Synthesis of some 3-substituted amino-4,5-tetramethylene thieno[2,3-d][ 1,2,3]-triazin-4(3H)-ones as potential antimicrobial agents

Article abstract of DOI:10.1016/j.ejmech.2010.05.061

A series of 3-Substituted amino-4,5-tetramethylene thieno[2,3-d] [1,2,3]-triazine-4(3H)-ones have been synthesized and characterized by UV,IR, 1H NMR, elemental and mass spectral analysis. The title compounds were evaluated for their antimicrobial activit

Full text of DOI:10.1016/j.ejmech.2010.05.061

European Journal of Medicinal Chemistry 45 (2010) 4365e4369
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis of some 3-substituted amino-4,5-tetramethylene thieno[2,3-d]
[ 1,2,3]-triazin-4(3H)-ones as potential antimicrobial agents
,
1
1
1
*
Janardhanan Saravanan , Shamanna Mohan , Jay Jyoti Roy
Department of Pharmaceutical Chemistry, P.E.S College of Pharmacy, 50 Ft Road. Hanumanthanagar, Bangalore -560 050, Karnataka, India.
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 3-Substituted amino-4,5-tetramethylene thieno[2,3-d] [1,2,3]-triazine-4(3H)-ones have been
synthesized and characterized by UV,IR, 1H NMR, elemental and mass spectral analysis. The title
compounds were evaluated for their antimicrobial activity by agar diffusion method against four bacteria
and three fungi using Ampicillin and Miconazole nitrate as standards. The compounds VIIIa, IXa, Xa and
XIa showed an antimicrobial efficacy considerably greater than the compounds Ia to VIIa with eH,
phenyl and electron donating (activating) groups like methyl, ethyl and tolyl substitutions at R, sug-
gesting that lipophillic groups like chloro, fluoro substitution on the phenyl ring plays an important role
in enhancing the antimicrobial properties of this class of compounds.
Received 21 March 2010
Received in revised form
26 May 2010
Accepted 27 May 2010
Available online 2 June 2010
Keywords:
Synthesis
From the screening results it can be concluded that the compounds having the lipophillic groups like
chlorophenyl and fluorophenyl groups at R exhibited appreciable antimicrobial activities. Whereas, the
compounds are having eH, phenyl and electron donating (activating) groups like methyl, ethyl and tolyl
substituents at R were less active against all the organisms used.
Gewald reaction
Thiophenes
1,2,3-Triazine-4-ones
Diazotization
Antimicrobial evaluation
Ó 2010 Elsevier Masson SAS. All rights reserved.
1. Introduction
1,2,3-triazine [12e17] represents an important nitrogen
heterocycle containing a 6 membered ring with 3 nitrogen atoms.
Resistance to antimicrobial agents (AMR) by pathogenic bacteria
towards available antibiotics is rapidly becoming a major world-
wide problem; the design of new compounds to deal with resistant
bacteria has become one of the most important areas of antibac-
terial research today. In addition, primary and opportunistic fungal
infections continue to increase rapidly because of the increased
number of immune compromised patients. As known, not only
biochemical similarity of the human cell and fungi forms a hand-
icap for selective activity, but also the easily gained resistance is the
main problem encountered in developing safe and efficient anti-
fungal agents.
Theoretically, three triazines are possible of them 1,2,3-triazine is
scarcely explored.
The aim of the present study is therefore to synthesize some
new condensed thiophenes like thieno-1,2,3-triazine-4-ones and to
investigate their efficacy on pathogenic strains of Gram-positive,
Gram-negative bacteria and fungi.
2. Chemistry
The title compounds were synthesized with an aim of exploring
their antimicrobial value.
Literature survey reveals that thiophenes such as substituted
thiophenes and condensed thiophenes are interesting compounds
being studied in medicine and they are reported to possess an
array of useful biological activities such as antibacterial [1,2],
antifungal [3e5], antiviral [6,7], antiprotozoal [8,9] and herbicidal
[10,11].
