Synthesis of functionally substituted isoxazole and isothiazole derivatives

Article abstract of DOI:10.1134/S1070428013100205

Acylation of benzene and toluene with 5-phenyl- and 5-(p-tolyl)isoxazole-3- carbonyl chlorides gave 5-phenyl(or p-tolyl)isoxazol-3-yl phenyl(or p-tolyl)ketones which were reduced to the corresponding alcohols with sodium tetrahydridoborate in propan-2-ol. Selective reduction of the carboxy group in 4,5-dichloroisothiazole-3-carboxylic acid was achieved by the action of BH ₃, and the aldehyde group in 4-formyl-2-methoxyphenyl 5-arylisoxazole-3-carboxylates and 4,5-dichloroisothiazole-3-carboxylates was reduced to hydroxymethyl group with sodium triacetoxyhydridoborate in benzene. Acylation of the resulting hydroxymethyl derivatives with 5-arylisoxazole- and 4,5-dichloroisothiazole-3-carbonyl chlorides afforded the corresponding esters containing two azole fragments in their molecules.

Full text of DOI:10.1134/S1070428013100205

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 10, pp. 1523–1533. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © V.I. Potkin, S.K. Petkevich, A.V. Kletskov, E.A. Dikusar, Yu.S. Zubenko, N.A. Zhukovskaya, V.V. Kazbanov, S.G. Pashkevich, 2013,
published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 10, pp. 1543–1553.
Synthesis of Functionally Substituted Isoxazole
and Isothiazole Derivatives
V. I. Potkina, S. K. Petkevicha, A. V. Kletskova, E. A. Dikusara, Yu. S. Zubenkoa,
N. A. Zhukovskayaa, V. V. Kazbanovb, and S. G. Pashkevichb
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 Physiology, National Academy of Sciences of Belarus, Minsk, Belarus
Received March 26, 2013
Abstract—Acylation of benzene and toluene with 5-phenyl- and 5-(p-tolyl)isoxazole-3-carbonyl chlorides
gave 5-phenyl(or p-tolyl)isoxazol-3-yl phenyl(or p-tolyl)ketones which were reduced to the corresponding
alcohols with sodium tetrahydridoborate in propan-2-ol. Selective reduction of the carboxy group in 4,5-di-
chloroisothiazole-3-carboxylic acid was achieved by the action of BH3, and the aldehyde group in 4-formyl-2-
methoxyphenyl 5-arylisoxazole-3-carboxylates and 4,5-dichloroisothiazole-3-carboxylates was reduced to
hydroxymethyl group with sodium triacetoxyhydridoborate in benzene. Acylation of the resulting hydroxy-
methyl derivatives with 5-arylisoxazole- and 4,5-dichloroisothiazole-3-carbonyl chlorides afforded the corre-
sponding esters containing two azole fragments in their molecules.
DOI: 10.1134/S1070428013100205
A number of isoxazole and isothiazole derivatives
were found to exhibit high biological activity. Isoxa-
zole heteroring constitutes a structural fragment of
various pharmaceuticals, in particular of antibacterial
drugs Sulfamethoxazole and Sulfisoxazole, Edonentan
used for the treatment of hypertension and cardiovas-
cular diseases, antidepressant Isocarboxazide, anti-
rheumatic Leflunomide, and anti-inflammatory
Valdecoxib [1]. Some isoxazole derivatives showed
antitumor effect [2]. Compounds possessing high
cytostatic activity were revealed among isothiazole
derivatives [3]. For instance, a compound belonging to
the (3-aryl-4-carboxamidoisothiazol-3-yl)urea series is
an efficient tyrosine kinase inhibitor and is studied as
promising antitumor agent (CP-547632) [4].
We have recently synthesized a series of func-
tionally substituted isothiazolylureas and their isoxa-
zolyl-substituted analogs (as CP-547632 isosteres),
some of which have shown cytotoxic effect (according
to bioassay at the Institute of Physiology, National
Academy of Sciences of Belarus), as well as the ability
to enhance the effect of known antitumor agents, in
particular of Cisplatin and Carboplatin, which makes it
possible to reduce therapeutic dose of these toxic drugs
[5]. However, there remains a problem related to water
solubility and tumor-seeking properties of isothiazole
and isoxazole derivatives. This problem may be solved
by selective and purposeful functionalization of
their molecules.
The goal of the present study was to develop meth-
ods of synthesis of functionally substituted isoxazoles
and isothiazoles possessing a hydroxy group which
enhances their hydrophilicity, as well as to obtain their
O-acyl derivatives containing several 1,2-azole frag-
ments in a single molecule. With a view to synthesize
functionally substituted 5-phenyl-(p-tolyl)isoxazoles
with a primary hydroxy group we selected as starting
compounds 5-phenyl- and 5-(p-tolyl)isoxazole-3-carb-
aldehydes I and II and 4-formyl-2-methoxyphenyl
5-phenyl- and 5-(p-tolyl)isoxazole-3-carboxylates III
and IV which are readily prepared from accessible
5-phenyl- and 5-(p-tolyl)isoxazole-3-carbaldehyde
oximes V and VI [6, 7]. We have improved the known
method of synthesis of I and II by hydrolysis of V and
VI with 70% H2SO4 [6]. Our experiments showed that
the hydrolysis of V and VI with 25% H2SO4 in the
presence of (CH2O)n ensures 84–88% yield of I and II
against 52–54% according to the known procedure.
1523

POTKIN et al.
1524
Scheme 1.
CHO
25% H2SO4, (CH2O)n
N
O
I, II
Ar1
NOH
MeO
CHO
N
Ar1
(1) Ac2O
(2) KOH, H2O–EtOH
(3) SOCl2, DMF
O
O
COCl
HO
CHO
Ar1
V, VI
O
N
Ar1
O
N
O
MeO
XV, XVI
III, IV
Ar1
COCl
COCl
O
O
N
N
O
XV, XVI
N
O
Ar1
Ar3
O
O
XXII, XXIII
OH
Cl
NaBH4, i-PrOH
I, II
N
Ar1
O
N
O
Cl
N
S
S
VII, VIII
XXI
N
O
Ph
O
Cl
O
Cl
XXIV
O
O
O
Ar1
N
XV, XVI
O
O
N
N
MeO
XXV, XXVI
O
Ar3
NaBH4
AcOH, PhH
Ar1
OH
III, IV
O
O
O
N
Ar1
MeO
IX, X
O
N
S
XXI
O
O
Cl
MeO
Cl
XXVII, XXVIII
O
HO
R
R
R
AlCl3
NaBH4, i-PrOH
XV, XVI
+
N
N
O
Ar1
Ar1
O
XI–XIV
XVII–XX
Ar1
O
Ar1
N
S
N
O
Ar3
O
XV, XVI
XXI
Cl
O
XVII–XX
O
O
N
O
Cl
N
Ar2
XXIX–XXXVI
Ar2
XXXVII–XXXIX
I, III, V, VII, IX, XI, XV, XVII, XVIII, XXII, XXV, XXVII, XXIX–XXXII, XXXVII, XXXVIII, Ar1 = Ph; II, IV, VI, VIII, X,
XIII, XIV, XVI, XIX, XX, XXIII, XXVI, XXVIII, XXXIII–XXXVI, XXXIX, Ar1 = 4-MeC6H4; XI, XIII, XVII, XIX, R = H;
XXIX, XXX, XXXIII, XXXIV, XXXVII, XXXIX, Ar2 = Ph; XII, XIV, XVIII, XX, R = Me; XXII, XXXI, XXXII, XXXV,
XXXVI, XXXVIII, Ar2 = 4-MeC6H4; XXII, XXV, XXIX, XXXI, XXXIII, XXXV, Ar3 = Ph; XXIII, XXVI, XXX, XXXII,
XXXIV, XXXVI, Ar3 = 4-MeC6H4.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 10 2013

SYNTHESIS OF FUNCTIONALLY SUBSTITUTED ISOXAZOLE
1525
The aldehyde group in I and II was reduced with
sodium tetrahydridoborate in propan-2-ol, and the cor-
responding hydroxymethyl derivatives, 5-phenyl- and
5-(p-tolyl)isoxazol-3-ylmethanols VII and VIII, were
obtained in 75% yield. However, this procedure turned
out to be inapplicable to the reduction of the aldehyde
group in III and IV because of hydrolysis of the ester
group with formation of sodium 5-arylisoxazole-3-
carboxylates and 4-hydroxymethyl-2-methoxyphenol.
We succeeded in selectively reducing the aldehyde
group in esters III and IV with the use of NaBH4 in
AcOH to generate in situ sodium triacetoxyhydrido-
borate Na[BH(OAc)3] as a mild reducing agent. As
a result, the corresponding 4-hydroxymethyl-2-me-
thoxyphenyl 5-arylisoxazole-3-carboxylates IX and X
were formed in 83–87% yield.
Isoxazole derivatives containing a secondary hy-
droxy group were synthesized by reduction of aryl
5-arylisoxazol-3-yl ketones XI–XIV which were pre-
pared in turn by Friedel–Crafts acylation of benzene
and toluene with 5-arylisoxazole-3-carbonyl chlorides
XV and XVI in the presence of aluminum chloride.
