Synthesis of hydroxybenzaldehyde derivatives containing an isoxazole heteroring

Article abstract of DOI:10.1134/S1070428012010216

5-Phenyl(p-tolyl)isoxazole-3-carboxylic acids were synthesized starting from 3-hydroxyiminomethyl-5-phenyl(p-tolyl)isoxazoles, and their reactions with p-hydroxybenzaldehyde, vanillin, isovanillin, o-vanillin, and ethyl vanillin gave the corresponding esters. The latter were brought into condensation with aromatic amines to obtain Schiff bases which were reduced to amines. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S1070428012010216

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 1, pp. 127–136. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © V.I. Potkin, R.A. Gadzhily, E.A. Dikusar, S.K. Petkevich, N.A. Zhukovskaya, A.G. Aliev, Sh.F. Nagieva, 2012, published in Zhurnal
Organicheskoi Khimii, 2012, Vol. 48, No. 1, pp. 132–141.
Synthesis of Hydroxybenzaldehyde Derivatives
Containing an Isoxazole Heteroring
V. I. Potkina, R. A. Gadzhilyb, E. A. Dikusara, S. K. Petkevicha, N. A. Zhukovskayaa,
A. G. Alievb, and Sh. F. Nagievab
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 Institute of Polymeric Materials, National Academy of Sciences of Azerbaijan,
Sumgait, Azerbaijan
Received May 28, 2011
Abstract—5-Phenyl(p-tolyl)isoxazole-3-carboxylic acids were synthesized starting from 3-hydroxyimino-
methyl-5-phenyl(p-tolyl)isoxazoles, and their reactions with p-hydroxybenzaldehyde, vanillin, isovanillin,
o-vanillin, and ethyl vanillin gave the corresponding esters. The latter were brought into condensation with
aromatic amines to obtain Schiff bases which were reduced to amines.
DOI: 10.1134/S1070428012010216
Isoxazole heteroring is a structural fragment of
molecules of many compounds possessing biological
activity [1]. Vanillin and some substituted benzalde-
hydes also exhibit biological activity; in particular,
they inhibit DNA–protein kinase and control DNA
double strand break repair following NHEJ path (non-
homologous DNA end-joining) [2].
of nitriles V and VI strongly depended on the presence
of water in the reaction mixture, which led to the
formation of the corresponding carboxamides as by-
products.
The structure of compounds I, II, V, and VI was
determined on the basis of their elemental composi-
1
tions and IR, H and 13C NMR, and mass spectra. The
IR spectra of nitriles V and VI contained absorption
bands at 2254–2257 cm–1 due to stretching vibrations
of the C≡N bond, and carboxylic acids I and II dis-
played carbonyl stretching vibration band at 1707 cm–1.
The C≡N carbon atom resonated in the 13C NMR spec-
tra of V and VI at δC 110 ppm; no such signal was
present in the spectra of acids I and II, but a signal
typical of carboxy group appeared at δC 171 ppm. The
mass spectra of compounds I, II, V, and VI contained
the molecular ion peaks and peaks from fragment ions.
The goal of the present study was to synthesize
compounds containing substituted benzaldehyde and
isoxazole residues in a single molecule, which could
be promising for biological assays. Isoxazole fragment
was introduced into molecules of p-hydroxybenzalde-
hyde, vanillin, isovanillin, o-vanillin, and ethyl vanillin
with the use of 5-phenyl- and 5-(p-tolyl)isoxazole-3-
carbonyl chlorides VII and VIII which were synthe-
sized from the corresponding accessible 3-hydroxy-
iminomethyl-5-phenyl(p-tolyl)isoxazoles III and IV
according to the procedure described by us previously
[3]. 5-Arylisoxazole-3-carbaldehyde oximes III and
IV were converted into carbonitriles V and VI by the
action of acetic anhydride in pyridine. Hydrolysis of V
and VI in aqueous–alcoholic potassium hydroxide
gave carboxylic acids I and II, and the latter were
treated with thionyl chloride to obtain target acid
chlorides VII and VIII (Scheme 1). The yields of
isoxazolecarbonitriles V and VI were 91–98%, and
acids I and II were isolated in 78–88% yield. The yield
By reaction of carboxylic acid chlorides VII and
VIII with p-hydroxybenzaldehyde, vanillin, isovanil-
lin, o-vanillin, and ethyl vanillin in diethyl ether in the
presence of an equimolar amount of triethylamine we
obtained 84–93% of the corresponding esters IX–
XVIII. Esters IX–XVIII showed in the IR spectra
absorption bands belonging to stretching vibrations of
the ester and aldehyde carbonyl groups at 1748–1765
1
and 1679–1702 cm–1, respectively. In the H NMR
spectra of IX–XVIII protons in the alkoxy groups
127

POTKIN et al.
128
Scheme 1.
KOH
EtOH–H2O
CN
COOH
NOH Ac2O, C5H5N
R1
R1
R1
N
N
N
O
O
O
III, IV
V, VI
I, II
R2
HO
O
CHO
CHO
COCl
O
SOCl2
R1
R1
R2
N
N
O
O
VII, VIII
IX–XVIII
R3
O
NH2
R3
N
O
R1
R2
N
O
XIX–XXXIX
O
R3
N
H
NaBH(OAc)3
O
OMe
N
O
XL–LII
I, III, V, VII, IX–XIII, XIX–XXXI, R1 = H; II, IV, VI, VIII, XIV–XVIII, XXXII–XXXIX, R1 = 4-Me; XIX, XX, R2 = H; XXI–
XXIX, XXXII–XXXVII, R2 = MeO; XXX, XXXI, XXXVIII, XXXIX, R2 = EtO; XIX, XXI, XXIV, XXVII, XXX, XXXII,
XXXIV, XXXVI, XXXVIII, XL, XLI, R3 = 4-Ph; XXII, XXV, XXVIII, XXXIII, XXXV, XXXVII, XXXIX, XLII, R3 = 4-Br;
XX, XXIII, XXVI, XXIX, XXXI, R3 = 2-OH; IX, X, XIII, XIV, XV, XVIII, 4-CHO; XI, XVI, 5-CHO; XII, XVII, 6-CHO; XIX–
XXIII, XXX–XXXIII, XXXVIII–XXXIX, 4-CH=NC6H4R3; XXIV–XXVI, XXXIV, XXXV, 5-CH=N–C6H4R3; XXVII–XXIX,
XXXVI, XXXVII; 6-CH=N-C6H4R3; XL, 4-CH2NHC6H4R3; XLI, XLII, 5-CH2NHC6H4R3.
resonated in the region δ 3.87–4.16 ppm, aromatic
proton signals appeared at δ 7.13–8.01 ppm, and signal
from the aldehyde proton was observed in the region
δ 9.89–10.22 ppm; the latter signal was absent in the
spectra of the initial acid chlorides. In the 13C NMR
spectra of IX–XVIII, the aldehyde carbonyl carbon
signal was located in a weaker field relative to the
signal from the ester carbonyl carbon atom. The mo-
lecular ion peaks were observed in the mass spectra of
compounds IX–XVIII.
Schiff bases XIX–XXXIX were synthesized by
condensation of esters IX–XVIII with aromatic
amines (biphenyl-4-amine, p-bromoaniline, and
o-aminophenol) in boiling benzene with simultaneous
removal of the liberated water. In this case, the con-
ventional procedure for the synthesis of Schiff bases in
anhydrous methanol [5] turned out to be inapplicable,
for the reaction was accompanied by transesterification
with formation of methyl 5-phenyl- and 5-(p-tolyl)-
isoxazole-3-carboxylates. The reaction in benzene was
complete in 1.5 h, the yields were 70–77%, and the
ester group in the initial compounds remained intact.
Schiff bases XIX–XXXIX were identified by IR and
1H and 13C NMR spectroscopy, elemental analysis, and
molecular weight determination by cryoscopy.
The presence of an aldehyde group in esters of the
vanillin series provides the possibility for their trans-
formation into Schiff bases. We previously showed that
Schiff bases of the vanillin series containing an isothia-
zole fragment and their reduction products (secondary
amines) exert synergistic effects in a mixture with
a neonicotinoid insecticide (Kerber) [4]. We synthe-
sized hetero analogs of these compounds, in which the
isothiazole heteroring was replaced by isoxazole.
