Intramolecular carbolithiation‐cyclization‐electrophilic substitution: solvent effect and mechanistic study

Abstract

The intramolecular carbolithiation‐cyclization‐electrophilic substitution sequence proves to be a promising strategy for synthetic organic chemists. Our current research in this area focuses on the one‐pot halogen/lithium exchange of 2‐bromophenyl‐3‐phenylprop‐2‐enyl ether, followed by intramolecular carbolithiation, and trapping of the new lithiated cyclic intermediate by several electrophiles, affording 3‐substituted 2,3‐dihydrobenzofurans with some diastereoselectivity. Within this context, a study on the product distribution solvent dependence was carried out using different types of solvents, namely: polar coordinating, polar non‐coordinating, and non‐polar solvents. The results show that the coordinating features of the solvent affect specially the carbolithiation step, whereas the halogen/lithium exchange seems to be barely affected. Theoretical calculations were carried out to investigate the unexpected diastereoselectivity of the tandem reaction, where two stereocenters are generated. Insights gained from our mechanistic investigations enabled us to propose an inversion of configuration at the lithiated intermediate prior to the reaction, being the electrophile the likely cause for the observed distereoselectivity. Copyright © 2013 John Wiley & Sons, Ltd.

Lithium–Olefin π-Complexes and the Mechanism of Carbolithiation: Synthesis, Solution Behavior, and Crystal Structure of (2,2-Dimethylpent-4-en-1-yl)lithium

“…(4) Carbolithiation is accelerated in coordinating solvents, which suggests that a Lewis base is coordinated to the intermediate responsible for carbolithiation. The last of these conclusions is consistent with previous observations of inter- and intramolecular carbolithiation reactions. ,,,, …”

“…The last of these conclusions is consistent with previous observations of inter-and intramolecular carbolithiation reactions. 15,19,24,64,65 Solvation of the lithium centers by a Lewis base can have several chemical consequences, one of which is disaggregation of the organolithium cluster. 1,5,40,66−68 In fact, Mattalia et al have proposed that disaggregation is largely responsible for the increased rate of carbolithiation in the presence of Lewis bases.…”

“…One approach is to study such interactions at low temperatures by techniques such as 1 H– 6 Li HOSEY and resonance Raman spectroscopy. Another approach is to disfavor insertion of the olefin into the Li–C bond, for example, by employing ω-alkenyl lithium species with five or fewer carbon atoms in the chain (for which the open-ring form is thermodynamically more stable owing to the ring strain of the cyclized reaction product), or by carrying out the studies in hydrocarbon rather than ether solvents . Thus, IR and 1 H NMR studies of 3-butenyllithium in hydrocarbon solvents found that Li–olefin interactions cause the CC stretching frequency to decrease by 6 cm –1 , and the olefinic protons to be deshielded with respect to the corresponding hydrocarbon 1-butene. , In contrast, in diethyl ether, the olefinic protons are shielded compared to 1-butene as expected from inductive effects.…”