Reaction of esters of 2-arylcyclo-propanecarboxylic acids with nitrous acid. Synthesis of aryl-substituted 3-ethoxycarbonyl-4,5-dihydroisoxazoles and 3-ethoxycarbonylisoxazoles

Article abstract of DOI:10.1007/s10593-009-0315-6

Esters of 2-arylcyclopropanecarboxylic acids react with nitrous acid generated in situ with regioselective insertion of the nitrosyl cation into the cyclopropane ring. Depending on the substrate/nitrosylating agent ratio, the reaction proceeds with the formation of either aryl-substituted 3-ethoxycarbonyl-4,5-dihydroisoxazoles or the corresponding isoxazoles. The nature and position of the substituents in the aromatic ring of the starting 2-arylcyclopropanecarboxylic acid esters affect the reaction rate but have no effect on the regioselectivity of the attack by the nitrosyl cation on the three-membered ring. A dependence of the reactivity of isomeric substrates on their stereochemistry and position of the nitro group in the aromatic ring is noted for 2- and 4-nitrophenyl derivatives of esters of cis- and trans-2-arylcyclopropanecarboxylic acids.

Full text of DOI:10.1007/s10593-009-0315-6

Chemistry of Heterocyclic Compounds, Vol. 45, No. 5, 2009
REACTION OF ESTERS OF 2-ARYLCYCLO-
PROPANECARBOXYLIC ACIDS WITH NITROUS
ACID. SYNTHESIS OF ARYL-SUBSTITUTED
3-ETHOXYCARBONYL-4,5-DIHYDROISOXAZOLES
AND 3-ETHOXYCARBONYLISOXAZOLES
A. Z. Kadzhaeva1, E. V. Trofimova2, A. N. Fedotov2*, K. A. Potekhin2,
R. A. Gazzaeva1, S. S. Mochalov2, and N. S. Zefirov2
Esters of 2-arylcyclopropanecarboxylic acids react with nitrous acid generated in situ with
regioselective insertion of the nitrosyl cation into the cyclopropane ring. Depending on the
substrate/nitrosylating agent ratio, the reaction proceeds with the formation of either aryl-substituted
3-ethoxycarbonyl-4,5-dihydroisoxazoles or the corresponding isoxazoles. The nature and position of the
substituents in the aromatic ring of the starting 2-arylcyclopropanecarboxylic acid esters affect the
reaction rate but have no effect on the regioselectivity of the attack by the nitrosyl cation on the
three-membered ring. A dependence of the reactivity of isomeric substrates on their stereochemistry and
position of the nitro group in the aromatic ring is noted for 2- and 4-nitrophenyl derivatives of esters of
cis- and trans-2-arylcyclopropanecarboxylic acids.
Keywords: 5-aryl-3-ethoxycarbonyl-4,5-dihydroisoxazoles, 5-aryl-3-ethoxycarbonylisoxazoles, ethyl
esters of 2-arylcyclopropanecarboxylic acids, insertion of the nitrosyl cation into the cyclopropane ring.
The reaction of arylcyclopropanes with nitrosylating agents, which proceeds through insertion of the
nitrosyl cation or nitrosyl radical into the cyclopropane ring, may be seen as one of the most efficient methods
for the synthesis of aryl-substituted 4,5-dihydroisoxazoles and isoxazoles, which are potential pharmaceutical
agents and important precursors for the preparation of biologically-active compounds, including natural products
[1-6].
_______
* To whom correspondence should be addressed, e-mail: fed@org.chem.msu.ru.
1K. L. Hetagurov North-Ossetian State University, Vladikavkaz 362040 , North Ossetia, Russia; e-mail:
kad_alania@mail.ru.
2M. V. Lomonosov Moscow State University, Moscow 119992, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 753-765, May, 2009. Original
article submitted October 6, 2008.
0009-3122/09/4505-0595©2009 Springer Science+Business Media, Inc.
595

The arylcyclopropanes studied in these transformations have been either phenylcyclopropanes [7-9] or
benzylcyclopropanes [10] substituted in the aromatic ring or have contained only alkyl and aryl groups [11, 12]
or halogen atoms [13, 14] as the second substituent in the cyclopropane ring. Hence, the possible series of
substituted 4,5-dihydroisoxazoles and corresponding isoxazoles obtained by this method has been limited to
heterocycles with nonfunctional substituents.
In the present work, we attempted to employ this transformation of arylcyclopropanes in the synthesis of
functionally-substituted 4,5-dihydroisoxazoles and isoxazoles. For this purpose, we synthesized a series of ethyl
esters of 2-aryl-1-cyclopropanecarboxylic acids and studied their behavior relative to nitrosylation by nitrous
acid. The required 2-aryl-1-ethoxycarbonylcyclopropanes were synthesized as mixtures of the cis and trans
isomers by the reaction of ethyl diazoacetate with the corresponding styrenes.
CO2Et
N2CHCO2Et
xylene, 140°C
R
R
1a–e
2a–e
a R = H, b R = F, c R = Cl, d R = Me, e R = OMe
In order to clarify the effect of the cis or trans arrangement of the substituents in the small ring on the
reactivity of substrates 2a-e, a mixture of isomeric 1-ethoxycarbonyl-2-phenylcyclopropanes 2a was separated
into pure cis-2a and trans-2a. In addition, cis- and trans-1-ethoxycarbonylcyclo-2-phenylpropanes unsubstituted
in the aromatic ring were used in the synthesis of o- and p-nitro-substituted ethoxycarbonylphenylcyclopropanes
cis-2f, cis-2g, trans-2f, and trans-2g.
