Synthesis, characterization and fungicidal activities of novel fluorinated 3,5-disubstituted-4H-1,2,4-triazol-4-amines

Article abstract of DOI:10.1016/j.jfluchem.2011.12.015

Thiocarbohydrazide and substituted benzoyl hydrazine were used as starting materials to synthesize fifteen fluorinated 3,5-disubstituted-4H-1,2,4-triazol- 4-amines. All the title compounds were characterized using IR, ¹H and ¹⁹F NMR

Full text of DOI:10.1016/j.jfluchem.2011.12.015

Journal of Fluorine Chemistry 135 (2012) 323–329
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis, characterization and fungicidal activities of novel fluorinated
3,5-disubstituted-4H-1,2,4-triazol-4-amines
Min Chen a,b, Xian-Feng Wang a,b, Si-Si Wang b,c, Yi-Xiao Feng c, Feng Chen c, Chun-Long Yang a,b,c,
*
a Key Laboratory of Monitoring and Management of Crop Diseases and Pest Insects, Ministry of Agriculture, Nanjing Agricultural University, Nanjing 210095, PR China
b Jiangsu Key Laboratory of Pesticide Science, Nanjing Agricultural University, Nanjing 210095, PR China
c Department of Chemistry, College of Science, Nanjing Agricultural University, Nanjing 210095, PR China
A R T I C L E I N F O
A B S T R A C T
Article history:
Thiocarbohydrazide and substituted benzoyl hydrazine were used as starting materials to synthesize
fifteen fluorinated 3,5-disubstituted-4H-1,2,4-triazol-4-amines. All the title compounds were
characterized using IR, 1H and 19F NMR spectroscopy, mass spectrometry (MS) and elemental
analysis. The structures of compounds 6g and 7 were confirmed by X-ray diffraction crystallography.
The preliminary bioassay results showed that these compounds exhibited certain fungicidal activities
against Rhizoctonia solani, Fusarium graminearum, Botrytis cinerea and Colletotrichum capsici at the
Received 14 October 2011
Received in revised form 26 December 2011
Accepted 26 December 2011
Available online 31 December 2011
Keywords:
concentration of 100
mg/mL.
Fluorinated 1,2,4-triazol-4-amine
Sulfide
ß 2012 Elsevier B.V. All rights reserved.
Crystal structure
Fungicidal activity
1. Introduction
2. Results and discussion
1,2,4-Triazole fungicides, which inhibit the biosynthesis of
ergosterin in fungi, show strong fungicidal activities, broad
fungicidal spectrum and excellent inner absorption properties.
Fluorine as a unique atom can modulate the physical properties of
a molecule, and the fungicidal activities were often enhanced by
introducing fluorine into triazole derivatives [1–4]. Flusilazole,
fluotrimazole, epoxiconazole and flutriafol, which are successful
examples of fluorinated 1,2,4-triazole fungicides, have been widely
used in plant protecting [5,6].
In recent years, 1,2,4-triazol-4-amine and its many derivatives
have been synthesized, some of them were found to present notable
fungicidal activities [7–11]. But most of these 1,2,4-triazol-4-amine
derivatives have not shown practical application value in plant
pathogen control, because their bioactivities were not high enough.
In this article, a single fluorine atom and the trifluoromethyl group
were introduced at the 5-position of 1,2,4-triazol-4-amine respec-
tively to synthesize fluorinated 3,5-disubstituted-4H-1,2,4-triazol-
4-amine derivatives, with a view to reveal the influence of fluorine
on the fungicidal activities of 1,2,4-triazol-4-amines.
2.1. Chemistry
The synthetic routes for the target compounds are illustrated
in Schemes 1 and 2. The intermediate 4-amino-5-(trifluoro-
methyl)-4H-1,2,4-triazole-3-thiol (2) was prepared by the
reaction of trifluoroacetic acid (TFA) with thiocarbohydrazide
(TCH, 1) in refluxing water for 5 h according to the reported
method [12–18].
The intermediates 4-amino-5-(4-fluorophenyl)-4H-1,2,4-tria-
zole-3-thiol (5a) and 4-amino-5-(4-(trifluoromethyl)phenyl)-4H-
1,2,4-triazole-3-thiol (5b) were synthesized from 4-fluorobenzoyl
hydrazine (3a) and 4-(trifluoromethyl)benzoyl hydrazine (3b) via
a facile two-step procedure including salt formation and cycliza-
tion according to the reported method [17–20].
The synthesis of the target compounds 6a–i were performed by
the alkylation of 2, 5a–b with three different alkyl bromide in
aqueous solution in the presence of NaOH as a base (Scheme 1). 3-
(Methylthio)-5-(trifluoromethyl)-4H-1,2,4-triazol-4-amine
(6j)
was synthesized by alkylation of intermediate 2 with iodo-
methane. Then, 6j was oxidized by 30% H2O2 aqueous solution in
acetic acid to give 3-(methylsulfonyl)-5-(trifluoromethyl)-4H-
1,2,4-triazol-4-amine (7) [21,22]. The reaction of 7 with p-
nitropenol in refluxing anhydrous toluene afforded 3-(4-nitro-
phenoxy)-5-(trifluoromethyl)-4H-1,2,4-triazol-4-amine (8) in 28%
yield (Scheme 2) [23,24].
* Corresponding author at: Key Laboratory of Monitoring and Management of
Crop Diseases and Pest Insects, Ministry of Agriculture, Nanjing Agricultural
University, Nanjing 210095, PR China.
