Addition of nitrile oxides to allyl esters of aryl-(hetaryl)carboxylic acids

Article abstract of DOI:10.1023/A:1016031305715

3,5-Disubstituted isoxazolines with an aryl(hetaryl) carboxymethyl group in position 5 have been synthesized. The addition reaction of nitrile oxides to allyl esters of aryl(hetaryl) carboxylic acids occurs regiospecifically with the formation of the 5-su

Full text of DOI:10.1023/A:1016031305715

Chemistry of Heterocyclic Compounds, Vol. 38, No. 4, 2002
ADDITION OF NITRILE OXIDES
TO ALLYL ESTERS OF ARYL-
(HETARYL)CARBOXYLIC ACIDS*
V. Dirnens, O. Slyadevskaya, and E. Lukevics
3,5-Disubstituted isoxazolines with an aryl(hetaryl) carboxymethyl group in position 5 have been
synthesized. The addition reaction of nitrile oxides to allyl esters of aryl(hetaryl) carboxylic acids
occurs regiospecifically with the formation of the 5-substituted isomer. Initial pharmacological
screening showed that 5-(4-bromobenzoyloxy)methyl-3-(3,4-dimethoxyphenyl)isoxazoline possesses
marked nootropic activity.
Keywords: isoxazolines, nitrile oxides, hydroxamic acid chlorides.
Isoxazolines are valuable synthons for obtaining various functionally substituted compounds (β-hydroxy
ketones and acids, γ-amino alcohols, α,β-cyanohydrins, amino sugars, and complex heterocycles) [1-4], and
also, thanks to the ability to interact with receptors, they possess marked biological activity [5-8].
One of the main methods of synthesis of these compounds is the [2 + 3] cycloaddition reaction of nitrile
oxides or silyl nitronates to alkenes [9-12]. Derivatives of aryl(hetaryl) carboxylic acids 16-30, containing an
isoxazoline fragment in the ester group, have been synthesized by the addition of oxides of substituted aryl
nitriles 8-15 to allyl esters of aryl(hetaryl) carboxylic acids 1-7.
O
R2C N–O
R1
C
O
R1
8–15
C
OCH
2CH
CH2
C
OCH2CH=CH2
1–7
R2
R2
O
N
16–30
R1
Com-
pound
Com-
pound
R1
R2
4-Br–C6H4–
4-Br–C6H4–
4-Br–C6H4–
4-Br–C6H4–
4-Br–C6H4–
4-Br–C6H4–
4-I–C6H4–
C6H5–
2-Cl–C6H4–
2-Cl–C6H4–
2,4-Cl2–C6H3–
2,4-Cl2–C6H3–
2,4-Cl2–C6H3–
5-Br–Furyl-
4-CH3O–C6H4–
4-Cl–C6H4–
4-CH3O–C6H4–
4-Cl–C6H4–
4-O2N–C6H4–
4-CH3O–C6H4–
4-Cl–C6H4–
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2-CH3O–C6H4–
3-CH3O–C6H4–
4-CH3O–C6H4–
3,4-(CH3O)2–C6H3–
2-Cl–C6H4–
4-CH3O–C6H4–
2-Quinolyl-
4-O2N–C6H4– 4-CH3O–C6H4–
_______
* Dedicated to Professor O. Neilands on the occasion of his Jubilee.
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: dirnens@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 4, pp. 499-502, April, 2002. Original article submitted March 7, 2001.
434
0009-3122/02/3804-0434$27.00©2002 Plenum Publishing Corporation

