2-Isoxazolines with an electron-acceptor substituent at C(5) in reactions with nucleophilic reagents

Article abstract of DOI:10.1007/s10593-007-0053-6

Depending on the substituent at position 5 of the heterocycle, reaction of 2-isoxazolines with K-selectride, molybdenum hexacarbonyl, dimsyl sodium, and butyl lithium gave 1,3-cyclo-decomposition, aromatization of the isoxazoline ring, or reduction of the functional groups in the substituted isoxazolines.

Full text of DOI:10.1007/s10593-007-0053-6

Chemistry of Heterocyclic Compounds, Vol. 43, No. 3, 2007
2-ISOXAZOLINES WITH AN ELECTRON-ACCEPTOR SUBSTITUENT
AT C(5) IN REACTIONS WITH NUCLEOPHILIC REAGENTS
E. V. Koroleva1, N. F. Bondar2, Ya. M. Katok3, N. A. Chekanov1,
and T. V. Chernikhova1
Depending on the substituent at position 5 of the heterocycle, reaction of 2-isoxazolines with
K-selectride, molybdenum hexacarbonyl, dimsyl sodium, and butyl lithium gave 1,3-cyclo-
decomposition, aromatization of the isoxazoline ring, or reduction of the functional groups in the
substituted isoxazolines.
Keywords: derivatives of 2-isoxazoline, dimsyl sodium, molybdenum hexacarbonyl, K-selectride,
cyclodecomposition.
We described previously the reaction of 3-R-5-(4-pyridyl)-2-isoxazols with K-selectride (KBH(s-Bu)3)
and other organometallic reagents (butyl lithium, dimsyl sodium, and molybdenum hexacarbonyl) which
occurred by decomposition of the isoxazoline ring at the N–O and C(3)–C(4) bonds to give nitriles and
4-vinylpyridine [1-4]. However, 2-isoxazolines with phenyl, 2-pyridyl, or 2-oxo-1-pyrrolidyl substituents at C(5)
did not give products of cyclodecomposition in such reactions [2, 5].
Similar 1,3-cyclodecomposition under the influence of bases was known for a series of
5-acylisoxazolines and 5-nitroisoxazolines [6, 7]. Only products of 1,4-cyclodecomposition were isolated from
reactions of 2-isoxazolines with metal polycarbonyls [8, 9].
The decomposition of the heterocycle of 2-isoxazolines at two bonds is formally the reverse of the
synthesis of the heterocycle and not infrequently complicates the typical decomposition of the ring of
2-isoxazolines, which normally occurs at one of the bonds of the N–O–C unit. It is generally considered that
1,3-cyclodecomposition under the influence of bases goes via the generation of an anion at the C(5) atom of the
ring [6,7, 10]. However, the most acidic hydrogens are at C(3) in 3-substituted 2-isoxazolines and at C(4) in
3-unsubstituted isoxazolines [11, 12]. 5-endo-Deprotonation is generally uncharacteristic but may occur when
there are an electron-acceptor substituents at C(5), capable of creating a considerable increase in the acidity of the
H-5 proton and facilitating the stabilization of the anion formed.
To determine the limit of the applicability of the 1,3-cyclodecomposition reaction it was expedient to
compare the reactions of 2-isoxazolines, having electron-acceptor substituents at C(5), with typical bases, on the
one hand, and with nucleophilic organometallic reagents, on the other hand. The cryptobasic reducing agent
K-selectride has a nucleophilic character. Molybdenum hexacarbonyl reacts with 2-isoxazolines with the
intermediate formation of a vinyl-nitrene complex with delocalization of the π-d electrons from the metal into
the C=N–O π-orbital of the heterocycle, which makes easy rupture of the N–O bond possible [10, 13].
