Triethyl Phosphite1

(EtO)3P

[122-52-1]  · C6H15O3P  · Triethyl Phosphite  · (MW 166.18)

(can react with electrophiles to form phosphonates or phosphates; can function as a reducing agent for a variety of functional groups; forms a stable complex with copper(I) iodide)

Physical Data: bp 155-157 °C/760 mmHg; d 0.958 g cm-3.

Solubility: sol most organic solvents.

Form Supplied in: clear, free flowing liquid in >97% purity.

Handling, Storage, and Precautions: should be stored in a dry place, preferably in a fume hood due to its pungent odor. The reagent is purified1b by treating with sodium (to remove water and dialkyl phosphonate), followed by decanting and distillation. The purified material may then be stored over activated molecular sieves.

Transesterification.

Hoffman reported that triethyl phosphite is easily transesterified when heated in the presence of aliphatic alcohols.2 The uncatalyzed transformation occurs in three distinct steps which proceed at approximately equal rates. Transesterification using trimethanolethane in the presence of triethylamine affords the corresponding crystalline phosphite (eq 1).3

Organophosphonates.

Triethyl phosphite4 has been used extensively in the synthesis of phosphonates via the Arbuzov reaction.5,6 This general protocol works well with a variety of electrophiles and is carried out by simply heating the reactants between 100 °C and 150 °C using phosphite as solvent. Phosphonates bearing electron withdrawing groups b to phosphorus represent a valuable class of reagents which have been creatively applied to the stereoselective synthesis of alkenes (eqs 2-6).6g-k Acyl phosphonates, prepared from the corresponding acid halides, have been utilized as intermediates in the overall reduction of acids to aldehydes (eq 7),7 and as intermediates in the preparation of vinylphosphonates (eq 8).8

A nonclassical Arbuzov approach to a-methoxybenzylphosphonates employs the treatment of acetals of aromatic aldehydes with triethyl phosphite in the presence of Boron Trifluoride Etherate (eq 9).9 In contrast, direct arene phosphorylation has been achieved through treatment of aromatic substrates with triethyl phosphite and Cerium(IV) Ammonium Nitrate.10 In this case the active species is believed to be a phosphite radical cation (eq 10).

Vinyl Phosphates.

Perkow11,12 discovered that a-halo aldehydes and ketones are converted to vinyl phosphates upon treatment with triethyl phosphite (eq 11). These intermediates are easily reduced to alkenes under dissolving metal conditions (eq 12).13 In cases where the vinyl phosphate is acyclic, treatment with a strong base generally provides good yields of the corresponding alkyne (eq 13).14

Deoxygenation.

Triethyl phosphite is capable of deoxygenating a variety of organic substrates. Hydroperoxides, for example, are rapidly converted to alcohols after treatment with one equivalent of the reagent at ambient temperature (eq 14).15 The reduction of peroxides generated in situ via enolate oxidation is a powerful technique for achieving regio and stereoselective a-hydroxylation (eq 15).16 In addition to reducing hydroperoxides, triethyl phosphite has been utilized for the deoxygenation of endo-peroxides (eq 16),17 diaroyl peroxides (eq 17)18 and the reductive coupling of phthalic anhydride (eq 18).19

Scott reported that terminal epoxides can be reduced using forcing conditions while internal epoxides are generally unaffected, even at temperatures approaching 200 °C.20 In contrast, Saegusa and co-workers discovered that a-keto acids are easily reduced to a-hydroxy acids under mild conditions in good to excellent yields (eq 19).21

The deoxygenation of nitrogenous functionalities using triethyl phosphite has also received attention.22 Reductive cyclization of aromatic nitro-containing compounds has provided entry into a variety of heterocycles (eqs 20 and 21).23 It has been suggested that a highly reactive nitrene intermediate is involved in the cyclization process.24 Aryl nitroso compounds subjected to these conditions experience a similar fate, although the reactive intermediate in this case is believed to be polar in nature (eq 22).25

Azides are also subject to reduction by triethyl phosphite via a modified Staudinger process (eq 23).26

Desulfurization.