The reaction was carried out in "one pot" sequentially by 1) conversion of a substituted aryl(hetaryl)
oxime with N-chlorosuccinimide in chloroform to the corresponding arylhydroxamic acid chloride; 2) addition
of the unsaturated compound, and 3) addition of triethylamine as dehydrohalogenating agent to generate the
nitrile oxide.
The reaction proceeds regioselectively, only one regioisomer, the 5-substituted isoxazoline, is always
formed.
Initial pharmacological screening for psychotropic activity showed that 5-(4-bromobenzoyloxy)methyl-
3-(3,4-dimethoxyphenyl)isoxazoline (20) at a dose of 5 mg/kg possesses marked nootropic activity.
TABLE 1. Characteristics of Isoxazoline Derivatives 16-30
Found, %
——————
Com-
pound
Empirical
formula
Calculated, %
mp, °С
Yield, %
C
H
N
C17H14BrNO3
C18H16BrNO4
C18H16BrNO4
C18H16BrNO4
C19H18BrNO5
C17H13BrClNO3
C18H16INO4
56.59
56.69
3.84
3.92
3.85
3.89
146
105
87
70
68
69
72
69
71
70
67
69
68
65
67
51
50
52
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
55.45
4.13
3.54
55.40
4.13
3.59
55.26
55.40
4.12
4.13
3.60
3.59
55.40
4.09
3.60
140
134
72
55.40
4.13
3.59
54.38
54.30
4.25
4.32
3.27
3.33
51.56
3.29
3.56
51.74
3.32
3.55
49.61
49.45
3.71
3.69
3.13
3.20
146
185
62
C18H16N2O6
60.42
4.53
7.77
60.67
4.53
7.86
C18H16ClNO4
C17H13Cl2NO3
C18H15Cl2NO4
C17H12Cl3NO3
C17H12Cl2N2O5
C16H14BrNO5
C20H15ClN2O3
62.57
62.52
4.64
4.66
4.02
4.05
58.39
3.76
4.02
76
58.31
3.74
4.00
56.91
56.86
3.99
3.97
3.62
3.68
125
104
136
143
146
52.92
3.16
3.63
53.08
3.14
3.64
51.69
51.67
3.09
3.06
7.14
7.09
50.51
3.70
3.70
50.55
3.71
3.68
65.37
65.49
4.14
4.12
7.68
7.64
TABLE 2. 1H NMR Spectra of Isoxazolines 16-30
Com-
Chemical shifts, δ, ppm, coupling constants, J (Hz)
pound
1
2
3.23 (1H, dd, J = 6.5, J = 15.8, CH); 3.54 (1H, dd, J = 9.8, J = 15.8, CH);
16
17
4.49 (2H, m, OCH2); 5.12 (1H, m, CH); 7.36-7.78 (7H, m, H arom); 7.89 (2H, d, J = 7.9, H arom)
3.34 (1H, dd, J = 6.3, J = 16.7, CH); 3.67 (1H, dd, J = 9.8, J = 16.7, CH);
3.81 (3H, s, OCH3); 4.48 (2H, m, OCH2); 5.08 (1H, m, CH); 6.84-7.07 (2H, m, H arom);
7.41 (1H, dd, J =1.5, J = 7.5, H arom), 7.56 (2H, d, J = 8.2, H arom),
7.78 (1H, dd., J = 1.5, J = 7.5, H arom), 7.94 (2H, d, J = 8.2, H arom)
3.21 (1H, dd, J = 6.8, J = 15.9, CH); 3.54 (1H, dd, J = 9.4, J = 15.9, CH);
18
3.85 (3H, s, OCH3); 4.43 (1H, dd, J = 5.2, J = 10.9, OCH2);
4.52 (1H, dd, J = 3.2, J = 10.9, OCH2); 5.11 (1H, m, CH); 6.92-7.18 (1H, m, H arom);
7.25-7.33 (3H, m, H arom); 7.58 (2H, d, J = 8.4, H arom); 7.87 (2H, d, J = 8.4, H arom)
435

