Tetrafluoroisopropylation of alkenes and alkynes enabled by photocatalytic consecutive difluoromethylation with CF2HSO2Na.

Direct assembly of complex fluorinated motifs from simple fluorine sources is an attractive frontier of synthetic chemistry. Reported herein is an unconventional protocol for achieving tetrafluoroisopropylation by using commercially available CF2HSO2Na as a convenient source of the tetrafluoroisopropyl [(CF2H)2CH] group, which finds widespread applications in life science and material science. Visible-light-induced hydrotetrafluoroisopropylation of alkenes and carbotetrafluoroisopropylation of alkynes have been thus developed. Various structurally diverse α-tetrafluoroisopropyl carbonyls and cyclopentanones are selectively constructed under mild conditions. A photocatalytic triple difluoromethylation cascade, driven by consecutive reductive radical/polar crossover processes, leads to the direct assembly of a tetrafluoroisopropyl moiety from CF2HSO2Na. This C1-to-C3 fluoroalkylation protocol provides a practical strategy for the rapid construction of polyfluorinated compounds that are otherwise difficult to access, thus significantly enhancing the boundary of fluoroalkylation chemistry.

Controllable Synthesis of Cyclopenta[b]indolines via Photocatalytic Fluoroalkylative Radical Cyclization Cascade of Ynamides.

A de novo method for direct construction of cyclopenta[b]indolines via a photocatalytic fluoroalkylative radical cyclization cascade of ynamides has been established, which proceeds via a sequence of radical addition, 1,5-HAT, 5-endo-trig cyclization, intramolecular arylation, and oxidative deprotonation. This protocol allows for the controllable assembly of a tricyclic architecture with three contiguous stereocenters, showcasing its high efficiency, compatibility, and regio- and diastereoselectivity for accessing pharmacologically significant fluoroalkylated cyclopenta[b]indolines. It represents one of the very few examples of tetrafunctionalization of alkynes.

Fluorine-Effect-Enabled Photocatalytic 4-Exo-Trig Cyclization Cascade to Access Fluoroalkylated Cyclobutanes.

Cyclobutanes are popular structural units in bioactive compounds and versatile intermediates in synthetic chemistry, but their synthesis is challenging owing to high ring strain. In this study, a novel method for highly regio- and diastereoselective synthesis of fluoroalkylcyclobutanes bearing vicinal quaternary and tertiary stereocenters is realized by a photocatalytic 4-exo-trig cyclization cascade of thioalkynes or trifluoromethylalkenes. Density functional theory calculations reveal that a unique fluorine effect, arising from hyperconjugative π→σ*C-F interactions, accounts for the regio-reversed radical addition at the sterically hindered alkene carbon, which facilitates an unprecedented 4-exo-trig ring closure. This chemistry enables the direct and controllable construction of medicinally valuable quaternary-carbon-containing cyclobutanes from readily available raw materials, nicely complementing the existing methods.

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.

Eu(OTf)3 -Catalyzed Formal Dipolar [4π+2σ] Cycloaddition of Bicyclo-[1.1.0]butanes with Nitrones: Access to Polysubstituted 2-Oxa-3-azabicyclo[3.1.1]heptanes.

Herein, we have synthesized multifunctionalized 2-oxa-3-azabicyclo[3.1.1]heptanes, which are considered potential bioisosteres for meta-substituted arenes, through Eu(OTf)3 -catalyzed formal dipolar [4π+2σ] cycloaddition of bicyclo[1.1.0]butanes with nitrones. This methodology represents the initial instance of fabricating bicyclo[3.1.1]heptanes adorned with multiple heteroatoms. The protocol exhibits both mild reaction conditions and a good tolerance for various functional groups. Computational density functional theory calculations support that the reaction mechanism likely involves a nucleophilic addition of nitrones to bicyclo[1.1.0]butanes, succeeded by an intramolecular cyclization. The synthetic utility of this novel protocol has been demonstrated in the concise synthesis of the analogue of Rupatadine.

