Aerobic Catalytic Cross-Dehydrogenative Coupling of Furans with Indoles Provides Access to Fluorophores with Large Stokes Shift.

Sustainability in chemical processes is a crucial aspect in contemporary chemistry with sustainable catalysis as a vital parameter of the same. There has been a renewed focus on utilizing earth-abundant metal catalysts to expand the repertoire of organic reactions. Furan is a versatile heterocycle of natural origin used for multiple applications. However, it has scarcely been used in cross-dehydrogenative coupling. In this work, we have explored the cross-dehydrogentive coupling of furans with indoles using commonly available, inexpensive FeCl3 ⋅ 6H2 O (<0.25 $/g) as catalyst in the presence of so called 'ultimate oxidant' - oxygen, without the need for any external ligand or additive. The reactions were found to be scalable and to work even under partially aqueous conditions. This makes the reaction highly economical, practical, operationally simple and sustainable. The methodology provides direct access to π-conjugated short oligomers consisting of furan, thiophene and indole. These compounds were found to show interesting fluorescence properties with remarkably large Stokes shift (up to 205 nm). Mechanistic investigations reveal that the reaction proceeds through chemoselective oxidation of indole by the metal catalyst followed by nucleophilic trapping by furan.

Oxidative N-N Bond Formation Versus the Curtius Rearrangement.

The oxidative formation of N-N bonds from primary amides has been recently reported and then retracted in the journal Nature Communications by Kathiravan, Nicholls, and co-authors, utilizing a hypervalent iodane reagent. Unfortunately, the authors failed to recognize the Curtius reaction taking place under the described reaction conditions. Thus, the claimed N-N coupling products were not formed. Instead, the Curtius rearrangement urea coupling products were obtained. We demonstrate this herein by means of NMR and x-ray analysis, as well as with the support of an alternative synthetic route.

n-Bu4NI/K2S2O8-MEDIATED C-N COUPLING BETWEEN ALDEHYDES AND AMIDES.

n-Bu4NI/K2S2O8 mediated C-N coupling between aldehydes and amides is reported. A strong electronic effect is observed on the aromatic aldehyde substrates. The transformylation from aldehyde to amide takes place exclusively when an aromatic aldehyde bears electron-donating groups at either the ortho or para position of the formyl group, while the cross-dehydrogenative coupling dominates in the absence of these groups. Both the density functional theory (DFT) thermochemistry calculations and experimental data support the proposed single electron transfer mechanism with the formation of an acyl radical intermediate in the cross-dehydrogenative coupling. The n-Bu4NI/K2S2O8 mediated oxidative cyclization between 2-aminobenzamide and aldehydes is also reported, with four quinazolin-4(3H)-ones prepared in 65-99% yields.

Dual Catalysis of Gold Nanoclusters: Photocatalytic Cross-Dehydrogenative Coupling by Cooperation of Superatomic Core and Molecularly Modified Staples.

Thiolate-protected gold nanoclusters (AuNCs) have attracted significant attention as nano-catalysts, revealing a superatomic core and gold-thiolate staples as distinct structural units. Here, we demonstrate the unprecedented dual catalytic activity of thiolate-protected [Au25 (SR)18 ]- nanoclusters, involving both photosensitized 1 O2 generation by the Au13 superatomic core and catalytic carbon-carbon bond formation facilitated by Au2 (SR)3 staples. This synergistic combination of two different catalytic units enables efficient cross-dehydrogenative coupling of terminal alkynes and tertiary aliphatic amines to afford propargylamines in high yields of up to 93 %. Mixed-ligand AuNCs bearing both thiolate and alkynyl ligands revealed the intermediacy of the alkynyl-exchanged AuNCs toward both photosensitization and C-C bond-forming catalytic cycles. Density functional theory calculations also supported the intermediacy of the alkynyl-exchanged AuNCs. Thus, the use of ligand-protected metal nanoclusters has enabled the development of an exceptional multifunctional catalyst, wherein distinct nanocluster components facilitate cooperative photo- and chemo-catalysis.

