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!