Ethyl 3,3-Diethoxypropanoate

[10601-80-6]  · C9H18O4  · Ethyl 3,3-Diethoxypropanoate  · (MW 190.27)

(synthesis of heterocycles; Pictet-Spengler reaction;1 malonaldehyde monoacetal;2 enantiomeric pure g-amino-b-hydroxybutanoic acid3)

Alternate Name: ethyl 3,3-diethoxypropionate.

Physical Data: bp 92-95 °C/15 mmHg; d 0.978 g cm-3.

Solubility: sol water, diethyl ether.

Form Supplied in: colorless liquid; widely available.

Analysis of Reagent Purity: n20D = 1.4117.

Preparative Methods: can be obtained by treatment of 1,1,1-trichloro-4-ethoxy-3-buten-2-one with ethanol in the presence of catalytic amounts of Potassium Carbonate. The trichloromethyl ketone is prepared from Ethyl Vinyl Ether and Trichloroacetyl Chloride.4

Purification: fractional vacuum distillation through a short Vigreux column.

Handling, Storage, and Precautions: ethyl 3,3-diethoxypropanoate is the stable, protected derivative of the unstable 3-oxopropanoate. It can be stored at room temperature for several months without decomposition.

Ethyl 3,3-diethoxypropanoate is a useful starting material for the synthesis of heterocycles such as coumarins (eq 1),5 isoxazoles,6 pyrimidines,7 porphyrins,8 imidazolinones,9 and thiadiazines (eq 2).10 Also spermine metabolites,11 steroids,1 herbicides,12 antihypertensives,13 photographic sensitizers,14 cephalosporins,15 lycopodium alkaloids,16 nucleic acids,17 prostaglandin (PGF2a) precursor,18 pentaerythriol19 as well as related alcohols can be obtained from ethyl 3,3-diethoxypropanoate.

Ethyl 3,3-diethoxypropanoate can be used for Pictet-Spengler reactions (eq 3),1 and various other condensation reactions.5,8-10,20

Different monoprotected malonaldehydes can be obtained from ethyl 3,3-diethoxypropanoate by transacetalization and reduction with Diisobutylaluminum Hydride/Et2O at -78 °C2a,b or with Lithium Aluminum Hydride followed by oxidation with Dimethyl Sulfoxide-Oxalyl Chloride.4 The malonaldehyde monoacetals were employed in the synthesis of dihydropyrans21a and secologanin derivatives21b,c by tandem Knoevenagel hetero-Diels-Alder reactions.22 They can also be used in Wittig reactions with various phosphorus ylides, and in addition of Grignard reagents, carbanions generated from nitroalkanes, and other organometallic compounds.2c They are also valuable substrates for the synthesis of heterocycles such as pyrazoles, isoxazoles, and pyrimidines.2c

Ethyl 3,3-diethoxypropanoate is used for the total synthesis of both enantiomers of 3-amino-2-hydroxybutanoic acid (GABOB) by enzymatic kinetic resolution of its cyanohydrin acetate (eq 4).3 As a substitute of ethyl 3,3-diethoxypropanoate and the unstable 3-oxopropanoate, the stable 4,4,4-trichloro-3-oxobutanal may be used since the a,a,a-trichlorocarbonyl group can easily be transformed into an ester moiety with 1,8-Diazabicyclo[5.4.0]undec-7-ene in the presence of an alcohol.21a,b

In addition, diformylacetates, which are useful educts for the synthesis of 1,4-dihydropyridines and NADH analogs as well as sugar derivatives (see Methyl Diformylacetate), can be obtained from ethyl 3,3-diethoxypropanoate by formylation.

Related Reagents.

Diethyl Ethoxymethylenemalonate; 3-Ethoxyacrolein; Ethyl Hydroxymethyleneacetate, Sodium Salt; Malondialdehyde; Methyl Diformylacetate.

1. (a) Matabo, K.; Fukushima, A.; Takahata, H.; Hirai, Y.; Yamazaki, T. CPB 1982, 30, 1300. (b) Takahata, H.; Okajima, H.; Yamazaki, T. CPB 1980, 28, 3632.
2. (a) Hager, M. W.; Liotta, D. C. TL 1992, 33, 7083. (b) Hager, M. W.; Liotta, D. C. JACS 1991, 113, 5117. (c) Botteghi, C.; Soccolini, F. S 1985, 592.
3. Lu, Y.; Miet, C.; Kunesch, N.; Poisson, J. TA 1990, 1, 707.
4. (a) Tietze, L. F.; Voss, E.; Hartfiel, U. OS 1990, 69, 238. (b) Tietze, L. F.; Meier, H.; Voss, E. S 1988, 274.
5. Crosby, D. G.; Berthold, R. V. JOC 1962, 27, 3083.
6. Kusumi, T.; Chang, C. C.; Wheeler, M.; Kubo, I.; Nakanishi, K. TL 1981, 22, 3451.
7. Bretschneider, H.; Fliri, H.; Kloetzer, W. (Hoffmann-La Roche A.-G.) Ger. Offen. 2 352 152, 1974 (CA 1974, 81, 25 690k).
8. (a) Lecas-Nawrocka, A.; Levisalles, J.; Mariacher, C.; Renko, Z.; Rose, E. CJC 1984, 62, 2054. (b) Collman, J. P.; Chong, A. O.; Jameson, G. B.; Oakley, R. T.; Rose, E.; Schmittou, E. R.; Ibers, J. A. JACS 1981, 103, 516.
9. Bock, V.; Klötzer, W.; Singewald, N.; Strieder, G. S 1987, 1058.
10. (a) Lee, C. H.; Kohn, H. JHC 1990, 27, 2107. (b) Goya, P.; Stud, M. JHC 1978, 15, 253.
11. Israel, M.; Zoll, E. C.; Muhammad, N.; Modest, E. J. JMC 1973, 16, 1.
12. (a) Schlegel, G.; Mildenberger, H.; Bauer, K.; Bieringer, H. (Hoechst A.-G.) Ger. Offen. 3 531 007, 1987 (CA 1987, 106, 175 954y). (b) Humburg, G.; Willms, L.; Mildenberger, H.; Bauer, K.; Bieringer, H.; Buerstell, H. (Hoechst A.-G.) Eur. Pat. Appl. 98 569, 1984 (CA 1984, 101, 7206j).
13. Witkowski, J. T.; Czarniecki, M. F. (Schering Corp.) U.S. Patent 4 634 689, 1987 (CA 1987, 106, 120 067f).
14. Cumming, W. J. (Polaroid Corp.) U. S. Patent 4 634 773, 1987 (CA 1987, 106, 139 831x).
15. Montavon, M.; Reiner, R. (Hoffmann-La Roche, Inc.) U. S. Patent 4 348 518, 1982 (CA 1983, 98, 71 813b).
16. Inubushi, Y.; Harayama, T. H 1981, 15, 611.
17. Holy, A. CCC 1974, 39, 3177.
18. Becking, L.; Schäfer, H. J. TL 1988, 29, 2801.
19. Vik, J. E. ACS 1973, 27, 239.
20. Laitem, L.; Christiaens, L.; Llabres, G. BCF 1974, 681.
21. (a) Tietze, L. F.; Meier, H.; Nutt, H. CB 1989, 122, 643. (b) Tietze, L. F.; Meier, H.; Nutt, H. LA 1990, 253. (c) Tietze, L. F.; Glüsenkamp, K. H.; Holla, W. AG 1982, 21, 787.
22. Tietze, L. F.; Beifuss, U. AG 1993, 32, 131.

Lutz F. Tietze & Holger Geissler

Georg-August-Universität zu Göttingen, Germany

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