Abstract
AbstractThe mechanochemical, solvent‐free, highly regioselective, rhodium‐catalyzed C−H methylation of (hetero)arenes is reported. The reaction shows excellent functional‐group compatibility and is demonstrated to work for the late‐stage C−H methylation of biologically active compounds. The method requires no external heating and benefits from considerably shorter reaction times than previous solution‐based C−H methylation protocols. Additionally, the mechanochemical approach is shown to enable the efficient synthesis of organometallic complexes that are difficult to generate conventionally.
Highlights
The methylation of bioactive molecules can dramatically improve their potency by enhancing lipophilicity, binding interactions, metabolic stability and numerous other properties.[1]
These reactions were performed in stainless steel (SS) milling vessels (14 mL internal volume) equipped with a single SS ball (10 mm diameter) using a mixer mill (MM) capable of oscillating at frequencies up to 36 Hz
Formed under oxidative conditions suggest that CÀH rhodation is not the turnover-limiting step.[11f]
Summary
The methylation of bioactive molecules can dramatically improve their potency by enhancing lipophilicity, binding interactions, metabolic stability and numerous other properties (benefits collectively referred to as the “magic methyl effect”).[1]. The legal regulation of which is becoming increasingly stringent.[4] More generally, solvent waste presents a formidable challenge for the sustainability of chemical synthesis;[5] in the pharmaceutical industry alone, an estimated 85 % of waste by mass is attributable to solvent use.[6] In light of these concerns, mechanochemistry offers an enticing alternative to established, solution-based approaches.[7] The use of mechanical action (e.g. grinding or milling) for reagent mixing and activation can provide powerful advantages. We describe a mechanochemical catalytic CÀH methylation that entirely avoids solvent as a reaction medium and that can be used even for the late-stage functionalization (LSF) of bioactive molecules
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