We previously described a preparative synthesis of
acid chlorides XV and XVI from the corresponding
carboxylic acids by heating with 5 equiv of thionyl
chloride [7]. Addition of a catalytic amount of dimeth-
ylformamide to the reaction mixture allowed us to
shorten the reaction time from 4 to 3 h and reduce the
amount of SOCl2 from 5 to 1.2 equiv, the high yield
(98%) of XV and XVI being retained.
Like 5-arylisoxazole-3-carbaldehydes I and II,
ketones XI–XIV were reduced with NaBH4 in propan-
2-ol; the reaction time was 4 h, and the yields of aryl
(5-arylisoxazol-3-yl)methanols XVII–XX were 77–
99%. In this case, the use of Na[BH(OAc)3], as in the
reduction of aldehydes I and II, did not ensure com-
plete conversion of the substrates and acceptable reac-
tion rate, and the yields of the target alcohols were
considerably lower.
The acylation of hydroxy-containing 5-arylisoxa-
zole derivatives VII–X and XVII–XX with 5-arylisox-
azole-3-carbonyl chlorides XV and XVI and 4,5-di-
chloroisothiazole-3-carbonyl chloride (XXI) afforded a
number of esters XXII–XXXIX containing two
1,2-azole fragments in their molecules (Scheme 1).
The synthesis of functionalized isothiazole deriva-
tives containing a secondary hydroxy group was de-
scribed by us previously [8]. Functionally substituted
isothiazoles having a primary hydroxy group were syn-
thesized by reduction of the carboxy group in 4,5-di-
chloroisothiazole-3-carboxylic acid (XXIa) and of the
aldehyde group in 4-formyl-2-methoxyphenyl 4,5-di-
Scheme 2.
O
O
Cl
Cl
Cl
Cl
OH
OH
SOCl2, DMF
BF3, THF
N
N
N
Cl
Cl
Cl
S
S
S
XXI
XXIa
XLI
Cl
S
Cl
S
O
O
CHO
NaBH4
AcOH, PhH
MeO
HO
CHO
OH
XXI
Cl
Cl
O
O
N
N
MeO
O
MeO
XLII
XL
O
Cl
O
XVI
XXI
Cl
Me
O
N
O
N
S
Cl
S
MeO
MeO
XLIII
O
Cl
O
O
Cl
Cl
O
N
S
N
XLIV
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 10 2013

POTKIN et al.
1526
chloroisothiazole-3-carboxylate (XL). Acid XXIa was
reduced with borane in THF under argon, and (4,5-di-
chloroisothiazol-3-yl)methanol (XLI) was selectively
formed in 71% yield. Ester XL was prepared acylation
of vanillin with 4,5-dichloroisothiazole-3-carbonyl
chloride (XXI) [9]. As in the synthesis of acid
chlorides XV and XVI, we succeeded in considerably
improving the procedure for the preparation of
chloride XXI [10, 11] by adding a catalytic amount of
DMF to a mixture of acid XXIa and thionyl chloride.
As a result, the amount of SOCl2 was reduced from
5 [10] or 15 equiv [11] to 1.2 equiv, and the reaction
time was shortened from 16 to 3 h. By selective reduc-
tion of the aldehyde group in XL with Na[BH(OAc)3]
in benzene we obtained 4-hydroxymethyl-2-methoxy-
phenyl 4,5-dichloroisothiazole-3-carboxylate (XLII) in
97% yield. The acylation of XLII with 5-(p-tolyl)isox-
azole-3-carbonyl chloride (XVI) and 4,5-dichloroiso-
thiazole-3-carbonyl chloride (XXI) gave esters XLIII
and XLIV, respectively, which are hetero analogs of
XXV–XXVIII (Scheme 2).
mode of signal transmission in nervous tissue changed,
depending on their concentration. Biological testing of
the synthesized compounds in vitro and in vivo is now
in progress.
EXPERIMENTAL
The IR spectra were recorded in KBr on a Nicolet
1
Protégé-460 spectrometer. The H and 13C NMR spec-
tra were measured on a Bruker Avance-500 spectrom-
eter from solutions in CDCl3 using the residual proton
and carbon signals of the solvent as reference (CHCl3,
δ 7.26 ppm; CDCl3, δC 77.2 ppm). The mass spectra
(electron impact, 70 eV) were obtained on a Hewlett
Packard 5890/5972 GC/MS system (HP-5MS capillary
column, 30 m×0.25 mm, film thickness 0.25 μm;
injector temperature 250°C).
5-Phenyl and 5-(4-methylphenyl)-1,2-oxazole-3-
carbaldehydes I and II (general procedure). A sus-
pension of 23 mmol of oxime V or VI and 46 mmol of
paraformaldehyde in 70 ml of 25% H2SO4 was heated
for 6 h under reflux. The mixture was cooled and
extracted with chloroform, the extract was dried over
calcium chloride and evaporated, and the solid residue
was recrystallized from hexane. The yields of alde-
hydes I and II were 84 and 88%, respectively; their
physical constants and spectral parameters were con-
sistent with those reported in [6].
Aryl 5-arylisoxazol-3-yl ketones XI–XIV (general
procedure). A mixture of 10 mmol of acid chloride XV
or XVI, 12 mmol of anhydrous AlCl3, and 200 mmol
of anhydrous benzene or toluene was stirred for 30 min
at 20°C and for 3 h at 80°C. The mixture was then
diluted with 100 ml of chloroform, treated with 10 ml
of water, thoroughly stirred, and poured into water
acidified to pH 3–4. The organic phase was separated,
washed with water, a dilute solution of potassium
carbonate, and water again, and dried over calcium
chloride. The solvent was distilled off under reduced
pressure, and the solid residue was recrystallized from
chloroform–hexane (1:2).
The structure of the newly synthesized compounds
was determined on the basis of their elemental com-
1
positions and IR, H and 13C NMR, and mass spectra.
Hydroxy derivatives VII–X, XVII–XX, XLI, and
XLII displayed no IR absorption bands in the region
1649–1712 cm–1, which are typical of carbonyl stretch-
ing vibrations in the spectra of the corresponding
initial compounds, while broadened bands due to
stretching vibrations of hydroxy group appeared at
3248–3476 cm–1. The hydroxy proton in hydroxy-
methyl derivatives IX, X, and XLII resonated in the
1H NMR spectra at δ 2.07–2.53 ppm, and the OH
signal of alcohols VII, VIII, and XLI was located at
δ 3.16–3.33 ppm. Secondary alcohols XVII–XX
showed OH signal in the region δ 2.87–3.84 ppm. The
CH2OH signal of VII–X, XLI, and XLII appeared at
δ 4.63–4.79 ppm, and the CHOH proton in XVII–XX
gave rise to a singlet at δ 5.97–6.02 ppm.
The mass spectra of ketones XI–XIV, their reduc-
tion products XVII–XX, and primary alcohols VII–X
and XLI contained the molecular ion peaks and those
resulting from their fragmentation. The isotope ratio of
the molecular ion clusters of XLI and XLII was
100:65:11, indicating the presence of two chlorine
atoms in their molecules [12].
The obtained hydroxy derivatives were found to be
low-toxic on intraperitoneal and intragastric adminis-
tration in white rats. Some primary alcohols showed
neurotropic activity in rat brain slice preparations; the
Phenyl(5-phenyl-1,2-oxazol-3-yl)methanone
(XI). Yield 97%, mp 86–87°C. IR spectrum, ν, cm–1:
1655 (C=O), 1610, 1597, 1579, 1571, 1493, 1449,
1
1441, 1426 (C=C, C=N). H NMR spectrum, δ, ppm:
7.06 s (1H, 4-H), 7.49 m (3H, Harom), 7.54 d.d (2H,
3
3
Harom, J = 7.6 Hz), 7.66 d.d (1H, Harom, J = 7.6 Hz),
7.85 d (2H, Harom, 3J = 7.6 Hz), 8.35 d (2H, Harom, 3J =
7.6 Hz). 13C NMR spectrum, δC, ppm: 100.40 (C4),
126.14 (2C, CHarom), 128.74 (2C, CHarom), 129.30 (2C,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 10 2013

SYNTHESIS OF FUNCTIONALLY SUBSTITUTED ISOXAZOLE
1527
CHarom), 130.85 (2C, CHarom), 130.88 (CHarom), 134.21
(CHarom); 126.85, 135.88, 162.57, 170.92 (Cquat);
185.94 (C=O). Found, %: C 77.21; H 4.32; N 5.65.
m/z 249 [M]+. C16H11NO2. Calculated, %: C 77.10;
H 4.45; N 5.62. M 249.28.
10 mmol, was added to a solution of 10 mmol of
carbonyl compound I, II, or XI–XIV, and the mixture
was stirred for 4 h, poured into water, and extracted
with chloroform. The extract was dried over sodium
sulfate and evaporated on a rotary evaporator, and the
residue was purified by recrystallization from diethyl
ether–hexane (2:1).