E-mail address: chunlongyang@yahoo.com.cn (C.-L. Yang).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.12.015

324
M. Chen et al. / Journal of Fluorine Chemistry 135 (2012) 323–329
N
N
N N
S
CF3COOH
H2O
R2
F3C
SH
F3C
S
N
N
N
NH2NHCNHNH2
NH2
NH2
6a-c
1
2
R1
CONHNH2
3a-b
N
N
N
R2
F
S
R2Br
N
F
CS2 KOH
SH
N
NaOH
NH2
6d-f
6g-i
NH2
O
S
5a
NH2NH2•H2O
R1
CNHNHCSK
4a-b
Compounds R1
N
N
R2
F3C
S
N
N
N
NH2
3a 4a
3b, 4b CF3
,
F
F3C
SH
N
Compounds R2
6a 6d 6g
C2H5
NH2
,
,
5b
6b, 6e, 6h n-C4H9
6c, 6f, 6i CH2Ph
Scheme 1. Synthesis of some 3,5-disubstituted-4H-1,2,4-triazol-4-amines.
2.2. Structure
2.3. X-ray crystal structures of compounds 6g and 7
The IR spectrum of the target compounds showed the
peaks at 3368–3126 cmÀ1 due to the N–H stretching vibration
of amino-group at the 4-postion of 1,2,4-triazole. The broad
and strong absorption peaks at 1329–1110 cmÀ1 were assigned
to the C–F stretching vibration. The strong peaks at 1337 cmÀ1
In the crystal structure of 3-(ethylthio)-5-(4-(trifluoromethyl)-
phenyl)-4H-1,2,4-triazol-4-amine (6g) (Fig. 1), the intramolecular
hydrogen bond C(8)–H(8)ÁÁÁN(1) (Table 1), together with the atoms
C(3), C(2) and N(2), formed a new six-membered ring. The
trifluoromethyl group connecting to the benzene ring appeared in
a disordered state. Due to the strong electron withdrawing effect of
and 1157 cmÀ1 of compound
7 could be attributed to
˚
asymmetric and symmetric stretching vibration of the sulfone,
respectively.
trifluoromethylgroup, thebondlengthofC(6)–C(9)[1.496(2) A]was
˚
shorter than the normal length of C–C single bond (1.53 A). The bond
lengths of S(1)–C(1) [1.7401(16) A], C(2)–C(3) [1.471(2) A] and
The 1H NMR spectrum of the target compounds showed signals
˚
˚
˚
at
triazole. The signal for the protons of CH3 in 7 appeared at the low
field, 3.61 ppm, due to the influence of the sulfone. The peaks
between 4.26–4.38 ppm were corresponding to the protons of
CH2 of the benzyl group at the 3-position of compounds 6c, 6f and
6i. The signals for the proton of SH at the 3-position of compounds
d
4.33–5.78 ppm for the protons of NH2 at the 4-postion of 1,2,4-
N(1)–N(2) [1.4051(19) A] were shorter than their normal bond
lengths because of the presence of an electronic delocalization. The
bond C(2)–C(3) connected the benzene ring to the triazole ring to
form a large conjugated system. In the packing diagram of the
compound 6g (Fig. 2), the molecules connected each other through
intermolecular hydrogen bonds N(1)–H(1A)ÁÁÁN(3) and N(1)–
d
d
2 and 5a–b were found between
spectrum showed peaks at
2, 5b, 6a–c, 6g–j, 7 and 8, and at
compounds 5a and 6d–f.
Moreover, all the target compounds showed parent ion [M+]
peaks in their MS spectra. All the elemental analysis data matched
their molecular formulas.
d
10.86–13.95 ppm. The 19F NMR
H(1B)ÁÁÁS(1) (Table 1). There were
pÁÁÁp stacking interactions
d
À63.42 to À66.24 ppm for compounds
between the approximately parallel triazole rings. The dihedral
d
À107.33 to À110.66 ppm for
angle was 12.094(38)8. Thecentroid–centroid and centroid-to-plane
˚
˚
distances were 3.4612(3) A and 3.3841(14) A, respectively. More-
˚
p), 3.0914(3) A;
over, there were intermolecular C–HÁÁÁ
p
(d(HÁÁÁ
˚
d(CÁÁÁp
), 3.7766(17) A; n(C–HÁÁÁ
p), 131.930(105)8) interactions of
C(7)–H(7) to the benzene ring.
N
N
N
N N
CH3I, NaOH
H2O
30%H2O2
HOAc
CH3
F3C
SH
F3C
S
N
N
NH2
NH2
6j
2
O
S
N N
N
N
NO2
HO
NO2
CH3
F3C
O
F3C
N
toluene
O
NH2
NH2
7
8
Scheme 2. Synthesis of 3-(4-nitrophenoxy)-5-(trifluoromethyl)-4H-1,2,4-triazol-4-amine.

M. Chen et al. / Journal of Fluorine Chemistry 135 (2012) 323–329
325
Fig. 1. ORTEP diagram of compound 6g.
Fig. 3. ORTEP diagram of compound 7.
Table 1
Hydrogen bonds geometry of compounds 6g and 7 (A,8).
