Towards Continuous Flow, Highly Enantioselective Allylic Amination: Ligand Design, Optimization and Supporting

Abstract

A family of enantiopure diphenylphosphinooxazolines (PHOX) containing in their structures a sterically tunable alkoxymethyl group (-CH 2 OR) has been optimized for the palladium-catalyzed asymmetric allylic amination. The optimal catalyst (R = CH 3 ), depicting very high catalytic activity and broad scope applicability, has been further modified to include an w-alkynyloxy substituent of variable length for polymer supporting via click chemistry, and has been anchored onto slightly cross-linked azidomethyl polyA C H T U N G T R E N N U N G (styrene). The length of a polymethylene chain connecting the PHOX unit with the 1,2,3-triazole linker has been optimized, and the first polymer-supported PHOX ligands for the highly enantioselective allylic amination have been prepared in this manner. Conditions for catalyst recovery and reuse in microwave-promoted amination reactions have been established, and the system has been finally adapted to continuous flow operation.

Palladium‐Catalyzed Enantioselective Allylic Substitution in the Presence of Monodentate Furanoside Phosphoramidites

“…88 % ee ${[\alpha ]_{\rm{D}}^{20} }$ =−26.5 ( c =0.7, CHCl 3 ), lit 24. ${[\alpha ]_{\rm{D}}^{23} }$ =+28.2 ( c =0.82, CHCl 3 ), 94 % ee ( S ), [ lit 25. ${[\alpha ]_{\rm{D}}^{23} }$ =−30.5 ( c =0.82, CHCl 3 ), 98 % ee ( R )].…”

Catalytic Enantioselective Flow Processes with Solid‐Supported Chiral Catalysts

“…Several ligands have been developed to control the enantioselectivity of the process, and bidentate phosphinooxazolines (PHOX) are amongst the most successful. After optimizing the ligand structure, the anchoring strategy via CuAAc and the length of the linker, the flow experiment depicted in Figure was carried out with 27 . Based on the observation made in batch that use of low‐power microwave irradiation significantly improved the results, the whole set‐up was assembled without metallic pieces and placed inside the MW cavity in open‐vessel mode.…”

“…After optimizing the ligand structure, the anchoring strategy via CuAAc and the length of the linker, the flow experiment depicted in Figure 26 was carried out with 27. [99] Based on the observation made in batch that use of low-power microwave irradiation significantly improved the results, the whole set-up was assembled without metallic pieces and placed inside the MW cavity in open-vessel mode. Thus, working at 0.12 mL min À1 , the system was running for 3 h, in which the conversion decreased from the initial 85 % to 54 %, probably pointing out to palladium leaching.…”

Stereoselective organic reactions promoted by immobilized chiral catalysts in continuous flow systems

“…In 2009, the Pericas group reported the synthesis of polymer-supported enantiopure diphenylphosphinooxazolines (PHOX) to be used as ligands for Pd in the enantioselective allylic amination. 43 The strategy involved the copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition between the PHOX bearing a terminal alkyne and Merrifield resin-supported azide, followed by the formation of the Pd π-allyl complex. The complex was first studied under batch conditions in the reaction between (rac)-(E)-3-acetoxy-1,3-diphenyl-prop-1-ene and benzylamine to determine the best conditions.…”