Reaction of halogenated cyclopropanes and nitrosyl cation: Preparation of isoxazoles

Full text of DOI:10.1021/jo962297i

J . Org. Chem. 1997, 62, 5229-5231
5229
Coplanarity of the two rings seems to be an essential
transition state for the ring-opening of a cyclopropane
ring.9 Meanwhile, the aryl ring can delocalize the anion
at the benzylic position for the electrophilic attack of the
nitrosyl cation, as shown in Scheme 1. Aryl-nitrated
products were obtained as the major or even sole products
from 2-methyl- (11) or 2-methoxy- (14) phenyldichloro-
cyclopropanes (eq 1). The regioselectivity of nitration is
Rea ction of Ha logen a ted Cyclop r op a n es
a n d Nitr osyl Ca tion : P r ep a r a tion of
Isoxa zoles
Shaw-Tao Lin,* Shing-Huey Kuo, Fu-May Yang
Department of Applied Chemistry,
Providence University, Sha-Lu, Taichung Hsien,
433-01, Taiwan, Republic of China
Received December 10, 1996
In tr od u ction
Isoxazole derivatives have anticonvulsant,1 antibacte-
rial,2 antiasthmatic,3 and other pharmacological activi-
ties.3 Isoxazoles are typically prepared by the reaction
of nitrile oxides with alkynes or by cyclization of the
adducts of R,â-unsaturated ketones (or aldehydes) and
hydroxylamines.4 More recently, isoxazolines have been
prepared by the nitrosation of cyclopropanes using a
mixture of sodium nitrite and trifluoroacetic acid,5 dini-
trogen tetraoxide,6 cupric nitrate in acetic anhydride,7
and nitrosyl cation in acetonitrile.8 These isoxazolines
can be converted into isoxazoles via dehydrogenation. In
our previous work, we prepared 5-halogenoisoxazoles by
the nitration of dihalogenated cyclopropanes using a
mixture of nitric acid and sulfuric acid at room temper-
ature.9 This process takes place only when the phenyl
group bears a strong electron-withdrawing group, such
as NO2 or CN. We can now prepare the isoxazoles by
the reaction of dihalogenocyclopropane and nitrosyl
cation, taking advantage of the halogen as a leaving
group (Scheme 1). In contrast to previous reports that
cyclopropanes must contain aryl groups for rearrange-
ment,5-9 these isoxazoles were formed by the reaction of
nitrosyl cation with either the arylcyclopropanes or
alkylcyclopropanes.
controlled by activation of the phenyl ring by a methoxyl
(or methyl) group and the cyclopropyl ring as well as by
a steric effect which reduces the possibility of the forma-
tion of a coplanar state between the two rings for the
nucleophilic reaction of the cyclopropyl ring. The donor
nature of the dihalogenocyclopropyl ring has been dem-
onstrated by character of examining SCS (substituent
chemical shifts) in 13C NMR analyses.10 As expected,
treating 1-bromo-2-phenylcyclopropane with the nitrosyl
salt yields 3-phenylisoxazole as the major product along
with benzoic acid from the oxidation reaction. In this
study, we found that 2,2-dichlorobicyclo[4.1.0]heptane
(17) can undergo a similar reaction to give alkyl-
substituted isoxazoles 33. It is important to note that
this is in contrast to previous reports that have stated
that only the cyclopropyl rings which contain an aryl
group are subjected to opening and the formation of
isoxazolines or isoxazoles.5-9
Resu lts a n d Discu ssion
Halogenated cyclopropanes were reacted with nitrosyl
tetrafluoroborate (1.2 equiv) in acetonitrile solution at
room temperature for 2 h. During this reaction, the color
of the solution changed from yellow for the initial mixture
to a final green color, which depended on the nature of
the substituent of the phenyl ring. The yields of the
isoxazoles obtained by reacting 17 cyclopropanes with
nitrosyl cation are summarized in Table 1. As this table
shows, the yields of the various isoxazoles depended on
the nature and the position of the substituents on the
phenyl ring. Lower yields of isoxazoles were obtained
with ortho-substituents, possibly because that the ortho-
substituents hinder the formation of a coplanar transition
state between the phenyl ring and the cyclopropane ring.
(1) Tatee, T.; Kurashige, S.; Shiozawa, A.; Narita, K.;. Takei, M.;
Ito, S.; Miyazaki, H.; Yamanaka, H.; Mizugaki, M.; Sakamodo,T.;
Fukada, H. Chem. Pharm. Bull. 1986, 34, 1634.
