Trimethyl Phosphonoacetate1

[5927-18-4]  · C5H11O5P  · Trimethyl Phosphonoacetate  · (MW 182.13)

(with a base gives a phosphoryl-stabilized carbanion that reacts with aldehydes,1 ketones,1a-c ketenes,2 pyrylium salts,3 triflates,4a alkyl halides,4b alcohols,5 amines,5 azides,6 and CS27)

Alternate Name: dimethyl (methoxycarbonyl)methylphosphonate.

Physical Data: bp 118 °C/0.85 mmHg; d 1.125 g cm-3.

Solubility: sol common organic solvents.

Form Supplied in: colorless liquid; widely available.

Handling, Storage, and Precautions: store under N2.

Reactions with Aldehydes and Ketones.

n-Butyllithium,1d,8 Sodium Amide,9 Sodium Hydride,1d,10b Potassium Hydride,1d Potassium t-Butoxide,8,10 Sodium Methoxide,11 KOMe,12 Potassium Hexamethyldisilazide (KHMDS),13 and other bases deprotonate (MeO)2P(O)CH2CO2Me in solvents such as THF, DME, MeCN, DMF, DMSO, MeOH, benzene, toluene, and dioxane to give a phosphoryl-stabilized carbanion, [(MeO)2P(O)-CHCO2Me]X+. The anion reacts with aldehydes and ketones to give an (E)-a,b-unsaturated ester as the major product (eq 1)14 in a Horner-Wadsworth-Emmons (HWE) reaction (see also Triethyl Phosphonoacetate). Hemiacetals (eq 2)15 also react with [(MeO)2P(O)-CHCO2Me]X+ to give an a,b-unsaturated ester. In some instances, (MeO)2P(O)CH2CO2Me and the aldehyde undergo a Knoevenagel condens ation (eq 3).16

The aldehyde reactivity in HWE reactions with (MeO)2P(O)CH2CO2Me is seemingly unaffected by complexation (eq 4)2,17a or conjugation (eqs 4 and 5).17 Cyclohexanones with a C-2 equatorial alkyl group are unreactive to [(MeO)2P(O)-CHCO2Me]X+ under normal conditions.18 Reaction occurs if the substituent can readily attain a conformation or configurational (epimerization) conversion to an axial position. Compounds containing 2 equivalent carbonyl groups undergo a double HWE reaction.19

Other basic conditions for the HWE reaction with (MeO)2P(O)CH2CO2Me have been developed to accommodate base-sensitive aldehydes and to minimize undesired side reactions.11c,16 Potassium Carbonate has been used in heterogeneous liquid-liquid conditions in the absence of organic solvents (eq 5).17b,20,21 Sodium Hydroxide has also been used in liquid-liquid conditions20 in the presence of a phase-transfer catalyst and both NaOH20 and K2CO320 have been used in solid-liquid two-phase conditions. Other bases used include Cesium Carbonate,15c,20 Barium Hydroxide,20 Lithium Hydroxide,22 and a combination of Lithium Chloride and either Diisopropylethylamine (DIPEA) (eq 6),20,23 1,8-Diazabicyclo[5.4.0]undec-7-ene,20 or Triethylamine.20 HWE reactions have also been carried out in the presence of crown ethers13b and the treatment of polymer-bound phosphonates at rt with aldehydes and ketones gives alkenes in high yields and with high (E) stereoselectivity.24

The (E/Z) ratio of unsaturated esters formed in the reaction of [(MeO)2P(O)-CHCO2Me]X+ with aldehydes is dependent on the metal cation (X+), reaction temperature, solvent, and the degree of a-substitution of the aldehyde.1d None of the effects alone is very large, but the combination of effects allows for a degree of control on the stereoselectivity of the reaction. (E) Selectivity is promoted with a-trisubstituted aldehydes, Li+, rt, and nonchelating solvents such as benzene and DME. Formation of (Z)-unsaturated esters is promoted with a-mono and disubstituted aldehydes, and Na+ or K+ at -78 °C in THF. The (E/Z) stereochemistry in HWE reactions of trialkyl phosphonates is also influenced by the nature of the phosphonate carboxylic ester substituent.1c