__________________________________________________________________________________________
Institute of the Chemistry of New Materials, Belarus National Academy of Sciences, Minsk 220141;
e-mail: evk@ichnm.basnet.by. 2Belorussian Agricultural Technological University, Minsk 220050; 3Belorussian
State Technological University, Minsk 220050. Translated from Khimiya Geterotsiklicheskikh Soedinenii,
No.3, 447-455, March, 2007. Original article submitted May 16, 2005. Revised version submitted June 13, 2006
362
0009-3122/07/4303-0362©2007 Springer Science+Business Media, Inc.

3-Aryl-5-nitro- and 5-acetyl-3-aryl-2-isoxazolines 1a,b, 2a,b were prepared from arylhydroxamic acid
chlorides and nitroethylene or methyl vinyl ketone under 1,3-dipolar cycloaddition reaction conditions.
5-Acetyl-3-(3-ethoxycarbonyl-1-propyl)-2-isoxazoline (2c) was obtained by 1,3-cycloaddition to methyl vinyl
ketone of the nitroxide dipole in situ, generated by the reaction of phenyl isocyanate from ethyl ester of
4-nitrovalerianic acid. The small yield of the cycloadducts may be explained by polymerization of the alkene
starting materials under conditions of the cycloaddition reaction.
On reaction of the 3-aryl-5-nitroisoxazolines 1a,b with K-selectride the isoxazols 3a,b, products of the
aromatization of the heterocycle, were the principal products isolated. We had previously observed this with
5-imidazolyl-2-isoxazoline [14]. In the reaction of isoxazoline 1a with K-selectride, in addition to
3-veratrylisoxazol 3a the nitrile 4a was isolated in 20% yield. In the reaction products from the reaction of
isoxazoline 1b with K-selectride benzamide 5b was isolated with 3-phenylisoxazol 3b. The former was probably
the product of hydrolysis of benzonitrile 4b, formed initially by 1,3-cyclodecomposition of the isoxazoline 1b.
The analogous amides 5a,c were not observed. Aromatization of 5-nitro-3-phenyl-2-isoxazoline 1b to give the
isoxazol 3b also occurred on reaction with sodium methoxide at -30°C.
R
ii
i
RCH NOH
+
N
NO2
NO2
O
1a,b
R
R
NH2
RC
N
N
+
+
O
O
4a
5b
3a,b
iii, iv
1b
3b
3a,b
iii
R
i, v
Me
N
Ac
RCH=NOH
+
O
R
O
ii
2a,b
Me
N
O
OH
6a,b
4c + Ac2
vii, viii
vi
2c
RCH2NO2
+
Ac
iii
3c
1–6 a R = 3,4-(MeO)2C6H3, b R = Ph, c R = EtO2C(CH2)3
i Cl2, Et3N, CHCl3, -10 °C – room temp.; ii KBH(s-Bu)3, –45 °C; iii Mo(CO)6, AcCN, 70 °C;
iv MeONa, THF, -30 °C; v NCS, CHCl3, Py, 20 °C; vi PhNCO, petroleum ether, 40-50 °C;
vii NaCH2SOMe, THF, 20 °C; viii n-BuLi, –45 °C – +15 °C
363

In the reaction of 5-acetyl-3-aryl-2-isoxazolines 2a,b with K-selectride quantitative reduction of the
carbonyl group with formation of 5-(1-hydroxyethyl)-2-isoxazolines 6a,b was observed.
When the 2-isoxazolines 1b, 2a-c were treated with dimsyl sodium in DMSO under standard conditions the
reaction mixture underwent resinification. The reaction of 5-acetyl-3-(3-ethoxycarbonylpropyl)-2-isoxazoline (2c)
with dimsyl sodium was carried out successfully in a heterogeneous medium: the isoxazoline was stirred with a
suspension of dimsyl sodium in THF. The product of cyclodecomposition, ethyl 4-cyanobutanoate 4c, was isolated.
The nitrile 4c was also isolated from the reaction of the same isoxazoline 2c with butyl lithium. The product from
the second fragment of decomposition of the isoxazoline ring was not isolated. It should be noted that reaction of 5-
alkyl-, 5-penyl-, 5-(pyridyl-2)- and 5-(2-oxopyrrolidin-1-yl)-2-isoxazolines with dimsyl sodium gave 1,5-
decomposition of the heterocycle to give the corresponding enoximes [2, 3].
