Synthesis and transformations of derivatives of 2-aryl-5-(3,5-dimethyl-1H- pyrazol-1-yl)-1,3-oxazole-4-carboxylic acid

Article abstract of DOI:10.1134/S1070363210110216

On the basis of methyl esters of 2-aryl-5-hydrazino-1,3-oxazole-4- carboxylic acids the earlier unknown methyl esters of 2-aryl-5-(3,5-dimethyl-1H- pyrazol-1-yl)-1,3-oxazole-4-carboxylic acids as well as their functional derivatives were synthesized. The latter were used for further transformations, in particular, for introducing the residues of highly basic aliphatic amines into the 5 position of oxazole, and the oxazol-2-yl moiety into the 4 position of the oxazole ring. Pleiades Publishing, Ltd., 2010.

Full text of DOI:10.1134/S1070363210110216

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 11, pp. 2358–2365. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © V.M. Prokopenko, S.G. Pil’o, A.N. Vasilenko, V.S. Brovarets, 2010, published in Zhurnal Obshchei Khimii, 2010, Vol. 80, No. 11,
pp. 1895–1902.
Synthesis and Transformations of Derivatives
of 2-Aryl-5-(3,5-dimethyl-1Н-pyrazol-1-yl)-
1,3-oxazole-4-carboxylic Acid
V. M. Prokopenko, S. G. Pil’o, A. N. Vasilenko, and V. S. Brovarets
Institute of Bioorganic Chemistry and Oil Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02660 Ukraine
e-mail: brovarets@bpci.kiev.ua
Received November 24, 2009
Abstract―On the basis of methyl esters of 2-aryl-5-hydrazino-1,3-oxazole-4-carboxylic acids the earlier
unknown methyl esters of 2-aryl-5-(3,5-dimethyl-1Н-pyrazol-1-yl)-1,3-oxazole-4-carboxylic acids as well as
their functional derivatives were synthesized. The latter were used for further transformations, in particular, for
introducing the residues of highly basic aliphatic amines into the 5 position of oxazole, and the oxazol-2-yl
moiety into the 4 position of the oxazole ring.
DOI: 10.1134/S1070363210110216
The functionalization of the 1,3-oxazole ring is one
of the most important protocols for synthesis of new
compounds promising for the search for various potential
bioregulators.
and V → VII. As follows from Scheme 1, the pyrazole
ring remains intact in all processes. However, we have
also studied the reactions of compounds III in which
the pyrazole fragment plays the role of a good leaving
group, which is typical f this structure [9, 10]. Thus, by
heating compounds III with highly basic amines
(monoethanolamine, its methyl ether, N,N-dimethyl-
ethylenediamine, benzylamine, furfurylamine) in
dioxane the derivatives of 5-aminooxazole IV formed
which cannot be prepared by the known oxazole cycliza-
tion [11, 12].
Among the functionally substituted oxazoles the
derivatives of 1,3-oxazole-4-carboxylic acid are of con-
siderable interest. Various heterocyclic compounds
were synthesized on their basis [1–3], and compounds
possessing strong bactericidal and antiblastic activity
were found [4–6]. Therefore, the development of new
approaches to synthesis of substituted oxazoles with
biophore substituents is a problem of today.
It should be noted that reaction III → IV can be
complicated by the Cornforth rearrangement, which is
typical for 4-carbonyl-substituted oxazoles [13–16].
Therefore, to unequivocally confirm the structure of the
products of the reaction of the derivatives of 1,3-oxazole-
4-carboxylic acid III with amines additional spec-
troscopic studies were required. To this end we have
The goal of the present work was to synthesize the
derivatives of oxazole-4-carboxylic acid having in the
4 position of the ring the 3,5-dimethyl-1Н-pyrazol-1-yl
moiety (Scheme 1), which is an important fragment in
many biologically active organic compounds [7, 8].
