Optically pure alkylnitriles are important structural motifs found in agrochemicals, pharmaceuticals, and natural products, which can be further transferred to acids, amines and amides. Direct asymmetric cyanation of sp ³ C—H bonds represents the most efficient synthetic pathway to these optically pure alkylnitriles. However, selective functionalization of sp ³ C—H bonds remains a crucial issue due to the inertness of sp ³ C—H bonds as well as the difficulties in the control of stereo- and regioselectivity. Inspired by enzymatic oxygenases and halogenases, such as cytochrome P450 and nonheme iron enzymes, the radical-based C—H functionalization has received much attention, which was initiated with a hydrogen atom transfer (HAT) process. Recently, numerous reports have been disclosed for the highly efficient functionalization of C—H bonds with an intramolecular HAT process as a key step to govern the reactivity and site selectivity. Our group has developed a copper-catalyzed radical relay process for the enantioselective cyanation and arylation of benzylic C—H bonds using TMSCN and ArB(OH)₂ as nucleophiles respectively. Mechanistic studies indicated that a benzylic radical generated via a radical replay process can be trapped by a reactive chiral copper(II) cyanide enantioselectively, delivering optically pure benzyl nitriles efficiently. Herein, we communicate the catalytic asymmetric cyanation of remote C—H bonds by merging photoredox catalysis with copper catalysis. This reaction proceeds under mild reaction conditions and exhibits good functional group compatibility as well as wide substrates scope. Additionally, the nitrile group was further reduced to amide under hydrogen atmosphere. This reaction provides an efficient pathway to synthesize chiral δ-cyano alcohols and 1,6-amino alcohols. The general procedure is as following: in a dried sealed tube, substrate 1 (0.2 mmol, 1.0 equiv.), Cu(CH₃CN)₄PF₆ (0.01 mmol, 5 mol%), L (0.015 mmol, 7.5 mol%) and Ir(ppy)₃ (0.002 mmol, 1 mol%) were dissolved in dichloromethane (4.0 mL) under N₂ atmosphere, and stirred for 30 min. Then, TMSCN (50 μL, 0.4 mmol, 2 equiv.) was added slowly under N₂ atmosphere. The tube was sealed with a Teflon-lined cap, and the mixture was stirred under the irradiation of blue LED for 1~7 d. The reaction mixture was diluted with dichloromethane, filtered through a short pad of celite. A solution of TBAF (3 equiv.) and HOAc (3 equiv.) was added to the filtration. The mixture was stirred for 5 min and then washed with water (3×10 mL) and dried over anhydrous Na₂SO₄. After filtration and concentration, the residue was purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate) to afford target product.

The introduction of difluoromethyl groups into organic molecules not only can dramatically alter physical properties of nonfluorinated counterparts, but also provide valuable CF₂-containing building blocks for the synthesis of other difluoromethylenated compounds. Therefore, there is a growing demand to develop efficient and practical methods for the introduction of the difluoromethyl motif. Although significant advances have been made in the preparation of difluoromethylated arenes, these reactions usually required pre-functionalized substrates, precious metal catalysts, elevated temperature, and so on. In the past decade, visible light-driven photoredox catalysis has been proved to be powerful in synthetic radical chemistry. Particularly, direct difluoroalkylations of arenes have been achieved using precious-metal photocatalysts such as ruthenium or iridium polypyridyl complexes. Herein, we are committed to developing a cheap copper-based phororedox system for direct difluoroalkylation of arenes. The key to this approach is the in-situ formation of cuprous photocatalyst from cuprous iodide, an imine ligand (2,9-dichloro-1,10-phenanthroline) and a triaryl phosphine ligand (4,5-bis(diphenylphos- phino)-9,9-dimethyl xanthene). With catalytic amount of reagents mentioned above, the direct difluoroalkylation between arenes and difluoroalkylation reagents (BrCF₂CO₂Et or BrCF₂CONR ¹R ²) took place smoothly under 6 W blue LED irradiation at room temperature. A variety of electron-rich arenes, including electron-donating aromatics, indoles, furans, thiophenes, and pyrimidines, could be carbonyldifluoromethylated in moderate to excellent yields. In addition, high yields were obtained for the intramolecular and intermolecular aminocarbonyldifluoromethylation by the catalytic system. Preliminary mechanistic studies reveal that [Cu(dcp)(xantphos)]I (dcp=2,9-dichloro-1,10-phenanthroline, xantphos=4,5-bis(diphenyl phosphino)-9,9-dimethyl xanthene), in situ-formed from CuI, dcp, and xantphos should be the real photocatalyst to catalyze the visible light-driven difluoroalkylation. Difluormethyl radicals, produced by single electron transfer from the excited photocatalyst to difluoroalkylation reagents, should be involved in the difluoroalkylation. In summary, visible-light driven difluoroalkylation of arenes with difluoroalkylation reagents via Cu-catalysis has been developed. The use of the bidentate phosphine ligand and the imine ligand is essential for high efficiency as they could bind to cuprous iodide to generate the photocatalyst in situ. The typical procedure is as follows: a mixture of arenes (0.6 mmol), CuI (0.02 mmol), dcp (0.02 mmol), xantphos (0.02 mmol), K₃PO₄ (0.4 mmol) and CH₂Cl₂ (2 mL) were loaded in a flame-dried reaction vial which was subjected to evacuation with argon for 30 min. Subsequently, BrCF₂CO₂Et (0.2 mmol) was added to the mixture via syringe, and the mixture continued degassing for 5 min. After degassing procedure, the vial was sealed with wax, and irradiated by blue light for 24 h. The reaction was monitored by TLC. Further purification of the evaporated mixture by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate) gave the desired product.

