Synthesis of functional isoxazole derivatives proceeding from (5-arylisoxazol-3-yl)chloromethanes

Article abstract of DOI:10.1134/S1070428015080102

Reaction of 3-chloromethyl-5-phenyl(p-tolyl)isoxazoles with substituted phenols under the conditions of Williamson reaction afforded the corresponding 3-aryloxymethyl-5-phenyl(p-tolyl)isoxazoles. Treating the latter with sodium methylate, sodium phenyl(benzyl, furfuryl)thiolates and morpholine in methanol resulted in the replacement of the chlorine atom in 3-chloromethyl-5-phenyl(p-tolyl)isoxazoles by methoxy-, phenyl-(benzyl, furfuryl)sulfanyl groups and morpholine residue.

Full text of DOI:10.1134/S1070428015080102

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 8, pp. 1119–1130. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © V.I. Potkin, N.A. Bumagin, S.K. Petkevich, E.A. Dikusar, E.V. Semenova, P.V. Kurman, R.M. Zolotar’, S.G. Pashkevich, T.A. Guri-
novich, V.A. Kul’chitskii, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 8, pp. 1140–1150.
Synthesis of Functional Isoxazole Derivatives Proceeding
from (5-Arylisoxazol-3-yl)chloromethanes
V. I. Potkina, N. A. Bumaginb, S. K. Petkevicha, E. A. Dikusara, E. V. Semenovaa,
P. V. Kurmanc, R. M. Zolotar’c, S. G. Pashkevichd,
T. A. Gurinovichd, and V. A. Kul’chitskiid
a Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus,
ul. Surganova 13, Minsk, 220072 Belarus
e-mail: potkin@ifoch.bas-net.by
b Lomonosov Moscow State University, Moscow, Russia
c Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus
d Physiology Institute, National Academy of Sciences of Belarus, Minsk, Belarus
Received June 11, 2015
Abstract—Reaction of 3-chloromethyl-5-phenyl(p-tolyl)isoxazoles with substituted phenols under the conditions
of Williamson reaction afforded the corresponding 3-aryloxymethyl-5-phenyl(p-tolyl)isoxazoles. Treating the
latter with sodium methylate, sodium phenyl(benzyl, furfuryl)thiolates and morpholine in methanol resulted in
the replacement of the chlorine atom in 3-chloromethyl-5-phenyl(p-tolyl)isoxazoles by methoxy-, phenyl-
(benzyl, furfuryl)sulfanyl groups and morpholine residue.
DOI: 10.1134/S1070428015080102
Functionally substituted isoxazoles attract a cons-
tantly growing attention due to the high biological acti-
vity exhibited by specimens of this compounds class
[1]. The isoxazole heterocycle is a fragment of
molecules of quite a number of pharmaceuticals, e.g.,
of leflunomide (drug for treating rheumatoid arthritis),
isocarboxazid (antidepressant), valdecoxib (antiphlo-
gistic drug), edonentan (antihypertensive drug), sulfa-
methoxazole, sulfisoxazole (antibacterial drugs) [2–5].
Among isoxazole derivatives kinase inhibitors,
antagonists of glutamate receptors, and antitumor
agents were found [6–9]. We recently performed the
synthesis of substituted isoxazolylureas, and they were
found to increase the cytotoxicity of antitumor
pharmaceuticals cisplatin and carboplatin thus
permitting the reduction of the therapeutic dose of
these very toxic substances [10].
tion of the complexes on various carriers opens a way
to reusable catalytic systems [12].
The complexing properties of substituted isoxazoles
and their biological activity are considerably deter-
mined by the functional surrounding of the heterocycle
[13, 14]. Therefore the development of approaches to
the formation of desired exocyclic functionality of
isoxazoles, synthesis of their new derivatives
promising for biotesting and application as ligands in
metal complex catalysts are extremely important tasks.
The aim of our work consisted in the preparation of
5-arylisoxazoles derivatives containing in the position
3 of the heterocycle substituents of diverse nature, in
particular, pharmacophoric fragments. As initial
compounds available 5-(arylisoxazol-3-yl)methanols 1
and 2 were chosen whose synthesis had been formerly
developed based on successive transformations of
trichloroethylene dimer [15].
Beside the biologic action isoxazoles are able to
form complexes with palladium(II) that exhibit a high
catalytic activity in the cross-coupling reactions in
water and water-alcoholic media and can be
successfully applied to the preparation of various
practically valuable substances [11]. The immobiliza-
The exocyclic hydroxymethyl group of compounds
1 and 2 was first converted into a chloromethyl
fragment by treating with thionyl chloride to obtain the
corresponding 5-aryl-3-chloromethylisoxazoles 3 and
1119

POTKIN et al.
1120
Scheme 1.
O
O
O
R1
N
N
R1
N
O
O
21
19, 20
O
N
K
E
2
C
OH
t
O
3
O
H
HO
,
OH
O
Cl
OH
R2
R3
SOCl2
R2 R3
R1
N
R1
R1
N
N
CH2Cl2
K2CO3, EtOH
O
O
O
1, 2
5_18
3, 4
MeO
K2CO3,
EtOH
HO
16
R4NH2,
MeO
MeOH,
AcOH
O
N
O
R1
N
O
22, 23
MeO
N
Me
O
Br2,
26, 27
CHCl3
MeO
Br
O
Br
R1
N
O
R1 = H (1, 3, 5, 6, 9–13, 19, 22, 24), Me (2, 4, 7, 8, 14–18, 20, 21, 23, 25); R2 = R3 = H (5, 6); R2 = H, R3 = 4-Me3CCH2CMe2 (7, 8);
R2 = H, R3 = 2-CHO (9, 14), 4-CHO (10, 15); R2 = 2-OMe, R3 = 4-CHO (11, 16); R2 = 2-OEt, R3 = 4-CHO (12, 17);
R2 = 2-OMe, R3 = 5-CHO (13, 18); R4 = Ph (26), 4-PhC6H4 (27).
4 in 74–87% yield. Further transformations were
carried out using the synthetic potential of the reactive
chloromethyl group.
By treating 5-aryl-3-chloromethylisoxazoles 3 and
4 with substituted synthetic and natural phenols (among
them salicylaldehyde, vanillin, their analogs, 8-hydroxy-
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SYNTHESIS OF FUNCTIONAL ISOXAZOLE DERIVATIVES PROCEEDING
1121
quinoline, eugenol, and also estrone, etc.) in ethanol in the
presence of potassium carbonate under the conditions of
Williamson reaction we synthesized 3-aryloxymethyl-
5-arylisoxazoles 5–23. The process was performed in an
argon atmosphere under reflux of reaction mixture for
5 days, the yields of ethers 5–23 were 76–92% (Scheme 1).
A number or the compounds contain reactive substi-
tuents, for instance, an aldehyde fragment (derivatives of
aldehydephenols), keto group (estrone), allyl residue (deri-
vatives of eugenol). Therefore it is possible to bring the
synthesized ethers into further directed transformations.
(arylisoxazol-3-yl)methanols 1 and 2. The presence of
the chloromethyl fragment is confirmed by the singlet
signals in the 1H NMR spectra of isoxazoles 3 and 4 in
the region 4.61–4.62 ppm and the signals δ 35.82 ppm
13
in the C NMR spectra. In the IR spectra of ethers 5–
27 the absorption bands are observed of the С=С
bonds in the phenol residues, and also of the С=С and
С=О bonds in the corresponding substituents in the
1
aromatic fragments of the molecules. In the H NMR
spectra of compounds 5–27 the СH2О groups give rise
to singlets at 5.16–5.47 ppm, the single proton H4 of
the isoxazole heterocycle appears as a singlet in the
region 6.52–7.23 ppm. Besides the multiplets of
aromatic protons are observed, and in the spectra of
aldehydophenols derivatives 9–18, singlets of aldehyde
fragments in the range 9.84–10.53 ppm. The presence
of the azomethine fragment in compounds 26 and 27 is
We carried out the bromination of eugenol deriva-
tives 22 and 23 with elemental bromine in tetrachloro-
methane under mild conditions at room temperature.
The reaction proceeded selectively by bromine
addition to the exocyclic double bond, it completed
within 10 h, and the yields of dibromo adducts 24 and
25 were 81–84%. The presence of two reactive
bromine atoms in obtained compounds 24 and 25
increases their synthetic potential. Besides the
introduction of halogen atoms increases as a rule the
biologic activity of the substance and makes it more
attractive for bio testing, in particular, for investigating
the pesticide activity [16, 17].
1
indicated by the singlets at 8.35–8.42 ppm in the H
NMR spectra, and also the signals at δ 159.58–
159.78 ppm in the 13С NMR spectra. Azomethines 26
and 27 apparently form as Е-isomers as show the close
values δ of the azomethine group signals and similar
signals in the spectra of analogous compounds [18].
1H and 13С NMR spectra of compounds 28–39
contain the signals of molecular fragments of the
nucleophile residues of the corresponding multiplicity
[singlet of the methoxy group (36 and 37), multiplets
of thiol residues (28–35) and of morpholine rest (38
and 39)], and in the IR spectra the absorption bands are
present characteristic of the bonds forming these
fragments.