1
13
The key products in all these transformations are
methyl esters of 2-aryl-5-(3,5-dimethyl-1Н-pyrazol-1-
yl)-1,3-oxazole-4-carboxylic acids III prepared by the
sequence of transformations I → II → III. The first
step in this process has been performed earlier [1],
whereas the cyclization II → III is studied for the first
time. Compounds III were used for the synthesis of
acids V, that underlay the preparation of their acyl
chlorides VI and N-substituted amides VII (Table 1)
by the sequences of transformations V → VI → VII
performed a complex Н and С NMR study using the
homonuclear COSY, NOESY and heteronuclear HMQC,
HMBC experiments. All correlations are compiled in
Table 2. Also, using the quantum-chemical program
PRIRODA [17], the 13С chemical shifts for structure IVf
and a hypothetical structure of the Cornforth rearrange-
ment IVA were calculated (see Fig. 1).
Comparison of the results of quantum-chemical
calculations with the experimental data from Table 2
2358

SYNTHESIS AND TRANSFORMATIONS OF DERIVATIVES
2359
Scheme 1.
H
N
O
O
3.5 H2NNH2 H2O
Ar
OMe
OMe
N
O
Ar
Cl
Cl
NHNH2
IIа, IIb
O
Iа, Ib
O
O
O
O
OMe
NHAlk
IVa−IVf
OMe
N
N
AlkNH2
N
Ar
Ar
N
O
O
IIIа, IIIb
(1) NaOH
(2) AcOH
O
O
OH
Cl
N
SOCl2
N
N
N
Ar
Ar
N
N
O
O
Vа, Vb
VIа, VIb
O
NHR
N
N
RNH2, Py
(1) 1,1'-carbonyldiimidazole
(2) RNH2
Ar
N
O
VIIа−VIIf
Ar = Ph (I–VIа, VIIа, VIIc, VIIe), 4-MeC6H4 (I–IIIb, IVb–IVf, Vb, VIb, VIIb, VIId, VIIf); Alk = CH2CH2OH (IVа,
IVb), CH2CH2OMe (IVc), CH2CH2NMe2 (IVd), CH2Ph (IVe);
VIId), 4-MeC6H4 (VIIe, VIIf).
R = H (VIIа, VIIb), CH2Ph (VIIc,
(IVf);
CH2
O
suggests the formation of methyl esters of 4-oxazole-
carboxylic acid IV rather than the alternative amides of
the type IVA.
and IX → XI → XIII. The final products of these
transformations are the derivatives of 1,3-oxazole,
which contain in the 4 position of the ring the 5-amino-
4-cyano-1,3-oxazol-2-yl (compounds XII) or 5-amino-
4-dimethoxyphosphoryl-1,3-oxazol-2-yl (compounds
XIII) fragments.
The full assignment of the signals in the 1Н and 13С
NMR spectra of compound IVf is given in Fig. 2.
The modification of substituents at the С4 atom of
the oxazole ring was performed by the example of
amides VIIa, VIIb along the sequences of trans-
formations VII → VIII → IX, as well as IX → X → XII
The composition of all new oxazole derivatives
shown in Schemes 1 and 2 was confirmed by elemental
analysis (Table 1), and their structure, by the IR and 1Н
NMR spectra (Table 3). Thus, the presence of the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 11 2010

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PROKOPENKO et al.
Table 1. Yields, constants and elemental analysis data of compounds III–XIII
mp, °С
Found, %
H
Calculated, %
Comp.
no.
