Iodine catalysed synthesis and antibacterial evaluation of thieno-[2,3-d]pyrimidine derivatives

Article abstract of DOI:10.3184/030823409X12537299044500

A new route via iodine catalysed heterocyclisation of 2-amino-4,5- dimethylthiophene-3-carboxamide with aromatic aldehydes affording a series of thieno[2,3-d]pyrimidine derivatives in a single step have been developed. Some of these compounds exhibited an

Full text of DOI:10.3184/030823409X12537299044500

JOURNAL OF CHEMICAL RESEARCH 2009
NOVEMBER, 653–655
RESEARCH PAPER 653
Iodine catalysed synthesis and antibacterial evaluation of thieno-
[2,3-d]pyrimidine derivatives
Mehdi Bakavolia*, Ghodsieh Bagherzadehb, Maryam Vaseghifarb, Ali Shiria and
Parvaneh Pordelic
aDepartment of Chemistry, School of Sciences, Ferdowsi University of Mashhad, 91775-1436 Mashhad, Iran
bDepartment of Chemistry, School of Sciences, Birjand University, Birjand, Iran
cDepartment of Biology, School of Sciences, Ferdowsi University of Mashhad, 91775-1436 Mashhad, Iran
A new route via iodine catalysed heterocyclisation of 2-amino-4,5-dimethylthiophene-3-carboxamide with aromatic
aldehydes affording a series of thieno[2,3-d]pyrimidine derivatives in a single step have been developed. Some of
these compounds exhibited antibacterial activities comparable to Streptomycin as reference drug.
Keywords: thieno[2,3-d]pyrimidine, iodine, heterocyclisation, antibacterial evaluation, oxidative catalyst
Thienopyrimidine derivatives as annulated five-membered
heteroaromatic ring systems are structurally analogues of
biogenic purines with a very wide spectrum of biological
activities. A review article covering the literature on
thienopyrimidinesupto2004hasbeenpublished.1 Furthermore,
new biological activities such as antimicrobial,2-8 antiviral,9,10
antidepressant,11 analgesic and anti-inflammatory12,13 have
been recently reported for these compounds. Various synthetic
approaches have been utilised for the synthesis of this class
of heterocycles including using ZnCl2/Et3N reagent system,14
microwave irradiation,15 base-catalysed cyclocondensation
of ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate with
aryl isocyanates,16 synthesis through tandem [2,3] and [3,3]
sigmatropic rearrangement,17 reaction of aromatic and
heterocyclic carboxylic acids using montmorillonite K-10
under solventless conditions18 and parallel solution-phase
combinatorial techniques.19
various aromatic aldehydes in the presence of molecular
iodine. The results of the antibacterial test on the new products
are reported.
Results and discussion
Chemistry
The starting material 2-amino-4,5-dimethylthiophene-3-carbo-
nitrile (1) was prepared according to Gewald procedure.26
The subsequent hydrolysis of this compound in acidic media
afforded the 2-amino-4,5-dimethylthiophene-3-carboxamide
(2). This compound was the precursor for the synthesis of
various derivatives of thieno[2,3-d]pyrimidine (3a–i).
The reaction of compound (2) with aromatic aldehydes
proceeded in one pot at room temperature within a short
period of time after the addition of molecular iodine to furnish
the corresponding thieno[2,3-d]pyrimidine (3a–i) in 70–88%
yield. (Table 1)
Currently special interest has been devoted to molecular
iodine, as a readily available, mild and environmentally friendly
Lewis acid and as an oxidising agent for the construction of
heterocyclic rings through an oxidative heterocyclisation
reaction.20 Prompted by these findings and due to our
interest in the synthesis of fused-pyrimidines of biological
importance,21-25 we now report the synthesis of thieno[2,3-d]
pyrimidine derivatives through oxidative cyclocondensation
of 2-amino-4,5-dimethylthiophene-3-carboxamide (2) with
The structures and purities of these compounds were
ascertained from their spectral and microanalytical data.
