Diisopropylamide, lithium

J-BuOK in 80 ml of THF is added dropwise with moderate rate of stirring (Note 1). During this addition, which takes about 10 minutes, the internal temperature is maintained closely around —100 °C. The complex is a clear solution having the same light-yellow colour as the solution of butyllithium in hexane. It can - and should - be used directly after its preparation. When the solution is kept for 2 h at — 65 °C and diethyl disulfide is added subsequently, (2-ethylthio)tetrahydrofuran, (b.p. 56°/14mmHg, n 0 1.4838), is obtained in 70% yield. Above —40 °C the a-potassiated tetrahydrofuran undergoes a rapid cycloelimination with formation of ethene and potassium ethenolate (H2C=CH—OK). 

In the case of vigorous stirring the solution is swept up to the upper part of the flask, where the glass is less cooled, so that reaction with the THF may occur. 

4 Butyllithium, Complexed with Sodium- or Potassium f-Butoxide and TMEDA in Hexane or Pentane 

10 Mol (9.6 or 11.3 g) of powdered sodium or potassium f-butoxide and 50 ml of hexane or pentane are placed into the flask. The mixture is cooled to — 70 °C and a solution of 0.10 mol of butyllithium in 70 ml of hexane is added over a few seconds with efficient stirring. The suspension is then cooled to —40 °C and 0.10 mol of TMEDA is added in one portion. In the case of sodium terf-butoxide a homogeneous solution is formed, the addition of TMEDA to the BuLi-potassium teH-butoxide mixture results in a fine suspension. The mixtures are kept below — 30 °C since at 0 °C or higher the TMEDA is attacked by the base. 

A solution of 0.055 mol (Note 1) of butyllithium in hexane (38 ml) is added (using a syringe) to a flask containing 40 ml of Et20 or THF and cooled to below 0 °C. Subsequently a mixture of 0.055 mol (5.5 g) of diisopropylamine and 20 ml of THF or Et20 is added dropwise over a few minutes. Temperature control during this addition is not essential however,in the metallation reaction, which is usually carried out with the lithium dialkylamide at low temperatures, the solution may be cooled to 0 °C or lower. The formation of LDA is very fast, even in the temperature 

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J. Rebek, Jr., (1987) first developed a new synthesis of Kemp s acid and then extensively explored its application in model studies. The synthesis involves the straightforward hydrogenation (A. Steitz, 1968), esterification and methylation of inexpensive 1,3,5-benzenetricar-boxylic acid (trimesic acid 30/100 g). The methylation of the trimethyl ester with dimethyl sulfate, mediated by lithium diisopropylamide (V. J. Shiner, 1981), produced mainly the desired aff-cis-1,3,5-trimethyl isomer, which was saponified to give Kemp s acid. 

Lithium diisopropylamide is a strong enough base to abstract a proton from the a carbon atom of an ester but because it is so sterically hindered it does not add readily to the carbonyl group To illustrate... 

Lithium diisopropylamide is commercially available Alternatively it may be prepared by the reaction of butyllithium with [(CH3)2CH]2NH (see Problem 14 4a for a related reaction)... 

Section 21 10 It is possible to generate ester enolates by deprotonation provided that the base used is very strong Lithium diisopropylamide (LDA) is often used for this purpose It also converts ketones quantitatively to their enolates... 

Metahation of 2-fluoropyridine with lithium diisopropylamide (LDA) gives 2-fluoro-3-hthiopyridine, thereby providing entry to 3-substituted pyridines (388). This technique has been used to make fluorine analogues of the antitumor eUipticines (389). 

Cyclization can be achieved under much milder conditions by using -butyllithium or lithium diisopropylamide to form a dilithio derivative of the anilide (28). 

