Photoinduced activation of alkyl chlorides.

In recent years, the activation of unactivated alkyl chlorides through light-induced processes has emerged as a promising field in radical chemistry, and has led to new transformations in organic synthesis. Direct utilization of alkyl chlorides as C(sp3)-hybridized electrophiles enables the facile construction of carbon-carbon and carbon-heteroatom bonds. Furthermore, recent studies in medicinal chemistry indicate that their presence is associated with high levels of success in clinical trials. This review summarizes the recent advances in the photoinduced activation of unactivated alkyl chlorides and discusses the mechanistic aspects underlying these reactions. We anticipate that this review will serve as a valuable resource for researchers in the field of unactivated chemical bond functionalization, and inspire considerable developments in organic chemistry, drug synthesis, materials science and other related disciplines.

Nickel-Catalyzed Highly Selective Radical C-C Coupling from Carboxylic Acids with Photoredox Catalysis.

Controlling the cross-coupling reaction between two different radicals is a long-standing challenge due to the process occurring statistically, which would lead to three products, including two homocoupling products and one cross-coupling product. Generally, the cross-coupling selectivity is achieved by the persistent radical effect (PRE) that requires the presence of a persistent radical and a transient radical, thus resulting in limited radical precursors. In this paper, a highly selective cross-coupling of alkyl radicals with acyl radicals to construct C(sp2)-C(sp3) bonds, or with alkyl radicals to construct C(sp3)-C(sp3) bonds have been achieved with the readily available carboxylic acids and their derivatives (NHPI ester) as coupling partners. The success originates from the use of tridentate ligand (2,2' : 6',2''-terpyridine) to enable radical cross-coupling process to Ni-mediated organometallic mechanism. This protocol offers a facile and flexible access to structurally diverse ketones (up to 90 % yield), and also a new solution for the challenging double decarboxylative C(sp3)-C(sp3) coupling. The broad utility and functional group tolerance are further illustrated by the late-stage functionalization of natural-occurring carboxylic acids and drugs.

Gold-Manganese Bimetallic Redox Coupling with Light.

The classical Au(I)/Au(III) redox couple chemistry has been limited to constructing C-C and C-X bonds, and thus, the exploration of the elementary reaction of gold redox coupling is very significant to enrich its organometallic features. Herein, we report the first visible-light-mediated, external oxidant-free Au(I)/Au(III) redox couple using commercially available Mn2(CO)10 to generate Mn-Au(III)-Mn intermediates for bimetallic redox coupling. A wide range of structurally diverse heterodinuclear and polynuclear L-Au(I)-Mn-L' complexes (19 examples, up to >99% yields) are readily constructed, providing a robust strategy for the concise construction of Au-Mn complexes under mild reaction conditions. The mechanistic studies together with DFT calculations support the radical oxidative addition of •Mn(CO)5 to gold and bimetallic reductive elimination mechanisms from highly active Mn-Au(III)-Mn species, representing an important step toward an elementary reaction in gold chemistry research. Furthermore, the resulting Au-Mn complexes exhibit unique catalytic activity, with which divergent reductive coupling of nitroarenes can readily afford azoxybenzenes, azobenzenes, and hydrazobenzenes in moderate to good yields.

Site-Selective Arylation of Carboxamides from Unprotected Peptides.

The amidated peptides are an important class of biologically active compounds due to their unique biological properties and wide applications as potential peptide drugs and biomarkers. Despite the abundance of free amide motifs (Asn, Gln, and C-terminal amide) in native peptides, late-stage modification of the amide unit in naturally occurring peptides remains very rare because of the intrinsically weak nucleophilicity of amides and the interference of multiple competing nucleophilic residues, which generally lead to undesired side reactions. Herein, chemoselective arylation of amides in unprotected polypeptides has been developed under an air atmosphere to afford the N-aryl amide peptides bearing various functional motifs. Its success relies on the combination of gold catalysis and silver salt to differentiate the relative inert amide among a collection of reactive nucleophilic amino acid residues (e.g., -NH2, -OH, and -COOH), favoring the C-N bond coupling toward amides over other more nucleophilic groups. Experimental and DFT studies reveal a crucial role of the silver cation, which serves as a transient coordination mask of the more reactive reaction sites, overcoming the inherently low reactivity of amides. The excellent biocompatibility of this strategy has been applied to functionalize a wide range of peptide drugs and complex peptides. The application could be further extended to peptide labeling and peptide stapling.

Radical deuteration.

Deuterated chemicals are becoming irreplaceable in pharmaceutical engineering, material science and synthetic chemistry. Many excellent reviews have discussed acid/base-dependent or metal-catalyzed deuteration reactions, but radical deuterations have been discussed less. With the development of radical chemistry, there has been a rapid growth in radical deuterium-labelling technology. Diverse mild, cheap and efficient strategies for deuterium atom installation have been reported, and this review summarizes the recent achievements of radical deuteration classified by the reaction types.

