A convenient procedure for transformation of tertiary cyclopropanols into 5-substituted isoxazoles

Article abstract of DOI:10.1055/s-2006-956475

Tertiary cyclopropanols, when treated with an excess of amyl nitrite at room temperature, are smoothly converted into dimeric β-nitrosoketones. Heating the methanolic solutions of the latter under reflux gives 5-substituted isoxazoles in good yields. Geor

Full text of DOI:10.1055/s-2006-956475

LETTER
3427
A Convenient Procedure for Transformation of Tertiary Cyclopropanols into
5-Substituted Isoxazoles
T
ransformation of
z
Tertiary Cy
m
c
lopropanols into 5
i
-Substi
t
tuted Is
r
oxazole
y
s
H. Churykau, Oleg G. Kulinkovich*
Department of Organic Chemistry, Belarusian State University, Nezavisimosty Av. 4, 220030 Minsk, Belarus
Fax +375(17)2265609; E-mail: kulinkovich@bsu.by
Received 28 September 2006
has a substantial synthetic potential. At the same time, the
Abstract: Tertiary cyclopropanols, when treated with an excess of
amyl nitrite at room temperature, are smoothly converted into
dimeric b-nitrosoketones. Heating the methanolic solutions of the
latter under reflux gives 5-substituted isoxazoles in good yields.
procedure proposed for the generation of cyclopropyl ni-
trites by treating cyclopropanols with nitrosyl chloride
(NOCl) in the presence of pyridine9b has some significant
disadvantages. First, a careful control of the reagent added
is required because an excess of NOCl was found to cause
decomposition of cyclopropyl nitrite. Furthermore, the
decomposition of cyclopropyl nitrites may also be in-
duced by pyridine hydrochloride, which must be removed
by low-temperature filtration. It should also be noted that
the protocol for the conversion of b-nitrosoketones into
the respective isoxazoles9b was not described in detail.
Key words: cyclopropanols, nitrosation, b-nitrosoketones, isox-
azoles, isoxazolines
Substituted cyclopropanols can be easily prepared by a
number of procedures, including the reductive cyclopro-
panation of esters with dialkoxytitanacyclopropane re-
agents,1,2 desilylation of cyclopropanol silyl ethers,3,4
alkylation of cyclopropanone hemiacetals,5 reductive cy-
clization of b-halogeno ketones6 as well as using some
other methods.7 Synthetic applications of these com-
pounds are based mainly on the C1–C2 or C1–C3 cyclopro-
pane ring-opening reactions.7 In many cases, the
conversion of cyclopropanols or their derivatives into
alkyl ketones, a,b-unsaturated ketones, 2-substituted
alkyl halides, as well as to some other compounds, occurs
in a highly selective manner, and has a considerable pre-
parative value.7,8
At the end of 1960s, De Puy and co-workers9 observed a
remarkably high activity of cyclopropyl nitrites in the re-
actions involving homolytic cleavage of the N–O bond,
which proceeded at temperatures 100–250 °C lower than
for nitrites not associated with a cyclopropyl ring. These
transformations proceeded via opening of the cyclo-
propane ring and resulted in formation of dimeric b-ni-
trosoketones or 5-hydroxy-D2-isoxazolines. Also, b-
nitrosoketones were reported to be transformed into isox-
azoles upon standing or with some heating.9b Since the
cleavage of the N–O bond in isoxazoles is widely used for
the preparation of various 1,3-bifunctional compounds in-
cluding some natural products,10 the transformation of cy-
clopropanols 1 into isoxazoles 3 via b-nitrosoketones 2
Here, we report a simple and efficient experimental pro-
cedure resulting in transformation of cyclopropanols 1
into isoxazoles 3 via b-nitrosoketones 2 (Scheme 1). We
found that keeping the mixture, composed of monosubsti-
tuted cyclopropanol 1a–g,11 an excess of freshly prepared
amyl nitrite,12 and small amount of benzene at room tem-
perature for two to three days yielded dimeric b-ni-
trosoketones 2a–g almost quantitatively (as was
1
determined by H NMR). After the removal of benzene
and excess of amyl nitrite under reduced pressure crystal-
line compounds 2a–d were isolated as mixtures of Z and
E isomers.13 Under these conditions monosubstituted cy-
clopropanols bearing alkyl (see Table 1, entries 1 and 2),
aryl (entry 4), alkenyl (entry 5), halogenalkyl (entry 3),
alkoxyalkyl (entries 6 and 7) substituents were converted
into b-nitrosoketones 2 in high yields, whereas 1,2-disub-
stituted cyclopropanol 1h gave the corresponding product
only in a poor yield (entry 8).
The transformation of b-nitrosoketones 2 to isoxazoles 3
proceeded clearly in methanolic solutions heated under
reflux for two to three days (Scheme 1) and the products
were isolated in good yields. In order to avoid transacetal-
ization, the cyclization of nitroso compound 2g was car-
ried out under reflux in ethanol. Although the reaction was
C5H11ONO, C6H6
r.t., 48–78 h
O–
N+
O
MeOH, reflux,
10–72 h
OH
R
N
N+
O–
R
R
O
R
67–92% over two steps
O
1
3
2
Scheme 1
SYNLETT 2006, No. 20, pp 3427–3430
1
8
.1
2
.2
0
0
6
Advanced online publication: 08.12.2006
DOI: 10.1055/s-2006-956475; Art ID: G29206ST
© Georg Thieme Verlag Stuttgart · New York

