Redox transformation of adducts from cycloaddition of diazoacetic ester to β-arylacryloyloxiranes

Article abstract of DOI:10.1007/s10593-005-0264-7

It was established that, in addition to ethyl 4-aryl-3-(2,3-epoxyalkanoyl)- 4,5-dihydro-1H-pyrazole-5-carboxylates, the reaction of diazoacetic ester with β-arylacryloyloxiranes also gives ethyl 4-aryl-3(5)-(3-hydroxy-2- methylalkanoyl)-1H-pyrazole-5(3)-c

Full text of DOI:10.1007/s10593-005-0264-7

Chemistry of Heterocyclic Compounds, Vol. 41, No. 8, 2005
REDOX TRANSFORMATION OF ADDUCTS
FROM CYCLOADDITION OF DIAZOACETIC
ESTER TO β-ARYLACRYLOYLOXIRANES
S. G. Mikhalenok, N. M. Kuz'menok, and A. M. Zvonok
It was established that, in addition to ethyl 4-aryl-3-(2,3-epoxyalkanoyl)-4,5-dihydro-1H-pyrazole-5-
carboxylates, the reaction of diazoacetic ester with β-arylacryloyloxiranes also gives ethyl 4-aryl-3(5)-
(3-hydroxy-2-methylalkanoyl)-1H-pyrazole-5(3)-carboxylates. The latter are formed from the tautomeric
ethyl 4-aryl-5-(2,3-epoxyalkanoyl)-4,5-dihydro-1H-pyrazole-3-carboxylates as
intramolecular oxidative–reductive disproportionation.
a
result of
Keywords: β-arylacryloyloxiranes, diazoacetic ester, 4,5-dihydro-1H-pyrazoles, 1,3-dipolar
cycloaddition, spectral characteristics.
The cycloaddition of diazomethane to β-arylacryloyloxiranes, leading to the formation of 4-aryl-3-(2-
methyl-2,3-epoxypropionyl)-4,5-dihydro-1H-pyrazoles, has been investigated systematically [1]. The formation
of a mixture of two diastereomeric trans-4,5-dihydro-1H-pyrazole-5-carboxylates and in some cases a third
substance, which was tentatively assigned the structure of the cis isomer, was detected [2].
In order to extend the range of substituted epoxyalkanoyl-4,5-dihydro-1H-pyrazoles as synthons for the
structural analogs of the alkaloid vitasomnine and to determine the structure of the minor adducts formed in the
reaction we continued investigations into the cycloaddition of diazoacetic ester to β-arylacryloyloxiranes. By
heating the β-acryloyloxiranes 1a-i with diazoacetic ester in dioxane for 7-20 h we obtained 30-72% yields of
ethyl 4-aryl-3-(2-methyl-2,3-epoxyalkanoyl)-4,5-dihydro-1H-pyrazole-5-carboxylates 2a-i (Scheme 1) as
mixtures of two diastereomers (~1:1), differing in the relative configuration of the chiral center of the oxirane
ring. During chromatographic separation of the mother solutions after isolating the 4,5-dihydro-1H-pyrazoles
2a-e,g,i we obtained 5-28% yields of previously unidentified [2] ethyl 4-aryl-3(5)-(3-hydroxyalkanoyl)-1H-
pyrazole-5(3)-carboxylates 3a-e,g,i. Compounds 3a-e,g were individual compounds, while the pyrazole 3i was
isolated in the form of a diastereomeric mixture (1:1). In the reaction of compounds 1f,h with diazoacetic ester
the presence of the pyrazoles 3f,h in the reaction mixture was demonstrated by TLC and 1H NMR spectroscopy.
The structures of the obtained compounds 2a-i and 3a-i were confirmed by data from elemental analysis
1
and IR and H NMR spectra (Tables 1 and 2). Thus, the IR spectra of compounds 2a-i contain bands for the
stretching vibrations of the carbonyl and ester C=O groups in the regions of 1645-1659 and 1744-1750 cm-1 [3].
In the 1H NMR spectra of compounds 2a-i there are two AB spin systems of signals for the vicinal protons of the
4,5-dihydro-1H-pyrazole ring and the geminal protons of the epoxide ring,* a quartet and triplet for the ethyl
_______
* In the case of 2i a doublet for the protons of the methyl group and a quartet for the methine proton.
__________________________________________________________________________________________
Belarus State Technical University, Minsk 220050, Belarus; e-mail: serge_msg@yahoo.com. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, 1150-1160, August, 2005. Original article submitted
October 15, 2003.
0009-3122/05/4108-0977©2005 Springer Science+Business Media, Inc.
