Methyl Diformylacetate

(dione)

[50427-65-1]  · C5H6O4  · Methyl Diformylacetate  · (MW 130.11) (enol)

[39947-70-1]

([2 + 2] cycloaddition1 (de Mayo reaction);2 [4 + 2]cycloaddition (hetero-Diels-Alder reaction with inverse electron demand);3 transformation to enamino aldehydes and their photochemical and thermal cycloadditions;4 Wittig reaction5)

Physical Data: bp 54-55 °C/3.5 mmHg.

Solubility: slightly sol water; sol aqueous alkali and diethyl ether.

Form Supplied in: colorless liquid.

Preparative Methods: by Panizzi's formylation procedure6 of commercially available methyl 3,3-dimethoxypropanoate7 with methyl formate,1i by diformylation of potassium monomethyl malonate with dimethyl formamide and phosphorus oxychloride followed by decarboxylation, and by ozonolysis of dimethyl 2,5-cyclohexadiene-1,4-dicarboxylate.8

Purification: fractional vacuum distillation.

Handling, Storage, and Precautions: stable for at least 6 months if stored at -20 °C; it is a highly acidic compound. Use in a fume hood.

Methyl diformylacetate (1) undergoes photochemical [2 + 2] cycloadditions ([2 + 2] photoannulation) with alkenes. Thus irradiation of (1) and the alkene (2) leads primarily to the cis-fused cyclobutane derivative (3), which by retro-aldol cleavage to a 1,5-dialdehyde and cyclization gives the hemiacetal (4). Treatment of (4) with methanol in the presence of IR-120 cation exchange resin yields the methyl acetal (5) (eq 1), which was converted into the iridoid-glucoside loganin.1i,j In a similar way, methyl diformylacetate has been used for the synthesis of hydroxyloganin, secologanin derivatives, and sarracenin.1a-g

In the photoaddition of methyl diformylacetate with Isobutene the two possible regioisomeric dihydropyrans (6) and (7) were formed in the ratio 2.5:1 (eq 2).1c

Methyl diformylacetate can also be employed as heterodiene in [4 + 2] cycloaddition with reactive dienophiles like enol ethers to give dihydropyrans. Thus the hetero-Diels-Alder reaction with inverse electron demand of (1) and 1-methoxycyclopentene at 20 °C for 200 h leads to the diastereomers (8) and (9) in the ratio 3:1 with 82% yields (eq 3).3a Methyl O-acyldiformylacetates are more reactive in the cycloadditions and the diastereomeric ratio is almost inverted. The use of chiral O-acyl derivatives allows an asymmetric induction.3a Triformylmethane may be used in a similar way.3b

Enamino aldehydes (8) were prepared by condensation of methyl diformylacetate with amines in the presence of a drying agent such as flame-dried Na2SO4 (eq 4).4a The [2 + 2] photoannulation of (8) with alkenes gives 2-hydroxytetrahydropyridines, which easily undergo elimination of water on treatment with an acid to afford 1,4-dihydropyridines. The reaction is highly selective; thus with electron-donating alkenes only 3-substituted 2-hydroxytetrahydropyridines are obtained (eq 5), and with electron-accepting alkenes only 4-substituted 2-hydroxytetrahydropyridines are obtained (eq 6).4

In a sequential transformation,9 which consists of a [2 + 2] photoannulation of an enamino aldehyde, obtained from (1), and an intramolecular C-C bond formation of the intermediate iminium salt, benzo[a]quinolizidines, quinolizidines, and pyrido[1,2-a]azepines can be synthesized.4a,f

N-Acyl-enamino aldehydes from (1) react with enol ethers in a hetero-Diels-Alder reaction with inverse electron demand to give 4-aminodihydropyrans with the skeleton of branched amino sugars of the garosamine type.4c

Methyl diformylacetate5b and its acetylated form5a were also used as carbonyl compounds for a Wittig reaction, with moderate yields.

Related Reagents.

3-Ethoxyacrolein; Ethyl 3,3-Diethoxypropanoate; Ethyl 3-Ethoxyacrylate; Ethyl Hydroxymethyleneacetate, Sodium Salt; Malondialdehyde.


1. (a) Tietze, L. F.; Glüsenkamp, K. H.; Nakane, M.; Hutchinson, C. R. AG 1982, 94, 81. (b) Baldwin, S. W.; Crimmins, M. T. JACS 1982, 104, 1132. (c) Baldwin, S. W.; Crimmins, M. T.; Cheek, V. I. S 1978, 210. (d) Hutchinson, C. R.; Mattes, K. C.; Nakane, M.; Partridge, J. J.; Uskoković, M. R. HCA 1978, 61, 1221. (e) Kinast, G.; Tietze, L. F. CB 1976, 109, 3626. (f) Tietze, L. F. JACS 1974, 96, 946. (g) Tietze, L. F. CB 1974, 107, 2499. (h) Partridge, J. J.; Chadha, N. K.; Uskoković, M. R. JACS 1973, 95, 532. (i) Büchi, G.; Carlson, J. A.; Powell Jr., J. E.; Tietze, L. F. JACS 1973, 95, 540. (j) Büchi, G.; Carlson, J. A.; Powell Jr., J. E.; Tietze, L. F. JACS 1970, 92, 2165.
2. De Mayo, P. ACR 1971, 4, 41.
3. (a) Tietze, L. F.; Glüsenkamp, K. H. AG 1983, 95, 901. (b) Tietze, L. F.; Glüsenkamp, K. H.; Harms, K.; Remberg, G. TL 1982, 23, 1147.
4. (a) Tietze, L. F.; Wünsch, J. R.; Noltemeyer, M. T 1992, 48, 2081. (b) Tietze, L. F.; Bergmann, A.; Brüggemann, K. S 1986, 190. (c) Tietze, L. F.; Voss, E.; Harms, K.; Sheldrick, G. M. TL 1985, 26, 5273. (d) Tietze, L. F.; Bergmann, A.; Brüggemann, K. TL 1983, 24, 3579. (e) Tietze, L. F.; Brüggemann, K. AG 1982, 94, 550. (f) Tietze, L. F.; Brüggemann, K. AG 1979, 91, 575.
5. (a) Ramage, R.; MacLeod, A. M. T 1986, 42, 3251. (b) Ramage, R.; MacLeod, A. M. CC 1984, 1008.
6. Panizzi, L. G 1946, 76, 56.
7. Methyl 3,3-dimethoxypropanoate can also be prepared by acylation of methyl vinyl ether followed by methanolysis in the presence of potassium carbonate: Tietze, L. F.; Meier, H.; Voss, E. S 1988, 274.
8. (a) Hutchinson, C. R.; Nakane, M.; Gollman, H.; Knutson, P. L. OS 1986, 64, 144. (b) Nakane, M.; Gollman, H.; Hutchinson, C. R.; Knutson, P. L. JOC 1980, 45, 2536.
9. Tietze, L. F.; Beifuss, U. AG(E) 1993, 32, 131.

Lutz F. Tietze & Holger Geissler

Georg-August-Universität zu Göttingen, Germany



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