Flow Chemistry - Publications

To find out more about flow chemistry experiments using the FlowSyn system, please consult the following publications in the academic press.

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Publication 26: Flow Synthesis of the Neurotensin-1 Receptor Probe Meclinertant (SR48692)

A synthesis of the neurotensin 1 receptor probe Merclinertant (SR48692) has been reported using a range of continuous flow through synthesis, in-line reaction monioring and purification techniques. This strategy has been contrasted with a more conventional batch synthesis approach.

Notably the safe use of phosgene gas (generated in situ), the superheating of solvents to accelerate reaction rates, the processing of a reagent suspension under continuous flow-through conditions and the application of semi-permeable membrane technology to facilitate work-up and purification were all techniques that could be beneficially applied in the synthetic scheme.

Publication 25: 2-Amino-Adamantane-2-Carboxylic Acid

A new flow-through, multi-step synthesis of the achiral unnatural amino acid 2-amino-2-adamantane-2-carboxylic acid has recently been reported by Ley's group.

The synthetic route employs a series of transformations that employ different mesoflow reactors. Notably all intermediates were isolated in high purity without the need for column chromatographic purification, thereby rendering the route suitable for scale-up.The automated flow synthesiser could be used successfully under the harsh reaction conditions.

Publication 24: Direct Synthesis of Amides under Flow-Through Conditions

Amides can be synthesised continuously by condensation of carboxylic acids and amines under flow-through conditions in the presence of activated catalysts prepared from structured mesoporous silicas.

Structured mesoporous silicas (SBAs) are benign materials that were found to offer increased reaction rates in comparison to chromatographic silicas and are therefore particularly suited to continuous processing.

Publication 23: Stereospecific synthesis of Alpha-Hydroxyacids by Diazotisation of Amino Acids

Alpha-hydroxy acids are useful chiral starting materials in total synthesis. They may be conveniently obtained by direct diazotisation and hydrolysis of the corresponding alpha-amino acids.

Under continuous flow-through conditions, diazotisation may be achieved safely on scale.

In addition, a flexible and fully automated protocol for continuous liquid-liquid extraction is presented which allows for the continuous extractive work-up and isolation of multi-gram quantities of these useful compounds.

Publication 22: Efficient Reduction of Nitroarenes under Continuous Flow Conditions using an In-situ generated Nanoparticular Iron Oxide

An efficient continuous flow-through process for the reduction of nitroarenes in the presence of nanoparticular Fe2O3 is reported. 

The nanoparticles were conveniently produced in-situ using soluble Fe(acac)3 in the presence of hydrazine as the reducing agent and remain in solution throughout. After product isolation, aggregation of the nanoparticles occurs facilitating their removal using a magnet.

Notably multi-gram quantities of compounds could be readily processed.

Publication 21: Continuous Flow Reaction Monitoring using a Miniature On-line Mass Spectrometer

A revolutionary new miniature ESI mass spectrometer has been used to directly monitor on-line the products emerging from a mesoscale flow synthesiser.

In this way, it was possible to observe unstable reaction intermediates and by monitoring trends in selected ion peak heights it was possible to quickly identify optimal reaction conditions for synthesis of the desired reaction product.

In general, this approach provides a detailed and informative snapshot of a flow-through chemical process. Analysis by on-line MS is usefully complementary to alternative methods of both on-line and in-line monitoring of flow chemistries.

Publication 20: SynGas-Mediated Hydroformylation of Styrenes under Flow-Through Conditions

A continuous flow-through approach to the hydroformylation of alkenes using SynGas (1:1 H2:CO) under homogeneous conditions in a 'tube-in-tube' reactor under conditions is reported.

A range of conditions were studied for a model substrate to determine the dependence on reaction temperature, residence time, gas pressure, solvent and rhodium pre-catalyst/ligand composition. In this way, it was possible to identify conditions that afforded the desired aldehyde product in both high yield and with high selectivity.

Moreover the approach was extended to demonstrate who the starting styrene could also be formed under continuous flow-through conditions prior to hydroformylation.

Publication 19: Small Molecule Library Synthesis using Segmented Flow

A straightforward strategy for the rapid synthesis of compound libraries thiazoles and pyrazoles under continuous flow-through conditions is presented.

Sequential reactions were performed in small segments ('plugs') of DMF as reaction solvent, each segment being separated from its neighbour by a plug of immiscible fluorous solvent (F-40).

