Benzyl-4,5-dihydroisoxazoles from benzylcyclo-propanes: Regioselective insertion of an n=o fragment into the three-membered carbocycle of benzylcyclopropanes by the action of nitrous acid

Article abstract of DOI:10.1007/s10593-012-1125-9

The action of equimolar amounts of nitrous acid formed in situ on benzylcyclopropanes with electron-donor and electron-withdrawing substituents in the aromatic part of the substrate lead, at certain temperatures, exclusively to the insertion of an N=O fragment into the three-membered carbocycle with subsequent formation of a heterocyclic isoxazoline (4,5-dihydroisoxazole) system.

Full text of DOI:10.1007/s10593-012-1125-9

Chemistry of Heterocyclic Compounds, Vol. 48, No. 8, November, 2012 (Russian Original Vol. 48, No. 8, August, 2012)
BENZYL-4,5-DIHYDROISOXAZOLES FROM BENZYLCYCLO-
PROPANES: REGIOSELECTIVE INSERTION OF AN N=O
FRAGMENT INTO THE THREE-MEMBERED CARBOCYCLE OF
BENZYLCYCLOPROPANES BY THE ACTION OF NITROUS ACID
R. A. Gazzaeva1* E. V. Trofimova2, A. Z. Kadzhaeva1,
A. N. Fedotov2, and S. S. Mochalov2
The action of equimolar amounts of nitrous acid formed in situ on benzylcyclopropanes with electron-
donor and electron-withdrawing substituents in the aromatic part of the substrate lead, at certain
temperatures, exclusively to the insertion of an N=O fragment into the three-membered carbocycle with
subsequent formation of a heterocyclic isoxazoline (4,5-dihydroisoxazole) system.
Keywords: benzylcyclopropanes, benzyl-4,5-dihydroisoxazoles, nitrous acid, heterocyclization induced
by the nitrosyl cation, nitrosylation, SET mechanism,.
The behavior of phenylcyclopropanes in their reactions with nitrosylating reagents such as HNO2 and
N2O4 has been studied by now in detail. It was found that arylcyclopropanes capable of undergoing oxidation
by the nitrosyl cation to give the corresponding radical cations are converted regioselectively by the single-
electron transfer (SET) mechanism to nitroaromatic derivatives with retention of the three-membered carbocycle
[1, 2]. Arylcyclopropanes incapable of being oxidized undergo insertion of an N=O fragment into the small ring
and give products with modification of the cyclopropane ring [1, 3, 4]. The behavior found for
cyclopropylbenzenes was found to be largely characteristic also for the nitrosylation reactions of
benzylcyclopropanes, in which the aryl fragments are not directly bound to the three-membered carbocycle (the
conjugation system is disrupted) and which, in principle, may be seen as methylcyclopropanes substituted at the
methyl group. At the same time, in some cases, significant differences are found in the behavior of phenyl- and
benzylcyclopropanes in the nitrosylation reaction, at least in the reaction with N2O4. For example, in previous
work [1, 2], we have shown that 4-methoxyphenyl- and 4-methoxybenzylcyclopropanes, which are susceptible
to single-electron oxidation by the nitrosyl cation, react with N2O4 to give different types of reaction products
although both reactions, as should have been expected, proceed with retention of the three-membered
carbocycles.
_______
*To whom correspondence should be addressed, e-mail: gazzaevar@mail.ru.
1K. L. Khetagurov North-Ossetian State University, 46 Vatutina St., Vladikavkaz 362040, Russia.
2M. V. Lomonosov Moscow State University, 1, Build. 3 Leninskie Gory, Moscow 119992, Russia;
ssmoch@org.chem.msu.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1309-1317, August, 2012.
Original article submitted May 19, 2011.
1220
0009-3122/12/4808-1220©2012 Springer Science+Business Media New York

We should note that, in contrast to phenylcyclopropanes, whose transformations by the action of nitrous
acid have been the subject of extensive study [5-9], the reactions of benzylcyclopropanes with this reagent have
hardly been investigated at all. In a brief communication [10], we reported that 4-isopropylbenzylcyclopropane
is transformed by the action of nitrous acid into 5-(4-isopropylbenzyl)isoxazoline and, in this regard, the
behavior of this benzylcyclopropane correlates with the behavior of its analog, namely, 4-iso-propylphenyl-
cyclopropane.
