Diethyl Ethoxymethylenemalonate

(R = Et)

[87-13-8]  · C10H16O5  · Diethyl Ethoxymethylenemalonate  · (MW 216.23) (R = Me)

[22398-14-7]  · C7H10O5  · Dimethyl Methoxymethylenemalonate  · (MW 174.15)

(push-pull alkene;1 1,4-addition-elimination (AdN-E);2 quinoline derivatives;3 1,4-addition;4 [3 + 2] cycloadditions;5 Diels-Alder reaction;6 protecting group for amino sugars7 and amino acids;8 oxo-Meldrum's acid9)

Physical Data: R = Et: bp 108-110 °C/0.25 mmHg; d 1.070 g cm-3. R = Me:2h mp 44-45 °C; bp 106 °C/0.7 mmHg.

Solubility: sol ethanol and diethyl ether.

Form Supplied in: clear liquid; widely available.

Analysis of Reagent Purity: n20D = 1.4612-1.4623.

Preparative Method: prepared by heating Triethyl Orthoformate, Diethyl Malonate, Acetic Anhydride, and catalytic amounts of Zinc Chloride.10

Purification: fractional vacuum distillation.

The ethoxy group of diethyl ethoxymethylenemalonate or dimethyl methoxymethylenemalonate can be substituted by various nucleophiles in an AdN-E mechanism. Malonates (eq 1),2c,e,g,h Grignard reagents,2i enolates,2b quaternary salts of heterocyclic bases containing an active methylene group,2a,f amines,2d,k hydrazines,11 etc., can be used as nucleophiles in this way. In contrast, only 1,4-addition is observed with organometallic compounds at low temperature (eq 2)4a-c or in the oxymercuration-demercuration reaction (eq 3).4d,12

Quinoline derivatives are prepared in a sequential substitution-cyclization process (eq 4).3 In similar reactions, various heterocycles such as 1,8-naphthyridines, 2H-pyrido[1,2-a]pyrimidin-4-ones,3d,e pyrazolinones,11,13 pyrones,2b,c xanthyrones,2e,h guanidine derivatives,14 pyrroles,15 1,2,4-triazoles,16 3-oxo-1,2,6-thiadiazine 1,1-dioxides,17 8-oxoimidazo[1,2-a]pyridiumides,2a 3H-pyrrolo[1,2-a]indol-3-one derivatives,18 and 1H-1,4-benzodiazepines19 can be obtained.

Cyclopentenones are formed in [3 + 2] cycloadditions of dimethyl methoxymethylenemalonate and cyclopropenone acetals (eq 5).5b,e Similarly, reaction with benzonitrilium isopropylide, which is generated in situ by a photoinduced cleavage of the corresponding azirine, leads to pyrrolines,5f and reaction with diazo compounds to pyrazolines.5a,c,d,20

Diethyl ethoxymethylenemalonate is also used for the protection of the amino group of amino sugars and amino acids. The N-protecting group of amino acids can be removed using Bromine in chloroform.8 Elimination of the 2,2-diacylvinyl group of amino sugars has been described using Chlorine, Ammonia, or Amberlite IRA-400 (HO-) resin.7

b-Ribofuranosylmalonates can be synthesized stereoselectively through high-pressure Diels-Alder reaction of furan with dimethyl acetoxymethylenemalonate.6 The unstable diethyl methylenemalonate is obtained from diethyl ethoxymethylenemalonate by catalytic reduction and elimination of ethanol.21 Ozonolysis of methoxymethylene-Meldrum's acids22 yields oxo-Meldrum's acids after workup with Phosphorus(III) Chloride.9

Related Reagents.

Diethyl Malonate; 3-Ethoxyacrolein; 3-Ethoxyacrylonitrile; Ethyl 3,3-Diethoxypropanoate; Ethyl 3-Ethoxyacrylate; Ethyl Ethoxymethyleneacetoacetate; Ethyl Ethoxymethylenecyanoacetate; Ethyl Hydroxymethyleneacetate, Sodium Salt.

