Enantioselective Alkylation of 2-Alkylpyridines Controlled by Organolithium Aggregation

Abstract

Direct enantioselective α-alkylation of 2-alkylpyridines provides access to chiral pyridines via an operationally simple protocol that obviates the need for prefunctionalization or preactivation of the substrate. The alkylation is accomplished using chiral lithium amides as noncovalent stereodirecting auxiliaries. Crystallographic and solution NMR studies provide insight into the structure of well-defined chiral aggregates in which a lithium amide reagent directs asymmetric alkylation.

Regioselective Benzylic C–H Alumination and Further Functionalization of 2-Alkylpyridines by Yttrium Catalyst

“…Among various existing approaches for the synthesis of alkylpyridines with some complicated or functionalized structures, one of the most frequently used methods is to apply benzylic C–H bond functionalization to more simple and readily available alkylpyridines, such as 2,6-lutidine. By treating an alkylpyridine with a stoichiometric amount of a strong base, such as n BuLi, deprotonation of a benzylic C–H bond can easily occur to afford a benzylic anion, which can participate in nucleophilic substitution/addition to some reactive electrophiles, such as alkyl halides and carbonyl groups . Moreover, by the use of Pd-, Ir-, or Ni-catalysts, such benzylic anions can also react with relatively weak electrophiles, such as aryl halides and allylic esters/carbonates, to afford the corresponding arylated and allylic alkylated products.…”

A monomeric methyllithium complex: synthesis and structure

“…Since Wilhelm Schlenk and Joanna Holtz's pioneering work in 1917, 1 organolithium complexes (RLi; R: alkyl, aryl, alkenyl, alkynyl) have enabled numerous organic, inorganic, organometallic and polymerisation reactions, acting as the cornerstone of organometallic chemistry, [2][3][4][5] and is still an active research frontier. 6 RLi complexes exist as aggregates in solutions and solid-state. [7][8][9][10][11] On the one hand, these aggregates stabilise the highly polar and reactive Li-C bond; but in general, the aggregates also deactivate the RLi reagents.…”

Synthesis, Structure, and DFT Analysis of the THF Solvate of 2‐Picolyllithium: A 2‐Picolyllithium Solvate with Significant Carbanionic Character

“…Evidence of the importance of functionalizing the pyridine scaffold stems from the impressive statistic that it is the second most frequently encountered nitrogen‐based heterocycle in pharmaceuticals (behind its saturated derivative piperidine) with over 60 % of these pyridines exhibiting C2 substitution . Pyridines possessing alkyl substituents at the 2‐position are particularly important ligands in asymmetric catalysis . These compounds can trace their Celtic routes back to 19th Century Glasgow where Anderson first obtained picoline from the distillation of coal tar in 1846 and Sir William Ramsay refined a successful early synthetic procedure in the 1870's .…”

“…[2] Pyridines possessing alkyl substituents at the 2-position are particularly important ligands in asymmetric catalysis. [3] These compounds can trace their Celtic routes back to 19th Century Glasgow where Anderson first obtained picoline from the distillation of coal tar in 1846 [4] and Sir William Ramsay refined a successful early synthetic procedure in the 1870's. [5] Inorganic groups can also be grafted onto the 2-position following a metallation-metathesis process as recently illustrated through the synthesis of 2-borylmethylpyridines, such as C 5 H 4 N-CH 2 -B(C 6 F 5 ) 2 .…”