Synthesis and biological activities of N-(1,2,4-triazole-4-yl)-N′- (fluorine-containing-phenyl)carbamimidothioates

Article abstract of DOI:10.1016/S0022-1139(02)00010-6

A series of N-(1,2,4-triazole-4-yl)-N-pm-(fluorine-containing-phenyl) carbamimidothioates 5a-i were synthesized by reacting 4-amine-1,2,4-trizaole with corresponding aryl isothiocyanates in ethanol at room temperature and, in a subsequent step, with methy

Full text of DOI:10.1016/S0022-1139(02)00010-6

Journal of Fluorine Chemistry 115 (2002) 79±82
0
Synthesis and biological activities of N-(1,2,4-triazole-4-yl)-N -
(¯uorine-containing-phenyl)carbamimidothioates
*
Dawei Cui, Zhibin Li, Gonghua Song , Xuhong Qian
Institute of Pesticides and Pharmaceuticals, East China University of Science and Technology, P.O. Box 544,
30 Meilong Road, Shanghai 200237, PR China
1
Received 25 June 2001; received in revised form 8 November 2001; accepted 15 January 2002
Abstract
0
A series of N-(1,2,4-triazole-4-yl)-N -(¯uorine-containing-phenyl)carbamimidothioates 5a±i were synthesized by reacting 4-amine-1,2,4-
trizaole with corresponding aryl isothiocyanates in ethanol at room temperature and, in a subsequent step, with methyl iodide. The antifungal
activities of the title compounds against the fungi Rhizoctonia solan and Pyricularia orizae were screened. # 2002 Elsevier Science B.V. All
rights reserved.
0
Keywords: Synthesis; Biological activity; N-(1,2,4-Triazole-4-yl)-N -(¯uorine-containing-phenyl)carbamimidothioates
1
. Introduction
2. Results and discussion
Trehalose, which is degraded strictly by trehalase, is
The designed compounds were prepared by Scheme 2.
The ¯uorine-containing-phenyl isothiocyanates (3) were
prepared by treating ¯uorine-containing-phenyl amines with
carbon disul®de, sodium hydroxide and ethyl chloroformate
[7].
regarded as a major resource of blood sugar in insects as
well as major storage sugar in fungi. Therefore, trehalase
inhibitors may be expected to be potential insecticides or
fungicides [1].
Recently, some natural trehalase inhibitors were isolated,
such as deoxynojirimycin [2], salbostain [3], validamycins
The ¯uorine-containing-phenyl isothiocynates (3) w ere
treated with 4-amino-1,2,4-triazole in C H OH at room tem-
perature to give the thioureas (4). This is followed by reacting
2
5
[
4], validoxylamines [5], and trehazolin (1) [6], with the last
one exhibiting the strongest antifungal activities towards the
plant pathogenic fungi, Rhizoctonia solan and Pyricularia
orizae.
thiourea with methyl iodide in CH OH and then ammonia to
3
1
give the target compound (5). Surprisingly, H NMR spectra
indicated the presence of two isomers 5a and 5b.
In the course of screening for novel trehalase inhibitors,
we reported recently a new group of compounds (2) based on
the structural model of trehazolin [7]. These compounds
showed positive fungicidal activities toward P. orizae. In
order to promote the activity and elucidate the structure±
activity relationship for such compounds, we designed and
synthesized another group of compounds (5) by introducing
Compounds 5a±i were screened for the antifungal activ-
ities against the fungi R. solan and P. orizae at the con-
centration of 100 and 500 mg/ml by spore germination
method [8] (Table 1). The fungicidal data indicated that
the toxicity of the compound depends on the number and
position of the ¯uorine atoms on the aryl rings. Those
containing three ¯uorine atoms on the aryl ring had stronger
toxicity as a whole. Compounds with o-¯uorine substituted
and without m-substituted showed higher activities. The
results also indicated that the compounds synthesized in
this study were less active to R. solan and P. orizae than
compounds 2 [7]. It means that the introduction of 1,2,4-
triazole was unsuccessful.
1,2,4-triazole, an effective unit in fungicides, to the structure
Scheme 1).
(
*
Due to poor water solubilities of compounds 5a±i, their
inhibitory activities toward trehalase in vitro cannot be
determined by the standard method [6].
Corresponding author. Tel.: ‡86-21-642-52945;
fax: ‡86-21-642-51386.
E-mail address: ghsong@ecust.edu.cn (G. Song).
0022-1139/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 0 1 0 - 6

