Visible‐Light‐Accelerated C−H Sulfinylation of Heteroarenes

Heteroaromatic sulfoxides are a frequent structural motif in natural products, drugs, catalysts, and materials. We report a metal‐free visible‐light‐accelerated synthesis of heteroaromatic sulfoxides from sulfinamides and peroxodisulfate. The reaction proceeds at room temperature with blue‐light irradiation and allows the C−H sulfinylation of electron‐rich heteroarenes, such as pyrroles and indoles. An electrophilic aromatic substitution mechanism is proposed based on the substrate scope, substitution selectivity, and competition experiments with different nucleophiles.     

Visible‐Light‐Induced Direct Oxidative C−H Amidation of Heteroarenes with Sulfonamides

A direct oxidative C?H amidation of heteroarenes with sulfonamides via nitrogen‐centered radicals has been achieved. Nitrogen‐centered radicals are directly generated from oxidative cleavage of N?H bonds under visible‐light photoredox catalysis. Sulfonamides, which are easily accessed, are used as tunable nitrogen sources and bleach (aqueous NaClO solution) is used as the oxidant. A variety of heteroarenes, including indoles, pyrroles and benzofurans, can undergo this amidation with high yields (up to 92 %). These reactions are highly regioselective, and all the products are isolated as single regioisomer.     

Photoelectrochemical C−H Alkylation of Heteroarenes with Organotrifluoroborates

A photoelectrochemical method for the C?H alkylation of heteroarenes with organotrifluoroborates has been developed. The merger of electrocatalysis and photoredox catalysis provides a chemical oxidant‐free approach for the generation and functionalization of alkyl radicals from organotrifluoroborates. A variety of heteroarenes were functionalized using primary, secondary, and tertiary alkyltrifluoroborates with excellent regio‐ and chemoselectivity.     

Synergistic Manganese(I) C−H Activation Catalysis in Continuous Flow: Chemoselective Hydroarylation

Chemoselective hydroarylations were accomplished by a novel synergistic Brønsted acid/manganese(I)‐catalyzed C−H activation manifold. Thus, alkynes bearing O‐leaving groups could, for the first time, be employed for C−H alkenylations without concurrent β‐O elimination, thereby setting the stage for versatile late‐stage diversifications. Also described is the first manganese‐catalyzed C−H activation in continuous flow, thus enabling efficient hydroarylations within only 20 minutes.     

Visible‐Light‐Enabled Ruthenium‐Catalyzed meta‐C−H Alkylation at Room Temperature

Visible‐light‐induced ruthenium catalysis has enabled remote C?H alkylations with excellent levels of position control under exceedingly mild conditions at room temperature. The metallaphotocatalysis occurred under exogenous‐photosensitizer‐free conditions and features an ample substrate scope. The robust nature of the photo‐induced mild meta‐C?H functionalization is reflected by the broad functional group tolerance, and the reaction can be carried out in an operationally simple manner, setting the stage for challenging secondary and tertiary meta‐C?H alkylations by ruthenaphotoredox catalysis.     

Methylenecyclopropane Annulation by Manganese(I)‐Catalyzed Stereoselective C−H/C−C Activation

C−H/C−C functionalizations with methylenecyclopropanes (MCPs) were accomplished with a versatile base‐metal catalyst. A robust manganese(I) complex enabled the expedient annulation of MCPs by synthetically meaningful ketimines to deliver, upon one‐pot hydroarylation, densely substituted polycylic anilines in a step‐economical fashion. Mechanistic studies provided strong support for a facile organometallic C−H manganation, while typical cobalt, ruthenium, rhodium, and palladium catalysts were found completely ineffective.     

Visible‐Light‐Driven Palladium‐Catalyzed Radical Alkylation of C−H Bonds with Unactivated Alkyl Bromides

Reported herein is a novel visible‐light photoredox system with Pd(PPh₃)₄ as the sole catalyst for the realization of the first direct cross‐coupling of C(sp³)−H bonds in N‐aryl tetrahydroisoquinolines with unactivated alkyl bromides. Moreover, intra‐ and intermolecular alkylations of heteroarenes were also developed under mild reaction conditions. A variety of tertiary, secondary, and primary alkyl bromides undergo reaction to generate C(sp³)−C(sp³) and C(sp²)−C(sp³) bonds in moderate to excellent yields. These redox‐neutral reactions feature broad substrate scope (>60 examples), good functional‐group tolerance, and facile generation of quaternary centers. Mechanistic studies indicate that the simple palladium complex acts as the visible‐light photocatalyst and radicals are involved in the process.     