By the condensation of vanillin derivative 16 with
aniline or p-biphenylamine in boiling anhydrous
methanol with added glacial acetic acid we obtained
the corresponding azomethines 26 and 27 in 77 and
79% yields respectively.
We brought the initial 3-(chloromethyl)isoxazoles 3
and 4 into the nucleophilic substitution reactions with
other nucleophiles as well. By the treatment with
sodium methylate, sodium phenyl(benzyl, furfuryl)
thiolates, and morpholine in methanol the chlorine
atom was substituted for methoxy fragment, phenyl
(benzyl, furfuryl)sulfanyl groups, and morpholine
residue respectively. The reactions with sodium
methylate and morpholine were carried out in boiling
methanol, the reaction with sodium thiolates readily
occurred at 20°С. The yield of the products of chlorine
substitution for the nucleophile residues was 82–97%,
only in the case of mercaptoethanol derivative the
yield of sulfide 31 did not exceed 66% (Scheme 2).
Scheme 2.
SR'
R'SH, MeONa
N
R
MeOH
O
28_35
OMe
MeONa
N
R
3, 4
MeOH
O
36, 37
N
O
The synthesized compounds 3–39 were identified
based on the data of elemental analysis, IR, 1H and 13С
NMR, and mass spectra.
HN
O
N
R
MeOH
O
38, 39
IR spectra of 3-(chloromethyl)isoxazoles 3 and 4
lack the absorption band of stretching vibrations of the
ОH group that is present in the spectra of initial 5-
R = H (28–31, 36, 38), Me (32–35, 37, 39); R' = Ph (28, 32),
Bn (29, 33), 2-FuCH2 (30, 34), CH2CH2OH (31, 35).
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POTKIN et al.
1122
Synthesized derivatives of aldehydophenols 9–18
7.44 m (3Harom), 7.75 m (2Harom). 13С NMR spectrum,
δ, ppm: 35.82 (СH2), 99.11 (СHisox), 125.88 (2СHarom),
129.09 (2СHarom), 130.54 (1СHarom), 127.04, 161.47,
170.90 (3Сquat). Found, %: C 61.95; H 4.02; Cl 18.50;
N 7.21. [M]+ 193. C10H8ClNO. Calculated, %: C
62.03; H 4.16; Cl 18.31; N 7.23. M 193.63.
and azomethines 26 and 27 are isosteres of sinergists
of insecticides [19, 20] and are now under bio testing
in binary mixtures with neonicotinoid insecticide
Kerber against Colorado potato beetle. Derivatives of
morpholine 38 and 39 are structural analogs of
compounds possessing antitumor activity and increasing
the cytotoxic action of cisplatin and carboplatin drugs
[10, 14], and they have been transferred to Physiology
Institute, National Academy of Sciences of Belarus’,
for medico-biologic investigations. A series of obtained
isoxazole derivatives are promising as ligands for
palladium complexes and modifier of polymer
matrices for development of cross-coupling catalysts.
5-(4-Methylphenyl)-3-(chloromethyl)isoxazole
(4). Yield 74%, mp 47.5–48°С. IR spectrum, ν, cm–1:
3136, 3058, 3024, 2920, 2854, 1619, 1599, 1587,
1566, 1513, 1458, 1450, 1429, 1409, 1266, 1114,
1047, 1019, 948, 927, 827, 803, 739, 726, 715, 673,
634, 505. 1H NMR spectrum, δ, ppm: 2.37 s (3H, Me),
4.61 s (1H, СH2), 6.54 s (1Hisox), 7.23 d (2Harom, J 8 Hz),
7.63 d (2Harom, J 8 Hz). 13С NMR spectrum, δ, ppm:
21.48 (Me), 35.82 (СH2), 98.45 (СHisox), 125.76
(2СHarom), 129.71 (2СHarom), 124.31, 140.82, 161.36,
171.05 (4Сquat). Found, %: C 63.54; H 4.90; Cl 17.12;
N 6.68. [M]+ 207. C11H10ClNO. Calculated, %: C 63.62;
H 4.85; Cl 17.07; N 6.75. M 207.66.
EXPERIMENTAL
IR spectra were recorded on
a
Fourier
spectrophotometer Nicolet Protégé-460 from pellets
1
with KBr (compounds 36 and 37, from thin films). H
and 13С NMR spectra were registered on a
spectrometer Bruker Avance-500 in CDCl3 (3–9, 14,
and 21–37) and (CD3)2SO (10–13 and 15–20). The
chemical shifts were measured from the residual
signals of the deuterated solvents [CDCl3: δH 7.26, δС
77.2 ppm; (CD3)2SO: δH 2.50, δС 40.1 ppm]. Mass
spectra were measured on an instrument Agilent 5975
inert MSD/6890N Network GC System in the electron
impact mode, ionizing electrons energy 70 eV; capilla-
ry column HP-5MS (30 m × 0.25 mm × 0.25 µm);
stationary phase 5% PhMe Silicone; vaporizer
temperature 250°С.
Ethers (5–23). General procedure. A mixture of
20 mmol of chloromethylisoxazole 3 and 4, 60 mmol
of substituted phenol, and 8.29 g (60 mmol) of
anhydrous K2CO3 in 40 mL of 96% ethanol was boiled
at reflux for 5 days in an argon atmosphere. On
cooling the reaction mixture was poured in 100 mL of
10% water NaCl solution. The separated precipitate
was filtered off, washed with 500 mL of water, and
dried at 30–35°С. The final purification was performed
by column chromatography on silica gel (100–160 µm),
eluent benzene (for compounds 5–18 and 21–23), or
by low temperature crystallization from a mixture
benzene–hexane, 1 : 1 (for compounds 19 and 20).
Chloromethylisoxazoles (3 and 4). General
procedure. To 20 mmol of an appropriate alcohol 1
and 2 in 40 mL of anhydrous dichloromethane at 10°С
was added 2.86 g (24 mmol) of thionyl chloride. The
reaction mixture was stirred at 20°С till the end of HCl
liberation (2 h), then it was boiled for 4 h more. On
cooling the solution was poured in 150 mL of water,
the organic layer was separated, washed with water
solution of sodium hydrogen carbonate, and dried with
calcium chloride. The solvent was distilled off at a
reduced pressure, the residue was recrystallized from
hexane.
5-Phenyl-3-(phenoxymethyl)isoxazole (5). Yield
90%, mp 61–62°С. IR spectrum, ν, cm–1: 3127, 3065,
3040, 2922, 2853, 1600, 1588, 1574, 1496, 1470,
1453, 1434, 1368, 1292, 1246, 1227, 1171, 1154,
1
1110, 1081, 1051, 1023, 923, 847, 807, 752, 689. H
NMR spectrum, δ, ppm: 5.21 s (2H, СH2), 6.66 s
(1Hisox), 6.98–7.08 m (3Harom), 7.33 t (2Harom, J 7.4 Hz),
7.40–7.51 m (3Harom), 7.73–7.83 m (2Harom). 13С NMR
spectrum, δ, ppm: 61.84 (СH2), 98.96 (СHisox), 114.87
(2СHarom), 121.71 (1СHarom), 125.97 (2СHarom), 129.10
(2СHarom), 129.76 (2СHarom), 130.43 (1СHarom),
127.33, 158.16, 161.62, 170.59 (4Сquat). Found, %: C
76.91; H 5.28; N 5.23. [M]+ 251. C16H13NO2. Calcula-
ted, %: C 76.48; H 5.21; N 5.57. M 251.28.
5-Phenyl-3-(chloromethyl)isoxazole (3). Yield
87%, mp 70–71°С. IR spectrum, ν, cm–1: 3119, 3058,
3043, 3022, 2925, 2853, 1646, 1612, 1591, 1574,
1502, 1464, 1452, 1423, 1265, 1152, 1048, 1012, 949,
3-{[4-(2,4,4-Trimethylpentan-2-yl)phenoxy]me-
thyl}-5-phenylisoxazole (6). Yield 92%, mp 118–119°С.
IR spectrum, ν, cm–1: 3133, 3064, 3043, 2954, 2884,
1
921, 821, 766, 735, 693, 685, 667, 619, 507. H NMR
spectrum, δ, ppm: 4.62 s (1H, СH2), 6.61 s (1Hisox),
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SYNTHESIS OF FUNCTIONAL ISOXAZOLE DERIVATIVES PROCEEDING
1123
2872, 1610, 1593, 1573, 1509, 1467, 1453, 1395,
1385, 1373, 1364, 1284, 1246, 1232, 1183, 1131,
1112, 1098, 1052, 1019, 947, 929, 856, 826, 814, 763,
682, 585. 1H NMR spectrum, δ, ppm: 0.74 s (9H, 3Me),
1.36 s (6H, 2Me), 1.73 s (2H, СH2), 5.19 s (2H, ОСH2),
1685 (С=О), 3134, 3070, 3047, 3040, 3008, 2958,
2922, 2883, 2855, 2783, 1599, 1574, 1490, 1473,
1459, 1450, 1443, 1428, 1406, 1375, 1303, 1292, 1257,
1241, 1191, 1166, 1105, 1049, 947, 850, 762, 754, 686,
679, 636, 529. 1H NMR spectrum, δ, ppm: 5.30 s (2H,
СH2), 6.66 s (1Hisox), 7.07 t (1Harom, J 7.5 Hz), 7.11 d
(1Harom, J 8.4 Hz), 7.42–7.47 m (3Harom), 7.54 d.d
(1Harom, J 7.9, 1.8 Hz), 7.74–7.79 m (2Harom), 7.85 d.d
(1Harom, J 7.7, 1.8 Hz), 10.53 s (1H, =СHО). 13С NMR
spectrum, δ, ppm: 62.34 (СH2), 98.69 (СHisox), 112.85
(1СHarom), 121.76 (1СHarom), 125.95 (2СHarom), 128.88
(1СHarom), 129.13 (2СHarom), 130.60 (1СHarom), 136.11
(1СHarom), 125.25, 127.05, 160.24, 160.73, 170.98
(5Сquat), 189.39 (С=О). Found, %: C 73.56; H 4.88; N
4.86. [M]+ 279. C17H13NO3. Calculated, %: C 73.11; H
4.69; N 5.02. M 279.30.