(4-Methylphenyl)(5-phenyl-1,2-oxazol-3-yl)-
methanone (XII). Yield 91%, mp 116–117°C. IR
spectrum, ν, cm–1: 1650 (C=O), 1604, 1592, 1571,
(5-Phenyl-1,2-oxazol-3-yl)methanol (VII). Yield
75%, mp 97–99°C. IR spectrum, ν, cm–1: 3327 (OH),
1613, 1592, 1574, 1502, 1470, 1453 (C=C, C=N),
1062 (C–O). 1H NMR spectrum, δ, ppm: 3.29 br.s (1H,
OH), 4.79 s (2H, CH2), 6.58 s (1H, 4-H), 7.42 m (3H,
1
1563, 1495, 1441, 1427 (C=C, C=N). H NMR spec-
trum, δ, ppm: 2.44 s (3H, CH3), 7.03 s (1H, 4-H),
3
7.32 d (2H, Harom, J = 8.1 Hz), 7.49 m (3H, Harom),
7.83 d (2H, Harom, 3J = 8.1 Hz), 8.26 d (2H, Harom, 3J =
8.1 Hz). 13C NMR spectrum, δC, ppm: 21.90 (CH3),
100.40 (C4), 126.05 (2C, CHarom), 129.22 (2C, CHarom),
129.42 (2C, CHarom), 130.76 (CHarom), 130.95 (2C,
CHarom); 126.82, 133.31, 145.27, 162.64, 170.68
(Cquat); 185.38 (C=O). Found, %: C 77.62; H 4.77;
N 5.35. m/z 263 [M]+. C17H13NO2. Calculated, %:
C 77.55; H 4.98; N 5.32. M 263.31.
H
arom), 7.73 m (2H, Harom). 13C NMR spectrum, δC,
ppm: 57.00 (CH2), 98.50 (C4), 125.95 (2C, CHarom),
129.11 (2C, CHarom), 130.41 (CHarom); 127.33, 164.46,
170.43 (Cquat). Found, %: C 68.69; H 5.01; N 8.09.
m/z 175 [M]+. C10H9NO2. Calculated, %: C 68.56;
H 5.18; N 8.00. M 175.19.
[5-(4-Methylphenyl)-1,2-oxazol-3-yl]methanol
(VIII). Yield 75%, mp 102–104°C. IR spectrum, ν,
cm–1: 3454 (OH), 1614, 1598, 1567, 1513, 1479, 1462
(C=C, C=N), 1071 (C–O). 1H NMR spectrum, δ, ppm:
2.38 s (3H, CH3), 3.33 br.s (1H, OH), 4.79 s (2H,
CH2), 6.52 s (1H, 4-H), 7.22 d (2H, Harom, 3J = 7.4 Hz),
7.61 d (2H, Harom, 3J = 7.4 Hz). 13C NMR spectrum, δC,
ppm: 21.60 (CH3), 57.01 (CH2), 97.89 (C4), 125.89
(2C, CHarom), 129.77 (2C, CHarom); 124.66, 140.69,
164.42, 170.62 (Cquat). Found, %: C 69.79; H 6.03;
N 7.33. m/z 189 [M]+. C11H11NO2. Calculated, %:
C 69.83; H 5.86; N 7.40. M 189.22.
[5-(4-Methylphenyl)-1,2-oxazol-3-yl]phenyl-
methanone (XIII). Yield 96%, mp 120–121°C. IR
spectrum, ν, cm–1: 1661 (C=O), 1610, 1595, 1578,
1
1566, 1506, 1452, 1445, 1431 (C=C, C=N). H NMR
spectrum, δ, ppm: 2.38 s (3H, CH3), 6.97 s (1H, 4-H),
3
7.26 d (2H, Harom, J = 7.8 Hz), 7.52 d.d (2H, Harom
,
3J = 7.6 Hz), 7.63 d.d (1H, Harom, J = 7.6 Hz), 7.71 d
3
3
3
(2H, Harom, J = 7.8 Hz), 8.35 d (2H, Harom, J =
7.6 Hz). 13C NMR spectrum, δC, ppm: 21.56 (CH3),
99.69 (C4), 125.94 (2C, CHarom), 128.60 (2C, CHarom),
129.86 (2C, CHarom), 130.75 (2C, CHarom), 134.04
(CHarom); 124.02, 135.82, 141.13, 162.43, 170.95
(Cquat); 185.80 (C=O). Found, %: C 77.47; H 5.10;
N 5.30. m/z 263 [M]+. C17H13NO2. Calculated, %:
C 77.55; H 4.98; N 5.32. M 263.31.
Phenyl(5-phenyl-1,2-oxazol-3-yl)methanol
(XVII). Yield 99%, mp 141–142°C. IR spectrum, ν,
cm–1: 3449 (OH), 1612, 1591, 1572, 1494, 1466, 1451,
1
1422 (C=C, C=N). H NMR spectrum, δ, ppm:
3.84 br.s (1H, OH), 6.02 s (1H, CH), 6.43 s (1H, 4-H),
(4-Methylphenyl)[5-(4-methylphenyl)-1,2-oxaz-
ol-3-yl]methanone (XIV). Yield 93%, mp 139–141°C.
IR spectrum, ν, cm–1: 1649 (C=O), 1604, 1567, 1509,
7.31 d.d (1H, Harom, 3J = 7.2 Hz), 7.39 m (5H, Harom),
3
7.49 d (2H, Harom, J = 7.5 Hz), 7.68 m (2H, Harom).
13C NMR spectrum, δC, ppm: 69.20 (CH), 97.86 (C4),
125.92 (2C, CHarom), 126.40 (2C, CHarom), 128.33
(CHarom), 128.81 (2C, CHarom), 129.01 (2C, CHarom),
130.35 (CHarom); 127.30, 140.89, 167.22, 170.32
(Cquat). Found, %: C 76.80; H 5.00; N 5.46. m/z 251
[M]+. C16H13NO2. Calculated, %: C 76.48; H 5.21;
N 5.57. M 251.29.
1
1442 (C=C, C=N). H NMR spectrum, δ, ppm: 2.41 s
(3H, CH3), 2.45 s (3H, CH3), 6.98 s (1H, 4-H), 7.29 d
(2H, Harom, 3J = 8 Hz), 7.33 d (2H, Harom, 3J = 8.1 Hz),
3
3
7.73 d (2H, Harom, J = 8 Hz), 8.27 d (2H, Harom, J =
8.1 Hz). 13C NMR spectrum, δC, ppm: 21.61 (CH3),
21.89 (CH3), 99.75 (C4), 125.96 (2C, CHarom), 129.38
(2C, CHarom), 129.88 (2C, CHarom), 130.92 (2C,
CHarom); 124.10, 133.33, 141.11, 145.18, 162.59,
170.85 (Cquat); 185.42 (C=O). Found, %: C 77.72;
H 5.62; N 5.16. m/z 277 [M]+. C18H15NO2. Calculated,
%: C 77.96; H 5.45; N 5.05. M 277.33.
(4-Methylphenyl)(5-phenyl-1,2-oxazol-3-yl)-
methanol (XVIII). Yield 77%, mp 107–109°C. IR
spectrum, ν, cm–1: 3338, 3248 (OH), 1613, 1592, 1574,
1
1513, 1463, 1452, 1412 (C=C, C=N). H NMR spec-
3
Reduction of aldehydes I and II and ketones XI–
XIV (general procedure). Sodium tetrahydridoborate,
trum, δ, ppm: 2.34 s (3H, CH3), 3.36 d (1H, OH, J =
3
3.3 Hz), 5.98 d (1H, CH, J = 3.3 Hz), 6.43 s (1H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 10 2013

POTKIN et al.
1528
3
4-H), 7.18 d (2H, Harom, J = 7.9 Hz), 7.37 d (2H,
40 μm), and the solvent was distilled off under reduced
pressure to isolate acid chloride XV, XVI, or XXI in
98% yield. The physical constants and spectral param-
eters of the products were consistent with published
data [7, 10].
Reduction of the aldehyde group in compounds
III, IV, and XL (general procedure). Glacial acetic
acid, 36 mmol, was added in portions under stirring to
a suspension of 12 mmol of sodium tetrahydridoborate
in 50 ml of anhydrous benzene, 10 mmol of aldehyde
III, IV, or XL was then added, and the mixture was
stirred for 4 h. The mixture was treated with 100 ml of
water and 100 ml of chloroform, the organic phase was
separated and dried over sodium sulfate, the solvent
was distilled off under reduced pressure, and the resi-
due was recrystallized from hexane–chloroform (4:1).
3
Harom, J = 7.9 Hz), 7.41 m (3H, Harom), 7.71 m (2H,
H
arom). 13C NMR spectrum, δC, ppm: 21.31 (CH3),
69.29 (CH), 97.85 (C4), 125.95 (2C, CHarom), 126.39
(2C, CHarom), 129.04 (2C, CHarom), 129.54 (2C,
CHarom), 130.35 (CHarom); 127.41, 138.00, 138.21,
167.28, 170.31 (Cquat). Found, %: C 77.05; H 5.54;
N 5.33. m/z 265 [M]+. C17H15NO2. Calculated, %:
C 76.96; H 5.70; N 5.28. M 265.32.
