Novel method for the synthesis of 4-(azol-5-yl)isoxazoles

Full text of DOI:10.1007/s10593-013-1225-1

Chemistry of Heterocyclic Compounds, Vol. 48, No. 12, March, 2013 (Russian Original Vol. 48, No. 12, December, 2012)
NOVEL METHOD FOR THE SYNTHESIS
OF 4-(AZOL-5-YL)ISOXAZOLES
V. A. Bakulev1*, I. V. Efimov1, N. A. Belyaev1, S. S. Zhidovinov1,
Yu. A. Rozin1, N. N. Volkova1, A. A. Khabarova1, and O. S. El'tsov1
Keywords: isothiazoles, isoxazoles, nitrile oxides, oxadiazoles, 1,2,3-thiadiazoles, cycloaddition.
In contrast to monocyclic and condensed isoxazoles, which are widely represented in the scientific and
patent literature, bicyclic assemblies of isoxazoles with other azoles are poorly studied [1, 2]. In particular,
isoxazoles linked to 1,2,3-thiadiazole and isothiazole rings have not been reported in the literature. Current
methods for the preparation of 4-(azol-5-yl)isoxazoles are not numerous and include the construction of either
an azole or an isoxazole ring. The formation of an isoxazole ring through reactions of various derivatives of
1,3-dicarbonyl compounds, -ketoesters, -ketonitriles, and malononitrile derivatives with hydroxylamine has
been used for the preparation of 4-(azol-5-yl)isoxazoles [1]. The cycloaddition reaction of azolylacetylenes to
nitrile oxides [1, 3] represents an alternative way of preparing this type of compound. Despite the good yields,
for the majority of reactions these methods are limited by the poor availability of the starting compounds. The
Suzuki cross-coupling reaction is complex in experimental settings and hence has a limited use for the synthesis
of 4-(azol-5-yl)isoxazoles [4].
Az
Me2NCH(OMe)2
Az Me
N-methyl-
imidazole
NMe2
NMe2
1a–c
5
2a–c
Az
Az
H
O
O
N
4
–Me2NH
N
Dioxane
Cl
3
Ar
Ar
Ar
N+ O
4a,b
6a–c
–HCl
5a–c
Ar
NOH
3а,b
O
Ph
Ph
NC
EtO
N
N
1, 2, 5, 6 a Az =
, b Az =
, c Az =
N
N
N
S
O
S
3–6 a Ar = 2-FC6H4, 3b, 4b, 5b,c 6b,c Ar = 2,6-Cl2C6H3
_______
*To whom correspondence should be addressed, e-mail: vasiliy.bakulev@toslab.com.
1Ural Federal University named after the First President of Russia B. N. Yeltsin, 19 Mira St., Yekaterinburg
620002, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 2002-2005, December, 2012.
Original article submitted September 27, 2012.
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0009-3122/13/4812-1880©2013 Springer Science+Business Media New York

Through systematic studies of the reactions of 3-azolylenamines [5, 6] we have developed a novel,
experimentally simple, and regioselective method for preparing 4-(azol-5-yl)isoxazoles by the reaction of
hydroxamoyl chlorides with 3-azolylenamines. In the case of the derivatives of 1,2,3-thiadiazole, 1,2,4-oxa-
diazole, and isothiazole 1a-c it was found that enamines 2a-c take part in a reaction with the hydroxamoyl
chlorides 3a,b in the absence of bases, to give the bicyclic compounds 6a-c in 60-67% yields.
The mechanism of the reaction can be represented as a [3+2] cycloaddition of enamines 2a-c to the
nitrile oxides 4a,b, which are formed in situ from the hydroxamoyl chlorides 3a,b through elimination of HCl.
In the final stage, aromatization of the intermediate isoxazoline 5a-c occurs with the elimination of
dimethylamine. The proposed mechanism can explain the regioselectivity of the enamine 2a-c reaction with
hydroxamoyl chlorides 3a,b as a result of the most favorable coulomb interaction of atom 3 of the enamine
bearing the negative charge with the positively charged atom at position 3 of the nitrile oxides 4a,b.
