Transition‐Metal‐Free Matsuda‐Heck Type Cross‐Coupling and Mechanistic Evidence for a Radical Mechanism

The Matsuda-Heck reaction, usually performed with palladium catalysts, can be carried out under transition metal free conditions in the presence of a KOtBu / DMF couple. This system allows, under mild temperature conditions (20 °C), the selective and direct synthesis of stilbenes from aryldiazonium salts. Mechanistic studies suggest a radical pathway in which the DMF acts as the initiator of the overall process. Herein, we present a new way to perform the traditionally palladium catalysed Matsuda-Heck reaction under both ligand and transition metal free conditions (Scheme 1). The latter is a versatile method allowing the preparation of stilbene derivatives by selective alkene functionalization from arenediazonium salts, which constitute highly attractive aryl halide surrogates. Arenediazonium salts are easily prepared from widely available and inexpensive anilines, are often reactive under mild conditions, and the leaving group is inert (N2) towards the reaction mixture. 7] The use of alkenes as starting materials, some of the most widespread chemical compounds, is another advantage of the method. However, the presence of palladium based catalysts for most Matsuda-Heck reactions is not favourable, owing to the high cost and toxicity issues, and limits the attractiveness for largescale or industrial applications. For the Matsuda-Heck process, the C(sp2)-C(sp2) bond formation proceeds via the intermediate formation of a reactive cationic palladium intermediate resulting from the initial oxidative addition of Pd at the C(sp2)-N bond of the arenediazonium salts. This carbon-carbon bond formation can also be achieved by the Meerwein reaction, a long known coppermediated coupling between aryldiazoniums and electron-deficient alkenes. The method, which suffers from several drawbacks that have limited its application in synthesis, proceeds via reversible oxidation of copper(I) to copper(II), associated to the initial formation of an aryl radical. The generation of the latter from arenediazonium has also been performed with an excess amount of iron [14-17] or titanium salts, without transition metals [20-24] or through visible-light induced photoredox strategies, often catalyzed by Eosin Y or ruthenium complexes (Ru(bpy)3Cl2). However, with these methods, when the generated aryl radical couples with an alkene, the double bond is often not conserved, which constitutes a great challenge. We previously discovered that the α-arylation of enolizable ketones, usually performed with nickel, palladium or copper catalysts, could be carried out using a simple KOtBu/DMF system that is able to generate aryl radicals in the initiation process. Taking into account the well-known possibility of forming aryl radicals from arene diazonium salts, we assumed that the Matsuda-Heck process could be performed with this system to give stilbenes, which are very important intermediates and targets in the chemical, pharmaceutical, and materials industries. We report herein that a KOtBu/DMF couple alone promotes the direct and selective synthesis of stilbenes by a Matsuda-Heck type-cross-coupling, performed in the absence of ligand and palladium catalyst. We also propose a radical mechanistic pathway based on the literature, alongside experimental and theoretical studies (Scheme 1). Scheme 1. The Matsuda-Heck reaction: traditional method with palladium catalysts and pathway described herein with KOtBu/DMF system. To start our investigations, we reacted 4methoxybenzenediazonium tetrafluoroborate 1a with styrene in DMF (2 mL) for 18 h at 20 °C in the presence of 2 equivalents of KOtBu. In these conditions, the desired stilbene 2a (trans isomer) was selectively obtained in 39% yield (Table 1, entry 2). Using other bases such as KOAc or NaOtBu gave only traces of 2a (Table 1, entries 3, 4) and replacing the solvent with acetonitrile, toluene or 1,2-dichoroethane also led to negligible amounts of product (Table 1, entries 5–7). While increasing the amount of KOtBu was moderately beneficial, we noticed the crucial role of the concentration since reducing the volume of DMF to 220 L and 500 L afforded 2a in 45 % and 71 % yields respectively (Table 1, entries 9, 10). Finally, we obtained a very good yield of stilbene 2a using resublimed KOtBu (purchased from Alfa Aesar 99.994%), thus ruling out the possibility of a reaction catalyzed by undesirable metallic contaminants (table 1, entry 11). Table 1. Synthesis of stilbene 2a from 4-methoxybenzenediazonium tetrafluoroborate 1a and styrene: reaction conditions.