N,N-Dimethylacetamide Dimethyl Acetal1

(1; R = Me)

[18871-66-4]  · C6H15NO2  · N,N-Dimethylacetamide Dimethyl Acetal  · (MW 133.19) (2; R = Me)

[867-89-0]  · C5H11NO  · N,N-Dimethylacetamide Dimethyl Acetal  · (MW 101.15) (3; R = Et)

[19429-85-7]  · C8H19NO2  · N,N-Dimethylacetamide Diethyl Acetal  · (MW 161.24) (4; R = Et)

[816-65-9]  · C6H13NO  · N,N-Dimethylacetamide Dimethyl Acetal  · (MW 115.17)

(Eschenmoser-Claisen rearrangements;2 monoacylation of diols;3 triazine synthesis4)

Physical Data: mixture of (1) and (2) bp 105-110 °C; d 0.911 g cm-3. Mixture of (3) and (4) bp 126-129 °C. (2) bp 104-105 °C. (4) bp 126 °C.

Solubility: sol benzene, toluene, xylene, DMF, chloroform.

Form Supplied in: amide acetal (1) is commercially available, usually as a mixture of (1) and (2). The commercial mixture is 85-95% pure; methanol (5-10%) may be present as a stabilizer.

Preparative Methods: O-methylation of N,N-dimethylacetamide with Dimethyl Sulfate (or diethyl sulfate), followed by reaction with Sodium Methoxide (or ethoxide). Fractional distillation affords mixtures of (1) and (2) (or 3 and 4). Treatment with calcium metal and redistillation gives the ketene O,N-acetals (2) (58%) (or 4; 74%).5

Introduction.

Amide acetal reagent (1) is in equilibrium with its enamine (eq 1).5 The stabilized carbenium ion, which is an intermediate in this equilibrium, adds to nucleophiles under neutral conditions.

Eschenmoser-Claisen Rearrangement.

Condensation of (1) with allylic alcohols followed by loss of a second equivalent of methanol gives ketene N,O-acetals, which undergo 3,3-sigmatropic rearrangement to afford g,d-unsaturated amides (eq 2).

In a general procedure, the allylic alcohol and dimethylacetamide dimethyl acetal are heated at reflux in a high boiling solvent such as xylene or DMF with simultaneous distillation of methanol. Other suitable solvents include diglyme, dioxane, toluene, and benzene. Several papers indicate that the Eschenmoser-Claisen reaction proceeds at lower temperatures with higher yields and shorter reaction times than the classical Claisen and the orthoester Claisen rearrangements.6 However, it suffers the disadvantage that the product is a disubstituted amide, a functional group which is not always easily converted to other groups.7 Several examples of transformations of disubstituted amides to other functional groups are included in the discussion below.

Eschenmoser and co-workers demonstrated that the amide acetal rearrangement of cyclohexenols is stereospecific, i.e. the cis-4-substituted cyclohexenol gives a single stereoisomer of the cyclohexeneacetamide product (eq 3), whereas the trans-cyclohexenol affords its stereoisomer (eq 4).8

Benzyl alcohols rearrange to o-methylbenzeneacetamides (eq 5).

The amide acetal rearrangement, like the Claisen rearrangement, generally proceeds through a chairlike transition state with all substituents in equatorial positions, an arrangement which leads to trans geometry of the double bond in the product and chirality transfer (eq 6).9

The products of the Eschenmoser-Claisen rearrangement with 3-(trimethylsilyl)allyl alcohols (eq 7) undergo protonolysis and desilylation with Hydrogen Fluoride to give b,g-unsaturated amides which can be converted into the corresponding esters.10

The Eschenmoser-Claisen method was used for the rearrangement of an allyl alcohol bearing two organometallic groups because of its nearly neutral conditions (eq 8). The product, obtained in 74% yield with 90% chirality transfer, was reduced with Lithium Triethylborohydride to the primary homoallylic alcohol.11

Parker and co-workers found that terminal propargyl alcohols condense with dimethylacetamide diethyl acetal (3) to form an intermediate which undergoes amine migration. This enamine subsequently rearranges through an orthoester Claisen rearrangement (eq 9).12 A side product is the enol ether, which is formed from the enol derived from the enamine. Hydrolysis of the products gives a g-keto ester.

Substituted propargyl alcohols undergo the simple Claisen-type rearrangement to give allenic amides (eq 10).

