Deprotonations lithium hexamethyldisilazide

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). 

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... 

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. 

The cyclic sulfonimidate 132 reacts readily with carbon nucleophiles, for example, methyllithium, to afford the methylsulfoximine 133 which can be deprotonated by an excess of lithium hexamethyldisilazide (LHMDS) and reacted with a second equivalent of the sulfonimidate yielding the bis(sulfoximine) 134 in a one-pot sequence with 62% yield (Scheme 20) <2004ASC1295>. 

The synthesis and structural study of the stable P-heterocylic carbene 49 and related structures (e.g., structures 48 and 52 see Figure 3) have attracted some recent research activity <2005AGE1700, 2002JA2506, 2006AGE2598, 2006AGE7447>. The synthesis of the stable P-heterocylic carbene 49 was accomplished in two steps (1) a formal [3+2] cycloaddition of the readily available phosphaalkene 123 with acetonitrile in the presence of silver triflate afforded salt 124, and (2) the isolated and recrystallized salt 124 was deprotonated by lithium hexamethyldisilazide in tetrahydrofuran (THF) to afford carbene 49 as relatively stable light-yellow crystals (Scheme 10) <2005AGE1700>. 

Deprotonation of the terminal acetylene in epoxydiyne 7 was next attempted with lithium hexamethyldisilazide in toluene at low temperature. The resulting lithium acetylide added readily to cyclopentenone 69... 

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. 

Kowalski and coworkers reported that lithium enolates of a-bromo ketones can be converted to the corresponding ketone dilithio a,a-dianions by Li—Br exchange with r-BuLi (Scheme if. To generate lithium enolates of a-bromo ketones, either method A or B can be used deprotonation of a-bromo ketones by one equivalent of lithium hexamethyldisilazide (LHMDS) (method A) or deacetylation of enol acetates of a-bromo... 

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... 

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). ... 

On the other hand, enantiomeric excesses up to 94% are reached even at —78 °C, provided that Lithium Hexamethyldisilazide (LH-MDS) (3 equiv) is used for deprotonation instead of LDA (2 equiv) (eq 3). ... 

Deprotonation of alkylnitriles with LDA or lithium hexamethyldisilazide (LHMDS" ) and treatment of the resultant ambident a-nitrile anions with 1° and 2°-alkyl halides affords C-alkylated products in good yield. However, the a-anions of highly substituted nitriles may undergo N-alkylation to give amides on aqueous workup. 

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

The sites of deprotonation of a series of A -benzyl lactams have been determined. For five- and six-membered lactams, kinetic deprotonation occurred exclusively a to the carbonyl, while seven-and eight-membered lactams gave exclusively the products arising from deprotonation at the benzylic position. The alkylation of the anion derived from (121), however, gave an approximately 3 1 ratio of (122) to (123) (R = Bu", allyl and Bn) (Equation (5)) <87JA4405>. By contrast, the deprotonation of A -(BOC)caprylolactam with lithium hexamethyldisilazide in THF at — 78°C gave the expected enolate, which could be alkylated with iodomethane (81% yield) or phenylselenyl chloride (65% yield) <90SL63>. 

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). ... 

Early process development studies had shown that the SnAt reaction between 21 and 22 worked best when a strong base was used. Based on these early studies, a process using lithium hexamethyldisilazide (LHMDS) was developed, and was effective for the production of early clinical supplies (Scheme 14). There were, however, two major issues with this reaction. First, it required 2 equiv of base and 2 equiv of aminopyridine 22. Second, the aminopyridine 22 needed to be treated with LHMDS, followed by portion-wise addition of chloropyrimidine 21. The requirement for 2 equiv of base was due to the increased acidity of the product 20 relative to the starting material 22. The requirement for 2 equiv of 22 was less obvious, but additional studies eventually revealed that this second equivalent of deprotonated 22 was acting as a weaker second equivalent of base (relative to LHMDS). This was important because both the chloropyrimidine 21 and the product 20 are unstable to LHMDS. 

An alternative approach to alkylidene carbenes uses the deprotonation or halogen-lithium exchange of vinyl haUdes. Hence, treatment of the vinyl chloride 103 with potassium hexamethyldisilazide (KHMDS) resulted in the formation of the cyclopentene 104 via the intermediate alkylidene carhene (4.83). The carbene... 

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