3428
D. H. Churykau, O. G. Kulinkovich
LETTER
Table 1 The Conversion of Cyclopropanols 1 to b-Nitrosoketones 2 and 5-Substituted Isoxazoles 3
Entry
1
Cyclopropanol
b-Nitrosoketonea–c
Yield (%)d
68
Isoxazolee,f
Yield (%)g
91
OH
O
N
C6H13
O
C6H13
ON
C6H13
3a
1a
2
2a
2
3
4
5
77
79
92
85
80
84
OH
O
O
O
O
N
C8H17
O
C8H17
ON
C8H17
3b
1b
2
2b
OH
N
Cl
Cl
O
O
O
Cl
ON
3c
2
1c
2c
62
OH
N
Ph
Ph
ON
Ph
3d
2
1d
2d
>90h
OH
N
8
8
ON
8
3e
1e
2
2e
6
>90h
68
OH
O
N
C10H21
C10H21
O
C10H21
OTHP
ON
OH
OTHP
3f
1f
2
2f
7
8
>90h
~33h
67i
OH
O
O
O
O
O
N
O
O
O
O
ON
3g
1g
1h
2
2g
36h
OH
C5H11
N
ON
C5H11
C5H11
O
2
3h
2h
a Typical procedure for the preparation of b-nitrosoketones 2 was followed. See ref.14 for details.
b For selected data of b-nitrosoketones 2, see ref.15
c Products, as indicated by IR, are dimers.15,16
d Isolated yields of crystalline compounds (mixture of Z and E isomers).
e Typical procedure for the transformation of b-nitrosoketones 2 to isoxazoles 3 was followed. For details, see ref.17
f For selected data of isoxazoles 3, see ref.18
g Isolated yields of isoxazoles 3 after distillation or column chromatography on silica gel.
h Determined by 1H NMR spectra.
i Cyclization was carried out in EtOH.
completed after ten hours in this case, the use of ethanol compounds after a brief reflux of nitroso compounds 2 in
for cyclization of nitroso compound 2a led to a mixture of methanol. Thus, 5-hexyl-5-hydroxy-D2-isoxazoline 419
isoxazole 3a and 5-ethoxy-5-hexyl-D2-isoxazoline.
was isolated in an almost quantitative yield after heating a
methanolic solution of nitrosoketone 2a under reflux for
two hours and subsequent removal of the solvent in vacuo
(Scheme 2).
The conversion of b-nitrosoketones 2 into isoxazoles 3
proceeded via the intermediate formation of 5-hydroxy-
D2-isoxazolines 4 that could be isolated as individual
Synlett 2006, No. 20, 3427–3430 © Thieme Stuttgart · New York