˚
100
m
g/mL are summarized in Table 2. The fungicide propicona-
Compd. D–HÁÁÁA
d(D–H) d(HÁÁÁA) d(DÁÁÁA)
n(DHA)
zole was used as a control drug. Compounds 5a–b, 6e–i and 8
showed observable fungicidal activities of more than 50% against
Rhizoctonia solani. Among them, compounds 5b and 6g exhibited
the highest activities with inhibitory rates of 74.9% and 72.2%,
respectively. Against Fusarium graminearum, Botrytis cinerea and
Colletotrichum capsici, all the title compounds showed low
fungicidal activities with the inhibitory rates of less than 50%,
except for compound 5b which exhibited notable inhibitory
rates of 77.5% against B. cinerea and 67.9% against C. capsici,
and compound 8 showed a medium inhibitory rate of 51.9% against
C. capsici.
6g
N(1)–H(1A)ÁÁÁN(3)a
0.92(2)
0.88(2)
0.93
2.12(2)
2.68(2)
2.37
3.036(2)
175.3(16)
N(1)–H(1B)ÁÁÁS(1)b
C(8)–H(8)ÁÁÁN(1)
3.3927(16) 138.5(18)
3.021(2)
127
7
N(4)–H(4D)ÁÁÁN(4)a 0.86
2.60
3.044(3)
3.117(3)
3.426(3)
3.286(3)
3.342(3)
113.6
138.6
152
N(4)–H(4E)ÁÁÁO(1)a
C(4)–H(4A)ÁÁÁO(2)b
C(4)–H(4B)ÁÁÁF(1)c
C(4)–H(4C)ÁÁÁO(2)d
0.86
0.96
0.96
0.96
2.42
2.548
2.462
2.485
144
149
Symmetry code: for the compound 6g: (a) Àx, 1/2 + y, 1/2 À z, (b) x, 1/2 À y, 1/2 + z;
for the compound 7: (a) 1 À x, 1 À y, 2 À z, (b) x, 1 + y, z, (c) 1/2 À x, À1/2 + y, 3/2 À z,
(d) 3/2 À x, 1/2 + y, 3/2 À z.
By the preliminary structure–activity relationship analysis, it
was concluded that compounds 5a–b and 6d–i had better
fungicidal activities than compounds 2 and 6a–b. And this could
be due to the introducing of the fluorinated benzenes. Especially,
when the connection mode of trifluoromethyl group at the 5-
position of 1,2,4-triazole was changed from directly to indirectly
via a phenyl group, the corresponding compounds’ fungicidal
activities obviously were enhanced. Meanwhile, compound 8 had
better fungicidal activities than compounds 6j and 7, and
compound 6c had better fungicidal activities than compounds 2,
6a and 6b, which meant that introducing the phenyl group at the 3-
position of 1,2,4-triazole could also improve the fungicidal
activities when the trifluoromethyl group was connected directly
at the 5-position of 1,2,4-triazole.
The bond lengths of the sulfone group in compound 7 (Fig. 3)
˚
˚
were 1.4337(16) A (S(1)–O(1)) and 1.4350(19) A (S(1)–O(2)),
˚
accordant with the normal length (1.43 A). There were as many
as five intermolecular hydrogen bonds, N(4)–H(4E)ÁÁÁO(1), C(4)–
H(4A)ÁÁÁO(2), C(4)–H(4 C)ÁÁÁO(2), N(4)–H(4D)ÁÁÁN(4) and C(4)–
H(4B)ÁÁÁF(1), between the neighboring molecules. They jointly
constituted a stable 3-D supramolecular network structure with
many cavities (Fig. 4).
2.4. Fungicidal activities
The screening results of in vitro fungicidal activities of
compounds 2, 5a–b, 6a–j, 7 and 8 at the concentration of
Fig. 2. Crystal packing diagram of compound 6g showing the intermolecular interactions.

326
M. Chen et al. / Journal of Fluorine Chemistry 135 (2012) 323–329
4. Experimental
4.1. General procedures
The melting points of the products were determined on a
WRS-1B digital melting-point apparatus and are uncorrected. IR
spectra were recorded on a Thermo Nicolet 380 FT-IR spectrom-
.
eter with KBr pellets in the range of 4000–400 cmÀ1 1H and 19F
NMR spectra were taken on a Bruker AV spectrometer at 400 and
376 MHz with CDCl3 or DMSO-d6 as the solvent. The chemical
shifts are reported in ppm relative to the appropriate standards,
TMS for 1H and CFCl3 for 19F. Mass spectra were recorded on a
GC/MS-QP2010 spectrometer using a direct injection technique.
The elemental analyses were performed on an Elementar Vario
EL III element analyzer. The X-ray diffraction was performed
with a Brucker Smart APEX II CCD diffractometer. A suitable
crystal for compound 6g was grown in absolute ethanol and for
compound 7 the crystal was grown in water. All the reagents
were analytical reagent grade or were chemically pure. The
solvents were dried prior to use as needed. All the reactions were
monitored by TLC.
4.1.1. Preparation of 4-amino-5-(trifluoromethyl)-4H-1,2,4-triazole-
3-thiol (2)
Fig. 4. Crystal packing diagram of compound
7 showing the intermolecular
interactions.
A mixture of TCH (1) (10.6 g, 0.1 mol) and TFA (11.4 g, 0.1 mol)
in water (30 mL) was refluxed for 5 h under stirring. The reaction
solution was cooled and filtered. The filter residue was washed
with cold water (10 mL) and recrystallized from water to give the
pure compound 2.
Table 2
Fungicidal activities of compounds 2, 5a–b, 6a–j, 7 and 8 (100
m
g/mL, inhibitory
rate percent).
Colorless crystal; m.p. 140.3–141.0 8C; Yield: 85%; IR(KBr,
a
cmÀ1
)
n
: 3314, 3200, 1630, 1460, 1242, 1193, 1147, 1082, 1005,
764; 1H NMR (400 MHz, CDCl3)
(ppm): 11.64(s, 1H, SH), 4.83 (s,
2H, NH2); 19F NMR (376 MHz, CDCl3)
Compd.
