Synthesis and biological activity of 1H-1,2,4-triazole alcohol derivatives

Article abstract of DOI:10.1080/15533170802371224

Eight new 1H-1,2,4-triazole alcohol derivatives containing a ferrocenyl moiety were synthesized. In addition, four unexpected compounds, which are the hydroxyl of the title compounds being methylated by methanol, were obtained. The structures of all these new compounds have been confirmed with 1H NMR spectra, MS, and elemental analyses. The antifungal and plant growth regulatory activities of these compounds are discussed. Copyright Taylor & Francis Group, LLC.

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Synthesis and Biological Activity of 1 H -1,2,4-
Triazole Alcohol Derivatives
Jianbing Liu a , Hong Dai a , Wei Liu a & Jianxin Fang a
a State Key Laboratory and Institute of Elemento-Organic Chemistry and Tianjin Key
Laboratory of Pesticide Science , Nankai University , Tianjin, P. R. China
Published online: 16 Oct 2008.
To cite this article: Jianbing Liu , Hong Dai , Wei Liu & Jianxin Fang (2008) Synthesis and Biological Activity of 1 H -1,2,4-
Triazole Alcohol Derivatives, Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 38:8,
647-651
To link to this article: http://dx.doi.org/10.1080/15533170802371224
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Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 38:647–651, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533170802371224
Synthesis and Biological Activity of 1H-1,2,4-Triazole
Alcohol Derivatives
Jianbing Liu, Hong Dai, Wei Liu, and Jianxin Fang
State Key Laboratory and Institute of Elemento-Organic Chemistry and Tianjin Key Laboratory
of Pesticide Science, Nankai University, Tianjin, P. R. China
1H-1,2,4-triazole groups. In our previous paper,[27] we reported
Eight new 1H-1,2,4-triazole alcohol derivatives containing a
ferrocenyl moiety were synthesized. In addition, four unexpected
compounds, which are the hydroxyl of the title compounds being
methylated by methanol, were obtained. The structures of all these
new compounds have been confirmed with 1H NMR spectra, MS,
and elemental analyses. The antifungal and plant growth regula-
tory activities of these compounds are discussed.
syntheses and biological activities of some 1H-1,2,4-triazole
keto compounds 3 containing ferrocenyl moiety (Scheme 1).
In order to compare the biological activities of the ketones 3
with their corresponding alcohol derivatives 4 (Scheme 1) and
to study their structure-activity relationship (SAR), eight title
compounds were synthesized by reducing 1H-1,2,4-triazole ke-
tones (Scheme 1). The structures of all these new compounds
1
Keywords 1H-1,2,4-triazole, ferrocenyl moiety, antifungal activity,
have been confirmed by H NMR spectra, MS, and elemental
analyses.
plant growth regulatory activity, synthesis
EXPERIMENTAL
INTRODUCTION
All reactions were monitored by thin-layer chromatography.
The H NMR spectra were measured on a Bruker AC 300
Ferrocenyl derivatives, which have been widely applied
in catalysis,[1] materials,[2] and new biologically active
compounds,[3,4] have attracted the attention of chemists for
many years.[5–10] Recently, biochemists have paid much atten-
tion to the biochemical study of ferrocenyl derivatives,[11–14]
and many ferrocenyl derivatives have been reported to have
antitumor,[11,12] antifungal,[13,14] insecticidal,[15] and plant
growth regulatory activities.[9–11]
H-1,2,4-triazole derivatives not only possess diverse
pharma-cological properties, such as antifungal,[16] antiinfl-
ammatory,[17] antiviral,[18] antimicrobial,[19] anti-tumoral,[20]
anti-convulsant,[21] analgesic,[22] and anti-hypotensive activi-
ties[23] but also reveal insecticidal, herbicidal, antifungal, and
plant growth regulatory activities.[24–26] Biochemists have paid
much interest to the study of the biolo-gical activities of 1H-
1,2,4-triazole compounds for many years.
1
(Bruker Co., Ltd Washington, USA), using tetramethylsilane
(TMS) as internal standard and CDCl3 as solvent. Chemical
shift values (δ) are given in ppm. MS spectra were under-
taken with a VG ZAB-HS spectrometer (VG Analytical Co.