The reaction of 5-nitro-3-phenylisoxazoline 1b with molybdenum hexacarbonyl at the temperature of the
boiling solvent – acetonitrile (70°C) gave the isoxazol 3b (90% yield) with the evolution of nitrogen dioxide.
Under these conditions 5-acetyl-2-isoxazolines 2a-c gave the corresponding isoxazols 3a-c as the basic product
but with strong resinification of the reaction mixture.
It is known that the mobility of proton H-4 in the isoxazol ring is greater than that of proton H-5. As a result
of the –I- and –M-effects of the nitro group the acidity of the H–C(5) of the heterocycle in the isoxazoline is increased
and deprotonation occurs effectively at both positions 5 and 4. When the 5-R-substituent possesses –I- and –M-
effects, removal of proton H-4 occurs and if the 5-R-substituent is a good leaving group, then aromatization
occurs. So if the 5-R-substituent is a nitro, imidazolyl, or carboxyl group, then in the reactions of 5-
nitroisoxazolines 1a,b with nucleophilic reagents aromatization of the heterocycle occurs.
In the case of 5-pyridylisoxazolines, the pyridyl substituent, which possesses a negative inductive effect,
facilitates the formation of an anion at C(5) atom, but the +M-effect of the substituent possibly predetermines the
subsequent decomposition of the ring because of the impossibility of stabilizing the negative charge on C(5).
From this point of view cyclodecomposition should be observed with isoxazolines containing heteroaromatic
substituents – pyridine, thiophene, pyrrole. The bases should be sufficiently strong to allow deprotonation of
isoxazoline ring. It should be noted that the number of the bases capable to deprotonate atom C(5) of the
isoxazoline cycle is limited for the substituents of the type OMe, OH, NR1, NR2 where –I-effect < +M-effect.
However, in such cases deprotonation of the H–C(5) may occur effectively under the influence of organometallic
compounds with nucleophilic character in the intermediate complex.
So in reaction of 2-isoxazolines with nucleophilic reagents four reaction pathways are possible for
conversion of the isoxazoline ring – 1,2-cleavage, 1,5-cleavage, 1,3-cyclodecomposition, and aromatization.
The structure of the substituent at C(5) of the isoxazoline ring determines the results of its reaction with a
nucleophilic reagent. Electron-acceptor substituents facilitate the formation of the C(5)-anion An, the driving
force of the subsequent ketonitrile cyclodecomposition is the formation of the stable nitrile 4. The second
direction for the stabilization of the C(5) is achieved when the substituent at C(5) is an excellent leaving group: its
removal with the formation of H-(5-R) leads to the corresponding isoxazole. An exclusion is evidently the
reaction with metal polycarbonyls, since in the intermediate state a complex is formed as a result of coordination
via the unshared electron pair of the nitrogen atom of the isoxazoline. Subsequent decomposition of this complex
occurs with cleavage at the N–O bond. Since in the reaction of isoxazolines 1 and 2 with molybdenum
hexacarbonyl we isolated only the products of aromatization, it may be suggested that the complex formed is
stabilized only by loss of the C(5)-substituent with formation of the isoxazol 3.
However in a case we described [4], the 1,3-cyclodecomposition of 2-isoxazolines with Mo(CO)6 evidently
occurred via formation of a complex of the polycarbonyl with the nitrogen atom of the pyridyl substituent at C(5).
2-Isoxazolines are very weak bases, the basicity of which correlates of the electron-acceptor properties
of the substituent. Because of the conjugation of the isoxazol and benzene rings, phenyl-substituted isoxazoles
and isoxazolines are an order less basic than those with alkyl substituents [15]. Therefore the presence of
acceptor substituents on 2-isoxazolines determines their high reactivity in reactions with nucleophiles.