1
For example, the H NMR spectrum of compound (3g) did
not show the signals at d 6.78 and 7.85 ppm belonging to NH2
moiety of the precursor but instead showed a singlet signal for
NH proton at d 12.37 ppm which was removed on deuteration.
Furthermore, the spectrum showed a doublet–doublet peak
at the aromatic region (d 8.14 and 8.43 ppm, J = 9 Hz)
confirming the presence of the aromatic ring system and the
O
Me
Me
Me
CN
NH2
NH2
NH2
O
CN
CN
ii
i
S
+
+
Me
S
S
(2)
(1)
iii
O
Me
3a, Ar = C6H5-; 3b, Ar = 4-Me-C6H4-; 3c, Ar = 4-Cl-
C6H4-; 3d, Ar = 4-Br-C6H4-; 3e, Ar = 4-MeO-C6H4-;
3f, Ar = 3-MeO-C6H4-; 3g, Ar = 4-NO2-C6H4-;ꢀ3h,
Ar = 3-NO2-C6H4-;ꢀ3i, Ar = 2-OH-C6H4-
NH
Me
Ar
N
S
(3
a
-i
)
i, Et2NH, EtOH, 60°C; ii, conc. H2SO4; iii, ArCHO, I2, CH3CN, rt.
Scheme 1
* Correspondent. E-mail: mbakavoli@yahoo.com
PAPER: JC090761

654 JOURNAL OF CHEMICAL RESEARCH 2009
Table 1 Times, yields and melting points for the synthesised compound (3a–i)
Compound
Ar
Time/min
Yield/%a
M.p./°C
M.p./°C [Ref.]b
3a
3b
3c
3d
3e
3f
3g
3h
3i
C6H5–
35
70
50
45
90
80
20
30
60
80
78
75
70
88
78
70
72
74
294
315–316
337–338
342
320–322
312
370–372
334
330–332
293–297 [27]
4-Me–C6H4–
4-Cl–C6H4–
4-Br–C6H4–
4-MeO–C6H4–
3-MeO–C6H4–
4-NO2–C6H4–
3-NO2–C6H4–
2-HO–C6H4–
314–316 [27]
338–340 [27]
342–344 [27]
323–325 [28]
–
–
–
–
aIsolated yields. bProducts are characterised from their spectra and microanalytical data comparison with the authentic samples.
occurrence of heterocyclisation. The IR spectrum was also
devoid of the stretching vibration bands resembling the NH2
moiety of the precursor but instead exhibited only one band
at 3350 cm-1 for the NH moiety. The molecular ion peak of
compound (3g) was observed at m/z 301 (M+) corresponding
to the molecular formula C14H11N3O3S.
broad spectrum antibiotic.
As can be concluded from the data in Table 2, compound (3f)
has shown the highest sensitivity against E. coli and St. aureus,
and moderately sensitive against B. Sabtilis. Compound (3c)
exhibited the best activity against E. coli while compound
(3i) showed slight to moderate activity against P. aeruginosa.
All the other compounds were found to exhibit slightly
sensitive against the mentioned organisms.
Biological activities
The in vitro antibacterial activity of the newly synthesised
compounds (3a–i) were screened for the antibacterial activity
against several pathogenic representative Gram-positive
bacteria (Staphylococcus aureus PTCC 1074 and Bacillus
subtilis PTCC 1365); Gram-negative bacteria (Escherichia
coli HB101 BA 7601C and Pseudomonas aeruginosa PTCC
1431) using disc diffusion sensitivity test.29 Mueller–Hinton
agar media were sterilised (15 min at 121°C) and poured
into the plates to a uniform depth of 5 mm and allow to
solidify. The microbial suspension (1–2 × 108 CFU mL-1)
(0.5 McFarland Nephelometery Standards) was streaked over
the surface of media using a sterile cotton swab (15 min at
180°C) to ensure confluent growth of the organisms. The tested
compounds were dissolved in dimethylformamide (DMF) and
diluted with ethanol to get a solution of 100–500 μg mL-1
concentration. The discs measuring 6.25 mm in diameter
(Whatman no. 1 filter paper) were impregnated with prepared
solution of compounds (3a–i) and placed on Muller-Hinton
agar media previously inoculated with bacterial suspension.