In this work, we attempted to elucidate whether the nature of the substituents in the aromatic part of
benzylcyclopropanes affects their behavior upon reaction with nitrous acid formed in situ. For this purpose, we
synthesized a series of substituted benzylcyclopropanes and studied the behavior of these compounds under
conditions for the nitrosylation of phenylcyclopropanes.
In previous work [11], we reported that benzylcyclopropane 1 and its 2- and 4-nitro-substituted analogs
4 and 5, in contrast to phenylcyclopropane and 2- and 4-nitrophenylcyclopropanes, react with trifluoroacetic
acid at 20°C to give the products of its addition at the small ring. In the present work, we demonstrate that
trifluoroacetic acid addition products are not observed in significant amounts during preparation of solutions of
the starting benzylcyclopropanes 1, 4, and 5 in trifluoroacetic acid and the addition of equimolar amounts of
NaNO2 at 20°C. The major direction of the reaction in this case is insertion of an N=O fragment into the three-
membered carbocycle and formation of isoxazolines 10, 13, and 14 (Table 1). However, under the same
conditions, 4-tert-butylbenzylcyclopropane (2) gives mainly tar, while 4-methoxybenzylcyclopropane (3) is
converted virtually quantitatively into the trifluoroacetic acid addition product 15. 3,4-Ethylene-
dioxybenzylcyclopropane (6) and 3,4-dimethoxybenzylcyclopropane (7) form complex mixtures, from which
only trace amounts of 2-nitro-4,5-ethylenedioxybenzylcyclopropane (8) (3% yield) and 4,5-dimethoxy-2-nitro-
benzylcyclopropane (9) (6% yield) could be isolated.
These findings indicate that isoxazoline formation predominates if the rate of trifluoroacetic acid addition
to the small ring of benzylcyclopropanes at 20°C is lower than the rate of insertion of an N=O fragment into the
three-membered carbocycle, as in the case of benzylcyclopropane (1) or 2-nitro- (4) and 4-nitrobenzylcyclo-
propanes (5) (Table 1). If, on the other hand, the benzylcyclopropane has an electron-donor substituent, opening
of the cyclopropane ring by the action of trifluoroacetic acid predominates. This hypothesis is supported by the
results of the reactions of benzylcyclopropanes 1-3, 6, and 7 with an equimolar amount of nitrous acid at
reduced temperatures. Thus, under conditions hindering opening of the cyclopropane ring by the action of
trifluoroacetic acid (at -10°C), benzylcyclopropanes 1-3 give virtually exclusively the 5-benzyl-isoxazolines 10-
12 (Table 1). Nitro derivatives 4 and 5 cannot be converted into isoxazolines 13 and 14 under these conditions.
H 4b
H4a
5
1 equiv. NaNO2
1 equiv. NaNO2
Me
3
3
TFA, 20°C, 1 h
O
OCOCF3
TFA, 20°C, 1 h
88%
N
MeO
R
R
15
1–5
10–14
TABLE 1. Composition and Yields of Products from the Reaction of
Benzylcyclopropanes 1-5 with HNO2
Yield, %
Starting compound
R
Isoxazoline
20°С
-10 °С
Н
87
19
0
89
76
74
0
1
2
3
4
5
10
11
12
13
14
4-(t-Bu)
4-ОMe
2-NO2
4-NO2
67
64
0
1221

R
R
R
R
NaNO2, TFA
CHCl3, –10°C
+
+
R1
O
R1
O
R1
R1
NO2
18, 19
N
N
NO2
6, 7
8, 9
16, 17
TABLE 2. Composition and Yields of Products from the Reaction of
Benzylcyclopropanes 6 and 7 with HNO2
Reaction products
(yield, %)
Starting
compound
HNO2,
equiv.
R
R1
Conversion, %
ОСН2СН2О
1
1
2
8 (11); 16 (21); 18 (19)
9 (18); 17 (21); 19 (17)
9 (31); 17 (27); 19 (26)
54
61
91
6
7
7
OMe
OMe
OMe
OMe
It is interesting that at -10°C, benzylcyclopropanes 6 and 7, in which the benzene fragments are largely
saturated with electron-donor substituents, form products of aromatic ring nitration 8 and 9 and products of
N=O insertion into the three-membered carbocycle 16, 17 and 18, 19. In this case, a significant fraction of the
starting cyclopropanes 6 and 7 remains unchanged (Table 2).
