Synthesis of some new 2-(4-methoxybenzothiazol-2′-yl amino)-4-(2-chloro-4-trifluoromethylanilino)-6-(substituted thioureido)-1,3,5- triazine as antifungal agents

Article abstract of DOI:10.1080/10426500902717754

2,4,6-Trichloro 1,3,5-triazine was selectively reacted with new nucleophilic reagents such as 4-methoxy-2-aminobenzothiazole, 2-chloro-4-trifluoromethyl-aniline, and phenylsubstituted thiourea in alkaline medium to give 2-(4-methoxybenzothiazol-2′-ylamino

Full text of DOI:10.1080/10426500902717754

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Phosphorus, Sulfur, and Silicon and the
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Synthesis of Some New 2-(4-
Methoxybenzothiazol-2′-yl amino)-4-
(2-chloro-4-trifluoromethylanilino)-6-
(substituted thioureido)-1,3,5-triazine as
Antifungal Agents
Vineeta Sareen a , Vineeta Khatri a , Prakash Jain a & Kanti Sharma b
a Department of Chemistry , University of Rajasthan , Jaipur,
Rajasthan, India
b Department of Chemistry , R.L. Saharia Govt. P.G. College ,
Kaladera, Jaipur, Rajasthan, India
Published online: 28 Dec 2009.
To cite this article: Vineeta Sareen , Vineeta Khatri , Prakash Jain & Kanti Sharma (2009) Synthesis of
Some New 2-(4-Methoxybenzothiazol-2′-yl amino)-4-(2-chloro-4-trifluoromethylanilino)-6-(substituted
thioureido)-1,3,5-triazine as Antifungal Agents, Phosphorus, Sulfur, and Silicon and the Related
Elements, 185:1, 140-146
To link to this article: http://dx.doi.org/10.1080/10426500902717754
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Phosphorus, Sulfur, and Silicon, 185:140–146, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902717754
SYNTHESIS OF SOME NEW
2-(4-METHOXYBENZOTHIAZOL-2ꢀ-YL
AMINO)-4-(2-CHLORO-4-TRIFLUOROMETHYLANILINO)-6-
(SUBSTITUTED THIOUREIDO)-1,3,5-TRIAZINE AS
ANTIFUNGAL AGENTS
Vineeta Sareen,1 Vineeta Khatri,1 Prakash Jain,1
and Kanti Sharma2
1Department of Chemistry, University of Rajasthan, Jaipur, Rajasthan, India
2Department of Chemistry, R.L. Saharia Govt. P.G. College, Kaladera,
Jaipur, Rajasthan, India
2,4,6-Trichloro 1,3,5-triazine was selectively reacted with new nucleophilic reagents such
as 4-methoxy-2-aminobenzothiazole, 2-chloro-4-trifluoromethyl-aniline, and phenylsub-
stituted thiourea in alkaline medium to give 2-(4-methoxybenzothiazol-2ꢀ-ylamino)-4-
(phenylthioureido)-6-(substitutedthioureido)-1,3,5-triazines. The structures of these
1
compounds were confirmed by IR, H NMR, 19F NMR, mass spectral data, and elemental
analysis. The compounds show fungicidal activity against Alternaria alternata, Aspergillus
niger, and Macrofomina.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Fungicidal activity; 2-(4-methoxybenzothiazol-2ꢁ-ylamino)-4-(2-chloro-4-trifluor-
omethylanilino)-6-chloro-1,3,5-triazine; 2-(4-methoxybenzothiazol-2ꢁ-ylamino)-4-(2-chloro-
4-trifluorophenylanilino)-6-(4-fluorophenyl thioureido)-1,3,5-triazine; 2-(4-methoxybenzothi-
azol-2ꢁ-ylamino)-4,6-dichloro-1,3,5-triazine
INTRODUCTION
It has been observed that the benzothiazole nucleus is associated with a broad spec-
trum of biological activities such as antimicrobial,1–4 anti-inflammatory,5 etc. Similarly
s-triazine derivatives have attained significance in agriculture as herbicides6 and fungi-
cides.6 They are also used for the treatment of HIV infection.7
We thought it would be interesting to construct a system that may combine these
biolabile8,9 rings together in a molecular framework to see the additive effects towards
antifungal activities. Further, the fluorinated derivatives are also prepared to enhance the
biological activity.10
Received 8 July 2008; accepted 2 December 2008.
Address correspondence to Kanti Sharma, Department of Chemistry, R.L. Saharia Govt. P.G. College,
Kaladera, Jaipur, 303801, Rajasthan, India. E-mail: drkanti@gmail.com
140

