Diethyl Methoxymethylphosphonate

(1a; R = Me)

[332806-04-5]  · C6H15O4P  · Diethyl Methoxymethylphosphonate  · (MW 182.16) (1b; R = MeOCH2CH2)

[70080-14-7]  · C8H19O5P  · Diethyl Methoxyethoxymethylphosphonate  · (MW 226.21) (1c; R = THP)

[71855-51-3]  · C10H21O5P  · Diethyl Tetrahydropyranyloxymethylphosphonate  · (MW 252.25) (1d; R = TBDMS)

[71855-52-4]  · C11H27O4PSi  · Diethyl (t-Butyldimethylsilyl)oxymethylphosphonate  · (MW 282.39) (1e; R = TMSCH2CH2)

[90490-19-0]  · C10H25O4PSi  · Diethyl (Trimethylsilyl)ethoxymethylphosphonate  · (MW 268.36)

(Horner-Emmons reagents for carbonyl homologation;1-4 preparation of vinyl ethers1-4 and ketene O,S-thioacetals5)

Physical Data: (1a): bp 65-67 °C/0.1 mmHg;6 nD20 1.4250. (1b): bp 105 °C/0.8 mmHg.1 (1c): bp 105 °C/0.1 mmHg.1 (1d): bp 85 °C/0.1 mmHg.1 (1e): bp 80-82 °C/0.05 mmHg.7

Solubility: sol organic solvents (THF, diglyme, ether, ethyl acetate, DMF); low sol water.

Analysis of Reagent Purity: the phosphonates are isolable and can be fully characterized by standard analytical and spectroscopic techniques.1,6,7 (1a) 31P NMR (C6D6) d -22 ppm.8

Preparative Methods: phosphonates (1a) (85%),1 (1b) (74%),1 and (1e) (82%)7 are readily prepared by the Michaelis-Arbuzov reaction of Chloromethyl Methyl Ether, 2-Methoxyethoxymethyl Chloride (MEMCl), and 2-(Trimethylsilyl)ethoxymethyl Chloride (SEMCl), respectively, with Triethyl Phosphite. Reagents (1c) (82%) and (1d) (45%) are prepared from HOCH2PO(OEt)2 and 3,4-Dihydro-2H-pyran/Phosphorus Oxychloride or t-Butyldimethylchlorosilane/Imidazole respectively.1

Handling, Storage, and Precautions: dialkyl phosphonates are irritants and their chloromethyl ether precursors are highly toxic carcinogens (or cancer suspect agents). Organolithium reagents and the other bases employed for the conversions of (1) are caustic and some are potentially pyrophoric. Proper handling and special safety practices information should be obtained from the supplier and individuals should thoroughly familiarize themselves with these techniques prior to using these reagents.

Vinyl Ethers from the Horner-Emmons Alkenation.9

Dialkyl alkoxymethylphosphonates such as (1) are a-deprotonated at low temperatures (e.g. -60 °C) with strong base (Lithium Diisopropylamide,10 n-Butyllithium/Potassium t-Butoxide5), and the reaction of the resulting anion (Kluge reagent)1 with aldehydes and ketones gives 1,2-adducts which undergo thermal elimination (M = Li, THF, reflux, aryl derivatives (2-4 h), aliphatic (16-72 h)).1 Alternatively, these intermediates can be quenched to give isolable a-alkoxy-b-hydroxyalkylphosphonates which, after treatment with t-BuOK, undergo a more facile elimination (THF, reflux, 5 min). Polyunsaturated aldehydes are converted to polyenyl ethers using (1a) in 40-50% with high (E) stereoselectivities.3 The MEM derivative (1b) is a more effective reagent for this process,1b while (1d) is ineffective because of the lability of the silyl group with respect to rearrangement.1a Kluge employed (1c) for the homologation of an intermediate ketone in his approach to the construction of the ajmaline nucleus (eq 1).2 Heathcock also found the reagent effective for the homologation of mesityl oxide (eq 2, ca. 90% nonconjugated isomer),4 a useful intermediate in the stereoselective synthesis of the C-1 to C-7 moiety of erythronolide A.

