[109-87-5]  · C3H8O2  · Dimethoxymethane  · (MW 76.10)

(widely used OH-protecting reagent, applicable to alkanols, phenols, and carboxylic acids; stable above pH 4; resistant to bases; resistant to nucleophiles; resistant to organometallic reagents; resistant to catalytic hydrogenation; resistant to hydride reduction; labile with Lewis acids; resistant to most oxidants; convenient reagent for the chloromethylation of arenes; applicable to the C-6 methylenation of steroids; useful solvent for the preparation of Grignard reagents and organolithium derivatives)

Physical Data: bp 41-42 °C; mp -104.8 °C; d 0.863 g cm-3; fp -17 °C.

Solubility: sol water (24% at 16 °C), chloroform, 1,2-dichloroethane, dichloromethane, THF.

Methoxymethylation of Alcohols and Related Compounds.

Dimethoxymethane is a convenient reagent for the protection of alcohols as their methoxymethyl (MOM) ethers. The MOM protecting group is superior to such common alternatives as the tetrahydropyranyl (THP) group in that it avoids the complication of introducing additional chirality during its installation. This is particularly important when the alcohol to be protected is chiral and hence the introduction of a second asymmetric center during the protection would generate a diastereomeric mixture, complicating purification, assignment of NMR signals, etc.

The MOM protecting group has been widely applied in synthesis. Classically it has been installed under basic conditions using Chloromethyl Methyl Ether.1 Application of this procedure is therefore limited to species stable to basic conditions and nucleophiles. Additionally, the use of chloromethyl methyl ether has been sharply curtailed since it has been shown to be a potent carcinogen.2 Conversely, dimethoxymethane is comparatively nontoxic. O-Methoxymethylation using dimethoxymethane under acidic conditions has greatly expanded the applicability of this protecting group. Treatment of alcohols with a large excess of dimethoxymethane, and Phosphorus(V) Oxide at rt, affords the corresponding methoxymethyl ethers (94-99%) (eq 1). In most cases, no further purification is required.3

MOM ethers can be formed via acid-catalyzed acetal exchange effected with p-Toluenesulfonic Acid. The reaction can be driven to completion by the removal of the methanol formed with molecular sieves or by azeotropic distillation with methylene chloride cosolvent. This method advantageously avoids the use of the very large excesses of phosphorus pentoxide usually required, which complicates the workup of large scale preparations of alkanolic or phenolic methoxymethyl ethers. Preparation of 10-20 kg quantities of material has been demonstrated.4

A general methodology for the preparation of methoxymethyl derivatives, using the methoxymethyl cation generated from Zn0/BrCH2CO2Et/dimethoxymethane, has also been described. Methoxymethyl derivatives of phenols, thiols, imides, alkyl carboxylates, aryl carboxylates, and alkynes can be prepared in good to high yields (45-88%). In addition, esterification of acid chlorides can be effected using dimethoxymethane and anhydrous Zinc Bromide (eq 2).5

Methoxymethyl ethers of primary alcohols may be conveniently prepared, in high yields, using Nafion-H catalyst (MeOCH2OMe, 41 °C, 10-24 h). Reaction of secondary alcohols requires elevated temperatures. The solid catalyst is separated by filtration and the product purified by chromatography. Tertiary alcohols yield alkenic dehydration products. Bridgehead tertiary alcohols yield methyl ethers.6

Iodotrimethylsilane also catalyzes the acetal exchange with dimethoxymethane to yield methoxymethyl ethers of primary and secondary alcohols under mild reaction conditions (25 °C, 1-6 h, 76-95%). In the low yielding examples (76-80%), the remaining starting materials are recovered. Tertiary alcohols yield the corresponding alkyl iodides rather than MOM ethers. The reaction can also be carried out using in situ generated iodotrimethylsilane (Allyltrimethylsilane-Iodine).7

The treatment of primary and secondary alcohols with dimethoxymethane in the presence of catalytic amounts of Lithium Bromide and p-toluenesulfonic acid at rt affords the corresponding dimethoxymethyl derivatives (25 °C, 15 min to 2 h, 71-100%), under particularly mild conditions. Examples include allylic, propargylic, cyclic, and neopentyl alcohols. Tertiary alcohols are not completely protected even after 24 h at reflux temperature. 1,3-Diols yield cyclic acetals.8

Cleavage of Methoxymethyl Derivatives.