A comparison of the alkenation of ketones and aldehydes using (MeO)2P(O)CH2CO2Me under HWE conditions and Ph3PCHCO2Me under Wittig conditions suggests that the former gives superior (E) stereoselectivity and occurs under milder reaction conditions (e.g. eq 5).17b,25 a,b-Unsaturated esters are prepared from aromatic, saturated, and unsaturated aliphatic aldehydes with high (Z) stereoselectivity under Still-modified HWE conditions, using bis(trifluoroethyl) phosphonoesters (CF3CH2O)2P(O)CHRCO2Me (R = H, Me) and/or strongly dissociated base systems like KN(TMS)2/18-crown-6.13a,25c,26 A predominance of (Z)-alkene has also been reported using (MeO)2P(O)CH2CO2Me under these conditions (eq 7).13b,26a

The reduction of a saturated ester or lactone with Diisobutylaluminum Hydride at -78 °C in the presence of [(MeO)2P(O)-CHCO2Me]Na+ gives a good yield (60-80%) of the homologous ester with little or no overreduction of the starting material or product ester (eq 8).20,27

Reactions with Ketenes.

The anion of trimethyl phosphonoacetate, derived from reaction with Sodium Hydride, reacts with tricarbonyl(vinylketene)iron(0) complexes to give (E)- and (Z)-tricarbonyl(vinylallene)iron(0) complexes in the ratio of 7:3 (eq 9).2 Oxidation of the vinylallene complexes with Iron(III) Chloride leads to the release of the organic ligands as 5-alkyl-5-styrylfuran-2(5H)-ones (eq 9).2

Other Reactions.

[(MeO)2P(O)-CHCO2Me]Na+ reacts with pyrylium salts (eq 10).3 a-Substituted phosphonates are prepared by alkylating [(MeO)2P(O)-CHCO2Me]Na+ with either an alkyl triflate (eq 11)4a or iodide4b (see also Triethyl Phosphonoacetate). Differentially substituted phosphonoacetates and phosphonoacetamides are prepared by reacting (MeO)2P(O)CH2CO2Me with 4-Dimethylaminopyridine and an alcohol or amine, respectively.5 The reaction of [(MeO)2P(O)-CHCO2Me]Na+ with an azide gives an a-diazo phosphonate.6 Reaction with CS2 gives an 1,1-alkenedithiolate (eq 12) that can be alkylated, oxidized, protonated, and phosgenated.7 Trialkyl phosphonates react with epoxides,20 but only under forcing conditions.28


