Synthesis and biological activities of fluorine-containing N,N′-diphenylcarbamimidothioates

Article abstract of DOI:10.1016/S0022-1139(01)00352-9

A series of fluorine-containing N,N′-diphenylcarbamimidothioates 6a-i have been synthesized by treatment of the corresponding arylamine with the aryl isothiocyanate in ethanol at room temperature followed by treatment with methyl iodide. The antifungal activities against the fungi Rhizoctonia solani and Pyricoraria orizae of the title compounds have been screened.

Full text of DOI:10.1016/S0022-1139(01)00352-9

Journal of Fluorine Chemistry 108 12001) 143±146
Synthesis and biological activities of ¯uorine-containing
N,N0-diphenylcarbamimidothioates
Zhibin Lia, Xuhong Qianb,*, Gonghua Songa, Zhong Lia
aInstitute of Pesticides and Pharmaceuticals, East China University of Science and Technology, P.O. Box 544,
130 Meilong Road, Shanghai 200237, PR China
bState Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116012, PR China
Received 5October 2000; accepted 3 January 2001
Abstract
A series of ¯uorine-containing N,N0-diphenylcarbamimidothioates 6a-i have been synthesized by treatment of the corresponding
arylamine with the aryl isothiocyanate in ethanol at room temperature followed by treatment with methyl iodide. The antifungal activities
against the fungi Rhizoctonia solani and Pyricoraria orizae of the title compounds have been screened. # 2001 Elsevier Science B.V. All
rights reserved.
Keywords: Synthesis; Biological activity; Fluorine-containing N,N0-diphenylcarbamimidothioates
1. Introduction
Some trehalase inhibitors have been isolated from natural
sources, such as deoxynojirimycin [5], salbostain [6],
validamycins [7], validoxylamines [8] and the most potent
one, trehazolin 11) [9]. It exhibits strong antifungal activity
toward the plant pathogenic fungus, Rhizoctonia solani and
Pyricoraria orizae. In the course of screening for novel
trehalase inhibitors, we have designed a new group of
compounds 6 based on the structural model of trehazolin.
Trehalase 1EC 3.2.1.28), which speci®cally hydrolyses
trehalose to two glucose moieties, is widely distributed in
animals, plants, microorganisms and insects. The substrate
trehalose is a main source of glucose in insects, yeast and
fungi. In insects, trehalose is a principal blood sugar and is
used to support various energy-requiring functions [1,2]. In
yeast and fungi, trehalose is a major storage sugar and is
responsible for the germination of ascospores [3,4]. There-
fore, trehalase is a promising target for insecticides and
fungicides.
2. Results and discussion
The designed compounds were prepared by Scheme 1.
The aryl isothiocyanates 13) are commonly prepared from
arylamines by treatment with carbon disul®de, aqueous
ammonia and lead nitrate [10]. Other synthetic methods
from monoarylthioureas [11] and phosphoramidates [12]
have also been reported. However, most of these methods are
* Corresponding author.
E-mail address: ecu.bin@263.net 1X. Qian).
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 1 0 1 ) 0 0 3 5 2 - 9

144
Z. Li et al. / Journal of Fluorine Chemistry 108 42001) 143±146
Scheme 1.
laborious and suffer from low yields. We designed a more
straightforward and convenient route on the basis of the
Kaluza reaction [13], by treatment of arylamines with
carbon disul®de, sodium hydroxide and chloroformate [14].
The aryl isothiocyanates 13) were treated with ¯uorine-
containing anilines in C2H5OH at room temperature to give
the thioureas 15), which were treated with methyl iodide in
CH3OH followed by treatment with ammonia to give 16).
Compounds 6a-i were screened for their antifungal activ-
ity against the fungi R. solani and P. orizae by the spore
germination method [15] at 100 ppm concentration. The
fungicidal data 1Table 1) indicate that all of the compounds
are highly toxic to the test fungi at 100 ppm concentration.
The toxicity of the compound depends upon the number and
position of the ¯uorines on the aryl rings. Introduction of
chlorine on the aryl rings decreases the fungitoxicity of the
compounds.
Because compounds 6a-i were not soluble in water, their
inhibitory activity toward trehalase in vitro cannot be deter-
mined by standard methods [9].