The IR spectra of XIX–XXXIX lacked absorption
bands typical of aldehyde carbonyl group (1679–
1702 cm–1), whereas bands assignable to azomethine
C=N bond appeared at 1620–1636 cm–1. No aldehyde
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SYNTHESIS OF HYDROXYBENZALDEHYDE DERIVATIVES
129
proton signal (δ 9.89–10.21 ppm) was observed in the
1H NMR spectra of XIX–XXXIX, and the CH=N
proton resonated as a singlet at δ 8.34–8.77 ppm,
which is typical of E configuration of the azomethine
fragment; the corresponding signal of Z isomers is
usually located in a weaker field due to deshielding by
benzene ring [6]. Aminophenol derivatives displayed
5-Arylisoxazole-3-carboxylic acids I and II (gen-
eral procedure). A solution of 1.3 g (23.17 mmol) of
potassium hydroxide in 20 ml of water was added to
a solution of 10.85 mmol of nitrile V or VI in 30 ml of
ethanol, the mixture was heated to the boiling point
and was stirred under reflux until ammonia no longer
evolved. The mixture was then poured into water and
acidified to pH 3 with hydrochloric acid, and the
precipitate was filtered off, washed with water, dried
under reduced pressure, and recrystallized from
chloroform.
1
in the H NMR spectra a broadened singlet from the
hydroxy proton in the region δ 8.85–11.98 ppm. The
number and position of signals in the 13C NMR spectra
of Schiff bases XIX–XXXIX were consistent with
the structure of carbon-containing moieties in their
molecules.
5-Phenylisoxazole-3-carboxylic acid (I). Yield
78%, mp 163–165°C. IR spectrum, ν, cm–1: 1707
(C=O); 1609, 1570, 1503 (C=C, C=N). 1H NMR spec-
trum, δ, ppm: 7.21 s (1H, 4-H), 7.53 m (3H, Harom),
7.91 m (2H, Harom), 11.79 br.s (1H, OH). 13C NMR
spectrum, δ, ppm: 100.45 (C4), 125.92 (2C, CHarom),
129.37 (2C, CHarom), 130.90 (CHarom); 126.89, 157.49,
160.31 (Ci, C3, C5); 171.54 (C=O). Found, %: C 63.73;
H 3.98; N 7.65. m/z 189 [M]+. C10H7NO3. Calculated,
%: C 63.49; H 3.73; N 7.40. M 189.17
Schiff bases XXII, XXIV, and XXV were reduced
under mild conditions with sodium triacetoxy(hy-
drido)borate Na[BH(OAc)3] (benzene, 20–23°C). The
reduction was complete in 18–20 h, and the corre-
sponding secondary amines XL–XLII were selectively
formed in 85–90%; the process was not accompanied
by side reduction of the ester group. Amines XL–XLII
1
were identified on the basis of their IR and H and
5-(4-Methylphenyl)isoxazole-3-carboxylic acid
13C NMR spectra, elemental analyses, and molecular
weights determined by cryoscopy. The presence of
an amino group in their molecules followed from IR
absorption band at 3399–3420 cm–1 and broadened
(II). Yield 88%, mp 189–191°C. IR spectrum, ν, cm–1:
1
1707 (C=O); 1612, 1593, 1492 (C=C, C=N). H NMR
spectrum, δ, ppm: 2.36 s (3H, Me), 7.12 s (1H, 4-H),
3
3
7.33 d (2H, Harom, J = 8 Hz), 7.78 d (2H, Harom, J =
8 Hz). 13C NMR spectrum, δC, ppm: 20.67 (Me), 99.82
(C4), 125.87 (2C, CHarom), 129.95 (2C, CHarom);
124.21, 141.28, 157.44, 160.42 (C1′, C4′, C3, C5),
171.71 (C=O). Found, %: C 65.25; H 4.79; N 6.97.
m/z 203 [M]+. C11H9NO3. Calculated, %: C 65.02;
H 4.46; N 6.89. M 203.19.
1
singlets at δ 4.12–4.44 ppm (NH) in the H NMR
spectra; the CH2N protons resonated as a singlet at
δ 4.25–4.35 ppm.
The newly synthesized compounds are now tested
as insecticide potentiating agents and enzyme inhibi-
tors in DNA repair processes.
5-Arylisoxazole-3-carbonitriles V and VI (gener-
al procedure). Acetic anhydride, 75 mmol, was added
to a solution of 50 mmol of 5-aryl-3-hydroxyimino-
methylisoxazole III or IV [3] in 20 ml of anhydrous
pyridine, the mixture was stirred for 7 h at 90–95°C,
poured into water, and acidified to pH 5 with hydro-
chloric acid, and the precipitate was filtered off, dried
under reduced pressure, and recrystallized from
hexane–chloroform (2:1).
EXPERIMENTAL
The IR spectra were recorded in KBr on a Nicolet
Protégé-460 spectrometer with Fourier transform. The
1H and 13C NMR spectra were measured on a Bruker
Avance-500 spectrometer from solutions in CDCl3 (V–
XVIII, XXI–XXV, XXVII–XXXIX, XLII), acetone-
d6 (I, II), or DMSO-d6 (XIX, XX, XXVI, XL, XLI);
1
the H chemical shifts were determined relative to
5-Phenylisoxazole-3-carbonitrile (V). Yield 91%,
tetramethylsilane, and the 13C chemical shifts, relative
to the corresponding solvent signals (CDCl3,
δC 77.2 ppm; acetone-d6, δC 30.2 ppm; DMSO-d6,
δC 40.1 ppm). The mass spectra were obtained on
a Hewlett–Packard 5890/5972 GC–MS system (HP-
5MS column, 30 m×0.25 mm, film thickness 0.25 μm;
injector temperature 250°C; electron impact, 70 eV).
The molecular weights of compounds XIX–XLII were
determined by cryoscopy in benzene.
mp 89–91°C. IR spectrum, ν, cm–1: 2254 (C≡N); 1609,
1
1588, 1563, 1490 (C=C, C=N). H NMR spectrum, δ,
ppm: 6.82 s (1H, 4-H), 7.53 m (3H, Harom), 7.79 m
(2H, Harom). 13C NMR spectrum, δC, ppm: 101.51 (C4),
110.10 (C≡N), 126.12 (2C, CHarom), 129.41 (2C,
CHarom), 131.71 (CHarom); 125.46, 140.10, 172.67 (Ci,
C3, C5). Found, %: C 70.33; H 3.68; N 16.57. m/z 170
[M]+. C10H6N2O. Calculated, %: C 70.58; H 3.55;
N 16.46. M 170.17.
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POTKIN et al.
130
5-(4-Methylphenyl)isoxazole-3-carbonitrile (VI).
4-Formylphenyl 5-phenylisoxazole-3-carboxylate
(IX). Yield 92%, mp 145–146°C. IR spectrum, ν, cm–1:
1749 (C=O, ester); 1697 (CH=O); 1598, 1572, 1502,
1439 (C=C, C=N); 1241, 1211, 1155, 1124 (C–O).
1H NMR spectrum, δ, ppm: 7.08 s (1H, 4-H), 7.47–
8.01 m (9H, Harom), 10.04 s (1H, CHO). 13C NMR
spectrum, δC, ppm: 100.25 (C4), 122.32 (2C, CHarom),
126.01 (2C, CHarom), 129.27 (2C, CHarom), 131.15
(CHarom), 131.37 (2C, CHarom); 126.30, 134.57, 154.52,
156.06, 157.84 (Carom, C3, C5); 172.45 (C=O), 190.80
(CHO). Found, %: C 69.93; H 3.88; N 4.27. m/z 293
[M]+. C17H11NO4. Calculated, %: C 69.62; H 3.78;
N 4.78. M 293.27.
Yield 98%, mp 98–100°C. IR spectrum, ν, cm–1: 2257
(C≡N); 1610, 1589, 1563, 1505 (C=C, C=N). 1H NMR
spectrum, δ, ppm: 2.43 s (3H, Me), 6.76 s (1H, 4-H),
3
3
7.31 d (2H, Harom, J = 8 Hz), 7.67 d (2H, Harom, J =
8 Hz). 13C NMR spectrum, δC, ppm: 21.72 (Me),
101.03 (C4), 110.31 (C≡N), 126.18 (2C, CHarom),
130.20 (2C, CHarom); 122.88, 140.12, 142.48, 172.98
(C1′, C4′, C3, C5). Found, %: C 71.89; H 4.52; N 15.47.
m/z 184 [M]+. C11H8N2O. Calculated, %: C 71.73;
H 4.38; N 15.21. M 184.19.
5-Arylisoxazole-3-carbonyl chlorides VII and
VIII (general procedure). A mixture of 14.87 mmol of
carboxylic acid I or II and 75.12 mmol of thionyl
chloride was heated for 4 h under reflux. Excess
thionyl chloride was removed under reduced pressure,
and the solid residue was recrystallized from hexane.