1. Reviews on push-pull alkenes: (a) Sandstroem, J. Top. Stereochem. 1983, 14, 83. (b) Rudorf, W. D. Wiss. Z. Martin-Luther-Univ. Halle-Wittenberg Math. Naturwiss. Reihe 1983, 32, 57. (c) Kristen, H.; Peseke, K. Wiss. Z. Wilhelm-Pieck-Univ. Rostock Math. Naturwiss. Reihe 1976, 25, 1123.
2. (a) Matsuda, Y.; Gotou, H.; Katou, K.; Matsumoto, H.; Yamashita, M.; Takahashi, K.; Ide, S. H 1990, 31, 977. (b) Boger, D. L.; Mullican, M. D. OS 1987, 65, 98. (c) Ihara, M.; Noguchi, K.; Ohsawa, T.; Fukumoto, K.; Kametani, T. JOC 1983, 48, 3150. (d) Neidlein, R.; Jeromin, G. CB 1982, 115, 714. (e) Baker, S. R.; Crombie, L.; Dove, R. V. JCS(P1) 1981, 165. (f) Kakehi, A.; Ito, S.; Watanabe, K.; Kitagawa, M.; Takeuchi, S.; Hashimoto, T. JOC 1980, 45, 5100. (g) Kametani, T.; Ohsawa, T.; Ihara, M. H 1980, 14, 951. (h) Crombie, L.; Games, D. E.; James, A. W. G. JCS(P1) 1979, 464. (i) Nabar, D. P.; Sunthankar, S. V. BCJ 1969, 42, 2991. (k) Hurd, C. D.; Sherwood Jr., L. T. JOC 1948, 13, 471.
3. (a) Link, H.; Bernauer, K.; Englert, G. HCA 1982, 65, 2645. (b) Kametani, T.; Kigasawa, K.; Hiiragi, M.; Wakisaka, K.; Kusama, O.; Sugi, H.; Kawasaki, K. JHC 1977, 14, 1175. (c) Albrecht, R. LA 1972, 762, 55. (d) Markees, D. G.; Schwab, L. S. HCA 1972, 55, 1319. (e) Lappin, G. R. JACS 1948, 70, 3348. (f) Price, C. C.; Roberts, R. M. JACS 1946, 68, 1204. (g) Gould Jr., R. G.; Jacobs, W. A. JACS 1939, 61, 2890.
4. (a) Hibino, S.; Sugino, E.; Kuwada, T.; Ogura, N.; Sato, K.; Choshi, T. JOC 1992, 57, 5917. (b) Cahiez, G.; Alami, M. T 1989, 45, 4163. (c) Schöllkopf, U.; Schröder, J. LA 1988, 87. (d) Boeckman, R. K., Jr.; Flann, C. J. TL 1983, 24, 4923.
5. (a) Hamaguchi, M.; Nagai, T. CC 1987, 1299. (b) Boger, D. L.; Brotherton, C. E. JACS 1986, 108, 6695. (c) Abdallah, H.; Grée, R.; Carrié, R. CJC 1985, 63, 3031. (d) Abdallah, H.; Grée, R.; Carrié, R. T 1985, 41, 4339. (e) Boger, D. L.; Brotherton, C. E. JACS 1984, 106, 805. (f) Stegmann, W.; Gilgen, P.; Heimgartner, H.; Schmid, H. HCA 1976, 59, 1018.
6. (a) Katagiri, N.; Akatsuka, H.; Haneda, T.; Kaneko, C.; Sera, A. JOC 1988, 53, 5464. (b) Katagiri, N.; Haneda, T.; Kaneko, C. CPB 1986, 34, 4875.
7. Gómez-Sánchez, A.; Borrachero Moya, P.; Bellanato, J. Carbohydr. Res. 1984, 135, 101.
8. Alaiz, M.; Girón, J.; Hidalgo, F. J.; de la Maza, M. P.; Millán, F.; Zamora, R.; Vioque, E. S 1989, 544.
9. Schank, K.; Schuhknecht, C. CB 1982, 115, 2000.
10. Parham, W. E.; Reed, L. J. OSC 1955, 3, 395.
11. (a) Tietze, L. F.; Brumby, T.; Pretor, M.; Remberg, G. JOC 1988, 53, 810. (b) Coqueret, X.; Bourelle-Wargnier, F.; Chuche, J.; Toupet, L. CC 1983, 1144.
12. Kametani, T.; Ohsawa, T.; Ihara, M. JCS(P1) 1981, 1563.
13. Coqueret, X.; Bourelle-Wargnier, F.; Chuche, J. JOC 1985, 50, 909.
14. Bosin, T. R.; Hanson, R. N.; Rodricks, J. V.; Simpson, R. A.; Rapoport, H. JOC 1973, 38, 1591.
15. Donkor, A.; Prager, R. H.; Taylor, M. R.; Thomson, M. J. AJC 1992, 45, 1781.
16. (a) Miyamoto, Y.; Yamazaki, C. JHC 1989, 26, 763. (b) Miyamoto, Y.; Yamazaki, C. JHC 1989, 26, 327.
17. Hansen, H.; König, K.-H.; Rohr, W. LA 1979, 950.
18. Mérour, J. Y.; Piroëlle, S. JHC 1991, 28, 1869.
19. Sashida, H.; Kaname, M.; Tsuchiya, T. CPB 1990, 38, 2919.
20. The photoinduced rearrangement or thermolysis of pyrazoles is used in the syntheses of cyclopropanes: see Refs. 5a,d.
21. Feely, W.; Boekelheide, V. OSC 1963, 4, 298.
22. Preparations of various alkoxymethylene Meldrum's acids are described in: Bihlmayer, G. A.; Derflinger, G.; Derkosch, J.; Polansky, O. E. M 1967, 98, 564.

Lutz F. Tietze & Holger Geissler

Georg-August-Universität zu Göttingen, Germany

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