[4442-11-9] · C5H10LiN · Lithium Piperidide · (MW 91.10)
(nucleophilic base used to probe aromatic substitution and benzyne-type reactions;1-7 useful base to effect elimination of dihalocarbenoids to prepare a-halo ketones,8 dichloro alkenes,9 and chloro alkynes9)
Preparative Method: lithium piperidide in piperidine is prepared by adding a calculated amount of standardized Phenyllithium or n-Butyllithium in hexane to a solution of Piperidine (dried over KOH or activated alumina and distilled from KOH or sodium) in DME or Et2O at 0 °C under an inert atmosphere.1
Handling, Storage, and Precautions: best prepared in situ prior to use. Use in a fume hood.
In 1956, Wittig2 used lithium piperidide to explore benzyne formation. Its dual properties of strong basicity and nucleophilicity have led to the use of lithium piperidide as a probe for exploring nucleophilic aromatic substitution via the addition-elimination and benzyne pathways on a range of systems (haloimidazoles,3 -pyridines,4 -quinazolines,5 -benzenes6); for example, substitution of 1- and 3-bromo-10-methylacridones1 (eq 1) is not accompanied by rearrangement and presumably proceeds entirely by the addition-elimination mechanism (Table 1).
2-Bromo-10-methylacridone reacts with lithium piperidide in piperidine at 27 °C much more slowly than the 1- and 3-isomers to give rearrangement products, indicating the intermediacy of arynes (1) and (2); the direction of addition is controlled by the inductive effect of the heterocyclic nitrogen atom and the carbonyl group.
Reaction of lithium piperidide with methoxy aromatics in refluxing THF leads to products resulting from direct ipso substitution (eq 2).7
Lithium b-alkoxy carbenoids are quite unstable even at -120 °C and undergo a-elimination.8 A subsequent migration of a group from the neighboring alkoxy carbon to the carbenoid center leads to the formation of an a-bromo enolate and constitutes a facile one-step preparation of a-halo ketones (eq 3). It is particularly suitable for the synthesis of C
b-Silyloxy carbenoids,9 however, generally undergo b-elimination, leading to the formation of dihalo alkenes which, with excess base, undergo elimination to halo alkynes in good yields (eq 5).
Carbamoyl- and acyllithium species are potentially useful intermediates, but their instability has prompted an extensive search for their synthetic equivalents. Widdowson12 has shown that the carbamoyl anions, produced by bubbling carbon monoxide into a solution of lithium piperidide in THF (-78 °C), can be
bottled as the corresponding carbamoyltin reagents (eq 6). These are useful in Stille13 cross-coupling reactions, yielding a variety of aroyl, alkenoyl, and hetaroyl amides in good yields (eq 7). This may be useful for the synthesis of 11C-labeled compounds for biological and clinical studies, such as positron emission tomography.14
Victor Snieckus & Mark Rogers-Evans
University of Waterloo, Ontario, Canada