Tris(trimethylsilyl) Phosphite1

P(OSiMe3)3

[1795-31-9]  · C9H27O3PSi3  · Tris(trimethylsilyl) Phosphite  · (MW 298.60)

(preparation of bis(trimethylsilyl) phosphonate esters by the Arbuzov reaction with halogen-containing compounds or by the Abramov reaction with carbonyl compounds, followed by facile hydrolysis to the corresponding phosphonic acids, RP(O)(OH)2)

Physical Data: bp 84 °C/5 mmHg,2 86.5 °C/18 mmHg,3 83-84 °C/16 mmHg,4 90-92 °C/16 mmHg,4 78-81 °C/8 mmHg; d 0.893 g cm-3.

Form Supplied in: liquid; commercially available.

Preparative Methods: by silylation of anhydrous phosphorous acid (dried by repeated azeotropic evaporation of a solution in THF with dry benzene) with excess Chlorotrimethylsilane and excess Triethylamine in dimethoxyethane,2 toluene,3 or Et2O-THF,5 followed by evaporation of the solvent and vacuum distillation of the residue. The residue, which contains a mixture of tris(trimethylsilyl) phosphite and bis(trimethylsilyl) phosphonate [HP(O)(OTMS)2], can also be heated with sodium (140 °C, 13-22 h), followed by vacuum distillation to obtain pure tris(trimethylsilyl) phosphite.4

Purification: vacuum distill before use.

Handling, Storage, and Precautions: extremely hygroscopic; use in a fume hood.

Arbuzov Reagent with Aliphatic Halides.

The reagent, P(OTMS)3, reacts with alkyl halides such as n-butyl bromide5 to give bis(trimethylsilyl) esters of phosphonic acids. 2,3-Diacyloxyiodopropanes (1) (n = 0, X = I) react with an excess of P(OTMS)3; after removal of the excess P(OTMS)3 and trimethylsilyl iodide under high vacuum (<1 mmHg) at 80-90 °C, bis(trimethylsilyl) 2,3-diacylphosphonates (2) are obtained, which are easily hydrolyzed to the corresponding phosphonic acids (3) (eq 1).2,6,7 3,4-Dipalmitoyloxy-1-bromobutane (1) (n = 1, X = Br) is converted into 3,4-dipalmitoyloxybutanephosphonic acid by the same process.8 The advantage of P(OTMS)3 compared with trialkyl phosphites in the preparation of phosphonic acids is the extreme ease with which the bis(trimethylsilyl) ester groups of (2) undergo neutral aqueous hydrolysis. The mild hydrolysis conditions9 allow otherwise labile groups such as carboxylate esters to remain unaffected during desilylation.

Ether-linked phosphonolipids are available by the Arbuzov reaction of 2,3-dialkoxyiodopropanes,7,10,11 3,4-dialkoxy-1-bromobutanes,7 and other long-chain alkyl bromides12 with P(OTMS)3, followed by facile desilylation (eq 1).

Formation of Alkyloxycarbonyl-, Aryloxycarbonyl-, and Acylphosphonates.

Alkyloxy- and aryloxycarbonylphosphonate bis(trimethylsilyl) derivatives, ROCOP(O)(OTMS)2, are prepared from the Arbuzov reaction of alkyl or aryl chloroformates with P(OTMS)3.13,14 Pivaloyl chloride reacts with P(OTMS)3 to give an acylphosphonate derivative.15

Formation of Thiophosphonates.

Thiophosphonic acids (4) are prepared from the Arbuzov reaction of thiosuccinimides and thiophthalimides containing various S-alkyl and S-aryl groups with P(OTMS)3 (eq 2).16

Arbuzov Reaction with Halomethyl-Containing Compounds.

A variety of chloromethyl- or bromomethyl-containing compounds react with P(OTMS)3 to give the Arbuzov products, RCH2COCH2P(O)(OTMS)217,18 or RCH2P(O)(OTMS)2.19

Other Arbuzov Reactions.

Aryl halides react with P(OTMS)3 in the presence of catalytic nickel chloride, forming arylphosphonates after hydrolysis of the silyl esters.20 1b-Glycosyl triflates react with P(OTMS)3, giving a-D-glucopyranosyl-1-phosphonic acid after hydrolysis.21

Addition to Carbonyl Compounds.

P(OTMS)3 adds to alkyl-substituted a-halocarbonyl compounds to form 1:1 adducts, which on hydrolysis yield a-hydroxyphosphonic acids (5) (eq 3).4,22 In contrast, trialkyl phosphites react with bromoacetone to give b-oxophosphonates. P(OTMS)3 also adds to methyl ketones.23

O-Silylated salicaldehyde reacts with P(OTMS)3, giving a dihydroxy derivative of benzylphosphinic acid after hydrolysis.24

Isocyanates and isothiocyanates react with P(OTMS)3 to give carbamoyl- and thiocarbamoylphosphonates, RNHC(X)P(O)(OH)2 where X = O or S, after treatment with aniline in methanol.25

Other Addition Reactions.

Addition of excess P(OTMS)3 to N-glycosyl-C-aryl nitrones at low temperature in the presence of catalytic HClO4 or zinc triflate gives N-hydroxy-a-aminophosphonic acids.26 Addition to aldimines yields N-substituted phosphonates, (HO)2P(O)CH(R)NH2.27 N-(Phosphonomethyl)glycine derivatives can be made by a modified Abramov reaction of imines or imine precursors with P(OTMS)3.18a,28 Conjugate additions also take place;1 for example, addition to acrylonitrile gives (TMSO)2P(O)CH2CH(TMS)CN in 52% yield.29

Related Reagents.