The selective functionalization of unactivated sp ³ carbon-hydrogen (C—H) bond is an attractive strategy in modern organic transformation. The hydrogen atom transfer (HAT) catalysis has recently shown its advances in remotely selective activation of an inert C—H bond with great functional group compatibility, generating new carbon-carbon (C—C) bonds and carbon-heteroatom (C—O, C—N, C—X) bonds. Therefore, the remote sp ³ C—H functionalization has become an intensively investigated research area, drawing extensive attention in synthetic community. Particularly, the 1,5-hydrogen atom abstraction of nitrogen radicals, the key step of the Hoffman-L?ffler-Freytag (HLF) reaction, has been widely applied in the preparation of heterocycles. Comparing to the well-studied area of nucleophilic N-species, N-centered radical based reactions are still underdeveloped. The limited utility is partially due to the required use of hazardous radical initiators, elevated temperatures, or high-energy UV irradiation for the generation of N-radicals. Recently, visible-light photoredox catalysis has been leading efficient accesses to Nitrogen-radicals under mild conditions. The visible-light-induced nitrogen radical formation has also stimulated the development of the remote sp ³ C—H functionalization by photoredox catalysis. The classic HLF reaction requires pre-functionalization at N-center in the substrate to promote the formation of N-radical. Recently, a direct N—H single electron transfer (SET) oxidation was realized by photoredox catalysis in Knowles and Rovis’s group, generating N-radicals efficiently. The processes significantly simplified the preparation of the HLF reaction substrates and broaden the application of this classic reaction. In addition, the visible-light-induced nitrogen radical-directed reaction on modified imines provided possibilities for the remote sp ³ C—H functionalization of ketones, as ketone is the product of imine hydrolysis. Moreover, the application of chiral Lewis acid catalysis combined with visible-light photoredox catalysis enabled the asymmetric alkylation of the unactivated remote sp ³ C—H position, which achieves both regioselective and stereoselective functionalization. In conclusion, this strategy takes advantage of mild generation of N-radicals upon visible-light excitation. Subsequent 1,5-hydrogen atom transfer (1,5-HAT) and intermolecular radical coupling would realize the remote functionalization of unactivated sp ³ C—H bonds. The strategies have been successfully applied in remote C(sp ³)—H amidation, fluorination, chlorination, iodination, alkylation, vinylation, allylation, oxygenation, thioetherification, cyanation and alkynylation. In this review, we focus on visible-light-induced nitrogen radical directed functionalization of remote sp ³ C—H bonds, summarized the methodologies, and briefly reviewed their synthetic applications in pharmaceuticals and natural products.

The production and transformation of alkynes occupys an important position in organic synthetic chemistry. Within this realm, propargylic functionalization of alkynes is a feasible way towards this purpose. Especially, the propargylic functionalization via radical pathways has flourished in the last decade, which is believed to be a significant complement to the classic metal-catalyzed propargylation reaction involving cationic intermediates. According to the reaction modes, these advancements will be highlighted by classifying into four types. The first one is the propargylic functionalization reactions involving propargylic radicals. Generally, propargylic radicals can be generated through single electron reduction of alkyne substrates by low-valence metal catalysts or excited state of photocatalysts, then participated in the following cross-coupling reactions to achieve alkyne products. In this part, asymmetric variants have been also well developed. The second one is the preparation of allene compounds through the allenyl radical pathway. For these processes, propargylic radicals can isomerize to allenyl radicals, which can participate in the copper- or nickel-catalyzed coupling reaction to produce significant allene compounds. The third one is the dehydrative alkylation reaction of propargyl alcohols that involve propargylic radical intermediates, too. Such radical intermediates can be further oxidized to propargylic cation intermediates, followed by a deprotonation to form substituted 1,3-enyne compounds. The forth one is the synthesis of vinylic alkoxyamines through a propargylic radical route. Initially, propargyl alcohols can be converted to propargylic radical species by the joint action of copper catalysts and TEMPO. The generated propargylic radical species can be captured by TEMPO to form vinylic alkoxyamines. Finally, an outlook on the radical propargylic functionalizations will be provided at the end of this review.

Azaheterocycles have been broadly applied in the development of therapeutic agents, agrochemicals and functional material molecules. Azaheterocycles equipped with perfluoroalkyl group usually manifest superior physical and biological properties than their parent molecules, such as showing improved metabolic stability and high lipophilicity. The synthesis of perfluoroalkyl modified azaheterocycles has attracted considerable research interest in recent years. The strategy of intramolecular aminoperfluoroalkylation of alkenes, which functionalize C=C bond with an external perfluoroalkyl group and an internal amine nucleophile in one pot, provides a streamlined synthesis of perfluoroalkyl substituted azaheterocycles. This strategy has been applied by Liu, Sodeoka and other research groups in the synthesis of perfluoroalkyl substituted aziridines, pyrrolidines, lactams and pyrazolines featuring the use of pendent amine, amide, hydrazone or urea group as internal amine source. We have previously developed a copper(I)-catalyzed intramolecular aminotrifluoromethylation reaction of O-homoallyl benzimidates with Togni reagent I for the synthesis of trifluoromethyl containing chiral 1,3-oxazines using a chiral BOX ligand. However, this method is limited to aminotrifluoromethylation reaction as other perfluoroalkyl substituted hypervalent iodine reagents are not easily accessible. Herein, we report our recent research results on the synthesis of perfluoroalkyl substituted 1,3-oxazines using commercial available perfluoroalkyl iodides as perfluoroalkyl source. This intramolecular aminoperfluoroalkylation reaction proceeds selectively in the presence of Cu(OAc)₂ catalyst, 1,10-phenanthroline ligand and AgOAc additive. A broad range of O-homoallyl benzimidates and perfluoroalkyl iodides are compatible with the reaction conditions, affording perfluoroalkyl substituted 1,3-oxazines in moderate to good yields. The 1,3-oxazine product can be prepared in gram scale and readily hydrolyzed under mild conditions to give perfluoroalkyl substituted 1,3-amino alcohols. Preliminary mechanism studies revealed that this intramolecular aminoperfluoroalkylation reaction initiated with the addition of a perfluoroalkyl radical to the terminal alkene, and the subsequent functionalization with the benzimidate motif via intramolecular substitution generated 1,3-oxazine products.

