Synthesis and biological evaluation of novel ferrocene-substituted triadimefon- and triadimenol-analogues

Article abstract of DOI:10.1080/15533170701608791

To search potent antifungal agents, a series of new ferrocene-containing analogues of commercial fungicides, namely triadimefon and triadimenol, were synthesized by replacement of the tert-butyl group of original agents with ferrocene group. These organometallic derivatives were found to be unactive against various fungi, but show promising plant growth regulatory activity.

Full text of DOI:10.1080/15533170701608791

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Synthesis and Reactivity in Inorganic, Metal-Organic,
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Synthesis and Biological Evaluation of Novel
Ferrocene‐Substituted Triadimefon‐ and
Triadimenol‐Analogues
Zhong Jin a , Yan Hu a , Ling Shao a & Jianxin Fang a
a State Key Laboratory and Institute of Elemento‐Organic Chemistry , Nankai University ,
Tianjin, P. R. China
Published online: 01 Oct 2007.
To cite this article: Zhong Jin , Yan Hu , Ling Shao & Jianxin Fang (2007) Synthesis and Biological Evaluation of Novel
Ferrocene‐Substituted Triadimefon‐ and Triadimenol‐Analogues, Synthesis and Reactivity in Inorganic, Metal-Organic, and
Nano-Metal Chemistry, 37:8, 601-604
To link to this article: http://dx.doi.org/10.1080/15533170701608791
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Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 37:601–604, 2007
Copyright # 2007 Taylor & Francis Group, LLC
ISSN: 1553-3174 print/1553-3182 online
DOI: 10.1080/15533170701608791
Synthesis and Biological Evaluation of Novel Ferrocene-
Substituted Triadimefon- and Triadimenol-Analogues
Zhong Jin, Yan Hu, Ling Shao, and Jianxin Fang
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin, P. R. China
agricultural and horticultural fungicides. However, these fungi-
To search potent antifungal agents, a series of new ferrocene- cides are suspected of having teratogenic potential such as cra-
containing analogues of commercial fungicides, namely triadime-
fon and triadimenol, were synthesized by replacement of the
tert-butyl group of original agents with ferrocene group. These or-
ganometallic derivatives were found to be unactive against various
fungi, but show promising plant growth regulatory activity.
niofacial and axial skeletal defects on the basis of
developmental toxicity studies on rodent mammals with exten-
sive application in agriculture and horticulture.[9–11] It has also
been ascertained that triadimefon and triadimenol can produce
a neurotoxic syndrome in rats characterized by increased motor
activity, stereotyped behavior and altered monoamine metab-
olism due to inhibition of dopamine uptake.[12] In addition,
triadimefon had a significant stimulating side effect on respir-
ation at a concentration of 1–100 mg/kg and on inhibition of
nitrification in soil at a concentration of 100 mg/kg.[13] As
our ongoing project of searching potent antifungal and plant
growth regulatory agents involving 1H-1,2,4-triazole com-
pounds with improving biological activities, we herein
reported the chemistry and biological evaluation results of a
series of novel triadimefon- and triadimenol-analogues
modified with ferrocenyl unit.
