Bases Lithium hexamethyldisilazide

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. 

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... 

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. 

Page et al. (see [298] and references therein) have shown that generally excellent stereocontrol in organic reactions can be obtained by using DITOX (1,3-dithiane-l-oxide) derivatives as chiral auxiliaries. The one-pot stereo-controlled cycloalkanone synthesis given here outlines some aspects of the chemistry worked out for efficient acylation-alkylations steps. Of note are the use of N-acyl imidazoles under mixed base (sodium hexamethyldisilazide/n-butyllithium) conditions to yield the lithium enolates of 2-acyl-l,3-dithiane-l-oxides) and the sequential alkylation-cyclization of the latter (steps (iv) and (v)). 

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... 

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). 

The dibenzo derivative of a cyclic acetylenic silane 96 was synthesized by mono-deprotonation of 1,2-diethynyl-benzene with 1 equiv of lithium hexamethyldisilazide (LiHMDS) followed by treatment with 0.5equiv of dichlor-odiphenylsilane (formation of 95). A repeat of the deprotonation step, followed by silylation cycle, gave 96 in 77% yield after column chromatography (Scheme 19). One-step preparation of 96 using 2 equiv of base and 2 equiv of the silylation agent also yielded the desired product, however, the yield was 50% of those of the previous method... 

Methyl ethers are usually prepared by some variant of the Williamson ether synthesis in which an alcohol reacts with either iodomethane, dimethyl sulfate, or methyl triflate (HAZARD) in the presence of a suitable base. A word of caution dimethyl sulfate and methyl triflate, tike all powerful alkylating agents, are potentially carcinogenic and therefore should only be handled in a well-ventilated fume hood. For the 0-methylation of phenols (pKa 10) a comparatively weak base such as potassium carbonate in conjunction with dimethyl sulfate is sufficient,193 whereas simple aliphatic alcohols require stronger bases such as sodium hydride [Scheme 4.111]22 or lithium hexamethyldisilazide [Scheme 4.112].203 The latter transformation is notable for the fact that 0-methyiation was accomplished without competing elimination. 

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. ... 

Owing to the importance of the amine, probably acting as a ligand of lithium or a proton carrier [ammonium salt of (2R,3R)-DPTA], a process was proposed allowing the introduction of different amines and consequently a modification of the selectivity of the protonation after deprotonation of a Schiff base of methyl valinate with Lithium Hexamethyldisilazide (LHMDS), the liberated HMDS was replaced by a more basic primary, secondary, or tertiary amine prior to the addition of (2R,3R)-DPTA (eq 5) (Table 3). In some cases, higher ee were observed compared to the classical procedure with LHMDS (34% ee) or LDA (47% ee). ... 

Lithium hexamethyldisilazide (LHMDS, LiNfTMSjj) and PhjCLi are useful bases for y-deprotonation of enones to generate conjugated enolates. 

What is needed for the alkylation is rapid conversion of the ester into a reasonably stable enolate, so rapid in fact that there is no unenolised ester left. In other words the rate of proton removal must be faster than the rate of combination of enolate and ester. These conditions are met when lithium enolates are made from esters with lithium amide bases at low temperature, often 78 °C. Hindered bases must be used as otherwise nucleophilic displacement will occur at the ester carbonyl group to give an amide. Popular bases are LDA (Lithium Di-isopropyl Amide, 66), lithium hexamethyldisilazide 67, and lithium tetramethylpiperidide 68, the most hindered of all. These bases are conveniently prepared from the amine, e.g. 65 for LDA, and BuLi in dry THF solution. 

The strong base (LHMDS, lithium hexamethyldisilazide) removes a proton from the methyl group so that the anion is stabihzed both by the nitrile and the pyridine nitrogen atom. Acylation occurs outside the ring to preserve the aromaticity. If you drew the hthium atom covalently bound to nitrogen, your answer is better than ours. 

The (Z)/( ) stereoselectivity of enolate formation is dictated by the structure of the starting carbonyl compound and the base used for deprotonation. Compared to LDA, Lithium 2,2,6,6-Tetra-methylpiperidide usually favors ( )-enolates whereas Lithium Hexamethyldisilazide preferentially leads to (Z)-enolates (eq 10). With a caveat for any generalization, enolate configuration usually determines the stereochemical result in the product for example, using a hindered ester and a bulky aldehyde combination, excellent stereoselectivities in aldol reactions are observed (eq 11). ... 

In a study on the electrophilic azide transfer to chiral enolates, Evans found that the use of potassium bis(trimethylsilyl)amide was crucial for this process. The KN(TMS)2 played a dual role in the reaction as a base, it was used for the stereoselective generation of the (Z)-enolate (1). Reaction of this enolate with trisyl azide gave an intermediate triazene species (2) (eq 4). The potassium counterion from the KN(TMS)2 used for enolate formation was important for the decomposition of the triazene to the desired azide. Use of other hindered bases such as Lithium Hexamethyldisilazide allowed preparation of the intermediate triazene however, the lithium ion did not catalyze the decomposition of the triazene to the azide.This methodology has been utilized in the synthesis of cyclic tripeptides. 

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... 

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