Synthesis of substituted 2-azolyl-1-pyridylethan-1-ols

Article abstract of DOI:10.1023/B:COHC.0000014414.45065.f2

Through the reaction of (2-aryloxiran-2-yl)pyridines with triazole or imidazole a series of novel 2-azolyl-1-pyridylethan-1-ols has been synthesized with different positioning of the nitrogen atom in the pyridine fragment for pharmacological and agrochemi

Full text of DOI:10.1023/B:COHC.0000014414.45065.f2

Chemistry of Heterocyclic Compounds, Vol. 39, No. 11, 2003
SYNTHESIS OF SUBSTITUTED
2-AZOLYL-1-PYRIDYLETHAN-1-OLS
A. V. Kuzenkov
Through the reaction of (2-aryloxiran-2-yl)pyridines with triazole or imidazole a series of novel
2-azolyl-1-pyridylethan-1-ols has been synthesized with different positioning of the nitrogen atom in the
pyridine fragment for pharmacological and agrochemical screening. The compounds prepared showed
high fungicidal activity.
Keywords: 2-azolylethanols, 1-pyridylethanols, Corey-Chaykovsky reaction.
A large number of azolyl fungicides have been used successfully as chemical agents for plant protection
and as medicinal preparations [1]. An important group amongst these are the substituted 2-azolylethanols and
these show inhibition of lanosterol C-14 demethylase which is one of the key enzymes taking part in the
construction of fungal pathogen cell membranes [2].
Recently, many compounds of the 2-azolylethanol series have been prepared with different alkyl and
aryl substituents but pyridyl-substituted 2-azolylethanols have not been studied up to the present. Introduction of
a pyridine fragment must increase the solubility of the compound in water and change the pKa and systemic
properties thus modifying the fungicidal activity spectrum.
We have obtained 1-aryl-2-azolyl-1-pyridylethanols and 2-azolyl-1-cyclohexyl-1-pyridylethanols.
In the first stage the 2-, 3-, and 4-benzoylpyridines, 2-(4-fluorobenzoyl)pyridine, and cyclohexyl
3-pyridyl ketone are epoxidated using the Corey-Chaykovsky reaction [3] by treatment with trimethylsulfonium
iodide and potassium tert-butoxide. The oxiranes formed are unstable and rapidly isomerize at room
temperature, hence they are used in the subsequent synthesis without purification. The oxiranes obtained are
then treated with imidazole or triazole by heating with solid NaOH catalyst in DMF (Scheme 1).
Scheme 1
O
HN
OH
z
, NaOH
Me3SI, t-BuOK
O
N
R
N
N
DMSO
R
DMF
N
N
N
R
1–10
1, 2, 7, 8 Py-2, 3, 4, 9, 10 Py-3, 5, 6, Py-4; 1–6 R = Ph, 7, 8 R = 4-FC6H4,
9, 10 R = c-C6H11; 1, 3, 5, 7, 9 Z = N, 2, 4, 6, 8, 10 Z = CH
__________________________________________________________________________________________
D. I. Mendeleev University of Chemical Engineering, Moscow 125047; e-mail: sensei@hotbox.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1693-1697, November, 2003. Original
article submitted May 15, 2003.