977

978

TABLE 1. The Characteristics of Compounds 2c,d,f,i, 3a-e,g,i, and 4a,b,d*
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
Н
N
2c
2d
2f
C16H17ClN2O4
C16H17FN2O4
С17H20N2O5
С17H20N2O4
С16H18N2O4
C16H17BrN2O4
C16H17ClN2O4
C16H17FN2O4
С16H17N3O6
C16H17BrN2O4
С17H20N2O4
C18H20N2O5
C18H19BrN2O5
C18H19FN2O5
57.26
57.06
60.21
59.99
61.49
61.44
64.29
64.54
63.68
63.56
50.20
50.41
57.30
57.06
60.18
59.99
55.12
55.33
50.22
50.41
64.35
64.54
62.51
62.78
51.19
51.08
59.84
59.66
5.18
5.09
5.57
5.35
6.26
6.07
6.40
6.37
6.12
6.00
4.31
4.49
5.22
5.09
5.46
5.35
4.74
4.93
4.40
4.49
6.52
6.37
5.73
5.85
4.64
4.52
5.50
5.29
8.43
8.32
8.88
8.75
8.56
8.43
9.03
8.86
9.40
9.27
7.49
7.35
8.48
8.32
8.92
8.75
12.27
12.10
7.50
7.35
9.05
8.86
8.31
8.13
6.79
6.62
7.90
7.73
126-128
125-128
122-123
143-145
125-127
142-145
136-137
128-129
172-173
123-125
Oil
49
55
30
54
28
28
22
18
25
26
5
2i
3a
3b
3c
3d
3e
3g
3i
4a
4b
4d
Oil
78
71
69
Oil
Oil
_______
* The characteristics of compounds 2a,b,e,g,h were described in [2].
TABLE 2. The Spectral Characteristics of Compounds 2c,d,f,i, 3a-e,g,i and
4a,b,d*
IR
Com-
pound
1Н NMR spectrum, δ, ppm (J, Hz)*2
spectrum,
ν, cm-1
1
2
3
2c
3261,
1744,
1645
1
8.50 (1Н, br. s, NH), 7.55 (2Н, d, J = 8.7, НAr-3',5'), 7.11 (2Н, d, J = 8.7,
НAr-2',6'), 4.70 (1Н, d, J = 4.0, Н-4), 4.33 (1Н, d, J = 4.0, Н-5), 4.23 (2Н, q,
J = 7.1, CH2CH3), 3.08 (1Н, d, J = 5.5, Нep), 2.82 (1Н, d, J = 5.5, Нep),
1.60 (3Н, s, СН3ep), 1.30 (3Н, t, J = 7.1, СН2СН3)
2
8.50 (1Н, br. s, NH), 7.55 (2Н, d, J = 8.7, НAr-3',5'), 7.11 (2Н, d, J = 8.7,
НAr-2',6'), 4.68 (1Н, d, J = 4.0, Н-4), 4.32 (1Н, d, J = 4.0, Н-5), 4.23 (2Н, q,
J = 7.1, CH2CH3), 3.26 (1Н, d, J = 5.5, Нep), 2.81 (1Н, d, J = 5.5, Нep),
1.60 (3Н, s, СН3ep), 1.30 (3Н, t, J = 7.1, СН2СН3)
2d
3256,
1748,
1650
1
7.10 (2Н, dd, J = 9.0, 4JHF = 5.8, НAr-2',6'), 7.00 (2Н, dd, J = 9.0, 3JHF = 9.0,
НAr-3',5'), 6.90 (1Н, br. s, NH), 4.66 (1Н, d, J = 3.9, Н-4), 4.27 (1Н, d, J = 3.9,
Н-5), 4.24 (2Н, q, J = 7.1, CH2CH3), 3.07 (1Н, d, J = 5.5, Нep), 2.82 (1Н, d,
