Photocatalytic Alkylation of C(sp3)−H Bonds Using Sulfonylhydrazones**

The ability to construct C(sp³)−C(sp³) bonds from easily accessible reagents is a crucial, yet challenging endeavor for synthetic organic chemists. Herein, we report the realization of such a cross-coupling reaction, which combines N-sulfonyl hydrazones and C(sp³)−H donors through a diarylketone-enabled photocatalytic hydrogen atom transfer and a subsequent fragmentation of the obtained alkylated hydrazide. This mild and metal-free protocol was employed to prepare a wide array of alkyl-alkyl cross-coupled products and is tolerant of a variety of functional groups. The application of this chemistry further provides a preparatively useful route to various medicinally-relevant compounds, such as homobenzylic ethers, aryl ethyl amines, β-amino acids and other moieties which are commonly encountered in approved pharmaceuticals, agrochemicals and natural products.     

Carbene-Catalyzed Intermolecular Dehydrogenative Coupling of Aldehydes with C(sp3)−H Bonds

The development of catalyst-controlled methods for direct functionalization of two distinct C−H bonds represents an appealing approach for C−C formations in synthetic chemistry. Herein, we describe an organocatalytic approach for straightforward acylation of C(sp³)−H bonds employing readily available aldehyde as “acyl source” involving dehydrogenative coupling of aldehydes with ether, amine, or benzylic C(sp³)−H bonds. The developed method affords a broad range of ketones under mild conditions. Mechanistically, simple ortho-cyanoiodobenzene is essential in the oxidative radical N-heterocyclic carbene catalysis to give a ketyl radical and C(sp³) radical through a rarely explored intermolecular hydrogen atom transfer pathway, rendering the acylative C−C formations in high efficiency under a metal- and light-free catalytic conditions. Moreover, the prepared products show promising anti-bacterial activities that shall encourage further investigations on novel agrochemical development.     

Formal Insertion of Alkenes Into C(sp3)−F Bonds Mediated by Fluorine-Hydrogen Bonding

C−F Insertion reactions represent an attractive approach to prepare valuable fluorinated compounds. The high strength of C−F bonds and the low reactivity of the fluoride released upon C−F bond cleavage, however, mean that examples of such processes are extremely scarce in the literature. Here we report a reaction system that overcomes these challenges using hydrogen bond donors that both activate C−F bonds and allow for downstream reactions with fluoride. In the presence of hexafluoroisopropanol, benzyl and propargyl fluorides undergo efficient formal C−F bond insertion across α-fluorinated styrenes. This process, which does not require any additional fluorinating reagent, occurs under mild conditions and delivers products featuring the gem-difluoro motif, which is attracting increasing interest in medicinal chemistry. Moreover, readily available organic bromides can be engaged directly in a one-pot process that avoids the isolation of organic fluorides.     

Electrochemical NiH-Catalyzed C(sp3)−C(sp3) Coupling of Alkyl Halides and Alkyl Alkenes

Herein, an electrochemically driven NiH-catalyzed reductive coupling of alkyl halides and alkyl alkenes for the construction of Csp³−Csp³ bonds is firstly reported. Notably, alkyl halides serve dual function as coupling substrates and as hydrogen sources to generate NiH species under electrochemical conditions. The tunable nature of this reaction is realized by introducing an intramolecular coordinating group to the substrate, where the product can be easily adjusted to give the desired branched products. The method proceeds under mild conditions, exhibits a broad substrate scope, and affords moderate to excellent yields with over 70 examples, including late-stage modification of natural products and drug derivatives. Mechanistic insights offer evidence for an electrochemically driven coupling process. The sp³-carbon-halogen bonds can be activated through single electron transfer (SET) by the nickel catalyst in its low valence state, generated by cathodic reduction, and the generation of NiH species from alkyl halides is pivotal to this transformation.     

Organopotassium-Catalyzed Silylation of Benzylic C(sp3)−H Bonds

Benzylsilanes have found increasing applications in organic synthesis as bench-stable synthetic intermediates, yet are mostly produced by stoichiometric procedures. Catalytic alternatives based on the atom-economical silylation of benzylic C(sp³)−H bonds remain scarcely available as specialized directing groups and catalytic systems are needed to outcompete the kinetically-favored silylation of C(sp²)−H bonds. Herein, we describe the first general and catalytic-in-metal undirected silylation of benzylic C(sp³)−H bonds under ambient, transition metal-free conditions using stable tert-butyl-substituted silyldiazenes (tBu−N=N−SiR₃) as silicon source. The high activity and selectivity of the catalytic system, exemplified by the preparation of various mono- or gem-bis benzyl(di)silanes, originates from the facile generation of organopotassium reagents, including tert-butylpotassium.     