4-Formyl-2-methoxyphenyl 5-phenylisoxazole-3-
carboxylate (X). Yield 90%, mp 174–175°C. IR spec-
trum, ν, cm–1: 1756 (C=O, ester); 1702 (CH=O); 1601,
1572, 1501 (C=C, C=N); 1276, 1225, 1145, 1123
1
(C–O). H NMR spectrum, δ, ppm: 3.92 s (3H, MeO),
5-Phenylisoxazole-3-carbonyl chloride (VII).
Yield 98%, mp 89–91°C. IR spectrum, ν, cm–1: 1763
(C=O); 1606, 1571, 1498 (C=C, C=N). 1H NMR spec-
trum, δ, ppm: 6.96 (4-H), 7.52 m (3H, Harom), 7.81 m
(2H, Harom). 13C NMR spectrum, δC, ppm: 99.51 (C4),
126.13 (2C, CHarom), 129.44 (2C, CHarom), 131.54
(CHarom); 126.62, 159.60, 160.84 (Ci, C3, C5); 173.48
(COCl). Found, %: C 57.99; H 3.17; Cl 17.45; N 6.93.
m/z 207 [M]+. C10H6ClNO2. Calculated, %: C 57.85;
H 2.91; Cl 17.08; N 6.75. M 207.61.
7.07 (1H, 4-H), 7.39–7.86 m (8H, Harom), 9.99 s (1H,
CHO). 13C NMR spectrum, δC, ppm: 56.21 (CH3),
100.37 (C4), 111.12 (CHarom), 123.32 (CHarom), 124.62
(CHarom), 126.01 (2C, CHarom), 129.24 (2C, CHarom),
131.05 (CHarom); 126.45, 135.81, 144.02, 151.87,
155.90, 157.26 (Carom, C3, C5); 172.30 (C=O), 190.93
(CHO). Found, %: C 67.06; H 4.12; N 4.05. m/z 323
[M]+. C18H13NO5. Calculated, %: C 66.87; H 4.05;
N 4.33. M 323.30.
5-Formyl-2-methoxyphenyl 5-phenylisoxazole-
3-carboxylate (XI). Yield 93%, mp 162–163°C. IR
spectrum, ν, cm–1: 1749 (C=O, ester); 1684 (CH=O);
1610, 1582, 1572, 1510, 1444, 1433 (C=C, C=N);
5-(4-Methylphenyl)isoxazole-3-carbonyl chloride
(VIII). Yield 97%, mp 102–104°C. IR spectrum, ν,
cm–1: 1766 (C=O); 1610, 1566, 1509 (C=C, C=N).
1H NMR spectrum, δ, ppm: 2.42 s (3H, Me), 6.88
1
(4-H), 7.29 d (2H, Harom, 3J = 8 Hz), 7.67 d (2H, Harom
,
1282, 1234, 1210, 1133, 1104 (C–O). H NMR spec-
3J = 8 Hz). 13C NMR spectrum, δC, ppm: 21.68 (Me),
98.91 (C4), 126.05 (2C, CHarom), 130.10 (2C, CHarom);
123.43, 142.10, 159.53, 160.84 (C1′, C4′, C3, C5);
173.66 (C=O). Found, %: C 59.85; H 3.79; Cl 16.32;
N 6.57. m/z 221 [M]+. C11H8ClNO2. Calculated, %:
C 59.61; H 3.64; Cl 16.00; N 6.32. M 221.64.
trum, δ, ppm: 3.93 s (3H, MeO), 7.07 (1H, 4-H), 7.14–
7.85 m (8H, Harom), 9.89 s (1H, CHO). 13C NMR spec-
trum, δC, ppm: 56.37 (CH3), 100.36 (C4H), 112.32
(CHarom), 123.34 (CHarom), 125.99 (2C, CHarom), 129.23
(2C, CHarom), 130.68 (CHarom), 131.03 (CHarom);
126.45, 130.05, 139.52, 155.93, 156.12, 157.57 (Carom
,
C3, C5); 172.25 (C=O), 189.81 (CHO). Found, %:
C 67.15; H 4.27; N 3.99. m/z 323 [M]+. C18H13NO5.
Calculated, %: C 66.87; H 4.05; N 4.33. M 323.30.
5-Phenyl- and 5-(4-methylphenyl)isoxazole-3-
carboxylic acid esters IX–XVIII (general procedure).
Acid chloride VII or VIII, 10 mmol, was added in
portions under stirring to a solution of 10 mmol of the
corresponding hydroxy aldehyde (p-hydroxybenzalde-
hyde, vanillin, isovanillin, o-vanillin, or ethyl vanillin)
and 10 mmol of anhydrous triethylamine in 50 ml of
anhydrous diethyl ether. The mixture was left to stand
for 24 h at 20–23°C, and the precipitate was filtered
off, washed with diethyl ether, water (3×200 ml), and
a saturated solution of NaHCO3 (3×200 ml), and dried
in air for 2–3 days at 25–30°C.
2-Formyl-6-methoxyphenyl 5-phenylisoxazole-
3-carboxylate (XII). Yield 84%, mp 126–127°C. IR
spectrum, ν, cm–1: 1759, 1751 (C=O, ester); 1698
(CH=O); 1606, 1582, 1571, 1484, 1443 (C=C, C=N);
1
1284, 1224, 1189, 1119 (C–O). H NMR spectrum, δ,
ppm: 3.87 s (3H, MeO), 7.10 (1H, 4-H), 7.27–7.85 m
(8H, Harom), 10.21 s (1H, CHO). 13C NMR spectrum,
δC, ppm: 56.41 (CH3), 100.45 (C4), 118.09 (CHarom),
121.46 (CHarom), 126.00 (2C, CHarom), 127.54 (CHarom),
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SYNTHESIS OF HYDROXYBENZALDEHYDE DERIVATIVES
131
129.22 (2C, CHarom), 131.00 (CHarom); 126.47, 129.08,
140.39, 151.61, 155.77, 157.55 (Carom, C3, C5); 172.28
(C=O), 188.32 (CHO). Found, %: C 67.21; H 4.20;
N 3.92. m/z 323 [M]+. C18H13NO5. Calculated, %:
C 66.87; H 4.05; N 4.33. M 323.30.
134°C. IR spectrum, ν, cm–1: 1764 (C=O, ester); 1683
(CH=O); 1609, 1579, 1510, 1456, 1438 (C=C, C=N);
1
1279, 1261, 1206, 1138, 1111 (C–O). H NMR spec-
trum, δ, ppm: 2.42 s (3H, Me), 3.92 s (3H, MeO), 7.01
(1H, 4-H), 7.13–7.84 m (7H, Harom), 9.89 s (1H, CHO).
13C NMR spectrum, δC, ppm: 21.54 (CH3), 56.37
(OCH3), 99.76 (C4), 112.30 (CHarom), 123.35 (CHarom),
125.93 (2C, CHarom), 129.90 (2C, CHarom), 130.66
(CHarom); 123.76, 130.03, 139.53, 141.50, 155.86,
156.13, 157.65 (Carom, C3, C5); 172.46 (C=O), 189.82
(CHO). Found, %: C 67.99; H 4.58; N 3.70. m/z 337
[M]+. C19H15NO5. Calculated, %: C 67.65; H 4.48;
N 4.15. M 337.33.
2-Ethoxy-4-formylphenyl 5-phenylisoxazole-
3-carboxylate (XIII). Yield 89%, mp 106–107°C. IR
spectrum, ν, cm–1: 1760 (C=O, ester); 1701, 1689
(CH=O); 1600, 1578, 1505, 1435 (C=C, C=N); 1276,
1
1225, 1145, 1123 (C–O). H NMR spectrum, δ, ppm:
1.37 t (3H, Me), 4.16 q (2H, CH2O), 7.07 (1H, 4-H),
13
7.40–7.86 m (8H, Harom), 9.97 s (1H, CHO). C NMR
spectrum, δC, ppm: 14.50 (CH3), 64.83 (CH2), 100.28
(C4), 112.09 (CHarom), 123.24 (CHarom), 124.39
(CHarom), 125.99 (2C, CHarom), 129.23 (2C, CHarom),
131.03 (CHarom); 126.44, 135.74, 144.28, 151.13,
155.92, 157.24 (Carom, C3, C5); 172.24 (C=O), 190.98
(CHO). Found, %: C 68.03; H 4.55; N 3.88. m/z 337
[M]+. C19H15NO5. Calculated, %: C 67.65; H 4.48;
N 4.15. M 337.33.
