Lithium diisopropylamide/Butyllithium

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)... 

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

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. 

Because carbonyl compounds are only weakly acidic, a strong base is needed for enolate ion formation. If an alkoxide such as sodium ethoxide is used as base, deprotonation takes place only to the extent of about 0. l% because acetone is a weaker acid than ethanol (pKa - 16). If, however, a more powerful base such as sodium hydride (NaH) or lithium diisopropylamide ILiNO -CjHy ] is used, a carbonyl compound can be completely converted into its enolate ion. Lithium diisopropylamide (LDA), which is easily prepared by reaction of the strong base butyllithium with diisopropylamine, is widely used in the laboratory as a base for preparing enolate ions from carbonyl compounds. 

Several reviews cover hetero-substituted allyllic anion reagents48-56. For the preparation of allylic anions, stabilized by M-substituents, potassium tm-butoxide57 in THF is recommended, since the liberated alcohol does not interfere with many metal exchange reagents. For the preparation of allylic anions from functionalized olefins of medium acidity (pKa 20-35) lithium diisopropylamide, dicyclohexylamide or bis(trimethylsilyl)amide applied in THF or diethyl ether are the standard bases with which to begin. Butyllithium may be applied advantageously after addition of one mole equivalent of TMEDA or 1,2-dimethoxyethane for activation when the functional groups permit it, and when the presence of secondary amines should be avoided. 

Metalation ofa-sulfinyl dimethylhydrazones with terf-butylmagnesium bromide, butyllithium or lithium diisopropylamide, and reaction of the generated azaenolates with aldehydes, provides aldol adducts (e.g., 6) as mixtures of diastereomers. Reductive desulfurization leads to fi-hydroxy dimethylhydrazones (e.g., 7) which are cleaved to the desired /(-hydroxy ketones in 25% overall yield10 u. The enantiomeric excesses are about 50%, except for (- )-3-hydroxy-4-methyl-1-phenyl-1-pentanone (8) which was obtained in 88% ee. 

Generation in situ. Butyllithium (primary, secondary, or tertiary) can be generated by sonication of a mixture of lithium wire and a butyl chloride at 15° in dry THF. The corresponding butane is evolved under these conditions and LiCl precipitates the reaction is generally complete within 15 min. The highly useful lithium diisopropylamide can be prepared by sonication of a mixture of diisopropylamine, lithium, and butyl chloride in dry THF or ether. The yield is 91% and the solution can be used directly for deprotonation. Other lithium amides, even LiTMP, can be prepared in the same way. 

Nearly quantitative generation of l,3-bis(methylthio)allyllithium was proved, as this solution yielded l,3-bis(methyIthio)propene (88-89%) and l,3-bis(methylthio)-l-butene (89%) by reaction with methanol and methyl iodide, respectively. The checkers found that lithium diisopropylamide can be replaced by w-butyllithium without any trouble for the generation of l,3-bis(methylthio)allyllithium, simplifying the procedure considerably at least in this particular case. Subsequent reaction with propionaldehyde gave l,3-bis(methylthio)-l-hexen-4-ol in 85% yield, and no appreciable amount of by-product, such as the addition product of w-hutyllithium with propionaldehyde or with the intermediate 1.3-bis(methylthio)propene, was formed. 

S. (2R,5S)-2-tert-Butyl-5-methyI-l-aza-3-oxabicyclo[3.3.0Joctan-4-one. In a 250-mL, round-bottomed flask equipped with a magnetic stirrer, 18.3 mL (0.131 mol) of diisopropylamine (Note 10) is mixed with 120 mL of dry tetrahydrofuran (THF, Note 11) under argon. At -78°C bath temperature, 88.6 mL of a 1.6 M solution of butyllithium (0.142 mol) in hexane is added and the mixture is allowed to warm to room temperature for 20 min. After the mixture is recooled to -78°C, the lithium diisopropylamide (LDA) solution is added over a period of 20 min (Note 12) to a Solution of 20.0 g (0.109 mol) of (2R,5S)-2-tert-butyl-l-aza-3-oxabicyclo[3.3.0]octan-4-one in 600 mL of dry THF in a 1-L, round-bottomed flask, precooled to -78°C. Tetrahydrofuran (20 mL) is used to rinse the 250-mL flask. After keeping the resulting solution at -78°C tor 45 min, 8.8 mL (0.142 mol) of iodomethane (Note 13) is added Over a period of 10 min. The resulting mixture is allowed to warm to 0°C over a period Of 3 hr, and 300 mL of a saturated aqueous solution of ammonium chloride is added. 

