Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 60, Issue 15, Pages 8276-8283Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202016548
Keywords
C− H functionalization; chlorination; halogenation; late-stage functionalization; radical reactions
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Funding
- NIH [S10OD024998, R35-GM130387]
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A highly selective method for chlorination of tertiary and benzylic C(sp(3))-H bonds has been developed, utilizing azidoiodinane and a copper(II) chloride complex to generate the corresponding chlorides in high yields. The reaction shows exceptional functional group tolerance, allowing for chlorination of diverse substrates and late-stage chlorination of derivatives of natural products and active pharmaceutical ingredients.
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.
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