title: Catalytic C-H bond silylation of aromatic heterocycles.
abstract: This protocol describes a method for the direct silylation of the carbon-hydrogen (C-H) bond of aromatic heterocycles using inexpensive and abundant potassium tert-butoxide (KOt-Bu) as the catalyst. This catalytic cross-dehydrogenative coupling of simple hydrosilanes and various electron-rich aromatic heterocycles enables the synthesis of valuable silylated heteroarenes. The products thus obtained can be used as versatile intermediates, which facilitate the divergent synthesis of pharmaceutically relevant compound libraries from a single Si-containing building block. Moreover, a variety of complex Si-containing motifs, such as those produced by this protocol, are being actively investigated as next-generation therapeutic agents, because they can have improved pharmacokinetic properties compared with the original all-carbon drug molecules. Current competing methods for C-H bond silylation tend to be incompatible with functionalities, such as Lewis-basic heterocycles, that are often found in pharmaceutical substances; this leaves de novo synthesis as the principal strategy for preparation of the target sila-drug analog. Moreover, competing methods tend to be limited in the scope of hydrosilane that can be used, which restricts the breadth of silicon-containing small molecules that can be accessed. The approach outlined in this protocol enables the chemoselective and regioselective late-stage silylation of small heterocycles, including drugs and drug derivatives, with a broad array of hydrosilanes in the absence of precious metal catalysts, stoichiometric reagents, sacrificial hydrogen acceptors or high temperatures. Moreover, H2 is the only by-product generated. The procedure normally requires 48-75 h to be completed.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Anton A
authors.initials: AA
authors.lastname: Toutov
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Wen-Bo
authors.initials: WB
authors.lastname: Liu
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Kerry N
authors.initials: KN
authors.lastname: Betz
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Stoltz
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Grubbs
mesh_terms: D000440:Butanols / Q000737:chemistry; D002384:Catalysis; D060326:Chemistry Techniques, Synthetic / Q000379:methods; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D006841:Hydrocarbons, Aromatic / Q000138:chemical synthesis / Q000737:chemistry*; D006865:Hydrogenation; D004364:Pharmaceutical Preparations / Q000138:chemical synthesis / Q000737:chemistry*; D012821:Silanes / Q000138:chemical synthesis / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D000440:Butanols; D006571:Heterocyclic Compounds; D006841:Hydrocarbons, Aromatic; D004364:Pharmaceutical Preparations; D012821:Silanes; D054852:Small Molecule Libraries; C077664:tert-butoxide, potassium