Thiochromones are prevalent structures in various biological active molecules, natural products and potent drug candidates. However, only few methods for the synthesis of thiochromones were reported, and the traditional methods suffer from harsh conditions such as high temperature, strong acid, etc. Recently, synthesis of thiochromones from alkynones had been independently developed by the group of Larock, Mu?ller and Fu. Compared to traditional substances, alkynones are easy to be prepared and handled. More recently, Wu and co-authors improved this synthetic approach via a palladium-catalyzed carbonylative four-component reaction. Despite these great advances, syntheses of diversely functionalized thiochromones, especially 2-functionalized thiochromones which were not easily prepared via the above approaches, are still in demand and highly desirable. As part of our on-going interest in the synthesis of heterocyclic compounds via radical cascade reactions, herein, we developed a radical-involved annulation of methylthiolatedalkynones with diverse radical precursors to access 2-substituted thiochromones. Various substituents such as F, Br and OMe on aromatic ring were all compatible with the reaction, affording the desired 2-substituted thiochromones in moderate to good yields. The most advantage of this protocol is the compatibility of diverse radical precursors including H-phosphorus oxides, aryl aldehydes, arylthiols, BrCF₂COOEt, acetone and acetonitrile. Moreover, a series of control experiments were performed to interpret the reaction pathway as a radical process instead of electrophilic cyclization process. Mechanism studies showed that radical involved C(sp ²)—S bond formation and C(sp ³)—S cleavage are the key steps. A general procedure for the radical annulation of alkynones with acetone and acetonitrile is as followed. To the mixture of alkynones 1 (0.2 mmol), in a schlenk flask was added a solution of tert-butyl peroxybenzoate (TBPB) (0.4 mmol) in acetone or acetonitrile (2 mL) under nitrogen atmosphere. The reaction was stirred at 130 or 120 ℃ for 12 h. Upon completion, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography using a petroleum ether/ethyl acetate (V:V, 8:1~5:1) to afford the corresponding products 6.

Allylic substitutions catalyzed by transition metals are important and practical reactions, which can construct carbon-carbon bonds and carbon-heteroatom bonds efficiently and stereoselectively. Various transition metal catalysts, such as Pd, Ir, Cu, Ni, Rh and Ru, have been widely used in this reaction. To date, various “soft”, or stabilized nucleophiles (pKa<25), including malonates, acetoacetates and enolates, have been used in allylic substitutions. Conversely, the high reactivity of “hard”, or non-stabilized alkyl nucleophiles (pKa>25) has limited their utility in catalytic processes and their compatibility with functional groups. Visible light photoredox catalysis has been widely used in organic synthesis because it can generate high reactive intermediates, such as free radicals and radical ions, under mild conditions using green and clean energy, and has gradually developed into an important synthetic tool. Furthermore, merging photoredox catalysis with transition metal catalysts has become a popular strategy for expanding the synthetic utility of visible-light photocatalysis, and has led to the discovery of novel reaction modes. Due to the high activity of the intermediates in photoredox catalysis, the selectivity of these reactions, especially stereoselectivity, is still a challenge. In view of the importance of allyl substitutions, the allyl substitution co-catalyzed by transition metals and photoredox has attracted the interest of chemists. The synergistic strategy can realize allylic substitutions which are difficult to be achieved by single transition metal catalysis. The regioselectivity and stereoselectivity of these reactions also show different characteristics. It is expected to become an important complement to allylic substitution catalyzed by single metal. In this review, recent advances on allylic substitution co-catalyzed by different transition metals and photoredox are summarized. Meanwhile, the mechanism of representative transformations will be briefly introduced and the prospective in this area will be given.

CO₂ is an ideal C1 source in chemical transformations. It is of great significance to utilize CO₂ in chemical conversion to synthesize high value-added compounds, including carboxylic acids and carbonyl-containing heterocycles. On the other hand, the difunctionalization of olefins is an important organic reaction, which can efficiently convert easily available olefins into important compounds with structural diversity. However, due to the low reactivity of CO₂ and the difficulty in controlling the selectivity, the difunctionalization of olefins with CO₂ is highly challenging. Recently, the significant progress of radical chemistry has provided new strategies and promoted the development of novel transformations in this field. This Perspective summarizes the recent progress of the radical-type difunctionalization of olefins with CO₂, including the oxy-alkylation, carbocarboxylation, silacarboxylation, thiocarboxylation, and dicarboxylation of alkenes with CO₂. At the same time, we also highlight the mechanism with radicals and four kinds of pathways are proposed: (1) Free radicals attack olefins to form new carbon radical intermediates. The radicals are then oxidized to form carbocations, which are further captured by carbonates or carbamates. It is also possible for direct C—O bonding reaction or sequent C—I and C—O bonds formation. (2) The new carbon radical intermediates, in-situ generated through attack of alkenes with radicals, are reduced via single electron transfer into carbanions, which could attack CO₂ to form C—C bonds. (3) CO₂ is reduced into CO₂ radical anions in the highly reductive reaction conditions. Once generated, the CO₂ radical anions might attack olefins to form carboxylate bearing more stable carbon radical intermediates (such as benzylic ones) and further form C—C bonds or carbon-heteroatom bonds. (4) Olefins are reduced via single electron transfer into alkenyl free radical anions in the highly reductive reaction conditions. These anions may attack CO₂ to form carboxylate bearing carbon radical intermediates and are further reduced to generate carbanions. Finally they may attack another CO₂ to form succinic acid derivatives. We point out the challenges and predict the future development in the field, including the more challenging substrates, more reaction types, better selectivities, and deeper mechanistic understanding.