A frequently encountered application of triethyl phosphite is the conversion of cyclic thiocarbonates to the corresponding alkenes (Corey-Winter synthesis).27 The reaction proceeds stereospecifically via a carbene intermediate and often results in good yields of desired alkene (eqs 24 and 25).28

The conversion of thiiranes to alkenes proceeds readily, in contrast to epoxide reduction.29 For example, the episulfides of cis- and trans-2-butene are reduced smoothly and with high stereospecificity. Thiols30 and disulfides31 are reduced efficiently as well. In some cases, reductive desulfurization can be coupled with carbon-carbon bond formation. For example, reaction of di-n-butyl disulfide with triethyl phosphite in the presence of carbon monoxide gives a nearly quantitative yield of the corresponding homologated thioester (eq 26).32

In a completely unrelated example, [2,2]paracyclophane was synthesized from the corresponding bis-thioether via photochemical extrusion of sulfur mediated by triethyl phosphite (eq 27).33 The concept of linking proximal carbon atoms with the extrusion of sulfur was used successfully by Eschenmoser in his synthesis of a vitamin B12 intermediate (eq 28),34 while a modification of Barton's method allowed the synthesis of the highly strained diquadricyclanylidene (eq 29).35

A bimolecular coupling mediated by triethyl phosphite was applied to the synthesis of an interesting unsymmetrical tetrathiafulvalene, although yields were low due to competing homo coupling (eq 30).36

Carbonyl Adducts.

Triethyl phosphite reacts with a-diketones to form isolable cyclic phosphate esters. Upon additional heating, the corresponding alkynes are obtained (eq 31).37

Use in Cuprate Chemistry.

When added to solutions of cis-divinylcuprates, trimethyl phosphite facilitates the transfer of both vinyl groups via stabilization of the vinylcopper intermediate (eq 32).38

Copper(I) Iodide-Triethyl Phosphite is formed in 89% yield by the reaction of triethyl phosphite and Copper(I) Iodide in refluxing benzene.39 The salt has been used to form arylcopper intermediates which participate in a modified Ullmann coupling sequence (eq 33).40

Related Reagents.

Trimethyl Phosphite.


