Lithium diisopropyl amide

Lithium aluminum tri-tert-bu-toxyhydride, 53, 53 Lithium amide, bis(trimethyl-silyl), 53, 66 Lithium amide, diisopropyl-,... 

The mixed (heterogeneous) complexes of a lithium amide (LDA or LiTMP) and a ketone lithium enolate (acetone, cyclohexanone or diisopropyl ketone) have been examined by semiempirical methods (MNDO) by Romesberg and Collum48. If the stabilization associated with these mixed complexes was not determined, the solvation (by THF and HMPA) of the mixed cyclic dimers and trimers was calculated to be generally exothermic (but decreasingly with the steric demand of the enolate) and led to disolvated entities. A set of solvated dimers, trimers and tetramers, cyclic or not, has thus been identified... 

The beauty of this reaction lies in the fact that nearly all the facts needed to elucidate the mechanism are, in one way or another, in the products. Although the formation of II might seem somewhat tantalizing at first, a second glance will reveal that simply isomerization of I will suffice to account for it. A rather unusual isomerization, however, because activation of the a carbon of the ester as a nucleophile and introduction of foimaldehyde (from where ) at this carbon need justification. The first argument may be reformulated as the formation of an ester enolate, which is made possible by the advent of lithium amide superbases such as lithium diisopropyl amide (LDA) in aprotic tetrahydrofuran (THF)-hexamethyl-phosphoramide (HMPA) solvent mixtures. The participation of an ester enolate is emphasized by the formation of condensed diester IV. 

Magensium amides have been prepared and studied for use as bases [31 Eq. (24)]. Unlike lithium amides, these bases are much more thermally stable. The amine derivatives diisopropyl and tetramethylpiperidyl were deprotonated using either ethylmagnesium bromide or dibutylmagnesium. 

Tetramethylpiperidlne, purchased from Tokyo Kasei Kogyo Company, Ltd. or Aldrich Chemical Company, Inc., was used. The use of this sterically-hindered lithium amide is crucial for high diastereoselectivlty. If lithium diisopropyl amide Is used, the diastereoselectivlty of the reaction... 

The first successful attempt to deprotonate a simple alkylborane is shown in equation (12). fi-Methyl-9-BBN (10) was reacted with a variety of lithium amides and the yield of (12) estimated by deuterium incorporation on quenching with D2O. Neither lithium diethylamide nor lithium diisopropyl-amide gave any of (12) at all, but the hindered piperidide (11) (LITMP) produced up to 75% of (12) using 100% excess of base. 

Methyl 3-aminothiophene-2-carboxylate can be easily transformed into the IV,A-dimethyl or N,N-diethyl (but not A,A-diisopropyl) amide by treatment with 2 equiv. of the corresponding lithium amide. The reaction conditions are mild, and the yields are good <92TL6453). Trifluoroacetamides of aminothiophene and aminobenzo[i]thiophene have been prepared by Curtins rearrangement of the corresponding acylazides (toluene or benzene) and treatment of the resultant isocyanates with CFJCO2H at room temperature <92H(34)149>. 

MonofluoToalkanes and vicinal difluoroalkanes are dehydrofluonnated if strong enough bases are applied [10 12] In 5-fluorononane and fluorocyclodo-decane, elimination by means of sodium methoxide in methanol gives cis- and trans allcenes in respective yields of 8 and 21% and in ratios of 1 2 2 2 4, however, the bulky lithium diisopropyl amide m tetrahydrofuran produces trdns-isomers almost exclusively The strength of the base does not have much effect on the rate of elimination, but the lithium cation causes considerable acceleration [10] (equation 10)... 

LDA (Section 21.10) Abbreviation for lithium diisopropyl-amide LiN[CH(CH3)2]. LDA is a strong, sterically hindered base, used to convert esters to their enolates. 

Stork and Takahashi took -glyceraldehyde synthon from the chiral pool and condensed it with methyl oleate, using lithium diisopropyl amide as catalyst for the mixed aldol reaction, leading to The olefinic linkage is a latent form... 