Electrosynthesis of bridged or fused sulfonamides through complex radical cascade reactions: divergence in medium-sized ring formation.

Radical cascade addition is one of the most important and efficient strategies for the synthesis of valuable heterocycles with structural diversity and complexity. Organic electrochemistry has emerged as an effective tool for the sustainable molecular synthesis. Herein, we describe an electrooxidative radical cascade cyclization of 1,6-enynes to access two new classes of sulfonamides, containing medium-sized rings. Differences in the activation barrier for radical addition between alkynyl and alkenyl moieties contribute to the chemo-selective addition and regioselective 7- and 9-membered ring-formation. Our finding features good substrate scope, mild conditions, and high efficiency under metal-free and chemical oxidant-free conditions. In addition, the electrochemical cascade reaction allows for the concise synthesis of sulfonamides with bridged or fused ring systems containing medium-sized heterocycles.

Catalyst-Substrate Helical Character Matching Determines the Enantioselectivity in the Ishihara-Type Iodoarenes Catalyzed Asymmetric Kita-Dearomative Spirolactonization.

Catalyst design has traditionally focused on rigid structural elements to prevent conformational flexibility. Ishihara's elegant design of conformationally flexible C2-symmetric iodoarenes, a new class of privileged organocatalysts, for the catalytic asymmetric dearomatization (CADA) of naphthols is a notable exception. Despite the widespread use of the Ishihara catalysts for CADAs, the reaction mechanism remains the subject of debate, and the mode of asymmetric induction has not been well established. Here, we report an in-depth computational investigation of three possible mechanisms in the literature. Our results, however, reveal that this reaction is best rationalized by a fourth mechanism called "proton-transfer-coupled-dearomatization (PTCD)", which is predicted to be strongly favored over other competing pathways. The PTCD mechanism is consistent with a control experiment and further validated by applying it to rationalize the enantioselectivities. Oxidation of the flexible I(I) catalyst to catalytic active I(III) species induces a defined C2-symmetric helical chiral environment with a delicate balance between flexibility and rigidity. A match/mismatch effect between the active catalyst and the substrate's helical shape in the dearomatization transition states was observed. The helical shape match allows the active catalyst to adapt its conformation to maximize attractive noncovalent interactions, including I(III)···O halogen bond, N-H···O hydrogen bond, and π···π stacking, to stabilize the favored transition state. A stereochemical model capable of rationalizing the effect of catalyst structural variation on the enantioselectivities is developed. The present study enriches our understanding of how flexible catalysts achieve high stereoinduction and may serve as an inspiration for the future exploration of conformational flexibility for new catalyst designs.

Cu-catalyzed cascade difluoroalkylation/5-endo cyclization/ß-fluorine cleavage of ynones.

A copper-catalyzed, redox-neutral cascade difluoroalkylation/5-endo annulation/ß-fluorine cleavage of ynones is developed, providing a direct and stereoselective method to access synthetically important α-monofluoroalkenyl cyclopentanones. Mechanistic studies suggest an unprecedented CuII-assisted ß-fluorine fragmentation, which may be valuable for the challenging but important C-F bond activation. Moreover, the in situ generated difluorocarbene was found to serve as an effective reductant for the regeneration of copper(I) catalyst, thus avoiding the addition of external reductants.

Transition State Stabilization by SCF2 -H⋠⋠⋠O Bifurcated Hydrogen Bond.

The difluoromethylthio group (SCF2 H), which is generally considered a highly lipophilic weak hydrogen bonding donor, has attracted special interest from the pharmaceutical and agrochemical industry. Remarkably, there have been relatively few literature investigations of SCF2 H hydrogen bonding interactions. Here, we report the determination of the hydrogen bond acidity parameter A of the SCF2 H in the most popularly used electrophilic difluoromethylthiolating reagent. We present kinetic and computational evidence of the RSCF2 -H⋅⋅⋅O2 bifurcated hydrogen bond for stabilizing the SCF2 H-transferring transition state, which could cause a reversal of apparent electrophilic reactivity of difluoromethylthiolating and trifluoromethylthiolating reagents. Solvent effects on the RSCF2 -H⋅⋅⋅O2 bifurcated hydrogen bonds will also be discussed.