(solvent for
crystallization)
Yield, %
Formula
C
N (Cl)
C
H
N (Cl)
88
92
45
51
58
61
72
85
95
93
89
91
88
92
146–148 (EtOH)
143–145 (EtOH)
144–147(EtOH)
163–167 (2-propanol)
108–111 (2-propanol)
114–116 (МfCN)
150–154 (EtOH)
189–192 (EtOH)
210–212 (МfCN)
192–195 (МfCN)
142–148а
64.73
64.52
59.47
60.77
62.12
63.25
70.89
65.31
63.65
64.58
–
5.15
5.45
5.30
5.79
6.19
6.95
5.75
5.21
4.58
5.00
13.99
13.31
10.77
10.29
9.71
C16H15N3O3
C17H17N3O3
C13H14N2O4
C14H16N2O4
C15H18N2O4
C16H21N3O3
C19H18N2O3
C17H16N2O4
C15H13N3O3
C16H15N3O3
64.64
65.58
59.54
60.86
62.06
63.35
70.79
65.38
63.60
64.64
59.71
60.86
63.82
64.85
70.95
71.48
70.95
71.48
5.09
5.50
5.38
5.84
6.25
6.98
5.63
5.16
4.63
5.09
4.01
4.47
5.00
5.44
5.41
5.74
5.41
5.74
14.13
13.50
IIIа
IIIb
IVа
IVb
IVc
IVd
IVe
IVf
10.68
10.14
9.65
13.87
8.64
13.85
8.69
9.02
8.97
14.80
14.08
14.83
Vа
14.13
Vb
–
13.74 (12.28) C15H12ClN3O2
13.47 (11.95) C16H14ClN3O2
13.93 (11.75)
13.31 (11.23)
19.85
VIа
VIb
VIIа
VIIb
VIIc
VIId
VIIe
VIIf
126–132 а
–
–
189–192 (EtOH)
184–187 (EtOH)
63.95
64.98
70.99
71.41
70.90
71.43
5.10
5.51
5.45
5.79
5.45
5.69
19.84
18.61
14.90
14.53
15.00
14.31
C15H14N4O2
C16H16N4O2
C22H20N4O2
C23H22N4O2
C22H20N4O2
C23H22N4O2
18.91
85 (90)b 139–142 (2-propanol)
79 (83)b 140–143 (2-propanol)
15.04
14.50
90
86
150–152 (EtOH)
190–194
15.04
14.50
(EtOH–DMF, 1:1)
169–171 (МfCN)
164–168 (МfCN)
165–168а
89
92
66
60
82
47.46
48.68
–
3.48
3.81
–
13.01 (24.90) C17H15Cl3N4O3
(24.14) C18H17Cl3N4O3
47.52
48.72
45.56
46.78
53.75
3.52
3.86
3.15
3.49
3.26
13.04 (24.75)
12.63 (23.97)
12.50 (31.64)
12.12 (30.68)
17.41 (17.63)
VIIIа
VIIIb
IXа
12.48 (30.91) C17H14Cl4N4O2
11.98 (29.91) C18H16Cl4N4O2
17.61 (18.54) C18H13Cl2N5O2
170–174а
–
–
IXb
212–214
53.62
3.15
Xа
(МfCN–dioxane, 4:1)
213–215
79
54.75
3.57
17.20 (17.47) C19H15Cl2N5O2
11.67 (19.78) C19H20Cl3N4O5Pc
54.82
3.63
16.82 (17.03)
Xb
(МfCN–dioxane, 4:1)
130–134а
86
86
88
55
62
–
–
43.74
63.45
67.27
55.31
57.94
3.86
4.84
5.65
5.25
5.67
10.74 (20.39)
20.18
XI
261–263 (МfCN)
210–215 (МfCN)
150–153 (toluene)
158–162 (toluene)
63.33
67.29
55.24
57.86
4.75
5.61
5.13
5.60
20.96
19.52
14.39
14.18
C22H20N6O3
C24H24N6O2
C23H26N5O6Pd
C24H28N5O5Pe
XIIа
XIIb
XIIIа
XIIIb
19.61
14.02
14.08
a
Melting points are given for nonrecrystallized products. b Yields of compounds VIIc, VIId obtained by method c are given in brackets.
c Found, %: Р 5.81. Calculated, %: Р 5.94. d Found, %: Р 6.09. Calculated, %: Р 6.20. e Found, %: Р 6.15. Calculated, %: Р 6.23.
pyrazole fragment is proved by 1Н NMR spectra, which
contain the signals of two methyl groups at 2.20–2.21 ppm
and the singlet signal С4Н at 6.11–6.19 ppm. The
methoxycarbonyl group in compounds III, IV in the
IR spectra is characterized by the absorption band in
the range 1647–1721 cm–1, and in the 1Н NMR spectra,
by the singlet signals at 3.74–3.79 ppm. The participa-
tion of the dichlorovinylamide and trichloroethyl-
amide fragments in cyclization of compounds X and XI
can be concluded from the disappearance of the amide
group signals in the IR spectra in the ranges 1640–
1800 and 3000–3600 cm–1. The presence of the cyano
group in compounds X and XII is proved by the presence
of strong bands at 2222–2229 cm–1 in the IR spectra.