To avoid cross-contamination, each reaction segment was followed by a segment of pure DMF solvent.

Similar results were obtained compared to those using a batch microwave, but the individual reactions were able to be performed more rapidly in a sequential manner.

Publication 18: Continuous Production of Oxamic Acid Derivatives in the Mild, Metal-free reduction of Diazonium Salts to Hydrazines

The use of ascorbic acid for the mild, metal-free reduction of in situ formed diazonium salts is presented. 

The oxamic acid derivatives thus formed have the potential to act as latent hydrazines.

The ability to perform this chemistry under continuous flow-through conditions reduces considerably the risk of explosion when dealing with both diazonium salts and hydrazines on scale.

Publication 17: Synthesis of Mono-acyl 1,4-Diamines from Hydrazoic Acid under Continuous Flow-through Conditions

A fast and efficient high temperature protocol for the ring opening of 2-oxazolines to generate mono-acyl 1,4-diamines under continuous flow-through conditions has been reported by Kappe's group in Graz.

Their approach involves the in situ generation of hydrazoic acid by methanolysis of trimethylsilylazide and concomitant reaction with an appropriate 2-oxazoline.

Ring opening of 2-oxazolines under acidic conditions is an important route to the mono-acyl 1,4-diamine moiety found in neuraminidase inhibitors such as GSK's Zanamivir. The ability to perform this reaction in a continuous manner without the potential of accumulating explosive hydrazoic acid in the head space of a batch reactor affords an inherently safer process for large scale synthesis.

Publication 16: Preparation of Cisplatin under Microwave and Continuous Flow-through Conditions

Inorganic Flow Chemistry: The preparation of cisplatin, one of the most widely used anti-cancer drugs in the world, is reported on a small scale in a batch microwave reactor and this procedure is scaled up by translation to flow.

Notably, this approach produces cisplatin in high isolated yield free from Magnus' salt, a commonly encountered impurity that is particularly difficult to remove.

Publication 15: A Scaleable Continuous Flow-Through Synthesis of Nabumetone and Related 4-Aryl-2-butanones

Kappe's group have explored a variety of continuous flow-through approaches to the synthesis of the NSAID Nabumetone and related fragrant 4-aryl-2-butanones.

Their strategy illustrates how reaction optimisation may initially be performed on a small scale in the batch microwave and then directly scaled by translation to electrically heated continuous flow-through devices.

Seemless scaling of the flow synthesis platform up to a throughput of 2.7L/h is also demonstrated as an elegant illustration of the ease and reproducibility that it is possible to achieve through the scaling of continuous flow-though processes without the need for reoptimisation of reaction conditions.

Publication 14: Continuous Flow Oxidation of Alcohols with Bleach in the Presence of Catalytic Tetrabutyammonium Bromide

Oxidation: The continuous flow-through oxidation of alcohols to aldehydes, and aldehydes in the presence of methanol to methyl esters is reported to occur in ethyl acetate in the presence of 12.5% bleach and catalytic tetrabutylammonium bromide.
The oxidation conveniently occurs at room temperature within 5-30 min under segmented flow conditions.
Publication 13: Synthesis of Aryl Boronic Acids via Low Temperature Metal-Halogen Exchange

Boronic acids are versatile intermediates in synthesis that are typically used to form C-C, C-O and C-N bonds under metal catalysed conditions.

Although many are commercially available, the formation of boronic acids from bespoke halogenated intermediates is often required, particularly in drug discovery programmes.

Typically this is done via low temperature metal halogen exchange reactions.

In a recent publication, workers from Cambridge demonstrate the use of the new 'Polar Bear' cryo-flow reactor in combination with the direct pumping of n-butyllithium solutions from the reagent bottle for extended periods of time to afford boronic acids on demand in synthetically useful quantities.

Publication 12: Palladium Catalysed Alkoxycarbonylation in Flow

Carbonylation under flow-through conditions: The direct alkoxycarbonylation of aryl halides in the presence of carbon monoxide is an important and useful reaction in synthesis that is well suited to continuous flow-through implementation. Leadbeater’s Group have reported that efficient gas/liquid mixing can be achieved under segmented flow conditions affording high conversion to carbonylated product with a preparatively useful throughput of up to 0.2 mole/hr.

Under the reported conditions reactions are typically complete in 5-10 min at 120oC in the presence of only 0.5 mol% of palladium acetate catalyst.