[5-(4-Methylphenyl)-1,2-oxazol-3-yl]phenyl-
methanol (XIX). Yield 87%, mp 167–168°C. IR spec-
trum, ν, cm–1: 3444 (OH), 1614, 1596, 1585, 1567,
1
1514, 1470, 1452, 1432 (C=C, C=N). H NMR spec-
3
trum, δ, ppm: 2.36 s (3H, CH3), 5.35 d (1H, OH, J =
3
4.2 Hz), 5.98 d (1H, CH, J = 4.2 Hz), 6.74 s (1H,
3
4-H), 7.29 m (3H, Harom), 7.36 d.d (2H, Harom, J =
3
7.5 Hz), 7.53 d (2H, Harom, J = 7.7 Hz), 7.72 d (2H,
4-(Hydroxymethyl)-2-methoxyphenyl 5-phenyl-
1,2-oxazole-3-carboxylate (IX). Yield 87%, mp 151–
152°C. IR spectrum, ν, cm–1: 3476 (OH), 1748 (C=O),
1609, 1590, 1575, 1514, 1470, 1450, 1439, 1423
(C=C, C=N), 1229, 1149, 1129, 1119 (C–O–C).
1H NMR spectrum, δ, ppm: 2.18 br.s (1H, OH), 3.84 s
Harom, 3J = 7.7 Hz). 13C NMR spectrum, δC, ppm: 21.72
(CH3), 69.49 (CH), 98.55 (C4), 126.77 (2C, CHarom),
127.36 (2C, CHarom), 128.73 (CHarom), 129.51 (2C,
CHarom), 130.91 (2C, CHarom); 126.15, 141.60, 143.68,
169.23, 170.79 (Cquat). Found, %: C 76.78; H 5.89;
N 5.30. m/z 265 [M]+. C17H15NO2. Calculated, %:
C 76.96; H 5.70; N 5.28. M 265.32.
3
(3H, CH3), 4.70 s (2H, CH2), 6.96 d (1H, Harom, J =
8 Hz), 7.06 s (1H, 4-H), 7.07 s (1H, Harom), 7.16 d (1H,
3
(4-Methylphenyl)[5-(4-methylphenyl)-1,2-oxaz-
ol-3-yl]methanol (XX). Yield 96%, mp 113–114°C. IR
spectrum, ν, cm–1: 3342, 3266 (OH), 1617, 1595, 1567,
Harom, J = 8 Hz), 7.50 m (3H, Harom), 7.84 m (2H,
Harom). 13C NMR spectrum, δC, ppm: 56.08 (CH3),
65.03 (CH2), 100.55 (C4), 111.25 (CHarom), 119.06
(CHarom), 122.62 (CHarom), 126.13 (2C, CHarom), 129.35
(2C, CHarom), 131.09 (CHarom); 126.29, 138.39, 140.90,
151.16, 156.40, 158.11 (Cquat); 172.22 (C=O). Found,
%: C 66.76; H 4.73; N 4.45. m/z 325 [M]+. C18H15NO5.
Calculated, %: C 66.46; H 4.65; N 4.31. M 325.32.
1
1511, 1463, 1443, 1424 (C=C, C=N). H NMR spec-
trum, δ, ppm: 2.34 s (3H, CH3), 2.38 s (3H, CH3),
3
3
3.34 d (1H, OH, J = 3.8 Hz), 5.97 d (1H, CH, J =
3
3.8 Hz), 6.37 s (1H, 4-H), 7.18 d (2H, Harom, J =
3
7.9 Hz), 7.21 d (2H, Harom, J = 8 Hz), 7.37 d (2H,
3
3
H
arom, J = 7.9 Hz), 7.59 d (2H, Harom, J = 8 Hz).
4-Hydroxymethyl-2-methoxyphenyl 5-(4-methyl-
phenyl)-1,2-oxazole-3-carboxylate (X). Yield 83%,
mp 171–172°C. IR spectrum, ν, cm–1: 3472 (OH),
1752 (C=O), 1610, 1594, 1575, 1509, 1466, 1442,
1422 (C=C, C=N), 1232, 1150, 1128, 1118 (C–O–C).
1H NMR spectrum, δ, ppm: 2.07 br.s (1H, OH),
2.42 s (3H, CH3), 3.83 s (3H, OCH3), 4.70 s (2H,
13C NMR spectrum, δC, ppm: 21.31 (CH3), 21.62
(CH3), 69.29 (CH), 97.20 (C4), 125.88 (2C, CHarom),
126.39 (2C, CHarom), 129.52 (2C, CHarom), 129.71 (2C,
CHarom); 124.70, 138.04, 138.16, 140.62, 167.21,
170.51 (Cquat). Found, %: C 77.55; H 6.01; N 5.09.
m/z 279 [M]+. C18H17NO2. Calculated, %: C 77.40;
H 6.13; N 5.01. M 279.35.
3
CH2), 6.96 d (1H, Harom, J = 8 Hz), 7.01 s (1H, 4-H),
3
5-Phenyl and 5-(4-methylphenyl)-1,2-oxazol-3-
carbonyl chlorides XV and XVI and 4,5-dichloro-
1,2-thiazole-3-carbonyl chloride (XXI) (general
procedure). Thionyl chloride, 1.43 g (12 mmol), was
added to 10 mmol of the corresponding acid, 3 drops
of DMF were then added, and the mixture was heated
under reflux until it became homogeneous (~3 h).
Excess thionyl chloride was distilled off under reduced
pressure, the residue was dissolved in hexane, the
solution was passed through a layer of silica gel (5–
7.07 s (1H, Harom), 7.16 d (1H, Harom, J = 8 Hz),
3
7.30 m (2H, Harom, J = 7.5 Hz), 7.73 m (2H, Harom
,
3J = 7.5 Hz). 13C NMR spectrum, δC, ppm: 21.71
(CH3), 56.08 (CH3), 65.05 (CH2), 99.96 (C4), 111.24
(CHarom), 119.06 (CHarom), 122.64 (CHarom), 126.07
(2C, CHarom), 130.02 (2C, CHarom); 124.01, 138.42,
140.84, 141.54, 151.18, 156.34, 158.19 (Cquat); 172.42
(C=O). Found, %: C 67.27; H 5.34; N 4.21. m/z 339
[M]+. C19H17NO5. Calculated, %: C 67.25; H 5.05;
N 4.13. M 339.34.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 10 2013

SYNTHESIS OF FUNCTIONALLY SUBSTITUTED ISOXAZOLE
1529
4-Hydroxymethyl-2-methoxyphenyl 4,5-di-
chloro-1,2-thiazole-3-carboxylate (XLII). Yield 97%,
mp 111–113°C. IR spectrum, ν, cm–1: 3327 (OH),
3186, 3005, (=C–H), 2976, 2935, 2917, 2853 (C–H),
1743 (C=O), 1609, 1515, 1483, 1465, 1451, 1418
(C=C, C=N), 1205, 1150 (C–O–C), 871, 821 (C–Cl).
1H NMR spectrum, δ, ppm: 2.53 br.s (1H, OH), 3.79 s
83%, mp 142–143°C. IR spectrum, ν, cm–1: 1753
(C=O), 1615, 1594, 1576, 1506, 1461, 1456, 1432
1
(C=C, C=N), 1249, 1148 (C–O–C). H NMR spec-
trum, δ, ppm: 2.40 s (3H, CH3), 5.54 s (2H, CH2),
6.69 s and 6.90 s (1H each, 4-H, 4′-H), 7.28 d (2H,
3
Harom, J = 8 Hz), 7.45 m (3H, Harom), 7.68 d (2H,
3
Harom, J = 8 Hz), 7.77 m (2H, Harom). 13C NMR spec-
3
(3H, CH3), 4.63 s (2H, CH2), 6.91 d (1H, Harom, J =
trum, δC, ppm: 21.64 (CH3), 58.97 (CH2), 99.33 and
99.54 (C4, C4′), 126.01 (4C, CHarom), 129.15 (2C,
CHarom), 129.97 (2C, CHarom), 130.59 (CHarom); 123.87,
127.15, 141.54, 156.25, 159.55, 159.78, 171.07 (Cquat);
172.40 (C=O). Found, %: C 69.72; H 4.75; N 7.81.
C21H16N2O4. Calculated, %: C 69.99; H 4.48; N 7.77.
8 Hz), 7.02 s (1H, Harom), 7.12 d (1H, Harom, 3J = 8 Hz).
13C NMR spectrum, δC, ppm: 56.03 (CH3), 64.78
(CH2), 111.11 (CHarom), 118.93 (CHarom), 122.49
(CHarom); 126.42, 138.24, 140.89, 150.99, 151.05,
153.46 (Cquat); 157.01 (C=O). Found, %: C 42.87;
H 3.04; Cl 20.99; N 3.95; S 9.25. m/z 333 [M]+.
C12H9Cl2NO4S. Calculated, %: C 43.13; H 2.71;
Cl 21.22; N 4.19; S 9.60. M 334.18.
[5-(4-Methylphenyl)-1,2-oxazol-3-yl]methyl
5-(4-methylphenyl)-1,2-oxazole-3-carboxylate
(XXIII). Yield 73%, mp 133–134°C. IR spectrum, ν,
cm–1: 1736 (C=O), 1616, 1596, 1569, 1513, 1451,
1437, 1412 (C=C, C=N), 1237, 1147 (C–O–C).