6.67 s (1Hisox), 6.94 d (2Harom, J 8.5 Hz), 7.32 d (2Harom
,
J 8.5 Hz), 7.40–7.52 m (3Harom), 7.73–7.83 m (2Harom).
13С NMR spectrum, δ, ppm: 31.79 (2MeC), 31.93
(3MeC), 57.15 (СH2), 61.96 (ОСH2), 99.08 (СHisox),
114.12 (2СHarom), 126.02 (2СHarom), 127.40 (2СHarom),
129.14 (2СHarom), 130.47 (1СHarom), 32.48, 38.16, 127.37,
143.42, 155.87, 161.87, 170.57 (7Сquat). Found, %: C
79.66; H 8.27; N 3.35. [M]+ 363. C24H29NO2.
Calculated, %: C 79.30; H 8.04; N 3.85. M 363.50.
5-(4-Methylphenyl)-3-(phenoxymethyl)isoxazole
(7). Yield 92%, mp 103–104°С. IR spectrum, ν, cm–1:
3121, 3066, 3033, 3023, 3013, 2963, 2922, 2855,
1618, 1600, 1587, 1519, 1496, 1474, 1454, 1437,
1369, 1242, 1172, 1080, 1056, 1018, 920, 841, 821,
755, 692, 515. 1H NMR spectrum, δ, ppm: 2.41 sс (3H,
Me), 5.20 s (2H, СH2), 6.61 s (1Hisox), 6.97–7.09 m
(3Harom), 7.27 d (2Harom, J 8 Hz), 7.33 t (2Harom, J 7.6 Hz),
7.68 d (2Harom, J 8 Hz). 13С NMR spectrum, δ, ppm:
21.61 (Me), 61.89 (СH2), 98.36 (СHisox), 114.88
(2СHarom), 121.68 (1СHarom), 125.92 (2СHarom), 129.76
(2СHarom), 129.79 (2СHarom), 124.67, 140.75, 158.21,
161.56, 170.81 (5Сquat). Found, %: C 77.20; H 5.85; N
7494. [M]+ 265. C17H15NO2. Calculated, %: C 76.96; H
5.70; N 5.28. M 265.31.
4-[(5-Phenylisoxazol-3-yl)methoxy]benzaldehyde
(10). Yield 81%, mp 105–106°С. IR spectrum, ν, cm–1:
1696 (С=О), 3151, 3069, 3008, 2960, 2923, 2852,
2821, 2796, 1597, 1576, 1507, 1454, 1423, 1385,
1307, 1257, 1233, 1217, 1164, 1110, 1051, 1038,
1007, 928, 866, 832, 814, 797, 764, 688, 607. 1H NMR
spectrum, δ, ppm: 5.38 s (2H, СH2), 7.17 s (1Hisox),
7.25 d (2Harom, J 8.8 Hz), 7.47–7.53 m (3Harom), 7.86–
7.89 m (2Harom), 7.89 d (2Harom, J 8.8 Hz), 9.89 s (1H,
=СHО). 13С NMR spectrum, δ, ppm: 62.20 (СH2),
100.57 (СHisox),115.83 (2СHarom), 126.22 (2СHarom),
129.81 (2СHarom), 131.14 (1СHarom), 132.40 (2СHarom),
127.17, 130.81, 161.37, 163.19, 170.28 (5Сquat),
191.88 (С=О). Found, %: C 73.52; H 4.85; N 5.20.
[M]+ 279. C17H13NO3. Calculated, %: C 73.11; H 4.69;
N 5.02. M 279.30.
5-(4-Methylphenyl)-3-{[4-(2,4,4-trimethylpen-
tan-2-yl)-phenoxy]methyl}isoxazole (8). Yield 91%,
mp 109–110°С. IR spectrum, ν, cm–1: 3136, 3100,
3065, 3038, 2956, 2922, 2886, 2866, 1616, 1598,
1581, 1568, 1511, 1473, 1459, 1442, 1365, 1285,
1252, 1188, 1180, 1113, 1055, 1020, 920, 825, 813,
798, 581, 509. 1H NMR spectrum, δ, ppm: 0.74 s (9H,
3Me), 1.37 s (6H, 2Me), 1.73 s (2H, СH2), 2.41 s (3H,
3-Methoxy-4-[(5-phenylisoxazol-3-yl)-methoxy]-
benzaldehyde (11). Yield 79%, mp 132–133°С. IR
spectrum, ν, cm–1: 1679 (С=О), 3139, 3078, 3049,
3014, 2963, 2925, 2855, 2840, 2767, 1600, 1588, 1576,
1512, 1467, 1456, 1426, 1405, 1375, 1347, 1279, 1268,
1231, 1158, 1138, 1048, 1032, 1012, 863, 838, 811,
Me), 5.18 s (2H, ОСH2), 6.61 s (1Hisox), 6.95 d (2Harom
,
1
798, 762, 730, 690, 642. H NMR spectrum, δ, ppm:
J 8.8 Hz), 7.27 d (2Harom, J 8.1 Hz), 7.32 d (2Harom, J
8.8 Hz), 7.68 d (2Harom, J 8.1 Hz). 13С NMR spectrum,
δ, ppm: 21.62 (Me), 31.78 (2MeС), 31.91 (3MeС),
57.13 (СH2), 61.99 (ОСH2), 98.43 (СHisox), 114.09
(2СHarom), 125.93 (2СHarom), 127.36 (2СHarom), 129.79
(2СHarom), 32.47, 38.14, 124.75, 140.68, 143.31,
155.93, 161.74, 170.70 (8Сquat). Found, %: C 79.90; H
8.27; N 3.45. [M]+ 377. C25H31NO2. Calculated, %: C
79.54; H 8.28; N 3.71. M 377.53.
3.85 s (3H, ОMe), 5.37 s (2H, СH2), 7.17 s (1Hisox),
7.34 d (1Harom, J 8.3 Hz), 7.44 d (1Harom, J 1.8 Hz),
7.50–7.55 m (3Harom), 7.57 d.d (1Harom, J 8.3, 1.8 Hz),
7.88–7.91 m (2Harom), 9.86 s (1H, =СHО). 13С NMR
spectrum, δ, ppm: 56.25 (ОMe), 62.52 (СH2), 100.81
(СHisox), 110.61 (1СHarom), 113.54 (1СHarom), 126.30
(2СHarom), 126.32 (1СHarom), 129.93 (2СHarom), 131.26
(1СHarom), 127.18, 131.01, 150.02, 153.07, 161.36,
170.31 (6Сquat), 192.15 (С=О). Found, %: C 70.12; H
4.98; N 4.25. [M]+ 309. C18H15NO4. Calculated, %: C
69.89; H 4.89; N 4.53. M 309.32.
2-[(5-Phenylisoxazol-3-yl)methoxy]benzaldehyde
(9). Yield 78%, mp 125–126°С. IR spectrum, ν, cm–1:
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POTKIN et al.
1124
4-[(5-Phenylisoxazol-3-yl)methoxy]-3-ethoxyben-
125.91 (2СHarom), 128.86 (1СHarom), 129.82 (2СHarom),
136.11 (1СHarom), 124.39, 125.28, 140.97, 160.31,
160.69, 171.20 (6Сquat), 189.41 (С=О). Found, %: C
74.06; H 5.22; N 4.41. [M]+ 293. C18H15NO3.
Calculated, %: C 73.71; H 5.15; N 4.78. M 293.32.
zaldehyde (12). Yield 76%, mp 86–87°С. IR spec-
trum, ν, cm–1: 1692 (С=О), 3141, 3078, 3065, 3016,
2976, 2925, 2883, 2852, 2823, 2784, 1588, 1511,
1455, 1436, 1397, 1333, 1266, 1228, 1169, 1134,
1
1121, 1036, 1005, 863, 807, 765, 688. H NMR
4-{[5-(4-Methylphenyl)isoxazol-3-yl]methoxy}-
benzaldehyde (15). Yield 88%, mp 93–94°С. IR
spectrum, ν, cm–1: 1686 (С=О), 3127, 3076, 3041,
3010, 2974, 2924, 2853, 2757, 1618, 1602, 1579, 1517,
1509, 1470, 1439, 1396, 1368, 1315, 1254, 1215,
1162, 1109, 948, 916, 864, 839, 813, 803, 745, 716,
509. 1H NMR spectrum, δ, ppm: 2.35 s (3H, Me), 5.37
s (2H, СH2), 7.10 s (1Hisox), 7.26 d (2Harom, J 8.8 Hz),
7.33 d (2Harom, J 8.1 Hz), 7.77 d (2Harom, J 8.1 Hz), 7.90
d (2Harom, J 8.8 Hz), 9.89 s (1H, =СHО). 13С NMR
spectrum, δ, ppm: 21.56 (Me), 62.19 (СH2), 99.91
(СHisox), 115.84 (2СHarom), 126.18 (2СHarom), 130.38
(2СHarom), 132.39 (2СHarom), 124.52, 130.81, 141.10,
161.31, 163.21, 170.43 (6Сquat), 191.91 (С=О). Found,
%: C 74.23; H 5.19; N 4.35. [M]+ 293. C18H15NO3.