Inhibitory rate (%)
d
R. solani
F. graminearum
B. cinerea
C. capsici
d
(ppm): À66.24 (s, 3F, ArCF3);
2
24.4 Æ 3.5
63.2 Æ 4.0
74.9 Æ 0.8
23.0 Æ 9.7
18.4 Æ 6.4
42.8 Æ 14.6
19.9 Æ 9.2
51.7 Æ 4.3
68.2 Æ 6.6
72.2 Æ 2.3
53.3 Æ 10.5
50.2 Æ 5.9
12.9 Æ 3.0
42.6 Æ 3.6
51.2 Æ 5.2
3.2 Æ 1.4
23.7 Æ 1.7
37.9 Æ 4.4
À0.5 Æ 3.2
2.2 Æ 1.7
À0.3 Æ 2.5
42.1 Æ 6.2
77.5 Æ 2.5
0.0 Æ 2.7
9.2 Æ 4.3
18.2 Æ 3.4
9.9 Æ 2.2
18.4 Æ 5.4
13.7 Æ 4.3
27.6 Æ 3.1
5.9 Æ 2.6
7.4 Æ 4.0
3.7 Æ 3.7
11.2 Æ 2.3
36.6 Æ 3.2
7.1 Æ 3.6
26.5 Æ 3.9
67.9 Æ 5.3
9.6 Æ 1.2
MS: m/z (%): 184[M+](100), 126(11), 111(5), 96(8), 85(1), 78(12),
69(30), 60(23), 57(13), 45(8); Anal. Calcd. for C3H3F3N4S: C, 19.57;
H, 1.64; N, 30.43. Found: C, 19.45; H, 1.59; N, 30.06.
5a
5b
6a
6b
6c
6d
6e
6f
6g
6h
6i
6.0 Æ 2.2
19.6 Æ 3.0
13.2 Æ 4.4
21.2 Æ 1.6
21.8 Æ 1.3
23.9 Æ 1.9
13.2 Æ 3.1
16.4 Æ 2.4
À0.8 Æ 2.8
15.5 Æ 0.9
27.7 Æ 1.6
18.7 Æ 1.1
6.2 Æ 1.0
4.1.2. General procedures for the synthesis of 4-amino-5-(4-
substituted)phenyl)-4H-1,2,4-triazole-3-thiols (5a–b)
46.0 Æ 2.2
18.7 Æ 7.0
24.7 Æ 1.1
16.2 Æ 7.5
12.2 Æ 0.7
1.7 Æ 1.6
4-Fluorobenzoyl hydrazine (3a) (15.4 g, 0.1 mol) was added to
a solution of potassium hydroxide (6.72 g, 0.12 mol) and absolute
ethanol (200 mL) under stirring. After 3a was dissolved, carbon
disulfide (9.12 g, 0.12 mol) was added dropwise into the solution,
the mixture was kept stirring at room temperature for 36 h. The
precipitate was filtered and washed with dry ether (75 mL). The
crude product potassium salt 4a (13.4 g, 0.05 mol) was dissolved
in hot water (50 mL) and filtered. Then, 85% hydrazine (5.8 g,
0.1 mol) and the filtrate containing the compound 4a were
refluxed for 4 h until the reaction mixture changed its color to
green. A yellow solid was precipitated by diluting with cold water
(150 mL) and acidifying with concentrated hydrochloric acid.
After filtering, the solid was washed with cold water (20 mL), and
recrystallized from ethanol to give the analytically pure com-
pound 5a. This method was suitable for the synthesis of
compound 5b.
6j
7
5.4 Æ 0.7
8
51.9 Æ 2.2
Propiconazole
100.0
95.4 Æ 0.7
100.0
100.0
a
The values are expressed as means Æ SD of three replicates.
3. Conclusions
In summary, fluorine was introduced to the 5-position of 1,2,4-
triazole to design and synthesize fifteen fluorinated 3,5-disubsti-
tuted-4H-1,2,4-triazol-4-amines. The structures of these com-
pounds were well supported by spectroscopic data, elemental
analysis and single crystal X-ray diffraction analysis. The antifun-
gal bioassay results demonstrated that the title compounds
showed different fungicidal activities at the concentration of
4.1.2.1. 4-Amino-5-(4-fluorophenyl)-4H-1,2,4-triazole-3-thiol
(5a). Yellow crystal; m.p. 205.7–205.8 8C; Yield: 35%; IR(KBr,
100
m
g/mL. Compound 5b was the best with inhibitory rates of
cmÀ1
)
n
: 3240, 3149, 1642, 1608, 1503, 1452, 1325, 1216, 1161,
1070, 1017, 953, 846, 731, 684; 1H NMR (400 MHz, DMSO-d6)
(ppm): 13.95(s, 1H, SH), 8.09 (dd, J = 8.7, 5.6 Hz, 2H, PhH), 7.47–
7.30 (m, 2H, PhH), 5.78 (s, 2H, NH2); 19F NMR (376 MHz, CDCl3)
74.9%, 77.5% and 67.9% against R. solani, B. cinerea and C. capsici,
respectively. The structure–activity relationship analysis revealed
that introducing the fluorinated phenyl, especially the 4-trifluor-
omethyl phenyl group, at the 5-position of 1,2,4-triazol-4-amine,
or introducing a phenyl group at the 3-position while the
trifluoromethyl group was connected at the 5-position directly
were helpful to improve the fungicidal activities.
