Sodium Hexamethyldisilazide1

NaN(SiMe3)2

[1070-89-9]  · C6H18NNaSi2  · Sodium Hexamethyldisilazide  · (MW 183.42)

(useful as a sterically hindered base and as a nucleophile)

Alternate Names: NaHMDS; sodium bis(trimethylsilyl)amide.

Physical Data: mp 171-175 °C; bp 170 °C/2 mmHg.

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

Form Supplied in: (a) off-white powder (95%); (b) solution in THF (1.0 M); (c) solution in toluene (0.6 M).

Analysis of Reagent Purity: THF solutions of the reagent may be titrated using 4-phenylbenzylidenebenzylamine as an indicator.2

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

Introduction.

Sodium bis(trimethylsilyl)amide is a synthetically useful reagent in that it combines both high basicity3 and nucleophilicity,4 each of which may be exploited for useful organic transformations such as selective formation of enolates,5 preparation of Wittig reagents,6 formation of acyl anion equivalents,7 and the generation of carbenoid species.8 As a nucleophile, it has been used as a nitrogen source for the preparation of primary amines.9,10

Sterically Hindered Base for Enolate Formation.

Like other metal dialkylamide bases, sodium bis(trimethylsilyl)amide is sufficiently basic to deprotonate carbonyl-activated carbon acids5 and is sterically hindered, allowing good initial kinetic vs. thermodynamic deprotonation ratios.11 The presence of the sodium counterion also allows for subsequent equilibration to the thermodynamically more stable enolate.5f More recently, this base has been used in the stereoselective generation of enolates for subsequent alkylation or oxidation in asymmetric syntheses.12 As shown in eq 1, NaHMDS was used to selectively generate a (Z)-enolate; alkylation with Iodomethane proceeded with excellent diastereoselectivity.12a In this case, use of the sodium enolate was preferred as it was more reactive than the corresponding lithium enolate at lower temperatures.

The reagent has been used for the enolization of carbonyl compounds in a number of syntheses.13 For ketones and aldehydes which do not have enolizable protons, NaHMDS may be used to prepare the corresponding TMS-imine.14

Generation of Ylides for Wittig Reactions.

In the Wittig reaction, salt-free conditions have been shown to improve (Z):(E) ratios of the alkenes which are prepared.15 NaHMDS has been shown to be a good base for generating ylides under lithium-salt-free conditions.6 It has been used in a number of syntheses to selectively prepare (Z)-alkenes.16 Ylides generated under these conditions have been shown to undergo other ylide reactions such as C-acylations of thiolesters and inter- and intramolecular cyclization.6 Although Wittig-based syntheses of vinyl halides exist,17 NaHMDS has been shown to be the base of choice for the generation of iodomethylenetriphenylphosphorane for the stereoselective synthesis of (Z)-1-iodoalkenes from aldehydes and ketones (eq 2).18

NaHMDS has been shown to be the necessary base for the generation of the ylide anion of sodium cyanotriphenylphosphoranylidenemethanide, which may be alkylated with various electrophiles and in turn used as an ylide to react with carbonyl compounds.19 NaHMDS was used as the base of choice in a Horner-Emmons-Wadsworth-based synthesis of terminal conjugated enynes.20

Intramolecular Alkylation via Protected Cyanohydrins (Acyl Anion Equivalents).

Although NaHMDS was not the base of choice for the generation of protected cyanohydrin acyl carbanion equivalents in the original references,21 it has been shown to be an important reagent for intramolecular alkylation using this strategy (eqs 3 and 4).7,22 The advantages of this reagent are (a) that it allows high yields of intramolecularly cyclized products with little intermolecular alkylation and (b) the carbanion produced in this manner acts only as a nucleophile without isomerization of double bonds a,b to the anion or other existing double bonds in the molecule. Small and medium rings as well as macrocycles22a have been reported using this methodology (eqs 3 and 4).

Generation of Carbenoid Species.

Metal bis(trimethylsilyl)amides may be used to effect a-eliminations.23 It is proposed that these nucleophilic agents undergo a hydrogen-metal exchange reaction with polyhalomethanes to give stable carbenoid species.23b NaHMDS has been used to generate carbenoid species which have been used in a one-step synthesis of monobromocyclopropanes (eqs 5 and 6).23c,d NaHMDS has been shown to give better yields than the corresponding lithium or potassium amides in this reaction.

A similar study which evaluated the use of NaHMDS versus n-Butyllithium for the generation of the active carbenoid species from 1,1-dichloroethane and subsequent reaction with alkenes, forming 1-chloro-1-methylcyclopropanes, suggested that the amide gave very similar results to those with n-butyllithium.24

In an initial report, the carbenoid species formed by the treatment of diiodomethane with NaHMDS was shown to react as a nucleophile, displacing primary halides and leading to a synthesis of 1,1-diiodoalkanes; this is formally a 1,1-diiodomethylene homologation (eq 7).25 This methodology is limited in that electrophiles which contain functionality that allows facile E2 elimination (i.e. allyl) form a mixture of the desired 1,1-diiodo compound and the iododiene. In the case of Allyl Bromide, addition of 2 equiv of the sodium reagent allows isolation of the iododiene as the major product.

Synthesis of Primary Amines.

The nucleophilic properties of this reagent may be utilized in the SN2 displacement of primary alkyl bromides, iodides, and tosylates to form bis(trimethylsilyl)amines (1) (eq 8).9a HCl hydrolysis of (1) allows isolation of the corresponding hydrochloride salt of the amine, which may be readily separated from the byproduct, bis(trimethylsilyl) ether. In one example a secondary allylic bromide also underwent the conversion with good yield.

Aminomethylation.

NaHMDS may be used as the nitrogen source in a general method for the addition of an aminomethyl group (eq 9).10 The reagent is allowed to react with chloromethyl methyl ether, forming the intermediate aminoether. Addition of Grignard reagents to this compound allows the displacement of the methoxy group, leaving the bis(trimethylsilyl)-protected amines. Acidic hydrolysis of these allows isolation of the hydrochloride salt of the corresponding amine in good yields.

Related Reagents.

Lithium Hexamethyldisilazide; Potassium Hexamethyldisilazide.


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Brett T. Watson

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



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