3. Experimental
Melting points were taken on a digital melting point
apparatus made in Shanghai. Infrared spectra were measured
on KBr disk using a Nicolet FT-IR-20SX instrument. Mass
Table 1
Antifungal activity data of compounds 6a-i
1
spectra were measured on a Hitachi M80 instrument. H
Compound
Antifungal activity at 100 ppm 1%)
NMR spectra were obtained using a Brucker WP100SY
1100 MHz) spectrometer with 1CD3)2CO as the solvent and
TMS as internal standard. Combustion analyses for elemen-
tal composition were made with an Italian MOD.1106
analyzer. All reactions were monitored by TLC.
R. solani
P. orizae
6a
6b
6c
6d
6e
6f
81.6
78.9
100
100
89.5100
84.2
100
100
100
100
92.3
100
100
3.1. Preparation of aryl isothiocyanates 43)
77.6
92.1
6g
6h
6I
38.3
The aryl isothiocyanates 13) were prepared according to
our reported procedures [14] shown in Scheme 1. Yields and
65.8

Z. Li et al. / Journal of Fluorine Chemistry 108 42001) 143±146
145
boiling points are listed as follows.
1NH); 1350 1C=S). 1H NMR 1CD3COCD3) d: 7.70 1td,
J ˆ 6:1, 8.9 Hz, 1H, H-60), 7.48 1m, 1H, H-6), 7.22 1td,
J ˆ 2:3, 8.9 Hz, 1H, H-5), 7.12 1m, 1H, H-50), 7.051td,
J ˆ 2:8, 8.4 Hz, 1H, H-30). Anal. Calc. for C13H7F5N2S
1318.19): C, 49.07; H, 2.22; N, 8.80%. Found: C, 49.21; H,
2.21; N, 8.78%.
ꢀ 2-Fluorophenyl isothiocyanate 13a): yield 68%, bp 103±
1048C/8 Torr [14];
ꢀ 4-fluorophenyl isothiocyanate 13b): yield 72%, bp 95±
978C/8 Torr [14];
ꢀ 2,4-difluorophenyl isothiocyanate 13c): yield 89%, bp 85±
868C/8 Torr [14];
N-12,3,4-tri¯uorophenyl)-N0-13,4-di¯uorophenyl)thiourea
15f): yield 86%, mp 155±1568C. IR 1KBr) 1cmÀ1): 3200
ꢀ 2,3,4-trifluorophenyl isothiocyanate 13e): yield 86%, bp
1
1NH); 1350 1C=S). H NMR 1CD3COCD3) d: 7.77 1ddd,
80±828C/8 Torr [16];
J ˆ 1:5, 2.6, 7.4 Hz, 1H, H-60), 7.48 1m, 1H, H-6), 7.33 1m,
2H, H-20 and H-5), 7.21 1qd, J ˆ 1:2, 9.4 Hz, 1H, H-50).
Anal. Calc. for C13H7F5N2S 1318.19): C, 49.07; H, 2.22; N,
8.80%. Found: C, 49.15; H, 2.20; N, 8.85%.
ꢀ 3-chloro-4-fluorophenyl isothiocyanate 13h): yield 82%,
bp 110±1128C/8 Torr [17];
ꢀ 2-fluoro-4-chlorophenyl isothiocyanate 13i): yield 85%,
bp 108±1098C/8 Torr [14].
N,N0-Di12,3,4-tri¯uorophenyl)thiourea 15g): yield 91%,
mp 170±1718C. IR 1KBr) 1cmÀ1): 3160 1NH); 1350
1
3.2. Preparation of N,N0-fluorosubstituted
diphenylthioureas 45)
1C=S). H NMR 1CD3COCD3) d: 7.46 1m, 2H, H-6 and
0
H-60), 7.23 1td, J ˆ 2:3, 9.4 Hz, 2H, H-5and H-5 ). Anal.
Calc. for C13H6F6N2S 1336.25): C, 46.44; H, 1.80; N, 8.33%.
Found: C, 46.30; H, 1.81; N, 8.35%.
General procedure: to a solution of the ¯uorine-contain-
ing aniline 4 10.01 mol) in 50 ml of ethanol was added
dropwise, the aryl isothiocyanate 3 10.01 mol) over a period
of 10 min. Then the reaction mixture was stirred for 1 h at
room temperature and left overnight. The solvent was
removed under reduced pressure to give the crude product,
which was recrystallized from ethanol to give a white solid.
The following new compounds were prepared.
N,N0-Di13-chloro-4-¯uorophenyl)thiourea 15h): yield
93%, mp 145±1468C. IR 1KBr) 1cmÀ1): 3190 1NH); 1330
1C=S). 1H NMR 1CD3COCD3) d: 7.82 1dd, J ˆ 2:5, 6.5 Hz,
2H, H-2 and H-20), 7.49 1ddd, J ˆ 2, 2.7, 4.2, 9.0 Hz, 2H, H-
0
6 and H-60), 7.30 1t, J ˆ 9:0 Hz, 2H, H-5and H-5 ). Anal.
