ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 5, pp. 763–765. © Pleiades Publishing, Ltd.

, 2018.
Original Russian Text © A.V. Kuzenkov, V.V. Zakharychev, A.N. Volkova, 2018, published in Zhurnal Organicheskoi Khimii, 2018, Vol. 54, No. 5, pp. 766–770.

Synthesis and Fungicidal Activity

of Substituted 3-(1,2-Oxazolidin-3-yl)pyridines
A. V. Kuzenkova,* V. V. Zakharycheva, and A. N. Volkovaa
a
Mendeleev University of Chemical Technology of Russia, Miusskaya pl. 9, Moscow, 125047 Russia
*e-mail: kuzalex71@yandex.ru

Received November 1, 2017

Abstract—Substituted 3-(1,2-oxazolidin-3-yl)pyridines were synthesized by 1,3-dipolar cycloaddition of ethyl

acrylate, styrene, and their derivatives to N-(pyridin-3-ylmethylidene)-N-phenylaminoxide. The obtained
compounds exhibit a fungicidal activity.

DOI: 10.1134/S1070428018050147

Formerly we synthesized a series of substituted
derivatives of N-hydroxy(pyridin-3-yl)methanimine
possessing a fungicidal activity [1–4]. Among the
products of 1,3-dipolar cycloaddition to derivatives of
N-(pyridin-3-ylmethylidene)aminoxide ligands were
prepared of nicotine-acetylcholine receptors [5] and
compounds effective against Erysiphe graminis f. sp.
hordei [6]. (Regretfully, in the patent [6] all structural
formulas were drawn with mistakes and no one of
them corresponded to the text; no proofs of the
structure were mentioned; a wrong structure was
possibly ascribed to some compounds). In [7] 3-[2,3-
dimethyl-5-(4-chlorophenyl)-1,2-oxazolidin-3-yl]-
pyridine (SYP-Z048, pyrisoxazole) was reported as a
new experimental fungicide for agriculture.
We prepared derivatives of 3-(1,2-oxazolidin-3-yl)
pyridine 1a–1e and found in them a fungicidal activity.
In the synthesis of compounds 1а–1е nitrones 2a and
2b were utilized obtained in the reaction of
phenylhydroxylamine and its 4-chloro derivative with
pyridine-3-carbaldehyde [5]. The reaction was
performed in diverse solvents (dichloromethane, THF,
dioxane) at various temperatures. In dichloromethane
the products did not form, and in THF and dioxane the
yields were insufficient. The process was successful in
ethanol at room temperature. Apparently this is due to
the polar character of nitrone and its effective solvation
with a protic solvent.
1,3-Cycloaddition of ethyl acrylate, styrene, and
their derivatives to N-(pyridin-3-ylmethylidene)-N-
phenylaminoxides 2а and 2b was carried out in toluene
at boiling for 15–20 h with monitoring the reaction
progress by TLC. We obtained a series of 3-(1,2-
oxazolidin-3-yl)pyridine derivatives 1a–1e. The
attempt to purify the reaction products by conversion
in hydrochlorides failed, therefore compounds 1a–1e
were isolated by column chromatography on silica
gel.

R2
NHOH 3
R
R1 R3
CHO N
R1 + R2 N O
N
N _
O
N

R1
2a, 2b 1a_1e
1, R = R = H, R = Ph (a); R = H, R = COOEt, R = C6H4F-4 (b); R = Cl, R = COOEt, R = H (c); R1 = Cl, R2 = H,
1 2 3 1 2 3 1 2 3

R3 = Ph (d); R1 = Cl, R2 = H, R3 = C6H4Br-4 (e); 2, R1 = H (a), Cl (b).

