New system for nitrosation of alkyl-substituted gem-dichlorocyclopropanes

Article abstract of DOI:10.1016/j.mencom.2011.07.004

Treatment of alkyl-substituted gem-dichlorocyclopropanes with NOCl-AlCl₃ system affords alkyl-5-chloroisoxazoles.

Full text of DOI:10.1016/j.mencom.2011.07.004

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 188–189
New system for nitrosation of alkyl-substituted gem-dichlorocyclopropanes
Oksana B. Bondarenko,* Anna Yu. Gavrilova, Dilovar S. Murodov, Nikolai V. Zyk and Nikolai S. Zefirov
Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation.
Fax: +7 495 939 4652; e-mail: bondarenko@org.chem.msu.ru
DOI: 10.1016/j.mencom.2011.07.004
Treatment of alkyl-substituted gem-dichlorocyclopropanes with NOCl–AlCl3 system affords alkyl-5-chloroisoxazoles.
gem-Dihalocyclopropanes play a noticeable role in organic syn-
thesis foremost due to their exceptional availability.1 Today they
put together a really tremendous massive of organic compounds
which differ by great structural variety; therefore, their applica-
tion as synthons is very promising.1(c),2 Earlier we have success-
fully applied an adduct of NOCl with sulfur trioxide as nitrosating
reagent for transformation of alkyl-gem-dichlorocyclopropanes
into alkyl-5-chloroisoxazoles.3
NOCl + AlCl3
NO+[AlCl4]–
Alk
O
Cl
N
Alk
Cl
Alk
Cl
Cl
Cl
Cl
NO+
O
– H+
N
– HCl
Cl
1
Alk
NO+
Note that isoxazole derivatives every year find more wide
application as objects for pharmacological investigations. They
exhibit antibacterial, antiasthmatic, and other pharmacological
activities and are active principle of some drugs† different in
their functions.4
Taking into account the practical value of isoxazoles we directed
our efforts at searching for alternative conditions for nitrosation
of alkyl-substituted gem-dichlorocyclopropanes. For this purpose
we used here cheap and available reagents: nitrosyl chloride and
aluminum chloride.
O
N
2
Cl
Cl
Alk
Cl
Cl
Cl
– H+
Alk
– HCl
O
O
N
Alk
N
N
O
3
Scheme 2
In fact, 2-alkyl-1,1-dichlorocyclopropanes 1a,b under the action
of nitrosyl chloride activated with aluminum chloride afford a
mixture of regioisomeric 4-alkyl- 2a,b and 3-alkyl-5-chloroisox-
azoles 3a,b in high yields (Scheme 1).‡
The formation of isoxazoles 2, 3 can be presented as outlined
in Scheme 2.
We have also studied the behaviour of 2-benzyl-1,1-dichloro-
cyclopropane 1c under the suggested conditions of nitrosation.
2-Benzyl-1,1-dichlorocyclopropane 1c is of certain interest, as
on the one hand it can be classified as alkyl-substituted cyclo-
propane, and on the other hand it has an additional reaction site,
benzene ring. Note, that the reaction of compound 1c with the
other previously known nitrosating reagents proceeds non-selec-
tively. Thus, nitrosation of cyclopropane 1c with sodium nitrite
in trifluoroacetic acid is accompanied by nitration of the aromatic
ring that results in the formation of a mixture of products.5 The
treatment of compound 1c with complex NOCl·2SO3 leads, fore-
most, to sulfochlorination of the aromatic ring.6 The excess of
the reagent makes it possible to nitrosate the cyclopropane ring
in the products of sulfochlorination affording isoxazolylarylsul-
fochlorides.
Alk
Alk
Cl
NOCl / AlCl3
Cl
Alk
Cl
CH2Cl2
–20 20 °C
Cl
N
O
N O
1a–c
2a–c
3a,b
a Alk = Bu, 93% (2a : 3a = 1.3 : 1)
b Alk = hexyl, 90% (2b : 3b = 1.4 : 1)
c Alk = Bn, 60% (2c only)
Scheme 1
†
Arava (treatment: leflunomide which is a pyrimidine synthesis inhibitor
indicated in adults for the treatment of active rheumatoid arthritis); Bextra
(treatment: valdecoxib which is used for its anti-inflammatory, analgesic,
and antipyretic activities in the management of osteoarthritis and for the
treatment of dysmenorrhea or acute pain); Marplan (treatment: isocarbox-
azid which is effective in the treatment of major depression, dysthymic
disorder and atypical depression and useful in the treatment of panic disorder
and the phobic disorders); Sulfafurazole (a short-acting sulfonamide with
antibacterial activity against a wide range of gram-negative and gram-
positive organisms).4
General procedure for preparing 5-chloroisoxazoles. A glass ampoule
was loaded in sequence with 0.001 mol of AlCl3 and cooled (–20°C)
solution of 0.002 mol of NOCl in 2 ml of dichloromethane, quickly closed
with a joint stopper, and the mixture was vigorously stirred under ambient
conditions for 0.5 h without any additional cooling. Then, the ampoule
was placed into an ice bath, and 0.001 mol of corresponding alkyl-gem-
dichlorocyclopropane was added, whereupon the ampoule was additionally
cooled to –20°C and sealed. The reaction mixture was stirred for 24 h being
graduallyheated to room temperature.Afterwards, the ampoule was opened,
the resultant mixture was quenched with 1 m sodium bicarbonate solution
and extracted with CH2Cl2 (3×10 ml). The combined organic layers were
washed with water and dried over Na2SO4. The solvent was evaporated
under reduced pressure and the products were isolated by chromatography
‡
The 1H and 13C NMR spectra were recorded on a Bruker Avance-400
spectrometer with working frequencies of 400 and 100 MHz in CDCl3
with TMS as an internal standard. The mass spectrum was registered on
a Finnigan MAT SSQ 7000 GC-MS instrument equipped with 25 m quartz
capillary OV-1 column in the electron-impact ionization mode at an ioniza-
tion energy of 70 eV with temperature programming from 70 (2 min) to
280°C (10 min) at a rate of 20K min–1. The melting point was measured
in a block in an open capillary.
1
(Silica gel 40/100, blend – ethyl acetate:light petroleum, 1:10). The H
and 13C NMR spectra of isoxazoles 2a,b and 3a,b were as described
elsewhere.3
© 2011 Mendeleev Communications. All rights reserved.
– 188 –

