Synthesis of some new 2-(4-nitrobenzothiazol-2'-ylamino)-4-(2-chloro-4- trifluoromethylanilino)-6-(substituted thioureido)-1,3,5-triazines as antifungal agents

Article abstract of DOI:10.1080/10426500701544474

Some new 2-(4-nitrobenzothiazol-2'-ylamino)-4-(2-chloro-4-trifluoro- methylanili- no)-6-(substituted thioureido)-1,3,5-triazine 4 have been prepared by reacting 2,4,6-trichloro-1,3,5-triazine with nucleophilic reagents, 2-amino-4-nitrobenzothiazol 1, 2-ch

Full text of DOI:10.1080/10426500701544474

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Phosphorus, Sulfur, and Silicon
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Synthesis of Some New 2-
(4-Nitrobenzothiazol-2′-
ylamino)-4-(2-chloro-4-
trifluoromethylanilino)-6-
(substituted Thioureido)-1,3,5-
triazines as Antifungal Agents
Vineeta Sareen a , Vineeta Khatri a , Urmila Garg a
Prakash Jain a & Kanti Sharma b
,
a Department of Chemistry , University of
Rajasthan , Jaipur, India
b Department of Chemistry , S.K. Govt. P.G.
College , Sikar, Rajasthan, India
Published online: 03 Dec 2007.
To cite this article: Vineeta Sareen , Vineeta Khatri , Urmila Garg , Prakash Jain &
Kanti Sharma (2007) Synthesis of Some New 2-(4-Nitrobenzothiazol-2′-ylamino)-4-
(2-chloro-4-trifluoromethylanilino)-6-(substituted Thioureido)-1,3,5-triazines as
Antifungal Agents, Phosphorus, Sulfur, and Silicon and the Related Elements, 182:12,
2943-2948, DOI: 10.1080/10426500701544474
To link to this article: http://dx.doi.org/10.1080/10426500701544474
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Phosphorus, Sulfur, and Silicon, 182:2943–2948, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701544474
Synthesis of Some New
2-(4-Nitrobenzothiazol-2ꢀ-ylamino)-4-(2-chloro-4-
trifluoromethylanilino)-6-(substituted
Thioureido)-1,3,5-triazines as Antifungal Agents
Vineeta Sareen
Vineeta Khatri
Urmila Garg
Prakash Jain
Department of Chemistry, University of Rajasthan, Jaipur, India
Kanti Sharma
Department of Chemistry, S.K. Govt. P.G. College, Sikar, Rajasthan,
India
Some new 2-(4-nitrobenzothiazol-2ꢀ-ylamino)-4-(2-chloro-4-trifluoro-methylanili-
no)-6-(substituted thioureido)-1,3,5-triazine 4 have been prepared by reacting 2,4,6-
trichloro-1,3,5-triazine with nucleophilic reagents, 2-amino-4-nitrobenzothiazol 1,
2-chloro-4-trifluoromethylaniline 2 and different substituted thioureas 3 to give
the title compound. These compounds are evaluated for their antimicrobial activ-
1
ity. The structure of all of these compounds has been confirmed by IR, H NMR,
19
F NMR, mass spectral data and elemental analysis.
Keywords 2-(4-Nitrobenzothiazol-2ꢀ-ylamino)-4,6-dichloro-1,3,5-triazine; 2-(4-Nitro-
benzothiazol-2ꢀ-ylamino)-4-(2-chloro-4-trifluoromethyl-anilino) -6-chloro-1,3,5-triazine,
2- (4-Nitrobenzothiazol-2ꢀ-ylamino) -4-(2-chloro-4-trifluoromethylanilino)-6-(substituted
thioureido)-1,3,5-triazine; antimicrobial activity
INTRODUCTION
Benzothiazoles, s-triazines, and thioureas exhibit various biologi-
cal activities.1 In continuation of our work on triazines,2,3 we have
synthesized some new fluorinated derivatives of 2,4,6-trisubstituted
1,3,5-triazine with enhanced fungicidal activity. Fungicidal activity
was evaluated against Alternaria alternata, Aspergillus niger, and
Macrophomina. Three chlorine atoms of 2,4,6-trichloro-1,3,5-triazine
Received October 30, 2006; accepted June 18, 2007.
Address correspondence to Kanti Sharma, Department of Chemistry, S.K. Govt. P.G.
College, Sikar, Rajasthan 332001, India. E-mail: drkanti@gmail.com
2943

