Photomediated Spirocyclization of N-Benzyl Propiolamide with N-Iodosuccinimide for Access to Azaspiro[4.5]deca-6,9-diene-3,8-dione.

A metal- and oxidant-free route for affording azaspiro[4.5]deca-6,9-diene-3,8-dione via photomediated iodinated spirocyclization of N-(4-methoxybenzyl) propiolamide has been developed. The reaction underwent a radical addition/ipso-cyclization/dearomatization process at room temperature and successfully constructed C-C and C-I bonds. This green and convenient approach could be generally expanded to produce a range of iodinated spirocyclization products in moderate to good yields.

Regioselective C3-Fluoroalcoholation of Indoles with Heptafluoroisopropyl Iodide via Palladium-Catalyzed C(sp2)-C(sp3) Cross-Coupling in the Presence of O2.

An efficient method for C3-fluoroalcoholation of indole derivatives was developed by merging C-F cleavage and C-C bond coupling, using free (NH)-indoles and heptafluoroisopropyl iodides as precursors. Preliminary mechanistic studies indicate that the bimetallic co-mediated C-F bond cleavage and the trifluoroacetate moiety play an essential role. Notably, this strategy constructs derivatizations through the modifiable carbon-oxygen bond. A broad range of structurally valuable organofluorine products was obtained, which shows excellent functional group tolerance. Furthermore, easily accessible materials were utilized and circumvented two troublesome steps of installing and removing an external auxiliary. This is the first report to introduce 3-fluoroalcoholated indoles via fluorohalides. This reaction offers a straightforward and efficient platform to access worthwhile fluorinated free (NH)-heteroarenes derivatives.

An Electrochemical Route for Special Oxidative Ring-Opening of Indoles.

A novel electrochemical protocol for the oxidative cleavage of indoles has been developed, which offers a simple way to access synthetically useful anthranilic acid derivatives. In undivided cells, a wide variety of indoles and alcohol compounds are examined to afford amide ester aromatics without using extra oxidants and stoichiometric metal catalysts, which avoids the formation of undesired by-products and exhibits high atom economy. The products we described in this perspective represent a synthetic intermediate in numerous drug molecules and industrial chemical reagents and remarkably show potential application in the future.

Palladium-Catalyzed C2-Regioselective Perfluoroalkylation of the Free (NH)-Heteroarenes.

A highly regioselective and atom-efficient strategy for the construction of fused free (NH) heteroarenes through a palladium-catalyzed perfluoroalkyl insertion reaction has been accomplished. This protocol employed multiple iodofluoroalkanes as practical and available perfluoroalkyl sources to provide an operationally simple and versatile route for the synthesis of perfluoroalkylated indoles. Moreover, indoles without the assistance of guide groups were utilized as substrates, achieving C(sp2)-H site-selective functionalization of indoles in yields up to 95%. Furthermore, this protocol was also used for late-stage C2 perfluoroalkylation of bioactive compounds such as auxin, tryptophan, and melatonin analogues.

Oxidant- and Catalyst-Free Synthesis of Sulfonated Benzothiophenes via Electrooxidative Tandem Cyclization.

A green and practical electrochemical method for the synthesis of C-3-sulfonated benzothiophenes from 2-alkynylthioanisoles and sodium sulfinates was developed under oxidant- and catalyst-free conditions. Moderate to good yields of sulfonated benzothiophenes bearing important and useful functional groups have been achieved at a constant current. Preliminary mechanistic studies indicated a tandem radical addition-cyclization pathway. Moreover, the protocol is easy to scale up and exhibits good reaction efficiency.

C-5 selective chlorination of 8-aminoquinoline amides using dichloromethane.

An oxidant-free electrochemical regioselective chlorination of 8-aminoquinoline amides at ambient temperature in batch and continuous-flow was achieved. Inert DCM was used as the chlorinating reagent. Owing to the continuous-flow setup, the reaction scale up can be achieved conveniently with higher productivity. Moreover, this method has good position-control, and water and air tolerance. Costly quaternary ammonium salts were avoided. Radical-trapping, H/D exchange, KIE and cyclic voltammetry experiments were conducted to gain insight into the reaction mechanism.

