Synthesis and fungicidal activity of substituted 2-(4-chlorophenoxy)-1-(3- pyridyl)ethan-1-ols

Article abstract of DOI:10.1007/s10593-010-0430-4

A series of new substituted 2-(4-chlorophenoxy)-1-(3-pyridyl)ethan-1-ols has been obtained by the interaction of substituted 3-(oxiranyl)pyridines with 4-chlorophenol or sodium 4-chlorophenoxide for pharmacological and agrochemical screening. Fungicidal a

Full text of DOI:10.1007/s10593-010-0430-4

Chemistry of Heterocyclic Compounds, Vol. 45, No. 11, 2009
SYNTHESIS AND FUNGICIDAL
ACTIVITY OF SUBSTITUTED
2-(4-CHLOROPHENOXY)-1-(3-
PYRIDYL)ETHAN-1-OLS
A. V. Kuzenkov1* and V. V. Zakharychev1
A series of new substituted 2-(4-chlorophenoxy)-1-(3-pyridyl)ethan-1-ols has been obtained by the
interaction of substituted 3-(oxiranyl)pyridines with 4-chlorophenol or sodium 4-chlorophenoxide for
pharmacological and agrochemical screening. Fungicidal activity has been shown for the obtained
compounds.
Keywords: substituted 2-chlorophenoxy-1-(3-pyridyl)ethan-1-ols, 1-(3-pyridyl)ethan-1-ols, 3-(2-oxiranyl)-
pyridines, fungicides.
The fungicidal activity of 3-substituted pyridines was detected for the first time in the sixties of the last
century (in α,α-disubstituted 3-pyridylcarbinols) [1]. Certain derivatives of 3-substituted pyridine disrupting the
biosynthesis of ergosterol in fungi are used in agriculture [2]. Previously we synthesized a series of substituted
2-azolyl-1-(3-pyridyl)ethan-1-ols possessing fungicidal activity [3-5]. In the present work we have shown that
the fungicidal activity of 1-(3-pyridyl)ethan-1-ols does not depend on the presence of an azole fragment in their
structure.
The fungicidal activity of 2-phenoxy-1-(3-pyridyl)ethan-1-ols was detected comparatively recently [6].
Our investigations on the dependence of fungicidal activity of 1-(3-pyridyl)ethan-1-ols on their structure have
led to the synthesis of 2-(4-chlorophenoxy)-1-(3-pyridyl)ethan-1-ols possessing high fungal toxicity.
For their synthesis we used the reaction of 2-substituted 3-(2-oxiranyl)pyridines with 4-chlorophenol or
sodium 4-chlorophenoxide. Choice of just such a phenol for their synthesis is explained by the fact that the
presence of a chlorine atom in position 4 of the phenyl nucleus is important for the display of fungal toxicity by
compounds of this type [7].
We obtained 2,2-disubstituted oxiranes by the Corey–Chaykovsky reaction [8], by treating the
appropriate ketones with trimethylsulfonium iodide [9, 10].
It was established experimentally that 2-(4-chlorophenoxy)-1-(3-pyridyl)ethan-1-ols 1-3 were obtained
in good yield on heating the oxiranes to 60oC with 4-chlorophenol in DMF with NaOH as catalyst. However
such a means of carrying out the reaction proved to be unsuitable for the synthesis of their vinylogs, the
_______
* To whom correspondence should be addressed, e-mail: lexsender1@rambler.ru.
1D. Mendeleev University of Chemical Technology of Russia, Moscow 125047, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1658-1662, November, 2009.
Original article submitted November 29, 2006.
0009-3122/09/4511-1331©2009 Springer Science+Business Media, Inc.
1331