Continuous Visible‐Light Photoflow Approach for a Manganese‐Catalyzed (Het)Arene C−H Arylation

Manganese photocatalysts enabled versatile room‐temperature C−H arylation reactions by means of continuous visible‐light photoflow, thus allowing for efficient C−H arylations in 30 minutes with ample scope. The robustness of the manganese‐catalyzed photoflow strategy was shown by visible light‐induced gram‐scale synthesis, clearly outperforming the batch performance.     

Photochemical C−H Hydroxyalkylation of Quinolines and Isoquinolines

We report herein a visible light‐mediated C?H hydroxyalkylation of quinolines and isoquinolines that proceeds via a radical path. The process exploits the excited‐state reactivity of 4‐acyl‐1,4‐dihydropyridines, which can readily generate acyl radicals upon blue light absorption. By avoiding the need for external oxidants, this radical‐generating strategy enables a departure from the classical, oxidative Minisci‐type pattern and unlocks a unique reactivity, leading to hydroxyalkylated heteroarenes. Mechanistic investigations provide evidence that a radical‐mediated spin‐center shift is the key step of the process. The method's mild reaction conditions and high functional group tolerance accounted for the late‐stage functionalization of active pharmaceutical ingredients and natural products.     

Cobalt‐Catalyzed Oxidative C−H/C−H Cross‐Coupling between Two Heteroarenes

The first example of cobalt‐catalyzed oxidative C?H/C?H cross‐coupling between two heteroarenes is reported, which exhibits a broad substrate scope and a high tolerance level for sensitive functional groups. When the amount of Co(OAc)₂?4 H₂O is reduced from 6.0 to 0.5 mol %, an excellent yield is still obtained at an elevated temperature with a prolonged reaction time. The method can be extended to the reaction between an arene and a heteroarene. It is worth noting that the Ag₂CO₃ oxidant is renewable. Preliminary mechanistic studies by radical trapping experiments, hydrogen/deuterium exchange experiments, kinetic isotope effect, electron paramagnetic resonance (EPR), and high resolution mass spectrometry (HRMS) suggest that a single electron transfer (SET) pathway is operative, which is distinctly different from the dual C?H bond activation pathway that the well‐described oxidative C?H/C?H cross‐coupling reactions between two heteroarenes typically undergo.     

Mn‐Catalyzed Dehydrocyanative Transannulation of Heteroarenes and Propargyl Carbonates through C−H Activation: Beyond the Permanent Directing Effects of Pyridines/Pyrimidines

Pyridines/pyrimidines are common and effective directing groups in C?H activation. However, they are poorly functionalizable heteroarenes. Reported in this work is Mn‐catalyzed dehydrocyanative transannulation between three classes of heteroarenes and propargyl carbonates. The pyridyl/pyrimidyl groups in the heteroarenes initially function as directing groups to enable C?H allenylation; they then undergo intramolecular Diels–Alder/retro‐Diels–Alder reactions with the allene moiety to afford fused carbo/heterocycles. Three key intermediates at different stages of the reaction were isolated.     

Regioselective Arene C−H Alkylation Enabled by Organic Photoredox Catalysis

Expanding the toolbox of C?H functionalization reactions applicable to the late‐stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition‐metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic C?H bond. However, these high‐energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C?H functionalization reactions with diazoacetate derivatives, furnishing sp²–sp³ coupled products with moderate‐to‐good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transition‐metal catalyst.     

Manganese‐Catalyzed C−H Alkynylation: Expedient Peptide Synthesis and Modification

Manganese(I)‐catalyzed C−H alkynylations with organic halides occurred with unparalleled substrate scope, and thus enabled step‐economical C−H functionalizations with silyl, aryl, alkenyl, and alkyl haloalkynes. The versatility of the manganese(I) catalysis manifold enabled C−H couplings with haloalkynes featuring, among others, fluorescent labels, steroids, and amino acids, thereby setting the stage for peptide ligation as well as the efficient molecular assembly of acyclic and cyclic peptides. A plausible catalytic cycle was proposed.     

