Methoxymethyl(diphenyl)phosphine Oxide1

[4455-77-0]  · C14H15O2P  · Methoxymethyl(diphenyl)phosphine Oxide  · (MW 246.26)

(Horner-Wittig reagent for the preparation of methoxyvinyl ethers and hence homologous aldehydes;2 the anion has greater stability and nucleophilicity than the analogous phosphonium ylide)

Physical Data: mp 114-116 °C; bp 138-139 °C/0.1 mmHg.

Solubility: sol THF, DME, CH2Cl2; insol H2O.

Form Supplied in: white solid; commercially available.

Handling, Storage, and Precautions: commercial material (97-98%) is satisfactory as received. The toxicological properties of the reagent are unknown.

General Considerations.

Methoxymethyl(diphenyl)phosphine oxide has been widely3 used in the Horner-Wittig reaction converting both aldehydes and ketones, including enolizable ones, into methoxyvinyl ethers (and hence to higher aldehydes) (eq 1). The reagent is available commercially or by routes A (90%),2 B (89%),4 or C (25%).5 Its anion, generated from Lithium Diisopropylamide in THF, is more stable than the corresponding phosphonium ylide (Ph3+P--CHOMe) and readily adds to the carbonyl substrate giving good yields of isolable b-hydroxyphosphine oxides. Alkene formation does not usually occur spontaneously (for exceptions, see eqs 4 and 6) because the lithium counterion binds strongly to the oxygen of the initial adduct, preventing attack by oxygen on phosphorus. In the case where R1 &neq; R2 the diastereoisomeric alcohols can often be separated by fractional crystallization or chromatographically. Completion of the Horner-Wittig reaction is achieved by treating the adducts with Sodium Hydride (or Potassium Hydride) at ambient temperature. This elimination is stereospecifically syn, with each diastereomer giving a single geometric isomer. The methoxyvinyl ether(s) are readily separated from the phosphinate byproduct. Mild acid hydrolysis furnishes the homologous aldehyde.

The more nucleophilic and sterically less demanding nature of the Ph2P(O)CH2OMe anion is illustrated by the examples in eqs 2-4.6,7 In each case the ketone was inert towards the analogous phosphonium ylide. Diastereoselective attack of the anion on the 2-acylindole (1)8 leads to single vinyl ether (2) (eq 4).

With enones, the anion undergoes 1,2-addition to afford 1-methoxy-1,3-dienes (eqs 5-7).9,10 The phosphonium ylide, in contrast (eq 7), underwent 1,4-addition with the bicyclic ketone (3) to furnish the fused methoxycyclopropane (4).11

Isolation of a single b-hydroxyphosphine oxide is exemplified in eq 8.12 The (RS,SR) adduct (5), which crystallized preferentially, was required to prepare (E,E)-1-methoxy-4-trimethylsilyl-1,3-butadiene, a Diels-Alder substrate.

Lactones13 also react with the phosphonate anion, thus providing an alternative stratagem to obtain vinyl ether (6) (eq 9).

1. Maryanoff, B. E.; Reitz, A. B. CRV 1989, 89, 863.
2. Earnshaw, C.; Wallis, C. J.; Warren, S. JCS(P1) 1979, 3099.
3. For example (a) Kuroda, C.; Inoue, S.; Kato, S.; Satoh, J. Y. JCR(M) 1993, 458. (b) Huby, N. J. S.; Kinsman, R. G.; Lathbury, D.; Vernon, P. G.; Gallagher, T. JCS(P1) 1991, 145. (c) Ikota, N.; Yoshino, O.; Koga, K. CPB 1991, 39, 2201. (d) Nemoto, H.; Kurobe, H.; Fukumoto, K.; Kametani, T. JOC 1986, 51, 5311. (e) Narula, A. S.; Sethi, S. P. TL 1984, 25, 685. (f) Magari, H.; Hirota, H.; Takahashi, T.; Matsuo, A.; Uto, S. Nozaki, H.; Nakayama, M.; Hayashi, S. CL 1982, 1143.
4. Earnshaw, C.; Wallis, C. J.; Warren, S. CC 1977, 314.
5. Maleki, M.; Miller, A.; Lever, O. W. Jr. TL 1981, 22, 365.
6. Patel, D. V.; Schmidt, R. J.; Gordon, E. M. JOC 1992, 57, 7143.
7. Evans, E. H.; Hewson, A. T.; March, L. A.; Nowell, I. W.; Wadsworth, A. H. JCS(P1) 1987, 137.
8. Bonjoch, J.; Linares, A.; Pérez, M.-L.; Bosch, J. JHC 1990, 27, 1979.
9. Abad, A.; Arnó, M.; Peiró, M.; Zarogozá, R. J. T 1991, 47, 3829.
10. Bosch, M. P.; Camps, F.; Coll, J.; Guerrero A.; Tatsuoka, T.; Meinwald, J. JOC 1986, 51, 773.
11. Parkes, K. E. B.; Pattenden, G. JCS(P1) 1988, 1119.
12. Pegram, J. J.; Anderson, C. B. TL 1991, 32, 2197.
13. Harrison, P. J. TL 1989, 30, 7125.

Chris Wallis

Glaxo Research & Development, Stevenage, UK

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