The inhibition zones as a criterion for antimicrobial activity
were measured in millimetres at the end of an incubation
period of 24 h at 37°C. The results of these evaluations are
given in Table 1. Streptomycin (binds to the 16SrRNA of the
bacterial ribosome, interfering with the binding of formyl-
methionyl-tRNA to the 30S subunit therefore prevents
initiation of protein synthesis and leads to death of microbial
cell) was chosen as a standard drug at a concentration of 10 µg
mL-1. Streptomycin is an antibiotic that inhibits both gram
positive and gram negative bacteria, and is therefore a useful
In conclusion, we have described a new route to the synthesis
of
2-aryl-5,6-dimethylthieno[2,3-d]pyrimidine-4(3H)-ones
(3a–i)viaheterocyclisationof2-amino-4,5-dimethylthiophene-
3-carboxamide (2) with various aromatic aldehydes in
acetonitrile at room temperature in the presence of molecular
iodine as an oxidative catalyst and their antibacterial
evaluations.
Experimental
Melting points were recorded on an Electrothermal type 9100
melting point apparatus and are not corrected. The 1H NMR
(100 MHz) spectra were recorded on a Bruker AC 100 spectrometer.
Chemical shifts are reported in ppm downfield from TMS as internal
standard; coupling constants J are given in Hertz. The mass spectra
were scanned on a Varian Mat CH-7 at 70 eV. Elemental analysis was
performed on a Thermo Finnigan Flash EA micro analyser.
Synthesis of 2-amino-4,5-dimethylthiophene-3-carboxamide (2):
2-Amino-4,5-dimethylthiophene-3-carbonitrile (0.25 mol, 3.80 g) was
added gradually to 10–15 mL conc. H2SO4 and stirred for 2 h at
65–70°C. Then, the mixture was neutralised in an ice-bath by 25%
ammonia. The resulting solid was filtered and recrystallised from
water. (Yield = 80%, m.p. 182–183°C, lit.30 184–185°C).
General procedure for the preparation of thieno[2,3-d]pyrimidine
(3a–i): To
a
solution of 2-amino-4,5-dimethylthiophene-3-
carboxamide (2) (1 mmol, 0.17 g) and various aromatic aldehydes
(1.2 mmol) in acetonitrile (10 mL), molecular iodine (1.3 mmol,
0.33 g) was added. The mixture was stirred at room temperature for
15–30 min. After the reaction was completed (monitored by TLC),
10 mL 5% Na2S2O3 solution was added and the resulting
precipitate was filtered off. Further purification can be obtained by
recrystallisation from ethanol.
Table 2 Antibacterial data of the synthesised compounds (3a–i)a
Compound
Gram-positive bacteria
Gram-negative bacteria
Staphylococcus
aureus PTCC 1074
Bacillus subtilis
PTCC 1365
Escherichia coli
HB 101 BA 7601C
Pseudomonas
aeruginosa PTCC 1431
3a
11(–)
10(–)
8(–)
10(–)
7(–)
9.5(–)
12( + )
7(–)
9(–)
8(–)
7(–)
3b
8(–)
8.5(–)
13( + )
11(–)
3c
10.5(–)
13( + )
9.5(–)
16.5( + + )
9(–)
7(–)
11(–)
9(–)
3d
8(–)
9(–)
10(–)
7(–)
7(–)
11( + )
3e
10.5(–)
16( + + )
9(–)
9(–)
10(–)
3f
3g
3h
7(–)
8.5(–)
3i
Streptomycin
(Standard)
13
9
15
10
aZones of inhibition in millimetre; ( + + ) highly sensitive; ( + ) moderately sensitive; (–) slightly sensitive.