2-Formyl-6-methoxyphenyl 5-(4-methylphenyl)-
isoxazole-3-carboxylate (XVII). Yield 85%, mp 159–
160°C. IR spectrum, ν, cm–1: 1765 (C=O, ester); 1697,
1679 (CH=O); 1611, 1585, 1487, 1450 (C=C, C=N);
1
1280, 1226, 1176, 1109 (C–O). H NMR spectrum, δ,
ppm: 2.42 s (3H, Me), 3.87 s (3H, MeO), 7.04 (1H,
4-H), 7.27–7.74 m (7H, Harom), 10.22 s (1H, CHO).
13C NMR spectrum, δC, ppm: 21.53 (CH3), 56.40
(OCH3), 99.84 (C4), 118.08 (CHarom), 121.34 (CHarom),
125.95 (2C, CHarom), 127.51 (CHarom), 129.89 (2C,
CHarom); 123.79, 129.10, 140.51, 141.47, 151.61,
155.69, 157.62 (Carom, C3, C5); 172.50 (C=O), 188.29
(CHO). Found, %: C 67.96; H 4.52; N 3.79. m/z 337
[M]+. C19H15NO5. Calculated, %: C 67.65; H 4.48;
N 4.15. M 337.33.
4-Formylphenyl 5-(4-methylphenyl)isoxazole-
3-carboxylate (XIV). Yield 90%, mp 188–189°C. IR
spectrum, ν, cm–1: 1750 (C=O, ester); 1701 (CH=O);
1597, 1510, 1446 (C=C, C=N); 1233, 1213, 1155,
1
1108 (C–O). H NMR spectrum, δ, ppm: 2.43 s (3H,
Me), 7.02 s (1H, 4-H), 7.31–8.00 m (8H, Harom),
10.04 s (1H, CHO). 13C NMR spectrum, δC, ppm:
21.69 (CH3), 99.78 (C4), 122.45 (2C, CHarom), 126.07
(2C, CHarom), 130.05 (2C, CHarom), 131.49 (2C, CHarom);
2-Ethoxy-4-formylphenyl 5-(4-methylphenyl)is-
oxazole-3-carboxylate (XVIII). Yield 86%, mp 134–
135°C. IR spectrum, ν, cm–1: 1748 (C=O, ester); 1701
(CH=O); 1602, 1504, 1434 (C=C, C=N); 1264, 1232,
123.74, 134.67, 141.77, 154.67, 156.11, 158.04 (Carom
,
C3, C5); 172.77 (C=O), 190.93 (CHO). Found, %:
C 70.66; H 4.49; N 4.19. m/z 307 [M]+. C18H13NO4.
Calculated, %: C 70.35; H 4.26; N 4.56. M 307.30.
1
1155, 1115 (C–O). H NMR spectrum, δ, ppm: 1.37 t
(3H, CH3CH2), 2.43 s (3H, Me), 4.16 q (2H, CH2O),
7.02 (1H, 4-H), 7.32–7.75 m (7H, Harom), 9.97 s (1H,
CHO). 13C NMR spectrum, δC, ppm: 14.51 (CH3CH2),
21.56 (CH3), 64.83 (CH2), 99.68 (C4), 112.05 (CHarom),
123.25 (CHarom), 124.43 (CHarom), 125.95 (2C, CHarom),
129.91 (2C, CHarom); 123.78, 135.73, 141.51, 144.34,
151.16, 155.86, 157.33 (Carom, C3, C5); 172.46 (C=O),
190.99 (CHO). Found, %: C 68.67; H 5.05; N 3.62.
m/z 351 [M]+. C20H17NO5. Calculated, %: C 68.37;
H 4.88; N 3.99. M 351.35.
4-Formyl-2-methoxyphenyl 5-(4-methylphenyl)-
isoxazole-3-carboxylate (XV). Yield 88%, mp 159–
160°C. IR spectrum, ν, cm–1: 1755 (C=O, ester); 1702,
1691 (CH=O); 1599, 1501, 1445, 1397 (C=C, C=N);
1
1274, 1220, 1142, 1120 (C–O). H NMR spectrum, δ,
ppm: 2.42 s (3H, Me), 3.91 s (3H, MeO), 7.01 (1H,
4-H), 7.30–7.74 m (7H, Harom), 9.98 s (1H, CHO).
13C NMR spectrum, δC, ppm: 21.54 (CH3), 56.19
(OCH3), 99.77 (C4), 111.12 (CHarom), 123.32 (CHarom),
124.60 (CHarom), 125.94 (2C, CHarom), 129.90 (2C,
CHarom); 123.75, 135.78, 141.51, 144.03, 151.86,
155.82, 157.33 (Carom, C3, C5); 172.49 (C=O), 190.94
(CHO). Found, %: C 68.01; H 4.55; N 3.79. m/z 337
[M]+. C19H15NO5. Calculated, %: C 67.65; H 4.48;
N 4.15. M 337.33.
Schiff bases XIX–XXXIX (general procedure).
A solution of 1 mmol of 5-arylisoxazole-3-carboxylate
IX–XVIII and 1 mmol of the corresponding amine
(biphenyl-4-amine, p-bromoaniline, or o-aminophenol)
in 20 ml of anhydrous benzene was heated for 1.5 h in
a flask equipped with a Dean–Stark trap. The mixture
was diluted with 30 ml of hexane and cooled to 5–
5-Formyl-2-methoxyphenyl 5-(4-methylphenyl)-
isoxazole-3-carboxylate (XVI). Yield 90%, mp 133–
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POTKIN et al.
132
10°C, and the precipitate was filtered off, washed with
hexane, and dried in air for 6–8 h at 20–23°C.
(E)-4-(4-Bromophenyliminomethyl)-2-methoxy-
phenyl 5-phenylisoxazole-3-carboxylate (XXII).
Yield 71%, mp 132–133°C. IR spectrum, ν, cm–1: 1752
(C=O, ester); 1622 (CH=N); 1610, 1598, 1504, 1479,
1464, 1449, 1419 (C=C, C=N); 1278, 1222, 1147,
(E)-4-(Biphenyl-4-yliminomethyl)phenyl 5-phen-
ylisoxazole-3-carboxylate (XIX). Yield 74%,
mp 207–208°C. IR spectrum, ν, cm–1: 1748 (C=O,
ester); 1628 (CH=N); 1598, 1571, 1503, 1448, 1438
(C=C, C=N); 1228, 1201, 1162, 1118 (C–O). 1H NMR
spectrum, δ, ppm: 7.20 (1H, 4-H), 7.40–8.11 m (14H,
1
1122, 1111, 1070, 1006, 988 (C–O). H NMR spec-
trum, δ, ppm: 3.92 s (3H, MeO), 7.07 (1H, 4-H), 7.09–
7.85 m (12H, Harom), 8.40 s (1H, CH=N). 13C NMR
spectrum, δC, ppm: 56.14 (OCH3), 100.37 (C4), 110.79
(CHarom), 122.60 (2C, CHarom), 122.89 (CHarom), 123.19
(CHarom), 125.99 (2C, CHarom), 129.21 (2C, CHarom),
130.98 (CHarom), 132.24 (2C, CHarom); 119.53, 126.48,
H
arom), 8.75 s (1H, CH=N). 13C NMR spectrum, δC,
ppm: 101.24 (C4), 125.22 (CHarom), 125.78 (2C,
CHarom), 126.37 (2C, CHarom), 127.01 (CHarom), 127.37
(2C, CHarom), 128.56 (2C, CHarom), 128.85 (2C, CHarom),
129.31 (2C, CHarom), 130.04 (2C, CHarom), 131.16 (2C,
CHarom), 140.59 (CH=N); 114.15, 121.62, 122.20,
122.62, 131.08, 134.37, 156.35, 159.40 (Carom, C3, C5);
171.40 (C=O). Found, %: C 78.69; H 4.67; N 5.92.
M 432. C29H20N2O3. Calculated, %: C 78.36; H 4.54;
N 6.30. M 444.48.
135.53, 141.80, 150.66, 151.54, 156.07, 157.55 (Carom
,
C3, C5); 159.54 (CH=N), 172.18 (C=O). Found, %:
C 60.62; H 3.76; Br 16.50; N 5.61. M 465.
C24H17BrN2O4. Calculated, %: C 60.39; H 3.59;
Br 16.74; N 5.87. M 477.31.
