TRIMETHYL PHOSPHATE 1
NH2 2 equiv (MeO)3PO NMe2
Trimethyl Phosphate
197 °C
3 + 2 H3PO4 (2)
3
90%
Cl Cl
O
P
MeO OMe
MeO
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
[512-56-1] C3H9O4P (MW 140.09)
1,2,4-triazoles,3a benzotriazoles,3a quinolines,3b purines,3c,3d
InChI = 1/C3H9O4P/c1-5-8(4,6-2)7-3/h1-3H3
pyrimidines,3e,3f and phenothiazines.3g
InChIKey = WVLBCYQITXONBZ-UHFFFAOYAV
(MeO)3PO
(esterification of carboxylic acids;1 N,N-dimethylation of
Et3N
N N
anilines;2 N-methylation of nitrogen heterocycles3) 85 °C
3 H3PO4 (3)
3 +
60%
ć%
N N
Physical Data: bp 197 C; d 1.197 g cm-3.
H Me
Solubility: sol H2O(1g cm-3), ethanol, ether.
Form Supplied in: liquid; widely available.
Purification: distillation at ambient or reduced pressure.
Ring Opening of Isoxazolidines. Trimethyl phosphate reacts
Handling, Storage, and Precautions: stable for extended periods
with N-alkylisoxazolidines to form, depending on the substitution
of storage. It is a cancer suspect agent and possible mutagen
pattern of the isoxazolidine, Ä…,²-enones5a (eq 4) or tertiary allylic
and should be handled with due caution.
alcohols.5b
(MeO)3PO
Ph
diglyme
O
155 °C
Esterification of Carboxylic Acids. Trimethyl phosphate is
(4)
MeN
Ph
Ph Ph
95%
O
an effective reagent for the preparation of methyl esters of hin-
dered carboxylic acids (eq 1).1a and serves as an alternative to toxic
Dimethyl Sulfate.4 It can also effect the O-methylation of unpro-
Methylation ofÄ…-Lithio Sulfoxides. Trimethyl phosphate re-
tected amino acids,1b although some N,O-dimethylated product
acts with Ä…-lithio sulfoxides to form the corresponding Ä…-methyl
is observed.
sulfoxides.6 The coordinating ability of the reagent with the
lithium counterion can lead to a reversal of product stereochem-
istry compared with similar alkylations with Iodomethane.6a,6b
Use as a Solvent. Trimethyl phosphate is an excellent dipolar
aprotic solvent for a variety of synthetic transformations. In aro-
matic halogenation reactions7 and the halogenative cleavage of
(MeO)3PO (excess)
cyclic acetals,8 trimethyl phosphate acts as an acid scavenger, very
NaOH (aq)
25 100 °C rapidly reacting with liberated hydrogen halide to form methyl
CO2H
halide. Trimethyl phosphate also has an accelerating effect on the
HO2C 90%
diphosgene-mediated conversion of carboxamides to nitriles,9 and
on the phosphoryl chloride-mediated direct phosphorylation of
unprotected nucleosides to 5 -nucleotides.10
CO2Me
(1)
MeO2C
1. (a) Harris, M. M.; Patel, P. K., Chem. Ind. (London) 1973, 1002.
(b) Hughes, D. L.; Bergan, J. J.; Grabowski, E. J. J., J. Org. Chem.
1986, 51, 2579.
2. (a) Thomas, D. G.; Billman, J. H.; Davis, C. E., J. Am. Chem. Soc. 1946,
68, 895. (b) Billman, J. H.; Radike, A.; Mundy, B. W., J. Am. Chem.
Soc. 1942, 64, 2977. (c) Sheppard, W. A., Org. Synth., Coll. Vol. 1973,
5, 1085. (d) Fletcher, T. L.; Taylor, M. E.; Dahl, A. W., J. Org. Chem.
1955, 20, 1021. (e) Barker, A.; Barker, C. C., J. Chem. Soc. 1953, 2034.
3. (a) Yamauchi, K.; Kinoshita, M., J. Chem. Soc., Perkin Trans. 1 1973,
N,N-Dialkylation of Anilines. Trimethyl phosphate reacts 2506. (b) Frank, J.; Meszaros, Z.; Dutka, F.; Komives, T.; Marton, A. F.,
Tetrahedron Lett. 1977, 4545. (c) Yamauchi, K.; Hayashi, M.; Kinoshita,
with anilines to give N,N-dimethylated products (eq 2).2a,2b A
M., J. Org. Chem. 1975, 40, 385. (d) Sekine, M.; Satoh, T., J. Org. Chem.
wide variety of substitution is tolerated, although substituents
1991, 56, 1224. (e) Yamauchi, K.; Kinoshita, M., J. Chem. Soc., Perkin
which significantly decrease the basicity of nitrogen, such as p-
Trans. 1 1973, 391. (f) Black, T. H.; Gatto, C., Synth. Commun. 1989,
nitro, are not. All three methyl groups of the reagent molecule are
19, 843. (g) Cadogan, J. I. G.; Kulik, S.; Thomson, C.; Todd, M. J., J.
utilized in these alkylations.
Chem. Soc. (C) 1970, 2437.
Avoid Skin Contact with All Reagents
2 TRIMETHYL PHOSPHATE
4. Werner, A.; Seybold, W., Chem. Ber. 1904, 37, 3658. 8. Venkataramu, S. D.; Cleveland, J. H.; Pearson, D. E., J. Org. Chem. 1979,
44, 3082.
5. (a) Liguori, A.; Sindona, G.; Uccella, N., Tetrahedron 1984, 40, 1901.
(b) Chiacchio, U.; Liguori, A.; Romeo, G.; Sindona, G.; Uccella, N., 9. Mai, K.; Patil, G., Tetrahedron Lett. 1986, 27, 2203.
Heterocycles 1993, 36, 799.
10. (a) Yoshikawa, M.; Kato, T.; Takenishi, T., Bull. Chem. Soc. Jpn. 1969,
6. (a) Biellmann, J. F.; Vicens, J. J., Tetrahedron Lett. 1978, 467. 42, 3505. (b) Mishra, N. C.; Broom, A. D., J. Chem. Soc., Chem.
(b) Chassaing, G.; Lett, R.; Marquet, A., Tetrahedron Lett. 1978, 471. Commun. 1991, 1276.
(c) Sato, T.; Itoh, T.; Fujisawa, T., Tetrahedron Lett. 1987, 28,
5677.
John M. Fevig
7. (a) Pearson, D. E.; Frazer, M. G.; Frazer, V. S.; Washburn, L. C., Synthesis
The DuPont Merck Pharmaceutical Company,
1976, 621. (b) Mirsadeghi, S.; Prasad, G. K. B.; Whittaker, N.; Thakker,
Wilmington, DE, USA
D. R., J. Org. Chem. 1989, 54, 3091.
A list of General Abbreviations appears on the front Endpapers