Continuous Flow Synthesis of Metal–NHC Complexes**

Abstract

The use of weakb ases and mild conditions is currently the most sustainable and attractive synthetica pproach for the preparation of late-transition metal complexes, some of which are widely used in catalysis, medicinal chemistry and materials science.H erein, the use of cuprate, aurate or palladate speciesf or ac ontinuous flow preparation of Cu I ,A u I and Pd II-NHC complexes is reported. All reactions examined proceed under extremely mild conditions and make use of technicalg rade acetonea s solvent. The scalability of the process was exemplified in a multigram-scale synthesis of [Cu(IPr)Cl]. N-Heterocyclic carbenes (NHCs) have become am ost popular ligand family for the synthesis of organometallic compounds with uses in catalysis. [1] The surprising stabilityo ft he metal-NHC bond has also permitted the study and use of transition metal-NHC complexes in medicinal chemistry [2] and mostr ecently in materials science. [3] The nowadays ubiquitousu se of this fascinating class of ligandsh as been ad riving force encouraging the development of sustainable, efficient and userfriendly routes leadingt otheir syntheses. [4] Although not quite sustainable, the most commonly used synthetic strategy,b ased on the seminal work of Arduengo, [5] involves the generation of free NHC by deprotonation of the corresponding azolium salt with as trong base (e.g. NaH, KOtBu)a nd subsequent coordination to am etal. The most significant drawbacks of the free carbene route lies in the need for strictly anhydrous conditions. Additionally,t his route is not suitable for complexes requiring the use of metal precursors sensitivet ostrong bases.

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

“…We have recently developed a scalable continuous flow procedure – inspired by the weak base batch protocol – for the synthesis of NHC‐copper(I), ‐gold(I) and ‐palladium(II) complexes from the corresponding imidazolium salt and metal precursor, in unprecedentedly short reaction times [18] . The efficacy of this process to access other complexes was further assessed in the synthesis of a range of gold(I)‐aryl complexes [19] .…”

“…We have recently developed a scalable continuous flow procedure -inspired by the weak base batch protocol -for the synthesis of NHC-copper(I), -gold(I) and -palladium(II) complexes from the corresponding imidazolium salt and metal precursor, in unprecedentedly short reaction times. [18] The efficacy of this process to access other complexes was further assessed in the synthesis of a range of gold(I)-aryl complexes. [19] Encouraged by these initial findings, we hypothesized that the use of continuous flow protocols towards NÀ H and SÀ H activation, in a way to further demonstrate the weak base versatility and potential, could further capitalize on our mechanistic understanding of the underlying chemistry to provide easy access to complexes possessing catalytic and photochemical potential.…”

Rapid and mild synthesis of Au–NHC complexes in a simple two-phase flow reactor

“…have recently reported a methodology using a continuous flow solid-phase reactor for the synthesis of Au(I)-, Cu(I)-and Pd(II)-NHC complexes using the common ligand IPr. 18 They achieved impressive yields of up to 93% for the Au(I)-IPr complex, using short (2 min) residence times. However, solid phase flow reactors suffer from several disadvantages when compared to liquid-liquid reactors.…”

“…This is a particular issue for gold chemistry, due to gold's propensity for forming nanoparticles. 18 Liquid-liquid reactors suffer from no such issues: preparation of the reactor generally consists of simply loading reactant solutions into pumps, and a reactor can be immediately reused after flushing with a suitable solvent.…”

Continuous Flow Synthesis of [Au(NHC)(Aryl)] (NHC=N‐Heterocyclic Carbene) Complexes

“…[13] We have recently developed an operationally simple and readily scalable continuous flow procedure for the preparation of NHC-supported copper, gold and palladium complexes from the imidazolium salt and appropriate metal source. [14] A solution of the corresponding -ate complex in technical grade acetone was hereto injected into a packed bed reactor charged with triturated K 2 CO 3 , yielding the desired product in no time. Fostered by these fascinating results, we were incited to extend this protocol to the synthesis of various other organometallic species.…”