Calculated, %: C 73.71; H 5.15; N 4.78. M 293.32.
spectrum, δ, ppm: 1.34 t (3H, MeСH2, J 7 Hz), 4.09 q
(MeСH2, J 7 Hz), 5.38 s (2H, ОСH2), 7.14 s (1Hisox),
7.33 d (1Harom, J 8.3 Hz), 7.42 d (1Harom, J 1.8 Hz),
7.48–7.53 m (3Harom), 7.54 d.d (1Harom, J 8.3, 1.8 Hz),
7.85–7.89 m (2Harom), 9.85 s (1H, =СHО). 13С NMR
spectrum, δ, ppm: 15.12 (MeСH2), 62.56 (MeСH2),
64.56 (ОСH2), 100.66 (СHisox), 111.79 (1СHarom),
113.88 (1СHarom), 126.00 (1СHarom), 126.22 (2СHarom),
129.83 (2СHarom), 131.16 (1СHarom), 127.15, 131.02,
149.24, 153.18, 161.42, 170.24 (6Сquat), 192.02 (С=О).
Found, %: C 70.87; H 5.47; N 4.01. [M]+ 323.
C19H17NO4. Calculated, %: C 70.58; H 5.30; N 4.33. M
323.35.
4-Methoxy-3-[(5-phenylisoxazol-3-yl)methoxy]-
benzaldehyde (13). Yield 87%, mp 103–104°С. IR
spectrum, ν, cm-1: 1680 (С=О), 3142, 3080, 3062,
3007, 2956, 2924, 2852, 2766, 1598, 1584, 1512,
1469, 1455, 1433, 1406, 1372, 1263, 1238, 1158,
4-{[5-(4-Methylphenyl)isoxazol-3-yl]methoxy}-3-
methoxybenzaldehyde (16). Yield 86%, mp 103–104°С.
IR spectrum, ν, cm–1: 1686 (С=О), 3142, 3076, 3060,
3032, 2958, 2920, 2852, 2763, 1619, 1600, 1587,
1513, 1476, 1463, 1445, 1422, 1400, 1374, 1344,
1281, 1264, 1231, 1159, 1135, 1045, 1033, 1013, 915,
1
1133, 1018, 808, 764, 690, 639. H NMR spectrum, δ,
ppm: 3.88 s (3H, ОMe), 5.32 s (2H, СH2), 7.14 s
(1Hisox), 7.19 d (1Harom, J 8.3 Hz), 7.48–7.54 m (3Harom),
7.59 s (1Harom), 7.60 d.d (1Harom, J 8.3, 1.8 Hz), 7.88–
7.91 m (2Harom), 9.84 s (1H, =СHО). 13С NMR spec-
trum, δ, ppm: 56.55 (ОMe), 62.49 (СH2), 100.71
(СHisox), 112.31 (1СHarom), 112.36 (1СHarom), 126.22
(2СHarom), 127.47 (1СHarom), 129.81 (2СHarom), 131.12
(1СHarom), 127.20, 130.16, 148.16, 155.09, 161.55,
170.19 (6Сquat), 191.77 (С=О). Found, %: C 70.10; H
5.04; N 4.20. [M]+ 309. C18H15NO4. Calculated, %: C
69.89; H 4.89; N 4.53. M 309.32.
1
860, 819, 798, 754, 727, 510. H NMR spectrum, δ,
ppm: 2.35 s (3H, Me), 3.85 s (3H, ОMe), 5.35 s (2H,
СH2), 7.09 s (1Hisox), 7.34 m (3Harom), 7.44 d (1Harom, J
1.8 Hz), 7.57 d.d (1Harom, J 8.2, 1.8 Hz), 7.78 d
(2Harom, J 8.1 Hz), 9.86 s (1H, =СHО). 13С NMR
spectrum, δ, ppm: 21.58 (Me), 56.19 (ОMe), 62.49
(СH2), 100.08(СHisox), 110.54 (1СHarom), 113.46
(1СHarom), 126.20 (2СHarom), 126.27 (1СHarom), 130.40
(2СHarom), 124.51, 130.96, 141.12, 149.98, 153.05,
161.23, 170.43 (7Сquat), 192.03 (С=О). Found, %: C
70.92; H 5.37; N 4.11. [M]+ 323. C19H17NO4.
Calculated, %: C 70.58; H 5.30; N 4.33. M 323.35.
2-{[5-(4-Methylphenyl)isoxazol-3-yl]methoxy}-
benzaldehyde (14). Yield 91%, mp 140–141°С. IR
spectrum, ν, cm–1: 1686 (С=О), 3139, 3067, 3031,
3011, 2952, 2920, 2887, 2858, 2783, 1619, 1600,
1568, 1517, 1490, 1470, 1458, 1438, 1408, 1373,
1305, 1269, 1253, 1242, 1194, 1185, 1164, 1105,
1055, 1050, 948, 921, 851, 837, 819, 756, 715, 643,
499. 1H NMR spectrum, δ, ppm: 2.30 s (3H, Me), 5.21
s (2H, СH2), 6.52 s (1Hisox), 6.98 t (1Harom, J 7.5 Hz),
7.03 d (1Harom, J 8.4 Hz), 7.17 d (2Harom, J 8 Hz), 7.46
d.d (1Harom, J 7.9, 1.8 Hz), 7.58 d (2Harom, J 8 Hz),
7.77 d.d (1Harom, J 7.7, 1.8 Hz), 10.45 s (1H, =СHО).
13С NMR spectrum, δ, ppm: 21.59 (Me), 62.41 (СH2),
98.08 (СHisox), 112.88 (1СHarom), 121.74 (1СHarom),
4-{[5-(4-Methylphenyl)isoxazol-3-yl]methoxy}-3-
ethoxybenzaldehyde (17). Yield 85%, mp 61–62°С.
IR spectrum, ν, cm–1: 1693 (С=О), 3140, 3083, 3055,
3028, 2975, 2921, 2868, 2823, 2785, 1620, 1586,
1514, 1462, 1449, 1397, 1336, 1273, 1231, 1177, 1133,
1
1120, 1037, 1008, 948, 848, 810, 791, 737, 505. H
NMR spectrum, δ, ppm: 1.34 t (3H, MeСH2, J 7 Hz),
2.34 s (3H, Me), 4.10 q (MeСH2, J 7 Hz), 5.37 s (2H,
ОСH2), 7.07 s (1Hisox), 7.33 m (3Harom), 7.42 d (1Harom
,
J 1.8 Hz), 7.54 d.d (1Harom, J 8.3, 1.8 Hz), 7.76 d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 8 2015

SYNTHESIS OF FUNCTIONAL ISOXAZOLE DERIVATIVES PROCEEDING
1125
(2Harom, J 8.1 Hz), 9.85 s (1H, =СHО). 13С NMR
spectrum, δ, ppm: 15.12 (MeСH2), 21.56 (Me), 62.56
(MeСH2), 64.56 (ОСH2), 100.10 (СHisox), 111.80
(1СHarom), 113.88 (1СHarom), 125.99 (1СHarom), 126.16
(2СHarom), 130.37 (2СHarom), 124.50, 131.01, 141.09,
149.24, 153.20, 161.33, 170.40 (7Сquat), 192.00 (С=О).
Found, %: C 71.65; H 5.84; N 4.21. [M]+ 337.
C20H19NO4. Calculated, %: C 71.20; H 5.68; N 4.15. M
337.37.
(3H, Me), 5.45 s (2H, СH2), 7.16 s (1Hisox), 7.35 d
(2Harom, J 8.1 Hz), 7.38 d (1Harom, J 7.2 Hz), 7.53 t
(1Harom, J 7.9 Hz), 7.55–7.61 m (2Harom), 7.80 d
(2Harom, J 8.1 Hz), 8.34 d.d (1Harom, J 8.3, 1.5 Hz),
8.88 d.d (1Harom, J 4, 1.5 Hz). 13С NMR spectrum, δ,
ppm: 21.60 (Me), 62.68 (СH2), 100.27 (СHisox), 111.23
(1СHarom), 121.27 (1СHarom), 122.58 (1СHarom), 126.21
(2СHarom), 127.30 (1СHarom), 130.43 (2СHarom), 136.49
(1СHarom), 149.84 (1СHarom), 124.61, 130.06, 144.22,
150.06, 154.17, 162.62, 170.31 (7Сquat). Found, %: C
76.27; H 5.28; N 8.49. C20H16N2O2. Calculated, %: C
75.93; H 5.10; N 8.86.