Manganese(I)‐Catalyzed Regio‐ and Stereoselective 1,2‐Diheteroarylation of Allenes: Combination of C−H Activation and Smiles Rearrangement

Heteroarenes are important structural motif in functional molecules. A Mn^I‐catalyzed 1,2‐diheteroarylation of allenes via a C−H activation/Smiles rearrangement cascade is presented. The reaction occurred under additive‐free or even solvent‐free conditions, which allowed the creation of two C−C and one C−N bonds in a single operation. A series of structurally diverse bicyclic or tricyclic compounds bearing an exocyclic double bond were constructed in good to excellent efficiency. The decarboxylative ring‐opening of the products led to the facile synthesis of vicinal biheteroaryls. Synthetic applications were demonstrated and preliminary mechanistic studies were conducted.     

Electrophotocatalytic Decarboxylative C−H Functionalization of Heteroarenes

Decarboxylative C?H functionalization reactions are highly attractive methods for forging carbon–carbon bonds considering their inherent step‐ and atom‐economical features and the pervasiveness of carboxylic acids and C?H bonds. An ideal approach to achieve these dehydrogenative transformations is through hydrogen evolution without using any chemical oxidants. However, effective couplings by decarboxylative carbon–carbon bond formation with proton reduction remain an unsolved challenge. Herein, we report an electrophotocatalytic approach that merges organic electrochemistry with photocatalysis to achieve the efficient direct decarboxylative C?H alkylation and carbamoylation of heteroaromatic compounds through hydrogen evolution. This electrophotocatalytic method, which combines the high efficiency and selectivity of photocatalysis in promoting decarboxylation with the superiority of electrochemistry in effecting proton reduction, enables the efficient coupling of a wide range of heteroaromatic bases with a variety of carboxylic acids and oxamic acids. Advantageously, this method is scalable to decagram amounts, and applicable to the late‐stage functionalization of drug molecules.     

Catalytic C−H Trifluoromethoxylation of Arenes and Heteroarenes

The intermolecular C?H trifluoromethoxylation of arenes remains a long‐standing and unsolved problem in organic synthesis. Herein, we report the first catalytic protocol employing a novel trifluoromethoxylating reagent and redox‐active catalysts for the direct (hetero)aryl C?H trifluoromethoxylation. Our approach is operationally simple, proceeds at room temperature, uses easy‐to‐handle reagents, requires only 0.03 mol % of redox‐active catalysts, does not need specialized reaction apparatus, and tolerates a wide variety of functional groups and complex structures such as sugars and natural product derivatives. Importantly, both ground‐state and photoexcited redox‐active catalysts are effective. Detailed computational and experimental studies suggest a unique reaction pathway where photoexcitation of the trifluoromethoxylating reagent releases the OCF₃ radical that is trapped by (hetero)arenes. The resulting cyclohexadienyl radicals are oxidized by redox‐active catalysts and deprotonated to form the desired products of trifluoromethoxylation.     

Visible‐Light‐Mediated Remote Aliphatic C−H Functionalizations through a 1,5‐Hydrogen Transfer Cascade

A redox‐neutral, light‐mediated functionalization of unactivated C(sp³)−H bonds via iminyl radicals is presented here. A 1,5‐H transfer followed by the functionalization of a C(sp²)−H bond takes place in aqueous media producing a variety of elaborated fused ketones. Mechanistic investigations have revealed 1,5‐H transfer as the reversible, rate‐determining step in this transformation. Divergent scaffolds are also accessible via C(sp³)−N bond formation upon a careful choice of the reaction additives.     

Manganese‐Catalyzed C−H Functionalizations: Hydroarylations and Alkenylations Involving an Unexpected Heteroaryl Shift

A manganese‐catalyzed regio‐ and stereoselective hydroarylation of allenes is reported. The C−H functionalization method provides access to various alkenylated indoles in excellent yields. Moreover, a hydroarylation/cyclization cascade involving an unexpected C−N bond cleavage and aryl shift has been developed, which provides a new synthetic approach to substituted pyrroloindolones.     

Mild C−H/C−C Activation by Z‐Selective Cobalt Catalysis

Cationic cobalt complexes enable unprecedented cobalt‐catalyzed C?H/C?C functionalizations with unique selectivity features. The versatile cobalt catalyst proved broadly applicable, enabled efficient C?H/C?C cleavage at room temperature, and delivered Z‐alkenes with excellent diastereocontrol.