Diethyl Phosphonite

[762-04-9]  · C4H11O3P  · Diethyl Phosphonite  · (MW 138.10)

(weak acid whose anion can function as a nucleophile at phosphorus, engaging in SN2 displacement reactions and carbonyl additions; can hydrophosphonylate imines, ketenes, and enamines; can phosphonylate vinyl and aryl halides with Pd0 catalysis; can function as an amine-protecting group1)

Alternate Names: diethyl phosphite; DEP.

Physical Data: bp 50-51 °C/2 mmHg; d 1.072 g cm-3.

Solubility: sol water, THF, alcohol.

Form Supplied in: colorless liquid.

Handling, Storage, and Precautions: should be stored in absence of moisture and freshly distilled before use if any suspicion exists regarding purity.

Nucleophilic Displacement.

The anion of DEP can be formed using strong bases (i.e. alkali metals, alkoxides, or hydrides) and can undergo a variety of displacement reactions which are generally known as Michaelis-Becker reactions.1 The mechanism of these reactions is viewed as proceeding via classical SN2 attack by phosphorus on the electrophilic center.2 A variety of phosphonates have been prepared by this method (eqs 1 and 2).3,4

As with trialkyl phosphites, reaction of DEP anion with a-halo ketones results in Perkov-type products produced from phosphorus attack at the carbonyl carbon rather than that bearing the halide (eq 3).5

Reaction of the anion with a-halo esters6 or a-halo phosphonates7 is reported to proceed cleanly with simple displacement of the halogen.

Reactions with Multiple Bond Systems.

In addition to displacement reactions, the anion of DEP can add to a carbonyl carbon, forming the corresponding a-hydroxy phosphonate. This reaction, known as the Pudovik reaction, has been shown to be catalytic in the amount of phosphite salt necessary to promote the reaction.8 Typically, a small amount of alkoxide is added to the reaction mixture (eqs 4 and 5).9,10

It has been shown that the rate of the reaction increases in a manner directly proportional to the solvating power of the medium.11 Other approaches which have been successfully employed to promote the Pudovik reaction with aldehydes or ketones include (a) neutral amine bases (eq 6),12 (b) chiral amine bases where asymmetric induction resulted,13 (c) phase-transfer catalysis,14 (d) solid phase basic catalysis with alumina,15 and (e) solid phase basic catalysis with fluoride salts (eq 7).16

In addition to carbonyl systems, DEP adds to imines (eq 8),17 ketene acetals (O,N-;S,N-;N,N-) (eq 9),18 and enamines (eq 10).19

Another aspect of multiple bond addition by DEP is conjugate addition to a,b-unsaturated esters,20 amides,21 and nitriles20 via the sodium salt and the addition to nitroalkenes in the presence or absence of neutral amine bases.22 With a,b-unsaturated ketones and aldehydes, product mixtures arise, resulting from competing 1,2- vs.1,4-addition and can be influenced by factors such as steric hindrance and reaction temperature.

Palladium-Catalyzed Phosphonylation.

Complexes of palladium(0) have been used to catalyze the addition of DEP to aryl (eq 11)23 and vinyl (eq 12)24 halides. As is typical, the bromo and iodo compounds were significantly more reactive than the chloro. For the arylation reactions, good yields were obtained irrespective of substitution. In the case of the vinylation reactions, addition occurs stereospecifically.

Amine Protecting Group.

The use of DEP in peptide synthesis has found successful application as both an amine protecting group and carboxylic acid activating group.25 Interestingly, the amine protection aspect of its use has been exploited in other areas of organic synthesis (eq 13).26

Radical Reactions.

The photostimulation of aryl iodides in the presence of DEP as its sodium or potassium salt presents a highly efficient approach to prepare diethyl arylphosphonate esters.27 This reaction has been explored mechanistically and is believed to be operating via a radical chain SN1 mechanism. With diiodo, iodobromo and iodochloro (except meta) arenes, bis substitution occurs. Other radical reactions which involve DEP include use as a hydrogen atom source in radical deoxygenations28 and radical additions to terpenes.29

Specialized Reactions.

DEP is known to react with diazo compounds, in the presence of copper(II) salts, to form diethyl phosphonates.30 The reaction is sensitive to stoichiometry and has been largely applied with a-diazo esters and 2-diazo-1,3-diketones (eq 14).30

A reagent prepared from the sodium salt of DEP and Tellurium metal (either catalytic or stoichiometric) is useful for the deoxygenation of terminal epoxides to the corresponding alkenes.31 The deoxygenation occurs on nonterminal epoxides but is significantly slower and therefore allows for selective reaction to take place.

Phosphate esters can be prepared from reacting triflates with potassium DEP.32 The reactivity follows the order aryl > cyclohexenyl > cyclopropyl > alkyl.

When gem-dibromocyclopropanes or gem-dibromoalkenes are reacted with DEP (neat) in the presence of Triethylamine, high yields (90%) of the monobromo compounds are obtained.33 This method contrasts with other approaches generally involving the use of metallic reagents.

