t-Butoxymethyllithium1

[87996-22-3]  · C5H11LiO  · t-Butoxymethyllithium  · (MW 94.08)

(hydroxymethyl anion equivalent2)

Solubility: sol THF.

Preparative Methods: generated in situ by a tin-lithium exchange reaction between butyllithium and an a-stannyl ether3 or by metalation of t-butyl methyl ether with an s-butyllithium/potassium t-butoxide reagent.2

Handling, Storage, and Precautions: stable at low temperature (-10 °C or less) in solution.

Reagent Preparation.

A general method for the preparation of t-butoxymethyllithium and closely related reagents, such as methoxymethyllithium [14704-15-5], ethoxymethyllithium [104681-85-8], and benzyloxymethyllithium [71316-95-5], involves the use of a tin-lithium exchange reaction. Several of these reagents have been made by treatment of a-chloro ethers with a complex of Tin(II) Chloride and Lithium Bromide in THF to generate a-trihalostannyl ethers. These ethers undergo tin-lithium exchange with n-Butyllithium to give the desired reagents (eq 1).3a This transmetalation will also proceed smoothly with butyllithium and alkoxymethyltributyltin (eq 2). In this case, the tributyltin compound is formed from benzyl alcohol/NaOH/tributylstannylmethyl iodide,3b benzyloxymethyl Grignard/Tri-n-butylchlorostannane,3b Chloromethyl Methyl Ether/tributylstannyl Grignard,3c or diethoxymethyltributyltin/Acetyl Chloride/Tri-n-butylstannane.3c

The transmetalation strategy has also been used to form alkoxymethyllithium reagents from alkoxymethyl telluride by lithium-tellurium exchange.4 This reaction proceeds in solvents of low polarity, such as toluene and hexane, in which tin-lithium exchange is sluggish.

For t-butoxymethyllithium, a more practical preparation for large-scale work is the direct metalation of t-butyl methyl ether (TBME) with s-Butyllithium and Potassium t-Butoxide (eq 3).2 The metalation is done in neat TBME to form t-butoxymethylpotassium, which is converted to the desired reagent by addition of a solution of LiBr in THF. t-Butoxymethyl- and methoxymethylpotassium have also been prepared by metalation of the corresponding ethers with butylpotassium.5

A third option for generating methoxymethyllithium involves treatment of Chloromethyl Methyl Ether with Lithium metal (eq 4).6 This reaction proceeds smoothly in dimethoxymethane, but does not work in ether or THF.

1,2-Addition to Carbonyls.

One of the most common uses of alkoxymethyllithium reagents is addition to ketones and aldehydes to generate monoalkylated 1,2-diols in good yields (eq 5).2,3c,7 Subsequent reaction with Acetic Anhydride/Iron(III) Chloride cleaves the t-butyl group and forms a diacetate, which can be hydrolyzed to a diol.2 A variety of carbonyl compounds can participate in the 1,2-addition reaction, including a,b-unsaturated ketones8-10 and aldehydes,11 amides,12 and lactones.13

1,4-Addition to Carbonyls.

When converted to an organocopper reagent by reaction with 1 equiv of copper(I) bromide N dimethyl sulfide, t-butoxymethyllithium can be used for conjugate addition of t-butoxymethyl to a,b-unsaturated carbonyls (eq 6).2,14 In addition, the copper reagent can be used in enantioselective conjugate additions.15 A complexed copper reagent formed from a chiral ligand derived from (-)-ephedrine, Copper(I) Iodide, and t-butoxymethyllithium reacts efficiently with 2-cyclohexenone to give (R)-3-(t-butoxymethyl)cyclohexanone (75% yield, 89% ee).

Other Reactions.

t-Butoxymethyllithium can be used to convert acid chlorides to t-butoxymethyl ketones in one step (eq 7).2 Addition of 1 equiv of Copper(I) t-Butoxide to the lithium reagent generates an organocopper derivative which reacts cleanly with acid chlorides.

The alkoxymethyllithium reagents also provide a convenient route to alkyl a-stannyl and a-silyl ethers. Alkoxymethyllithium reacts with either Chlorotrimethylsilane or trialkyltin chloride to yield trimethylsilylmethyl methyl ether6b or t-butyl a-stannyl ether,2 respectively (eq 8). In addition, t-butoxymethyllithium can be alkylated efficiently with Benzyl Bromide to give Ph(CH2)2O-t-Bu in 84% yield.2

Related Reagents.