(2) Polo, C.; Rmos, V.; Toroba, T.; Antequera, T. Ann. Quim. Sec. C
1990, 84, 329.
(3) Venkateshwarlu, V.; Krishnamurthy, A.; Rao, C. J . Indian J .
Chem. Sec. B 1989, 27B, 565.
(4) Freeman, J . P. Chem. Rev. 1983, 83, 341.
(5) Shabarov, Y. S.; Saginova, L. G.; Gazzaeva, R. A. Zh. Org. Khim.
(Engl. Transl.), 1983, 19, 2319; Saginova, L. G.; Kukhareva, I. L.;
Lebedev, A. T.; Shabarov, Y. S. Zh. Org. Khim. (Engl. Transl.), 1992,
28, 1631. Bianchi, G.; C. DeMicheli, C.; Gandolfi, R. J . Chem. Soc.,
Perkin Trans. 1, 1976, 1518.
(6) Smirnova, M. M.; Geiderikh, A. V.; Mochalov, S. S.; Shabarov,
Y. S. Zh. Org. Khim. (Engl.), 1992, 28, 1070.
(7) Sychkova, L. D.; Shabarov, Y. S. Zh. Org. Khim. (Engl. Transl.),
1985, 21, 261.
(8) Mizuno, K.; Ichinose, N.; Tamai, T.; Otsuji, Y. J . Org. Chem.
1992, 57, 4669.
(9) Lin, S. T.; Lin, L. H.; Yao, Y. F. Tetrahedron Lett. 1992, 3155;
Lin, S. T.; Yang, Y. M. J . Chem. Res. (S) 1996, 276; (M) 1996, 1554.
S0022-3263(96)02297-9 CCC: $14.00 © 1997 American Chemical Society

5230 J . Org. Chem., Vol. 62, No. 15, 1997
Ta ble 1. P h ysica l P r op er ties a n d Sp ectr a l Da ta of Com p ou n d s 18-33
Notes
molecular
formula
anal. found (calcd)
C, H, N
reactant product
mp/°C (color)
42 (white)a
yield (%)
89
1H NMR (CDCl3)
1
2
3
4
18
19
20
21
C9H6NOCl
C9H6NOBr
60.24, 3.32, 6.20
(60.19, 3.37, 6.25)
48.33, 2.89, 6.42
(48.25, 2.70, 6.25)
6.48 (1H, s); 7.46 (3H, m), 7.73 (2H, m)
6.60 (1H, s); 7.45 (3H, m); 7.63 (2H, m)
40.2-42.0 (white)
169.9-171.3b (yellow)
147.0d (white)
83
82c
82
6.58 (1H, s); 7.94 (2H, d, J ) 8.8 Hz);
8.33 (2H, d, J ) 8.8 Hz)
6.59 (1H, s), 7.68 (1H, t, J ) 8.0 Hz),
8.14 (1H, d, J ) 10.9 Hz), 8.32 (1H, d,
J ) 10.9 Hz), 8.57 (1H, s)
6.31 (1H, s), 7.68 (3H, m), 8.05 (1H, m)
6.47 (1H, s), 7.44 (2H, d, J ) 8.5 Hz);
7.69 (2H, d, J ) 8.5 Hz)
6.47 (1H, s); 7.42 (2H, m); 7.63 (1H, dd,
J ) 1.9, 7.0 Hz); 7.75 (1H, d, J ) 1.9 Hz)
6.46 (1H, s), 7.62 (4H, m)
5
6
22
23
61.5-62.0e (white)
98.6 (white)
65
97
C9H5NOCl2
C9H5NOCl2
C9H5NOBrCl
50.53, 2.45, 6.67
(50.50, 2.35, 6.54)
50.46, 2.48, 6.55
(50.50, 2.35, 6.54)
41.80, 1.99, 5.45
(41.82, 1.95, 5.42)
62.21, 4.20, 7.18
(62.03, 4.16, 7.23)
62.09, 4.19, 7.20
(62.03, 4.16, 7.23)
7
8
24
25
26
27
59.5 (white)
99.5 (yellow)
40.7 (yellow)
43.4 (yellow)
95
85
66
65
9
C
C
10N8NOCl
10H8NOCl
2.24 (3H, 2); 6.45 (1H, s); 7.26 (2H, d, J )
8.0 Hz); 7.64 (2H, d, J ) 8.0 Hz)
2.41 (3H, s); 6.47 (1H, s); 7.33 (2H, d,
J ) 7.3 Hz); 7.49 (1H, d, J ) 7.3 Hz);
7.58 (1H, s)
2.46 (3H, s); 6.35 (1H, s); 7.27-7.36 (3H, m),
7.44-7.47 (1H, m)
3.86 (3H, s), 6.40 (1H, s), 6.98 (2H, d, J )