The structure of the reaction products formed upon the nitrosylation of cyclopropanes 6 and 7 and their
ratio indicate that the reaction of the starting benzylcyclopropanes with an equimolar amount of nitrous acid
proceeds concurrently in two directions: 1) nitration in the aromatic ring and 2) N=O insertion into the small
ring. Nitrobenzylisoxazolines 18 and 19 are the products of a secondary process, and are formed presumably
from the nitrobenzylcyclopropanes 8 and 9 by their subsequent reaction with HNO2 at the small ring. This
hypothesis is supported by the finding that isoxazolines 16 and 17, as we have shown in dedicated experiments,
do not undergo nitration upon treatment with an additional equivalent of HNO2 under the given conditions. It is
interesting to note that isoxazolines 16 and 18 upon repeated treatment with HNO2 not only do not undergo
nitration, but also do not undergo dehydrogenation to give isoxazoles, although isoxazolines formed from
ethoxycarbonylphenylcyclopropanes are known to readily form the corresponding isoxazoles upon the action of
this reagent [9].
According to the scheme below, nitrous acid under the reaction conditions may serve as a source of both
nitrosylating and nitrating species [12].
H+
–2NO
4HNO2
2N2O3
2NO2
N2O4
NO2+ + HNO2
–2H2O
Hence, it is clear that an equimolar amount of HNO2 is inadequate for the complete conversion of
cyclopropanes 6 and 7 into the identified reaction products 8, 9, and 16-19, as indicated by the high recovery of
the starting compounds 6 and 7. Additional support for this hypothesis lies in the finding that the recovery of the
starting compound was only 9% when the reaction of 3,4-dimethoxybenzylcyclopropane (7) was carried out
with two equivalents of HNO2, while the reaction mixture was similar to that identified when the cyclopropane
7 reacted with an equimolar amount of HNO2 (Table 1).
NaNO2, TFA
16–19
6–9
CHCl3, –40°C
Starting compound
Isoxazoline
Yield, %
65
63
98
86
6
7
8
9
16
17
18
19
1222

It appeared then that if the reaction of benzylcyclopropanes 6 and 7 is carried out with an equimolar
amount of HNO2 at -40°C, nitration of the aromatic ring is completely suppressed and only the
5-benzylisoxazolines 16 and 17 are formed. It is interesting that nitrobenzylcyclopropanes 8 and 9 are converted
under these conditions into nitroisoxazolines 18 and 19 in virtually quantitative yields.
Hence, the behavior of benzylcyclopropanes, which are, in essence, arylalkylcyclopropanes, in their
reaction with HNO2 correlates with the behavior of analogous phenylcyclopropanes. The regioselectivity of the
reactions of benzylcyclopropanes with nitrous acid, similarly as for phenylcyclopropanes, may be regulated by
the capacity of these compounds to undergo single-electron oxidation upon reaction with the nitrosyl cation.
Thus, if we refer to the calculated values of -εHOMO for phenyl- and benzylcyclopropanes (Table 3),
which, according to the Koopmans theorem [13], correlates reasonably well with the ionization potential of
cyclopropylarenes (and, thus, with their oxidation potential), we readily note that the -εHOMO values of
phenylcyclopropanes and their analogous benzylcyclopropanes are so similar that for each pair of analogous
arylcyclopropanes (for example, for 4-methoxyphenylcyclopropane and 4-methoxybenzylcyclopropane (3) or
3,4-dimethoxyphenylcyclopropane and 3,4-dimethoxybenzylcyclopropane (7)) we should expect similar
behavior upon reaction with nitrous acid. Indeed, in the case of benzylcyclopropanes 1, 2, 4, and 5, whose
ionization potentials lie higher than the limiting values determining the reaction direction given in our previous
work [2], the transformations by the action of HNO2, as should have been expected, proceed only with insertion
of an N=O fragment into the three-membered carbocycle and formation of 5-benzylisoxazolines 10, 11, 13,
and 14.
The transformations of 4-methoxybenzylcyclopropane (3) in its reaction with N2O4 [2] largely proceed
according to predictions from ionization potential calculations (Table 3), with retention of the three-membered
carbocycle. The reaction of 4-methoxybenzylcyclopropane (3) with an equimolar amount of HNO2 generated in
situ proceeds only with modification of the cyclopropane ring.