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0009-3122/03/3911-1492$25.00©2003 Plenum Publishing Corporation

TABLE 1. Physicochemical Characteristics of Compounds 1-10
Found, %
Calculated, %
H
——————
Com-
pound
Empirical
formula
Ethanol
mp, °С
Yield, %
54
С
N
1-Phenyl-1-(2-pyridyl)-2-(1,2,4-triazol-1-yl)-
C15H14N4O
67.51
67.65
5.38
5.30
20.97
21.04
105-107
1
2-(Imidazol-1-yl)-1-phenyl-1-(2-pyridyl)-
C16H15N3O
C15H14N4O
C16H15N3O
C15H14N4O
C16H15N3O
C15H13FN4O
C16H14FN3O
C15H20N4O
C16H21N3O
72.35
5.76
15.76
150-152
Oil
65
52
71
65
77
25
48
77
94
2
72.43
5.70
15.84
1-Phenyl-1-(3-pyridyl)-2-(1,2,4-triazol-1-yl)-
2-(Imidazol-1-yl)-1-phenyl-1-(3-pyridyl)-
67.59
67.65
5.36
5.30
21.01
21.04
3
72.37
5.79
15.78
95-97
4
72.43
5.70
15.84
1-Phenyl-1-(4-pyridyl)-2-(1,2,4-triazol-1-yl)-
2-(Imidazol-1-yl)-1-phenyl-1-(4-pyridyl)-
67.61
67.65
5.33
5.30
21.07
21.04
153-155
87-89
5
72.35
5.75
15.76
6
72.43
5.70
15.84
1-(4-Fluorophenyl)-1-(2-pyridyl)-2-(1,2,4-triazol-1-yl)-
1-(4-Fluorophenyl)-2-(imidazol-1-yl)-1-(2-pyridyl)-
1-Cyclohexyl-1-(3-pyridyl)-2-(1,2,4-triazol-1-yl)-
1-Cyclohexyl-2-(imidazol-1-yl)-1-(3-pyridyl)-
63.40
63.37
4.63
4.61
19.65
19.71
123-125
174-176
102-103
89-91
7
67.79
5.02
14.77
8
67.83
4.98
14.83
66.11
66.15
7.48
7.40
20.52
20.57
9
70.75
7.83
15.41
10
70.82
7.80
15.49

TABLE 2. 1H NMR Spectra of Compounds 1-10
Com-
Chemical shifts, δ, ppm. (J, Hz)
pound
5.1-5.2 (2H, AB-system, J1 = 0.8, J2 = 0.1, СН2); 6.45 (1H, s, ОН); 7.27 (3H, m, 3НPh);
7.53 (4H, m, 3-Н, 4-HPy, 2НPh); 7.74 (2H, m, 5-HPy, СН triazole); 8.18 (1H, s, СН
triazole); 8.60 (1H, m, 6-НPy)
1
2
3
4.80-4.95 (2H, AB-system, J1 = 4, J2 = 0.8, СН2); 6.25 (1Н, s, ОН);
6.70 (1H, s, СН imidazole); 7.24 (5H, m, 3НPh, 3-НPy, СН imidazole); 7.51 (2H, m, 2НPh);
7.58 (1H, d, J = 0.5, 4-НPy); 7.74 (1H, t, J = 0.33, 5-НPy); 8.60 (1H, d, J = 0.1, 6-НPy)
5.03-5.20 (2H, AB-system, J1 = 3.5, J2 = 0.7, СН2); 6.50 (1H, s, ОН);
7.30 (4H, m, 4-НPy, 3НPh); 7.52 (2Н, m, 2НPh); 7.73 (1H, s, СН triazole);
7.80 (1H, d, J = 0.4, 5-НPy); 8.25 (1H, s, СН triazole); 8.40 (1H, d, J = 0.1, 2-НPy);
8.68 (1Н, d, J = 0.08, 6-НPy)
4.80-4.95 (2H, AB-system, J1 = 4.2, J2 = 1.0, CH2); 6.41 (1H, s, ОН);
4
6.25 (1H, s, СН imidazole); 6.82 (s, 1Н, 4-Н imidazole);
7.28 (5H, m, 3НPh, СН imidazole, 5-НPy); 7.50 (2H, m, 2НPh); 7.80 (1H, d, J = 0.4, 4-НPy);
8.40 (1H, d, J = 0.2, 2-НPy); 8.65 (1H, d, J = 0.1, 6-НPy)
5.0-5.2 (2H, AB-system, J1 = 4, J2 = 0.9, СН2); 6.50 (1H, s, ОН); 7.29 (3H, m, 3НPh);
7.50 (4H, m, 2 3-НPy, 2НPh); 7.75 (1H, s, СН triazole); 8.28 (1H, s, 3-Н triazole);
8.45 (2H, m, 2H-2 Py)
5
6
7
8
4.80-4.95 (2H, AB-system, J1 = 4.1, J2 = 0.9, СН2); 6.43 (1H, s, ОН);
6.65 (1H, s, СН imidazole); 6.83 (1H, s, СН imidazole);
7.28 (4H, m, 3НPh, СН imidazole); 7.50 (4H, m, 2H-3 Py, 2НPh); 8.50 (2Н, m, 2H-2 Py)
