Reversal of the Regioselectivity of Iron-Promoted Hydrogenation and Hydrohalogenation of gem-Difluoroalkenes.

The reaction regioselectivity of gem-difluoroalkenes is dependent on the intrinsic polarity. Thus, the reversal of the regioselectivity of the addition reaction of gem-difluoroalkenes remains a formidable challenge. Herein, we described an unprecedented reversal of regioselectivity of hydrogen atom transfer (HAT) to gem-difluoroalkenes triggered by Fe-H species for the formation of difluoroalkyl radicals. Hydrogenation of the in situ generated radicals gave difluoromethylated products. Mechanism experiments and theoretical studies revealed that the kinetic effect of the irreversible HAT process resulted in the reversal of the regioselectivity of this scenario, leading to the formation of a less stable α-difluoroalkyl radical regioisomer. On basis of this new reaction of gem-difluoroalkene, the iron-promoted hydrohalogenation of gem-difluoroalkenes for the efficient synthesis of aliphatic chlorodifluoromethyl-, bromodifluoromethyl- and iododifluoromethyl-containing compounds was developed. Particularly, this novel hydrohalogenation of gem-difluoroalkenes provided an effect and large-scale access to various iododifluoromethylated compounds of high value for synthetic application.

Formaldehyde-Mediated Hydride Liberation of Alkylamines for Intermolecular Reactions in Hexafluoroisopropanol.

The ability of alkylamines to spontaneously liberate hydride ions is typically restrained, except under specific intramolecular reaction settings. Herein, we demonstrate that this reactivity can be unlocked through simple treatment with formaldehyde in hexafluoroisopropanol (HFIP) solvent, thereby enabling various intermolecular hydride transfer reactions of alkylamines under mild conditions. Besides transformations of small molecules, these reactions enable unique late-stage modification of complex peptides. Mechanistic investigations uncover that the key to these intermolecular hydride transfer processes lies in the accommodating conformation of solvent-mediated macrocyclic transition states, where the aggregates of HFIP molecules act as dexterous proton shuttles. Importantly, negative hyperconjugation between the lone electron pair of nitrogen and the antibonding orbital of amine's α C-H bond plays a critical role in the C-H activation, promoting its hydride liberation.

Nickel-catalysed asymmetric hydromonofluoromethylation of 1,3-enynes for enantioselective construction of monofluoromethyl-tethered chiral allenes.

An unprecedented nickel-catalysed enantioselective hydromonofluoromethylation of 1,3-enynes is developed, allowing the diverse access to monofluoromethyl-tethered axially chiral allenes, including the challenging deuterated monofluoromethyl (CD2F)-tethered ones that are otherwise inaccessible. It represents the first asymmetric 1,4-hydrofunctionalization of 1,3-enynes using low-cost asymmetric nickel catalysis, thus opening a new avenue for the activation of 1,3-enynes in reaction development. The utility is further verified by its broad substrate scope, good functionality tolerance, mild conditions, and diversified product elaborations toward other valuable fluorinated structures. Mechanistic experiments and DFT calculations provide insights into the reaction mechanism and the origin of the enantioselectivity.

Photoredox Nickel-Catalysed Stille Cross-Coupling Reactions.

The Stille cross-coupling reaction is one of the most common strategies for the construction of C-C bonds. Despite notable strides in the advancement of the Stille reaction, persistent challenges persist in hindering its greener evolution. These challenges encompass multiple facets, such as the high cost of precious metals and ligands, the demand for various additives, and the slow reaction rate. In comparison to the dominant palladium-catalysed Stille reactions, cost-effective nickel-catalysed systems lag behind, and enantioconvergent Stille reactions of racemic stannanes remain undeveloped. Herein, we present a pioneering instance of nickel-catalysed enantioconvergent Stille cross-coupling reactions of racemic stannane reagents, resulting in the formation of C-C bonds in good to high yields with excellent stereoselectivity. This strategy provides a practical, scalable, and operationally straightforward method for the synthesis of C(sp3 )-C(sp3 ), C(sp3 )-C(sp2 ), and C(sp3 )-C(sp) bonds under exceptionally mild conditions (without additives and bases, ambient temperature). The innovative use of synergistic photoredox/nickel catalysis enables a novel single-electron transmetalation process of stannane reagents, providing a new research paradigm of Stille reactions.

Construction of Complex Macromulticyclic Peptides via Stitching with Formaldehyde and Guanidine.

