M0047

Molecules 1998, 3, M47

**Ethyl-(R,S)-5-acetyl-4,5-dihydro-3-isoxazole Acetate**

Pier Giovanni Baraldi*, Barbara Cacciari, Romeo Romagnoli and Giampiero Spalluto

Department of Pharmaceutical Sciences, University of Ferrara, Via Fossato di Mortara 17-19, I-44100 Ferrara, Italy
Tel. 0039-(0)532-291293, Fax 0039-(0)532-291296 ([email protected] or [email protected])

Received: 3 February 1998 / Published: 18 February 1998

The isoxazoline 3 was prepared by the [3+2] cycloaddition of the nitroderivative 1 [1] with methyl vinyl ketone 2 under Mukaiyama conditions [2].

Phenyl isocyanate (2.5 ml, 23 mmol) was slowly added (4 h) to a mixture of ethyl-nitropropionate 1 (1.46 g, 10 mmol) and methyl vinyl ketone 2 (1.6 ml, 20 mmol) in dry benzene (60 ml) containing a few drops of Et₃N. The mixture was stirred at room temperature for two days. The suspension was filtered to eliminate the precipitate of diphenylurea and to the filtrate was added H₂O (100 ml). The resulting biphasic system was stirred for two hours at room temperature. After separation, the organic phase was dried and concentrated in vacuo. The crude residue was purified by flash chromatography (ether/light petroleum = 7:3) to give the desired compound 3 as a yellow oil (1 g, 50%).

TLC (ether/light petroleum = 6:4) R_f 0.42

IR (neat, cm^-1): 2985, 1737, 1722, 1599, 1555, 1503, 1444, 1400, 1381, 1260, 1203, 1096, 1027.

¹HNMR (CDCl₃) d: 4.9 (dd, 1H, J = 9.4 Hz, 4.2 Hz, CH₂CHO); 4.18 (q, 2H, J = 7.2 Hz, CO₂CH₂CH₃); 3.07 (dd, 1H, J = 17.2 Hz, J = 9.4 Hz, CHHCHO); 2.76 (dd, 1H, J = 17.2 Hz, 4.2 Hz, CHHCHO); 2.54 (d, 2H, J = 7 Hz, CH₂CO₂); 2.17 (s, 3H, COCH₃); 1.25 (t, 3H, J = 7.2 Hz, CO₂CH₂CH₃)

Anal. calc. for C₉H₁₃NO₄ (199.20): C 54.26, H 6.58, N 7.03; found: C 54.61, H 6.65, N 7.10

Acknowledgment: We gratefully acknowledge the Ministero Pubblica Istruzione (Grant 40% and 60%) for their generous support.

References

1. Taylor, M. D.; Badger, E. W.; Steffen, R. P.; Haleen, S. J.; Pugsley, T. A.; Shih, Y. H.; Weishaar, R. E. 2-(2-Aryl-2-oxoethylidene)-1,2,3,4-tetrahydropyridines. Novel isomers of 1,4-dihyropyridine calcium channel blockers. J. Med. Chem. 1988, 31, 1659.
2. Mukaiyama, T.; Hoshino, T. The reactions of primary nitro paraffins with isocyanates. J. Am. Chem. Soc. 1960, 82, 5339.
3. Baraldi, P. G.; Bigoni, A.; Cacciari, B.; Caldari, C.; Manfredini, S.; Spalluto, G. Nitrile oxide [3+2] cycloaddition: application to the synthesis of 6-substituted 3(2H)- pyridazinones and 6- substituted 4,5-Dihydro-4-hydroxy-3 (2H)-pyridazinones. Synthesis 1994, 11, 1158.

Sample availability: Available from the authors.