N-Butyllithium

These conditions are so harsh that they are applicable only to indoles with the most inert substituents. Cyclization can be achieved at much lower temperatures by using alkyllithium reagents as the base. For example, treatment of o-methylpivalanilide with 3 eq. of n-butyllithium at 25 C gives 2-terr-butylindole in 87% yield[2]. These conditions can be used to make... 

A stirred solution of o-methylpivalanilide (50 mmol) in dry THE (100 ml) was maintained at 15°C under a nitrogen atmosphere. A 1.5 M solution of n-butyllithium in hexane (3 equiv.) was added dropwise. The solution was then maintained at room temperature for 16h. The solution was cooled in an ice-bath and treated with 2 N HCl (60 ml). The organic layer was separated and the aqueous layer was further extracted with benzene. The combined layers were dried (MgS04). The product was obtained in 87% yield and recrystallized from ether-cyclohexane. 

Another o-aminobenzyl anion equivalent is generated by treatment of A-trimethylsilyl-o-toluidinc with 2.2 eq. of n-butyllithium. Acylation of this intermediate with esters gives indoles[2]. This route, for example, was used to prepare 6.2D, a precursor of the alkaloid cinchonamine. 

In a related procedure A -melhyl-o-loluidine can be A-lithiated, carboxylated and C-lithiated by sequential addition of n-butyllithium, CO2, and n-butyl-lithium[5]. The resulting dilithiated intermediate reacts with esters to give 1.2-disubstituted indoles. 

The 2-[2-thienyl]selenazole is formylated in the 5-position by action of n-butyllithium. dimethyl formamide. and hydrolysis (106). 

Benzylthiazole reacts with n-butyllithium to give 2- and 5-substituted products, but as expected from the particular properties of the 2-methyiene group, the proportion of 2-lithium derivatives is much more important (223). 

Methylthiophene is metallated in the 5-position whereas 3-methoxy-, 3-methylthio-, 3-carboxy- and 3-bromo-thiophenes are metallated in the 2-position (80TL5051). Lithiation of tricarbonyl(i7 -N-protected indole)chromium complexes occurs initially at C-2. If this position is trimethylsilylated, subsequent lithiation is at C-7 with minor amounts at C-4 (81CC1260). Tricarbonyl(Tj -l-triisopropylsilylindole)chromium(0) is selectively lithiated at C-4 by n-butyllithium-TMEDA. This offers an attractive intermediate for the preparation of 4-substituted indoles by reaction with electrophiles and deprotection by irradiation (82CC467). 

Trialkyl- and triaryl-phosphines react with 1,3-benzodithiolylium ions to give a phos-phonium salt which is deprotonated by n-butyllithium to give (221) (76TL3695). 

Modification of functional groups incorporated in a heterocycle is possible via ylide reactions. The 5-methylisoxazole (578) on reaction with n-butyllithium and methanesulfenyl... 

The isoxazoles (585) were formed regioselectively from the (dioxoalkyl)phosphonium salts (584) with hydroxylamine hydrochloride, the direction of cyclization being different from that of the nonphosphorus-containing 1,3-dioxo compound (see Chapter 4.16). Aqueous sodium hydroxide converted (585) into the isoxazole (586) and triphenylphosphine oxide. Treatment of (585) with n-butyllithium and an aldehyde gave the alkene (587). With hydrazine or phenylhydrazine analogous pyrazoles were formed (80CB2852). 

Recently (82CC450) the conversion of aromatic hydrazides into indazolones in good yield when treated with three equivalents of n-butyllithium has been described. For example, benzoylhydrazine afforded indazolone in an 80% yield (Scheme 51). 

The ring opening of 3-substituted isoxazoles proceeds differently, and the reaction can take various courses depending on the nature of the substituent. The reaction has been effected by sodium hydroxide and sodium ethoxide in alcoholic or aqueous media and by sodium amide and also n-butyllithium in inert solvents. 

Thiophene, bromotetrahydromethyl-pyrolysis, 3, 902 Thiophene, 5-t-butyl-2-methyl-dealkylation, 4, 800 Thiophene, chloro-polymerization, 4, 758 reaction with n-butyllithium, 4, 831 synthesis, 4, 835, 882, 933 Thiophene, 2-chloromercurio-reactions... 

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. 

N,N-Dimethy1aniline from Nakarai Chemicals was dried over calcium hydride and freshly distilled. Three molar equivalents of N,N-dimethylaniline are used to achieve complete conversion of the n-butyllithium, because In the present particular case free n-butyllithium, if present, causes the isomerization of the (Z)-alkene to the (E)-isomer. 

Ether was distilled from sodium ketyl of benzophenone. The dissolution of n-butyllithium in ether was slightly exothermic. 

Methyl-2-propen-l-ol, purchased from Aldrich Chemical Company, was distilled from anhydrous potassium carbonate. It was added directly to the n-butyllithium solution using a long needle. The checkers quickly replaced the pressure-equalizing dropping funnel with a serum cap to carry out this addition. The funnel was fitted to a small dry flask to prevent the introduction of moisture during the addition period and replaced on the reaction flask immediately afterwards. 

A variable pressure oil pump was used in this distillation. Approximately 10 g of a volatile component, consisting mostly of hexamethyl-disiloxane, was obtained at room temperature (15 (in) before the forerun. The forerun contained the desired product and mineral oil from the n-butyllithium solution. The pot residue was about 5 g. The submitters find the disilyl compound thus obtained is contaminated with a trace amount of mineral oil and 4-6% of a vinylsilane, probably 2-methyl-l-trimethylsiloxy-3-trimethylsilyl-2-propene. This impurity becomes quite significant if the reaction medium is less polar than the one described (e.g., too much hexane from n-butyllithium is allowed to remain behind). The spectral properties of the desired product... 

Fig. 7.2. Crystal structures of n-butyllithium. (A) (n-BuLi TMEDA)2 (B) (n-BuLi THF)4 hexane (C) [n-BuLi DME4] (D) [(n-BuLi TMEDA]. Hydrogen atoms have been omitted. (RcprcvJuccd from./ Am. Chem. Soc., 115, 1568, 1873 (1993).

The conjugate base of 1,3-dithiane has proven valuable in synthetic applications as a nucleophile (Part B, Chapter 13). The anion is generated by deprotonation using n-butyllithium ... 

Most other studies have indicated considerably more complex behavior. The rate data for reaction of 3-methyl-l-phenylbutanone with 5-butyllithium or n-butyllithium in cyclohexane can be fit to a mechanism involving product formation both through a complex of the ketone with alkyllithium aggregate and by reaction with dissociated alkyllithium. Evidence for the initial formation of a complex can be observed in the form of a shift in the carbonyl absorption band in the IR spectrum. Complex formation presumably involves a Lewis acid-Lewis base interaction between the carbonyl oxygen and lithium ions in the alkyllithium cluster. 

Kyba and eoworkers prepared the similar, but not identical compound, 26, using quite a different approach. In this synthesis, pentaphenylcyclopentaphosphine (22) is converted into benzotriphosphole (23) by reduction with potassium metal in THF, followed by treatment with o "t/20-dichlorobenzene. Lithium aluminum hydride reduction of 23 affords l,2-i>/s(phenylphosphino)benzene, 24. The secondary phosphine may be deprotonated with n-butyllithium and alkylated with 3-chlorobromopropane. The twoarmed bis-phosphine (25) which results may be treated with the dianion of 24 at high dilution to yield macrocycle 26. The overall yield of 26 is about 4%. The synthetic approach is illustrated in Eq. (6.16), below. 

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