Continuous‐Flow N‐Heterocyclic Carbene Generation and Organocatalysis

Abstract

Two methods were assessed for the generation of common N-heterocyclic carbenes (NHCs) from stable imidazol(in)ium precursors using convenient and straightforward continuous-flow setups with either a heterogeneous inorganic base (Cs2CO3 or K3PO4) or a homogeneous organic base (KN(SiMe3)2). In-line quenching with carbon disulfide revealed that the homogeneous strategy was most efficient for the preparation of a small library of NHCs. The generation of free nucleophilic carbenes was next telescoped with two benchmark NHC-catalyzed reactions; namely, the transesterification of vinyl acetate with benzyl alcohol and the amidation of N-Boc-glycine methyl ester with ethanolamine. Both organocatalytic transformations proceeded with total conversion and excellent yields were achieved after extraction, showcasing the first examples of continuous-flow organocatalysis with NHCs.

Interaction of N‐Heterocyclic Carbenes and Simple Carbenes with Small Molecules (One to Three Atoms) Excluding Metals: Formation of Covalent C–X Bonds

“…The NHC:CS 2 adducts were prepared bubbling CS 2 through the corresponding NHCs , but in a paper, continuous flow technique was used , and in another instead NHCs, their dimers (enetetramines) were used . These adducts are useful ligands; very few papers reported another type of reactivity, for instance, one is related to capture of CS 2 .…”

Electron-transfer-initiated benzoin- and Stetter-like reactions in packed-bed reactors for process intensification

“…The synthetic utility of the umpolung methodology has therefore spurred intensive research on process intensification through the heterogeneization of NHC catalysts [5–9] for facilitating the post-reaction phase and improving NHCs’ stability towards air and moisture [10–11]. Quite surprisingly, however, implementation of continuos-flow techniques with micro- and meso-reactors is rare in this field [12–17]. Indeed, microreactor technology is today a powerful tool for the fine chemical and pharmaceutical industries facilitating the automation of the production processes with reduced costs and improved safety and sustainability [18–21].…”

“…Indeed, microreactor technology is today a powerful tool for the fine chemical and pharmaceutical industries facilitating the automation of the production processes with reduced costs and improved safety and sustainability [18–21]. Very recently, Monbaliu and co-workers described a convenient continuous-flow setup for the generation of common free NHCs under homogeneous conditions and their subsequent utilization in transesterification and amidation processes by the reaction telescoping approach [12]. Similarly, the group of Brown reported on the oxidative esterification and amidation of aldehydes in undivided microfluidic electrolysis cells mediated by homogeneous NHCs [13–14].…”

“…The asymmetric version of acyloin-type reactions was also investigated in our laboratory operating packed-bed bioreactors functionalized with a suitable thiamine diphosphate (ThDP)-dependent enzyme supported on mesoporous silica [17]. Overall, the so far reported umpolung flow processes [12–17] required quite sophisticated procedures, eventually complicated by the separation of homogeneous azolium salt pre-catalysts [25]. In this contribution, we describe a convenient and straightforward continuos-flow protocol for the effective production of benzoin and Stetter-like products that relies on the use of a readily and commercially available supported base as packing material of fixed-bed microreactors.…”

Optical and XPS evidence for the electrochemical generation of an N-heterocyclic carbene and its CS2adduct from the ionic liquid [bmim][PF6]

“…57 However, great care has to be exercised for its correct interpretation, since the process also interferes with the delicate acid-base equilibrium of the imidazolium salt(s). The basicity of the corresponding anion plays a critical role, which will be discussed in more detail in the next section.…”