From functional materials to biologically active compounds, the role of organic synthesis has been expanding continuously. Accordingly, the power and speed of organic synthesis should be enhanced to meet future demands for synthesis of various organic molecules. In this context, conventional step-by-step synthesis is being supplemented with integrated synthesis that combines multiple reactions in a single operation in one pot or in a flow system without isolating the intermediates. Reaction integration can be classified into three types: (a) Time and space integration, where all reaction components are mixed at once to perform a sequence of reactions simultaneously in a single batch reactor, (b) time integration, where reaction components are added at intervals of time to perform a sequence of reactions in a single batch reactor, and (c) space integration, where a sequence of reactions is performed in different reactors using a continuous flow system. Prof. Jun-ichi Yoshida opened a new field of organic synthesis based on time integration and space integration of reactions using unstable reactive intermediates. The following is a brief summary of his achievements.

1. Reaction Integration Using Cationic Reactive Intermediates
Organic cations have been widely used in organic synthesis as intermediates, but they are usually unstable, and therefore, should be generated in the presence of nucleophiles. Yoshida developed the "cation pool" method that involves generation and accumulation of unstable organic cations in the absence of nucleophiles by low-temperature electrolysis followed by a subsequent reaction with a nucleophile. Based on the "cation pool" method he developed new transformations based on time integration of reactions, such as integration of electrochemical oxidation and a radical reaction and that of electrochemical oxidation and chemical oxidation. In addition, he applied the method to the synthesis of functional materials such as dendronized polymers using dendritic cations.
He also studied space integration of cationic reactions using flow microreactors, which enable manipulation of highly unstable short-lived cationic intermediates by taking advantage of short residence times, and developed new transformations such as cationic three-component coupling reactions. The invention of a new method for living cationic polymerization based on the use of cationic active polymer ends before they decompose by virtue of short residence times is also noteworthy. The method does not need capping agents that are indispensable for conventional living cationic polymerization.

2. Reaction Integration Using Anionic Reactive Intermediates
Flow microreactors make it possible to conduct extremely fast reactions that are complete within seconds or less. Yoshida named such chemistry "flash chemistry" and successfully applied it not only to integration of cationic reactions but also to integration of anionic reactions. Organolithium species serve as powerful cabanion equivalents and are widely used in organic synthesis, but such species often suffer from difficulty in controlling their reactions because of high reactivity and low stability. For example, o-bromophenyllithium generated by lithiation of o-dibromobenzene easily decomposes to give benzyne, and therefore the reactions should be carried out at very low temperatures, such as -110℃, to use it for the subsequent reaction with electrophiles. However, Yoshida found that the reaction can be conducted at higher temperatures by using flow microreactors by virtue of the short residence times. Based on this finding, he developed a simple and straightforward method for synthesis of o-disubstituted benzenes from o-dibromobenzene by repeating the sequence of lithiation-reaction with an electrophile based on space integration. This method could also be successfully applied to the synthesis of other multisubstituted benzenes and photochromic diarylethenes. He also achieved space integration of different types of reactions, such as integration of lithiation and transition metal catalyzed cross-coupling.
In general, organolithium species react very rapidly with electrophilic functional groups such as carbonyl groups, and therefore such groups should be protected prior to an organolithium reaction, if they are not involved in the desired transformation. If organolithium chemistry could be free from such a limitation, its power would be greatly enhanced. Yoshida showed that a flow microreactor enables such protecting-group-free organolithium reactions by greatly reducing the residence time. For example, aryllithium species bearing ketone carbonyl groups are generated by lithiation of the corresponding aryl halides and can be reacted with various electrophiles such as aldehydes using a flow microreactor. The present method was successfully applied to the formal synthesis of a natural polyphenol, Pauciflorol F.
Yoshida also showed that flow microreactors allow generation and use of configurationally unstable chiral organolithium species in a reaction with an electrophile before they epimerize. Based on this method, the enantioselective carbolithiation of conjugated enynes followed by reaction with electrophiles was accomplished to obtain enantiomerically enriched chiral allenes. In addition, Yoshida invented a method for analyzing reactions using temperature-residence time contour maps to obtain a deeper insight into the features of reactions under continuous flow conditions. The method serves as a powerful tool for developing new synthetic reactions in flow systems.
In summary, Prof. Yoshida developed various transformations that are difficult to achieve by conventional methods based on the concept of reaction integration via short-lived, highly reactive intermediates. Such reaction integration greatly enhanced the power and capability of organic synthesis and opened a new aspect of this field. His contribution is highly valued worldwide, and therefore he deserves The Chemical Society of Japan Award.