2944
V. Sareen et al.
(cyanuric chloride) have been replaced subsequently by 2-amino-4-
nitrobenzothiazole (which in turn is prepared by condensing nitroani-
line with ammonium thiocyanate,3 2-chloro-4-trifluoromethyl aniline
and substituted thioureas in alkaline medium selectivity to give the
title compound 4 (Scheme-1).
SCHEME 1

Triazines as Antifungal Agents
2945
RESULTS AND DISCUSSION
2-(4-Nitrobenzothiazol-2ꢀ-ylamino)-4,6-dichloro-1,35-triazine
2
has
been prepared by treating cyanuric chloride in acetone with 2-amino-
4-nitrobenzothiazol 1 at 0–5◦C and stirring for 3 h. The second chlorine
atom of 2 has been replaced by 2-chloro-4-trifluoromethylaniline
at 30–40◦C in acetone by constant stirring for 3 h to give 2-(4-
nitrobenzothiazol-2ꢀ-ylamino)-4-(2-chloro-4-trifluoromethylanilino)-6-
chloro-1,3,5-trizine 3. The third chlorine atom of 3 has been replaced
by different substituted thioureas at 80–90◦C in acetone to give 2-(4-
nitrobenzothiazol-2ꢀ-ylamino)-4-(2-chloro-4-trifluoromethylanilino)-6-
(substituted thioureido)-1,3,5-triazine 4.
Compound 2 showed the presence of >NH group in both of its IR
spectrum (3160 cm–1) and 1H NMR spectrum which showed a signal at
δ 9.2 ppm.
–1
The IR spectrum of compound 3 showed peak at 3150 cm (broad
1
band for >NH) and its H NMR shows peak at δ 9.7 (a singlet for two
>NH protons). Further, in 19F NMR it shows peak at δ −5 to −10 ppm
for ≥C CF3 group. Mass spectrum shows M+ at m/z 501.9. Compound
4a showed peaks at 3140 (>NH, broad) 3080 (>NHCSNH<) and 1115
(CS) cm–1 in IR spectrum. 1H NMR show peaks at δ 9.8 (brs, two > NH),
δ 4.9 (>NHCSNH<) and δ.5–7.8 ppm for aromatic protons. In 19F NMR
peaks at δ −5 to 10 for (≥C–CF3) and −30 to −40 ppm for (≥C–F) group
was observed. Finally, mass spectrum of 4a shows M+ at m/z 635.5.
FUNGICIDAL ACTIVITY
Compounds 4a–g were screened for antifungal activity against Al-
ternaria alternata, Aspergillus niger and Macrophomina using agar
diffusion techniques4. Culture media were prepared using aseptic and
sterilization techniques. Incubation period is 72 h at 28◦C. All the solu-
tions of the test compounds were prepared by dissolving 1 mg of testing
sample in 1 ml of acetone. This gives the conc. of sample 1000 µg/mL or
1000 ppm. Different solutions such a 500 and 100 ppm were prepared
from the sample solution. Pure cultures of Alternaria alternata. As-
pergillus niger, and Macrophomina were raised in conical flask (100 mL)
containing potato dextrose agar (PDA) medium. The sporequery ob-
tained from 10-day old cultures were used for testing the efficacy of test
compounds against inhibition of spore germination. Sterilized acetone
was used as control. Percent spore inhibition is calculated by formula
as –
Number of spores ungerminated
% inhibition =
× 100
(1)
Total number of spores