TABLE 3. HOMO Energies From AM1 and HF/6-31G** Calculations for
Some Aryl- and Benzylcyclopropanes
-εHOMO, eV
Cyclopropanes
АМ1
HF/6-31G**
Arylcyclopropanes:
Phenylcyclopropane
9.21
9.10
8.82
8.52
8.49
8.95
9.32
8.39
8.40
8.06
8.02
7.72
8.19
8.67
4-Methylphenylcyclopropane
4-Methoxyphenylcyclopropane
6-Cyclopropyl-1,4-benzodioxane
3,4-Dimethoxyphenylcyclopropane
6-Bromo-7-cyclopropyl-1,4-benzodioxane
7-Cyclopropyl-6-nitro-1,4-benzodioxane*
Benzylcyclopropanes:
Benzylcyclopropane (1)
9.37
—
8.67
8.54
8.04
8.01
7.70
8.22
8.85
4-tert-Butylbenzylcyclopropane (2)
4-Methoxybenzylcyclopropane (3)
6-Cyclopropylmethyl-1,4-benzodioxane (6)
3,4-Dimethoxybenzylcyclopropane (7)
6-Bromo-7-cyclopropylmethyl-1,4-benzodioxane
7-Cyclopropylmethyl-6-nitro-1,4-benzodioxane (8)*
8.82
8.81
8.49
8.96
9.58
_______
*The values of -εHOMO of o- and p-nitrophenylcyclopropanes and o- (4) and
p-nitrobenzylcyclopropanes (5) were not calculated since, a priori, they should
be lower than the values of their corresponding hydrocarbons.
1223

In order to explain this peculiar case of 4-methoxybenzylcyclopropane (3) transformation to 5-(4-meth-
oxybenzyl)isoxazoline (12), we refer to the finding that the formation of isoxazolines from arylcyclopropanes
may be accomplished not only by an electrophilic mechanism involving addition of nitrosyl cation to the three-
membered carbocycle with subsequent cyclization to give an isoxazoline, but also through an SET mechanism
[4]. In that case, the predictability of the reaction mechanism on the basis of the calculated -εHOMO values of the
cyclopropane substrates remains in force. Single-electron oxidation of the substrate 3 by nitrosyl cation
obviously occurs upon using equimolar amounts of nitrous acid at -10°C, and the corresponding radical cation
•
3a is formed. Under our conditions, there was no possibility for the formation of sufficient amount of NO2
radicals required for the formation of products with a retained cyclopropane fragment, such as the products
formed from cyclopropane 3 by the action of N2O4 (see the scheme). Thus, the generated NO• radicals react with
the three-membered carbocycle to give an intermediate (A), which, according to our previous findings [4], may
be responsible for the formation of isoxazoline 12.
1 equiv.
NaNO2
+
.
.
+
NO
12
(74%)
N
–H+
TFA
–10°C
MeO
O
A
3
MeO
O2N
.
N2O4
NO2
+
CH2Cl2
–30°C
OMe
3a
MeO
(45%)
NO2
(17%)
The findings of Mizuno et al. [14] also support our proposed explanation for the formation of
isoxazoline 12. These workers found that the arylcyclopropane substrate, which is clearly oxidized to give the
corresponding radical cation as the result of radical-ion recombination with NO•, leads to the formation of
analogs of ion A, which then cyclize to give the corresponding isoxazolines.
The calculated -εHOMO values of benzylcyclopropanes 6 and 7 (Table 3) indicate that their capacity to
undergo single-electron oxidation should be even higher than for 4-methoxybenzylcyclopropane (3). The
reaction of cyclopropanes 6 and 7 with an equimolar amount of nitrous acid at -40°C gives only the
corresponding isoxazolines 16 and 17, rather than products with retained cyclopropane fragments, just as
predicted by analysis of the ionization potentials. Thus, the transformations of benzylcyclopropanes 6 and 7 to
give heterocycles by the action of equimolar amounts of HNO2 proceeds analogously to the transformation of
cyclopropane 3.
