[917-54-4]  · CH3Li  · Methyllithium  · (MW 21.98)

(methylating agent for several functional groups; cleaves protecting groups; synthesis of other methyl organometallics, i.e. of Cu, Ga, Ti, Mg, Si, Ir, B; can function as a base; reduces transition metals)

Physical Data: unsolvated solid is pyrophoric; densities listed below.

Solubility: insol hydrocarbon solvents; moderately sol ethereal solvents; reacts exothermically with water and protic solvents to generate methane.

Form Supplied in: commonly available as >1.4 M in diethyl ether, d >0.732 g mL-1; >1.5 M in diethyl ether (with ~1.0 equiv of LiBr), d >0.852 g mL-1. New formulations are >1 M in THF/cumene with 0.08 M Me2Mg,1 d 0.86 g mL-1; 70 wt % solid2 complexed with 22 wt % diethyl ether, 6% LiCl, and ~1% LiOH.

Analysis of Reagent Purity: titration of 0.5 N s-butanol in toluene (10 mL) with methyllithium via tared syringe at 15 °C using 2,2-biquinoline as an indicator.

Handling, Storage, and Precautions: methyllithium in diethyl ether is pyrophoric in absence of LiBr, according to US Dept of Transportation regulations (49 CFR 173, Appendix E), while all other available formulations (solution and solid) are nonpyrophoric. Store in a cool, dry place in a tightly sealed container under an inert atmosphere.


Most preparations involve use of diethyl ether3 or THF1 from which solvated solids4,5 may be isolated. Unsolvated methyllithium1,6 preparations would allow systematic investigation of solvent7 and halide8 effects. Aggregation and crystal studies have been reported.9

Addition Reactions.

Methyllithium can have different stereoselectivity compared to methyl Grignards in 1,2-additions to cyclic carbohydrates,10 heterocycles,11 and acyclic12 substrates. The origin of the high diastereoselectivity in nucleophilic addition to ketones (eq 1) is based on chelation control.13a Stereoselectivity can also be affected by prior complexation of the carbonyl compound with aluminum and other Lewis acids.13b

Conversion of organolithiums to organometallics of titanium,14 cerium,15 and zinc16 has lead to improved chemo- and stereoselectivity. For instance, conversion of MeLi to a chiral titanate prior to 1,2-addition to benzaldehyde resulted in 91% ee (eq 2).14a

Methyl ketones can be prepared from acids17 and esters, usually with greater success by subsequent treatment with Chlorotrimethylsilane.18,19 Methyllithium is a convenient deacylating agent for alkoxycarboxyl- and benzoyl-protected secondary hydrazides.20 Addition of methyllithium with Lithium Bromide to silyl ketone (1) gave silyl enol ethers (2) with high stereochemical purity when warmed to 0 °C (eq 3).21

Similarly, almost quantitative yields of 2,2-difluoroenol silyl ethers were obtained from a perfluoroacylsilane.22 Enolates, free of amine, can be prepared by cleavage of silyl enol ethers23 and enol trifluoromethanesulfinates with methyllithium.24

Of 1,2-additions to carbon-nitrogen multiple bonds, nitriles, imines, and oxazolidine are the most useful substrates. For instance, addition of methyllithium in cumene/THF to protected cyanohydrins gave excellent yield of methyl steroidal ketones after hydrolysis.25 Addition of aryl heterocycles, such as tetrazines26 and pyrazines,27 are problematic.

Conjugate addition is routinely achieved by prior transformation to the corresponding cuprate28,29 or even aluminate.30 In absence of any co-metals, methyllithium will undergo 1,4-addition to naphthalimines31 in the presence of Hexamethylphosphoric Triamide (eq 4). Without HMPA, methyllithium undergoes 1,2-additions to naphthalimines31 and oxazolidines.32

Secondary allylic alcohols, 3-substituted with SO2Ph and SiMe3, will undergo conjugate addition to give only the syn-adduct.33 Asymmetric addition to sulfines in the presence of chiral ligands had only modest stereoselectivity.34

Miscellaneous Reactions.