763
764 KUZENKOV et al.
Suppression (А) of radial growth of fungi mycelium in vitro by compounds 1а–1е in the concentration 30 mg/L as compared
with untreated control
А ± confidence interval, % (P 0.95)
Compound no. Rhizoctonia
Venturia inaequalis Fusarium oxysporum Fusarium moniliforme
solani
1а 61±6 47±3
1b 61±7 0 40±2
1c 29±6 34±6
1d 61±6 57±7
1e – 42±6
Triadimefon
60±5 54±4
(control)
The structure of compounds obtained was
established from the 1Н NMR spectra by comparison
of the proton signals in the isoxazolidine ring with the
data from [5, 8]. In [5] a mixture of regioisomers was
obtained, and G. Singh et al. basing on 1Н NMR
spectra registered in CDCl3 (Bruker AC-200, 200 МHz)
succeeded in identifying the diastereomers.
Our reactions proceeded regioselectively without
the formation of isomeric isoxazolidines. The
regioselectivity of the addition may be understood in
the framework of the theory of the interaction between
LUMO (dipole–nitrone) and HOMO (dipolarophile–
olefin). Electron-excessive phenyl-substituted olefins
formed adducts with an aryl fragment in the position 5
of the isoxazolidine ring. In the reaction of nitrone
with electron-deficient acrylates the regioselectivity
suffered the “inversion” due to the change in the
interaction of the frontier molecular orbitals, and the
electron-acceptor group occurred in the position 4. In
the case of ethyl 3-(4-fluorophenyl)acrylate the influence
of the aryl and ester fragments was concerted and only
4-carboxylate 1b formed as well. It is proved by the
position of proton signals at the С4 (3.65–4.35 ppm)
whereas the protons at С5 are shifted downfield (4.77–
5.20 ppm). The integral intensity of signals in the
corresponding regions shows the degree of substitution
at the atoms С4 or С5. The results obtained are in
agreement with the published data on the addition of
electron-deficient dipolarophiles like methylacrylates
[5] and nitroalkenes [9, 10]. We failed to establish the
diastereomeric composition of the reaction products.
The low yield of compound 1b may be due to steric
hindrances impeding cyclization. The relatively moderate
yield of compound 1c is apparently caused by the high
reactivity of ethyl acrylate prone to polymerization
under the reaction conditions.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 5 2018
Helmintho-sporium
sativum
44±2 54±4 92±4
62±5 25±5
17±3 51±3 38±4
5±4 36±5 85±4
21±4 25±5 22±5
72±5 85±7 60±5
The compounds obtained were tested in vitro for
the fungicidal activity against five phytopathogenic
fungi: Venturia inaequalis Wint, Rhizoctonia solani
Kühn, Fusarium oxysporum Schlecht, Fusarium
moniliforme Sheldon and Helminthosporium sativum
Pammel, King et Bakke using the procedure of
Vserossiyskiy Nauchno-Issledovatel'skii Institut
Khimicheskikh Sredstv Zashchity Rasteniy (Moscow)
[11] (see the table). The strains of fungi were obtained
from this Institute. As a reference a commercial
fungicide triadimefon [3,3-dimethyl-1-(1,2,4-triazol-1-
yl)-1-(4-chlorophenoxy)butan-2-one] was used
containing 98% of active substance (Joint Stock Co
“Shchelkovo Agrokhim”).
EXPERIMENTAL
1
Н NMR spectra were registered on a spectrometer
Bruker AM300 (300 МHz) in DMSO-d6.
3-(2,5-Diphenyl-1,2-oxazolidin-3-yl)pyridine
(1a). A mixture of 0.35 g (2 mmol) of compound 2a,
0.23 mL (2 mmol) of styrene, and 10 mL of toluene
was boiled for 20 h. The solvent was distilled off, the
reaction product was subjected to column