Iron-Catalyzed Asymmetric α-Alkylation of 2-Acylimidazoles via Dehydrogenative Radical Cross-Coupling with Alkanes.

The direct α-alkylation of acyclic carbonyls with nonactivated hydrocarbons through C(sp3 )-H functionalization is both extremely promising and notably challenging, especially when attempting to achieve enantioselectivity using iron-based catalysts. We have identified a robust chiral iron complex for the oxidative cross-coupling of 2-acylimidazoles with benzylic and allylic hydrocarbons, as well as nonactivated alkanes. The readily available and tunable N,N'-dioxide catalysts of iron in connection with oxidants exhibit precise asymmetric induction (up to 99 % ee) with good compatibility in moderate to good yields (up to 88 % yield). This protocol provides an elegant and straightforward access to optically active acyclic carbonyl derivatives starting from simple alkanes without prefunctionalization. Density functional theory (DFT) calculations and control experiments were made to gain insight into the nature of C-C bond formation and the origin of enantioselectivity. We propose a radical-radical cross-coupling process enabled by the immediate interconversion between chiral ferric species and ferrous species.

Anchoring Catalytic Metal Nodes within a Single-Crystalline Pyrazolate Metal-Organic Framework for Efficient Heterogeneous Catalysis.

The synthesis of single-crystalline and robust pyrazolate metal-organic frameworks (Pz-MOFs) capable of facilitating challenging organic transformations is fundamentally significant in catalysis. Here we demonstrate a metal-node-based catalytic site anchoring strategy by synthesizing a single-crystalline and robust Pz-MOF (PCN-1004). PCN-1004 features one-dimensional (1D) copper-Pz chains interconnected by well-organized ligands, forming a porous three-dimensional (3D) network with two types of 1D open channels. Notably, PCN-1004 displays exceptional stability in aqueous solutions across a broad pH range (1 to 14), attributed to the robust copper-Pz coordination bond. Significantly, PCN-1004 functions as an outstanding catalyst in cross dehydrogenative coupling reactions for constructing C-O/C-S bonds, even in the absence of directing groups, achieving yields of up to ~99 %, with long cycle lives and high substrate compatibility. PCN-1004 outperforms all previously reported porphyrin-based homogeneous and heterogeneous catalysts. Control experiments and computations elucidate the pivotal catalytic role of the copper-Pz chains and reveal a free radical pathway for the reaction. This work not only demonstrates the successful implementation of a metal-node-based catalytic site anchoring strategy for the efficient catalysis of challenging organic transformations but also highlights the synergistic effect of a robust framework, 1D open channels, and active sites in enhancing catalytic efficiency within MOFs.

Correction: Synthesis of highly substituted fluorenones via metal-free TBHP-promoted oxidative cyclization of 2-(aminomethyl)biphenyls. Application to the total synthesis of nobilone.

[This corrects the article DOI: 10.3762/bjoc.17.181.].

Phenotellurazine redox catalysts: elements of design for radical cross-dehydrogenative coupling reactions.

Redox active phenotellurazine catalysts have been recently utilized in two different cross-dehydrogenative coupling reactions. In this study, we revisit the design of the phenotellurazine redox catalysts. In particular, we investigate the level of cooperativity between the Te- and N-centers, the effect of secondary versus tertiary N-centers, the effect of heterocyclic versus non-heterocyclic structures, and the effect of substitution patterns on the redox catalytic activity.

Recent Advances in Aerobic Oxidative of C-H Bond by Molecular Oxygen Focus on Heterocycles.