Publication 11: Hydrogenation in flow: Homogeneous and heterogeneous catalysis using Teflon AF-2400 to effect gas–liquid contact at elevated pressure

Gas addition under flow-through conditions: Ley’s group in Cambridge, describe a tube-in-tube gas liquid reactor/saturation module based on a gas-permeable Teflon AF-2400 membrane, which allows both heterogeneous and homogeneous catalytic hydrogenation reactions to be efficiently carried out at elevated pressure in flow. The study demonstrates that a continuous hydrogen gas saturated solvent stream can be produced in seconds and that, if necessary, excess gas can be conveniently removed by using a second module to which a partial vacuum is applied.

The introduction of other gases such as CO, CO2, ethene, and ethyne under flow-through conditions can be achieved in a similar way.

Publication 10: Safe and Efficient Tetrazole Synthesis in Continuous Flow

Safer flow: Jamison's group at MIT have reported an expedient synthesis of 5-substituted tetrazoles in flow that is safe, scalable, requires no metal promoter, and uses a near-equimolar amount of sodium azide; yet nonetheless displays a broad substrate scope.

The hazards associated with hydrazoic acid are essentially eliminated, shock-sensitive metal azides such as zinc (II) azide are avoided, and any residual sodium azide is quenched in-line with sodium nitrite.

Publication 9: MW and Flow Syntheses of Pseudomonas Quinolone Signal (PQS)

Spring and collaborators at Cambridge have recently reported expedient syntheses of Pseudomonas quinolone quorum sensing signal and related structural analogues using microwave and flow-through protocols.

The flow-through approach facilitated the scale up synthesis of PQS in multi-gram quantities.

Publication 8: Bohlmann-Rahtz Cyclodehydration Reaction

In a study to exemplify the use of continuous flow processing to scale up microwave batch reactions, Bagley's group in Cardiff examined the Bohlmann-Rahtz pyridine synthesis. They found that both glass microreactors and stainless steel coil reactors were equally effective, the latter giving a higher throughput.

Discreprancies observed between optimised conditions in batch and flow-through microwave reactors and conductively heated continuous flow reactors were attributed to a lack of certainty in accurately measuring the temperature at the point of reaction in the microwave devices.

Publication 7: Preventing Premature Product Precipitation in Flow

The introduction of a suitable organic solvent into the outflow line of a continuous flow reactor is shown to be a useful and pragmatic solution to prevent reaction products from precipitating prematurely.

In particular, this approach facilitates the direct scale up of many microwave protocols without the need to first identify a 'better' solvent or perform extensive reaction optimisation or modification.

Publication 6: Permanganate Oxidation in Continuous Flow

The continuous flow-through oxidation of alcohols and aldehydes in the presence of aqueous potassium permanganate affords carboxylic acids. Under similar conditions nitroalkanes afford the corresponding carbonyls and carboxylic acids.

This process is readily scalable and, when run under pulsed ultrasonication conditions, blockage of the flowpath by the co-formation of manganese dioxide slurries did not occur.

Publication 5: Bioinspired Silicas in Flow

Continuous processing offers considerable scope for the preparation of new materials possessing specifically engineered properties.

Patwardhan and Perry have shown how engineered silica particles can be reproducibly prepared under bioinspired conditions in a continuous flow coil reactor. Functionalised silicas prepared encapsulating the enzyme invertase were shown to retain enzymic activity, and additionally silica and colloidal gold composites were prepared that retained optical activity.

Such materials hold considerable potential for application in biocatalysis and photonics.

Publication 4: Tetrazole formation

Kappe's group have recently described an elegant method for the continuous flow synthesis of 5-substituted 1H-tetrazole derivatives via addition of in situ generated hydrazoic acid to organic nitriles. Under optimized conditions tetrazole compounds are formed with quantitative conversion in residence times of a few minutes, providing excellent purities and yields of isolated product.

Publication 3: Hofman rearrangement

The Hofman rearrangement of amides into their corresponding carbamates works well under flow-through conditions.

Publication 2: Alpha-ketoesters

A continuous flow-through approach to alpha-keto esters has been reported that utilises a combination of supported reagents to deliver products in high yield and purity with out the need for further purification.

Publication 1: BDA Tartrates

A readily scalable synthesis of BDA protected tartrates has been reported by a continuous flow-through strategy utilising immobilised reagents and scavengers packed into reactor columns.

Copyright Uniqsis Ltd 2013