Methyllithium was the base of choice for the metalation of o-allylbenzamide, which cyclizes to a naphthol derivative (eq 5).35

Rearrangement of gem-dibromides of cyclopropyl derivatives with methyllithium leads to mixtures of allenes36a and monobromide derivatives.36 Substituted epoxides,37 silacyclopentane,38 and cyclotriphosphazene39 can be ring opened. The transmetalation of trimethylstannyl compounds to form vinyl-, allenyl-, and propargyllithium reagents is usually best done with methyllithium.40 Zero-valence Pd for coupling alkenyl halides and organolithiums can be prepared from Palladium(II) Chloride and methyllithium.41 Even preparation and utility of transition metal-activated organic compounds of molybdenum42a and tungsten42b are reported.

Related Reagents.

Dilithium Trimethylcuprate; Dichlorodimethyltitanium; Lithium Cyano(methyl)cuprate; Lithium Dimethylcuprate; Methylcopper; Methylmagnesium Bromide; Methyltitanium Triisopropoxide; Lithium Trimethylzincate.

1. Morrison, R. C.; Rathman, T. L. (FMC Lithium Division) U.S. Patent 4 976 886, 1990.
2. Rittmeyer, P. Brit. Assoc. for Chem. Spec., Chem. Spec. Europe; Publisher: Location, 1993; p 17.
3. Houk, K. N.; Rondan, N. G.; Schleyer, P. v. R.; Kaufmann, E.; Clark, T. JACS 1985, 107, 2821.
4. Ogle, C. A.; Huckabee, B. K.; Johnson, H. C., IV; Sims, P. F.; Winslow, S. D.; Pinkerton, A. A. OM 1993, 12, 1960.
5. Deberitz, J.; Weiss, W. (Metallgesellschaft A.-G.) Eur. Patent 340 819, 1989 (CA 1990, 112, 77 529t).
6. Brown, T. L.; Rogers, M. T. JACS 1957, 79, 1859.
7. (a) Fujisawa, T.; Funabora, M.; Ukaji, Y.; Sato, T. CL 1988, 59. (b) Ko, K.-Y.; Eliel, E. L. JOC 1986, 51, 5353.
8. Savignac, P.; Teulade, M.-P.; Patois, C. HC 1990, 1, 211.
9. (a) West, P.; Waack, R. JACS 1967, 89, 4395. (b) Köster, H.; Thoennes, D.; Weiss, E. JOM 1978, 160, 1. (c) Weiss, E.; Lucken, E. A. C. JOM 1964, 2, 197.
10. (a) Yoshimura, J.; Sato, K. Carbohydr. Res. 1983, 123, 341. (b) Mukaiyama, T.; Soai, K.; Sato, T.; Shimizu, H.; Suzuki, K. JACS 1979, 101, 1455.
11. (a) Wade, P. A.; Price, D. T.; Carroll, P. J.; Dailey, W. P. JOC 1990, 55, 3051. (b) Wade, P. A.; Price, D. T.; McCauley, J. P.; Carroll, P. J. JOC 1985, 50, 2804.
12. Hosokawa, T.; Yagi, T.; Ataka, Y.; Murahashi, S.-I. BCJ 1988, 61, 3380.
13. (a) Chikashita, H.; Nakamura, Y; Uemura, H. Itoh, K. CL 1992, 439. (b) Maruoka, K.; Itoh, T.; Sakurai, M.; Nonoshita, K.; Yamamoto, H. JACS 1988, 110, 3588.
14. (a) Seebach, D.; Beck, A. K.; Imwinkelried, R.; Roggo, S.; Wonnocott, A. HCA 1987, 70, 954. (b) Reetz, M. T.; Kyung. S. H.; Huellmann, M. T 1986, 42, 2931. (c) Reetz, M. T.; Hugel, H.; Dresely, K. T 1987, 43, 109. (d) Schmidt, B; Seebach, D. AG(E) 1991, 30, 99.
