Synthesis of isoxazolinylxanthines

Article abstract of DOI:10.1007/s10593-007-0031-z

1-[5-(3-Arylisoxazolin-2-yl)methyl]-3,7-dimethylxanthines have been synthesized by the [2+3] cycloaddition of arylnitrile oxides to allyltheobromine. 7-{5-[3-(2,4-Dichlorophenyl)isoxazolin-2-yl]methyl}-1,3- dimethylxanthine was obtained by the addition of

Full text of DOI:10.1007/s10593-007-0031-z

Chemistry of Heterocyclic Compounds, Vol. 43, No. 2, 2007
SYNTHESIS OF ISOXAZOLINYLXANTHINES
V. Dirnens, I. Skrastina, J. Popelis, and E. Lukevics
1-[5-(3-Arylisoxazolin-2-yl)methyl]-3,7-dimethylxanthines have been synthesized by the [2+3]
cycloaddition of arylnitrile oxides to allyltheobromine. 7-{5-[3-(2,4-Dichlorophenyl)isoxazolin-
2-yl]methyl}-1,3-dimethylxanthine was obtained by the addition of 2,4-dichlorobenzonitrile oxide to
allyltheobromine. The addition of arylnitrile oxides to structural isomers of methylxanthines proceeds
regioselectively with the formation of 3,5-disubstituted isoxazolines.
Keywords: allyltheobromine, allyltheophylline, arylnitrile oxides, isoxazoline.
Methylxanthines (theobromine, theophylline, caffeine) are a group of alkaloids possessing
bronchodilating and lung stimulating action. Fits of uncontrolled coughing are the usual symptoms of colds,
allergic reactions, and asthma. Up to the present time the most widespread agent against coughing is codeine
(methylmorphine), having a limited spectrum of application due to its narcotic action. More recent investigation
has shown that 3,7-dimethylxanthine (3,7-dimethyl-2,6-dioxo-3,7-dihydro-1H-purine, theobromine) is a more
effective agent, not possessing the side reactions of codeine (fatigue and the risk of dependence) [1].
Consequently 3,7-dimethylxanthine is a promising compound for the synthesis of new agents against fits of
uncontrolled coughing.
The isoxazoline heterocycle is also a valuable synthon for obtaining β-hydroxy ketones [2-7], γ-amino
alcohols [8-10], α,β-unsaturated oximes [11, 12], and β-hydroxy nitriles [13], and its introduction into the
dioxopurine molecule enables broadening of the range of synthetic derivatives of theobromine and caffeine.
Compounds containing an isoxazoline fragment in the molecule also possess pharmacological activity [14-22].
The isoxazoline ring is synthesized by two routes differing in principle. These are the cycloaddition of
nitrile oxides and silyl esters of a nitronic acid to an alkene or by conversion of ketone derivatives under the
action of hydroxylamine. β-Chloro ketones, α,β-unsaturated ketones, and quaternary salts of Mannich bases [23]
serve as starting materials in the latter reaction. The reaction is strongly dependent on pH, on the ketone:
O
Me
+
N
O
–
Me
R
C
O
CH2
N
N
H2C=CHCH2
N
2a–f
N
O
N
O
N
R
N
N
O
N
Me
1
Me
3a–f
2, 3 a R = Ph, b R = 4-BrC6H4, c R = 2-ClC6H4, d R = 4-Me2NC6H4, e R = 2,4-Cl2C6H3,
f R = 3,4-(MeO)2C6H3
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: dirnens@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii. No. 2, pp. 245-248, February, 2007. Original article submitted December 2,
2006.
0009-3122/07/4302-0193©2007 Springer Science+Business Media, Inc.
193

hydroxylamine ratio, and also on the substituents. Consequently a series of side products are formed in it, viz.
oximes, dihydroxyamino ketones, hydroxyamino oximes, disubstituted hydroxylamines, dioximes, and
isoxazoles. Due to this the yield of the desired compound is frequently far less than in the cycloaddition reaction.
While continuing investigations on the synthesis of compounds in which a –CH2– bridge is found
between the nitrogen atom of the heterocycle and the isoxazoline ring, we have carried out a [2+3] cycloaddition
of nitrile oxides 2a-f, generated from hydroxamic chlorides in the presence of triethylamine, to
N-allyltheobromine 1.
O
CH2
Me
O
N
N
N
Cl
O
N
N
Cl
Me
5
The corresponding 7-{5-[3-(2,4-dichlorophenyl)isoxazolin-2-yl]methyl}-1,3-dimethylxanthine 5 was
obtained by the addition of 2,4-dichlorobenzonitrile oxide 4 to allyltheophylline.
The reaction was carried out in `one-pot’ sequentially: 1) conversion of arylaldoxime by the action of
N-chlorosuccinimide in chloroform to the corresponding hydroxamic chloride; 2) addition of the unsaturated
compound; 3) addition of triethylamine as the dehydrohalogenating agent to generate the nitrile oxide. The
yields of products 3a-f, 5 were 50-83%.
1
According to the data of H NMR spectra (Table 2) the cycloaddition reaction in both cases proceeds
regiospecifically with the formation of 5-heterylmethyl-substituted isoxazolines.
TABLE 1. Physicochemical Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp*, °С
Yield, %
C
H
N
3a
3b
3c
3d
3e
3f
5
C17H17N5O3
60.26
60.17
47.78
48.82
54.80
54.62
59.33
59.67
49.98
50.02
57.12
57.14
50.18
50.02
5.01
5.05
3.80
3.86
4.20
4.31
5.78
5.80
3.68
3.70
5.26
5.30
3.65
3.70
20.61
20.64
16.80
16.74
18.32
18.74
22.06
21.98
17.12
17.15
17.56
17.53
17.18
17.15
186.5
185
163
233
184
217
197
83
74
74
59
50
77
57
C17H16BrN5O3
C17H16ClN5O3
C19H22N6O3
C17H15Cl2N5O3
C19H21N5O5
C17H15Cl2N5O3
_______
*Ethanol was the solvent for crystallization.
194