A large number of medicinal compounds which have been
discovered belong to a major class of heterocycles containing
Nitrogen and Sulphur. The versatile synthetic applicability and
biological activity of these heterocycles has helped the medicinal
chemists to plan, organize and implement new approaches towards
the discovery of novel drugs.
Thiophenes and its derivatives are an important class of
heterocyclic compounds, particularly, 2-amino substituted thio-
* Corresponding author. Tel.: þ91 80 2660 0741, þ91 9880118910; fax: þ91 80
2650 6928.
phenes reported to possess
a wide spectrum of biological
properties such as antibacterial, antifungal, antiviral, analgesic,
anti-inflammatory, antioxidant, antitumor and So on. Thiophene
E-mail addresses: drjayes@gmail.com (J. Saravanan), smohan100@hotmail.com
(S. Mohan), jayroy06@gmail.com (J.J. Roy).
1
containing
b-lactam antibiotics like Ticarcillin, Cefoxitin, Cepha-
Tel.: þ91 80 2660 0741, þ919448870387, þ919163621164;
fax: þ91 80 2660 0113.
lothin and Cephalorodine have shown good antibacterial activity.
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.05.061

4366
J. Saravanan et al. / European Journal of Medicinal Chemistry 45 (2010) 4365e4369
Table 1
Similarly antifungal Ticonazole and Sertaconazole also contain
thiophene.
O
1,2,3-triazines represent a widely used lead structure with
multitude of interesting applications in numerous fields. Diazo-
nium ion condensation with an adjacent nucleophilic function to
form a 5 or 6 membered ring has proved valuable for synthesizing
various nitrogen heterocycles. Diazotization of an amino group
bearing aryl and heteroaryl carboxamides at the ortho position is
often used for the construction of 1,2,3-triazine rings [18].
The synthetic route employed for the synthesis of the title
compounds is outlined in Fig. 1. As large numbers of 2-amino
thiophene-3-carboxylic esters were reported [19,20], it was
thought that the conversion of esters to their corresponding ani-
lides could be an attractive method for the synthesis of 2-amino-
thiophen-3-carboxanilides. However, these 2-aminothiophen-3-
carboxylic esters when made to react with nitrogen nucleophiles,
such as amines could not undergo intermolecular condensation.
This is not unexpected in view of the fact that the presence of ortho
amine function leads to the decrease in the deficiency of electron
density at the carbonyl group of the ester function. In general, it
appears that thiophene amino esters are less reactive than
anthranilic acid esters. The starting compounds 2-amino-3-(N-
substituted carboxamido)-4,5-tetramethylene thiophenes IeXII
were synthesized involving three steps by the adaptation of well
known and versatile Gewald reaction [21]. Later, the compounds
IeXII were diazotized to yield a series of 3 - Substituted amino-5,6-
Tetramethylene thieno[2,3-d] [1,2,3]-triazin-4(3H)-ones IaeXIIa. In
this reaction, the starting compounds 2-amino-3-(N-substituted
carboxamido)-4,5-tetramethylene thiophenes (IeXII) reacts with
NaNO2 in presence of HCl to give respective triazine-4-ones. The
physical properties are reported in the Table 1.
N
N
R
S
N
IaeXIIa
Comp no.
R
M.P ꢀC
% Yield
Rf (Solvent
CHCl3:MeOHl)
(70:30)
Ia
IIa
-H
Methyl
Ethyl
Phenyl
2-Methylphenyl
3-Methylphenyl
4-Methylphenyl
4-Fluorophenyl
2-Chlorophenyl
3-Chlorophenyl
4-Chlorophenyl
168e169
103e105
131e134
112e114
121e122
138e140
175e176
154e156
145e146
158e160
110e112
125e126
52
46
49
47
51
64
71
67
76
71
62
79
0.48
0.56
0.62
0.71
0.59
0.80
0.63
0.41
0.77
0.35
0.72
0.84
IIIa
IVa
Va
VIa
VIIa
VIIIa
IX a
Xa
XIa
XIIa
3-Chloro-4-fluorophenyl
The zone of inhibition was measured in mm. The test compounds
were dissolved in DMF to get the concentration of 50 g/ml. The
m
fresh sub culture of bacteria in isotonic sodium chloride solution
was added to the sterile assay medium at 40e45 ꢀC and mixed well.
