Mechanistic studies of 2-lithio-1,3-dithiane reactions with radical probes

The Regioselectivity of Addition of Organolithium Reagents to Enones and Enals: The Role of HMPA

“…The addition chemistry to α,β-unsaturated carbonyl compounds can only be of practical synthetic utility if one of the two regioisomers is generated selectively. The synthetic importance of these reactions is reflected by the extensive efforts directed toward elucidating the effects that changes in solvent, temperature, and steric bulk as well as main group and transition metal additives have on the regioselectivity of addition of organolithium reagents to enones and enals. ,− …”

“…One plausible explanation for the propensity of SIP's to add 1,4 is that the higher HOMO of the SIP vs the CIP promotes a single electron transfer (SET) reaction, leading to conjugate addition. However, a mechanistic study using radical probes failed to demonstrate that trapable radicals were involved in the reactions of lithiodithianes …”

“…The synthetic importance of these reactions is reflected by the extensive efforts directed toward elucidating the effects that changes in solvent, temperature, and steric bulk as well as main group and transition metal additives have on the regioselectivity of addition of organolithium reagents to enones and enals. 2, [7][8][9][10][11][12][13][14][15] The first demonstration that the 1,4:1,2 ratio could in some cases be controlled by proper choice of temperature or solvent appeared in 1977, 7 when it was found that the kinetic preference for 1,2 addition by metalated 2-phenyl-1,3-dithiane could be overcome by performing the reaction at higher temperatures and in more polar solvent, leading to the thermodynamically favored 1,4 product. A year later, for a reaction determined to be entirely under kinetic control, the opposite temperature dependence was observed: lower temperatures favored the 1,4 product and higher temperatures favored the 1,2 product.…”

“…However, a mechanistic study using radical probes failed to demonstrate that trapable radicals were involved in the reactions of lithiodithianes. 13 Other explanations have been proposed to account for the effect of HMPA in promoting 1,4 addition. Ab initio calculations indicate that the carbonyl coefficient of the enone LUMO is increased relative to that of the remote carbon when lithium coordinates to the carbonyl, and hence coordination should promote 1,2 addition.…”

Regioselectivity of Addition of Organolithium Reagents to Enones: The Role of HMPA

“…This hypothesis could not be directly tested since no information about the solution structures of organolithium reagent − HMPA complexes was available. Here we apply our multinuclear NMR technique 1b to quantify the amount of separated ion in solution and correlate this with changes in regioisomeric and diastereomeric product ratios to test this hypothesis …”