(E)-4-(2-Hydroxyphenyliminomethyl)-2-me-
thoxyphenyl 5-phenylisoxazole-3-carboxylate
(XXIII). Yield 75%, mp 93–94°C. IR spectrum, ν,
cm–1: 1754 (C=O, ester); 1625 (CH=N); 1599, 1585,
1485, 1467, 1440 (C=C, C=N); 1289, 1254, 1225,
(E)-4-(2-Hydroxyphenyliminomethyl)phenyl
5-phenylisoxazole-3-carboxylate (XX). Yield 75%,
mp 154–155°C. IR spectrum, ν, cm–1: 1751 (C=O,
ester); 1629 (CH=N); 1598, 1582, 1506, 1480, 1446
(C=C, C=N); 1240, 1223, 1200, 1162, 1116 (C–O).
1
1194, 1157, 1123, 1109, 1031 (C–O). H NMR spec-
trum, δ, ppm: 3.91 s (3H, MeO), 6.90–7.85 m (13H,
1H NMR spectrum, δ, ppm: 6.80–8.19 m (13H, Harom
,
Harom, 4-H), 8.64 s (1H, CH=N), 11.82 br.s (1H, OH).
4-H), 8.77 s (1H, CH=N), 9.07 s (1H, OH). 13C NMR
spectrum, δ, ppm: 101.33 (C4), 116.02 (CHarom), 119.03
(CHarom), 119.42 (CHarom), 122.10 (2C, CHarom), 125.84
(2C, CHarom), 129.32 (CHarom), 129.39 (2C, CHarom),
130.27 (2C, CHarom), 131.15 (CHarom), 158.01 (CH=N);
115.80, 134.76, 137.59, 151.26, 151.79, 156.44, 157.79
(Carom, C3, C5); 171.44 (C=O). Found, %: C 72.20;
H 4.35; N 6.84. M 367. C23H16N2O4. Calculated, %:
C 71.87; H 4.20; N 7.29. M 384.38.
13C NMR spectrum, δC, ppm: 56.13 (OCH3), 100.39
(C4), 111.01 (CHarom), 115.19 (CHarom), 116.22 (CHarom),
120.23 (CHarom), 122.88 (CHarom), 123.00 (CHarom),
125.99 (2C, CHarom), 128.33 (CHarom), 129.22 (2C,
CHarom), 131.00 (CHarom); 126.47, 135.39, 135.48,
141.81, 151.52, 152.20, 156.06, 157.56 (Carom, C3, C5);
156.41 (CH=N), 172.21 (C=O). Found, %: C 69.88;
H 4.50; N 6.54. M 406. C24H18N2O5. Calculated, %:
C 69.56; H 4.38; N 6.76. M 414.41.
(E)-4-(Biphenyl-4-yliminomethyl)-2-methoxy-
phenyl 5-phenylisoxazole-3-carboxylate (XXI).
Yield 74%, mp 124–125°C. IR spectrum, ν, cm–1: 1750
(C=O, ester); 1626 (CH=N); 1588, 1505, 1484, 1448,
1417 (C=C, C=N); 1277, 1223, 1197, 1150, 1122,
(E)-5-(Biphenyl-4-yliminomethyl)-2-methoxy-
phenyl 5-phenylisoxazole-3-carboxylate (XXIV).
Yield 71%, mp 157–158°C. IR spectrum, ν, cm–1: 1749
(C=O, ester); 1629 (CH=N); 1610, 1593, 1573, 1513,
1485, 1448 (C=C, C=N); 1278, 1225, 1207, 1134
1
1
1031 (C–O). H NMR spectrum, δ, ppm: 3.96 s (3H,
(C–O). H NMR spectrum, δ, ppm: 3.90 s (3H, MeO),
MeO), 7.09 (1H, 4-H), 7.26–7.87 m (17H, Harom),
8.51 s (1H, CH=N). 13C NMR spectrum, δC, ppm:
56.19 (OCH3), 100.40 (C4), 110.79 (CHarom), 121.39
(2C, CHarom), 122.86 (CHarom), 123.13 (CHarom), 126.02
(2C, CHarom), 126.95 (2C, CHarom), 127.27 (CHarom),
127.92 (2C, CHarom), 128.82 (2C, CHarom), 129.33 (2C,
CHarom), 130.98 (CHarom); 135.87, 139.14, 140.58,
7.07 (1H, 4-H), 7.10–7.88 m (17H, Harom), 8.44 s (1H,
CH=N). 13C NMR spectrum, δC, ppm: 56.16 (OCH3),
100.36 (C4), 121.38 (2C, CHarom), 112.28 (CHarom),
122.49 (CHarom), 125.99 (2C, CHarom), 126.91 (2C,
CHarom), 127.85 (2C, CHarom), 128.33 (CHarom), 128.79
(2C, CHarom), 129.01 (CHarom), 129.20 (2C, CHarom),
130.94 (CHarom); 123.38, 129.75, 138.82, 139.41,
140.61, 150.97, 153.59, 156.11, 157.73 (Carom, C3, C5);
158.21 (CH=N), 172.12 (C=O). Found, %: C 76.20;
H 4.83; N 5.58. M 467. C30H22N2O4. Calculated, %:
C 75.94; H 4.67; N 5.90. M 474.51.
141.67, 150.85, 151.55, 156.13, 157.61, 159.82 (Carom
,
C3, C5); 158.99 (CH=N), 172.18 (C=O). Found, %:
C 76.28; H 4.79; N 5.66. M 462. C30H22N2O4. Calcu-
lated, %: C 75.94; H 4.67; N 5.90. M 474.51.
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SYNTHESIS OF HYDROXYBENZALDEHYDE DERIVATIVES
133
(E)-2-(4-Bromophenyliminomethyl)-6-methoxy-
phenyl 5-phenylisoxazole-3-carboxylate (XXVIII).
Yield 74%, mp 120–121°C. IR spectrum, ν, cm–1: 1764
(C=O, ester); 1635 (CH=N); 1608, 1575, 1480, 1447,
1433 (C=C, C=N); 1280, 1217, 1171, 1113, 1068
(E)-5-(4-Bromophenyliminomethyl)-2-methoxy-
phenyl 5-phenylisoxazole-3-carboxylate (XXV).
Yield 72%, mp 134–135°C. IR spectrum, ν, cm–1: 1749
(C=O, ester); 1629 (CH=N); 1610, 1571, 1512, 1481,
1442 (C=C, C=N); 1278, 1232, 1197, 1132, 1019
1
1
(C–O). H NMR spectrum, δ, ppm: 3.87 s (3H, MeO),
(C–O). H NMR spectrum, δ, ppm: 3.89 s (3H, MeO),
7.00–7.84 m (13H, Harom, 4-H), 8.59 s (1H, CH=N).
13C NMR spectrum, δC, ppm: 56.24 (OCH3), 100.43
(C4), 115.06 (CHarom), 120.10 (CHarom), 122.59 (2C,
CHarom), 125.97 (2C, CHarom), 127.30 (CHarom), 129.20
(2C, CHarom), 130.99 (CHarom), 132.15 (2C, CHarom);
119.73, 126.44, 129.07, 132.48, 150.70, 151.35,
155.92, 157.67 (Carom, C3, C5); 155.07 (CH=N), 172.21
(C=O). Found, %: C 60.76; H 3.72; Br 16.20; N 5.44.
M 466. C24H17BrN2O4. Calculated, %: C 60.39;
H 3.59; Br 16.74; N 5.87. M 477.31.
7.06–7.85 m (13H, Harom, 4-H), 8.34 s (1H, CH=N).
13C NMR spectrum, δC, ppm: 56.17 (OCH3), 100.34
(C4), 112.28 (CHarom), 122.60 (2C, CHarom), 123.35
(CHarom), 125.98 (2C, CHarom), 128.32 (CHarom), 129.21
(2C, CHarom), 130.96 (CHarom), 132.17 (2C, CHarom);
119.19, 126.48, 129.41, 139.41, 150.78, 153.76,
156.06, 157.71 (Carom, C3, C5); 158.76 (CH=N), 172.14
(C=O). Found, %: C 60.81; H 3.70; Br 16.35; N 5.52.
M 468. C24H17BrN2O4. Calculated, %: C 60.39;
H 3.59; Br 16.74; N 5.87. M 477.31.