Decarboxylation of N-hydroxyphthalimide (NHPI) esters represents a powerful tool to generate carbon radicals, which has wide applications in the construction of C—C bonds and C—X bonds. Traditionally, the radical decarboxylation of NHPI esters has been enabled by transition-metal catalysis and photoredox catalysis. Recently, several visible light-mediated photosensor-free decarboxylation reactions have been reported with the use of special electron-donor systems. While notable, it’s still highly desirable to develop transition-metal-free, mild, and general methods to realize the radical decarboxylation of NHPI esters. Herein, we report 4-dimethylaminopyridine (DMAP)-boryl radical enabled Giese reaction and Barton decarboxylation of NHPI esters. The reaction starts from the generation of DMAP-boryl radical in the presence of a radical initiator, which then adds specifically to the carbonyl oxygen atom of NHPI ester 2, followed by β-fragmentation to give a nucleophilic carbon radical intermediate. Addition of the carbon radical to electron-deficient alkenes affords the Giese reaction product 4. On the other hand, hydrogen atom transfer from thiol to the nucleophilic carbon radical results in the Barton decarboxylation products 5. The reactions exhibit a broad substrate scope and excellent functional group tolerance. NHPI esters of primary, secondary, and tertiary alkyl carboxylic acids, including bio-active natural products and drugs, proceed smoothly to give the corresponding products in moderate to good yields. A variety of electron-deficient alkenes, such as vinyl esters, vinyl amides and vinyl sulphones, can be used as the Michael acceptors. A general procedure for the Giese reaction is as following: a solution of NHPI ester 2 (0.5 mmol), 4-dimethylaminopyridine-borane (0.6 mmol), AIBN (0.1 mmol) and electron- deficient alkenes 3 (0.4 mmol) in toluene (4.0 mL) was stirred at 80 ℃ for 4 h under nitrogen atmosphere. After evaporation of solvent, the crude residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to afford Giese reaction product 4. A general procedure for the Barton decarboxylation is as following: a solution of NHPI ester 2 (0.5 mmol), 4-dimethylaminopyridine-borane (0.55 mmol), TBHN (0.1 mmol) and PhSH (0.1 mmol) in benzotrifluoride (5.0 mL) was stirred at 80 ℃ for 1 h under nitrogen atmosphere. After evaporation of solvent, the crude residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to afford decarboxylative reduction product 5.

4-Quinolones are structural motifs prevalent in natural products and biologically active compounds. However, it remains challenging to synthesize 4-quinolones that bears diverse substituents at 2- and 3-positions. Herein we report an efficient and modular method for the synthesis of 4-quinolones from easily available N-aryl-O-propargyl carbamates and CO. The reactions employ 2-iodoxybenzoic acid (IBX) as an oxidant to oxidize the N-H group of the carbamate to generate an amide radical, which undergoes radical cyclization cascade with CO to afford the 4-quinolone product. The reactions provide speedy access to a series of 2,3-disubstituted 4-quinolones by varying the substituents of the carbamate substrate. Late stage functionalization employing Ni-catalysis allows the conversion of an OMe group on the 4-quinonone benzene ring to alkyl substituents, further increasing the diversity of the 4-quinone product. The synthetic potential is further demonstrated by running the synthesis on gram scale and by preparation of an enantiomerically enriched 4-quinolone product. The typical procedure is detailed as follows: A magnetic stirring bar, the carbamate substrate (0.25 mmol), IBX (1.0 mmol), and anhydrous dimethyl sulfoxide (DMSO, 10 mL) were placed in a 50 mL stainless steel autoclave. The autoclave was sealed, vacuumed and purged five times with CO, and finally pressurized with 10 MPa of CO. The reaction vessel was heated at 90 ℃ for 12 h and then cooled to r.t.. Excess CO was released in a fume hood. The reaction mixture was diluted with ethyl acetate (20 mL) and 5% NaHCO₃ (15 mL). The phases were separated. The aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic solution was washed with 5% NaHCO₃ (20 mL) and brine (20 mL). The organic solution was dried over anhydrous MgSO₄, filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel eluting with ethyl acetate/hexanes to give the desired product.