Trinuclear Gold-Catalyzed 1,2-Difunctionalization of Alkenes.

Activated alkyl halides have been extensively explored to generate alkyl radicals with Ru- and Ir- photocatalysts for 1,2-difunctionalization of alkenes, but unactivated alkyl bromides remain challenging substrates due to their strong reduction potential. Here we report a three-component 1,2-difunctionalization reaction of alkenes, unactivated alkyl bromides and nucleophiles (e.g., amines and indoles) using a trinuclear gold catalyst [Au3 (tppm)2 ](OTf)3 . It can achieve the 1,2-aminoalkylation and 1,2-alkylarylation readily. This protocol has a broad reaction scope and excellent functional group compatibility (>100 examples with up to 96 % yield). It also affords a robust formal [2+2+1] cyclization strategy for the concise construction of pyrrolidine skeletons under mild reaction conditions. Mechanistic studies support an inner-sphere single electron transfer pathway for the successful cleavage of inert C-Br bonds.

Dimeric Manganese-Catalyzed Hydroalkenylation of Alkynes with a Versatile Silicon-Based Directing Group.

Herein, we present a manganese-catalyzed, branched-selective hydroalkenylation of terminal alkynes, under mild conditions through facile installation of a versatile silanol as a removable directing group. With an alkenyl boronic acid as the coupling partner, this reaction produces stereodefined (E,E)-1,3-dienes with high regio-, chemo- and stereoselectivity. The protocol features mild reaction conditions such as room temperature and an air atmosphere, while maintaining excellent functional group compatibility. The resulting 1,3-dienesilanol products serve as versatile building blocks, as the removal of the silanol group allows for the synthesis of both branched terminal 1,3-dienes for downstream coupling reactions, as well as stereoselective construction of linear (E,E)-1,3-dienes and (E,E,E)- or (E,E,Z)-1,3,5-trienes. In addition, a Diels-Alder cycloaddition can smoothly and selectively deliver silicon-containing pentasubstituted cyclohexene derivatives. Mechanistic investigations, in conjunction with DFT calculations, suggest a bimetallic synergistic activation model to account for the observed enhanced catalytic efficiency and good regioselectivity.

Manganese/Cobalt Bimetallic Relay Catalysis for Divergent Dehydrogenative Difluoroalkylation of Alkenes.

The involvement of manganese radical for halogen atom transfer (XAT) reactions has been esteemed as one reliable method but encountered with limited catalytic models. In this paper, a novel bimetallic relay catalysis of Mn2 (CO)10 and cobaloxime has been developed for divergent dehydrogenative difluoroalkylation of alkenes using commercially available difluoroalkyl bromides. A wide range of structurally diverse terminal, cyclic and internal alkenes as well as tetrasubstituted alkenes are found to be good coupling partners to deliver difluoroalkylated allylic products and difluoromethylated cyclic products, accompanied with the production of H2 as the by-product. This bimetallic relay strategy features broad substrate scope, mild reaction conditions and excellent functional group compatibility. Its success represents an important step-forward to expedite the construction of a rich library of difluoroalkylated products.

Unlocking Migratory Insertion in Gold Redox Catalysis.

Exploration of elementary reactions in organometallic catalysis is an important method with which to discover new reactions. In this article, we report a gold(I)-catalyzed iodo-alkynylation of benzyne involving the merging of challenging migratory insertion and an oxidative addition process in gold catalytic cycle. A wide range of structurally diverse alkynyl iodides are good coupling partners in this iodo-alkynylation transformation. Both aliphatic and aromatic alkynyl iodides can react with benzynes smoothly to afford highly functionalized 1,2-disubstituted aromatics in moderate to good yields. Its good functional group compatibility and late-stage application of complex molecules demonstrate its synthetic robustness. Studies of the mechanism reveals the feasibility of oxidative addition and the DFT calculations demonstrate the possible migratory insertion of benzyne into AuIII -carbon bonds in the AuI /AuIII redox catalytic cycle, representing an important step towards an elementary reaction in gold chemistry research.

Nickel-catalyzed Thioester Transfer Reaction with sp2-Hybridized Electrophiles.

We report a thioacylation transfer reaction based on nickel-catalyzed C-C bond cleavage of thioesters with sp2-hybridized electrophiles. Aryl bromides, iodides, and alkenyl triflates can participate in thioester transfer reaction of aryl thioesters, affording a wide range of structurally diverse new thioesters in yields of up to 98% under mild reaction conditions. With this protocol, it is possible to construct alkenyl thioesters from the corresponding ketones through the generation of alkenyl triflates.

Thiocarbamoyl Fluoride Synthesis by Deconstructive Diversification of Arylated Tetrahydroisoquinolines.

