Lithium Hexamethyldisilazide


[4039-32-1]  · C6H18LiNSi2  · Lithium Hexamethyldisilazide  · (MW 167.37)

(strong nonnucleophilic base)

Alternate Names: LHMDS; lithium bis(trimethylsilyl)amide.

Physical Data: distillable low-melting solid; mp 70-72 °C, bp 115 °C/1 mmHg.2 LHMDS is a cyclic trimer in the solid state,3 whereas in benzene solution it exists in a monomer-dimer equilibrium.4 LHMDS is less soluble, less basic, more stable, and much less sensitive to air compared to Lithium Diisopropylamide. pKa 29.5 (THF, 27 °C).1

Solubility: sol most nonpolar solvents, e.g. aromatic hydrocarbons, hexanes, THF.

Form Supplied in: colorless crystalline solid, 1 M solution in THF or hexanes, 1.3 M solution in THF, 1 M solution in THF/cyclohexane.

Preparative Methods: conveniently prepared by the reaction of Hexamethyldisilazane with n-Butyllithium in hexane. For most uses the hexane is then evaporated and replaced with THF.5

Handling, Storage, and Precautions: a flammable, moisture sensitive solid; stable in a nitrogen atmosphere. Use in a fume hood.

Ketone Enolates.

A high yielding synthesis of 6-aryl-4,6-dioxohexanoic acids, precursors to antiinflammatory agents, is achieved using LHMDS (eq 1).6 This process is applicable to large scale and involves relatively high reaction temperatures. The use of LDA gives reduced yields and small amounts of a diisopropylamide byproduct.

Ester Enolates.

Enantiomerically pure amino acids may ultimately be prepared via stereospecific ester enolate generation using an oxazolidine chiral auxiliary (eq 2).7 Moderate diastereoselectivity is observed using Potassium Hexamethyldisilazide.

Lithio ethyl acetate is prepared in quantitative yield by reaction of LHMDS with ethyl acetate in THF at -78 °C.8a Reaction with carbonyl compounds leads to condensation products in high yield (eqs 3 and 4).8 No racemization of the a-silyloxy esters occurs (eq 4).

Kinetic Enolates.

LHMDS is the recommended base for the generation of kinetic enolates. The resulting enolates are more regiostable than those generated with the corresponding sodium base, Sodium Hexamethyldisilazide. Thus reaction of D4-3-keto steroids with LHMDS yields 2,4-dienolate ions which can be methylated at C-2 or trapped as 2,4-dienolsilyl ethers (eq 5).9 Use of Potassium t-Butoxide/t-BuOH produces the thermodynamically more stable 3,5-dienolate. Acid-catalyzed conditions yields the 3,5-enol ether. Enolates generated with LHMDS may serve as ketone protecting groups during metal hydride reductions (eq 6).10

LHMDS has also been used in directed aldol condensations. The compatibility of the base with a silyl ether moiety is of note in the synthesis of (±)-[6]-gingerol (eq 7).11

Darzens Condensation.

The Darzens reaction invariably fails with aldehydes due to competing base-catalyzed self-condensation reactions.12 With LHMDS as base, even acetaldehyde provides the desired glycidic ester products in high yield (eq 8).13

Intramolecular Cyclizations.

LHMDS-mediated intramolecular cyclizations have been demonstrated (eq 9).14 The choice of counter cation has a dramatic effect on the stereochemistry of the cyclization.

Ester Enolate Claisen Rearrangement.

LHMDS is comparable to LDA for the stereoselective Ireland-Claisen rearrangement of ester enolates (eq 10).15

Intramolecular Double Michael Addition.

LHMDS-mediated sequential Michael reactions constitute the key component of a total synthesis of the diterpene alkaloid atisine (eq 11).16

Synthesis of Primary Amines.

N,N-Bis(trimethylsilyl)methoxymethylamine, formally a +CH2NH2 equivalent, is obtained in high yield by treating chloromethyl methyl ether with LHMDS. Treatment of the bis-silylamine with organometallic reagents followed by mild solvolysis gives primary amines in good to excellent yield (eq 12).17


Aldehydes, even enolizable ones, undergo Peterson reactions with LHDMS to give N-trimethylsilylaldimines (eq 13),18 which are valuable intermediates for a variety of systems, including primary amines,18a,19 b-lactams,18 and a-methylene-g-lactams (eq 14).20 Extension of this chemistry to include a-keto ester substrates allows for the preparation of a-amino esters.21

N,N-Bis(trimethylsilyl)aminomethyl Acetylide.

The reaction of LHMDS with propargyl bromide constitutes a straightforward route to a g-amino lithium acetylide, a useful precursor to a wide variety of unsaturated protected primary amines (eq 15).22

For example, reaction with aromatic aldehydes gives a-alkynyl amino alcohols, which can be trapped as their silyl ethers. Base-catalyzed isomerization to an allenic isomer followed by hydrolysis and concomitant cyclization affords 2-substituted pyrroles (eq 16).22


b-Ketosilanes may be prepared from a-bromo ketones using LHMDS to generate intermediate silyl enol ethers followed by metal-halogen exchange (eq 17).23 They undergo facile rearrangement to silyl enol ethers and are also substrates, after carbonyl reduction, for overall Peterson alkenation.