Microfluidic synthesis of pyrrolidin-2-ones via photoinduced organocatalyzed cyclization of styrene, α-bromoalkyl esters and primary amines.

A green and efficient reaction route for the synthesis of pyrrolidin-2-ones via photoinduced organocatalyzed three-component cyclization of styrene, tertiary α-bromoalkyl esters and primary amines in a microchannel reactor under visible light conditions has been developed. Moreover, the overall process can be carried out under mild conditions without using a metal. In addition, a reasonable reaction mechanism was proposed based on control experiments.

Continuous-flow electrosynthesis of selenium-substituted iminoisobenzofuran via oxidative cyclization of olefinic amides and diselenides.

A green and efficient approach for the synthesis of selenium-substituted iminoisobenzofuran using 2-vinylbenzamides and diselenides in a continuous electrochemical microreactor has been developed. This strategy enabled the preparation of a series of iminoisobenzofuran derivatives in moderate to good yields under metal-free and oxidant-free conditions. The application of the electrochemical flow system successfully overcomes the difficulty of process control in traditional electrochemistry and achieves efficient transformation of electricity. Moreover, the continuous-flow system combined with electrosynthesis overcomes the difficulty in realizing a scale-up reaction in conventional batch-type electrolysis.

Continuous Electrochemical Synthesis of Iso-Coumarin Derivatives from o-(1-Alkynyl) Benzoates under Metal- and Oxidant-Free.

A non-oxidant and metal-free strategy for synthesizing iso-coumarin by using a continuous electrochemical microreactor to initiate an oxidative cyclization reaction of o-(1-alkynyl) benzoate and radicals. This efficient and clean continuous electrosynthesis method not only avoids the complicated gas protection operation and production of by-products in the batch processes, but also help to overcome the difficulty that batch metal catalysis and electrocatalysis are difficult to scale up, and has the potential for pilot-scale experiment.

Visible-light-promoted N-centered radical generation for remote heteroaryl migration.

Herein, an efficient visible-light-mediated N-H heteroarylation via remote heteroaryl ipso-migration has been accomplished. Moderate to good yields were obtained with good functional group tolerance. Moreover, a simple and readily available organic photoredox catalyst was employed, avoiding the use of complex and costly noble metal compounds.

The ruthenium-catalyzed meta-selective C-H nitration of various azole ring-substituted arenes.

The efficient ruthenium-catalyzed meta-selective CAr-H nitration of azole ring substituted arenes has been developed. In this work, Ru3(CO)12 was used as the catalyst, AgNO2 as the nitro source, HPcy3+·BF4- as the ligand, pivalic acid as the additive, and DCE as the solvent, and a wide spectrum of arenes bearing thiazole, pyrazolyl or removable oxazoline directing groups were tolerated in this meta-selective CAr-H nitration, affording the nitrated products in moderate to good yields. Moreover, this study reveals a gentler and environmentally friendly way to access meta-nitration arenes compared to the traditional process.

AIBN/NaBr-promoted aerobic oxidation of benzylic alcohols via a radical process.

An economic and practical AIBN-initiated aerobic oxidation system of benzylic alcohols, hetero aryl alcohols and allyl alcohols was developed for the first time. Moderate to excellent yields were obtained with a broad substrate scope. Moreover, a proposed mechanism of a radical process was assumed and confirmed by the key intermediate detected.

Copper-TEMPO-catalyzed synthesis of α-ketoamides via tandem sp(3)C-H aerobic oxidation and amination of phenethyl alcohol derivatives.

An efficient copper-TEMPO-catalyzed one-pot synthesis of α-ketoamides from phenethyl alcohol derivatives was developed firstly. Moreover, molecular oxygen in open air was employed as the oxidant with a broad substrate scope, which makes this methodology more practical. Based on some control experiments, a plausible mechanism was proposed.

Electro-oxidative quinylation of sulfides to sulfur ylides in batch and continuous flow.