J = 5.5, Нep), 1.60 (3Н, s, СН3ep), 1.30 (3Н, t, J = 7.1, СН2СН3)
2
7.10 (2Н, dd, J = 9.0, 4JHF = 5.8, НAr-2',6'), 7.00 (2Н, dd, J = 9.0, 3JHF = 9.0,
НAr-3',5'), 6.90 (1Н, br. s, NH), 4.64 (1Н, d, J = 4.0, Н-4), 4.24 (1Н, d, J = 4.0,
Н-5), 4.24 (2Н, q, J = 7.1, CH2CH3), 3.26 (1Н, d, J = 5.5, Нep), 2.80 (1Н, d,
J = 5.5, Нep), 1.58 (3Н, s, СН3ep), 1.30 (3Н, t, J = 7.1, СН2СН3)
979

TABLE 2 (continued)
1
2
3
2f
3296,
1752,
1650
1
7.10 (2Н, d, J = 8.6, НAr-2',6'), 6.99 (1Н, br. s, NH), 6.81 (2Н, d, J = 8.6,
НAr-3',5'), 4.63 (1Н, d, J = 3.8, Н-4), 4.27 (1Н, d, J = 3.8, Н-5), 4.23 (2Н, q,
J = 7.1, CH2CH3), 3.76 (3H, s, OCH3), 3.05 (1Н, d, J = 5.5, Нep), 2.80 (1Н, d,
J = 5.5, Нep), 1.60 (3Н, s, СН3ep), 1.22 (3Н, t, J = 7.1, СН2СН3)
2
7.10 (2Н, d, J = 8.6, НAr-2',6'), 6.99 (1Н, br. s, NH), 6.81 (2Н, d, J = 8.6,
НAr-3',5'), 4.60 (1Н, d, J = 3.7, Н-4), 4.24 (1Н, d, J = 3.7, Н-5), 4.23 (2Н, q,
J = 7.1, CH2CH3), 3.76 (3H, s, OCH3), 3.25 (1Н, d, J = 5.5, Нep), 2.80 (1Н, d,
J = 5.5, Нep), 1.60 (3Н, s, СН3ep), 1.22 (3Н, t, J = 7.1, СН2СН3)
2i
3261,
1750,
1649
1
7.15-7.35 (5Н, m, C6H5), 7.01 (1Н, br. s, NH), 4.63 (1Н, d, J = 4.1, Н-4),
4.28 (1Н, d, J = 4.1, Н-5), 4.23 (2Н, q, J = 7.1, CH2CH3), 3.27 (1Н, q, J = 5.2,
Нep), 1.54 (3Н, s, СН3ep), 1.35 (3Н, d, J = 5.2, СН3ep),
1.30 (3Н, t, J = 7.1, СН2СН3)
2
7.15-7.35 (5Н, m, C6H5), 7.01 (1Н, br. s, NH), 4.67 (1Н, d, J = 4.1, Н-4),
4.31 (1Н, d, J = 4.1, Н-5), 4.23 (2Н, q, J = 7.1, CH2CH3), 3.15 (1Н, q, J = 5.2,
Нep), 1.53 (3Н, s, СН3ep), 1.35 (3Н, d, J = 5.2, СН3ep),
1.30 (3Н, t, J = 7.1, СН2СН3)
3a
3b
3c
3d
3e
3g
3i
3340,
3140,
1710,
1670
7.30-7.45 (5Н, m, C6H5), 4.24 (2Н, q, J = 7.0, СН2СН3), 3.84 (1Н, br. dd,
J = 7.3, J = 11.0, СННОН), 3.71 (1Н, br. dd, J = 3.8, J = 11.0, СННОН),
3.52-3.70 (2Н, m, СНСН3, OH), 1.15 (3Н, t, J = 7.0, СН2СН3), 1.15 (3Н, d,
J = 6.3, СНСН3)
3345,
3140,
1711,
1673
7.42 (2Н, d, J = 8.7, НAr-3',5'), 7.12 (2Н, d, J = 8.7, НAr-2',6'), 4.22 (2Н, q,
J = 7.0, СН2СН3), 3.86 (1Н, br. dd, J = 7.1, J = 11.0, СННОН), 3.73 (1Н, br.