The medium was poured into each of the petridishes. The test
solution of different derivatives was added to the previously
marked wells and the media was allowed to stand for 5 min. The
petridishes were covered and set aside for 1 h and then incubated
at 37 ꢀC for 24 h and the zones of inhibition were measured and the
average of three readings was calculated. The activity was
compared with Ampicillin. The antifungal activity was carried in
the same way at28 ꢀC for 48 h and compared with Miconazole
3. Biological assay
3.1. Antimicrobial activity
nitrate (50 mg/ml) as standard. The readings are tabulated in Tables
3 and 4 respectively.
The standard strains were procured from the American Type
Culture Collection (ATCC) and Gene Bank, Institute of Microbial
Technology, Chandigarh, India. Antibacterial [22] and antifungal
[23] activity of the title compounds were carried out by agar cup
4. Results and discussion
diffusion method at a concentration of 50 mg/ml using four stan-
dard bacterial strains viz; Staphylococcus aureus, Staphylococcus
epidermidis, Escherichia coli, Salmonella typhi and three fungi viz;
Aspergillus niger, Candida albicans & Cryptococcus neoformans.
The MIC of compounds was determined by tube dilution method.
The result of the MIC of the compound is illustrated in the Table 2.
Very few condensed 1,2,3-triazin-4-ones have been reported
with antibacterial and antifungal activity. Diazonium ion conden-
sation with an adjacent nucleophilic function has proved valuable
for the construction of the desired 6 membered 1,2,3-triazines as
our title compounds.
O
O
O
C
NH - R
NH-R
1
CH2
+
NH2
S
CN
I-XII
O
O
N
O
N
NH -
R
2
N
H
N-Cl
R
N
N
R
NH
S
2
H C l
S
S
Via Diazonium Chloride
Intermediate
I-XII
Ia-XIIa
Fig. 1. Reagents and Conditions: (1) C6H12, CH3COOH, CH3COONH4, S, C2H5OH,(C2H5)2 NH. (2) NaNO2/HCl, CH3COOH, 0e5 ꢀC. R]eH, methyl, ethyl, phenyl, 2-methylphenyl, 3-
methylphenyl, 4-methylphenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-chloro-4-fluorophenyl.

J. Saravanan et al. / European Journal of Medicinal Chemistry 45 (2010) 4365e4369
4367
Table 2
Minimum inhibitory concentration of the titled compounds and Ampicillin, Mico-
nazole nitrate as a standard in g/ml concentrtation.
Table 4
Comp no.
R
Antifungal activity
Zone of Inhibition in mm
m
Compd No.
Antimicrobial activity
Antifungal activity
An
Ca
Cn
Gm þVe
Gm ꢁVe
Ia
IIa
eH
Methyl
Ethyl
Phenyl
2-Methylphenyl
3-Methylphenyl
4-Methylphenyl
4-Fluorophenyl
2-Chlorophenyl
3-Chlorophenyl
4-Chlorophenyl
3-Chloro-4-fluorophenyl
Miconazole nitrate
04
06
06
06
06
08
08
10
14
13
16
10
16
03
04
05
04
04
04
05
08
08
08
10
07
12
NA
NA
NA
NA
NA
06
05
08
09
08
10
08
14
Sa
Se
E.coli
St
An
Ca
Cn
IIIa
IVa
Va
VIa
VIIa
VIIIa
IXa
Xa
Ia
IIa
IIIa
IVa
Va
VIa
VIIa
VIIIa
IXa
Xa
XIa
XIIa
Ampicillin
37.5
37.5
37.5
25
25
25
37.5
37.5
37.5
25
25
25
25
6.75
12.5
12.5
12.5
12.5
50
50
50
37.5
37.5
37.5
37.5
12.5
25
25
25
25
4
37.5
37.5
37.5
37.5
25
37.5
37.5
37.5
37.5
25
50
50
50
50
37.5
37.5
37.5
37.5
25
25
25
37.5
e
125
125
125
125
75
75
75
75
50
25
25
25
25
25
6.75
12.5
12.5
12.5
12.5
0.5
12.5
12.5
12.5
12.5
12.5
12.5
12.5
12.5
12.5
25
XIa
XIIa
50
37.5
50
An ¼ Aspergillus niger, Ca ¼ Candida albicans & Cn ¼ Cryptococcus neoformans.