Lithium acetyhde also can be prepared directly in hquid ammonia from lithium metal or lithium amide and acetylene (134). In this form, the compound has been used in the preparation of -carotene and vitamin A (135), ethchlorvynol (136), and (7j--3-hexen-l-ol (leaf alcohol) (137). More recent synthetic processes involve preparing the lithium acetyhde in situ. Thus lithium diisopropylamide, prepared from //-butyUithium and the amine in THF at 0°C, is added to an acetylene-saturated solution of a ketosteroid to directly produce an ethynylated steroid (138). 

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. 

The i -alkoxycarbonyhnethylxanthate esters treated with lithium diisopropylamide (LDA) and an aldehyde or ketone give excellent yields of a,P-unsaturated esters (56) ... 

Although less researched than the 2-position, modifications at the 6-position of intact penems have been reported. Generation of the dianion of the penem (52, R = CH ) using a strong base such as / -butyUithium or lithium diisopropylamide, followed by reaction with electrophiles yields 6-substituted 2-methylpenems in moderate yield (128). The enhanced acidity of the 6-proton in the bromopenem (88) [114409-16-4] h.a.s been exploited to prepare the... 

Side-chain lithiation with lithium diisopropylamide and subsequent alkylation or acylation is a practical method for the preparation of various alkyl-, alkenyl- and acyl-methyl-pyridazines 78CPB2428, 78CPB3633, 79CPB916) (Scheme 47). 

There are some recent examples of this type of synthesis of pyridazines, but this approach is more valuable for cinnolines. Alkyl and aryl ketazines can be transformed with lithium diisopropylamide into their dianions, which rearrange to tetrahydropyridazines, pyrroles or pyrazoles, depending on the nature of the ketazlne. It is postulated that the reaction course is mainly dependent on the electron density on the carbon termini bearing anionic charges (Scheme 65) (78JOC3370). 

N-Alkylations, especially of oxo-di- and tetra-hydro derivatives, e.g. (28)->(29), have been carried out readily using a variety of reagents such as (usual) alkyl halide/alkali, alkyl sulfate/alkali, alkyl halide, tosylate or sulfate/NaH, trialkyloxonium fluoroborate and other Meerwein-type reagents, alcohols/DCCI, diazoalkanes, alkyl carbonates, oxalates or malon-ates, oxosulfonium ylides, DMF dimethyl acetal, and triethyl orthoformate/AcjO. Also used have been alkyl halide/lithium diisopropylamide and in one case benzyl chloride on the thallium derivative. In neutral conditions 8-alkylation is observed and preparation of some 8-nucleosides has also been reported (78JOC828, 77JOC997, 72JOC3975, 72JOC3980). 

The reaction of 3,5-diphenyl-2-isoxazoline with lithium diisopropylamide produced with 2 equivalents of base a chalcone oxime, while in the presence of 1 equivalent and an alkyl iodide, ring alkylation occurred at the 4-position of the nucleus (Scheme 48) (80LA80, 78TL3129). 

Most applications of this derivative have been for the preparation and modification of amino acids, although some applications in the area of carbohydrates have been reported. The derivative is stable to n-butyllithium and lithium diisopropylamide. 

The vinyl group has been used to protect the nitrogen of benzimidazole during metalation with lithium diisopropylamide. It is introduced with vinyl acetate [Hg(OAc)2, H2SO4, reflux, 24 h] and cleaved by ozonolysis (MeOH, —78°). ... 

The TBDMS derivative of a /3-lactam nitrogen is reported to be stable to lithium diisopropylamide, citric acid, Jones oxidation, and BH3-diisopropylamine, but not to Pb(OAc)4 oxidation. 

Lithium diisopropylamide [4111-54-0] M 107.1, b 82-84 /atm, 84 /atm, d 0.722, flash point -6 . It is purified by refluxing over Na wire or NaH for 30min and then distilled into a receiver under... 

Common reagents such as lithium diisopropylamide (LDA see Chapter 11, Problem 5) react with carbonyl compounds to yield lithium enolate salts and diisopropylamine, e.g., for reaction with cyclohexanone. 

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