Ex-situ generation and synthetic utilization of bare trifluoromethyl anion in flow via rapid biphasic mixing.

Fluoroform (CF3H) is the simplest reagent for nucleophilic trifluoromethylation intermediated by trifluoromethyl anion (CF3-). However, it has been well-known that CF3- should be generated in presence of a stabilizer or reaction partner (in-situ method) due to its short lifetime, which results in the fundamental limitation on its synthetic utilization. We herein report a bare CF3- can be ex-situ generated and directly used for the synthesis of diverse trifluoromethylated compounds in a devised flow dissolver for rapid biphasic mixing of gaseous CF3H and liquid reagents that was designed and structurally optimized by computational fluid dynamics (CFD). In flow, various substrates including multi-functional compounds were chemoselectively reacted with CF3-, extending to the multi-gram-scale synthesis of valuable compounds by 1-hour operation of the integrated flow system.

Scalable Subsecond Synthesis of Drug Scaffolds via Aryllithium Intermediates by Numbered-up 3D-Printed Metal Microreactors.

Continuous-flow microreactors enable ultrafast chemistry; however, their small capacity restricts industrial-level productivity of pharmaceutical compounds. In this work, scale-up subsecond synthesis of drug scaffolds was achieved via a 16 numbered-up printed metal microreactor (16N-PMR) assembly to render high productivity up to 20 g for 10 min operation. Initially, ultrafast synthetic chemistry of unstable lithiated intermediates in the halogen-lithium exchange reactions of three aryl halides and subsequent reactions with diverse electrophiles were carried out using a single microreactor (SMR). Larger production of the ultrafast synthesis was achieved by devising a monolithic module of 4 numbered-up 3D-printed metal microreactor (4N-PMR) that was integrated by laminating four SMRs and four bifurcation flow distributors in a compact manner. Eventually, the 16N-PMR system for the scalable subsecond synthesis of three drug scaffolds was assembled by stacking four monolithic modules of 4N-PMRs.

Regioselective Synthesis of α-Functional Stilbenes via Precise Control of Rapid cis-trans Isomerization in Flow.

The rapid cis-trans isomerization of α-anionic stilbene was regioselectively controlled by using flow microreactors, and its reaction with various electrophiles was conducted. The reaction time was precisely controlled within milliseconds to seconds at -50 °C to selectively give the cis- or trans-isomer in high yields. This synthetic method in flow was well-applied to synthesize precursors of commercial drug compound, (E)- and (Z)-tamoxifen with high regioselectivity and productivity.

Enhanced Controllability of Fries Rearrangements Using High-Resolution 3D-Printed Metal Microreactor with Circular Channel.

High-resolution 3D-printed stainless steel metal microreactors (3D-PMRs) with different cross-sectional geometry are fabricated to control ultrafast intramolecular rearrangement reactions in a comparative manner. The 3D-PMR with circular channel demonstrates the improved controllability in rapid Fries-type rearrangement reactions, because of the superior mixing efficiency to rectangular cross-section channels (250 µm × 125 µm) which is confirmed based on the computational flow dynamics simulation. Even in case of very rapid intramolecular rearrangement of sterically small acetyl group occurring in 333 µs of reaction time, the desired intermolecular reaction can outpace to the undesired intramolecular rearrangement using 3D-PMR to result in high conversion and yield.

A numbering-up metal microreactor for the high-throughput production of a commercial drug by copper catalysis.

Microreactors are emerging as an efficient, sustainable synthetic tool compared to conventional batch reactors. Here, we present a new numbering-up metal microreactor by integrating a flow distributor and a copper catalytic module for high productivity of a commercial synthetic drug. A flow distributor and an embedded baffle disc were manufactured by CNC machining and 3D printing of stainless steel (S/S), respectively, whereas a catalytic reaction module was composed of 25 copper coiled capillaries configured in parallel. Eventually, the numbering-up microreactor system assembled with functional modules showed uniform flow distribution and high mixing efficiency regardless of clogging, and achieved high-throughput synthesis of the drug "rufinamide", an anticonvulsant medicine, via a Cu(i)-catalyzed azide-alkyne cycloaddition reaction under optimized conditions.

From p-Xylene to Ibuprofen in Flow: Three-Step Synthesis by a Unified Sequence of Chemoselective C-H Metalations.

Ibuprofen was prepared from an inactive and inexpensive p-xylene by three-step flow functionalizations through chemoselective metalations of benzyl positions in sequence using an in situ generated LICKOR-type superbase. The flow approach in the microreactor facilitated the comprehensive exploration of over 100 conditions in the first-step reaction by varying concentrations, temperatures, solvents, and equivalents of reagents, enabling optimal conditions to be found with 95 % yield by significantly suppressing the formation of byproducts, followed by the second C-H metalation step in 95 % yield. Moreover, gram-scale synthesis of ibuprofen in the final step was achieved by biphasic flow reaction of solution-phase intermediate with CO2 , isolating 2.3 g for 10 min of operation time.