Ltd., UK) using the EI method. Elemental analyses were de-
termined with a Yanaco CHN Corder MT-3 elemental ana-
lyzer (Yanaco Co., Ltd., Japan). Melting points were deter-
mined with an X-4 digital melting point apparatus (Shanghai
Hegong Scientific Instroment Co., Ltd. Shanghai, P.R. China)
and the thermometer was uncorrected. The biological activity
of compounds 4 and 5 was assayed at the Biological Assay
Centre, Nankai University, according to procedures described
previously.[13]
Encouraged by this, we are interested in exploring the bio-
logical activities of compounds that contain both ferrocenyl and
General Procedure for the Synthesis of the Title
Compounds 4 and 5
To a stirred solution of the intermediate 3 (0.0025 mol) in
MeOH (15 mL), (0.114 g, 0.003 mol) NaBH4 in patches over
a period of 20 min at room temperature. The mixtures were
stirred in another 6 h at r.t., then (0.3 mL, 0.0036 mol) 12 M
HCl was added. After stirring for 2 h, a solution of NaHCO3
(0.6 g, 0.0072 mol) in H2O (10 mL) was added drop-wise.
After being stirred for 1 h, the solution was extracted with
Et2O (3 × 30 mL). The extract was washed with H2O (10
mL) and then dried with anhydrous Na2SO4. After evaporation
Received 20 June 2008; accepted 20 July 2008.
We gratefully acknowledge the National Natural Science Founda-
tion of China (NNSFC) (Nos. 20672063, 20772068) and the National
Key Project of Scientific and Technical Supporting Programs Funded
by Ministry of Science & Technology of China (No. 2006BAE01A01-
5) for financial support.
Address correspondence to Jianxin Fang, State Key Laboratory
and Institute of Elemento-Organic Chemistry, Weijin Road 94, Nankai
University, Tianjin 300071, P. R. China. E-mail: fjx@nankai.edu.cn
647

648
LIU ET AL.
SCHEME 1.
of Et2O, the remaining solid was recrystallized from 1H, OH), 4.08 (s, 5H, FcH), 4.25–4.30 (s, 4H, FcH), 4.80 (d, d,
AcOEt/petroleum ether (60–90◦C; V/V = 1/3) or purified by J = 14.1 Hz, 2H, CH2), 5.33 (s, 1H, CH), 6.70 (s, 1H, =CH),
silica gel column chromatography to give a yellow solid 4 and 7.01–7.07 (m, 2H, PhH), 7.34–7.39 (m, 2H, PhH), 7.96 (s, 1H,
5 in various yields.
TrH), 8.05 (s, 1H, TrH); EI-MS (M+) m/z: 417. Anal. Calcd.
4a: 2-((1H-1,2,4-Triazol-1-yl)methyl)-3-ferrocenyl-1-(2,5- for C22H20FFeN3O: C 63.33, H 4.83, N 10.07. Found: C 63.37,
dimethoxyphenyl)prop-2-en-1-ol. Yield 78.9%; yellow solid; H 4.96, N 10.18.
1
m.p. 178–180◦C; H NMR δ (300 MHz, CDCl3): 3.43 (s, 1H,
4c: 2-((1H-1,2,4-Triazol-1-yl)methyl)-3-ferrocenyl-1-(2-
OH), 3.77(s, 3H, OCH3), 3.81 (s, 3H, OCH3), 4.07 (s, 5H, FcH), bromophenyl) prop-2-en-1-ol. Yield 77%; yellow solid; m.p.
4.22 (s, 2H, FcH), 4.24 (s, 2H, FcH), 4.95 (s, 2H, CH2), 5.52 159–161◦C; 1H NMR δ (300 MHz, CDCl3): 3.77 (s, 1H, OH),
(s, 1H, CH), 6.61 (s, 1H, PhH), 6.89–6.84 (m, 2H, PhH), 7.03 4.10 (s, 5H, FcH), 4.27 (s, 4H, FcH), 4.95 (d, d, J = 12.6 Hz,
(s, 1H, =CH), 7.95 (s, 1H, TrH), 8.05 (s, 1H, TrH); EI MS 2H, CH2), 5.62 (s, 1H, CH), 6.64 (s, 1H, =CH), 7.17 (t, J =
(M+)m/z: 460. Anal. Calcd. for C24H26FeN3O3: C 62.76, H 7.5 Hz, 1H, PhH), 7.35 (t, J = 7.5 Hz, 1H, PhH), 7.55(t, J =
5.49, N 9.15. Found: C 62.53, H 5.41, N 9.17.