dd, J = 4.0, J = 11.0, СННОН), 3.50-3.70 (2Н, m, СНСН3, OH), 1.15 (3Н, t,
J = 7.0, СН2СН3), 1.15 (3Н, d, J = 6.2, СНСН3)
3346,
3142,
1710,
1671
7.45 (2Н, d, J = 8.6, НAr-3',5'), 7.13 (2Н, d, J = 8.6, НAr-2',6'), 4.22 (2Н, q,
J = 7.0, СН2СН3), 3.85 (1Н, br. dd, J = 7.1, J = 11.0, СННОН), 3.73 (1Н,
br. dd, J = 4.0, J = 11.0, СННОН), 3.50-3.70 (2Н, m, СНСН3, OH),
1.15 (3Н, t, J = 7.0, СН2СН3), 1.15 (3Н, d, J = 6.2, СНСН3)
7.29 (2Н, dd, J = 9.0, 4JHF = 5.6, НAr-2',6'), 7.06 (2Н, dd, J = 9.0, 3JHF = 9.0,
НAr-3',5'), 4.22 (2Н, q, J = 7.2, СН2СН3), 3.87 (1Н, br. dd, J = 8.5, J = 12.0,
СННОН), 3.71 (1Н, br. dd, J = 4.0, J = 12.0, СННОН), 3.50-3.75 (2Н, m,
СНСН3, OH), 1.15 (3Н, t, J = 7.2, СН2СН3), 1.14 (3Н, d, J = 6.6, СНСН3)
3349,
3141,
1712,
1670
3345,
3140,
1710,
1675
8.17 (2Н, d, J = 8.7, НAr-3',5'), 7.59 (2Н, d, J = 8.7, НAr-2',6'), 4.22 (2Н, q,
J = 7.1, СН2СН3), 3.86 (1Н, br. dd, J = 7.6, J = 11.5, СННОН), 3.72 (1Н,
br. dd, J = 4.0, J = 11.5, СННОН), 3.50-3.74 (2Н, m, СНСН3, OH),
1.15 (3Н, t, J = 7.1, СН2СН3), 1.15 (3Н, d, J = 6.2, СНСН3)
3345,
3140,
1710,
1675
3380,
3160,
1708,
1680
7.10-7.49 (4Н, m, НAr), 7.10-7.49 (4Н, m, НAr), 4.22 (2Н, q, J = 7.1, СН2СН3),
3.85 (1Н, br. dd, J = 7.9, J = 11.1, СННОН), 3.73 (1Н, br. dd, J = 4.0,
J = 11.1, СННОН), 3.50-3.75 (2Н, m, СНСН3, OH), 1.15 (3Н, d, J = 6.2,
СНСН3), 1.15 (3Н, t, J = 7.1, СН2СН3)
1
7.20-7.49 (5Н, m, C6H5), 4.22 (2Н, q, J = 7.1, СН2СН3), 4.01 (1Н, dq,
J = 6.4, J = 7.1, СН(СН3)ОН), 3.42 (1Н, dq, J = 7.1, J = 7.1, СНСН3),
1.18 (3Н, d, J = 6.4, СНСН3), 1.15 (3Н, d, J = 7.1, СНСН3), 1.11 (3Н, t,
J = 7.1, СН2СН3)
2
7.20-7.49 (5Н, m, C6H5), 4.22 (2Н, q, J = 7.1, СН2СН3), 4.16 (1Н, dq,
J = 3.0, J = 6.4, СННОН), 3.37 (1Н, dq, J = 3.0, J = 7.1, СНСН3), 1.18 (3Н,
d, J = 6.4, СНСН3), 1.15 (3Н, d, J = 7.1, СНСН3),
1.13 (3Н, t, J = 7.1, СН2СН3)
4a
3160,
1735,
1709,
1677
7.20-7.50 (6Н, m, C6H5, NH), 4.28 (1Н, dd, J = 7.5, J = 12.0, СННОAc),
4.23 (2Н, q, CH2СН3), 4.16 (1Н, dd, J = 5.1, J = 12.0, СННОAc),
3.65-3.90 (1Н, m, CHCH3), 1.96 (3Н, s, COCH3), 1.14 (3Н, t, J = 7.1,
СН2CH3), 1.13 (3Н, d, J = 6.6, CHCH3)
4b
4d
—
7.44 (2Н, d, J = 8.6, НAr-3',5'), 7.11 (2Н, d, J = 8.6, НAr-2',6'), 4.04-4.45 (4Н,
m, CH2ОАc, CH2СН3), 3.49-3.92 (1Н, m, CHCH3), 1.97 (3Н, s, COCH3),
1.14 (3Н, t, J = 7.0, СН2CH3), 1.12 (3Н, d, J = 6.6, CHCH3)
7.10 (2Н, dd, J = 9.0, 4JHF = 5.9, НAr-2',6'), 7.07 (2Н, dd, J = 9.0, 3JHF = 9.0,
НAr-3',5'), 4.04-4.45 (4Н, m, CH2ОАc, CH2СН3), 3.51-3.90 (1Н, m, CHCH3),
1.97 (3Н, s, COCH3), 1.14 (3Н, t, J = 7.0, СН2CH3),
—
1.12 (3Н, d, J = 6.6, CHCH3)
_______
* The characteristics of compounds 2a,b,e,g,h were described in [2].
*2 1 – Diastereomer 1; 2 – diastereomer 2.
980

protons of the ester group with a spin–spin coupling constant of 7.1-7.2 Hz, and downfield signals for the
protons of the aromatic ring and the NH protons. The transoid orientation of the ester group and the aromatic
ring in the pyrazole ring of the diastereomers 2a-i are confirmed by the spin–spin coupling constants of the
vicinal protons (J = 3.9-4.9 Hz) and also by data from the Overhauser effect [2].