364

1
It should be noted that H NMR data confirm the presence of conjugation of the substituent at C(5) with
the isoxazoline ring. For example, the equivalence of the H-4 protons in the spectrum of 5-nitro-3-phenyl-
isoxazoline 1b indicates that the heterocycle and the nitro group are in the same plane. The convergence of the
chemical shifts of the H-4 protons which is observed in the 1H NMR spectra of the 5-acetyl-substituted 2a-c and
also 5-(2-pyridyl)- [5] and 5-imidazolyl-2-isoxazolines [14] reflects the tendency to flattening of the molecule.
The possibility of the charge redistribution due to the conjugation effect with substituent arises in the flater
system. The neighboring reaction center of the heteroatom of the substituent with an unshared pair of electrons
also affects the charge on C(5) in the nitroisoxazolines 1a,b and 5-(2-pyridyl)- and 5-imidazolyl-2-isoxazolines.
R
R
R1
1,2-decomposition
R
+
N
N
R1 = Ac, NO2
R1
O
O
R1 = Alk, Ph, 2-Py,
2-oxopyrrolidyl
O
OH
Mo(CO)6
3
Mo(CO)6
aromatization
KBH(s-Bu)3
R
N
or
R
MeS(O)CH2Na
or BuLi
R1
O
N
R1
O
R = 4-Py, Ac,
NO2, Im
An
R1 = Alk, Ph,
2-Py, 2-oxopyrrolidyl
MeS(O)CH2Na
1,3-cyclodecomposition
Me
H
R
R
C
N
+
R1
O
N
O
R1
4
1,5-decomposition
R1
R
N
OH
EXPERIMENTAL
1H NMR spectra of CDCl3 solutions with TMS as internal standard were recorded with a Bruker AC-200
(200 MHz) spectrometer. IR spectra of thin films or KBr disks were recorded with UR-20 instrument. Mass
spectra were recorded with a Varian MAT-311 instrument with an ionizing energy of 70 eV. The course of
reactions and the purity of the products synthesized were monitored by TLC on Silufol UV-254 (Serva) and
Kieselgel 60 F254 (Merck) plates with 1:1 hexane-ether eluent. Development was carried out with UV light,
iodine, and anisic developer (90% ethanol, 5% H2SO4, 5% anisaldehyde). Column chromatography was carried
out on 40-100µ silica gel (Czechoslovakia) or Kieselgel 60 (Merck).
365

Oximes of the corresponding aromatic aldehydes were obtained by known methods and their
physicochemical characteristics coincided with those cited in the literature.
3-(3,4-Dimethoxyphenyl)-5-nitro-2-isoxazoline (1a). Veratraldoxime (5.2 mmol) was added to a
solution of N-chlorosuccinimide (5.2 mmol) in chloroform (30 ml) and pyridine (0.01 ml). After the precipitate
had dissolved completely nitroethylene (2.6 mmol) in chloroform (10 ml) was added to the reaction mixture and
then over several minutes triethylamine in chloroform (5.2 mmol) was added slowly during 3 h. The reaction
mixture was stirred for 48 h, evaporated, water was added to the residue, and the product was extracted with
ether or chloroform. The required product 1a was separated by chromatography as an amorphous solid mass.
1
Yield 45%. IR spectrum, ν, cm-1: 700, 765, 1365, 1565, 1600. H NMR spectrum, δ, ppm (J, Hz): 3.86 (3H, s,
OCH3); 3.87 (3H, s, CH3); 4.12 (2H, d, J4,5 = 5.5, CH2 isox); 6.20 (1H, t, J5,4 = 5.5, CH isox); 6.48 (1H, d,
J
2',6' = 1.7, H-2'); 6.56 (1H, dd, J6',5' = 10.0, J6',2' = 1.7, H-6'); 7.58 (1H, d, J5',6' = 10.0, H-5'). Mass spectrum,
m/z (Irel, %): 252 [M]+ (20), 206 [M–NO2]+ (65), 115 [M–(MeO)2C6H3]+ (35), 46 [NO2]+ (100), Found, %:
C 52.36; H 4.91; N 11.13. C11H12N2O5. Calculated, %: C 52.38; H 4.80; N 11.11.
