Dimethyl Sulfate1

[77-78-1]  · C2H6O4S  · Dimethyl Sulfate  · (MW 126.13)

(effective methylating reagent1)

Physical Data: bp 188 °C; mp -32 °C; d 1.333 g cm-3; fp 83 °C.

Form Supplied in: water-white liquid; widely available.

Handling, Storage, and Precautions: extremely toxic and carcinogenic; use in a fume hood with adequate protection.2

O-Alkylation.

Dimethyl sulfate is a powerful alkylating agent and has been used for the methylation of almost every imaginable nucleophile over the years.1 The variety of oxygen nucleophiles include carboxylic acids,3 alcohols,4 phenols,5 lactams,6 oximes,7 pyridine N-oxides,8 hydroxylamines,9 hydroxamic acids,10 and hydroperoxides.11

Carboxylic acids react with dimethyl sulfate in the presence of Dicyclohexyl(ethyl)amine (DICE) to afford methyl esters in high yield.3 The method is reported to be facile and particularly useful when ester formation using Diazomethane or strongly acidic conditions is not possible. For example, b-9,10,12-trihydroxyoctadecanoic acid is readily converted to its methyl ester in 97% yield using this procedure (eq 1). Another example of this type of esterification was demonstrated with the preparation of bile acid methyl esters (eq 2).12 These steroidal carboxylic acids were methylated using Potassium Carbonate as a base in refluxing acetone. Both of the aforementioned procedures avoid significant side reactions such as dehydration or ether formation resulting from competing alkylation of free hydroxy groups.

Syntheses of aryl and alkyl methyl ethers using dimethyl sulfate have also been reported. Simple alcohols and phenols may be alkylated using dimethyl sulfate in slightly hydrated solid/liquid heterogeneous media with 1,4-dioxane or triglyme/potassium hydroxide and small amounts of water to give the corresponding methyl ethers in excellent yield.4 For example, t-butyl alcohol is converted to t-butyl methyl ether in nearly quantitative yield (eq 3). The procedure calls for the use of only a stoichiometric amount of dimethyl sulfate, which reduces problems associated in the workup and the potential toxicity of remaining dimethyl sulfate. In addition, methylation of alcohols using dimethyl sulfate and Alumina as a solid adsorbent reaction medium affords excellent yields of the corresponding alkyl alcohols.13 Phenols and carboxylic acids, however, gave lower yields of methylated product using this procedure. A second example involves the stereospecific formation of highly substituted tetrahydrofurans. Treatment of a 2,5-dihydroxy-4-phenyl sulfide with dimethyl sulfate in dichloromethane at 0 °C cleanly afforded the substituted tetrahydrofuran in excellent yield (eq 4).14 It has been suggested that the reaction proceeds via methylation of a free hydroxy group followed by solvolysis of methanol assisted by the neighboring thiophenyl group. Subsequent cyclization gave the tetrahydrofuran as a single stereoisomer.

Several methods have been described for preparing aryl methyl ethers from phenols using dimethyl sulfate. For example, defucogilvocarcin M was completed by methylating a sterically hindered C-12 hydroxyl group using dimethyl sulfate and potassium carbonate (eq 5).5 In addition, the synthesis of a carbazole alkaloid was completed via the selective alkylation of a 5-indolyl alcohol using dimethyl sulfate and Sodium Hydride to give 4-deoxycarbazomycin B in 96% yield (eq 6).15

The O-methylation of lactams to afford O-alkylimino ethers has also been reported. For example, the large-scale preparation of O-methylcaprolactim proceeds in good yield using caprolactam and 1 equiv of dimethyl sulfate in benzene (eq 7).6 The treatment of caprolactam with excess dimethyl sulfate gives N-methyllactam as the major product.

