N-Cyclohexylhydroxylamine1

[2211-64-5]  · C6H15NO  · N-Cyclohexylhydroxylamine  · (MW 115.18) (.HCl)

[25100-12-3]  · C6H16ClO  · N-Cyclohexylhydroxylamine Hydrochloride  · (MW 151.64)

(condenses with a wide variety of aldehydes to afford N-cyclohexyl nitrones;2 condenses with alkynes to afford N-cyclohexyl nitrones;3 reagent in the conversion of 1,2-dicarboxylic acids to a,b-unsaturated carboxylic acids;4 hydroxylamination reagent for allyl esters under palladium(0) catalysis5)

Alternate Name: hydroxyaminocyclohexane.

Physical Data: mp 140-141 °C; hydrochloride salt, mp 166-171 °C.

Form Supplied in: available commercially as the free hydroxylamine and as the hydrochloride salt.

Preparative Methods: oxime reduction;6-13 nitroalkene reduction;14-16 nitro reduction;17-19 amine oxidation.20,21

Purification: by sublimation.

Handling, Storage, and Precautions: hygroscopic; use in a fume hood.

Introduction.

Because of the similarity and overlap of their uses, N-Benzylhydroxylamine and N-t-Butylhydroxylamine, as well as N-cyclohexylhydroxylamine, are all discussed here. Indeed, most of their chemistry is that of any of the N-monosubstituted hydroxylamines. They undergo a wealth of condensation reactions analogous to those of amines as well as ones unique to the hydroxylamine group, affording an array of nitrogen-containing compounds too numerous to list. In terms of their use as synthetic reagents, however, they function primarily in the conversion of carbonyl compounds into nitrones. While N-benzyl-, N-t-butyl-, and N-cyclohexylhydroxylamine all participate in a few specialized reactions, it is their role in the preparation of nitrone intermediates which has led to their general usage.

Synthesis and Reactions of Nitrones.

N-Benzyl-, N-t-butyl-, and N-cyclohexylhydroxylamine condense with carbonyl compounds under a variety of dehydrating conditions to afford nitrones (eq 1).2 These reactions proceed smoothly with aldehydes, but poorly or not at all with ketones, especially when the hydroxylamine has a bulky substituent, as in the compounds under consideration. Nitrones are also produced in some cases by the condensation of N-cyclohexylhydroxylamine3 and N-t-butylhydroxylamine3,22 with alkynes (eq 2). The nitrones thus formed undergo a number of reactions,23 the most studied of which are 1,3-dipolar cycloadditions.24,25 This chemistry encompasses a large number of unsaturated dipolarophiles, providing many different types of heterocyclic product, and is beyond the scope of this discussion.

There are, however, other reactions of nitrones which can be more clearly considered as functional group transformations. In particular, N-cyclohexyl-a-chloro nitrones are converted by silver ion to N-vinylnitrosonium ions, which readily undergo cycloaddition to unactivated alkenes (eq 3).26 Formation of the cyanide adduct, followed by base induced rearrangement and hydrolysis, provides g-lactones (eq 4).27 In the case of a,b-dichloro nitrones, the same sequence affords a-methylene-g-butyrolactones (eq 4).28 Alternatively, treatment with base leads to an enamine-like structure, which undergoes thermal cycloreversion to yield, after hydrolysis, a product in which the original alkene has been oxidatively cleaved (eq 4).29 Alkynes undergo analogous chemistry with the N-cyclohexyl-a-chloro nitrones, ultimately providing a,b-enones (eq 5).30 Interestingly, in a polar solvent the a-chloro nitrone undergoes substitution reactions with alkenes and arenes, resulting in b,g-unsaturated aldehydes (eq 6).31 Similar chemistry is observed for the related N-cyclohexyl-a-epoxy nitrones (eq 7).32,33

N-t-Butyl and N-cyclohexyl nitrones undergo acylation-rearrangement when treated with an acid chloride and triethylamine, affording a-acyloxy imines. These intermediates can be hydrolyzed to a-acyloxy aldehydes (eq 8), corresponding to an overall a-oxygenation of the aldehyde from which the nitrone was prepared.34 Alternatively, reduction of the imines affords vicinal N-alkylamino alcohols (eq 8), corresponding to overall a-oxygenation and reductive amination.35

Alkene Aminations.

Hydroxyamination of allyl esters under palladium(0) catalysis can be accomplished with both N-benzyl- and N-cyclohexylhydroxylamine (eq 9).5 The reaction proceeds with retention of configuration and allylic transposition. Amination of unactivated alkenes, again via allylic transposition, has been accomplished using molybdenum-based metallooxaziridines, prepared from N-t-butylhydroxylamine and a dioxomolybdenum(VI) complex (eq 10).36

Decarboxylation and Cyclization Reactions.

The oxidative decarboxylation of 1,4-dicarboxylic acids to a,b-unsaturated acids can be accomplished regiospecifically using N-cyclohexylhydroxylamine.4 The initially formed tetrahydro-1,2-oxazine-3,6-dione can be fragmented in either of two complementary fashions to afford a,b-unsaturated carboxylic acids (eq 11).

