Potassium Hexamethyldisilazide

KN(SiMe3)2

[40949-94-8]  · C6H18KNSi2  · Potassium Hexamethyldisilazide  · (MW 199.53)

(sterically hindered base)

Alternate Names: KHMDS; potassium bis(trimethylsilyl)amide.

Solubility: sol THF, ether, benzene, toluene.1

Form Supplied in: commercially available as moisture-sensitive, tan powder, 95% pure, and 0.5 M solution in toluene.

Analysis of Reagent Purity: solid state structures of [KN(SiMe3)2]23 and [KN(SiMe3)2.2 toluene]24 have been determined by X-ray diffraction; solutions may be titrated using fluorene,2 2,2-bipyridine,5 and 4-phenylbenzylidene benzylamine6 as indicators.

Preparative Methods: prepared and isolated by the procedure of Wannagat and Niederpruem.1 A more convenient in situ generation from Potassium Hydride and Hexamethyldisilane is described by Brown.2

Handling, Storage, and Precautions: the dry solid and solutions are inflammable and must be stored in the absence of moisture. These should be handled and stored under a nitrogen atmosphere. Use in a fume hood.

Use as a Sterically Hindered Base for Enolate Generation.

Potassium bis(trimethysilyl)amide, KN(TMS)2, has been shown to be a good base for the formation of kinetic enolates from carbonyl groups bearing a-hydrogens.7 For example, treatment of 2-methylcyclohexanone with KN(TMS)2 at low temperature followed by trapping with Triethylborane and Iodomethane gave good selectivity for 2,6-dimethylcyclohexanone (eq 1). In comparison, the use of Potassium Hydride for this transformation gave good selectivity for 2,2-dimethylcyclohexanone, which is the product derived from the thermodynamic enolate (eq 2).8

This reagent has been shown to be a good base for the generation of highly reactive potassium enolates;9 for example, treatment of various ketones and esters bearing a-hydrogens with KN(TMS)2 followed by 2 equiv of N-F-saccharinsultam allowed isolation of the difluorinated product (eq 3).

In a study on the electrophilic azide transfer to chiral enolates, Evans10 found that the use of potassium bis(trimethylsilyl)amide was crucial for this process. The KN(TMS)2 played a dual role in the reaction; as a base, it was used for the stereoselective generation of the (Z)-enolate (1). Reaction of this enolate with trisyl azide gave an intermediate triazene species (2) (eq 4). The potassium counterion from the KN(TMS)2 used for enolate formation was important for the decomposition of the triazene to the desired azide. Use of other hindered bases such as Lithium Hexamethyldisilazide allowed preparation of the intermediate triazene; however, the lithium ion did not catalyze the decomposition of the triazene to the azide.10a This methodology has been utilized in the synthesis of cyclic tripeptides.10b

Treatment of carbonyl species bearing acidic a-hydrogens with potassium bis(trimethylsilyl)amide has also been shown to generate anions which, due to the larger, less coordinating potassium cation, allow the negative charge to be stabilized by other features in the molecule rather than as the potassium enolate. Treatment of 9-acetyl-cis,cis,cis,cis-cyclonona-1,3,5,7-tetraene with this reagent gave an anionic species which was characterized by spectroscopic methods to be more like the [9]annulene anion than the nonafulvene enolate. In this case the negative charge is more fully stabilized by delocalization into the ring to form the aromatic species rather than as the potassium enolate. Use of the bis(trimethylsilyl)amide bearing the more strongly coordinating lithium cation led to an intermediate which appeared to be lithium nonafulvene enolate. Addition of Chlorotrimethylsilane to each of these intermediates gave the same nonafulvenesilyl enol ether (eq 5).11

Selective Formation of Linear Conjugated Dienolates.

Potassium bis(trimethylsilyl)amide has been shown to be an efficient base for the selective generation of linear-conjugated dienolates from a,b-unsaturated ketones.12 As shown in eqs 6 and 7, treatment of both cyclic and acyclic a,b-unsaturated enones with KN(TMS)2 in a solvent mixture of DMF/THF (2:1) followed by quenching with Methyl Chloroformate gave excellent selectivities for the products derived from the linear dienolate anion. In comparison, the use of lithium bases for this reaction gave products derived from the cross-conjugated dienolate anions. This methodology, however, did not work for 1-cyclohexenyl methyl ketone, in which case the product from the cross-conjugated dienolate anion was isolated exclusively (eq 8).

Stereoselective Generation of Alkyl (Z)-3-Alkenoates.

