E. Rajanarendar et al. / Tetrahedron Letters 47 (2006) 4957–4959
4959
oxide (2.5 ml) were added whilst maintaining the reaction
at ꢀ25 °C. The reaction mixture was stirred at this
temperature for 24 h. It was then filtered and cooled to
ꢀ10 °C, and L-tartaric acid (1.5 g in 15 ml of H2O) was
added and the reaction stirred for 1 h. The precipitate
formed was removed by filtration and the organic layer
cooled to ꢀ10 °C, and 10% NaOH solution (6 g in 25 ml
of H2O) saturated with NaCl was added and stirring
continued for 1 h. The separated organic layer was washed
with H2O, dried over Na2SO4 and concentrated under
reduced pressure. The crude product was purified
by column chromatography by elution with ethyl
acetate/hexane (1:10). Compound 4a, mp 156–158 °C; IR
cmꢀ1; 3250 (s), 1600, 980, 1H NMR (300 MHz, CDCl3)
d 2.52 (s, 3H, CH3), 7.40–7.62 (m, 5H, Ar–H), 7.76 (s, 1H,
C6–H), 7.85 (s, 1H, NH, D2O exchangeable). MS (EI): m/z
198 (M+). 13C NMR (75 MHz): d 12.5 (C-7), 100.2 (C-30),
110.4 (C-6), 128.5 (Ar–C), 129.4 (C-5), 130.2 (Ar–C), 132.8
(Ar–C), 136.3 (Ar–C), 143.2 (C-3), 152.4 (C-60). Com-
pound 4b, mp 143–149 °C, IR cmꢀ1; 3300 (s), 1610, 975,
1H NMR (300 MHz, CDCl3): d 2.42 (s, 3H, CH3), 2.80 (s,
3H, CH3), 7.29–7.50 (m, 4H, ArH), 7.81 (s, 1H, C6–H),
7.93 (s, 1H, NH, D2O exchangeable); MS (EI): m/z 212
(M+). 13C NMR (75 MHz): d 11.3 (C-7), 21.1 (Ar–CH3),
100.1 (C-30), 112.6 (C-6); 127.3 (Ar–C), 128.5 (C-5), 130.0
(Ar–C), 133.1 (Ar–C), 137.8 (Ar–C), 145.5 (C-3), 156.0 (C-
60).
strategy permits the introduction of a diverse array of
substituents onto the benzene ring. To the best of our
knowledge, this report is the first of its kind to construct
a pyrrole ring employing a Sharpless epoxidation
process.
When epoxidation of 1 was carried out with m-chloro-
perbenzoic acid or hydrogen peroxide, the reaction
resulted only in the formation of epoxide 210 (Scheme
2). Hence, the one-pot synthesis of pyrrolo[2,3-d]-isox-
azoles 4 could only be achieved under Sharpless epox-
idation conditions.
The synthesis of pyrrolo[2,3-d]-isoxazoles 4 could also
be accomplished by adopting a different methodology.
3,5-Dimethyl-4-aminoisoxazole 5 was benzoylated by
treatment with an aromatic acid chloride in dichloro-
methane11 (Table 2). The resulting benzamide 6 was sub-
jected to cyclization to give the title compounds 4 by
reaction with anhydrous potassium carbonate and dry
acetone in the presence of the phase transfer catalyst tri-
ethylbenzylammonium chloride (TEBA)12 (Scheme 3).
The products obtained were found to be the same as
those prepared via the Sharpless epoxidation process
1
from mps., H NMR, 13C NMR and mass spectra.