7.5 Hz, 1H, PhH), 7.67 (t, J = 7.5 Hz, 1H, PhH), 7.96 (s, 1H,
4b: 2-((1H-1,2,4-Triazol-1-yl)methyl)-3-ferrocenyl-1-(4- TrH), 8.02 (s, 1H, TrH); EI-MS (M+) m/z: 477. Anal. Calcd.
fluorophenyl) prop-2-en-1-ol. Yield 67%; yellow solid; m.p. for C22H20BrFeN3O: C 55.26, H 4.22, N 8.79. Found: C 55.48,
126–127◦C; 1H NMR δ (300 MHz, CDCl3): 3.99 (d, J = 3 Hz, H 4.52, N 8.59.
SCHEME 2.

SYNTHESIS AND BIOLOGICAL ACTIVITIY OF 1H-1,2,4-TRIAZOLE ALCOHOL DERIVATIVES
649
1
169◦C; H NMR δ (300 MHz, CDCl3): 3.44 (s, 3H, OCH3),
3.95 (s, 2H, C5H4), 4.13 (s, 5H, C5H4), 4.35 (s, 2H, C5H4), 5.03
(s, 2H, CH2), 5.65 (s, 1H, CH), 6.68(s, 1H, =CH), 7.31–7.78
(m, 4H, ArH), 7.96 (s, 1H, TrH), 8.03 (s, 1H, TrH); EI-MS
(M+) m/z: 447. Anal. Calcd. for C23H22ClFeN3O: C 61.70, H
4.95, N 9.38. Found: C 62.01, H 5.13, N 9.63.
4d: 2-((1H-1,2,4-Triazol-1-yl)methyl)-3-ferrocenyl-1-(2,5-
dichlorophenyl) prop-2-en-1-ol. Yield 68.2%; yellow solid; m.p.
167–168◦C; 1H NMR δ (300 MHz, CDCl3): 4.08 (s, 5H, FcH),
4.23 (s, 2H, FcH), 4.28 (s, 2H, FcH), 4.92 (d, d, J = 14.1 Hz,
2H, CH2), 5.59 (d, J = 3.3 Hz, 1H, CH), 6.63 (s, 1H, =CH),
7.23 (d, J = 2.4 Hz, 1H, PhH), 7.03 (s, 1H, PhH), 7.71 (d, J =
2.4 Hz, 1H, PhH), 8.00 (s, 1H, TrH), 8.08 (s, 1H, TrH); EI-MS
(M+) m/z: 467. Anal. Calcd. for C22H19Cl2FeN3O: C 56.44,
H 4.09, N 8.99. Found: C 56.17, H 3.94, N 9.04.
5k: 1-(2-((4-Fluorophenyl(methoxy)methyl)-3-(ferrocenyl)
allyl-1H-1,2,4-triazole. Yield 24.6%; yellow solid; m.p. 145–
1
147◦C; H NMR δ (300 MHz, CDCl3): 3.46 (s, 3H, OCH3),
4e: 2-((1H-1,2,4-Triazol-1-yl)methyl)-3-ferrocenyl-1-(3-
chlorophenyl) prop-2-en-1-ol. Yield 74.2%; yellow solid; m.p.
160–162◦C; 1H NMR δ (300 MHz, CDCl3): 3.88 (s, 1H, OH),
4.02 (s, 5H, FcH), 4.23 (s, 4H, FcH), 4.90 (d, d, J = 14.1 Hz, 2H,
CH2), 5.61 (s, 1H, CH), 6.60 (s, 1H, =CH), 7.19–7.25 (m, 3H,
PhH), 7.66 (s, 1H, PhH), 7.90 (s, 1H, TrH), 7.98 (s, 1H, TrH);
EI-MS (M+) m/z: 433. Anal. Calcd. for C22H20ClFeN3O: C
60.92, H 4.65, N 9.69. Found: C 61.19, H 4.43, N 9.78.
4f: 2-((1H-1,2,4-Triazol-1-yl)methyl)-3-ferrocenyl-1-(2,4-
dichlorophenyl) prop-2-en-1-ol. Yield 69.1%; yellow solid; m.p.