As inexpensive and readily available feedstocks, alkenes possess a unique reactivity profile and thus have been extensively applied in synthetic chemistry. Specifically, radical-triggered difunctionalization of alkenes provides a valuable synthetic strategy for their high utilization by incorporating two functional groups across the C=C π system. Despite the great achievements gained in this field, the vast majority of well-developed methods generally focus on activated alkenes, because its nascent alkyl radical needs to be stabilized by adjacent functional groups (e.g. aryl, carbonyl, heteroatom) via p-π conjugate effect. However, radical induced difunctionalization of unactivated alkenes remains elusive. Herein, a new protocol for Fe(III) mediated hydroalkynylation of unactivated olefins is reported. By using the characteristics of the in-situ-generated hydrogen radical from the interaction of Fe(acac)₃ and phenylsilane, hydrogen radical-triggered intramolecular 1,2-alkynyl migration was realized in this reaction, which led to the synthesis of a series of α-alkynyl ketones with moderate to good yields. Based on the experimental results and literature reports, a reasonable reaction mechanism was proposed, which involved hydrogen radical addition, 3-exo-dig cyclization (anti-Baldwin rules) and C—C bond breaking/recombination. Moreover, the reaction features good tolerance of functional groups, in which estrone-derived 1,4-enyne could be accommodated. A typical procedure for hydroalkynylation of unactivated alkenes is as follows: Fe(acac)₃ (1.2 equiv., 0.24 mmol) and NaHCO₃ (1.0 equiv., 0.2 mmol) are added to the 10-mL pressure tube. Then 1,4-enynes (1.0 equiv., 0.2 mmol) and phenylsilane (2.0 equiv., 0.4 mmol) are dissolved in 1.0 mL ethyl alcohol, respectively. Both of them are injected into this vial. The reaction system was sealed and stirred at 100 ℃ until the 1,4-enynes consumed that is determined by thin layer chromatography (TLC). After the reaction completes, the resulting mixture is extracted with EtOAc for three times, then the organic phase is concentrated and evaporated on a rotary evaporator. The residue was purified by chromatography on silica gel with petroleum ether/ethyl acetate (V∶V=75∶1) as the eluent to afford α-alkynyl ketones.

The cross dehydrogenative coupling (CDC) via highly selective C—H bond functionalization represents one of the most atom-economical, environmentally-benign and efficient synthetic strategies. For a long time, the cleavage of C—H bonds initiated by free radicals has been regarded as unselective and useless. However, more and more studies have shown that free radical mediated strategies could also achieve C—H bond functionalization in high selectivity recently. In general, it’s well-known that nucleophilic free radical species tend to extract hydrogen atoms on electron-deficient C—H bonds, while electrophilic free radicals abstract hydrogen atoms on electron-rich C—H bonds. A recent study by our group shows that after thermal decomposition of peroxy tert-butyl ether, the electron-rich methyl radicals are produced. Then the radical cleavage of the C(sp ³)—H bond in ketone/ester would happen prior to the α-carbonyl-C—H bond. Subsequently, the electrophilic α-carbonyl-C-centered radical selectively reacted with electron-rich olefins to afford new C—C bonds. Here, a free-radical initiated highly selective cross dehydrogenative coupling reaction of simple ketones and esters with electron-rich heteroarenes was demonstrated. The ketones and esters were used as solvent, and they would afford the corresponding α-carbonyl C-centered radicals, which then add to heteroaromatics leading to a series of C(2)-functionalized heterocycles. The chemoselectivity of this system was well-controlled by application of the polar effect of free radicals. In addition, this protocol features fast, simple operation, good functional group tolerance and site specific etc. The potential of this method was demonstrated through the synthesis of non-steroidal anti-inflammatory and analgesic drug tolmetin. It is expected to have wide applications in synthetic organic chemistry. Typical reaction conditions are as follows: a mixture of heteroarenes (1 equiv., 0.20 mmol), TBPA (3 equiv., 0.06 mmol) and ketones/esters (6 mL) was heated under reflux at 130 ℃ for about 1 h. After completion of the reaction, the crude product was cooled to room temperature, the excess solvent was recovered by rotary evaporator and the residue was further purified by column chromatography on silica gel to obtain the desired product (eluent: petroleum ether/ethyl acetate).

Due to the prevalence of organosulfur compounds in pharmaceuticals, agrochemicals, and functional materials, the development of new efficient and practical methods for the construction of C—S bonds is highly desirable in organic synthesis. Recently, the radical sulfonylation of alkenes has attracted considerable attention because of its efficient and versatile synthesis of organosulfur compounds under mild reaction conditions. The previous methods usually involve the formation of one C—S bond. In contrast, the thiosulfonylation of alkenes represents a highly attractive protocol for the concurrent formation of two distinct C—S bonds. Herein, a novel visible-light photocatalytic remote thiolation of aldehydes triggered by the radical sulfonylation of unactivated alkenes has been developed, with readily available thiosulfonates as both the sulfonating and thiolating reagents, successfully giving 6- or 7-sulfonylated thioesters in moderate to high yields with broad substrate scope and excellent atom-economics. As compared to the traditional methods that are limited to 1,2- or 1,1-thiosulfonylation of alkenes, the reaction described here constitutes the first example of 1,6- or 1,7-thiosulfonylation of functionalized alkenes, thus offering a good complementary protocol to the existing methods. Preliminary mechanistic studies suggest a radical pathway consisting of the formation of sulfonyl radical, alkene sulfonylation, intramolecular 1,n-hydrogen atom transfer (1,n-HAT), and thiolation of acyl radical. A representative procedure for the visible-light induced remote thiolation of aldehydes initiated by the sulfonylation of alkenes with thiosulfonates is as following: To a mixture of thiosulfonates 2 (0.5 mmol), Ir(ppy)₃ (1 mol%), and K₂HPO₄ (0.5 mmol) in 4 mL of MeCN was added alkenyl aldehydes 1 (0.25 mmol) under a N₂ atmosphere. After 18 h of irradiation with 15 W blue LEDs at 25 ℃, the reaction mixture was quenched with water, extracted with EtOAc, dried over anhydrous Na₂SO₄, concentrated, and purified by column chromatography with silica gel (EtOAc/petroleum ethers=1∶5) to give products 3 or 4.