A number of similar hydroxymethyl anion equivalents have been developed, including (methoxymethoxy)methyllithium,16 (ethoxyethoxy)methyllithium,17 and (benzyloxymethoxy)methyllithium.18 These reagents are usually formed by protection of trialkylstannylmethanol, followed by a tin-lithium exchange reaction. Seebach has generated LiOCH2Li by treating tributylstannylmethanol with 2 equiv of butyllithium.19 Others have used alkoxymethylmagnesium halides,6a,20 metalated esters,21 and metalated amides22 as hydroxymethyl anion equivalents.

Dialkoxymethyllithium reagents have been used as one-carbon nucleophiles to generate a variety of functionalized acetals.23 These reagents are prepared by reductive lithiation of phenylthio-substituted precursors or transmetalation of tri-n-butylstannyl compounds.

See also 1-(Benzyloxymethoxy)propyllithium, (Diisopropoxymethylsilyl)methylmagnesium Chloride, 1-Lithio-1-methoxycyclopropane, 1-Methoxyallyllithium, and Tri-n-butyl[(methoxymethoxy)methyl]stannane.


1. FF 1986, 12, 350.
2. Corey, E. J.; Eckrich, T. K. TL 1983, 24, 3165.
3. (a) Corey, E. J.; Eckrich, T. M. TL 1983, 24, 3163. (b) Still, W. C. JACS 1978, 100, 1481. (c) Duchene, A.; Mouko-Mpegna, D.; Quintard, J.-P. BSF(2) 1985, 787 (CA 1986, 105, 171 454s).
4.Hiiro, T.; Atarashi, Y.; Kambe, N.; Fujiwara, S.-I.; Ogawa, A.; Ryu, I.; Sonoda, N. OM 1990, 9, 1355.
5. Lehmann, R.; Schlosser, M. TL 1984, 25, 745.
6. (a) FF 1967, 1, 672 and references cited therein. (b) Cunico, R. F.; Gill, H. S. OM 1982, 1, 1.
7. Matsuda, F.; Tomiyosi, N.; Yanagiya, M.; Matsumoto, T. CL 1987, 2097.
8. Forsyth, C. J.; Clardy, J. JACS 1988, 110, 5911.
9. Parker, K. A.; Andrade, J. R. JOC 1979, 44, 3964.
10. Wipf, P.; Kim, Y. JOC 1993, 58, 1649.
11. Hart, D. J.; Yang, T.-K. TL 1982, 23, 2761.
12. Uyehara, T.; Suzuki, I.; Yamamoto, Y. TL 1989, 30, 4275.
13. Collum, D. B.; McDonald, III, J. H.; Still, W. C. JACS 1980, 102, 2120.
14. Kerdesky, F. A. J.; Holms, J. H.; Schmidt, S. P.; Dyer, R. D.; Carter, G. W. TL 1985, 26, 2143.
15. Corey, E. J.; Naef, R.; Hannon, F. J. JACS 1986, 108, 7114.
16. See Tri-n-butyl[(methoxymethoxy)methyl]stannane and references cited therein.
17. Remiszewski, S. W.; Stouch, T. R.; Weinreb, S. M. T 1985, 41, 1173.
18. Posner, G. H.; Weitzberg, M.; Jew, S. SC 1987, 17, 611.
19. Meyer, N.; Seebach, D. CB 1980, 113, 1290.
20. (a) Taeger, V. E.; Fiedler, C.; Chiari, A.; Berndt, H. P. JPR 1965, 28, 1 (CA 1965, 63, 16 373d). (b) Castro, B. BSF(2) 1967, 1533 (CA 1967, 67, 100 176p).
21. Beak, P.; McKinnie, B. G. JACS 1977, 99, 5213.
22. Schlecker, R.; Seebach, D. HCA 1978, 61, 512.
23. Shiner, C. S.; Tsunoda, T.; Goodman, B. A.; Ingham, S.; Lee, S.; Vorndam, P. E. JACS 1989, 111, 1381.

Karen R. Romines

The Upjohn Company, Kalamazoo, MI, USA



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