Diastereo- and Enantioselective Synthesis of Bisbenzannulated Spiroketals and Spiroaminals by Ir/Ag/Acid Ternary Catalysis.

We reported herein an iridium/silver/acid ternary catalytic system to access bisbenzannulated [6,6]-spiroketals in high efficiency with generally high diastereo- and enantioselectivities (up to >20 : 1 dr, >99 % ee). In this procedure, readily available o-alkynylacetophenones undergo cycloisomerization to generate isochromenes in situ that participate in stereoselective allylation/spiroketalization sequence with 2-(1-hydroxyallyl)phenols. Meanwhile, 2-(1-hydroxyallyl)anilines were also compatible in this cascade reaction, furnishing structurally novel bisbenzannulated [6,6]-spiroaminals with good diastereoselectivities (8 : 1-12 : 1 dr) and excellent enantioselectivities (98 %->99 % ee). Moreover, experimental studies and theoretical calculations were performed to illustrate the reaction mechanism and stereochemistry.

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.

Regio- and Enantioselective γ-Allylic Alkylation of In Situ-Generated Free Dienolates via Scandium/Iridium Dual Catalysis.

An unprecedented asymmetric γ-allylic alkylation of free dienolates via Sc/Ir dual catalysis is reported, which affords a range of synthetically versatile γ-allylic crotonaldehydes in high efficiency with excellent chemo-, regio-, and enantioselectivities. The dienolates bearing no essential auxiliary groups were generated in situ by scandium triflate-mediated Meinwald rearrangement of vinyloxiranes atom-economically. With the assistance of computational density functional theory calculations, a Sc/Ir bimetallic catalytic cycle was proposed to illustrate the reaction mechanism.

Solvent-controlled photocatalytic divergent cyclization of alkynyl aldehydes: access to cyclopentenones and dihydropyranols.

Divergent synthesis is a powerful strategy for the fast assembly of different molecular scaffolds from identical starting materials. We describe here a solvent-controlled photocatalytic divergent cyclization of alkynyl aldehydes with sulfonyl chlorides for the direct construction of highly functionalized cyclopentenones and dihydropyranols that widely exist in bioactive molecules and natural products. Density functional theory calculations suggest that a unique N,N-dimethylacetamide-assisted 1,2-hydrogen transfer of alkoxy radicals is responsible for the cyclopentenone formation, whereas a C-C cleavage accounts for the selective production of dihydropyranols in acetonitrile and water at 50 °C. Given the simple and mild reaction conditions, excellent functional group compatibility, forming up to four chemical bonds, and tunable selectivity, it may find wide applications in synthetic chemistry.

The Acidities of Nucleophilic Monofluoromethylation Reagents: An Anomalous α-Fluorine Effect.

Fluorine incorporation into organic molecules is expected to lower the pKa of neighboring functionality via its strong electron-withdrawing effect, and this strategy has been widely exploited in diverse disciplines. Herein, we report a striking anomalous α-fluorine substitution effect on the α-Csp3 -H acidity. We have experimentally measured the pKa values of a series of popular nucleophilic monofluoromethylating reagents α-fluoro(phenylsulfonyl)methane derivatives as well as their C-H analogues by Bordwell's overlapping indicator method in dimethyl sulfoxide solution. Contrary to expectations, we found that α-fluorine substituent does not generally enhance but rather weaken the α-Csp3 -H acidity of most (phenylsulfonyl)methane derivatives. DFT computations reproduce and provide insight into the anomalous α-fluorine effect. A correlation was identified between the C-H pKa of (phenylsulfonyl)methane derivatives and Mayr's nucleophilicity parameter (N) of the corresponding carbanions.

Internal Alkyne-Directed Fluorination of Unactivated C(sp3)-H Bonds.