LETTER
Transformation of Tertiary Cyclopropanols into 5-Substituted Isoxazoles
3429
(14) Preparation of b-Nitrosoketones 2; Typical Procedure:
Freshly prepared amyl nitrite (17 mL, 124 mmol) was added
at 5 °C under Ar atmosphere to a solution of 1a (4.9 g, 31
mmol) in anhyd benzene (5 mL) in one portion. The mixture
was stirred for 3 h and was kept at r.t. until the reaction was
completed as monitored by TLC (2–3 d, see ref. 20). The
mixture was concentrated in vacuo and was used for the
preparation of isoxazoles without further purification. In
order to obtain solid samples of 2a (as a mixture of Z and E
isomers), the residue was diluted with petroleum ether,
cooled and the crystals were filtered off. Single E isomer of
2a (3.45 g, 20.2 mmol, 65%) was obtained by the
O
OH
MeOH, reflux, 2 h
>95%
N
ON
C6H13
C6H13
O
2
2
4
Scheme 2
In conclusion, a simple and efficient procedure has been
developed to prepare 5-substituted isoxazoles from easily
available tertiary cyclopropanols by treating the latter
with freshly prepared amyl nitrite and subsequent heating
of methanolic solutions of the b-nitrosoketones formed.
crystallization from hot MeOH as a yellowish solid (mp 86–
87 °C).
(15) Analytical data of selected nitrosoketones 2.
2a: 1H NMR (400 MHz, CDCl3): d = 0.83 (t, J = 6.8 Hz, 3
H), 1.18–1.30 (m, 6 H), 1.49–1.59 (m, 2 H), 2.44 (t, J = 7.4
Hz, 2 H), 2.90 (t, J = 6.2 Hz, 2 H), 4.40 (t, J = 6.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 13.84, 22.31, 23.41, 28.64,
31.39, 36.40, 42.74, 53.48, 206.63. IR (CCl4): 1722, 1371,
1250 cm–1. Anal. Calcd for C9H17NO2 (171.24): C, 63.13; H,
10.01. Found: C, 63.28; H, 9.75.
Acknowledgment
This work was carried out with the support of the Ministry of Edu-
cation of the Republic of Belarus.
2c: 1H NMR (400 MHz, CDCl3): d = 2.04–2.13 (m, 2 H),
2.72 (t, J = 7.0 Hz, 2 H), 2.97 (t, J = 6.1 Hz, 2 H), 3.58 (t,
J = 6.2 Hz, 2 H), 4.47 (t, J = 6.1 Hz, 2 H). 13C NMR (100
MHz, CDCl3): d = 26.10, 36.69, 39.44, 44.21, 53.60, 205.58.
IR (CCl4): 1720, 1370, 1247 cm–1. Anal. Calcd for
C6H10ClNO2 (163.61): C, 44.05; H, 6.16. Found: C, 43.90;
H, 5.89.
References and Notes
(1) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.;
Pritytskaya, T. S. J. Org. Chem. USSR (Engl. Transl.) 1989,
25, 2027. (b) Kulinkovich, O. G.; Sviridov, S. V.;
Vasilevskii, D. A. Synthesis 1991, 234. (c) Kulinkovich, O.
G.; Savchenko, A. I.; Sviridov, S. V.; Vasilevsky, D. A.
Mendeleev Commun. 1993, 230.
(16) Bellamy, L. J. Advances in Infrared Group Frequencies;
Methuen & Co. Ltd.: Bungay / Suffolk, 1968.
(2) For recent review, see: Kulinkovich, O. G. Russ. Chem. Rev.
(Engl. Transl.) 2004, 53, 1065.
(17) Preparation of Isoxazoles; Typical Procedure: Crude b-
nitrosoketone 2a, prepared from 1e (4.9 g, 31 mmol) and
amyl nitrite (17.0 mL, 124 mmol) as described above (see
ref. 14) was diluted with anhyd MeOH (45 mL). The
solution was heated under reflux until TLC indicated that no
b-nitrosoketone 2a and intermediate isoxazoline 4a
remained (2–3 days, see ref. 20). After removal of the
solvent under reduced pressure, the isoxazole 3a was
isolated by column chromatography (SiO2, PE–EtOAc as
eluent) as a yellowish oil (4.4 g, 91%).
(3) (a) Denis, J. M.; Conia, J. M. Tetrahedron Lett. 1972, 13,
4593. (b) Le Goaller, R.; Pierre, J.-L. Bull. Soc. Chim. Fr.
1973, 1531. (c) Rubotton, G. M.; Lopes, M. I. J. Org. Chem.
1973, 38, 2097.
(4) (a) Ryu, I.; Murai, S. In Houben–Weyl, 4th ed., Vol. E17; de
Meijere, A., Ed.; Thieme: Stuttgart, 1996, 1985.
(b) Kuwajima, I.; Nakamura, E. Top. Curr. Chem. 1990,