d
d
(ppm): À108.21 to À108.28 (m, 1F, PhF); MS: m/z (%):
210[M+](100), 139(30), 121(51), 109(16), 95(29) 75(11), 69(17),
57(28), 45(26); Anal. Calcd. for C8H7FN4S: C, 45.71; H, 3.36; N,
26.65. Found: C, 45.53; H, 3.28; N, 26.51.

M. Chen et al. / Journal of Fluorine Chemistry 135 (2012) 323–329
327
4.1.2.2. 4-Amino-5-(4-(trifluoromethyl)phenyl)-4H-1,2,4-triazole-3-
Anal. Calcd. for C10H11FN4S: C, 50.41; H, 4.65; N, 23.51. Found: C,
50.29; H, 4.63; N, 23.20.
thiol (5b). Yellow powder; m.p. 214.8–215.5 8C; Yield: 46%; IR(KBr,
cmÀ1
)
n
: 3280, 3144, 3011, 1618, 1540, 1508, 1471, 1323, 1153,
1118, 1064, 1017, 956, 847, 748; 1H NMR (400 MHz, CDCl3)
(ppm): 10.86(s, 1H, SH), 8.32 (d, J = 8.2 Hz, 2H, PhH), 7.80 (d,
4.1.3.5. 3-(Butylthio)-5-(4-fluorophenyl)-4H-1,2,4-triazol-4-amine
d
(6e). White powder; m.p. 179.1 8C (decompose); Yield: 19%;
J = 8.3 Hz, 2H, PhH), 4.90 (s, 2H, NH2); 19F NMR (376 MHz, CDCl3)
IR(KBr, cmÀ1
)
n
: 3260, 3136, 2964, 2932, 1647, 1605, 1535,
1481, 1450, 1382, 1233, 1160, 1096, 978, 835, 729, 683; 1H NMR
(400 MHz, CDCl3) (ppm): 8.19 (dd, J = 8.7, 5.3 Hz, 2H, PhH), 7.17 (t,
d
(ppm): À63.60 (s, 3F, PhCF3); MS: m/z (%): 260[M+](100), 241(5),
229(5), 189(22), 172(25), 145(23), 121(14), 113(3), 95(6), 81(5),
69(17), 60(25), 45(9); Anal. Calcd. for C9H7F3N4S: C, 41.54; H, 2.71;
N, 21.53. Found: C, 41.67; H, 2.78; N, 21.47.
d
J = 8.6 Hz, 2H, PhH), 5.41 (s, 2H, NH2), 3.24 (t, J = 7.4 Hz, 2H,
SCH2CH2), 1.79–1.71 (m, 2H, SCH2CH2CH2), 1.52–1.43 (m, 2H,
CH2CH2CH3), 0.96 (t, J = 7.4 Hz, 3H, CH2CH3); 19F NMR (376 MHz,
4.1.3. General procedures for the synthesis of 3-(alkylthio)-5-
substituted-4H-1,2,4-triazol-4-amines (6a–i)
CDCl3)
d
(ppm): À110.59 to À110.66 (m, 1F, PhF); MS: m/z (%):
266[M+](13), 251(11), 233(6), 219(98), 210(100), 206(20), 195(5),
179(7), 164(4), 149(6), 139(46), 122(70), 109(6), 95(37), 75(16),
57(16), 45(7); Anal. Calcd. for C12H15FN4S: C, 54.12; H, 5.68; N,
21.04. Found: C, 53.97; H, 5.71; N, 21.29.
NaOH (0.6 g, 0.015 mol) and 4-amino-5-substituted-4H-1,2,4-
triazole-3-thiol (2, 5a–b) (0.01 mol) were dissolved in water
(15 mL). After the mixture was cooled to room temperature, the
appropriate alkyl halide (0.012 mol) was added dropwise with
stirring. The reaction mixture was stirred for 4 h (monitored by
TLC), then the solid product was collected by filtration, washed
with water and recrystallized from ethanol to give the title
compounds 6a–i with yields of 19–74% based on the corresponding
compounds 2 and 5a–b.
4.1.3.6. 3-(Benzylthio)-5-(4-fluorophenyl)-4H-1,2,4-triazol-4-amine
(6f). Colorless powder; m.p. 175.6–176.4 8C; Yield: 74%; IR(KBr,
cmÀ1
)
n
: 3250, 3141, 2979, 1647, 1607, 1537, 1482, 1450, 1240,
1162, 1097, 987, 835, 716, 699; 1H NMR (400 MHz, CDCl3)
d
(ppm):
8.04 (dd, J = 8.6, 5.4 Hz, 2H, PhH), 7.33–7.27 (m, 5H, PhH), 7.16 (t,
J = 8.6 Hz, 2H, PhH), 4.33 (s, 2H, NH2), 4.26 (s, 2H, SCH2); 19F NMR
4.1.3.1. 3-(Ethylthio)-5-(trifluoromethyl)-4H-1,2,4-triazol-4-amine
(376 MHz, CDCl3)
d
(ppm): À108.58 (s, 1F, PhF); MS: m/z (%):
(6a). Colorless crystal; m.p. 75.4–76.4 8C; Yield: 33%; IR(KBr,
300[M+](22), 283(4), 267(1), 251(1), 178(5), 148(3), 121(25),
106(41), 91(100), 65(23), 57(5), 45(4); Anal. Calcd. for C15H13FN4S:
C, 59.98; H, 4.36; N, 18.65. Found: C, 59.62; H, 4.30; N, 18.39.