H
H
H
CO2Et
H
CO2Et
NO2
H
CO2Et
H
HNO3 (d 1.5)
+
Ac2O; -50°C
NO2
cis-2g
cis-2f
cis-2а
H
H
H
CO2Et
CO2Et
CO2Et
HNO3 (d 1.5)
H
H
H
+
Ac2O; -50°C
O2N
NO2
trans-2f
trans-2g
trans-2а
We should note that the steric arrangement of the substituents had no significant effect on the ratio of
the ortho and para nitro isomers in the nitration of pure isomers cis-2a and trans-2a under the conditions
employed. In each case, the mixture consisted of virtually equal amounts of nitro compounds cis-2f and cis-2g
(from cis-2a) as well as trans-2f and trans-2g (from trans-2a).
596

In principle, polysubstituted ethoxycarbonylcyclopropanes lacking aromatic substituents, which are
classified, according to Reissig [15] and Yu [16], as donor-acceptor cyclopropanes, have been used in the
synthesis of ethoxycarbonylhydrofurans [17, 18] and ethoxycarbonylpyrroles [19]. Examples have been
reported, in which reactions, proceeding with the participation of these ethoxycarbonylcyclopropanes, take place
either with insertion of the reagent into the cyclopropane ring and the ethoxycarbonyl fragment is retained in the
final reaction product or attack of the reagent directed toward any of the substituents in the cyclopropane ring
and termination of the reaction with intramolecular participation of the ethoxycarbonyl group such that the
three-membered carbocycle is retained [17, 18]. As shown in this work, monoaryl-substituted
ethoxycarbonylcyclopropanes undergo reaction with an equimolar amount of nitrous acid formed in situ only
with insertion of an N=O group into the cyclopropane fragment and resultant formation of the corresponding
3-ethoxycarbonyl-4,5-dihydroisoxazoles. The reaction proceeds virtually without complication with
ethoxycarbonylcyclopropanes 2a-d, in which the phenyl groups either lack substituents (2a) or the phenyl group
substituents are weak electron-donor groups or halogen atoms (2b-d). In the case of isomeric 1-ethoxycarbonyl-
2-phenylcyclopropanes (cis-2a and trans-2a), we found that the geometrical structure of the substrates and their
stereochemistry do not affect the formation of 3-ethoxycarbonyl-5-phenyl-4,5-dihydroisoxazoles (3a, Table 1).
H
4
CO2Et
3
H
NaNO2 (1 equiv.)
H
2a–d
N
2
CF3CO2H, 20°C, 30 min
O
5
1
R
3a–d
Subsequently, we learned that if the para position of the benzene ring in 2-arylethoxy-
carbonylcyclopropanes is occupied by a substituent capable of stabilizing the nascent benzylic carbenium ion
(2e), the reaction proceeds to give multiple products although all the compounds formed correspond to insertion
of an N=O fragment into the cyclopropane ring.
EtO2C
H
EtO2C
EtO2C
H
N
N
N
H
H
H
O
O
O
H
H
(1 equiv.)
NaNO2
2e
+
+
CF3CO2H,
20°C, 30 min
NO2
OMe
4e (21%)
OMe
OMe
3e (44%)
3f (18%)
Apparently anomalous reaction products 3f and 4e obtained in the reaction of
ethoxycarbonylcyclopropane 2e with nitrous acid, in principle, may be formed as the result of nitration and
oxidation of an intermediate, 3-ethoxycarbonyl-4,5-dihydroisoxazole 3e by nitrous acid, which can be the source
of both the O2N• radical and ON+ cation [20]. In order to check this hypothesis, we carried out the reaction of
3-ethoxycarbonyl-5-(4-methoxyphenyl)- 4,5-dihydroisoxazole (3e) with an additional equivalent of HNO2.
597

TABLE 1. Characteristics of Compounds 3a-h and 4a-g
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
(method)
mp, °C*
С
H
N
3a
3b
3c
3d
3e
3f
C12H13NO3
65.62
65.75
60.73
60.76
56.71
56.80
66.65
66.95
62.50
62.65
52.91
53.06
54.59
54.54
54.48
54.54
66.11
66.36
61.03
61.28
56.92
57.26
67.28
67.53
62.93
63.16
53.15
53.42
54.94
54.96
6.05
5.94
5.10
5.06
4.83
4.73
6.08
6.44
6.17
6.02
4.58
4.76
4.74
4.54
4.84
4.54
5.08
5.07
4.36
4.26
4.22
3.98
5.51
5.63
5.12
5.26
4.05
4.11
3.71
3.82
6.18
6.39
5.91
5.91
5.82
5.51
6.18
6.01
5.48
5.62
9.56
9.52
10.91
10.61
10.57
10.61
6.26
6.47
5.76
5.96
5.68
5.57
5.86
6.06
5.28
5.67
9.75
9.59
10.57
10.69
Oil
94 (A)
C12H12FNO3
C12H12ClNO3
C13H15NO3
C13H15NO4
C13H14N2O6
C12H12N2O5
C12H12N2O5
C12H11NO3
C12H10FNO3
C12H10ClNO3
C13H13NO3
C13H13NO4
C13H12N2O6
C12H10N2O5
Oil
83 (A)
Oil
81 (A)
Oil
79 (A)
68-69
117-118
Oil
51 (A)
24 (A)
3g
3h
4a
4b
4c
4d
4e
4f
72 (A)
Oil
54 (A)
43-44
98-99
127-128
52-53
86-87
161-162
178-179
88 (A), 71 (B)
81 (A), 69 (B)
78 (A), 74 (B)
94 (A), 68 (B)
86 (A), 34 (B)
79 (A), 16 (B)
87 (A), 65 (B)
4g
_______
*Recrystallization solvents: chloroform–hexane for 3e and ethanol for 3f and 4a-g
Only 3-ethoxycarbonyl-5-(4-methoxyphenyl)isoxazole (4e) is formed in this case. It is interesting that
both 4,5-dihydroisoxazole 3f and 4,5-dihydroisoxazoles 3a-d are converted upon similar treatment into the
corresponding 5-aryl-3-ethoxycarbonylisoxazoles 4a-f in high yield (Table 1).