Nitrobenzylcyclopropanes 8 and 9 react with an equimolar amount of HNO2 to give the nitro-
isoxazolines 18 and 19 in virtually quantitative yield. These transformations presumably take place through a
direct attack of nitrosyl cation on the cyclopropane ring, that is, in complete accord with the reaction mechanism
predicted on the basis of the calculated ionization potentials (Table 3).
It is interesting to note that although the nitrobenzylcyclopropanes 4, 5, 8, and 9 react with nitrous acid
through the same mechanism involving an insertion of nitrosyl cation into the small ring, the reactivity of
cyclopropanes 8 and 9, which have electron-donor substituents, is significantly higher than the reactivity of
nitrocyclopropanes 4 and 5, which lack such substituents.
Hence, the reaction of benzylcyclopropanes with an equimolar amount of HNO2 generated in situ may
be considered an efficient method for the synthesis of less readily available benzyl-4,5-dihydroisoxazoles and,
apparently, the corresponding isoxazoles.
1224

EXPERIMENTAL
1
13
The IR spectra were recorded on a UR-20 spectrometer in vaseline mull, while the H and C NMR
spectra were recorded on a Varian BXR-400 spectrometer (400 and 100 MHz, respectively) with TMS as
internal standard when using DMSO-d6 as the solvent, or the residual solvent proton when using CDCl3 (δ 7.26
ppm). The mass spectra were recorded on a Finnigan SSQ 7000 GC-MS instrument using a 30m2mm capillary
column with DB-1 stationary phase and temperature program from 50 to 300°C (10°C/min). The helium carrier
gas flow rate was 40 ml/min, and the ionization energy was 70 eV. The elemental analysis was carried out on a
Vario-11CHN analyzer. The melting points were measured on a Model 1A9100 Electrothermal Digital Melting
Point Apparatus. The separation of the reaction mixtures was carried out on columns or thin-layer plates using
Brockmann Grade II Activity alumina as the support. The eluents were A) 1:3 ether–petroleum ether and B)
1:1:3 ether–chloroform–petroleum ether. Petroleum ether with bp 40-70°C was used.
The starting benzylcyclopropanes 1-9 were synthesized as described in [2, 11, 15].
Reaction of Benzylcyclopropanes 1-9 with Nitrous Acid (General Method). NaNO2 (0.69 g,
0.01 mol) was gradually added with stirring to a solution of benzylcyclopropane 1-9 (0.01 mol) in
trifluoroacetic acid (10 ml) at 20°C (or at -10°C or at -40°C, in both cases with the addition of chloroform). The
reaction mixture was stirred at the given temperature for 1 h and poured into water (120 ml). The reaction
products were extracted with chloroform (230 ml). The extract was washed with 2% aqueous Na2CO3, then
water, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was subjected
to chromatography on alumina columns or plates using system A as the eluent.
The reaction of benzylcyclopropane (1) (1.32 g, 0.01 mol) at -10°C with the addition of chloroform
(5 ml) gave 1.43 g (89%) 5-benzyl-4,5-dihydroisoxazole (10) as a viscous oil. 1Н NMR spectrum (DMSO-d6),
, ppm (J, Hz): 2.68 (1Н, ddd, J = 17.6, J = 7.4, J = 1.9, Н-4а); 2.77 (1H, dd, J = 13.8, J = 6.3) and 2.87 (1Н,
dd, J = 13.8, J = 6.3, PhСН2); 2.98 (1H, ddd, J = 17.6, J = 10.4, J = 1.8, Н-4b); 4.69 (1Н, dq, J = 10.4, J = 6.8,
13
Н-5); 7.25–7.32 (6Н, m, H Ph, Н-3). C NMR spectrum, , ppm: 40.0 (C-4); 40.8 (PhCH2); 79.0 (C-5); 126.6
(p-C); 128.5 (m-C); 129.5 (o-C); 137.3 (i-С); 146.2 (С-3). Mass spectrum, m/z (Irel, %): 161 [M]+ (37), 158 (96),
146 (8), 110 (6), 93 (100), 67 (7). Found, %: С 74.36; Н 6.75; N 8.52. C10H11NO. Calculated, %: С 74.51; Н 6.88;
N 8.69.
