Diethyl Chlorophosphite

[589-57-1]  · C4H10ClO2P  · Diethyl Chlorophosphite  · (MW 156.55)

(synthesis of allenyl phosphonates,11 b-ketophosphonates;8,12 phosphorylation of alcohols;15 coupling agent19)

Alternate Names: diethyl phosphorochloridite; diethyl chlorophosphonite; ethyl phosphorochloridite.

Physical Data: bp 153-155 °C/760 mmHg, 56-57.5 °C/30 mmHg; d 1.082 g cm-3; fp 1 °C.

Solubility: benzene, THF, diethyl ether, methylene chloride, acetonitrile.

Form Supplied in: colorless liquid.

Preparative Methods: the reaction of Phosphorus(III) Chloride with Triethyl Phosphite,1 anhydrous ethanol,2 or Sodium Ethoxide3 has been employed, although diethyl chlorophosphite is commercially available.

Purification: vacuum distillation.

Handling, Storage, and Precautions: the neat liquid is flammable and combustion produces toxic byproducts. Caution should be taken when handling the material due to its toxicity. Bottles of diethyl chlorophosphite should be sealed and stored under N2 to prevent contact with moisture, which produces HCl vapor. Use in a fume hood.

General Notes.

Diethyl chlorophosphite is a reactive electrophile for the introduction of phosphorus into organic compounds. It is known to react readily with a variety of nucleophiles including amines,4 amides,5 alcohols (see below), and various organometallic derivatives including Grignard reagents,6 enolates, and Reformatsky reagents.7 Oxidation of the initial phosphorus(III) species to a phosphorus(V) species, typically from phosphite to phosphate or phosphonite to phosphonate, is accomplished with a number of reagents including air (O2),8 Iodine,9 Ozone,5 and t-Butyl Hydroperoxide.10

Arbuzov-Type Rearrangements Leading to Allenyl and Allyl Phosphonates.

Reaction of diethyl chlorophosphite with propargyl alcohols in the presence of base results in the rapid formation of allenylphosphonates (eq 1).11 This general method is believed to proceed through a cyclic transition state with rearrangement occurring at or below rt in many cases. Substitution greatly affects the rate of rearrangement. Allenylphosphonates react with a variety of nucleophiles, including alkoxides and secondary amines, to form b-ketophosphonates after hydrolysis of the intermediate enamine or enol ether (eq 2).12

Allyl alcohols can be similarly treated to afford allylphosphonates where the selectivity in alkene geometry is dependent upon substitution (eq 3).13 Rearrangement of the intermediate diethyl allyl phosphites takes place at 70-100 °C. A related rearrangement involves the conversion of 2,3-butadienyl phosphites (homoallenyl phosphites) to 1,3-butadienyl-2-phosphonates.

Phosphorylation of Alcohols.

Protein phosphorylation is now recognized as a critical reaction in the control of cell metabolism.14 Diethyl chlorophosphite has been shown to be a more effective and reactive phosphorus electrophile than diphenyl chlorophosphonate.15 In the case of N-protected serine derivatives (eq 4), an excess of the phosphite is required due to the competitive reaction with the carboxylic acid.9 Oxidation to the phosphate takes place under a variety of conditions already described.

Organophosphates are also available from alcohols using diethyl chlorophosphite. In compounds containing multiple alcohol functionalities, such as derivatives of inositol (eq 5), chlorophosphites are preferred over more traditional phosphorus(V) reagents which suffer from not only lower relative reactivity, but also the tendency of the intermediate phosphate triesters to form cyclic phosphates or undergo acid-induced rearrangements.16 Phosphate triesters can be dealkylated to the phosphates with Bromotrimethylsilane.10

Diethyl Chlorophosphite as a Coupling Agent.

Schmidt and Martin have demonstrated the use of phosphite as a leaving group in the sialylation of sugars with catalytic Trimethylsilyl Trifluoromethanesulfonate. Their procedure allows for higher yields than could be obtained using other methods for the formation of the glycosidic bond.17 Diethyl chlorophosphite activation of amines allows for the formation of peptides.18 In certain cases, diethyl anilinophosphite (formed by the reaction of the chlorophosphite with aniline) has also been used as the phosphite source. The researchers found that the corresponding phosphorus(V) reagents do not work as well with this coupling protocol. Reaction of 3-(diethyl phosphonite) thymidine derivatives with a 5-azidothymidine leads to the formation of the dinucleotide at room temperature with extrusion of N2 (eq 6). This coupling procedure is easily accomplished and high yielding.19

Preparation of Horner-Wadsworth-Emmons Alkenation Reagents.

