title: Synthesis and late-stage functionalization of complex molecules through C-H fluorination and nucleophilic aromatic substitution.
abstract: We report the late-stage functionalization of multisubstituted pyridines and diazines at the position α to nitrogen. By this process, a series of functional groups and substituents bound to the ring through nitrogen, oxygen, sulfur, or carbon are installed. This functionalization is accomplished by a combination of fluorination and nucleophilic aromatic substitution of the installed fluoride. A diverse array of functionalities can be installed because of the mild reaction conditions revealed for nucleophilic aromatic substitutions (S(N)Ar) of the 2-fluoroheteroarenes. An evaluation of the rates for substitution versus the rates for competitive processes provides a framework for planning this functionalization sequence. This process is illustrated by the modification of a series of medicinally important compounds, as well as the increase in efficiency of synthesis of several existing pharmaceuticals.
authors.affiliation: Department of Chemistry, University of California , Berkeley, California 94720, United States.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Fier
authors.forename: John F
authors.initials: JF
authors.lastname: Hartwig
mesh_terms: D002244:Carbon / Q000737:chemistry; D005461:Fluorine / Q000737:chemistry*; D006841:Hydrocarbons, Aromatic / Q000138:chemical synthesis*; D006859:Hydrogen / Q000737:chemistry; D007700:Kinetics; D009584:Nitrogen / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000138:chemical synthesis; D011725:Pyridines / Q000138:chemical synthesis
chemical_list: D006841:Hydrocarbons, Aromatic; D004364:Pharmaceutical Preparations; D011725:Pyridines; D005461:Fluorine; D002244:Carbon; D006859:Hydrogen; D009584:Nitrogen