3-{[5-(4-Methylphenyl)isoxazol-3-yl]-methoxy}-
4-methoxybenzaldehyde (18). Yield 89%, mp 134–
135°С. IR spectrum, ν, cm–1: 1680 (С=О), 3138, 3079,
3034, 3017, 2974, 2923, 2871, 2849, 2766, 1617,
1599, 1586, 1518, 1507, 1475, 1436, 1403, 1367,
1263, 1236, 1225, 1160, 1137, 1049, 1021, 948, 901,
864, 822, 806, 793, 764, 640, 503. 1H NMR spectrum,
δ, ppm: 2.36 s (3H, Me), 3.89 s (3H, ОСH3), 5.30 s
(2H, СH2), 7.08 s (1Hisox), 7.22 d (1Harom, J 8.3 Hz),
7.34 d (2Harom, J 8.1 Hz), 7.58 d (1Harom, J 1.8 Hz), 7.61
d.d (1Harom, J 8.3, 1.8 Hz), 7.78 d (2Harom, J 8.1 Hz),
9.84 s (1H, =СHО). 13С NMR spectrum, δ, ppm: 21.59
(Me), 56.59 (ОMe), 62.48 (СH2), 100.08 (СHisox),
112.37 (1СHarom), 112.38 (1СHarom), 126.19 (2СHarom),
127.47 (1СHarom), 130.40 (2СHarom), 124.54, 130.15,
141.08, 148.16, 155.09, 161.47, 170.32 (7Сquat),
191.84 (С=О). Found, %: C 70.87; H 5.44; N 4.09.
[M]+ 323. C19H17NO4. Calculated, %: C 70.58; H 5.30;
N 4.33. M 323.35.
(8R,9S,13S,14S)-13-Methyl-3-{[5-(4-methylphe-
nyl)isoxazol-3-yl]methoxy}-6,7,8,9,11,12,13,14,15,16-
decahydro-17H-cyclopenta[a]phenanthren-17-one
(21). Yield 74%, mp 156–157°С. IR spectrum, ν, cm–1:
3130, 3066, 3035, 2955, 2936, 2918, 2884, 2864,
2853, 2818, 1746, 1618, 1607, 1599, 1501, 1468,
1455, 1372, 1253, 1234, 1166, 1043, 1024, 1019, 921,
812, 795, 504. 1H NMR spectrum, δ, ppm: 0.91 s (3H,
Mealiph), 1.40–1.66 m (6Haliph), 1.93–2.09 m (3Haliph),
2.10–2.19 m (1Haliph), 2.21–2.29 m (1Haliph), 2.35–2.39
m (1Haliph), 2.40 s (3H, 4-Me), 2.46–2.54 m (1Haliph),
2.85–2.93 m (2Haliph), 5.16 s (2H, ОСH2), 6.59 s
(1Hisox), 6.75 d (1Harom, J 2.7 Hz), 6.82 d.d (1Harom, J
8.6, 2.7 Hz), 7.22 d (1Harom, J 8.6 Hz), 7.26 d (1Harom, J
8.1 Hz), 7.67 d (1Harom, J 8.1 Hz). 13С NMR spectrum,
δ, ppm: 14.01 (Mealiph), 21.65 (СH), 21.74 (СH2),
26.04 (СH2), 26.65 (СH2), 29.81 (СH2), 31.73 (СH2),
36.02 (СH2), 38.44 (СH), 44.14 (СH), 50.57 (СH),
61.97 (СH2), 98.39 (СHisox), 112.51 (1СHarom), 114.94
(1СHarom), 125.95 (2СHarom), 126.66 (1СHarom), 129.82
(2СHarom), 48.15, 124.74, 133.14, 138.17, 140.77,
156.28, 161.75, 170.79 (8Сquat), 221.03 (С=О). Found,
%: C 79.02; H 7.15; N 3.09. [M]+ 441. C29H31NO3.
Calculated, %: C 78.88; H 7.08; N 3.17. M 441.57.
5-Phenyl-3-[(quinolin-8-yloxy)methyl]isoxazole
(19). Yield 80%, mp 72–73°С. IR spectrum, ν, cm–1:
3044, 2953, 2850, 1599, 1575, 1497, 1465, 1424,
1387, 1371, 1324, 1312, 1281, 1268, 1231, 1109,
1
1034, 873, 823, 803, 789, 745, 732, 506. H NMR
spectrum, δ, ppm: 5.47 s (2H, СH2), 7.23 s (1Hisox),
7.39 d (1Harom, J 7.2 Hz), 7.48–7.59 m (6Harom), 7.90 d
(2Harom, J 6.7 Hz), 8.33 d.d (1Harom, J 8.1, 1.1 Hz),
8.88 d.d (1Harom, J 3.7, 1.1 Hz). 13С NMR spectrum, δ,
ppm: 62.70 (СH2), 100.90 (СHisox), 111.27 (1СHarom),
121.29 (1СHarom), 122.55 (1СHarom), 126.23 (2СHarom),
127.27 (1СHarom), 129.84 (2СHarom), 131.12 (1СHarom),
136.46 (1СHarom), 149.82 (1СHarom), 127.24, 129.72,
140.36, 154.16, 161.88, 170.13 (6Сquat). Found, %: C
75.79; H 4.86; N 8.97. C19H14N2O2. Calculated, %: C
75.48; H 4.67; N 9.27.
3-[(4-Allyl-2-methoxyphenoxy)methyl]-5-phenyl-
isoxazole (22). Yield 91%, mp 61–62°С. IR spectrum,
ν, cm–1: 3151, 3074, 3063, 3038, 2990, 2950, 2934,
2923, 2857, 2829, 1636, 1612, 1591, 1574, 1517,
1469, 1450, 1433, 1419, 1373, 1336, 1305, 1261,
1230, 1192, 1158, 1142, 1042, 1017, 993, 949, 921,
1
912, 831, 810, 771, 694. H NMR spectrum, δ, ppm:
3.34 d (2H, СH2СH=СH2, J 6.7 Hz), 3.89 s (3H,
ОMe), 5.04–5.12 m (2H, СH2СH=СH2), 5.25 s (2H,
ОСH2), 5.90–6.00 m (1H, СH2СH=СH2), 6.69 s
(1Hisox), 6.71 d.d (1Harom, J 8.2, 2 Hz), 6.75 d (1Harom, J
2 Hz), 6.94 d (1Harom, J 8.2 Hz), 7.40–7.47 m (3Harom),
7.73–7.80 m (2Harom). 13С NMR spectrum, δ, ppm:
39.95 (СH2СH=СH2), 55.99 (ОMe), 63.29 (СH2), 99.10
5-(4-Methylphenyl)-3-[(quinolin-8-yloxy)methyl]-
isoxazole (20). Yield 82%, mp 66–67°С. IR spectrum,
ν, cm–1: 3042, 2958, 2921, 2854, 1600, 1578, 1502,
1469, 1425, 1384, 1371, 1327, 1262, 1109, 1035, 822,
1
803, 790, 744, 513. H NMR spectrum, δ, ppm: 2.37 s
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 8 2015

POTKIN et al.
1126
(СHisox), 112.57 (1СHarom), 114.74 (1СHarom), 115.93
(СH2СH=СH2), 120.67 (1СHarom), 125.97 (2СHarom),
129.08 (2СHarom), 130.36 (1СHarom), 137.57 (СH2–
СH=СH2), 127.43, 134.41, 145.87, 149.75, 161.87,
170.50 (6Сquat). Found, %: C 61.95; H 4.02; N 7.21.
[M]+ 321. C20H19NO3. Calculated, %: C 74.75; H 5.96;
N 4.36. M 321.38.
7.41–7.48 m (3Harom), 7.75–7.80 m (2Harom). 13С
NMR spectrum, δ, ppm: 36.14 (CH2Br), 41.61
(ArCH2CHBr), 52.56 (CHBr), 56.10 (ОMe),
63.14 (ОСH2), 99.08 (СHisox), 113.49 (1СHarom),
114.36 (1СHarom), 121.89 (1СHarom), 125.98 (2СHarom),
129.10 (2СHarom), 130.41 (1СHarom), 127.38, 130.83,
146.73, 149.60, 161.67, 170.59 (6Сquat). Found, %: C
49.89; H 4.12; Br 32.91; N 7.21. [M – HBr]+ 399.
C20H19Br2NO3. Calculated, %: C 49.42; H 3.98; Br
33.21; N 2.91. M 481.18.
3-[(4-Allyl-2-methoxyphenoxy)methyl]-5-(4-me-
thylphenyl)isoxazole (23). Yield 92%, mp 84–85°С.
