[67-62-9]  · CH5NO  · O-Methylhydroxylamine  · (MW 47.07)

(for electrophilic amination;1 for conversion of aldehydes and ketones to methoxyimines)

Alternate Name: methoxyamine.

Physical Data: mp -86.4 °C; bp 48.1 °C; pKb 9.40.

Solubility: miscible with water, alcohol, ether, hexane.

Form Supplied in: white HCl salt (mp 149 °C).

Analysis of Reagent Purity: IR2 and 1H NMR.3

Preparative Methods: from methylation of adduct of sodium nitrite and sodium metabisulfite,4 or fractional distillation from the HCl salt in sodium hexyloxide/hexanol.5

Handling, Storage, and Precautions: a highly mobile and poisonous clear colorless liquid and should be refrigerated. Methoxyamine is a severe irritant. Use in a fume hood.

Introduction of the Methoxyimino Function.

The methoxyimino (O-methyl oxime ether) group is easily introduced by treating ketones or aldehydes with the HCl salt of methoxyamine. The methoxyimino function is a convenient and often most effective way of protecting ketones or aldehydes during alkaline transformations.6 For example, the ring of the dioxabicyclooctane (1) was opened with methoxyamine.HCl to afford the 6-methoxyiminooxepane (2) (eq 1).7 Attempts to trap the intermediate ketones as the dithioacetal led to intractable product mixtures. After acetylating the 3-hydroxy group, the desired oxepan-6-one was recovered in 73% yield by treating the methoxyimine in acetone with 2 N HCl at rt for 3 h.

a,b-Unsaturated methoxyimines are readily prepared by treating the corresponding ketones or aldehydes with methoxyamine.HCl.8 Except in cases of a,b-unsaturated aldehydes or highly reactive a,b-unsaturated ketones, the free base of methoxyamine undergoes 1,4-addition regioselectively (see below).

As a NH2+ Synthon.

Lithium salts of strongly basic carbanions can be stoichiometrically converted to the corresponding primary amines by treating with 2 equiv of methyllithium-methoxyamine (eq 2).9

To prepare the methyllithium-methoxyamine adduct (3), a hexane solution of methoxyamine is added dropwise to an ether solution of Methyllithium at -78 °C. Then, to obtain the primary amine, an organolithium is added, the reaction mixture is allowed to warm to -15 °C for 2 h, and then quenched with water. Examples of primary amines prepared via eq 2 are provided in Table 1.

Lithium a-lithiophenylacetate, 2-lithiocyclohexanone, 2-lithiothiophene, 2-lithiofuran, or 3-lithiopyridine could not be aminated via eq 2.

The best yields of primary amines from (3) are obtained with organolithium compounds.10 While organozinc, magnesium, and copper compounds are aminated with (3), the yields are generally low.

As a -NH+ Synthon.

Since the nitrogen of methoxyamine functions both as a nucleophilic and electrophilic center, methoxyamine can be used to prepare secondary amines and nitrogen heterocycles. The methoxyamine (4) was prepared by converting acetophenone to the methoxyimine with methoxyamine.HCl in methanol/pyridine at reflux overnight, followed by reduction with Borane-Pyridine complex and HCl in methanol at -10 °C to 10 °C for 10 min (eq 3).11

It was found that treating (4) with methyllithium followed by n-Butyllithium afforded the secondary amine (5) (eq 4).

The electrophilic aminations of carbanions with N-monosubstituted methoxyamines are executed as with methoxyamine (see above). However, only 1 equiv of the methyllithium adduct is required. Furthermore, because the amination reaction occurs by a SN2 displacement,5 it must be conducted at higher temperatures when the nitrogen of the N-monosubstituted methoxyamine is sterically hindered.10 Other examples of secondary amines prepared by the above approach have been published.10,11

Intramolecular electrophilic amination of the N-substituted methoxyamines (6) provides the corresponding nitrogen heterocycles (7) (eq 5).10,11

The methoxyamines (6) were prepared by reductive amination of the corresponding aldehydes with methoxyamine and pyridine-borane complex (see above). Then they were treated with methyllithium in the presence of t-Butyllithium, to effect halogen-metal exchange,12 and, after warming to -15 °C for 3 h, the nitrogen heterocycles (7) were isolated as the N-acetyl derivatives. The yields of (7), based on the starting aldehyde, when n = 1, or its progenitor, when n = 2, 3, and 4, were 16, 15, 25, and 9%, respectively.

Treating a,b-unsaturated ketones with the free base of methoxyamine at rt results in 1,4-addition.8 Treating the resulting b-methoxyamino ketones (8) with 2 equiv of Sodium Methoxide yields the trans-ketoaziridines (9) stereoselectively (eq 6).8,13,14

Alternatively, the trans-ketoaziridines are obtained directly by treating the a,b-unsaturated ketones with methoxyamine in the presence of alkoxide. The yields of (9), when R1 = phenyl and R2 = 4-methoxyphenyl or 4-methylphenyl, were 46 and 61%, respectively.

