Continuous flow chemistry: a discovery tool for new chemical reactivity patterns

Hartwig, Jan; Metternich, Jan B.; Nikbin, Nikzad; Kirschning, Andreas; Ley, Steven V.

doi:10.1039/c4ob00662c

Cited by 67 publications

(44 citation statements)

References 42 publications

(13 reference statements)

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“…Interesting examples relative to drug development are proposed by Roberge et al [16]. Results relative to reaction paths unrealizable in batch mode are also presented [17]. Finally, flow chemistry has been very effectively described as a way to expand the process window [11,12].…”

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confidence: 99%

Chemical reaction engineering, process design and scale-up issues at the frontier of synthesis: Flow chemistry

Rossetti

Compagnoni

2016

Chemical Engineering Journal

200

103

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Flow chemistry has been proposed in modern organic chemistry as a mean for process intensification, to improve the control over reaction performance and to achieve higher yield. However, many open issues can be evidenced regarding the true possibility of scale-up, as well as currently lacking information for process design and economical evaluation. This review proposes some recent examples of flow synthesis deepening in particular the scale-up and engineering issues. Required information is evidenced, as well as some transport and kinetic data required for the practical implementation of the results.

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confidence: 99%

Chemical reaction engineering, process design and scale-up issues at the frontier of synthesis: Flow chemistry

Rossetti

Compagnoni

2016

Chemical Engineering Journal

200

103

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“…The aim of this Communication is to demonstrate that recent advances in flow chemistry, particularly the development of self-optimizing reactors, not only can accelerate the identification of byproducts but also can lead to the discovery of unexpected reactions. [3] Self-optimizing reactors combine a computer-controlled continuous reactor with in-line analysis to adjust reaction conditions automatically to control the outcome of the reaction, [4] see Figure 1. We have previously demonstrated that, for a reaction that can give rise to two different products, such a reactor can be optimized to maximize the yield of either product.…”

Section: Introductionmentioning

confidence: 99%

Automated Serendipity with Self‐Optimizing Continuous‐Flow Reactors

et al. 2015

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A self‐optimizing approach is used as a tool for targeting known and unknown materials in the continuous reaction of aniline, dimethyl carbonate (DMC) and tetrahydrofuran (THF) in supercritical CO2 on γ‐Al2O3. The study led to the formation of methylated anilines or carbamate derivatives and unusual addition products with THF including pyrrolidines and N‐alkylated anilines. The identification of these products leads to the development of a plausible mechanism for the reactions. The system not only demonstrates a high flexibility that the self‐optimization approach provides, including the ability to optimize for a variety of products by using a single catalyst, but also the ability to discover unexpected and original synthetic reactions.

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“…6 In recent times, transition metal chemistry has dominated C-C bond cross-coupling strategies. [7][8][9][10][11][12][13] This powerful approach has been central to the planning and execution of modern synthesis programs both in academia and industry.…”

Section: Introductionmentioning

confidence: 99%

“…[2][3][4][5] While many such sequences are known, there is still room to exploit new reactivity patterns and different chemical combinations derived from reactive intermediates. 6 In recent times, transition metal chemistry has dominated C-C bond cross-coupling strategies. [7][8][9][10][11][12][13] This powerful approach has been central to the planning and execution of modern synthesis programs both in academia and industry.…”

Section: Introductionmentioning

confidence: 99%

Iterative reactions of transient boronic acids enable sequential C–C bond formation

et al. 2016

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(2016). Iterative reactions of transient boronic acids enable sequential C-C bond formation. Nature Chemistry, 8 (4), 360-363. Copyright and re-use policySee http://shura.shu.ac.uk/information.html Sheffield Hallam University Research Archivehttp://shura.shu.ac.uk The ability to form multiple carbon-carbon bonds in a controlled sequence and thus rapidly build molecular complexity in an iterative fashion is an important goal in modern chemical synthesis. In recent times, transition metal-catalysed coupling reactions have dominated in the development of C-C bond forming processes. A desire to reduce the reliance on precious metals and a need to obtain products with very low levels of metal impurities has brought a renewed focus on metal-free coupling processes. Here, we report the in situ preparation of reactive allylic and benzylic boronic acids, obtained by reacting flow-generated diazo compounds with boronic acids, and their application in controlled iterative C-C bond forming reactions is described. Thus far we have shown the formation of up to three C-C bonds in a sequence including the final trapping of a reactive boronic acid species with an aldehyde to generate a range of new chemical structures. Iterative reactions of transient boronic acids enable sequential C-C bond formation IntroductionThe generation of C-C bonds is at the heart of synthetic organic chemistry. 1 The ability to form multiple C-C bonds using iterative or one-pot methods allows a rapid increase in molecular complexity.2-5 While many such sequences are known, there is still room to exploit new reactivity patterns and different chemical combinations derived from reactive intermediates. 6 In recent times, transition metal chemistry has dominated C-C bond cross-coupling strategies. [7][8][9][10][11][12][13] This powerful approach has been central to the planning and execution of modern synthesis programs both in academia and industry. Nevertheless, the desire of industry to reduce its reliance on the use of precious metals in coupling reactions and the need for very low metal levels in active pharmaceutical ingredients has increased interest in metal-free coupling processes considerably. 14 Boronic esters 15 and acids 16 are considered to be important coupling partners as they are versatile intermediates for the preparation of a wide variety of molecules. For example, Barluenga 17 and others [18][19][20] recently demonstrated the powerful application of a reductive metal-free cross-coupling between tosylhydrazones and boronic acids. The reaction likely proceeds via a carbene-like species which on combination with a boronic acid initiates a sequence of reactions that terminates in the formation of a coupling product. However, high temperatures are necessary to affect these coupling processes so that any further exploitation of potentially useful intermediates in the reaction has not been possible so far.From our own mechanistic studies based on the use of flow-generated diazo compounds, 21 in the metal-free cross-coupling with aryl boronic a...

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Continuous flow chemistry: a discovery tool for new chemical reactivity patterns

Abstract: A new reactivity pattern and extended reaction scope has been obtained by transferring a reaction from batch mode to flow.

Cited by 67 publications

References 42 publications

Chemical reaction engineering, process design and scale-up issues at the frontier of synthesis: Flow chemistry

Chemical reaction engineering, process design and scale-up issues at the frontier of synthesis: Flow chemistry

Automated Serendipity with Self‐Optimizing Continuous‐Flow Reactors

Iterative reactions of transient boronic acids enable sequential C–C bond formation

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