5.08-5.14 (2H, AB-system, J1 = 7.4, J2 = 0.7, CH2); 6.55 (1H, s, ОН); 7.07 (2Н, m, 2НPh);
7.27 (1Н, m, 4-НPy); 7.50 (2Н, m, 2НPh); 7.57 (1Н, m, 3-НPy); 7.72 (1Н, s, СН triazole);
7.76 (1Н, m, 5-НPy); 8.20 (1Н, s, СН triazole); 8.58 (1Н, m, 6-НPy)
4.81-4.89 (2Н, AB-system, J1 = 8.8, J2 = 1.1, CH2); 6.49 (1H, s, ОН);
6.64 (1H, s, CH imidazole); 6.77 (1Н, c, CH imidazole); 7.09 (2Н, m, 2НPh);
7.27 (2H, m, 4-НPy, СН imidazole); 7.53 (2Н, m, 2НPh); 7.58 (1Н, m, 3-HPy);
7.75 (1Н, t, J = 0.3, 5-НPy); 8.58 (1Н, d, J = 0.1, 6-НPy)
0.80-1.95 (11Н, m, СН cyclohexane); 4.68–5.87 (2H, AB-system, J = 14.2, СН2);
4.68 (1H, s, ОН); 7.26 (1H, dd, J1 = 0.38, J2 = 0.3, 5-НPy);
7.69 (1H, dt, J1 = 0.38, J2 = 0.07, 4-НPy); 7.76 (1 Н, s, СН triazole);
8.00 (1Н, s, СН triazole); 8.37 (1Н, dd, J1 = 0,2, J2 = 0,07, 6-НPy);
8.54 (1Н, d, J = 0.07, 2-НPy)
0.80-1.95 (11Н, m, СН cyclohexane); 4.45 (2H, AB-system, J = 1.89, СН2);
5.31 (1Н, s, ОН); 6.63 and 6.82 (2Н, both s, each 1H, CH imidazole);
7.25 (1Н, dd, J1= 0.42, J2= 0.28, 5-НPy); 7.32 (1Н, s, СН imidazole);
7.72 (1Н, d, J = 0.42, 4-НPy); 8.36 (1Н, d, J = 0.28, 6-НPy); 8.56 (1Н, s, 2-НPy)
9
10
The yields of the azolylpyridylethanols depend on the nature of the radical in the oxiranylpyridine ring
and the nature of the azole and increase from 25% for 1-(4-fluorophenyl)-1-(2-pyridyl)-2-(1,2,4-triazol-1-
yl)ethanol (7) to 94% for 1-cyclohexyl-2-(imidazol-1-yl)-1-(3-pyridyl)ethanol (10). It was a characteristic that
the yield was higher for the imidazole derivative than the triazole for the same oxirane and the compound with
an alicyclic radical gave a higher yield than did an aromatic (Table 1).
All of the compounds obtained showed high fungicidal activity.
EXPERIMENTAL
1H NMR spectra were obtained on a Bruker AC-400 instrument (400 MHz) using DMSO-d6 solvent.
2-, 3-, and 4-Benzoylpyridines are commercially available, 2-(4-fluorobenzoyl)pyridine was prepared
by acylation of fluorobenzene using 2-pyridinecarboxylic acid chloride [5].
Cyclohexyl 3-Pyridyl Ketone. BuLi (15%, 65 ml, 100 mmol) was added with stirring to a solution of
3-bromopyridine (15.8 g, 100 mmol) in absolute ether (60 ml) cooled to -70°C. The reaction product was then
stirred for 10 min and a solution of cyclohexanecarboxylic acid dimethylamide (15.5 g, 100 mmol) in absolute
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THF (100 ml) was added dropwise with stirring. Cooling was stopped and the mixture was left overnight. The
mixture was evaporated in vacuo, a saturated solution of NH4Cl (50 ml) was added, and the product was
extracted with ether (3 × 100 ml). The ether extract was washed with saturated salt solution, dried over MgSO4,
solvent was distilled off, and the residue was distilled in vacuo to give cyclohexyl 3-pyridyl ketone (13.7 g,
72%); bp 140-155°C (1 mm Hg) (bp 141-142°C at 1 mm Hg [6]).