Zone of inhibition in mm at a concentration of 50 g/ml.
1.56
6.25
e
e
m
Miconazole nitrate
10
12.5
20
The formation of the thienotriazine-4-ones was confirmed by
their preliminary observations including M.P, Rf values, UV
absorption maxima and IR spectra, compared to their starting
materials.
The formation of the starting compound I was confirmed by
its IR spectra where the two strong stretching band at
3180 cmꢁ1e3350 cmꢁ1 are due to the presence of primary amide
group and two prominent peaks between 3300 and 3500 cmꢁ1 of
primary amine and stretching band at 1666 cmꢁ1 accounting for
amide carbonyl group. The compound II illustrates only one
amide peak at 3320 cmꢁ1 due to the presence of 2ꢀ amide and an
additional stretching band at 2900 cmꢁ1 and a bending absorp-
tion at 1360 cmꢁ1 for the methyl group present in the compound.
The compound III has additional band at 1455 cmꢁ1 accounting
for the methylene group Compared to the compound II. The
formation of remaining compounds (No. IV to XII) were
confirmed by the presence of strong stretching band at
3050e3010 cmꢁ1 due to aromatic ]CeH and a pair stretching
band at 1600 and 1490 cmꢁ1 accounting for C]C.
The UV absorption spectra of the new thienotriazines exhibi-
ted a bathochromic shift (20e25 nm) from their starting materials
due to aryl cyclization. The formation of the thienotriazines were
also confirmed by the shift of IR peaks between 1630 and
1640 cmꢁ1 as seen in the starting materials to 1690e1700 cmꢁ1 in
the final compounds indicating the aryl cyclization due to the
cyclic keto group and absence of the prominent peaks between
3300 and 3460 cmꢁ1 of eNH2 in triazines compared to their
starting thiophenes. The 1H NMR of the compounds adds to the
proof for the formation of the new thienotriazines. The 1H NMR of
the compound Ia show the singlet peak at 8.1 and the absence of
the singlet peak at 4.9 due to the primary amino group add to the
proof for the formation of the new thienotriazines. In the 1H NMR
of the compound IIa showed the singlet peak at 2.74 accounts for
the presence of methyl group. For the remaining compounds
(Nos. IVaeXIIa) the attachment of Un/substituted phenyl groups
was confirmed by the presence of the corresponding peaks
between 6.5 and 8.0.
Table 3
The results of antimicrobial study of the title compounds were
illustrated in the Tables 2e4.
O
From the antimicrobial activity results of the title compounds it
was concluded that the compounds with liphophilic substitutions
at the phenyl ring were more effective against all the organisms
used than the unsubstituted phenyl ring. Particularly the
compound VIIIa with 4-fluorophenyl substitution exhibited
N
N
R
S
N
IaeXIIa
excellent inhibition at MIC 6.75
m
g/mL against tested gram þve
Comp no. R
Antibacterial activity Zone of
Inhibition in mm
bacteria and 12.5 g/mL against gram eve bacteria. In case of the
m
antifungal activity the compound having 4-chlorophenyl substitu-
tion at R as in XIa shown promising activity.