IR spectrum, ν, cm–1: 3130, 3076, 3063, 3043, 3031,
2999, 2976, 2958, 2941, 2919, 2865, 2833, 1638,
1611, 1593, 1514, 1464, 1437, 1414, 1368, 1261,
1229, 1185, 1143, 1094, 1054, 1036, 999, 921, 841,
816, 756, 510. 1H NMR spectrum, δ, ppm: 2.38 s (3H,
Me), 3.34 d (2H, СH2СH=СH2, J 6.7 Hz), 3.89 s (3H,
ОMe), 5.03–5.13 m (2H, СH2СH=СH2), 5.24 s (2H,
ОСH2), 5.90–6.01 m (1H, СH2СH=СH2), 6.64 s
3-{[4-(2,3-Dibromopropyl)-2-methoxyphenoxy]-
methyl}-5-(4-methylphenyl)isoxazole (25). Yield
84%, mp 93–94°С. IR spectrum, ν, cm–1: 3134, 3083,
3058, 3033, 3016, 2954, 2920, 2853, 2830, 1618,
1600, 1590, 1518, 1463, 1450, 1428, 1382, 1354,
1335, 1263, 1227, 1208, 1174, 1145, 1120, 1088,
1035, 1016, 948, 924, 842, 803, 646, 571, 545, 504. 1H
NMR spectrum, δ, ppm: 2.38 s (3H, Me), 3.06–3.12,
3.36–3.42 m (2H, CH2Br), 3.57–3.63, 3.77–3.82 m
(2H, ArCH2CHBr), 3.90 s (3H, ОMe), 4.28–4.37 m
(1H, CHBr), 5.24 s (2H, ОСH2), 6.63 s (1Hisox), 6.80
d.d (1Harom, J 8.2, 1.9 Hz), 6.85 d (1Harom, J 1.9 Hz),
6.97 d (1Harom, J 8.2 Hz), 7.24 d (2Harom, J 8.1 Hz),
7.65 d (2Harom, J 8.1 Hz). 13С NMR spectrum, δ, ppm:
21.58 (Me), 36.14 (CH2Br), 41.57 (ArCH2CHBr),
52.55 (CHBr), 56.05 (ОMe), 63.10 (ОСH2), 98.44
(СHisox), 113.44 (1СHarom), 114.30 (1СHarom), 121.84
(1СHarom), 125.87 (2СHarom), 129.73 (2СHarom),
124.64, 130.73, 140.65, 146.73, 149.54, 161.54,
170.72 (7Сquat). Found, %: C 51.22; H 4.36; Br 31.89;
N 2.45. [M – HBr]+ 413. C21H21Br2NO3. Calculated,
%: C 50.93; H 4.27; Br 32.27; N 2.83. M 495.20.
(1Hisox), 6.71 d.d (1Harom, J 8.2, 1.8 Hz), 6.75 d (1Harom
,
J 1.8 Hz), 6.95 d (1Harom, J 8.2 Hz), 7.24 d (2Harom, J
8.1 Hz), 7.66 d (2Harom, J 8.1 Hz). 13С NMR spectrum,
δ, ppm: 21.52 (Me), 39.89 (СH2СH=СH2), 55.92
(ОMe), 63.24 (СH2), 98.44 (СHisox), 112.51 (1СHarom),
114.66 (1СHarom), 115.85 (СH2СH=СH2), 120.61
(1СHarom), 125.84 (2СHarom), 129.69 (2СHarom), 137.52
(СH2СH=СH2), 124.68, 134.29, 140.56, 145.87,
149.69, 161.73, 170.62 (7Сquat). Found, %: C 75.53; H
4.28; N 3.90. [M]+ 335. C21H21NO3. Calculated, %: C
75.20; H 6.31; N 4.18. M 335.40.
Bromination of ethers (22 and 23). General
procedure. To 20 mmol of allyl isoxazole derivative
22 or 23 in 40 mL of anhydrous CCl4 at 10°С was
added 3.4 g (21 mmol) of Br2. The solution was stirred
at 20°С till complete discoloration (10 h). The solvent
was distilled off at a reduced pressure, the residue was
purified by column chromatography on silica gel (100–
160 µm), eluent benzene, and by low temperature
crystallization from a mixture of benzene with hexane.
Isoxazole-containing azomethines (26 and 27).
General procedure. To a solution of 3 mmol of
substituted benzaldehyde 16 in 30 mL of anhydrous
methanol was added 3.1 mmol of aniline or p-
biphenylamine and 0.05 mL of glacial acetic acid. The
mixture was boiled for 6 and cooled to 5°С. The
separated precipitate was filtered off, washed with
5 mL of cold methanol, dried in a vacuum, and
recrystallized from a mixture benzene–hexane, 1 : 1.
3-{[4-(2,3-Dibromopropyl)-2-methoxyphenoxy]
methyl}-5-phenylisoxazole (24). Yield 81%, mp 74–
75°С. IR spectrum, ν, cm–1: 3130, 3061, 3043, 3025,
3000, 2963, 2921, 2852, 1614, 1592, 1575, 1515,
1463, 1452, 1428, 1418, 1379, 1334, 1289, 1262,
1248, 1226, 1210, 1167, 1143, 1086, 1071, 1034,
1015, 912, 845, 807, 764, 685, 573, 555, 499. 1H NMR
spectrum, δ, ppm: 3.07–3.12, 3.37–3.42 m (2H,
CH2Br), 3.58–3.62, 3.78–3.81 m (2H, ArCH2CHBr),
3.90 s (3H, ОMe), 4.30–4.36 m (1H, CHBr), 5.26 s (2H,
ОСH2), 6.69 s (1Hisox), 6.80 d.d (1Harom, J 8.2, 1.9 Hz),
6.85 d (1Harom, J 1.9 Hz), 6.97 d (1Harom, J 8.2 Hz),
(E)-1-(3-Methoxy-4-{[5-(4-methylphenyl)isoxa-
zol-3-yl]methoxy}phenyl)-N-phenylmethanimine
(26). Yield 77%, mp 109–110°С. IR spectrum, ν, cm–1:
3145, 3078, 3059, 3040, 3017, 2955, 2922, 2875,
2852, 1625, 1600, 1583, 1511, 1467, 1458, 1439,
1420, 1376, 1266, 1234, 1213, 1160, 1143, 1052,
1030, 921, 814, 791, 771, 694, 506. 1H NMR
spectrum, δ, ppm: 2.39 s (3H, Me), 4.00 s (3H, ОMe),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 8 2015

SYNTHESIS OF FUNCTIONAL ISOXAZOLE DERIVATIVES PROCEEDING
1127
5.33 s (2H, CH2), 6.64 s (1H, СHisox), 7.08 d (1Harom, J
8.2 Hz), 7.20 t (2Harom, J 7.5 Hz), 7.22–7.30 m
(4Harom), 7.38 t (2Harom, J 7.8 Hz), 7.64–7.68 m
(3Harom), 8.35 s (1H, СH=N). 13С NMR spectrum, δ,
ppm: 21.60 (Me), 56.21 (ОMe), 62.96 (CH2), 98.39
(СHisox), 109.68 (1СHarom), 113.25 (1СHarom), 120.99
(2СHarom), 124.35 (1СHarom), 125.85 (1СHarom), 125.95
(2СHarom), 129.26 (2СHarom), 129.80 (2СHarom), 159.78
(СH=N), 124.63, 130.78, 140.80, 150.14, 150.49,
152.28, 161.17, 171.01 (8Сquat). Found, %: C 75.46; H
5.44; N 7.09. C25H22N2O3. Calculated, %: C 75.36; H
5.57; N 7.03.
914, 825, 766, 749, 691, 679, 490. 1H NMR spectrum,
δ, ppm: 4.12 s (2H, СH2), 6.46 s (1Hisox), 7.17 t
(1Harom, J 7.4 Hz), 7.25 t (2Harom, J 7.4 Hz), 7.33–7.43
m (5Harom), 7.64–7.72 m (2Harom). 13С NMR spectrum,
δ, ppm: 29.08 (СH2), 99.26 (СHisox), 125.78 (2СHarom),
126.90 (1СHarom), 128.96 (2СHarom), 129.12 (2СHarom),
129.83 (2СHarom), 130.23 (1СHarom), 127.28, 134.78,
161.98, 170.18 (4Сquat). Found, %: C 71.98; H 4.75; N
5.20; S 12.12. [M]+ 267. C16H13NOS. Calculated, %: C
71.88; H 4.90; N 5.24; S 11.99. M 267.35.
3-[(Benzylsulfanyl)methyl]-5-phenylisoxazole
(29). Yield 90%, mp 97–98°С. IR spectrum, ν, cm–1:
3125, 3083, 3066, 3054, 3024, 3003, 2962, 2925,
2853, 2816, 1613, 1593, 1573, 1493, 1464, 1451,
1425, 1410, 1327, 1259, 1228, 1136, 1070, 1049,
1028, 946, 913, 810, 764, 734, 699, 684, 666, 562,
(E)-N-[(1,1'-Biphenyl)-4-yl]-1-(3-methoxy-4-{[5-
(4-methylphenyl)isoxazol-3-yl]methoxy}phenyl)-
methanimine (27). Yield 79%, mp 173–174°С. IR
spectrum, ν, cm–1: 3130, 3082, 3055, 3027, 2961,
2920, 2852, 1633, 1621, 1595, 1585, 1510, 1461,
1431, 1418, 1376, 1362, 1334, 1276, 1238, 1219,
1191, 1153, 1140, 1049, 1032, 1005, 968, 948, 911,
1
487, 474. H NMR spectrum, δ, ppm: 3.48 s (2H,
СH2), 3.55 s (2H, СH2), 6.34 s(1Hisox), 7.10 t (1Harom, J
7.1 Hz), 7.14–7.25 m (4Harom), 7.25–7.35 m (3Harom),
7.56–7.66 m (2Harom). 13С NMR spectrum, δ, ppm:
25.60 (SСH2), 35.65 (SСH2Ph), 99.31 (СHisox), 125.78
(2СHarom), 127.18 (1СHarom), 128.56 (2СHarom), 128.98
(2СHarom), 129.23 (2СHarom), 130.20 (1СHarom),
127.36, 137.58, 162.29, 170.13 (4Сquat). Found, %: C
72.63; H 5.32; N 5.00; S 11.46. [M]+ 281. C17H15NOS.
