Investigation into the reaction of 2-amino- 4,5-dimethylthiophene-3- carboxamide with iso(and Isothio)cyanates under microwave irradiation

Article abstract of DOI:10.1002/hc.20557

The reaction of 2-amino-4,5-dimethyl-thiophene-3-carboxamide with iso(and isothio) cyanates for the synthesis ofthieno[2,3-d]pyrimidines has been investigated. The reactions under microwave irradiation in the presence of N,N-dimethyl acetamide as solvent

Full text of DOI:10.1002/hc.20557

Heteroatom Chemistry
Volume 20, Number 6, 2009
Investigation into the Reaction of 2-Amino-
4,5-dimethylthiophene-3-carboxamide
with Iso(and Isothio)cyanates under
Microwave Irradiation
Abolghasem Davoodnia,1 Mohammad Rahimizadeh,2
Hoda Atapour-Mashhad,1 and Niloofar Tavakoli-Hoseini1
1Department of Chemistry, Faculty of Sciences, Islamic Azad University, Mashhad Branch,
Mashhad, Iran
2Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad, Iran
Received 12 April 2009
significant analgesic [1,2], fungicidal [3], antibacte-
ABSTRACT: The reaction of 2-amino-4,5-dimethyl-
rial [4], antiviral [5], and antiinflammatory [6] ac-
thiophene-3-carboxamide with iso(and isothio)
tivities. Also, some thieno[2,3-d]pyrimidines show
cyanates for the synthesis of thieno[2,3-d]pyrimidines
central nervous system depressing activity [7] and
has been investigated. The reactions under microwave
are useful as muscle relaxants [8], sedatives [8], di-
irradiation in the presence of N,N-dimethyl acetamide
uretics [9], pesticides, and herbicides [10]. Various
as solvent gave 5,6-dimethylthieno[2,3-d]pyrimidine-
methods have already been proposed for the synthe-
2,4(1H,3H)-dione, 5,6-dimethyl-2-thioxo-2,3-dihy-
sis of these compounds, and the most general ones
drothieno[2,3-d]pyrimidin-4(1H)-one, and 2-aryla-
involve cyclocondensation of suitably functionalized
mino-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one
thiophenes with different electrophiles such as chlo-
derivatives. These reactions probably proceed through
roformamidine [11], α-substituted acetonitriles [12],
intermediates 4,5-dimethyl-2-substitutedcarbamoth-
formic acid [13], phosgene [14], ethyl chloroformate
ioylaminothiophene-3-carboxamides. Two of these
[14], and guanidine [15]. To the best of our knowl-
ꢀ
C
intermediates were isolated.
2009 Wiley Periodicals,
edge, reaction of 2-amino-4,5-dimethylthiophene-3-
carboxamide 1 with isocyanates and isothiocyanates
for the synthesis of thieno[2,3-d]pyrimidines under
microwave irradiation has not been reported in the
literature.
Inc. Heteroatom Chem 20:346–349, 2009; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.20557
In pursuing these studies and in continua-
tion of our work on the synthesis of thieno[2,3-
d]pyrimidine derivatives [16–19] and due to our in-
terest in the utilization of microwave irradiation for
the synthesis of heterocyclic compounds [20–23],
in this paper we tried to synthesize some thieno
[2,3-d]pyrimidine derivatives with regard to the re-
action of compound 1 with isocyanates and isoth-
iocyanates under microwave irradiation conditions
(Scheme 1).
INTRODUCTION
Thieno[2,3-d]pyrimidines are a large group of hete-
rocycles with diverse and interesting biological ac-
tivities. These compounds are reported to possess
Correspondence
to:
Abolghasem
Davoodnia;
e-mail:
adavoodnia@yahoo.com, adavoodnia@mshdiau.ac.ir.
c
ꢀ
2009 Wiley Periodicals, Inc.
346