PAPER: JC090761

JOURNAL OF CHEMICAL RESEARCH 2009 655
6
7
8
9
N.A. Hassan, M.I. Hegab, A.E. Rashad, A.A. Fahmy and F.M.E. Abdel-
Megeid, Nucleosides Nucleotides, Nucleic Acids, 2007, 26, 379.
A. Abdel, H.M. Eissa and A.A. Moneer, Arch. Pharm. Res., 2004, 27,
885.
M.M.H. Bhuiyan, K.M.M. Rahman, M.K. Hossain, A. Rahim, M.I. Hossain
and M.A. Naser, Acta Pharm., 2006, 56, 441.
2-(3-Methoxyphenyl)-5,6-dimethyl-3,4-dihydrothieno[2,3-d]
pyrimidin-4(3H)-one (3f): H NMR (DMSO-d6, ppm) d 2.32 (s, 3H,
1
CH3), 2.39 (s, 3H, CH3), 3.98 (s, 3H, CH3), 7.13–7.63 (m, 4H, Ar),
12.48 (br s, 1H, NH); IR spectrum (n, cm–1): 3330 (NH), 1670 (C=O);
m/z 286 (M+); Anal. Calcd for C15H14N2O2S: C, 62.92; H, 4.93; N,
9.78; S, 11.20. Found: C, 62.82; H, 4.85; N, 9.69; S, 10.98%.
5,6-Dimethyl-2-(4-nitrophenyl)-3,4-dihydrothieno[2,3-d]
pyrimidin-4(3H)-one (3g): 1H NMR (DMSO-d6, ppm) d 2.33 (s, 3H,
CH3), 2.39 (s, 3H, CH3), 8.14 (d, J = 9 Hz, 2H, Ar), 8.43 (d, J = 9 Hz,
2H, Ar), 12.37 (br s, 1H, NH); IR spectrum (n, cm–1): 3350 (NH),
1655 (C=O), m/z 301 (M+); Anal. Calcd for C14H11N3O3S: C, 55.80;
H, 3.68; N, 13.95; S, 10.64. Found: C, 55.78; H, 3.65; N, 13.89; S,
10.58%.
M.N. Nasr and M.M. Gineinah, Arch. Pharm., 2002, 335, 289.
10 A.E. Rashad and M.A. Ali, Nucleosides Nucleotides, Nucleic Acids, 2006,
25, 17.
11 W.W. Wardakhan, O.M.E. Abdel-Salam and G.A. Elmegeed, Acta Pharm.,
2008, 58, 1.
12 V.Alagarsamy, S. Meena, K.V. Ramseshu, V.R. Solomon, K. Thirumurugan,
K. Dhanabal and M. Murugan, Eur. J. Med. Chem., 2006, 41, 1293.
13 V. Alagarsamy, D. Shankar, S. Meena, K. Thirumurugan and
T.D.A. Kumar, Drug Dev. Res., 2007, 68, 134.
14 H. Maruoka, F. Okabe and K. Yamagata, J. Heterocycl. Chem., 2008, 45,
541.
15 M.S. Phoujdar, M.K. Kathiravan, J.B. Bariwal, A.K. Shah and K.S. Jain,
Tetrahedron Lett., 2008, 49, 1269.
16 A. Davoodnia, H. Behmadi, A. Zare-Bidaki, M. Bakavoli and N. Tavakoli-
Hosseini, Chin. Chem. Lett., 2007, 18, 1163.
17 M.C. Krishna, P. Nilasish and C.K. Sudip, Lett. Org. Chem., 2006, 3,
709.
18 M. Kidwai, V. Bansal and R. Thakur, J. Sulfur Chem., 2006, 27, 57.
19 A.V. Bogolubsky, S.V. Ryabukhin, S.V. Stetsenko, A.A. Chupryna,
D.M. Volochnyuk and A.A. Tolmachev, J. Comb. Chem., 2007, 9, 661.
