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Site Selective Chlorination of C(sp 3 )−H Bonds Suitable for Late‐Stage Functionalization
Author(s) -
Fawcett Alexander,
Keller M. Josephine,
Herrera Zachary,
Hartwig John F.
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202016548
Subject(s) - surface modification , chemistry , molecule , chlorine , functional group , chloride , combinatorial chemistry , chlorine atom , copper chloride , copper , organic chemistry , medicinal chemistry , polymer
C(sp 3 )−Cl bonds are present in numerous biologically active small molecules, and an ideal route for their preparation is by the chlorination of a C(sp 3 )−H bond. However, most current methods for the chlorination of C(sp 3 )−H bonds are insufficiently site selective and tolerant of functional groups to be applicable to the late‐stage functionalization of complex molecules. We report a method for the highly selective chlorination of tertiary and benzylic C(sp 3 )−H bonds to produce the corresponding chlorides, generally in high yields. The reaction occurs with a mixture of an azidoiodinane, which generates a selective H‐atom abstractor under mild conditions, and a readily‐accessible and inexpensive copper(II) chloride complex, which efficiently transfers a chlorine atom. The reaction's exceptional functional group tolerance is demonstrated by the chlorination of >30 diversely functionalized substrates and the late‐stage chlorination of a dozen derivatives of natural products and active pharmaceutical ingredients.