Investigation into the Reaction of 2-Amino-4,5-dimethylthiophene-3-carboxamide with Iso(and Isothio)cyanates 347
X
R
O
NH
O
H3C
NH
H3C
NH
X=O
H3C
NH2
O
S
S
N
H3C
S
S
H
for 2a–f
7a–k
4
O
O
O
H3C
H3C
H3C
NH2
NH
NH2
MW
X=S
R
N
C
X
+
N
H
H3C
H3C
NH2
H3C
NH
S
for 2i–k
S
R
N
5
X
H
O
1
2a–k
3a–k
H3C
NH
X=S
NHR
N
for 2g and 2h
H3C
S
a: X = O, R = Ph
g: X = S, R = Ph
6g and 6h
b: X = O, R = 4-O2NC6H4
c: X = O, R = 3-ClC6H4
d: X = O, R = 2-MeC6H4
e: X = O, R = 4-MeC6H4
f: X = O, R = Et
h: X = S, R = 4-O2NC6H4
i: X = S, R = 3-MeC6H4
j: X = S, R = 4-MeC6H4
k: X = S, R = Et
SCHEME 1
RESULTS AND DISCUSSION
to furnish the cyclized products 4, 5, 6g, and 6h. At-
tempts to isolate these intermediates failed when we
monitored the reactions under careful observation.
Finally, we were interested to study the role of
DMA in these reactions. For this purpose, the reac-
tions were carried out under microwave irradiation
in the absence of DMA. Omission of DMA of the re-
action mixture has no effect on the formation of the
products except for 2h and 2k.
When compound 1 was allowed to interact with
isothiocyanates 2h and 2k under microwave irradia-
tion in solvent-free conditions and monitored the re-
action mixture by TLC (CHCl3:MeOH, 95:5), surpris-
ingly we observed that unexpected products, with
different Rf s of those expected for compounds 6h
and 5, respectively, were formed. During workup
and identification, it was established that a conden-
sation and not a cyclocondensation reaction had oc-
curred, and the intermediates 3h and 3k were iso-
lated. The reaction did not proceed to form cyclic
products even after prolonged irradiation, but when
these intermediates were irradiated in the presence
of DMA the cyclization reaction occurred and the
cyclic products 6h and 5 were obtained, respectively.
The structure of new products 3h, 3k, 6g, and 6h was
established from their spectral and microanalytical
data and for known compounds 4 and 5 by compar-
ison with authentic samples (see the Experimental
section).
The starting material 1 was prepared according
to the literature method [24]. First, treatment
of this compound with isocyanates 2a–f under
microwave irradiation in the presence of N,N-
dimethylacetamide (DMA) as solvent was explored.
When the reactants were mixed together and irra-
diated at 700 W for the indicated time, using a do-
mestic microwave oven model LG MS-543XD, we
observed that the similar product was formed in
all reactions and identified as 5,6-dimethylthieno-
[2,3-d]pyrimidine-2,4(1H,3H)-dione 4 [25]. There-
fore, the cyclization reactions occurred via leaving
the amino groups instead of water (Scheme 1).
Next, reaction of compound 1 with isothio-
cyanates 2g–k under same conditions was investi-
gated. When this compound was allowed to interact
with isothiocyanates 2g and 2h under microwave
irradiation in the presence of DMA, the arylamino
derivatives 6g and 6h were obtained, respectively,
whereas irradiation of this compound with isothio-
cyanates 2i–k produced compound 5 [26]. It is obvi-
ous that the formation of the products 6g, 6h, and 5
has proceeded through leaving hydrogen sulfide and
the amino groups, respectively.
The formation of the all above-mentioned prod-
ucts was assumed to proceed via the seemingly reac-
tive intermediates 3a–k with subsequent cyclization
Heteroatom Chemistry DOI 10.1002/hc

