Sustainable Electrochemical Decarboxylative Acetoxylation of Aminoacids in Batch and Continuous Flow

2021 ◽  
Author(s):  
Manuel Köckinger ◽  
Paul Hanselmann ◽  
Dominique Roberge ◽  
Piero Geotti-Bianchini ◽  
C. Oliver Kappe ◽  
...  
Keyword(s):  
Continuous Flow ◽  
Organic Molecules ◽  
Oxidative Decarboxylation ◽  
Active Ingredients ◽  
Synthetic Intermediates

Introduction of acetoxy groups to organic molecules is important for the preparation of many active ingredients and synthetic intermediates. A commonly used and attractive strategy is the oxidative decarboxylation of...

scholarly journals Sustainable Electrochemical Decarboxylative Acetoxylation of Aminoacids in Batch and Continuous Flow

2021 ◽  
Author(s):  
Manuel Köckinger ◽  
Paul Hanselmann ◽  
Dominique M. Roberge ◽  
Pierro Geotti-Bianchini ◽  
C. Oliver Kappe ◽  
...  
Keyword(s):  
Amino Acids ◽  
Continuous Flow ◽  
Flow Mode ◽  
Oxidative Decarboxylation ◽  
Pharmaceutical Ingredients ◽  
Synthetic Amino Acids ◽  
Electrochemical Approach ◽  
Synthetic Intermediates ◽  
Space Time Yield ◽  
Aliphatic Carboxylic Acids

Introduction of acetoxy groups to organic molecules is important for the preparation of many active ingredients and synthetic intermediates. A commonly used and attractive strategy is the oxidative decarboxylation of aliphatic carboxylic acids, which entails the generation of a new C(sp3)-O bond. This reaction has been traditionally carried out using excess amounts of harmful lead(IV) acetate. A sustainable alternative to stoichiometric oxidants is the Hofer-Moest reaction, which relies in the 2-electron anodic oxidation of the carboxylic acid. However, examples showing electrochemical acetoxylation of amino acids are scarce. Herein we present a general and scalable procedure for the anodic decarboxylative acetoxylation of amino acids in batch and continuous flow mode. The procedure has been applied to the derivatization of several natural and synthetic amino acids, including key intermediates for the synthesis of active pharmaceutical ingredients. Good to excellent yields were obtained in all cases. Transfer of the process from batch to a continuous flow cell signficantly increased reaction throughput and space-time yield, with excellent product yields obtained even in a single-pass. The sustainability of the electrochemical protocol has been examined by evaluating its green metrics. Comparison with the conventional method demonstrates that an electrochemical approach has a significant positive effect on the greenness of the process

scholarly journals Sustainable Electrochemical Decarboxylative Acetoxylation of Aminoacids in Batch and Continuous Flow

2021 ◽  
Author(s):  
Manuel Köckinger ◽  
Paul Hanselmann ◽  
Dominique M. Roberge ◽  
Pierro Geotti-Bianchini ◽  
C. Oliver Kappe ◽  
...  
Keyword(s):  
Amino Acids ◽  
Continuous Flow ◽  
Flow Mode ◽  
Oxidative Decarboxylation ◽  
Pharmaceutical Ingredients ◽  
Synthetic Amino Acids ◽  
Electrochemical Approach ◽  
Synthetic Intermediates ◽  
Space Time Yield ◽  
Aliphatic Carboxylic Acids

Introduction of acetoxy groups to organic molecules is important for the preparation of many active ingredients and synthetic intermediates. A commonly used and attractive strategy is the oxidative decarboxylation of aliphatic carboxylic acids, which entails the generation of a new C(sp3)-O bond. This reaction has been traditionally carried out using excess amounts of harmful lead(IV) acetate. A sustainable alternative to stoichiometric oxidants is the Hofer-Moest reaction, which relies in the 2-electron anodic oxidation of the carboxylic acid. However, examples showing electrochemical acetoxylation of amino acids are scarce. Herein we present a general and scalable procedure for the anodic decarboxylative acetoxylation of amino acids in batch and continuous flow mode. The procedure has been applied to the derivatization of several natural and synthetic amino acids, including key intermediates for the synthesis of active pharmaceutical ingredients. Good to excellent yields were obtained in all cases. Transfer of the process from batch to a continuous flow cell signficantly increased reaction throughput and space-time yield, with excellent product yields obtained even in a single-pass. The sustainability of the electrochemical protocol has been examined by evaluating its green metrics. Comparison with the conventional method demonstrates that an electrochemical approach has a significant positive effect on the greenness of the process

