Practical and innate carbon-hydrogen functionalization of heterocycles.

Nature (2012-12-04)
Yuta Fujiwara, Janice A Dixon, Fionn O'Hara, Erik Daa Funder, Darryl D Dixon, Rodrigo A Rodriguez, Ryan D Baxter, Bart Herlé, Neal Sach, Michael R Collins, Yoshihiro Ishihara, Phil S Baran
ABSTRACT

Nitrogen-rich heterocyclic compounds have had a profound effect on human health because these chemical motifs are found in a large number of drugs used to combat a broad range of diseases and pathophysiological conditions. Advances in transition-metal-mediated cross-coupling have simplified the synthesis of such molecules; however, C-H functionalization of medicinally important heterocycles that does not rely on pre-functionalized starting materials is an underdeveloped area. Unfortunately, the innate properties of heterocycles that make them so desirable for biological applications--such as aqueous solubility and their ability to act as ligands--render them challenging substrates for direct chemical functionalization. Here we report that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for the mild (moderate temperature, 50 °C or less), direct and operationally simple formation of medicinally relevant C-C bonds while reacting in a complementary fashion to other innate C-H functionalization methods (Minisci, borono-Minisci, electrophilic aromatic substitution, transition-metal-mediated C-H insertion and C-H deprotonation). We prepared a toolkit of these reagents and studied their reactivity across a wide range of heterocycles (natural products, drugs and building blocks) without recourse to protecting-group chemistry. The reagents can even be used in tandem fashion in a single pot in the presence of water and air.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Zinc difluoromethanesulfinate, 95%
Sigma-Aldrich
Zinc trifluoromethanesulfinate
Sigma-Aldrich
Zinc trifluoroethanesulfinate
Sigma-Aldrich
Late Stage Functionalization Toolkit
Sigma-Aldrich
Zinc isopropylsulfinate, 95%
Sigma-Aldrich
Zinc n-propylsulfinate, 95% (H-NMR)
Sigma-Aldrich
Zinc benzylsulfinate

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