This paper describes a liquid-liquid biphasic flow reaction system that is simple to control. In a liquid-liquid biphasic flow reaction, the slug-flow in the tube reactors generally improves the reaction rate. However, we show that larger tube diameters decreased the reaction rate and the formation of the slug-flow was influenced by the tube diameter, the size of the mixer, and the pump mechanism. These results indicated that technical difficulties with the slug-flow could be an obstacle to scale-up. To resolve this problem, we suggest the use of a Taylor vortex flow reactor to achieve a higher reaction rate than with batch and slugflow systems.

This work presents a case study of process development using continuous flow synthesis. In developing a process for manufacturing drug substances in batch reactors, we unexpectedly obtained a significant amount of a trimerized byproduct on addition of MeMgBr to an aldehyde. Consideration of a plausible generation mechanism for the byproduct indicated that it arose from a reaction between the starting material and the Mg salt of the target product. This led us to try applying continuous flow synthesis to the process to shorten the time during which the starting material coexists with the Mg salt of the target product. This led to drastic suppression of the byproduct under very mild conditions and the establishment of a more robust process than that for batch reactors.

The asymmetric alkynylation of aliphatic and aromatic aldehydes with propiolates was mediated by dialkylzinc and a novel prolinol catalyst without high reagent loading and any additives, such as Ti(Oi-Pr)(4), to give the corresponding γ-hydroxy-α,β-acetylenic esters with high enantiomeric excess of up to 95%.

This work presents a guideline for managing process safety under continuous flow conditions. In our previous work, we developed a Grignard reaction for use under such conditions. This reaction was completed in seconds and entailed a large amount of heat generation. To manage the heat of reaction, we quantitatively analyzed the reaction rate using ReactIR with a flow cell. The difference between quantitative values from HPLC and ReactIR was less than 1%, and the reaction rate was 94% in 0.4 s. Based on the reaction rate and the heat of reaction, we simulated the distribution of the internal temperature along the tube length and found the maximum difference from the measured internal temperatures to be 5 °C. This accuracy was suitable for evaluating and managing the heat of reaction. Our methodology can facilitate the discussion of process safety under continuous flow conditions.

This work established the integration of a continuous flow reaction and continuous crystallization using Taylor vortex flow reactors. We previously developed liquid–liquid biphasic flow alkylation using a Taylor vortex flow reactor, which is a scalable flow reactor with high mixing efficiency. To maximize the efficiency of this methodology, we evaluated process parameters and instrumental parameters, such as the rotating speed and tilt of the reactor, and optimized the reaction conditions. As a result, the throughput increased more than 20-fold compared to our previous work, and a long-run experiment verified its robustness. Liquid–liquid biphasic flow alkylation, quenching, phase separation, continuous crystallization, and filtration were integrated by using Taylor vortex flow reactors for both the flow reaction and continuous crystallization. The integrated system using two Taylor vortex flow reactors provided the alkylated product continuously from the solution of the starting material.

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A one-pot convenient access to chiral 2-oxazolidinones is described. Diethylzinc-mediated asymmetric alkynylation of aldehydes with propiolates in the presence of b-sulfonamide alcohol as the chiral ligand, followed by treatment with isocyanates, yielded chiral 4-alkylidene-2-oxazolidinones.Avid interest in modern organic chemistry has been directed toward the development of simple and convenient ways to access useful heterocyclic compounds under mild and environmentally friendly conditions. Multicomponent reactions (MCR) have recently emerged as a valuable tool for the preparation of chemical libraries of druglike heterocyclic compounds. 1 2-Oxazolidinones play prominent roles in daily life. They are widely used in pharmaceutical manufacturing, 2 agriculture, and industry, and as chiral auxiliaries in organic synthesis. 3 Among the many methods for the syntheses of 2-oxazolidinones, 4 the 5-exo cyclization of O-propargyl or O-allyl carbamates is one of the most attractive methods because it enables easy access to various substituted 2-oxazolidinones. The base-promoted cyclization of Opropargyl carbamates has long been established. 5 The intermolecular hydroamination of O-propargyl carbamates in the presence of a transition metal, such as Cu 2+ or Au + salt, has also been reported. 6 Baba and co-workers reported that the addition of allyltin reagents to a,b-unsaturated aldehyde, followed by treatment with isocyanates, gave 2-oxazolidinones in one-pot reactions. 7 Herein, we report the one-pot, three-component synthesis of chiral 4-alkylidene-2-oxazolidinones with aldehydes, propiolates, and isocyanates.Although the asymmetric alkynylation of carbonyl compounds by zinc acetylides is a well-known method for the synthesis of chiral propargyl alcohol derivatives, 8 the resulting zinc alkoxides have been scarcely used for further transformation as most zinc-oxygen bonds are hydrolyzed to propargyl alcohols despite their sufficient nucleophilicity. We devised a one-pot synthesis of chiral 2-oxazolidinones, which involved asymmetric alkynylation of aldehydes with propiolates, followed by treatment with isocyanates. Initial screening of the reaction conditions demonstrated that the conditions developed by Wang's group 9 gave the best results for our purpose.Diethylzinc-mediated (3.0 equiv) asymmetric alkynylation of cyclohexanecarbaldehyde (1.0 equiv) with ethyl propiolate (3.0 equiv) in the presence of Ti(Oi-Pr) 4 (30 mol%) and 1,2-dimethoxyethane (DME, 1.0 equiv) using b-sulfonamide alcohol (30 mol%) as the chiral ligand in toluene at room temperature, followed by treatment with tosyl isocyanate (3.2 equiv), afforded (R,E)-4-alkylidene-3-tosyloxazolidin-2-one 1a in 77% yield with good enantioselectivity 10 and complete E-stereoselectivity 11 (Table 1, entry 1). 12,13 To demonstrate the generality of this method, we examined the scope and limitations of the present one-pot synthesis (Table 1). The reaction with methyl or tert-butyl propiolates in place of ethyl propiolate also proceeded under the same conditions and ...

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