[593-77-1]  · CH5NO  · N-Methylhydroxylamine  · (MW 47.07) (.HCl)

[4229-44-1]  · CH6ClNO  · N-Methylhydroxylamine Hydrochloride  · (MW 83.53)

(ambident nucleophile; reagent for the preparation of N-methyl nitrones from aldehydes and ketones, of N-methylhydroxamic acids from carboxylic acids and related functional groups, and of heterocyclic compounds)

Physical Data: mp 38.5 °C; bp 115 °C, 60-63 °C/20 mmHg;n20D 1.4164. HCl salt: mp 88-90 °C.

Solubility: very sol H2O, methanol, ethanol; sparingly sol diethyl ether. HCl salt: sol H2O, ethanol.

Form Supplied in: widely available as the HCl salt, a clear-to-white solid (hygroscopic).

Preparative Methods: usually prepared in solution form by treatment of the HCl salt with a suitable base; used directly upon preparation as it gradually decomposes upon standing.

Handling, Storage, and Precautions: the HCl salt is a possible irritant; avoid skin and eye contact, avoid inhaling particles. The salt is hygroscopic and must be protected from moisture during storage.

Formation and Reactions of Nitrones.

The condensation of N-methylhydroxylamine with aldehydes and ketones leads readily to the formation of N-methyl nitrones. In some cases, such as N-methyl-C-phenyl nitrone, the condensation product can be isolated and characterized prior to subsequent reactions; the more usual practice, however, is the in situ generation of nitrones as a prelude to subsequent cycloaddition reactions,1 the most common of the reactions of nitrones. N-Methyl nitrones have been shown to undergo cycloadditions with mono-, di-, and trisubstituted alkenes as well as mono- and disubstituted alkynes. Consistent with FMO theory, N-methyl-C-phenyl nitrone gives 5-substituted isoxazolidines with monosubstituted alkenes such as 1-hexene and styrene; however, strongly electron-withdrawing substituents alter the cycloaddition regiochemistry.2 Methyl acrylate and phenyl vinyl sulfone give mixtures of cycloadducts, while nitroethylene gives only the 4-substituted isoxazolidine.

Intramolecular cycloadditions of N-methyl nitrones (eq 1) have been extensively studied since the 1960s.3 The influence of a number of factors (e.g. length of chain connecting alkene and nitrone, type of atoms in the connecting chain, presence of chiral centers, alkene geometry) on the regiochemistry and stereochemistry have been reported.1 Fused polycyclic ring systems are often obtained, while in selected cases bridged cycloadducts are found. In one case a reverse Cope elimination reaction has been observed in competion with N-methyl nitrone formation and cycloaddition.4 There are a number of examples of natural product total synthesis, including (+)-chanoclavine I,5 (-)-bisabolol,6 and hirsutene,7 in which intramolecular N-methyl nitrone cycloadditions have been utilized.

In addition to [3 + 2] cycloaddition reactions, N-methyl nitrones can also be used as precursors to vinylnitrosonium cations for [4 + 2] cycloadditions.8

Additional reagents derived from N-methylhydroxylamine are described in the literature for the preparation of nitrones. These include N-methylhydroxylamine-O-sulfonic acid,9 which has been shown to react with imines to afford nitrones, and N-methyl-N,O-bis(trimethylsilyl)hydroxylamine,10 which allows formation and cycloaddition of nitrones under nonbasic, aprotic conditions.

Other Reactions.

Carboxylic acids and related functional groups are readily converted to N-methylhydroxamic acids through N-acylation (eq 2).11

If N-methylhydroxylammonium chloride is acylated under nonbasic conditions, however, O-alkanoylhydroxylamines are obtained as the O-acylation product.12 a,b-Unsaturated compounds readily undergo conjugate addition, giving b-amino-N-hydroxy-N-methylcarboxylate esters which cyclize in the presence of base to isoxazolidin-5-ones (eq 3).13 Unsaturated sugar lactones also give isoxazolidin-5-ones,14 while sugar enolones give the simple conjugate addition product.15 Interestingly, when N-methylhydroxylamine is slowly generated in the presence of both aqueous formaldehyde and an unsaturated carbonyl compound, the preferred reaction is formation of N-methyl nitrone followed by cycloaddition to the unsaturated carbonyl compound (eq 4).16 Isoxazolidin-5-ones are also readily prepared by the Reformatsky reaction of purified nitrones, such as N-methyl-C-phenyl nitrone, with a-bromo esters in the presence of zinc.17

1. (a) Confalone, P. N.; Huie, E. M. OR 1989, 36, 1. (b) Tufariello, J. J. 1,3-Dipolar Cycloaddition Chemistry, Padwa, A. Ed.; Wiley: New York, 1984; Vol. 2, pp 83-168. (c) Padwa, A. 1,3-Dipolar Cycloaddition Chemistry, Wiley: New York, 1984; Vol. 2, pp 279-303. (d) Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L. G 1989, 119, 253. (e) Black, D. S. C.; Crozier, R. F.; Davis, V. C. S 1975, 205.
2. (a) Huisgen, R.; Grashey, R.; Hauck, H.; Seidl, H. CB 1968, 101, 2043. (b) Houk, K.; Bimanand, A.; Mukherjee, D.; Sims, J.; Chang, Y.-M.; Kaufman, D.; Domelsmith, L. H 1977, 7, 293. (c) Padwa, A.; Fisera, L.; Koehler, K. F.; Rodriguez, A.; Wong, G. S. JOC 1984, 49, 276.
3. LeBel, N. A.; Hwang, D. OSC 1988, 6, 620.
4. Ciganek, E. JOC 1990, 55, 3007.
5. Oppolzer, W.; Grayson, J. I. HCA 1980, 63, 1706.
6. (a) Iwashita, T.; Kusumi, T.; Kakisawa, H. CL 1979, 947. (b) Schwartz, M. A.; Swanson, G. C. JOC, 1979, 44, 953.
7. Funk, R. L.; Bolton, G. L. JOC 1984, 49, 5021.
8. Denmark, S. E.; Cramer, C. J.; Dappen, M. S. JOC 1987, 52, 877.
9. Abou-Gharbia, M.; Jouillié, M. M. S 1977, 318.
10. Hwu, J. R.; Robl, J. A.; Wang, N.; Anderson, D. A.; Ku, J.; Chen, E. JCS(P1) 1989, 1823.
11. For example see: Summers, J. B.; Gunn, B. P.; Mazdiyasui, H.; Goetze, A. M.; Young, P. R.; Bouska, J. B.; Dyer, R. D.; Brooks, D. W.; Carter, G. W. JMC 1987, 30, 2121.
12. Geffken, D. CZ 1986, 110, 377 (CA 1988, 108, 21 316w).
13. Baldwin, J. E.; Harwood, L. W.; Lombard, H. J. T 1984, 40, 4363.
14. Panfil, I.; Maciejewski, S.; Belzecki, C.; Chmielewski, M. TL 1989, 30, 1527.
15. Tronchet, J. M. J.; Bizzozero, N.; Zsely, M.; Barbalat-Rey, F.; Dolatshahi, N.; Bernardinelli, G.; Geoffroy, M. Carbohydr. Res. 1991, 212, 65.
16. Fornefeld, E. J.; Pike, A. J. JOC 1979, 44, 835.
17. Stamm, H.; Hoenicke, J. LA 1971, 749, 146 (CA 1971, 75, 140 745v).

Ralph A. Whitney

Queen's University at Kingston, Ontario, Canada

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.