The reagents have not always been successful and several examples include the attempted homologation of thienocyclohexanones,11 bicyclic ketones,12,13 amides,14 and penicillanic acid derivatives.15 However, some polycyclic systems are effectively homologated employing (1) (50-60%),16 but for others,12 Methoxymethylenetriphenylphosphorane may be better. The sequential a-alkylation of (1e) (s-Butyllithium, RX) has been used to prepare branched a-hydroxyalkylphosphonates.7 Related a-alkylated derivatives of (1) have been investigated as alkenating agents with mixed results.17

Ketene O,S-Thioacetals from (1).

An extension of these processes has been effectively employed for the synthesis of ketene O,S-thioacetals.5c Deprotonation of (1a) with LiBu/t-BuOK followed by sulfuridation and methylation produces the corresponding O,S-thioacetals of formylphosphonates.5 These are lithiated with t-Butyllithium at -78 °C and condensed with aldehydes and ketones to afford ketene O,S-thioacetals in ca. 80% yield as essentially 1:1 (E)/(Z) mixtures (eq 3).


1. (a) Kluge, A. F.; Cloudsdale, I. S. JOC 1979, 44, 4847. (b) Kluge, A. F. TL 1978, 3629.
2. Cloudsdale, I. S.; Kluge, A. F.; McClure, N. L. JOC 1982, 47, 919.
3. Vo-Quang, Y.; Carniato, D.; Vo-Quang, L.; Le Goffic, F. CC 1983, 1505.
4. Heathcock, C. H.; Young, S. D.; Hagen, J. P.; Pilli, R.; Badertscher, U. JOC 1985, 50, 2095.
5. (a) Mikolajczyk, M.; Grzejszczak, S.; Chefczynska, A.; Zatorski, A. JOC 1979, 44, 2967. (b) Mikolajczyk, M.; Grzejszczak, S.; Costisella, B.; Zatorski, A. TL 1976, 477. (c) Mikolajczyk, M.; Grzejszczak, S.; Zatorski, A.; Mlotkowska, B.; Gross, H.; Costisella, B. T 1978, 34, 3081.
6. Green, M. JCS 1963, 1324.
7. Zbiral, E.; Binder, J. TL 1984, 25, 4213.
8. Gray, G. A. JACS 1971, 93, 2132.
9. Thomas, R.; Boutagy, J. CR 1974, 74, 87.
10. Warren, S.; Wallis, C. J.; Earnshaw, C. JCS(P1) 1979, 3099.
11. Abarca, B.; Ballesteros, R.; Jones, G. JHC 1984, 21, 1585.
12. Piers, E.; Tse, H. L. A. CJC 1993, 71, 983.
13. Denmark, S. E.; Henke, B. R. JACS 1991, 113, 2177.
14. Winterfeldt, E.; Thielmann, T.; Thielmann, M.; Hakam, K. T 1987, 43, 2035.
15. Brenner, D. G. JOC 1985, 50, 18.
16. de Meijere, A; Kirchmeyer, S. HCA 1990, 73, 1182.
17. (a) Boar, R. B.; Patel, A. C. JCS(P1) 1985, 1201. (b) Zimmer, H.; Koenigkramer, R. E. JOC 1980, 45, 3994. (c) Yates, P.; Stevens, K. E. T 1981, 37, 4401. (d) Zimmer, H.; Burkhouse, D. S 1984, 330. (e) Zimmer, H.; Koenigkramer, R. E. TL 1980, 21, 1017. (f) Ley, S. V.; Lygo, B.; Organ, H. M.; Wonnacott, A. T 1985, 41, 3825.

John A. Soderquist & Anil M. Rane

University of Puerto Rico, Rio Pedras, Puerto Rico



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