80
D. Cui et al. / Journal of Fluorine Chemistry 115(2002) 79±82
Scheme 1.
0
3
. Experimental
3.2. Preparation of N-(1,2,4-triazole-4-yl)-N -(fluorine-
containing-phenyl)carbamimidothioates (5)
Infrared spectra were taken on a Nicolet FT-IR-20SX
spectrometer using KBr disks; mass spectra on a Hitachi
3.2.1. General procedure
1
M80 instrument; H NMR spectra on a Brucker WP100SY
(
To a solution of thiourea (4; 0.005 mol) in 50 ml of
methanol was added methyl iodide (0.85 g, 0.006 mol).
The mixture was heated to re¯ux for 12 h. The solvent
was removed under reduced pressure, and to the residue
100 MHz) spectrometer with DMSO-6d as solvent and
TMS as internal standard. Melting points were measured
by a digital melting point apparatus made in Shanghai.
Elemental compositions were obtained by using an Italian
MOD.1106 analyzer. All reactions were monitored by TLC.
was added 50 ml of H O and 10 ml of concentrated aqueous
2
ammonia. The precipitated product was ®ltered, washed
with H O, and recrystallized from C H OH to give a white
solid. The following new compounds were prepared.
2
2 5
0
3.1. Preparation of N-(1,2,4-triazole-4-yl)-N -(fluorine-
containing-phenyl)thioureas (4)
0
Methyl N-(1,2,4-triazole-4-yl)-N -(2-¯uoro-phenyl)car-
bamimidothioates (5a): yield 65%, mp 218±219 8C. IR
(KBr; cm ): 3120 (NH); 1580 (C=N). H NMR (DMSO-
À1
1
3
.1.1. General procedure
To a solution of 4-amine-1,2,4-trizaole (0.01 mol) in
0 ml of ethanol was added dropwise aryl isothiocyanate
3; 0.01 mol) over a period of 10 min. The reaction mixture
6d): 2.48 (s, 1.14H, b-SCH ), 2.56 (s, 1.86H, a-SCH ),
7.19±7.58 (m, 4H, a- and b-ArH), 8.42 (s, 1.22H, a-tria-
zole-H), 8.52 (s, 0.78H, b-triazole-H). MS (EI, 70 eV) m/e
3
3
5
(
was stirred for 8 h at room temperature. The solvent was
removed under reduced pressure to give crude product,
which was recrystallized from ethanol to give a white solid.
(%): 251 (56) [M], 232 (62) [M±F], 203 (23) [M±CH SH],
182 (68) [M±C H N ], 136 (100) [M±C H N ±SCH ], 109
3
2
3
3
2
3
3
3
(40) [M±C H N S], 83 (50) [M±C H FNS]. Analysis: Calc.
4
6
4
8 7
Scheme 2.