1. For an excellent review of carbon-phosphorus bond forming reactions including detailed experimental examples, see: Engel, R. Synthesis of Carbon-Phosphorus Bonds, CRC: Boca Raton, FL, 1988.
2. (a) Farnham, W. B.; Murray, R. K.; Mislow, K. JACS 1970, 92, 5809. (b) Doak, G. O.; Freedman, L. D. CR 1961, 60, 31. (c) Hudson, R. F. Structure and Mechanism in OrganoPhosphorus Chemistry, Academic: New York, 1965; p 131.
3. Boeckman, R. K.; Perni, R. B.; Macdonald, J. E.; Thomas, A. J. OS 1987, 66, 194.
4. Koh, Y. J.; Oh, D. Y. TL 1993, 34, 2147.
5. Russell, G. A.; Ros, F. JACS 1985, 107, 2506.
6. Brittelli, D. R. U. S. Patent 4 307 232, 1981.
7. Burton, D. J.; Flynn, R. M. U. S. Patent 4 478 761, 1984.
8. (a) Abramov, V. S. DOK 1950, 73, 487. (b) Abramov, V. S. ZOB 1952, 22, 647. (c) Miller, C. D.; Miller, R. C.; Rogers, W. JACS 1958, 80, 1562. (d) Kharash, M. S.; Mosher, R. A.; Bengelsdorf, I. S. JOC 1960, 25, 1000.
9. Mlotkowska, B.; Trapp, B. E.; Engel, R. CR 1985, 117, 95.
10. Castagnino, E.; Corsano, S.; Strappavrachia, G. P. TL 1985, 26, 93.
11. (a) Vorontsova, N. A.; Vlasov, O. N.; Melinikov, N. N. JGU 1978, 48, 2415. (b) Gartman, G. A.; Pak, V. D.; Simenova, E. V. JGU 1979, 49, 2295.
12. (a) Kluge, A. F. OS 1985, 64, 80. (b) Kluge, A. F.; Clousdale, I. S. JOC 1979, 44, 4847.
13. (a) Wynberg, H.; Smardiijk, A. A. TL 1983, 24, 5899. (b) Smardijk, A. A.; Noorda, S.; vanBolhuis, F.; Wynberg, H. TL 1985, 26, 493.
14. Zhdanov, Y. A.; Glebova, Z. I.; Kistyan, G. K.; Polenov, V. A.; Uzlova, L. A. JGU 1984, 54, 1478.
15. Texier-Boullet, F.; Foucaud, A. S 1982, 916.
16. Zhdanov, Y. A.; Glebova, Z. I.; Kistyan, G. K.; Uzlova, L. A. JGU 1984, 54, 1079.
17. Lukszo, J.; Tyka, R. S 1977, 239.
18. Fukuda, M.; Kan, K.; Okamoto, Y.; Sakurai, H. BCJ 1975, 48, 2103.
19. Opitz, G.; Geissinger, H.; Schubert, H. W. LA 1963, 665, 91.
20. Isbell, A. F.; Berry, J. P.; Tansey, L. W. JOC 1972, 37, 4399.
21. Barycki, J.; Mastalerz, P.; Soroka, M. TL 1970, 3147.
22. (a) Kim, D. Y.; Lee, K.; Oh, D. Y. JCS(P1) 1992, 2451. (b) Shin, C.; Yonezawa, Y.; Katayama, K.; Yoshimura, J. BCJ 1973, 46, 1727.
23. Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. S 1981, 56.
24. Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. TL 1980, 21, 3595.
25. (a) Zhao, Y.; Zhang, D.; Xue, C. Int. J. Pept. Prot. Res. 1991, 37, 457. (b) Ji, G.; Xue, C.; Zeng, J.; Li, L.; Chai, W.; Zhao, Y. S 1988, 444.
26. Zhao, Y.; Xi, S.; Song, A.; Ji, G. JOC 1984, 49, 4549.
27. (a) Bunnett, J. F.; Creary, X. JOC 1974, 39, 3612. (b) Bunnett, J. F.; Scamehorn, R. G.; Traber, R. P. JOC 1976, 41, 3677. (c) Bunnett, J. F.; Traber, R. P. JOC 1978, 43, 1867.
28. Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. TL 1992, 33, 2311.
29. (a) Battiste, D. R.; Haseldine, D. L. SC 1984, 14, 993. (b) Kenney, R. L.; Fisher, G. S. JOC 1974, 39, 682.
30. Polozov, A. M.; Polezhaeva, N. A.; Mustaphin, A. H.; Khotinen, A. V.; Arbuzov, B. A. S 1990, 515.
31. Clive, D. L. J.; Menchen, S. M. CC 1977, 658.
32. Creary, X.; Benage, B.; Hilton, K. JOC 1983, 48, 2887.
33. Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. JOC 1981, 46, 3745.

Kenneth Green

American Cyanamid Co., Pearl River, NY, USA

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