scholarly journals Non-Aqueous Continuous-Flow Electrophoresis (NACFE): Separation Complement for Continuous-Flow Organic Synthesis

2019 ◽  
Author(s):  
Nikita A. Ivanov ◽  
Yimo Liu ◽  
Sven Kochmann ◽  
Sergey N. Krylov
Keyword(s):  
Steady State ◽  
Organic Synthesis ◽  
Flow Separation ◽  
Continuous Flow ◽  
Organic Molecules ◽  
Water Electrolysis ◽  
Organic Salt ◽  
Aqueous Electrolytes ◽  
Differential Distribution ◽  
Steady State Operation

<div>Continuous-flow organic synthesis naturally requires continuous-flow separation of reaction components. The most common continuous-flow separation approach is liquid-liquid extraction based on differential distribution of molecules between organic and aqueous phases. This approach has limited selectivity; it can hardly separate different hydrophobic organic molecules from each other. Continuous-flow electrophoresis can facilitate much more selective separation in a single phase, but it is currently limited to aqueous electrolytes which are incompatible with many hydrophobic organic molecules. Further, water electrolysis in aqueous electrolytes results in generation of large volumes of gas making steady-state operation a major technical challenge. Here, we introduce non-aqueous continuous-flow electrophoresis (NACFE) in which the electrolyte is a solution of an organic salt in an aprotic organic solvent. We demonstrate that NACFE can maintain stable separation of multiple species during 10 hours. The non-aqueous nature of NACFE and its ability to support steady-state operation make it suitable for its incorporation into continuous-flow organic synthesis.</div>

Robust Organic Photosensitizers Immobilized on a Vinylimidazolium Functionalized Support for Singlet Oxygen Generation under Continuous-Flow Conditions

Synlett ◽  
2020 ◽  
Vol 31 (05) ◽  
pp. 497-501 ◽  
Author(s):  
Koichiro Masuda ◽  
Yao Wang ◽  
Shun-ya Onozawa ◽  
Shigeru Shimada ◽  
Nagatoshi Koumura ◽  
...  
Keyword(s):  
Singlet Oxygen ◽  
Rose Bengal ◽  
Crucial Role ◽  
Continuous Flow ◽  
Organic Molecules ◽  
Continuous Operation ◽  
Flow Conditions ◽  
Oxygen Generation ◽  
Singlet Oxygen Generation ◽  
Flow Reaction

Rose Bengal was immobilized on a vinylimidazolium functionalized support, and the heterogeneous organic photosensitizer thus prepared was applied for photooxidation reactions of organic molecules under continuous-flow conditions. Substituents of the cation part of the support were found to play a crucial role in determining the lifetime of the catalyst. More than 11 days continuous operation of a flow reaction was achieved.

scholarly journals Development of a continuous process for α-thio-β-chloroacrylamide synthesis with enhanced control of a cascade transformation

2016 ◽  
Vol 12 ◽  
pp. 2511-2522 ◽  
Author(s):  
Olga C Dennehy ◽  
Valérie M Y Cacheux ◽  
Benjamin J Deadman ◽  
Denis Lynch ◽  
Stuart G Collins ◽  
...  
Keyword(s):  
Continuous Flow ◽  
Continuous Process ◽  
Continuous Processing ◽  
Synthetic Intermediates ◽  
Selective Generation ◽  
Flow Reaction ◽  
Process Strategy

