Acetonitrile N-Oxide1

[7063-95-8]  · C2H3NO  · Acetonitrile N-Oxide  · (MW 57.05)

(reactive 1,3-dipolar reagent useful for [3 + 2] cycloadditions,2 isoxazolines (intermediates useful for natural product synthesis),3 isoxazoles,4 heterocycle synthesis5)

Physical Data: reactive intermediate generated in situ.

Solubility: sol petroleum ether, ether, benzene, dichloromethane, ethanol, chloroform; insol cold (-60 °C) petroleum ether.

Analysis of Reagent Purity: spectroscopic data have been recorded at low temperature:6,7 NMR (-40 °C) 1H: CH3 (d 2.26); 13C: CH3 (d 0.8), CN (d 35.6); IR (EtOH), 2315 cm-1.

Preparative Methods: the reagent is most commonly generated in situ from Nitroethane by treatment with Phenyl Isocyanate/Triethylamine at rt (the Mukiayama method).8 Other reagents (AcCl, Ac2O, or POCl39) may be used in place of PhNCO. Acetonitrile oxide may be generated by flash vacuum pyrolysis (FVP) of 3,4-dimethylfuroxan,6,10 by hypochlorite oxidation of acetaldehyde oxime,4b or from acetohydroxamoyl chloride.7 Decomposition (mainly dimerization to 3,4-dimethylfuroxan) is reported1b to take place within minutes of generation at 18 °C (however, see Brandi7).

1,3-Dipolar Cycloaddition.

Isoxazolines from cycloaddition of acetonitrile oxide to alkenes (eqs 1 and 2)11,12 are often used intermediates for synthesis of natural products.3,13 For example, isoxazolines may be elaborated into a,b-unsaturated carbonyl compounds,14 1,3-amino alcohols,15 3-hydroxycarbonyl compounds16 (and 2-alkylated or 2-hydroxylated derivatives),17 and pyrroles.18

The regioselectivity2 and diastereoselectivity12,19 of the cycloaddition of nitrile oxides to alkenes has been reviewed. Optically active isoxazolines are formed from acryloyl derivatives bearing bornyl,8b cyclitols,20 or sultams21 as chiral auxiliaries.

Alkynes produce isoxazoles (eqs 3 and 4),4 whereas other unsaturated substrates yield a variety of heterocycles (e.g. thioesters -> 1,4,2-oxathiazolines,5 imines -> 1,2,4-oxadiazolines,22 and isothiocyanates -> imino-1,4,2-oxathiazoles23).

Related Reagents.

Triphenylacetonitrile N-Oxide.


1. (a) Grundmann, C. ACR 1970, 3, 344. (b) Grundmann, C.; Gruenanger, P. The Nitrile Oxides; Springer: Berlin, 1971. (c) Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis; Feuer, H., Ed.; VCH: New York, 1988. (d) Advances in Cycloaddition; Curran, D. P., Ed.; JAI: London, 1988; Vol. 1, pp 129-189.
2. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1, pp 337-344.
3. Kozikowski, A. ACR 1984, 17, 410.
4. (a) Kondo, Y.; Uchiyama, D.; Sakamoto, T.; Yamanaka, H. TL 1989, 30, 4249. (b) Theobald, H. Ger. Patent 2 754 832 (CA 1979, 91, 140 372b).
5. (a) Yung, T. W. K.; Sammes, M. P. TL 1991, 32, 4329. (b) Huisgen, R.; Mack, W. CB 1972, 105, 2815.
6. Mitchell, W. R.; Paton, R. M. TL 1979, 2443.
7. Brandi, A.; DeSarlo, F.; Guarna, A. JCS(P1) 1976, 1827.
8. (a) Mukaiyama, T.; Hoshino, T. JACS 1960, 82, 5339. (b) Olsson, T.; Stern, K.; Sundell, S. JOC 1988, 53, 2468.
9. Kashima, C.; Tsuzuki, A.; Tajima, T. JHC 1984, 21, 201.
10. Cunico, R. F.; Bedell, L. JOM 1985, 281, 135. (b) Cunico, R. F.; Bedell, L. JOC 1983, 48, 2780.
11. Curran, D. P.; Singleton, D. H. TL 1983, 24, 2079.
12. Armstrong, S. K.; Warren, S.; Collington, E. W.; Naylor, A. TL 1991, 32, 4171.
13. Jaeger, V.; Mueller, I.; Schohe, R.; Frey, M.; Ehrler, R.; Haefele, B.; Schroeter, D. Lect. Heterocycl. Chem., 1985, 8, 79.
14. Grund, H.; Jager, V. LA 1980, 80.
15. (a) Lathbury, D. C.; Parsons, P. J. CC 1982, 291. (b) Jager, V.; Buss, V.; Schwab, W. LA 1980, 122.
16. Kozikowski, A. P.; Adamczyk, M. TL 1982, 23, 3123. (b) Curran, D. P. JACS 1982, 104, 4024.
17. Jager, V.; Schwab, W. AG(E) 1981, 20, 603.
18. Mukerji, S. K.; Sharma, K. K.; Torsell, K. B. G. T 1983, 39, 2231.
19. (a) LeGall, T.; Lellouche, J. P.; Toupet, L.; Beaucourt, J. P. TL 1989, 30, 6517. (b) Kozikowski, A. P.; Ghosh, A. K. JOC 1984, 49, 2762. (c) Kozikowski, A. P.; Ghosh, A. K. JACS 1982, 104, 5788.
20. Akiyama, T.; Okada, K.; Ozaki, S. TL 1992, 33, 5763.
21. Oppolzer, W.; Kingma, A. J.; Pillai, S. K. TL 1991, 32, 4893.
22. Aitken, R. A.; Raut, S. V. SL 1991, 189.
23. Borsus, J. M.; L'Abbe, G.; Smets, G. T 1975, 31, 1537.

Dallas K. Bates

Michigan Technological University, Houghton, MI, USA



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