Look to join Flow Chemistry Society’s 4th International Conference on Flow Chemistry (Mumbai, Jan 21-22, 2016)– just take a look at the jam-packed list of presenters.
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.
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.
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?
Enjoy the read!
Enjoying the efforts of of Christopher Hone and his jflowchemistry blog. His latest article on catalyst, organic and liquid phase models for flow reaction chemistry was intriguing to say the least. There is a lot of interest in the ability to mix organic and aqueous phases – and then add reactive gas into the mix as it were. His description of Yap and co-workers at the National University of Singapore indicates that feasibility studies are ongoing to have a cleaner picture of what is controlling this sort of reaction (mass flow, heat transfer). What I enjoyed most is the subtleties of moving from a fixed bed or homogeneous catalysis into a design with the catalyst immobilized in the aqueous phase and work out the parameters — mixing, organic phase wetting, and finally introduction of gas. With the improvement and advancement of catalyst design — nanocatalyst — we may well see a number of new things being applied to flow design in the near future.
Nice job Chris — keep em coming! Happy reading to the audience!
Stepping outside traditional synthetic labs into specialty applications is not always something we are looking for in the literature, but it is an excellent way to see different techniques which might be utilized in your own labs. Neil Vasdev’s group at the Harvard Medical School specializes in labeling compounds for more advanced analysis – imaging techniques as tracers for the study of advanced disease states. His group has been using flow chemistry and flow hydrogenation for some time so I thought it be interesting for everyone to see the work.
Two recent publications illustrate their research. In the first publication Chem Commun 2013, 49, 8755 the group uses three examples where they incorporate a label for study into an advanced intermediate C11 or F18 through a microfluidic reaction, followed by a strategic deprotection of a benzyl group or CBz under flow hydrogenation. Without going into significant detail, the group absolutely needed an optimized profile for these sorts of reactions due to the nature of the labeling and ran a number of studies with variations of solvent, temperature and pressure. It is worth the read to understand the significance of finding a fast, reliable method for multiple processes for their strategies. Labeling and incorporation of more substituents are being explored using these technologies then the literature provides — and the number of uses for flow hydrogenation can’t be undervalued with all of the transformations within.
The second paper, which I found to be even more interesting because it shows the application of the strategy — the imaging of the compounds made. I would be remiss if I didn’t mention Steven Liang from MGH as a critical part of both papers…..but the paper describes a specific compound made under microfluidic flow conditions for the labeling and subsequent study. Mol Imaging. 2014 Sep 1;13:1-5 is where you can find the citation but if you are exceptional at google (hehe) then you can find a pdf of the article.
Enjoy the articles but keep an eye toward uses of these flow techniques in your own discovery efforts — several new applications show up every week. Happy Reading!
There is a lot of talk about how to traverse moving from batch to flow, and how to make the process of finding a good method quicker under flow conditions. There are some factors keeping us from crossing the goal line: I’ve done it this way for so long and it works – why change (cryogenic or several mainstay transformations)?; the reaction takes too much time in a flow set up; and product survivability. I cringe when I hear these things – largely because the mantra for the last 50 years has been if it is going to 50% at 100C, then just heat it up! — Well you can call me a bit of a dummy and you would be right, but flow chemistry can offer efficiencies that a traditional batch reaction can’t — we know that — mass transfer, time spent at specific temperature can be minimized, and I could go on. Listen this isn’t a blanket that I get to throw over all chemistry, but having come from a microwave background, I think the space available for chemical transformations is untapped — we just haven’t gone there often enough……I just can’t simply buy into chemists simply doing the same reaction over and over for 20 years without finding themselves in a new reaction transformation — there is a lot of it out there and we need to untap this potential.
Let’s just improvise here and generate some discussion — -78C for an anion generation — doesn’t need to be that way for flow: the residence time doesn’t equate with 20-30 mins, then quench with an electrophile. Because the the flow in a microreactor allows kinetic conversion, the reaction can be almost immediate followed by diverting the reactive intermediate in several directions — although I have done this following cooling and anion generation in batch nearly 10000 times — and reverse added this to several other flasks….it just isn’t the best way to do it.
Reactions take longer at lower temperature — I guess you can call that a blanket. There are expanding examples of reactions and transformations that moving from batch to flow that simply do not decrease the time spent — that is without raising the temperature — or even temp/pressure if you have the opportunity. In a sense I am talking about reactions that go from 100C to 150-200C, but also reactions we don’t normally think of at temps of 350C. How many of these can you point to from experience? Well many of the products out there survive at these high temps and survive them for short and long reaction times….pharma, Ag, petro, etc. But the nice thing is that it is generally held that many transformations at these high temps can be done in a short time, and with limited “reaction time” at these high temperatures……get used to it; expansing methods are being developed.