CO2Et
N
H
CO2Et
N
H
H
H
( 1 equiv.)
NaNO2
O
O
CF3CO2H, 20°C, 4–12 h
R
R
X
X
3a–f
4a–f
4 a–e X = H; a R = H, b R = F, c R = Cl, d R = Me, e R = OMe,
f X = NO2, R = OMe
Hence, 5-aryl-3-ethoxycarbonyl-4,5-dihydroisoxazoles 3a-f may readily be oxidized under nitrosylation
conditions and 3-ethoxycarbonyl-5-(4-methoxy-3-nitrophenyl)-4,5-dihydroisoxazole (3f) is not formed by
nitration of 4,5-dihydroisoxazole 3e. This latter finding suggests that two processes, namely, the insertion of an
598

NO fragment into the cyclopropane ring and nitration in the phenyl ring activated by a methoxy group, occur in
parallel in the reaction of substrate 2e with nitrous acid but at different rates. Since the formation of a nitronium
+
cation (NO2 ) required for the electrophilic nitration of aromatic ring, appears unlikely under the reaction
conditions employed, we may assume that both processes in our case occur through the single-electron oxidation
of substrate 2e with subsequent reaction of radical cation 5 with ON• or O2N• radicals.
CO2Et
CO2Et
+
+
N=O
.
+
NO
.
NO
2e
3e
a
A
OMe
5
OMe
CO2Et
CO2Et
.
+
+
– H
NO2
MeO
MeO
b
H
NO2
NO2
B
2h
a – ether–hexane, 1:4, b – ether–chloroform–petroleum ether (40–70oC), 1:1:3
We should note that the proposed scheme for the conversion of ethoxycarbonylcyclopropane 2e
involving the one-electron oxidation of this compound is in accord both with the scheme proposed by Ichinose
et al. [11] for the insertion of nitric oxide into the cyclopropane ring of 1,2-diarylcyclopropanes, whose first
ionization potential permits oxidation of the starting substrates by the nitrosyl cation to the corresponding
radical cations and a scheme involving nitration of arylcyclopropanes by dinitrogen tetroxide through a
single-electron transfer (SET) mechanism [8]. Nitroaromatic compound 2h formed due to the complexing action
of the electron-donor and electron-withdrawing substituents apparently may be comparable in their reactivity
with unsubstituted 1-ethoxycarbonyl-2-phenylcyclopropane (2a), which accounts for its subsequent
transformation into nitro-substituted 3-ethoxycarbonyl-4,5-dihydroisoxazole (3f) at a rate as far as we can
estimate from the yields of reaction products 3e,f, only 2.5 times less than the rate of the conversion of
ethoxycarbonylcyclopropane 2e.
An experiment on the consecutive transformation of 2-aryl-1-ethoxycarbonylcyclopropanes 2a-e
initially by the action of one equivalent of HNO2 to give the corresponding 5-aryl-3-ethoxy-
carbonyl-4,5-dihydroisoxazoles 3a-e and then by the oxidation of these products by an additional one equivalent
of nitrous acid to give the corresponding isoxazoles 4a-f suggested that the conversion of
arylethoxycarbonylcyclopropanes 2a-e to give substituted 3-ethoxycarbonylisoxazoles may be achieved by a
single treatment of the starting substrates with two equivalents of nitrous acid. Indeed, such treatment of 2a-e
gave 5-aryl-3-ethoxycarbonylisoxazoles 4a-f in high yield (Table 1). As expected, ethoxycarbonyl-
cyclopropane 2e was converted into a 2:1 mixture of two isoxazoles 4e,f.
While 2-aryl-1-ethoxycarbonylcyclopropanes with electron-donor or weakly electron-withdrawing
substituents in the benzene ring can be readily converted by the action of a corresponding amount of nitrous acid into
either 4,5-dihydroisoxazoles 3a-f or isoxazoles 4a-f, the behavior of nitrophenyl derivatives of ethoxy-
carbonylcyclopropanes 2f,g under the conditions employed is quite different. We very unexpectedly found that
trans-etoxycarbonyl(o-nitrophenyl)- (trans-2f) and trans-ethoxycarbonyl(p-nitrophenyl)cyclopropanes (trans-2g) do
not react either with an equimolar amount of nitrous acid or with a large excess of nitrous acid over a very
599

prolonged period (240 h). In contrast, cis-nitrophenylcyclopropanes (cis-2f and cis-2g) are converted quite
readily to the corresponding 4,5-dihydroisoxazoles 3g,h by the action of even equimolar amounts of nitrous
acid. The reaction with cis-1-ethoxycarbonyl-2-(p-nitrophenyl)cyclopropane (cis-2g) proceeds much more
rapidly than the reaction with the corresponding ortho isomer.
