Triethyl Phosphonoacetate1


[867-13-0]  · C8H17O5P  · Triethyl Phosphonoacetate  · (MW 224.22)

(treatment with a base gives a phosphoryl-stabilized carbanion that reacts with aldehydes,1 ketones,1 nitrones,2 epoxides,3 nitroso compounds,4 ketenes,5 alkyl halides,6c and halogenating agents6a,b)

Alternate Names: ethyl (diethoxyphosphinyl)acetate; diethyl (ethoxycarbonyl)methylphosphonate.

Physical Data: bp 152-153 °C/20 mmHg; d 1.130 g cm-3.

Solubility: sol common organic solvents.

Form Supplied in: colorless liquid; widely available.

Handling, Storage, and Precautions: irritant; store under N2.

Reactions with Aldehydes and Ketones.

(EtO)2P(O)CH2CO2Et in either DME, THF, DMF, MeCN, dioxane, benzene, or toluene is deprotonated by Sodium Hydride,7 Sodium Amide,8 metal alkoxides,9 and other bases to give a phosphoryl-stabilized carbanion, [(EtO)2P(O)-CHCO2Et] M+. Subsequent reaction of the carbanion with an aldehyde or ketone gives an (E)-a,b-unsaturated ester as the major product in a Horner-Wadsworth-Emmons (HWE) reaction (eqs 1-4)1 (see also Trimethyl Phosphonoacetate). The phosphate ester byproduct is water soluble, unlike the Wittig byproduct (Ph3PO), and is easily removed at the completion of the reaction. Ketones and aliphatic aldehydes often give the (Z)-a,b-unsaturated ester in addition to the (E)-isomer,1c,d the isomer ratio being influenced by the reaction solvent (eq 1).7a Some ketones and aldehydes that are unreactive to Wittig alkenation conditions (e.g. 3-keto steriods9,10 and glucose derivatives11) will react with the carbanion of (EtO)2P(O)CH2CO2Et. The Peterson alkenation reaction of lithio ethyl trimethylsilylacetate with aldehydes and ketones offers a mild alternative to both the HWE and Wittig approaches to a,b-unsaturated esters.12 The Peterson reaction often gives the (Z)-isomer as the major product.12b (Z)-Alkenes are also obtained from HWE reactions using bis(2,2,2-trifluoroethyl) phosphonates (see also Trimethyl Phosphonoacetate).13

Milder reaction conditions have been developed to increase yields, accommodate sensitive substrates and minimize undesired side reactions such as double bond migrations, Knoevenagel condensation, Cannizzaro reaction, and Michael addition.1 HWE reactions of aldehydes and (EtO)2P(O)CH2CO2Et have been carried out in two-phase liquid-liquid conditions (aqueous NaOH/CH2Cl2) in the presence of a phase transfer catalyst, thus eliminating the need for anhydrous solvents.14 Superior yields and reduced reaction times were obtained using aromatic aldehydes and ketones under solid-liquid two-phase conditions (powdered NaOH or KOH/THF) (eq 2).14b,c

Aliphatic and particularly aromatic aldehydes give high yields of (E)-a,b-unsaturated esters using (EtO)2P(O)CH2CO2Et and K2CO3 (eq 2)15 or Cs2CO316 under solid-liquid conditions. K2CO3 has also been used in highly concentrated (6-10 molar) aqueous solutions under heterogeneous liquid-liquid conditions in the absence of organic solvent (eq 2).15a,c The combination of aqueous K2CO3 and (EtO)2P(O)CH2CO2Et has been employed elsewhere, e.g. under these conditions glutaraldehyde and succinaldehyde give 1-ethoxycarbonyl-6-cyclohexenol and 1-ethoxycarbonyl-5-cyclopentenol, respectively,17 and aqueous formaldehyde gives ethyl a-(hydroxymethyl)acrylate15a rather than the normal HWE product. The use of D2O, rather than water, gives a general preparation of a-deuterated a,b-unsaturated esters18 (%D > 90).

