Hexamethyldisilazides

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... 

The (racemic) tmns disulfoxide of 1,3-dithiolane 59 is readily deprotonated at C2 by lithium hexamethyldisilazide, and the resulting anion reacts with aldehydes at -78°C with moderate to excellent diastereoselectivity to give mainly the products 60, although subsequent cleavage of these to give the a-hydroxyaldehydes was not described (97JOC1139). 

The a-bromoketone (non-enolizable on the a side) was treated with lithium hexamethyldisilazide (1 eq.) at -78 °C in THF, and then TMSCI (1 eq.) was added and the solution allowed to come to ambient temperature. It was then re-cooled to -78°C, and n-BuLi (2 eq.) was added, and the solution was allowed to come to ambient temperature. The mixture was poured into saturated ammonium chloride solution. Normal work-up and distillation gave the /3-ketosilane (50-80%). 

Lithium bis(trimethylsilyl)cuprate, 29, 52 Lithium diaikylamides, 100 Lithium l-(dimethylamino)naphthalenide (LDMAN), 68, 69. 77 Lithium dimethylcopper, 131 Lithium hexamethyldisilazide, 73. 78 Lithium t-octyl-t-butylamide, 100 2.6-Lutidine, 93.94... 

Non-enolizable aldehydes are transformed into N-trimethylsilylaldimines on treatment with lithium hexamethyldisilazide (22) such imines provide valuable routes to N-unsubstituted / -lactams ... 

To a solution of the silylated glycinate (50 mmol) in ether (50 ml), cooled to —10 to 0°C, was added a solution of sodium hexamethyldisilazide (55 mmol) in ether (100ml) with stirring. Stirring was continued at ambient temperature for a short time, and then the alkyl halide (50 mmol) was added dropwise. The mixture was heated under reflux for 10-15 h, cooled, filtered, and the product was distilled directly (52-70%). 

Silyl enol ethers, 23, 77, 99-117,128 Silyl enolates, 77 Silyl peroxides, 57 Silyl triflate, 94 Silyl vinyl lithium, 11 (E)-l -Silylalk-1 -enes, 8 Silylalumimum, 8 Silylation, 94 reductive, 26 a-C-Silylation, 113 O-Silylation.99,100 / -SilyIketone, 54 non-cydic, 55 Silylmagnesium, 8 Silyloxydienes, 112 Sodium hexamethyldisilazide, 89 Sodium thiosulphate pentahydrate, 59 Stannylation, see Hydrostannylation Stannylethene, 11 (Z)-Stilbene, 70 (E)-Stilbene oxide, 70 /3-Styryltrimethylsilane, 141 Swern oxidation. 84,88... 

In the reaction of 1,3-dithiane oxide anions with iV-acylimidazoles the optimum procedure involved a sodium hexamethyldisilazide/butyllithium mixture as base [101]... 

C-Alkylations of l,4-dihydro-27/-pyrazino[2,l-A]quinazoline-3,6-diones at positions C-l and CM were studied in detail. Compounds of type 57 could be alkylated diastereoselectively at C-l, owing to the geometry of the piperazine ring, which is locked in a flat boat conformation with the R4 or R1 substituent in a pseudoaxial position to avoid steric interaction with the nearly coplanar C(6)-carbonyl group. Alkylation of 57 (R2 = Me, Bn, R4 = Me) in the presence of lithium hexamethyldisilazide (LHMDS) with benzyl and allyl halides resulted, under kinetic control, in the 1,4-trans-diastereomer 59 as the major product, with retention of the stereocenter at CM (Scheme 5). 

Azatriquinadiene (2,3-dihydroazatriquinacene) 39 has been efficiently synthesized from enamine 389. Enamine 389 on treatment with bromine followed by aqueous work-up afforded the tetrabromohemiaminal 390. Dehydrohalogenation of 390 with potassium hexamethyldisilazide (KHMDS) and compound 391 on reduction with lithium aluminium hydride yielded the target molecule azatriquinadiene 39 in good overall yield (Scheme 85) <2000JOC7253>. 

While it is important for all ester substrates that lithium hexamethyldisilazide be added before warming in order to avoid yield loss, the addition of lithium ethoxide (LiOEt) Is specific for the naphthyl ester and is not generally necessary (see Discussion). Thus for other esters the ethanol can be omitted in this step and the amount of butyllithium can be reduced to 0.20 mol. 

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... 

Tertiary A-allylthioamides have been converted into thioamidium salts by the formation of complexes with Lewis acid. Further treatment with lithium hexamethyldisilazide (LiHMDS) affords the corresponding 1,2-disubstituted pyrroles (Scheme 25).52... 

When one of the reacting partners in the Wittig-Horner reaction, either the phosphine oxide or the carbonyl compound, has a double bond, the product is a diene. The Wittig-Horner reaction was utilized by Smith and coworkers in the total synthesis of milbemycin (equation 98)170. They found that when sodium hexamethyldisilazide was employed as a base, the desired E-diene selectivity is high (85%). Some examples from the literature where the Wittig-Horner reaction has been utilized for the construction of E-double bonds present in dienes and polyenes are given in Table 19171. 

Vedejs et al. developed a method for the iodination of oxazoles at C(4) via 2-lithiooxazoles by exploiting the aforementioned equilibrium between cyclic (5) and acyclic (6) valence bond tautomers of 2-lithiooxazole [4]. When 5-(p-tolyl)oxazole (8) was treated with lithium hexamethyldisilazide (LiHMDS) in THF followed by treatment with 1,2-diiodoethane as the electrophile, 2-iodooxazole 9 was obtained exclusively. On the other hand, when 50 volume% of DMPU was added prior to the addition of the base, 4-iodooxazole 10 was isolated as the predominant product (73%) with ca. 2% of 9 and ca. 5% of the 2,4-diiodooxazole derivative. 

Meyers lactams are widely used in synthesis of substituted synthons of interest and their functionalization is carried out under strong base conditions giving C-alkyl derivatives. Alkylation of bicyclic lactam 182 with electrophiles (alkyl, allyl, benzyl halides, chlorophosphonate), and a strong base (j-BuLi, LiHMDS, or KHMDS HMDS = hexamethyldisilazide) in THF at — 78 °C gave an endo-exo mixture of products where the major one is the rro/o-compound 183 in good yields. The ratios were determined by H NMR spectroscopy and are usually up to... 

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