The oxidation of 4,5-dihydroisoxazole 3g by a second equivalent of HNO2, as in the case of the
reactions of 3a-f, leads to 3-ethoxycarbonyl-5-(p-nitrophenyl)isoxazole (4g), which may be obtained directly
from ethoxycarbonylcyclopropane cis-2g using two equivalents of nitrous acid.
CO2Et
N
H
H
H
NaNO2 (1 equiv.)
O
cis-2f
CF3CO2H, 20°C, 120 h
NO2
3h (54%)
H
CO2Et
N
H
H
NaNO2 (1 equiv.)
NaNO2 (1 equiv.)
O
cis-2g
CF3CO2H,
20°C, 12 h
CF3CO2H, 20°C, 2 h
O2N
3g (72%)
CO2Et
NaNO2 (2 equiv.)
N
O
cis-2g
CF3CO2H, 20°C, 12 h
O2N
4g
It is interesting that the inability of trans-ethoxycarbonylnitrophenylcyclopropanes to give any reaction
products under the conditions employed indicates that the formation of 4,5-dihydroisoxazoles from the
cis isomers does not include a step involving single-electron oxidation of the starting substrates by the nitrosyl
cation. Apparently, the nitrosyl cation directly attacks the cyclopropane carbon atom attached to the
ethoxycarbonyl group.
An important goal in this investigation was to discuss the following. In the case of
2-arylethoxycarbonylcyclopropanes 2a-e, we showed that both the pure trans isomer of 2a and the trans isomers
of 2b-e within the starting isomer mixtures are converted in high yield by the action of HNO2 into the
corresponding 4,5-dihydroisoxazoles 3a-f. In contrast, trans-nitrophenyl derivatives of ethoxy-
carbonylcyclopropanes trans-2f and trans-2g are nevertheless converted to the corresponding nitrophenyl
derivatives of 4,5-dihydroisoxazoles 3g,h even though more slowly than the cis isomers of 2a-e. Hence, we may
assume that the cis isomers of the ethoxycarbonylcyclopropanes studied are significantly more reactive relative
to nitrous acid than the corresponding trans isomers. We assume that the discrepancy in behavior of
trans-ethoxycarbonylcyclopropanes (trans-2a-e) and the nitrophenyl derivatives of trans-2g and trans-2g is
probably linked to a difference in the mechanism of their reaction with HNO2.
We have already proposed that the reactions of 2-aryl-1-ethoxycarbonylcyclopropanes 2a-e with HNO2
proceed through a SET mechanism. If this is true and the conversion of cyclopropanes 2a-e to the corresponding
4,5-dihydroisoxazoles 3a-e is accomplished through
a
step involving generation of
a
radical
600

TABLE 2. IR and Mass Spectra of Compounds 3 and 4
IR spectrum, ν, cm–1
Compound
Mass spectrum, m/z (Irel, %)
C=O
NO2
3a
3b
3с
3d
3e
3f
1720
1725
1725
1720
1720
1715
1725
1725
1740
1735
1730
1740
1745
1725
1745
219 [M]+ (61.9)
237 [M]+ (52.4), 236 [M–1] (86.3)
253 [M]+ (56.5)
233 [M]+ (27.2)
1535, 1365
1545, 1345
1535, 1375
294 [M]+ (16.1)
3g
3h
4a
4b
4c
4d
4e
4f
217 [M]+ (36.1)
235 [M]+ (68.6)
251 [M]+ (25.2)
231 [M]+ (74.5)
247 [M]+ (28.6)
292 [M]+ (100)
262 [M]+ (37.8)
1535, 1360
1555, 1325
4g
cation 5, whose analogs, as shown by Mizuno et al. [12], may account for the cis-trans isomerization of
1,2-disubstituted cyclopropanes, we may justifiably assume that all the conversions of isomeric
ethoxycarbonylcyclopropanes 2a-e are achieved either through cis-ethoxycarbonylcyclopropanes cis-2a-e,
which react rapidly with HNO2 and whose regeneration in the reaction medium occurs due to isomerization of
the trans isomers (trans-2a-e) to the corresponding cis species, or that radical cations 5 formed from both
cis- and trans-ethoxycarbonylcyclopropanes upon single-electron oxidation by the nitrosyl cation have identical
structures equally capable of undergoing radical cation doubling to give intermediates A, which are responsible
for the formation of substituted 4,5-dihydroisoxazoles 3a-e. In all likelihood, ethoxycarbonylnitrophenyl-
cyclopropanes 2f and 2g are incapable of undergoing oxidation by the nitrosyl cation and form radical
cations 5*. The reaction of these compounds should be initiated by direct attack of the nitrosyl cation on the
cyclopropane carbon atom attached to the ethoxycarbonyl group, which, in the case of the trans isomers
(trans-2f and trans-2g) is sterically hindered.
The structure of the products and the stereochemistry of the insertion of the N=O fragment into the
three-membered carbocycle of the aryl-substituted ethoxycarbonylcyclopropanes under the conditions employed
1
were unequivocally indicated not only by the IR, H NMR, and mass spectra and comparison of the data from
these spectra with the data of spectra of reported isomeric ethoxycarbonyl-4,5-isoxazoles [21], but also by
studying the structure of the isoxazole obtained by the reaction of 1-ethoxycarbonyl-2-(p-tolyl)cyclo-
propane (2d) with nitrous acid by X-ray diffraction crystallographic analysis, which showed that heterocycle 4d
has the structure of 3-ethoxycarbonyl-5-(p-tolyl)isoxazole*2. In other words, the insertion of the N=O fragment
into the cyclopropane ring of the starting esters is initiated by attack of ON• or ON+ on the small ring carbon
atom attached to the ethoxycarbonyl group.