Finally, in the 1Н NMR spectra of all these compounds
the signals of the aromatic and aliphatic protons with
the proper ratio of integral intensities are registered.
Therefore, methyl esters of 2-aryl-5-(3,5-dimethyl-
1Н-pyrazol-1-yl)-1,3-oxazole-4-carboxylic acids were
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 11 2010

SYNTHESIS AND TRANSFORMATIONS OF DERIVATIVES
Table 2. NOESY, HMQC, HMBC correlations found for compound IVfa
2361
1Н, δ, ppm
13C, δ, ppm
1Н, δ, ppm
COSY
NOESY
HMQC
HMBC
2.32
3.71
4.56
6.38
7.27
7.58
7.71
7.88
7.27
–
7.27
–
21.66
51.26
130.33, 140.20
163.27
7.88
6.38, 7.88
4.56
40.58
160.08, 152.65, 108.27
152.65, 143.23
7.58
108.27, 111.25
130.33
143.23
125.61
–
2.32, 7.71
6.38
2.32, 7.71
–
21.66, 124.48, 130.33
108.27, 152.64
7.27
7.27
125.61, 140.20, 149.72
160.08
4.56
4.56
a
For assignment of the signals in compound IVf see Fig. 2.
163.69
O
105.19
154.54
O
110.40
OMe
N
N
N
Cornforth rearrangement
Ar
H
O
NH
Ar
O
OMe
O
163.42
149.74
148.45
160.24
O
IVе
IVА
Fig. 1. Assignment of signals (ppm) in the 13С NMR spectra of compound IVf and the hypothetical structure of the Cornforth
rearrangement IVA based on quantum chemical calculations.
6.38
111.25
H
6.38
108.27
4
H
7.58
143.23
3
H
5
7.88
H
a
O
O
2
163.27
O
103.98
152.65
N
4
5
H
3.71
51.26
H
H
4.56
40.58
b
N
H
H
H
O
2
160.08
124.48
149.72
7.71
1
125.61
6
2
3
c
5
7.27
130.33
H
4
140.20
H
H
H
2.32
21.66
Fig. 2. Principal correlations (shown by arrows) and assignment of signals (ppm) in the 1Н and 13С NMR spectra of compound IVf.
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2362
PROKOPENKO et al.
Scheme 2.
OH
O
O
CCl3
NH2
N
N
H
N
N
O
Δ
+
N
Cl3C
Ar
Ar
N
N
H
O
O
VIIа, VIIb
VIIIа, VIIIb
SOCl2
Cl
O
CCl3
N
H
N
2 NaCN
P(OMe)3
Ar = Ph
N
Ar
N
O
IXa, IXb
P(O)(OMe)2
CCl3
O
CN
O
Cl
Cl
N
H
N
H
N
O
N
N
Ph
N
Ar
N
N
O
XI
Xа, Xb
4.5 HNR1R2
3.5 HNR1R2
NR1R2
NR1R2
O
O
P(O)(OMe)2
CN
N
N
N
N
N
N
Ph
XIIIа, XIIIb
O (XIIа, XIIIа),
Ar
N
N
O
O
XIIа, XIIb
Ar = Ph (VII−Xа, XIIа), 4-MeC6H4 (VII−Xb, XIIb); NR1R2 = N
N
(XIIb, XIIIb).
synthesized and their reaction with highly basic
aliphatic amines was studied; also, the modification of
the 4 position of the oxazole ring was performed
important for the search for compounds with various
biological activity among the synthesized substances.
VXR-300 spectrometer, 1Н–13С NMR spectra with hetero-
nuclear correlation were obtained on a Mercury-400
spectrometer (400 and 100 MHz, respectively) in
DMSO-d6, with TMS as an internal standard. Mass
spectra were taken on an Agilent 1100/DAD/MSD VL
G1965 instrument. Melting points were measured on a
Fisher-Johns unit.