cmÀ1
)
n
: 3263, 3163, 2976, 2937, 1644, 1528, 1484, 1405, 1386,
1276, 1165, 1001, 760; 1H NMR (400 MHz, CDCl3)
(ppm): 4.75 (s,
2H, NH2), 3.36 (q, J = 7.4 Hz, 2H, CH2CH3), 1.50 (t, J = 7.4 Hz, 3H,
CH2CH3); 19F NMR (376 MHz, CDCl3)
d
d
(ppm): À64.24 (s, 3F, ArCF3);
4.1.3.7. 3-(Ethylthio)-5-(4-(trifluoromethyl)phenyl)-4H-1,2,4-tria-
MS: m/z (%): 212[M+](38), 195(31), 184(100), 151(28), 138(23),
126(16), 111(11), 96(14), 69(45), 45(19); Anal. Calcd. for
C5H7F3N4S: C, 28.30; H, 3.33; N, 26.40. Found: C, 28.59; H, 3.40;
N, 26.51.
zol-4-amine (6g). White powder; m.p. 178.7–179.1 8C; Yield: 60%;
IR(KBr, cmÀ1
)
n
: 3293, 3126, 2982, 2933, 1616, 1471, 1383, 1328,
1161, 1127, 1110, 1067, 1018, 975, 853, 696; 1H NMR (400 MHz,
CDCl3) (ppm): 8.30 (d, J = 8.2 Hz, 2H, PhH), 7.73 (d, J = 8.3 Hz, 2H,
PhH), 5.42 (s, 2H, NH2), 3.30 (q, J = 7.4 Hz, 2H, SCH2CH3), 1.45 (t,
J = 7.4 Hz, 3H, CH2CH3); 19F NMR (376 MHz, CDCl3)
(ppm):
d
4.1.3.2. 3-(Butylthio)-5-(trifluoromethyl)-4H-1,2,4-triazol-4-amine
d
(6b). Colorless crystal; m.p. 119.5–120.4 8C; Yield: 64%; IR(KBr,
À63.70 (s, 3F, PhCF3); MS: m/z (%): 288[M+](27), 274(9), 269(10),
260(100), 240(5), 229(5), 210(21), 189(16), 172(38), 145(43),
121(21), 95(9), 75(14), 57(21), 45(20); Anal. Calcd. for
cmÀ1
)
n
: 3285, 3178, 1956, 2938, 1626, 1526, 1489, 1404, 1274,
1185, 1161, 1001, 760; 1H NMR (400 MHz, CDCl3)
d
(ppm): 4.74 (s,
2H, NH2), 3.34 (t, J = 7.4 Hz, 2H, SCH2CH2), 1.85–1.77 (m, 2H,
SCH2CH2CH2), 1.55–1.46 (m, 2H, CH2CH2CH3), 0.98(t, J = 7.4 Hz, 3H,
C11H11F3N4S: C, 45.82; H, 3.85; N, 19.44. Found: C, 45.97; H,
3.86; N, 19.21.
CH2CH3); 19F NMR (376 MHz, CDCl3)
d
(ppm): À64.24 (s, 3F, ArCF3);
MS: m/z (%): 240[M+](6), 207(9), 198(65), 184(100), 169(8),
149(41), 121(20), 111(15), 97(15), 85(33), 69(63), 57(83),
45(40); Anal. Calcd. for C7H11F3N4S: C, 35.00; H, 4.61; N, 23.32.
Found: C, 34.87; H, 4.67; N, 23.45.
4.1.3.8. 3-(Butylthio)-5-(4-(trifluoromethyl)phenyl)-4H-1,2,4-tria-
zol-4-amine (6h). White powder; m.p. 180.1–180.4 8C; Yield: 28%;
IR(KBr, cmÀ1
)
n
: 3264, 3147, 2965, 2935, 1621, 1442, 1391, 1328,
1170, 1127, 1067, 1017, 979, 846, 707; 1H NMR (400 MHz, CDCl3)
(ppm): 8.32 (d, J = 8.2 Hz, 2H, PhH), 7.73 (d, J = 8.3 Hz, 2H, PhH),
d
4.1.3.3. 3-(Benzylthio)-5-(trifluoromethyl)-4H-1,2,4-triazol-4-amine
5.49 (s, 2H, NH2), 3.29 (t, J = 7.4 Hz, 2H, SCH2CH2), 1.79–1.71 (m,
2H, SCH2CH2CH2), 1.51–1.39 (m, 2H, CH2CH2CH3), 0.95 (t,
(6c). White powder; m.p. 143.0–144.3 8C; Yield: 66%; IR(KBr,
cmÀ1
)
n
: 3259, 3159, 3034, 2943, 1627, 1525, 1454, 1406,
1363, 1263, 1204, 1172, 1151, 1020, 780, 759, 706; 1H NMR
(400 MHz, CDCl3) (ppm): 7.39–7.30 (m, 5H, PhH), 4.41 (s, 2H,
NH2), 4.38 (s, 2H, SCH2); 19F NMR (376 MHz, CDCl3)
(ppm):
J = 7.3 Hz, 3H, CH2CH3); 19F NMR (376 MHz, CDCl3)
d(ppm):
À63.42 (s, 3F, PhCF3); MS: m/z (%): 316[M+](8), 297(6), 283(5),
269(93), 260(100), 256(19), 229(9), 214(2), 189(20), 172(31),
145(28), 121(19), 95(6), 75(6), 60(17), 57(14), 45(16); Anal. Calcd.
for C13H15F3N4S: C, 49.35; H, 4.78; N, 17.72. Found: C, 49.65; H,
4.80; N, 17.86.
d
d
À64.48 (s, 3F, ArCF3); MS: m/z (%): 274[M+](11), 257(5), 149(3),
121(4), 106(8), 91(100), 77(3), 69(21), 57(3), 45(4); Anal. Calcd.
for C10H9F3N4S: C, 43.79; H, 3.31; N, 20.43. Found: C, 43.92; H,
3.38; N, 20.56.
