Synthesis of 4,5-dihydroisoxazoles from arylcyclopropanes and nitrosyl chloride

Article abstract of DOI:10.1023/B:RUJO.0000003196.89457.a4

Arylcyclopropanes readily react with nitrosyl chloride in liquid sulfur dioxide to give the corresponding 5-aryl-4,5-dihydroisoxazoles in good yield. The reaction is most selective at -40 to -50°C; at higher temperature, the contribution of side processes

Full text of DOI:10.1023/B:RUJO.0000003196.89457.a4

Russian Journal of Organic Chemistry, Vol. 39, No. 7, 2003, pp. 1021 1024. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 7, 2003,
pp. 1084 1087.
Original Russian Text Copyright
2003 by Bondarenko, Gavrilova, Saginova, Zyk.
Synthesis of 4,5-Dihydroisoxazoles from Arylcyclopropanes
and Nitrosyl Chloride
O. B. Bondarenko, A. Yu. Gavrilova, L. G. Saginova, and N. V. Zyk
Faculty of Chemistry, Moscow State University, Vorob’evy gory, Moscow, 119899 Russia
e-mail: bondarenko@org.chem.msu.ru
Received July 26, 2002
Abstract Arylcyclopropanes readily react with nitrosyl chloride in liquid sulfur dioxide to give the corre-
sponding 5-aryl-4,5-dihydroisoxazoles in good yield. The reaction is most selective at 40 to 50 C; at higher
temperature, the contribution of side processes becomes appreciable. The complete conversion of arylcyclo-
propanes containing donor substituents is attained with the use of 1.5 equiv of nitrosyl chloride, while the
rate of the transformation of compounds with nonactivated aromatic rings considerably increases on raising
the molar ratio NOCl arylcyclopropane.
Dihydroisoxazole moiety is widely used in the syn-
thesis of biologically active and natural compounds
[1]. Dihydroisoxazole ring remains unchanged in
many organic reactions, thus making it possible to
modify side chains. In addition, latent difunctional
character of the heteroring provides the possibility
for generation of a variety of functional groups in the
final stages of synthetic sequences.
propane (III), trans-1-(4-methoxyphenyl)-2-phenyl-
cyclopropane (IV), phenylcyclopropane (V), nitro-
phenylcyclopropane (VI, a mixture of ortho and para
isomers at a ratio of 4:1), and 4-acetylphenylcyclo-
propane (VII). We found that nitrosyl chloride readily
adds to aryl- and 1,2-diarylcyclopropanes in liquid
sulfur dioxide to afford, respectively, 5-aryl- and
3,5-diaryl-4,5-dihydroisoxazoles VIII XII in high
yield (Scheme 1).
There are several radically different approaches to
construction of a dihydroisoxazole ring. The most
general approach is based on 1,3-dipolar cycloaddition
of nitrile oxides generated by various methods to
unsaturated compounds [2]. Only a few examples
have been reported on the synthesis of dihydroisoxa-
zoles from arylcyclopropanes by the action of nitrosat-
ing agents. The latter were sodium nitrite in the
presence of trifluoroacetic acid [3], nitrosonium tetra-
fluoroborate, and nitrogen(II) oxide (under irradiation)
[4]. Undoubtedly, search for new nitrosating agents is
important from the viewpoint of extending the scope
of application of the above reaction and its synthetic
potential.
Scheme 1.
The present communication describes a preparative
route to 5-aryl-4,5-dihydroisoxazoles from aryl- and
1,2-diarylcyclopropanes and nitrosyl chloride. It
should be noted that we have found no published data
on the use of nitrosyl chloride for nitrosation of aryl-
cyclopropanes.
As starting compounds we used trans-1,2-diphenyl-
cyclopropane (I), trans-1,2-bis(4-fluorophenyl)cyclo-
propane (II), trans-1,2-bis(4-methoxyphenyl)cyclo-
I, VIII, R = H, R = Ph; II, IX, R = F, R = 4-FC6H4;
III, X, R = OMe, R = 4-MeOC6H4; IV, XI, R = OMe,
R = Ph; V, XII, R = R = H.
In the reaction of 1,2-diphenylcyclopropane (I)
with 5 equiv of nitrosyl chloride, the substrate conver-
sion attained 100% in 3 h at 50 C. The product,
3,5-diphenyl-4,5-dihydroisoxazole (VIII) was ob-
tained in 82% yield (Table 1). With methylene
1070-4280/03/3907-1021$25.00 2003 MAIK Nauka/Interperiodica

