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7. Grunanger, P.; Vita-Finzi, P. Isoxazoles, Part I. In
Chemistry of Heterocyclic Compounds; John Wiley: New
York, 1991; Vol. 49.
dichloromethane (5 mL). After stirring for 24 h at room
temperature, the reaction mixture was diluted with water
and extracted with dichloromethane. The combined
extracts were dried (MgSO4) and concentrated under
reduced pressure. The residue was subjected to flash
chromatography on silica gel (cyclohexane/ethyl acetate:
6/4 to 4/6) to give 660mg (58%) of a mixture of the two
regioisomers 3f and 4f, which could be separated after
another two tedious chromatographies (cyclohexane/ethyl
acetate: 7/3). Cycloadduct 3f: 1H NMR (300 MHz,
CDCl3): d 7.17 (d, 1H, J ¼ 2:1 Hz), 7.13 (dd, 1H,
J ¼ 8:3, 2.1 Hz), 6.81 (d, 1H, J ¼ 8:3 Hz), 6.62 (s, 2H),
5.65 (d, 1H, J ¼ 9:9 Hz), 4.59 (d, 1H, J ¼ 9:9 Hz), 3.84 (s,
9H), 3.81 (s, 3H), 3.41 (q, 2H, J ¼ 7:1 Hz), 3.19 (m, 2H),
1.25 (t, 3H, J ¼ 7:1 Hz), 1.15 (t, 3H, J ¼ 7:1 Hz), 0.99 (s,
9H), 0.14 (s, 6H). Cycloadduct 4f: 1H NMR (300 MHz,
CDCl3): d 7.24 (dd, 1H, J ¼ 8:5, 2.1 Hz), 7.07 (d, 1H,
J ¼ 2:1 Hz), 6.75 (d, 1H, J ¼ 8:5 Hz), 6.46 (s, 2H), 5.54 (d,
1H, J ¼ 5:7 Hz), 5.05 (d, 1H, J ¼ 5:7 Hz), 3.79 (s, 9H),
3.77 (s, 3H), 3.45 (m, 4H), 1.27 (t, 3H, J ¼ 7:0Hz), 1.25 (t,
3H, J ¼ 7:0 Hz), 0.92 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H).
8. (a) Carruthers, W. In Cycloaddition Reactions in Organic
Synthesis. Tetrahedron Organic Chemistry Series; Perg-
amon, 1990; (b) Gothelf, K. V.; Jorgensen, K. A. Chem.
Rev. 1998, 98, 263–269.
9. Grundmann, C. Synthesis 1970, 344–359.
10. Huisgen, R.; Cristl, M. Chem. Ber. 1973, 106, 3345–3367.
11. Lee, G. A. Synthesis 1982, 508–509.
12. Pettit, G. R.; Singh, S. B.; Cragg, G. M. J. Org. Chem.
1985, 50, 3404–3406.
13. Aldehyde 2c and nitrile 2d are commercially available.
Alkyne 2a and olefin 2b were prepared according to
literature methods.14;15 Ethyl cinnamate 2e was obtained
from the corresponding carboxylic acid (EtOH, H2SO4
cat., reflux): mp 68–69 °C; 1H NMR (300 MHz, CDCl3): d
7.60(d, 1H, J ¼ 15:9 Hz), 6.75 (s, 2H), 6.35 (d, 1H,
J ¼ 15:9 Hz), 4.26 (q, 2H, J ¼ 7:1 Hz), 3.88 (s, 9H), 1.34
(t, 3H, J ¼ 7:1 Hz). Cinnamide 2f was obtained by
treatment with diethylamine (2 equiv, toluene, rt, 1 h) of
3,4,5-trimethoxycinnamic chloride prepared from the cor-
responding acid and oxalic chloride (1.1 equiv, toluene,
€
20. Bianchi, G.; De Micheli, C.; Gandolfi, R.; Grunanger, P.;
Vita Finzi, P. J. Chem. Soc., Perkin Trans. 1 1973, 1148–
1155.
21. So, for amide derivatives spacing, Dd5;4 is larger for isomer
3f (1.06) than for isomer 4f (0.49).
22. All the deprotected cycloadducts give satisfactory elemen-
tal analyses, 1H, 13C NMR and mass data. Assessment
of their ability to inhibit in vitro polymerization is now
under investigation.
1
reflux, 3 h): mp 132–134 °C; H NMR (300 MHz, CDCl3):
d 7.62 (d, 1H, J ¼ 15:3 Hz), 6.73 (s, 2H), 6.70(d, 1H,
J ¼ 15:3 Hz), 3.89 (s, 6H), 3.87 (s, 3H), 3.49 (q, 4H,
J ¼ 7:1 Hz), 1.23 (br s, 6H).
14. Lawrence, N. J.; Ghani, F. A.; Hepworth, L. A.; Hadfield,
J. A.; McGown, A. T.; Pritchard, R. G. Synthesis 1999, 9,
1656–1660.
15. Ramacciotti, A.; Fiaschi, R.; Napolitano, E. Tetrahedron:
Asymmetry 1996, 7, 1101–1104.
16. Houk, K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. J. Am.
Chem. Soc. 1973, 95, 7301–7315.
17. Syassi, B.; Bougrin, K.; Soufiaoui, M. Tetrahedron Lett.
1997, 38, 8855–8858.
18. Weidner-Wells, M. A.; Fraga-Spano, S. A.; Turchi, I. J.
J. Org. Chem. 1998, 63, 6319–6328.
23. Cycloadditions were also attempted with the 1,3-dipole
entity having the phenolic group protected as a 4-
methoxybenzyl (PMB).24 With both dipolarophiles inves-
tigated, 2a and 2d, coupling was slightly more efficient
(respective yields: 46% vs 38%, 11% vs 6%), probably due
to a lesser steric hindrance. But the deprotecting step,
realized with trifluoroacetic acid, was less effective. At last
protection of the phenol function with a silyl group seems
more effective.
19. Typical procedure for the cycloadditions: Oxime
7
(562 mg, 2.0mmol) in dichloromethane (2 mL) at 0 °C
was dropwise added, in 1 h, to a mixture of amide 2f
(587 mg, 2.0mmol), triethylamine (28 lL, 0.2 mmol) and
13% aqueous sodium hypochlorite (1.9 mL, 3.2 mmol) in
24. Vlahov, R.; Krikorian, D.; Spassov, G.; Chinova, M.;
Vlahov, I.; Parushev, S.; Snatzke, G.; Ernst, L.; Kieslich,
K.; Abraham, W.-R.; Sheldrick, W. S. Tetrahedron 1989,
45, 3329–3345.