The palladium-catalyzed Suzuki-Miyaura coupling reaction between aryl halides and arylboronic acids is one of the most useful methodologies for the construction of a biaryl unit constituting a partial structure of some natural products, pharmaceuticals, and functional polymers, such as organic electroluminescence (EL) materials [1
]. However, palladium metal as the active catalyst species should be removed from the product as an undesired waste after the reaction when the homogeneous catalyst was used. In addition to the effort and cost for the required removal process of the palladium waste, the unrecoverability of the expensive palladium catalysts is also a drawback. Therefore, the development of practical protocols for the Suzuki-Miyaura cross-coupling reaction is demanded from the perspective of green chemistry.
In the past few years, the use of heterogeneous flow systems in synthetic organic chemistry has become increasingly popular [4
]. The systems use an apparatus for delivering a substrate solution into a cartridge filled with a heterogeneous catalyst. Since the flow channel in the catalyst cartridge passing the substrate solution is sufficiently narrow, the reaction efficiency should be enhanced due to the intimate contact of the catalyst with the substrate and reagents in comparison to a batch-type reaction using flasks or reaction vessels. The immobilized transition-metal catalyst, which often indicates a risk of ignition under atmospheric conditions, is enclosed in a completely-sealed cartridge during the flow-type reaction; hence, the reactions could be carried out in a safe manner. Furthermore, the removal of the metal residue from each reaction solution should not be necessary, and the catalyst can be reused unless metal leaching is observed. Taking great advantage of these features, we recently developed effective flow-type hydrogenation methods using several different types of catalysts possessing broad substrate applicabilities [8
]. Several flow Suzuki-Miyaura cross-coupling reactions have also been reported using a heterogeneous catalyst [6
] as well as a homogeneous catalyst [6
]. The supports for the heterogeneous palladium catalysts included a polyionic polymer [9
], phosphine ligand-functionalized silica [10
], activated carbon [11
], and alumina [11
]. Although the heterogeneous flow Suzuki-Miyaura coupling reactions in these reports efficiently proceeded, there is still room for improvement; thus, the reaction solution was continuously passed through the catalyst cartridge many times in the closed circulation reaction system to complete the reaction in the case of polyionic polymer-supported palladium [9
]. The palladium catalyst on phosphine ligand-functionalized silica is commercially available but rather expensive [10
]; high temperature (150 °C) and excess amount of base (3 equiv) were applied in the preceding paper by Mateos et al.
using readily available 10% Pd/C or 10% Pd/Al2
as a catalyst [11
]. An efficient batch-type ligand-free Suzuki-Miyaura coupling reaction catalyzed by Pd/C at room temperature in aqueous media has been developed in our laboratory [16
]. In this paper, we have demonstrated a practical protocol for the ligand-free Pd/C-catalyzed flow Suzuki-Miyaura reaction under mild conditions (25–100 °C), which is completed within only 20 s during the single-pass of the substrate solution through the catalyst cartridge.