Abstract
A general and regioselective method for the chlorination of activated arenes has been developed. The transformation uses iron(III) triflimide as a powerful Lewis acid for the activation of N-chlorosuccinimide and the subsequent chlorination of a wide range of anisole, aniline, acetanilide, and phenol derivatives. The reaction was utilized for the late-stage mono- and dichlorination of a range of target compounds such as the natural product nitrofungin, the antibacterial agent chloroxylenol, and the herbicide chloroxynil. The facile nature of this transformation was demonstrated with the development of one-pot, tandem, iron-catalyzed dihalogenation processes allowing highly regioselective formation of different carbon-halogen bonds. The synthetic utility of the resulting dihalogenated aryl compounds as building blocks was established with the synthesis of natural products and pharmaceutically relevant targets.
Highlights
Aromatic chlorides are an important class of compounds, widely used in organic chemistry as synthetic intermediates for coupling or substitution reactions, allowing the preparation of natural products and medicinally active compounds.[1]
The widespread developments in transition-metal-catalyzed chelation-directed aryl C−H activation have led to a number of methods for ortho-chlorination (Scheme 1a).[14]
A chelation-directed aryl C−H activation process for metachlorination was developed by Yu and co-workers using a palladium-catalyzed pyridone ligand promoted protocol (Scheme 1b).[15]
Summary
Aromatic chlorides are an important class of compounds, widely used in organic chemistry as synthetic intermediates for coupling or substitution reactions, allowing the preparation of natural products and medicinally active compounds.[1] Because of the relative stability of the carbon−chlorine bond, aryl chlorides are found as components in a vast array of natural products (e.g., phenols 1−3, Figure 1)[2−5] and used as structural spread use of these methods, they can involve harsh conditions and long reaction times and give poor regioselectivity and control. The synthetic utility of these compounds for targeted synthesis is reported
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