Keywords ferrocene, triadimefon, triadimenol, plant growth regu-
latory activity
INTRODUCTION
Over the past decades, as ameliorants for improving bio-
logical activities, several structural variations of established
drugs have been developed by modification with metallocenic
organometallic compounds, especially ferrocene, for the che-
motherapy of drug-resistance in cancer and tropical diseases.[1]
Ferrocene and relative derivatives have been characterized by
their high stability, non-toxicity, readily membrane-permeation,
the accessibility of a large number of derivatives, and their
favorable electrochemical properties, both of which made
them very suitable for biological applications and for conju-
gation with biomolecules.[2] To date, several structural modifi-
cation of established drugs with ferrocenyl moiety have been
reported, including ferrocene fluconazole,[3] ferrocene
aspirin,[4] the anti-malarial drugs chloroquine (termed ferro-
quine),[5] quinine, mefloquine, and artemisinin,[6,7] and the
anti-cancer drug tamixofen (termed ferrocifen).[8]
RESULTS AND DISCUSSION
Synthesis of Ferrocene-Substituted Triadimefon Analogues
6a–i
As outlined in Scheme 1, the starting a-bromoacetylferro-
cene 3 was synthesized according to the method developed
by Tarraga and co-workers.[14] Subsequently, substitution by
1H-1,2,4-triazole was accomplished to deliver a-triazolylace-
tylferrocene 4 as description in our previous work.[15] After
further bromination in the a-position of carbonyl group,
bromide 5 was produced successfully in satisfied yield. With
K2CO3 as a base, replacement of bromine atom by substituted
phenol smoothly provided the desired triadimefon analogues
6a–h in moderate yields.
1H-1,2,4-Triazole derivatives, such as triadimefon 1 and
triadimenol 2, are well known to be highly active as
Received 12 March 2007; accepted 2 May 2007.
We gratefully acknowledge the National Natural Science Foun-
dation of China (NNSFC) (Nos. 29872022, 20172030) for financial
support.
Address correspondence to Prof. Jianxin Fang, State Key Labora-
tory and Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, P. R. China. E-mail: fjx@nankai.edu.cn
Synthesis of Ferrocene-Substituted Triadimenol Analogues
7a–e
Reduction of triadimefon analogues 6 was finally accom-
plished to provide ferrocene-substituted triadimenol analogues
7a–e in the acetonitrile-methanol solvent system (V:V 1:1)
601

602
Z. JIN ET AL.
TABLE 1
Plant growth regulatory activity of compounds 6a–h and
7a–ea
Relative
ratiob (%)
Compd.
X
Gradec
6
6b
6c
6d
6e
6f
6g
H
4-Br
þ 50.6
þ 19.8
2 11.0
þ 40.4
2 4.1
2 4.0
þ 2.7
þ
2
2
2
3-Me-4-Cl
3-Me-6-Cl
3,4-Me2
4-I
2
2
2
2,6-Cl2
3-Me
SCH. 1.
6h
Triadimefon
2 19.8
þ 57.1
þ 95.2
þ 132.8
þ 84.9
þ 77.6
þ 33.5
þ 144.2
þ
7a
7b
7c
7d
H
4-Br
þ
using sodium borohydride as reducing agent. After purification
by recrystallation or column chromatography, the target com-
pounds 7a–e were ultimately obtained in moderate yields.
þþ
þ
3-Me-4-Cl
3-Me-6-Cl
3,4-Me2
þ
1
Synthesis and detail structure characterization, including H
NMR, MS, and elemental analysis, of compounds 6a–h and
7a–e were reported in the experimental section.
7e
Triadimenol
2
þþ
aAt a concentration of 10 mg/L.
b
þ: promotion activity, 2: inhibitory activity.
c
Antifungal Activity
þþþ: ꢀ150%, þþ: ꢀ100%, þ: ꢀ50%, 2: ,50%
Both compounds 6a–h and 7a–e were evaluated for anti-
fungal activities against mildew and rusts on intravital wheat
plants, including five selected fungi Isariopsis clavispora,
Bremia lactucae, Cladosporium fulvum, Erysiphe graminis,
and Altermaria mali, according to our procedures described
previously.[15] Although compounds 7a–e showed obviously
more potential antifungal activities than the corresponding pre-
cursor 6a–h, all of them displayed much lower antifungal
activity against all selected fungi than parent triadimefon and
tridimenol.[15]
regulatory activity of these ferrocene-modified analogues,
further biological evaluations including wheat gemmale
elongation experiments have to be carried out and the results
will be reported in the future.