The keto ester (10) and methoxyamine.HCl react to afford the methoxyimine (11).15 Radical cyclization of (11) with Tri-n-butylstannane and Azobisisobutyronitrile (AIBN) affords the indan (12) (eq 7).

It was found that (12) could be rearranged to the quinoline (13) with Lithium Aluminum Hydride (LAH) (eq 8).16

Kostyanovsky and co-workers treated the N-tosylate (14) with methoxyamine and obtained the diaziridine (15) (eq 9).17

As a -NH- Synthon.

The N-O linkage can be reductively cleaved under mild conditions.18 Consequently, the N-methoxy group should function as an activating/protecting group when preparing disubstituted nitrogen compounds with methoxyamine. This strategy was elegantly demonstrated in the synthesis of b-lactam precursors of monobactam antibiotics.19 L-Serine (16) was treated sequentially with Di-t-butyl Dicarbonate (Boc2O) and methoxyamine.HCl, in one pot, to afford the Boc-protected hydroxamate (17) (eq 10).

The condensation to (17), which occurred in 30 min at rt, was mediated by 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride (EDCI). The mesylate (18), prepared by treating (17) with Methanesulfonyl Chloride, was easily cyclized to the 1-methoxyazetidinone (19) (eq 11).

Reductive cleavage of the N-methoxy group of (19) afforded the b-lactam (20) (eq 12).

L-Threonine and L-allo-threonine were also converted to the respective b-lactams in comparable yields using the above sequence. The conversion of amino acid to b-lactam proceeded stereospecifically in all cases.

Anti-Bredt b-lactams are also prepared using the above strategy.20 However, the hydroxamate was cyclized under Mitsunobu conditions.21 Thus treatment of the hydroxamate (21) with Triphenylphosphine and Diethyl Azodicarboxylate (DEAD) generated the 1-methoxyazetidinone (22) (eq 13).

The primary amide versions do not cyclize to the b-lactams by either of the above methods. This is due to competing proton transfers. An alkoxy or acyloxy substituent on the amide nitrogen lowers the pKa of the amide enough that cyclization becomes competitive.22 The methoxy substituent appears to be particularly advantageous due to the ease with which it is reductively cleaved.19

1. Erdik, E.; Ay, M. CRV 1989, 89, 1947.
2. Davies, M.; Spiers, N. A. JCS 1959, 3971.
3. Fujii, T.; Wu, C. C.; Yamada, S. CPB 1967, 15, 345.
4. Hjeds, H. ACS 1965, 19, 1764.
5. Beak, P.; Basha, A.; Kokko, B.; Loo, D. JACS 1986, 108, 6016.
6. Fried, J. H.; Nutile, A. N. JOC 1962, 27, 914.
7. Wachter, M. P.; Hajos, Z. G.; Adams, R. E.; Werblood, H. M. JOC 1985, 50, 2216.
8. Blatt, A. H. JACS 1939, 61, 3494.
9. Beak, P.; Kokko, B. J. JOC 1982, 47, 2822.
10. Beak, P.; Selling, G. W. JOC 1989, 54, 5574.
11. Beak, P.; Kokko, B. TL 1983, 561.
12. Jones, R. G.; Gilman, H. Organic Reactions; Wiley: New York, 1951; Vol. 6, pp 339-366.
13. Cromwell, N. H.; Barker, N. G.; Wankel, R. A.; Vanderhorst, P. J.; Olson, F. W.; Anglin, J. H. JACS 1951, 73, 1044.
14. Ponsold, K.; Drefahl, G.; Schoenecker, B. CB 1964, 97, 2014 (CA 1964, 61, 8364c).
15. Booth, S. E.; Jenkins, P. R.; Swain, C. J. CC 1991, 1248.
16. Booth, S. E.; Jenkins, P. R.; Swain, C. J. CC 1993, 147.
17. Schustov, G. V.; Tavakalyan, N. B.; Kostyanovsky, R. G. AG(E) 1981, 20, 200.
18. Keck, G. E.; Webb, R. TL 1979, 1185.
19. Floyd, D. M.; Fritz, A. W.; Pluscec, J.; Weaver, E. R.; Cumarusti, C. M. JOC 1982, 47, 5160.
20. Williams, R. M.; Lee, B. H. JACS 1986, 108, 6431.
21. Mitsunobu, O.; Wada, M.; Sano, T. JACS 1972, 94, 679.
22. Miller, M. J.; Mattingly, P. G.; Morrison, M. A.; Kerwin, J. F. JACS 1980, 102, 7026.

Bruce J. Kokko

James River Corporation, Neenah, WI, USA

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