5-Nitro-3-phenyl-2-isoxazoline (1b). Chlorine was passed through a solution of benzaldoxime
(12 mmol) in dry chloroform at -15°C until the reaction mixture became an intense green color. The excess
chlorine and hydrogen chloride were removed in vacuum. The reaction mixture was warmed to room
temperature and nitroethylene (13 mmol) was added. Triethylamine (2ml) in dry chloroform (10 ml) was added
slowly dropwise with stirring until the solution was weakly basic, after which the mixture was stirred for 2-3 h.
After removal of the chloroform, dry ether was added and the precipitate of Et3N·HCl was filtered off. The ether
was evaporated off, and the product was separated by column chromatography on silica gel followed by
recrystallization from ether–hexane to give isoxazoline 1b (4.2 mmol) as colorless crystals, stable below 0°C,
decomposing very slowly at room temperature and rapidly at temperatures above 50°C. Yield 35%. IR spectrum,
1
ν, cm-1: 700, 765, 850, 1370, 1575, 1590. H NMR spectrum, δ, ppm, (J, Hz): 4.00 (2H, d, J4,5 = 5.5, CH2 isox);
6.26 (1H, t, J5,4 = 5.5, CH isox); 7.37-7.71 (5H, m, C6H5). Mass spectrum, m/z (Irel, %): 192 [M]+ (20), 146 [M–NO2]+
(52), 116 [M–C6H5]+ (25), 77 [C6H5]+ (45), 46 [NO2]+ (100). Found, %: C 56.30; H 4.25; N 14,63. C9H8N2O3.
Calculated, %: C 56.25; H 4.20; N 14.58.
5-Acetyl-3-(3,4-dimethoxyphenyl)-2-isoxazoline (2a) and 5-acetyl-3-phenyl-2-isoxazoline (2b) were
obtained analogously from veratraldoxime and benzaldoxime, respectively, with an excess of vinyl methyl
ketone (15 mmol). Triethylamine in dry chloroform (2 ml in 10 ml chloroform) was added to remove the excess
of hydrogen chloride only after the reaction was completed. The products were isolated by column
chromatography.
Isoxazoline 2a. Yield 40%. IR spectrum, ν, cm-1: 710, 760, 1365, 1575, 1600, 1735. 1H NMR spectrum,
δ, ppm, (J, Hz): 2.30 (3H, s, CH3CO); 3.5-3.65 (2H, m, CH2 isox); 5.25 (1H, dd, J5,4 = 10, J = 6.5, CH isox);
3.84 (3H, s, OCH3); 3.85 (3H, s, OCH3); 6.52 (1H, d, J2',6' = 2.0, H-2'); 6.56 (1H, dd, J6',5' = 10.0, J6',2' = 2.0,
H-6'); 7.60 (1H, d, J5',6' = 10.0, H-5'). Mass spectrum, m/z (Irel, %): 249 [M]+ (30), 206 [M–Ac]+ (60), 43 [Ac]+
(100). Found, %: C 62.61; H 6.11; N 5.66. C13H15NO4. Calculated, %: C 62.64; H 6.07; N 5.62.
1
Isoxazoline 2b. Mp 62-64°C. Yield 45%. IR spectrum, ν, cm-1: 1365, 1580, 1610, 1736. H NMR
spectrum, δ, ppm (J, Hz): 2.38 (3H, s, CH3); 3.47 (1H, dd, Jgem = 17.0, J4,5 = 11.7, H-4 isox); 3.65 (1H, dd,
Jgem = 17.0, J4,5 = 6.5, H-4 isox), 5.01 (1H, dd, J5,4 = 11.7, J5,4 = 6.5, H-5 isox); 7.42 (3H, m, C6H5); 7.65 (2H, m,
C6H5). Mass spectrum, m/z (Irel, %): 189 [M]+ (20), 146 [M–Ac]+ (60), 112 [M–C6H5]+ (25), 77 [C6H5]+ (45),
43 [Ac]+ (100). Found, %: C 69.91; H 5.81; N 7.46. C11H11NO2. Calculated, %: C 69.83; H 5.86; N 7.40.
