Transition‐Metal‐Free Approach for the Direct Arylation of Thiophene: Experimental and Theoretical Investigations towards the (Het)‐Aryne Route

Abstract

This paper presents the results of our investigations on the arylation of thiophene using the transition‐metal‐free “aryne coupling” methodology. The reaction was studied by both experiment and computation (density functional theory) and comparison with phenyllithium was established. In parallel, the effects of the ligand and the salt on the coupling reaction were examined. The results underline the remarkable effect of such additives on the coupling reaction and the potency of the method to construct hetaryl–aryl backbones which open up promising access to a wide range of heterobiaryl structures using the novel “Het‐Aryne” route.

Transition‐Metal‐Free Heterobiaryl Synthesis via Aryne Coupling

“…From these results, it could be reasonable to speculate that DME strongly promotes the bromine‐lithium exchange required for the formation of the lithiated partners [2b,f,j‐Li] using t BuLi as base (2.0 equiv.) when carried out in toluene/DME, and probably to a lesser extent, those required for the coupling step too, as already discussed in a preliminary work . In addition, the complete absence of “homocoupling” product from 1a when the reaction was carried out in toluene as solvent, may be consistent with this hypothesis.…”

“…We began this work by examining the extension of the scope of the heteroarene coupling partner in the (Het)‐Aryne coupling previously developed by our group . To this end, we decided to study three (hetero)‐aromatic series (Table ) in order to evaluate the electronic influence of the heteroaromatic lithiated partner generated in the aryne coupling: first, π‐deficient systems – represented by the popular pyridinic moiety – , second, some π electron‐rich systems – with a more specific focus on thiophene derivatives – and last, two electron‐neutral aromatic derivatives being used as references.…”

“…Note that, in parallel, several metalation routes were envisioned for the formation of lithiated partners in order to obtain further insight on the influence of the basic system employed during the aryne coupling. To facilitate the cross‐comparison of results, we initiated this work using a uniform set of experimental conditions (Table ) derived from those originally developed with precursor 1a for the coupling step, as described hereafter. Thus, our first attempts were carried out by adding 1,2‐dibromobenzene 1a (1.2 equiv.)…”

“…Based on our previous investigation regarding the remarkable effect of the chelating DME in a non‐coordinating solvent on the coupling reaction of 3‐bromothiophene 2b , we decided then to evaluate the influence of this additive when added to the reaction of 3‐bromopyridine 2f and bromobenzene 2j using toluene as solvent (Table ). We found that the conversion rates are very close to the reaction yields, which proves that lithiation constitutes the limiting step for aryne couplings and that all the lithiated intermediates formed [2b, f, j‐Li] react with the precursor 1a .…”

“…In this context, Leroux et al reported an efficient transition metal free aryl‐aryl coupling protocol, the so‐called “Aryne coupling” reaction . Very recently, we extended the reaction to the construction of hetaryl‐aryl backbones, developing thus the “(Het)‐Aryne” version of the reaction (Scheme ) . However, our study essentially focused on the thiophene ring as a model partner.…”