1. (a) Preparation: Schuetz, R. D.; Jacobs, R. L. JOC 1961, 26, 3467. (b) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals; Pergamon: New York, 1988; p 297.
2. Hoffmann, F. W.; Ess, R. J., Usinger, R. P., Jr. JACS 1956, 78, 5817.
3. Wadsworth, W. S., Jr.; Emmons, W. D. JACS 1962, 84, 610.
4. (a) Schuetz, R. D.; Jacobs, R. L. JOC 1961, 26, 3467 (b) Ford-Moore, A. H.; Perry, B. J. OSC 1963, 4, 955.
5. 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. CR 1971, 71, 315. (d) Bhattacharya, A. K.; Thyagarajan, G. CRV 1981, 81, 415. (e) Cadogan, J. I. G. Organophosphorus Reagents in Organic Synthesis; Academic: New York, 1979.
6. (a) Horner, L.; Hoffmann, H.; Wipple, H. G. CB 1958, 91, 61. (b) Horner, L.; Hoffmann, H.; Wipple, H. G.; Klahre, G. CB 1959, 92, 2499. (c) Wadsworth, W. S., Jr.; Emmons, W. D. JACS 1961, 83, 1733. For reviews, see: (d) Wadsworth, W. S. OR 1977, 25, 73. (e) Boutagy J.; Thomas, R. CRV 1974, 74, 87. (f) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, 3rd ed.; Plenum: New York, 1990; Part B, pp 100-102. (g) See Ref. 3c. (h) Wadsworth, W. S., Jr.; Emmons, W. D. OS 1965, 45, 44. (i) Rousch, W. R. JACS 1978, 100, 3599. (j) Nicolaou, K. C.; Bertinato, P.; Piscopio, A. D.; Chakraborty, T. K.; Minowa, N. CC 1993, 619. (k) See Ref. 5c.
7. Horner, L.; Roder, H. CB 1970, 103, 2984.
8. Kojima, M.; Yamashita, M.; Yoshida, H.; Ogata, T. S 1979, 147.
9. Burkhouse, D.; Zimmer, H. S 1984, 330.
10. Kottmann, H; Skarzewski, J.; Effenberger, F. S 1987, 797.
11. Perkow, N.; Ullerich, K.; Meyer, F. N 1952, 39, 353.
12. For reviews of the Perkow reaction, see: (a) Lichtenthaler, F. W. CR 1961, 61, 608. (b) See Ref 5a.
13. (a) Fetizon, M.; Jurion, M.; Anh, N. T. CC 1969, 112. (b) Ireland, R. E.; Pfister, G. TL 1969, 2145. For reduction of enol phosphates to the corresponding saturated hydrocarbons, see: (c) Coates, R. M.; Shah, S. K.; Mason, R. W. JACS 1982, 104, 2198 and (d) Heathcock, C. H.; Davidsen, S. K.; Mills, S.; Sanner, M. A. JACS 1986, 108, 5650.
14. (a) Craig, J. C.; Moyle, M. JCS 1963, 3712. (b) Negishi, E.; King, A. O.; Klima, W. L. JOC 1980, 45, 2526. (c) McMurry, J. E.; Bosch, G. K. JOC 1987, 52, 4885.
15. Karasch, M. S.; Mosher, R. A.; Bengelsdorf, I. S. JOC 1960, 25, 1000.
16. (a) Kido, F.; Kitahara, H.; Yoshikoshi, A. JOC 1986, 51, 1478. (b) Hartwig, W.; Born, L. JOC 1987, 52, 4352. (c) Gardner, J. N.; Carlon, F. E.; Gnoj, O. JOC 1968, 33, 3294. (d) Gardner, J. N.; Popper, T. L.; Carlon, F. E.; Gnoj, O.; Herzog, H. L. JOC 1968, 33, 3695.
17. (a) Kametani, T.; Ogasawara, K. CI(L) 1968, 1772. (b) Horner, L.; Jurgeleit, W. LA 1955, 591, 138.
18. Burn, A. J.; Cadogan, J. I. G.; Bunyan, P. J. JCS 1963, 1527.
19. Ramirez, F.; Yamanaka, H.; Basedow, O. H. JACS 1961, 83, 173.
20. (a) Scott, C. B. JOC 1957, 22, 1118. (b) Neureiter, N. P.; Bordwell, F. G. JACS 1959, 81, 578.
21. Saegusa, T.; Kobayashi, S.; Kimura, Y.; Yokoyama, T. JOC 1977, 42, 2797.
22. Cadogan, J. I. G. S 1969, 11.
23. (a) Cadogan, J. I. G.; Cameron-Wood, M.; Mackie, R. K.; Searle, R. J. G. JCS 1965, 4831. (b) Cadogan, J. I. G.; Searle, R. J. G. CI(L) 1963, 1282. (c) Sundberg, R. J. JOC 1965, 30, 3604. (d) Cadogan, J. I. G.; Mackie, R. K.; Todd, M. J. CC 1966, 491. (e) Grundmann, C. CB 1964, 97, 575.
24. Brooke, P. K.; Herbert, R. B.; Holliman, E. G. TL 1973, 761.
25. Smolinsky, G.; Feuer, B. I. JOC 1966, 31, 3882.
26. (a) Koziara, A.; Osowska-Pacewicka, K.; Zawadzki, S.; Zwierzak, A. S 1985, 202. (b) Koziara, A.; Zwierzak, A. TL 1987, 28, 6513.
27. (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.
28. For a review, see: Block, E. OR 1983, 30, 457.
29. (a) Davis, R. E. JOC 1958, 23, 1767. (b) Schuetz, R. D.; Jacobs, R. L. JOC 1958, 23, 1799.
30. (a) Hoffman, F. W.; Ess, R. J.; Simmons, T. C.; Hanzel, R. S. JACS 1956, 78, 6414. (b) Walling, C.; Rabinowitz, R. JACS 1959, 81, 1243.
31. Jacobson, H. I.; Harvey, R. G.; Jensen, E. V. JACS 1955, 77, 6064.
32. Walling, C.; Basedow, O. H.; Savas, E. S. JACS 1960, 82, 2181.
33. Brink, M. S 1975, 807.
34. Eschenmoser, A. QR 1970, 24, 366.
35. Sauter, H.; Horster, H. G.; Prinzbach, H. AG(E) 1973, 12, 991.
36. Spencer, H. K.; Cava, M. P.; Garito, A. F. CC 1976, 966.
37. (a) Mukaiyama, T.; Nambu, H.; Kumamoto, T. JOC 1964, 2243. (b) Ramirez, F.; Desai, N. B. JACS 1963, 85, 3252.
38. Alexakis, A.; Cahiez, G.; Normant, J. F. S 1979, 826.
39. Nishizawa, Y. BCJ 1961, 34, 1170.
40. (a) Ziegler, F. E.; Fowler, K. W.; Kanfer, S. JACS 1976, 98, 8282. (b) Ziegler, F. E.; Fowler, K. W.; Sinha, N. D. TL 1978, 2767. (c) Ziegler, F. E.; Fowler, K. W.; Rodgers, W. B.; Wester, R. T. OS 1987, 65, 108.

Anthony D. Piscopio

Pfizer, Groton, CT, USA



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