4.1.3.9. 3-(Benzylthio)-5-(4-(trifluoromethyl)phenyl)-4H-1,2,4-tria-
zol-4-amine (6i). White powder; m.p. 202.9–203.8 8C; Yield: 53%;
4.1.3.4. 3-(Ethylthio)-5-(4-fluorophenyl)-4H-1,2,4-triazol-4-amine
IR(KBr, cmÀ1
)
n
: 3299, 3160, 3084, 3030, 2939, 1621, 1495, 1455,
1411, 1329, 1137, 1118, 1069, 1017, 977, 848, 706; 1H NMR
(400 MHz, CDCl3) (ppm): 8.20 (d, J = 8.1 Hz, 2H, PhH), 7.73 (d,
J = 8.2 Hz, 2H, PhH), 7.34–7.25 (m, 5H, PhH), 4.36 (s, 2H, NH2), 4.26
(s, 2H, SCH2); 19F NMR (376 MHz, CDCl3)
(6d). Colorless crystal; m.p. 167.8–169.5 8C; Yield: 53%; IR(KBr,
cmÀ1
)
n
: 3244, 3140, 2986, 2928, 1608, 1528, 1484, 1462, 1380,
d
1240, 1157, 989, 841, 734, 685; 1H NMR (400 MHz, CDCl3)
d
(ppm):
8.19 (dd, J = 8.8, 5.2 Hz, 2H, PhH), 7.17 (t, J = 8.6 Hz, 2H, PhH), 5.49
(s, 2H, NH2), 3.26 (q, J = 7.4 Hz, 2H, SCH2CH3), 1.44 (t, J = 7.4 Hz, 3H,
d
(ppm): À63.47 (s, 3F,
PhCF3); MS: m/z (%): 350[M+](18), 333(4), 317(1), 229(1), 171(4),
152(4), 145(7), 121(8), 106(29), 91(100), 77(5), 65(19), 45(4); Anal.
Calcd. for C16H13F3N4S: C, 54.84; H, 3.74; N, 16.00. Found: C, 54.94;
H, 3.69; N, 16.07.
CH2CH3); 19F NMR (376 MHz, CDCl3)
d
(ppm): À107.33 (s, 1F, PhF);
MS: m/z (%): 238[M+](48), 223(10), 210(100), 195(3), 179(4),
160(24), 139(33), 122(89), 109(12), 95(59), 75(30), 57(34), 45(11);

328
M. Chen et al. / Journal of Fluorine Chemistry 135 (2012) 323–329
Table 3
4.1.4. Preparation of 3-(methylthio)-5-(trifluoromethyl)-4H-1,2,4-
triazol-4-amine (6j)
Selected crystal data and refinement details of compounds 6g and 7.
Compound 2 (5.52 g, 0.03 mol), NaOH (2 g, 0.05 mol) and water
(15 mL) were stirred at room temperature until solid was
dissolved. Then CH3I (5.68 g, 0.04 mol) was added dropwise into
the solution with stirring. The reaction mixture was stirred for
0.5 h, and then filtered. The residue was recrystallized from
ethanol to give 6j.
Compd.
6g
7
Chemical formula
FW
Crystal size (mm3)
Color, shape
Crystal system
Space group
C11H11F3N4S
288.30
C4H5F3N4O2S
230.18
0.21 Â 0.26 Â 0.28
Colorless, block
Monoclinic
P21/c
0.20 Â 0.25 Â 0.27
Colorless, block
Monoclinic
P21/n
Colorless crystal; m.p. 105.6–106.4 8C; Yield: 81%; IR(KBr,
˚
a (A)
14.1323(16)
10.7066(12)
8.3446(10)
90
10.0642(13)
5.9384(8)
14.0629(18)
90
cmÀ1
)
n
: 3352, 3283, 3200, 2938, 1638, 1529, 1403, 1383, 1267,
1204, 1145, 982, 878, 758; 1H NMR (400 MHz, CDCl3)
(ppm): 4.76
(s, 2H, NH2), 2.78 (s, 3H, CH3S); 19F NMR (376 MHz, CDCl3)
(ppm):
˚
b (A)
˚
c (A)
d
a
b
g
(8)
(8)
(8)
d
94.8630(10)
90
98.7970(10)
90
À64.21 (s, 3F, ArCF3); MS: m/z (%): 198[M+](25), 181(42), 149(30),
119(12), 97(24), 85(38), 69(100), 57(95), 45(31); Anal. Calcd. for
C4H5F3N4S: C, 24.24; H, 2.54; N, 28.27. Found: C, 24.20; H, 2.49; N,
28.25.
3
˚
V (A )
1258.1(3)
4
830.59(19)
4
Z
Density (calculated) (mg/m3)
(mmÀ1
F (0 0 0)
1.522
1.841
m
)
0.286
0.423
592
464
4.1.5. Preparation of 3-(methylsulfonyl)-5-(trifluoromethyl)-4H-
1,2,4-triazol-4-amine (7)
Reflections collected
9531
6756
Independent reflections
2474
1913
Observed [I > 2
d
(I)] reflections
2177
1813
The compound 6j (1.9 g, 0.01 mol) was added into glacial HOAc
(8 mL), and then the solution was heated to 40 8C. After
NaWO2ÁH2O (0.05 g) as a catalyst was added under stirring, the
reaction mixture was heated to 50 8C. Next, 30% H2O2 (2.83 g,
0.025 mol) was added dropwise to the solution and the reaction
temperature was kept at 50 8C until compound 6j disappeared
(observed by TLC). The mixture was poured into water (10 mL). The
resulting precipitate was filtered and crystallized from water to
afford the analytically pure compound 7.