SYNTHESIS OF ANTIFUNGAL AGENTS
141
RESULTS AND DISCUSSION
In continuation of our work on triazines,11,12 we have synthesized some new flu-
orinated derivatives of 2,4,6-trisubstituted 1,3,5-triazine with enhanced fungicidal activ-
ity. The fungicidal activity was evaluated against Alternaria alternata, Aspergillus niger,
and Macrophomina. Three chlorine atoms of 2,4,6-trichloro-1,3,5-triazine (cyanuric chlo-
ride) have been replaced subsequently by 2-amino-4-methoxybenzothiazole (which in turn
is prepared by condensing p-methoxyaniline with ammonium thiocyanate,11 2-chloro-4-
trifluoromethyl aniline, and substituted thioureas in alkaline medium selectively to give the
title compound 4 (Scheme 1).
2-(4-Methoxybenzothiazol-2ꢁ-ylamino)-4,6-dichloro-1,3,5-triazine 2 was prepared
by treating cyanuric chloride in acetone with 2-amino-4-methoxy benzothiazol 1 at
0–5◦C and stirring for 3 h. The second chlorine atom of 2 was replaced by 2-chloro-4-
trifluoromethylaniline at 35–45◦C in acetone by constant stirring for 3 h to give 2-(4-
methoxybenzothiazol-2ꢁ -ylamino)-4-(2-chloro-4-trifluoromethylanilino)-6-chloro-1,3,5
-triazine 3. The third chlorine atom of 3 was replaced by different substituted thioureas
at 85–90◦C in acetone to give 2-(4-methoxybenzothiazol-2ꢁ-ylamino)-4-(2-chloro-4-
trifluoromethyl- anilino)-6-(substituted thioureido)-1,3,5-triazine 4.
2,4,6-Trichloro-1,3,5-triazine derivatives (cyanuric chloride) react selectively with
nucleophilic reagents.13 Cyanuric chloride is a weak base. If one of its chlorines is replaced
by -NHR, R, or SR, the basicity is increased because of the electron releasing effect of
these groups substituted at ∝-positions of the ring nitrogen atoms.
Compound 2 showed the presence of >NH group in both its IR spectrum 3150 cm−1
and 1H NMR spectrum, which showed a broad singlet at δ 9.8 (>NH).
The IR spectrum of compound 3 showed peak at 3150 cm−1 (broad band for >NH)
and its 1H NMR shows peak at δ 8.8 (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 487.
Compound 4a showed peaks at 3120 (>NH, broad), 3050 (>NHCSNH<), and 1115 (CS)
cm−1 in IR spectrum. 1H NMR show peaks at δ 8.9 (brs, two, >NH), δ 4.8 (>NHCSNH<),
δ 6.5–7.8 ppm for aromatic protons, and δ 3.4 ppm (s, OCH3). In 19F NMR, peaks at δ
−5 to −10 for ≥C CF3 and −30 to −40 ppm for ≥C CF group were observed. Finally,
mass spectrum of 4a shows M+ at m/z 619.5.
FUNGICIDAL ACTIVITY
Compounds 4a–i were screened for fungicidal activity against Alternaria alternata,
Aspergillus niger, and Macrophomina using the agar diffusion technique.14 (See the Sup-
plemental Materials online for more detailed information.)
EXPERIMENTAL
Purity of all the compounds was checked on silica gel G plates using iodine vapor
as the detecting agent. Melting points were determined in open capillary tubes using
Gallenkamp melting point apparatus and are uncorrected. IR spectra were recorded on a
Perkin Elmer 577 spectrophotometer in KBr pellets. 1H NMR spectra (chemical shifts in δ
ppm) were recorded at 89.99 MHz using GEOL (model AL-300) apparatus with TMS as