The reaction of 4-tert-butylbenzylcyclopropane (2) (1.88 g, 0.01 mol) at -10 °C gave 1.60 g (76%)
1
5-(4-tert-butylbenzyl-4,5-dihydroisoxazole (11) as a viscous oil. Н NMR spectrum (CDCl3), , ppm (J, Hz):
1.27 (9Н, s, С(СН3)3); 2.70-2.82 (2Н, m) and 2.93-3.07 (2Н, m, ArСН2, 4-CН2); 4.75-4.83 (1Н, m, H-5); 7.04-
7.09 (1Н, m, H-3); 7.19 (2Н, d, J = 8.3, Н Ar); 7.36 (2Н, d, J = 8.3, Н Ar). Mass spectrum, m/z (Irel, %): 217 [M]+
(40), 202 (28), 174 (5), 161 (6), 157 (10), 147 (100), 143 (12), 133 (72), 128 (9), 117 (50), 105 (30), 91 (48), 77
(24), 70 (21), 65 (19), 57 (74), 51 (20), 41 (84). Found, %: С 77.45; H 8.72; N 6.52. C14H19NO. Calculated, %:
С 77.38; H 8.81; N 6.45.
The reaction of 4-methoxybenzylcyclopropane (3) (1.62 g, 0.01 mol) at 20°C gave 2.43 g (88%)
1-(4-methoxyphenyl)-2-trifluoroacetoxybutane (15) as a viscous oil. 1Н NMR spectrum (CDCl3), , ppm (J, Hz):
0.95 (3Н, t, J = 6.8, СН2CH3); 1.72-1.78 (2Н, m, СН2СН3); 2.90 (2Н, d, J = 5.2, ArCH2); 3.83 (3Н, s, ОСН3);
5.15–5.18 (1Н, m, ArСН2CH); 6.87 (2Н, d, J = 8.2, Н Ar); 7.13 (2Н, d, J = 8.2, Н Ar). Mass spectrum, m/z (Irel,
%): 276 [M]+ (37), 241 (5), 229 (2), 181 (7), 162 (64), 152 (8), 147 (25), 135 (5), 121 (100), 109 (5), 91 (8), 83
(9), 78 (9), 69 (10), 63 (4), 51 (5), 36 (8). Found, %: С 56.31; Н 5.32. C13H15F3O3. Calculated, %: С 56.52;
Н 5.47.
The reaction of 4-methoxybenzylcyclopropane (3) (1.62 g, 0.01 mol) at -10°C with the addition of
chloroform (5 ml) gave 1.41 g (74%) 5-(4-methoxybenzyl)-4,5-dihydroisoxazole (12) as a viscous oil.
1Н NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.63-2.71 (2Н, m), 2.79 (1Н, dd, J = 14.0, J = 6.7) and 2.96
(1Н, ddd, J = 17.6, J = 10.4, J = 1.6, ArCH2, 4-CН2); 3.71 (3H, s, OCH3); 4.62 (1H, dq, J = 10.4, J = 6.8, Н-5);
6.86 (2H, d, J = 8.6, Н Ar); 7.17 (2H, d, J = 8.6, Н Ar); 7.30 (1Н, s, H-3). Mass spectrum, m/z (Irel, %): 191
1225

[M]+ (59), 161 (8), 146 (25), 131 (8), 121 (100), 115 (8), 107 (5), 103 (6), 91 (14), 77 (20), 70 (5), 63 (10), 51
(15), 43 (4), 39 (16). Found, %: С 68.85; Н 6.69; N 7.44. C11H13NO2. Calculated, %: С 69.09; Н 6.85; N 7.32.
The reaction of 2-nitrobenzylcyclopropane (4) (1.77 g, 0.01 mol) at 20°C gave 1.38 g (67%) 5-(2-nitro-
benzyl)-4,5-dihydroisoxazole (13) as a viscous oil. IR spectrum, ν, сm-1: 1560, 1335 (NO2). 1Н NMR spectrum
(CDCl3), , ppm (J, Hz): 2.76 (1Н, ddd, J = 17.7, J = 6.8, J = 1.8) and 3.10 (1Н, ddd, J = 17.2, J = 9.8, J = 1.6,
4-CH2); 3.09 (1Н, dd, J = 14.2, J = 8.8) and 3.21 (1Н, dd, J = 14.2, J = 4.1, ArCH2); 4.84-4.91 (1Н, m, H-5);
7.15 (1Н, br. s, H-3); 7.41 (1Н, dt, J = 7.6, J = 1.5, H Ar); 7.46 (1Н, d, J = 7.6, H Ar); 7.55 (1H, dt, J = 7.6,
J = 1.5, H Ar); 7.93 (1H, d, J = 8.3, H Ar). Mass spectrum, m/z (Irel, %): 206 [M]+ (5), 189 (10), 137 (22), 128
(11), 120 (88), 115 (7), 105 (5), 92 (50), 90 (11), 89 (25), 78 (30), 70 (100), 65 (36), 63 (17), 51 (18), 42 (40),
39 (11). Found, %: С 58.11; H 4.71; N 13.76. C10H10N2O3. Calculated, %: С 58.25; H 4.89; N 13.59.