D. Cui et al. / Journal of Fluorine Chemistry 115(2002) 79±82
81
À1
1
Table 1
(
6
KBr; cm ): 3120 (NH); 1590 (C=N). H NMR (DMSO-
Antifungal activity data for compounds 5a±i and 2a±i
d): 2.43 (s, 0.53H, b-SCH ), 2.53 (s, 2.47H, a-SCH ), 7.00±
3
3
Compound
R. solan (%)
00 mg/ml
P. orizae (%)
7.84 (m, 3H, a- and b-ArH), 8.54 (s, 2H, a- and b-triazole-
H). MS (EI, 70 eV) m/e (%): 269 (57) [M], 221 (26) [M±
CH SH], 200 (55) [M±C H N ], 186 (41) [M±C H N ], 172
1
00 mg/ml
5
100 mg/ml
3
2
3
3
2 4 4
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
60.0
46.7
40.0
43.3
40.0
68.3
46.7
46.7
63.3
8.3
0.0
0.0
0.0
0.0
58.3
0.0
0.0
9.7
66.7
33.3
73.3
33.3
26.7
26.7
26.7
26.7
26.7
(
(
(
47) [M±C H N ±CH ], 154 (100) [M±C H N ±SCH ], 127
2 4 4 3 2 3 3 3
61) [M±C H N S]. Analysis: Calc. for C H F N S
4
6
4
10 9 2 5
269.27): C, 44.61; H, 3.37; N, 26.01%. Found: C, 44.60;
H, 3.35; N, 26.06%.
Methyl N-(1,2,4-triazole-4-yl)-N -(2,3,4-tri¯uoro-phe-
0
g
h
i
nyl)carbamimidothioates (5e): yield 75%, mp 224±
À1
25 8C. IR (KBr; cm ): 3130 (NH); 1520 (C=N). 1H
2
NMR (DMSO-6d): 2.43 (s, 0.90H, b-SCH ), 2.57 (s,
3
2
2
2
2
2
2
2
2
2
a
b
c
d
e
f
81.6
78.9
89.5
84.2
100
100
100
100
100
100
100
100
2
.10H, a-SCH ), 7.20±7.39 (m, 2H, a- and b-ArH), 8.43
3
(
(
[
s, 1.36H, a-triazole-H), 8.55 (s, 0.64H, b-triazole-H). MS
EI, 70 eV) m/e (%): 287 (44) [M], 268 (10) [M±F], 239 (16)
M±CH SH], 218 (100) [M±C H N ], 172 (99) [M±
3
2 3 3
77.6
92.1
38.3
65.8
C H N ±SCH ], 145 (44) [M±C H F ]. Analysis: Calc.
2 2 3 3 6 2 3
g
h
i
for C H F N S (287.26): C, 41.81; H, 2.81; N, 24.38%.
1
0 8 3 5
92.3
100
Found: C, 41.80; H, 2.79; N, 24.36%.
0
Methyl
phenyl)carbamimidothioates (5f): yield 55%, mp 218±
N-(1,2,4-triazole-4-yl)-N -(3-chloro-4-¯uoro-
(
2a) R1 ˆ F, R2 ˆ H, R3 ˆ H, R4 ˆ F, R5 ˆ H, R6 ˆ H; (2b) R1 ˆ H,
R2 ˆ H, R3 ˆ F, R4 ˆ H, R5 ˆ H, R6 ˆ F; (2c) R1 ˆ F, R2 ˆ H, R3 ˆ F,
R4 ˆ F, R5 ˆ H, R6 ˆ F; (2d) R1 ˆ F, R2 ˆ H, R3 ˆ F, R4 ˆ H, R5 ˆ F,
R6 ˆ F; (2e) R1 ˆ F, R2 ˆ F, R3 ˆ F, R4 ˆ F, R5 ˆ H, R6 ˆ F; (2f)
R1 ˆ F, R2 ˆ F, R3 ˆ F, R4 ˆ H, R5 ˆ F, R6 ˆ F; (2g) R1 ˆ F, R2 ˆ F,
R3 ˆ F, R4 ˆ F, R5 ˆ F, R6 ˆ F; (2h) R1 ˆ H, R2 ˆ Cl, R3 ˆ F, R4 ˆ H,
R5 ˆ Cl, R6 ˆ F; (2i) R1 ˆ F, R2 ˆ H, R3 ˆ Cl, R4 ˆ F, R5 ˆ H,
R6 ˆ Cl.
19 8C. IR (KBr; cm ): 3120 (NH); 1570 (C=N). 1
À1
2
H
NMR (DMSO-6d): 2.43 (s, 0.59H, b-SCH ), 2.54 (s,
2.41H, a-SCH ), 7.18±7.99 (m, 3H, a- and b-ArH), 8.55
(s, 2H, a- and b-triazole-H). MS (EI, 70 eV) m/e (%): 287
3
3
(
23) [M ‡ 2], 285 (69) [M], 237 (25) [M±CH SH], 202 (54)
3
[M±C H N ], 170 (100) [M±C H N ±SCH ], 143 (52) [M±
C H N S], 129 (44) [M±C H N S]. Analysis: Calc. for
2
3
4
2
3
3
3
4
6
4
4 6 5
for C H FN S (251.2839): C, 47.80; H, 4.01; N, 27.87%.
1
C H ClFN S (285.73): C, 42.04; H, 3.17; N, 24.51%.
10 9 5
0
10
5
Found: C, 47.81; H, 4.02; N, 27.78%.
0
Found: C, 42.00; H, 3.15; N, 24.54%.
0
Methyl N-(1,2,4-triazole-4-yl)-N -(4-¯uoro-phenyl)car-
bamimidothioates (5b): yield 68%, mp 228±229 8C. IR
Methyl N-(1,2,4-triazole-4-yl)-N -(3-chloro-phenyl)car-
bamimidothioates (5g): yield 77%, mp 199±201 8C. IR
(KBr; cm ): 3120 (NH); 1570 (C=N). H NMR
À1
1
À1
1
(
KBr; cm ): 3120 (NH); 1580 (C=N). H NMR
(
DMSO-6d): 2.39 (s, 0.79H, b-SCH ), 2.64 (s, 2.21H,
