Organolithium reagents, reaction with amides

CARBONYL ADDITIONS, CERIUM(III) CHLORIDE-PROMOTED, 76, 237 Carbonyl compounds, reactions with organolithiums or Grignard reagents, 76, 228 Carboxylic acid amides, 77, 27 Cells, storage of, 76, 80 Centrifugation, 76, 78... 

Pyridine is an aromatic 6n electron heterocycle, which is isoelectronic with benzene, but electron deficient. Nucleophiles thus add almost invariably to carbon C2 of the imine-like C=N double bond. Perhaps the best known nucleophilic addition is the Chichibabin reaction with sodium amide in liquid ammonia, giving 2-aminopyr-idine. Reactions of the quinoline moiety of cinchona alkaloids can be more complex. Although expected 2 -addition can be achieved easily with organolithium reagents to yield 13 (Scheme 12.6) [9], LiAlH4, for example, has been shown to attack C4 en route to quincorine and quincoridine (Schemes 12.4 and 12.5). C4 selectivity is due to chelation of aluminum by the C9 OH oxygen. 

Alkyltriphenylphosphonium halides are only weakly acidic, and a strong base must be used for deprotonation. Possibilities include organolithium reagents, the anion of dimethyl sulfoxide, and amide ion or substituted amide anions, such as LDA or NaHMDS. The ylides are not normally isolated, so the reaction is carried out either with the carbonyl compound present or with it added immediately after ylide formation. Ylides with nonpolar substituents, e.g., R = H, alkyl, aryl, are quite reactive toward both ketones and aldehydes. Ylides having an a-EWG substituent, such as alkoxycarbonyl or acyl, are less reactive and are called stabilized ylides. 

Conversions of carboxylic acids to ketones are typically performed in stepwise fashion6 via intermediates such as acid chlorides,7 anhydrides,8 thioesters,9 or N-alkoxy amides,10 or by the direct reaction of carboxylic adds with lithium reagents.11 In this latter method trimethylsifyl chloride has been shown to be an effective reagent for trapping the tetrahedral alkoxide intermediates and for quenching excess organolithium reagent. 

Reactions of Esters Esters are much more stable than acid chlorides and anhydrides. For example, most esters do not react with water under neutral conditions. They hydrolyze under acidic or basic conditions, however, and an amine can displace the alkoxyl group to form an amide. Lithium aluminum hydride reduces esters to primary alcohols, and Grignard and organolithium reagents add twice to give alcohols (after hydrolysis). 

The high propensity of organolithium compounds to form mixed complexes with other organolithium species in solution has been utilized successfully in synthesis using chiral lithium amides. Either the chiral lithium amides have been added to organolithium reagents in an effort to achieve asymmetry in addition reactions, or various additives have been introduced to alter the reactivity or selectivity of the chiral lithium amides themselves, e.g. in deprotonation reactions. 

The presence of the phenyl ring is not essential for the carbometallation to proceed. For example, treatment of diallylamines, or related systems, with alkyllithium reagents leads to several trianionic intermediates [87] (Scheme 7-74). The interaction of the lithium atom of the amide with the alkyl group of the organolithium reagent together with the simultaneous proximity effect allows the coordination of the double bond to the lithium atom and consequently the addition reaction occurs. 

A(-(Arylthiomethyl)amines, which are easily prepared and reportedly have better shelf stability than the corresponding )V-(alkoxymethyl)amines, have also been utilized to prepare tertiary amines. Alkenyl cuprate addition to )V,A -diethylphenylthiomethylamine produces allylic amines in high yield (entry 1, Table 6). Both alkenyl groups of the cuprate react. 5-(Dialkylaminomethyl) dithiocarbamates (entry 2, Table 6), sulfonates (entry 3, Table 6) and amides also generate iminium salts in situ. Of a variety of amides examined, imides such as dialkylaminomethyl-succinimides (entry 4, Table 6) and -phthali-mides provide the best overall yields. Organolithium reagents are rarely utilized in aminomethylation reactions. However, )V-chloromethylamines condense readily with lithiated anisole derivatives (entry S, Table 6). ... 

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