Cleavage of methoxymethyl ethers to expose the parent alcohols is conventionally carried out under protic acid conditions: 2 N HOAc (90 °C, 40 h),9 HCl (aq) (MeOH, 62 °C, 15 min),10 6 M HCl (THF-H2O, 50-55 °C, 6-8 h),11 CF3CO2H (H2O-THF),12 HCl (g) (MeCN).13 Alternatively, the deprotection may be carried out using Lewis acids under anhydrous conditions: PhSH/BF3.Et2O,14 Me3SiCl/Et4NBr (0 °C)15 (selective cleavage of MOM ether in the presence of acetonide), Me3SiBr/n-Bu4NBr (0 °C, 25 min to 12 h).16 Selective cleavage of MOM esters in the presence of MOM ethers under mild conditions can be effected with Bu3SiBr (trace MeOH).17 More recently, nonacidic and aprotic conditions for the cleavage of MOM ethers have been developed. The reaction has been carried out with very high yields: Me2BBr (-78 °C, 1 h, 90-93%).18 Similarly, MOM ethers of 1,2- or 1,3-diols are cleaved in high yields under mild conditions using (i-PrS)2BBr (-78 °C). Protic or Lewis acids yield cyclic diol formals with these substrates.19 Activation of MOM ethers via hydride abstraction to facilitate cleavage can be effected with TrBF4 (25 °C).20

Chloromethylation of Arenes.

Dimethoxymethane reacts under Friedel-Crafts conditions to accomplish the chloromethylation of aryls. Chloromethylation of thioanisole using dimethoxymethane/AlCl3 affords p-methylthiobenzyl chloride (74%), contaminated with a trace of o-methylthiobenzyl chloride (150:1) (eq 3).21

Alternative procedures employing chloromethyl methyl ether in acetic acid22 or aqueous formaldehyde and hydrochloric acid23 show inferior selectivity and yield. Similarly, p-nitrophenol can be chloromethylated (69%) using dimethoxymethane and HCl (eq 4).24

6-Methylenation of 3-Oxo-D4-steroids.

A simple, single step, 6-methylenation of 3-oxo-D4-steroids using dimethoxymethane has been described (eq 5). The protocol replaces a multi-step series of reactions.

A number of Lewis or protic acids are effective: POCl3, p-TsOH, H2SO4, HClO4, HX, Amberlyst H-15, P4O10/silica gel, PCl5, EtOP(O)Cl2. Of these, Phosphorus Oxychloride is the most suitable. The reaction can also be carried out using diethoxyethane and other formaldehyde acetals. Of these, diethoxymethane and dimethoxymethane yield superior results.25

Solvent for Preparation of Grignard and Organolithium Reagents.

Dimethoxymethane has been utilized as a solvent for the preparation of Grignard reagents from chloromethyl methyl ether (eq 6). While the reaction can be carried out in more common solvents, such as THF, dimethoxymethane is the solvent of choice owing to enhanced stability of the Grignard reagent in this medium.26

Methoxymethyllithium can be prepared from chloromethyl methyl ether in dimethoxymethane solvent (eq 7).27 The reaction is unsuccessful in more common solvents, such as diethyl ether or THF.

Related Reagents.

Chloromethyl Methyl Ether.