9.0 Hz), 7.68 (2H, d, J ) 9 Hz)
3.86 (3H, s); 6.47 (1H, s); 7.02 (2H, m);
7.34 (2H, m)
10
11
12
13
28
29
30
viscous liq orange
57.8-59.0 (yellow)
viscous liq (yellow)
55f
63
60
C10H8NOCl
62.14, 4.26, 7.33
(62.03, 4.16, 7.23)
57.44, 3.89, 6.64
(57.30, 3.85, 6.68)
57.26, 3.89, 6.59
(57.30, 3.85 6.68)
C
C
10H8NO2Cl
10H8NO2Cl
14
15
46g
45h
31
32
33
viscous liq (colorless)
101.5-102.9 (yellow)
34.2-35.8 (white)
C9H7NO
13H8NOCl
C7C8NOCl
74.40, 4.89, 9.71
(74.46, 4.86, 9.65)
68.06, 3.64, 6.18
(67.99, 3.51, 6.10)
53.38, 5.01, 8.99
(53.35,5.12, 8.89)
5.00 (1H, d, J ) 3.5 Hz), 5.84 (1H, d, J )
3.5 Hz), 7.28 (2H, m), 7.37 (3H, m)
6.63 (1H, s); 7.55 (3H, m); 7.90 (3H, m);
8.20 (1H, s)
16
17
73
43
C
1.76 (4H, m); 2.43 (2H, m); 2.70 (2H, m)
a
b
d
Literature16 45-47 °C. Literature9 167-169 °C. c 5% of nitrobenzoic acid (34) as a byproduct. Literature9 147.5-148.9 °C.
e Literature9 59 °C. f 17% of 1-(2-methyl-5-nitrophenyl)-2,2-dichlorocyclopropane (35) as a byproduct from 1-(2-methylphenyl)-2,2-
dichlorocyclopropane: yellow powder, mp 90.7 °C; 1H NMR 1.99 (1H, dd, J ) 7.6, 16.1 Hz), 2.12 (1H, d, J ) 7.6 Hz), 2.56 (3H, s), 2.81 (1H,
t, J ) 16.1 Hz), 7.12 (1H, d, J ) 8.5 Hz), 7.90 (1H, s), 8.10 (1H, d, J ) 8.5 Hz); MS (relative intensity) m/z 245 (M+, 7), 129 (100). Anal.
Calcd (found) for C10H9NO2Cl2; C 48.80 (48.75), H 3.69 (3.76), N 5.69 (5.61). g 46% of 1-(2-methoxy-5-nitrophenyl)-2,2-dichlorocyclopropane
(36) was obtained as the only product with 38% of the starting compound recovered from 1-(2-methoxyphenyl)-2,2-dichlorocyclopropane:
red solid, mp. 124 °C; 1H NMR 1.88-2.08 (2H, m), 2.89 (1H, dd, J ) 9.5, 19.0 Hz), 4.05 (3H, s), 7.05 (1H, d, J ) 9.0 Hz), 7.90 (1H, d, J
) 2.7 Hz), 8.24 (1H, dd, J ) 2.7, 9.0 Hz); MS (relative intensity) m/z 261 (M+, 23), 145 (100). Anal. Calcd (found) for C10N9NO2Cl2: C 45.83
h
(45.89), H 3.46 (3.55), N 5.34 (5.28). 17% of benzoic acid (37) as a byproduct.
Sch em e 1
the fragmentation of this series of compounds is relatively
simple. The major fragments are the molecular ion
[M - Cl]+ (as the base peak), [M - Cl - CO]+ c, and
[M - Cl - CO - HCN]+ (presumably a benzocyclopro-
penium cation).12 The formation of [M - Cl]+ as a base
peak occurs because the chlorine atom is an ionization
center as well as the fragmentation center in this series.
Con clu sion
The reaction of the halogenated cyclopropanes with
nitrosyl cation is a feasible and effective method for
preparing isoxazoles. The formation of isoxazole instead
of the isoxazoline is due to the halogen group acting as
an adequate leaving group in the formation of isoxazoline.