1. (a) Boutagy, J.; Thomas, R. CRV 1974, 74, 87. (b) Wadsworth, W. S., Jr. OR 1977, 25, 73. (c) Maryanoff, B. E.; Reitz, A. B. CRV 1989, 89, 863. (d) Thompson, S. K.; Heathcock, C. H. JOC 1990, 55, 3386.
2. Saberi, S. P.; Thomas, S. E. JCS(P1) 1992, 259.
3. Zimmerman, S. C. TL 1988, 29, 983.
4. (a) Fleet, G. W. J.; Shing, T. K. M.; Warr, S. M. JCS(P1) 1984, 905. (b) Marshall, J. A.; DeHoff, B. S. TL 1986, 27, 4873.
5. Hatakeyama, S.; Satoh, K.; Sakurai, K.; Takano, S. TL 1987, 28, 2713.
6. Maas, G.; Regitz, M. CB 1976, 109, 2039.
7. Schaumann, E.; Grabley, F.-F. LA 1979, 1715.
8. Etemad-Moghadam, G.; Seyden-Penne, J. T 1984, 40, 5153.
9. Carling, R. W.; Leeson, P. D.; Moseley, A. M.; Baker, R.; Foster, A. C.; Grimwood, S.; Kemp, J. A.; Marshall, G. R. JMC 1992, 35, 1942.
10. (a) Hanessian, S.; Lavallee, P. CJC 1981, 59, 870. (b) Bensel, N.; Marschall, H.; Weyerstahl, P.; Zeisberg, R. LA 1982, 1781.
11. (a) Wicha, J.; Bal, K. JCS(P1) 1978, 1282. (b) Sierra, M. G.; Cravero, R. M.; de los Angeles Laborde, M.; Rúveda, E. A. JCS(P1) 1985, 1227. (c) Hellwinkel, D.; Kosack, T. LA 1985, 226.
12. Hughes, P.; Clardy, J. JOC 1989, 54, 3260.
13. (a) Tudanca, P. L. L.; Jones, K.; Brownbridge, P. JCS(P1) 1992, 533. (b) Sun, C.-q.; Guillaume, D.; Dunlap, B.; Rich, D. H. JMC 1990, 33, 1443.
14. Ihara, M.; Takahashi, T.; Shimizu, N.; Ishida, Y.; Sudow, I.; Fukumoto, K.; Kametani, T. JCS(P1) 1989, 529.
15. (a) Ichihara, A.; Ubukata, M.; Oikawa, H.; Murakami, K.; Sakamura, S. TL 1980, 21, 4469. (b) Trost, B. M.; Rivers, G. T.; Gold, J. M. JOC 1980, 45, 1835. (c) Bloch, R.; Seck, M. TL 1987, 28, 5819. (d) Shishido, K.; Sukegawa, Y.; Fukumoto, K.; Kametani, T. JCS(P1) 1987, 993. (e) Allevi, P.; Ciuffreda, P.; Colombo, D.; Monti, D.; Speranza, G.; Manitto, P. JCS(P1) 1989, 1281.
16. Chen, S. F.; Kumar, S. D.; Tishler, M. TL 1983, 24, 5461.
17. (a) Martina, D.; Brion, F. TL 1982, 23, 865. (b) Jones, R. C. F.; Jones, R. F. TL 1990, 31, 3363. (c) Irie, H.; Kitagawa, T.; Miyashita, M.; Zhang, Y. CPB 1991, 39, 2545. (d) Boger, D. L.; Curran, T. T. JOC 1992, 57, 2235.
18. Harding, K. E.; Tseng, C.-Y. JOC 1975, 40, 929.
19. Paquette, L. A.; Fischer, J. W.; Browne, A. R.; Doecke, C. W. JACS 1985, 107, 686.
20. See discussion on Triethyl Phosphonoacetate.
21. Jako, I.; Uiber, P.; Mann, A.; Wermuth, C.-G.; Boulanger, T.; Norberg, B.; Evrard, G.; Durant, F. JOC 1991, 56, 5729.
22. Delmarche, I.; Mosset, P. TL 1993, 34, 2465.
23. (a) Trost, B. M.; Sudhakar, A. R. JACS 1987, 109, 3792. (b) Meinke, P. T.; O'Connor, S. P.; Mrozik, H.; Fisher, M. H. TL 1992, 33, 1203.
24. Cainelli, G.; Contento, M.; Manescalchi, F.; Regnoli, R. JCS(P1) 1980, 2516.
25. (a) Le Doussal, B.; Le Coq, A.; Gorgues, A.; Meyer, A. T 1983, 39, 2185. (b) Hackler, R. E.; Dreikorn, B. A.; Johnson, G. W.; Varie, D. L. JOC 1988, 53, 5704. (c) Bernardi, A.; Cardani, S.; Scolastico, C.; Villa, R. T 1988, 44, 491. (d) Gruseck, U.; Heuschmann, M. CB 1990, 123, 1905.
26. (a) Still, W. C.; Gennari, C. TL 1983, 24, 4405. (b) Misiti, D.; Zappia, G. TL 1990, 31, 7359.
27. Takacs, J. M.; Helle, M. A.; Seely, F. L. TL 1986, 27, 1257.
28. Bardili, B.; Marschall-Weyerstahl, H.; Weyerstahl, P. LA 1985, 275.

Andrew Abell & Jane Taylor

University of Canterbury, Christchurch, New Zealand



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