Exploration of Aryllithium-Derived Copper Reagents for Quaternary-Stereogenic-Center-Forming Allylic Substitution of γ,γ-Disubstituted Secondary Allylic Picolinates

Abstract

The allylic substitution of γ,γ-disubstituted secondary allylic picolinates (esters of 2-PyCO₂H) with aryllithium-based copper reagents was carried out in order to construct quaternary carbons. Initially, 2-methyl-7-phenylhept-2-en-4-yl picolinate was reacted with phenyl copper reagents derived from phenyllithium with Cu(acac)₂, Cu(OMe)₂, CuBr·Me₂S, and CuCN in 1–3:1 ratios in the presence of excess magnesium bromide. Although the S_N2′ product with a quaternary carbon was formed, the regioselectivity was 90% at most. Instead, phenyllithium/copper(I) thiophene-2-carboxylate/magnesium bromide (Ph/Cu = 1.5–2:1, Mg/Li = >1) was found to produce >98% regioselectivity and sufficient reactivity. This system was successful with eight aryllithium based copper reagents possessing sterically congested, electron-donating, or electron-withdrawing substituents. The anti stereochemical course was established by using an enantiomerically enriched geranaldehyde-derived picolinate.

Key words

allylic substitution - aryl lithium - anti S_N2′ - copper reagents - picolinate - quaternary carbon

• References and Notes

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Although being Cu(II) species, Cu(acac)₂ is likely reduced to Cu⁺ species by ArMgBr; see:
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