Mild Copper‐Catalyzed Fluorination of Alkyl Triflates with Potassium Fluoride

A chemoselective catalytic fluorination of alkyl triflates is described using potassium fluoride as a fluoride source. Excellent yields of the desired alkyl fluorides are obtained after one hour at 45 °C using 2 mol % of the copper catalyst. With 10 mol % of the catalyst, full conversion can be achieved in less than 10 minutes at 45 °C, and thus makes this procedure potentially suited for the preparation of ¹⁸F‐labeled PET probes. As a result of the mild reaction conditions, only the substitution products are observed with no evidence of common side reactions, such as elimination. Reported is a preliminary study of the reaction scope, which demonstrates that the fluorination can be performed in the presence of a wide range of functional groups. Evidence suggests an unusual role of the [IPrCuOTf] catalyst as a phase‐transfer catalyst and points to [IPrCuF] as the active fluorinating reagent (IPr=1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene).     

Site‐Selective Late‐Stage Aromatic [18F]Fluorination via Aryl Sulfonium Salts

Site‐selective functionalization of C?H bonds in small complex molecules is a long‐standing challenge in organic chemistry. Herein, we report a broadly applicable and site‐selective aromatic C?H dibenzothiophenylation reaction. The conceptual advantage of this transformation is further demonstrated through the two‐step C?H [¹⁸F]fluorination of a series of marketed small‐molecule drugs.     

Copper-Mediated Fluorination of Aryl Trisiloxanes with Nucleophilic Fluoride

A method for the nucleophilic fluorination of heptamethyl aryl trisiloxanes to form fluoroarenes is reported. The reaction proceeds in the presence of Cu(OTf)₂ and KHF₂ as the fluoride source under mild conditions for a broad range of heptamethyltrisiloxyarenes with high functional group tolerance. The combination of this method with the silylation of aryl C−H bonds enables the regioselective fluorination of non-activated arenes controlled by steric effects following a two-step protocol.     

Manganese‐Catalyzed Hydrofunctionalization of Alkenes

The manganese‐catalyzed hydrosilylation and hydroboration of alkenes has been developed using a single manganese(II) precatalyst and reaction protocol. Both reactions proceed with excellent control of regioselectivity and in high yields across a variety of sterically and electronically differentiated substrates (25 examples). Alkoxide activation, using NaO^tBu, was key to precatalyst activation and reactivity. Catalysis was achieved across various functional groups and on gram‐scale for both the developed methodologies with catalysts loadings as low as 0.5 mol %.     

Manganese‐Catalyzed Hydroarylation of Unactivated Alkenes

Transition‐metal‐catalyzed hydroarylation of unactivated alkenes with strategic use of remote coordinating functional groups has received significant attention recently to address the issues of both low reactivity and poor selectivity. The bidentate 8‐aminoquinoline amide group is the most successfully adopted in unactivated alkenes for Pd and Ni catalysis. We describe the first manganese‐catalyzed hydroarylation of unactivated alkenes bearing diverse simple functionalities with arylboronic acids. A series of δ‐ and γ‐arylated amides, ketones, pyridines, and amines was accessed with excellent regioselectivity and in high yields. Hydroalkenylation of unactivated alkenes was also shown to be applicable under this manganese‐catalysis regime. The method features earth‐abundant manganese catalysis, easily available substrates, broad functional‐group tolerance, and excellent regioselective control.     

Manganese‐Catalyzed Cross‐Coupling of Thiols with Aryl Iodides

A manganese‐catalyzed cross‐coupling reaction of thiols with aryl iodides, furnishing aryl thioethers in good to excellent yields has been reported; the system shows good functional group tolerance and enables the sterically demanding aryl iodides to couple with thiols.     

Copper‐Catalyzed Aerobic Decarboxylation/Ketooxygenation of Electron‐Deficient Alkenes

A copper‐catalyzed ketooxygenation of electron‐deficient alkenes was developed. This approach combines O?H alkylation, aerobic decarboxylation, and oxygenation in one transformation. Mechanistic investigation of this reaction showed that the copper salt is responsible for both generating the amidoxyl radical and promoting aerobic decarboxylation.     

