Methylketene Dimethyl Acetal1

[5434-53-6]  · C5H10O2  · Methylketene Dimethyl Acetal  · (MW 102.15)

(electron-rich alkene which can act as propionyl carbocation equivalent in reactions with electrophiles; undergoes [2 + 2] cycloadditions with electron-deficient alkenes, aldehydes, and imines; also participates in inverse Diels-Alder reactions and 1,3-dipolar cycloadditions)

Alternate Name: 1,1-dimethoxypropene.

Physical Data: bp 99 °C.

Preparative Methods: best method is from acrolein dimethyl acetal by isomerization of the double bond with potassium amide.2 The method is also applicable for other dialkoxy analogs.

Handling, Storage, and Precautions: sensitive to moisture, especially in the presence of traces of acids. It can be stored for longer time in dry base-rinsed vessels under nitrogen.

General Reactivity.

Dimethoxypropene belongs to the class of the ketene acetals. These compounds react as strong electron-rich alkenes due to the electron-donating ability of the two alkoxy groups.

Over the years, the chemistry of the ketene acetals has been reviewed several times.1a,c,d Electronically symmetrical ketene acetals sometimes show different chemistry than the electronically asymmetrical ketene acetals like the 1,1-dialkoxyethylenes. In cycloadditions, the former give mostly stable cycloadducts, whereas the latter give unstable cycloadducts or products derived from dipolar intermediates. In this respect, dimethoxypropene shows an intermediate behavior.3 Since the mid-1970s, much attention has also been paid to the alkyl trialkylsilylketene acetals. In reactions with electron-poor double bonds these compounds often yield acyclic products, whereas the dialkylketene acetals yield cycloadducts.1c 1,1-Dimethoxypropene has been more extensively studied since the mid-1980s due to its easy availability and because it can act as propionyl carbocation equivalent.

Acids, alcohols, and thiols react rapidly with ketene acetals, but these reactions have not been explored for synthetic purposes. The main application of 1,1-dimethoxypropene lies in the field of cycloaddition reactions.

Carbenes.

Ethyl Diazoacetate reacts with 1,1-dimethoxypropene in the presence of Copper(II) Acetylacetonate to give ethyl 2,2-dimethoxy-3-methylcyclopropane-1-carboxylate, which can be methanolized in situ to ethyl 4,4,4-trimethoxy-3-methylbutanoate (eq 1).4

The analogous reaction with diazo ketones which was investigated for 1,1-diethoxypropene yields 2,2-diethoxy-3-methyldihydrofurans (eq 2).5

Cyclobutanes.

Electron-deficient alkenes undergo polar [2 + 2] cycloadditions with 1,1-dimethoxypropene (eq 3).6

The resulting cyclobutanes can be further hydrolyzed into cyclobutanones7 or g-funtionalized esters.

Oxetanes.

Carbonyl compounds having electron-withdrawing substituents add to 1,1-dimethoxypropene to give 2,2-dimethoxy-3-methyloxetanes. In the presence of Lewis acids the cycloaddition can be performed with normal aldehydes.2

This cycloaddition can also be achieved under high pressure without Lewis acids. The combination of Lewis acids and high pressure extends the scope of the reaction to include ketones.8 The reaction has very high regioselectivity. Furthermore the cis/trans stereoselectivity is controlled by the reaction conditions.9 Interestingly, the photochemical cycloaddition gives mainly the products with the reverse regiochemistry.10,11 As reactive orthoesters, the oxetanes are easily hydrolyzed to b-hydroxy esters or methanolyzed to b-hydroxy orthoesters (eq 4).12

Oxetanes obtained in this way from a- or b-oxy-functionalized aldehydes or ketones are interesting precursors for the synthesis of 3-methyl-4-hydroxy-g- or d-lactones (eq 5).13,14

The oxetanes from a,b-epoxy aldehydes have been further converted into 4-hydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-ones (eq 6).15

Cycloaddition reactions of a-diketones with 1,1-dimethoxypropene afford mono- and bis-oxetanes which can be further converted to bis-g-lactones (eq 7).16

a,b-Unsaturated aldehydes undergo cycloadditions to the kinetically favored oxetanes at low temperatures in the presence of Lewis acids, whereas above rt the thermodynamically more stable 2,2-dimethoxydihydropyrans are formed (eq 8). Cyclobutanes are the main products under high pressure without Lewis acid catalyst.17

Azetidines.

