Lithium Reagents

There are a wide variety of methods for introduction of substituents at C3. Since this is the preferred site for electrophilic substitution, direct alkylation and acylation procedures are often effective. Even mild electrophiles such as alkenes with EW substituents can react at the 3-position of the indole ring. Techniques for preparation of 3-lithioindoles, usually by halogen-metal exchange, have been developed and this provides access not only to the lithium reagents but also to other organometallic reagents derived from them. The 3-position is also reactive toward electrophilic mercuration. 

Quantitative Analysis of All llithium Initiator Solutions. Solutions of alkyUithium compounds frequentiy show turbidity associated with the formation of lithium alkoxides by oxidation reactions or lithium hydroxide by reaction with moisture. Although these species contribute to the total basicity of the solution as determined by simple acid titration, they do not react with allyhc and henzylic chlorides or ethylene dibromide rapidly in ether solvents. This difference is the basis for the double titration method of determining the amount of active carbon-bound lithium reagent in a given sample (55,56). Thus the amount of carbon-bound lithium is calculated from the difference between the total amount of base determined by acid titration and the amount of base remaining after the solution reacts with either benzyl chloride, allyl chloride, or ethylene dibromide. 

In contrast to pyridine chemistry, the range of nucleophilic alkylations that can be effected on neutral azoles is quite limited. Lithium reagents can add at the 5-position of 1,2,4-oxadiazoles (Scheme 16) (70CJC2006). Benzazoles are attacked by organometallic compounds at the C=N a-position unless it is blocked. 

JV-Fluoro-Z -t-butylbenzenesulfanamide (Table 3a, A) reacts with t iny/lithium reagents prepared from lodoalkenes to give high yields of fluoroalkenes with higli stereoselectivity [84] (Table 4)... 

Alkyltrifluorosilanes and disubstituted difluorosilanes are themselves quite reactive with nucleophiles such as lithium amide bases [102, 103 104], alkyl-lithium reagents [1051, Gngnard reagents [105], or alkoxides [105] (equations 82 and 83)... 

All that has been said in this section applies with equal force to the use of organo-lithium reagents in the synthesis of alcohols. Grignard reagents are one source of nucleophilic carbon organolithium reagents are another. Both have substantial carbanionic char acter in their- car bon-metal bonds and undergo the same kind of reaction with aldehydes and ketones. 

Reaction of Iminium Salts with Lithium Reagents... 

Grignard and alkyl lithium reagents were found to add to the carbonyl group of a tricyclic vinylogous amide. However, the same compound underwent the usual vinylogous reduction with lithium aluminum hydride (712). Grignard additions to di- and trichloroenamines gave a-chloro- and dichloroketones (713). 

The in situ generation of the carbon dioxide adduct of an indole provides sufficient protection and activation of an indole for metalation at C-2 with r-butyl-lithium. The lithium reagent can be quenched with an electrophile, and quenching of the reaction with water releases the carbon dioxide. ... 

Alkylation of 1-indanone with 2-dimethylaminoethyl chloride affords the substituted ketone (1). Condensation with the lithium reagent obtained from 2-ethylpyridine affords the alcohol (2). Dehydration under acidic conditions gives dimethyl-pyrindene (3). ... 

Under a nitrogen atmosphere 0.23 g (1 mmol) of tm-butyl (S)-4-formyl-2,2-dimethyl-3-oxazolidinecar-boxylate(3) is dissolved in 5 mL ofabs. THF. The clear solution is stirred, cooled to —78 °C, then a solution of 1.3 mmol of the Grignard or lithium reagent is added dropwise. The mixture is stirred at — 78 °C for a further 1 h, then quenched by the addition of 20 mL of sat. aq NH4C1. After dilution with II20 the aqueous... 

The addition of aziridinyl anions to aldehydes gave the alcohols 31 in good yields15. As with the oxiranyl anions, the diastereoselectivity of the addition reaction could be substantially enhanced by transmetalation of the lithium reagent with chlorotris(dimethylamino)titanium. 

Addition reactions of the a-seleno lithium reagent 26 to carbonyl compounds have been undertaken 27. The a-seleno lithium reagents are configurationally labile at — 78 °C 27 28 and, therefore, the diastereoselectivity observed with 26 ( 90 10) does not significantly depend on the nature of the electrophile but rather reflects the thermodynamic ratio of the diastereomeric lithium compounds. 

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