1H NMR spectrum, δ, ppm: 2.39 s (3H, CH3), 2.40 s
(3H, CH3), 5.53 s (2H, CH2), 6.63 s and 6.90 s (1H
each, 4-H, 4′-H), 7.26 m (4H, Harom), 7.67 m (4H,
Harom). 13C NMR spectrum, δC, ppm: 21.61 (CH3),
21.64 (CH3), 59.02 (CH2), 98.73 and 99.55 (C4, C4′),
125.95 (2C, CHarom), 126.02 (2C, CHarom), 129.84 (2C,
CHarom), 129.98 (2C, CHarom); 123.90, 124.48, 140.94,
141.54, 156.27, 159.49, 159.79, 171.28 (Cquat); 172.39
(C=O). Found, %: C 70.49; H 4.97; N 7.53.
C22H18N2O4. Calculated, %: C 70.58; H 4.85; N 7.48 .
(5-Phenyl-1,2-oxazol-3-yl)methyl 4,5-dichloro-
1,2-thiazole-3-carboxylate (XXIV). Yield 70%,
mp 123–125°C. IR spectrum, ν, cm–1: 1729 (C=O),
1615, 1593, 1577, 1473, 1455, 1436, 1405 (C=C,
C=N), 1219, 1179 (C–O–C), 844, 807 (C–Cl). 1H NMR
spectrum, δ, ppm: 5.53 s (2H, CH2), 6.67 s (1H, 4-H),
7.45 m (3H, Harom), 7.77 m (2H, Harom). 13C NMR spec-
trum, δC, ppm: 56.20 (CH2), 99.31 (C4), 126.01 (2C,
CHarom), 129.16 (2C, CHarom), 130.61 (CHarom); 126.13,
127.13, 151.10, 153.49, 158.71, 159.42 (Cquat); 171.08
(C=O). Found, %: C 47.28; H 2.39; Cl 19.78; N 7.93;
S 9.13. C14H8Cl2N2O3S. Calculated, %: C 47.34;
H 2.27; Cl 19.96; N 7.89; S 9.03.
(4,5-Dichloro-1,2-thiazol-3-yl)methanol (XLI).
A 1 M solution of 15 mmol of BH3 in THF was added
dropwise at –20°C under stirring in an argon atmo-
sphere to 3.0 g (15 mmol) of 4,5-dichloro-1,2-thiazole-
3-carboxylic acid (XXIa), and the mixture was stirred
for 12 h, allowing it to gradually warm up to room
temperature. Methanol, 50 ml, was then added, the
mixture was stirred for 1 h, the solvent was removed
on a rotary evaporator, the residue was treated with
100 ml of 1 N aqueous HCl, and the mixture was
heated for 12 h under reflux and evaporated to dryness.
The residue was purified by column chromatography
on silica gel (100–160 μm) using hexane–acetone
(5:2) as eluent. Yield 71%, mp 49–50°C. IR spectrum,
ν, cm–1: 3341 (OH), 2940, 2866 (CH), 1517, 1442,
1422, 1393, 1312 (C=C, C=N), 1098, 1067, 971, 845,
815 (C–Cl), 622, 560, 506. 1H NMR spectrum, δ, ppm:
3.16 br.s (1H, OH), 4.67 s (2H, CH2O). 13C NMR
spectrum, δC, ppm: 61.28 (CH2O); 123.20, 148.31,
168.04 (Cquat). Found, %: C 26.22; H 2.01; Cl 38.77;
N 7.59; S 17.50. m/z 183 [M]+. C4H3Cl2NOS. Calculat-
ed, %: C 26.10; H 1.64; Cl 38.53; N 7.61; S 17.42.
M 184.04.
Esters XXII–XXXIX, XLIII, and XLIV (general
procedure). Acid chloride XV, XVI, or XXI, 10 mmol,
was added in portions under stirring to a solution of
10 mmol of compound VII–X or XVII–XX and
10 mmol of anhydrous triethylamine in 50 ml of anhy-
drous diethyl ether. The mixture was heated for 5 h
under reflux, and the precipitate was filtered off,
washed with diethyl ether and water (3×100 ml), and
dried under reduced pressure over P2O5.
3-Methoxy-4-[(5-phenyl-1,2-oxazol-3-yl)carbon-
yloxy]benzyl 5-phenyl-1,2-oxazole-3-carboxylate
(XXV). Yield 84%, mp 146–147°C. IR spectrum, ν,
cm–1: 1739 (C=O), 1610, 1592, 1573, 1510, 1462,
1445, 1422 (C=C, C=N), 1247, 1238, 1222, 1152,
1132 (C–O–C). 1H NMR spectrum, δ, ppm: 3.86 s (3H,
CH3), 5.43 s (2H, CH2), 6.95 s and 7.06 s (1H each,
3
(5-Phenyl-1,2-oxazol-3-yl)methyl 5-(4-methyl-
phenyl)-1,2-oxazole-3-carboxylate (XXII). Yield
4-H, 4′-H), 7.12 d (1H, Harom, J = 8 Hz), 7.15 s (1H,
3
H
arom), 7.22 d (1H, Harom, J = 8 Hz), 7.48 m (6H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 10 2013

POTKIN et al.
1530
Harom), 7.80 m (2H, Harom), 7.83 m (2H, Harom).
13C NMR spectrum, δC, ppm: 56.15 (CH3), 67.36
(CH2), 100.13 and 100.51 (C4, C4′), 113.11 (CHarom),
121.29 (CHarom), 122.92 (CHarom), 126.05 (2C, CHarom),
126.08 (2C, CHarom), 129.27 (2C, CHarom), 129.30 (2C,
CHarom), 130.99 (CHarom), 131.05 (CHarom), 126.62 (2C,
4-[(4,5-Dichloro-1,2-thiazol-3-yl)carbonyloxy-
methyl]-2-methoxyphenyl 5-(4-methylphenyl)-1,2-
oxazole-3-carboxylate (XXVIII). Yield 87%,
mp 144–145°C. IR spectrum, ν, cm–1: 3135, 3085,
3055, 3024 (=C–H), 2973, 2923, 2853 (C–H), 1743,
1724 (C=O), 1608, 1567, 1515, 1477, 1448, 1418
(C=C, C=N), 1243, 1233, 1213, 1159, 1138 (C–O–C),
Cquat); 134.61, 139.36, 151.23, 156.28, 156.75, 157.86,
1
159.92 (Cquat); 172.00 and 172.19 (C=O). Found, %:
C 67.79; H 4.15; N 5.73. C28H20N2O7. Calculated, %:
C 67.74; H 4.06; N 5.64.
865, 811 (C–Cl). H NMR spectrum, δ, ppm: 2.42 s
(3H, CH3), 3.85 s (3H, OCH3), 5.43 s (2H, CH2),
3
7.00 s (1H, 4-H), 7.12 d (1H, Harom, J = 8 Hz), 7.15 s
3
(1H, Harom), 7.21 d (1H, Harom, J = 8 Hz), 7.30 d (2H,
3-Methoxy-4-{[5-(4-methylphenyl)-1,2-oxazol-3-
yl]carbonyloxy}benzyl 5-(4-methylphenyl)-1,2-ox-
azole-3-carboxylate (XXVI). Yield 79%, mp 173–
174°C. IR spectrum, ν, cm–1: 1750, 1729 (C=O), 1611,
1594, 1570, 1510, 1471, 1446, 1424 (C=C, C=N),
3
3
H
arom, J = 8 Hz), 7.73 d (2H, Harom, J = 8 Hz).
13C NMR spectrum, δC, ppm: 21.72 (CH3), 56.20
(OCH3), 67.62 (CH2), 99.95 (C4), 113.12 (CHarom),
121.32 (CHarom), 123.00 (CHarom), 126.08 (2C, CHarom),
130.02 (2C, CHarom); 124.00, 125.96, 134.51, 139.43,
141.54, 150.93, 151.28, 154.10, 156.26, 157.97 (Cquat);
159.00 and 172.44 (C=O). Found, %: C 53.39; H 3.47;
Cl 13.77; N 5.27; S 5.91. C23H16Cl2N2O6S. Calculated,
%: C 53.19; H 3.11; Cl 13.65; N 5.39; S 6.17.