To obtain complete conversion of ketones to enolates, it is necessary to use aprotic solvents so that solvent deprotonation does not compete with enolate formation. Stronger bases, such as amide anion ( NH2), the conjugate base of DMSO (sometimes referred to as the dimsyl anion),2 and triphenylmethyl anion, are capable of effecting essentially complete conversion of a ketone to its enolate. Lithium diisopropylamide (LDA), which is generated by addition of w-butyllithium to diisopropylamine, is widely used as a strong... 

The alkylations are performed in the usual way. Deprotonation is achieved with a strong base, usually lithium diisopropylamide or sometimes butyllithium, added to the amide 1 in tetrahydrofuran at low temperature, usually —78 C7. Sometimes a mixture of solvents is used. To ensure complete enolate formation, warming to 20 °C is usually employed. An excess of alkylating agent is added at —78 or — 20 °C and the products 2 and 3 are isolated in the conventional way (see Tables 7 and 8). 

The chiral complex 2 also requires the use of strong bases to achieve deprotonation no exchange is observed upon treatment with sodium hydroxide-rf/water-dicarbonyl complex 1, monophosphane complexes, such as 2, undergo clean a-deprotonation at — 78 °C with butyllithium or lithium diisopropylamide to generate the enolate 7, which under-... 

Rhenium-acyl complexes, such as 1, are isoelectronic with the iron-acyl complexes discussed above and many reactivity patterns are common to the two groups of compounds. Treatment of complex 1 with strong bases, such as butyllithium or lithium diisopropylamide, results in abstraction of a cyclopentadienyl proton which is followed by rapid migration of the acyl ligand to the cyclopentadienyl ring to produce the metal-centered anion 384. Alkylation of 3generates a metal-alkyl species, such as 4. 

An oven-dried. 50-mL, 3-necked flask equipped wilh a pressure-equalizing dropping funnel, reflux condenser, nitrogen inlet, magnetic stirrer, and vacuum takeoff adapter is evacuated (vacuum pump) and refilled three times with nitrogen. 10 mL of THF and 0.735 mL (5.25 mmol) of diisopropylamine are then added via a double-ended needle. The solution is cooled to 0"C and 2.2 mL of a 2.4 M solution of butyllithium (5.25 mmol) in hexane are added. The lithium diisopropylamide is allowed to form at 0 °C for 15 min and is then cooled to — 20 C. 5 mmol of the chiral acyclic ketone iminc in 5 mL of THF are added (5 min) and anion formation allowed to continue for 1 h at 20 C. The anion solution is then heated to reflux for 2 h and cooled to —78 C. A solution of 5.25 mmol of the iodoalkane in 5 mL of THF is then added, and alkylation is allowed to proceed at — 78 °C for 1 h. Workup and hydrolysis, as described for the cyclic ketones (see Section 1.1.1.4.1.2.L), yields the a-alkylatcd acyclic ketones (see Table 4). 

A solution of 1.05 equiv of butyllithium in hexane (1.6 M) are added dropwise via syringe to a solution of 1.05 equiv of diisopropylaminc in diethyl ether (0.25-0.5 M) under argon at O C and stirred for 15 min lo generate a solution of 1.05 equiv of lithium diisopropylamide. After dropwise addition of 1.0 equiv of the SAMP-hydrazone, the mixture is stirred at 0 °C for 4 h, cooled to — 110 °C, and 1.05 equiv of the electrophile... 

A variety of 2-alkyl-4,5-dihydrooxazoles were prepared from the corresponding chiral 2-methyl-4,5-dihydrooxazole by metalation with butyllithium or lithium diisopropylamide. followed by alkylation with the appropriate alkyl iodide, alkyl bromide or benzyl chloride2. 

As for their achiral analogues13, metalation of chiral 4,5-dihydrooxazoles can be performed with butyllithium, ATt-butyllithium, or lithium diisopropylamide at —78 °C in tetrahydrofuran. 

To a solution of lithium diisopropylamide. prepared from 5.04 mL (35.6 mmol) of diisopropylamine, 22.3 mL (35.6 mmol) of a 1.6 M solution of butyllithium in hexane and 34 mL of THF at —78 C is added dropwise a solution of 5.44 g (32.4 mmol) of ( + )-l-[(R)-ethylsulfinyl]-4-methylbcnzene sulfoxide in 37 mL of THF. A suspension of lithium bromoacetate, prepared from 6.75 mL (48.6 mmol) of bromoacetic acid and 5.15 g (64.84 mmol) of lithium hydride in 50 mL of THF, is added at the same temperature to the yellow solution of the sulfinyl anion. The mixture is stirred for 5 min at — 78 °C, sat. aq NH4C1 is added, and then 10 M hydrochloric acid is added dropwise until the solution reaches pH 2. The mixture is extracted with ethyl acetate, the extracts are concentrated, chromatography of the residue gives the product yield 4.24 g (58%) mp 53-55rC (hexane/diethyl ether). 

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