As part of the dramatic changes associated with the need for preparing compound libraries in pharmaceutical and agrochemical research laboratories, the search for new technologies that allow automation of synthetic processes has become one of the main topics. Despite this strong trend for automation high-throughput chemistry is still carried out in batches, whereas flow-through processes are rather restricted to production processes. This is far from understandable because the main advantages of that approach are facile automation, reproducibility, safety, and process reliability, because constant reaction parameters can be assured. Indeed, methods and technologies are missing that allow rapid transfer from the research level to process development without time-consuming adaptation and optimization of methods from the laboratory scale to production plant scale. Continuous-flow processes are considered as a universal lever to overcome these restrictions and, only recently, joint efforts between synthetic and polymer chemists and chemical engineers have resulted in the first continuous-flow devices and microreactors; these allow rapid preparation of compounds with minimum workup. Many of these approaches use immobilized reagents and catalysts, which are embedded in a structured flow-through reactor. It is generally accepted, that for achieving best reaction and kinetic parameters for convective-flow processes monolithic materials are ideally suited as solid phases or polymer supports. In addition, immobilization techniques have to be developed that allow facile regeneration of the active species in the reactor.

Heterogeneous catalysis for organic synthesis under continuous‐flow conditions becomes possible by a new reactor‐based approach. Continuous‐flow reactors with a monolithic glass/polymer composite interior are loaded with palladium particles by ion exchange followed by reduction. When incorporated into a continuous‐flow setup (PASSflow) this reactor allows the transfer‐hydrogenation of alkenes, alkynes, nitro‐substituted aromatic compounds and benzyl ethers in the flow‐through mode. In addition, the activity of the catalysts is well suited to achieve Suzuki, Sonogashira and Heck cross‐coupling reactions in the absence of phosphanes or any other ligands, resulting in a greatly simplified purification. As an extension to this concept a bifunctional support was prepared inside the reactor consisting of Pd particles and an ion‐exchange group (hydroxide form). In the Suzuki− Miyaura reaction the reactor serves as a base for immobilisation and activation of the boronic acid as boronate and as a catalyst for promoting the C−C coupling reaction under continuous‐flow conditions. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

The realm of combinatorial chemistry is strongly based on the concept of parallel chemistry and its ease of automation. Although this batch-type approach in general may be considered a success story, some limitations remain rarely addressable by conventional approaches. Particularly, scaling-up problems such as the re-synthesis of multigram amounts of active compounds as well as the synthesis of building blocks and scaffolds in large amounts may prove to be problematic. Our expertise in continuous chemistry prompted us to develop a microreaction system for sequential organic synthesis that should overcome these limitations. In the present contribution we describe this system as well as its application to the first library approach towards fluoro-quinolone antibiotics such as Ciprofloxacin solely using microreaction technology. A known one-pot batch procedure for the synthesis of this compound class was split in its individual reaction steps, which were successfully adapted to a continuous conduct. After some optimisation studies the overall sequence was suitable for chemical diversification. Particularly it was shown, that the first step of the synthesis -the acylation reaction of a b-dimethylamino acrylate with trifluoro-benzoic acid chloride -was accessible to synthesis of high quantities without any difficulties to yield a primary building block suitable for subsequent library synthesis. In a first diversification step, the Michael addition of a set of primary amines was followed by nucleophilic ring closure providing the difluoroquinolone system, which was subjected to a second diversification step by means of a nucleophilic aromatic substitution reaction. Thus, a number of Ciprofloxacin analogues could be synthesised in good overall yield and purity. Isolated yields ranged from 71 to 85% in the first diversification step and from 59 to 99% in the second step.

As part of the dramatic changes associated with automation in pharmaceutical and agrochemical research laboratories, the search for new technologies has become a major topic in the chemical community. Commonly, high-throughput chemistry is still carried out in batches whereas flow-through processes are rather restricted to production processes, despite the fact that the latter concept allows facile automation, reproducibility, safety, and process reliability. Indeed, methods and technologies are missing that allow rapid transfer from the research level to process development. Continuous flow processes are considered as a universal lever to overcome these restrictions and only recently, joint efforts between synthetic and polymer chemists and chemical engineers have resulted in the first continuous flow devices and microreactors which allow rapid preparation of compounds with minimum workup. Importantly, more and more developments combine the use of immobilized reagents and catalysts with the concept of structured continuous flow reactors. Consequently, the present article focuses on this new research field, which is located at the interface of continuous flow processes and solid-phase-bound catalysts.

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