2-(2-Phenyloxiran-2-yl)pyridine. A solution of potassium tert-butoxide (4.63 g, 63 mmol) in DMSO
(31 ml) was added dropwise over 30 min to a mixture of 2-benzoylpyridine (9.15 g, 50 mmol),
trimethylsulfonium iodide (14.28 g, 70 mmol), and DMSO (31 ml) cooled to 0°C. Stirring was continued for
15 min, the product was cooled in ice and salt, water (150 ml) was added dropwise over 30 min, and then
extracted with CHCl3 (3 × 30 ml). The extract was washed with water (3 × 30 ml) and saturated salt solution
(20 ml). The solution was dried over MgSO4 and solvent was removed in vacuo to give the 2-(2-oxiranyl-2-
1
phenyl)pyridine (6.3 g, 64%) as a reddish oil. H NMR spectrum, δ, ppm (J, Hz): 3.26-3.45 (2H, AB-system,
J1 = 3.8, J2 = 0.3, CH2); 7.40 (7H, m, 2HPy, 5HPh); 7.83 (1H, t, J = 0.3, 4-HPy); 8.60 (1H, m, 6-HPy).
1
3-(2-Phenyloxiran-2-yl)pyridine. Yield 68%. Oil. H NMR spectrum, δ, ppm (J, Hz): 3.35-3.39 (2H,
AB-system, J = 0.93, CH2); 7.37 (6H, m, 3-HPy, 5HPh); 7.73 (1H, m, 4-HPy); 8.55 (2H, m, 2-, 6-HPy).
1
4-(2-Phenyloxiran-2-yl)pyridine. Yield 85%. Oil. H NMR spectrum, δ, ppm (J, Hz): 3.28-3.42 (2H,
AB-system, J1 = 3, J2 = 0.3, CH2); 7.24 (2H, m, 2HPh); 7.40 (5H, m, 3-HPy, 3HPh); 8.55 (2H, m, 2-HPy).
1
3-(2-Cyclohexyloxiran-2-yl)pyridine. Yield 85%. Oil. H NMR spectrum, δ, ppm (J, Hz): 0.75-1.75
(11H, m, CH cyclohexane); 2.70-3.10 (2H, AB-system, J = 8, CH2); 7.38 (1H, dd, J1 = 0.42, J2 = 0.21, 5-HPy);
7.66 (1H, dt, J1 = 0.42, J2 = 0.1, 4-HPy); 8.45 (1H, dd, J1 = 0.21, J2 = 0.1, 2-HPy); 8.47 (1H, d, J = 0.1, 6-HPy).
1
The analysis of the 2-[2-(4-fluorophenyl)oxiran-2-yl]pyridine by H NMR spectroscopy gave
unsatisfactory results due to its instability.
1-Phenyl-1-(2-pyridyl)-2-(1,2,4-triazol-1-yl)ethanol (1). Water (0.033 ml) and sodium hydroxide
(0.11 g) were added to a solution of 2-(2-oxiranyl-2-phenyl)pyridine (1.65 g, 8.3 mmol) and triazole (0.57 g,
8.3 mmol) in DMF (5.63 ml). The product was stirred for 4 h at 120°C, cooled, and poured into water (40 ml).
The precipitated crystals were filtered off, washed with water, and recrystallized from toluene to give compound
1 (1.2 g, 54%); mp 105-107°C.
The remaining azolylpyridylethanols were prepared similarly.
1-Phenyl-1-(3-pyridyl)-2-(1,2,4-triazol-1-yl)ethanol (3) separated as an oil and was purified by
reprecipitation from toluene.
The yields, melting points, and elemental analytical data for the azolylpyridylethanols prepared are
given in Table 1 and 1H NMR spectroscopic data in Table 2.
The author thanks V. V. Zakharychev for help with editing this material and S. V. Popkov for the
donation of the 2-(4-fluorobenzoyl)pyridine.
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