Deconjugative isomerization of 2-alkenoates to 3-alkenoates occurs via g-deprotonation of the a,b-unsaturated ester to form an intermediate dienolate anion. In most cases, the a-carbon is more reactive to protonation13 and allows for the isolation of the 3-alkenoate. If the C-4 position bears a methyl group, this transformation is usually stereospecific, leading to the (Z)-3-alkenoate; however, when groups larger than a methyl occupy the C-4 position, the reaction becomes increasingly stereorandom.13d Potassium bis(trimethylsilyl)amide, however, was shown to be a good base for the stereoselective isomerization of 2,4-dimethyl-3-pentyl (E)-2-dodecenoate, which bears a long C-4 substituent, to the corresponding (Z)-3-dodecenoate (eq 9).14a

This reagent has been used to stereoselectively prepare (Z)-3-alkenoate moieties for use in the syntheses of insect pheromones.14

Generation of a-Keto Acid Equivalents (Dianions of Glycolic Acid Thioacetals).

Potassium bis(trimethylsilyl)amide was found to be the optimal reagent for the generation of the dianion of glycolic acid thioacetals. This reagent may be used to effect a nucleophilic a-keto acid homologation. Treatment of the starting bis(ethylthio)acetic acid with KN(TMS)2 proceeded to give the corresponding soluble dianionic species. This underwent alkylation with a variety of halides and tosylates (eq 10) and subsequent hydrolysis allowed isolation of the desired a-keto acids.15

The dianion was also shown to undergo ring-opening reactions with epoxides and aziridines (eq 11).

Generation of Ylides and Phosphonate Anions.

Ylides.

In the Wittig reaction, lithium salt-free conditions have been shown to improve (Z/E) ratios of the alkenes which are prepared;16 Sodium Hexamethyldisilazide has been shown to be a good base for generating these conditions. In a Wittig-based synthesis of (Z)-trisubstituted allylic alcohols, potassium bis(trimethylsilyl)amide was shown to be the reagent of choice for preparing the starting ylides.17 These were allowed to react with protected a-hydroxy ketones and depending upon the substitution pattern of the ylide and/or the ketone, stereoselectivities ranging from good to excellent were achieved (eqs 12-14).

Phosphonates.

In a Horner-Emmons-based synthesis of di- and trisubstituted (Z)-a,b-unsaturated esters, the strongly dissociated base system of potassium bis(trimethylsilyl)amide/18-Crown-6 was used to prepare the desired phosphonate anions. This base system, coupled with highly electrophilic bis(trifluoroethyl)phosphono esters, gave phosphonate anions which, when allowed to react with aldehydes, gave excellent selectivity for the (Z)-a,b-unsaturated esters (eq 15).18

Intramolecular Cyclizations.

Haloacetal Cyclizations.

Intramolecular closure of a carbanion onto an a-haloacetal has been shown to be a valuable method for the formation of carbocycles.19a Potassium bis(trimethylsilyl)amide was found to be the most useful base for the formation of the necessary carbanions. This methodology may be used for the formation of single carbocycles (eq 16), for annulation onto existing ring systems (eq 17), and for the formation of multiple ring systems in a single step (eq 18). In the case of annulations forming decalin or hydrindan systems, this ring closure proceeded to give largely the cis-fused bicycles (eq 17). For the reaction shown in eq 18, in which two rings are being formed, the stereochemistry of the ring closure was found to be dependent upon the counter ion of the bis(trimethylsilyl)amide; use of the potassium base allowed isolation of the cis-decalin system as the major product (95%), whereas use of lithium bis(trimethylsilyl)amide led to the isolation of the trans-decalin (95%).19

Intramolecular Lactonization.

In a general method for the formation of 14- and 16-membered lactones via intramolecular alkylation,20 potassium bis(trimethylsilyl) amide was shown to be a useful base for this transformation (eq 19).

Intramolecular Rearrangement.

Potassium bis(trimethylsilyl)amide was shown to be a good base for the generation of a diallylic anion which underwent a biogenetically inspired intramolecular cyclization, forming (±)-dicytopterene B (eq 20).21

Synthesis of Vinyl Fluorides.

Addition of potassium bis(trimethylsilyl)amide to b-fluoro-b-silyl alcohols was shown to selectively effect a Peterson-type alkenation reaction to form vinyl fluorides (eq 21).22 Treatment of a primary b-fluoro-b-silyl alcohol with KN(TMS)2 led cleanly to the terminal alkene. Use of a syn-substituted secondary alcohol led to the stereoselective formation of the (Z)-substituted alkene (eq 22); reaction of the anti-isomer, however, demonstrated no (Z:E) selectivity.

Oxyanionic Cope Rearrangement.

Potassium bis(trimethylsilyl)amide/18-crown-6 was shown to be a convenient alternative to potassium hydride for the generation of anions for oxyanionic Cope rearrangements (eq 23).23

Stereoselective Synthesis of Functionalized Cyclopentenes.

Potassium bis(trimethylsilyl)amide was shown to be an effective base for the base-induced ring contraction of thiocarbonyl Diels-Alder adducts (eq 24).24 Lithium Diisopropylamide has also been shown to be equally effective for this transformation.


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22. Shimizu, M.; Yoshioka, H. TL 1989, 30, 967.
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Brett T. Watson

Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, USA



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