5-Acetyl-3-(3-ethoxycarbonylpropyl)-2-isoxazoline (2c). A small excess of methyl vinyl ketone
(14 mmol) and phenyl isocyanate (30 mmol) was added to a solution of ethyl ω-nitrovalerate (12 mmol) in dry
petroleum ether (15 ml). Triethylamine (12 mmol) was added rapidly and the reaction mixture was stirred free
from moisture on a water bath at 40-50°C for 1 h. The precipitate of diphenylurea was filtered off, washed with
chloroform and methanol, and the combined filtrates were evaporated on a rotary evaporator. The required
product was isolated by column chromatography on silica gel with gradient elution with an ether–hexane
366

1
mixture to give compound 2c (4.8 mmol, 40%) as an oil. IR spectrum, ν, cm-1: 1610, 1735. H NMR spectrum,
δ, ppm (J, Hz): 1.26 (3H, t, J = 7.0, CH3); 1.90 (2H, m, CH2); 2.28 (3H, s, CH3C=O); 2.36 (4H, m, 2CH2),
3.13 (2H, m, CH2 isox); 4.52 (2H, q, J = 7.0, CH2CH3); 4.82 (1H, dd, J5,4 = 11.0, J = 6.8, CH isox). Mass
spectrum, m/z (Irel, %): 195 [M]+ (25), 152 [M–Ac]+ (60), 43 [Ac]+ (100). Found, %: 61.93 H 8.95 N 6.53.
C11H17NO2. Calculated, %: C 61.95; H 8.98; N 6.57.
Reactions of 3-Aryl-5-nitro- (1a,b) and 5-Acetyl-3-aryl-2-isoxazolines (2a,b) with K-selectride. An
isoxazoline (0.5 mmol) in THF (7 ml, freshly distilled over LiAlH4) was placed in a flask flushed with argon and
cooled to -45°C, and a solution of K-selectride (Aldrich) (2 ml, 1M) was added to the stirred solution with a
syringe. The mixture was stirred at -45°C for 3 h, then 30% H2O2 (2 ml) and potassium hydroxide (1 ml, 5M)
were added at -10°C with stirring for 10 min at 0 to +5°C, diluted with water (2 ml), and the reaction mixture
was then evaporated. The aqueous suspension was extracted with ether, the extract was washed with water, and
dried over MgSO4. The products were isolated by column chromatography as crystals or oils.
3-(3,4-Dimethoxyphenyl)isoxazole (3a). Yield 35%. IR spectrum, ν, cm-1: 700, 770, 880, 960, 1610. 1H
NMR spectrum, δ, ppm (J, Hz): 3.85 (3H, s, OCH3); 3.87 (3H, s, OCH3); 6.53 (1H, d, J2',6' = 2.0, H-2');
6.58 (1H, dd, J6',5' = 10.0, J6',2' = 2.0, H-6'); 6.70 (1H, d, J4,5 = 1.9, H-4 isox); 7.62 (1H, d, J5',6' = 10.0, H-5');
8.54 (1H, d, J5,4 = 1.9, H-5 isox). Mass spectrum, m/z (Irel, %): 205 [M]+ (80), 137 [(MeO)2C6H3)]+ (45), 120
(45). Found, %: C 64.42; H 5.51; N 6.86. C11H11NO3. Calculated, %: C 64.38; N 5.40; N 6.83.
3,4-Dimethoxybenzonitrile (4a). Yield 20%. Mp 67-68°C [16]. IR spectrum, ν, cm-1: 810, 1030, 1580,
1
1610, 2220. H NMR spectrum, δ, ppm: 3.85 (3H, s, OCH3); 3.90 (3H, s, OCH3); 6.46 (1H, d, J2',6' = 1.7,
H-2' arom); 6.50 (1H, dd, J6',5' = 10.0, J6',2' = 1.7, H-6' arom); 7.46 (1H, d, J5',6' = 10.0, H-5' arom). Mass
spectrum, m/z (Irel, %): 163 [M]+ (100), 120 (45), 77 [C6H5]+ (35).