A continuous process strategy has been developed for the preparation of α-thio-β-chloroacrylamides, a class of highly versatile synthetic intermediates. Flow platforms to generate the α-chloroamide and α-thioamide precursors were successfully adopted, progressing from the previously employed batch chemistry, and in both instances afford a readily scalable methodology. The implementation of the key α-thio-β-chloroacrylamide casade as a continuous flow reaction on a multi-gram scale is described, while the tuneable nature of the cascade, facilitated by continuous processing, is highlighted by selective generation of established intermediates and byproducts.

scholarly journals Visualization of Streams of Small Organic Molecules in Continuous-Flow Electrophoresis

2019 ◽  
Author(s):  
Nikita A. Ivanov ◽  
Sven Kochmann ◽  
Sergey N. Krylov
Keyword(s):  
Continuous Flow ◽  
Organic Molecules ◽  
Limit Of Detection ◽  
Flow Chemistry ◽  
Quantitative Detection ◽  
Component Mixture ◽  
Seamless Integration ◽  
Small Organic Molecules ◽  
Separation Chamber ◽  
Rectangular Chamber

Continuous-flow electrophoresis (CFE) separates a stream of a multi-component mixture into multiple streams of individual components inside a thin rectangular chamber. CFE will be able to benefit flow chemistry when it is capable of generically detecting streams of small organic molecules. Here we propose a general approach for molecular stream visualization via analyte-caused obstruction of excitation of a fluorescent layer underneath the separation chamber – fluorescent sublayer-based visualization (FSV). We designed and fabricated a CFE device with one side made of quartz and another side made of UV-absorbing visibly-fluorescent, chemically-inert, machinable plastic. This device was demonstrated to support non-aqueous CFE of small organic molecules and quantitative detection of their streams in real-time with a limit of detection below 100 µM. Thus, CFE may satisfy conditions required for its seamless integration with continuous flow organic synthesis in flow chemistry.<br>

Non-Aqueous Continuous-Flow Electrophoresis (NACFE): Separation Complement for Continuous-Flow Organic Synthesis

2019 ◽  
Author(s):  
Nikita A. Ivanov ◽  
Yimo Liu ◽  
Sven Kochmann ◽  
Sergey N. Krylov
Keyword(s):  
Steady State ◽  
Organic Synthesis ◽  
Flow Separation ◽  
Continuous Flow ◽  
Organic Molecules ◽  
Water Electrolysis ◽  
Organic Salt ◽  
Aqueous Electrolytes ◽  
Differential Distribution ◽  
Steady State Operation

<div>Continuous-flow organic synthesis naturally requires continuous-flow separation of reaction components. The most common continuous-flow separation approach is liquid-liquid extraction based on differential distribution of molecules between organic and aqueous phases. This approach has limited selectivity; it can hardly separate different hydrophobic organic molecules from each other. Continuous-flow electrophoresis can facilitate much more selective separation in a single phase, but it is currently limited to aqueous electrolytes which are incompatible with many hydrophobic organic molecules. Further, water electrolysis in aqueous electrolytes results in generation of large volumes of gas making steady-state operation a major technical challenge. Here, we introduce non-aqueous continuous-flow electrophoresis (NACFE) in which the electrolyte is a solution of an organic salt in an aprotic organic solvent. We demonstrate that NACFE can maintain stable separation of multiple species during 10 hours. The non-aqueous nature of NACFE and its ability to support steady-state operation make it suitable for its incorporation into continuous-flow organic synthesis.</div>

Non-Aqueous Continuous-Flow Electrophoresis (NACFE): Separation Complement for Continuous-Flow Organic Synthesis

2019 ◽  
Author(s):  
Nikita A. Ivanov ◽  
Yimo Liu ◽  
Sven Kochmann ◽  
Sergey N. Krylov
Keyword(s):  
Steady State ◽  
Organic Synthesis ◽  
Flow Separation ◽  
Continuous Flow ◽  
Organic Molecules ◽  
Water Electrolysis ◽  
Organic Salt ◽  
Aqueous Electrolytes ◽  
Differential Distribution ◽  
Steady State Operation