Summary
For promotion of their biological activity, the corresponding
ferrocene-substituted analogues 6 and 7 of commercial agro-
chemicals triadimefon 1 and triadimenol 2 were synthesized
by replacement of tert-butyl group with ferrocene unit. On
the basis of bioassay results, both types of the ferrocene-ana-
logues did not reveal antifungal activity of parent compounds.
Meanwhile, ferrocene-substituted analogues 7 showed a com-
parative plant growth regulatory activity related to parent
compound. Furthermore, halogen substituents may largely
increase their biological activity, while electronic-donating
groups will decrease their plant growth regulatory activity.
Plant Growth Regulatory Activity
Plant growth regulatory activities of new ferrocene-substi-
tuted triadimefon and triadimenol derivatives 6a–h and 7a–e
were tested using cucumber cotyledon rhizogenesis
method.[15] The plant growth refulatory activity data were
shown in Table 1.
Like the parent triadimefon 1, compounds 6a–h almost did
not revealed efficient plant growth regulatory activity. In com-
parison with unactive compounds 6a–h, most ferrocene-
analogues 7, except compound 7e, showed obvious plant
regulatory activity as the same as the corresponding triadime-
nol 2. Among them, compound 7b displayed the comparative
activity related to parent triadimenol.
EXPERIMENTAL
All reactions were carried out under nitrogen atmosphere.
Melting points were determined on a Taike apparatus with
1
With respect to structure-activity relationship, halogen sub- thermometer uncorrected. H NMR spectra were recorded on
stituents, such as chloro-, bromo-, etc., may increase their plant a Brucker AC-300 spectrometer in DMSO-d6 or CDCl3
growth regulatory activity while electronic-donating group solution with TMS as the internal standard. Elemental
including methyl will cause the decrease of biological analyses were determined on a Yanaco CHN CORDER MT-
activity. However, to verify efficiently the plant growth 3 elemental anlyser.

NOVEL FERROCENE COMPOUNDS OF FUNGICIDES
603
Representative Procedure for Synthesis of Ferrocene-
Triadimefon Derivatives (6a– h)
7.58(s, 1H, Tr-CH), 7.33ꢀ6.47(m, 3H, aryl), 5.03ꢀ4.51
(d, 4H, C5H4), 4.27(s, 5H, C5H5); EI-MS (Mþ) m/z: 456.
Anal. Calc. for C20H15Cl2FeN3O2: C 52.67, H 3.31, N 9.21.
Found: C 52.60, H 3.20, N 9.08.
To a suspension solution of 2-bromo-2-(1H-1,2,4-triazol-1-yl)
acetylferrocene 5 (2 mmol) and anhydrous potassium carbonate
(2.2 mmol) in dry acetonitrile (10 mL) was added substituted
phenols (2.2 mmol) in 1 portion at room temperature. The
mixture was stirred and warmed to reflux for 2 h. the cooled
mixture was run into a 10% aqueous NaOH solution (50 mL)
and resulting precipitate was collected by filtration. Recrystalli-
zation from ethyl acetate-petroleum ether (v/v 1:1) gave the
title compounds 6a–h.
6h: Yield 47%; orange solid; m.p. 129–1318C; 1H NMR
d (300 MHz, DMSO-d6): 8.93(s, 1H, TrH), 8.13(s, 1H, TrH),
7.44(s, 1H, Tr-CH), 6.91ꢀ6.28(m, 4H, aryl), 4.95ꢀ4.76
(d, 4H, C5H4), 4.31(s, 5H, C5H5), 2.30(s, 3H, ArCH3); EI-
MS (Mþ) m/z: 401. Anal. Calc. for C21H19FeN3O2: C 62.86,
H 4.77, N 10.47. Found: C 62.86, H 4.92, N 10.58.
6a: Yield 70%; red solid; m.p. 107–1088C; 1H NMR
d (300 MHz, DMSO-d6): 8.92(s, 1H, TrH), 8.11(s, 1H, TrH),
7.44(s, 1H, Tr-CH), 7.37ꢀ7.18(m, 5H, aryl), 4.95ꢀ4.75
(d, 4H, C5H4), 4.28(s, 5H, C5H5); EI-MS (Mþ) m/z: 387.