172–174◦C; 1H NMR δ (300 MHz, CDCl3): 4.09 (s, 5H, FcH),
4.25 (s, 2H, FcH), 4.30 (s, 2H, FcH), 4.96 (d, d, J = 14.1 Hz,
2H, CH2), 5.61 (d, J = 3.3 Hz, 1H, CH), 6.67 (s, 1H, =CH),
7.25 (d, J = 2.4 Hz, 1H, PhH), 7.03 (s, 1H, PhH), 7.77 (d, J =
2.4 Hz, 1H, PhH), 8.02 (s, 1H, TrH), 8.10 (s, 1H, TrH); EI-MS
(M+) m/z: 467. Anal. Calcd. for C22H19Cl2FeN3O: C 56.44,
H 4.09, N 8.99. Found: C 56.17, H 3.94, N 9.04. Found: C 56.38,
H 3.77, N 8.96.
4g: 2-((1H-1,2,4-Triazol-1-yl)methyl)-3-ferrocenyl-1-(2-
chlorophenyl) prop-2-en-1-ol. Yield 76.1%; yellow solid;
168–170◦C; 1H NMR δ (300 MHz, CDCl3): 3.94 (s, 1H, OH),
4.08 (s, 5H, FcH), 4.27 (s, 4H, FcH), 4.92 (d, d, J = 14.1 Hz,
2H, CH2), 5.67 (s, 1H, CH), 6.66 (s, 1H, =CH), 7.21–7.37 (m,
3H, PhH), 7.68 (d, J = 7.5 Hz, 1H, PhH), 7.94 (s, 1H, TrH),
8.00 (s, 1H, TrH); EI-MS (M+) m/z: 433. Anal. Calcd. for
C22H20ClFeN3O: C 60.92, H 4.65, N 9.69. Found: C 61.20, H
4.44, N 10.08.
3.96 (s, 2H, C5H4), 4.15 (s, 5H, C5H4), 4.36 (s, 2H, C5H4),
5.07 (s, 2H, CH2), 5.69 (s, 1H, CH), 6.72 (s, 1H, =CH), 7.23–
7.30 (m, 2H, ArH), 7.79–7.85 (m, 2H, ArH), 7.99 (s, 1H, TrH),
8.06 (s, 1H, TrH); EI-MS (M+) m/z: 431. Anal. Calcd. for
C23H22FFeN3O: C 64.05, H 5.14, N 10.05. Found: C 64.33, H
5.40, N 9.63.
5l: 1-(2-((2,4-Dichlorophenyl(methoxy)methyl)-3-(ferroce
nyl)allyl-1H-1,2,4-triazole. Yield 27.0%; yellow solid; m.p.
145–147◦C; 1H NMR δ (300 MHz, CDCl3): 3.48 (s, 3H, OCH3),
3.97 (s, 2H, C5H4), 4.19 (s, 5H, C5H4), 4.45 (s, 2H, C5H4), 5.09
(s, 2H, CH2), 5.73 (s, 1H, CH), 6.75(s, 1H, =CH), 7.41–7.80
(m, 3H, ArH), 8.01 (s, 1H, TrH), 8.07 (s, 1H, TrH); EI-MS
(M+) m/z: 481. Anal. Calcd. for C23H21Cl2FeN3O: C 64.84,
H 4.74, N 9.41. Found: C 65.11, H 4.98, N 9.65.
RESULTS AND DISCUSSION
Synthesis
The intermediates 3 were prepared according to the
literature.[27] Title compounds 4 were prepared by reducing
intermediates 3 using NaBH4 as reducing agent in CH3OH
with yields of 70–80%. Compounds 4 were purified by sil-
ica gel column chromatography or by recrystallizing from
AcOEt/petroleum ether (60–90◦C) (V/V = 1/3). An unexpected
compound, 5i, the hydroxyl of the compound 4c being methy-
lated by methanol, was attained when we separated 4c with sil-
ica gel column chromatography. In order to investigate whether
another reaction could also produce a methylated product, we
studied the reaction further, and we found that when the ben-
zene cycle contains a donor group, the reaction can be isolated
to attain a methylated product. The reason may be the forma-
tion of C+ under the effect of concentrated hydrochloric acid
(Scheme 2). As the donor effect of the substituted group on the
benzene cycle can stabilize the C+, the title compounds that the
benzene cycle contain donor group can be methylated easily by
the resolution CH3OH.
4h: 2-((1H-1,2,4-Triazol-1-yl)methyl)-3-ferrocenyl-1-(3-
bromophenyl) prop-2-en-1-ol. Yield 67.2%; yellow solid; m.p.