Deconstructive functionalization of cyclic amines can provide access to chemicals with diverse skeletons. We report the conversion of tertiary amines to thiocarbamoyl fluorides, a reaction enabled by photoredox catalysis and tolerating different functional groups while avoiding strong oxidants. A one-pot synthetic method from tertiary amines and AgF has been developed to get access to trifluoromethylamines. The synthesized thiocarbamoyl fluorides can be further transferred into esters.

Photoredox-Controlled ß-Regioselective Radical Hydroboration of Activated Alkenes with NHC-Boranes.

In this Communication, we report an unprecedented ß-regioselective radical inverse hydroboration (compared with ionic hydroboration) of α,ß-unsaturated amides with NHC-BH3 enabled by photoredox catalysis. Density functional theory (DFT) calculations show that the unique photoredox cycle is a key factor to control the ß-regioselective radical hydroboration, by lowering the energy barrier in comparison with other pathways. This protocol provides a general and convenient route to construct a wide range of structurally diverse ß-borylated amides in synthetically useful yields under mild conditions.

Cooperative Au/Ag Dual-Catalyzed Cross-Dehydrogenative Biaryl Coupling: Reaction Development and Mechanistic Insight.

An operationally simple and highly selective Au/Ag bimetallic-catalyzed cross-dehydrogenative biaryl coupling between pyrazoles and fluoroarenes has been developed. With this reaction, a wide range of biheteroaryl products can be obtained in moderate to good yields with excellent functional group compatibility. The exact role of silver salts, previously overlooked in most gold-catalyzed transformations, has been carefully investigated in this biaryl coupling. Insightful experimental and theoretical studies indicate that silver acetate is the actual catalyst for C-H activation of electron-poor arenes, rather than the previously reported gold(I)-catalyzed process. An unprecedented Au/Ag dual catalysis is proposed, in which silver(I) is responsible for the activation of electron-poor fluoroarenes via a concerted metalation-deprotonation pathway, and gold(III) is responsible for the activation of electron-rich pyrazoles via an electrophilic aromatic substitution process. Kinetic studies reveal that ArFnAu(III)-mediated C-H activation of pyrazoles is most likely the rate-limiting step.

Exploration of C-H Transformations of Aldehyde Hydrazones: Radical Strategies and Beyond.

The chemistry of hydrazones has gained great momentum due to their involvement throughout the evolution of organic synthesis. Herein, we discuss the tremendous developments in both the methodology and application of hydrazones. Hydrazones can be recognized not only as synthetic equivalents to aldehydes and ketones but also as versatile synthetic building blocks. Consequently, they can participate in a range of practical synthetic transformations. Furthermore, hydrazone derivatives display a broad array of biological activities and have been widely applied as pharmaceuticals. Owing to the weak directing group effect of simple aldehydes and ketones in C-H bond functionalizations, the C-H bond functionalizations of hydrazones that have been developed in the past five years represent a significant step forward. These novel transformations open a new door to a broader library of functionalized and complex small molecules. Moreover, a wide range of biologically important N-heterocycles (dihydropyrazoles, pyrazoles, indazoles, cinnolines, etc.) can be efficiently synthesized in an atom- and step-economical manner through single, double, or triple C-H bond functionalizations of hydrazones. Both radical C-H functionalizations and transition-metal-catalyzed directing-group strategies have enhanced the synthetic utility of hydrazones in the chemical community because these strategies solve the long-standing challenge of C-H functionalizations adjacent to aldehydes and ketones. We began this study based on our ongoing interest in visible-light photoredox catalysis. Visible-light photoredox catalysis has become a powerful tool in contemporary synthetic chemistry due to its remarkable advantages in sustainability and use of radical chemistry. By exploiting a photoredox-catalyzed aminyl radical polar crossover (ARPC) strategy, we successfully achieved visible-light-induced C(sp2)-H difluoroalkylation, trifluoromethylation, and perfluoroalkylation of aldehyde-derived hydrazones. This intriguing result was later applied in the C(sp2)-H amination of hydrazones and a cascade cyclization reaction for the synthesis of polycyclic compounds. Encouraged by this redox-neutral C-H functionalization of aldehyde hydrazones, we extended the oxidative C-H/P-H cross-coupling method, which represents a novel and efficient method for the synthesis of α-iminophosphine oxides. Furthermore, an elegant [3 + 2] cycloaddition of azides and aldehyde hydrazones for the synthesis of functionalized tetrazoles was advantageously developed during our investigation of the oxidative C(sp2)-H azidation of aldehyde hydrazones with TMSN3. The sequential C(sp2)-H/C(sp3)-H bond functionalization of aldehyde-derived hydrazones with simple 2,2-dibromo-1,3-dicarbonyls was achieved by employing relay photoredox catalysis, and it provides a novel method of accessing bioactive fused dihydropyrazole derivatives. The notable feature of this approach was further reflected in the formal [4 + 1] annulation of aldehyde-derived N-tetrahydroisoquinoline hydrazones with 2-bromo-1,3-dicarbonyls. To complement these radical C-H functionalization strategies, we recently applied a directing-group strategy in the Rh-catalyzed C(aldehyde)-H functionalization of aldehyde-derived hydrazones for the synthesis of distinctive and bioactive 1H-indazole scaffolds. In summary, this Account presents recent contributions to the exploration, development, mechanistic insights, and synthetic applications of C-H bond functionalizations of aldehyde hydrazones.