Intermolecular Enantioselective Benzylic C(sp3)−H Amination by Cationic Copper Catalysis**

Chiral benzylic amines are privileged motifs in pharmacologically active molecules. Intramolecular enantioselective radical C(sp³)−H functionalization by hydrogen-atom transfer has emerged as a straightforward, powerful tool for the synthesis of chiral amines, but methods for intermolecular enantioselective C(sp³)−H amination remain elusive. Herein, we report a cationic copper catalytic system for intermolecular enantioselective benzylic C(sp³)−H amination with peroxide as an oxidant. This mild, straightforward method can be used to transform an array of feedstock alkylarenes and amides into chiral amines with high enantioselectivities, and it has good functional group tolerance and broad substrate scope. More importantly, it can be used to synthesize bioactive molecules, including chiral drugs. Preliminary mechanistic studies indicate that the amination reaction involves benzylic radicals generated by hydrogen-atom transfer.     

C−H Activation of Unbiased C(sp3)−H Bonds: Gold(I)-Catalyzed Cycloisomerization of 1-Bromoalkynes**

Selective functionalization of non-activated C(sp³)−H bonds is a major challenge in chemistry, so functional groups are often used to enhance reactivity. Here, we present a gold(I)-catalyzed C(sp³)−H activation of 1-bromoalkynes without any sort of electronic, or conformational bias. The reaction proceeds regiospecifically and stereospecifically to the corresponding bromocyclopentene derivatives. The latter can be readily modified, comprising an excellent library of diverse 3D scaffolds for medicinal chemistry. In addition, a mechanistic study has shown that the reaction proceeds via a so far unknown mechanism: a concerted [1,5]-H shift / C−C bond formation involving a gold-stabilized vinylcation-like transition state.     

Metal-Free,N-Iodosuccinimide-Induced Regioselective Iodophosphoryloxylation of Alkenes with P(O)−OH Bonds

A simple and efficient method for the regioselective iodophosphoryloxylation of alkenes with P(O)−OH bonds has been established by using NIS (N-iodosuccinimide) as the iodination reagent under transition-metal-free conditions. The present protocol is compatible with different functional groups, and suitable for various alkenes and P(O)−OH compounds. A variety of functionalized β-iodo-1-ethyl phosphinic/phosphoric acid esters are obtained in good to excellent yields, which could be further transformed to diversified building blocks for the synthesis of bioactive compounds, pharmaceuticals and functional materials.     

Nickel-Catalyzed C−I-Selective C(sp2)−C(sp3) Cross-Electrophile Coupling of Bromo(iodo)arenes with Alkyl Bromides

Despite several methodologies established for C(sp²)−I selective C(sp²)−C(sp³) bond formations, achieving arene-flanked quaternary carbons by cross-coupling of tertiary alkyl precursors with bromo(iodo)arenes in a C(sp²)−I selective manner is rare. Here we report a general Ni-catalyzed C(sp²)−I selective cross-electrophile coupling (XEC) reaction, in which, beyond 3° alkyl bromides (for constructing arene-flanked quaternary carbons), 2° and 1° alkyl bromides are also demonstrated to be viable coupling partners. Moreover, this mild XEC displays excellent C(sp²)−I selectivity and functional group compatibility. The practicality of this XEC is demonstrated in simplifying the routes to several medicinally relevant and synthetically challenging compounds. Extensive experiments show that the terpyridine-ligated Ni^I halide can exclusively activate alkyl bromides, forming a Ni^I−alkyl complex through a Zn reduction. Attendant density functional theory (DFT) calculations reveal two different pathways for the oxidative addition of the Ni^I−alkyl complex to the C(sp²)−I bond of bromo(iodo)arenes, explaining both the high C(sp²)−I selectivity and generality of our XEC.     