(E)-2-(2-Hydroxyphenyliminomethyl)-6-me-
thoxyphenyl 5-phenylisoxazole-3-carboxylate
(XXIX). Yield 77%, mp 110–111°C. IR spectrum, ν,
cm–1: 1748 (C=O, ester); 1626 (CH=N); 1610, 1575,
1488, 1478, 1448, 1439 (C=C, C=N); 1278, 1226,
(E)-5-(2-Hydroxyphenyliminomethyl)-2-me-
thoxyphenyl 5-phenylisoxazole-3-carboxylate
(XXVI). Yield 76%, mp 153–154°C. IR spectrum, ν,
cm–1: 1770 (C=O, ester); 1626 (CH=N); 1610, 1597,
1573, 1513, 1483, 1450 (C=C, C=N); 1279, 1248,
1
1
1170, 1120, 1067 (C–O). H NMR spectrum, δ, ppm:
1207, 1137, 1112 (C–O). H NMR spectrum, δ, ppm:
3.89 s (3H, MeO), 6.70–7.87 m (13H, Harom, 4-H),
8.71 s (1H, CH=N), 8.85 s (1H, OH). 13C NMR spec-
trum, δC, ppm: 56.30 (OCH3), 100.48 (C4), 115.09
(CHarom), 115.20 (CHarom), 116.09 (CHarom), 120.21
(CHarom), 125.94 (CHarom), 126.06 (2C, CHarom), 127.33
(CHarom), 129.15 (CHarom), 129.22 (2C, CHarom), 131.03
(CHarom); 121.39, 111.79, 116.72, 119.34, 126.50,
130.76, 151.48, 157.74 (Carom, C3, C5); 151.87 (CH=N),
172.38 (C=O). Found, %: C 69.97; H 4.65; N 6.50.
M 404. C24H18N2O5. Calculated, %: C 69.56; H 4.38;
N 6.76. M 414.41.
3.91 s (3H, MeO), 6.90–7.85 m (13H, Harom, 4-H),
8.64 s (1H, CH=N), 11.82 br.s (1H, OH). 13C NMR
spectrum, δC, ppm: 56.91 (OCH3), 101.88 (C4), 113.43
(CHarom), 116.55 (CHarom), 119.17 (CHarom), 120.03
(CHarom), 122.61 (CHarom), 126.47 (CHarom), 126.55
(2C, CHarom), 129.96 (CHarom), 130.00 (2C, CHarom),
131.83 (CHarom); 125.73, 130.48, 137.92, 139.32,
152.12, 153.61, 156.68, 158.02 (Carom, C3, C5); 157.78
(CH=N), 172.37 (C=O). Found, %: C 69.92; H 4.54;
N 6.38. M 402. C24H18N2O5. Calculated, %: C 69.56;
H 4.38; N 6.76. M 414.41.
(E)-4-(Biphenyl-4-yliminomethyl)-2-ethoxy-
phenyl 5-phenylisoxazole-3-carboxylate (XXX).
Yield 71%, mp 126–127°C. IR spectrum, ν, cm–1: 1752
(C=O, ester); 1627 (CH=N); 1599, 1587, 1504, 1482,
1436, 1430, 1392 (C=C, C=N); 1276, 1223, 1195,
(E)-2-(Biphenyl-4-yliminomethyl)-6-methoxy-
phenyl 5-phenylisoxazole-3-carboxylate (XXVII).
Yield 72%, mp 133–134°C. IR spectrum, ν, cm–1: 1747
(C=O, ester); 1634 (CH=N); 1610, 1573, 1480, 1445,
1438 (C=C, C=N); 1278, 1229, 1171, 1124, 1066
1
1156, 1123, 1041 (C–O). H NMR spectrum, δ, ppm:
1
(C–O). H NMR spectrum, δ, ppm: 3.89 s (3H, MeO),
1.38 t (3H, Me), 4.20 q (2H, CH2O), 7.07 (1H, 4-H),
7.30–7.86 m (17H, Harom), 8.48 s (1H, CH=N).
13C NMR spectrum, δC, ppm: 14.64 (CH3), 64.73
(OCH2), 100.31 (C4), 121.40 (2C, CHarom), 122.78
(CHarom), 122.95 (CHarom), 126.00 (2C, CHarom), 126.94
(2CHarom), 127.26 (CHarom), 127.90 (2CHarom), 128.34
(CHarom), 128.82 (2CHarom), 129.21 (2C, CHarom),
130.96 (CHarom); 126.55, 135.77, 139.08, 140.58,
141.97, 150.85, 150.90, 156.15, 157.59 (Carom, C3, C5);
159.05 (CH=N), 172.13 (C=O). Found, %: C 76.67;
H 5.14; N 5.30. M 476. C31H24N2O4. Calculated, %:
C 76.21; H 4.95; N 5.73. M 488.53.
7.09 (1H, 4-H), 7.14–7.86 m (17H, Harom), 8.69 s (1H,
CH=N). 13C NMR spectrum, δC, ppm: 56.28 (OCH3),
100.49 (C4), 114.86 (CHarom), 120.11 (CHarom), 121.41
(2C, CHarom), 126.01 (2C, CHarom), 126.93 (2C, CHarom),
127.22 (CHarom), 127.27 (CHarom), 127.84 (2C, CHarom),
128.76 (2C, CHarom), 129.21 (2C, CHarom), 130.96
(CHarom); 126.53, 129.41, 139.28, 139.44, 140.54,
150.94, 151.36, 156.00, 157.71 (Carom, C3, C5); 154.45
(CH=N), 172.19 (C=O). Found, %: C 76.28; H 4.79;
N 5.48. M 465. C30H22N2O4. Calculated, %: C 75.94;
H 4.67; N 5.90. M 474.51.
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POTKIN et al.
134
(E)-2-Ethoxy-4-(2-hydroxyphenyliminomethyl)-
(E)-5-(Biphenyl-4-yliminomethyl)-2-methoxy-
phenyl 5-(4-methylphenyl)isoxazole-3-carboxylate
(XXXIV). Yield 72%, mp 182–183°C. IR spectrum, ν,
cm–1: 1772 (C=O, ester); 1627 (CH=N); 1612, 1595,
1575, 1504, 1483, 1454, 1432 (C=C, C=N); 1271,
phenyl 5-phenylisoxazole-3-carboxylate (XXXI).
Yield 74%, mp 139–140°C. IR spectrum, ν, cm–1: 1761
(C=O, ester); 1626 (CH=N); 1604, 1590, 1509, 1456,
1446, 1431, 1384 (C=C, C=N); 1281, 1214, 1183,
1
1
1139, 1118 (C–O). H NMR spectrum, δ, ppm: 1.39 t
1201, 1137, 1107 (C–O). H NMR spectrum, δ, ppm:
(3H, Me), 4.19 q (2H, CH2O), 6.90–7.87 m (13H,
2.41 s (3H, Me), 3.90 s (3H, MeO), 7.08 (1H, 4-H),
7.10–7.87 m (16H, Harom), 8.44 s (1H, CH=N).
13C NMR spectrum, δC, ppm: 21.55 (CH3), 56.16
(OCH3), 99.77 (C4), 112.27 (CHarom), 115.36 (CHarom),
121.37 (2C, CHarom), 125.93 (2C, CHarom), 127.17
(CHarom), 127.85 (2C, CHarom), 128.64 (2C, CHarom),
128.97 (CHarom), 129.87 (2C, CHarom); 123.84, 129.75,
138.81, 139.43, 140.62, 141.39, 150.98, 153.61,
156.05, 157.82 (Carom, C3, C5); 158.22 (CH=N), 172.33
(C=O). Found, %: C 76.57; H 5.10; N 5.28. M 474.
C31H24N2O4. Calculated, %: C 76.21; H 4.95; N 5.73.
M 488.53.
H
arom, 4-H), 8.65 s (1H, CH=N), 11.98 br.s (1H, OH).
13C NMR spectrum, δC, ppm: 14.63 (CH3), 64.80
(OCH2), 100.30 (C4), 112.01 (CHarom), 115.14 (CHarom),
116.08 (CHarom), 120.23 (CHarom), 122.79 (CHarom),
122.96 (CHarom), 126.02 (2C, CHarom), 129.12 (CHarom),
129.23 (2C, CHarom), 131.00 (CHarom); 126.53, 135.32,
135.45, 142.18, 150.88, 152.23, 156.09, 157.56 (Carom
,
C3, C5); 156.38 (CH=N), 172.18 (C=O). Found, %:
C 70.41; H 5.01; N 6.22. M 417. C25H20N2O5. Calcu-
lated, %: C 70.08; H 4.71; N 6.54. M 428.44.