2946
V. Sareen et al.
TABLE I Physical and Analytical Data of the Compounds 4a–h
Analysis % found (calcd.)
Yield M.P.
(%)
Mol. formula
(mol. wt.)
Compound
(◦C)
C
H
N
S
4a
75
205
C24H14N9O2S2ClF4
(635.5)
45.29
2.18
19.80
10.00
(45.31) (2.20) (19.82) (10.07)
45.28 2.19 19.80 10.00
(45.31) (2.20) (19.82) (10.07)
43.74
(43.76) (2.04) (18.38)
43.45 2.09 21.11
(47.47) (2.11) (21.13)
47.48 2.66 19.93
(47.50) (2.69) (19.95) (10.13)
46.61 2.40 20.38 10.34
(46.63) (2.42) (20.40) (10.36)
38.79 2.13 25.13 11.48
(38.81) (2.15) (25.15) (11.50)
43.30 2.55 21.64 10.99
(43.33) (2.57) (21.66) (11.00)
4b
4c
4d
4e
4f
70
60
65
70
50
70
60
174
200
160
185
180
165
190
C
24H14N9O2S2ClF4
(635.5)
C25H14N9O2S2ClF6
(685.5)
2.00
18.36
9.30
(9.33)
9.63
(9.66)
10.11
C24H14N10O4S2ClF3
(662.5)
C25H17N9O2S2ClF3
(631.5)
C
24H15N9O2S2ClF3
(617.5)
4g
4h
C18H12N10O2S2ClF3
(556.5)
C
21H15N9O2S2ClF3
(581.5)
Evaluation of the fungicidal activity shows that compounds 4a, 4b,
4c, and 4e showed maximum inhibition which may be attributed to
maximum fluoro substitution in compound 4a, 4b, and 4c, while in com-
pound 4e presence of CH3 group along with fluoro group also activates
the compound. The fungicidal screening results are recorded in Table II.
EXPERIMENTAL
Purity of all the compounds was checked on silica gel G plates using
iodine vapor as the detecting agent. Melting points were determined
TABLE II Fungicidal Screening Data of Compounds 4a–h
Average % inhibition of spore germination after 72 h
Alternaria alternata
Aspergillus niger
Macrofomina
Compound
100
500
1000
100
500
1000
100
500
1000
4a
4b
4c
4d
4e
4f
32
31
38
28
30
30
29
30
44
42
49
37
35
36
38
40
68
66
72
55
62
59
56
60
30
31
39
27
29
30
27
29
41
41
50
35
40
35
38
38
69
68
73
53
61
58
57
58
30
31
30
27
26
29
28
30
42
41
50
36
38
35
38
39
70
69
72
56
63
58
56
59
4g
4h