In the IR spectra of compounds 3a-e,g,i there are bands for the stretching vibrations of the C=O bonds of
the carbonyl and ester groups in the region of 1670-1680 and 1708-1712 cm-1, indicating that they are
conjugated with the pyrazole ring. The stretching vibrations of the NH bond appear in the form of a
characteristic band at 3140-3180 cm-1, while the band in the region of 3340-3380 cm-1 indicates the presence of a
1
hydroxyl group. In the H NMR spectra of the ethyl pyrazolecarboxylates 3a-i there are signals for the
characteristic system of bonded protons of the ethyl group in the form of a triplet with J = 7.1 Hz at 1.15 ppm
and a quartet at 4.42 ppm, while the appearance of a doublet for the protons of the methyl group with J = 6.3 Hz
at 1.15-1.25 ppm (two doublets in the case of compound 3i) confirms the reductive opening of the epoxide ring.
The form of the signals for the methylene protons previously belonging to the oxirane ring, changes substantially
as a result of its opening, i.e., the signal of each of these protons appears in the 1H NMR spectra of the pyrazoles
3a-h in the form of a doublet of doublets at 3.71-3.73 ppm (Jgem = 11.0-12.0, Jvic = 3.8-4.0) and 3.84-3.87 (Jgem
=
11.0-12.0, Jvic = 7.1-8.5 Hz). The signal of the methine proton is masked by a broad signal for the proton of the
hydroxyl group at 3.50-3.75 ppm. In compound 3i as a result of reductive opening of the oxirane ring signals for
the two methine protons appear in the form of a pair of doublets of quartets.
A characteristic feature of the mass spectrum of compound 3a is the low intensity of the molecular ion
peak m/z 302 and the presence of a peak for the radical-ion with m/z 284, due to the elimination of a water
molecule [M - H2O]+· (Scheme 2). The peak with the highest intensity belongs to the diacylphenylpyrazole
fragment with m/z 197, the increased stability of which is due to the ability to form a conjugated cyclic ion.
The presence of a free hydroxyl group was also confirmed by acetylation of the β-hydroxypropionyl-1H-
pyrazolecarboxylates 3a,b,d with acetic anhydride. In the 1H NMR spectra of the ethyl 4-aryl-3(5)-(3-acetoxy-2-
methylpropionyl)-1H-pyrazole-5(3)-carboxylates 4a,b,d a singlet appears for the protons of the acetyl group,
and a downfield shift of the signals for the protons of the methylene group is also observed.
In order to identify the precursors of the β-hydroxyalkanoyl-1H-pyrazolecarboxylates 3a-h and to
confirm their regioisomeric affiliation to the series of 1H-pyrazole-3(5)-carboxylate esters the diastereomeric
mixture of adducts 2a was heated in dioxane in a sealed tube. Detection of the β-hydroxypropionyl-1H-pyrazole
3a in significantly smaller amounts (not more than 3%) than in the reaction of the enone 1a with diazoacetic
ester after heating compound 2a for 10 h indicates that 4,5-dihydro-1H-pyrazole 2a is not the direct precursor of
the pyrazole 3a, although these substances are clearly formed from one intermediate 4,5-dihydro-3H-pyrazole
(A), which is the adduct from reaction of diazoacetic ester and the epoxyenone with the 1,3-dipole oriented
according to the Auwers rule. Moreover, by detailed analysis of the 1H NMR spectrum of the reaction mixture of
the enone 1a with diazoacetic ester after boiling for 3 h it was possible to detect the formation of ethyl
5-(2-methyl-2,3-epoxypropionyl)-4-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylates 5a (Scheme 3), formed as a
result of displacement of a proton from the carbon atom attached to the ester group in the initial adduct A, in
addition to the previously isolated diastereomers 2a tautomeric with them. The decrease in the content of
compounds 5a with the simultaneous increase of the β-hydroxypropionyl-1H-pyrazole 3a when the reaction
mixture is heated indicates that they are formed during intramolecular oxidation–reduction disproportionation of
compounds 5a, and this made it possible to propose the following mechanism for the transformation.
According to this mechanism, the rearrangement may take place synchronously through a six-membered
transition state, the formation of which is preceded by migration of a proton to the nitrogen atom from the
α-position in relation to the ester group and enolization of the acyl substituent, while a subsequent
1,5-sigmatropic shift leads to intramolecular oxidative–reductive disproportionation (path 1). Reductive opening
of the oxirane ring may also be realized as a result of displacement of the electron pair involving the oxygen
atom of the ester group through the intermediate azodienol (path 2), the formation of which also presupposes the
presence of mobile hydrogen atoms at positions 3 and 5 of the intermediate 4,5-dihydro-3H-pyrazole A.