_______
* The introduction of a nitro group into an organic molecule significantly enhances its first ionization potential
[22].
*2 The X-ray diffraction crystallographic analysis data will be published separately.
601

TABLE 3. Spectral Characteristics of Compounds 3a-h and 4a-g
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
3a
3b
3с
1.26 (3Н, t, J = 7.6, СН2СН3); 3.15 (1Н, dd, J1 = 18.2, J2 = 8.2, Н-4);
3.68 (1Н, dd, J1 = 18.2, J2 = 11.4, Н-4); 4.26 (2Н, q, J = 7.6, СН2СН3);
5.82 (1Н, dd, J1 = 11.4, J2 = 8.2, Н-5); 7.38 (5H, m, Н arom.)
1.35 (3Н, t, J = 7.4, СН2СН3); 3.16 (1Н, dd, J1 = 17.6, J2 = 8.8, Н-4);
3.65 (1Н, dd, J1 = 17.6, J2 = 12.2, Н-4); 4.35 (2Н, q, J = 7.4, СН2СН3);
5.75 (1Н, dd, J1 = 12.2, J2 = 8.8, Н-5); 7.05 (2Н, m, Н arom.); 7.28 (2H, m, Н arom.)
1.37 (3Н, t, J = 7.4, СН2СН3); 3.18 (1Н, dd, J1 = 18.8, J2 = 8.2, Н-4);
3.65 (1Н, dd, J1 = 18.8, J2 = 12.3, Н-4); 4.36 (2Н, q, J = 7.6, СН2СН3);
5.76 (1Н, dd, J1 = 12.3, J2 = 8.2, Н-5); 7.25 (2Н, d, J = 8.2, Н arom.);
7.35 (2H, d, J = 8.2, Н arom.)
3d
3e
3f
1.37 (3Н, t, J = 7.8, СН2СН3); 2.36 (3Н, s, СН3); 3.21 (1Н, dd, J1 = 18.2, J2 = 8.8, Н-4);
3.62 (1Н, dd, J1 = 18.2, J2 = 12.4, Н-4); 4.38 (2Н, q, J = 7.8, СН2СН3);
5.75 (1Н, dd, J1 = 12.4, J2 = 8.8, Н-5); 7.19 (2Н, d, J = 8.0, Н arom.);
7.23 (2H, d, J = 8.0, Н arom.)
1.38 (3Н, t, J = 7.6, СН2СН3); 3.21 (1Н, dd, J1 = 17.2, J2 = 8.6, Н-4);
3.56 (1Н, dd, J1 = 17.2, J2 = 12.0, Н-4); 3.78 (3Н, s, OCH3);
4.35 (2Н, q, J = 7.6, СН2СН3); 5.73 (1Н, dd, J1 = 12.0, J2 = 8.6, Н-5);
6.88 (2Н, d, J = 8.4, Н arom.); 7.24 (2H, d, J = 8.4, Н arom.)
1.41 (3Н, t, J = 7.7, СН2СН3); 3.21 (1Н, dd, J1 = 18.2, J2 = 8.8, Н-4);
3.68 (1Н, dd, J1 = 18.2, J2 = 12.2, Н-4); 3.95 (3Н, s, OCH3);
4.41 (2Н, q, J = 7.7, СН2СН3); 5.18 (1Н, dd, J1 = 12.2, J2 = 8.5, Н-5);
7.11 (2Н, d, J = 8.4, Н-5 arom.); 7.51 (2H, dd, J1 = 8.4, J2 = 2.4, Н-6 arom.);
7.81 (1Н, d, J2 = 2.4, Н-2 arom.)
3g
3h
1.28 (3Н, t, J = 7.5, СН2СН3); 3.15 (1Н, dd, J1 = 17.4, J2 = 8.6, Н-4);
3.75 (1Н, dd, J1 = 17.4, J2 = 12.4, Н-4); 3.95 (3Н, s, OCH3);
4.25 (2Н, q, J = 7.5, СН2СН3); 6.05 (1Н, dd, J1 = 12.4, J2 = 8.6, Н-5);
7.36 (2Н, d, J = 8.3, Н-2,6 arom.); 8.31 (2H, d, J = 8.3, Н-3,5 arom.)
1.31 (3Н, t, J = 7.6, СН2СН3); 3.16 (1Н, dd, J1 = 16.8, J2 = 8.4, Н-4);
3.91 (1Н, dd, J1 = 16.8, J2 = 12.2, Н-4); 4.52 (2Н, q, J = 7.6, СН2СН3);
6.31 (1Н, dd, J1 = 12.2, J2 = 8.4, Н-5); 7.61 (2Н, m, Н arom.);
7.79 (1H, m, Н arom.); 8.15 (1Н, d, J = 8.2, Н arom.)
4a
4b
4c
4d
4e
4f
1.45 (3Н, t, J = 6.8, СН2СН3); 4.49 (2Н, q, J = 7.6, СН2СН3); 6.95 (1Н, s, Н-4);
7.41 (5Н, m, Н arom.)