(DMSO-6d): 2.44 (s, 0.55H, b-SCH ), 2.54 (s, 2.45H, a-
3
3
a-SCH ), 7.16±7.68 (m, 4H, a- and b-ArH), 8.50 (s, 1.46H,
SCH ), 6.91±7.92 (m, 4H, a- and b-ArH), 8.55 (s, 2H, a- and
3
3
a-triazole-H), 8.53 (s, 0.54H, b-triazole-H). MS (EI, 70 eV)
b-triazole-H). MS (EI, 70 eV) m/e (%): 269 (26) [M ‡ 2],
m/e (%): 251 (84) [M], 203 (30) [M±CH SH], 182
267 (67) [M], 219 (63) [M±CH SH], 198 (38) [M±C H N ],
3
3
2 2 3
(
(
[
57) [M±C H N ], 136 (100) [M±C H N ±SCH ], 109
2
184 (55) [M±C H N ], 152 (100) [M±C H N ±SCH ], 111
2 3 4 2 2 3 3
3
3
2
3
3
3
60) [M±C H N S], 95 (51) [M±C H N S], 83 (55)
5
(67) [M±C H N S]. Analysis: Calc. for C H ClN S
4 6 5 10 10 5
4
6
4
4
6
M±C H FNS]. Analysis: Calc. for C H FN S (251.28):
8
(267.74): C, 44.86; H, 3.76; N, 26.16%. Found: C, 44.91;
H, 3.71; N, 26.12%.
7
10 10
5
C, 47.80; H, 4.01; N, 27.87%. Found: C, 47.77; H, 4.04; N,
7.83%.
Methyl N-(1,2,4-triazole-4-yl)-N -(2,4-di¯uorophenyl)-
carbamimidothioates (5c): yield 64%, mp 207±208 8C. IR
0
2
Methyl N-(1,2,4-triazole)-N -(4-chloro-phenyl)carbami-
midothioates (5h): yield 79%, mp 245±246 8C. IR (KBr;
cm ): 3120 (NH); 1570 (C=N). H NMR (DMSO-6d): 2.42
0
À1
1
À1
1
(
KBr; cm ): 3120 (NH); 1550 (C=N). H NMR (DMSO-
(s, 0.60H, b-SCH ), 2.51 (s, 2.40H, a-SCH ), 7.15±7.71 (m,
3
3
6
7
8
d): 2.40 (s, 1.23H, b-SCH ), 2.56 (s, 1.77H, a-SCH ), 7.10±
.60 (m, 3H, a- and b-ArH), 8.41 (s, 1.09H, a-triazole-H),
.53 (s, 0.91H, b-triazole-H). MS (EI, 70 eV) m/e (%): 269
4H, a- and b-ArH), 8.53 (s, 2H, a- and b-triazole-H). MS
(EI, 70 eV) m/e (%): 269 (26) [M ‡ 2], 267 (67) [M], 219
(60) [M±CH SH], 184 (55) [M±C H N ], 151 (100)
3
3
3
2 3 4
(
100) [M], 250 (78) [M±F], 222 (15) [M±CH S], 186 (53)
[M±C H N ±SCH ], 111 (40) [M±C H N S]. Analysis:
2 3 3 3 4 6 5
3
[
C H N ±SCH ], 127 (55) [M±C H N S]. Analysis: Calc.
M±C H N ], 172 (69) [M±C H N ±CH ], 154 (96) [M±
Calc. for C H ClN S (267.74): C, 44.86; H, 3.76; N,
10 10 5
2
4
4
2
4
4
3
26.16%. Found: C, 44.89; H, 3.74; N, 26.15%.
0
2
3
3
3
4 6 4
for C H F N S (269.2714): C, 44.61; H, 3.37; N. 26.01%.
1
Methyl N-(1,2,4-triazole)-N -phenyl-carbamimidothio-
À1
0 9 2 5
Found: C, 44.59; H, 3.36; N, 25.98%.
0
ates (5i): yield 83%, mp 204±205 8C. IR (KBr; cm ):
3120 (NH); 1580 (C=N). H NMR (DMSO-6d): 2.40 (s,
1
Methyl N-(1,2,4-triazole-4-yl)-N -(3,4-di¯uoro-phenyl)-
carbamimidothioates (5d): yield 70%, mp 187±189 8C. IR
0.77H, b-SCH ), 2.52 (s, 2.23H, a-SCH ), 7.11±7.66 (m,
3
3

82
D. Cui et al. / Journal of Fluorine Chemistry 115(2002) 79±82
5
H, a- and b-ArH), 8.52 (s, 2H, a- and b-triazole-H). MS
4. The spore germination were then detected by a
microscopy to determine the inhibitory rate of target
compounds.
(
EI, 70 eV) m/e (%): 233 (76) [M], 185 (30) [M±CH SH],
50 (59) [M±C H N ], 136 (70) [M±C H N ±CH ], 118
2 3 3 2 2 4 3
3
1
(
Calc. for C H N S (233.29): C, 51.49; H, 4.75; N, 30.02%.
98) [M±C H N ±SCH ], 77 (100) [M±C H N S]. Analysis:
2 2 3 3 4 6 5
1
0 11 5
Found: C, 51.47; H, 4.78; N, 30.05%.
References
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. Note
(
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[
[
[
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