A silver-mediated internal alkyne-guided fluorination of unactivated C(sp3)-H bonds is described. The reaction provides a facile access to γ-fluorinated fluoroalkylated (Z)-alkenes from readily available alkynes in promising yields with excellent regioselectivity, stereoselectivity, and site selectivity.

Mechanism and Origins of Enantioselectivities in Spirobiindane-Based Hypervalent Iodine(III)-Induced Asymmetric Dearomatizing Spirolactonizations.

The work of Kita et al. on asymmetric oxidative dearomatization of naphthol carboxylic acids to spirolactones mediated/catalyzed by a novel, conformationally rigid µ-oxo-bridged hypervalent iodine(III) species is a landmark discovery in enantioselective iodine(III) catalysis [Kita, Y.; et al. Angew. Chem., Int. Ed. 2008, 47, 3787. DOI: 10.1002/anie.200800464 ; J. Am. Chem. Soc. 2013, 135, 4558. DOI: 10.1021/ja401074u ]. We have investigated the detailed mechanism of this important transformation using density functional theory. Calculations revealed that proton transfer from the pendant carboxylic acid of naphthols to the bridging oxygen atom or the ligand of iodine(III) species, which enhances the nucleophilicity of the carboxylic oxygen and the nucleofugality of the iodoarene, is crucial for the dearomatizing spirolactonization. Halogen bonding between the resulting carboxylate and the electron-deficient iodine(III) center further stabilizes the dearomatizing spirolactonization transition states. Calculations also revealed a long-neglected cleaved µ-oxo iodine(III) species that is more reactive but less selective than the µ-oxo-bridged hypervalent iodine(III) species itself for the oxidative dearomatization of naphthols. The coexistence of two sequential dearomatizing spirolactonization processes in the reaction system results in a lower enantioselectivity. A new stereochemical model that is able to reproduce and rationalize the observed apparent enantioselectivities is proposed.

Transition-Metal-Free ipso-Trifluoromethylthiolation of Lithium Aryl Boronates.

A transition-metal-free direct trifluoromethylthiolation of the ipso-carbon of lithium aryl boronates with trifluoromethanesulfenate under mild conditions was described. In addition, late-stage site-selective C-H borylation/trifluoromethylation and C-Cl borylation/trifluoromethylthiolation of biologically active molecules was developed. Initial mechanistic study suggested that the Li+ cation plays a vital role by coordinating to the oxygen atom of an aryl boronate complex and the oxygen of the reagent, thus allowing the aryl group to directly attack the trifluoromethylthio group of the trifluoromethylthiolating reagent.

Asymmetric Cycloaddition of ortho-Hydroxyphenyl-Substituted para-Quinone Methides and Enamides Catalyzed by Chiral Phosphoric Acid.

A BINOL-based chiral phosphoric acid was employed as an efficient catalyst in enantioselective cycloaddition of ortho-hydroxyphenyl-substituted para-quinone methides and enamides, which gave rise to acetamido-substituted tetrahydroxanthenes with three adjacent stereogenic centers in high yields (up to 99%) and excellent stereoselectivities (up to >99:1 diastereomeric ratio and up to 98% ee).

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.

Atroposelective Catalytic Asymmetric Allylic Alkylation Reaction for Axially Chiral Anilides with Achiral Morita-Baylis-Hillman Carbonates.

A highly efficient method to access axially chiral anilides through asymmetric allylic alkylation reaction with achiral Morita-Baylis-Hillman carbonates by using a biscinchona alkaloid catalyst was reported. Through the atroposelective approach, a broad range of axially chiral anilide products with different acyl groups, such as substituted phenyl, naphthyl, alkyl, enyl, styryl, and benzyl, were generated with very good yields, moderate to excellent cis: trans ratios, and good to excellent enantioselectivities. The reaction can be scaled up, and the synthetic utility of axially chiral anilides was proved by transformations. Moreover, the linear free energy relationship analysis was introduced to investigate the reaction.