1. (a) Kluge, A. F.; Untch, K. G.; Fried, J. H. JACS 1972, 94, 7827. (b) Stork, G.; Takahashi, T. JACS 1977, 99, 1275.
2. (a) Occupational Safety and Health Administration, U.S. Department of Labor: Federal Register 1974, 39, 3756. (b) Jung, M. E.; Mazurek, R. M.; Lim, R. M. S 1978, 588.
3. Fuji, K.; Nakano, S.; Fujita, E. S 1975, 276.
4. Yardley, J. P.; Fletcher, H. S 1976, 244.
5. Dardoize, F.; Gaudemar, M.; Goasdoue, N. S 1977, 567.
6. Olah, G. A.; Husain, A.; Gupta, B. G. B.; Narang, S. C. S 1981, 471.
7. Olah, G. A.; Husain, A.; Narang, S. C. S 1983, 896.
8. Gras, J.-L.; Chang, Y.-Y. K. W.; Guerin, A. S 1985, 74.
9. Adawi Abdel-Rahman, M.; Elliott, H. W.; Binks, R.; Küng, W.; Rapoport, H. JMC 1966, 9, 1.
10. Auerbach, J.; Weinreb, S. M. CC 1974, 298.
11. Meyers, A. I., Durandetta, J. L.; Munavu, R. JOC 1975, 40, 2025.
12. Dauben, W. G.; Kessel, C. R.; Kishi, M.; Somei, M.; Tada, M.; Guillerm, D. JACS 1982, 104, 303.
13. Kieczykowski, G. R.; Quesada, M. L.; Schlessinger, R. H. JACS 1980, 102, 782.
14. Kieczykowski, G. R.; Schlessinger, R. H. JACS 1978, 100, 1938.
15. Woodward, R. B.; Logusch, E.; Nambiar, K. P.; Sakan, K.; Ward, D. E.; Au-Yeung, B. W.; Balaram, P.; Browne, L. J.; Card, P. J.; Chen, C. H.; Chenevert, R. B.; Fliri, A.; Froebel, K.; Gais, H. J.; Garratt, D. G.; Hayakawa, K.; Heggie, W.; Hesson, D. P.; Hoppe, D.; Hoppe, I.; Hyatt, J. A.; Ikeda, D.; Jacobi, P. A.; Kim, K. S. Kobuke, Y.; Kojima, K.; Krowicki, K.; Lee, V. J.; Leutert, T.; Malchenko, S.; Martens, J.; Matthews, R. S.; Ong, B. S.; Press, J. B.; Rajan Babu, T. V.; Rousseau, G.; Sauter, H. M.; Suzuki, M.; Tatsuta, K.; Toblert, L. M.; Truesdale, E. A.; Uchida, I.; Ueda, Y.; Uyehara, T.; Vasella, A. T.; Vladuchick, W. C.; Wade, P. A.; Williams, R. M.; Wong, H. N.-C. JACS 1981, 103, 3213.
16. Hanessian, S.; Delorme, D.; Dufresne, Y. TL 1984, 25, 2515.
17. Masamune, S. Aldrichim. Acta 1978, 11, 23.
18. Quindon, Y.; Morton, H. E.; Yoakim, C. TL 1983, 24, 3969.
19. Corey, E. J.; Hua, D. H.; Seitz, S. P. TL 1984, 25, 3.
20. (a) Nakata, T.; Schmid, G.; Vranesic, B.; Okigawa, M.; Smith-Palmer, T.; Kishi, Y. JACS 1978, 100, 2933. (b) Barton, D. H. R.; Magnus, P. D.; Smith, G.; Strackert, G.; Zurr, D. JCS(P1) 1972, 542.
21. Pines, S. H.; Czaja, R. F.; Abramson, N. L. JOC 1975, 40, 1920.
22. Buu-Hoi, N. P.; Hoán, N. JOC 1952, 17, 350.
23. (a) Goldberg, M. W.; Jampolsky, L. M. U.S. Patent 2 624 738. (b) Griece, R.; Owen, L. N. JCS 1963, 1947. (c) Bohme, H.; Lerche, G. CB 1967, 100, 2125.
24. Buehler, C. A.; Kirchner, F. K.; Deebel, G. F. OSC 1955, 3, 468.
25. Annen, K.; Hofmeister, H.; Laurent, H.; Wiechert, R. S 1982, 34.
26. Runge, F.; Taeger, E.; Fiedler, C.; Kahlert, E. JPR 1963, 19, 37.
27. (a) Schöllkopf, U.; Küppers, H. TL 1964, 1503. (b) Schöllkopf, U.; Küppers, H.; Traenckner, H.-J.; Pitteroff, W. LA 1967, 704, 120.

Paul Ch. Kierkus

BASF Corporation, Wyandotte, MI, USA

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