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!