chromatography on silica gel, 40–100 µm, 20 g, eluent
CH2Cl2–EtOH, 15 : 1. Yield 0.56 g (92%), light-
yellow oily substance. 1Н NMR spectrum, δ, ppm:
3.70 m (2Н, С4Н2isox), 4.77 d (1Н, С5Нisox, J 6.7 Hz),
4.82 m (1Н, С3Нisox), 6.84‒6.93 m (5Нarom), 7.30 m
(1HPy), 7.35–7.45 m (5Нarom), 7.89 m, 8.62 m, 8.73 m
(3НPy). Found, %: С 79.51; Н 6.02; N 9.10.
C20H18N2O. Calculated, %: С 79.44; Н 6.00; N 9.26.
Compounds 1b–1e were prepared similarly.
Ethyl 3-(pyridin-3-yl)-2-phenyl-5-(4-fluoro-
phenyl)-1,2-oxazolidine-4-carboxylate (1b). Yield
0.28 g (35%), light-yellow oily substance. 1Н NMR
 SYNTHESIS AND FUNGICIDAL ACTIVITY OF SUBSTITUTED 3-(1,2-OXAZOLIDIN-3-YL)...
spectrum, δ, ppm: 1.40 t (3Н, СН3, J 4.9 Hz), 4.10 q
(2Н, СН2O, J 4.9 Hz), 4.30 m (1Н, С4Нisox), 4.84 m
(1Н, С3Нisox), 4.92 m (1Н, С3Нisox), 6.84–6.93 m
(5Нarom), 7.30 m (1НPy), 7.68–7.74 (4Н, А2В2 system,
С6Н4F, J 9.5 Hz), 7.89 m, 8.62 m, 8.73 m (3НPy).
Found, %: С 70.00; Н 5.62; N 6.90. C23H21FN2O3.
Calculated, %: С 70.40; Н 5.39; N 7.14.
Ethyl 3-(pyridin-3-yl)-2-(4-chlorophenyl)-1,2-
isoxazolidine-4-carboxylate (1c). Yield 0.39 g (56%),
oily substance. 1Н NMR spectrum, δ, ppm: 1.40 t (3Н,
СН3, J 4.9 Hz), 4.10 q (2Н, СН2O, J 4.9 Hz), 4.35 m
(1Н, С4Нisox), 4.82 m (1Н, С3Нisox), 5.10–5.20 m (2Н,
С5Н2isox), 7.30 m (1НPy), 7.35–7.45 (4Н, А2В2 system,
С6Н4Cl, J 8.3 Hz), 7.89 m, 8.62 m, 8.73 m (3НPy).
Found, %: С 60.01; Н 5.22; N 8.67. C17H17ClN2O3.
Calculated, %: С 61.36; Н 5.15; N 8.42.
3-[5-Phenyl-2-(4-chlorophenyl)-1,2-oxazolidin-3-
yl]pyridine (1d). Yield 0.55 g (78%), light-yellow oily
substance. 1Н NMR spectrum, δ, ppm: 3.70 m (2Н,
С4Н2isox), 4.77 m (1Н, С5Нisox), 4.82 m (1Н, С3Нisox),
6.84–6.93 m (5Нarom), 7.30 m (1HPy), 7.35–7.45 (4Н,
А2В2 system, С6Н4Cl, J 8.3 Hz), 7.89 m, 8.62 m, 8.73
m (3НPy). Found, %: С 70.88; Н 5.50; N 7.95.
C20H17ClN2O. Calculated, %: С 71.32; Н 5.09; N 8.32.
3-[5-(4-Bromophenyl)-2-(4-chlorophenyl)-1,2-
isoxazolidin-3-yl]pyridine (1e). Yield 0.72 g (83%),
yellow oily substance. 1Н NMR spectrum, δ, ppm:
3.65 m (2Н, С4Н2isox), 4.77 m (1Н, С5Нisox), 4.85 m
(1Н, С3Нisox), 7.10–7.20 (4Н, А2В2 system, С6Н4Cl, J
8.3 Hz), 7.30 m (1HPy), 7.89 d (1НPy, J 4.8 Hz), 8.62 d
(1НPy, J 2.5 Hz), 8.73 m (1НPy), 11.50–11.60 (4Н,
system А2В2, С6Н4Br, J 8.1 Hz). Found, %: С 56.89; Н
3.96; N 6.08. C20H16BrClN2O. Calculated, %: С 57.78;
Н 3.88; N 6.74.
N-(Pyridin-3-ylmethylidene)-N-phenylaminoxide
(2a). In 3 mL of ethanol was dissolved 0.37 g
(0.0034 mol) of pyridine-3-carbaldehyde and 0.38 g
(0.0034 mol) of phenylhydroxylamine and the solution
was maintained at room temperature for 7 h. The
reaction mixture was diluted with water till it became
milk-white, the mixture was heated till it turned
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 5 2018
765
transparent and was left overnight at 5°С. The
precipitated crystals were filtered off and recrystallized
from benzene. Yield 0.64 g (95%), mp 87–88°С {88–
89°С (benzene–hexane) [5]}. 1Н NMR spectrum, δ,
ppm: 7.38 m (1НPy), 7.42–7.55 m (5Нarom), 7.93 m,
8.72 m (2НPy), 8.80 s (1НPy), 9.22 s (1Н, СН).
N-(Pyridine-3-ylmethylidene)-N-(4-chloro-
phenyl)-amin oxide (2b) was prepared similarly.
Yield 0.78 g (91%), mp 127–129°С. 1Н NMR spectrum,
δ, ppm: 7.33 m (1НPy), 7.38–7.48 (4Н, А2В2 system,
С6Н4Cl, J 8.4 Hz), 7.94 m, 8.70 m (2НPy), 8.80 s (1НPy),
9.22 s (1Н, СН). Found, %: С 60.88; Н 4.05; N 11.88.
C12H9ClN2O. Calculated, %: С 61.95; Н 3.90; N 12.04.
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