substituted 1-(4-chlorophenoxy)-4-phenyl-2-(3-pyridyl)but-3-en-2-ols. Due to the instability of the corresponding
oxiranes the treated reaction mixtures contained many by-products, and isolation of the desired compounds was
unsuccessful.
OH
R
O
ClC6H4OH
Cl
O
Me3S+ I–
O
or ClC6H4ONa
R
R
t-BuOK
DMF
or 2-PrOH
N
N
N
1–5
Cl
, 5 R =
1 R = Ph, 2 R = c-Hex, 3 R = t-BuCH2, 4 R =
CF3
TABLE 1. Characteristics of Compounds 1-5
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
H
N
1
2
3
4
5
C19H16ClNO2
C19H22ClNO2
C18H22ClNO2
C21H17Cl2NO2
C22H17ClF3NO2
69.94
70.05
5.03
4.95
4.33
4.30
Oil
72
54
60
22
13
68.65
68.77
6.77
6.68
4.25
4.22
75-76
67.52
67.60
6.98
6.93
4.41
4.38
145-146
92-93
Oil
65.17
65.30
4.52
4.44
3.70
3.63
62.83
62.94
4.16
4.08
3.37
3.34
TABLE 2. 1H NMR Spectra of Compounds 1-5
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
1
2
3
4.52-4.66 (2Н, АВ-system, J = 9.6, СН2О); 6.3 (1Н, s, ОН);
7.0-7.5 (4Н, А2В2-system, J = 8.8, C6H4Cl); 7.33 (6Н, m, C2H5, Н-4 Py);
7.86 (1Н, d, J = 8.4, Н-5 Py); 8.42 (1Н, d, J = 4.2, Н-6 Py); 8.68 (1Н, s, Н-2 Py)
0.8-1.9 (11Н, m, СН cyclohexyl); 4.12-4.35 (2Н, АВ-system, J = 8.4, СН2О);
5.3 (1Н, s, ОН); 6.93-7.28 (4Н, А2В2-system, J = 9.5, C6H4Cl);
7.33 (1Н, dd, J1 = 7.6, J2 = 3.8, Н-5 Py); 7.83 (1Н, d, J = 7.6, Н-4 Py);
0.75 (9Н, s, СН3); 1.95-2.00 (2Н, АВ-system, J = 14.8, СН2 aliph.);
4.02 (2Н, АВ-system, J = 8.1, СН2О); 5.3 (1Н, br. s, ОН);
6.90-7.28 (4Н, А2В2-system, J = 9.2, C6H4Cl);
7.32 (1Н, dd, J1 = 8.4, J2 = 4.2, Н-5 Py); 7.92 (1Н, d, J = 8.4, Н-4 Py);
8.41 (1H, d, J = 4.2, H-6 Py); 8.78 (1Н, s, Н-2 Py)
4
5
4.25 (2Н, AB-system, J = 9.6, СН2); 6.12 (1Н, s, ОН);
6.74-6.82 (2Н, AB-system, J = 14.4, СН methine);
6.95-7.20 (4Н, А2В2-system, J = 8.0, C6H4Cl);
7.06 (1Н, m, 5-Н Py); 7.38-7.50 (4Н, А2В2-system, J = 8.0, C6H4Cl);
7.95 (1Н, d, J = 4.2, 4-Н Py); 8.45 (1Н, d, J = 4.2, 6-Н Py); 8.80 (1Н, s, Н-2 Py)
4.40 (2Н, AB-system, J = 10.0, СН2); 6.15 (1Н, s, ОН);
6.78-6.89 (2Н, AB-system, J = 17, СН methine);
7.16 (1Н, dd, J1 = 8.4, J2 = 4.2, Н-5 Py);
7.40-7.54 (4Н, А2В2-system, J = 8.0, C6H4Cl); 7.59-7.82 (4Н, m, Н Ph);
7.92 (1Н, d, J = 4.2, Н-4 Py); 8.48 (1Н, d, J = 4.2, Н-6 Py); 8.77 (1Н, s, Н-2 Py)
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TABLE 3. Suppression of Radial Growth of Fungal Mycelia in vitro by
Compounds 1-5 at c = 30 mg/l in Comparison with Untreated Control
Drop in radial growth of fungal mycelium, %
Compound
Venturia
Fusarium
Fusarium
Helmintho-
Sclerotinia
inaequalis
moniliforme
oxysporum
sporium sativum sclerotiorum
1
99-100
99-100
70-89
50-69
0-49
90-98
90-98
90-98
50-69
0-49
99-100
99-100
70-89
0-49
90-98
99-100
99-100
50-69
50-69
50-69
0-49
0-49
2
3
0-49
4
50-69
0-49
5
70-89
70-89
Standard*
50-69
90-98
50-69
_______
*Standard was the commercial fungicide triadimefon (1-(4-chloro-
phenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one), containing
98% active substance ("Shchelkovo AgroKhim").
We obtained 1-(4-chlorophenoxy)-4-(4-chlorophenyl)-2-(3-pyridyl)but-3-en-2-ol (4) and 1-(4-chloro-
phenoxy)-2-(3-pyridyl)-4-[3-(trifluoromethyl)phenyl]but-3-en-2-ol (5), by treating oxiranes, obtained respecti-
vely from 3-(4-chlorophenyl)-1-(3-pyridyl)prop-2-en-1-one and 1-(3-pyridyl)-3-[3-(trifluoromethyl)phenyl]-
prop-2-en-1-one, with sodium 4-chlorophenoxide by heating (50-60oC) for 6 h in 2-propanol. The oxiranes were
not isolated in a pure form, but were put directly into the next reaction due to their instability. On using DMF as
solvent in these reactions the isolation of compounds was markedly complicated and products separated as
