Expanding Mg–Zn Hybrid Chemistry: Inorganic Salt Effects in Addition Reactions of Organozinc Reagents to Trifluoroacetophenone and the Implications for a Synergistic Lithium–Magnesium–Zinc Activation

Abstract

Numerous organic transformations rely on organozinc compounds made through salt‐metathesis (exchange) reactions from organolithium or Grignard reagents with a suitable zinc precursor. By combining X‐ray crystallography, NMR spectroscopy and DFT calculations, this study sheds new light on the constitution of the organometallic species involved in this important synthetic tool. Investigations into the metathesis reactions of equimolar amounts of Grignard reagents (RMgX) and ZnCl2 in THF led to the isolation of novel magnesium–zinc hybrids, [{(thf)2Mg(μ‐Cl)3ZnR}2] (R=Et, tBu, nBu or o‐OMe‐C6H4), which exhibit an unprecedented structural motif in mixed magnesium–zinc chemistry. Furthermore, theoretical modelling of the reaction of EtMgCl with ZnCl2 reveals that formation of the mixed‐metal compound is thermodynamically preferred to that of the expected homometallic products, RZnCl and MgCl2. This study also assesses the alkylating ability of hybrid 3 towards the sensitive ketone trifluoroacetophenone, revealing a dramatic increase in the chemoselectivity of the reaction when LiCl is introduced as an additive. This observation, combined with recent related breakthroughs in synthesis, points towards the existence of a trilateral Li/Mg/Zn synergistic effect.

Preparation of Solid Salt‐Stabilized Functionalized Organozinc Compounds and their Application to Cross‐Coupling and Carbonyl Addition Reactions

“…Recently, we have shown that MgCl 2 greatly enhances the reactivity of organozinc reagents towards carbonyl derivatives. [5i] In fact both MgCl 2 and LiCl [18] increase the intrinsic reactivity of organozinc reagents by boosting their nucleophilicity as well as the electrophilicity of the carbonyl compound (Lewis acid activation). [19] Such activation is also observed for arylzinc pivalates of type 3.…”

Transition‐Metal‐Free Heterobiaryl Synthesis via Aryne Coupling

“…The previous investigation evaluating the effect of ligands clearly underlined influences of such compounds on the reactivity of organolithiums . In this context, “salt effects” have attracted significant interest in recent years, leading to comprehensive spectroscopic and theoretical investigations, more specifically in organolithium chemistry where the effects of lithium halides are commonly encountered . Lithium salts are undoubtedly among the most widely studied salts, being ubiquitous in a large number of lithiation reactions – either because they are generated in the reaction, or because they are involuntarily brought by a contaminated commercial source.…”

Pincer‐Nickel‐Catalyzed Cross‐Coupling of Aryl Sulfamates with Arylzinc Chlorides

“…This may be due to the presence of a multimetallic synergistic effect in the reaction process 12. In addition, the role of LiCl may also involve (1) breaking the aggregation of ArZnCl with the coproduct of MgCl 2 through the formation of a trimetallic adduct, and (2) enhancing the reactivity of the zinc reagents by forming more nucleophilic zincates 9b,12,13. When the reaction time was shortened to 12 h, the reaction still gave a 99 % yield of the product (Table 1, entry 18).…”