Sa
Se
Ec
St
IIa
Methyl
Ethyl
Phenyl
2-Methylphenyl
3-Methylphenyl
4-Methylphenyl
4-Fluorophenyl
2-Chlorophenyl
3-Chlorophenyl
4-Chlorophenyl
16
18
20
20
24
28
32
30
32
34
26
40
18
16
17
18
20
28
32
30
30
32
24
36
12
16
12
14
14
20
26
24
26
26
24
28
14
16
12
12
14
18
24
20
24
26
20
26
The MIC study also confirms that the potency of the title
compounds are based on the substituents attached to the phenyl
group. Finally among the compounds screened, the compound XIa
with 4-chlorophenyl substituent at R on triazine4-one nucleus was
potent against all types of bacteria and fungi employed.
IIIa
IVa
Va
VIa
VIIa
VIIIa
IX a
Xa
5. Experimental
XIa
XIIa
3-Chloro-4-fluorophenyl
Ampicillin
Analytical TLC was performed on Silica plates- GF254 (Merck)
with visualization by UV or iodine vapors. Melting points were
determined in open capillaries on a Thermonic Melting point
apparatus and are uncorrected. The IR spectra (KBr, cmꢁ1) were run
Sa ¼ Staphylococcus aureus, Se ¼ Staphylococcus epidermidis, Ec ¼ Escherichia coli,
St ¼ Salmonella typhi.
Zone of inhibition in mm at a concentration of 50
mg/ml.

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J. Saravanan et al. / European Journal of Medicinal Chemistry 45 (2010) 4365e4369
on Perkin Elmer FTIR Spectrophotometer. 1H NMR (in CDCl3/DMSO-
d6) spectra were recorded using Bruker AMX-400 with TMS as
internal standard. MS spectra were recorded on (AMD-604).
Elemental analyses were performed on Carlo Erba 1108 elemental
analyzer and were within ꢂ0.4% of theoretical values. The result of
elemental analysis is tabulated in the Table 5. All the chemicals
used were of analytical grade.
mixture was cooled to a temperature below 5 ꢀC. To this mixture an
ice cold solution of NaNO2 (0.03 mol) in water (25 ml) was added
drop wise with constant stirring. Temperature was maintained
below 5 ꢀC. The product separated as bright yellow solid, which was
filtered, dried and washed with methanol to obtain pure triazines
(IaeXIIa).
5.2.1. 4,5-Tetramethylene thieno-[2,3-d][1,2,3]-triazin-4(3H)-ones:
(Ia)
5.1. General procedure for the syntheses of 2-aminoe3-N-
substituted carboxamido/carboxanilidoe4,5-tetra methylene
thiophenes (IeXII)
M.P: 168e169 ꢀC yield: 52% IR max cmꢁ1 ¼ eSCH 2940, eNH
3300e3200, eCO ꢁ1660. NMR: Solvent CDCl3, 8.2(s, 1H, eNH
proton), 2.6 (m, 4H, methylenic proton), 1.5 (m, 4H, methylenic
proton). MS (%) 207.04 (100%), 208.06 (9.7%), 209.05 (4.5%), 208.04
(1.1%).
A mixture of appropriate active methylenic ketone (0.04 mol),
substituted cyano acetamide/acetanilide (0.04 mol), ammonium
acetate (2 g) and glacial acetic acid (2 ml) in cyclohexane (80 ml)
was refluxed for 10 h in a Dean stark apparatus with an arrange-
ment for water separation. The reaction mixture was cooled,
diluted with cyclohexane and washed successively with water, 10%
aqueous sodium carbonate solution, and dried over anhydrous
sodium sulphate. The solvent was removed under vacuum. The
crude alpha (N-substituted carboxamido/carboxanilido) acetoni-
trile derivative thus obtained was employed directly for further
reaction.