viscous oils on diluting the reaction mixture with water. Yields of alkyl- and aryl-substituted derivatives 1-3
proved to be significantly greater than the yields of compounds 4 and 5 containing a styryl group (Table 1).
In every case no isomeric products of addition of phenol to oxirane, the 2-(4-chlorophenoxy) 2-(3-
pyridyl)ethan-1-ols, were detected.
The obtained compounds were tested in vitro for fungicidal activity against five phytopathogenic fungi,
viz. Venturia inaequalis Wint, Fusarium moniliforme Sheldon, Fusarium oxysporum Schlecht,
Helminthosporium sativum Pammel, King et Bakke, and Sclerotinia sclerotiorum (Lib.) de Bary, according to
the procedure of the All-Russian Research Institute for Chemical Plant Protection Agents (Moscow) [11] (Table
3). The strains of fungi were obtained from the Institute mentioned. All compounds displayed high fungicidal
activity.
EXPERIMENTAL
1
The H NMR spectra of compounds were obtained on a Bruker AC-400 (400 MHz) instrument in
DMSO-d6, internal standard was TMS.
The synthesis and properties of 3-(2-phenyl-2-oxiranyl)pyridine [9], 3-(2-cyclohexyl-2-oxiranyl)-
pyridine, 3-[2-(2,2-dimethylpropyl)-2-oxiranyl]pyridine [3], 3-(4-chlorophenyl)-1-(3-pyridyl)prop-2-en-1-one,
and 1-(3-pyridyl)-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-one [10] have been described previously.
2-(4-Chlorophenoxy)-1-phenyl-1-(3-pyridyl)ethan-1-ol (1). Sodium hydroxide (0.12 g) and water
(0.05 ml) were added to a solution of 3-(2-oxiranyl-2-phenyl)pyridine (0.346 g, 1.76 mmol) and 4-chlorophenol
(0.44 g, 3.4 mmol) in DMF (3 ml) and the mixture was heated at 120oC for 4 h. The reaction mixture was then
poured into water (30 ml) with stirring, extracted with chloroform (3×15 ml), the extract was washed three times
with 10% NaOH solution, with saturated NaCl solution, dried over MgSO4, and evaporated in vacuum.
Compound 1 (0.41 g, 72%) was obtained as an oil.
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2-(4-Chlorophenoxy)-1-cyclohexyl-1-(3-pyridyl)ethan-1-ol (2) and 1-(4-Chlorophenoxy)-4,4-di-
methyl-2-(3-pyridyl)pentan-2-ol (3) were obtained analogously.
1-(4-Chlorophenoxy)-4-(4-chlorophenyl)-2-(3-pyridyl)but-3-en-2-ol (4). A solution of potassium
t-butylate (0.7 g, 6.27 mmol) in DMSO (3 ml) was added dropwise in an inert atmosphere during 30 min to a
solution of 3-(4-chlorophenyl)-1-(3-pyridyl)prop-2-en-1-one (1.22 g, 5 mmol) and trimethylsulfonium iodide
(1.43 g, 7 mmol) in DMSO (3.5 ml) cooling with an ice–salt mixture. The reaction mixture was then stirred for
15 min and diluted dropwise with water (30 ml), extracted with ether (4×50 ml), the extract was washed with
saturated NaCl solution, and dried over MgSO4. A solution of 4-chlorophenol (0.77 g, 6 mmol) and sodium
isopropylate (0.23 g, 3 mmol) in 2-propanol (20 ml) was added to the obtained solution, and the ether distilled in
vacuum. The resulting solution was heated for 6 h at 50-60oC, cooled, poured into water (25 ml), and left
overnight. The separated oil was dissolved in chloroform, and the solution washed with 10% NaOH solution
(4×14 ml). The organic phase was dried over MgSO4, and the solvent distilled. The reaction product was
purified by column chromatography on silica gel (eluent chloroform–ethanol, 20:1), and compound 4 (0.42 g,
22%) was obtained.
1-(4-Chlorophenoxy)-4-[3-(trifluoromethyl)phenyl]-2-(3-pyridyl)but-3-en-2-ol (5) was obtained
analogously.
1
Yields and melting points of compounds 1-5 are given in Table 1, H NMR spectra in Table 2, and
results of biological testing in Table 3.
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2.
3.
4.
5.
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