Continuous Flow Synthesis of NHC‐Coinage Metal Amido and Thiolato Complexes: A Mechanism‐based Process Development

Abstract

The first continuous flow syntheses of amido and thiolato families are reported. Our studies focused on [M(NHC)(Cbz)] (Cbz=carbazolyl) and [M(NHC)(SPh)] (NHC=N‐heterocyclic carbene) as general proof‐of‐concepts and has led to a simple protocol with unprecedented short reaction times and high product yields. The scope of supporting ligands and substrates permits to assess the versatility of the process and a one‐pot synthesis starting from the imidazolium salt, metal source and carbazole substrate highlights the simplicity and sustainability of this operating design. The process was made possible through a detailed mechanistic understanding of the underlying reaction chemistry.

A Green Synthesis of Carbene‐Metal‐Amides (CMAs) and Carboline‐Derived CMAs with Potentin vitroandex vivoAnticancer Activity

“…(Scheme 1) We recently reported the synthesis of compound 1 b using a flow reaction setup in just two minutes of residence time as a proof of concept dealing with carbolinederived CMAs. [34] We showed that the limitations of the original batch protocol, regarding prolonged reaction times when sterically demanding ligands were used, [23a] could be overcome by using flow technology. Therefore, the fact that a CMA derived from the sterically demanding harmine can be accessed under the standard conditions without requiring an exceedingly long reaction time is notable.…”

“…Their complexes with Transition Metals have recently attracted ample attention for their applications in medicinal chemistry [41] . Although complexes with coinage metals have been reported, [41] CMAs of this type are not known, aside from one compound synthesized in our report as a proof of concept [34] . Herein, we report the sustainable synthesis of a range of carboline‐derived CMAs and we evaluate their antiproliferative properties on cell lines and organoids.…”

“…[23] Based on this, we also developed a flow procedure, reducing the reaction time to a few minutes. [34] Despite these advances, the synthesis of CMAs still requires the use of toxic solvents, primarily tetrahydrofuran, diethyl ether and pentane for purification reasons. Herein, we circumvent this problem by focusing instead on the removal of reaction waste material from the desired CMA, which is a much more general approach (see below).…”

“…[41] Although complexes with coinage metals have been reported, [41] CMAs of this type are not known, aside from one compound synthesized in our report as a proof of concept. [34] Herein, we report the sustainable synthesis of a range of carboline-derived CMAs and we evaluate their antiproliferative properties on cell lines and organoids. Importantly, we address for the first time the improvement of CMA purification, to render the entire process sustainable.…”

“…The procedure is scalable and has a wide scope with regards to the carbene type, metal and amine, thus providing the tools to create various CMA libraries in a facile manner [23] . Based on this, we also developed a flow procedure, reducing the reaction time to a few minutes [34] . Despite these advances, the synthesis of CMAs still requires the use of toxic solvents, primarily tetrahydrofuran, diethyl ether and pentane for purification reasons.…”