Anion Radical [2 + 2] Cycloaddition as a Mechanistic Probe:
Stoichiometry- and Concentration-Dependent Partitioning of
Electron-Transfer and Alkylation Pathways in the Reaction of the
Gilman Reagent Me<sub>2</sub>CuLi·LiI with Bis(enones)
Jingkui Yang
David F. Cauble
Adam J. Berro
Nathan L. Bauld
Michael J. Krische
10.1021/jo048499t.s002
https://acs.figshare.com/articles/journal_contribution/Anion_Radical_2_2_Cycloaddition_as_a_Mechanistic_Probe_Stoichiometry_and_Concentration_Dependent_Partitioning_of_Electron_Transfer_and_Alkylation_Pathways_in_the_Reaction_of_the_Gilman_Reagent_Me_sub_2_sub_CuLi_LiI_with_Bis_enones_/3315973
Exposure of easily reduced aromatic bis(enones) <b>1a</b><b>−</b><b>1e</b> to the methyl Gilman reagent Me<sub>2</sub>CuLi·LiI at 0 °C in tetrahydrofuran solvent provides the products of tandem conjugate addition−Michael
cyclization, <b>2a</b><b>−</b><b>2e</b>, along with the products of [2 + 2] cycloaddition, <b>3a</b><b>−</b><b>3e</b>. Complete partitioning
of the Gilman alkylation and [2 + 2] cycloaddition pathways may be achieved by adjusting the
loading of the Gilman reagent, the rate of addition of the Gilman reagent, and the concentration
of the reaction mixture. The Gilman alkylation manifold is favored by the rapid addition of excess
Gilman reagent at higher substrate concentrations, while the [2 + 2] cycloaddition manifold is
favored by slow addition of the same Gilman reagent at lower concentrations and loadings. Notably,
[2 + 2] cycloaddition to form <b>3a</b><b>−</b><b>3e</b> is catalytic in Gilman reagent. Kinetic data reveal that the
ratio of <b>2a</b> and <b>3a</b> changes such that the cycloaddition pathway becomes dominant upon increased
consumption of Gilman reagent. These data suggest a concentration-dependent speciation of the
Gilman reagent and differential reactivity of the aggregates present at higher and lower
concentrations. While the species present at higher concentration induce Gilman alkylation en
route to products <b>2a</b><b>−</b><b>2e</b>, the species present at lower concentration provide products of catalytic
[2 + 2] cycloaddition, <b>3a</b><b>−</b><b>3e</b>. Moreover, upon electrochemical reduction of the bis(enones) <b>1a</b><b>−</b><b>1e</b>,
or chemically induced single-electron transfer from arene anion radicals, the very same [2 + 2]
cycloadducts <b>3a</b><b>−</b><b>3e</b> are formed. The collective data suggest that [2 + 2] cycloadducts <b>3a</b><b>−</b><b>3e</b> arising
under Gilman conditions may be products of anion radical chain cyclobutanation that derive via
electron transfer (ET) from the Me<sub>2</sub>CuLi·LiI aggregate(s) present at low concentration. These
observations provide a link between the Gilman alkylation reaction and related ET chemistry and
suggest these reaction paths are mechanistically distinct. This analysis is made possible by the
recent observation that easily reduced bis(enones) are subject to intramolecular [2 + 2] cycloaddition
upon cathodic reduction or chemically induced ET from arene anion radicals, and is herewith
showcased as a novel method of testing for the intermediacy of enone anion radicals.
2004-11-12 00:00:00
ET
Gilman alkylation manifold
enone anion radicals
methyl Gilman reagent
Gilman alkylation
cycloaddition
arene anion radicals
concentration
Gilman alkylation reaction
Gilman reagent