1
1244, 1233, 1212, 1160, 1133 (C–O–C). H NMR
spectrum, δ, ppm: 2.40 s (3H, CH3), 2.41 s (3H, CH3),
3.86 s (3H, OCH3), 5.42 s (2H, CH2), 6.88 s and 7.00 s
3
(1H each, 4-H, 4′-H), 7.12 d (1H, Harom, J = 8 Hz),
7.14 s (1H, Harom), 7.22 d (1H, Harom, 3J = 8 Hz), 7.26 d
3
3
(2H, Harom, J = 8.1 Hz), 7.29 d (2H, Harom, J =
Phenyl(5-phenyl-1,2-oxazol-3-yl)methyl 5-phe-
nyl-1,2-oxazole-3-carboxylate (XXIX). Yield 79%,
mp 170–172°C. IR spectrum, ν, cm–1: 1736 (C=O),
1613, 1591, 1574, 1494, 1465, 1450, 1423 (C=C,
3
8.1 Hz), 7.68 d (2H, Harom, J = 8.1 Hz), 7.72 d (2H,
H
arom, 3J = 8.1 Hz). 13C NMR spectrum, δC, ppm: 21.64
(2C, CH3), 56.14 (CH3), 67.31 (CH2), 99.52 and 99.91
(C4, C4′), 113.09 (CHarom), 121.27 (CHarom), 122.91
(CHarom), 125.98 (2C, CHarom), 126.01 (2C, CHarom),
129.93 (2C, CHarom), 129.97 (2C, CHarom), 123.94 (2C,
1
C=N), 1239, 1136 (C–O–C). H NMR spectrum, δ,
ppm: 6.63 s (1H, CH), 6.99 s and 7.32 s (1H each, 4-H,
3
4′-H), 7.39 d.d (1H, Harom, J = 7.3 Hz), 7.43 m (5H,
3
Cquat); 134.61, 139.36, 141.42, 141.49, 151.23, 156.22,
Harom), 7.48 m (3H, Harom), 7.61 d (2H, Harom, J =
156.69, 157.94, 159.99 (Cquat); 172.19 and 172.39
(C=O). Found, %: C 68.88; H 4.84; N 5.41.
C30H24N2O7. Calculated, %: C 68.70; H 4.61; N 5.34.
7.3 Hz), 7.76 m (2H, Harom), 7.81 m (2H, Harom).
13C NMR spectrum, δC, ppm: 71.78 (CH), 98.29 and
100.31 (C4, C4′), 126.03 (2C, CHarom), 126.11 (2C,
CHarom), 127.21 (2C, CHarom), 129.13 (4C, CHarom),
129.28 (CHarom), 129.33 (2C, CHarom), 130.61 (CHarom),
131.09 (CHarom); 126.61, 127.16, 136.57, 156.50,
158.94, 163.30, 170.95 (Cquat); 172.16 (C=O). Found,
%: C 79.88; H 4.39; N 6.57. C26H18N2O4. Calculated,
%: C 79.92; H 4.29; N 6.63.
4-[(4,5-Dichloro-1,2-thiazol-3-yl)carbonyloxy-
methyl]-2-methoxyphenyl 5-phenyl-1,2-oxazole-3-
carboxylate (XXVII). Yield 83%, mp 135–136°C. IR
spectrum, ν, cm–1: 3144, 3128, 3053 (=C–H), 2983,
2948, 2924, 2853 (C–H), 1756, 1726 (C=O), 1608,
1590, 1572, 1518, 1474, 1438, 1403 (C=C, C=N),
1237, 1228, 1213, 1160, 1135 (C–O–C), 859, 809
Phenyl(5-phenyl-1,2-oxazol-3-yl)methyl
5-(4-methylphenyl)-1,2-oxazole-3-carboxylate
(XXX). Yield 58%, mp 129–131°C. IR spectrum, ν,
cm–1: 1742 (C=O), 1611, 1591, 1573, 1500, 1495,
1449, 1423 (C=C, C=N), 1238, 1136 (C–O–C).
1H NMR spectrum, δ, ppm: 2.41 s (3H, CH3), 6.63 s
(1H, CH), 6.93 s and 7.31 s (1H each, 4-H, 4′-H),
1
(C–Cl). H NMR spectrum, δ, ppm: 3.86 s (3H, CH3),
3
5.43 s (2H, CH2), 7.06 s (4-H), 7.12 d (1H, Harom, J =
8 Hz), 7.16 s (1H, Harom), 7.22 d (1H, Harom, 3J = 8 Hz),
7.50 m (3H, Harom), 7.84 m (2H, Harom). 13C NMR spec-
trum, δC, ppm: 56.19 (CH3), 67.61 (CH2), 100.55 (C4),
113.11 (CHarom), 121.32 (CHarom), 122.98 (CHarom),
126.13 (2C, CHarom), 129.35 (2C, CHarom), 131.09
(CHarom); 125.95, 126.68, 134.55, 139.39, 150.94,
151.26, 154.08, 156.31, 157.88 (Cquat); 159.00 and
172.23 (C=O). Found, %: C 52.38; H 2.91; Cl 14.36;
N 5.68; S 6.27. C22H14Cl2N2O6S. Calculated, %:
C 52.29; H 2.79; Cl 14.03; N 5.54; S 6.35.
3
7.29 d (2H, Harom, J = 8 Hz), 7.43 m (5H, Harom),
7.51 d (1H, Harom, 3J = 7.3 Hz), 7.60 d (2H, Harom, 3J =
3
7.3 Hz), 7.69 d (2H, Harom, J = 8 Hz), 7.75 m (2H,
Harom). 13C NMR spectrum, δC, ppm: 21.69 (CH3),
71.73 (CH), 98.30 and 99.71 (C4, C4′), 126.04 (4C,
CHarom), 127.20 (2C, CHarom), 129.12 (4C, CHarom),
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SYNTHESIS OF FUNCTIONALLY SUBSTITUTED ISOXAZOLE
1531
3
129.25 (CHarom), 129.99 (2C, CHarom), 130.59 (CHarom);
123.93, 127.41, 136.62, 141.54, 156.44, 159.02,
163.33, 170.93 (Cquat); 172.37 (C=O). Found, %:
C 74.23; H 4.89; N 6.55. C27H20N2O4. Calculated, %:
C 74.30; H 4.62; N 6.42.
H
arom, J = 8 Hz), 7.81 m (2H, Harom). 13C NMR spec-
trum, δC, ppm: 21.65 (CH3), 71.81 (CH), 97.66 and
100.31 (C4, C4′), 125.96 (2C, CHarom), 126.10 (2C,
CHarom), 127.21 (2C, CHarom), 129.10 (2C, CHarom),
129.24 (CHarom), 129.33 (2C, CHarom), 129.81 (2C,
CHarom), 131.07 (CHarom); 124.48, 126.63, 136.65,
140.93, 156.53, 158.95, 163.23, 171.14 (Cquat); 172.14
(C=O). Found, %: C 74.39; H 4.79; N 6.37.
C27H20N2O4. Calculated, %: C 74.30; H 4.62; N 6.42.
(4-Methylphenyl)(5-phenyl-1,2-oxazol-3-yl)-
methyl 5-phenyl-1,2-oxazole-3-carboxylate (XXXI).
Yield 88%, mp 140–141°C. IR spectrum, ν, cm–1: 1737
(C=O), 1614, 1590, 1572, 1516, 1498, 1463, 1449,
1
1439 (C=C, C=N), 1229, 1136 (C–O–C). H NMR
[5-(4-Methylphenyl)-1,2-oxazol-3-yl](phenyl)-
methyl 5-(4-methylphenyl)-1,2-oxazole-3-carbox-
ylate (XXXIV). Yield 82%, mp 180–181°C. IR spec-
trum, ν, cm–1: 1738 (C=O), 1616, 1594, 1568, 1517,
1510, 1469, 1446, 1412 (C=C, C=N), 1236, 1134
spectrum, δ, ppm: 2.36 s (3H, CH3), 6.62 s (1H, CH),
6.98 s and 7.27 s (1H each, 4-H, 4′-H), 7.24 d (2H,
3
Harom, J = 8 Hz), 7.44 m (3H, Harom), 7.49 m (5H,
Harom), 7.76 m (2H, Harom), 7.81 m (2H, Harom).
13C NMR spectrum, δC, ppm: 21.42 (CH3), 71.81 (CH),
98.32 and 100.32 (C4, C4′), 126.05 (2C, CHarom),
126.12 (2C, CHarom), 127.27 (2C, CHarom), 129.14 (2C,
CHarom), 129.34 (2C, CHarom), 129.80 (2C, CHarom),
130.58 (CHarom), 131.08 (CHarom); 124.11, 126.67,
133.67, 139.29, 156.59, 159.00, 163.45, 170.89 (Cquat);
172.13 (C=O). Found, %: C 74.51; H 4.93; N 6.47.
C27H20N2O4. Calculated, %: C 74.30; H 4.62; N 6.42.
1
(C–O–C). H NMR spectrum, δ, ppm: 2.38 s (3H,
CH3), 2.41 s (3H, CH3), 6.57 s (1H, CH), 6.93 s and
3
7.30 s (1H each, 4-H, 4′-H), 7.24 d (2H, Harom, J =
3
8 Hz), 7.29 d (2H, Harom, J = 8 Hz), 7.38 d.d (1H,
3
3
Harom, J = 7.3 Hz), 7.43 d.d (2H, Harom, J = 7.3 Hz),
7.60 d (2H, Harom, 3J = 7.3 Hz), 7.65 d (2H, Harom, 3J =
8 Hz), 7.70 d (2H, Harom, J = 8 Hz). 13C NMR spec-
3
trum, δC, ppm: 21.64 (CH3), 21.68 (CH3), 71.75 (CH),
97.67 and 99.71 (C4, C4′), 125.97 (2C, CHarom), 126.04
(2C, CHarom), 127.20 (2C, CHarom), 129.09 (2C,
CHarom), 129.21 (CHarom), 129.80 (2C, CHarom), 129.99
(2C, CHarom); 123.98, 124.51, 136.70, 140.91, 141.52,
156.47, 159.02, 163.27, 171.12 (Cquat); 172.34 (C=O).