There is a growing interest in constructing multicyclic peptide structures to expand the chemical space of peptides. Conventional strategies for constructing large peptide structures are limited by the typical reliance on the inflexible coupling between premade templates equipped with fixed reactive handles and peptide substrates via cysteine anchors. Herein, we report the development of a facile three-component condensation reaction of primary alkyl amine, formaldehyde, and guanidine for construction of complex macromulticyclic peptides with novel topologies via lysine anchors. Moreover, the reaction sequences can be orchestrated in different anchor combinations and spatial arrangements to generate various macrocyclic structures crosslinked by distinct fused tetrahydrotriazine linkages. The macrocyclization reactions are selective, efficient, versatile, and workable in both organic and aqueous media. Thus, the condensation reaction provides a smart tool for stitching native peptides in situ using simple methylene threads and guanidine joints in a flexible and programmable manner.

Highly γ-Selective Arylation and Carbonylative Arylation of 3-Bromo-3,3-difluoropropene via Nickel Catalysis.

A nickel-catalyzed highly γ-regioselective arylation and carbonylative arylation of 3-bromo-3,3-difluoropropene has been developed. The reaction proceeds under mild reaction conditions, providing the gem-difluoroalkenes with high efficiency and good functional group tolerance. The resulting gem-difluoroalkenes can serve as versatile building blocks for diversified synthesis. Preliminary mechanistic studies and density functional theory calculations reveal that both non-radical and radical pathways are possible for the reaction, and the radical pathway is more likely. The high γ-regioselectivity results from the ß-bromide elimination of alkylnickel(II) species or from the reductive elimination of nickel(III) species [(aryl)(CF2 =CHCH2 )NiIII (Ln )X]. The γ-selective carbonylation of 3-bromo-3,3-difluoropropene under 1 atm CO gas also provides a new way for nickel-catalyzed carbonylation.

Cooperative Stapling of Native Peptides at Lysine and Tyrosine or Arginine with Formaldehyde.

Stapling of peptides by intramolecular crosslinking of two neighboring amino acid side chains offers an important tool to modulate the structure and properties of peptides. In comparison to the stapling of artificially engineered peptide substrates, methods for stapling native peptides are more desirable for easier accessibility and genetic encodability. However, the existing strategy for selectivity control in the stapling of native peptides is relatively limited: the site of anchoring is often dominated by Cys, and the means for achieving the position selectivity among the same type of residues at different locations is lacking. We have developed a simple and powerful strategy for stapling native peptides at lysine residues with formaldehyde by the cooperation of nearby tyrosine or arginine residues. The stapling reactions can proceed with high efficiency and residue selectivity under mild conditions, and generate linchpins with distinct physiochemical properties. The new method for peptide stapling enables unique control of position-selectivity for substrates bearing multiple reaction sites by reactivity that can be readily built in the peptide sequence.

Near-Infrared Afterglow Luminescent Aggregation-Induced Emission Dots with Ultrahigh Tumor-to-Liver Signal Ratio for Promoted Image-Guided Cancer Surgery.

Afterglow imaging through the collection of persistent luminescence after the stopping of light excitation holds enormous promise for advanced biomedical uses. However, efficient near-infrared (NIR)-emitting afterglow luminescent materials and probes (particularly the organic and polymeric ones) are still very limited, and their in-depth biomedical applications such as precise image-guided cancer surgery are rarely reported. Here, we design and synthesize a NIR afterglow luminescent nanoparticle with aggregation-induced emission (AIE) characteristics (named AGL AIE dots). It is demonstrated that the AGL AIE dots emit rather-high NIR afterglow luminescence persisting over 10 days after the stopping of a single excitation through a series of processes occurring in the AIE dots, including singlet oxygen production by AIE luminogens (AIEgens), Schaap's dioxetane formation, chemiexcitation by dioxetane decomposition, and energy transfer to NIR-emitting AIEgens. The animal studies reveal that the AGL AIE dots have the innate property of fast afterglow signal quenching in normal tissues, including the liver, spleen, and kidney. After the intravenous injection of AGL AIE dots into peritoneal carcinomatosis bearing mice, the tumor-to-liver ratio of afterglow imaging is nearly 100-fold larger than that for fluorescence imaging. The ultrahigh tumor-to-liver signal ratio, together with low afterglow background noise, enables AGL AIE dots to give excellent performance in precise image-guided cancer surgery.