It should be noted that the reactions of the 3-azolylenamines with hydroxamoyl chlorides and nitrile
oxides have not been reported in the literature.
1
The structure of the compounds obtained was confirmed from H and 13C NMR, IR and UV
spectroscopy, and from elemental analysis data. The signals for the dimethylamino group of compounds 2b,c
(present in the 1H NMR spectra) were not observed in the 13C NMR spectra due to their low intensity. We have
previously observed a similar effect in the spectra of azolylenamines [5, 6].
IR spectra were recorded on a Bruker Alpha spectrometer (ATR method, ZnSe). 1H NMR and 13C NMR
spectra were recorded on a Bruker Avance II 400 spectrometer (400 and 100 MHz, respectively) using DMSO-d6
with TMS as internal standard. UV spectra were recorded on a Perkin-Elmer Lambda 45 spectrometer using
CH2Cl2. Elemental analysis for C, H, N was performed on a Perkin-Elmer 2400 II automatic analyzer and for
sulfur by titration of sulfate anion after combustion in oxygen. Melting points were recorded on a Stuart SMP 3
apparatus.
Preparation of Enamines 2a-c (General Method). Dimethyl formamide dimethyl acetal (265 l,
2 mmol) and N-methylimidazole (160 l, 2 mmol) were added to compound 1a-c (1 mmol) and heated for 1 h at
80°C. The reaction mixture was concentrated in vacuo, and hexane was added to the residue. The precipitate
that formed was filtered, dried, and recrystallized from EtOH [7].
Ethyl 5-[(E)-2-(dimethylamino)ethenyl]-1,2,3-thiadiazole-4-carboxylate (2a). Yield 0.160 g (71%).
1
Yellow crystals. Mp 114-115°C. The melting point and H NMR spectrum agreed with data given in the
literature [6].
Dimethyl-(E)-2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethenylamine (2b). Yield 0.150 g (70%). Colorless
1
crystals. Mp 79-83°C. H NMR spectrum, , ppm (J, Hz): 3.02 (6Н, br. s, N(CH3)2); 5.02 (1H, d, J = 13.1,
N–CH=СН); 7.38-7.50 (3H, m, Н Ph); 7.67 (1H, d, J = 13.1, N–CH=СН); 7.91-8.01 (2H, m, Н Ph). 13C NMR
spectrum, , ppm: 76.4 (CH); 126.8, 127.5, 128.9, 130.7 (C Ph); 151.2 (CH); 166.8 (C-3); 178.0 (C-5). Found,
%: C 66.92; H 6.19; N 19.57. C12H13N3O. Calculated, %: C 66.96; H 6.09; N 19.52.
5-[(E)-2-(Dimethylamino)ethenyl]-3-phenylisothiazole-4-carbonitrile (2c). Yield 0.176 g (69%).
1
Yellow crystals. Mp 150-152°C. H NMR spectrum, , ppm (J, Hz): 3.00 (6H, s, N(CH3)2); 5.47 (1H, d,
J = 13.1, N–CH=СН); 7.19 (1H, d, J = 13.1, N–CH=СН); 7.38-7.53 (3H, m, H Ph); 7.98 (2H, dd, J = 7.3,
J = 2.0, H Ph). 13C NMR spectrum, , ppm: 85.9 (CH); 97.2 (C-4); 116.3 (CN); 127.5, 128.6, 129.8, 133.5
(C Ph); 147.1 (CH); 167.0 (C-5); 177.3 (C-3). Found, %: C 65.89; H 5.11; N 16.49; S 12.51. C14H13N3S.
Calculated, %: C 65.85; H 5.13; N 16.46; S 12.56.
Ethyl 5-[3-(2-Fluorophenyl)isoxazol-4-yl]-1,2,3-thiadiazole-4-carboxylate (6a). 2-Fluorophenyl-
hydroxamoyl chloride (3a) (0.173 g, 1 mmol) was added to compound 2a (0.227 g, 1 mmol), followed by
absolute dioxane (5 ml), and the mixture was stirred for 12 h. The reaction mixture was concentrated in vacuo,
hexane was added, and the precipitate was filtered off, dried, and recrystallized from EtOH. Yield 0.190 g (60%).
