Lithium hexamethyldisilazane

Intramolecular cyclization of 2-phenysulfonylmethyl lactam 3 took place upon reaction with lithium hexamethyldisilazan via generating its a-sulfonyl carbanion to give a cyclized postulated intermediate that can be quenched with trimethylchlorosilane to afford the stable silyl ketal 4. The later ketal was desulfonylated by Raney-Ni and desilylated through treatment with tetrabutyl ammonium fluoride (BU4NF) to afford the carbacephem 5 (94M71) (Scheme 1). 

The induced stereoselectivity in these aldol additions with (///S)-2Tiydroxy-l,2,2-triphenylethyl acetate is improved by the use of an excess of base (e.g.. 3 equiv of lithium diisopropylamide or lithium hexamethyldisilazane) in the deprotonation step89. 

GABA HMG-CoA HMPA HT LDA LHMDS LTMP NADH NBH NBS NCS NIS NK NMP PMB PPA RaNi Red-Al RNA SEM SnAt TBAF TBDMS TBS Tf TFA TFP THF TIPS TMEDA TMG TMP TMS Tol-BINAP TTF y-aminobutyric acid hydroxymethylglutaryl coenzyme A hexamethylphosphoric triamide hydroxytryptamine (serotonin) lithium diisopropylamide lithium hexamethyldisilazane lithium 2,2,6,6-tetramethylpiperidine reduced nicotinamide adenine dinucleotide l,3-dibromo-5,5-dimethylhydantoin A-bromosuccinimide A-chlorosuccinimide A-iodosuccinimide neurokinin 1 -methyl-2-pyrrolidinone para-methoxybenzyl polyphosphoric acid Raney Nickel sodium bis(2-methoxyethoxy)aluminum hydride ribonucleic acid 2-(trimethylsilyl)ethoxymethyl nucleophilic substitution on an aromatic ring tetrabutylammonium fluoride tert-butyldimcthyisilyl fert-butyldimethylsilyl trifluoromethanesulfonyl (triflyl) trifluoroacetic acid tri-o-furylphosphine tetrahydrofuran triisopropylsilyl A, N,N ,N -tetramethy lethylenediamine tetramethyl guanidine tetramethylpiperidine trimethylsilyl 2,2 -bis(di-p-tolylphosphino)-l,r-binaphthyl tetrathiafulvalene... 

LiHMDS lithium hexamethyldisilazane, lithium bis(trimethylsilyl)amide... 

EDC FDPP Fmoc HOBt LiHMDS MAMP MCPBA MeOPEG NCA NMP PAL PASP PBP PEG SASRIN TEA TFA TMAD N-Ethyl-N - [ 3 - (dimethy lamino)propy 1] -c arbodiimide hydrochloride Pentafluoro phenyldiphenyl phosphate 9 -Fluoreny lme thoxy c arbony 1 Hydroxybenzotriazol Lithium hexamethyldisilazane Merrifield, alpha methoxy phenyl resin w-Chloroperbenzoic acid Methoxy polyethylene glycol /V-Carboxv a-aminoacid anhydride /V - M e t h v 1 pyrrol i do n e Peptide amide linker Polymer assisted solution phase Penicillin-binding proteins Polyethylene glycol Super acid sensitive resin Triethylamine Trifluoroacetic acid Tetramethylamine azodicarboxylate. 

The intramolecular aldol condensation route to fused tricyclic /3-lactams has been explored. The methylene group of an yV-tu-methoxycarbonyl alkyl chain is sufficiently acidic to react with a carbonyl group when treated with lithium hexamethyldisilazane (LHMDS) in THF at — 78 °C. Reaction times are short and yields high (Equation 59) <1996JOC7125>. 

Nucleophilic substitution with lithium hexamethyldisilazane (LiHMDS) proceeds with inversion to give silylated amino boronic ester 19.26 A solution of 19 is passed through a short plug of silica before its use in the desilylation reaction. Due to the instability of underivatized a-amino boronic esters,26 trifluoroacetic acid (TFA) is used to furnish the corresponding TFA salt 20.27 A second recrystallization from TFA and isopropylether further enhances the optical purity. A diastereomeric ratio (dr) > 97 3 is typically obtained from the process route. 

Chiral p-lactamsThe reaction of 1 with (C2H5)2Zn in THF provides a, which on treatment with lithium hexamethyldisilazane provides b, which reacts with the imine 2 to provide a single cis-azetidinone (3), an intermediate to thienamycin. 

