N,N-Dimethylpropionamide Dimethyl Acetal1

(1)

[19429-86-8]  · C7H17NO2  · N,N-Dimethylpropionamide Dimethyl Acetal  · (MW 147.25) (2)

[816-05-7]  · C6H13NO  · N,N-Dimethylpropionamide Dimethyl Acetal  · (MW 115.20)

(reagents for stereoselective Eschenmoser-Claisen rearrangements2 to give g,d-unsaturated amides, or, via subsequent protodesilation, to give b,g-unsaturated amides)

Physical Data: (1) and (2) mixture: bp 117-120 °C. (2): bp 117-118 °C.

Solubility: sol benzene and xylene.

Preparative Methods: a mixture of (1) and (2) is prepared by O-methylation of N,N-dimethylpropionamide with Dimethyl Sulfate, followed by reaction with Sodium Methoxide in methanol.3 Fractional distillation affords a mixture of (1) and (2). Treatment with calcium metal and distillation gives the N,O-ketene acetal (2) (57%). Either a mixture of (1) and (2) or pure (2) may be used in sigmatropic rearrangements.

Handling, Storage, and Precautions: the reagents are potentially toxic and flammable. They should be handled in a fume hood.

Eschenmoser-Claisen Rearrangement.

Reagents (1 + 2) or (2) condense with allyl alcohols to produce N,O-ketene acetal intermediates that undergo [3,3]-sigmatropic rearrangements to afford g,d-unsaturated amides. Studies performed by Sucrow and Richter show that the overall transformation of the allylic alcohol is highly stereoselective, with the trans allylic alcohol affording the erythro product and the cis allylic alcohol affording the threo product (eq 1).4

This result has been rationalized in terms of a chair-like transition state in which the methyl group from the acetal occupies the axial position anti to the bulky dialkyl amino group (eq 2).

An X-ray structure of a cyclic N,O-ketene acetal derived from reagent (1) showed that the methyl substituent occupied the position trans to the nitrogen (eq 3).5

trans b,g-Unsaturated carboxylic acid derivatives were prepared by amide acetal rearrangement of 3-(trimethylsilyl)allyl alcohols and subsequent desilylation with allylic rearrangement (eq 4).6

The propionamide acetal rearrangement was used to establish the threo stereochemistry in intermediates for prostaglandin H analog synthesis (eq 5).7

Other Applications.

The reaction of the reagent with an amide oxime gives 5-ethyl-1,2,4-oxadiazoles (eq 6).8

Related Reagents.

1,1-Dimethoxypropene, N,N-Dimethylacetamide Dimethyl Acetal; N,N-Dimethylformamide Diethyl Acetal; Dimethyl Sulfate; Methylketene Dimethyl Acetal; Triethyl Orthoacetate.


1. For reviews on amide acetal chemistry, see: (a) Pindur, U. In The Chemistry of Acid Derivatives; Patai, S., Ed.; Wiley: Chichester, 1992; Vol. 2, Suppl. B, p 1005. (b) Simchen, G. In Iminium Salts in Organic Chemistry; Böhme, H.; Viehe, H. G., Eds.; Wiley: New York, 1979, p 393. (c) Kantlehner, W. In The Chemistry of Acid Derivatives; Patai, S., Ed.; Wiley: Chichester, 1979; Part I, Suppl. B, p 533. (d) DeWolfe, R. H., Carboxylic Ortho Acid Derivatives; Academic: New York, 1970.
2. For recent reviews on Claisen rearrangements, see: (a) Wipf, P. COS 1991, 5, Chapter 7.2. (b) Kallmarten, J.; Wittman, M. D. Stud. Nat. Prod. Chem. 1989, 3, 233. (c) Blechert, S. S 1989, 71. (d) Ziegler, F. E. CRV 1988, 88, 1423. (e) Moody, C. J. Adv. Heterocycl. Chem. 1987, 42, 203.
3. (a) Bredereck, H.; Effenberger, F.; Beyerlin, H. P. CB 1964, 97, 3081. (b) Meerwein, H.; Florian, W.; Schon, N; Stopp, G. LA 1961, 641, 1.
4. Sucrow, W; Richter, W. CB 1971, 104, 3679.
5. Kumin, A; Maverick, E; Seiler, P; Vanier, N; Damm, L; Hobi, R.; Dunitz, J. D.; Eschenmoser, A. HCA 1980, 63, 1158.
6. Jenkins, P. R.; Gut, R.; Wetter, H; Eschenmoser, A. HCA 1979, 62, 1922.
7. Hwu, J. R.; Robl, J. A. CC 1986, 704.
8. Maddison, J. A.; Seale, P. W.; Tiley, E. P.; Warburton, W. K. JCS(P1) 1974, 81.

Kathlyn A. Parker & Lynn Resnick

Brown University, Providence, RI, USA



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