3-Phenylisoxazole (3b). Yield 40°C. Mp 143-145°C [17]. IR spectrum, ν, cm-1: 700, 770, 880, 960,
1610. 1H NMR spectrum, δ, ppm (J, Hz): 6.64 (1H, d, J4,5 = 1.9, H-4 isox); 7.45 (3H, dd, J = 5.0, J = 2.4, C6H5);
7.81 (2H, dd, J = 5.0, J = 2.4, C6H5); 8.44 (1H, d, J5,4 = 1.9, H-5 isox). Mass spectrum, m/z (Irel, %): 145 [M]+
(80), 103, 77 [C6H5]+ (45).
1
Benzamide (5b). Yield 20%. Mp 125-127°C. IR spectrum, ν, cm-1: 700, 760, 860, 1670. H NMR
spectrum, δ, ppm (J, Hz): 5.70 (br. s, NH2); 7.5-7.8 (5H, m, C6H5). Mass spectrum, m/z (Irel, %): 121 [M]+ (65),
105 [M–NH2]+ (90), 77 [C6H5]+ (100).
5-(1-Hydroxyethyl)-3-(3,4-dimethoxyphenyl)-2-isoxazoline (6a) was obtained analogously from
1
isoxazol 2a as a mixture of stereoisomers in 98% yield. Oil. IR spectrum, ν, cm-1: 605, 1610, 3420. H NMR
spectrum, δ, ppm (J, Hz): 1.25 (3H, d, J = 7, CH3); 2.60 (1H, br. s, OH); 3.32 (1H, dd, Jgem = 16.0, J4,5 = 8.0,
H-4 isox); 3.48 (1H, dd, Jgem = 16.0, J4,5 = 11, H-4 isox); 3.75 (1H, m, CH–OH); 3.94 (3H, s, CH3); 3.95 (3H, s,
CH3); 4.70 (1H, ddd, J5,4 = 8.0, J5,4 = 11.0, J5,1' = 5.5, H-5 isox); 6.86 (1H, d, J2',6' = 2.0, H-2'); 7.06 (1H, dd,
J
6',5' = 10.0, J6',2' = 2.0, H-6'); 7.3 (1H, d, J5',6' = 10.0, H-5'). Mass spectrum, m/z (Irel, %): 251 [M]+ (80), 206 (45),
120 (50), 45 [C(OH)Me]+ (100). Found, %: C 62.10; H 6.91; N 5.68. C13H17NO4. Calculated, %: C 62.14;
H 6.82; N 5.57.
5-(1-Hydroxyethyl)-3-phenyl-2-isoxazoline (6b) was obtained analogously from compound 2b as a
mixture of stereoisomers in 98% yield. Oil. IR spectrum, ν, cm-1: 1610, 3420. 1H NMR spectrum, δ, ppm (J, Hz):
1.26 and 1.16 (3H, d, J = 6.8, CH3); 2.62 (1H, br. s, OH); 3.16 (1H, dd, Jgem = 17.0, J4,5 = 8.0, H-4 isox); 3.36
(1H, dd, Jgem = 17.0, J4,5 = 10.5, H-4 isox); 3.75 (1H, m, CH-OH); 4.56 (1H, ddd, J5,4 = 8.0, J5,4 = 10.5, J5,1' = 5.5,
H-5 isox); 7.37 (3H, m, C6H5); 7.62 (2H, m, C6H5). Mass spectrum, m/z (Irel, %): 191 [M]+ , 146 (75), 77 [C6H5]+
(45), 45 [C(OH)Me]+ (100). Found: C 69.10; H 6.91; N 7.28. C11H13NO2. Calculated, %: C 69.09; H 6.85; N
7.32.