EXPERIMENTAL
Methyl 2-acylamino-3,3-dichlorovinyl-acrylates
(Ia, Ib) were obtained as described in [18].
IR spectra were taken on a Vertex 70 spectrometer
in KBr, Н NMR spectra were recorded on a Varian
1
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 11 2010

SYNTHESIS AND TRANSFORMATIONS OF DERIVATIVES
Table 3. Spectral data for synthesized compounds III–XIII
2363
Comp.
no.
IR spectrum (KBr), ν, cm–1
1H NMR spectrum, δ, ppm (DMSO-d6)
1721 (C=O)
1719 (C=O)
2.21 s (6Н, 2СН3), 3.79 s (3Н, OСН3), 6.19 s (1Н, СН), 7.61–8.02 m (5H, С6Н5)
IIIа
2.20 s (6Н, 2СН3), 2.40 s (3Н, СН3), 3.78 s (3Н, OСН3), 6.19 s (1Н, СН), 7.38–7.93 m (4H,
С6Н4)
IIIb
1681 (C=O)а, 3359 (NH, ОН) 3.51–3.60 m (4Н, 2СН2), 3.75 s (3Н, OСН3), 4.90 t (1Н, OH), 7.32 m (1Н, NH), 7.47–7.84 m
(5H, С6Н5)
1682 (C=O)а, 3307, 3378 2.35 s (3Н, СН3), 3.49-3.59 m (4Н, 2СН2), 3.74 s (3Н, OСН3), 4.89 m (1Н, OH), 7.28–7.72 m
IVа
IVb
IVc
IVd
IVe
IVf
(NH, ОН)
(5H, С6Н4, NH)
1673 (C=O)а, 3365 (NH)
2.35 s (3Н, СН3), 3.29 s (3Н, OСН3), 3.56 m (4Н, 2СН2), 3.74 s (3Н, OСН3), 7.31–7.72 m (5H,
С6Н4, NH)
1664 (C=O)а, 3371 (NH)
1647 (C=O)а, 3366 (NH)
1667 (C=O)а, 3357 (NH)
2.21 s [6Н, N(СН3)2], 2.35 s (3Н, СН3), 2.48–3.49 m (4Н, 2СН2), 3.74 s (3Н, OСН3), 7.22 t
(1Н, NH), 7.29–7.74 m (4H, С6Н4)
2.34 s (3Н, СН3), 3.75 s (3Н, OСН3), 4.60 m (2Н, СН2), 7.24–7.68 m (9H, С6Н4, С6Н5), 8.08 t
(1Н, NH)
2.32 s (3Н, СН3), 3.71 s (3Н, OСН3), 4.56 d (2Н, СН2), 6.38–7.71 m (7H, С6Н4, С4Н3О), 7.88 t
(1Н, NH)
1708 (C=O), 2440 (OHass.) 2.21 s (6Н, 2СН3), 6.17 s (1Н, СН), 7.60–8.03 m (5H, С6Н5), 13.61 br.s (1Н, ОН)
Vа
1731 (C=O), 2459 (OHass.) 2.22 s (6Н, 2СН3), 2.41 s (3Н, СН3), 6.11 s (1Н, СН), 7.38–7.90 m (4H, С6Н4), 13.27 br.s (1Н,
ОН)
Vb
1698 (C=O), 3260, 3467 2.20 s (6Н, 2СН3), 6.15 s (1Н, СН), 7.60–8.05 m (5H, С6Н5), 7.76 s, 7.90 s (2H, NH2)
VIIа
VIIb
VIIc
VIId
(NH2)
1693 (C=O), 3260, 3464 2.20 s (6Н, 2СН3), 2.40 s (3Н, СН3), 6.14 s (1Н, СН), 7.39–7.94 m (4H, С6Н4), 7.73 s, 7.87 s
(NH2)
(2H, NH2)
1660 (C=O), 3314 (NH)
2.18 s (6Н, 2СН3), 4.43 d (2Н, СН2), 6.14 s (1Н, СН), 7.24–8.06 m (10H, 2С6Н5), 9.14 br.s
(1H, NH)
1678 (C=O), 3403 (NH)
2.18 s (6Н, 2СН3), 2.39 s (3Н, СН3), 4.43 br.s (2Н, СН2), 6.13 s (1Н, СН), 7.25–7.96 m (9H,
С6Н4, С6Н5), 9.10 br.s (1H, NH)
1679 (C=O)
1672 (C=O)
2.24 m (9Н, 3СН3), 6.19 s (1Н, СН), 7.15–8.12 m (9H, С6Н4, С6Н5), 10.36 s (1H, NH)