1.47 (3Н, t, J = 6.8, СН2СН3); 4.48 (2Н, q, J = 6.8, СН2СН3); 6.88 (1Н, s, Н-4);
7.19 (2Н, m, Н arom.); 7.83 (2Н, m, Н arom.)
1.45 (3Н, t, J = 7.0, СН2СН3); 4.47 (2Н, q, J = 7.0, СН2СН3); 6.94 (1Н, s, Н-4);
7.48 (2Н, d, J = 8.4, Н arom.); 7.75 (2Н, d, J = 8.4, Н arom.)
1.47 (3Н, t, J = 6.6, СН2СН3); 2.42 (3Н, s, СН3); 4.48 (2Н, q, J = 6.6, СН2СН3);
6.87 (1Н, s, Н-4); 7.29 (2Н, d, J = 8.4, Н arom.); 7.71 (2Н, d, J = 8.4, Н arom.)
1.44 (3Н, t, J = 7.2, СН2СН3); 3.87 (3Н, s, ОСН3); 4.46 (2Н, q, J = 7.2, СН2СН3);
6.77 (1Н, s, Н-4); 6.92 (2Н, d, J = 8.2, Н-3,5 arom.); 7.71 (2Н, d, J = 8.2, Н-2,6 arom.)
1.47 (3Н, t, J = 6.9, СН2СН3); 4.06 (3Н, s, ОСН3); 4.49 (2Н, q, J = 6.9, СН2СН3);
6.94 (1Н, s, Н-4); 7.24 (1Н, d, J = 8.6, Н-5 arom.);
8.01 (1Н, dd, J1 = 8.6, J2 = 2.2, Н-6 arom.); 8.29 (1Н, d, J = 2.2, Н-2 arom.)
4g
1.37 (3Н, t, J = 6.4, СН2СН3); 4.41 (2Н, q, J = 6.4, СН2СН3);
7.71 (1Н, s, Н-4); 8.27 (2Н, d, J = 8.3, Н arom.); 8.41 (2Н, d, J = 8.3, Н arom.)
EXPERIMENTAL
1
The H NMR spectra were taken on Varian VXR-400 (400 MHz) and Bruker DRX-500 spectrometers
(500 MHz) in CDCl3 (2a-e, 3a-h, and 4a-f) and DMSO-d6 (4g) using the residual protons of the deuterated
solvent as the standard. The IR spectra were taken on a UR-20 spectrometer in vaseline mull or
hexachlorobutadiene. The mass spectra were taken on a Finnigan SSQ-7000 GC/MS using a 30 m capillary
602

column with DV-1 as the stationary phase, helium as the gas carrier, and temperature programming from 50 to
300°C (10 deg/min). The ionization energy was 70 eV. The purity of the products was monitored on plates or
columns packed with Silufol alumina (Brockmann activity II).
Chromatographic monitoring of the purity of 2a-h was carried out with 1:4 ether–hexane as the eluent,
while monitoring for 7a-h and 8a-h was carried out with 1:1:3 ether–chloroform–petroleum ether (40-70°C) as
the eluent.
Ethyl Esters of cis- and trans-2-Arylcyclopropanecarboxylic Acids 2a-e (General Method). A
mixture of corresponding styrene (0.17 mol) and ethyl diazoacetate (19.4 g, 0.17 mol) was added with vigorous
stirring to 50 ml dry o-xylene at reflux and stirred at 135-140°C until no further nitrogen was liberated (~6 h).
The mixture was distilled in vacuum. The reaction of styrene (17.7 g, 0.17 mol) by this procedure gave 17 g
(52%) of a mixture of ethyl esters of cis- and trans-2-phenylcyclopropanecarboxylic acid (2a); bp 126-127°C
(6 mm Hg) [23]. The ratio of the cis and trans isomers after distillation was 0.74. The mixture of cis- and
trans-2a (17 g) was dissolved in 50 ml methanol and maintained for 2 h at -50°C. The crystalline precipitate of
the ethyl ester of trans-2-phenylcyclopropanecarboxylic acid (trans-2a) was filtered off and washed with cold
methanol to give 8.2 g (48% of the mixture); mp 36-37°C [24, 25]. 1H NMR spectrum, δ, ppm (J, Hz): 0.19 (3H,
t, J = 7.6, CH2CH3); 1.34 (1H, m, H c-Pr); 1.47 (1H, m, H c-Pr); 1.91 (1H, m, H c-Pr); 2.43 (1H, m, H c-Pr);
4.12 (2H, q, J = 7.6, CH2CH3); 7.14 (3H, m, H arom); 7.25 (2H, m, H arom). Methanol was removed from the
mother liquor. The residue (8.6 g) was hydrolyzed as described by Burger [23] to give 7.3 g (78%) of a mixture
of cis- and trans-2-phenylcyclopropanecarboxylic acids. Crystallization of this mixture from heptane gave 3.5 g
(48%) cis-2-phenylcyclopropanecarboxylic acid, mp 105°C [26]. Esterification of this cis-acid in absolute
ethanol in the presence of concentrated sulfuric acid gave 3.4 g ethyl ester of cis-2-phenylcyclopropane-
1
carboxylic acid; bp 121-122°C (8 mm Hg), nD20 1.5172 [26]. H NMR spectrum, δ, ppm (J, Hz): 0.92 (3H, t,
J = 7.5, CH2CH3); 1.32 (1H, m, H c-Pr); 1.57 (1H, m, H c-Pr); 2.09 (1H, m, H c-Pr); 2.61 (1H, m, H c-Pr); 3.78
(2H, q, J = 7.5, CH2CH3); 7.21 (5H, m, H arom).