Aerobic oxidative cross-coupling represents one of the most straightforward and atom-economic methods for construction of C-C and C-X (X=N, O, S, or P) bonds using air as a sustainable external oxidant. The oxidative coupling of C-H bonds in heterocyclic compounds can effectively increase their molecular complexity by introducing new functional groups through C-H bond activation, or by formation of new heterocyclic structures through cascade construction of two or more sequential chemical bonds. This is very useful as it can increase the potential applications of these structures in natural products, pharmaceuticals, agricultural chemicals, and functional materials. This is a representative overview of recent progress since 2010 on green oxidative coupling reactions of C-H bond using O2 or air as internal oxidant focus on Heterocycles. It aims to provide a platform for expanding the scope and utility of air as green oxidant, together with a brief discussion on research into the mechanisms behind it.

Direct C(3)5-H Polyfluoroarylation of 2-Amino/alkoxy Pyridines Enabled by a Transient and Electron-deficient Palladium Intermediate.

Herein, we present an unprecedented azine-limited C5-H polyfluoroarylation of 2-aminopyridines enabled by a transient and electron-deficient perfluoroaryl-Pd species via C-H/C-H coupling. The protocol further allows C3(5)-H polyfluoroarylation of 2-alkoxypyridines guided by sterics and electronics for the first time. The late-stage C-H functionalization of drugs, drug derivatives, and natural product derivatives and synthesis of C5-aryl drug derivatives further demonstrated the method's utility. The preliminary mechanistic studies reveal that the synergistic combination of the bulky yet electrophilic perfluoroaryl-Pd species and the partial nucleophilicity of the C5-position of 2-amino/alkoxy-pyridines is the origin of reactivity and selectivity. Importantly, the first experimental evidence for the role of diisopropyl sulfide is provided.

Low-Valent-Tungsten-Catalyzed Aerobic Oxidative Cross-Dehydrogenative Coupling Reaction.

A straightforward and convenient protocol was established for the synthesis of thiophosphates and 3-sulfenylated indoles via low-valent-tungsten-catalyzed aerobic oxidative cross-dehydrogenative coupling reactions. These reactions occur under mild conditions and simple operations with commercially available starting materials, processing the advantage of excellent atom and step economy, broad substrate scope, and good functional groups tolerance. Moreover, this transformation could be practiced on the gram scale, which exhibits great potential in the preparation of drug-derived or bioactive molecules.

Copper-Catalyzed Intramolecular Olefinic C(sp2)-H Amidation for the Synthesis of γ-Alkylidene-γ-lactams.

Herein, we report the copper-catalyzed dehydrogenative C(sp2)-N bond formation of 4-pentenamides via nitrogen-centered radicals. This reaction provides a straightforward and efficient preparation method for γ-alkylidene-γ-lactams. Notably, we could controllably synthesize α,ß-unsaturated- or α,ß-saturated-γ-alkylidene-γ-lactams depending on the reaction conditions.

Cross-Dehydrogenative Coupling Polymerization via C-H Activation for the Synthesis of Conjugated Polymers.

Owing to their versatile (opto)electronic properties, conjugated polymers have found application in several organic electronic devices. Cross-coupling reactions such as Stille, Suzuki, Kumada couplings, and direct arylation reactions have proved to be effective for their synthesis. More atom-efficient oxidative direct arylation polymerization has also been reported for making homopolymers. However, growing interest toward donor-acceptor polymers has led to the recent emergence of cross-dehydrogenative coupling (CDC) polymerization to synthesize alternating copolymers without any prefunctionalization of monomers. Metal-catalyzed cross-coupling of two simple arenes via double C-H activation, or of an arene with an alkene via oxidative Heck-type reaction have been used so far for CDC polymerization. In this article, we discuss the development of CDC polymerization protocols along with the relevant small molecule CDC reactions for an improved understanding of these reactions.

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.

Electrochemical Dehydrogenative C-H Aminomethylation of Imidazopyridines and Related Heterocycles.