Dual Benzophenone/Copper-Photocatalyzed Giese-Type Alkylation of C(sp3)−H Bonds

Photocatalyzed Giese-type alkylations of C(sp³)−H bonds are very attractive reactions in the context of atom-economy in C−C bond formation. The main limitation of such reactions is that when using highly polymerizable olefin acceptors, such as unsubstituted acrylates, acrylonitrile, or methyl vinyl ketone, radical polymerization often becomes the dominant or exclusive reaction pathway. Herein, we report that the polymerization of such olefins is strongly limited or suppressed when combining the photocatalytic activity of benzophenone (BP) with a catalytic amount of Cu(OAc)₂. Under mild and operationally simple conditions, the Giese adducts resulting from the C(sp³)−H functionalization of amines, alcohols, ethers, and cycloalkanes could be synthesized. Preliminary mechanistic studies have revealed that the reaction does not proceed through a radical chain, but through a dual BP/Cu photocatalytic process, in which both Cu^II and low-valent Cu^I/0 species, generated in situ by reduction by the BP ketyl radical, may react with α-keto or α-cyano intermediate radicals, thus preventing polymerization.     

Synthesis of Cytotoxic Iron-Containing Macrocycles Through Unexpected C(sp2)−C(sp2) Bonds Formation

In previous reports, it has been demonstrated that cyclometalated iron(II/III) complexes can be prepared by reacting iron(0) precursors and mercurated or brominated derivatives. However, in this report, the reaction between [Fe₃(CO)₁₂] and mercurated 6-phenyl-2,2′-bipyridine or brominated 2,6-diphenyl-pyridine pincer derivatives led to compounds in which C(sp²)−C(sp²) bonds have been formed between two ligands. A 16-electron iron(II) complex ( 1Cl ) bearing a tetradentate ligand originating from the dimerization of 6-phenyl-2,2′-bipyridine was isolated, while a protonated 14-membered macrocycle with [FeBr₄]⁻ as counterion ( 2 ) was obtained from 2,6-diphenyl-pyridine. Studies by X-ray diffraction crystallography, NMR, UV-vis and cyclic voltammetry confirmed the structures. Additionally, the cytotoxicity of the new compounds toward gastric cancer cell lines was evaluated, and it was established that the presence of the iron(II) center was crucial for an elevated activity.     

Photoredox-Controlled Mono- and Di-Multifluoroarylation of C(sp3)−H Bonds with Aryl Fluorides

A controllable mono- and di-multifluoroarylation of acyclic and cyclic N-aryl amines with aryl fluorides by photocatalyzed dual C(sp³)−H/C(sp²)−F functionalization has been developed, providing new access to a wide array of valuable α-fluoroarylated amines. In addition, the one-pot consecutive hetero-di-multifluoroarylation of N-aryl pyrrolidines and N,N-dimethylanilines was achieved with high to excellent diastereoselectivity. This new defluorinative C(sp³)−C(sp²) coupling is distinguished by a broad scope, good regioselectivity, and mild conditions as well as gram-scale and late-stage applicability, and thus constitutes a significant advance in the arylation of unactivated C(sp³)−H bonds with aryl fluorides.     

Iridium(III)-Catalyzed Intermolecular C(sp3)−H Insertion Reaction of Quinoid Carbene: A Radical Mechanism

Described herein is an Ir^III/porphyrin-catalyzed intermolecular C(sp³)−H insertion reaction of a quinoid carbene (QC). The reaction was designed by harnessing the hydrogen-atom transfer (HAT) reactivity of a metal-QC species with aliphatic substrates followed by a radical rebound process to afford C−H arylation products. This methodology is efficient for the arylation of activated hydrocarbons such as 1,4-cyclohexadienes (down to 40 min reaction time, up to 99 % yield, up to 1.0 g scale). It features unique regioselectivity, which is mainly governed by steric effects, as the insertion into primary C−H bonds is favored over secondary and/or tertiary C−H bonds in the substituted cyclohexene substrates. Mechanistic studies revealed a radical mechanism for the reaction.     

PtII-Catalyzed Hydroxylation of Terminal Aliphatic C(sp3)−H Bonds with Molecular Oxygen

The practical application of Shilov-type Pt catalysis to the selective hydroxylation of terminal aliphatic C−H bonds remains a formidable challenge, due to difficulties in replacing Pt^IV with a more economically viable oxidant, particularly O₂. We report the potential of employing FeCl₂ as a suitable redox mediator to overcome the kinetic hurdles related to the direct use of O₂ in the Pt reoxidation. For the selective conversion of butyric acid to γ-hydroxybutyric acid (GHB), a significantly enhanced catalyst activity and stability (turnover numbers (TON)>30) were achieved under 20 bar O₂ in comparison to current state-of-the-art systems (TON<10). In this regard, essential reaction parameters affecting the overall activity were identified, along with specific additives to attain catalyst stability at longer reaction times. Notably, deactivation by reduction to Pt⁰ was prevented by the addition of monodentate pyridine derivatives, such as 2-fluoropyridine, but also by introducing varying partial pressures of N₂ in the gaseous atmosphere. Finally, stability tests revealed the involvement of Pt^II and FeCl₂ in catalyzing the non-selective overoxidation of GHB. Accordingly, in situ esterification with boric acid proved to be a suitable strategy to maintain enhanced selectivities at much higher conversions (TON>60). Altogether, a useful catalytic system for the selective hydroxylation of primary aliphatic C−H bonds with O₂ is presented.     