Hantzsch Esters were first synthesized by Arthur Rudolf Hantzsch in 1881, and widely used in pharmaceutical chemistry. The application of Hantsch Esters in organic synthesis in the early time was mainly focused on the dehydrogenation of 1,4-dihydrogen pyridines (DHPs) in the synthesis of functional pyridines. In 1955, Mauzerall and Westheimer found that Malachite Green could be reduced by Hantzsch Esters to generate the hydrogenated product. Then these DHPs were extensively used as a reductant for decades due to their electron and hydrogen donating properties. In recent years, scientist found that C—C bond cleavage at 4-position of 4-substituted Hantzsch Esters would lead alkyl transfer, and the alkylation process was a radical process. With the rapid development of free radical chemistry, various alkylation reactions using 4-substituted Hantzsch Esters as alkylation reagent have been developed, such as addition reactions of imines and alkenes; cross-coupling reactions with aryl halides; substitution reactions with functional aromatics; Tsuji-Trost reaction; radical insertion with sulfur dioxide; and asymmetric alkylation etc. The advantages in alkylation transfer by using 4-substituted Hantzsch Esters as alkyl source in the past five years were witnessed dramatically: (1) Highly toxic alkyl metal reagents could be avoided in the alkylation reactions; (2) Compared with the moisture sensitivity of alkyl metal reagents Hantzsch Esters are easily handling; (3) 1,4-Dihydrogen pyridines (DHPs) are biologically-inspired model molecular of reduced nicotinamide adenine dinucleotide (NADH), which would expand the application in biosynthesis. A brief summary in this field is presented in this review, and the advances are classified according to different reaction types. Although these creativity works were developed, there are still some challenges: (1) Could aromatic groups at 4-position of 4-substituted Hantzsch Esters serve as arylation reagents? (2) How to recover the rest pyridine part of Hantzsch Esters after alkylation; (3) New type reactions need to be developed for the asymmetric synthesis.

Radical-mediated difunctionalization of alkenes through the remote functional group migration (FGM) process paves an ingenious avenue for simultaneous cleavage and reconstruction of C—C bonds. Recently, our group has systematically disclosed the strategy of remote FGM for radical-mediated difunctionalization of unactivated alkenes. A portfolio of functional groups including cyano, heteroaryl, alkynyl, oximino, and carbonyl showcase the migratory aptitude, leading to new C—C bonds under radical conditions. Meanwhile, a series of other chemical bonds such as C—C, C—N, C—P, C—Si, and C—S are readily constructed in the reaction. Considering the synthetic utility and flexible transformation of alkynes, the radical alkynylation of unactivated alkenes via remote alkynyl migration we firstly reported provides an efficient approach for the incorporation of alkynes and has received considerable attention. On the other hand, fluorine- and sulfonyl-containing molecules play vital roles in organic and medicinal chemistry owing to their important chemical and physical characters. Therefore, the concomitant introduction of an alkynyl and a trifluoromethyl/sulfonyl group into one molecule is of great synthetic value. Herein we report a useful method for carbo-trifluoroalkylation/sulfonylation of unactivated olefins. The addition of extrinsic radical to alkene triggers the intramolecular FGM via a five-membered transition state along with a cascade of bond fission and formation. The typical procedure is as follows: a mixture of propargyl alcohol 1, sulfonyl chloride, fac-Ir(ppy)₃, and base is loaded in a flame-dried reaction vial which is subjected to evacuation/flushing with nitrogen three times. Solvent is added to the mixture via syringe and the mixture is then stirred at 25 ℃ until the starting material is consumed monitored by TLC. The mixture is concentrated, and purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate) to give the product.

The intramolecular aromatic ring systems migration reactions, namely Smiles rearrangement is a powerful method for (hetero)aryl group functionalization. It can be employed as a complementary strategy to arene functionalization, and has found its broad applications in synthetic chemistry. After the initial documentation in 1894 this chemistry was intensively investigated by Smiles. In its classical pathway, the migration of aromatic ring system takes place ipso nucleophilic substitution. Accordingly, the migrating (hetero)aryl groups are highly electronic and steric-dependent. Moreover, as new reaction modes reported, advances have been made in the areas for arene C—C, C—N and C—O bond formation and radical triggered Smiles rearrangement has also enriched migrating units. Recently, there has been a rapid growth in the transformation induced by visible-light photocatalysis. Harnessing visible light as the energy source for chemical reactions usually serves as an environmentally benign alternative in comparison with classical radical pathway. Furthermore, photoredox-induced rearrangement represents a valuable and efficient approach for facilitating both the radical-based bond-cleaving and bond-forming events in a single step. It has become an effective tool for both synthesis and late stage modification of bio-active molecules. The last five years has witnessed many important advances in exploring photo-induced Smiles reactions, which make this classic reaction regained its attention. Significant progress has been made for expediting the generation of N-centered, C-centered and O-centered from a variety of precursors before single electron transfer rearrangement. This powerful synthetic platform for efficient promotes (hetero) aromatic group construction under mild reaction conditions, and has become a useful method for the synthesis and late stage functionalization of pharmaceutically interest products. In this perspective, we focus on visible light induced Smiles chemistry, which the major breakthroughs are classified based on migrating-induced radical species, and their synthetic applications are discussed briefly.