Reactions of Isoxazolines 1b, 2a-c with Molybdenum Hexacarbonyl. Water (1 mmol) and
molybdenum hexacarbonyl (0.5 mmol) were added to a solution of an isoxazoline (1.0 mmol) in absolute
acetonitrile (20 ml). The mixture was heated to the boiling point of the solvent (at which point vigorous
evolution of nitrogen dioxide was observed), boiling was continued for 20 min, monitored by TLC. The reaction
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mass was diluted with a 1:1 mixture of hexane and ether, filtered through celite 545, and the filtrate was
evaporated. The residue was diluted with water and extracted with 1:1 hexane–ether. The solvent was removed
in vacuum to give the corresponding isoxazols 3a-c in yields of up to 90%.
1
3-(3-Ethoxycarbonylpropyl)isoxazole (3c). Yield 65%. IR spectrum, ν, cm-1: 1615, 1730. H NMR
spectrum, δ, ppm (J, Hz): 1.30 (3H, t, J = 7.0, CH3); 1.70 (2H, m, CH2); 2.40 (4H, m, CH2C=N, CH2COO);
4.51 (2H, q, J = 7.0, CH2CH3); 6.6 (1H, d, J4,5 = 2, H-4 isox); 8.3 (1H, d, J5,4 = 2, H-5 isox). Mass spectrum, m/z
(Irel , %): 183 [M]+ (70), 110 [M–EtO2C]+ (100). Found, %: C 59.01; H 7.24; N 7.60. C9H13NO3. Calculated, %:
C 59.00; H 7.15; N 7.65.
Reaction of 5-Nitro-3-phenyl-2-isoxazoline (1b) with Sodium Methoxide. A suspension of sodium
methoxide, prepared from sodium (90 mg) and methanol (0.15 ml), in THF (10 ml) was added to a solution of
isoxazoline 1b (0.2 g, 1.04 mmol) in dry THF (10 ml) at -35°C. After the sodium methoxide had been added the
mixture was stirred for 15 min more. Then a solution of hydrochloric acid (0.5 ml) in THF (2 ml) was added and
the reaction mixture was warmed to room temperature, and the precipitate was filtered off. The THF was
evaporated, the residue was dissolved in chloroform and dried over MgSO4. 3-Phenylisoxazole (3b) (0.14 g,
0.94 mmol) in 90% yield was obtained after removal of the chloroform.
Reaction of 5-Acetyl-3-(3-ethoxycarbonylpropyl)-2-isoxazoline (2c) with Dimsyl Sodium. NaH
(0.070 g, 3.2 mmol) was added to a solution of dry DMSO (0.220 mg, 3.2 mmol) in dry THF (5 ml) in a stream
of argon, the mixture was heated to 70°C and stirred for 20 min until evolution of hydrogen ceased. A solution
of the isoxazoline (0.20 g, 3.2 mmol) in dry THF (10 ml) was added to the suspension of dimsyl sodium in THF,
the mixture was stirred for 1 h and then neutralized with HCl (0.3 ml, 37%). The residue was filtered off, washed
with THF, and the solvent was evaporated.
Ethyl 4-cyanobutyrate 4c was isolated from the hexane extract as an oil [19]. Yield 45%. IR spectrum,
ν, cm-1: 1730, 2257. 1H NMR spectrum, δ, ppm (J, Hz): 1.33 (3H, t, J = 7.0, CH3); 1.86-2.06 (2H, m); 2.40-2.56
(4H, m, CH2COO, CH2CN); 4.50 (2H, q, CH2CH3). Mass spectrum, m/z: 141 [M]+.
Reaction of Compound 2c with Butyl Lithium. A solution of n-butyl lithium (1.5 mmol in hexane)
was added to a solution of the isoxazoline (0.5 mmol) in dry THF (15 ml) at -45°C in an atmosphere of argon
and stirring was continued for 2 h at the same temperature. The mixture was then allowed to warm to room
temperature, diluted with water, the THF was evaporated off, and the aqueous phase was extracted with ether.
The extract was dried with Na2SO4, and the solvent evaporated to give ethyl 4-cyanobutyrate (4c) in a yield
of 25%.
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