Electron-deficient imines undergo [2 + 2] cycloaddition with 1,1-dimethoxypropene to give 2,2-dimethoxy-3-methylazetidines. The scope of the reaction can be extended to weakly activated imines by application of high pressure (eq 9).18

p-Chlorophenyl isocyanate affords the b-lactam 1-p-chlorophenyl-4,4-dimethoxy-3-methylazetidin-2-one.19

Benzonitrile adds photochemically to 1,1-dimethoxypropene. The cycloadduct is not stable and it reacts further by ring opening to 1,1-dimethoxy-2-aza-3-phenylpenta-1,3-diene (eq 10).20

Diels-Alder Reactions.

Apart from cycloadditions with a,b-unsaturated carbonyl compounds, inverse electron-demand Diels-Alder reactions of 1,1-dimethoxypropene with electron-poor alkenes have been infrequently investigated. Only 1,1-dicyanobutadienes having a preferred cisoid conformation give Diels-Alder adducts. Transoid 1,1-dicyanobutadienes yield [2 + 2] cycloadducts. Interestingly, 5-nitropyrimidine reacts with 1,1-dimethoxypropene via an unstable Diels-Alder adduct to give 2-hydroxy-3-methyl-5-nitropyridine (eq 11).21

1,3-Dipolar Cycloadditions.

Most of the 1,3-dipolar cycloadditions have been studied with 1,1-dialkoxyethylenes. Ethyl Azidoformate and 1,1-dimethoxypropene form a triazoline cycloadduct at -15 °C, whereas at 35 °C ethyl N-(1,2-dimethoxypropylidene)carbamate is obtained.1b,d Three-membered ring compounds which can open up to 1,3-dipolar intermediates react with 1,1-dimethoxypropene to form five-membered cycloadducts, e.g. 2,2-dimethoxy-3-methyltetrahydrofurans from epoxides (eq 12) and 1,1-dimethoxy-2,2-dicyano-5-methylcyclopentanes from 1,1-dicyanocyclopropanes.1c

Related Reagents.

1,2-Diethoxy-1,2-bis(trimethylsilyloxy)ethylene; Ketene Bis(trimethylsilyl) Acetal; Ketene t-Butyldimethylsilyl Methyl Acetal; Ketene Diethyl Acetal; 1-Methoxy-1-(trimethylsilyloxy)propene; 1-Methoxy-2-trimethylsilyl-1-(trimethylsilyloxy)ethylene; Tetramethoxyethylene; Tris(trimethylsilyloxy)ethylene.


1. (a) McElvain, S. M. CRV 1949, 45, 453. (b) Seebach, D. MOC 1971, B.4/4, 340. (c) Scheeren, J. W. RTC 1986, 105, 71. (d) Scheeren, J. W. MOC 1993, B. E15, 1674.
2. Scheeren, J. W.; Aben, R. W. M.; Ooms, P. H. J.; Nivard, R. J. F. JOC 1977, 42, 3128.
3. Scheeren, J. W.; van Rossum, A. J. R.; Nivard, R. J. F. T 1983, 39, 1345.
4. Graziano, M. L.; Iesce, M. R. S 1985, 762.
5. Scarpati, R.; Cioffi, M.; Scherillo, G.; Nicolaus, R. A. G 1966, 96, 1164.
6. Scheeren, J. W.; Frissen, A. E. S 1983, 794.
7. Amice, Ph.; Conia, J. M. BSF 1974, 1015.
8. Aben, R. W. M.; Scheeren, J. W. TL 1983, 24, 4613.
9. Hofstraat, R. G.; Scheeren, J. W.; Nivard, R. J. F. JCS(P1) 1985, 561.
10. Schroeter, S. H.; Orlando, C. M., Jr. JOC 1969, 34, 1181.
11. Schore, N. E.; Turro, N. J. JACS 1975, 97, 2482.
12. Aben, R. W.; Scheeren, J. W. S 1978, 400.
13. Aben, R. W.; Hofstraat, R. G.; Scheeren, J. W. RTC 1981, 100, 355.
14. Hofstraat, R. G.; Lange, J.; Scheeren, J. W.; Nivard, R. J. F. JCS(P1) 1988, 2315.
15. Scheeren, J. W.; Lange, J. TL 1984, 25, 1609.
16. Bakker, C. G.; Scheeren, J. W.; Nivard R. J. F. RTC 1981, 100, 13.
17. Aben, R. W.; Scheeren, J. W. TL 1985, 26, 1889.
18. Aben, R. W.; Smit, R.; Scheeren, J. W. JOC 1987, 52, 365.
19. Graziano, M. L.; Cimminiello, G. S 1989, 54.
20. Cantrell, T. S. JOC 1977, 42, 4238.
21. Charushin, V. N.; Van der Plas, H. C. TL 1982, 23, 3965.

J. (Hans) W. Scheeren

University of Nijmegen, The Netherlands



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