Unlike the parent system, 5-methyl-5//-dibenz[c,e]azepine (1, R1 = Me R2 = H) on treatment with lithium diisopropyl amide fails to yield the tautomeric phenanthridine-imine (see Section 3.2.1.5.4.2.), but forms the 5-carbanion, which on quenching with deuterium oxide furnishes 5-methyl-[5-2H,]-5//-dibenz[e,e]azepine (l).83 5,7-Diphenyl-5//-dibenz[r,e]azepine (1. R1 = R2 = Ph) behaves similarly. In contrast, however, 5,7-dimethyl-5//-dibcnz[c,e]azepine (1, R1 = R2 = Me) yields theazaallyl anion 3, which on addition of deuterium oxide deuterates regiospecifically at the 7-methyl group to give derivative 4. 

The optimum conditions for obtaining a high diastereoselectivity are as follows Deprotonation of the sulfoxide must be carried out at 0 C with lithium diisopropyl amide (1 equiv). a lower temperature probably changes the organization of the lithium species and gives lower diastereoselectivity. The condensation reaction is very fast at —78 C, reaction time is usually around 10 minutes3. 

The stereochemistry of the silyl ketene acetal can be controlled by the conditions of preparation. The base that is usually used for enolate formation is lithium diisopropyl-amide (LDA). If the enolate is prepared in pure THF, the F-enolate is generated and this stereochemistry is maintained in the silyl derivative. The preferential formation of the F-enolate can be explained in terms of a cyclic TS in which the proton is abstracted from the stereoelectronically preferred orientation perpendicular to the carbonyl plane. The carboxy substituent is oriented away from the alkyl groups on the amide base. 

An investigation of lithium diisopropyl amide (LDA) by solid state NMR led to the observation of dramatic differences between the spectra of the solid polymer and the complex crystallized from THF. Li as well as "C and "N MAS spectra showed large sideband patterns in the former case and only a few sidebands in the latter. For both materials X-ray data are available and establish a helix structure for the polymeric material, which is insoluble in hydrocarbon or ethereal solvents, and a dimer structure of the THF complex (25, 26, Scheme 4). The obvious difference between both structures, apart from the solvent coordination in the THF complex, is the magnitude of the structural N-Li-N angle, which is close to 180° in the first case and close to 90° in the second (176° and 107°, respectively). Thus, a large difference for the electric field gradient around the Li cation is expected for the different bonding situations. 

Apparently a substantial spacer is also allowable between the aromatic ring and the carboxy group. Gemfibrozi 1 (52), a iiypotriglyceridemic agent which decreases the influx of steroid into the liver, is a clofibrate homologue. It is made readily by lithium diisopropyl amide-promoted alkylation of sodium iso-propionate with alkyl bromide 51. ... 

An amount of 4.1 equiv of lithium diisopropyl amide (LDA) is absolutely necessary for this reaction to go to completion. An equilibrium exists between the formation of the second anion of the B-keto ester and the formation of lithium diisopropyl amide from diisopropylamine. 

Q ,Q -disubstituted /1-ketoesters like 9, when treated with an alkoxide, can be cleaved into ordinary esters by the reverse of the condensation reaction, the retro-Claisen reaction. However the condensation of esters with only one a-hydrogen is possible in moderate yields by using a strong base, e.g lithium diisopropyl amide (LDA). ... 

Deprotonation of a dihydrothiazine ring, followed by a reaction with an electrophile, is most straightforward in benzothiazin-3-ones (general structure 35), which are deprotonated at the 2-position by lithium diisopropyl amide (LDA). The enolate can then react with a variety of electrophiles including deuterium oxide, methyl iodide, and aldehydes <1982T3059>. Compound 70 was prepared in this manner from 2,4-dimethyldihydro-l,4-benzothiazin-3-one (Equation 27) <1985T569>. 

The regio- and stereoselective alkylations of a number of bicyclic racemic dioxopiperazines have been reported3. For example, dioxopiperazine 9 is deprotonated by lithium diisopropyl-amide in tetrahydrofuran at — 78 °C to yield a monoanion. Alkylation with iodomethane in the presence of hexamethylphosphoric triamide gives products 10 and 11 in a 81 19 ratio and 75 % yield based on recovered starting material3. 

The chiral, nonracemic, 6-monosubstituted bicyclic lactams 1 are deprotonated by a strong base (usually lithium diisopropyl amide) and then alkylated with an iodoalkane or an allylic or benzylic bromide. Alkylation preferentially takes place from the side opposite to that of the substituent R1, which is usually an alkyl or an aryl group. While the diastereomeric ratios may be as low as 75 25, they are most often >90 10 (see Table 9). The minor diastereomer can in most cases be easily removed by liquid chromatography and/or recrystallization to yield the pure major diastereomer. 

---