(E)-4-(Biphenyl-4-yliminomethyl)-2-methoxy-
phenyl 5-(4-methylphenyl)isoxazole-3-carboxylate
(XXXII). Yield 73%, mp 158–159°C. IR spectrum, ν,
cm–1: 1748 (C=O, ester); 1627 (CH=N); 1596, 1507,
1483, 1447, 1417 (C=C, C=N); 1277, 1227, 1197,
(E)-5-(4-Bromophenyliminomethyl)-2-methoxy-
phenyl 5-(4-methylphenyl)isoxazole-3-carboxylate
(XXXV). Yield 76%, mp 137–138°C. IR spectrum, ν,
cm–1: 1770 (C=O, ester); 1636 (CH=N); 1609, 1572,
1507, 1482, 1453, 1428 (C=C, C=N); 1278, 1223,
1
1151, 1119, 1034 (C–O). H NMR spectrum, δ, ppm:
2.41 s (3H, Me), 3.93 s (3H, MeO), 7.01 (1H, 4-H),
7.30–7.75 m (16H, Harom), 8.48 s (1H, CH=N).
13C NMR spectrum, δC, ppm: 21.53 (CH3), 56.14
(OCH3), 99.79 (C4), 110.81 (CHarom), 121.40 (2C,
CHarom), 122.85 (CHarom), 123.09 (CHarom), 125.93 (2C,
CHarom), 126.92 (2C, CHarom), 127.25 (CHarom), 127.88
(2C, CHarom), 128.81 (2C, CHarom), 129.87 (2C,
CHarom); 123.85, 135.83, 139.10, 140.55, 141.40,
141.69, 150.84, 151.55, 156.06, 157.66 (Carom, C3, C5);
158.95 (CH=N), 172.35 (C=O). Found, %: C 76.52;
H 5.17; N 5.51. M 469. C31H24N2O4. Calculated, %:
C 76.21; H 4.95; N 5.73. M 488.53.
1
1200, 1138, 1107 (C–O). H NMR spectrum, δ, ppm:
2.42 s (3H, Me), 3.90 s (3H, MeO), 7.00–7.84 m (12H,
H
arom, 4-H), 8.34 s (1H, CH=N). 13C NMR spectrum,
δC, ppm: 21.54 (CH3), 56.14 (OCH3), 99.78 (C4),
110.81 (CHarom), 122.60 (2C, CHarom), 122.91 (CHarom),
123.18 (CHarom), 125.93 (2C, CHarom), 129.88 (2C,
CHarom), 132.24 (2C, CHarom); 119.52, 123.83, 135.51,
141.43, 141.87, 150.69, 151.57, 156.02, 157.62 (Carom
,
C3, C5); 159.54 (CH=N), 172.38 (C=O). Found, %:
C 61.45; H 4.08; Br 15.93; N 5.56. M 484.
C25H19BrN2O4. Calculated, %: C 61.11; H 3.90;
Br 16.26; N 5.70. M 491.33.
(E)-4-(4-Bromophenyliminomethyl)-2-methoxy-
phenyl 5-(4-methylphenyl)isoxazole-3-carboxylate
(XXXIII). Yield 76%, mp 167–168°C. IR spectrum, ν,
cm–1: 1746 (C=O, ester); 1623 (CH=N); 1597, 1507,
1476, 1465, 1448, 1416, 1377 (C=C, C=N); 1277,
1228, 1196, 1151, 1126, 1116, 1102, 1033, 991 (C–O).
1H NMR spectrum, δ, ppm: 2.42 s (3H, Me), 3.92 s
(3H, MeO), 7.01–7.73 m (12H, Harom, 4-H), 8.39 s
(1H, CH=N). 13C NMR spectrum, δC, ppm: 21.56
(CH3), 56.17 (OCH3), 99.75 (C4), 112.28 (CHarom),
122.53 (CHarom), 122.59 (2C, CHarom), 125.92 (2C,
CHarom), 129.11 (CHarom), 129.88 (2C, CHarom), 132.17
(2C, CHarom); 119.19, 123.81, 129.42, 139.43, 141.42,
150.82, 153.78, 156.00, 157.80 (Carom, C3, C5); 158.77
(CH=N), 172.36 (C=O). Found, %: C 61.37; H 3.82;
Br 15.90; N 5.44. M 480. C25H19BrN2O4. Calculated,
%: C 61.11; H 3.90; Br 16.26; N 5.70. M 491.33.
(E)-2-(Biphenyl-4-yliminomethyl)-6-methoxy-
phenyl 5-(4-methylphenyl)isoxazole-3-carboxylate
(XXXVI). Yield 77%, mp 178–179°C. IR spectrum, ν,
cm–1: 1780 (C=O, ester); 1620 (CH=N); 1610, 1599,
1578, 1520, 1481, 1450, 1437 (C=C, C=N); 1284,
1
1218, 1202, 1166, 1130, 1114, 1072 (C–O). H NMR
spectrum, δ, ppm: 2.41 s (3H, Me), 3.87 s (3H, MeO),
7.03 (1H, 4-H), 7.13–7.80 m (16H, Harom), 8.69 s (1H,
CH=N). 13C NMR spectrum, δC, ppm: 21.54 (CH3),
56.24 (OCH3), 99.88 (C4), 114.84 (CHarom), 120.04
(CHarom), 121.42 (2C, CHarom), 125.93 (2C, CHarom),
126.91 (2C, CHarom), 127.21 (CHarom), 127.24 (CHarom),
127.82 (2C, CHarom), 128.75 (2C, CHarom), 129.87 (2C,
CHarom); 123.82, 129.40, 139.25, 139.46, 140.52,
141.40, 150.92, 151.35, 155.92, 157.77 (Carom, C3, C5);
154.43 (CH=N), 172.38 (C=O). Found, %: C 76.54;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 1 2012

SYNTHESIS OF HYDROXYBENZALDEHYDE DERIVATIVES
135
H 5.11; N 5.48. M 478. C31H24N2O4. Calculated, %:
C 76.21; H 4.95; N 5.73. M 488.53.
135.40, 141.42, 142.14, 150.73, 150.88, 156.03,
157.62 (Carom, C3, C5); 159.65 (CH=N), 172.34 (C=O).
Found, %: C 62.11; H 4.18; Br 15.54; N 5.36. M 488.
C26H21BrN2O4. Calculated, %: C 61.79; H 4.19;
Br 15.81; N 5.54. M 505.36.
(E)-2-(4-Bromophenyliminomethyl)-6-methoxy-
phenyl 5-(4-methylphenyl)isoxazole-3-carboxylate
(XXXVII). Yield 75%, mp 174–175°C. IR spectrum,
ν, cm–1: 1764 (C=O, ester); 1622 (CH=N); 1608, 1576,
1481, 1448, 1432 (C=C, C=N); 1282, 1219, 1172,
Reduction of Schiff bases XXII, XXIV, and XXV
(general procedure). A solution of 5 mmol of Schiff
base XXII, XXIV, or XXV, 10 mmol of sodium
tetrahydridoborate, and 30 mmol of glacial acetic acid
in 50 ml of anhydrous benzene was stirred for 18–20 h.
The mixture was washed with water and a 5% solution
of NaHCO3, the solvent was removed under reduced
pressure, and the residue was purified by recrystalliza-
tion from benzene–hexane.
1
1105, 1068 (C–O). H NMR spectrum, δ, ppm: 2.41 s
(3H, Me), 3.87 s (3H, MeO), 7.00–7.75 m (12H, Harom
,
4-H), 8.59 s (1H, CH=N). 13C NMR spectrum, δC,
ppm: 21.55 (CH3), 56.24 (OCH3), 99.83 (C4), 115.06
(CHarom), 120.04 (CHarom), 122.60 (2C, CHarom), 125.92
(2C, CHarom), 127.27 (CHarom), 129.88 (2C, CHarom),
132.15 (2C, CHarom); 119.72, 123.76, 129.10, 139.48,
141.45, 150.72, 151.36, 155.85, 157.74 (Carom, C3, C5);
155.06 (CH=N), 172.42 (C=O). Found, %: C 61.49;
H 4.14; Br 15.88; N 5.31. M 479. C25H19BrN2O4.
Calculated, %: C 61.11; H 3.90; Br 16.26; N 5.70.
M 491.33.
