Diethyl Cyanomethylphosphonate

[2537-48-6]  · C6H12NO3P  · Diethyl Cyanomethylphosphonate  · (MW 177.14)

(modified Wittig reagent, Wadsworth-Emmons modification, producing a,b-unsaturated nitriles as products from reaction with aldehydes and ketones)

Physical Data: bp 101-102 °C/0.4 mmHg; d 1.095 g cm-3.

Solubility: sol THF, DME, methylene chloride.

Form Supplied in: oil; widely available.

Preparative Methods: prepared by the Michaelis-Arbuzov reaction1 utilizing Triethyl Phosphite and a haloacetonitrile.2 More recently, a preparation was reported utilizing Trimethyl Phosphite and Chloroacetonitrile.3 Thus a mixture of the two reagents was heated at 140-150 °C for 18 h under nitrogen to give a 75% yield of the closely related dimethyl cyanomethylphosphonate. Alternatively, Acetonitrile is treated with 2 equiv of Lithium Diisopropylamide in THF at -78 °C followed by diethyl chlorophosphate (Diethyl Phosphorochloridate) to provide a 47% yield of diethyl cyanomethylphosphonate.4

Handling, Storage, and Precautions: corrosive.

Modified Wittig Reagent.

The most common use of the reagent is the preparation of a,b-unsaturated nitriles from ketones or aldehydes. The stereochemistry of the a,b-unsaturated nitriles is variable, depending on the substrate5 and the reaction conditions.6 Pasto reported a (Z)-favored alkenation on 3-hydroxy-3-methylbutanal (eq 1).7 In contrast, Paquette reported the alkenation shown in eq 2 where the (E)-isomer predominates.8

Sodium Hydride in THF or DME is the most popular base-solvent combination used to effect the Horner-Emmons reaction with diethyl cyanomethylphosphonate. Other useful but less popular conditions include: phase transfer,9 polymer bound diethyl cyanomethylphosphonate,10 and electrochemical methods.11 A vast array of other reaction conditions have been reported in the literature.12

Other Uses.

Cyano-substituted cyclopropanes can be prepared by the reaction between diethyl cyanomethylphosphonate and epoxides (eq 3).2

Diethyl cyanomethylphosphonate anions react with aryl iodides in the presence of copper(I) to give a-arylated alkanenitriles (eq 4).13

Nitrones react with diethyl cyanomethylphosphonate to yield aziridines (eq 5).14

1. (a) Kosolapoff, G. M. Organophosphorus Compounds; Wiley: New York, 1950; Chapter 7. (b) Dawson, N. D.; Burger, A. JACS 1952, 74, 5312.
2. Wadsworth, W. S.; Emmons, W. D. JACS 1961, 83, 1733.
3. Takayanagi, H.; Morinaka, Y.; Kitano, Y. CA 1992, 116, 214 705w.
4. Kandil, A. A.; Porter, T. M.; Slessor, K. N. S 1987, 411.
5. Jones, G; Maisey, R. F. CC 1968, 543.
6. Deschamps, B.; Lefebvre, G.; Redjal, A.; Seyden-Penne, J. T 1973, 29, 2437.
7. Pasto, D. J.; L'Hermine, G. T 1993, 49, 3259.
8. Garratt, P. J.; Doecke, C. W.; Weber, J. C.; Paquette, L. A. JOC 1986, 51, 449.
9. Piechucki, C. S 1974, 869.
10. Cainelli, G.; Contento, M.; Manescalchi, F.; Regnoli, R. JCS(P1) 1980, 2516.
11. Niyazymbetov, M. E.; Petrosyan, V. A.; Keitel, I.; Costisella, B.; Schwarz, K. H. TL 1988, 29, 3007.
12. There are 508 references to diethyl cyanomethylphosphonate between 1968 and late 1993. Some current references are: (a) Caldwell, C. G.; Derguini, F.; Biggs, C. F.; Chen, A.-H.; Hu, S.; Wang, J.; Sastry, L.; Nakanishi, K. JOC 1993, 58, 3533. (b) Brown, T. J.; Chapman, F.; Mason, S.; Palfreyman, N.; Vicker, N.; Walsh, R. J. A. JMC 1993 36, 1604. (c) Buschauer, A.; Friese-Kimmel, A.; Baumann, G.; Schunack, W. Eur. J. Med. Chem. 1992, 27, 321. (d) Angle, S. R.; Rainier, J. D. JOC 1992, 57, 6883. (e) McDonough, L. M.; Davis, M. G. CA 1992, 117, 126 470f. (f) Neidlein, R.; Schröder, G. HCA 1992, 75, 825.
13. Suzuki, H.; Watanabe, K.; Qui, Y. CL 1985, 1779.
14. Breuer, E.; Zbaida, S.; Pesso, J.; Levi, S. TL 1975, 3103.

Brad DeHoff

Syntex Technology Center, Boulder, CO, USA

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