Hexamethyldisilazane

[999-97-3]  · C6H19NSi2  · Hexamethyldisilazane  · (MW 161.44)

(selective silylating reagent;1 aminating reagent; nonnucleophilic base2)

Alternate Name: HMDS.

Physical Data: bp 125 °C; d 0.765 g cm-3.

Solubility: sol acetone, benzene, ethyl ether, heptane, perchloroethylene.

Form Supplied in: clear colorless liquid; widely available.

Purification: may contain trimethylsilanol or hexamethyldisiloxane; purified by distillation at ambient pressures.

Handling, Storage, and Precautions: may decompose on exposure to moist air or water, otherwise stable under normal temperatures and pressures. Harmful if swallowed, inhaled, or absorbed through skin. Fire hazard when exposed to heat, flames, or oxidizers. Use in a fume hood.

Silylation.

Alcohols,3 amines,3 and thiols4 can be trimethylsilylated by reaction with hexamethyldisilazane (HMDS). Ammonia is the only byproduct and is normally removed by distillation over the course of the reaction. Hydrochloride salts, which are typically encountered in silylation reactions employing chlorosilanes, are avoided, thereby obviating the need to handle large amounts of precipitates. Heating alcohols with hexamethyldisilazane to reflux is often sufficient to transfer the trimethylsilyl group (eq 1).5 Completion of the reaction is indicated by either a change in the reflux temperature (generally a rise) or by the cessation of ammonia evolution.

Silylation with HMDS is most commonly carried out with acid catalysis.5 The addition of substoichiometric amounts of Chlorotrimethylsilane (TMSCl) to the reaction mixtures has been found to be a convenient method for catalysis of the silylation reaction.5,6 The catalytically active species is presumed to be hydrogen chloride, which is liberated upon reaction of the chlorosilane with the substrate. Alternatively, protic salts such as ammonium sulfate can be employed as the catalyst.7 Addition of catalytic Lithium Iodide in combination with TMSCl leads to even greater reaction rates.8 Anilines can be monosilylated by heating with excess HMDS (3 equiv) and catalytic TMSCl and catalytic LiI (eq 2). Silylation occurs without added LiI; however, the reaction is much faster in the presence of iodide, presumably due to the in situ formation of a catalytic amount of the more reactive Iodotrimethylsilane.

Hexamethyldisilazane is the reagent of choice for the direct trimethylsilylation of amino acids, for which TMSCl cannot be used due to the amphoteric nature of the substrate.9 Silylation of glutamic acid with excess hexamethyldisilazane and catalytic TMSCl in either refluxing xylene or acetonitrile followed by dilution with alcohol (methanol or ethanol) yields the derived lactam in good yield (eq 3).10

The efficiency of HMDS-mediated silylations can be markedly improved by conducting reactions in polar aprotic solvents. For example, treatment of methylene chloride solutions of primary alcohols or carboxylic acids at ambient temperatures with HMDS (0.5-1 equiv) in the presence of catalytic amounts of TMSCl (0.1 equiv) gives the corresponding silyl ether and the trimethylsilyl ester, respectively (eq 4).1 N-Silylation of secondary amines occurs in preference to primary alcohols when treated with 1 equiv of HMDS and 0.1 equiv TMSCl (eq 5). The silylation of secondary amines cannot be effected in the absence of solvent.5 Secondary and tertiary alcohols can also be silylated at ambient temperatures in dichloromethane with HMDS and TMSCl mixtures; however, stoichiometric quantities of the silyl chloride are required. Catalysis by 4-Dimethylaminopyridine (DMAP) is necessary for the preparation of tertiary silyl ethers.

DMF is a useful solvent for HMDS-induced silylation reactions, and reaction rates 10-20 times greater than those carried out in pyridine have been reported.11 DMSO is also an excellent solvent; however, a cosolvent such as 1,4-dioxane is required to provide miscibility with HMDS.12

Imidazole (ImH) catalyzes the silylation reaction of primary, secondary, and tertiary alkanethiols with hexamethyldisilazane.12 The mechanism is proposed to involve the intermediacy of N-(Trimethylsilyl)imidazole (ImTMS), since its preparation from hexamethyldisilazane and imidazole to yield 1-(trimethylsilyl)imidazole is rapid.13 The imidazole-catalyzed reactions of hexamethyldisilazane, however, are more efficient than the silylation reactions effected by ImTMS (eq 6 vs. eq 7) due to reversibility of the latter. Imidazole also catalyzes the reaction of HMDS with Hydrogen Sulfide, which provides a convenient preparation of hexamethyldisilathiane, a reagent which has found utility in sulfur transfer reactions.14

Silyl Enol Ethers.

