No abstract

The electrophilic halogenation of arenes is perhaps the simplest method to prepare aryl halides, which are important structural motifs in agrochemicals, materials, and pharmaceuticals. However, the nucleophilicity of arenes is weakened by the electron-withdrawing substituents, whose electrophilic halogenation reactions usually require harsh conditions and lead to limited substrate scopes and applications. Therefore, the halogenation of arenes containing electron-withdrawing groups (EWGs) and complex bioactive compounds under mild conditions has been a long-standing challenge. Herein, we describe Brønsted acid-catalyzed halogenation of arenes with electron-withdrawing substituents under mild conditions, providing an efficient protocol for aryl halides. The hydrogen bonding of Brønsted acid with the protic solvent 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) enables this transformation and thus solves this long-standing problem.

Electrophilic halogenation reactions have been a reliable approach to accessing organohalides. During the past decades, various catalytic systems have been developed for the activation of haleniums. However, there is still a short of effective catalysts, which could cover various halogenation reactions and broad scope of unsaturated compounds. Herein, TEMPO (2,2,6,6-tetramethylpiperidine nitroxide) and its derivatives are disclosed as active catalysts for electrophilic halogenation of olefins, alkynes, and aromatics. These catalysts are stable, readily available, and reactive enough to activate haleniums including Br+, I+ and even Cl+ reagents. This catalytic system is applicable to various halogenations including haloarylation of olefins or dibromination of alkynes, which were rarely realized in previous Lewis base catalysis or Lewis acid catalysis. The high catalytic ability is attributed to a synergistic activation model of electrophilic halogenating reagents, where the carbonyl group and the halogen atom are both activated by present TEMPO catalysis.

The electrophilic fluorination of unsaturated compounds provides a reliable approach to the generation of organofluorides, which are used widely in agrochemicals, pharmaceuticals, and other materials. Numerous active electrophilic fluorine reagents, such as the fluorine molecule (F 2 ) or xenon difluoride (XeF 2 ), have been applied in fluorination. However, these reagents suffer from their hazardous, toxic, corrosive, and poor selective properties, and the relatively weak electrophilicity of Selectfluor or N-fluorobenzenesulfonimide (NFSI) usually limits their broad applications. Herein, we disclose nitromethane (MeNO 2 ) as an efficient activator of Selectfluor and NFSI, as well as a stabilizer of carbocations.Therefore, the fluoro-azidation, fluoroamination, fluoroesterification of styrenes, and C-H fluorination of (hetero)arenes were well realized just by the facilitation of MeNO 2 . The mild reaction conditions and practicability made our current method a versatile protocol for accessing organofluorides.

An intermolecular reductive C–C coupling of electrophilic alkyl radicals and alkenes has been developed.

A novel intramolecular cyclization of alkyl azides for the synthesis of cyclic imines and tertiary amines has been developed. The aliphatic C–H or C–C bond was selectively cleaved with the efficient formation of two C–N single bonds or a CN double bond.

β-Halohydrins bearing transformable halo- and hydroxyl groups, are easily converted into various valuable blocks in organic and pharmaceutical synthesis. A diastereoselective β-halogenation of benzylic alcohols was achieved under simple and low-cost conditions, which provided a direct synthesis of β-halohydrins. The simple reaction conditions, easily available reagents, high diastereoselectivities, and additional oxidant-free make this reaction very attractive and practical.

The Pd‐catalyzed carbon‐carbon bond formation pioneered by Heck in 1969 has dominated medicinal chemistry development for the ensuing fifty years. As the demand for more complex three‐dimensional active pharmaceuticals continues to increase, preparative enzyme‐mediated assembly, by virtue of its exquisite selectivity and sustainable nature, is poised to provide a practical and affordable alternative for accessing such compounds. In this minireview, we summarize recent state‐of‐the‐art developments in practical enzyme‐mediated assembly of carbocycles. When appropriate, background information on the enzymatic transformation is provided and challenges and/or limitations are also highlighted.