981

982

983

To compare the probability of migration of a proton from the α positions to the ester and carbonyl
groups in the analogs of 1,3-disubstituted 4,5-dihydro-1H-pyrazoles, which are not capable of rearrangement,
1,3-diphenylprop-2-en-1-one was reacted with diazoacetic ester. The reasons for investigation of this reaction
were not only to simplify the stereochemical composition of the adducts compared with the studied enones but
also to resolve the existing contradiction in the literature about the interpretation of the structure of the adducts
from the cycloaddition of diazoacetic ester to chalcones [5-9]. It was established that the reaction of
1,3-diphenylprop-2-en-1-one with diazoacetic ester by boiling in dioxane leads to a mixture of two 4,5-dihydro-
1H-pyrazoles 6 and 7 (4.5:1) with the transoid arrangement of the substituents in the azole ring
(Jvic = 3.7-3.9 Hz) (Scheme 4).
Scheme 4
N
N
CO2Et
H
+
–
Ph
Ph
N
N
CHCO2Et +
Ph
H
H
O
O
Ph
H
N
H
N
N
N
CO2Et
H
CO2Et
Ph
Ph
+
H
H
H
Ph
Ph
O
O
7 (16 %)
6 (72 %)
On the basis of comparison of the chemical shifts of the vicinal protons of the 4,5-dihydro-1H-pyrazole
ring and the character and form of the multiplets for the methylene protons of the ethyl group the structure of
ethyl 5-benzoyl-4-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate (6) was assigned to the isomer formed in the
larger amount, and 3-benzoyl-4-phenyl-4,5-dihydro-1H-pyrazole-5-carboxylate (7) to the isomer in the smaller
amount. This assignment was also confirmed in the IR spectra of compound 6 by the low-frequency shift of the
bands for the stretching vibrations of the C=O bond of the ester group to 1707 cm-1 as a result of conjugation [6].
A characteristic feature of the 1H NMR spectra of compounds 6 and 5a is the form of the signals for the
methylene protons of the ethyl group, each of which represents a doublet of quartets (quartets in compounds 7
and 2a). It is clear that the formation of a mixture of isomeric 4,5-dihydro-1H-pyrazoles 6 and 7 in this reaction
confirms the possibility of the dual migration of protons from positions 3 and 5 of the initial 4,5-dihydro-3H-
pyrazole that is necessary for realization of the redox transformation.
In the general case, the intramolecular reductive opening of the oxirane ring and oxidation of the azole
ring represent a vinylogous rearrangement of the epoxides into allyl groups, of which is favored by subsequent
aromatization of the carbocyclic [10] or heterocyclic, as in our case, rings.
EXPERIMENTAL
The IR spectra were obtained on a Specord IR-75 spectrometer in tablets with potassium bromide. The
1H NMR spectra were recorded on Bruker AC-200 (200 MHz) and Bruker AVANCE (400 MHz) spectrometers
in deuterochloroform with HMDS as internal standard (δ 0.055 ppm). The mass spectra were obtained on a
Shimadzu QP-5000 instrument with 70-eV ionizing electrons.
The reactions and the individuality of the obtained compounds were monitored by TLC on Silufol and
Kieselgel 60 F254 plates with 1:1-1:5 diethyl ether–hexane as eluant and iodine vapor or 4% KMnO4 solution as
developer. The initial β-arylacryloyloxiranes 1a-i were obtained by the condensation of the respective
984

acyloxiranes and aromatic aldehydes in methanol in the presence of a 15% methanol solution of sodium
hydroxide [11]. The diazoacetic ester was synthesized by the method in [12].
The characteristics of compounds 2c,d,f,i, 3a-e,g,i, and 4a,b,d are given in Tables 1 and 2, and those of
compounds 2a,b,e,g,h were described earlier [2].
Ethyl 4-Aryl-3-(2,3-epoxyalkanoyl)-4,5-dihydro-1H-pyrazole-5-carboxylates 2a-i and Ethyl 4-Aryl-
3(5)-(3-hydroxy-2-methylalkanoyl)-1H-pyrazole-5(3)-carboxylates 3a-i. To a solution of diazoacetic ester
(5.81 g, 51 mmol) in dioxane (60 ml) we added the respective β-arylacryloyloxirane 1a-i (50 mmol). The
mixture was heated at 80-90°C with a reflux condenser for 7-20 h. The heating was stopped when the initial
epoxyenone had disappeared according to TLC. The dioxane was evaporated under vacuum, and the
diastereomeric mixtures of compounds 2a-i crystallized from the residue after the addition of diethyl ether or a
mixture of diethyl and petroleum ethers. In the case of the reaction mixtures from compounds 1a-e,g,i with
diazoacetic ester the mother solutions after removal of the solvent were submitted to column chromatography on
silica gel with linear gradient elution with mixtures of diethyl ether and petroleum ether (1:1) and diethyl ether.