These results demonstrate that this process can be
extended to a cyclopropane ring which does not bear an
aryl ring.
NMR and mass spectra were used to characterize these
isoxazole products. In general, the chemical shifts of the
C(4)-H appear as a singlet in the range from 6.30 to 6.60
ppm and slightly depend on the nature and the position
of the substituent in the phenyl ring. The 13C NMR
chemical shifts of the C(3) and C(5) were assigned to the
two most downfield signals due to the nature of the
heterocyclic ring and the electron-withdrawing effect of
the chlorine atom.11 The chemical shifts of C(3) and C(5)
slightly depend on the nature of the substituent on the
phenyl ring. This might be due to the large remote
distance from the substituent to both C(3) and C(5). The
increment of chemical shift for the phenyl ring is found
to be increased by -0.4, -1.7, 0.6, and 2.1 with the
addition of the 5-chloroisoxazole group to C1, C2, C3, and
C4 of the phenyl ring, respectively. In the mass spectra,
Exp er im en ta l Section
1H NMR and 13C NMR spectra were recorded at 250 MHz
and at 62.86 MHz, respectively, at an ambient temperature with
(10) Lin, S. T.; Yao, Y. F. J . Chin. Chem. Soc. 1992, 39, 415.
(11) Levy, G. C.; Lichter, R. L.; Nelson, G. L. Carbon-13 Nuclear
Magnetic Resonance Spectroscopy, 2nd ed.; J ohn Wiley & Sons: New
York, 1980; p 120.
(12) Shen, J .; Dunbar, R. C.; Olah, G. A. J . Am. Chem. Soc. 1974,
96, 6227.

Notes
J . Org. Chem., Vol. 62, No. 15, 1997 5231
deuteriochloroform as the solvent. 1-Aryl-2,2-dichlorocyclopro-
panes were prepared by treating styrene derivatives with CHCl3
in pentane in the presence of KOBut as described in the
literature procedures.13
1-(2-Nitrophenyl)- and 1-(4-nitrophenyl)-2,2-dichlorocyclopro-
panes were prepared directly by nitrating of 1-phenyl-2,2-
dichlorocyclopropane in acetic anhydride at -50 °C.14 1-Bromo-
2-phenylcyclopropanes were prepared by reducing 1,1-dibromo-
2-phenylcyclopropane using diethyl phosphite as a reducing
agent.15 Acetonitrile was dried and stored over CaH2 before use.
was stirred at rt for 1.5 h and then quenched with water. The
subsequent solution was extracted with ethyl acetate (50 mL ×
3). The combined organic solution was washed with water (50
mL × 3) and then dried over MgSO4. After filtration and
evaporation of the solvent, the resultant solid was recrystallized
from methanol, and the liquid products (18, 30, 31) were purified
by means of thin-layer chromatography (SiO2) with n-hexane/
EtOAc as an eluent. The yields, physical properties, and the
spectroscopic data of the products are summarized in Table 1.
Typical Procedure for the Reaction of 1-Aryl-2,2-dichlorocy-
clopropane and Nitrosyl Tetrafluoroborate. To a two-necked
flask containing NOBF4 (1.2 equiv, caution: very hygroscopic,
after opening must be stored over P4O10) was added cyclopropane
(50 mmol) in a dry acetonitrile solution (30 mL). The solution
Ack n ow led gm en t. Financial support by the Na-
tional Science Council of the Republic of China (NSC
86-2113-M-126-002) is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Tables of the mass
spectral and 13C NMR spectral data and a possible fragmenta-
tion mechanism of arylisoxazoles under EI conditions (3 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
(13) Kostikov, R. R.; Molchanov, A. P.; Golovanova, G. V.; Zenkevich,
I. G. Zh. Org. Khim. (Engl. Transl.) 1977, 13, 1712.
(14) Nefedov, O. M.; Shafran, R. N. Zh. Org. Khim. (Engl. Transl.)
1974, 10, 477; Novokreshchennykh, V. D.; Mochalov, S. S.; Shabarov,
Y. S. Zh. Org. Khim. (Engl. Transl.) 1979, 15, 485.
(15) Lin, S. T.; Leu, S. H.; Chen, C. Y. J . Chem. Res. (S) 1996, 130;
(M) 1996, 716.
(16) Micetich, R. G.; Chin, C. G. Can. J . Chem. 1970, 48, 1371.
J O962297I