Calc. for C13H8Cl2F2N2S 1333.18): C, 46.86; H, 2.42; N,
8.41%. Found: C, 46.68; H, 2.41; N, 8.39%.
N,N0-Di12-¯uorophenyl)thiourea 15a): yield 92%, mp
154±1558C. IR 1KBr) 1cmÀ1): 3140 1NH); 1350 1C=S).
1H NMR 1CD3COCD3) d: 7.84 1t, J ˆ 7:8 Hz, 2H, H-6
and H-60), 7.30 1m, 2H, H-4 and H-40), 7.20 1t, J ˆ 8:6 Hz,
4H, H-3, H-5, H-30 and H-50). Anal. Calc. for C13H10F2N2S
1264.29): C, 59.08; H, 3.81; N, 10.60%. Found: C, 59.21; H,
3.80; N, 10.62%.
N,N0-Di12-¯uoro-4-chlorophenyl)thiourea 15i): yield 87%,
mp 190±1928C. IR 1KBr) 1cmÀ1): 3150 1NH); 1320 1C=S).
1H NMR 1CD3COCD3) d: 7.84 1t, J ˆ 8:5Hz, 2H, H-6 and
H-60), 7.34 1dd, J ˆ 2:3, 10.1 Hz, 2H, H-3 and H-30), 7.27
1d, J ˆ 10:1 Hz, 2H, H-5and H-5 0). Anal. Calc. for
C13H8Cl2F2N2S 1333.18): C, 46.86; H, 2.42; N, 8.41%.
Found: C, 46.72; H, 2.40; N, 8.44%.
N,N0-Di14-¯uorophenyl)thiourea 15b): yield 94%, mp
200±2018C. IR 1KBr) 1cmÀ1): 3220 1NH); 1330 1C=S).
1H NMR 1CD3COCD3) d: 7.54 1dd, J ˆ 5:0, 8.9 Hz, 4H,
H-2, H-6, H-20 and H-60), 7.12 1t, 4H, J ˆ 8:9 Hz, 4H, H-3,
H-5, H-30 and H-50). Anal. Calc. for C13H10F2N2S 1264.29):
C, 59.08; H, 3.81; N, 10.60%. Found: C, 59.25; H, 3.83; N,
10.58%.
3.3. Preparation of fluorine-containing N,N0-
diphenylcarbamimidothioates 46)
General procedure: to a solution of the thiourea 5
10.005mol) in 50 ml of methanol was added methyl iodide
10.85g, 0.006 mol) and the mixture was heated to re¯ux for
6 h. Then the solvent was removed under reduced pressure,
and the residue was added 50 ml of H2O and 10 ml of
concentrated aqueous ammonia. The precipitated product
was ®ltered, washed with H2O, and recrystallized from
C2H5OH±H2O 14:1) to give a white solid. The following
new compounds were prepared.
N,N0-Di12,4-di¯uorophenyl)thiourea 15c): yield 88%, mp
160±1618C. IR 1KBr) 1cmÀ1): 3200 1NH); 1340 1C=S). H
1
NMR 1CD3COCD3) d: 7.68 1td, J ˆ 6:2, 9.0 Hz, 2H, H-6
and H-60), 7.30 1t, J ˆ 9:1 Hz, 2H, H-3 and H-30), 7.051m,
2H, H-5and H-5 0). Anal. Calc. for C13H8F4N2S 1300.27): C,
52.00; H, 2.69; N, 9.33%. Found: C, 52.23; H, 2.67; N,
9.35%.
N-12,4-di¯uorophenyl)-N0-13,4-di¯uorophenyl)thiourea
15d): yield 90%, mp 137±1388C. IR 1KBr) 1cmÀ1): 3200
1NH); 1350 1C=S). 1H NMR 1CD3COCD3) d: 7.78 1m, 1H,
H-60), 7.69 1td, J ˆ 6:1, 8.8 Hz, 1H, H-6), 7.30 1m, 2H, H-20,
H-3), 7.11 1m, 1H, H-50), 7.051m, 1H, H-5). Anal. Calc. for
C13H8F4N2S 1300.27): C, 52.00; H, 2.69; N, 9.33%. Found:
C, 52.18; H, 2.68; N, 9.28%.
