Trimethyl 2-Phosphonoacrylate

(1; R1 = Me, R2 = Me)

[55168-74-6]  · C6H11O5P  · Trimethyl 2-Phosphonoacrylate  · (MW 194.14) (2; R1 = Et, R2 = Et)

[20345-61-3]  · C9H17O5P  · Triethyl 2-Phosphonoacrylate  · (MW 236.23) (3; R1 = Me, R2 = Et)

[993-88-4]  · C8H15O5P  · Diethyl Methyl 2-Phosphonoacrylate  · (MW 222.20)

(reactive, bifunctional Michael acceptor for tandem conjugate addition-alkenation and annulation reactions; useful enophile for ene reactions and dienophile for Diels-Alder reactions)

Physical Data: (1) bp 90-92 °C/0.1 mmHg. (2) bp 98.5-99.5 °C/0.13 mmHg. (3) bp 95-98 °C/0.15 mmHg.

Solubility: sol Et2O, THF, EtOH, and most polar organic solvents.

Form Supplied in: (1) is commercially available; (2) and (3) must be synthesized.2,3

Analysis of Reagent Purity: IR and NMR spectroscopy and GC.

Preparative Method: (1) is prepared by heating Trimethyl Phosphonoacetate at reflux with a mixture of Paraformaldehyde, MeOH, and Piperidine (previously heated at reflux).

Handling, Storage, and Precautions: commercial (1) is supplied with 0.5% 2,6-di-t-butyl-p-cresol as a stabilizer.

Conjugate Addition-Alkenation.

3-Substituted 2-phosphonomethylacrylates1 can be prepared using phosphorus nucleophiles which undergo Michael addition to trimethyl 2-phosphonoacrylate. The resulting carbanion undergoes Horner-Emmons-type alkenation with aldehydes (eq 1). A similar sequence can be utilized to prepare functionalized dienes,1 trienes, and their analogs (eq 2).

A variety of carbanion nucleophiles add to vinyl phosphonates to produce stabilized phosphonate anions capable of undergoing reactions with aldehydes and ketones to give unsaturated esters (eq 3).2

Annulation.

Oxygen and nitrogen nucleophiles add to phosphonoacrylates and lead to the formation of heterocyclic compounds (eq 4). Michael addition of N-lithio-4-vinylazetidin-2-one to vinyl phosphonate gives an addition product which can be converted to D1-carbapenems4 via ozonolysis and intramolecular Horner-Wittig reaction (eq 5). An imine-enamine annulation was used in the synthesis of the indoloquinolizidine alkaloid (±)-deplancheine.4 Similarly, synthesis of six-membered carbocyclic compounds can be achieved by 2:1 condensation reactions of the phosphonoacrylate with cyclopentanone enolates (eq 6). Phosphonoacrylate annulation was also used in the construction of a [3.3.0]pyrazolidinone4 from the monocyclic pyrazolidinone.

Sulfur Nucleophiles.

Michael addition of mercaptoacetaldehyde to phosphonoacrylate gives methyl 2,5-dihydrothiophene-3-carboxylate, which thermally decomposes to methyl 1,3-butadiene-2-carboxylate (eq 7). Similarly, sulfur nucleophiles5 such as phenylthiolate and isopropylthiolate have been utilized in the synthesis of b-acetoxy- and b-hydroxy-a-methylene-g-butyrolactones (eq 8),5 confertin,5 and arteannuin B.5

Ene and Diene Reactions.

Trimethyl 2-phosphonoacrylate undergoes facile ene reactions6 with a variety of alkenes, using Ethylaluminum Dichloride as a Lewis acid catalyst (eq 9). It also undergoes [4 + 2] cycloadditions with isoprene (eq 10) and 6,6-diphenylfulvene.6 Irradiation of acyl-N-hydroxy-2-thiopyridones in the presence of trimethyl 2-phosphonoacrylate affords derivatives of phosphonic analogs of nucleotides.7

Related Reagents.

Diethyl Phosphonite; Ethyl Acrylate; Methyl 2-Methylthioacrylate; Methyl 2-Trimethylsilylacrylate; Triethyl Phosphite; Triethyl Phosphonoacetate; Vinyltriphenylphosphonium Bromide.


1. (a) Schoen, W. R.; Parsons, W. H. TL 1988, 29, 5201. (b) Minami, T.; Shigehumi, T.; Hirao, I. BCJ 1985, 58, 2139. (c) Minami, T.; Shigehumi, T.; Hirao, I.; Suganuma, H.; Agawa, T. JOC 1982, 47, 2360.
2. (a) Kleschick, W. A.; Heathcock, C. H. JOC 1978, 43, 1257. (b) Minami, T.; Suganuma, H.; Agawa, T. CL 1978, 285.
3. (a) Semmelhack, M. F.; Tomesch, J. C.; Czarny, M.; Boettger, S. JOC 1978, 43, 1259. (b) Pudovik, A. N.; Nikitina, V. I.; Kurguzova, M. A. JGU 1970, 40, 261.
4. (a) Venugopalan, B.; Hamlot, A. B.; Durst, T. TL 1981, 22, 191. (b) Calabi, L.; Danieli, B.; Lesma, G.; Palmisano, G. TL 1982, 23, 2139. (c) Minami, T.; Watanabe, K.; Hirakawa, K. CL 1986, 2027. (d) Ternansky, R. J.; Draheim, S. E. T 1992, 48, 777.
5. (a) McIntosh, J. M.; Sieler, R. A. JOC 1978, 43, 4431. (b) Corbet, J. P.; Benezra, C. JOC 1981, 46, 1141. (c) Semmelhack, M. F.; Yamashita, A.; Tomesch, J. C.; Hirotsu, K. JACS 1978, 100, 5565. (d) Goldberg, O.; Deja, I.; Rey, M.; Dreiding, A. S. HCA 1980, 63, 2455.
6. (a) Snider, B. B.; Phillips, G. B. JOC 1983, 48, 3685. (b) McIntosh, J. M.; Pillon, L. Z. CJC 1984, 62, 2089. (c) Siegel, H. S 1985, 798.
7. Barton, D. H. R.; Géro, S. D.; Quiclet-Sire, B.; Samadi, M. J. T 1992, 48, 1627.

Anubhav P. S. Narula

International Flavors & Fragrances, Union Beach, NJ, USA



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.