Diversity‐Oriented Synthesis of Substituted Benzo[b]thiophenes and Their Hetero‐Fused Analogues through Palladium‐Catalyzed Oxidative CH Functionalization/Intramolecular Arylthiolation

An efficient, high yielding route to multisubstituted benzo[b]thiophenes has been developed through palladium‐catalyzed intramolecular oxidative C?H functionalization–arylthiolation of enethiolate salts of α‐aryl‐β‐(het)aryl/alkyl‐β‐mercaptoacrylonitriles/acrylates or acrylophenones. The overall strategy involves a one‐pot, two‐step process in which enethiolate salts [generated in situ through base‐mediated condensation of substituted arylacetonitriles, deoxybenzoins, or arylacetates with (het)aryl (or alkyl) dithioates] are subjected to intramolecular C?H functionalization–arylthiolation under the influence of a palladium acetate (or palladium chloride)/cupric acetate catalytic system and tetrabutylammonium bromide as additive in N,N‐dimethylformamide (DMF) as solvent. In a few cases, the yields of benzo[b]thiophenes were better in a two‐step process by employing the corresponding enethiols as substrates. In a few examples, Pd(OAc)₂ (or PdCl₂) catalyst in the presence of oxygen was found to be more efficient than cupric acetate as reoxidant, furnishing benzothiophenes in improved yields by avoiding formation of side products. The method is compatible with a diverse range of substituents on the aryl ring as well as on the 2‐ and 3‐positions of the benzothiophene scaffold. The protocol could also be extended to the synthesis of a raloxifene precursor and a tubulin polymerization inhibitor in good yields. The versatility of this newly developed method was further demonstrated by elaborating it for the synthesis of substituted thieno‐fused heterocycles such as thieno[2,3‐b]thiophenes, thieno[2,3‐b]indoles, thieno[3,2‐c]pyrazole, and thieno[2,3‐b]pyridines in high yields. A probable mechanism involving intramolecular electrophilic arylthiolation via either a Pd‐S adduct or palladacycle intermediate has been proposed on the basis of experimental studies.     

Synthesis of Dibenzothiophenes by Pd‐Catalyzed Dual CH Activation from Diaryl Sulfides

Palladium‐catalyzed dual C?H functionalization of diaryl sulfides to form dibenzothiophenes (DBTs) by oxidative dehydrogenative cyclization is reported. This protocol afforded various DBTs in moderate to good yields with tolerance of a wide variety of substrates. Benzo[1,2‐b:4,5‐b′]bis[b]benzothiophene was successfully synthesized by this method, which was used as an organic semiconductor for field‐effect transistors.     

Ruthenium‐Catalyzed Cascade CH Functionalization of Phenylacetophenones

Three orthogonal cascade C? H functionalization processes are described, based on ruthenium‐catalyzed C? H alkenylation. 1‐Indanones, indeno indenes, and indeno furanones were accessed through cascade pathways by using arylacetophenones as substrates under conditions of catalytic [{Ru(p‐cymene)Cl₂}₂] and stoichiometric Cu(OAc)₂. Each transformation uses C? H functionalization methods to form C? C bonds sequentially, with the indeno furanone synthesis featuring a C? O bond formation as the terminating step. This work demonstrates the power of ruthenium‐catalyzed alkenylation as a platform reaction to develop more complex transformations, with multiple C? H functionalization steps taking place in a single operation to access novel carbocyclic structures.     

Ruthenium‐Catalyzed Oxidative Coupling of Primary Amines with Internal Alkynes through CH Bond Activation: Scope and Mechanistic Studies

The oxidative coupling of primary amines with internal alkynes catalyzed by Ru complexes is presented as a general atom‐economy methodology with a broad scope of applications in the synthesis of N‐heterocycles. Reactions proceed through regioselective C?H bond activation in 15 minutes under microwave irradiation or in 24 hours with conventional heating. The synthesis of 2,3,5‐substituted pyridines, benzo[h]isoquinolines, benzo[g]isoquinolines, 8,9‐dihydro‐benzo[de]quinoline, 5,6,7,8‐tetrahydroisoquinolines, pyrido[3,4g]isoquinolines, and pyrido[4,3g]isoquinolines is achievable depending on the starting primary amine used. DFT calculations on a benzylamine substrate support a reaction mechanism that consists of acetate‐assisted C?H bond activation, migratory‐insertion, and C?N bond formation steps that involve 28–30 kcal mol^?1. The computational study is extended to additional substrates, namely, 1‐naphthylmethyl‐, 2‐methylallyl‐, and 2‐thiophenemethylamines.     

