Trimethyl Phosphate

[512-56-1]  · C3H9O4P  · Trimethyl Phosphate  · (MW 140.09)

(esterification of carboxylic acids;1 N,N-dimethylation of anilines;2 N-methylation of nitrogen heterocycles3)

Physical Data: bp 197 °C; d 1.197 g cm-3.

Solubility: sol H2O (1 g mL-1), ethanol, ether.

Form Supplied in: liquid; widely available.

Purification: distillation at ambient or reduced pressure.

Handling, Storage, and Precautions: stable for extended periods of storage. It is a cancer suspect agent and possible mutagen and should be handled with due caution.

Esterification of Carboxylic Acids.

Trimethyl phosphate is an effective reagent for the preparation of methyl esters of hindered carboxylic acids (eq 1)1a and serves as an alternative to toxic Dimethyl Sulfate.4 It can also effect the O-methylation of unprotected amino acids,1b although some N,O-dimethylated product is observed.

N,N-Dialkylation of Anilines.

Trimethyl phosphate reacts with anilines to give N,N-dimethylated products (eq 2).2a,b A wide variety of substitution is tolerated, although substituents which significantly decrease the basicity of nitrogen, such as p-nitro, are not. All three methyl groups of the reagent molecule are utilized in these alkylations.

N-Alkylation of Nitrogen Heterocycles.

The title reagent has been used to N-methylate a wide variety of nitrogen heterocycles, including imidazoles,3a benzimidazoles (eq 3),3a pyrazoles,3a 1,2,4-triazoles,3a benzotriazoles,3a quinolines,3b purines,3c,d pyrimidines,3e,f and phenothiazines.3g

Ring Opening of Isoxazolidines.

Trimethyl phosphate reacts with N-alkylisoxazolidines to form, depending on the substitution pattern of the isoxazolidine, a,b-enones5a (eq 4) or tertiary allylic alcohols.5b

Methylation of a-Lithio Sulfoxides.

Trimethyl phosphate reacts with a-lithio sulfoxides to form the corresponding a-methyl sulfoxides.6 The coordinating ability of the reagent with the lithium counterion can lead to a reversal of product stereochemistry compared with similar alkylations with Iodomethane.6a,b

Use as a Solvent.

Trimethyl phosphate is an excellent dipolar aprotic solvent for a variety of synthetic transformations. In aromatic halogenation reactions7 and the halogenative cleavage of cyclic acetals,8 trimethyl phosphate acts as an acid scavenger, very rapidly reacting with liberated hydrogen halide to form methyl halide. Trimethyl phosphate also has an accelerating effect on the diphosgene-mediated conversion of carboxamides to nitriles,9 and on the phosphoryl chloride-mediated direct phosphorylation of unprotected nucleosides to 5-nucleotides.10

1. (a) Harris, M. M.; Patel, P. K. CI(L) 1973, 1002. (b) Hughes, D. L.; Bergan, J. J.; Grabowski, E. J. J. JOC 1986, 51, 2579.
2. (a) Thomas, D. G.; Billman, J. H.; Davis, C. E. JACS 1946, 68, 895. (b) Billman, J. H.; Radike, A.; Mundy, B. W. JACS 1942, 64, 2977. (c) Sheppard, W. A. OSC 1973, 5, 1085. (d) Fletcher, T. L.; Taylor, M. E.; Dahl, A. W. JOC 1955, 20, 1021. (e) Barker, A.; Barker, C. C. JCS 1953, 2034.
3. (a) Yamauchi, K.; Kinoshita, M. JCS(P1) 1973, 2506. (b) Frank, J.; Meszaros, Z.; Dutka, F.; Komives, T.; Marton, A. F. TL 1977, 4545. (c) Yamauchi, K.; Hayashi, M.; Kinoshita, M. JOC 1975, 40, 385. (d) Sekine, M.; Satoh, T. JOC 1991, 56, 1224. (e) Yamauchi, K.; Kinoshita, M. JCS(P1) 1973, 391. (f) Black, T. H.; Gatto, C. SC 1989, 19, 843. (g) Cadogan, J. I. G.; Kulik, S.; Thomson, C.; Todd, M. J. JCS(C) 1970, 2437.
4. Werner, A.; Seybold, W. CB 1904, 37, 3658.
5. (a) Liguori, A.; Sindona, G.; Uccella, N. T 1984, 40, 1901. (b) Chiacchio, U.; Liguori, A.; Romeo, G.; Sindona, G.; Uccella, N. H 1993, 36, 799.
6. (a) Biellmann, J. F.; Vicens, J. J. TL 1978, 467. (b) Chassaing, G.; Lett, R.; Marquet, A. TL 1978, 471. (c) Sato, T.; Itoh, T.; Fujisawa, T. TL 1987, 28, 5677.
7. (a) Pearson, D. E.; Frazer, M. G.; Frazer, V. S.; Washburn, L. C. S 1976, 621. (b) Mirsadeghi, S.; Prasad, G. K. B.; Whittaker, N.; Thakker, D. R. JOC 1989, 54, 3091.
8. Venkataramu, S. D.; Cleveland, J. H.; Pearson, D. E. JOC 1979, 44, 3082.
9. Mai, K.; Patil, G. TL 1986, 27, 2203.
10. (a) Yoshikawa, M.; Kato, T.; Takenishi, T. BCJ 1969, 42, 3505. (b) Mishra, N. C.; Broom, A. D. CC 1991, 1276.

John M. Fevig

The DuPont Merck Pharmaceutical Company, Wilmington, DE, USA

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