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A greener and sustainable flow chemistry protocol for the synthesis of 3,3-disubstituted indolenines through interrupted Fischer indolisation reaction is described. First, two model aldehydes were reacted with phenylhydrazine in order to explore the reaction feasibility in a ‘greener’ fashion in batch mode. The best outcomes were then used as the starting point for the implementation of the reaction in continuous flow. A thorough exploration of key parameters allowed the identification of the most efficient reagent mixing mode, and the optimum temperature and residence time. The newly developed method allowed straightforward reaction channelling towards the formation of the indolenines, thus reducing the competitive formation of side products. We further broadened the scope of the conceived methodology by exploring the possibility of a heterogeneous in-line reduction of the indolenines to their indoline counterparts. This rapid approach nicely complements known batch chemistry and could facilitate synthesis and scale up of 3,3-disubstituted indolenines and indolines, offering a coupling point for additional and subsequent flow reactions for multistep syntheses for further derivatization.

Over the past decade, the integration of synthetic chemistry with flow processing has resulted in a powerful platform for molecular assembly that is making an impact throughout the chemical community. Herein, we demonstrate the extension of these tools to encompass complex natural product synthesis. We have developed a number of novel flow-through processes for reactions commonly encountered in natural product synthesis programs to achieve the first total synthesis of spirodienal A and the preparation of spirangien A methyl ester. Highlights of the synthetic route include an iridium-catalyzed hydrogenation, iterative Roush crotylations, gold-catalyzed spiroketalization and a late-stage cis-selective reduction.

In order to use segmented chemical flow processing in more complex reaction sequences, a method has been developed to precisely control the addition of reagent streams during multi-step operations. Using in-line infra-red monitoring with a new LabVIEW software application, it is possible to control additional pumps to dispense further reagents in real time based upon the concentration of reaction intermediates. This enables precise mixing with perfect timing thus greatly increasing product quality and enabling segmented chemical flow processing to be used in extended reaction sequences. © The Royal Society of Chemistry 2011.

Herein we describe the application of a monolithic triphenylphosphine reagent to the Appel reaction in flow-chemistry processing, to generate various brominated products with high purity and in excellent yields, and with no requirement for further off-line purification.

A supported version of N-(tert-butyl)phenylsulfinim-idoyl chloride on a monolithic material is described, which can be incorporated into a flow chemical processing arrangement to oxidise a variety of substrates in both stoichiometric and catalytic processes to yield products in high yields and in high purity after in-line workup.

Diastereoselective chain-elongation reactions are important transformations for the assembly of complex molecular structures, such as those present in polyketide natural products. Here we report new methods for performing crotylation reactions and homopropargylation reactions by using newly developed low-temperature flow-chemistry technology. In-line purification protocols are described, as well as the application of the crotylation protocol in an automated multi-step sequence. Polyketides in flow: By using new low-temperature reactors, the scope of reactions conveniently performed in a flow process has been extended to encompass diastereoselective chain elongations. Various aldehydes undergo Roush crotylations and Marshall homopropargylation reactions smoothly in flow (see scheme), with incorporated in-line work-ups that drastically reduce the amount of time required for these transformations.

A newly developed ReactIR flow cell is reported as a convenient and versatile inline analytical tool for continuous flow chemical processing. The flow cell, operated with ATR technology, is attached directly into a reaction flow stream using standard OmniFit (HPLC) connections and can be used in combination with both meso- and microscale flow chemistry equipment. The iC IR analysis software (version 4.0) enables the monitoring of reagent consumption and product formation, aiding the rapid optimisation of procedures. Short-lived reactive intermediates can also be observed in situ, giving further mechanistic insight into complex transformations.