10. 3-Methyl-5-(3-phenyl-oxiranyl)-isoxazol-4-yl amine 2. A
mixture of 4-amino-3-methyl-5-styryl isoxazole (0.1 mol)
and m-chloroperbenzoic acid (0.1 mol) in dichlorometh-
ane (20 ml) was stirred at room temperature for 6 h. The
precipitated m-chlorobenzoic acid was filtered off and the
filtrate washed with 10% aq NaHCO3 solution. Dichloro-
methane was evaporated to give the crude product, which
was purified by column chromatography by elution with
benzene. 2 (Ar = Ph), mp 115–118 °C, IR cmꢀ1; 3350 (s),
1120 (s); 1H NMR (300 MHz CDCl3): d 2.35 (s, 3H, CH3),
3.82 (br s, 1H, NH), 5.10 (d, 1H, J = 7 Hz, –CH), 5.33 (d,
1H, J = 7 Hz, CH), 7.20–7.81 (m, 5H, ArH); MS (EI): m/z
216 (M+).
Acknowledgements
The authors are thankful to the Head of the Department
of Chemistry, Kakatiya University, Warangal, for facil-
ities and to Professor G. L. David Krupadanam, Profes-
sor of Chemistry, Osmania University, for useful
discussions.
References and notes
11. N-(3,5-dimethyl-4-isoxazole) benzamide 6. 3,5-Dimethyl-
4-amino isoxazole (0.1 mol) was dissolved in 20 ml of
dichloromethane, and benzoyl chloride (0.1 mol) was
added dropwise with stirring and the reaction continued
at room temperature for 1 h. The solid obtained on
cooling was filtered and recrystallized from ethanol. 6
(Ar = Ph), mp 181–183 °C; IR cmꢀ1, 3525 (s), 1685 (s), 1H
NMR (300 MHz, CDCl3): d 2.22 (s, 3H, CH3), 2.43 (s, 3H,
CH3), 7.62–8.01 (m, 5H, ArH), 9.80 (br s, 1H, NH, D2O
exchangeable); MS (EI): m/z 216 (M+).
1. Sudberg, R. J. Org. Chem. 1965, 30, 3604.
2. Paparao, C.; Venkateshwar Rao, K.; Sundaramurthy, V.
Synthesis 1981, 3, 234; Mali, R. S.; Yadav, V. J. Synthesis
1984, 862.
3. Coda, A. C.; Desimoni, G.; Coda, A. Heterocycles 1985,
23, 1893.
4. Stefanachi, A.; Leonetti, F.; Cappa, A.; Carothi, A.
Tetrahedron Lett. 2003, 44, 2121.
12. 3-Methyl-5-phenyl-4H-pyrrolo[2,3-d]-isoxazole 4a. To a
magnetically stirred mixture of benzamide 6, and anhy-
drous K2CO3 (6 equiv) and dry acetone (20 ml), triethyl-
benzyl-ammonium chloride (0.05 mol) was added and the
reaction mixture was stirred at reflux for 48 h. After
completion of the reaction, it was cooled and K2CO3 was
removed by filtration. The organic layer was distilled
under reduced pressure. The residue obtained was dis-
solved in ethyl acetate and washed with water, brine and
dried over MgSO4. The solvent was distilled under
vacuum to give a crude product, which was purified by
column chromatography by elution with ethyl acetate/
hexane (1:10).
5. Rajanarendar, E.; Srinivas, M.; Ramu, K. Synth. Com-
mun. 2003, 33, 3077.
6. Rajanarendar, E.; Ramu, K.; Karunakar, D.; Ramesh, P.
J. Heterocycl. Chem. 2005, 42, 711.
7. Rajanarendar, E.; Srinivas, M.; Karunakar, D.; Ramu, K.
Heterocycl. Commun. 2005, 11, 441.
8. Rajanarendar, E.; Ramesh, P.; Srinivas, M.; Mohan, G.;
Ramu, K. Synth. Commun. 2006, 36, 665.
9. 3-Methyl-5-aryl-4H-pyrrolo[2,3-d]-isoxazole 4. To a solu-
tion of (ꢀ)-diethyl tartarate (20 ml) in dichloromethane
(50 ml) at ꢀ25 °C, titanium tetraisopropoxide (7.5 ml) was
added and the contents stirred for 1 h. To this, 3-methyl-4-
amino-5-styrylisoxazole (100 mg) and tert-butyl hydroper-