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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Publication 9: MW and Flow Syntheses of Pseudomonas Quinolone Signal (PQS)
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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.
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Publication 8: Bohlmann-Rahtz Cyclodehydration Reaction
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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.
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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.
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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.
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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.
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Publication 4: Tetrazole formation
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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.
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Publication 3: Hofman rearrangement
The Hofman rearrangement of amides into their corresponding carbamates works well under flow-through conditions.
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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.
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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.
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