Electrochemistry in Flow: Nazlinine and more

Electrochemistry falls into one of those categories of expansion, where the chemists who perform these reactions are more similar to their specialties — as is the case with photochemistry. These simply don’t fall into the area of study, education or applied retrosynthetic strategies. However, flow chemistry allows us to level the playing field a bit, and asks us to include new reaction space which we would otherwise never draw on the chalkboard.

In a recent example (OL 2014), we are treated with a modification on a throwback Shono oxidation of cyclic amines (protected as a carbamate or amide in the generation of an acyl iminium species with a nucleophilic attack of MeOH). I particularly like this since I have used this reactions in the past, but it requires some care into the appropriate choice of anode and salt bridge — in this case electrolyte in flow).

The scheme to Nazlinine is shown below with a flow oxidation reaction followed by a microwave accelerated Pictet-Spangler to several additional non-natural Nazlinine analogs:

Screen Shot 2014-11-17 at 10.51.23 AM

The table below illustrates the use of a microreactor with choice of anode, electrolyte, flow rate and current (Carbon, 20% Et4NBF4, 43mA, flow,100-120 microliters/min).

Screen Shot 2014-11-17 at 10.51.38 AM

 

Expanding beyond pyrrolidine expands the utility and the chemical space for libraries around Nazlinine, but also into areas of related systems beyond the scope of the paper:

Screen Shot 2014-11-17 at 10.51.53 AM

 

Although not the focus of my post, the second reaction, which would otherwise take 15 hours to complete, was shortened to 30 min using microwave irradiation as a final step into Nazlinine and related compounds. You will notice a big effect in the acid choice — they found optimized results with CSA in H2O, but with a deprotection, imiminium formation, and more than one amine, screening additional acids will add additional opportunities here (med chemists — you know that I am talking to you).

Screen Shot 2014-11-17 at 10.52.32 AM

 

Enjoy the rest of the paper in looking at additional substitutions on the indole and extension of the exo-alkylamine. This should help you think of additional electrochemical reactions that are out there to be used — I can think of a few that I would want to incorporate (please note that references 1-2 in the paper include examples of electrochemical and photochemical reviews as excellent starting points when considering flow approaches). Happy Reading!

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