Practical radical aminomethylation of electron-deficient heterocycles

The aminomethylation of arenes and electron-rich aromatic heterocycles typically involves iminium ion chemistry, i.e., Mannich-type reactions.  But when the heterocycle is electron-poor, what then?  Recent work offers an attractive approach involving nucleophilic α-amino radicals.

David Mitchell and co-workers at Lilly recently published the scaleup of LY2784544, a JAK2 inhibitor.  Their paper is chock-full of interesting chemistry and is highly recommended for a read, but let’s look at just one slice: the installation of the morpholinomethyl group using a radical addition reaction.

In a first-generation approach, the intermediate shown below was subjected to Minisci’s method for radical alkylation.  Phthalimide-protected glycine was used as a source of pthalimidomethyl radicals.  Around 3.5 kg of the CH substitution product was obtained, but the route was abandoned due to reproducibility problems, relatively low regioselectivity, insoluble by-products, and the need for large amounts of silver nitrate.

In a second-generation route, iminium ion chemistry was explored, but none of the desired material was formed.  In their survey of iminium ion techniques, however, the Lilly group found one outlier:  Hwang and Uang’s method using N-methylmorpholine-N-oxide and VO(acac)2.  In the Uang work, electron-rich arenes such as phenols and naphthols were aminomethylated; there were no examples of electron-deficient heterocycles.  Nonetheless, after some optimization, the Lilly group was able use the Uang method to produce the desired aminomethylated material shown above in good yield on a 44 kg scale.

Mechanistically, Mitchell and co-workers believe the Uang chemistry is substrate-dependent.  For electrophilic substrates such as the current imidazopyridazine, the reaction proceeds by a radical mechanism involving the addition of a relatively nucleophilic α-amino radical to the pyridazine ring.  With electron-rich systems such as those found in Uang’s work, an iminium ion mechanism is probably operational.  Further mechanistic work is underway.

For those of you in drug discovery, do you think it would be interesting to carrying out such radical aminomethylations on existing drugs or related compounds?  I’m reminded of the recent bevy of direct trifluoromethylation reactions by Baran, MacMillan, and Qing, featured at C&EN and In The Pipeline.  Yes, aminomethyl groups and trifluoromethyl groups serve greatly different ends, but direct introduction of the former at rather unreactive sites would seem to be a nice option.

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2 responses to “Practical radical aminomethylation of electron-deficient heterocycles”

  1. Morris Slutsky says :

    Nice reaction! Doesn’t really seem very economical on it’s own – they do mention that the vanadium catalyst is ‘spent’ and they seem to be using a lot of it, they also are using a ton of the morpholine oxide. But I guess it’s got to be viewed as a tradeoff – as this elegant single-step reaction saving a lot of trouble from doing it any other way.

  2. milkshake says :

    Morpholine oxide price is non-issue, (NMO is used as an industrial solvent for making regenerated cellulose textile). Vanadyl compounds are cheap enough to be used stoechiometrically for manufacture for active drug ingredient, the main issue would be a removal of metal traces from the product and the cost of waste stream treatment.

    It could be useful method, especially if led to different regiochemistry compared to Mannich-based systems – i.e.with preference for more electron-poor ring of a molecule like camptothecin.

    I should mention that N-benzyl substituted morpholines have often quite fast metabolism/clearance but can have less HERG-channel (cardiotoxicity) liabilty than more basic sidechains. Ideally one would like to examinea a variety sidechains for the selection of a candidate compound for preclinical development

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