Lithiation-substitution of nitrogen-containing heterocycles

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Asymmetric lithiation-substitution reactions involve the generation of an organolithium species followed by trapping with an electrophile in an enantioselective manner.[1] Most typically, the substrate is a nitrogen-containing heterocycle linked to a directing group such as tert-butoxycarbonyl (Boc). The substrate is first mixed with a strong organolithium base and a chiral ligand; the resulting organolithium species is then treated with an electrophile such as a silyl chloride or metal halide salt. This method has been applied in organic synthesis for the efficient and highly enantioselective construction of tetrahedral stereocenters linked to nitrogen or oxygen.

Two distinct mechanisms are known for enantioselective lithiation-substitution reactions of nitrogen-containing heterocycles. In the asymmetric deprotonation pathway, the organolithium base is rendered chiral by coordination to the chiral ligand and as such it can distinguish between a pair of enantiotopic protons in the substrate. Selective removal of one of the two protons affords a chiral and configurationally stable organolithium intermediate, which undergoes substitution with retention of configuration. In the asymmetric substitution pathway, a racemic organolithium intermediate is first generated via treatment of the substrate with sec-butyllithium and TMEDA. Subsequent addition of a chiral ligand facilitates a dynamic resolution process, in which diastereomeric (and rapidly interconverting) organolithium species react at different rates with an added electrophile.


  1. O'Brien, P.; Kasten, K.; Seling, N. Org. React. 2019, 100, 5. (link)