[78191-00-1]  · C4H9NO2  · N-Methoxy-N-methylacetamide  · (MW 103.14)

(acetylation of carbon nucleophiles; formation and transient protection of ketones; C-nucleophile in enolate anion condensations; preparation of aldehydes)

Physical Data: bp 40-44 °C/20 mmHg.2

Solubility: sol ether and other organic solvents.

Analysis of Reagent Purity: 1H NMR d 2.12, 3.18, 3.70; 13C NMR d 19.58, 31.98, 60.86, 171.59; IR (neat) 2950, 1670, 1410, 1380 cm-1.2

Preparative Method: reaction of Acetyl Chloride with commercially available N,O-Dimethylhydroxylamine hydrochloride in pyridine, followed by distillation at reduced pressure (65%).2

Handling, Storage, and Precautions: the compound is stable but should be protected from moisture; use in a fume hood.

General Considerations.

The title compound (1) and its analogs are versatile reagents for the acetylation of organolithium and magnesium reagents to form methyl ketones.3 Lithium reagents have been reported to be superior to magnesium.4 The reactions are carried out in ethereal solvents at 0 or -78 °C. Coordination stabilizes the resulting tetrahedral adduct. Thus further reaction to form tertiary carbinols is generally not observed.5 The methyl ketone is generated by workup under mild acidic conditions (eq 1). Many examples have been reported. Higher homologs of the title compound have frequently been employed in acylation reactions and generally give favorable results. N-Methoxy-N-methylamides are sufficiently more reactive than the corresponding methyl esters that attack on difunctional starting materials occurs exclusively at the amide (eq 2).6,7

The tetrahedral complex has been used to mask the resulting ketone during subsequent transformations.8 The complex has also been used to facilitate an intramolecular Diels-Alder condensation by providing conformational constraints.9

Compound (1) is an excellent reagent for acetylation of strongly nucleophilic enolate anions (eq 3).2 It is less prone to enolate formation than ethyl acetate and uses a stoichiometric quantity of the nucleophile rather than 2 equiv commonly required in Claisen-type condensations. With less nucleophilic enolate anions, good results have been claimed in some cases10 and poor results in others.2,11 Tandem reaction of a bis(N-methoxy-N-methylamide) has been used in a biomimetic synthesis of pretetramide.12

The lithium salt (2) of the enolate anion of (1) can be prepared by treatment of (1) with Lithium Diisopropylamide. The corresponding zinc reagent (3) can be prepared from the bromoacetamide and powdered zinc.13 These reagents will condense with carbonyl compounds and the adducts can subsequently be used as acylating agents.

N-Methoxy-N-methylamides undergo reduction to aldehydes with Lithium Aluminum Hydride, Diisobutylaluminum Hydride, and other hydride reagents.3 i-Bu2AlH is more selective than LiAlH4 for stopping at the aldehyde.

Related Reagents.

Acetic Anhydride; Acetyl Chloride; Acetyl Cyanide; Acetyl Methanesulfonate; Acetyl p-Toluenesulfonate; N,O-Dimethylhydroxylamine; Imidazole.

1. Sibi, M. P. OPP 1993, 25, 15.
2. Oster, T. A.; Harris, T. M. TL 1983, 24, 1851.
3. Nahm, S.; Weinreb, S. M. TL 1981, 22, 3815.
4. Ward, J. S.; Merritt, L. JHC 1990, 27, 1709.
5. Cupps, T. L.; Boutin, R. H.; Rapoport, H. JOC 1985, 50, 3972.
6. Theisen, P. D.; Heathcock, C. H. JOC 1988, 53, 2374.
7. Guingant, A. TA 1991, 2, 415.
8. (a) Evans, D. A.; Bender, S. L.; Morris, J. JACS 1988, 110, 2506. (b) Evans, D. A.; Rieger, D. L.; Jones, T. K.; Kaldor, S. W. JOC 1990, 55, 6260.
9. Bergman, R.; Hansson, T.; Sterner, O.; Wickberg, B. CC 1990, 865.
10. (a) Turner, J. A.; Jacks, W. S. JOC 1989, 54, 4229. (b) Jones, W. D. Jr.; Schnettler, R. A.; Huber, E. W. JHC 1990, 27, 511.
11. (a) Jouin, P.; Poncet, J.; Dufour, M.-N.; Maugras, I.; Pantaloni, A.; Castro, B. TL 1988, 29, 2661. (b) DiMaio, J.; Gibbs, B.; Lefebvre, J.; Konishi, Y.; Munn, D.; Yue, S. Y. JMC 1992, 35, 3331.
12. Gilbreath, S. G.; Harris, C. M.; Harris, T. M. JACS 1988, 110, 6172.
13. Palomo, C.; Aizpurua, J. M.; Aurrekoetxea, N.; Lopez, M. C. TL 1991, 32, 2525.

Thomas M. Harris

Vanderbilt University, Nashville, TN, USA

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