Iron(III)-Catalyzed Chlorination of Activated Arenes

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.

In situ Generation of Hypervalent Iodine Reagents for the Electrophilic Chlorination of Arenes

“…3‐Chloro‐4‐methoxybenzoic Acid (2m) : Brown solid; M.p. 55–57 °C; 1 H NMR (250 MHz, CDCl 3 ) δ = 3.65 (3H, s), 6.73 (1H, d, J = 7.8 Hz), 7.65 (1H, dd, J = 7.8 Hz, J = 1.8 Hz), 7.72 (1H, d, J = 1.8 Hz); isolated yield: 162 mg (66 %) from 200 mg of 1m .…”

“…The synthesis of chloroarenes has been a staple in the chemical literature, with processes such as the Sandmeyer reaction, the electrophilic aromatic halogenation, and the stoichiometric ortho ‐metalation/chlorination sequence as some of the most popular approaches. As a complement to these classical methods, metal‐catalyzed chlorination has also received significant attention, with much efforts focused on transition metal catalyzed chelation‐directed aryl C–H ortho activation/chlorination (Ni, Rh, Pd and Ru); and more recently aryl C–H activation/ meta chlorination (Pd)[8d], and aryl C–H activation para chlorination (Fe) . However, the requirement of a directing group results in a somewhat limited substrate scope for these methods.…”

Proton Transfer Can Govern Regioselectivity Assisted by Iron Catalysis

“…Screening of various transition metal catalysts revealed that the use of palladium(II) or iron(III) triflates resulted in the formation of orthobrominated isomer as the major product (Table S1, entries 2-6). Here, it is noteworthy to mention that other Lewis acids such as CuCl 2 and FeCl 3 have been applied for selective para-halogenation of anilines (Urones et al, 2013;Jin et al, 2011;Mostafa et al, 2017). Among the solvents screened, the use of nonpolar solvent is beneficial and the highest o/p ratio of 97/3 was obtained in benzene in the presence of 2 mol% of Fe(OTf) 3 (90% yield; Table 1, entry 4).…”

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

“…In addition, to address the problem that N -halosuccinimides, especially NCS, are substantially less reactive, other versatile catalysts have also been employed. While Lewis or Brønsted acids are favorable to activate NXS, 21,30–42 the reactions rely on activated substrates or suffer from harsh conditions including high temperatures or super acidic conditions. 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.…”