Related Reagents.

Lithium Diethylamide; Lithium Diisopropylamide; Lithium Piperidide; Lithium Pyrrolidide; Lithium 2,2,6,6-Tetramethylpiperidide.

1. Wannagat, U.; Nierderprüm, H. CB 1961, 94, 1540.
2. (a) Mootz, D.; Zinnius, A.; Böttcher, B. AG(E) 1969, 8, 378. (b) Rogers, R. D.; Atwood, J. L.; Grüning, R. JOM 1978, 157, 229. For further structural information see (c) Lappert, M. F.; Power, P. P.; Sanger, A. R.; Srivastava, R. C. Metal and Metalloid Amides; Wiley: New York, 1980.
3. Kimura, B. Y.; Brown, T. L. JOM 1971, 26, 57.
4. Fraser, R. R.; Mansour, T. S. JOC 1984, 49, 3442.
5. (a) Rathke, M. W. OSC 1988, 6, 598. (b) Amonoo-Neizer, E. H.; Shaw, R. A.; Skovlin, D. O.; Smith, B. C. Inorg. Synth. 1966, 8, 19.
6. Murray, W.; Wachter, M.; Barton, D.; Forero-Kelly, Y. S 1991, 18.
7. Es-Sayed, M.; Gratkowski, C.; Krass, N.; Meyers, A. I.; de Meijere, A. SL 1992, 962.
8. (a) Rathke, M. W. JACS 1970, 92, 3222. (b) Mori, K.; Matsuda, H. LA 1992, 131. (c) Pettersson, L.; Magnusson, G.; Frejd, T. ACS 1993, 47, 196.
9. Tanabe, M.; Crowe, D. F. CC 1973, 564.
10. Barton, D. H. R.; Hesse, R. H.; Pechet, M. M.; Wiltshire, C. CC 1972, 1017.
11. Denniff, P.; Whiting, D. A. CC 1976, 712.
12. (a) Newman, M. S.; Magerlein, B. J. OR 1949, 5, 413. (b) Morrison, J. D.; Mosher, H. S. Asymmetric Organic Reactions; Prentice-Hall: New York, 1971.
13. Borch, R. F. TL 1972, 3761.
14. (a) Stork, G.; Gardner, J. O.; Boeckman, Jr., R. K.; Parker, K. A. JACS 1973, 95, 2014. (b) Stork, G.; Boeckman, Jr., R. K. JACS 1973, 95, 2016. (c) Stork, G.; Cohen, J. F. JACS 1974, 96, 5270.
15. (a) Ireland, R. E; Daub, J. P. JOC 1981, 46, 479. (b) Fujisawa, T.; Maehata, E.; Kohama, H.; Sato, T. CL 1985, 1457. (c) Sato, T.; Tsunekawa, H.; Kohama, H.; Fujisawa, T. CL 1986, 1553. (d) Ireland, R. E.; Wipf, P.; Armstrong, III, J. D. JOC 1991, 56, 650. (e) Panek, J. S.; Clark, T. D. JOC 1992, 57, 4323.
16. Ihara, M.; Suzuki, M.; Fukumoto, K.; Kabuto, C. JACS 1990, 112, 1164.
17. (a) Morimoto, T.; Takahashi, T.; Sekiya, M. CC 1984, 794. For other closely related examples of amine synthesis see: (b) King, F. D.; Walton, D. R. M. CC 1974, 256. (c) Murai, T.; Yamamoto, M.; Kondo, S.; Kato, S. JOC 1993, 58, 7440.
18. (a) Hart, D. J.; Kanai, K.-i.; Thomas, D. G.; Yang, T.-K. JOC 1983, 48, 289. (b) Cainelli, G.; Giacomini, D.; Panunzio, M.; Martelli, G.; Spunta, G. TL 1987, 28, 5369. (c) Andreoli, P.; Billi, L.; Cainelli, G.; Panunzio, M.; Bandini, E.; Martelli, G.; Spunta, G. T 1991, 47, 9061 and references cited therein. (d) Colvin, E. W. Silicon Reagents in Organic Synthesis; Academic: London, 1988; p 73 and references cited therein.
19. Leboutet, L.; Courtois, G.; Miginiac, L. JOM 1991, 420, 155.
20. El Alami, N.; Belaud, C.; Villieras, J. SC 1988, 18, 2073.
21. Matsuda, Y.; Tanimoto, S.; Okamoto, T.; Ali, S. M. JCS(P1) 1989, 279.
22. Corriu, R. J. P.; Huynh, V.; Iqbal, J.; Moreau, J. J. E.; Vernhet, C. T 1992, 48, 6231.
23. (a) Sampson, P.; Hammond, G. B.; Weimer, D. F. JOC 1986, 51, 4342. (b) Kowalski, C. J.; O'Dowd, M. L.; Burke, M. C.; Fields, K. W. JACS 1980, 102, 5411.

Matthew Gray & Victor Snieckus

University of Waterloo, Ontario, Canada

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