Lithium 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 ... 

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). 

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... 

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. 

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. 

An elegant cyclization-cleavage strategy has been devised for the removal of resin-bound 1,3-amino alcohol derivatives 392 as l,3-oxazin-2-ones 393 upon treatment with lithium hexamethyldisilazide (LiHMDS) (Equation 42) <20010L3177>. 

The cyclic cobalt-acyl complex 1 undergoes a-proton abstraction from the least-hindered face opposite the phosphane ligand upon treatment with lithium hexamethyldisilazide at 0 °C to generate the chiral enolate species 283. Treatment of 2 with primary iodoalkanes diastereoselec-tively produces the alkylated cobaltocycles 3 also via attack of the reagent on the face opposite the bulky phosphane. 

The palladium catalyzed intramolecular coupling of aryl halides and classical carbanions, sometimes considered a variant of the Buchwald-Hartwig coupling, might also be used for the formation of heterocyclic systems. 7V-(2 -bromophenyl)-propionamides were converted in the presence of the appropriate palladium catalyst and lithium hexamethyldisilazide to oxindoles (3.2.). Under the applied conditions a series of electron deficient and electron rich aniline derivatives, including 2-chloroanilines were transformed successfully.2... 

An alternate approach, which utilizes lithium amides such as lithium hexamethyldisilazide or lithium amide, was also efficient in converting 2-chloropyridine into 2-aminopyridine (7.73.), In these reactions 2-(dicyclohexylphosphino)biphenyl was used as catalyst and the silyl protecting group was removed by TBAF.94... 

---