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Site Selective Chlorination of C(sp³ )-H Bonds Suitable for Late-Stage Functionalization.

ABSTRACT: C(sp³ )-Cl bonds are present in numerous biologically active small molecules, and an ideal route for their preparation is by the chlorination of a C(sp³ )-H bond. However, most current methods for the chlorination of C(sp³ )-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(sp³ )-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.

SUBMITTER: Fawcett A

PROVIDER: S-EPMC8594412 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Many enzymes oxidize unactivated aliphatic C-H bonds selectively to form alcohols; however, biological systems do not possess enzymes that catalyse the analogous aminations of C-H bonds. The absence of such enzymes limits the discovery of potential medicinal candidates because nitrogen-containing groups are crucial to the biological activity of therapeutic agents and clinically useful natural products. In one prominent example illustrating the importance of incorporating nitrogen-based functionality, the conversion of the ketone of erythromycin to the -N(Me)CH2- group in azithromycin leads to a compound that can be dosed once daily with a shorter treatment time. For such reasons, synthetic chemists have sought catalysts that directly convert C-H bonds to C-N bonds. Most currently used catalysts for C-H bond amination are ill suited to the intermolecular functionalization of complex molecules because they require excess substrate or directing groups, harsh reaction conditions, weak or acidic C-H bonds, or reagents containing specialized groups on the nitrogen atom. Among C-H bond amination reactions, those forming a C-N bond at a tertiary alkyl group would be particularly valuable, because this linkage is difficult to form from ketones or alcohols that might be created in a biosynthetic pathway by oxidation. Here we report a mild, selective, iron-catalysed azidation of tertiary C-H bonds that occurs without excess of the valuable substrate. The reaction tolerates aqueous environments and is suitable for the functionalization of complex structures in the late stages of a multistep synthesis. Moreover, this azidation makes it possible to install a range of nitrogen-based functional groups, including those from Huisgen 'click' cycloadditions and the Staudinger ligation. We anticipate that these reactions will create opportunities to modify natural products, their precursors and their derivatives to produce analogues that contain different polarity and charge as a result of nitrogen-containing groups. It could also be used to help identify targets of biologically active molecules by creating a point of attachment--for example, to fluorescent tags or 'handles' for affinity chromatography--directly on complex molecular structures.

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Site Selective Chlorination of C(sp³ )-H Bonds Suitable for Late-Stage Functionalization.

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Site Selective Chlorination of C(sp3 )-H Bonds Suitable for Late-Stage Functionalization.

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Site Selective Chlorination of C(sp³ )-H Bonds Suitable for Late-Stage Functionalization.