Deoxygenative Arylation of Carboxylic Acids by Aryl Migration.

An unprecedented deoxygenative arylation of aromatic carboxylic acids has been achieved, allowing the construction of an enhanced library of unsymmetrical diaryl ketones. The synergistic photoredox catalysis and phosphoranyl radical chemistry allows for precise cleavage of a stronger C-O bond and formation of a weaker C-C bond by 1,5-aryl migration under mild reaction conditions. This new protocol is independent of substrate redox-potential, electronic, and substituent effects. It affords a general and promising access to 60 examples of synthetically versatile o-amino and o-hydroxy diaryl ketones under redox-neutral conditions. Furthermore, it also brings one concise route to the total synthesis of quinolone alkaloid, (±)-yaequinolone A2, and a viridicatin derivative in satisfying yields.

Distal radical migration strategy: an emerging synthetic means.

The remote radical migration strategy has gained considerable momentum. During the past three years, we have witnessed the rapid development of sustainable and practical C-C and C-H bond functionalization by means of long-distance 1,n-radical migration (n = 4, 5, 6) events. Its advent brings our chemical community a new platform to deal with the challenging migration transformations and thus complements the existing ionic-type migration protocols. In this review, the recent achievements in distal radical migration triggered C-C and C-H bond functionalization are summarized.

Deoxygenative Deuteration of Carboxylic Acids with D2 O.

We report a general, practical, and scalable means of preparing deuterated aldehydes from aromatic and aliphatic carboxylic acids with D2 O as an inexpensive deuterium source. The use of Ph3 P as an O-atom transfer reagent can facilitate the deoxygenation of aromatic acids, while Ph2 POEt is a better O-atom transfer reagent for aliphatic acids. The highly precise deoxygenation of complex carboxylic acids makes this protocol promising for late-stage deoxygenative deuteration of natural product derivatives and pharmaceutical compounds.

Synergistic Photoredox Catalysis and Organocatalysis for Inverse Hydroboration of Imines.

The first catalytic inverse hydroboration of imines with N-heterocyclic carbene (NHC) boranes has been realized by means of cooperative organocatalysis and photocatalysis. This catalytic combination provides a promising platform for promoting NHC-boryl radical chemistry under sustainable and radical-initiator-free conditions. The highly important functional-group compatibility and possible application in late-stage hydroborations represent an important step forward to an enhanced α-amino organoboron library.

Selective Hydroarylation of 1,3-Diynes Using a Dimeric Manganese Catalyst: Modular Synthesis of Z-Enynes.

The transition-metal-catalyzed selective hydroarylation of unsymmetrical alkynes represents the state-of-art in organic chemistry, and still mainly relies on the use of precious late-transition-metal catalysts. Reported herein is an unprecedented MnI -catalyzed hydroarylation of unsymmetrical 1,3-diyne alcohols with commercially available arylboronic acids with predictive selectivity. This method addresses the challenges in regio-, stereo-, and chemoselectivity. It offers a general, convenient and practical strategy for the modular synthesis of multisubstituted Z-configurated conjugated enynes. This protocol is distinguished by its operational simplicity, complete selectivity, excellent functional-group compatibility, and gram-scale potential. A dimeric MnI species, Mn2 (CO)8 Br2 , was proven to be a much more efficient catalyst precursor than Mn(CO)5 Br.

Synergistic Catalysis for the Umpolung Trifluoromethylthiolation of Tertiary Ethers.

The first transition-metal-free, site-specific umpolung trifluoromethylthiolation of tertiary alkyl ethers has been developed, achieving the challenging tertiary C(sp3 )-SCF3 coupling under redox-neutral conditions. The synergism of organophotocatalyst 4CzIPN and BINOL-based phosphorothiols can site-selectively cleave tertiary sp3 C(sp3 )-O ether bonds in complex molecules initiated by a polarity-matching hydrogen-atom-transfer (HAT) event. The incorporation of several competing benzylic and methine C(sp3 )-H bonds in alkyl ethers has little influence on the regioselectivity. Selective difluoromethylthiolation of C-O bonds has also been achieved. This represents not only an important step forward in trifluoromethylthiolation but also a promising means for site-selective C-O bond functionalization of unsymmetrical tertiary alkyl ethers.