Silylation of 1,3-dicarbonyl compounds can be accomplished in excellent yield by heating enolizable 1,3-dicarbonyl compounds with excess HMDS (3 equiv) and catalytic imidazole (eq 8).15

In combination with TMSI, hexamethyldisilazane is useful in the preparation of thermodynamically favored enol ethers (eq 9).16 Reactions are carried out at rt or below and are complete within 3 h.

Related thermodynamic enolization control has been observed using metallated hexamethyldisilazide to give the more substituted bromomagnesium ketone enolates.17 Metallation reactions of HMDS to yield Li, K, and Na derivatives are well known and the resulting nonnucleophilic bases have found extensive applications in organic synthesis (see Lithium Hexamethyldisilazide, Potassium Hexamethyldisilazide, Sodium Hexamethyldisilazide).2

Amination Reactions.

Hexamethyldisilazane is a useful synthon for ammonia in amination reactions. Preparation of primary amides by the reaction of acyl chlorides and gaseous Ammonia, for example, is not an efficient process. Treatment of a variety of acyl halides with HMDS in dichloromethane gives, after hydrolysis, the corresponding primary amide (eq 10).18 Omitting the hydrolysis step allows isolation of the corresponding monosilyl amide.19

Reductive aminations of ketones with HMDS to yield a-branched primary amines can be effected in the presence of Titanium(IV) Chloride (eq 11).20 The reaction is successful for sterically hindered ketones even though HMDS is a bulky amine and a poor nucleophile. The use of ammonia is precluded in these reactions since it forms an insoluble complex with TiCl4.

The reaction of phenols with diphenylseleninic anhydride and hexamethyldisilazane gives the corresponding phenylselenoimines (eq 12).21 The products thus obtained can be converted to the aminophenol or reductively acetylated using Zinc and Acetic Anhydride. The use of ammonia or tris(trimethylsilyl)amine in place of HMDS gives only trace amounts of the selenoimines.


1. Cossy, J.; Pale, P. TL 1987, 28, 6039.
2. Colvin, E. W. Silicon in Organic Synthesis, Butterworths: London, 1981.
3. Speier, J. L. JACS 1952, 74, 1003.
4. Bassindale, A. R.; Walton, D. R. M. JOM 1970, 25, 389.
5. Langer, S. H.; Connell, S.; Wender, I. JOC 1958, 23, 50.
6. Sweeley, C. C.; Bentley, R.; Makita, M.; Wells, W. W. JACS 1963, 85, 2497.
7. Speier, J. L.; Zimmerman, R.; Webster, J. JACS 1956, 78, 2278.
8. Smith, A. B., III; Visnick, M.; Haseltine, J. N.; Sprengeler, P. A. T 1986, 42, 2957.
9. Birkofer, L.; Ritter, A. AG(E) 1965, 4, 417.
10. Pellegata, R.; Pinza, M.; Pifferi, G. S 1978, 614.
11. Kawai, S.; Tamura, Z. CPB 1967, 15, 1493.
12. Glass, R. S. JOM 1973, 61, 83.
13. Birkofer, L.; Richter, P.; Ritter, A. CB 1960, 93, 2804.
14. Harpp, D. N.; Steliou, K. S 1976, 721.
15. Torkelson, S.; Ainsworth, C. S 1976, 722.
16. (a) Hoeger, C. A.; Okamura, W. H. JACS 1985, 107, 268. (b) Miller, R. D.; McKean, D. R. S 1979, 730.
17. Kraft, M. E.; Holton, R. A. TL 1983, 24, 1345.
18. Pellegata R.; Italia, A.; Villa, M. S 1985, 517.
19. Bowser, J. R.; Williams, P. J.; Kuvz, K. JOC 1983, 48, 4111.
20. Barney, C. L.; Huber, E. W.; McCarthy, J. R. TL 1990, 31, 5547.
21. Barton, D. H. R.; Brewster, A. G.; Ley, S. V.; Rosenfeld, M. N. CC 1977, 147.

Benjamin A. Anderson

Lilly Research Laboratories, Indianapolis, IN, USA



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