Anal. Calc. for C20H17FeN3O2: C 62.04, H 4.42, N 10.85.
Found: C 61.79, H 4.45, N 10.67.
Representative Procedure for Synthesis of Ferrocene-
Triadimenol Derivatives (7a–e)
To a stirred solution of 2-aryloxy-1-ferrocenyl-2-(1H-1,2,4-
triazol-1-yl)ethanone 6 (3 mmol) in acetonitrile (5 mL) and
methanol (5 mL) below 08C was added sodium boronhydride
(6 mmol) in small portions. After stirring at room temperature
for 30 minutes, the reaction mixture was poured into cooled
water (50 mL) and neutralized to pH 7 with 5% diluted hydro-
chloric acid. The product was precipitated and collected by
filtration. Recrystallization from ethyl acetate gave the title
compounds 7a–e as analytically pure samples.
6b: Yield 90%; orange solid; m.p. 165–1678C; 1H NMR
d (300 MHz, DMSO-d6): 8.98(s, 1H, TrH), 8.16(s, 1H, TrH),
7.49(s, 1H, Tr-CH), 7.58ꢀ7.19(m, 4H, aryl), 4.96ꢀ4.77
(d, 4H, C5H4), 4.30(s, 5H, C5H5); EI-MS (Mþ) m/z: 466.
Anal. Calc. for C20H16BrFeN3O2: C 51.54, H 3.46, N 9.02.
Found: C 51.48, H 3.54, N 9.11.
7a: Yield 65.2%; yellow solid; m.p. 1808C ; 1H NMR
d (300 MHz, DMSO-d6): 8.83(s, 1H, TrH), 8.01(s, 1H, TrH),
6.10(d, 1H, Tr-CH), 7.27ꢀ6.94(m, 5H, aryl), 4.34ꢀ4.11
(d, 4H, C5H4), 4.21(s, 5H, C5H5); EI-MS (Mþ) m/z: 389.
Anal. Calc. for C20H19FeN3O2: C 61.72, H 4.92, N 10.80.
Found: C 61.59, H 5.10, N 10.96.
1
6c: Yield 54.5%; orange solid; m.p. 137–1398C; H NMR
d (300 MHz, DMSO-d6): 8.95(s, 1H, TrH), 8.14(s, 1H, TrH),
7.25(s, 1H, Tr-CH), 7.46ꢀ7.07(m, 3H, aryl), 4.96ꢀ4.77
(d, 4H, C5H4), 4.30(s, 5H, C5H5), 2.31(s, 3H, ArCH3); EI-
MS (Mþ) m/z: 435. Anal. Calc. for C21H18ClFeN3O2: C
57.89, H 4.16, N 9.64. Found: C 57.79, H 4.12, N 9.50.
1
7b: Yield 61.5%; yellow solid; m.p. 181–1838C; H NMR
d (300 MHz, DMSO-d6): 8.81(s, 1H, TrH), 8.01(s, 1H, TrH),
6.10(d, 1H, Tr-CH), 7.43ꢀ6.92(m, 4H, aryl), 4.32ꢀ4.11
(d, 4H, C5H4), 4.21(s, 5H, C5H5); EI-MS (Mþ) m/z: 468.
Anal. Calc. for C20H18BrFeN3O2: C 51.31, H 3.88, N 8.98.
Found: C 51.40, H 4.01, N 9.03.
1
6d: Yield 50.3%; orange solid; m.p. 140–1428C; H NMR
d (300 MHz, DMSO-d6): 8.95(s, 1H, TrH), 8.14(s, 1H, TrH),
7.26(s, 1H, Tr-CH), 7.46ꢀ7.08(m, 3H, aryl), 4.96ꢀ4.77
(d, 4H, C5H4), 4.30(s, 5H, C5H5), 2.31(s, 3H, ArCH3); EI-
MS (Mþ) m/z: 435. Anal. Calc. for C21H18ClFeN3O2: C
57.89, H 4.16, N 9.64. Found: C 58.06, H 4.29, N 9.43.