166–167◦C; 1H NMR δ (300 MHz, CDCl3): 3.75 (s, 1H, OH),
4.06 (s, 5H, FcH), 4.21 (s, 4H, FcH), 4.92 (d, d, J = 12.6 Hz, 2H,
CH2), 5.60 (s, 1H, CH), 6.63 (s, 1H, =CH), 7.22–7.28 (m, 3H,
PhH), 7.47 (s, 1H, PhH), 7.90 (s, 1H, TrH), 7.99 (s, 1H, TrH);
EI-MS (M+) m/z: 477. Anal. Calcd. for C22H20BrFeN3O: C
55.26; H 4.22, N 8.79. Found: C 55.48, H 4.52, N 8.59.
5i: 1-(2-((2-Bromophenyl (methoxy)methyl)-3-(ferrocenyl)
allyl)-1H-1,2,4-triazole. Yield 26.3%; yellow solid; m.p. 163–
1
165◦C; H NMR δ (300 MHz, CDCl3): 3.42 (s, 3H, OCH3),
Biological Activities
3.94 (s, 2H, C5H4), 4.09 (s, 5H, C5H4), 4.29 (s, 2H, C5H4), 4.98
Title compounds 4 and unexpected compounds 5 were
(s, 2H, CH2), 5.62 (s, 1H, CH), 6.65 (s, 1H, =CH), 7.18–7.69 screened for their biological activities in vitro against
(m, 4H, ArH), 7.95 (s, 1H, TrH), 8.01 (s, 1H, TrH); EI-MS Gibberella zeae, Alternaria solani, Cercospora rachidicola,
(M+) m/z: 491. Anal. Calcd. for C23H22BrFeN3O: C 56.13, H Physalospora piricola, Phoma asparagi, Cladosporium cuc-
4.51; N 8.54. Found: C 56.82, H 4.60, N 8.64.
umerinum, Sclerotinia sclerotiorum, and Pyricularia oryzae at
5j: 1-(2-((3-Chlorophenyl(methoxy)methyl)-3-(ferrocenyl) a concentration of 50 µg/L, and the relative inhibitory ratios
allyl-1H-1,2,4-triazole. Yield 31.1%; yellow solid; m.p. 167– (%) against these fungi are listed in Table 1 The screening data

650
LIU ET AL.
TABLE 1
Fungicidal activity of the title compounds 4 and 5
Relative inhibitory ratio (%)
Comp.
G. zeae
A. solani
C. ara
P. piri
P. asp
C. cucu
S. scler
P. oryzae
4a
4b
4c
4d
4e
4f
4g
4h
5i
56.7
43.6
53.9
79.1
43.9
45.6
58.9
46.7
47.6
57.1
67.2
43.4
95.6
56.6
58.5
79.1
66.1
41.1
57.8
66.7
65.4
57.1
68.3
29.1
58.3
100
69.1
69.2
66.6
68.9
59.7
49.0
70.9
45.5
33.3
57.2
17.7
41.7
99.5
76.1
69.9
35.8
68.1
67.1
77.3
67.6
59.1
39.1
49.1
37.8
56.6
100
78.3
70.3
49.7
54.3
79.6
55.6
56.1
77.7
67.9
47.3
33.6
67.8
100
89.9
88.7
53.5
99.0
65.7
89.9
78.9
99.7
77.1
66.7
46.0
64.8
99.8
78.1
100
65.6
100
66.8
100
84.8
100
65.3
71.2
51.9
46.7
100
74.7
100
68.7
100
59.1
100
69.6
100
76.8
69.5
69.7
47.9
100
5j
5k
5l
*
*: Triadimenol, 1-(4-chlorophenoxy)-3, 3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
revealed that compounds 4 and 5 have some antifungal activity,
among which 4b, 4d, 4f, and 4h showed 100% inhibitory ratios
against S. sclerotiorum and P. oryzae, respectively; 4d and 4h
showed 99.0 and 99.7% against C. cucumerinum, respectively.
Although the antibacterial activity of compounds 4 was not sig-
nificant compared with known commercial agents, most of the
title compounds 4 show higher antifungal activity than com-
pounds 3.[27] From the antifungal activity of these two series
of compounds, we may speculate that converting the CO group
of the 1H-1,2,4-triazole keto compounds 3 containing ferro-
cenyl unit into CHOH (compounds 4) is useful for enhancing
the antifungal activity of the compounds, but converting OH
of the compounds 4 to OCH3 deduced their antifungal activ-
ity. Gasztonyi and Josepovits[28] reported that triadimefon was
transformed into higher fungitoxic triadimenol both in fungi
and in host plants and assumed this reduction process of the CO
group into the CHOH group as an activation process.
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