2.23–2.40 m (12Н, 4СН3), 6.17 s (1Н, СН), 7.16–7.99 m (8H, 2С6Н4), 10.29 s (1H, NH)
VIIe
VIIf
1660 (C=O), 3168, 3398 2.28 d (6Н, 2СН3), 5.86–5.89 m (1Н, СН), 6.25 s (1Н, СН), 7.59–8.07 m (5H, С6Н5, 1Н, ОН),
(NHass., ОНass.) 9.03 d (1H, NH)
1664 (C=O), 3168, 3300 2.22–2.40 m (9Н, 3СН3), 5.87 m (1Н, СН), 6.23 s (1Н, СН), 7.39–7.98 m (5H, С6Н4, ОН), 8.90
VIIIа
VIIIb
(NHass., ОНass.)
1673 (C=O), 2229 (CN)
2222 (CN)
br.s (1H, NH)
2.25 s (6Н, 2СН3), 6.22 s (1Н, СН), 7.63–8.08 m (5H, С6Н5), 10.89 s (1H, NH)
2.21 s (6Н, 2СН3), 3.40–3.72 m [8H, О(CH2)4N], 6.21 s (1Н, СН), 7.62–8.06 m (5H, С6Н5)
Xа
XIIа
XIIb
2225 (CN)
1.59 br.s, 3.38 br.s [10H, (CH2)5N], 2.23 d (6Н, 2СН3), 2.40 s (3Н, СН3), 6.22 s (1Н, СН),
7.41–7.92 m (4H, С6Н4)
1640–1800, 3000–3600 (no 2.21 s (6Н, 2СН3), 3.44–3.66 m [14H, О(CH2)4N, 2OСН3], 6.20 s (1Н, СН), 7.60–8.09 m (5H,
bands) С6Н5)
1640–1800, 3000–3600 (no 1.57–3.66 m [16H, (CH2)5N, 2OСН3], 2.23 br.s (6Н, 2СН3), 6.14 s (1Н, СН), 7.60–8.08 m (5H,
bands) С6Н5)
а Band with shoulder.
XIIIа
XIIIb
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PROKOPENKO et al.
Methyl 2-aryl-5-hydrazino-1,3-oxazole-4-carboxy-
was added, the precipitate was filtered off, and com-
lates (IIa, IIb) were obtained as described in [9].
pounds VIIc–VIIf were purified by crystallization.
c. A mixture of 0.005 mol of one of compounds Va,
Vb and 0.005 mol of 1,1'-carbonyldiimidazole in
20 ml of dry tetrahydrofuran was stirred at 30–40°С
for 1 h, to the warm solution 0.005 mol of the cor-
responding amine was added, the reaction mixture was
cooled to 20–25°С and stirred for 12 h at this tem-
perature. The solvent was removed in a vacuum, the
residue was treated with water, the precipitate was
filtered off, and compounds VIIc, VIId purified by
crystallization from 2-propanol. The mixed probe of
the samples of compounds VIIc and VIId prepared by
methods b and c did not give depression of the melting
Methyl 2-aryl-5-(3,5-dimethyl-1Н-pyrazol-1-yl)-
1,3-oxazole-4-carboxylates acids (IIIa, IIIb). A mix-
ture of 0.01 mol of compound IIa, IIb, 0.03 mol of
acetylacetone, and 1 ml of acetic acid in 20 ml of dry
methanol was refluxed for 6 h. After cooling the
precipitate was filtered off and compounds IIIa, IIIb
were purified by crystallization. Additional amount of
the products was isolated from the filtrate.