Other alkylation processes include the O-methylation of oximes, N-oxides, hydroxylamines, and hydroxamic acids. The preparation of oxime ethers using dimethyl sulfate has proven an effective methodology for the construction of sidechains designed for new cephalosporin antibiotics. Treatment of a-oxime esters with dimethyl sulfate afforded the a-methoximino esters, which were subsequently hydrolyzed to the acid and used as sidechains via acylation chemistry (eq 8).7

The methylation of pyridine, quinoline, and isoquinoline N-oxides to afford N-methoxy salts has also been investigated. For example, treatment of quinoline N-oxide with dimethyl sulfate provides the N-methoxy methylsulfate salt in excellent yield (eq 9).8 The resulting salts were subsequently treated with cyanide ion to afford cyanopyridines in a mild overall process.

A new route to 2-substituted indoles derived from 1-methoxyindole was recently described. Dimethyl sulfate proved to be the reagent of choice for the methylation of the unstable 1-hydroxyindole to give 1-methoxyindole in 51% yield (eq 10).9 The resulting methoxyindole undergoes O-lithiation at the 2-position using n-Butyllithium, and can be trapped with appropriate electrophiles. It should be noted that methylation of 1-hydroxyindole using Iodomethane afforded only very low yields of the desired methoxyindole.

Finally, a convenient synthesis of N,O-Dimethylhydroxylamine, a reagent used to prepare aldehydes from N-methoxy-N-methylamides, has been reported. It includes a key dimethylation of an intermediate ethyl hydroxycarbamate using dimethyl sulfate and sodium hydroxide (eq 11).10

N-Alkylation.

Dimethyl sulfate has also been a useful reagent for the preparation of N-methyl alkyl- and aryl-substituted amines, amides, and quaternary ammonium salts. Simple primary amines can be selectively methylated to afford secondary amines by first protecting the amine as a Schiff base or amidine ester,16 amide,17 or carbamate,18 followed by alkylation using dimethyl sulfate and hydrolysis of the resulting amide or iminium ion. For example, the methylation of amidines has been employed in a route to N-alkyl amino acids. The amidine of phenylalanine methyl ester was prepared from the amino ester using dimethylformamide dimethyl acetal (see N,N-Dimethylformamide Diethyl Acetal), followed by methylation and hydrolysis to afford the corresponding N-methylphenylalanine in good yield without racemization (eq 12).16 Certain substrates such as phenylglycine methyl ester required the use of Methyl Trifluoromethanesulfonate as the alkylating agent and lower reaction temperatures to retain optical purity throughout the process. The selective synthesis of substituted N-monoalkylaromatic amines has also been reported. For example, 2-nitroacetanilide is cleanly converted to 2-nitro-N-methylaniline in one pot using phase-transfer conditions (eq 13).17

Tertiary alkyl and aromatic amines are also conveniently quaternized using dimethyl sulfate. For example, a series of thioquinanthrenediinium salts for use as potential antibiotics were prepared via methylation of their quinoline precursors using dimethyl sulfate (eq 14).19

S-Alkylation.

The methylation of sulfur-containing compounds using dimethyl sulfate to afford sulfides and sulfonium ions has also been explored. For example, trimethylsulfonium methyl sulfate has been prepared on a large scale via methylation of dimethyl sulfide.20 This salt has been subsequently used as a precursor of Dimethylsulfonium Methylide, a popular reagent for the preparation of epoxides from ketones (eq 15). O-Alkyl S-methyl dithiocarbamates have also been prepared via condensation of an alkoxide with Carbon Disulfide, followed by methylation using dimethyl sulfate (eq 16).21 The resulting dithiocarbamates can then be reduced via radical chemistry to afford the alkane.

C-Alkylation.

