Synthesis of carbinoxamine via α-C(sp3)-H 2-pyridylation of O, S or N-containing compounds enabled by non-D-A-type super organoreductants and sulfoxide- or sulfide HAT reagents

The radical cations of tertiary amines (R3N) have been well-established as the precursors of HAT reagents in photochemical transformations. Similarly, thiols and thioacids bearing SH groups have also been widely applied as HAT reagents. Despite the fact that sulfoxides (R2SO) and sulfides (RSR) also bear lone pairs of electrons, these compounds have been barely reported as HAT reagents in photocatalysis. On the other hand, the alpha-C-H 4-pyridylation of O or N-containing compounds has been documented, whereas 2-pyridylation remains challenging. However, the antihistamine and anticholinergic agent carbinoxamine is an ether bearing 2-pyridyl, which has not been obtained by the existing alpha-photoarylation of ether. In this work, we report the discovery of a non-donor-acceptor (D-A) type organic photoreductant CBZ6 and sulfoxide/sulfide synergistically catalyzed general alpha-C(sp(3))-H arylation of ethers, thioethers and amines. By using as low as 1 mol% of CBZ6 as a recyclable organic photoreductant and sulfoxides or sulfides as a new type of HAT reagent, the 2- or 4-pyridylation of O, N, or S-containing compounds has been accomplished. This is the first base-free version of alpha-C-H 2-/4-pyridylation of O, N, or S-containing compounds. It is the first example of sulfoxides or sulfides working as HAT reagents. It is also the first general method for photocatalytic HAT 2-pyridylation of various ethers, amines or thioethers.

Automated summary

In this study, we report a new photocatalytic method for the 2- or 4-pyridylation of compounds containing O, N, or S groups, using the organic photoreductant CBZ6 and sulfoxides or sulfides as HAT reagents. This is the first base-free version of the alpha-C-H 2-/4-pyridylation of compounds containing ethers, amines, or thioethers.