An unprecedented strategy for preparing a series of sulfur ylides through electro-oxidative quinylation of sulfides in batch and continuous flow has been developed. Good to excellent yields were obtained with excellent functional group compatibility and good concentration tolerance under exogenous oxidant- and transition metal-free conditions. Advantageously, this electrosynthesis methodology was scalable with higher daily production and steady production was achieved attributing to the use of micro-flow cells.

Electrosynthesis of Spiro-indolenines via Dearomative Arylation of Indoles in Batch and Continuous Flow.

An electrosynthesis of spiro-indolenines in batch and continuous flow was achieved through dearomative arylation of indoles with good functional group compatibility. User-friendly undivided cells were used under catalyst- and oxidant-free conditions. Moreover, the use of a flow electrolysis cell gave high daily productivity and excellent scale-up potential under less supporting electrolyte and higher substrate concentration conditions.

Intramolecular trapping of spiro radicals to produce unusual cyclization products from usual migration substrates.

A conceptually new methodology to give unusual cyclization products from usual migration substrates was disclosed. The highly complex and structurally important and valuable spirocyclic compounds were produced through radical addition, intramolecular cyclization and ring opening instead of usual migration to the di-functionalization products of olefins. Furthermore, a plausible mechanism was proposed based on a series of mechanistic studies including radical trapping, radical clock, verification experiments of intermediates, isotope labeling and KIE experiments.

CF3SO2Na-Mediated Visible-Light-Induced Cross-Dehydrogenative Coupling of Heteroarenes with Aliphatic C(sp3)-H Bonds.

Minisci-type reaction is one of the important means to construct C(sp3)-H functionalization of heteroarenes. According to traditional methods, stoichiometric amounts of precious transition metal catalysts and chemical oxidants were required at high temperatures. Here, a green and gentle novel Minisci-type method was developed via visible-light-induced cross-dehydrogenative coupling of heteroarenes with aliphatic C(sp3)-H bonds under oxidant-free and transition-metal-catalyst-free conditions. Only the catalytic equivalent of CF3SO2Na and room temperature were required to maintain an efficient reaction.

Photomediated core modification of organic photoredox catalysts in radical addition: mechanism and applications.

Dihydrophenazines and their analogues have been widely used as strong reducing photoredox catalysts in radical chemistry, such as organocatalyzed atom transfer radical polymerization (O-ATRP). However, when dihydrophenazines were employed as organic photoredox catalysts (OPCs) to mediate O-ATRP, the initiator efficiency was nonquantitative due to cross-coupling between dihydrophenazines and radical species. Here, a new kind of core modification for dihydrophenazines, phenoxazines and phenothiazines was developed through this cross-coupling process. Mechanistic studies suggested that the radical species would be more likely to couple with OPC' radical cations rather than the ground-state OPC. Core modification of OPCs could stabilize the radical ions in an oxidative quenching catalytic cycle. Significantly, core modifications of OPCs could lower the energy of light required for photoexcitation. Compared with their noncore-modified counterparts, all the core-modified dihydrophenazines and phenoxazines exhibited efficient performance in controlling O-ATRP for the synthesis of poly(methyl methacrylate) with higher initiator efficiencies under the irradiation of simulated sunlight.

C- to N-Center Remote Heteroaryl Migration via Electrochemical Initiation of N Radical by Organic Catalyst.

Herein an exogenous oxidant- and metal-free electrochemical heteroaryl migration triggered by N radicals to construct new N-C bonds was developed. This methodology features a high atom economy and utilization rate of energy, and it is insensitive to water and air. Moreover, a user-friendly undivided cell was employed. The use of an organic catalyst makes it more efficient, green, and practical.

The copper(ii)-catalyzed and oxidant-promoted regioselective C-2 difluoromethylation of indoles and pyrroles.

A novel and efficient approach for the highly selective C-2 difluoromethylation of indole derivatives was developed by using sodium difluoromethylsulfinate (HCF2SO2Na) as the source of difluoromethyl groups and a Cu(ii) complex as the catalyst. Various substrates were well tolerated in this transformation and the desired products were obtained in moderate to good yields. Moreover, the late-stage C-2 difluoromethylation of bioactive molecules containing an indole ring was achieved in good yields. Generally, this reaction features excellent functional group compatibility, broad substrate scope and excellent C-2 selectivity.