Lewis acid-mediated Suzuki\u2013Miyaura cross-coupling reaction

Takashi Niwa,Miki Nakaoka,Daisuke Hashizume,Tadashi Takimoto,Hidehiro Sakurai,Takamitsu Hosoya,Yuta Uetake,Motoyuki Isoda

doi:10.1038/s41929-021-00719-6

Abstract

The palladium-catalysed Suzuki–Miyaura cross-coupling reaction of organohalides and organoborons is a reliable method for carbon–carbon bond formation. This reaction involves a base-mediated transmetalation process, but the presence of a base also promotes competitive protodeborylation. Herein, we established a Suzuki–Miyaura cross-coupling reaction via Lewis acid-mediated transmetalation of an organopalladium(II) intermediate with organoborons. Experimental and theoretical investigations indicate that the controlled release of the transmetalation-active intermediate enables base-independent transmetalation under heating conditions and enhances the applicable scope of this process. This system enables us to avoid the addition of a traditional base and, thus, renders substrates with base-sensitive moieties available. Results from this research further expand the overall utility of cross-coupling chemistry.

Highlights

The Suzuki–Miyaura cross-coupling (SMC) reaction is one of the reliable carbon–carbon bond forming processes, broadly applied in the synthesis of valuable compounds, such as pharmaceuticals1,2
A critical step in the SMC reaction is the transmetalation of organopalladium(II) species with organoborons, which conventionally requires the use of a base3
Sanford et al have recently reported that the use of acyl fluorides as electrophiles allows for a nickel-catalysed SMC reaction with organoboronic acids without using an exogenous base, in which the fluoride within the substrates promotes transmetalation11

Summary

Results

Since SMC reactions often require heating to complete a catalytic cycle, preventing the thermal decomposition of palladium intermediates is indispensable for the generalization of the traditional base-free methodology for carbon–carbon bond formation. To address this issue, we designed a coordinatively saturated cationic organopalladium(II) intermediate with labile ligands that are thermally stable and release the corresponding unsaturated and transmetalation-active species in equilibrium (Fig. 1c). The controlled release of cationic organopalladium(II) species should suppress the spontaneous degradation and prioritize the desired pathway even under heating conditions We envisioned that this masked intermediate can be generated via the dehalogenation of an aryl(halo)palladium(II) complex with a halophilic Lewis acid, where the -formed metal halides serve as labile ligands. R1 X + B R2 This work b Via cationic palladium(II) intermediate at room temperature (refs. 12,13)

H Zn H OO

40 With 5b

D Transmetalation active

Conclusions

Methods