An Immobilized‐Dirhodium Hollow‐Fiber Flow Reactor for Scalable and Sustainable C−H Functionalization in Continuous Flow

Abstract

A scalable flow reactor is demonstrated for enantioselective and regioselective rhodium carbene reactions (cyclopropanation and C−H functionalization) by developing cascade reaction methods employing a microfluidic flow reactor system containing immobilized dirhodium catalysts in conjunction with the flow synthesis of diazo compounds. This allows the utilization of the energetic diazo compounds in a safe manner and the recycling of the dirhodium catalysts multiple times. This approach is amenable to application in a bulk‐scale synthesis employing asymmetric C−H functionalization by stacking multiple fibers in one reactor module. The products from this sequential flow–flow reactor are compared with a conventional batch reactor or flow–batch reactor in terms of yield, regioselectivity, and enantioselectivity.

Exploiting Continuous Processing for Challenging Diazo Transfer and Telescoped Copper-Catalyzed Asymmetric Transformations

“…Davies has reported in situ formation of aryl α-diazoesters in flow, via oxidation of the corresponding hydrazones, followed by telescoped intermolecular cyclopropanation or C–H insertion with an immobilized rhodium(II) carboxylate catalyst. 50 Excellent yields and enantioselectivities were reported which matched the results from the corresponding batch reactions.…”

“…Over the past two decades, there has been tremendous progress in immobilization of rhodium carboxylate and carboxamidate catalysts, 41 − 46 with significant contributions from Davies, 47 − 50 Doyle, 51 , 52 and Hashimoto, 53 among others. Davies has reported in situ formation of aryl α-diazoesters in flow, via oxidation of the corresponding hydrazones, followed by telescoped intermolecular cyclopropanation or C–H insertion with an immobilized rhodium(II) carboxylate catalyst.…”

Controllable Si−C Bond Activation Enables Stereocontrol in the Palladium‐Catalyzed [4+2] Annulation of Cyclopropenes with Benzosilacyclobutanes

“…TheO H-functionalized silacycle proved to be quite stable under the reaction conditions.M oreover,f luoride-anion-induced Si À Cb ond cleavage resulted in alternative access to multisubstituted cyclopropane derivatives with excellent diastereoselectivity; such compounds are difficult to synthesize with high diastereoselectivity by cyclopropanation reactions (Scheme 5bd). [18] On the basis of our experimental results (see Scheme S3 and Figure S1 in the Supporting Information) and literature precedent [5][6][7][8][9] as well as our DFT study on the palladiumcatalyzed desymmetrization of silacyclobutanes with alkynes, [13] two plausible reaction pathways are proposed for this ring-expansion/cycloaddition reaction of cyclopropenes with benzosilacyclobutanes ( Figure 2). To better understand the reaction mechanism, we performed simplified DFT calculations with PMe 3 as am odel ligand (see Table S3;t he potential-energy-surface diagram and the related energy parameters identified for two possible reaction pathways are summarized in the Supporting Information).…”

Silver-catalyzed site-selective C(sp3)−H benzylation of ethers with N-triftosylhydrazones

“…1a ) 15 – 19 . Since the pioneering work of Adams and co-workers in 1989 20 , this methodology has been well-established 21 – 34 ; in particular, Davies, Pérez, Hartwig, and Arnold groups have made significant developments with donor/acceptor 26 – 31 and acceptor carbenes 21 – 23 , 32 – 34 . Such insertion chemistry has also been successfully applied to the synthesis of complex natural products 18 , 19 .…”