Amide acetal Claisen rearrangements have been used in the synthesis of C-glycopyranosides,6 pyranosides,13 sugars,14,15 and indole alkaloids.7,16 In Corey's synthesis of thromboxane B2, an amide product is transformed to a lactone by iodolactonization followed by deiodination with Tri-n-butylstannane (eq 11).14

Monoacylation of Diols.

Vicinal diols form (dimethylamino)ethylidene acetals, which can be cleaved with aqueous acetic acid to give monoacylated products.3 In unsymmetrical diols, the less hindered hydroxy group is selectively protected. For example, with this method 1,2-O-isopropylidene-a-D-glucofuranose is selectively acylated at the C-6 hydroxy group.

Heterocycle Synthesis.

N,N-Dimethylaminomethylenehydrazones are formed by addition of this reagent to a-ketohydrazones.4 Subsequent heating with ammonium acetate in acetic acid causes cyclization to give 1,2,4-triazines (eq 12).

1,2,4-Triazoles and 1,2,4-oxadiazoles can be synthesized in high yields in a two-step procedure with this reagent. First the dimethyl acetal condenses with an amide to give an N-acylamidine. Subsequently, reaction with acetic acid and hydrazine gives triazoles, whereas addition of hydroxylamines gives oxadiazoles (eq 13).17

Another method for the synthesis of 1,2,4-oxadiazoles is condensation of the amide acetal with an amidoxime (eq 14).18 Fused amino pyridines have been formed through the cyclocondensation of an amide acetal with an amino ketone.19

Related Reagents.

Diketene; N,N-Dimethylformamide Diethyl Acetal; N,N-Dimethylpropionamide Dimethyl Acetal; Dimethyl Sulfate; Ethyl 3,3-Diethoxyacrylate; Ethyl Vinyl Ether; 2-Methoxy-1,3-butadiene; 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) Hanessian, S.; Moralioglu, E. CJC 1972, 50, 233. (b) Hanessian, S.; Moralioglu, E. TL 1971, 12, 813.
4. (a) Ohsumi, T.; Neunoeffer, H. T 1992, 48, 5227. (b) Ohsumi, T.; Neunoeffer, H. H 1992, 33, 893.
5. (a) Meerwein, H.; Florian, W.; Schon, N.; Stopp, G. LA 1961, 641, 1. (b) Bredereck, H.; Effenberger, F.; Beyerlin, H. P. CB 1964, 97, 3081.
6. Moreau, P; Al Neirabeyeh, M.; Guillaumet, G.; Coudert, G. TL 1991, 32, 5525. (b) Tulshian, D. B.; Fraser-Reid, B. JOC 1984, 49, 518.
7. Ziegler, F. E.; Bennett, G. B. JACS 1973, 95, 7458.
8. (a) Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. HCA 1964, 47, 2425. (b) Felix, D; Gschwend-Steen, K.; Wick, A. E.; Eschenmoser, A. HCA 1969, 52, 1030.
9. Hill, R. K.; Soman, R.; Sawada, S. JOC 1972, 37, 3737.
10. Jenkins, P. R.; Gut, R.; Wetter, H.; Eschenmoser, A. HCA 1979, 62, 1922.
11. Lautens, M.; Huboux, A. H.; Chin, B.; Downer, J. TL 1990, 31, 5829.
12. (a) Parker, K. A.; Kosley, R. W. TL 1976, 5, 341. (b) Parker, K. A.; Petraitis, J. J.; Kosley, R. W.; Buchwald, S. L. JOC 1982, 47, 389.
13. Dickson, J. K.; Tsang, R.; Llera, J. M.; Fraser-Reid, B. JOC 1989, 54, 5350.
14. Corey, E. J.; Shibasaki, M; Knolle, J. TL 1977, 1625.
15. Holzapfel, C. W.; Huyser, J. J.; Merwe, T. L.; Heerden, F. R. H 1991, 32, 1445.
16. Lounasmaa, M.; Jokela, R.; Tirkkonen, B.; Miettinen, J.; Halonen, M. H 1992, 34, 321.
17. Lin, Y.; Lang, S. A.; Lovell, M. F.; Perkinson, N. A. JOC 1979, 44, 4160.
18. Kocevar, M; Stanovnik, B.; Tisler, M. JHC 1982, 19, 1397.
19. Boamah, P. Y.; Haider, N.; Heinisch, G.; Moshuber, J. JHC 1988, 25, 879.

Kathlyn A. Parker & Lynn Resnick

Brown University, Providence, RI, USA



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