The reaction of 4-nitrobenzylcyclopropane (5) (1.77 g, 0.01 mol) at 20°C gave 1.32 g (64%) 5-(4-nitro-
benzyl)-4,5-dihydroisoxazole (14) as a viscous oil. IR spectrum, ν, сm-1: 1550, 1330 (NO2). 1Н NMR spectrum
(CDCl3), , ppm (J, Hz): 2.71 (1H, ddd, J = 17.2, J = 6.8, J = 1.6) and 3.05 (1Н, ddd, J = 17.2, J = 9.4, J = 1.6,
4-CН2); 2.95 (1Н, dd, J = 14.1, J = 7.6) and 3.15 (1H, dd, J = 14.1, J = 4.8, ArCH2); 4.77-4.84 (1H, m, H-5);
7.11 (1Н, br. s, H-3); 7.42 (2H, d, J = 8.1, H Ar); 8.14 (2H, d, J = 8.1, H Ar). Mass spectrum, m/z (Irel, %): 206
[M]+ (5), 137 (100), 128 (5), 120 (54), 107 (48), 90 (44), 78 (27), 70 (98), 65 (15), 56 (5), 51 (8), 42 (50), 39
(11). Found, %: С 58.21; H 4.81; N 13.41. C10H10N2O3. Calculated, %: С 58.25; H 4.89; N 13.59.
The reaction of 6-cyclopropylmethyl-1,4-benzodioxane (6) (1.90 g, 0.01 mol) at -10°C with the addition
of chloroform (10 ml) gave 0.87 g (46%) starting benzodioxane 6, 0.14 g (11%)* 7-cyclopropylmethyl-
6-nitro-1,4-benzodioxane (8), 0.25 g (21%)* 5-(2,3-dihydro-1,4-benzodioxan-6-yl)methyl-4,5-dihydro-
isoxazole (16), and 0.27 g (19%)* 5-[(7-nitro-2,3-dihydro-1,4-benzodioxan-6-yl)methyl]-4,5-dihydro-
isoxazole (18).
Benzodioxane 8. Mp 86.5-87°C (87-88°C [15]).
Dihydroisoxazole 16 was obtained as a viscous oil. Н NMR spectrum (CDCl3), , ppm (J, Hz):
1
2.62-2.73 (2Н, m) and 2.91-3.02 (2Н, m, ArСН2, 4-CН2); 4.24 (4Н, s, ОСН2СН2О); 4.68-4.74 (1Н, m, Н-5);
6.68 (1Н, dd, J = 8.0, J = 1.7, H Ar); 6.74 (1Н, d, J = 1.7, H Ar); 6.78 (1Н, d, J = 8.0, H Ar); 7.09 (1Н, s, Н-3).
Mass spectrum, m/z (Irel, %): 219 [M]+ (39), 176 (11), 162 (10), 149 (100), 135 (24), 123 (11), 118 (7), 106 (7),
91 (13), 77 (32), 70 (5), 65 (29), 51 (26), 43 (7), 39 (34). Found, %: С 65.52; Н 5.82; N 6.48. C12H13NO3.
Calculated, %: С 65.74; Н 5.98; N 6.39.
Dihydroisoxazole 18 was obtained as light-yellow crystals. Mp 145-146 °С (EtOH). 1Н NMR spectrum
(DMSO-d6), , ppm (J, Hz): 2.74 (1Н, ddd, J = 16.3, J = 7.2, J = 1.7, Н-4a); 3.02-3.09 (3Н, m, ArСН2, Н-4b);
4.31-4.32 (4H, m, ОСН2СН2О); 4.65-4.75 (1Н, m, H-5); 7.01 (1Н, s, H Ar); 7.57 (1Н, s, H Ar); 7.43 (1Н, s,
H-3). Mass spectrum, m/z (Irel, %): 264 [M]+ (3), 194 (5), 178 (100), 163 (5), 157 (7), 136 (5), 123 (7), 106 (14),
92 (8), 78 (13), 70 (11), 63 (21), 51 (21), 42 (48). Found, %: С 54.38; H 4.44; N 10.76. C12H12N2O5. Calculated,
%: С 54.55; H 4.58; N 10.60.