TABLE 2. 1H NMR Spectra of Isoxazoline-containing Xanthines 3a-f and 5
O
O
Me
N
HA
N
HA
N
HB
HC
HB
HC
CH2
Me
O
CH2
N
N
N
N
O
O
R
R
N
N
N
O
Me
Me
5
3a–f
Com-
pound
Chemical shifts, δ, ppm (SSCS, J, Hz)
3.25 (1H, dd, J = 7.0, J = 15.9, CHC); 3.47 (1H, dd, J = 9.6, J = 15.9, CHB);
3a
3.54 (3H, s, CH3); 3.96 (3H, s, CH3); 4.09 (1H, dd, J = 5.6, J = 13.1, CH); 4.47 (1H, dd,
J = 6.6, J = 13.1, CH); 5.03-5.38 (1H, m, CHA); 7.36-7.47 (3H, m, Harom.);
7.52 (1H, s, N=CH); 7.63−7.78 (2H, m, Harom.
)
3b
3c
3.18 (1H, dd, J = 6.8, J = 15.4, CHC); 3.43 (1H, dd, J = 9.8, J = 15.4, CHB);
3.52 (3H, s, CH3); 3.89 (3H, s, CH3); 4.03 (1H, dd, J = 5.4, J = 13.1, CH); 4.41 (1H, dd,
J = 7.2, J = 13.1, CH); 4.98-5.32 (1H, m, CHA); 7.43 (4H, с, Harom.); 7.49 (1H, s, N=CH)
3.34 (1H, dd, J = 6.2, J = 16.2, CHC); 3.58 (3H, s, CH3); 3.65 (1H, dd, J = 9.2, J = 16.2,
CHB); 3.98 (3H, s, CH3); 4.07 (1H, dd, J = 5.4, J = 13.1, CH); 4.52 (1H, dd, J = 7.1,
J = 13.1, CH); 5.05-5.33 (1H, m, CHA); 7.18-7.27 (1H, m, Harom.);
7.29-7.43 (1H, m, Harom.); 7.47 (1H, s, N=CH); 7.56-7.72 (1H, m, Harom.
)
3d
3e
3f
2.96 (6H, s, 2CH3); 3.14 (1H, dd, J = 4.6, J = 16.4, CHC); 3.41 (1H, dd, J = 7.1, J = 16.4,
CHB); 3.47 (3H, s, CH3); 3.96 (3H, s, CH3); 3.98 (1H, dd, J = 5.2, J = 12.8, CH);
4.43 (1H, dd, J = 7.4, J = 12.8, CH); 4.92-5.23 (1H, m, CHA); 6.67 (2H, d, J = 8.6, Harom.);
7.45 (1H, s, N=CH); 7.47 (2H, d, J = 8.6, Harom.
)
3.32 (1H, dd, J = 6.4, J = 16.8, CHC); 3.58 (3H, s, CH3); 3.61 (1H, dd, J = 9.4, J = 16.8,
CHB); 3.93 (3H, s, CH3); 4.05 (1H, dd, J = 5.4, J = 13.1, CH); 4.47 (1H, dd, J = 7.2,
J = 13.1, CH); 5.05-5.38 (1H, m, CHA); 7.25 (1H, dd, J = 2.4, J = 8.2, Harom.);
7.43 (1H, d, J = 2.4, Harom.), 7.47 (1H, s, N=CH); 7.63 (1H, d, J = 8.2, Harom.
)
3.18 (1H, dd, J = 4.6, J = 14.8, CHC); 3.47 (1H, dd, J = 8.4, J = 14.8, CHB);
3.58 (3H, s, CH3); 3.92 (6H, s, 2CH3); 4.01 (3H, s, CH3); 4.02 (1H, dd, J = 4.8, J = 13.4,
CH); 4.47 (1H, dd, J = 7.2, J = 13.4, CH); 4.98-5.32 (1H, m, CHA); 6.81 (1H, d, J = 8.1,
Harom.); 7.01 (1H, dd, J = 1.5, J = 8.1, Harom.), 7.41 (1H, d, J = 1.5, Harom.),
7.52 (1H, s, N=CH)
5
3.32 (1H, dd, J = 6.6, J = 17.4, CHC); 3.33 (3H, s, CH3); 3.54 (3H, s, CH3);
3.67 (1H, dd, J = 9.8, J = 17.4, CHB); 4.45 (1H, dd, J = 6.4, J = 13.4, CH); 4.67 (1H, dd,
J = 3.6, J = 13.4, CH); 5.03-5.34 (1H, m, CHA); 7.23 (1H, dd, J = 2.2, J = 8.4, Harom.);
7.41 (1H, s, N=CH); 7.45 (1H, d, J = 8.4, Harom.), 7.72 (1H, s, Harom.
)
EXPERIMENTAL
1
The H NMR spectra of compounds 3a-f, 5 were recorded on a Bruker WR 90 (90 MHz) instrument in
CDCl3, internal standard was TMS.
The general procedure for obtaining isoxazolines 3a-f, 5 is described in [25], the characteristics of the
compounds obtained are given in Tables 1 and 2.
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