Carbon-carbon bond formation at α-amino carbon based on α-aminoalkyl radicals is an essential transformation in the synthesis of nitrogen-containing compounds. Recently, some novel photoredox catalytic protocols for this goal have been developed, in which α-aminoalkyl radicals were generated from a sequential oxidation/α-deprotonation of aromatic tertiary amines. Inspired by these studies and based on our previous works, we have developed the cross-coupling reaction of nitrones with aromatic tertiary amines via visible light photoredox catalysis. This method features a radical addition of α-aminoalkyl radicals to nitrones with advantages of simple operation, mild conditions, atom economy, a broad scope of nitrone substrates; and allows for an easy access to β-amino hydroxylamines, which could be readily converted into vicinal diamines. Compared with the UV-excited organophotosensitizer-promoted coupling reaction of nitrones with tertiary amines, visible light is a more safe and convenient light source, the photo-excited electron transfer (PET) by 1 mol% of Ir-photocatalyst is more efficient. In addition, nitrones exclusively server as excellent radical acceptors thus with a broader range of structures. A general procedure of this coupling reaction is as follows: To a 25 mL Schlenk tube equipped with a magnetic stir bar were added a nitrone (0.30 mmol), a tertiary amine (0.90 mmol), Ir(ppy)₂(dtbbpy)PF₆ (0.003 mmol, 1.0 mol%) and K₂HPO₄ (0.06 mmol, 20 mol%). After being evacuated and backfilled with argon for three times, DMSO (3 mL) was added to the tube. Then the tube was placed approximately 7 cm away from a 12 W blue LEDs, and the reaction mixture was stirred at r.t. under an argon atmosphere for 24 h. The reaction was quenched with saturated aqueous NaHCO₃ (25 mL), and the mixture was extracted with dichloromethane (DCM, 20 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the desired cross-coupling product β-amino hydroxylamine.

β,γ-Unsaturated ester and γ-ketone ester are important synthons, which can be used to convert into various heterocyclic compounds, natural products and pharmaceuticals. The development of efficient methods for the synthesis of β,γ-unsaturated ester and γ-ketone ester compounds has attracted much attention from synthetic chemists. By using Katritzky pyridinium salts as radical precursors, commercially available Ru(bpy)₃Cl₂?6H₂O as photocatalyst, K₂CO₃ as base, and dichloromethane (DCM) as solvent, we developed a simple and efficient method for the synthesis of a series of β,γ-unsaturated esters and γ-ketone esters by C—N bond activation. Bench-stable and easily handled redox-active Katritzky pyridinium salts derived from abundant amino acids were used as radical precursors for the alkylation of 1,1-diarylethylene and aryl enol silyl ether species upon irradiation with household blue LEDs. The reaction displays an excellent functional group tolerance and a potential utility for amino acids functionalization, allowing to access desired products in moderate to good yields. Moreover, under air conditions, the reaction has moderate compatibility. Scaling up the reaction in grams, the yield was higher and the target product was obtained with 91% yield. Control experiments demonstrated that the photocatalyst and visible light were both essential for the success of the reaction. Performing the reaction in the presence of radical scavenger TEMPO, did lead to no desired product 3a formation. Moreover, a TEMPO-trapped product was determined by MS analysis and NMR, indicating a radical-type mechanism of this reaction. It is of note that this protocol could offer a powerful complementary strategy for the use of amino acids that were also employed in photoredox-catalyzed decarboxylative reactions. A representative procedure for this reaction is as following: A 10 mL oven-dried Schlenk-tube was charged with 1a (111.5 mg, 0.20 mmol), Ru(bpy)₃Cl₂?6H₂O (3.0 mg, 2 mol%), K₂CO₃ (55.2 mg, 0.40 mmol) and a magnetic stirring bar. The tube was evacuated and back-filled three times with argon. A solution of 2a (53 μL, 0.30 mmol) in DCM (2 mL) was injected into the tube by syringe. The resulting mixture was stirred at room temperature upon irradiation with blue LEDs (22 W) and monitored by thin-layer chromatography (TLC). After completion, the solvent was then removed under reduced pressure and the residue was purified by flash column chromatography on silica gel to give 3a as an off-white solid (42.7 mg, 65% yield).

Substituted quinoxalin-2(1H)-ones represent an important class of fused heterocyclic compounds which are existing in numerous bioactive natural products, pharmaceuticals, and functional materials. As a result, there are many methods for the synthesis of this heterocyclic compounds over the past several years. In this context, the direct C—H functionalization of quinoxalin-2(1H)-ones have proved to be an effective protocol to diverse heterocycles, such as radical C(3)—H arylation, phosphonation, amination, and acylation of quinoxalin-2(1H)-ones. However, the direct C—H alkylation of quinoxalin-2(1H)-ones is still rare. Because of their importance, it is desirable to introduce alkyl substituents, especially those bearing functional groups, at the 3-position of quinoxalin-2(1H)-ones, which would probably promote their applications in new drug discovery and development. Thus, this article reports a visible light promoted C(3)-ketoalkylation of quinoxaline-2(1H)-ones via oxidative ring-opening of cycloalkanols. At room temperature, the reaction is carried out by using cycloalkanols as the ketoalkylating agent and potassium persulfate as oxidizing agent in a solution of methanol and water (V∶V=1∶2) for 16 h upon visible light irradiation. A variety of keto-functionalized alkyl moieties with different chain length have been successfully incorporated into the C(3)-position of quinoxalin-2(1H)-ones. Thus, the procedure provides a greener, environmentally friendly and simple method for the synthesis of quinoxalin-2(1H)-one derivatives. A representative procedure for this reaction is given as follows. An oven-dried quartz reaction tube (10 mL) equipped with a magnetic stir bar was charged with K₂S₂O₈ (2.0 equiv., 0.4 mmol), quinoxalin-2(1H)-one 1 (1.0 equiv., 0.2 mmol) and cycloalkanol 2 (1.5 equiv., 0.3 mmol). Then, the tube was evacuated and backfilled with nitrogen (three times). Subsequently, a solution of 1.3 mL of H₂O and 0.7 mL of MeOH were added under nitrogen. Then the reaction tube was sealed and was irradiated under blue light at room temperature for 16 h. After completion of the reaction, ethyl acetate was added to the reaction mixture, and washed with brine (10 mL), dried over Na₂SO₄ and concentrated in vacuo. Purification of the crude product by flash chromatography on silica gel (petroleum ether/ethyl acetate, V∶V=4∶1) affords the corresponding product.