So give you chemistry a bit more thought and challenge some of the traditional techniques used. That text book in the corner is starting to collect some dust: find some examples that would serve as a good model outside a batch process.
Well if it isn’t a magic methyl, it seems (gosh I guess I can do the statistics, but let’s go with intuition at this point) having a F has done wonders for drug candidates in their pursuit of the best compound in the class (comeon man, don’t make me list them). I know it happened to me in my research enough that I made sure it wasn’t going to be the analog that got away…….but it got me to thinking about flow methods for F insertion — what’s out there? Considering that handling some of these reagents, I would think continuous flow techniques would lend itself to better handling and more control.
A recent review from Hideki Amii, Aiichiro Nagaki Jun-ichi Yoshida (Gunma University and Kyoto University) in Beilstein JOC 2013 outlines several key aspects to F/flow, but how they can be combined strategies for effective fluorination. One thing to be sure, if you need to do it, this is a good paper to have. I will highlight a couple of reactions since there are too many to dump, but since it is an open access article, you should take a look for yourself in the process.
An extension of Buchwald’s work on the conversion of a aryl-triflate utilizes a CsF-packed bed reactor to obviate some of the issues with using huge excesses of CsF in batch and a need to vigorously stir the reaction with insoluble material.
As an alternative to aromatic fluorination, Yoshida and Nagaki developed an efficient electrophilic fluorination using NFSI and N-fluorosultam on a lithiated aromatic (which I think is great since they are using the technique in multiple capacities). In these examples, the fluorination was good with EWGs, EDGs and steric examples.
But was it often more appealing to me is the ability to displace a strategically located F — so a SNAR displacement with a carbon anion or an amine. The example below illustrates a typical example done under flow conditions.
And if you are really ambitious or an anitbacterial chemist — this approach was used in the synthesis of Cipro under flow conditions for a number of the steps. Additional examples are shown but I will leave it with you for fun.. Happy Reading!
The thought in the post is simply to open discussion to areas where flow chemistry can be used in places where traditional batch and kinetic deprotonation and finally subsequent reaction has held pretty well over the course of organic synthetic chemistry. It is on our minds — certainly an area where medicinal chemists can start to think about utilizing flow methodologies for gain in their march to library development.
Firstly, and I won’t spend too much time on this, but considering the kinetics, it is hard to jump from a reaction that should be really fast into flow-thinking (but I can assure you the time in flow is very fast). I know it was hard for me at first — things crashing out, length of time arguments and such, but I have to say there are a number of publications suggesting that this is a very controlled and good chemical way of doing things. If you haven’t had enough reviews – there is an excellent book on Lithium Compounds in Organic Chemistry that I would like to point you to: Lithium Compounds in Organic Synthesis: From Fundamentals to Applications, Wiley, 2014. In Chapter 17, Aiichiro Nagaki and Jun-Ichi Yoshida illustrate Microreactor Technology in Lithium Chemistry, including unstable lithium species, switching reaction pathways, protective-group free synthesis to reaction integration — and areas of anionic controlled polymer chemistry.
There is even a report from Chemjobber illustrating Merck’s ability to perform a dianion formation in flow with process improvements over the traditional batch route. The citation and comments provide a nice account of the chemistry and easing the resistance to adopting to newer technologies.
Another nice report can be found in Chemica Oggi (Chemistry Today July/Aug 2014) by JÖRG SEDELMEIER and FRANCESCO VENTURONI from Novartis Pharma in Basel, Switzerland where they show the rapid generation of thermally unstable organolithium intermediates and their reactions. I thought this was a significant contribution in the operation window of temperature that can be used in flow methodology (for both research and manufacturing).
Lastly, because I want to move the thinking into areas of drug discovery research – a recent report (Org Biomol Chem 2010) on the synthesis of imidazopyridazines as casein kinase inhibitors, shows a key step in a library approach to these compounds with a flow lithiation method to form advanced intermediates which were then taken (again in a flow manner) to final compound libraries (great proof of concept med chem approach). For the lithiation, the continuous flow or feed of the organometallic solution could be easily controlled by simple valve and loop selection (temp and feed) for the lithium source and resultant reactive deprotonated nucleophile. I was particularly impressed with the usage of the intermediates in the SAR of the target compounds. If played well, a group of 2 could have final compounds for testing in a day — well, lol, at least that is how my group strategized our analog development. Enjoy the papers and references!