The bromination of dihydrobenzo[( ]selenophene 20 led to the formation of the corresponding 1,1-dibromo derivative 21 (Scheme 1) <20030L2519>. Treatment of the latter with lithium hexamethyldisilazane (LiHMDS) produced benzo[f]selenophene 3 which was subsequently converted to the stable diester 23 via dilithiation. The structure of 23 was confirmed by X-ray crystallographic analysis. 

Lithium chloropropargylide, 279-280 Lithium cyanocuprates, 329-330 Lithium diisopropylamide, 280-283, 309 Lithium hexamethyldisilazane, 82, 283 Lithium hexamethyidisilazide, 82, 283 Lithium iodide, 283 Lithium isopropoxide, 283 Lithium o-lithiobenzylate, 86-87 Lithium methoxy(trimethylsilyl)methylide, 284... 

If potassium hexamethyidisilazane is replaced by lithium hexamethyldisilazane in the cyclization of (II), (13) is obtained as the predominant product (95% yield). A possible explanation for the remarkable effect of the cation on this cyclization has been suggested. 

A synthetic approach toward tunicamycin 267, based on this principle, has been reported. Tunicamycin shows a direct carbon link between C6 of a galactosamine residue and C5 of a uridine moiety. The formation of this link has been carried out by Wittig reactions on model compounds using Secrist s phosphorane [181]. As shown in Scheme 11.58, the phosphonium salt 263 was treated with lithium hexamethyldisilazane to generate the phosphorane, which was reacted with aldehyde 264. Reduction of the double bond and benzyl hydrogenolysis of 265 was followed by acetylation to provide the model compound 266. 

Unfortunately the optical purity was very low in these reactions. Nevertheless, the iodolactones were converted to the epoxides 255, and these were cyclized to 251 (R = Me) and 252 with lithium hexamethyldisilazane. The methyl ester 251 (R = Me) has also been made by copper-activated addition of methyl diazoacetate to the tricarbonyliron compound 256. The product, 257, was converted to 251 (R = Me) by a reaction sequence including ozonolysis to remove the side chain. 

One of these important bases, diisopropylaminomagnesium bromide, was first introduced by Frostick and Hauser in 1949 as a catalyst for the Claisen condensation. However, the most generally useful base has turned out to be lithium diisopropylamide (LDA), which was first used by Hamell and Levine for the same purpose in 1950 (equation 3). After the introduction of LDA, it was more than 10 years before it was used by Wittig for the stoichiometric deprotonation of aldimines in what has come to be known as the Wittig directed aldol condensation.In a seminal paper in 1970, Rathke reported that the lithium enolate of ethyl acetate is formed by reaction of the ester with lithium hexamethyldisilazane in THF. - Rathke found that THF solutions of the lithium enolate are stable indefinitely at -78 °C, and that the enolate reacts smoothly with aldehydes and ketones to give p-hydroxy esters (equation 4). 

An application of this process is seen in the synthesis of ( )-[6]-gingerol (1 equation 10). In this example, the regioselectivity of deprotonation is 92% at C-1 and 8% at C-3. With the weaker base lithium hexamethyldisilazane, the C-l C-3 ratio is only 3 1. The method has also been used to prepare nine other ( )-gingerols. 

Masamune and coworkers studied the deprotonation of 3-pentanone and ethyl cyclohexyl ketone with various bases. These workers confirmed that lithium hexamethyldisilazane gives more ( -isomer than... 

In their synthesis of the 1-carbacephem derivatives, Hatanaka and Ishimaru observed that the 3-lactam (132) cyclized to the desired carbacephem skeleton (133) with 3 equiv. of lithium hexamethyldisilazane (Scheme 42), but cyclized through the amine nitrogen to give (134) with I equiv.Presumably deprotonation of the amine occurs with the flrst equivalent of base. 

Kuwajima and coworkers used very hindered bases such as (2) to deprotonate methyl alkyl ketones regioselectively in the presence of enolizahle aldehydes,21 One example of this amazing process is shown in equation (11) the reaction is reported to work equally well with other methyl ketones, including 2-pentanone. The process was also demonstrated with other bases in the reaction of 3-methyl-2-buta-none with dihydrocinnamaldehyde (equation 12). Among the bases that are effective are LDA, lithium hexamethyldisilazane, lithium f-butoxide and even lithium ethoxide. However, base (2) is superior, giving the aldol in 83% yield. 

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