Novel regioselective aromatic chlorination via catalytic thiourea activation of N-chlorosuccinimide

The Catalyst-Controlled Regiodivergent Chlorination of Phenols

“…Traditional electrophilic halogenations − suffer from several drawbacks such as a reliance on harsh reaction conditions, reduced reactivity toward electron-poor arenes, and a lack of regioselectivity across many substrate classes. While recent advances − have largely addressed the first two issues, regioselectivity is still an unsolved problem as current electrophilic halogenations rely on substrate-controlled regioselectivity (Figure A) often resulting in a mixture of constitutional isomers. On the other hand, it becomes a synthetic challenge to obtain a nonfavored isomer when the substrate possess a strong innate preference.…”

“…These catalysts were able to effect the chlorination of diverse arenes according to the innate preference of a substrate with regioselectivities closely following those reported in literature. 8,10,12 Monitoring the course of the reaction by 31 P NMR (Figure S1) suggested the formation of an intermediate with a large degree of phosphonium character, 24 which would be expected if the chemistry proceeds through a catalyst−halenium 25,26 adduct such as 2 (Figure 1). This is corroborated by DFT (Scheme S1) studies that predict halogenation to proceed through such an intermediate.…”

Catalyst-Controlled Regioselective Chlorination of Phenols and Anilines through a Lewis Basic Selenoether Catalyst

“…Halogenation of aromatics via aromatic electrophilic substitution (S E Ar) is one of the most ubiquitous reactions in modern synthesis, largely because halogenated aromatics are among the most utilized precursors in modern cross-coupling chemistry and other common reactions. − Furthermore, the incorporation of halogen atoms is commonly used to modulate the physicochemical properties of small-molecule drug leads . While S E Ar has been extensively studied for over a century, − it often yields mixtures of constitutional isomers, representing a major synthetic challenge. For example, electron-rich aromatic scaffolds such as phenols and anilines yield a mixture of para- and ortho-functionalized products, with the para-constitutional isomer typically favored due to innate electronic properties. ,− …”

“…While S E Ar has been extensively studied for over a century, − it often yields mixtures of constitutional isomers, representing a major synthetic challenge. For example, electron-rich aromatic scaffolds such as phenols and anilines yield a mixture of para- and ortho-functionalized products, with the para-constitutional isomer typically favored due to innate electronic properties. ,− …”

DABCO as a practical catalyst for aromatic halogenation with N-halosuccinimides

“…Alternatively, Lewis bases, with O, N, S or P centre, have also been verified to catalyse the halogenation via interaction with NXS to form the activated halonium complexes. 43–53 Recently, Jiao's group 45 discovered an efficient late-stage chlorination of complex substrates in the presence of DMSO, providing a practical method for further applications. Miura 43 also developed a novel protocol using triptycenyl sulfide to realize electrophilic aromatic halogenation of a variety of unactivated compounds.…”