Mendeleev Commun., 2011, 21, 188–189
The reaction of 2-benzyl-1,1-dichlorocyclopropane 1c with
Cl
Cl
Cl
Cl
Cl
Cl
Cl
nitrosyl chloride in the presence of aluminum chloride proceeded
chemo- and regioselectively with the formation of 4-benzyl-5-
chloroisoxazole 2c (Scheme 1).§ The structure of compound 2c
was unambiguously proved based on its 1H and 13C NMR spectra
and elemental analysis data.¶ The 1H and 13C NMR spectra of 2c
absolutely correlate with those of 2a and 2b. Thus, the 1H NMR
spectrum of isoxazole 2c exhibits a narrow singlet in the field of
C=N double bond at d 8.13 ppm with intensity equal to one proton
referred to hydrogen atom of heterocycle. The 13C NMR spectrum
contains a set of eight signals three of which at d 113.4, 151.4,
and 153.1 ppm are referred to isoxazole ring, the signals at d 113.4
and 151.4 ppm belonging to tertiary carbon atoms and that in the
field of C=N double bond (d 153.1), to the carbon atom connected
with hydrogen. These data confirm that benzyl substituent is
located at C(4) carbon atom of the heterocycle.
n
n
n
NOCl / AlCl3
CH2Cl2
O
N
–20
20 °C
n
4a,b
5a, 90%
5b, 70%
a n = 1
b n = 2
Scheme 3
the reaction occurs with participation of only one of the cyclo-
propane rings (Scheme 3).
In summary, we have developed a chemoselective reagent
system for transformation of alkyl-substituted gem-dichlorocyclo-
propanes into substituted 5-chloroisoxazoles in high yields.
Thus, in the case of 2-benzyl-1,1-dichlorocyclopropane 1c, the
suggested nitrosation system allows us to get the result which is
impossible while using the other known nitrosating reagents.
By the example of biscyclopropanes 4a,b we have shown that
polycyclic gem-dichlorocyclopropanes can also be smoothly trans-
formed into the corresponding isoxazoles 5a,b.†† In both cases,
This work was supported by the Russian Foundation for
Basic Research (project no. 11-03-00707) and the program of the
Presidium of the Russian Academy of Sciences ‘Development of
Methods for Synthesizing Chemical Compounds and Creating
New Materials’.
References
§
According to the 1H NMR spectrum of the reaction mixture isoxazole
1 (a) W. P. Weber and G. W. Gokel, Phase Transfer Catalysis in Organic
Synthesis, Springer, Berlin, 1977; (b) W. Kirmse, Carbene Chemistry,
Academic Press, NewYork, 1964; (c) N. S. Zefirov, I. V. Kazimirchik and