Palladium‐Catalyzed CH Activation and Intermolecular Annulation with Allenes

A new and efficient Pd^II‐catalyzed intermolecular annulation of N‐benzoylsulfonamide with allenes for the synthesis of 3,4‐dihydroisoquinolin‐1(2H)‐ones is reported. This C?H functionalization is compatible with ambient air and moisture, and it can be applied to terminal or internal allenes with di?erent synthetically attractive functional groups. Control experiments and a kinetic isotope effect study are conducted and a plausible mechanism is proposed.     

Rhodium(III)‐Catalyzed N‐Nitroso‐Directed CH Addition to Ethyl 2‐Oxoacetate for Cycloaddition/Fragmentation Synthesis of Indazoles

Rh^III‐catalyzed N‐nitroso‐directed C?H addition to ethyl 2‐oxoacetate allows subsequent construction of indazoles, a privileged heterocycle scaffold in synthetic chemistry, through the exploitation of reactivity between the directing group and installed group. The formal [2+2] cycloaddition/fragmentation reaction pathway identified herein, a unique reactivity pattern hitherto elusive for the N‐nitroso group, emphasizes the importance of forward reactivity analysis in the development of useful C?H functionalization‐based synthetic tools. The synthetic utility of the protocol is demonstrated with the synthesis of a tricyclic‐fused ring system. The diversity of covalent linkages available for the nitroso group should enable the extension of the genre of reactivity reported herein to the synthesis of other types of heterocycles.     

General Method for the Synthesis of Salicylic Acids from Phenols through Palladium‐Catalyzed Silanol‐Directed CH Carboxylation

A silanol‐directed, palladium‐catalyzed C? H carboxylation reaction of phenols to give salicylic acids has been developed. This method features high efficiency and selectivity, and excellent functional‐group tolerance. The generality of this method was demonstrated by the carboxylation of estrone and by the synthesis of an unsymmetrically o,o′‐disubstituted phenolic compound through two sequential C? H functionalization processes.     

Manganese‐Catalyzed Dehydrogenative [4+2] Annulation of NH Imines and Alkynes by CH/NH Activation

Described herein is a manganese‐catalyzed dehydrogenative [4+2] annulation of N? H imines and alkynes, a reaction providing highly atom‐economical access to diverse isoquinolines. This transformation represents the first example of manganese‐catalyzed C? H activation of imines; the stoichiometric variant of the cyclomanganation was reported in 1971. The redox neutral reaction produces H₂ as the major byproduct and eliminates the need for any oxidants, external ligands, or additives, thus standing out from known isoquinoline synthesis by transition‐metal‐catalyzed C? H activation. Mechanistic studies revealed the five‐membered manganacycle and manganese hydride species as key reaction intermediates in the catalytic cycle.     

Metal‐Free Oxidative CC Bond Formation through CH Bond Functionalization

The formation of C?C bonds embodies the core of organic chemistry because of its fundamental application in generation of molecular diversity and complexity. C?C bond‐forming reactions are well‐known challenges. To achieve this goal through direct functionalization of C?H bonds in both of the coupling partners represents the state‐of‐the‐art in organic synthesis. Oxidative C?C bond formation obviates the need for prefunctionalization of both substrates. This Minireview is dedicated to the field of C?C bond‐forming reactions through direct C?H bond functionalization under completely metal‐free oxidative conditions. Selected important developments in this area have been summarized with representative examples and discussions on their reaction mechanisms.     

Nanomagnetically modified thioglycolic acid (γ‐Fe2O3@SiO2‐SCH2CO2H): Efficient and reusable green catalyst for the one‐pot domino synthesis of spiro[benzo[a]benzo[6,7]chromeno[2,3‐c]phenazine] and benzo[a]benzo[6,7]chromeno[2,3‐c]phenazines

Superparamagnetic nanoparticles of modified thioglycolic acid (γ‐Fe₂O₃@SiO₂‐SCH₂CO₂H) represent a new, efficient and green catalyst for the one‐pot synthesis of novel spiro[benzo[a ]benzo[6,7]chromeno[2,3‐c ]phenazine] derivatives via domino Knoevenagel–Michael–cyclization reaction of 2‐hydroxynaphthalene‐1,4‐dione, benzene‐1,2‐diamines, ninhydrin and isatin. This novel magnetic organocatalyst was easily isolated from the reaction mixture by magnetic decantation using an external magnet and reused at least six times without significant loss in its activity. The catalyst was fully characterized using various techniques. This procedure was also applied successfully for the synthesis of benzo[a ]benzo[6,7]chromeno[2,3‐c ]phenazines.     