142
V. SAREEN ET AL.
Cl
N
OCH3
N
S
N
N
H2N
C
+
Cl
Acetone
Cl
1
(0-5°C)
Cl
N
OCH3
N
N
N
S
HN
C
Cl
2
Cl
NH2
Acetone
(35-45°C)
CF3
Cl
OCH3
N
N
N
S
Cl
HN
C
NH
N
3
F3C
Acetone
(85-90°C)
R-NHCSNH2
NHCSNH-R
N
OCH3
N
N
Cl
NH C
NH
N
S
4
F3C
Scheme 1 (Continued)

SYNTHESIS OF ANTIFUNGAL AGENTS
143
4a; R = 4-FC6H4
4e; R = 2-OCH3C6H4
4f; R = 2-CH3C6H4
4g; R = 2-NO2C6H4
4h; R = C6H5
4b; R = 2-FC6H4
4c; R = 2-CF3C6H4
4d; R = 4-ClC6H4
4i; R = CH2 = CH–CH2–
Scheme 1 (Continued)
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 ionization
potential of 70 ev.
2-(4-Methoxybenzothiazol-2ꢀ-ylamino)-4,6-dichloro-1,3,5-triazine (2)
To 2,4,6-trichloro-1,3,5-triazine (18.4 g, 1 mmol) dissolved in acetone (100 mL)
cooled at 0◦C, 4-methoxy-2-aminobenzothiazole (18.0 g, 1 mmol) dissolved in acetone
(100 mL) was added with stirring of NaOH (4.0 g, 1 mmol) in water (50 mL). The mixture
was stirred for 3 h then poured into ice water and acidified with dil HCl. The resulting
solid was washed with acetone, dried, and recrystallized from ethanol. Mp 204◦C, yield
(78%), IR (KBr) vmax: 3160 (>NH); 1380( OCH3); 1H NMR(CDCl3): 9.8 (s, 1H, >NH
6.5–6.8 (m, 3H, aromatic), 3.8 (s, 3H, OCH3), MS: 328 (m/z). (Found C, 40.27, H, 2.16,
N, 21.26, s, 9.79, C11H7N5Cl2OS requires C, 40.24, H, 2.13, N, 21.34, S, 9.75%).
2-(4-Methoxybenzothiazol-2ꢀ-ylamino)-4-(2-chloro-4-trifluoromethylanilino)-
6-chloro-1,3,5-triazine (3)
A solution of 2 (3.26 g, .0.1 mmol) dissolved in acetone (100 mL) was added to 2-
chloro-4-trifluoroaniline (19.5 g, 1 mmol) in acetone (100 mL) slowly with stirring followed
by the addition of NaOH (4.0 g, 1 mmol) in water (50 mL). The reaction mixture was stirred
for 3 h at 35–45◦C, then poured in ice water and acidified with dil HCl. The resulting solid
was washed with acetone, dried, and recrystallized from ethanol. Mp 180◦C, yield (74%);
1
IR (KBr) vmax: 3130 (>NH), 1350 ( OCH3), H NMR: 8.8 (s, 2H >NH), 6.4–6.8 (m,
6H, aromatic), 3.8 (s, 3H, OCH3), 19F NMR: (−5) to (−10) (≥C F), MS: 487 (m/z).
(Found C, 44.33, H, 2.31, N, 17.35, S, 6.54, C18H11N6Cl2F3OS requires C, 44.35, H, 2.25,
N, 17.24, S, 6.57%).
2-(4-Methoxybenzothiazol-2ꢀ-ylamino)-4-(2-chloro-4-trifluoromethylanilino)-
6-(4-fluorophenylthioureido)-1,3,5-triazine (4a)
To a solution of 3 (4.85 g, 0.1 mmol) in acetone (50 mL), 4-fluorophenylthiourea
(1.55 g, 0.1 mmol) and NaOH (0.1 mmol) in water (10 mL) were added, and the mixture was
refluxed at 85–90◦C for 2 h. It was poured into water acidified with dil HCl, and the resulting