133, 3.
(5) (a) Wasserman, H. H.; Clark, G. M.; Turley, P. C. Top. Curr.
Chem. 1974, 47, 73. (b) Salaün, J. Chem. Rev. 1983, 83,
619. (c) Salaün, J. Top. Curr. Chem. 1988, 144, 1.
(6) Sunder, N. M.; Patil, P. A.; Narashimhan, N. S. J. Chem.
Soc., Perkin Trans. 1 1990, 1331.
(7) (a) Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597.
(b) Gibson, D. H.; De Puy, C. H. Chem. Rev. 1974, 74, 605.
(8) Kulinkovich, O. G. Eur. J. Org. Chem. 2004, 4517.
(9) (a) De Puy, C. H.; Jones, H. L.; Gibson, D. H. J. Am. Chem.
Soc. 1968, 90, 5306. (b) De Puy, C. H.; Jones, H. L.;
Gibson, D. H. J. Am. Chem. Soc. 1972, 90, 3924.
(10) (a) Akhrem, A. A.; Lakhvich, F. A.; Khripach, V. A. Chem.
Heterocycl. Compd. (Engl. Transl.) 1981, 853.
(b) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410.
(c) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.;
Simoni, D. Synthesis 1987, 857.
(11) Cyclopropanols 1a–h were synthesized by the reductive
cyclopropanation of the corresponding esters with
ethylmagnesium bromide (compounds 1a–g) or
propylmagnesium bromide (1h) in the presence of
titanium(IV) isopropoxide (see ref. 1).
(12) Utilization of amyl nitrite that was stored in a refrigerator for
more than two weeks led to a significant reduction of the
reaction rate and to a decrease in the yields of products.
(13) After crystallization from MeOH pure E isomer was
obtained.
(18) Analytical data of selected isoxazoles 3.
3c: 1H NMR (400 MHz, CDCl3): d = 2.13–2.22 (m, 2 H),
2.97 (t, J = 7.4 Hz, 2 H), 3.57 (t, J = 6.3 Hz, 2 H), 6.03–6.05
(m, 1 H), 8.14–8.17 (m, 1 H). 13C NMR (100 MHz, CDCl3):
d = 23.70, 30.14, 43.54, 100.58, 150.22, 170.93. IR (CCl4):
1606 cm–1. Anal. Calcd for C6H8ClNO (145.59): C, 49.50;
H, 5.54. Found: C, 49.33; H, 5.75.
3e: 1H NMR (400 MHz, CDCl3): d = 1.22–1.40 (m, 10 H),
1.65–1.73 (m, 2 H), 1.99–2.06 (m, 2 H), 2.76 (t, J = 7.7 Hz,
2 H), 4.92 (ddt, J1 = 10.2 Hz, J2 = 2.2 Hz, J3 = 1.1 Hz, 1 H),
4.98 (ddt, J1 = 16.9 Hz, J2 = 2.2 Hz, J3 = 1.5 Hz, 1 H), 5.80
(ddt, J1 = 16.9 Hz, J2 = 10.2 Hz, J3 = 6.7 Hz, 1 H), 5.95–5.97
(m, 1 H), 8.12–8.14 (m, 1 H). 13C NMR (100 MHz, CDCl3):
d = 26.49, 27.49, 28.83, 28.98, 28.99, 29.11, 29.24, 33.73,
99.76, 114.13, 139.10, 150.12, 173.02. IR (CCl4): 3079,
1640, 1593 cm–1. Anal. Calcd for C13H21NO (207.32): C,
75.32; H, 10.21. Found: C, 75.59; H, 10.02.
3g: 1H NMR (400 MHz, CDCl3): d = 1.16 (t, J = 7.0 Hz, 6
H), 3.09 (d, J = 5.7 Hz, 2 H), 3.29 (dq, J1 = 9.4 Hz, J2 = 7.0
Hz, 2 H), 3.66 (dq, J1 = 9.4 Hz, J2 = 7.0 Hz, 2 H), 4.78 (t,
J = 5.7 Hz, 1 H), 6.09 (d, J = 1.6 Hz, 1 H), 8.14 (d, J = 1.6
Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 15.06, 31.92,
61.91, 100.18, 101.56, 150.19, 168.18. IR (CCl4): 2874,
1734, 1597, 1125, 1064 cm–1. Anal. Calcd for C9H15NO3
(185.22): C, 58.36; H, 8.16. Found: C, 58.60; H, 8.01.
Synlett 2006, No. 20, 3427–3430 © Thieme Stuttgart · New York

3430
D. H. Churykau, O. G. Kulinkovich
LETTER
(19) Analytical data of 4: 1H NMR (400 MHz, CDCl3): d = 0.88
(t, J = 6.9 Hz, 3 H), 1.22–1.53 (m, 8 H), 1.82–1.97 (m, 2 H),
2.89 (dd, J1 = 18.4 Hz, J2 = 1.3 Hz, 1 H), 2.92 (dd, J1 = 18.4
Hz, J2 = 1.6 Hz, 1 H), 3.10 (br s, 1 H), 7.20–7.23 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 13.97, 22.44, 24.60, 29.13,
31.58, 37.95, 44.86, 106.61, 147.16. IR (CCl4): 3598, 3395,
1722, 1601 cm–1. Anal. Calcd for C9H17NO2 (171.24): C,
63.13; H, 10.01. Found: C, 63.28; H, 9.75.
(20) The reaction proceeded less smoothly under elevated
temperatures or in the presence of acidic or basic catalysts.
Synlett 2006, No. 20, 3427–3430 © Thieme Stuttgart · New York