To a mixture of the above crude intermediate and sulphur
(0.04 mol) in ethanol (40 ml) was added diethylamine (4.0 ml) drop
wise with stirring. The mixture was stirred for 1 h at 45e50 ꢀC,
chilled overnight and the solid obtained was filtered washed with
ethanol to yield yellow crystalline solids. Recrystallized from suit-
able solvents. Yield e 45e50%
5.2.2. 3-N-Methyl-4,5-tetramethylene thieno-[2,3-d][1,2,3]-triazin-
4-(3H)-ones:(IIa)
M.P: 103e105 ꢀC yield: 46% IR max cmꢁ1 ¼ Ar-CH 3024.83: -Ali-
CH 2978.54; Arom C]C 1506.46; eCO ꢁ1660; (CeN)ꢁ746.23 NMR:
Solvent -CDCl3: 3.1 (s, 3H, e CH3), 2.8 (m, 4H, methylenic protons),
1.4 (m, 4H, methylenic protons). MS (%) 221.06 (Mþ 100.0%), 222.07
(11.3%), 223.06 (4.6%), 222.06 (1.9%).
5.2.3. 3-N-Ethyl-4,5-tetramethylene thieno-[2,3-d][1,2,3]-triazin-4-
(3H)-ones:(IIIa)
M.P: 131e134 ꢀC yield: 49% IR max cmꢁ1 ¼ -Ar-CH 3027.53: -Ali-
CH 2988.42; Arom C]C 1505.46; e CO ꢁ1682; (CeN)ꢁ753. 32
NMR: Solvent e CDCl3 3.0 (q, 2H, -CH2), 1.3 (t,3H, eCH3), 2.4 (m,4H,
methylenic protons), 1.6 (m,4H, methylenic protons). MS (%) 235.08
(Mþ 100.0%), 236.08(13.3%), 237.07 (4.4%), 237.08 (1.1%), 236.07
(1.1%).
5.2. General method for the syntheses of 4,5-tetramethylene thieno
[2,3-d][1,2,3]-triazin-4(3H)-ones (IaeXIIa)
5.2.4. 3-N-Phenyl-4,5-tetramethylene thieno[2,3-d][1,2,3]-triazin-
4-(3H)-ones: (IVa)
A mixture of the corresponding 2-amino-3-N-(substituted car-
boxamido/carboxanilido)-4,5-substituted
(0.01 mol) in 30 ml of glacial acetic acid was warmed until the
starting material dissolved. The mixture was cooled to room
temperature, 20 ml of concentrated HCl was added and the reaction
M.P: 112-114 ꢀC yield: 47% IR max cmꢁ1 ¼ Ar-CH 3035.23: -Ali-
CH 2982.54; Arom C]C 1498. 63; e CO ꢁ1692; (CeN) ꢁ759.23
NMR: Solvent eCDCl3 7.25e7.5 (m, 5H, Arom), 2.5 (m,4H, methyl-
enic proton), 1.5 (m,4H, methylenic protons). MS (%) 283.08 (Mþ
100.0%), 284.08(17.7%), 285.07 (4.4%), 285.08 (1.8%), 284.07(1.1%).
thiophenes
(IeXII)
5.2.5. 3-N-(2-Methylphenyl)-4,5-tetramethylene thieno[2,3-d]
[1,2,3]-triazin-4-(3H)-ones:(Va)
Table 5
Elemental Analysis of the synthesized compounds (IaeXIIa).
M.P: 121e122 ꢀC yield: 51% IR max cmꢁ1 ¼ Ar-CH 3044.93: -Ali-
CH 2967.98; Arom C]C 1502.37; eCO ꢁ1710; (CeN) ꢁ739.25.
NMR: Solvent eCDCl3 7.1(t, 3H, Arom)-6.7(s, 1H, Arom), 2.3 (s, 3H,
methyl protons), 2.6 (m, 4H, methylenic proton), 1.7(m, 4H, meth-
ylenic protons). MS (%) 297.09 (Mþ 100.0%), 298.07 (17.3%), 299.08
(4.5%), 299.10 (1.4%), 298.091(1.1%).