K. L. Lukin, Tsikloprisoedinenie dikhlorkarbena k olefinam (Cycloaddition
of Dichlorocarbene to Olefins), Nauka, Moscow, 1985 (in Russian).
2 M. Fedorynski, Chem. Rev., 2003, 103, 1099 and references therein.
3 N. V. Zyk, O. B. Bondarenko, A. Yu. Gavrilova, A. O. Chizhov and N. S.
Zefirov, Izv. Akad. Nauk, Ser. Khim., 2011, 321 (in Russian).
3c was formed only in trace amounts (< 10%).
¶
2c: yield 60%. Rf 0.51 (ethyl acetate:light petroleum, 1:10). Red oil.
1H NMR (400 MHz, CDCl3) d: 3.77 (s, 2H, CH2Ph), 7.22 (dm, 2H, CHaryl
,
,
3J 7.3 Hz), 7.29 (tt, 1H, CHaryl, 3J 7.3 Hz, 4J 1.7 Hz), 7.37 (tt, 2H, CHaryl
4
3J 7.3 Hz, J 1.7 Hz), 8.13 (s, 1H, HC=N). 13C{1H} NMR (100 MHz,
CDCl3) d: 28.4 (CH2Ph), 113.4 (=C–Bn), 127.0 (Ca4rH), 128.3 (2CarH),
128.9 (2CarH), 137.7 (C1arH), 151.4 (=CCl), 153.1 (HC=N). Found (%):
C, 61.88; H, 4.30; N, 7.07. Calc. for C10H8ClNO (%): C, 62.02; H, 4.13;
N, 7.24.
4 http://www.nextbio.com.
5 A. Z. Kadzhaeva, E. V. Trofimova, R. A. Gazzaeva, A. N. Fedotov and
S. S. Mochalov, Vestn. Mosk. Univ., Ser. 2: Khim., 2009, 35 (Moscow
Univ. Chem. Bull., 2009, 64, 28).
6 O. B. Bondarenko,A.Yu. Gavrilova, L. G. Saginova and N.V. Zyk, Abstracts
of Papers, All-Russian Conference on Organic Chemistry (devoted to
75th anniversary of the foundation of N.D. Zelinsky Institute of Organic
Chemistry), Moscow, 2009, p. 108.
†† 5a: yield 90%. Rf 0.37 (ethyl acetate:light petroleum, 1:7), mp 58–60°C.
1H NMR (400 MHz, CDCl3) d: 2.11 (dd, 1H, CH, 3J 11.0 Hz, 3J 7.7 Hz),
2.18 (dd, 1H, CH, 3J 11.0 Hz, 3J 7.3 Hz), 2.82 (d, 1H, CH2, 2J 17.7 Hz),
2.98 (dd, 1H, CH2, 2J 17.7 Hz, 3J 7.7 Hz), 3.10 (d, 1H, CH2, 2J 18.6 Hz),
2
3
3.20 (dd, 1H, CH2, J 18.6 Hz, J 7.3 Hz). 13C{1H} NMR (100 MHz,
CDCl3) d: 14.7 (CH2), 17.0 (CH2), 25.0 (CH), 25.7 (CH), 63.2 (CCl2),
107.0 (C=CCl), 149.2 (C=CCl), 159.8 (C=N). MS (EI) m/z (Irel, %): 237
(M+, 10), 202 (M+ – Cl, 11), 174 (M+ – Cl – CO, 11), 166 (M+ – Cl – HCl,
16), 138 (M+ – Cl – HCl – CO, 28), 122 (CH2CHCHCCl2+, 40), 109
(CH2CHCCl2+, 100), 87 (CH2CHCHCCl+, 28), 51 (21). Found (%): C, 40.31;
H, 2.46; N, 5.92. Calc. for C8H6Cl3NO (%): C, 40.25; H, 2.51; N, 5.87.
The 1H and 13C NMR spectra of isoxazole 5b were as described else-
where.3
Received: 4th February 2011; Com. 11/3681
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