However, we've mentioned it again as a result of the publication featured below, Continuous proline catalysis via leaching of solid proline. (This paper is open access)

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They cover

- Michael Addition of nitromethane to a cinnamate ester

- Reduction of N-Boc Protected amines using lithium aluminium hydride.

- Optimisation and scale-up of an SNAr using a highly volatile reagent (which would require a pressurised bomb reactor if performed in batch)

Munich, Germany
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York, UK
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Boston, USA
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Mumbai, India
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Singapore
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François Lévesque¹

Peter H. Seeberger ¹ ²

 

¹Department for Biomolecular Systems, Max-Planck Institute for Colloids and Interfaces, Potsdam, Germany

²Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany

 

Malaria is a serious global health issue. Artemisinin combination treatments are the first-line drugs, but supplies are limited because artemisinin is obtained solely by extraction from Artemisia annua. A continuous-flow process that converts dihydroartemisinic acid into artemisinin (see scheme) is shown to be an inexpensive and scalable process that can ensure a steady, affordable supply of artemisinin.

 

Suzanne M. Opalka¹

Ashley R. Longstreet²  

D. Tyler McQuade²

 

¹Department of Chemistry and Chemical Biology, Cornell University, USA

²Department of Chemistry and Biochemistry, Florida State University, USA

 

Herein, we demonstrate that a homogeneous catalyst can be prepared continuously via reaction with a packed-bed of a catalyst precursor. Specifically, we perform continuous proline catalyzed a-aminoxylations using a packed-bed of L-proline. The system relies on a multistep sequence in which an aldehyde and thiourea additive are passed through a column of solid proline, presumably forming a soluble oxazolidinone intermediate. This transports a catalytic amount of proline from the packed-bed into the reactor coil for subsequent combination with a solution of nitrosobenzene, affording the desired optically active a-aminooxy alcohol after reduction. To our knowledge, this is the first example in which a homogeneous catalyst is produced continuously using a packed-bed. We predict that the method will not only be useful for other L-proline catalyzed reactions, but we also foresee that it could be used to produce other catalytic species in flow.

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Juan de M. Muñoz¹

Jesús Alcázarv

Antonio de la Hoz²

Angel Díaz-Ortiz²

¹Janssen,  Toledo, Spain

²Facultad de Ciencias Químicas, Universidad de Castilla-La Mancha, Spain

 

The reduction of esters to aldehydes is an important transformation in organic chemistry and several reducing agents have been described. However, the use of this reaction in medicinal and natural product chemistry is limited due to the instability of the intermediates and the high reactivity of the reaction products. In the current article, the general and selective reduction of esters with diisobutyl-tert-butoxyaluminum hydride in flow is reported. This reagent allows esters to be reduced in the presence of different functional groups, including those considered to be of similar or higher reactivity.

 

Rainer E. Martin ¹

Falk Morawitz ¹

Christoph Kuratli ¹

André M. Alker ² 

Alexander I. Alanine¹

 

 

Pyrimidine alkynes can be transformed into the corresponding annulated pyridines efficiently in flow. The superheating of organic solvents far beyond their boiling point enables toxic and difficult to workup solvents such as nitrobenzene or chlorobenzene, which are usually employed for these reactions, to be replaced by less harmful ones like toluene. The relative rate of reactivity for a series of structurally close starting materials was investigated and a scalable flow process was developed, providing facile access to a series of novel annulated pyridine building blocks. 

 

 

Kimberley A. Roper¹

Heiko Lange¹

Anastasios Polyzos¹

Malcolm B. Berry²

Ian R. Baxendale¹

Steven V. Ley¹

¹Innovative Technology Centre, University of Cambridge, UK

²GlaxoSmithKline, Stevenage,  UK

 

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.

Jens Wegner

Sascha Ceylan

Andreas Kirschning

 

Institut für Organische Chemie and Biomolekulares Wirkstoffzentrum (BMWZ), 

Leibniz Universität Hannover, Germany

 

Laboratory scaled flow-through processes have seen an explosive development over the past decade and have become an enabling technology for improving synthetic efficiency through automation and process optimization. Practically, flow devices are a crucial link between bench chemists and process engineers. The present review focuses on two unique aspects of modern flow chemistry where substantial advantages over the corresponding batch processes have become evident. Flow chemistry being one out of several enabling technologies can ideally be combined with other enabling technologies such as energy input. This may be achieved in form of heat to create supercritical conditions. Here, indirect methods such as microwave irradiation and inductive heating have seen widespread applications. Also radiation can efficiently be used to carry out photochemical reactions in a highly practical and scalable manner. A second unique aspect of flow chemistry compared to batch chemistry is associated with the option to carry out multistep synthesis by designing a flow set-up composed of several flow reactors. Besides their role as chemical reactors these can act as elements for purification or solvent switch.

 

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See you in March (in the Chinese New Year of the Dragon).