Ketones lithium hexamethyldisilazide

Parts A and B of the procedure correspond to preparation of lithium tetramethylpiperidide, and its use in the in situ preparation and addition of dibromomethyllithium to the ester 1 producing tetrahedral intermediate 2. In Part C a mixture of lithium hexamethyldisilazide and lithium ethoxide is prepared for addition in Part D to the solution of 2. The silazide base serves to deprotonate the mono and dibromo ketones that are formed on initial warming of the reaction to -20°C, thus protecting them as the enolate anions 4 and 3. Addition of the sec-butyllithium in Part... 

In solution, lithium hexamethyldisilazide (LiHMDS) is a strong enough base to deprotonate esters, ketones, and alcohols, with a pK of about 27 in DMSO solvent. In the gas phase, the bare anion is too weak to deprotonate methanethiol, much less the ketones, esters, and comparable carbon acids. The change in relative anionic basicity is on the order of 14 kcal/mol. 

Lithium hexamethyldisilazide, 165 Other a-substituted ketones p-(Tolylsulfinyl)methyllithium, 115 Methods to prepare some specific types of ketones Benzyl ketones... 

Silyl enolates generated from a-allyloxy ketones undergo the [2,3]-Wittig rearrangement in the presence of a catalytic Lewis base such as lithium 2-pyrrolidone, lithium acetamide, or lithium hexamethyldisilazide (Scheme ll).15... 

Kowalski and coworkers reported that lithium enolates of a-bromo ketones can be converted to the corresponding ketone dilithio a,a-dianions by Li—Br exchange with r-BuLi (Scheme if. To generate lithium enolates of a-bromo ketones, either method A or B can be used deprotonation of a-bromo ketones by one equivalent of lithium hexamethyldisilazide (LHMDS) (method A) or deacetylation of enol acetates of a-bromo... 

Only one equivalent of base is required for the trifluoroacetylation step apparently the chelated tetrahedral intermediate is stable at -78°C and the ft-dicarbonyl product is not generated until workup. Crucial to the success of the trifluoroacetylation reaction in some cases is the selection of lithium hexamethyldisilazide (LiHMDS) for the generation of the ketone enolate under otherwise identical conditions diazo transfer to several aryl ketones proceeds in dramatically reduced yield when lithium diisopropylamide is employed as base. 

The term amidolithium is the unambiguous name for the compounds RR NLi (R, R = alkyl, aryl, silyl, etc.) more often termed lithium amides. They derive their importance from the near-ubiquity of their bulkier members lithium diisopropy-lamide (LDA), lithium tetramethylpiperidide (LTMP), and lithium hexamethyldisilazide (LHMDS) in organic synthesis. Using such powerful but nonnucleophilic bases, many useful reactions may be performed, notably the enolization of ketones and esters, which can proceed both regio- and stereoselectively under kinetic control at low temperatures. ... 

This reaction can sometimes be useful in synthesis. In the Honda et al. formal synthesis of securinine,2h N-benzylamino-ketone (97) was treated with lithium hexamethyldisilazide and then sorbic anhydride. This gave dienyl ester 98 by O-alkylation of the initially formed enolate anion. When the nitrogen protecting group was... 

The products of the reaction of ketones with lithium hexamethyldisilazide have been studied by Collum and co-workers by an extensive use of the Li and NMR spectroscopy Vun couplings have been found to be particularly useful. 

With ketone 271 in hand, focus turned to construction of the furoindole scaffold via a Fischer indolization. The lithium enolate of ketone 271 was generated in situ using lithium hexamethyldisilazide in a mixture of l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU) and THF (Scheme 36). Although this enolate is noted not to be very reactive toward electrophiles, treatment with allyl iodide affected a facile alkylation to provide ketone 272. 

Zhao, P. Collum, D. B. (2003). Lithium Hexamethyldisilazide/Triethylamine-Mediated Ketone Enolization Remarkable Rate Accelerations Stemming from a Dimer-Based Mechanism. Journal of the American Chemical Society Vol.125, pp. 4008-4009, ISSN 0002-7863... 

Stork has demonstrated that the readily available protected cyanohydrins of aldehydes are useful acyl carbanion equivalents, and has now applied these in the preparation of small rings. Treatment of the ethoxyethyl-protected cyanohydrin of 4-chlorobutyraldehyde (17) with sodium hexamethyldisilazide gives the cyclo-butanone cyanohydrin derivative (18) in high yield. The cyanohydrin derivative is easily hydrolysed to the ketone, or may be reduced with lithium aluminium hydride to the P-amino-ether (19), which is also a useful synthetic intermediate. 

Related thermodynamic enolization control has been observed using metallated hexamethyldisilazide to give the more substituted bromomagnesium ketone enolates. 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 HexamethyldisUaade, Potassium Hexamethyldisilazide, Sodium Hexamethyldisilazide). ... 

---