Methyl N,N0-di12-¯uorophenyl)carbamimidothioates 16a):
yield 72%, mp 70±718C. IR 1KBr) 1cmÀ1): 3210 1NH); 1590
1
1C=N). H NMR 1CD3COCD3) d: 2.50 1s, 3H, ±SCH3),
6.85±7.95 1m, 8H, ArH). MS 1EI, 70 eV) m/z 1%): 278 114)
[M], 231 138) [M±SCH3], 230 129) [M±CH3SH], 168 1100)
[M±C6H5FN], 153 153) [M±C6H4FN±CH4], 110 138) [M±
C8H7FNS], 95126) [M±C 8H8FN2S]. Anal. Calc. for
C14H12F2N2S 1278.32): C, 60.42; H, 4.35; N, 10.07%.
Found: C, 60.47; H, 4.37; N, 10.08%.
N-12,3,4-tri¯uorophenyl)-N0-12,4-di¯uorophenyl)thiourea
15e): yield 87%, mp 144±1458C. IR 1KBr) 1cmÀ1): 3240

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Z. Li et al. / Journal of Fluorine Chemistry 108 42001) 143±146
1
Methyl N,N0-di14-¯uorophenyl)carbamimidothioates 16b):
3160 1NH); 1570 1C=N). H NMR 1CD3COCD3) d: 2.55
1s, 3H, ±SCH3), 7.51 1m, 1H, H-60), 7.05±7.24 1m, 2H, H-5
and H-50), 6.751m, 1H, H-6). MS 1EI, 70 eV) m/z 1%): 350
110) [M], 303 120) [M±SCH3], 302 139) [M±CH3SH], 204
1100) [M±C6H3F3N], 189 144) [M±C6H2F3N±CH4], 146
156) [M±C8H5F3NS]. Anal. Calc. for C14H8F6N2S
1350.28): C, 48.01; H, 2.30; N, 8.00%. Found: C, 47.94;
H, 2.32; N, 8.03%.
yield 78%, mp 79±808C. IR 1KBr) 1cmÀ1): 3150 1NH); 1580
1C=N). 1H NMR 1CD3COCD3) d: 2.42 1s, 3H, ±SCH3), 7.71
1m, 2H, H-20 and H-60), 7.051t, J ˆ 8:8 Hz, 4H, H-3, H-5,
H-30 and H-50), 6.90 1m, 2H, H-2 and H-6). MS 1EI, 70 eV)
m/z 1%): 279 147) [M ‡ 1], 278 163) [M], 231 158) [M±
SCH3], 230 182) [M±CH3SH], 168 1100) [M±C6H5FN], 153
148) [M±C6H4FN±CH4], 110 179) [M±C8H7FNS], 95162)
[M±C8H8FN2S]. Anal. Calc. for C14H12F2N2S 1278.32): C,
60.42; H, 4.35; N, 10.07%. Found: C, 60.54; H, 4.36; N,
10.05%.
Methyl N,N0-di13-chloro-4-¯uorophenyl)carbamimido-
thioates 16h): yield 85%, mp 118±1198C. IR 1KBr)
1cmÀ1): 3180 1NH); 1570 1C=N). H NMR 1CD3COCD3)
1
Methyl N,N0-di12,4-di¯uorophenyl)carbamimidothioates
16c): yield 83%, mp 79±808C. IR 1KBr) 1cmÀ1): 3210
1NH); 1560 1C=N). 1H NMR 1CD3COCD3) d: 2.51
1s, 3H, ±SCH3), 6.88±7.92 1m, 6H, ArH). MS 1EI, 70 eV)
m/z 1%): 314 17) [M], 267 117) [M±SCH3], 266 132)
[M±CH3SH], 186 1100) [M±C6H4F2N], 171 1100)
[M±C6H3F2N±CH4], 128 162) [M±C8H6F2NS]. Anal. Calc.
for C14H10F4N2S 1314.30): C, 53.50; H, 3.21; N, 8.91%.
Found: C, 53.46; H, 3.24; N, 8.87%.
d: 2.43 1s, 3H, ±SCH3), 7.94 1m, 1H, H-20), 7.58 1m, 1H, H-
60), 7.19 1t, J ˆ 9:0 Hz, 2H, H-5and H-5 0), 7.01 1s, 1H, H-2),
6.851s, 1H, H-6). MS 1EI, 70 eV) m/z 1%): 346 12) [M], 302
112) [M±CH3SH ‡ 4], 300 166) [M±CH3SH ‡ 2], 298 1100)
[M±CH3SH], 143 115) [M±C8H6ClFNS], 129 113) [M±
C8H7ClFN2S]. Anal. Calc. for C14H10Cl2F2N2S 1347.21):
C, 48.43; H, 2.90; N, 8.07%. Found: C, 48.62; H, 2.88; N,
8.09%.