Manganese‐Catalyzed β‐Methylation of Alcohols by Methanol

We report an earth‐abundant‐metal‐catalyzed double and single methylation of alcohols. A manganese catalyst, which operates at low catalyst loadings and short reaction times, mediates these reactions efficiently. A broad scope of primary and secondary alcohols, including purely aliphatic examples, and 1,2‐aminoalcohols can be methylated. Furthermore, alcohol methylation for the synthesis of pharmaceuticals has been demonstrated. The catalyst system tolerates many functional groups among them hydrogenation‐sensitive examples and upscaling is easily achieved. Mechanistic investigations are indicative of a borrowing hydrogen or hydrogen autotransfer mechanism involving a bimetallic K‐Mn catalyst. The catalyst accepts hydrogen as a proton and a hydride from alcohols efficiently and reacts with a chalcone via hydride transfer.     

Dimeric Manganese‐Catalyzed Hydroarylation and Hydroalkenylation of Unsaturated Amides

An unprecedented Mn(I)‐catalyzed selective hydroarylation and hydroalkenylation of unsaturated amides with commercially available organic boronic acids is reported. Alkenyl boronic acids have been successfully employed for the first time in Mn(I)‐catalyzed carbon–carbon bond formation. A wide array of β‐alkenylated amide products can be obtained in moderate to good yields, which offers practical access to five‐ and six‐membered lactams. This protocol has predictable regio‐ and chemoselectivity, excellent functional group compatibility and ease of operation in air, representing a significant step‐forward towards manganese‐catalyzed C?C coupling.     

Manganese‐Catalyzed Carbonylative Annulations for Redox‐Neutral Late‐Stage Diversification

An inexpensive, nontoxic manganese catalyst enabled unprecedented redox‐neutral carbonylative annulations under ambient pressure. The manganese catalyst outperformed all other typically used base and precious‐metal catalysts. The outstanding versatility of the manganese catalysis manifold was reflected by ample substrate scope, setting the stage for effective late‐stage manipulations under racemization‐free conditions of a wealth of marketed drugs and natural products, including alkaloids, amino acids, steroids, and carbohydrates.     

Late‐Stage Diversification through Manganese‐Catalyzed C−H Activation: Access to Acyclic,Hybrid, and Stapled Peptides

Bioorthogonal C?H allylation with ample scope was accomplished through a versatile manganese(I)‐catalyzed C?H activation for the late‐stage diversification of structurally complex peptides. The unique robustness of the manganese(I) catalysis manifold was reflected by full tolerance of sensitive functional groups, such as iodides, esters, amides, and OH‐free hydroxy groups, thereby setting the stage for the racemization‐free synthesis of C?H fused peptide hybrids featuring steroids, drug molecules, natural products, nucleobases, and saccharides.     

Recent Advances and Perspectives of Transition Metal‐Catalyzed Asymmetric Fluorination Reactions

The synthesis of fluorine‐containing molecules has received intensive attention in recent years due to the great value of fluorides, however, the transition metal‐catalyzed asymmetric construction of C—F bonds is much less developed. This review presents the recent advancement of transition metal‐catalyzed asymmetric fluorination reactions, in which the final C—F bond is from reductive elimination of organometallic complexes. In addition, the perspective of the field is also provided for the future studies of asymmetric fluorinations and the related transformations, such as trifluoromethylation, trifluoromethylthiolation and trifluoromethoxylation.     

18F‐Labeling of Aryl‐SCF3, ‐OCF3 and ‐OCHF2 with [18F]Fluoride

We report that halogenophilic silver(I) triflate permits halogen exchange (halex) nucleophilic ¹⁸F‐fluorination of aryl‐OCHFCl, ‐OCF₂Br and ‐SCF₂Br precursors under mild conditions. This Ag^I‐mediated process allows for the first time access to a range of ¹⁸F‐labeled aryl‐OCHF₂, ‐OCF₃ and ‐SCF₃ derivatives, inclusive of [¹⁸F]riluzole. The ¹⁸F‐labeling of these medicinally important motifs expands the radiochemical space available for PET applications.     

Manganese‐Catalyzed Redox‐Neutral C−H Olefination of Ketones with Unactivated Alkenes

Since 1987, stoichiometric cyclomanganation of ketones and subsequent reactions with olefins in the presence of either palladium salts or trimethylamine N‐oxide (Me₃N⁺O^?) have been reported, but the catalytic versions remain untouched so far. Herein, the first manganese‐catalyzed redox‐neutral C?H olefination of ketones with unactivated alkenes is described, and shows a distinct reactivity with its parent stoichimetric reactions. Remarkably, mechanistic experiments and DFT calculations uncovers a unique concerted bis‐metalation deprotonation (CBMD) mechanism of the Mn‐Zn‐enabled C?H bond activation.