White powder. Mp 110-111°C. IR spectrum, , cm-1: 1721 (С=О). UV spectrum, max, nm (log ): 272 (2.26).
1H NMR spectrum, , ppm (J, Hz): 1.16 (3H, t, J = 7.1, ОСН2CH3); 4.16 (2H, q, J = 7.1, ОCH2CH3); 7.26-7.40 (2Н,
m, H Ar); 7.50-7.66 (2Н, m, Н Ar); 9.64 (1H, s, Н-5). 13C NMR spectrum, , ppm: 13.6 (ОCH2CH3); 61.7
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(ОCH2CH3); 106.8 (C-4); 114.6 (d, JC–F = 14.7, i-C Ar); 116.3 (d, JC–F= 20.5, C-3 Ar); 125.2 (d, JC–F = 2.9, C Ar);
131.2 (d, JC–F = 2.2, C Ar); 133.1 (d, JC–F = 8.1, C-6 Ar); 148.2, 149.6 (C-4,5 thiadiazole); 156.3 (C-3); 158.9 (d,
JC–F = 249.4, C-2 Ar); 159.3 (C=O); 161.2 (C-5). Found, %: С 52.71; Н 3.23; N 13.13; S 10.14. C14H10FN3O3S.
Calculated, %: C 52.66; H 3.16; N 13.16; S 10.04.
5-[3-(2,6-Dichlorophenyl)isoxazol-4-yl]-3-phenyl-1,2,4-oxadiazole (6b) was obtained similarly from
the enamine 2b and 2,6-dichlorophenylhydroxamoyl chloride (3b). Yield 0.239 g (67%). White powder. Mp
1
147-150°C. UV spectrum, max, nm (log ): 243 (2.30). H NMR spectrum, , ppm: 7.44-7.65 (3H, m, H Ar);
7.65-7.80 (3H, m, H Ar); 7.85-7.99 (2H, m, H Ar); 10.32 (1H, s, H-5). 13C NMR spectrum, , ppm: 107.5 (C-4);
125.9, 127.4, 129.0, 129.7, 132.4, 133.7, 135.1 (С Ar); 156.5 (C-5); 164.9 (C-3); 167.8 (C-2,6 Ar); 167.9; 168.5
(C-3,5 oxadiazole). Found, %: С 57.21; Н 2.52; N 11.83. C17H9Cl2N3O2. Calculated, %: C 57.01; H 2.53;
N 11.73.
5-[3-(2,6-Dichlorophenyl)isoxazol-4-yl]-3-phenylisothiazole-4-carbonitrile (6c) was prepared
similarly from the enamine 2c and 2,6-dichlorophenylhydroxamoyl chloride (3b). Yield 0.258 g (65%). White
powder. Mp 164-165°C. IR spectrum, , cm-1: 2220 (C≡N). UV spectrum, max, nm (log ): 262 (2.41). 1H NMR
spectrum, , ppm (J, Hz): 7.52-7.64 (3H, m, H Ar); 7.70-7.84 (3H, m, H Ar); 7.85-7.99 (2H, m, H Ar); 10.08
13
(1H, s, Н-5). C NMR spectrum, , ppm: 109.9 (C-4); 113.6 (CN); 124.4; 127.6; 128.9; 129.1; 130.8; 131.8
(C-4 isothiazole); 134.2; 135.0; 156.1 (C-3); 159.7 (C-5); 162.0 (C-5 isothiazole); 167.3 (C-2,6 Ar); 167.4 (C-3
isothiazole). Found, %: C 57.36; H 2.26; N 10.51; S 8.09. C19H9Cl2N3OS. Calculated, %: C 57.30; H 2.28;
N 10.55; S 8.05.
The authors thank the Russian Foundation for Basic Research (grant 11-03-00579-a) for financial
support.
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