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Our research aims to change the way that organic chemists use unprotected alkylamines in synthesis, viewing them not merely as
N-nucleophiles but as potential C-nucleophiles for C–C bond formation. This can lead to 100% atom economic amine synthesis, without the need for N-(de)protection operations at any stage. It also opens up powerful new possibilities for site-selective C–H functionalisation of di- or polyamines. We have found that alkylation can be achieved directly at the α-C–H bonds of unprotected primary amines using photoredox catalysis, which constitutes a formal inversion (‘umpolung’) of their classical reactivity. Catalytic azide ion is deployed as a hydrogen atom transfer (HAT) catalyst, with azidyl radical being the active species.
For example, we have developed a practical, catalytic entry to α,α,α-trisubstituted (α-tertiary) primary amines and (spirocyclic)
γ-lactams by C–H functionalisation. The method does not require any in situ protection of the amino group, and proceeds with 100% atom economy.
We have also developed a catalytic, intermolecular hydroaminoalkylation of styrenes with primary amines. Again this methodology utilises organophotoredox catalysis, enabling a direct, modular, and sustainable preparation of γ-aryl amines. A broad range of functionalities were tolerated and the reactions could be run on multigram-scale in continuous flow. The method was applied to the shortest ever, protecting group-free synthesis of Novartis’ blockbuster drug Fingolimod.
We anticipate that this methodology will inspire new retrosynthetic disconnections for substituted amine derivatives in organic synthesis, and particularly for challenging α-tertiary primary amines.
Funding and support is gratefully acknowledged from:
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