Click, Click Zoom……new Cu catalyst developments, Click Huisgen cycloadditions

Rather than spend a chunk of time outlining developments of monoliths or scavengers, I decided that it would be better to push out some of the new ideas and exploration. We are aware that a number of groups are using Cu catalysts beds and cartridges, but a new publication uses a microchannel itself as the Cu source — followed closely behind the mixing of an azide and alkyne for the requisite step……love it. This process gives way to trying several types of catalysts to look at turnover numbers (TONs) and mechanisms themselves. For me, I would take the best and make a larger catalyst bed out of it so that scaling can be an option as well. Enough of that — collaborative groups out of Japan (Chemistry 2015) show us the way with their investigation of a Huisgen cycloaddition from the generation of 4 microchannel polymeric Cu membranes (will make you read into the formation — it looks elegant and formally pretty easy)– once formed azides and terminal acetylenes are flowed through the microchannels in a 3:1 mixture of Acetone:H2O at 50C in a residence time of 8 sec (some a few seconds longer, hahaha!– there is a difference in the the catalytic activity of each of the microchannel membranes but the reactivity is a significant enhancement over traditional catalysts and worth a note that flow can be a real progress to not only this chemistry but the concept in general.

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Microchannel A or catalyst A if you prefer shows the best results from their study and also helps us recognize the differences in the Cu source and a preferred mechanism. Read further into what they propose as to why the process is so efficient — I have included a snapshot of their photos of the channel following the formation and post 24 hrs. Several options are available in the selection of solvent for the reaction as well. Further reading indicates that the reaction is available for more complexity and added functional groups adding to its’ utility.

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I have included a table for their screening of the membrane A to show that this process is amenable to screening and library development – a criteria now maintained in the flow community for medicinal chemistry traction — hopefully there will be a number of people who take up the role of improving these possibilities rather than rely on commercial availability as a precursor. I see this as a natural trend to the development of these catalysts into a bed or bound so that it is amenable to standard medicinal chemistry processes (they did show some more advanced application to the development)……one can hope, right?

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Enjoy the read!

Advances in two critical areas of flow synthesis: Metalation and Photochemistry

Seems that photocatalysis has become front and center in 2015 with no signs of slowing down — much of this has been due to improved methodology and catalyst development – and finding profound chemistries to apply. For me, it has added new and exciting space to flow chemistry, basic research and drug discovery (well specialty chemicals as well). having said that, I still notice a hesitation in application simply because a large percentage of chemists haven’t spent a lot of time around these transformations — couple that with slow traction of chemists digging into flow methods. It is however, something the newer batch (haha!) of chemists are gravitating to and we will start to see a large number of dedicated publications in photo and improvements on flow metalations.

An interesting but not as recent as you would think comes out of the MIT flow group in 2012-2013 utilizing visible light photoredox catalysis in flow. As is with the case of general flow synthesis (over a catalyst bed or at high temp and pressure) the larger surface to volume ratio allows for more control of temp and reaction times — and in this case more efficient irradiation. Within the paper, both oxidative and reductive provide some extremely powerful synthetic manipulations under these conditions and provide a nice framework to advance some of the initial ideas. Overcoming traditional batch light penetration with simple PFA tubing suggests that scale-up of once difficult batch processes will be easily overcome.

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Take a look through some schemes that we would normally think of in medicinal chemistry efforts — Easy to perform and powerful — too bad I missed the boat on this one. Enjoy the read — it is thought provoking.

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The second area I have been keeping an ear to the ground comes in the newer development in metalation — usually in regard to arenes or heteroarenes and the requisite quench. Expansion out of nBuLi to other Lithiates or Mg, Zn and other possibilities certainly seems to pave a way for new reactions with commercial reactors or at least some ideas on how to apply to your own reactor. Having discussions with fellow chemists on their approach to activate arenes with subsequent quenches remains high on the list of powerful methodologies so improvements that traditional batch chemists can sink their teeth in flow will go a long way in pushing people over to new ways to do their work. A recent publication (Chemical Science, 2015) out of Knochel’s lab provides some insight into a modified flow/batch scheme with Cy2NLi activation in flow followed by a variety of quenches — great to see a commercially available reagent applied with success so that we understand what we can and can’t do….really valuable stuff. Looks to me that we can start to design all sorts of reactions — both high temp/high pressure or simplified kinetic processes over cooling liter reactions to -78C.

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Happy Reading!