144

SYNTHESIS OF ANTIFUNGAL AGENTS
145
Table II Spectral data of compounds 4a–i
Compound
IR (KBr) vmax (cm−1
)
1H NMR (CDCl3) δ (ppm)
4a
4b
4c
4d
4e
3120 (>NH, br); 3050 (>NHCSNH<);
1380 ( OCH3); 1115 (thioureido CS)
3130 (>NH, br); 3040 (>NHCSNH<);
1380 ( OCH3); 1120 (thioureido CS)
3120 (>NH, br); 3060 (>NHCSNH<);
1370 ( OCH3); 1130 (thioureido CS)
3140 (>NH, br); 3070 (>NHCSNH<);
1380 ( OCH3); 1140 (thioureido CS)
3120 (>NH, br); 3040 (>NHCSNH<);
1370 ( OCH3); 1120 (thioureido CS)
8.9 (s, 2H, >NH), 6.5–6.9 (m, 10H, aromatic), 4.8
(s, 2H, >NHCSNH<), 3.7 (s, 3H, −OCH3).
9.0 (s, 2H, >NH), 6.6–6.9 (m, 10H, aromatic), 4.7
(s, 2H, >NHCSNH<), 3.8 (s, 3H, −OCH3).
8.9 (s, 2H, >NH), 6.7–7.00 (m, 10H, aromatic), 5.0
(s, 2H, >NHCSNH<), 3.9 (s, 3H, −OCH3).
9.1 (s, 2H, >NH), 6.7–7.0 (m, 10H, aromatic), 5.0
(s, 2H, >NHCSNH<), 3.6 (s, 3H, −OCH3).
8.8 (s, 2H, >NH), 6.4–6.8 (m, 10H, aromatic), 4.7
(s, 2H, >NHCSNH<), 3.6 (s, 3H, −OCH3), 3.4
(s, 3H, −OCH3).
4f
3130 (>NH, br); 3050 (>NHCSNH<);
1360 ( OCH3); 1130 (thioureido CS)
9.0 (s, 2H, >NH), 6.5–6.8 (m, 10H, aromatic), 4.8
(s, 2H, >NHCSNH<), 3.7 (s, 3H, −OCH3), 1.8
(s, 3H, CH3).
4g
4h
4i
3140 (>NH, br); 3070 (>NHCSNH<);
1380 ( OCH3); 1140 (thioureido CS)
3140 (>NH, br); 3060 (>NHCSNH<);
1360 ( OCH3); 1130 (thioureido CS)
3130 (>NH, br); 3070 (>NHCSNH<);
1370 ( OCH3); 1140 (thioureido CS)
9.1 (s, 2H, >NH), 6.7–7.1 (m, 10H, aromatic), 5.1
(s, 2H, >NHCSNH<), 3.8 (s, 3H, −OCH3).
8.9 (s, 2H, >NH), 6.5–6.9 (m, 11H, aromatic), 4.7
(s, 2H, >NHCSNH<), 3.8 (s, 3H, −OCH3).
9.0 (s, 2H, >NH), 6.6–7.1 (m, 10H, aromatic), 5.0
(s, 2H, >NHCSNH<), 3.5 (s, 3H, −OCH3), 4.6
(s, 2H, CH2), 4.0 (d, 2H, CH2 ), 1.7 (t, 1H,
CH
)
solid was filtered, dried, and recrystallized from ethanol. Mp 172◦C, yield (62%); IR (KBr)
vmax; 3120 (>NH, br), 3050 (>NHCSNH<), 1380 ( OCH3), 1115 “(thioureido CS)”, 1H
NMR (CDCl3): 8.9 (s, 2H, >NH), 6.5–6.9 (m, 10H, aromatic), 4.8 (s, 2H, >NHCSNH<),
3.7 (s, 3H, OCH3), 19F NMR: (−5) to (−10) (≥C F), 30–40 (≥C F), MS: 620.5 (m/z).
Found C, 48.31, H, 2.71, N, 18.00, S, 10.29, C25H16N8ClF4OS2 requires C, 48.34, H, 2.73
N, 18.04, S, 10.31%.
Compounds 4b–i were prepared similarly. Their physical and analytical data are
recorded in Table I, and spectral data are recorded in Table II.
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