1022
BONDARENKO et al.
Table 1. Reaction of 1,2-diphenylcyclopropane (I) with nitrosyl chloride in different solvents
Yield, %
I-to-NOCl molar Temperature, Time, h
Solvent
ratio
C
VIII 1,3-dichloro-1,3-diarylpropane
I
SO2
13.8
9.1
4.2
4.2
1: 5
1: 4
1: 5
1: 5
50
0
0
3
3
4
3
82
9
8
6
CH2Cl2
Ether
Ethera
80
98
75
0
18
a
The substrate was 1,2-bis(4-methoxyphenyl)cyclopropane (III).
chloride as solvent, the yield of the target product
sharply decreased: After 3 h at 0 C, the yield of VIII
was as low as 9%; 6% of 1,3-diphenyl-1,3-dichloro-
propane was formed; and 80% of initial cyclopropane
I was recovered from the reaction mixture. No reac-
tion at all occurred in diethyl ether. Under analogous
conditions, more reactive 1,2-bis(4-methoxyphenyl)-
cyclopropane (III) was not converted into dihydro-
isoxazole: From the reaction mixture we isolated only
the corresponding 1,3-dichloride and initial cyclo-
propane III.
It was presumed [3] that nitrosation of arylcyclo-
propanes is an electrophilic process. In fact, increase
in the solvent polarity is likely to favor polarization
of nitrosyl chloride molecule and generation of active
electrophilic species. Liquid sulfur dioxide turned out
to be the most appropriate solvent for the reaction of
arylcyclopropanes with nitrosyl chloride.
in Table 2 show that at a V-to-NOCl ratio equal to
1:2, the conversion of compound V was about 50%
in 2 h, regardless of the temperature. The reaction
was most selective at 40 C; however, the yield of
5-phenyl-4,5-dihydroisoxazole (XII) did not exceed
38%, while the remaining 57% of V was recovered
from the reaction mixture. The conversion increased at
higher temperature, but the process was accompanied
by partial tarring and the yield of cinnamaldehyde
increased.
Scheme 2.
In order to maintain the reaction selectivity and
simultaneously increase the conversion of initial
hydrocarbon V, the reaction was carried out at 40 to
50 C using 5 equiv of nitrosyl chloride. In this case
we isolated 69% of 5-phenyl-4,5-dihydroisoxazole
(XII), but 10% of cinnamaldehyde was also obtained;
no other products were detected in the reaction
mixture. Analogous temperature dependences were
observed in the series of diarylcyclopropanes. When
the reaction mixture was quickly warmed up to room
temperature, the fraction of the corresponding 1,3-di-
chloro derivatives increased, and appreciable tarring
occurred (Table 3). Thus the optimal temperature
ensuring the maximal selectivity is 40 to 50 C.
With the goal of finding optimal temperature con-
ditions, we performed a series of experiments with
phenylcyclopropane (V): at 40, 20, and 0 C.
The results are summarized in Table 2. Apart from
5-phenyl-4,5-dihydroisoxazole (XII), a small amount
of cinnamaldehyde was obtained (Scheme 2). The data
Table 2. Effect of temperature and reactant ratio on the
yield of 5-phenyl-4,5-dihydroisoxazole (XII) and selec-
tivity of the reaction in liquid sulfur dioxide
Yield, %
We also tried to elucidate the effect of electronic
factors on the reaction under study. For this purpose,
we compared the behavior of arylcyclopropanes con-
taining donor (compounds III and IV) and acceptor
substituents (VI, VII) in the aromatic ring (Table 3).
As follows from the data given in Tables 2 and 3,
diarylcyclopropanes are more reactive toward nitrosyl
chloride than compound V despite the presence in
the former of bulky substituents. These data indicate
that the reaction of arylcyclopropanes with nitrosyl
chloride depends only slightly on the steric factor
V:NOCl, Tempera- Time,
mol/mol ture,
C
h
cinnam-
aldehyde
V
XII
1: 2
1: 2
1: 2
1: 5
0 5a
20
40
40
2
2
2
3
30
30
57
5
8
32
40
38
69
10
a
The reaction at 0 C was accompanied by considerable tarring.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 7 2003