Synthesis of Pyrrolophenanthridine Alkaloids Based on C(sp3)H and C(sp2)H Functionalization Reactions

Assoanine, pratosine, hippadine, and dehydroanhydrolycorine belong to the pyrrolophenanthridine family of alkaloids, which are isolated from plants of the Amaryllidaceae species. Structurally, these alkaloids are characterized by a tetracyclic skeleton that contains a biaryl moiety and an indole core, and compounds belonging to this class have received considerable interest from researchers in a number of fields because of their biological properties and the challenges associated with their synthesis. Herein, a strategy for the total synthesis of these alkaloids by using C? H activation chemistry is described. The tetracyclic skeleton was constructed in a stepwise manner by C(sp³)? H functionalization followed by a Catellani reaction, including C(sp²)? H functionalization. A one‐pot reaction involving both C(sp³)? H and C(sp²)? H functionalization was also attempted. This newly developed strategy is suitable for the facile preparation of various analogues because it uses simple starting materials and does not require protecting groups.     

Palladium‐Catalyzed Carbonylative Cyclization of Arenes by CH Bond Activation with DMF as the Carbonyl Source

A novel palladium‐catalyzed CO‐gas‐ and autoclave‐free protocol for the synthesis of 11H‐pyrido[2,1‐b]quinazolin‐11‐ones has been developed. Quinazolinones, which are omnipresent motif in many pharmaceuticals and agrochemicals, were prepared in good yields by C?H bond activation and annulation using DMF as the CO surrogate. A ¹³CO‐labelled DMF control experiment demonstrated that CO gas was released from the carbonyl of DMF with acid as the promotor. The kinetic isotope effect (KIE) value indicated that the C?H activation step may not be involved in the rate‐determining step. This methodology is operationally simple and showed a broad substrate scope with good to excellent yields.     

Direct Synthesis of Benzofuro[2,3‐b]pyrroles through a Radical Addition/[3,3]‐Sigmatropic Rearrangement/Cyclization/Lactamization Cascade

A straightforward synthetic method for the construction of benzofuro[2,3‐b]pyrrol‐2‐ones by a novel domino reaction through a radical addition/[3,3]‐sigmatropic rearrangement/cyclization/lactamization cascade has been developed. The domino reaction of O‐phenyl‐conjugated oxime ether with an alkyl radical allows the construction of two heterocycles with three stereogenic centers as a result of the formation of two C?C bonds, a C?O bond, and a C?N bond in a single operation, leading to pyrrolidine‐fused dihydrobenzofurans, which are not easily accessible by existing synthetic methods. Furthermore, asymmetric synthesis of benzofuro[2,3‐b]pyrrol‐2‐one derivatives through a diastereoselective radical addition reaction to a chiral oxime ether was also developed.     

Synthesis and Structure–Property Relationships of 2,2′‐Bis(benzo[b]phosphole) and 2,2′‐Benzo[b]phosphole–Benzo[b]heterole Hybrid π Systems

The first comprehensive study of the synthesis and structure–property relationships of 2,2′‐bis(benzo[b]phosphole)s and 2,2′‐benzo[b]phosphole–benzo[b]heterole hybrid π systems is reported. 2‐Bromobenzo[b]phosphole P‐oxide underwent copper‐assisted homocoupling (Ullmann coupling) and palladium‐catalyzed cross‐coupling (Stille coupling) to give new classes of benzo[b]phosphole derivatives. The benzo[b]phosphole–benzo[b]thiophene and ‐indole derivatives were further converted to P,X‐bridged terphenylenes (X=S, N) by a palladium‐catalyzed oxidative cycloaddition reaction with 4‐octyne through the C_β? H activation. X‐ray analyses of three compounds showed that the benzo[b]phosphole‐benzo[b]heterole derivatives have coplanar π planes as a result of the effective conjugation through inter‐ring C? C bonds. The π–π* transition energies and redox potentials of the cis and trans isomers of bis(benzo[b]phosphole) P‐oxide are very close to each other, suggesting that their optical and electrochemical properties are little affected by the relative stereochemistry at the two phosphorus atoms. The optical properties of the benzo[b]phosphole–benzo[b]heterole hybrids are highly dependent on the benzo[b]heterole subunits. Steady‐state UV/Vis absorption/fluorescence spectroscopy, fluorescence lifetime measurements, and theoretical calculations of the non‐fused and acetylene‐fused benzo[b]phosphole–benzo[b]heterole π systems revealed that their emissive excited states consist of two different conformers in rapid equilibrium.     