A facile and environmentally friendly electrochemical protocol is herein reported for the C(sp2 )-C(sp3 ) cross dehydrogenative coupling between imidazopyridines and N,N-dimethylanilines. The broad functional group compatibility includes halogens, ester, alcohol, sulfone as well as thiophene. This methodology is also suitable for benzo[d]imidazo[2,1-b]thiazole, thiazoimidazole and tetrahydroisoquinoline, and can be scaled up to 5 mmol. Mechanistic insights are discussed.

Synthesis of Unsymmetrical Biheteroarenes via Dehydrogenative and Decarboxylative Coupling: a Decade Update.

The design and development of robust and efficient methods for installing one heterocycle with another is endowed as a ubiquitous and powerful synthetic strategy to access complex organic biheterocycles in recent days due to their pervasive applications in medicinal as well as material chemistry. This perspective presents an overview on the recent findings and developments for the synthesis of unsymmetrical biheteroarenes via dehydrogenative and decarboxylative couplings with literature coverage mainly extending from 2011 to 2021. For simplification of the readers, the article has been subcategorized based on the catalysts used in the reactions.

Direct Dehydrogenative Access to Unsymmetrical Phenones.

The first non-directed dehydrogenative phenone coupling method of methylarenes with aromatic C-H bonds, displaying a large substrate scope, is herein reported. This reaction represents a far more direct atom- and step-efficient alternative to the classical Friedel-Crafts or Suzuki-Miyaura derived acylation reactions. The method can be carried out on a gram scale and was successfully applied to the synthesis of several Ketoprofen drug analogues.

The Rich Legacy and Bright Future of Transition-Metal Catalyzed Peroxide Based Radical Reactions.

This personal account is mainly focused on the author's involvement in the field of transition metal-catalyzed peroxide based radical reactions. Over the past decades, radical chemistry has flourished and become crucial in contemporary synthetic organic chemistry. Owing to the presence of a single electron in one orbital, radicals are very unstable and react very fast. To carry out desired transformations and to control the side reactions the stabilizations of these radicals is essential. Fortunately, the implementation of a suitable transition metal and peroxide combination into the radical reactions have proved beneficial. Transition metals not only stabilizes the radicals but also protects them from being quenched by undesired homo-coupling or fragmentation. Transition metal-catalyzed radical-radical reactions provide an innovative way for the construction and derivatization of carbocycles and heterocycles. The objective of this review is to give an overview of the construction and derivatization of heterocycles through the lens of radical chemistry, mainly focusing on research work done by our group.

Construction of Vicinal Quaternary Carbon Stereocenters Through Diastereo- and Enantioselective Oxidative 1,6-Conjugate Addition.

The asymmetric construction of vicinal quaternary carbon stereocenters with at least one moiety in acyclic systems is a formidable challenge. We disclose a solution involving diastereo- and enantioselective oxidative 1,6-conjugate addition. The practical asymmetric cross-dehydrogenative coupling of 2,2-diarylacetonitriles and diverse α-substituted cyclic 1,3-dicarbonyls proceeds, for vicinal quaternary carbon stereocenters with one center in acyclic systems, in excellent yields and stereoselectivities. The generality of the approach is further demonstrated by the stereoselective creation of vicinal quaternary carbon stereocenters with both centers in acyclic systems using acyclic ß-ketoesters as coupling partners. Computational studies elucidate the origins of both diastereo- and enantioselectivity.

Site-Selective Electrochemical Benzylic C-H Amination.

C-H/N-H cross-coupling is an ideal strategy to synthesize various amines but remains challenging owing to the requirement for sacrificial chemical oxidants and the difficulty in controlling the regio- and chemo-selectivity. Herein we report a site-selective electrochemical amination reaction that can convert benzylic C-H bonds into C-N linkages via H2 evolution without need for external oxidants or metal catalysts. The synthetic strategy involves anodic cleavage of benzylic C-H to form a carbocation intermediate, which is then trapped with an amine nucleophile leading to C-N bond formation. Key to the success is to include HFIP as a co-solvent to modulate the oxidation potentials of the alkylbenzene substrate and the aminated product to avoid overoxidation of the latter.