Found, %: C 74.51; H 5.09; N 6.15. C28H22N2O4. Cal-
culated, %: C 74.65; H 4.92; N 6.22.
(4-Methylphenyl)(5-phenyl-1,2-oxazol-3-yl)-
methyl 5-(4-methylphenyl)-1,2-oxazole-3-carbox-
ylate (XXXII). Yield 74%, mp 141–143°C. IR spec-
trum, ν, cm–1: 1742 (C=O), 1615, 1592, 1574, 1513,
1465, 1445, 1427 (C=C, C=N), 1230, 1138 (C–O–C).
1H NMR spectrum, δ, ppm: 2.36 s (3H, CH3), 2.41 s
(3H, CH3), 6.62 s (1H, CH), 6.92 s and 7.27 s (1H
3
each, 4-H, 4′-H), 7.23 d (2H, Harom, J = 8 Hz), 7.29 d
(4-Methylphenyl)[5-(4-methylphenyl)1,2-oxazol-
3-yl]methyl 5-phenyl-1,2-oxazole-3-carboxylate
(XXXV). Yield 87%, mp 151–153°C. IR spectrum, ν,
cm–1: 1737 (C=O), 1616, 1597, 1571, 1514, 1466,
1440, 1410 (C=C, C=N), 1231, 1136 (C–O–C).
1H NMR spectrum, δ, ppm: 2.36 s (3H, CH3), 2.38 s
(3H, CH3), 6.57 s (1H, CH), 6.98 s and 7.27 s (1H
each, 4-H, 4′-H), 7.23 m (4H, Harom), 7.48 m (5H,
(2H, Harom, 3J = 8 Hz), 7.44 m (3H, Harom), 7.48 d (2H,
Harom, 3J = 8 Hz), 7.70 d (2H, Harom, 3J = 8 Hz), 7.76 m
(2H, Harom). 13C NMR spectrum, δC, ppm: 21.41 (CH3),
21.71 (CH3), 71.75 (CH), 98.33 and 99.71 (C4, C4′),
126.05 (4C, CHarom), 127.25 (2C, CHarom), 129.13 (2C,
CHarom), 129.79 (2C, CHarom), 130.00 (2C, CHarom),
130.57 (CHarom); 123.97, 126.25, 133.69, 139.26,
141.53, 156.52, 159.06, 163.47, 170.86 (Cquat); 172.32
(C=O). Found, %: C 74.58; H 5.21; N 6.33.
C28H22N2O4. Calculated, %: C 74.65; H 4.92; N 6.22.
3
Harom), 7.64 d (2H, Harom, J = 8 Hz), 7.80 m (2H,
Harom). 13C NMR spectrum, δC, ppm: 21.40 (CH3),
21.65 (CH3), 71.85 (CH), 97.70 and 100.31 (C4, C4′),
125.98 (2C, CHarom), 126.11 (2C, CHarom), 127.26 (2C,
CHarom), 129.32 (2C, CHarom), 129.77 (2C, CHarom),
129.80 (2C, CHarom), 131.05 (CHarom); 124.54, 126.67,
133.73, 139.23, 140.89, 156.59, 158.98, 163.37,
171.07 (Cquat); 172.10 (C=O). Found, %: C 74.75;
H 5.20; N 6.36. C28H22N2O4. Calculated, %: C 74.65;
H 4.92; N 6.22.
[5-(4-Methylphenyl)-1,2-oxazol-3-yl](phenyl)-
methyl 5-phenyl-1,2-oxazole-3-carboxylate
(XXXIII). Yield 82%, mp 171–173°C. IR spectrum, ν,
cm–1: 1735 (C=O), 1615, 1597, 1573, 1513, 1493,
1467, 1450, 1445 (C=C, C=N), 1240, 1136 (C–O–C).
1H NMR spectrum, δ, ppm: 2.38 s (3H, CH3), 6.57 s
(1H, CH), 6.99 s and 7.31 s (1H each, 4-H, 4′-H),
7.24 d (2H, Harom, 3J = 8 Hz), 7.38 d.d (1H, Harom, 3J =
7.3 Hz), 7.43 d.d (2H, Harom, 3J = 7.3 Hz), 7.48 m (3H,
(4-Methylphenyl)[5-(4-methylphenyl)-1,2-oxaz-
ol-3-yl]methyl 5-(4-methylphenyl)-1,2-oxazole-3-
carboxylate (XXXVI). Yield 71%, mp 83–84°C. IR
3
Harom), 7.61 d (2H, Harom, J = 7.3 Hz), 7.65 d (2H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 10 2013

POTKIN et al.
1532
spectrum, ν, cm–1: 1740 (C=O), 1616, 1596, 1574,
cm–1: 1743 (C=O), 1618, 1597, 1567, 1514, 1470,
1435, 1402 (C=C, C=N), 1210, 1081 (C–O–C), 979,
1512, 1466, 1441, 1412 (C=C, C=N), 1231, 1135
1
1
833 (C–Cl). H NMR spectrum, δ, ppm: 2.38 s (3H,
(C–O–C). H NMR spectrum, δ, ppm: 2.36 s (3H,
CH3), 6.55 s (1H, CH), 7.23 d (2H, Harom, 3J = 8 Hz),
CH3), 2.38 s (3H, CH3), 2.41 s (3H, CH3), 6.58 s (1H,
3
7.27 s (1H, 4-H), 7.38 d.d (1H, Harom, J = 7.3 Hz),
CH), 6.92 s and 7.27 s (1H each, 4-H, 4′-H), 7.23 m
3
3
7.42 d.d (2H, Harom, J = 7.3 Hz), 7.60 m (2H, Harom),
(4H, Harom), 7.28 d (2H, Harom, J = 8 Hz), 7.49 d (2H,
3
7.63 d (2H, Harom, J = 8 Hz). 13C NMR spectrum, δC,
H
arom, 3J = 8 Hz), 7.64 d (2H, Harom, 3J = 8 Hz), 7.69 d
ppm: 21.64 (CH3), 72.10 (CH), 97.69 (C4), 125.95 (2C,
CHarom), 127.32 (2C, CHarom), 129.09 (2C, CHarom),
129.25 (CHarom), 129.79 (2C, CHarom); 124.45, 126.14,
136.57, 140.94, 151.00, 153.66, 157.89, 163.15 (Cquat);
171.10 (C=O). Found, %: C 56.79; H 3.29; Cl 16.12;
N 6.35; S 7.29. C21H14Cl2N2O3S. Calculated, %:
C 56.64; H 3.17; Cl 15.92; N 6.29; S 7.20.
3
(2H, Harom, J = 8 Hz). 13C NMR spectrum, δC, ppm:
21.37 (CH3), 21.61 (CH3), 21.67 (CH3), 71.77 (CH),
97.69 and 99.69 (C4, C4′), 125.95 (2C, CHarom), 126.01
(2C, CHarom), 127.24 (2C, CHarom), 129.74 (2C,
CHarom), 129.77 (2C, CHarom), 129.96 (2C, CHarom);
123.95, 133.75, 138.14, 139.18, 140.85, 141.47,
156.50, 159.03, 163.39, 171.03 (Cquat); 172.27 (C=O).
Found, %: C 75.11; H 5.41; N 6.15. C29H24N2O4. Cal-
culated, %: C 74.98; H 5.21; N 6.03.
4-[(4,5-Dichloro-1,2-thiazol-3-yl)carbonyloxy]-3-
methoxybenzyl 5-(4-methylphenyl)-1,2-oxazole-3-
carboxylate (XLIII). Yield 88%, mp 162–163°C. IR
spectrum, ν, cm–1: 3141, 3063, 3024 (=C–H), 2947,
2921, 2854 (C–H), 1750, 1731 (C=O), 1610, 1594,
1509, 1470, 1446, 1423 (C=C, C=N), 1247, 1165,
Phenyl(5-phenyl-1,2-oxazol-3-yl)methyl 4,5-di-
chloro-1,2-thiazole-3-carboxylate (XXXVII). Yield
82%, mp 111–113°C. IR spectrum, ν, cm–1: 1731
(C=O), 1613, 1591, 1573, 1494, 1465, 1449, 1426,
1406 (C=C, C=N), 1208, 1080 (C–O–C), 978, 833
(C–Cl). 1H NMR spectrum, δ, ppm: 6.60 s (1H, CH),
7.28 s (1H, 4-H), 7.42 m (6H, Harom), 7.60 m (2H,
1
1142 (C–O–C), 870, 821 (C–Cl). H NMR spectrum,
δ, ppm: 2.41 s (3H, CH3), 3.86 s (3H, CH3), 5.43 s
3
(2H, CH2), 6.89 s (1H, 4-H), 7.12 d (1H, Harom, J =
8 Hz), 7.14 s (1H, Harom), 7.21 d (1H, Harom, 3J = 8 Hz),
7.29 d (2H, Harom, 3J = 8.1 Hz), 7.70 d (2H, Harom, 3J =
8.1 Hz). 13C NMR spectrum, δC, ppm: 21.71 (CH3),
56.25 (OCH3), 67.37 (CH2), 99.58 (C4), 113.11
(CHarom), 121.35 (CHarom), 122.96 (CHarom), 126.06
(2C, CHarom), 130.00 (2C, CHarom); 124.03, 126.59,
134.69, 139.43, 141.49, 151.13, 151.25, 153.50,
156.75, 156.87 (Cquat); 160.07 and 172.27 (C=O). Mass
spectrum: m/z 518 [M]+. Found, %: C 53.65; H 3.19;
Cl 13.22; N 5.21; S 5.87. C23H16Cl2N2O6S. Calculated,
%: C 53.19; H 3.11; Cl 13.65; N 5.39; S 6.17.
