Modern drug discovery relies on the continual development of synthetic methodology to address the many challenges associated with the design of new pharmaceutical agents1. One such challenge arises from the enzymatic metabolism of drugs in vivo by cytochrome P450 oxidases, which use single-electron oxidative mechanisms to rapidly modify small molecules to facilitate their excretion2. A commonly used synthetic strategy to protect against in vivo metabolism involves the incorporation of electron-withdrawing functionality, such as the trifluoromethyl (CF3) group, into drug candidates3. The CF3 group enjoys a privileged role in the realm of medicinal chemistry because its incorporation into small molecules often enhances efficacy by promoting electrostatic interactions with targets, improving cellular membrane permeability, and increasing robustness towards oxidative metabolism of the drug4–6. Although common pharmacophores often bear CF3 motifs in an aromatic system, access to such analogues typically requires the incorporation of the CF3 group, or a surrogate moiety, at the start of a multi-step synthetic sequence. Here we report a mild, operationally simple strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes through a radical-mediated mechanism using commercial photocatalysts and a household light bulb. We demonstrate the broad utility of this transformation through addition of CF3 to a number of heteroaromatic and aromatic systems. The benefit to medicinal chemistry and applicability to late-stage drug development is also shown through examples of the direct trifluoromethylation of widely prescribed pharmaceutical agents.

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The design of enzyme-like complexity within metal–organic frameworks (MOFs) requires multiple reactions to be performed on a MOF crystal without losing access to its interior. Here, we show that seven post-synthetic reactions can be successfully achieved within the pores of a multivariate MOF, MTV-IRMOF-74-III, to covalently incorporate tripeptides that resemble the active sites of enzymes in their spatial arrangement and compositional heterogeneity. These reactions build up H2N-Pro-Gly-Ala-CONHL and H2N-Cys-His-Asp-CONHL (where L = organic struts) amino acid sequences by covalently attaching them to the organic struts in the MOFs, without losing porosity or crystallinity. An enabling feature of this chemistry is that the primary amine functionality (−CH2NHBoc) of the original MOF is more reactive than the commonly examined aromatic amines (−NH2), and this allowed for the multi-step reactions to be carried out in tandem within the MOF. Preliminary findings indicate that the complexity thus achieved can affect reactions that were previously accomplished only in the presence of enzymes.

A facile and efficient method for the α‐trifluoromethylation of carbonyl compounds and enolsilanes has been accomplished through application of a photoredox catalysis strategy. A one‐flask procedure for the direct α‐trifluoromethylation and α‐perfluoroalkylation of ketone, amide, and ester substrates as well as silylketene acetals is described (see scheme).

The δ C-H amination of unactivated, secondary C-H bonds to form a broad range of functionalized pyrrolidines has been developed via a triiodide (I3−)-mediated strategy. By in situ (i) oxidation of sodium iodide and (ii) sequestration of the transiently generated iodine (I2) as I3−, this approach precludes undesired I2− mediated decomposition that can otherwise limit synthetic utility to only weak C-H bonds. The mechanism of this triiodide-mediated cyclization of unbiased, secondary C-H bonds, via thermal or photolytic initiation, is supported by NMR and UV-Vis spectroscopic data and intercepted intermediates.