Compounds 3a-e,g,i, which had the lowest chromatographic mobility, crystallized from the final fractions.
Compound 3a. Mass spectrum, m/z (Irel, %): 302 [M]+ (12), 284 [M+–18] (0.5), 273 (11), 272 (11), 260
(11), 243 (19), 227 (18), 215 (6), 197 (100), 171 (6), 169 (8), 142 (21), 141 (24), 129 (13), 115 (31), 113 (34),
80 (16).
Compounds 3f,h were detected in the 1H NMR spectra of the reaction mixtures.
Compound 3f. 1H NMR spectrum, δ, ppm (J, Hz): 7.24 (2H, d, J = 8.6, HAr-2',6'); 7.00 (1H, br. s, NH);
6.82 (2H, d, J = 8.6, HAr-3',5'); 4.24 (2H, q, J = 7.0, CH2CH3); 3.84 (1H, br. dd, J = 7.3, J = 11.0, CHHOH); 3.77
(3H, s, OCH3); 3.71 (1H, br. dd, J = 3.8, J = 11.0, CHHOH); 3.52-3.70 (2H, m, CHCH3, OH); 1.15 (3H, d,
J = 6.3, CHCH3).
1
Compound 3h. H NMR spectrum, δ, ppm (J, Hz): 7.60-8.20 (4H, m, HAr); 4.24 (2H, q, J = 7.0,
CH2CH3); 3.84 (1H, br. dd, J = 7.3, J = 11.0, CHHOH); 3.72 (1H, br. dd, J = 3.8, J = 11.0, CHHOH); 3.52-3.70
(2H, m, CHCH3, OH); 1.15 (3H, d, J = 6.3, CHCH3); 1.15 (3H, t, J = 7.0, CH2CH3).
Ethyl 5-(2-Methyl-2,3-epoxypropionyl)-4-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylates (5a).
1
These compounds were detected in the H NMR spectra of samples of the reaction mixtures taken after boiling
1
for 3 and 10 h under the conditions described above. H NMR spectrum, δ, ppm (J, Hz). Diastereomer 1:
7.20-7.40 (5H, m, C6H5); 6.77 (1H, br. s, HN); 4.77 (1H, d, J = 6.4, CHpyraz); 4.17 (1H, dq, J = 7.1, J = 11.0,
CHHCH3); 4.14 (1H, dq, J = 7.1, J = 11.0, CHHCH3); 2.97 (1H, d, J = 4.4, CHep); 1.60 (3H, s, CH3); 2.92 (1H,
d, J = 4.4, CHep); 1.18 (3H, t, J = 7.1, CH2CH3). Diastereomer 2: 7.20-7.40 (5H, m, C6H5); 6.65 (1H, br. s, NH);
4.49 (1H, d, J = 4.2, CHpyraz); 4.31 (1H, d, J = 4.2, CHpyraz); 4.15 (1H, dq, J = 7.1, J = 11.0, CHHCH3); 4.12 (1H,
dq, J = 7.1, J = 11.0, CHHCH3); 2.90 (1H, d, J = 4.6, CHep); 2.87 (1H, d, J = 4.6, CHep); 1.56 (3H, s, CH3); 1.21
(3H, t, J = 7.1, CH2CH3)
Ethyl 4-Aryl-3(5)-(3-acetoxy-2-methylpropionyl)-1H-pyrazole-5(3)-carboxylates 4a,b,d. To
β-hydroxypropionylpyrazoles 3a,b,d (5 mmol) we added acetic anhydride (1 ml, 11 mmol) in acetic acid
(2.5 ml), and we boiled the mixture for 1 h. The mixture was diluted with twice the volume of water, neutralized
with an aqueous solution of sodium carbonate, and extracted with diethyl ether (3 × 25 ml). After drying over
sodium sulfate the ether was evaporated, and the isolated oil was chromatographed on silica gel with ether as
eluant. The acetates 4a,b,d were oily substances.
Ethyl 5-Benzoyl-4-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate (6) and Ethyl 4,5-dihydro-1H-
pyrazole-5-carboxylate (7). To a solution of 1,3-diphenylprop-2-en-1-one (5.2 g, 25 mmol) in dioxane (40 ml)
we added diazoacetic ester (2.96 g, 26 mmol). The mixture was boiled with a reflux condenser for 4 h. The
solvent was evaporated under vacuum, and the residue was crystallized from diethyl ether. We obtained 2.9 g of
4,5-dihydro-1H-pyrazole 6. The residue was chromatographed on silica gel with linear gradient elution with
mixtures of diethyl ether and petroleum ether (1:1) and diethyl ether. We obtained a further 3.0 g of compound 6
(mp 161-162°C, from 1:2 petroleum ether and ether, published data 162°C [7], 165°C [6]) (total yield 72%) and
1.3 g (16%) of compound 7 in the form of an oil.
