MS, m/z: 318 (M+);
anal. calcd. for C16H18N2O3S: C, 60.36; H, 5.70; N, 8.80; S, 10.07%.
Found: C, 60.69; H, 5.47; N, 8.61; S, 10.25%.
Ethyl 4,5-Dimethyl-2-[(4-methylphenyl)carbamoyl]amino
thiophene-3-carboxylate (2b)
Yield 87%; M.p. 178–180◦Ñ; 1H NMR (d6-DMSO): δ 1.30 (t, 3H, J =
7Hz, CH3), 2.15 (s, 6H, 2CH3), 2.23 (s, 3H, CH3), 4.21 (q, 2H, J = 7Hz,
CH2), 7.00–7.50 (dd, 4H, arom-H), 10.08 (s, 1H, NH), 10.60 (s, 1H, NH);

Isolation of Intermediates Using Microwave Irradiation
2971
FTIR (KBr disk): ν 3326, 3265 (two NH), 1695, 1656 cm−1 (two C=O);
MS, m/z: 332 (M+); anal. calcd. for C17H20N2O3S: C, 61.42; H, 6.06; N,
8.43; S, 9.65%. Found: C, 61.76; H, 6.19; N, 8.21; S, 9.46%.
Ethyl 4,5-dimethyl-2-[(3-methylphenyl)carbamoyl]amino
thiophene-3- carboxylate (2c)
1
Yield 82%; M.p. 159–160◦C; H NMR (d6-DMSO): δ 1.31 (t, 3H, J =
7Hz, CH3), 2.18 (s, 6H, 2CH3), 2.27 (s, 3H, CH3), 4.23 (q, 2H, J = 7Hz,
CH2), 6.75–7.40 (m, 4H, arom-H), 10.09 (s, 1H, NH), 10.59 (s, 1H, NH);
FTIR (KBr disk): ν 3330, 3279 (two NH), 1700, 1656 cm−1 (two C=O);
MS, m/z: 332 (M+); anal. calcd. for C17H20N2O3S: C, 61.42; H, 6.06; N,
8.43; S, 9.65%. Found: C, 61.23; H, 6.14; N, 8.64; S, 9.51%.
Ethyl 2-[(3-Chlorophenyl)carbamoyl]amino-
4,5-dimethylthiophene-3-carboxylate (2d)
1
Yield 92%; M.p. 172–174◦C; H NMR (d6-DMSO): δ 1.35 (t, 3H, J =
7Hz, CH3), 2.17 (s, 6H, 2CH3), 4.30 (q, 2H, J = 7Hz, CH2), 7.00–7.80 (m,
4H, arom-H), 10.40 (s, 1H, NH), 10.65 (s, 1H, NH); FTIR (KBr disk): ν
3345, 3241 (two NH), 1698, 1657 cm−1 (two C=O); MS, m/z: 352 (M+),
354 (M+2); anal. calcd. for C16H17ClN2O3S: C, 54.46; H, 4.86; N, 7.94;
S, 9.09%. Found: C, 54.72; H, 4.97; N, 8.11; S, 8.89%.
Ethyl 2-[(3,4-Dichlorophenyl)carbamoyl]amino-
4,5-dimethylthiophene-3-carboxylate (2e)
1
Yield 80%; M.p. 185–187◦C; H NMR (d6-DMSO): δ 1.31 (t, 3H, J =
7Hz, CH3), 2.18 (s, 6H, 2CH3), 4.23 (q, 2H, J = 7Hz, CH2), 7.25–7.90 (m,
3H, arom-H), 10.50 (s, 1H, NH), 10.67 (s, 1H, NH); FTIR (KBr disk): ν
3340, 3255 (two NH), 1703, 1655 cm−1 (two C=O); MS, m/z: 386 (M+),
388 (M+2), 390 (M+4); anal. calcd. for C16H16Cl2N2O3S: C, 49.62; H,
4.16; N, 7.23; S, 8.28%. Found: C, 49.38; H, 4.03; N, 7.41; S, 8.46%.
General Procedure for the Preparation of 3-Aryl-
5,6-dimethylthieno[2,3-d]pyrimidine-2,4 (1H,3H)-diones 3a–e
A mixture of ethyl 2-[(arylcarbamoyl)amino]-4,5-dimethylthiophene-3-
carboxylates 2a–e (1 mmol) and potassium t-butoxide (1 mmol) in t-
butanol (10 mL) was heated under reflux for 1 h. After this time, the
solvent was evaporated in vacuo, the residue was dissolved in water
(10 mL) and subsequently neutralized by 1N HCl. The crude product
was collected and recrystallized from ethanol to give compounds 3a–e
in 73, 82, 67, 71, and 66% yields respectively. Melting points, spectral

2972
A. Davoodnia et al.
and microanalytical data of these compounds have been reported in our
previous paper.19
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