Lithium hexamethyldisilazide, reaction with

Many organic syntheses requHe the use of stericaHy hindered and less nucleophilic bases than //-butyUithium. Lithium diisopropylamide (LDA) and lithium hexamethyldisilazide (LHS) are often used (140—142). Both compounds are soluble in a wide variety of aprotic solvents. Presence of a Lewis base, most commonly tetrahydrofuran, is requHed for LDA solubdity in hydrocarbons. A 30% solution of LHS can be prepared in hexane. Although these compounds may be prepared by reaction of the amine with //-butyUithium in the approprite medium just prior to use, they are also available commercially in hydrocarbon or mixed hydrocarbon—THF solvents as 1.0—2.0 M solutions. 

To a solution of 0 01 mol of lithium hexamethyldisilazide and 0 01 mol of HMPA dissolved in 50 mL of anhydrous THF at 78 °C was added 0 5 g (0 004 mol) of l-fluoro-3,3-dimethylbutanone m THF over 1 mm To the solution of the enolate was then rapidly added 0 003 mol of the aldehyde m THF After stimng an additional 2 mm, the reaction was quenched by rapid addition of a saturated ammonium chlonde soluuon Extractive workup with hexanes yielded on evaporation the product as a clear colorless oil isolated yield... 

Eliminations of epoxides lead to allyl alcohols. For this reaction to take place, the strongly basic bulky lithium dialkylamides LDA (lithium diisopropylamide), LTMP (lithium tetramethylpiperidide) or LiHMDS (lithium hexamethyldisilazide) shown in Figure 4.18 are used. As for the amidine bases shown in Figure 4.17, the hulkiness of these amides guarantees that they are nonnucleophilic. They react, for example, with epoxides in chemoselective E2 reactions even when the epoxide contains a primary C atom that easily reacts with nucleophiles (see, e.g., Figure 4.18). 

Asymmetric Diels-Alder reaction.1 The chiral menthyl (S)-3-(2-pyridylsul-finyl)acrylate (1) undergoes [4 + 2]cycloaddition with the furan 2 in the presence of (C2H5),A1C1 at - 20° to give the endo- and exo-adducts 3 in the ratio —2 1, both in about 93% de. The endo-adduct (3) was converted by known reactions to 4, which is opened by lithium hexamethyldisilazide (12,257) to the unsaturated acid in 56% yield. Remaining steps to methyl (- )-triacetoxyshikimate (5) include de-benzylation and acetylation. A similar sequence with exo-2 should provide ( + )-shikimic acid. 

When a bulky bis(adamantylethoxy) imidazolium salt was treated with potassium hydride the reaction did not afford the expected potassium-carbene.18 Instead, elimination of one alcohol arm produced a mono (adamantylethoxy) imidazole (9) (Scheme 5). Treatment of this with isopropyl iodide resulted in the alcohol imidazolium iodide salt, which undergoes deprotonation with lithium hexamethyldisilazide to afford the lithium alkoxy carbene (10) which was characterised by mass spectrometry and multinuclear NMR spectroscopy. The C2 carbon in 10 resonates at 186.3 ppm in the 13C NMR spectrum, which is a significantly lower frequency than the similar ligand in 7 which has lithium iodide incorporated into the structure. 

Deprotonation of 14 can also be achieved by reaction with lithium hexamethyldisilazide. Following deprotonation of the amino group the 13C NMR spectrum exhibits a resonance at 182.3 ppm for the C2 carbon, suggesting a stronger interaction of the carbene with the magnesium centre. 

Reaction of 2-[bis(methylthio)methylene]cyclohexanone 124 with lithium hexamethyldisilazide (LHMDS) and ethyl bromoacetate generates intermediate 125, which gives thiophene 126 and furan derivatives 127 (Scheme 30) <1997JOC1599>. 

Reactions of the Enolate of (1) with Electrophiles. Addition of the dioxolanones (1) to solutions of Lithium Diiso-propylamide or Lithium Hexamethyldisilazide in THF at dry-ice temperature generates the corresponding enolates which react with alkyl halides, - carbonyl compounds, and nitroalkenes almost exclusively from the face remote from the t-Bu group to give products of type (2). These can be hydrolyzed to simple ot-hydroxy-ot-methyl carboxylic acids or further elaborated. Four examples are shown in (3)-(6) in which the part of the molecule originating from lactic acid is indicated in bold. 

Alkynyltrimethylsilanes. Arylethynylsilanes are obtained from aromatic nitriles by reaction with tris(trimethylsilyl)methyllithium which is in turn derived from the silane (MeLi/THF, 65°). The initial adducts eliminate lithium hexamethyldisilazide on thermolysis in benzene. 

The aza Diels-Alder reactions of a, ff-unsaturated sulfinimines (140) represent a very efficient approach to enantiopure dihydro- and tetrahydropyridines (141) (Scheme 8.34, Table 8.11) for a reasonable reaction rate the 1-aza-l,3-butadiene moiety 140 must carry an electron-withdrawing group at the 3-position [65]. The compounds are accessible in only three steps starting from commercially available substrates. Thus, the enantiopure 1-aza-l,3-butadiene can be prepared from the enantiopure menthyl sulfinate with lithium hexamethyldisilazide followed by addition of acetic acid and an a, -unsaturated aldehyde. The cycloadditions of sulfinimines such as 140 run under mild conditions with high yields and excellent endo-selectivity in most cases when high pressure is applied. In these reactions two endo and two exo transition structures namely syn and anti to the sulfoxide moiety should be discussed. The cycloaddition of 140 and t-butyl vinyl ether was performed under various pressures ranging from 0.2 to 1.2 GPa. 

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... 

---