Research on Chemicals and Custom Synthesis

A series of continuous flow chemistry processes that facilitate the palladium-catalysed carbonylation of aryl and vinyl iodides and aryl bromides with a range of alkoxy, hydroxy and amino nucleophiles is reported. Harnessing a semipermeable Teflon® AF-2400 Tube-in-Tube assembly, these reactors permit the controlled transport of carbon monoxide into solution at elevated pressure to generate homogeneous flow streams, avoiding some potential issues associated with segmented flow gas-liquid reactors. As the volume of pressurised gas contained within the device is low, the hazards associated with this are potentially mitigated relative to comparable batch processes. We also show how the incorporation of a second in-line gas-flow reactor allows for the sequential introduction of two gases (carbon monoxide and a gaseous nucleophile) into the reaction stream.

The study of Pd-catalysed cyclisation reactions of alkenols using different catalytic systems is reported. These transformations affect the stereoselective construction of mono- and/or bicyclic oxaheterocyclic derivatives depending on a starting alkenol. The substrate scope and proposed mechanism of Pd-catalysed cyclisation reactions are also discussed. Moreover, the diastereoselective Pd-catalysed cyclisation of appropriate alkenols to tetrahydrofurans and subsequent cyclisation provided properly substituted 2,5-dioxabicyclo[2.2.1]heptane and 2,6-dioxabicyclo[3.2.1]octane, respectively. Such bicyclic ring subunits are found in many natural products including ocellenynes and aurovertines.

A concise, asymmetric formal synthesis of (+)-pyrenolide D from (E)-crotonaldehyde is described. The key steps include an enantioselective Sharpless dihydroxylation of protected hex-4-en-1-yn-3-ol and a highly diastereoselective palladium-catalysed oxycarbonylation of (2R,3S,4S)-hex-5-ene-2,3,4-triol using iron pentacarbonyl as the carbon monoxide source.

A simple tube-in-tube reactor based on the gas-permeable membrane Teflon AF-2400 was used in the continuous flow reaction of gaseous ammonia with isothiocyanates and one isocyanate. A colourimetric in-line titration technique is also reported as a simple method to quantify the amount of ammonia taken up by the solvent in the system.

A nine-step (longest linear) batch total synthesis of the cyclic hexadepsipeptide (−)-enniatin B is described. The synthesis minimizes precipitation during reaction conditions for adaptability to flow synthesis. The route was used to prepare >100 mg of the natural product.

We report on the development of a new prototype magnetic field induced flow mixer for application to flow equipment in research laboratories. This new device, designed for both agitating and mixing in tubular reactors has proven useful under a number of experiments. Furthermore, the simple design allows a variety of different sized devices to be assembled straightforwardly.

A newly developed microscale ReactIR flow cell was used as a convenient and versatile inline analytical tool for Grignard formation in continuous flow chemical processing. The LiCl-mediated halogen/Mg exchange reaction was used for the preparation of functionalized arylmagnesium compounds from aryl iodides or bromides. Furthermore, inline IR monitoring was used for the analysis of conversion and possible byproduct formation, as well as a potential tool for elucidation of mechanistic details. The results described herein indicate that the continuous flow systems are effective for highly exothermic reactions such as the Grignard exchange reaction due to fast mixing and efficient heat transfer.

We report a continuous flow, rhodium-catalysed hydroformylation of various styrenes using a tube-in-tube gas-liquid reactor. The flow process afforded selectively branched aryl aldehydes in good yields.

We report a palladium-catalysed ethylene Heck reaction for the vinylation of aryl iodides using a tube-in-tube gas-liquid reactor. The flow process afforded various styrenes in short reaction times, employing moderate ethylene pressure.

We report on the development of a continuous flow process for the palladium catalysed methoxycarbonylation of aryl, heteroaromatic and vinyl iodides and an aryl bromide using a Teflon AF-2400 based Tube-in-Tube reactor to mediate the selective permeation of carbon monoxide into solution at elevated pressures. The low volume of pressurised gas within the reactor (5.6 mL) offers the potential for an enhanced safety profile compared to batch processes. We also present preliminary results for the use of in situFTIR to measure solution concentrations of carbon monoxide and demonstrate the use of a second reactor to effect the removal of carbon monoxide from the flow stream.