Treatment of an a-hydroxy ketone with diethyl chlorophosphite in the presence of a Lewis acid results in a rapid rearrangement to the corresponding b-ketophosphonate (eq 7).20 Treatment of an a-hydroxy ester results in the formation of an H-phosphonate diester instead of the expected rearrangement product. Horner-Wadsworth-Emmons condensation reagents21 can also be prepared by the reaction of ketone or ester enolates with diethyl chlorophosphite followed by oxidation of the resultant phosphite (eq 8).8 This methodology offers several advantages to the Michaelis-Arbuzov reaction,22 including application to cyclic ketones and availability of starting materials. The competitive formation of enol phosphates by this method is not a problem as it is with phosphorylating agents.23 Reaction of diethyl chlorophosphite with phosphoryl-stabilized anions has been reported with the products leading to 1,3-butadienylphosphonites.24

1. Cook, H. G.; Ilett, J. D.; Saunders, B. C.; Stacey, G. J.; Watson, H. G.; Wilding, I. G. E.; Woodcock, S. J. JCS(P2) 1949, 2921.
2. Michalski, J.; Modro, T.; Zwierzak, A. JCS(P2) 1961, 4904.
3. Arbusow, A. E.; Arbusow, B. A. CB 1932, 65, 195.
4. Afarinka, K.; Cadogan, J. I.; Rees, C. W. CC 1992, 285.
5. Kawonobe, W.; Yamaguchi, K.; Nakahama, S.; Yamazaki, N. CL 1982, 825.
6. (a) Krasil'nikova, E. A.; Razumov, A. I.; Nevzoravo, O. L. JGU 1977, 47, 1095 (CA 1977, 87, 85 097). (b) Collins, D. J.; Drygala, P. F.; Swan, J. M. AJC 1983, 36, 2517.
7. Malenko, D. M.; Gololobov, Y. G. JGU 1976, 46, 2291 (CA 1976, 84, 43 785).
8. Lee, K.; Wiemer, D. F. JOC 1991, 56, 5556.
9. Perich, J. W.; Alewood, P. F.; Johns, R. B. S 1986, 572.
10. Liu, C.; Nahorski, S. R.; Potter, B. V. L. Carbohydr. Res. 1992, 234, 107.
11. Review: Mark, V. In Mechanisms of Molecular Migrations; Thyagarajan, B. S. Ed.; Wiley: New York, 1971; Vol. 2, p 319.
12. (a) Altenbach, H.-J.; Korff, R. TL 1981, 22, 5175. (b) Altenbach, H.-J.; Korff, R. AG(E) 1982, 21, 371.
13. Janecki, T.; Bodalski, R. S 1990, 799.
14. Cohen, P. Nature 1982, 296, 613.
15. (a) Alewood, P. F.; Perich, J. W.; Johns, R. B. SC 1982, 12, 821. (b) Perich, J. W.; Johns, R. B. AJC 1990, 43, 1609.
16. Meek, J. L.; Davidson, F.; Hobbs, F. W. JACS 1988, 110, 2317.
17. Martin, T. J.; Schmidt, R. R. TL 1992, 33, 6123.
18. Anderson, G. W.; Blodinger, J.; Young, R. W.; Welcher, A. D. JACS 1952, 74, 5304.
19. Letsinger, R. L.; Heavner, G. A. TL 1975, 2, 147.
20. Roussis, V.; Wiemer, D. F. JOC 1989, 54, 627.
21. For a review of the H-W-E condensation, see: Wadsworth, W. S. OR 1984, 25, Chapter 2.
22. Arbusow, B. E. PAC 1964, 9, 307.
23. (a) Hammond, G. B.; Calogeropoulou, T.; Wiemer, D. F. TL 1986, 27, 4265. (b) Sampson, P.; Hammond, G. B.; Wiemer, D. F. JOC 1986, 51, 4342.
24. Teulade, M.-P.; Savignac, P. TL 1989, 30, 6327.

Eric J. Stoner

Abbott Laboratories, North Chicago, IL, USA

Peter P. Giannousis

Ciba-Geigy Corporation, Summit, NJ, USA

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