Methyl N,N0-di12-¯uoro-4-chlorophenyl)carbamimido-
thioates 16i): yield 83%, mp 95±968C. IR 1KBr) 1cmÀ1):
3200 1NH); 1540 1C=N). 1H NMR 1CD3COCD3) d: 2.50 1s,
3H, ±SCH3), 6.91±7.92 1m, 6H, ArH). MS 1EI, 70 eV) m/z
1%): 346 16) [M], 302 113) [M±CH3SH ‡ 4], 300 167)
[M±CH3SH ‡ 2], 298 1100) [M±CH3SH], 204 112)
[M±C6H4ClFN ‡ 2], 202 135) [M±C6H4ClFN]. Anal. Calc.
for C14H10Cl2F2N2S 1347.21): C, 48.43; H, 2.90; N, 8.07%.
Found: C, 48.58; H, 2.91; N, 8.10%.
Methyl N-12,4-di¯uorophenyl)-N0-13,4-di¯uorophenyl)-
carbamimidothioates 16d): yield 87%, mp 78±798C. IR
1KBr) 1cmÀ1): 3160 1NH); 1580 1C=N). 1H NMR
1CD3COCD3) d: 2.49 1s, 3H, ±SCH3), 7.91 1m, 1H, H-60),
7.40 1m, 1H, H-20), 7.30 1m, 1H, H-50), 6.93±7.01 1m, 3H, H-
3, H-5and H-6). MS 1EI, 70 eV) m/z 1%): 314 110) [M], 267
178) [M±SCH3], 266 1100) [M±CH3SH], 186 123) [M±
C6H4F2N], 171 115) [M±C6H3F2N±CH4], 127 135) [M±
C8H6F2NS], 95126) [M±C 8H7F2N2S]. Anal. Calc. for
C14H10F4N2S 1314.30): C, 53.50; H, 3.21; N, 8.91%. Found:
C, 53.68; H, 3.22; N, 8.90%.
References
Methyl
N-12,3,4-tri¯uorophenyl)-N0-12,4-di¯uorophe-
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nyl)carbamimidothioates 16e): yield 69%, mp 50±518C.
IR 1KBr) 1cmÀ1): 3120 1NH); 1610 1C=N). 1H NMR
1CD3COCD3) d: 2.50 1s, 3H, ±SCH3), 6.73±7.80 1m, 5H,
ArH). MS 1EI, 70 eV) m/z 1%): 332 133) [M], 285151) [M±
SCH3], 284 1100) [M±CH3SH], 204 1100) [M±C6H4F2N],
146 123) [M±C8H6F2NS], 145136) [M±C H7F2NS], 128
8
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238.
128) [M±C8H5F3NS], 127 162) [M±C8H6F3NS]. Anal. Calc.
for C14H9F5N2S 1332.29): C, 50.60; H, 2.73; N, 8.43%.
Found: C, 50.42; H, 2.71; N, 8.46%.
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Methyl
N-12,3,4-tri¯uorophenyl)-N0-13,4-di¯uorophe-
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nyl)carbamimidothioates 16f): yield 77%, mp 86±878C.
IR 1KBr) 1cmÀ1): 3170 1NH); 1590 1C=N). 1H NMR
1CD3COCD3) d: 2.50 1s, 3H, ±SCH3), 7.82 1m, 1H, H-60),
7.41 1m, 1H, H-20), 7.22 1q, 1H, J ˆ 9:3 Hz, H-50), 7.10 1m,
1H, H-5), 6.80 1m, 1H, H-6). MS 1EI, 70 eV) m/z 1%): 332
[11] W.S. Wadsworth, W.D. Emmons, J. Org. Chem. 32 11967) 1279.
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1943, p. 627.
18) [M], 285121) [M±SCH ], 284 1100) [M±CH3SH], 204
3
116) [M±C6H4F2N], 145113) [M±C 8H7F2NS], 127 119) [M±
C8H6F3NS]. Anal. Calc. for C14H9F5N2S 1332.29): C, 50.60;
H, 2.73; N, 8.43%. Found: C, 50.71; H, 2.72; N, 8.45%.
Methyl N,N0-di12,3,4-tri¯uorophenyl)carbamimidothio-
ates 16g): yield 81%, mp 65±668C. IR 1KBr) 1cmÀ1):
[16] Y. Jinbo, H. Kondo, Y. Inoue, M. Taguchi, Y. Kotera, F. Sakamato, J.
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