348 Davoodnia et al.
br, 1H, NH), 10.80 (br, 1H, NH); IR (KBr, ν/cm−1):
3471, 3308, 3264, and 3212 (NH2 and two NH),
1647 (C O stretching and NH2 bending); MS, m/z:
257 (M+); Anal. Calcd for C10H15N3OS2: C, 46.67; H,
5.87; N, 16.33; S, 24.92; found C, 46.94; H, 5.59; N,
15.98; S, 24.67.
As it was shown in the previous paper [19], we
believe that the formation of the intermediates 3h
and 3k occurred via a nucleophilic attack of the
amino group in 2-position of thiophene at the car-
bon site of isothiocyanates 2h and 2k, respectively.
Therefore, the compounds 7h and 7k have not been
formed (Scheme 1).
In conclusion, the reaction of compound 1 with
iso(and isothio)cyanates 2a–k under microwave ir-
radiation in the presence of DMA as solvent gave the
cyclized products thieno[2,3-d]pyrimidines. In the
absence of DMA, two intermediates 3h and 3k were
isolated.
Synthesis of 5,6-Dimethylthieno[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione (4)
A
mixture of 2-amino-4,5-dimethylthiophene-3-
carboxamide 1 (0.002 mol) and isocyanates 2a–f
(0.003 mol) in the presence of DMA (1 mL) as solvent
was subjected to microwave irradiation at 700 W for
3–5 min. After the completion of the reaction (moni-
tored by TLC, CHCl3:MeOH, 95:5), cyclohexane was
added to the reaction mixture. The crude product
was collected and recrystallized from ethanol to give
compound 4 in 65–90% yields, mp. 335–337◦C (lit.
[25]. >310◦C).
EXPERIMENTAL
Melting points were recorded on an electrothermal
type 9100 melting point apparatus. The IR spectra
were obtained on a 4300 Shimadzu spectrophotome-
1
ter as KBr disks. The H 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.
Synthesis of 5,6-Dimethyl-2-thioxo-2,3-
dihydrothieno[2,3-d]pyrimidin-4(1H)-one (5)
Method A. A mixture of 2-amino-4,5-
dimethylthiophene-3-carboxamide 1 (0.0025 mol)
and isothiocyanates 2i–k (0.0040 mol) in the pres-
ence of DMA (1.2 mL) as solvent was subjected to
microwave irradiation at 700 W for 3–4 min. After
the completion of the reaction (monitored by TLC,
CHCl3:MeOH, 95:5), cyclohexane was added to the
reaction mixture. The crude product was collected
and recrystallized from ethanol to give compound 5
in 60%–75% yields.
Synthesis of 4,5-Dimethyl-2-substitutedcar-
bamothioylaminothiophene-3-carboxamides
(3h) and 3k)
General Procedure. A mixture of 2-amino-4,5-
dimethylthiophene-3-carboxamide 1 (0.002 mol)
and isothiocyanates 2h or 2k (0.003 mol) was sub-
jected to microwave irradiation at 700 W for 6 min.
After the completion of the reaction (monitored by
TLC, CHCl3:MeOH, 95:5), the crude product was col-
lected and recrystallized from ethanol/:ethyl acetate
to give compounds 3h and 3k in good yields.
Method B. 2-[(Ethylcarbamothioyl)amino]-4,5-
dimethylthiophene-3-carboxamide 3k (0.0008 mol)
in the presence of DMA (0.5 mL) as solvent was sub-
jected to microwave irradiation at 700 W for 2 min.
After the completion of the reaction (monitored by
TLC, CHCl3:MeOH, 95:5), the crude product was re-
crystallized from ethanol to give compound 5 in 71%
yield, mp. 268–270◦C (lit. [26]. 260◦C).
4,5-Dimethyl-2-{[(4-nitrophenyl)carbamothioyl]-
amino}thiophene-3-carboxamide (3h). Yield, 65%;
mp >350◦C; 1H NMR: δ (DMSO-d6) 2.20 (s, 6H,
2CH3), 7.35 (br, 2H, NH2), 7.70 (d, 2H, Ar-H,
J = 9 Hz), 8.20 (d, 2H, Ar-H, J = 9 Hz), 9.88 (br,
1H, NH), 10.65 (br, 1H, NH); IR (KBr, ν/cm−1): 3507,
3408, 3311, and 3237 (NH2 and two NH), 1675 (C O
stretching and NH2 bending), 1500, 1325 (NO2);
MS, m/z: 350 (M+); Anal. Calcd for C14H14N4O3S2: C,
47.99; H, 4.03; N, 15.99; S, 18.30; found C, 48.32; H,
4.38; N, 15.54; S, 18.08.
Synthesis of 5,6-Dimethyl-2-(phenylamino)-
thieno[2,3-d]pyrimidin-4(3H)-one (6g)
A
mixture of 2-amino-4,5-dimethylthiophene-3-
carboxamide 1 (0.002 mol) and phenyl isothio-
cyanate 2g (0.003 mol) in the presence of DMA
(1 mL) as solvent was subjected to microwave irradi-
ation at 700 W for 3 min. After the completion of the
reaction (monitored by TLC, CHCl3:MeOH, 95:5), cy-
clohexane was added to the reaction mixture. The
crude product was collected and recrystallized from
2-[(Ethylcarbamothioyl)amino]-4,5-dimethylthi-
ophene-3-carboxamide (3k). Yield, 80%; mp
1
>350◦C; H NMR: δ (DMSO-d6) 1.10 (t, 3H, CH3,
J = 8 Hz), 2.12 (s, 3H, CH3), 2.17 (s, 3H, CH3), 3.35
(q, 2H, CH2, J = 8 Hz), 7.33 (s br, 2H, NH2), 8.77 (s
Heteroatom Chemistry DOI 10.1002/hc