Triazines as Antifungal Agents
2947
in open capillary tubes using Gallenkamp melting point apparatus and
are uncorrected. IR spectra were recorded on a Perkin Elmer 577 spec-
1
trophotometer in KBr pellets. H NMR spectra (chemical shifts in δ
ppm) were recorded at 89.99 MHz using GEOL (model Al-300) appa-
ratus with TMS as the internal standard. In 19F NMR spectra TFA
was taken as an external standard. The mass spectra were recorded
on Kratos MS-30 and MS-50 spectrometer operating at an ionization
potential of 70 eV.
2-(4-Nitrobenzothiazol-2ꢀ-ylamino)-4,6-dichloro-
1,3,5-traizine (2)
A solution of 2-amino-4-nitrobenzothiazole (1.63 g, 0.1 mmol) in ace-
tone was added with constant stirring to a cooled solution (0–5◦C) of
2,4,6-trichloro-1,3,5-triazine (1.84 g, 0.1 mmol) in acetone. The solution
was kept alkaline during the reaction with sodium hydroxide (0.4 g,
0.1 mmol). The reaction mixture was stirred for 2 h at 0–5◦C. It was
then poured into the crushed ice, acidified with diluted HCl and re-
sulting solid was dried and crystallized from ethanol. m.p. 163◦C, yield
(71%); IR (KBr) νmax : 3160 (>NH); 1340 (N=O)2asym, 1520 (N=O)2sym
1
and 740 (≥C Cl); H NMR (CDCl3) : δ 9.2 (s, 1H, >NH), 6.6–7.5 (m,
3H, aromatic). (Found C, 34.97, H, 1.16, N, 24.47, S, 9.34, S, 9.34,
C10H4N6SCl2O2 requires C, 34.99, H, 1.17, N, 24.49, S, 9.36%).
2-(4-Nitrobenzothiazol-2ꢀ-ylamino)-4-(2-chloro-4-
trifluoromethylanilino)-6-chloro- 1,3,5-triazine (3)
2-(4-Nitrobenzothiazol-2ꢀ-ylamino)-2,4-dichloro-1,3,5-traizine (3.53 g,
0.1m mole) dissolved in acetone (100 ml) was added 2-chloro-4-
trifluoromethylaniline (1.80, 0.1 mmol) in acetone (100 ml) slowly with
constant stirring, followed by the addition of sodium hydroxide (0.4 g,
0.1mmol) in water (50 ml) stirred for 3 h at 30–40◦C poured into ice
water, acidified with diluted HCl, filtered, washed with water, dried,
and crystallized from ethanol. m.p., 180◦C, yield (65%); IR (KBr) νmax
:
3150 (br) (>NH), 1340, 1520 ( NO2), 745 (≥C Cl). 1H NMR (CDCl3) :
δ 9.7 (s, 2H, 2x > NH), 6.6–7.8 (m, 6H, aromatic), 19F NMR : δ (−5) to
(−10) (≥C CF3), MS : 501.9 (m/z). (Found C, 40.62, H, 1.57, N, 19.50, S,
6.35, C17H8N7O2Cl2SF3 requires C, 40.64, H, 1.59, N, 19.52, S, 6.37%).
2-(4-Nitrobenzothiazol-2ꢀ-ylamino)-4-(2-chloro-4-trifluoro-
methylanilino)-6-(substituted Thioureido)-1,3,5-triazine (4)
Compound 3 (1 mmol) dissolved in acetone was added to al-
lyl thiourea/thiosemicarbazide/substituted thiourea/arylthiourea (1

2948
V. Sareen et al.
mmole) in acetone (100 ml) slowly with constant stirring, followed by the
addition of sodium (1 mmol) in water (50 ml) and stirred for 3 h at 30–
40◦C poured into ice water, acidified with diluted HCl, filtered, washed,
dried, and crystallized from ethanol, 4a, m.p. 205◦C, yield (75%); IR
(KBr) νmax : 3140 (>NHbr) 3080 (>NHCSNH<), 1340, 1520 ( NO2),
1115 (thioureido CS), 740 (≥C Cl). 1H NMR (CDCl3)δ : 4.9 (s, 2H, NHC-
SNH), 9.8 (br, 2H, 2x > NH), 6.5–7.8 (m, 9H, aromatic), 19F NMR : δ
(−5) to (−12) (≥CF3), 30–40 (≥C F), MS : 635.5 (m/z). (Found C, 45.29,
H, 2.18 N, 19.80, S, 10.00. C24H14N9O2S2ClF4 require C, 45.31, 2.20, N,
19.82, S, 10.07%).
Compounds 4b–h were prepared similarly. Their physical and ana-
lytical data are recorded in Table I.
REFERENCES
[1] P.S. Desai and K.R. Desai, J. Indian Chem. Soc., 71, 155 (1994).
[2] V. Sareen, V. Khatri, U. Gupta, P. Jain, and K. Sharma, Indian J. Heterocyclic Chem.,
15(2), 193 (2005).
[3] V. Sareen, V. Khatri, P. Jain, and K. Sharma, Indian J. Chem. B, 45(5), 1288 (2006).
[4] M. C. Bryant, Antibiotics and Their Laboratory Control (Butterworth, London, 1968),
Vol. 26.