Heck continuous flow

Metal-catalyzed cross-couplings are key transformations for carbon-carbon bond formation. The applicability of continuous-flow systems to this important reaction type has been shown by a Heck reaction carried out in a stainless steel microreactor system (Snyder et al. 2005). A solution of phenyliodide 5 and ethyl acrylate 6 was passed through a solid-phase cartridge reactor loaded with 10% palladium on charcoal (Scheme 2). The process was conducted with a residence time of 30 min at 130°C, giving the desired ethyl cinnamate 7 in 95% isolated yield. The batch process resulted in 100% conversion after 30 min at 140°C using a preconditioned catalyst. 

Shore and coworkers [64] used a capillary reactor with a Pd thin film and microwave-assisted continuous-flow conditions for Suzttki-Miyara and Heck coupling reactions. The Pd film was prepared by passing Pd(OAc)2 solution into the 1150 pm eapillary at 150°C resulting in a highly porous catalyst composed of nanometer-size grains. 

Table 20 A selection of the results obtained for the Heck-Mizoriki reaction under continuous flow...

A system for the Heck reaction between methyl acrylate and iodobenzene has been developed comprising an imidazolium-functionalized polystyrene monolith, initially for use in batch. This system could be reused six times before any reduction in yield was observed. Accordingly, a continuous-flow reactor system was developed using DMF at 200 °C with a residence time of 3-4 min to achieve full conversion. This system was characterized by very low palladium loadings (0.02 mol%), and ICP-MS of the solution aliquots showed leaching of less than 1 ppm. Attempts at using EtOH as solvent to provide a more environmentally and procedurally benign protocol resulted in maximum yields of 85% [144]. 

More importantly, catalytic transformations such as transfer hydrogenations, Suzuki cross-coupling reactions, the Heck reaction, and the Sonogashira reaction were routinely performed in these PASSflow reactors under continuous flow conditions (Schemes 12-15) [41]. 

Shwalbe et al. reported the continuous flow Mizoroki-Heck reaction using DMF as a solvent [8], in which rapid catalyst screening and optimization of the reaction conditions were performed using a CYTOS-based microreaction system, which they call SEQUOS. 

Scheme 1.30 The Heck-Mizoroki-type reaction explored by McMullen et al. [82] under continuous flow conditions.

The Heck-Matsuda reaction has also been subjected to continuous flow chemistry conditions, as reported by Wirth et al. [100]. The reaction that was studied involved the reaction between an in situ generated diazonium ion and/r-fluorostyrene to give ( )-/ -fluorostilbene (Scheme 1.35) and the device used by this group relied on a segmented flow (liquid-liquid slug flow) to increase reaction rates in microfluidic flow. They used perfluorodecalin as an inert and immiscible liquid spacer. 

A continuous-flow Mizoroki-Heck reaction using monolithic Pd(0) nanoparticles was investigated [46,94]. Ley s group reported that the reactor afforded the desired product in high yield with high selectivity (Scheme 7.22). The reactor was reused... 

Glasnov, T.N., Findening, S and Kappe, C.O. (2009) Heterogeneous versus homogeneous palladium catalysts for ligandless Mizoroki-Heck reactions a comparison of batch/microwave and continuous-flow processing. Chem. Eur. J., 15 (4), 1001-1010. 

Odell L.R., Lindh J., Gustafsson T., Larhed M. Continuous flow palladium(II)-catalyzed oxidative Heck reactions with arylboronic acids. Eur. J. Org. Chem. 2010 (12) 2270-2274. 

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