Methyl 5-amino-2-aryl-1,3-oxazole-4-carboxy-
lates (IVa–IVf). A mixture of 0.002 mol of com-
pound IIIa, IIIb and 0.01 mol of the corresponding
amine in 10 ml of dry dioxane was refluxed for 18 h,
dioxane and excess of amine were removed in a
vacuum, the residue was treated with water, com-
pounds IVa–IVf were filtered off and purified by
crystallization.
1
point. IR and H NMR spectra of the samples were
identical.
2-Aryl-5-(3,5-dimethyl-1Н-pyrazol-1-yl)-1,3-oxa-
zole-4-carboxylic acids N-(1-hydroxy-2,2,2-trichloro-
ethyl)amides (VIIIa, VIIIb). A mixture of 0.007 mol
of one of compounds VIIa, VIIb, 10 ml of chloral, and
0.3 ml of concn. sulfuric acid was refluxed for 8 h,
cooled to room temperature, 80 ml of water was added,
the precipitate formed was filtered off, and compounds
VIIIa, VIIIb were purified by crystallization.
2-Aryl-5-(3,5-dimethyl-1Н-pyrazol-1-yl)-1,3-oxa-
zole-4-carboxylic acids (Va, Vb). A mixture of
0.01 mol of compound IIIa, IIIb and 0.011 mol of
sodium hydroxide in 20 ml of aqueous methanol was
refluxed for 4 h, cooled, acidified by acetic acid to pH
~4–5, methanol was removed in a vacuum, the residue
was treated with water, compounds Va, Vb were
filtered off and purified by crystallization.
2-Aryl-5-(3,5-dimethyl-1Н-pyrazol-1-yl)-1,3-oxa-
zole-4-carboxylic acids N-(1,2,2,2-tetrachloroethyl)-
amides (IXa, IXb). To a suspension of 0.005 mol of
compound VIIIa, VIIIb in 20 ml of dry benzene
0.01 mol of thionyl chloride was added, the mixture
was refluxed for 8 h, cooled to room temperature 20–
25°С, treated with 20 ml of dry hexane, the precipitate
formed was filtered off, dried, and compounds IXa,
IXb were used for further transformations without
additional purification.
2-Aryl-5-(3,5-dimethyl-1Н-pyrazol-1-yl)-1,3-oxa-
zole-4-carbonyl chlorides (VIa, VIb). A mixture of
0.01 mol of compound Va, Vb with 10 ml of thionyl
chloride was kept at room temperature for 24 h, thionyl
chloride removed in a vacuum, the residue was treated
with dry benzene, and after removal of solvent in a
vacuum compounds VIa, VIb were used for further
transformations without additional purification.
2-Aryl-5-(3,5-dimethyl-1Н-pyrazol-1-yl)-1,3-oxa-
zole-4-carboxylic acids N-(2,2-dichloro-1-cyano-
vinyl)amides (Xa, Xb). To a solution of 0.0066 mol of
potassium cyanide in 10 ml of water a solution of
0.003 mol of compound IXa, IXb in 20 ml of dry
dioxane was added dropwise during 10 min at cooling
with ice water and under vigorous stirring. The mix-
ture was stirred for 8 h, 70 ml of water was added, the
precipitate formed was filtered off, and compounds
Xa, Xb were purified by crystallization.
2-Aryl-5-(3,5-dimethyl-1Н-pyrazol-1-yl)-1,3-oxa-
zole-4-carboxylic acids amides (VIIa–VIIf). a. To
50 ml of 25% aqueous ammonia the solution of
0.005 mol of compound VIa, VIb in 20 ml of dry
dioxane was added dropwise at cooling with ice water
under stirring, the mixture was allowed to stay over-
night at room temperature, the precipitate formed was
filtered off, and compounds VIIa, VIIb were purified
by crystallization.