Compd Mol. Formula Mol. Elemental Analysis
No
Wt
Theoretical
207 C ¼ 52.16; H ¼ 4.38;
Found
Ia
C9H9N3OS
C ¼ 52.19; H ¼ 4.31;
N ¼ 20.27; S ¼ 15.47 N ¼ 20.27; S ¼ 15.44
IIa
C10H11N3OS
C11H13N3OS
221 C ¼ 54.29; H ¼ 5.01;
C ¼ 54.28; H ¼ 4.96;
N ¼ 18.99; S ¼ 14.49 N ¼ 19.42; S ¼ 14.11
IIIa
IVa
Va
235 C ¼ 56.17; H ¼ 5.5;
C ¼ 56.58; H ¼ 5.02;
N ¼ 17.87; S ¼ 13.61 N ¼ 18.34; S ¼ 13.27
5.2.6. 3-N-(3-methylphenyl)-4,5- tetramethylene thieno[2,3-d]
[1,2,3]-triazin-4-(3H)-ones:(VIa)
C15H13N3OS
283 C ¼ 63.58; H ¼ 4.62;
C ¼ 63.60; H ¼ 4.63;
N ¼ 14.84; S ¼ 11.32 N ¼ 14.82; S ¼ 11.33
297 C ¼ 64.62; H ¼ 5.08; C ¼ 64.64; H ¼ 5.07;
N ¼ 14.14; S ¼ 10.77 N ¼ 14.17; S ¼ 10.76
297 C ¼ 64.62; H ¼ 5.08; C ¼ 64.59; H ¼ 5.07;
N ¼ 14.14; S ¼ 10.77 N ¼ 14.12; S ¼ 10.78
297 C ¼ 64.62; H ¼ 5.08; C ¼ 64.66; H ¼ 5.09;
M.P: 138e140 ꢀC yield: 64% IR max cmꢁ1 ¼ Ar-CH 3013.34:
-Ali-CH 2963.25; Arom C]C 1507.26; eCO ꢁ1684; (CeN)
ꢁ742.25. NMR: Solvent e CDCl3 7.4(d, 2H, Arom), 7.1(s,1H, Arom),
6.7(s,1H, Arom) 2.4(s,3H, methyl protons), 1.7 (m, 4H, methylenic
protons), 2.2 (m,4H, methylenic protons MS (%) 297.80 (Mþ
100.0%), 298.69 (17.3%), 299.88 (4.5%), 299.10 (1.4%), 298.29
(1.1%).
C16H15N3OS
C16H15N3OS
C16H15N3OS
VIa
VIIa
VIIIa
IXa
Xa
N ¼ 14.14; S ¼ 10.77 N ¼ 14.15; S ¼ 10.78
C
15H12N3OSF 301 C ¼ 59.80; H ¼ 4.01;
C ¼ 59.91; H ¼ 4.02;
N ¼ 13.95; S ¼ 10.64 N ¼ 13.93; S ¼ 10.67
C15H12N3OSCl 317.5 C ¼ 56.69; H ¼ 3.81;
C ¼ 56.56; H ¼ 3.80;
N ¼ 13.22; S ¼ 10.07 N ¼ 13.26; S ¼ 10.09
5.2.7. 3-N-(4-methylphenyl)-4,5-tetramethylene thieno[2,3-d]
[1,2,3]-triazin-4-(3H)-ones:(VIIa)
C15H12N3OSCl 317.5 C ¼ 56.69; H ¼ 3.81;
C ¼ 56.72; H ¼ 3.82;
N ¼ 13.22; S ¼ 10.07 N ¼ 13.19; S ¼ 10.10
M.P: 175e176 ꢀC yield: 71% IR max cmꢁ1 ¼ -Ar-CH 3012.21: -Ali-
CH 2989.11; Arom C]C 1502.37; eCO ꢁ1697; (CeN) ꢁ762.31. NMR:
Solvent e CDCl3 7.2(d, 2H, Arom)ꢁ7.5 (d,2H, Arom), 2.3 (s,3H,
methyl protons), 2.8 (m,4H, methylenic proton), 1.5 (m,4H,
XIa
XIIa
C15H12N3OSCl 317.5 C ¼ 56.69; H ¼ 3.81;
C ¼ 56.60; H ¼ 3.82;
N ¼ 13.22; S ¼ 10.07 N ¼ 13.21; S ¼ 10.09
C
15H11N3OSClF 335.5 C ¼ 53.65; H ¼ 3.30;
C ¼ 53.75; H ¼ 3.31;
N ¼ 12.47; S ¼ 9.56
N ¼ 12.51; S ¼ 9.55

J. Saravanan et al. / European Journal of Medicinal Chemistry 45 (2010) 4365e4369
4369
methylenic proton). MS (%)297.80 (Mþ 100.0%), 297.14 (17.3%),
298.31 (4.5%), 299.62 (1.4%), 296.02 (1.1%).
