Sulfonyl fluorides have widespread applications in many fields. In particular, their unique biological activity has drawn considerable research interest in the context of chemical biology and drug discovery in the past years. Therefore, new and efficient methods for the synthesis of sulfonyl fluorides are highly in demand. In contrast to extensive studies on FSO2+‐type reagents, a radical fluorosulfonylation reaction with a fluorosulfonyl radical (FSO2.) remains elusive so far, probably owing to its instability and difficulty in generation. Herein, the development of the first radical fluorosulfonylation of alkenes based on FSO2 radicals generated under photoredox conditions is reported. This radical approach provides a new and general access to alkenyl sulfonyl fluorides, including structures that would otherwise be challenging to synthesize with previously established cross‐coupling methods. Moreover, extension to the late‐stage fluorosulfonylation of natural products is also demonstrated.

The site-selective functionalization of unactivated C(sp )-H bonds remains one of the greatest challenges in organic synthesis. Herein, we report on the site-selective δ-C(sp )-H alkylation of amino acids and peptides with maleimides via a kinetically less favored six-membered palladacycle in the presence of more accessible γ-C(sp )-H bonds. Experimental studies revealed that C-H bond cleavage occurs reversibly and preferentially at γ-methyl over δ-methyl C-H bonds while the subsequent alkylation proceeds exclusively at the six-membered palladacycle that is generated by δ-C-H activation. The selectivity can be explained by the Curtin-Hammett principle. The exceptional compatibility of this alkylation with various oligopeptides renders this procedure valuable for late-stage peptide modifications. Notably, this process is also the first palladium(II)-catalyzed Michael-type alkylation reaction that proceeds through C(sp )-H activation.

Enantioselective functionalizations of unbiased methylene C(sp )-H bonds of linear systems by metal insertion are intrinsically challenging and remain a largely unsolved problem. Herein, we report a palladium(II)-catalyzed enantioselective arylation of unbiased methylene β-C(sp )-H bonds enabled by the combination of a strongly coordinating bidentate PIP auxiliary with a monodentate chiral phosphoric acid (CPA). The synergistic effect between the PIP auxiliary and the non-C -symmetric CPA is crucial for effective stereocontrol. A broad range of aliphatic carboxylic acids and aryl bromides can be used, providing β-arylated aliphatic carboxylic acid derivatives in high yields (up to 96 %) with good enantioselectivities (up to 95:5 e.r.). Notably, this reaction also represents the first palladium(II)-catalyzed enantioselective C-H activation with less reactive and cost-effective aryl bromides as the arylating reagents. Mechanistic studies suggest that a single CPA is involved in the stereodetermining C-H palladation step.

Sulfonyl fluorides have widespread applications in many important fields, including ligation chemistry, chemical biology, and drug discovery. Therefore, new methods to increase the synthetic efficiency and expand the available structures of sulfonyl fluorides are highly in demand. Here, we introduce a new and powerful class of sulfonyl fluoride hubs, β‐chloro alkenylsulfonyl fluorides (BCASF), which can be constructed via radical chloro‐fluorosulfonyl difunctionalization of alkynes under photoredox conditions. BCASF molecules exhibit versatile reactivities and well undergo a series of transformations at the chloride site while keeping the sulfonyl fluoride group intact, including reduction, Suzuki coupling, Sonogashira coupling, as well as nucleophilic substitution with various nitrogen, oxygen, and sulfur nucleophiles. By using BCASF as a synthetic hub, a wide range of sulfonyl fluorides becomes readily accessible, such as cis alkenylsulfonyl fluorides, dienylsulfonyl fluorides, and ynenylsulfonyl fluorides, which are challenging or even not possible to synthesize before with the known methods. Moreover, further application of BCASF to the late‐stage modification of peptides and drugs is also demonstrated.

Recently, radical fluorosulfonylation is emerging as an appealing approach for the synthesis of sulfonyl fluorides, which are highly in demand in various disciplines, particularly in chemical biology and drug discovery. Here, we report the first establishment of radical hydro‐fluorosulfonylation of alkenes, which is enabled by using 1‐fluorosulfonyl 2‐aryl benzoimidazolium (FABI) as an effective redox‐active radical precursor. This method provides a new and facile approach for the synthesis of aliphatic sulfonyl fluorides from unactivated alkenes, and can be further applied to the late‐stage modifications of natural products and peptides, as well as ligation of drugs in combination with click chemistry. Remarkably, this system could enable the radical hydro‐fluorosulfonylation of alkynes, affording valuable alkenylsulfonyl fluoride products with a rare, high Z‐selectivity, which are normally less stable and more challenging to synthesize in comparison with the E‐configured products.