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Solubility: sol hydrocarbon and ethereal solvents, but should be used at low temperature in the latter solvent type: half-lives in diethyl ether and THF have been reported;10 reacts violently with H2O and other protic solvents.
Preparative Methods: may be prepared in high yield from n-butyl chloride13 or n-butyl bromide14 and Lithium metal in ether or hydrocarbon solvents.
A large number of heteroaromatic compounds,2 such as furans (see Furan),51 thiophenes (eq 7),52 oxazoles,53 and N-alkyl- and N-aryl substituted pyrroles (see 2-Lithio-N-phenylsulfonylindole),54 pyrazoles,55 imidazoles,56 triazoles,57 and tetrazoles,58 are lithiated under various conditions a to the ring heteroatom using n-BuLi. However, pyridine and other nitrogen heteroaromatics bearing the pyridine, pyrimidine, or pyrazine nucleus are generally not lithiated. Indeed, they have a tendency to undergo nucleophilic addition reactions with this reagent1b (see 2-Lithiopyridine).
When the a-position is benzylic, propargylic, or allylic, deprotonation takes place more readily and n-BuLi is generally the reagent of choice for these reactions.59,60 However, the more basic s-Butyllithium is a better reagent for deprotonation of alkyl allyl ethers61 and certain alkyl allyl thioethers62 which react slowly (if at all) with n-BuLi in THF at low temperatures (less than -65 °C).
Proton removal adjacent to a heteroatom is further facilitated if the lithium can be coordinated to proximate electron donors, such as a carbonyl oxygen, permitting the formation of dipole-stabilized carbanions.33 Thus various 2-alkenyl N,N-dialkylcarbamates undergo rapid a-deprotonation adjacent to oxygen on treatment with n-BuLi/TMEDA at -78 °C.63,64 The resulting dipole-stabilized lithium carbanions react with ketones and aldehydes in a highly regioselective fashion providing g-hydroxyalkylated enol esters (eq 8) which, following cleavage of the carbamoyl moiety (Titanium(IV) Chloride/H2O or MeOH), afford d-hydroxy carbonyl compounds (homoaldols) as lactols or lactol ethers.65 Similarly, aliphatic or aromatic amides66,67 (eq 9),67a phosphoramides,68 and some formamidine derivatives (e.g. 1,2,3,6-tetrahydropyridine,69 thiazolidine,69 1,3-thiazine,69 and tetrahydroisoquinolines70) are selectively lithiated a to the nitrogen at the activated position. Electrophilic substitution of the intermediate organolithiums followed by hydrolytic cleavage of the amide or formamidine group provides a synthetically valuable route to a-substituted (or g-substituted69) secondary amines.33 Use of the more basic s-BuLi (or t-Butyllithium) is generally required for deprotonation of the analogous nonbenzylic or nonallylic systems.
Formation of Enolate Anions and Enolate Equivalents.
Owing to its tendency to undergo nucleophilic addition with carbonyl groups and other electrophilic carbon-heteroatom multiple bonds (C=NR, C&tbond;N, C=S),1 n-BuLi is usually not the reagent of choice for the generation of enolate anions or enolate equivalents from active hydrogen compounds. This is done most conveniently using the less nucleophilic lithium dialkylamides (e.g. Lithium Diisopropylamide (LDA), Lithium 2,2,6,6-Tetramethylpiperidide (LiTMP), and Lithium Hexamethyldisilazide (LTSA)) prepared (often in situ) from sterically hindered secondary amines, typically by treatment with n-BuLi.93 However, less reactive carbonyl compounds such as amides (eq 14)94 and carboxylic acids95 as well as those containing carbon-nitrogen or carbon-sulfur multiple bonds, e.g. imines,96 oxazines,97 nitriles,98 some hydrazones,99 and thioamides,100 can be lithiated a to the electrophilic carbon with n-BuLi under various conditions. b-Keto esters can be alkylated at the a�-carbon using Sodium Hydride for the first deprotonation and n-BuLi for abstraction of the less acidic a�-proton followed by addition of alkyl halides.101 Lithiation of unsymmetrical imines using n-BuLi takes place regioselectively at the most substituted a-carbon (eq 15).96 In contrast, LDA directs metalation and subsequent alkylation predominantly to the less substituted a-position in similar systems.102 Lithium enolates of camphor imine esters, prepared by addition of n-BuLi, undergo highly diastereoselective Michael additions with a,b-unsaturated esters (eq 16).103 The tightly chelated structures of the intermediate enolates permit selective re face approach of the Michael acceptors, giving rise to the high degree of distereoselectivity observed.
Metal-Halogen Interchange and Transmetalation Reactions.
s-Butyllithium; t-Butyllithium; n-Butyllithium-Boron Trifluoride Etherate; n-Butyllithium-Potassium t-Butoxide; Methyllithium; Tungsten(VI) Chloride-n-Butyllithium.
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