TABLE 2 (continued)
1
2
3.21 (1H, dd, J = 6.4, J = 16.1, CH); 3.56 (1H, dd, J = 9.7, J = 16.1, CH);
3.85 (3H, s, OCH3); 4.47 (2H, m, OCH2); 5.09 (1H, m, CH);
6.96 (2H, d, J = 8.2, H arom), 7.56 (2H, d, J = 7.8, H arom); 7.67 (2H, d, J = 8.2, H arom);
7.92 (2H, d, J = 7.8, H arom)
19
3.21 (1H, dd, J = 6.7, J = 16.2, CH); 3.54 (1H, dd, J = 9.8, J = 16.2, CH);
20
21
22
23
24
3.92 (6H, s, 2 × OCH3); 4.47 (2H, m, OCH2); 5.12 (1H, m, CH);
6.89-7.12 (2H, m, H arom); 7.36-7.58 (3H, m, H arom); 7.89 (2H, d, J = 7.8, H arom)
3.38 (1H, dd, J = 6.6, J = 16.0, CH); 3.69 (1H, dd, J = 9.8, J = 16.0, CH);
4.47 (2H, m, OCH2); 5.09 (1H, m, CH); 7.27-7.65 (4H, m, H arom);
7.52 (2H, d, J = 7.5, H arom); 7.89 (2H, d, J = 7.5, H arom)
3.18 (1H, dd, J = 6.3, J = 15.5, CH); 3.52 (1H, dd, J = 9.8, J = 15.5, CH);
3.85 (3H, s, OCH3); 4.47 (2H, m, ОCH2); 5.08 (1H, m, СH);
6.96 (2H, d, J = 8.2, H arom); 7.65 (2H, d, J = 8.2, H arom); 7.76 (4H, s, H arom)
3.21 (1H, dd, J = 6.6, J = 15.9, CH); 3.56 (1H, dd, J = 9.6, J = 15.9, CH);
3.89 (3H, s, OCH3); 4.52 (2H, m, ОCH2); 5.12 (1H, m, СH);
6.98 (2H, d, J = 8.2, H arom); 7.67 (2H, d, J = 8.2, H arom); 8.27 (4H, s, H arom)
3.25 (1H, dd, J = 7.2, J = 16.0, CH); 3.54 (1H, dd, J = 9.9, J = 16.0, CH);
3.83 (3H, s, OCH3); 4.52 (2H, d, J = 4.4, OCH2); 5.09 (1H, m, CH);
6.96 (2H, d, J = 8.2, H arom); 7.21−7.47 (3H, m, H arom);
7.65 (2H, d, J = 8.2, H arom); 7.87 (1H, dd, J = 0.5, H arom, = 5.9, H arom)
3.25 (1H, dd, J = 6.9, J = 15.9, CH); 3.52 (1H, dd, J = 9.6, J = 15.9, CH);
4.47 (1H, dd, J = 4.2, J = 9.6, OCH2); 4.56 (1H, dd, J = 3.4, J = 9.6, OCH2);
5.13 (1H, m, CH); 7.18-7.47 (5H, m, H arom); 7.65 (2H, d, J = 8.1, H arom);
7.78-7.92 (1H, m, H arom)
25
26
3.23 (1H, dd, J = 7.2, J = 16.5, CH); 3.54 (1H, dd, J = 10.1, J = 16.5, CH);
3.87 (3H, s, OCH3); 4.43 (1H, dd, J = 4.4, J = 10.7, OCH2);
4.56 (1H, dd, J = 2.8, J = 10.7, OCH2); 5.11 (1H, m, CH); 6.98 (2H, d, J = 8.7, H arom);
7.24 (1H, dd, J = 1.5, J = 7.2, H arom); 7.52 (1H, d, J = 1.5, H arom);
7.67 (2H, d, J = 8.7, H arom); 7.87 (1Н, d, J = 7.2, H arom)
3.25 (1H, dd, J = 7.5, J = 15.9, CH); 3.54 (1H, dd, J = 9.8, J = 15.9, CH);
4.45 (1H, dd, J = 4.6, J = 10.1, OCH2); 4.58 (1H, dd, J =3.8, J = 10.1, OCH2);
5.16 (1H, m, CH); 7.21-7.34 (2H, m, H arom); 7.43 (2H, d, J = 8.0, H arom);
7.65 (2H, d, J = 8.0, H arom); 7.85 (1H, d, J = 7.9, H arom)
27
28
3.34 (1H, dd, J = 7.1, J = 15.2, CH); 3.61 (1H, dd, J = 10.2, J = 15.2, CH);
4.47 (1H, dd, J = 4.1, J = 10.1, OCH2); 4.67 (1H, dd, J =3.2, J = 10.1, OCH2);
5.24 (1H, m, CH); 7.23-7.49 (2H, m, H arom); 7.87 (2H, d, J = 8.2, H arom);
8.21-8.41 (1H, m, H arom); 8.32 (2H, d, J = 8.2, H arom)
3.18 (1H, dd, J = 6.6, J = 15.9, CH); 3.49 (1H, dd, J = 9.7, J = 15.9, CH);
29
30
3.83 (3H, s, OCH3); 4.45 (2H, m, OCH2); 5.08 (1H, m, CH); 6.47 (1H, d, J =3.1, H fur.);
6.96 (2H, d, J = 8.2, H arom); 7.14 (1H, d, J =3.1, H fur.); 7.65 (2H, d, J = 8.2, H arom)
3.32 (1H, dd, J = 6.2, J = 15.9, CH); 3.58 (1H, dd, J = 9.7, J = 15.9, CH);
4.67 (2H, d, J = 4.1, OCH2); 5.24 (1H, m, CH); 7.43 (2H, d, J = 8.3, H arom)
7.69 (2H, d, J = 8.3, H arom); 7.81-7.96 (3H, m, H arom); 8.12-8.38 (3H, m, H arom)
EXPERIMENTAL
1
The H NMR spectra of the synthesized compounds were recorded on a Bruker WP 90 (90.1 MHz) in
deuterochloroform, internal standard was TMS.
General Procedure for Obtaining Isoxazolines 16-30 [13]. Oxime (10 mmol) was added in one
portion to a suspension of N-chlorosuccinimide (10 mmol) in dry chloroform (20 ml). After this as the
N-chlorosuccinimide passed into solution (end of chlorination), the olefin (5 mmol) was added. Triethylamine
(11 mmol) in chloroform (11 ml) was added dropwise to the solution during 30 min. The reaction mixture was
maintained at room temperature a further 30 min, and then washed with water (2 × 21 ml). The organic layer
was dried with anhydrous sodium sulfate, and evaporated in vacuum. The isoxazolines were purified by
crystallization from acetonitrile or by column chromatography (SiO2, hexane–ethyl acetate, 20%).
The characteristics of the compounds obtained are given in Tables 1 and 2.
436

We thank Dr E. Alksnis for the allyl esters of the aryl(hetaryl) carboxylic acids.
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