Trimethyl Phosphite1

(MeO)3P

[121-45-9]  · C3H9O3P  · Trimethyl Phosphite  · (MW 124.09)

(reducing agent for various functional groups; can function as a potent thiophile for sulfur extrusion; forms a stable complex with copper(I) iodide and methylcopper)

Physical Data: bp 111-112 °C/760 mmHg; d 1.052 g cm-3.

Solubility: sol most organic solvents.

Form Supplied in: clear, free flowing liquid; commercially available in >99% purity.

Purification: treatment with sodium (to remove water and dialkyl phosphonate), followed by decanting and distillation.2

Handling, Storage, and Precautions: store in a dry place, preferably in a fume hood due to its pungent odor; purified material should be stored over activated molecular sieves.

Use in the Arbuzov and Perkow Reactions.

Although used less frequently than Triethyl Phosphite, trimethyl phosphite has seen significant application in the synthesis of organophosphonates (eq 1)3 and phosphates (eq 2)4 via Arbuzov and Perkow reactions, respectively. For example, an interesting a-diazophosphonate reagent developed by Seyferth has been applied to the one-step conversion of aldehydes to terminal alkynes (eq 3).5 Since the potentially hazardous diazophosphonate is purified by distillation, use of the relatively volatile dimethyl derivative is warranted.

Carbonyl Adducts.

Trimethyl phosphite reacts readily with 1,4- and 1,2-benzoquinones to give methyl esters of hydroquinone monophosphates (eq 4)6 and cyclic oxyphosphoranes (eq 5),6 respectively. Ramirez and co-workers reported that trimethyl phosphite promotes the dimerization of methyl pyruvate to give, after basic hydrolysis, a mixture of diastereomeric tartrates (eq 6).7

Deoxygenation.

The reductive decomposition of ozonides can be conveniently accomplished using trimethyl phosphite (eq 7).8 The innocuous byproduct, trimethyl phosphate, is easily removed from the crude reaction mixture either by extraction or evaporation.

The reagent has been equally efficacious in the conversion of nitrile oxides to nitriles (eq 8).9 Additionally, Seebach and co-workers have reported the synthesis of a cyclic ε-tetrazine via reduction of the corresponding N-oxide (eq 9).10

Desulfurization.

Trimethyl phosphite (in addition to triethyl phosphite) has been applied successfully to the Corey-Winter alkene synthesis.11 The key step of the sequence involves phosphite-mediated decomposition of a thiocarbonate derivative which proceeds stereospecifically and often results in good yields of desired alkene (eqs 10 and 11).12 Alkynes have also been synthesized using this method, albeit in lower overall yields (eq 12).13

Treatment of 1,3-dithiacyclohexane-2-thione14 with trimethyl phosphite affords the corresponding ylide quantitatively. The phosphorane has been applied the one-carbon homologation of aldehydes to carboxylic acids (eq 13).15

In addition, trimethyl phosphite has been used to capture intermediates formed during [2,3]-sigmatropic rearrangement of allylic sulfoxides (eq 14)16 and in the conversion of penicillin derivatives to azetidinones (eq 15).17

Dehalogenation.

Dershowitz18 has reported that vicinal dibromides are smoothly converted to alkenes by heating in the presence of trimethyl phosphite. The reagent was successfully applied to systems where other reagents, such as Sodium Iodide or Zinc dust proved unsatisfactory (eq 16). The dehydrohalogenation of a steroidal allylic bromide has also been reported (eq 17).19

Copper Complexes.

Copper(I) Iodide-Trimethyl Phosphite is formed in 84% yield by the reaction of trimethyl phosphite and Copper(I) Iodide in refluxing benzene.20 The salt has been used as a catalyst in the decomposition of diethyl diazomalonate to give ethers (eq 18)21 and cyclopropanes (eq 19).20 Furanones have been prepared using related methodology (eq 20).22

Trimethyl phosphite-methylcopper is a relatively stable complex of Methylcopper. The reagent adds readily, in a conjugate sense, to cyclohexenones, with a strong preference for axial attack (eq 21).23

Esterification.

Trimethyl phosphite has been used in the conversion of a sensitive indolecarboxylic acid to the corresponding methyl ester under neutral conditions (eq 22).24