15. (a) Imamoto, T.; Sugiura, Y. JOM 1985, 285, C21. (b) Paquette, L. A.; Learn, K. S.; JACS 1986, 108, 7873. (c) Denmark, S. E.; Weber, T.; Piotrowski, D. W. JACS 1987, 109, 2224. (d) Johnson, C. R.; Tait, B. D. JOC 1987, 52, 281.
16. (a) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. JACS 1986, 108, 6071. (b) Morita, Y. Suzuki, M. Noyori, R. JOC 1989, 54, 1785. (c) Erdik, E. T 1987, 43, 2203.
17. Bare, T. M.; House, H. O. OSC 1973, 5, 775.
18. Overman, L. E.; Rishton, G. M. OS 1993, 71, 56 and 63.
19. Rubottom, G. M.; Kim, C. JOC 1983, 48, 1550.
20. Tschamber, T.; Streith, J. H 1990, 30, 551.
21. Reich, H. J.; Holtan, R. C.; Bolm, C. JACS 1990, 112, 5609.
22. Jin, F.; Jiang, B.; Xu, Y. TL 1992, 33, 1221.
23. Bertz, S. H.; Jelinski, L. W.; Dabbagh, G. CC 1983, 388.
24. Lee, S.-H.; Hulce, M. SL 1992, 485.
25. Carruthers, N. I.; Garshasb, S. JOC 1992, 57, 961.
26. Wilkes, M. C. JHC 1991, 28, 1163.
27. Rizzi, G. P. JOC 1974, 39, 3598.
28. Lipshutz, B. H.; Sengupta, S. OR 1992, 41, 135.
29. Rossiter, B. E.; Swingle, N. M. CRV 1992, 92, 771.
30. Maruoka, K.; Nonoshita, K.; Yamamoto, H. TL 1987, 28, 5723.
31. Meyers, A. I.; Brown, J. D.; Laucher, D. TL 1987, 28, 5279.
32. Pridgen, L. N.; Mokhallalati, M. K.; Wu, M.-J. JOC 1992, 57, 1237.
33. Kitamura, M. Isobe, M; Ichikawa, Y.; Goto, T. JACS 1984, 106, 3252.
34. Rewinkel, J. B. M; Porskamp, P. A. T. W.; Zwanenburg, B. RTC 1988, 107, 563.
35. Sibi, M. P.; Dankwardt, J. W.; Snieckus, V. JOC 1986, 51, 271.
36. (a) Skatteboel, L.; Stenstroem, Y.; Stjerna, M.-B. ACS 1988, B42, 475. (b) Lukin, K. A.; Zefirov, N. S.; Yufit, D. S.; Struchkov, Y. T. T 1992, 48, 9977. (c) Molchanov, A. P.; Kalyamin, S. A.; Kostikov, R. R. JOU 1992, 28, 102 (CA 1992, 117, 170 833a)
37. (a) Wender, P. A.; Erhardt, J. M.; Letendre, L. J. JACS 1981, 103, 2114. (b) Alcaide, B.; Areces, P.; Borredon, E.; Biurrun, C.; Castells, J. P.; Plumet, J. H 1990, 31, 1997.
38. Maercker, A.; Stoetzel, R. JOM 1984, 269, C40.
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40. Reich, H. J.; Reich, I. L.; Yelm, K. E.; Holladay, J. E.; Gschneidner, D. JACS 1993, 115, 6625. Reich, H. J.; Mason, J. D.; Holladay, J. E. CC 1993, 1481.
41. Murahashi, S.-I.; Naota, T.; Tanigawa, Y. OS 1984, 62, 39.
42. (a) Kauffmann, T.; Jordan, J.; Voss, K.-U. AG(E) 1991, 30, 1138. (b) Kauffmann, T.; Kieper, G. AG(E) 1984, 23, 532.

Terry L. Rathman

FMC Corporation Lithium Division, Bessemer City, NC, USA

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