Calculated, %: C 72.57; H 5.37; N 4.98; S 11.39. M
281.37.
1
863, 825, 811, 769, 753, 717, 692, 619, 505. H NMR
spectrum, δ, ppm: 2.40 s (3H, Me), 4.02 s (3H, ОMe),
5.34 s (2H, CH2), 6.65 s (1H, СHisox), 7.10 d (1Harom, J
8.2 Hz), 7.26 d (2Harom, J 8 Hz), 7.27–7.32 m (3Harom),
7.35 t (1Harom, J 7.4 Hz), 7.45 t (2Harom, J 7.7 Hz),
7.60–7.65 m (4Harom), 7.67 d (2Harom, J 8.2 Hz), 7.69 d
(1Harom, J 1.8 Hz), 8.42 s (1H, СH=N). 13С NMR
spectrum, δ, ppm: 21.63 (Me), 56.24 (ОMe), 62.96
(CH2), 98.40 (СHisox), 109.67 (1СHarom), 113.24
(1СHarom), 121.51 (2СHarom), 124.44 (1СHarom), 125.97
(2СHarom), 127.04 (2СHarom), 127.31 (1СHarom), 127.97
(2СHarom), 128.93 (2СHarom), 129.82 (2СHarom), 159.58
(СH=N), 124.64, 130.81, 138.81, 140.78, 140.83,
150.15, 150.54, 151.39, 161.17, 171.04 (10Сquat).
Found, %: C 78.60; H 5.45; N 5.93. C31H26N2O3.
Calculated, %: C 78.46; H 5.52; N 5.90.
5-Phenyl-3-{[(furan-2-ylmethyl)sulfanyl]methyl}-
isoxazole (30). Yield 90%, mp 85–85.5°С. IR
spectrum, ν, cm–1: 3124, 3057, 3042, 2973, 2928,
2852, 1612, 1593, 1574, 1502, 1461, 1451, 1426,
1413, 1398, 1329, 1246, 1148, 1125, 1065, 1050,
1011, 946, 937, 913, 810, 767, 742, 710, 684, 667,
1
597, 488. H NMR spectrum, δ, ppm: 3.70 s (4H,
2СH2), 6.24–6.28 m (1Hfuran), 6.28–6.31 m (1Hfuran),
6.50 s (1Hisox), 7.33–7.37 m (1Hfuran), 7.38–7.46 m
(3Harom), 7.71–7.77 m (2Harom). 13С NMR spectrum, δ,
ppm: 25.81 (SСH2), 27.74 (SСH2Fu), 99.19 (СHisox),
108.44 (1СHfuran), 110.46 (1СHfuran), 125.73 (2СHarom),
128.94 (2СHarom), 130.19 (1СHarom), 142.32 (1СHfuran),
127.28, 150.40, 162.04, 170.16 (4Сquat). Found, %: C
66.56; H 4.80; N 5.10; S 11.93. [M]+ 271.
C15H13NO2S. Calculated, %: C 66.40; H 4.83; N 5.16;
S 11.82. M 271.33.
Reaction of chloromethylisoxazoles (3 and 4) with
thiols. General procedure. To a solution of sodium
methylate obtained by dissolving 0.21 g (9.1 mmol) of
Na in 30 mL of anhydrous methanol was added
8 mmol of thiol, the mixture was stirred for 30 min,
and then 8.3 mmol of chloromethylisoxazole 3 or 4
was added. The slurry was stirred for 2 h at 20°С,
150 mL of water was added, the precipitate was
filtered off, washed with water, and dried in a vacuum.
5-Phenyl-3-[(phenylsulfanyl)methyl]isoxazole
(28). Yield 82%, mp 61–62°С. IR spectrum, ν, cm–1:
3112, 3065, 3049, 3026, 3014, 3000, 2965, 2921,
2853, 1614, 1592, 1574, 1498, 1470, 1450, 1438,
1418, 1408, 1259, 1187, 1141, 1067, 1051, 1025, 946,
2-{[(5-Phenylisoxazole-3-yl)methyl]sulfanyl}-
ethanol (31). Yield 66%, mp 29–30°С. IR spectrum, ν,
cm–1: 3295 (ОH), 3118, 3058, 3043, 2956, 2922, 2874,
1614, 1593, 1574, 1500, 1451, 1423, 1293, 1261,
1187, 1154, 1071, 1048, 1018, 946, 918, 812, 764,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 8 2015

POTKIN et al.
1128
1
735, 691, 666, 494. H NMR spectrum, δ, ppm: 2.69 t
(2H, SСH2CH2OH, J 7.4 Hz), 2.90 br.s (1H, ОH),
3.70–3.79 m (4H, SСH2, SСH2СH2OH), 6.55 s
(1Hisox), 7.35–7.45 m (3Harom), 7.67–7.75 m (2Harom).
13С NMR spectrum, δ, ppm: 26.03 (SСH2), 34.38
(SСH2CH2OH), 60.63 (SСH2СH2OH), 99.19 (СHisox),
125.83 (2СHarom), 129.03 (2СHarom), 130.37 (1СHarom),
127.20, 162.36, 170.42 (3Сquat). Found, %: C 61.40; H
5.50; N 5.94; S 13.77. [M]+ 235. C12H13NO2S.
Calculated, %: C 61.25; H 5.57; N 5.95; S 13.63. M
235.30.
1144, 1122, 1113, 1068, 1048, 1068, 1048, 1009, 939,
912, 883, 828, 810, 798, 736, 710, 673, 596, 500. H
1
NMR spectrum, δ, ppm: 2.34 s (3H, Me), 3.65 s (2H,
СH2), 3.66 s (2H, SСH2Fu), 6.19–6.24 m (1Hfuran),
6.24–6.29 m (1Hfuran), 6.41 s (1Hisox), 7.21 d (2Harom, J
7.9 Hz), 7.32 s (1Hfuran), 7.61 d (2Harom, J 7.9 Hz). 13С
NMR spectrum, δ, ppm: 21.57 (Me), 25.95 (SСH2),
27.86 (SСH2 furan), 98.66 (СHisox), 108.56 (1СHfuran),
110.56 (1СHfuran), 125.81 (2СHarom), 129.74 (2СHarom),
142.44 (1СHfuran), 124.74, 140.59, 150.52, 162.09,
170.53 (5Сquat). Found, %: C 67.54; H 5.22; N 4.78; S
11.44. [M]+ 285. C16H15NO2S. Calculated, %: C 67.34;
H 5.30; N 4.91; S 11.23. M 285.36.
5-(p-Tolyl)-3-[(phenylsulfanyl)methyl]isoxazole
(32). Yield 82%, mp 78–79°С. IR spectrum, ν, cm–1:
3122, 3078, 3055, 3024, 2916, 2853, 1613, 1597,
1583, 1567, 1513, 1481, 1459, 1439, 1427, 1407,
1375, 1259, 1240, 1184, 1115, 1093, 1073, 1051,
1024, 1019, 997, 947, 918, 823, 793, 768, 734, 688,
502, 472. 1H NMR spectrum, δ, ppm: 2.39 s (3H, Me),
4.16 s (2H, СH2), 6.45 s (1Hisox), 7.18–7.26 m (3Harom),
7.30 t (2Harom, J 7.6 Hz), 7.36–7.43 m (2Harom), 7.62 d
(2Harom, J 8.2 Hz). 13С NMR spectrum, δ, ppm: 21.52
(Me), 29.16 (СH2), 98.69 (СHisox), 125.78 (2СHarom),
126.90 (1СHarom), 129.14 (2СHarom), 129.67 (2СHarom),
129.86 (2СHarom), 124.67, 134.92, 140.54, 161.94,
170.44 (5Сquat). Found, %: C 72.66; H 5.23; N 4.91; S
11.49. [M]+ 281. C17H15NOS. Calculated, %: C 72.57;
H 5.37; N 4.98; S 11.39. M 281.37.
2-({[5-(4-Methylphenyl)isoxazol-3-yl]methyl}-
sulfanyl)ethanol (35). Yield 83%, mp 53–54°С. IR
spectrum, ν, cm–1: 3336 (ОH), 3125, 3065, 3036, 3017,
2921, 2866, 1620, 1600, 1567, 1513, 1464, 1431,
1406, 1365, 1295, 1244, 1182, 1148, 1112, 1064,
1047, 1020, 1002, 946, 913, 802, 728, 715, 671, 631,
497. 1H NMR spectrum, δ, ppm: 2.39 s (3H, Me), 2.56
t (1H, ОH, J 7.4 Hz), 2.71 t (2H, SСH2CH2OH, J
7.4 Hz), 3.70–3.79 m (4H, SСH2, SСH2СH2OH), 6.50
s (1Hisox), 7.25 d (2Harom, J 8.1 Hz), 7.64 d (2Harom
,
J 8.1 Hz). 13С NMR spectrum, δ, ppm: 21.61
(Me), 26.07 (SСH2), 34.58 (SСH2CH2OH), 60.62
(SСH2CH2OH), 98.58 (СHisox), 125.88 (2СHarom),
129.79 (2СHarom), 124.63, 140.78, 162.33, 170.77
(4Сquat). Found, %: C 62.79; H 5.94; N 5.60; S 13.04.