20 A.K. Banerjee, W. Vera, H. Mora, M.S. Laya, L. Bedoya and E.V. Cabrera,
J. Sci. Ind. Res., 2006, 65, 299.
5,6-Dimethyl-2-(3-nitrophenyl)-3,4-dihydrothieno[2,3-d]
pyrimidin-4(3H)-one (3h): 1H NMR (DMSO-d6, ppm) d 2.32 (s, 3H,
CH3), 2.39 (s, 3H, CH3), 7.83–8.26 (m, 4H, Ar), 12.28 (br s, 1H,
NH); IR spectrum (n, cm–1): 3350 (NH), 1650 (C=O); m/z 301 (M+);
Anal. Calcd for C14H11N3O3S: C, 55.80; H, 3.68; N, 13.95; S, 10.64.
Found: C, 55.75; H, 3.64; N, 13.90; S, 10.55%.
2-(2-Hydroxyphenyl)-5,6-dimethyl-3,4-dihydrothieno[2,3-d]
1
pyrimidin-4(3H)-one (3i): H NMR (DMSO-d6, ppm) d 2.36 (s, 3H,
CH3), 2.40 (s, 3H, CH3), 6.83–7.16 (m, 4H, Ar), 8.75 (br s, 1H, OH),
12.08 (br s, 1H, NH); IR spectrum (n, cm–1): 3390 (OH), 3330 (NH),
1640 (C=O); m/z 272 (M+); Anal. Calcd for C14H12N2O2S: C, 61.75;
H, 4.44; N, 10.29; S, 11.77. Found: C, 61.72; H, 4.43; N, 10.24; S,
11.69%.
21 M. Bakavoli, M. Nikpour and M. Rahimizadeh, J. Heterocycl. Chem.,
2006, 43, 1327.
22 M. Rahimizadeh M. Nikpour, and M. Bakavoli, J. Heterocycl. Chem.,
2007, 44, 463.
23 M. Bakavoli, M. Nikpour, M. Rahimizadeh M.R. Saberi and H. Sadeghian,
Bioorg. Med. Chem., 2007, 15, 2120.
24 M. Bakavoli, H. Sadeghian, Z. Tabatabaei, E. Rezai, M. Rahimizadeh and
M. Nikpour, J. Mol. Mod., 2008, 14, 471.
25 M. Bakavoli, M. Rahimizadeh, A. Shiri, H. Eshghi and M. Nikpour,
Heterocycles, 2008, 75, 1745.
Received 28 August 2009; accepted 23 September 2009
Paper 09/0761 doi: 10.3184/030823409X12537299044500
Published online: 17 November 2009
References
1
V.P. Litvinov, Russian Chem. Bull., 2004, 53, 487.
26 K. Gewald, E. Schinke and H. Bottcher, Chem. Ber., 1966, 99, 94.
27 A. Davoodnia, H. Eshghi, A. Salavaty and N. Tavakoli-Hoseini, J. Chem.
Res., 2008, 1.
28 F. Sauter, P. Stanetty, H. Potuzak and M. Baradar, Monatsh Chem., 1976,
107, 669.
29 R. Cruickshank, J.P. Duguid, B.P. Marion and R.H.A. Swain, Medicinal
microbiology, Churchill Livingstone, London, 1975, Vol. II, pp 196–202.
30 F. Sauter and W. Dienhammer, Monatsh. Chem., 1973, 104, 1586.
2
R.V. Chambhare, B.G. Khadse, A.S. Bobde and R.H. Bahekar, Eur. J.
Med. Chem., 2003, 38, 89.
A.H. Moustafa, H.A. Saad, W.S. Shehab and M.M. El-Mobayed,
Phosphorus, Sulfur Silicon, 2008, 183, 115.
M.I. Hegab, N.A. Hassan, A.E. Rashad, A.A. Fahmy and F.M.E. Abdel-
Megeid, Phosphorus, Sulfur Silicon, 2007, 182, 1535.
V. Alagarsamy, V.R. Solomon, R. Meenac, K.V. Ramaseshu,
K. Thirumurugan and S. Murugesan, Med. Chem., 2007, 3, 67.
3
4
5
PAPER: JC090761