Furfural reacts with (EtO)2P(O)CH2CO2Et and activated Barium Hydroxide catalyst at 70 °C in dioxane containing a trace of water to give (E)-ethyl 3-(2-furyl)acrylate in quantitative yield.19 Reaction times are reduced in comparison with other solid-liquid procedures.19 No secondary reactions were observed, in contrast to aqueous base catalysis, and the method is applicable to hindered aldehydes.19 A reduction in both the amount of Ba(OH)2 catalyst required and the reaction time is obtained using sonochemical, rather than thermal activation.20

The reaction of an aldehyde with (EtO)2P(O)CH2CO2Et and Diisopropylethylamine (DIPEA)21,22 or 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)21,23 in a stirred suspension of Lithium Chloride in dry MeCN gives excellent yields of (E)-a,b-unsaturated esters (eq 3).21 The method is widely used with base-sensitive aldehydes.21-23 Few reports have appeared using a ketone rather than an aldehyde under these conditions.21,24 The use of DIPEA, rather than DBU, has been reported to give less epimerization of the aldehyde component (eq 4).22b An interesting extension of this reaction proceeds by an in situ oxidation and HWE coupling (eq 5).22c The combination of (EtO)2P(O)CH2CO2Et, TEA, LiCl and an aldehyde also gives high yields of an a,b-unsaturated ester.25 The use of (CF3CH2O)2P(O)CH2CO2Et has extended the scope of this reaction to include ketones.25,26 Other catalysts of the HWE reaction include Alumina, and Potassium Fluoride-Alumina.27 Polymer-bound phosphonates have also received some attention.28

Diisobutylaluminum Hydride (DIBAL) reduction of saturated esters29 and lactones29a at -78 °C in the presence of the NaH-derived carbanion of (EtO)2P(O)CH2CO2Et gives good yields of the homologous esters with >90% (E) stereochemistry and with little or no overreduction of either the starting material or product ester (eq 6).29a The reaction of (EtO)2P(O)CH2CO2Et with either glucopyranoses11b or hydroxy phthalides in the presence of 1 mol % of tetra-n-hexylammonium bromide30 gives ring-opened alkenes in good yields.

The addition of an acyl phosphonate [e.g. (EtO)2P(O)COPh] to the NaH-derived phosphoryl carbanion of (EtO)2P(O)CH2CO2Et, gives the (Z)-alkene as the major product.31 The analogous Wittig alkenation reaction gives (E)-alkenes.31

Other Reactions.

Nitrones react with (EtO)2P(O)CH2CO2Et and NaH in DME or alkali metal alkoxides in alcoholic solvents to give aziridines and cyclic enamines (eq 7).2 Cyclopropanes are prepared by refluxing an epoxide with (EtO)2P(O)CH2CO2Et,3a or the corresponding sodium phosphoryl carbanion in dioxane or DME3b (eq 8).3c,d

7-Pteridinones are prepared by treating the sodium phosphoryl carbanion of (EtO)2P(O)CH2CO2Et with 4,6-diamino-5-nitrosopyrimidines (eq 9).4 Ketenes react with the NaH-derived carbanion of (EtO)2P(O)CH2CO2Et in DME at 50 °C to give allenes (eq 10).5,6a a-Alkylated and arylated phosphonates are prepared by reacting the carbanion of (EtO)2P(O)CH2CO2Et with an allyl6c and benzyl32 halide, respectively. Triethyl phosphonoacetate is also readily halogenated at the a-position.6a,b

Related Reagents.

Trimethyl Phosphonoacetate.

