Installing the needed F using microreactor flow methods

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.

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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.

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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.

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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!

 

 

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