Department of Chemistry, University of California, Berkeley, Berkeley, CA, 94720, USA.
Angew Chem Int Ed Engl. 2021 Apr 6;60(15):8276-8283. doi: 10.1002/anie.202016548. Epub 2021 Mar 4.
C(sp )-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 )-H bond. However, most current methods for the chlorination of C(sp )-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 )-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.
C(sp 3 )-Cl 键存在于许多具有生物活性的小分子中，而将其制备为 C(sp 3 )-H 键的氯化物是一种理想的途径。然而，目前大多数用于 C(sp 3 )-H 键氯化的方法在官能团的耐受性和位点选择性方面还不够完善，无法应用于复杂分子的后期官能团化。我们报道了一种用于高选择性地氯化叔碳和苄基 C(sp 3 )-H 键以生成相应氯化物的方法，通常产率很高。该反应使用叠氮碘烷和易得且廉价的氯化铜(II)配合物的混合物进行，在温和条件下，该混合物会生成选择性的氢原子供体，而氯化铜(II)配合物则有效地转移一个氯原子。该反应具有出色的官能团耐受性，通过对 30 多种具有不同官能团的底物进行氯化，以及对十几个天然产物和活性药物成分的衍生物进行后期氯化，证明了这一点。