1. (a) Boutagy, J.; Thomas, R. CRV 1974, 74, 87. (b) Wadsworth, W. S., Jr. OR 1977, 25, 73. (c) Larsen, R. O.; Aksnes, G. PS 1983, 16, 339. (d) Maryanoff, B. E.; Reitz, A. B. CRV 1989, 89, 863.
2. (a) Zbaida, S.; Breuer, E. JOC 1982, 47, 1073. (b) Breuer, E.; Zbaida, S. JOC 1977, 42, 1904.
3. (a) Denney, D. B.; Vill, J. J.; Boskin, M. J. JACS 1962, 84, 3944. (b) Smith, D. J. H. Organophosphorus Reagents in Organic Synthesis; Cadogan, J. I. G., Ed.; Academic: London, 1979; pp 214-217 and references therein. (c) Fraser-Reid, B.; Carthy, B. J. CJC 1972, 50, 2928. (d) Fitzsimmons, B. J.; Fraser-Reid, B. T 1984, 40, 1279.
4. (a) Youssefyeh, R. D.; Kalmus, A. CC 1970, 1371. (b) Taylor, E. C.; Evans, B. E. CC 1971, 189.
5. Kresze, G.; Runge, W.; Ruch, E. LA 1972, 756, 112.
6. (a) Wadsworth, W. S., Jr.; Emmons, W. D. JACS 1961, 83, 1733. (b) McKenna, C. H.; Khawli, L. A. JOC 1986, 51, 5467. (c) Kirschleger, B.; Queignec, R. S 1986, 926.
7. (a) Wender, P. A.; Eissenstat, M. A.; Filosa, M. P. JACS 1979, 101, 2196. (b) Baggiolini, E. G.; Iacobelli, J. A.; Hennessy, B. M.; Batcho, A. D.; Sereno, J. F.; Uskokovic, M. R. JOC 1986, 51, 3098.
8. Takahashi, H.; Fujiwara, K.; Ohta, M. BCJ 1962, 35, 1498.
9. Bose, A. K.; Dahill, R. T., Jr. JOC 1965, 30, 505.
10. Bose, A. K.; Dahill, R. T., Jr. TL 1963, 959.
11. (a) Tadano, K.; Idogaki, Y.; Yamada, H.; Suami, T. JOC 1987, 52, 1201. (b) Monti, D.; Gramatica, P.; Speranza, G.; Manitto, P. TL 1987, 28, 5047.
12. (a) Shimoji, K.; Taguchi, H.; Oshima, K.; Yamamoto, H.; Nozaki, H. JACS 1974, 96, 1620. (b) Strekowski, L.; Visnick, M.; Battiste, M. A. TL 1984, 25, 5603.
13. Still, W. C.; Gennari, C. TL 1983, 24, 4405.
14. (a) Piechucki, C. S 1974, 869. (b) Texier-Boullet, F.; Foucaud, A. S 1979, 884. (c) Texier-Boullet, F.; Foucaud, A. TL 1980, 21, 2161.
15. (a) Villieras, J.; Rambaud, M. S 1983, 300. (b) Mouloungui, Z.; Delmas, M.; Gaset, A. SC 1984, 14, 701. (c) Villieras, J.; Rambaud, M.; Graff, M. TL 1985, 26, 53. (d) Mouloungui, Z.; Elmestour, R.; Delmas, M.; Gaset, A. T 1992, 48, 1219.
16. Mouloungui, Z.; Murengezi, I.; Delmas, M.; Gaset, A. SC 1988, 18, 1241.
17. Graff, M.; Al Dilaimi, A.; Seguineau, P.; Rambaud, M.; Villieras, J. TL 1986, 27, 1577.
18. Seguineau, P.; Villieras, J. TL 1988, 29, 477.
19. Sinisterra, J. V.; Mouloungui, Z.; Delmas, M.; Gaset, A. S 1985, 1097.
20. (a) Fuentes, A.; Marinas, J. M.; Sinisterra, J. V. TL 1987, 28, 2951. (b) Sinisterra, J. V.; Fuentes, A.; Marinas, J. M. JOC 1987, 52, 3875.
21. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T. TL 1984, 25, 2183.
22. (a) Dauben, W. G.; Greenfield, L. J. JOC 1992, 57, 1597. (b) Guanti, G.; Banfi, L.; Narisano, E.; Riva, R. TL 1992, 33, 2221. (c) Blackwell, C. M.; Davidson, A. H.; Launchbury, S. B.; Lewis, C. N.; Morrice, E. M.; Reeve, M. M.; Roffey, J. A. R.; Tipping, A. S.; Todd, R. S. JOC 1992, 57, 5596.
23. (a) Takacs, J. M.; Myoung, Y. C. TL 1992, 33, 317. (b) Gravier-Pelletier, C.; Dumas, J.; Le Merrer, Y.; Depezay, J.-C. T 1992, 48, 2441.
24. Courtneidge, J. L.; Bush, M.; Loh, L.-S. JCS(P1) 1992, 1539.
25. (a) Rathke, M. W.; Nowak, M. JOC 1985, 50, 2624. (b) Tsukamoto, T.; Kitazume, T. CC 1992, 540. (c) Tietze, L. F.; Wünsch, J. R. AG(E) 1991, 30, 1697.
26. Rathke, M. W.; Bouhlel, E. SC 1990, 20, 869.
27. Texier-Boullet, F.; Villemin, D.; Ricard, M.; Moison, H.; Foucaud, A. T 1985, 41, 1259.
28. Qureshi, A. E.; Ford, W. T. Brit. Polym. J. 1984, 16, 231.
29. (a) Takacs, J. M.; Helle, M. A.; Seely, F. L. TL 1986, 27, 1257. (b) Johnson, S. J.; Kesten, S. R.; Wise, L. D. JOC 1992, 57, 4746. (c) Ikemoto, N.; Schreiber, S. L. JACS 1992, 114, 2524.
30. Trost, B. M.; Rivers, G. T.; Gold, J. M. JOC 1980, 45, 1835.
31. Harris, R. L. N.; McFadden, H. G. AJC 1984, 37, 417.
32. Rodriguez, M.; Heitz, A.; Martinez, J. TL 1990, 31, 7319.

Andrew Abell

University of Canterbury, Christchurch, New Zealand

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