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!

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Flow ideas: Expanding the possibilities in Med Chem

Just read an article (Molecules 2014) on flow through hydrogenations through the eyes of a medicinal chemist….sort of. A combination out of Baxendale and Ley is a contribution in the area of heterocyclic construction using an appropriately placed hydrogenation of an aromatic nitro group, strategically located to take place in a subsequent reaction to form advanced riboflavins, quinoxalinones and benzodiazepines…..each important in their place as strong pharmacophores.

Two things that stick out to me as important: how do they arrive at a final working method and what were the issues….when you read an article by these authors it will inevitably have this information present and that is the type of discussion that will help push the area of flow chemistry forward. For instance, in the first scheme below, the group needs a diamine functionality and over-reduction of an aromatic halogen took place with Pd/C but not with PtO2 (ha, how many times have you read a BIOMCL — the things that don’t work are not discussed)— and this is likely made more challenging by the fact that they had to heat the reaction to 45C for the reaction to work well and use MeOH to keep the materials in solution for the duration of the reaction. The nice thing about the reaction is that it was easily be performed and optimized for catalyst using the H-Cube by ThalesNano. Another piece of anecdotal information — the diamine is typically not stable for any appreciable length of time — but can be used in the subsequent step. The scheme below indicates the two possibilities for the reaction — and note that the condensation here was done in batch fashion for 10 hrs at room (must decompose the diamine with heat because 10 hours is a long time).

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Although they applied the same methodology to a quinoxalinone series, I am going turn our attention to the work done on benzodiazepines. Work on the scaffold is traditionally considered older — with new developments as a rarity — I know my early research included an aza-version of this and it felt like a total synthesis. For the storyline, some conditions needed some attention in order to move to a complete flow system. For example to build the amino-nitro diarene, they chose a microwave mediated SNAR reaction of a fluoro-nitro arene and the requisite aniline. Fortunately, I have discussed this type of reaction in a past post so there is some development utilizing this approach — in this case, however, the aniline is deprotonated with LHDMS and irradiated in the presence of the fluoroarene to produce the diaryl scaffold in high yields in a short amount of time. The product was redissolved and hydrogenated and cyclo-dehydrated to provide the benzodiazepine in high yield. To adequately handle the dehydration, an in-line MgSO4 filled glass Omnifit column was placed subsequent to the flow hydrogenation (again – H-Cube with in-line MgSO4).

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The great thing about the microwave method is that it provided a good reaction starting point for a medicinal chemist planning a library for some initial screening hits. The bad news is that scale-up in this fashion would require a different microwave or a continuous flow method if additional testing or to get the compound through an entire cascade an on its’ way to animal studies….this group recognizes this as a key criteria in developing the technology and therefore worked out a method for the first step in a continuous format. Prior to jumping into the flow conditions, the 2-step process provided a nice route into the desired compounds with microwave (1) and flow (2) method.

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In moving over to the flow conditions, the base and mixing were critical for the execution. Although the scheme helps you follow the format, three separate lines were used to form a good process with n-BuLi in channel A, the amino-benzophenone in channel B and the fluoroarene waiting in channel C, with the appropriate mixing chambers and T or Y-lines adjusted to provide the mixing and timestamps for delivery of reactants/reagents. The initial solutions for deprotonation were cooled to 0C, mixed for a quick reaction and flowed into a flow stream of the electrophile. Once this last mixing is started, the flow went into a heated coil loop (52 ml) at 115C for the cyclization to proceed. Once the product was formed, the group added a process to quench and work-up the reaction so that the desired solution of organic product (plus the addition of MeOH if needed) would flow into the H-Cube midi under similar conditions indicated above (5 bar, 45C, 2.2 ml/min, coil loop, PtO2) provide up to 120 mmol or 38.1 g. The in-line work-up process is certainly worth a detailed read — this is an area of discussion that chemists will eventually develop innovative ways of handling reactions that include lithiations mid-stream (and other transformations)…although we would like to make everything plug-and-play, we need to make sure to understand what’s in the line to have a successful flow method in the lab. Happy Reading!

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