Direct Synthesis of a Covalently Self-Assembled Peptide Nanogel from a Tyrosine-Rich Peptide Monomer and Its Biomineralized Hybrids.

There has been significant progress in the self-assembly of biological materials, but the one-step covalent peptide self-assembly for well-defined nanostructures is still in its infancy. Inspired by the biological functions of tyrosine, a covalently assembled fluorescent peptide nanogel is developed by a ruthenium-mediated, one-step photo-crosslinking of tyrosine-rich short peptides under the visible light within 6 minutes. The covalently assembled peptide nanogel is stable in various organic solvents and different pH levels, unlike those made from vulnerable non-covalent assemblies. The semipermeable peptide nanogel with a high density of redox-active tyrosine acts as a novel nano-bioreactor, allowing the formation of uniform metal-peptide hybrids by selective biomineralization under UV irradiation. As such, this peptide nanogel could be useful in the design of novel nanohybrids and peptidosomes possessing functional nanomaterials.

Control of tandem isomerizations: flow-assisted reactions of o-lithiated aryl benzyl ethers.

Tandem chemical changes are often difficult to control at will, because they proceed rapidly through multiple unstable reactive intermediates. It is desirable to develop a novel method for controlling such tandem changes to obtain desired products with high selectivity. Herein, we report a flow microreactor platform for controlling tandem isomerizations of o-lithiated aryl benzyl ethers based on precise residence time control.

Flow-Assisted Synthesis of [10]Cycloparaphenylene through Serial Microreactions under Mild Conditions.

Cycloparaphenylene (CPP) has been recognized as an attractive template for the bottom-up synthesis of carbon nanotubes with uniform diameter, and is important for the chemistry of graphitic as well as ring-shaped macromolecules. However, the reported routes from halogenated benzenes have suffered from low yields even under time- and labor-consuming multistep conditions. Herein we report a flow-assisted synthesis of [10]CPP in four steps under mild conditions. For the synthesis, a selective nucleophilic addition of the unprotected diketone without the double-added byproduct was achieved within 3 s in high yield. Subsequently, the obtained compound was reacted with dilithiated benzene at 25 °C to form a U-shaped precursor for CPP in a separate microreactor, which was finally dimerized and aromatized to obtain [10]CPP by a two-step in-flask reaction. Precise control of time and flow facilitated by the flow-assisted system enabled the development of an efficient synthetic route for [10]CPP.

Integrated one-flow synthesis of heterocyclic thioquinazolinones through serial microreactions with two organolithium intermediates.

The synthesis of pharmaceutical compounds via short-lived intermediates in a microreactor is attractive, because of the fast flow and high throughput. Additionally, intermediates can be utilized sequentially to efficiently build up a library in a short time. Here we present an integrated microfluidic synthesis of biologically active thioquinazolinone libraries. Generation of o-lithiophenyl isothiocyanate and subsequent reaction with aryl isocyanate is optimized by controlling the residence time in the microreactor to 16 ms at room temperature. Various S-benzylic thioquinazolinone derivatives are synthesized within 10 s in high yields (75-98%) at room temperature. These three-step reactions involve two organolithium intermediates, an isothiocyanate-functionalized aryllithium intermediate, and a subsequent lithium thiolate intermediate. We also demonstrate the gram-scale synthesis of a multifunctionalized thioquinazolinone in the microfluidic device with a high yield (91%) and productivity (1.25 g in 5 min).

A pressure-tolerant polymer microfluidic device fabricated by the simultaneous solidification-bonding method and flash chemistry application.

Pressure-tolerant polymer-glass microfluidic reactors with excellent bonding strength have been fabricated by the simultaneous solidification-bonding (SSB) method, in which a viscous and reactive matrix polymer was cast on the glass substrate with pre-patterned wax as a sacrificial template. Elaborate interfacial chemistry between the matrix polymer and the functionalized glass surface was designed to achieve simultaneous solidification and chemical bonding under UV or/and mild thermal conditions (<200 °C with no pressure). Highly pressure-tolerant microchannels were obtained by complete removal of the liquid wax template at 80 °C. Versatility was demonstrated by fabricating microreactors from various polymers with different interfacial chemistry, which were all stable at 1000 psi with the highest burst pressure of 2000 psi. In particular, the fluoropolymer-glass microreactor can withstand a burst pressure that is two orders of magnitude higher than that of the microchannel made by the conventional method. Finally, the polymer-glass microfluidic device was used for the synthesis of a natural product, tryptanthrin, by flash chemistry under high pressure induced conditions (synthetic yield: 90%, flow rate: 10.5 mL min(-1), reaction time: 14 ms). The transparent microfluidic device can be used as a useful platform for miniaturizing spectroscopic tools for chemical analysis studies under high pressure conditions.

Three-dimensional flash flow microreactor for scale-up production of monodisperse PEG-PLGA nanoparticles.

We present a pressure-tolerant 3D parallel polyimide (PI) film microreactor operating at up to ~160 bars with direct 3D flow focusing geometry for mass production of PEG-PLGA nanoparticles in a ~10(1) gram-scale (g h(-1)).