Ethyl Esters of cis- and trans-2-(4-Fluorophenyl)cyclopropanecarboxylic Acid (2b). Analogously,
p-fluorostyrene was used to give 17.3 g (48%) of a mixture of esters 2b; bp 170-171°C (10 mm Hg), the
1
cis/trans ratio was 0.34. H NMR spectrum, δ, ppm (J, Hz): trans-2b: 1.29 (3H, t, J = 7.4, CH2CH3); 1,33 (1H,
m, H c-Pr); 1.58 (1H, m, H c-Pr); 1.84 (1H, m, H c-Pr); 2.51 (1H, m, H c-Pr); 4.19 (2H, q, J = 7.4, CH2CH3);
6.95 (2H, m, H arom); 7.11 (2H, m, H arom); cis-2b: 1.01 (3H, t, J = 7.4, CH2CH3); 1.25 (1H, m, H c-Pr); 1.67
(1H, m, H c-Pr); 2.12 (1H, m, H c-Pr); 2.53 (1H, m, H c-Pr); 3.89 (2H, q, J = 7.4, CH2CH3); 6.98 (2H, m,
H arom), 7.24 (2H, m, H c-Pr).
Ethyl Esters of cis- and trans-2-(4-Chlorophenyl)cyclopropanecarboxylic Acid (2c). Analogously,
23.5 g p-chlorostyrene gave 19 g (49%) of a mixture of the cis and trans isomers of this ester; bp 179-181°C
1
(10 mm Hg), the cis/trans ratio was 0.28. H NMR spectrum, δ, ppm (J, Hz): trans-2c: 1.24 (3H, t, J = 7.2,
CH2CH3); 1.32 (1H, m, H c-Pr); 1.47 (1H, m, H c-Pr); 1.87 (1H, m, H c-Pr); 2.42 (1H, m, H c-Pr); 4.11 (2H, q,
J = 7.2, CH2CH3); 7.11 (2H, d, J = 8.2, H arom); 7.24 (2H, d, J = 8.2, H arom); cis-2c: 0.99 (3H, t, J = 7.4,
CH2CH3); 1.28 (1H, m, H c-Pr); 1.56 (1H, m, H c-Pr); 2.03 (1H, m, H c-Pr); 2.51 (1H, m, H c-Pr); 4.15 (2H, q,
J = 7.4, CH2CH3); 7.27 (2H, d, J = 8.2, H arom); 7.24 (2H, d, J = 8.2, H arom).
Ethyl Esters of cis- and trans-2-(4-Methylphenyl)cyclopropanecarboxylic Acid (2d) were obtained
by the above method from 20.1 g p-methylstyrene as a mixture of cis and trans isomers. The yield of 2d was
1
17.7 g (51%); bp 135-137°C (11 mm Hg), the cis/trans ratio was 0.48. H NMR spectrum, δ, ppm (J, Hz):
trans-2d: 1.32 (3H, t, J = 7.6, CH2CH3); 1.37 (1H, m, H c-Pr); 1.62 (1H, m, H c-Pr); 1.91 (1H, m, H c-Pr); 2.53
(1H, m, H c-Pr); 2.35 (3H, s, CH3); 4.21 (2H, q, J = 7.6, CH2CH3); 7.01 (2H, d, J = 8.4, H arom); 7.08 (2H, d,
J = 8.4, H arom); cis-2d: 1.06 (3H, t, J = 7.6, CH2CH3); 1.35 (1H, m, H c-Pr); 1.72 (1H, m, H c-Pr); 2.07 (1H,
m, H c-Pr); 2.56 (1H, m, H c-Pr); 3.92 (2H, q, J = 7.6, CH2CH3); 7.16 (2H, d, J = 8.4, H arom); 7.19 (2H, d,
J = 8.4, H arom).
603

Ethyl Esters of cis- and trans-2-(4-Methoxyphenyl)cyclopropanecarboxylic Acid (2e). Analogously,
23 g p-methoxystyrene gave 20.9 g (56%) of a mixture of the cis and trans isomers of 2e; bp 179-181°C
1
(10 mm Hg), the cis/trans ratio was 0.36. H NMR spectrum, δ, ppm (J, Hz): trans-2e: 1.32 (3H, t, J = 7.3,
CH2CH3); 1.27 (1H, m, H c-Pr); 1.62 (1H, m, H c-Pr); 1.85 (1H, m, H c-Pr); 2.51 (1H, m, H c-Pr); 3.77 (3H, s,
OCH3); 4.19 (2H, q, J = 7.3, CH2CH3); 6.81 (2H, d, J = 8.2, H arom); 7.05 (2H, d, J = 8.2, H arom); cis-2e: 1.03
(3H, t, J = 7.3, CH2CH3); 1.33 (1H, m, H c-Pr); 1.65 (1H, m, c-Pr); 2.02 (1H, m, H c-Pr); 2.52 (1H, m, H c-Pr);
3.80 (3H, s, OCH3); 3.92 (2H, q, CH2CH3); 6.87 (2H, d, J = 8.2, H arom); 7.21 (2H, d, J = 8.2, H arom).
Ethyl Esters of cis- and trans-2-(o-Nitrophenyl)cyclopropanecarboxylic Acid (2f) and cis- and
trans-2-(p-Nitrophenyl)cyclopropanecarboxylic Acid (2g) were obtained by the nitration of cis-2a in
27% yield as described in our previous work [27]. The ratio of the ortho and para isomers was 0.98. Column
chromatography of 4.5 g of the mixture of product isomers led to the isolation of cis-2f and cis-2g.
