FlowSyn Application Notes

3-Hydroxy-4-quinolones can be prepared in 5 min at 220oC under continuous flow-through conditions. The reaction is readily scalable.

• Note 24: 3-hydroxy-4-quinolone

Many useful reactions in chemical synthesis can be considerably accelerated when run at high temperature under microwave-assisted conditions. However, for scale-up the need to empty and refill conventional batch microwave vessels coupled with repetitive heating up and cooling down cycles is both inconvenient and decreases throughput. In this Application Note we describe the continuous flow synthesis of 2-methylbenzimidazole which can be achieved more conveniently in 30 seconds at 200oC under continuous flow-through conditions in the FlowSyn.

• Note 23: Benzimidazoline Synthesis

Nitration is an important synthetic procedure that is often difficult to control. Under continuous flow-through conditions, however, exotherms are typically well controlled and nitration can be safely performed on a large scale.

• Note 22: Flow Nitration

Electrophilic bromination is a rapid and exothermic reaction that can be difficult to control to prevent bis-bromination in batch. Both temperature and mixing can be well controlled using a mixer chip in flow, leading to a highly reproducible outcome.

• Note 21: Electrophilic Bromination

Transfer hydrogenation is a synthetically useful technique that enables hydrogenation to be effected without the need for hydrogen gas. Under superheated conditions in the flow reactor, a benign solvent such as ethanol may be used at high temperature, and is easily removed by evaporation at the end of the reaction.

• Note 20: Transfer Hydrogenation

The Suzuki-Miyaura cross-coupling reaction is widely used in synthesis for the preparation of biaryls. However, under homogeneous batch conditions the need to remove the metal catalyst can make product purification difficult. This difficulty can largely be circumvented by operating in a continuous flow-through regime using an immobilised source of palladium.

• Note 19: Suzuki Miyaura

Flow-through conditions afford a high degree of control over reaction parameters. It is frequently possible to perform selective reactions by optimisation of flow conditions. An example follows in which selective reduction of the nitro group can be reproducibly achieved simply by increasing the flow rate.

• Note 18: Transfer hydrogenation of aminoquinoline

The Newman-Kwart rearrangement is a useful method for converting Ar-O to Ar-S bonds that can be further derivatised following basic hydrolysis of the S-thiocarbamate

• Note 17: Newman Kwart Rearrangement

The rate of the Fischer indole synthesis can be significantly increased by running at high temperature and pressure under conditions similar to those encounter in a batch microwave reactor.

• Note 16: Fischer Indole Synthesis

Mark C. Bagley,* Vincenzo Fusillo, M. Caterina Lubinu. School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, UK

• Note 15: Bohlman Rahtz

Catch-and-release is a powerful technique that can is well-suited to implementation in flow. In this Application Note a small set of S-alkyl thiobenzimidazolines is prepared as an illustration of this strategy.

• Note 14: 'Catch and Release' Array Synthesis

Thomas Wirth* and Johan Brandt, School of Chemistry, Cardiff University, Park Place, Cardiff, CF10 3AT, UK

• Note 12: Condensation Reaction

Thomas Wirth*, Johan Brandt, School of Chemistry, Cardiff University, Park Place, Cardiff, CF10 3AT, UK

• Note 11: Ester Hydrolysis under Segmented Plug Flow Conditions

Pressurised continuous flow reactors provide a convenient method for performing reactions with ammonia at elevated temperature. [Mark C. Bagley,* Vincenzo Fusillo, M. Caterina Lubinu. School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, UK]

• Note 10: Hantzsch DHP

Flow chemistry provides an intrinsically safer procedure for the Curtius rearrangement whereby the quantity of potentially explosive acyl azide intermediate is minimised through continuous processing to the stable final carbamate product.

• Note 9: Curtius Rearrangement

Zyvox™ (Upjohn) was the first example of a new class of oxazolidinone antibiotics that are active against MRSA. In this example, the scale-up abilities of FlowSyn™ are demonstrated by performing the first step in a possible synthesis of this compound on a 100 g scale.

• Note 8: Scale-up Synthesis of a Zyvox Intermediate

An alternative example to that given in Application Note 6 to afford a thio-heterocycle in high purity following in-line purification

• Note 7: Chlorothio- benzimidazolinone Synthesis

Thiono-acylation followed by an in-line flow through purification is a convenient approach to thiobenzimidazolinones

• Note 6: 2-Thiobenzimidazolinone Synthesis

Condensation chemistry can work well under flow-through conditions. Even when, as in this case, there is no provision for removal of the water.

• Note 5: Esterification (2)

FlowSyn Application Note 4: Esterification

• Note 4: Esterification (1)

Flow optimization was used to investigate the effects of temperature and residence time. Scale up of these conditions afforded 84% yield of the product with a throughput of 261g/day.

• Note 3: Knorr Pyrazole Synthesis

The Ester Hydrolysis reaction was optimized using various temperatures, reaction times and stoichiometry. The reaction was scaled up to provide 92% yield and 105g/day throughput.

• Note 2: Ester Hydrolysis

Nucleophilic aromatic substitution works extremely well under continuous flow- through conditions

• Note 1: SNAr