Well I am off to do some training this week on flow chemistry. Should be a lot of fun and I am excited to be in front of some exception people at ThalesNano and experience Budapest this week. Should be able to post some of the things I have been reading in the next couple of days. Something along the line of gas additions in flow — so many opportunities to do things in flow from this perspective: insertion couplings, reactive gases, etc. Stay tuned!
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!
There is a new short course on flow chemistry being offered by Scientific Update in Nice France (June 2-3 2015) with Oliver Kappe and Will Watson as instructors…..should be a great course with Oliver as a leader in the field of new flow chemistry information and current state-of-the-art techniques. I have included the information on the side – In the News (can also be found on the Kappe Group site). Anyone in the field should plan to visit and join the group in France for the latest education in flow chemistry….looks good to me!
OK it was an extended time away from posting — I totally blame the Turkey, Ham, Beer, Stuffing, Pie — at least I have tapered off over the years.
So what’s sitting on my desk — after several pontifications, I have gotten back to thinking about how chemists think about their chemistry and where it can go in flow processes — so, OK, retrosynthesis — but I often think in classes of fragments and what they can do (think of it as a review on enaminone transformations so to speak). In this case, Ian Baxendale got me thinking about ynones or alpha, beta-acteylenic ketones — used quite a bit right? furans, flavones, pyrazoles, pyrimidines and heck back at Bayer I used them in a number of dipolarcycloadditions and intramolecular cyclizations to isoxazoles and pyrroles……you get the point……if interested in a nice article on using a flow approach to ynones and their divergent reaction with different nucleophiles then (Chem Eur Journal 2010) is the ticket.
In the three schemes below we see the utility of using several clean-up and scavenging steps to develop an outnumbering process to libraries of heterocycles with a single ynone. By starting with a simple acid chloride under Sonogashira coupling conditions (Pd(OAc)2, Hunig’s Base) with an acetylene at 100C over a 30 min period, the ynone is formed and used with several reagents (hydrazines, guanidines, etc) to form libraries. To take this to the crux, 4 columns were used to clean up the ynone or post nucleophilic reaction: polyol for the acid chloride, CaCO3 for the HCl and knock the ammonium salts, sulfonic acid for the tertiary amines and finally an immobilized thiourea for the Pd catalyst prior to diverting the product to additional steps. On a personal level, this really shows the power of combining purification techniques (many which have fallen through the educational cracks of developing a thought process around what’s going on in a reaction — I was lucky enough to learn most of this because I had too many nitrogens around my compounds of interest) with the power of flow methodology.
Happy Reading! Good to be back!