Scientists at LyraChem, based in Newcastle-upon-Tyne, United Kingdom, and Newcastle University reported on intensified azeotropic
distillation as an approach for optimizing direct amidation (10). The direct synthesis of amides from the corresponding carboxylic
acids and amines was shown to operate under varying degrees of mixed kinetic and mass-transfer rate control when water was
removed by azeotropic distillation (10). A systematic approach was developed to quantify the contribution of boil-up rate
to conversion rate and decouple the physical rates from the chemistry. Intensive boiling was used to improve the removal of
water during azeotropic distillation and enhance conversion. The researchers reported that some acylations previously thought
to be difficult or impossible could be achieved in the absence of coupling agents under green conditions. A cascade of continuous
stirred-tank flow reactors operating under intensified conditions was assessed for scale-up of direct amidation reactions
and compared to a production-scale batch reactor. The researchers reported that the use of the continuous stirred-tank flow
reactors operating under intensified conditions could provide the necessary high rates of heat transfer and, therefore, offer
advantages over a conventional batch reactor system (10).
Asymmetric synthesis is an important area of research for producing single enantiomer drugs. Researchers in the Department
of Chemistry, School of Science at the University of Tokyo, recently reported on the use of continuous-flow chemistry with
chiral heterogeneous catalysts in asymmetric carbon–carbon bond formation (11). They developed and applied a chiral calcium
catalyst based on calcium chloride with a chiral ligand to the asymmetric 1,4-addition of 1,3-dicarbonyl compounds to nitroalkenes
as a model system (11). The researchers sought to improve the low catalyst turnover number (TON) of asymmetric
carbon–carbon bond-forming issues (12). To address product inhibition, the calcium catalyst was applied to continuous flow
with a chiral heterogeneous catalyst. The continuous-flow system, using a newly synthesised, polymer-supported Pybox, was
successfully used, and the catalyst TON was improved 25-fold compared with those of the previous Ca(OR)2 catalysts (11).
Researchers at the Department of Synthetic and Biological Chemistry in the Graduate School of Engineering, Kyoto University
Nishikyo-ku, in Kyoto, Japan applied a flash-chemistry approach using flow microreactors to produce a highly reactive palladium
catalyst with a tri-tert-butylphosphine (tBu3P) ligand for a Suzuki–Miyaura coupling (12, 13). The flash chemistry enabled
the use of highly reactive unstable species as a catalysts for chemical synthesis. Fast micromixing of a solution of [Pd(OAc)2]
and that of tBu3P in an 1:1 mole ratio gave a solution of a highly reactive unstable species, which was transferred to a vessel
by using a flow microreactor, in which Suzuki–Miyaura coupling was conducted (13). The coupling reactions were completed in
5 minutes at room temperature, thereby preventing deboronation of the used aryl and heteroarylboronic acids (12).
In another study, researchers from the Institute of Science and Technology in Ikoma, Japan, and the School of Pharmacy and
Molecular Sciences at James Cook University in Townsville, Australia reported on the diastereoselective [2+2] photocycloaddition
of a chiral cyclohexenone with ethylene in a continuous flow microcapillary reactor (14). The researchers reported that the
microcapillary reactors have higher conversions and selectivity than the batch system even after shorter irradiation times
due to better temperature control, light penetration and generation of gas–liquid slug flow with improved mass transfer in
the microreactor (14).
In another development, researchers at the Institute of Organic Chemistry at Aachen University in Germany reported on the
asymmetric organocatalytic hydrogenation of benzoxazines, quinolines, quinoxalines and 3H-indoles in continuous-flow microreactors
using Fourier transform infrared (FTIR) spectroscopy in-line analysis (15). Reaction monitoring was achieved by using an in-line
ReactIR flow cell, which allowed for optimization of the reaction parameters. The researchers reported that the reductions
proceeded well, and the desired products were isolated in high yields and with good enantioselectivities (15).