<div>Continuous-flow organic synthesis naturally requires continuous-flow separation of reaction components. The most common continuous-flow separation approach is liquid-liquid extraction based on differential distribution of molecules between organic and aqueous phases. This approach has limited selectivity; it can hardly separate different hydrophobic organic molecules from each other. Continuous-flow electrophoresis can facilitate much more selective separation in a single phase, but it is currently limited to aqueous electrolytes which are incompatible with many hydrophobic organic molecules. Further, water electrolysis in aqueous electrolytes results in generation of large volumes of gas making steady-state operation a major technical challenge. Here, we introduce non-aqueous continuous-flow electrophoresis (NACFE) in which the electrolyte is a solution of an organic salt in an aprotic organic solvent. We demonstrate that NACFE can maintain stable separation of multiple species during 10 hours. The non-aqueous nature of NACFE and its ability to support steady-state operation make it suitable for its incorporation into continuous-flow organic synthesis.</div>

Recent Trends in Group 9–Catalyzed C−H Borylation Reactions: Different Strategies to Control Site-, Regio-, and Stereoselectivity

Synthesis ◽  
2021 ◽  
Author(s):  
Lukas Veth ◽  
Hanusch Grab ◽  
Pawel Dydio
Keyword(s):  
Organic Chemistry ◽  
Transition Metal ◽  
Medicinal Chemistry ◽  
Organic Molecules ◽  
Recent Literature ◽  
Control Site ◽  
High Abundance ◽  
Future Potential ◽  
Recent Trends ◽  
Synthetic Intermediates

Organoboron compounds continue contributing substantially to advances in organic chemistry with their increasing role as both synthetic intermediates and target compounds for medicinal chemistry. Particularly attractive methods of their synthesis are based on the direct borylation of C−H bonds of available starting materials since no additional pre-functionalization steps are required. However, due to the high abundance of C−H bonds with similar reactivity in organic molecules, synthetically useful C−H borylation protocols demand sophisticated strategies to achieve high regio- and stereoselectivity. For this purpose, selective transition-metal-based catalysts have been developed, with group 9-centered catalysts being among the most commonly utilized. Recently, a multitude of diverse strategies has been developed to push the boundaries of C−H borylation reactions with respect to their regio- and enantioselectivity. Herein, we provide an overview of approaches for the C−H borylation of arenes, alkenes, and alkanes based on group 9-centered catalysts with a focus on the recent literature. Lastly, an outlook is given to assess the future potential of the field.

scholarly journals Late-stage trifluoromethylthiolation of benzylic C-H bonds

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Wentao Xu ◽  
Wenliang Wang ◽  
Tao Liu ◽  
Jin Xie ◽  
Chengjian Zhu
Keyword(s):  
Continuous Flow ◽  
Large Scale ◽  
Organic Molecules ◽  
Initiation Mechanism ◽  
Radical Initiation ◽  
Simple Protocol ◽  
Synthetic Methodologies ◽  
Site Selective ◽  
Complex Organic ◽  
Fluoroalkyl Group

Abstract The benzylic positions in drugs are sites that readily react with cytochrome P450 oxidases via single-electron oxidation. New synthetic methodologies to incorporate a fluoroalkyl group at the benzylic site are continually being developed, and in this paper, we report a metal-free and site-selective organophotoredox-catalyzed trifluoromethylthiolation of benzylic C-H bonds for a wide variety of alkyl arenes and heteroarenes. The precise and predictive regioselectivity among various C(sp3)-H bonds originates from an inner-sphere benzylic radical initiation mechanism, and avoids the use of external oxidants or hydrogen atom abstractors. Its practicality stems from the trifluoromethylthiolation of a series of drugs and complex organic molecules, which is overwhelmingly selective for benzyl groups. This operationally simple protocol can provide a general and practical access to structurally diverse benzylic trifluoromethyl sulfides produced from ubiquitous benzylic C-H bonds. Large scale trifluoromethylthiolation can be achieved with continuous flow photoredox technology.

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