Hydroxoiridium-Catalyzed Hydroalkylation of Terminal Alkenes with Ureas by C(sp3)−H Bond Activation

Direct alkylation of a methyl group, on di- and trisubstituted ureas, with terminal alkenes by C(sp³)−H bond activation proceeded in the presence of a hydroxoiridium/bisphosphine catalyst to give high yields of the corresponding addition products. The hydroxoiridium/bisphosphine complex generates an amidoiridium intermediate by reaction with ureas having an N−H bond.     

Photoinduced C(sp3)−N Bond Cleavage Leading to the Stereoselective Syntheses of Alkenes

Herein we report a versatile Mizoroki–Heck-type photoinduced C(sp³)−N bond cleavage reaction. Under visible-light irradiation (455 nm, blue LEDs) at room temperature, alkyl Katritzky salts react smoothly with alkenes in a 1:1 molar ratio in the presence of 1.0 mol % of commercially available photoredox catalyst without the need for any base, affording the corresponding alkyl-substituted alkenes in good yields with broad functional-group compatibility. Notably, the E/Z-selectivity of the alkene products can be controlled by an appropriate choice of photoredox catalyst.     

A Chemoselective Polarity-Mismatched Photocatalytic C(sp3)−C(sp2) Cross-Coupling Enabled by Synergistic Boron Activation**

We report the development of a C(sp³)−C(sp²) coupling reaction using styrene boronic acids and redox-active esters under photoredox catalysis. The reaction proceeds through an unusual polarity-mismatched radical addition mechanism that is orthogonal to established processes. Synergistic activation of the radical precursor and organoboron are critical mechanistic events. Activation of an N-hydroxyphthalimide (NHPI) ester by coordination to boron enables electron transfer, with decomposition leading to a nucleofuge rebound, activating the organoboron to radical addition. The unique mechanism enables chemoselective coupling of styrene boronic acids in the presence of other alkene radical acceptors. The scope and limitations of the reaction, and a detailed mechanistic investigation are presented.     

Oxodealkenylative Cleavage of Alkene C(sp3)−C(sp2) Bonds: A Practical Method for Introducing Carbonyls into Chiral Pool Materials

Reported herein is a one-pot protocol for the oxodealkenylative introduction of carbonyl functionalities into terpenes and terpene-derived compounds. This transformation proceeds by Criegee ozonolysis of an alkene, reductive cleavage of the resulting α-alkoxy hydroperoxide, trapping of the generated alkyl radical with 2,2,6,6-tetramethylpiperidin-1-yl (TEMPO), and subsequent oxidative fragmentation with MMPP. Using readily available starting materials from chiral pool, a variety of carbonyl-containing products have been accessed rapidly in good yields.     

Three-component Oxytrifluoromethylation of Alkenes: Highly Efficient and Regioselective Difunctionalization of CC Bonds Mediated by Photoredox Catalysts

Here comes the sun: A facile vicinal difunctionalization of alkenes, oxytrifluoromethylation, was established by visible-light-driven photoredox catalysis. Judicious choice of the CF(3) source is key. Nucleophiles such as water, alcohols, and carboxylic acids can be used in this highly efficient (2-4?h) and regioselective (100?%) transformation using light-emitting diode (LED) lamps and natural sunlight. SET=single-electron transfer.     

Ruthenium-Catalyzed Remote Difunctionalization of Nonactivated Alkenes for Double meta-C(sp2)−H/C-6(sp3)−H Functionalization

Twofold distal C−H functionalization was accomplished by difunctionalization of nonactivated alkenes to provide rapid access to multifunctionalized molecules. The multicomponent ruthenium-catalyzed remote 1,n-difunctionalization (n=6,7) of nonactivated alkenes with fluoroalkyl halides and heteroarenes in a modular manner is reported. The meta-C(sp²)−H/C-6(sp³)−H distal functionalization featured mild conditions, unique selectivity, and broad substrate scope with a domino process for twofold remote C(sp²)−H/C(sp³)−H activation of the sequential formation of three different carbon-centered radicals. A plausible mechanism was proposed based on detailed experimental and computational studies.