Trimethyl Phosphite.


1. Review of reactions of silyl esters of phosphorus: (a) Engel, R. Synthesis of Carbon-Phosphorus Bonds; CRC Press: Boca Raton, FL, 1988. (b) Wozniak, L.; Chojnowski, J. T 1989, 45, 2465.
2. Deroo, P. W.; Rosenthal, A. F.; Isaacson, Y. A.; Vargas, L. A.; Bittman, R. Chem. Phys. Lipids 1976, 16, 60.
3. Hata, T.; Sekine, M. JACS 1974, 96, 7363.
4. Sekine, M.; Okimoto, K.; Yamada, K.; Hata, T. JOC 1981, 46, 2097.
5. Belokrinitskii, M. A.; Orlov, N. F. Kremniiorg. Mater. 1971, 145 (CA 1973, 78, 29 929f).
6. Rosenthal, A. F.; Vargas, L. A.; Isaacson, Y. A.; Bittman, R. TL 1975, 977.
7. Doerr, I. L.; Tang, J-C.; Rosenthal, A. F.; Engel, R.; Tropp, B. E. CPL 1977, 19, 185.
8. Tang, J-C.; Tropp, B. E.; Engel, R.; Rosenthal, A. F. CPL 1976, 17, 169.
9. Rabinowitz, R. JOC 1963, 28, 2975.
10. Salari, H.; Howard, S.; Bittman, R. Biochem. Biophys. Res. Commun. 1992, 187, 603.
11. Schmitt, J. D.; Nixon, A. B.; Emilsson, A.; Daniel, L. W.; Wykle, R. L. CPL 1992, 62, 263.
12. Shashidhar, M. S.; Keana, J. F. W.; Volwerk, J. J.; Griffith, O. H. CPL 1990, 56, 159.
13. Vaghefi, M. M.; McKernan, P. A.; Robins, R. K. JMC 1986, 29, 1389.
14. Iyer, R. P.; Phillips, L. A.; Biddle, J. A.; Thakker, D. R.; Egan, W. TL 1989, 30, 7141.
15. Kuyl-Yeheskiely, E.; Spierenburg, M.; Van den Elst, H.; Tromp, M.; Van der Marel, G. A.; Van Boom, J. H. RTC 1986, 105, 505.
16. Müller, C. E.; Roth, H. J. TL 1990, 31, 501.
17. Herrin, T. R.; Fairgrieve, J. S.; Bower, R. R.; Shipkowitz, N. L.; Mao, J. C. H. JMC 1977, 20, 660.
18. (a) Moegelin, W.; Stieblitz, B.; Balszuweit, A.; Issleib, K. Ger. (East) Patent 286 590, 1991 (CA 1991, 115, 29 631k). (b) Stieblitz, B.; Moegelin, W.; Balszuweit, A.; Issleib, K. Ger. (East) Patent 286 589, 1991 (CA 1991, 115, 29 631j).
19. Dreef, C. E.; Valentijn, A. R. P. M.; De Vroom, E.; Van der Marel, G. A.; Van Boom, J. H. TL 1988, 29, 1199.
20. (a) Demik, N. N.; Kabachnik, M. M.; Novikova, Z. S.; Beletskaya, I. P. IZV 1991, 1461 (CA 1991, 115, 183 460k). (b) Demik, N. N.; Kabachnik, M. M.; Novikova, Z. S.; Beletskaya, I. P. IZV 1992, 2432 (CA 1993, 118, 169 216r).
21. Vaghefi, M. M.; Bernacki, R. J.; Dalley, N. K.; Wilson, B. E.; Robins, R. K. JMC 1987, 30, 1383.
22. Sekine, M.; Okimoto, K.; Hata, T. JACS 1978, 100, 1001.
23. (a) Nifant'ev, E. E.; Kukhareva, T. S.; Popkova, T. N.; Bekker, A. R. ZOB 1987, 57, 2003 (CA 1988, 109, 129 113n). (b) Alekseichuk, I. A.; Ofitserov, E. N.; Konovalova, I. V. ZOB 1992, 62, 786 (CA 1993, 118, 213 409g). (c) Ofitserova, E. Kh.; Ivanova, O. E.; Ofitserov, E. N.; Konovalova, I. V.; Pudovik, A. N. ZOB 1981, 51, 505 (CA 1981, 95, 41 800r).
24. (a) Nifant'ev, E. E.; Kukhareva, T. S.; Popkova, T. N.; Davydochkina, O. V. ZOB 1986, 56, 304 (CA 1986, 105, 209 046a). (b) Popkova, T. N.; Kukhareva, T. S.; Bekker, A. R.; Nifant'ev, E. E. ZOB 1986, 56, 1813 (CA 1988, 108, 21 960b).
25. Sekine, M.; Yamagata, H.; Hata, T. TL 1979, 3013.
26. Huber, R.; Vasella, A. HCA 1987, 70, 1461.
27. (a) Zon, J. Pol. J. Chem. 1981, 55, 643 (CA 1982, 96, 199 793w). (b) Avdeenko, A. P.; Ryazantsev, V. P.; Mishchenko, A. I. ZOB 1986, 56, 2491 (CA 1987, 107, 176 131k).
28. Mao, M. K.; Franz, J. E. S 1991, 920.
29. Nakano, M.; Okamoto, Y.; Sakurai, H. S 1982, 915.

Robert Bittman

City University of New York, Flushing, NY, USA



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