985

Compound 6. IR spectrum, ν, cm-1: 1707 (C=Oester), 1680 (C=Cketo). 1H NMR spectrum, δ, ppm (J, Hz):
7.86 (2H, dd, J = 1.0, J = 8.3, HPh-2',6'); 7.63 (1H, tt, J = 1.0, J = 7.4, HPh-4'); 7.48 (2H, dd, J = 7.4, J = 8.3,
HPh-3',5'); 7.30-7.42 (5H, m, C6H5); 7.00 (1H, br. s, NH); 5.19 (1H, d, J = 3.9, H-5); 4.46 (1H, d, J = 3.9, H-4);
4.16 (1H, dq, J = 7.1, J = 10.5, CHHCH3); 4.10 (1H, dq, J = 7.1, J = 10.5, CHHCH3); 1.20 (3H, t, J = 7.1,
CH2CH3). Found %: C 70.75; H 5.58; N 8.88. C19H18N2O3. Calculated %: C 70.79; H 5.63; N 8.69.
1
Compound 7. IR spectrum, ν, cm-1: 1720 (C=Oest), 1660 (C=Cketo), 3320 (NH). H NMR spectrum,
δ, ppm (J, Hz): 8.10 (2H, m, HPhCO-2',6'); 7.30-7.50 (8H, m, 5HPh–C, 3HPhCO-3',4',5'); 7.02 (1H, br. s, NH); 4.90
(1H, d, J = 3.7, H-5); 4.36 (1H, d, J = 3.7, H-4); 4.26 (2H, q, J = 7.1, CH2CH3); 1.31 (3H, t, J = 7.1, CH2CH3).
Found %: C 70.92; H 5.80; N 8.94. C19H18N2O3. Calculated %: C 70.79; H 5.63; N 8.69.
Heating of Ethyl 3-(2-Methyl-2,3-epoxypropionyl)-4-phenyl-4,5-dihydro-1H-pyrazole-5-carboxylate
(2a) in Dioxane. A solution of the diastereomeric 4,5-dihydro-1H-pyrazoles 2a (0.6 g, 2.0 mmol) in dioxane
(5 ml) was heated in a sealed tube at 85-90°C for 10 h. The presence of the pyrazole 3a was detected during
analysis of the reaction mixture by 1H NMR spectroscopy.
REFERENCES
1.
2.
A. M. Zvonok, N. M. Kuz'menok, and L. S. Stanishevskii, Khim. Geterotsikl. Soedin., 679 (1982).
A. M. Zvonok, N. M. Kuz'menok, I. G. Tishchenko, and L. S. Stanishevskii, Vestsi AN BSSR. Ser. Khim.
Navuk, No. 6, 76 (1982).
3.
4.
D. Brown, A. Floyd, and M. Sainsbury, Spectroscopy of Organic Compounds [Russian translation], Mir,
Moscow (1992).
A. R. Katritzky (editor), Physical Methods in the Chemistry of Heterocyclic Compounds [Russian
translation], Khimiya, Moscow-Leningrad (1966).
5.
6.
7.
E. P. Kohler and L. L. Steele, J. Am. Chem. Soc., 41, 1093 (1919).
I. E.-S. El-Kholy, F. K. Rafla, and M. M. Mishrikey, J. Chem. Soc. (C), 1578 (1970).
H. M. Faidallah, M. S. I. Makki, A. M. I. El-Massry, and S. Y. Hassan, Rev. Roum. Chim., 42, 1144
(1997).
8.
9.
A. N. Lycholai and A. P. Molchanov, Chemistry and Computational Simulation. Butlerov Commun., IV
Diazo/P-19 (2001). (http://chem.kstu.ru/jchem&cs/english/n4/appl4/ivdiazo/p-9/p-19.htm).
I. E.-S. El-Kholy, M. M. Mishrikey, H. M. Fuid-Alla, and M. A. Nashed, J. Heterocycl. Chem., 16, 849
(1979).
10.
11.
12.
R. P. Kurtz and D. J. House, J. Org. Chem., 46, 202 (1981).
L. S. Stanishevskii, I. G. Tishchenko, and A. Ya. Guzikov, Zh. Org. Khim., 6, 1565 (1970).
N. Searle, in: Syntheses of Organic Products [Russian translation], Vol. 8, Izd-vo Inostr. Lit., Moscow
(1958), p. 9.
986