Investigation into the Reaction of 2-Amino-4,5-dimethylthiophene-3-carboxamide with Iso(and Isothio)cyanates 349
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ethanol to give compound 6g. Yield, 80%; mp 315–
318◦C; 1H NMR: δ (DMSO-d6) 2.17 (s, 3H, CH3), 2.20
(s, 3H, CH3), 7.1–7.7 (m, 5H, phenyl), 10.60 (s br, 1H,
NH), 11.82 (br, 1H, NH); IR (KBr, ν/cm−1): 3310,
3171 (two NH), 1648 (C O); MS, m/z: 271 (M+);
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15.49; S, 11.82; found C, 61.62; H, 4.59; N, 15.70; S,
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Method A. A mixture of 2-amino-4,5-dimethyl-
thiophene-3-carboxamide 1 (0.002 mol) and 4-
nitrophenyl isothiocyanate 2h (0.003 mol) in the
presence of DMA (1 mL) as solvent was subjected
to microwave irradiation at 700 W for 5 min. After
the completion of the reaction (monitored by TLC,
CHCl3:MeOH, 95:5), cyclohexane was added to the
reaction mixture. The crude product was collected
and recrystallized from ethanol to give compound
6h in 72% yield.
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[15] Link, H. Helv Chim Acta 1990, 73, 797–803.
[16] Davoodnia, A.; Bakavoli, M.; Barakouhi, Gh.;
Tavakoli-Hoseini, N. Chin Chem Lett 2007, 18, 1483–
1486.
[17] Davoodnia, A.; Behmadi, H.; Zare-Bidaki, A.;
Bakavoli, M.; Tavakoli-Hoseini, N. Chin Chem Lett
2007, 18, 1163–1165.
[18] Davoodnia, A.; Eshghi, H.; Salavaty, A.; Tavakoli-
Hoseini, N. J Chem Res 2008, 1, 1–2.
[19] Davoodnia, A.; Bakavoli, M.; Soleimany, M.;
Tavakoli-Hoseini, N. Monatsh Chem 2009, 140, 355–
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[20] Davoodnia, A.; Bakavoli, M.; Khorramdelan, F.;
Roshani, M. Indian J Heterocycl Chem 2006, 16, 147–
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[21] Davoodnia, A.; Rahimizadeh, M.; Rivadeh, Sh.;
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Method
B. 4,5-Dimethyl-2-{[(4-nitrophenyl)-
carbamothioyl]amino}thiophene-3-carboxamide 3h
(0.0007 mol) in the presence of DMA (0.5 mL) as
solvent was subjected to microwave irradiation
at 700 W for 3 min. After the completion of the
reaction (monitored by TLC, CHCl3:MeOH, 95:5),
the crude product was recrystallized from ethanol
to give compound 6h in 75% yield.
mp 277–279◦C; 1H NMR:
δ
(DMSO-d6)
2.18 (s, 3H, CH3), 2.21 (s, 3H, CH3), 7.72 (d, 2H,
Ar-H, J = 9.5 Hz), 8.13 (d, 2H, Ar-H, J = 9.5 Hz),
10.30 (br, 1H, NH), 10.64 (br, 1H, NH); IR (KBr,
ν/cm−1): 3375, 3221 (two NH), 1674 (C O), 1497,
1329 (NO2); MS, m/z: 316 (M+); Anal. Calcd for
C14H12N4O3S: C, 53.16; H, 3.82; N, 17.71; S, 10.14;
found C, 52.76; H, 4.18; N, 17.97; S, 9.92.
[22] Davoodnia, A.; Roshani, M.; Malaeke, S. H.; Bakavoli,
M. Chin Chem Lett 2007, 19, 525–528.
[23] Davoodnia, A.; Roshani, M.; Saleh Nadim, E.;
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Heteroatom Chemistry DOI 10.1002/hc