The reaction of 3,4-dimethoxybenzylcyclopropane (7) (1.92 g, 0.01 mol) at -10°C with the addition of
chloroform (10 ml) gave 0.75 g (39%) starting cyclopropane 7, 0.26 g (18%)* 4,5-dimethoxy-2-nitro-
benzylcyclopropane (9), 0.28 g (21%)* 5-(3,4-dimethoxybenzyl)-4,5-dihydroisoxazole (17), and 0.28 g
(17%)* 5-(4,5-dimethoxy-2-nitrobenzyl)-4,5-dihydroisoxazole (19).
Nitrobenzylcyclopropane 9 was obtained as light-yellow crystals. Mp 74-75°C (75-76°C [15]).
1
Dihydroisoxazole 17 was obtained as a viscous oil. Н NMR spectrum (CDCl3), , ppm (J, Hz):
2.66-2.80 (2Н, m) and 2.97-3.04 (2Н, m, ArСН2, 4-CН2); 3.86 (3H, s, OCH3); 3.88 (3H, s, OCH3); 4.77-4.81
(1H, m, H-5); 6.71-6.82 (3H, m, Н Ar); 7.08 (1Н, s, Н-3). Mass spectrum, m/z (Irel, %): 221 [M]+ (51), 176 (9),
161 (7), 151 (100), 137 (14), 121 (11), 115 (8), 107 (30), 103 (6), 91 (23), 77 (26), 70 (8), 65 (26), 55 (5), 51
(23). Found, %: С 64.92; Н 6.69; N 6.45. C12H15NO3. Calculated, %: С 65.14; Н 6.83; N 6.33.
_______
*Calculated relative to the consumed starting compound.
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Dihydroisoxazole 19 was obtained as light-yellow crystals. Mp 156-157 °С (EtOH). 1Н NMR spectrum
(DMSO-d6), , ppm (J, Hz): 2.77 (1Н, ddd, J = 17.7, J = 6.8, J = 1.8, Н-4a); 3.00–3.09 (2Н, m) and 3.18 (1Н,
dd, J = 13.6, J = 7.3, ArСН2, Н-4b); 3.84 (3H, s, OCH3); 3.86 (3H, s, OCH3); 4.71 (1H, dt, J = 16.8, J = 6.6, Н-5);
7.07 (1H, s, Н Ar); 7.58 (1H, s, Н Ar); 7.37 (1Н, s, Н-3). Mass spectrum, m/z (Irel, %): 266 [M]+ (12), 196 (5),
180 (100), 165 (7), 152 (16), 136 (11), 125 (12), 120 (7), 107 (10), 92 (17), 82 (7), 77 (25), 70 (16), 63 (21), 57
(12), 51 (19), 42 (64). Found, %: С 53.81; Н 5.19; N 10.71. C12H14N2O5. Calculated, %: С 54.13; Н 5.30; N 10.52.
The reaction of 6-cyclopropylmethyl-2,3-dihydrobenzo[1,4]dioxane (6) (1.90 g, 0.01 mol) at -40°C
gave 1.42 g (65%) dihydroisoxazole 16.
The reaction of 3,4-dimethoxybenzylcyclopropane (7) (1.92 g, 0.01 mol) at -40°C with the addition of
chloroform (10 ml) gave 1.42 g (63%) 5-(3,4-dimethoxybenzyl)-4,5-dihydroisoxazole (17).
The reaction of 7-nitro-6-cyclopropylmethyl-2,3-dihydrobenzo[1,4]dioxane (8) (2.35 g, 0.01 mol) at
-40°C gave 2.59 g (98%) dihydroisoxazole 18.
The reaction of 4,5-dimethoxy-2-nitrobenzylcyclopropane (9) (2.37 g, 0.01 mol) at -40°C gave 2.29 g
(86%) isoxazoline 19.
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