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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 ? 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.

SUBMITTER: Fier PS

PROVIDER: S-EPMC4227713 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Synthesis and late-stage functionalization of complex molecules through C-H fluorination and nucleophilic aromatic substitution.

Fier Patrick S PS Hartwig John F JF

Journal of the American Chemical Society 20140701 28

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 ...[more]

PMID: 24918484

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