An Efficient Synthesis of Pyrrolo[1,2‐a] or Pyrido[1,2‐a]benzo[4,5]imidazo[1,2‐c]quinazoline Derivatives in Ionic Liquids Catalyzed by Iodine

2‐(1H ‐benzo[d ]imidazol‐2‐yl)anilines reacted with haloketones including 5‐chloropentan‐2‐one and 6‐chlorohexan‐2‐one catalyzed by iodine, giving benzo[4,5]imidazo[1,2‐c ]pyrrolo[1,2‐a ]quinazoline and 6H ‐benzo[4,5]imidazo[1,2‐c ]pyrido[1,2‐a ]quinazoline derivatives, respectively. This domino‐type reaction formed two new heterocycles and three new covalent bonds in one‐pot procedure and provided a green method for the synthesis of fused pentacyclic heterocycles bearing both quinazoline and benzimidazole moieties in ionic liquids.     

Heteroatom‐Guided,Palladium‐Catalyzed,Site‐Selective CH Arylation of 4H‐Chromenes: Diastereoselective Assembly of the Core Structure of Myristinin B through Dual CH Functionalization

A highly site‐selective, heteroatom‐guided, palladium‐catalyzed direct arylation of 4H‐chromenes is reported. The C?H functionalization is driven not only by the substituents and structure of the substrate but also by the coupling partner being used. The diastereoselective assembly of the core structure of Myristinin B has been achieved by using a dual C?H functionalization strategy for regioselective direct arylation.     

Redox‐Neutral Rhodium‐Catalyzed CH Functionalization of Arylamine N‐Oxides with Diazo Compounds: Primary C(sp3)H/C(sp2)H Activation and Oxygen‐Atom Transfer

An unprecedented rhodium(III)‐catalyzed regioselective redox‐neutral annulation reaction of 1‐naphthylamine N‐oxides with diazo compounds was developed to afford various biologically important 1H‐benzo[g]indolines. This coupling reaction proceeds under mild reaction conditions and does not require external oxidants. The only by‐products are dinitrogen and water. More significantly, this reaction represents the first example of dual functiaonalization of unactivated a primary C(sp³)? H bond and C(sp²)? H bond with diazocarbonyl compounds. DFT calculations revealed that an intermediate iminium is most likely involved in the catalytic cycle. Moreover, a rhodium(III)‐catalyzed coupling of readily available tertiary aniline N‐oxides with α‐diazomalonates was also developed under external oxidant‐free conditions to access various aminomandelic acid derivatives by an O‐atom‐transfer reaction.     

Iridium(I)‐Catalyzed Regioselective CH Activation and Hydrogen‐Isotope Exchange of Non‐aromatic Unsaturated Functionality

Isotopic labelling is a key technology of increasing importance for the investigation of new C?H activation and functionalization techniques, as well as in the construction of labelled molecules for use within both organic synthesis and drug discovery. Herein, we report for the first time selective iridium‐catalyzed C?H activation and hydrogen‐isotope exchange at the β‐position of unsaturated organic compounds. The use of our highly active [Ir(cod)(IMes)(PPh₃)][PF₆] (cod=1,5‐cyclooctadiene) catalyst, under mild reaction conditions, allows the regioselective β‐activation and labelling of a range of α,β‐unsaturated compounds with differing steric and electronic properties. This new process delivers high levels of isotope incorporation over short reaction times by using low levels of catalyst loading.     

Palladium‐Catalyzed Synthesis of Benzophenanthrosilines by C−H/C−H Coupling through 1,4‐Palladium Migration/Alkene Stereoisomerization

A new and efficient synthesis of 8H‐benzo[e]phenanthro[1,10‐bc]silines from 2‐((2‐(arylethynyl)aryl)silyl)aryl triflates under palladium catalysis has been developed. The reaction mechanism was experimentally investigated and a catalytic cycle involving C?H/C?H coupling through a new mode of 1,4‐palladium migration with concomitant alkene stereoisomerization is proposed.     

Copper‐Catalyzed Regioselective ortho CH Cyanation of Vinylarenes

A copper‐based catalytic technique for the regioselective ortho C? H cyanation of vinylarenes has been developed. This method provides an effective means for the selective functionalization of vinylarene derivatives. A copper‐catalyzed cyanative dearomatization mechanism is proposed to account for the regiochemical course of this reaction.