Ethyl Ester of cis-2-(o-Nitrophenyl)cyclopropanecarboxylic Acid (cis-2f) was obtained as a viscous oil.
1
The yield was 2.3 g (51% of the mixture). H NMR spectrum, δ, ppm (J, Hz): 1.05 (3H, t, J = 6.8, CH2CH3); 1.48
(1H, m, H c-Pr); 1.65 (1H, m, H c-Pr); 2.52 (1H, m, H c-Pr); 2.93 (1H, m, H c-Pr); 3.91 (2H, q, J = 6.8, CH2CH3);
7.37 (1H, t, J = 8.2, H-4 arom); 7.48 (1H, d, J = 8.2, H-6 arom); 7.55 (1H, t, J = 8.2, H-5 arom); 7.91 (1H, d, J = 8.2,
H-3 arom); M+ 235. Found, %: C 61.19; H 5.62; N 5.81. C12H13NO4. Calculated, %: C 61.27; H 5.57; N 5.96.
Ethyl Ester of cis-2-(p-Nitrophenyl)cyclopropanecarboxylic Acid (cis-2g) was obtained as a viscous
1
oil. The yield was 2.07 g (46% of the mixture). H NMR spectrum, δ, ppm (J, Hz): 1.03 (3H, t, J = 6.8,
CH2CH3); 1.48 (1H, m, H c-Pr); 1.75 (1H, m, H c-Pr); 2.21 (1H, m, H c-Pr); 2.61 (1H, m, H c-Pr); 3.90 (2H, q,
J = 6.8, CH2CH3); 7.45 (2H, d, J = 8.6, H-2,6 arom); 8.12 (2H, d, J = 8.6, H-3,5 arom). M+ 235. Found, %:
C 61.42; H 5.34; N 5.71. C12H13NO4. Calculated, %: C 61.27; H 5.57; N 5.96.
Ethyl
Esters
of
trans-(o-Nitrophenyl)cyclopropanecarboxylic
Acid
(trans-2f)
and
trans-2-(p-Nitrophenyl)cyclopropanecarboxylic Acid (trans-2g) were obtained in 72% yield analogously by
the nitration of trans-2a. The ratio of the ortho and para nitro isomers was 1.02. Chromatography on an alumina
column yielded 3 g of isomers trans-2f and trans-2g.
Ethyl Ester of trans-2-(o-Nitrophenyl)cyclopropanecarboxylic Acid (trans-2f) was obtained as a
1
viscous oil. The yield was 1.45 g (48% of the mixture of isomers trans-2f and trans-2g). H NMR spectrum, δ,
ppm (J, Hz): 1.25 (3H, t, J = 7.6, CH2CH3); 1.35 (1H, m, H c-Pr); 1.67 (1H, m, H c-Pr); 1.85 (1H, m, H c-Pr);
2.97 (1H, m, H c-Pr); 4.21 (2H, q, J = 7.6, CH2CH3); 7.24 (1H, d, J = 8.4, H-6 arom); 7.38 (1H, t, J = 8.4,
H-4 arom); 7.55 (1H, t, J = 8.4, H-5 arom); 7.93 (1H, d, J = 8.4, H-3 arom). M+ 235. Found, %: C 60.91; H 5.64;
N 6.04. C12H13NO4. Calculated, %: C 61.27; H 5.57; N 5.96.
Ethyl Ester of trans-2-(p-Nitrophenyl)cyclopropanecarboxylic Acid (trans-2g) was obtained as a
1
viscous oil. The yield was 1.32 g (44% of mixture). H NMR spectrum, δ, ppm (J, Hz): 1.24 (3H, t, J = 7.6,
CH2CH3); 1.38 (1H, m, H c-Pr); 1.71 (1H, m, H c-Pr); 2.01 (1H, m, H c-Pr); 2.59 (1H, m, H c-Pr); 4.18 (2H, q,
J = 7.6, CH2CH3); 7.19 (2H, d, J = 9.6, H-2,6 arom); 8.12 (2H, d, J = 9.6, H-3,5 arom). M+ 235. Found, %:
C 61.06; H 5.71; N 6.08. C12H13NO4. Calculated, %: C 61.27; H 5.57; N 5.96.
Reaction of 2-Arylcyclopropanecarboxylic Acid Esters 2a-h with HNO2 (General Method). A
sample of NaNO2 was added in portions over 10 min with stirring to a solution of ethyl ester of
2-arylcyclopropanecarboxylic acid (0.01 mol) in trifluoroacetic acid (8 ml, 0.01 mol) at 20°C. In Method A,
NaNO2 (0.01 mol) was added and stirring was continued for 30 min. In Method B, NaNO2 (0.02 mol) was added
and stirring was continued for 6-12 h. The reaction mixture was then poured into 60 ml water and extracted with
two 15 ml chloroform portions. The extracts were washed with 2 N aq. Na2CO3 and dried over CaCl2. The
solvent was distilled off and the residue was subjected to chromatography on an alumina column to give 5-aryl-
3-ethoxycarbonyl-4,5-dihydroisoxazoles 3a-h or 5-aryl-3-ethoxycarbonyl-4,5-isoxazoles 4a-h (Tables 1 and 2).
604

This work was carried out with the financial support of a grant to the Leading Scientific School of
Academician N. S. Zefirov.
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