1. Schuetz, R. D.; Jacobs, R. L. JOC 1961, 26, 3467.
2. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.; Pergamon: New York, 1988; p 297.
3. For reviews of the Arbuzov reaction, see: (a) Arbuzov, B. A. PAC 1964, 9, 307. (b) Kosolapoff, G. M. OR 1951, 6, 273. (c) Redmore, D. CRV 1971, 71, 315. (d) Bhattacharya, A. K.; Thyagarajan, G. CRV 1981, 81, 415. (e) Cadogen, J. I. G. Organophosphorus Reagents in Organic Synthesis; Academic: New York, 1979. For application to the synthesis of alkenes, see: (f) Horner, L.; Hoffman, H.; Wipple, H. G. CB 1958, 91, 61. (g) Horner, L.; Hoffman, H.; Wipple, H. G. CB 1959, 92, 2499. (h) Wadsworth, W. S., Jr.; Emmons, W. D. JACS 1961, 83, 1733. For reviews see: (i) Wadsworth W. S. OR 1977, 25, 73. (j) Boutagy, J.; Thomas, R. CRV 1974, 74, 87. (k) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, 3rd ed.; Plenum: New York, 1990; Part B, pp 100-102. (l) Wadsworth, W. S., Jr.; Emmons, W. D. OS 1965, 45, 44. (m) Roush, W. R. JACS 1978, 100, 3599. (n) Nicolaou, K. C.; Bertinato, P.; Piscopio, A. D.; Chakraborty, T. K.; Minowa, N. CC 1993, 619 and references cited therein.
4. (a) Perkov, N.; Ullerich, K.; Meyer, F. N 1952, 39, 353. For reviews of the Perkow reaction, see: (b) Lichtenthaler, F. W. CRV 1961, 61, 607. (c) Arbuzov, B. A. PAC 1964, 9, 307.
5. (a) Seyferth, D.; Marmor, R. S.; Hilbert, P. J. JOC 1971, 36, 1379. (b) Colvin, E. W.; Hamill, B. J. CC 1973, 151. (c) Colvin, E. W.; Hamill, B. J. JCS(P1) 1977, 869. (d) Gilbert, J. C.; Weerasooriya, U. JOC 1979, 44, 4997. (e) Nakatsuka, M.; Ragan, J. A.; Sammakia, T.; Smith, D. B.; Uehling, D. E.; Schreiber, S. L. JACS 1990, 112, 5583.
6. Ramirez, F.; Desai, N. B. JACS 1963, 85, 3252.
7. Ramirez, F.; Desai, N. B.; Ramanathan, N. TL 1963, 323.
8. (a) Knowles, W. S.; Thompson, Q. E. JOC 1960, 25, 1031. (b) Stille, J. K.; Foster, R. T. JOC 1963, 28, 2703. (c) Stevens, R. V.; Beaulieu, N.; Chan, W. H.; Daniewski, A. R.; Takishi, T.; Waldner, A.; Willard, P. G.; Zutter, U. JACS 1986, 108, 1039. (d) Murray, R. W. ACR 1968, 1, 313.
9. Grundmann, C.; Frommeld, H. D. JOC 1965, 30, 2077.
10. (a) Seebach, D.; Enders, D.; Renger, B.; Brugel, W. AG(E) 1973, 12, 495. (b) Seebach, D.; Enders, D. AG(E) 1972, 11, 301.
11. (a) Corey, E. J.; Winter, R. A. E. JACS 1963, 85, 2677. (b) Corey, E. J.; Carey, F. A.; Winter, R. A. E. JACS 1965, 87, 934.
12. For a review see: Block, E. OR 1983, 30, 457.
13. Bauer, D. P.; Macomber, R. S. JOC 1976, 41, 2640.
14. Mills, W. H.; Saunders, B. C. JCS 1931, 537.
15. Corey, E. J.; Markl, G. TL 1967, 3201.
16. (a) Brown, W. L.; Fallis, A. G. TL 1985, 26, 607. (b) Bickart, P.; Carson, F. W.; Jacobus, J.; Miller, E. G.; Mislow, K. JACS 1968, 90, 4869. (c) Tang, R.; Mislow, K. JACS 1970, 92, 2100. (d) Grieco, P. CC 1972, 702. (e) Evans, D. A.; Andrews, G. C. ACR 1974, 7, 147. (f) Hoffman, R. W.; Goldman, S.; Maak, N.; Gerlach, R.; Frickel, F.; Steinbach, G. CB 1980, 113, 819. (g) Isobe, M.; Iio, H.; Kitamura, M.; Goto, T. CL 1978, 541.
17. Suarato, A.; Lombardi, P.; Galliani, C.; Franceschi, G. TL 1978, 4059.
18. Dershowitz, S.; Proskauer, S. JOC 1961, 26, 3595.
19. Hunziker, F.; Mullner, F. X. H 1958, 41, 70.
20. Peace, B. W.; Carman, F.; Wulfman, D. F. S 1971, 658.
21. Pelliciari, R.; Cogolli, P. S 1975, 269.
22. Bien, S.; Gillon, A. TL 1974, 3073.
23. House, H. O.; Fischer, W. F., Jr. JOC 1968, 33, 949.
24. (a) Szmuskovicz, J. OPP 1972, 4, 51. (b) Kamai, G.; Kukhtin, V. A.; Strogova, O. A. CA 1957, 51, 11 994b.

Anthony D. Piscopio

Pfizer, Groton, CT, USA



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