No. of parameters
Goodness-of-fit
209
128
1.015
1.012
R1 [I > 2
R2 [I > 2
Largest diff. peak and hole (e A
d
(I)]
0.0348
0.0433
v
d
(I)]
0.0986
0.1234
À3
˚
)
0.238 and À0.232
0.681 and À0.653
296(2) K. Both crystal structures were solved by direct methods
SHELX-97 and refined using SHELXL-97 [25,26]. All the non-
hydrogenatomswererefinedbyfull-matrixleast-squarestechnique
on F2 with anisotropic thermal parameters. All the hydrogen atoms
were positioned geometrically and refined using a riding model,
except the N–H hydrogen atoms of compound 6g were located from
the difference Fourier map and were set as isotropic. PLATON
program was used for structure analysis and drawings preparation
[27]. The selected crystallographic data are given in Table 3.
The crystallographic data have been deposited with Cambridge
Crystallographic Data Centre, CCDC No. 844716 for the compound
6g and CCDC No. 844715 for the compound 7. Copies of this
information can be obtained free of charge from the Director,
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: +44 1223 336
033; or e-mail: deposit@ccdc.cam.ac.uk).
Colorless crystal; m.p. 147.7–148.6 8C; Yield: 37%; IR(KBr,
cmÀ1
)
n
: 3368, 3284, 3214, 2931, 1629, 1529, 1366, 1337, 1210,
1157, 956, 663, 775; 1H NMR (400 MHz, CDCl3)
(ppm): 5.42 (s, 2H,
NH2), 3.61 (s, 3H, CH3SO2); 19F NMR (376 MHz, CDCl3)
(ppm):
d
d
À63.80 (s, 3F, ArCF3); MS: m/z (%): 230[M+](10), 211(12), 181(4),
166(95), 150(48), 123(6), 111(14), 96(18), 81(16), 69(100), 57(42),
45(25); Anal. Calcd. for C4H5F3N4O2S: C, 20.87; H, 2.19; N, 24.34.
Found: C, 20.99; H, 2.23; N, 24.31.
4.1.6. Preparation of 3-(4-nitrophenoxy)-5-(trifluoromethyl)-4H-
1,2,4-triazol-4-amine (8)
p-Nitrophenol (1.11 g 0.008 mol), NaOH (0.34 g, 0.0085 mol)
and anhydrous toluene (20 mL) were refluxed for 3 h. Then the
compound 7 (0.92 g, 0.004 mol) was added to the solution. The
reaction mixture was refluxed for 8 h at which time the reaction
was completed. After cooling, the mixture was filtered. The filtrate
was washed twice with water (10 mL), twice with 20% sodium
hydroxide solution (10 mL) and twice with water (10 mL). The
organic layer was dried using anhydrous magnesium sulfate over
night and filtered. The solvent was removed at reduced pressure to
give compound 8 as a yellow powder, which was purified by
recrystallization from ethanol.
4.3. Fungicidal assay
The inhibition effects of the title compounds 2, 5a–b, 6a–j, 7 and
8 against phytopathogenic fungi (R. solani, F. graminearum, B.
cinerea and C. capsici) were tested using a radial growth inhibition
technique according to the reported method [28]. Each compound
was diluted with MeOH (0.5 mL) and added to potato sucrose agar
medium (PSA) respectively to obtain a concentration of 100
mg/mL
Yellow powder; m.p. 150.9–151.0 8C; Yield: 28%; IR(KBr, cmÀ1
: 3359, 3293, 3080, 1623, 1522, 1486, 1347, 1293, 1241, 1166,
1140, 999, 858; 1H NMR (400 MHz, CDCl3)
(ppm): 8.37 (d,
J = 8.8 Hz, 2H, PhH), 7.74 (d, J = 9.0 Hz, 2H, PhH), 4.89 (s, 2H, NH2);
19F NMR (376 MHz, CDCl3)
(%): 289[M+](13), 270(8), 259(7), 242(5), 207(3), 167(3), 149(8),
137(62), 122(20), 111(14), 92(19), 75(100), 63(29), 50(262), 45(9);
Anal. Calcd. for C9H6F3N5O3: C, 37.38; H, 2.09; N, 24.22. Found: C,
37.31; H, 2.07; N, 24.19.
)
before pouring into the Petri dishes. Each compound was tested in
triplicate. The parallel controls were maintained with MeOH
(0.5 mL) mixed with PSA medium. The discs of mycelia felt (0.5 cm
diameter) of fungi were transferred aseptically to the center of
Petri dishes. The treatments were incubated at 25 Æ 1 8C in the
dark. The diameters of the colonies were measured after the colonies
in the control treatments had covered two-thirds of the Petri dishes.
The growth inhibition rates were calculated with the following
equation: I = [(C À T)/C] Â 100%. Here, I was the growth inhibition
rate (percent), C was the colony diameter of the parallel control (mm),
and T was the colony diameter of the title compound treatment (mm).
n
d
d
(ppm): À64.91 (s, 3F, ArCF3); MS: m/z
4.2. Crystal structure determination
Acknowledgments
The single crystals of compounds 6g and 7 were selected and
glued on the tip of a glass fiber. Both cell dimensions and intensities
were measured on a Bruker Smart APEX II CCD diffractometer with
˚
We thank the financial support of the Fundamental Research
Funds for the Central Universities of China (KYZ200918). And we
graphite monochromatized Mo K
a radiation (l = 0.71073 A) at

M. Chen et al. / Journal of Fluorine Chemistry 135 (2012) 323–329
329
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crystal data collection.
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