SYNTHESIS OF 4,5-DIHYDROISOXAZOLES FROM ARYLCYCLOPROPANES
Table 3. Effect of temperature and reactant ratio on the yield of dihydroisoxazoles
Yield, %
1023
Comp.
no.
Temperature,
C
Cyclopropane: NOCl,
mol/mol
Time,
h
isoxazole
1,3-diaryl-1,3-dichloropropane
I
20
1: 2
1: 5
10
3
67
82
10
8
50 to 40
II
20
1: 2
1: 5
10
3
64
86
16
9
50 to 40
III
IV
20
1: 2
1: 5
1: 1.5
1: 2
1: 5
1: 1.5
1: 5
1: 1.5
1.5
3
3.5
1.5
3
3.5
3
20
30
6
87
73
42
85
60
60
8
22
48
8
50 to 40
50 to 40
20
50 to 40
50 to 40
50 to 40
20
VIa
VIIb
Traces
a
100% of initial phenylcyclopropane VI was recovered.
95% of initial phenylcyclopropane VII was recovered.
b
but is governed by electronic requirements. Donor
substituents in the aromatic ring favor successful
reaction. However, as the number of donor substit-
uents increases (compounds III and IV), the yield
of 1,3-dichlorides as by-products increases. In the
reaction of cyclopropane III with 5 equiv of nitrosyl
chloride, the corresponding 1,3-dichloride was the
only product. Acceptor substituents in the aromatic
ring deactivate the small ring so strongly that
4-acetylphenylcyclopropane (VI) failed to react with
nitrosyl chloride under standard conditions (Table 3).
When the reaction of nitrophenylcyclopropane (VII)
with nitrosyl chloride was performed at room tem-
chloride and 8 10 ml of liquid sulfur dioxide were
added. The ampule was sealed, allowed to warm up
to a specified temperature, shaken until the mixture
became homogeneous, and kept for a required time
at that temperature. The ampule was then opened,
the solution was carefully evaporated, and 20 ml of
methylene chloride was added. The organic layer
was neutralized with a solution of sodium carbonate
and washed with water, the aqueous phase was treated
with methylene chloride, and the combined organic
extracts were dried over sodium sulfate. The solvent
was evaporated, and the product was purified by
recrystallization or column chromatography. The
melting points of the isolated dihydroisoxazoles and
1
perature over a period of 24 h, the H NMR spectrum
1
their spectral parameters, as well as the H NMR
of the reaction mixture contained signals of 5-(2-nitro-
phenyl)-4,5-dihydroisoxazole whose intensity did not
exceed 5% of those of initial cyclopropane VII.
spectra of 1,3-diaryl-1,3-dichlorocyclopropanes and
cinnamaldehyde, were consistent with those reported
previously [3, 5].
3,5-Bis(4-fluorophenyl)-4,5-dihydroisoxazole
(IX) was synthesized from 0.23 g (0.001 mol) of
cyclopropane II and 0.32 g (0.005 mol) of NOCl in
methylene chloride at 50 C (reaction time 3 h).
Recrystallization from ethanol gave 0.22 g (86%) of
EXPERIMENTAL
The H and 13C NMR spectra were recorded on
a Varian XR-400 instrument in CDCl3 using HMDS
as internal reference. The melting points were
determined in an open capillary.
General procedure for the synthesis of dihydro-
isoxazoles from arylcyclopropanes and nitrosyl
chloride. An ampule was charged with 0.003 mol
of arylcyclopropane and cooled to 60 C, and
a required amount of NOCl as a solution in methylene
1
1
the product with mp 111.5 C. H NMR spectrum, ,
2
3
ppm (J, Hz): 3.26 d.d (1H, CH2, J = 16.9, J = 8.2),
2
3
3.73 d.d (1H, CH2, J = 16.9, J = 11.0), 5.71 d.d
3
3
(1H, CHO, J = 11.0, J = 8.2), 7.06 m (4H, Harom),
7.34 m (2H, Harom), 7.66 m (2H, Harom). 13C NMR
spectrum, C, ppm (J, Hz): 43.25 (CH2), 82.04
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 7 2003

1024
BONDARENKO et al.
3
(CHO), 115.71 d (m-CF, JCF = 22.8), 115.93 d
vol. 36, p. 3361; Pulkkinen, J., Vepsalainen, J., and
Laatikainen, R., Tetrahedron Lett., 1994, vol. 35,
p. 9749.
3
4
(m-CF, JCF = 22.3), 125.61 d (p-CF, JCF = 4.2),
127.65 d (o-CF, JCF = 7.9), 128.68 d (o-CF, JCF
8.5), 136.53 d (p-CF, JCF = 4.1), 155.14 (C N),
162.62 d (CF, JCF = 246.6), 163.82 d (CF, JCF
2
2
=
4
2. Saramella, P., 1,3-Dipolar Cycloaddition Chemistry,
1
1
Padwa, A., Ed., New York: Wiley, 1984.
=
251.1). Found, %: C 69.24; H 4.23; N 5.31.
C15H11F2NO. Calculated, %: C 69.50; H 4.25; N 5.41.
This study was financially supported by the Rus-
sian Foundation for Basic Research (project no. 02-
03-33347) and by the Ministry of Education of the
Russian Federation (Universitety Rossii Program,
project no 990879).
3. Shabarov, Yu.S., Saginova, L.G., and Gazzaeva, R.A.,
Khim. Geterotsikl. Soedin., 1983, p. 738; Gazzae-
va, R.A., Shabarov, Yu.S., and Saginova, L.G., Khim.
Geterotsikl. Soedin., 1984, p. 309; Saginova, L.G.,
Kukhareva, I.L., Lebedev, A.T., and Shabarov, Yu.S.,
Zh. Org. Khim., 1991, vol. 27, p. 1852.
4. Mizuno, K., Ichinose, N., Tamai, T., and Otsuji, Y.,
J. Org. Chem., 1992, vol. 57, p. 4669.
5. Miranda, M.A., Perez-Prieto, J., Font-Sanchis, E.,
Konya, K., and Scaiano, J.C., J. Org. Chem., 1997,
vol. 62, p. 5713; Grigor’ev, E.V. and Saginova, L.G.,
Khim. Geterotsikl. Soedin., in press; The Aldrich
Library of PMR Spectra, Pouchert, C.J. and Camp-
bell, J.R., Eds., 1974.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 7 2003