O,O-Dimethyl-(2,2,2-trichloro-1-{[5-(3,5-dimethyl-
1Н-pyrazol-1-yl)-2-phenyl-oxazole-4-carbonyl]amino}-
ethyl)phosphonate (XI). A mixture of 0.002 mol of
compound Xa and 0.0022 mol of trimethyl phosphite
in 5 ml of dry benzene was refluxed for 4 h. After
b. To the solution of 0.005 mol of the cor-
responding amine in 10 ml of dry dioxane 0.0075 mol
of pyridine and 0.005 mol of compound VIa, VIb was
added. The solution was heated to boiling and allowed
to stay overnight at room temperature, 80 ml of water
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 11 2010

SYNTHESIS AND TRANSFORMATIONS OF DERIVATIVES
2365
4. Clarke, H.T., Johnson, J.R., and Robinson, R., The
Chemistry of Penicillin, Princeton: Princeton University
Press, 1949, p. 688.
cooling, the mixture was treated with dry hexane, the
precipitate formed was filtered off, dried, and com-
pound XI was used for further transformations without
additional purification.
5. Turchi, I.J., Oxazoles. The Chemistry of Heterocyclic
Compounds, New York: Wiley, 1986, vol. 45, p. 109.
2-[2-Aryl-5-(3,5-dimethyl-1Н-pyrazol-1-yl)-1,3-
oxazol-4-yl]-5-morpholino(piperidino)-4-cyano-1,3-
oxazoles (XIIa, XIIb). A mixture of 0.001 mol of
compound Xa, Xb and 0.0035 mol of morpholine or
piperidine in 15 ml of dry tetrahydrofuran was stirred
at room temperature for 24 h. The precipitate formed
was filtered off, treated with water, and compounds
XIIa, XIIb were purified by crystallization. Additional
amount of these compounds was isolated from the
filtrate.
6. Palmer, D.C., Oxazoles: Synthesis, Reactions and Spec-
troscopy. Part A, Hoboken: Wiley, 2003, vol. 60, p. 255.
7. Bratenko, M.K., Vovk, M.V., and Sidorchuk, I.J., Farm.
Zh., 1999, no. 1, p. 68.
8. Bratenko, M.K., Panimarchuk, O.I., Chornous, V.A.,
Vovk, M.V., and Burdenyuk, I.P., Farm. Zh., 2007, no. 6,
p. 64.
9. Glidewell, C., Lightfoot, P., Royles, B.J.L., and
Smith, D.M., J. Chem. Soc., Perkin Trans. 2, 1997,
p. 1167.
4-Dimethoxyphosphoryl-2-[5-(3,5-dimethyl-1Н-
pyrazol-1-yl)-2-phenyl-1,3-oxazol-4-yl]-5-morpho-
lino(piperidino)-1,3-oxazoles (XIIIa, XIIIb). A mix-
ture of 0.001 mol of compound XI and 0.004 mol of
morpholine or piperidine in 8 ml of dry tetrahyd-
rofuran was stirred at room temperature for 5 days, the
precipitate formed was filtered off, the filtrate was
evaporated in a vacuum, the residue was treated with
water, the precipitate formed was filtered off, and
compounds XIIIa, XIIIb were purified by crys-
tallization.
10. Ishmetova, R.I., Latosh, N.I., Ganebhykh, I.N., Igna-
tenko, N.K., Tolshchina, S.G., and Rusinov, G.L., Russ.
J. Org. Chem., 2009, vol. 45, no. 7, p. 1102.
11. Drach, B.S., Mis’kevich, G.N., and Martynyuk, A.P.,
Zh. Org. Khim., 1978, vol. 14, no. 3, p. 508.
12. Matsumur, K., Miyashita, O., Shimadzu, H., and Hasi-
moto, N., Chem. Pharm. Bull., 1976, vol. 24, no. 5,
p. 941.
13. Dewar, M.J.S., J. Am. Chem. Soc., 1974, vol. 96, no. 19,
p. 6148.
14. Dewar, M.J.S. and Turchi, I.T., J. Org. Chem., 1975,
vol. 40, no. 10, p. 1521.
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