The Chemical Playbook: Reactive Substrates on Demand

A post from a former co-worker of mine, David Dickson, on LinkedIn got me thinking about reactive intermediates and complicated transient materials that we often encounter in batch synthetic processes — and how do you harness these in an opportunistic way for medicinal chemists or techniques which can be scaled-out for process development — let’s open up the chemical space again. And although there are a number of these published, Dave pointed out  a nice publication (Chem Sci 2014) out of the Ley group where one might think to generate reactive species On-Demand, pulling back a way for a medicinal chemists let’s say, to make it when you need it strategy (btw, this probably goes without saying but the power within the flow methods allow a creative med chemists a virtual playground of possibilities.

So back to the article: Aryl azide generation and transformations have been covered, but the ability to use hydrazones in a similar capacity:sp2 and sp3 couplings provides a number of new handles (scaffolds) that would otherwise be avoided due to the chemistry — intermediates that can themselves be modified again at a later stage. Below we see the thought process of generating a diazo substrate which is ‘translocated’ to a new chemical environment.

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Examples of continuous flow of stabilized diazo have been shown in the past — and although extremely useful, the addition of several reagents limits the scope and utility — so the mild MnO2 oxidative-decomposition into the reactive and unstable diazo intermediate was set to react with a partner while in flow (several oxidative reactions of this type are well known in the literature). In the example shown below: the simple reaction with an aryl boronic acid in contact with the transient intermediate produces the Ar-coupled alkyl compounds in high yield at RT.

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Examples of the type of library or large amounts of an advanced intermediate is shown below (some nice asymmetrical bis-aryls — nice.

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The Ley group details the reaction thought process and mechanism behind the tranformation and illustrates in these examples that electronics play a role in the kinetics of the reaction sequence, and that now that these transformations are done under less extreme conditions, we are learning what can and can not be done. Enjoy the paper and thanks Dave for pointing it out…..should be a thump on the head for the ability to take reactive intermediates and diverting these to several different partners to harness several different types of chemistry in demand. Happy Reading!

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