N-t-Butylaziridinones can be prepared from N-t-butylhydroxylamine and phenylacetyl chloride, by way of intermediate hydroxamic acids (eq 12).37 The use of Trifluoromethanesulfonic Anhydride is critical; if a sulfonyl chloride is employed, the aziridinone is observed transiently, but it undergoes rapid ring opening by chloride.

Related Reagents.

N-Benzylhydroxylamine; N,O-Bis(trimethylsilyl)hydroxylamine; O-(t-Butyldimethylsilyl)hydroxylamine; N-t-Butylhydroxylamine; C-(1-Chloroethyl) N-Cyclohexyl Nitrone; N,O-Dimethylhydroxylamine; Hydroxylamine; N-Methyl-N,O-bis(trimethylsilyl)hydroxylamine; N-Methylhydroxylamine.


1. For a general review of hydroxylamines, see: Roberts, J. S. In Comprehensive Organic Chemistry; D. H. R. Barton and W. D. Ollis, Eds.; Pergamon: Oxford, 1979; Vol. 2, pp 185-217.
2. Hamer, J.; Macaluso, A. CRV 1964, 64, 473.
3. Sanders, J. A.; Hovius, K.; Engberts, J. B. F. N. JOC 1974, 39, 2641.
4. Gygax, P.; Eschenmoser, A. HCA 1977, 60, 507.
5. Murahashi, S.-I.; Imada, Y.; Taniguchi, Y.; Kodera, Y. TL 1988, 29, 2973.
6. Feuer, H.; Vincent, B. F., Jr.; Bartlett, R. S. JOC 1965, 30, 2877.
7. Yoon, N. M.; Gyoung, Y. S. JOC 1985, 50, 2443.
8. Ciurdaru, V.; Hodosan, F. Rev. Roum. Chim. 1977, 22, 1027.
9. Gribble, G. W.; Leiby, R. W.; Sheehan, M. N. S 1977, 856.
10. Jpn. Patent 49 209, 1975 (CA 1976, 85, 13 954g).
11. Ghosh, A. R.; Das Gupta, T. K. Acta Cienc. Indica, Chem. 1987, 13, 16 (CA 1989, 110, 74 869b).
12. Cho, B. T.; Seong, S. Y. Bull. Korean Chem. Soc. 1988, 9, 322 (CA 1989, 110, 211 697k).
13. Yoon, N. M.; Shon, Y. S.; Ahn, J. H. Bull. Korean Chem. Soc. 1992, 13, 199 (CA 1992, 117, 25 601u).
14. Mourad, M. S.; Varma, R. S.; Kabalka, G. W. JOC 1985, 50, 133.
15. Kabalka, G. W.; Guindi, L. H. M.; Varma, R. S. T 1990, 46, 7443.
16. Varma, R. S.; Kabalka, G. W. OPP 1985, 17, 254.
17. Sanchez, R.; Vest, G.; Scott, W.; Engel, P. S. JOC 1989, 54, 4026.
18. Br. Patent 1 092 027, 1967 (CA 1968, 68, 29 325z).
19. Br. Patent 1 110 184, 1968 (CA 1968, 69, 7876y).
20. Russell, J. L.; Kollar, J. U.S. Patent 3 960 954, 1976 (CA 1976, 85, 108 354n).
21. Kawaguchi, T.; Matsubara, T.; Kato, H. Jpn. Patent, 1966, 19 495 (CA 1967, 66, 85 529q).
22. Aurich, H. G.; Hahn, K. CB 1979, 112, 2769.
23. Balasubramanian, N. OPP 1985, 17, 23.
24. Confalone, P. N.; Huie, E. M. OR 1988, 36, 1.
25. Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vol. 2, pp 83-168.
26. Kempe, U. M.; Das Gupta, T. K.; Blatt, K.; Gygax, P.; Felix, D.; Eschenmoser, A. HCA 1972, 55, 2187.
27. Das Gupta, T. K.; Felix, D.; Kempe, U. M.; Eschenmoser, A. HCA 1972, 55, 2198.
28. Petrzilka, M.; Felix, D.; Eschenmoser, A. HCA 1973, 56, 2950.
29. Gygax, P.; Das Gupta, T. K.; Eschenmoser, A. HCA 1972, 55, 2205.
30. Shatzmiller, S.; Eschenmoser, A. HCA 1973, 56, 2975.
31. Shatzmiller, S.; Gygax, P.; Hall, D.; Eschenmoser, A. HCA 1973, 56, 2961.
32. Denmark, S. E.; Cramer, C. J.; Dappen, M. S. JOC 1987, 52, 877.
33. Riediker, M.; Graf, W. HCA 1979, 62, 205.
34. Cummins, C. H.; Coates, R. M. JOC 1983, 48, 2070.
35. Coates, R. M.; Cummins, C. H. JOC 1986, 51, 1383.
36. Liebeskind, L. S.; Sharpless, K. B.; Wilson, R. D.; Ibers, J. A. JACS 1978, 100, 7061.
37. Bladon, C. M.; Kirby, G. W. CC 1982, 1402.

Clark H. Cummins

Dow Chemical Company, Midland, MI, USA



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