NMR: Solvent eCDCl3 7.7(s,1H, Arom), 7.4(d,2H, Arom), 2.4 and 1.5
(m,8H, tetramethylenic protons). MS (%) 335.03 (Mþ 100.0%),
337.04(37%), 336.03 (18.2%), 338.05 (6.4%), 319.03(4.4%), 321.03
(1.4%), 319.05(1.3%).
5.2.8. 3-N-(4-flouorophenyl)e4,5-tetramethylene thieno[2,3-d]
[1,2,3]- triazin-4-(3H)-ones:(VIIIa)
M.P: 154-156 ꢀC yield: 67%. IR max cmꢁ1 ¼ -Ar-CH 3015.61: -Ali-
CH 2981.93; Arom C]C 1510.43; eCO ꢁ1694; (CeN)ꢁ777.26. NMR:
Solvente CDCl3 7.1 (d, 2H, Arom), 7.8 (d,2H, Arom), 2.6 (m,4H,
methylenic proton) 1.5 (m,4H, methylenic protons). MS (%) 301.07
(Mþ 100.0%), 302.07 (18.6%), 303.06 (5.2%), 303.09 (1.7%),
Acknowledgement
The authors are thankful to Peoples Education Society
management for providing all necessary facilities to carry out the
research work.
5.2.9. 3-N-(2-chlorophenyl)e4,5- tetramethylene thieno[2,3-d]
[1,2,3]-triazin-4-(3H)-ones: (IXa)
M.P: 145e146 ꢀC yield: 76% IR max cmꢁ1 ¼ -Ar-CH 3098.35: -Ali-
CH 2968.57; Arom C]C 1508.24; eCO e1688; (CeN) ꢁ773.42
NMR: Solvent eCDCl3 7.9 (s,1H, Arom), 7.2(d,2H, Arom), 6.8 (s,1H,
Arom), 2.5 (m,4H, methylenic protons), 1.6 (m,4H, methylenic
protons). MS (%) 317.04 (Mþ 100.0%), 319.04(32.5%), 318.04 (18.6%),
320.04 (6.4%), 319.03(4.4%), 321.03(1.4%), 319.05(1.3%).
References
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-Ali-CH 2978.57; Arom C]C 1508.24; eCO ꢁ1688; (CeN) ꢁ773.42
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5.2.11. 3-N-(4-chlorophenyl)-4,5-tetramethylene thieno[2,3-d]
[1,2,3]-triazin-4-(3H)-ones: (XIa)
M.P: 110e112 ꢀC yield: 62% IR max cmꢁ1 ¼ Ar-CH 3098.35: -Ali-
CH 2968.57; Arom C]C 1508.24; eCO ꢁ1688; (CeN) ꢁ773.42
NMR: Solvent eCDCl3 7.2(d,2H, Arom), 7.8 (d,2H, Arom), 2.8 (m,4H,
methylenic protons),1.6 (m,8H, methylenic protons). MS (%) 317.04
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5.2.12. 3-N-(3-Chloro-4-fluorophenyl)e4,5-tetramethylene thieno
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