title: Practical and innate carbon-hydrogen functionalization of heterocycles.
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.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Janice A
authors.initials: JA
authors.lastname: Dixon
authors.forename: Fionn
authors.initials: F
authors.lastname: O'Hara
authors.forename: Erik Daa
authors.initials: ED
authors.lastname: Funder
authors.forename: Darryl D
authors.initials: DD
authors.lastname: Dixon
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Rodriguez
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Baxter
authors.forename: Bart
authors.initials: B
authors.lastname: Herlé
authors.forename: Neal
authors.initials: N
authors.lastname: Sach
authors.forename: Michael R
authors.initials: MR
authors.lastname: Collins
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishihara
authors.forename: Phil S
authors.initials: PS
authors.lastname: Baran
mesh_terms: D000388:Air; D000478:Alkylation; D001688:Biological Products / Q000737:chemistry; D002244:Carbon / Q000737:chemistry*; D015195:Drug Design; D006859:Hydrogen / Q000737:chemistry*; D006860:Hydrogen Bonding; D007202:Indicators and Reagents / Q000737:chemistry; D008745:Methylation; D009584:Nitrogen / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000737:chemistry; D013441:Sulfinic Acids / Q000737:chemistry; D014867:Water; D015032:Zinc / Q000737:chemistry
chemical_list: D001688:Biological Products; D007202:Indicators and Reagents; D004364:Pharmaceutical Preparations; D013441:Sulfinic Acids; D014867:Water; D002244:Carbon; D006859:Hydrogen; D015032:Zinc; D009584:Nitrogen