Several processes involving the formation of C-C bonds via methylation of organometallics using dimethyl sulfate have been reported. For example, a series of 2-methylbutyrolactones and -valerolactones were prepared via asymmetric alkylation using chiral oxazolines and Lithium Diisopropylamide followed by treatment with dimethyl sulfate (eq 17).22 The resulting oxazoline was then hydrolyzed to afford the optically active lactone. Aryllithium species also undergo rapid alkylation using dimethyl sulfate as the electrophile. For example, 3,4-bis(tributylstannyl)furan undergoes a single tin-lithium exchange and upon treatment with dimethyl sulfate and N,N-Dimethylpropyleneurea (DMPU) affords the monomethylated product (eq 18).23 The resulting compounds were then subjected to various palladium-mediated cross-coupling reactions to give 3,4-disubstituted unsymmetrical furans. Dimethyl sulfate was found to be superior to methyl iodide for this particular application.


1. (a) Suter, C. M. The Organic Chemistry of Sulfur; Wiley: New York, 1944; pp 48-74. (b) Kaiser, E. T. The Organic Chemistry of Sulfur; Plenum: New York, 1977; p 649. (c) Use as methylating agent: Fieser, L.; Fieser, M. FF 1967, 1, 293 and further references cited therein.
2. (a) Material Safety Data Sheets (MSDS) on dimethyl sulfate are available from various vendors. (b) Merck Index 11th ed.; 1989, p 3247. (c) Review of carcinogenicity studies: IARC Monographs 1974, 4, 271. (d) Mutagenicity studies: Hoffman, G. R. Mutat. Res. 1980, 75, 63.
3. Stodola, F. H. JOC 1964, 29, 2490.
4. Achet, D.; Rocrelle, D.; Murengezi, I.; Delmas, M.; Gaset, A. S 1986, 642.
5. Hart, D. J.; Merriman, G. H. TL 1989, 30, 5093.
6. Benson, R. E.; Cairns, T. L. JACS 1948, 70, 2115.
7. Kukolja, S.; Draheim, S. E.; Pfeil, J. L.; Cooper, R. D. G.; Graves, B. J.; Holmes, R. E.; Neel, D. A.; Huffman, G. W.; Webber, J. A.; Kinnick, M. D.; Vasileff, R. T.; Foster, B. J. JMC 1985, 28, 1886.
8. Feely, W. E.; Beavers, E. M. JACS 1959, 81, 4004.
9. Kawasaki, T.; Kodama, A.; Nishida, T.; Shimizu, K.; Somei, M. H 1991, 32, 221.
10. Goel, O. P.; Krolls, U. OPP 1987, 75.
11. Hock, H.; Lang, S.; Duyfjes, W. CB 1942, 75, 300.
12. Ballini, R.; Carotti, A. SC 1983, 1197.
13. Ogawa, H.; Ichimura, Y.; Chihara, T.; Shousuke, T.; Taya, K. BCJ 1986, 59, 2481.
14. Williams, D. R.; Phillips, J. G.; Barner, B. A. JACS 1981, 103, 7398.
15. Knolker, H. J.; Bauermeister, M.; Blaser, D.; Boese, R.; Pannek, J. B. AG 1989, 225.
16. O'Donnel, M. J.; Bruder, W. A.; Daugherty, B. W.; Liu, D.; Wojciechowski, K. TL 1984, 3651.
17. Kalkote, U. R.; Choudhary, A. R.; Natu, A. A.; Lahoti, R. J.; Ayyangar, N. R. SC 1991, 1889.
18. Clark-Lewis, J. W.; Thompson, M. J. JCS 1957, 442.
19. Maslankiewicz, A.; Zieba, A. H 1992, 33, 247.
20. Kutsuma, T.; Nagayama, I.; Okazaki, T.; Sakamoto, T.; Akaboshhi, S. H 1977, 8, 397.
21. Barton, D. H. R.; McCombie, S. W. JCS(P1) 1975, 1574.
22. Meyers, A. I.; Yamamoto, Y.; Mihelich, E. D.; Bell, R. A. JOC 1980, 45, 2792.
23. Yang, Y.; Wong, H. N. C. CC 1992, 1723.

Gregory Merriman

Hoechst-Roussel Pharmaceuticals, Somerville, NJ, USA



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