4-(Biphenyl-4-ylaminomethyl)-2-methoxyphenyl
5-phenylisoxazole-3-carboxylate (XL). Yield 85%,
mp 133–134°C. IR spectrum, ν, cm–1: 3399 (NH);
1753 (C=O, ester); 1610, 1595, 1530, 1508, 1489,
1459, 1446, 1418 (C=C, C=N); 1272, 1221, 1189,
1
1149, 1123, 1032, 987 (C–O). H NMR spectrum, δ,
(E)-4-(Biphenyl-4-yliminomethyl)-2-ethoxy-
phenyl 5-(4-methylphenyl)isoxazole-3-carboxylate
(XXXVIII). Yield 70%, mp 188–189°C. IR spectrum,
ν, cm–1: 1748 (C=O, ester); 1624 (CH=N); 1595, 1508,
1483, 1446, 1431 (C=C, C=N); 1276, 1228, 1188,
1157, 1118, 1040 (C–O). 1H NMR spectrum, δ, ppm:
1.38 t (3H, CH3CH2), 2.43 s (3H, Me), 4.20 q (2H,
CH2O), 7.02 (1H, 4-H), 7.30–7.75 m (16H, Harom),
8.48 s (1H, CH=N). 13C NMR spectrum, δC, ppm:
14.64 (CH3CH2), 21.56 (CH3), 64.72 (OCH2), 99.72
(C4), 111.82 (CHarom), 121.39 (2C, CHarom), 122.79
(CHarom), 122.95 (CHarom), 125.94 (2C, CHarom), 126.94
(2C, CHarom), 127.89 (2C, CHarom), 128.81 (2C, CHarom),
129.88 (2C, CHarom), 127.25 (CHarom); 123.86, 135.74,
139.07, 140.58, 141.41, 141.98, 150.86, 150.90,
156.08, 157.67 (Carom, C3, C5); 159.07 (CH=N), 172.33
(C=O). Found, %: C 76.82; H 5.34; N 5.32. M 489.
C32H26N2O4. Calculated, %: C 76.48; H 5.21; N 5.57.
M 502.56.
ppm: 3.80 s (3H, MeO), 4.35 s (2H, CH2N), 4.42 br.s
(1H, NH), 7.03 (1H, 4-H), 7.19–8.01 m (17H, Harom).
13C NMR spectrum, δC, ppm: 46.86 (CH2N), 56.45
(OCH3), 101.86 (C4), 112.44 (CHarom), 113.33 (2C,
CHarom), 119.79 (CHarom), 122.99 (CHarom), 126.02 (2C,
CHarom), 126.33 (CHarom), 126.53 (2C, CHarom), 128.32
(2C, CHarom), 129.31 (2C, CHarom), 129.99 (2C, CHarom),
131.79 (CHarom); 128.32, 131.57, 137.65, 140.86,
141.15, 148.80, 151.02, 156.71, 158.09 (Carom, C3, C5);
172.24 (C=O). Found, %: C 76.03; H 5.25; N 5.39.
M 467. C30H24N2O4. Calculated, %: C 75.61; H 5.08;
N 5.88. M 476.52.
5-(Biphenyl-4-ylaminomethyl)-2-methoxyphenyl
5-phenylisoxazole-3-carboxylate (XLI). Yield 88%,
mp 118–119°C. IR spectrum, ν, cm–1: 3420 (NH);
1762 (C=O, ester); 1611, 1595, 1526, 1512, 1490,
1447 (C=C, C=N); 1269, 1210, 1138, 1114 (C–O).
1H NMR spectrum, δ, ppm: 3.78 s (3H, MeO), 4.31 s
(2H, CH2N), 4.44 br.s (1H, NH), 7.20 (1H, 4-H), 7.34–
8.01 m (17H, Harom). 13C NMR spectrum, δC, ppm:
46.01 (CH2N), 55.56 (OCH3), 101.85 (C4), 113.32 (2C,
CHarom), 126.00 (2C, CHarom), 126.32 (CHarom), 126.52
(2C, CHarom), 126.99 (CHarom), 127.56 (CHarom), 127.77
(2C, CHarom), 129.31 (2C, CHarom), 129.53 (CHarom),
129.99 (2C, CHarom), 131.79 (CHarom); 128.25, 131.57,
133.67, 138.88, 141.14, 148.68, 149.85, 156.68, 157.94
(Carom, C3, C5); 172.24 (C=O). Found, %: C 75.86;
H 5.19; N 5.47. M 467. C30H24N2O4. Calculated, %:
C 75.61; H 5.08; N 5.88. M 476.52.
(E)-4-(4-Bromophenyliminomethyl)-2-ethoxy-
phenyl 5-(4-methylphenyl)isoxazole-3-carboxylate
(XXXIX). Yield 74%, mp 174–175°C. IR spectrum, ν,
cm–1: 1749 (C=O, ester); 1630 (CH=N); 1594, 1507,
1482, 1444, 1429 (C=C, C=N); 1275, 1227, 1158,
1
1120, 1103, 1043 (C–O). H NMR spectrum, δ, ppm:
1.37 t (3H, CH3CH2), 2.43 s (3H, Me), 4.20 q (2H,
CH2O), 7.02 (1H, 4-H), 7.09–7.75 m (11H, Harom),
8.39 s (1H, CH=N). 13C NMR spectrum, δC, ppm:
14.62 (CH3CH2), 21.56 (CH3), 64.71 (OCH2), 99.69
(C4), 111.80 (CHarom), 122.59 (2C, CHarom), 122.83
(CHarom), 123.04 (CHarom), 125.93 (2C, CHarom), 129.88
(2C, CHarom), 132.23 (2C, CHarom); 119.47, 123.83,
5-(4-Bromophenylaminomethyl)-2-methoxy-
phenyl 5-phenylisoxazole-3-carboxylate (XLII).
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POTKIN et al.
136
Yield 86%, mp 153–154°C. IR spectrum, ν, cm–1: 3404
(NH); 1759 (C=O, ester); 1608, 1594, 1511, 1483,
1448 (C=C, C=N); 1269, 1220, 1209, 1140, 1140,
vol. 37, p. 635; Li, W.-T., Hwang, D.R., Chen, Ch.-P.,
Shen, Ch.-W., Huang, C.-L., Chen, T.-W., Lin, C.-H.,
Chang, Y.-L., Chang, Y.-Y., Chang, Y.-K., Lo, Y.-K.,
Tseng, H.-Y., Lin, C.-C., Song, J.-S., Chen, S.-J.,
Wu, S.-H., and Chen, C.-T., J. Med. Chem., 2003, vol. 46,
p. 1706; Dallanoce, C., Frigerio, F., De Amici, M.,
Dorsch, S., Klotz, K.N., and De Micheli, C., Bioorg.
Med. Chem., 2007, vol. 15, p. 2533.
1
1069, 1027 (C–O). H NMR spectrum, δ, ppm: 3.82 s
(3H, MeO), 4.12 br.s (NH), 4.25 s (CH2N), 6.47–
7.84 m (13H, Harom, 4-H). 13C NMR spectrum, δC,
ppm: 47.29 (CH2N), 56.04 (OCH3), 100.36 (C4),
114.43 (2C, CHarom), 121.64 (CHarom), 125.97 (2C,
CHarom), 126.31 (CHarom), 128.33 (CHarom), 129.19 (2C,
CHarom), 130.92 (CHarom), 131.94 (2C, CHarom); 126.52,
131.68, 132.16, 139.10, 146.86, 150.16, 156.20, 157.86
(Carom, C3, C5); 172.06 (C=O). Found, %: C 60.28;
H 4.18; Br 16.22; N 5.43. M 470. C24H19BrN2O4.
Calculated, %: C 60.14; H 4.00; Br 16.67; N 5.84.
M 479.32.
2. Durant, S. and Karran, P., Nucl. Acids Res., 2003, vol. 31,
p. 5501.
3. Petkevich, S.K., Potkin, V.I., and Kaberdin, R.V., Russ. J.
Org. Chem., 2004, vol. 40, p. 1146.
4. Potkin, V., Zubenko, Y., Bykhovetz, A., Zolotar, R., and
Goncharuk, V., Nat. Prod. Commun., 2009, vol. 4,
p. 1205.
5. Dikusar, E.A., Kozlov, N.G., Potkin, V.I., Yuvchen-
ko, A.P., and Tlegenov, R.T., Zameshchennye benzalde-
This study was performed under financial support
by the Belarussian Republican Foundation for Basic
Research and by the National Academy of Sciences of
Azerbaijan (project no. Kh10Az-001).
gidy vanilinovogo ryada
v organicheskom sinteze:
poluchenie, primenenie, biologicheskaya aktivnost’ (Sub-
stituted Benzaldehydes of the Vanillin Series in Organic
Synthesis: Preparation, Application, and Biological
Activity), Minsk: Pravo i Ekonomika, 2011.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 1 2012