[M]+ 249. C13H15NO2S. Calculated, %: C 62.63; H
6.06; N 5.62; S 12.86. M 249.33.
3-[(Benzylsulfanyl)methyl]-5-(4-methylphenyl)-
isoxazole (33). Yield 86%, mp 132–133°С. IR
spectrum, ν, cm–1: 3126, 3083, 3062, 3026, 3006,
2962, 2924, 2854, 1619, 16000, 1567, 1514, 1493,
1466, 1453, 1431, 1413, 1319, 1228, 1136, 1070,
1047, 946, 914, 797, 769, 743, 699, 678, 564, 498. H
NMR spectrum, δ, ppm: 2.41 s (3H, Me), 3.63 s (2H,
SСH2C6H5), 3.70 s (2H, SСH2), 6.46 s (1Hisox), 7.23–
Reaction of chloromethylisoxazoles (3 and 4)
with sodium methylate. General procedure. To a
solution of sodium methylate obtained by dissolving
0.11 g of Na (4.78 mmol) in 30 mL of anhydrous
methanol was added 3.3 mmol of chloromethyl-
isoxazole 3 and 4, the mixture was boiled for 8 h,
afterwards 150 mL of water was added, the reaction
product was extracted with dichloromethane, the
extract was dried with calcium chloride, and the
solvent was removed in a vacuum. Obtained
compounds 36 and 37 did not require further
purification.
1
7.29 m (3Harom), 7.30–7.38 m (4Harom), 7.67 d (2Harom
,
J 8.2 Hz). 13С NMR spectrum, δ, ppm: 21.64 (Me),
25.78 (SСH2), 35.79 (SСH2C6H5), 98.79 (СHisox),
125.88 (2СHarom), 127.30 (1СHarom), 128.70 (2СHarom),
129.36 (2СHarom), 129.79 (2СHarom), 124.84, 137.72,
140.63, 162.37, 170.53 (5Сquat). Found, %: C 73.30; H
5.69; N 4.68; S 10.95. [M]+ 295. C18H17NOS.
Calculated, %: C 73.19; H 5.80; N 4.74; S 10.85. M
295.40.
3-(Methoxymethyl)-5-phenylisoxazole (36). Yield
92%, oily substance. IR spectrum, ν, cm–1: 3129, 3063,
3042, 2989, 2930, 2895, 2823, 1614, 1593, 1574,
1502, 1464, 1452, 1427, 1365, 1260, 1193, 1182,
1158, 1109, 1074, 1049, 1024, 962, 949, 908, 807,
766, 691, 499. 1H NMR spectrum, δ, ppm: 3.36 s (3H,
Me), 4.50 s (2H, СH2), 6.51 s (1Hisox), 7.33–7.39 m
5-(4-Methylphenyl)-3-{[(furan-2-ylmethyl)sulfa-
nyl]methyl}isoxazole (34). Yield 82%, mp 115–116°С.
IR spectrum, ν, cm–1: 3126, 3063, 3030, 2965, 2925,
2856, 1618, 1600, 1567, 1513, 1504, 1466, 1454,
1431, 1416, 1400, 1383, 1317, 1256, 1247, 1213,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 8 2015

SYNTHESIS OF FUNCTIONAL ISOXAZOLE DERIVATIVES PROCEEDING
1129
(3Harom), 7.68–7.73 m (2Harom). 13С NMR spectrum, δ,
ppm: 58.33 (Me), 65.66 (СH2), 98.60 (СHisox), 125.61
(2СHarom), 128.82 (2СHarom), 130.04 (1СHarom),
127.19, 161.87, 170.01 (3Сquat). Found, %: C 69.80; H
5.97; N 7.33. [M]+ 189. C11H11NO2. Calculated, %: C
69.83; H 5.86; N 7.40. M 189.21.
802, 505. 1H NMR spectrum, δ, ppm: 2.37 s (3H, Me),
2.52 t (4H, 2CH2N, J 4.5 Hz), 3.60 s (2H, СH2), 3.71 t
(4H, 2CH2O, J 4.5 Hz), 6.49 s (1Hisox), 7.23 d (2Harom
,
J 8 Hz), 7.64 d (2Harom, J 8 Hz). 13С NMR spectrum, δ,
ppm: 21.55 (Me), 53.64 (2C, 2CH2N), 53.90 (CH2),
66.96 (2C, 2CH2O), 99.02 (СHisox), 125.79 (2СHarom),
129.73 (2СHarom), 124.83, 140.50, 161.67, 170.29
(4Сquat). Found, %: C 69.87; H 7.00; N 10.69. [M]+
258. C15H18N2O2. Calculated, %: C 69.74; H 7.02; N
10.84. M 258.32.
3-(Methoxymethyl)-5-(4-methylphenyl)isoxazole
(37). Yield 95%, oily substance. IR spectrum, ν, cm–1:
3131, 3058, 3032, 2988, 2925, 2894, 2862, 2823,
1619, 1599, 1568, 1515, 1466, 1451, 14391365, 1316,
1260, 1188, 1109, 1046, 1021, 949, 907, 822, 799,
The study was carried out under the financial
support of the Russian Foundation for Basic Research
(project no. 14-08-90012-Bel_а) and Belarus’
Republic Foundation for Basic Research, grant no.
Х14Р-003.
1
758, 716, 681, 507. H NMR spectrum, δ, ppm: 2.34 s
(3H, Me), 3.39 s (3H, OMe), 4.52 s (2H, СH2), 6.49 s
(1Hisox), 7.20 d (2Harom, J 8 Hz), 7.62 d (2Harom, J
8 Hz). 13С NMR spectrum, δ, ppm: 21.38 (Me), 58.47
(OMe), 65.83 (СH2), 98.06 (СHisox), 125.69 (2СHarom),
129.62 (2СHarom), 124.65, 140.43, 161.91, 170.38
(4Сquat). Found, %: C 70.88; H 6.41; N 6.96. [M]+ 203.
C12H13NO2. Calculated, %: C 70.92; H 6.45; N 6.89. M
203.24.
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Reaction of chloromethylisoxazoles (3 and 4)
with morpholine. General procedure. To a solution
of 3 mmol of chloromethylisoxazole 3 and 4 in 15 mL
of anhydrous methanol was added 1.05 g (12 mmol) of
morpholine, and the mixture was boiled for 12 h. Then
it was diluted with 150 mL of brine, the precipitate
was filtered off, washed with water, dried in a vacuum,
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4. Pinto, P. and Dougados, M., Acta Reumatol. Port.,
4-[(5-Phenylisoxazol-3-yl)methyl]morpholine
(38). Yield 87%, mp 90.5–91°С. IR spectrum, ν, cm–1:
3132, 3070, 3053, 2961, 2934, 2858, 2803, 2751,
1612, 1593, 1574, 1502, 1467, 1451, 1350, 1331,
1290, 1267, 1210, 1133, 1114, 1074, 1047, 1005, 947,
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1
911, 865, 820, 801, 764, 688, 615, 496. H NMR
spectrum, δ, ppm: 2.52 t (4H, 2CH2N, J 4.5 Hz), 3.61 s
(2H, СH2), 3.71 t (4H, 2CH2O, J 4.5 Hz), 6.55 s
(1Hisox), 7.37–7.50 m (3Harom), 7.71–7.82 m (2Harom).
13С NMR spectrum, δ, ppm: 53.64 (2C, 2CH2N), 53.86
(CH2), 66.94 (2C, 2CH2O), 99.63 (СHisox), 125.86
(2СHarom), 129.06 (2СHarom), 130.25 (1СHarom),
127.52, 161.70, 170.12 (3Сquat). Found, %: C 68.98; H
6.45; N 11.40. [M]+ 244. C14H16N2O2. Calculated, %:
C 68.83; H 6.60; N 11.47. M 244.29.
9. Kamal, A., Bharathi, E.V., Reddy, J.S., Ramaiah, M.J.,
Dastagiri, D., Reddy, K., Viswanath, A., Reddy, T.L.,
Shaik, T.B., Pushpavalli, S.N.C.V.L., and Bhadra, M.P.,
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Chernov, A.N., Talabaev, M.V., Demidchik, Yu.E.,
Petkevich, S.K., Kazbanov, V.V., Gurinovich, T.A.,
4-{[5-(4-Methylphenyl)isoxazol-3-yl]methyl}-
morpholine (39). Yield 97%, mp 97–98°С. IR
spectrum, ν, cm–1: 3132, 3059, 3043, 2975, 2960,
2935, 2919, 2858, 2810, 1618, 1600, 1587, 1569,
1516, 1471, 1447, 1354, 1335, 1294, 1271, 1261,
1135, 1112, 1078, 1045, 1005, 947, 910, 866, 818,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 8 2015

POTKIN et al.
1130
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