M 519.35.
H
arom), 7.73 m (2H, Harom). 13C NMR spectrum, δC,
ppm: 72.05 (CH), 98.29 (C4), 125.99 (2C, CHarom),
127.30 (2C, CHarom), 129.10 (4C, CHarom), 129.27
(CHarom), 130.57 (CHarom); 126.11, 127.12, 136.50,
150.99, 153.62, 157.87, 163.21 (Cquat); 170.88 (C=O).
Found, %: C 55.94; H 2.98; Cl 16.35; N 6.44; S 7.51.
C20H12Cl2N2O3S. Calculated, %: C 55.70; H 2.80;
Cl 16.44; N 6.50; S 7.43.
(4-Methylphenyl)(5-phenyl-1,2-oxazol-3-yl)-
methyl 4,5-dichloro-1,2-thiazole-3-carboxylate
(XXXVIII). Yield 80%, mp 102–103°C. IR spectrum,
ν, cm–1: 1739 (C=O), 1613, 1593, 1574, 1516, 1464,
1452, 1417, 1404 (C=C, C=N), 1208, 1080 (C–O–C),
4-[(4,5-Dichloro-1,2-thiazol-3-yl)carbonyloxy]-3-
methoxybenzyl 4,5-dichloro-1,2-thiazole-3-carbox-
ylate (XLIV). Yield 54%, mp 137–138°C. IR spec-
trum, ν, cm–1: 3016 (=C–H), 2941 (C–H), 1749, 1731
(C=O), 1608, 1513, 1461, 1407 (C=C, C=N), 1236,
1
979, 833 (C–Cl). H NMR spectrum, δ, ppm: 2.36 s
3
(3H, CH3), 6.60 s (1H, CH), 7.23 d (2H, Harom, J =
8 Hz), 7.25 s (1H, 4-H), 7.43 m (3H, Harom), 7.49 d
3
(2H, Harom, J = 8 Hz), 7.74 m (2H, Harom). 13C NMR
1
spectrum, δC, ppm: 21.38 (CH3), 72.07 (CH), 98.31
(C4), 125.99 (2C, CHarom), 127.36 (2C, CHarom), 129.09
(2C, CHarom), 129.76 (2C, CHarom), 130.54 (CHarom);
126.07, 127.18, 133.58, 139.26, 150.92, 153.73,
157.93, 163.34 (Cquat); 170.80 (C=O). Found, %:
C 56.82; H 3.37; Cl 16.15; N 6.19; S 7.31.
C21H14Cl2N2O3S. Calculated, %: C 56.64; H 3.17;
Cl 15.92; N 6.29; S 7.20.
1214, 1156 (C–O–C), 876, 839, 815 (C–Cl). H NMR
spectrum, δ, ppm: 3.85 s (3H, CH3), 5.42 s (2H, CH2),
7.11 d (1H, Harom, 3J = 8 Hz), 7.15 s (1H, Harom), 7.20 d
3
(1H, Harom, J = 8 Hz). 13C NMR spectrum, δC, ppm:
56.20 (CH3), 67.59 (CH2), 113.06 (CHarom), 121.31
(CHarom), 122.95 (CHarom); 125.93, 126.55, 134.53,
139.39, 150.91, 151.10, 151.20, 153.43, 154.08 (Cquat);
156.80 and 158.97 (C=O). Mass spectrum: m/z 512
[M]+. Found, %: C 37.79; H 1.73; Cl 27.13; N 5.01;
S 11.94. C16H8Cl4N2O5S2. Calculated, %: C 37.37;
H 1.57; Cl 27.58; N 5.45; S 12.47. M 514.19.
[5-(4-Methylphenyl)-1,2-oxazol-3-yl](phenyl)-
methyl 4,5-dichloro-1,2-thiazole-3-carboxylate
(XXXIX). Yield 87%, mp 125–127°C. IR spectrum, ν,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 10 2013

SYNTHESIS OF FUNCTIONALLY SUBSTITUTED ISOXAZOLE
1533
Rastinejad, F., Marx, M.A., Schaeffer, T., Whalen, P.M.,
and Roberts, W.G., Cancer Res., 2003, vol. 63, p. 7301.
REFERENCES
1. Murugesan, N., Gu, Z., Spergel, S., Young, M., Chen, P.,
Mathur, A., Leith, L., Hermsmeier, M., Liu, E.C.,
Zhang, R., Bird, E., Waldron, T., Marino, A., Koplo-
witz, B., Humphreys, W.G., Chong, S., Morrison, R.A.,
Webb, M.L., Moreland, S., Trippodo, N., and
Barrish, J.C., J. Med. Chem., 2003, vol. 46, p. 125;
Gardner, T.S., Wenis, E., and Lee, J., J. Med. Chem.,
1959, vol. 2, p. 133; Pinto, P. and Dougados, M., Acta
Reumatol. Port., 2006, vol. 31, p. 215; Talley, J.J.,
Brown, D.L., Carter, J.S., Graneto, M.J., Koboldt, C.M.,
Masferrer, J.L., Perkins, W.E., Rogers, R.S., Shaffer, A.F.,
Zhang, Y.Y., Zweifel, B.S., and Seibert, K., J. Med.
Chem., 2000, vol. 43, p. 775.
2. Shailaja, M., Manjula, A., and Vittal Rao, B., Indian J.
Chem., Sect. B, 2011, vol. 50, p. 214; Rzeski, W.,
Ikonomidou, Ch. and Turski, L., Biochem. Pharmacol.,
2002, vol. 64, p. 1195; Kamal, A., Bharathi, E.V.,
Reddy, J.S., Ramaiah, M.J., Dastagiri, D., Reddy, K.,
Viswanath, A., Reddy, T.L., Shaik, T.B., Pushpa-
valli, S.N.C.V.L., and Bhadra, M.P., Eur. J. Med. Chem.,
2011, vol. 46, p. 691.
5. Kulchitsky, V.A., Potkin, V.I., Zubenko, Yu.S., Cher-
nov, A.N., Talabaev, M.V., Demidchik, Yu.E., Petke-
vich, S.K., Kazbanov, V.V., Gurinovich, T.A.,
Roeva, M.O., Grigoriev, D.G., Kletskov, A.V., and
Kalunov, V.N., Med. Chem., 2012, vol. 8, p. 22.
6. Potkin, V.I., Dikusar, E.A., and Petkevich, S.K., Dokl.
Nats. Akad. Navuk Belarusi, 2008, vol. 52, p. 60.
7. Potkin, V.I., Gadzhily, R.A., Dikusar, E.A., Petke-
vich, S.K., Zhukovskaya, N.A., Aliev, A.G., and Nagie-
va, Sh.F., Russ. J. Org. Chem., 2012, vol. 48, p. 127.
8. Potkin, V.I., Kletskov, A.V., Petkevich, S.K., Khotyano-
vich, M.O., Zubenko, Yu.S., and Kul’chitskii, V.A.,
Russ. J. Org. Chem., 2013, vol. 49, p. 283.
9. Dikusar, E.A., Nechai, N.I., Potkin, V.I., Kaberdin, R.V.,
Kozlov, N.G., and Kovganko, N.V., Khim. Prirodn.
Soedin., 2003, vol. 39, p. 186; Potkin, V.I., Zuben-
ko, Yu.S., Bykhovetz, A.I., Zolotar, R.M., and Goncha-
ruk, V.M., Nat. Prod. Commun., 2009, vol. 4, p. 1205.
10. Nechai, N.I., Dikusar, E.A., Potkin, V.I., and Kaber-
din, R.V., Russ. J. Org. Chem., 2004, vol. 40, p. 1009.
11. Zapol’skii, V.A., Namyslo, J.C., de Meijere, A., and Kauf-
3. Clerici, F., Gelmi, M.L., Pellegrino, S., and Pocar, D.,
Bioactive Heterocycles III, Khan, M.T.H., Ed., Berlin:
Springer, 2007, p. 179.
4. Beebe, J.S., Jani, J.P., Knauth, E., Goodwin, P.,
Higdon, C., Rossi, A.M., Emerson, E., Finkelstein, M.,
Floyd, E., Harriman, S., Atherton, J., Hillerman, S.,
Soderstrom, C., Kou, K., Gant, T., Noe, M.C., Foster, B.,
mann, D.E., Beilst. J. Org. Chem., 2012, vol. 8, p. 621.
12. Takhistov, V.V., Prakticheskaya mass-spektrometriya
organicheskikh soedinenii (Practical Mass Spectrometry
of Organic Compounds), Leningrad: Leningr. Gos.
Univ., 1977, p. 265; Takhistov, V.V., Rodin, A.A., and
Maksimova, B.N., Usp. Khim., 1991, vol. 60, p. 2143.
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