Aryl halides are key building blocks in organic synthesis for the construction of valuable natural products, medicinal and agricultural chemicals via transition metal-catalyzed coupling or substitution reactions. Halogenation is one of the most fundamental and important reactions in organic synthesis. Electrochemical transition-metal-catalyzed C—H functionalization has emerged as a powerful tool for molecular synthesis with the prospect of avoiding the use of costly and toxic oxidants or reductants, thereby reducing the footprint of undesirable, toxic byproducts. The palladium-catalyzed electrochemical C—H chlorination of benzamide derivatives directed by PIP amine directing group under divided cells has been demonstrated, in which readily available inorganic halides salts serve as halogen sources. The reaction features a broad substrate scope, high functional group tolerance, and compatibility of thiophene substrates. This reaction could be conducted on a gram scale, which is important for future application. Additionally, the sequential bromination and chlorination of C(sp ²)—H bond constructs highly functionalized aromatic carboxylic acid derivatives. The typical procedure is as follows: The electrolysis was carried out in an H-type divided cell (anion-exchange membrane), with a RVC anode (10 mm×10 mm×12 mm) and a platinum cathode (10 mm×10 mm×0.2 mm). The anodic chamber was charged with Pd(OAc)₂ (5.6 mg, 0.025 mmol, 10 mol%) and benzamide derivative (0.25 mmol, 1.0 equiv.) and dissolved in DMF (10 mL). LiCl (847.8 mg, 20.0 mmol) was added in the cathodic chamber and dissolved in water (10 mL). Then the reaction mixture was electrolyzed under a constant current of 5 mA at 90 ℃ until the complete consumption of the starting material as monitored by TLC or ¹H NMR. After the reaction, EtOAc (50 mL) was added to dilute the mixture and then washed with water (20 mL×3) and then with brine (20 mL). The organic fraction was dried over Na₂SO₄ and concentrated. The resulting residue was purified by silica gel flash chromatography to give the chlorination product.

Catalytic synthesis of organic sulfinamides has great significance and value in organic synthesis, material science, and bioscience. Traditional synthetic methods for sulfinamides are often confronted with various challenges, such as tedious reaction steps, harsh reaction conditions. Direct activation of S—H and N—H bonds to synthesis sulfinamides is the most effective and atomic economic way, which can realize the N—S bonds construction without pre-functionalization of the substrates. To establish a versatile and efficient technology for such reaction, an electrochemical cross coupling hydrogen evolution (CCHE) reaction, which is often used as an environmentally friendly and efficient way to construct new bonds, for synthesis of sulfinamides has been successfully developed by using thiols and amines as the easily available and inexpensive substrates. A series of sulfinamides were prepared with excellent yields and good compatibility of functional groups under extremely mild reaction conditions. Experimental results showed that sulfenamides, which were constructed as intermediate products via radical pathway, were further oxidized to sulfinamides. H₂ ¹⁸O labeling experiment confirmed that the oxygen of sulfinyl group comes from the trace water in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP). In addition, tetrabutylammonium iodide (TBAI) played important dual roles of intermediate and electrolyte in this reaction system. The typical procedure is as follows: A 20 mL oven-dried reaction vital equipped with a magnetic stir bar was charged with thiol 1 (0.2 mmol), amine 2 (0.3 mmol) and TBAI (0.05 mol/L) in HFIP (5 mL), and exhausted via puncture needle for 15 minutes with argon. The mixture was then electrolysed with carbon foam plate (anode) and platinum plate (cathode) as the electrodes in an undivided cell for 6 hours in 10 mA constant current at room temperature. After the reaction, the mixture was evaporated under reduced pressure to remove the solvent and the residue was purified by chromatography on silica gel to get the desired sulfinamide 3.

Organic azides are widely used in chemical synthesis, drug discovery, bioconjugation, and material science, owing to their flexible transformations to useful chemicals such as amines, amides, isocyanates and heterocycles. In light of the diverse value of azide-containing compounds, numerous synthetic methods have been established to access this significant functionality. Among them, direct C—H azidation reactions have attracted particular attention due to their cost- and atom-efficiency. Previous methods for the preparation of azido-substituted anilines require the employment of stoichiometric amount of harsh oxidants such as hyperoxides and hypervalent iodine reagents. To synthesize these valuable compounds in an economical and environmentally benign manner, a simple and efficient copper-catalyzed ortho C—H azidation of anilines using molecular oxygen as terminal oxidant has been developed. The reaction proceeded smoothly with the assistance of pyridine at room temperature, and afforded the synthetically useful azido-substituted anilines in moderate to good yields. Notably, the process of dehydrogenation coupling of anilines to azo compounds was significantly suppressed in this protocol. This method allows for the highly regioselective formation of C—N₃ bonds under mild reaction conditions, and exhibits good functional group and substrate scope compatibility. A general procedure for the azidation of anilines is as follows: a mixture of aniline (0.4 mmol) and CuBr (5.7 mg, 0.04 mmol) is loaded in a 20 mL Schlenk tube, which is equipped with a magnetic stir bar and subjected to evacuation/flushing with oxygen three times. Subsequently, DCM (4.0 mL), pyridine (6.3 mg, 0.08 mmol) and TMSN₃ (92.2 mg, 0.8 mmol) are added to the Schlenk tube via syringe, and the formed mixture is stirred at room temperature until the amount of target product no longer increases, which is monitored by TLC. After completion of the reaction, the solution is concentrated under vacuum and further purified by column chromatography on silica gel to give the desired product (eluent: petroleum ether/ethyl acetate).