TMEDA-LDA

In general, ketones are predicted to metalate via the open dimer pathway whereas imine metallations proceed more readily via monomers. By contrast, increased steric demands of the substrates promote the monomer pathways. It is reasonable to ascribe this to a decrease in congestion in monomers relative to open dimers. Indeed, for metalla-tion of imine 2 with LDA in THF (4 must be a real species) the rate behavior was consistent with the mechanism specified by M-1. When 2 2 TMEDA-LDA complex 1 was used for deprotonation of 3, a solvent-free open dimer proved to be a plausible reactive intermediate (Sch. 5) [28]. Accordingly, the rate of imine metalation depends strongly on the solvent and substrate used [29]. Kinetic evidence obtained in the enolization experiment with sterically demanding ester 5 showed disolvated LDA monomers to be the reactive form, providing the first direct support for Ireland s hypothesis of cyclic transition state... 

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... 

In order to extend this method in the sense of a tandem Michael/a-alkylation protocol, in a first step the intermediate P-aminosulfones had to be N,N-dibenzylated, followed by metallation with LDA in the presence of TMEDA and... 

As shown in Scheme 1.2.12, the aldehyde or ketone SAMP hydrazones 50 were metallated using LDA to generate the desired azaenolate, and then TMEDA was added. Subsequent Michael addition with methyl-2-cyclopentenone carboxylate (51) resulted in a clean 1,4-addition leading to the desired adducts 52 in good yields. 

The AH- 1,2-diazepine (99) reacted with butyllithium at -78 °C via addition to the 2,3-imine bond, but LDA gave the anion (100) which dimerized in the presence of oxygen. Reaction of (99) with Na/K at -20 °C in THF however led to the formation of (101) via ring contraction of (100) (72TL4891). Interestingly, however, when (100) was generated with LDA at 0 °C in TMEDA as solvent, no ring contraction was observed and the anion... 

The 3-pyridyl O-carbamate affords, under the sec-BuLi/TMEDA conditions, only 4-substituted products. A reinvestigation of LDA metalation (85JOC5436) has shown that high-yield conversion of 320 into the 4-TMS (319) and 2,4-bis-TMS (321) derivatives can be effected (Scheme 97) [90UP1]. Furthermore, LiTMP metalation of 319 followed by electrophile quench leads to derivatives 322, thus demonstrating the TMS protection route to 2-substituted 3-oxygenated pyridines. Another, potentially useful result is the 2-position selective ipso carbodesilylation of 321 with benzoyl chloride, yielding 323. 

The deuteriated (97%) imines 363 and 365, and the hydrazone 364 have been prepared396-399 by treating 2,6,6-trideuterio-2-methylcyclohexanone and 2,2,6,6-tetradeuteriocyclohexanone with the corresponding deuteriated ammonium salts (RND3CI) and used in the KIE studies of the metalation of the above C=N compounds with lithium diisopropylamide (LDA) in THF, in N, N, N A -tetramethyl ethylenediamine (TMEDA) and in dimethylethylamine (DMEA) solvents (equation 200). The rates, d[imine]/dt of that of imines 363 and 364 metalation are zero order with respect to [THF], [TMEDA]... 

Metallation of 365 in THF/hexane mixtures is also described by rate equation 201, but that of 365 ( bearing pendant Me2N moieties ) in TMEDA and DMEA, described by rate equation 202, suggests a mechanism involving rate-limiting metallation via dimeric LDA dimer stripped free of donor solvents, shown in equation 204. 

Scheme 1. Key a) alkaline HOOH, THF b) NaSPh, THF c) m-CPBA, CH2CI2, -78 °C d) 2 LDA, HMPA or DMTP, THF, -35 °C then 2-(2-bromoethyl)-2,5,5-trimethyl-1,3-dioxane e) AI(Hg) amalgam, wet THF f) p-CH3PhS02NHNH2, neat, 1 mm Hg g) 4 BuLi, TMEDA, 0 °C then DMF h) DIBAH, Et20, -78 °C then TMSCI, pyridine, CH2CI2 i) t-BuLi, THF, -30 °C then HOAc, -78 °C j) propionic anhydride, DMAP, pyridine, CH2CI2.

Arenes cannot usually be deprotonated with LDA alone, but require mixtures of organosodium [365] or organolithium compounds and tertiary amines [181, 218, 219]. These amines, for instance TMEDA, lead to a partial dissociation of oligomeric BuLi-solvent aggregates and thereby to more powerful metalating reagents [366, 367]. Thus, although benzene cannot be deprotonated with BuLi alone, a mixture of BuLi and TMEDA leads to quantitative lithiation [181]. 

Silyl ketene acetals from esters.1 Ireland has examined various factors in the enolization and silylation of ethyl propionate (1) as a model system. As expected from previous work (6, 276-277), use of LDA (1 equiv.) in THF at —78 -+ 25° results mainly in (E)-2, formed from the (Z)-enolate. The stereoselectivity is markedly affected by the solvent. Addition of TMEDA results in a 60 40 ratio of (Z)- and (E)-2 and lowers the yield significantly. Use of THF/23% HMPA provides (Z)- and (E)-2 in the ratio of 85 15 with no decrease in yield. This system has been widely used for (E)-selective lithium enolate formation from esters and ketones. Highest stereoselectivity is observed by addition of DMPU, recently introduced as a noncar-... 

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