1
7c: Yield 62.5%; yellow solid; m.p. 152–1558C; H NMR
d (300 MHz, DMSO-d6): 8.81(s, 1H, TrH), 8.01(s, 1H, TrH),
6.12(d, 1H, Tr-CH), 7.29ꢀ6.80(m, 3H, aryl), 4.32ꢀ4.11
(m, 4H, C5H4), 4.21(s, 5H, C5H5), 2.22(s, 3H, ArCH3); EI-
MS (Mþ) m/z: 437. Anal. Calc. for C21H20ClFeN3O2: C
57.62, H 4.61, N 9.60. Found: C 57.65, H 4.73, N 9.75.
6e: Yield 35%; orange solid; m.p. 130–1328C; 1H NMR
d (300 MHz, DMSO-d6): 8.90(s, 1H, TrH), 8.11(s, 1H, TrH),
7.37(s, 1H, Tr-CH), 7.11ꢀ6.94(m, 3H, aryl), 4.95ꢀ4.76
(d, 4H, C5H4), 4.31(s, 5H, C5H5), 2.20(s, 3H, ArCH3),
2.15(s, 3H, ArCH3); EI-MS (Mþ) m/z: 415. Anal. Calc. for
C22H21FeN3O2: C 63.63, H 5.10, N 10.12. Found: C 63.53,
H 5.27, N 10.18.
1
7d: Yield 58.7%; yellow solid; m.p. 152–1548C; H NMR
d (300 MHz, DMSO-d6): 8.81(s, 1H, TrH), 8.01(s, 1H, TrH),
6.12(d, 1H, Tr-CH), 7.29ꢀ6.80(m, 3H, aryl), 4.32ꢀ4.11
(m, 4H, C5H4), 4.18(s, 5H, C5H5), 2.22(s, 3H, ArCH3); EI-
MS (Mþ) m/z: 437. Anal. Calc. for C21H20ClFeN3O2: C
57.62, H 4.61, N 9.60. Found: C 57.70, H 4.63, N 9.71.
1
6f: Yield 60.5%; orange solid; m.p. 162–1648C; H NMR
d (300 MHz, DMSO-d6): 8.95(s, 1H, TrH), 8.14(s, 1H, TrH),
7.47(s, 1H, Tr-CH), 7.72ꢀ7.05(m, 4H, aryl), 4.95ꢀ4.76
(d, 4H, C5H4), 4.30(s, 5H, C5H5); EI-MS (Mþ) m/z: 513.
Anal. Calc. for C20H16FeIN3O2: C 46.82, H 3.14, N 8.19.
Found: C 46.92, H 3.33, N 8.12.
1
7e: Yield 53.1%; yellow solid; m.p. 163–1658C; H NMR
d (300 MHz, DMSO-d6): 8.79(s, 1H, TrH), 8.00(s, 1H, TrH),
6.01(d, 1H, Tr-CH), 6.97ꢀ6.63(m, 3H, aryl), 4.31ꢀ4.11
6g: Yield 63%; orange solid; m.p. 165–1678C; 1H NMR (d, 4H, C5H4), 4.21(s, 5H, C5H5), 2.11(s, 3H, ArCH3),
d (300 MHz, DMSO-d6): 8.34(s, 1H, TrH), 8.16(s, 1H, TrH), 2.07(s, 3H, ArCH3); EI-MS (Mþ) m/z: 417. Anal. Calc. for

604
Z. JIN ET AL.
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C22H23FeN3O2: C 63.32, H 5.56, N 10.07. Found: C 63.25, H
5.42, N 10.08.
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