Direct C–H functionalization of difluoroboron dipyrromethenes (BODIPYs) at β-position by iodonium salts

A copper-catalyzed direct C–H arylation or vinylation of BODIPYs at the β-position by iodonium salts has been developed, which provides facile access to a variety of mono-substituted BODIPY dyes. Interestingly, β-styryl BODIPY compound 9b exhibits apparent cytotoxicity after laser irradiation, which has great potential for photodynamic therapy.

A copper-catalyzed direct C–H arylation or vinylation of BODIPYs at the β-position by iodonium salts has been developed and β-styryl BODIPY 9b has great potential for photodynamic therapy.     

Cationic palladium(ii)-catalyzed synthesis of substituted pyridines from α,β-unsaturated oxime ethers

An efficient method for the synthesis of multi-substituted pyridines from β-aryl-substituted α,β-unsaturated oxime ethers and alkenes via Pd-catalyzed C–H activation has been developed. The method, using Pd(OAc)₂ and a sterically hindered pyridine ligand, provides access to various multi-substituted pyridines with complete regioselectivity. Mechanistic studies suggest that the pyridine products are formed by Pd-catalyzed electrophilic C–H alkenylation of α,β-unsaturated oxime followed by aza-6π-electrocyclization. The utility of this method is showcased by the synthesis of 4-aryl-substituted pyridine derivatives, which are difficult to synthesize efficiently using previously reported Rh-catalyzed strategies with alkenes.

An efficient method for the synthesis of multi-substituted pyridines from α,β-unsaturated oxime ethers via cationic Pd(ii)-catalyzed C–H activation has been developed.     

Site-selective,catalytic, and diastereoselective sp3 C–H hydroxylation and alkoxylation of vicinally functionalized lactams

The C–H bond functionalization of sp³ carbon centres presents a significant challenge due to the inert nature of hydrocarbons as well as the need to selectively functionalize one of the numerous aliphatic C–H bonds embodied in organic molecules. Here, we describe catalytic, diastereoselective, and site-selective sp³ C–H hydroxylation/alkoxylation protocols featuring dihydroisoquinolones, γ-, and δ-lactams, which bear vicinal stereocenters. The hydroxylation strategy utilizes oxygen, a waste-free oxidant and affords attractive fragments for potential drug discovery. Fe-catalyzed dehydrative coupling of the resulting tertiary alcohols with simple primary alcohols has led to the construction of highly versatile unsymmetrical dialkyl ethers.

Catalytic, diastereoselective, and site-selective sp³ C–H hydroxylation and alkoxylation protocols featuring lactams that bear vicinal stereocenters, is described.     

Oxidative functionalization of aliphatic and aromatic amino acid derivatives with H2O2 catalyzed by a nonheme imine based iron complex

The oxidation of a series of N-acetyl amino acid methyl esters with H₂O₂ catalyzed by a very simple iminopyridine iron(ii) complex 1 easily obtainable in situ by self-assembly of 2-picolylaldehyde, 2-picolylamine, and Fe(OTf)₂ was investigated. Oxidation of protected aliphatic amino acids occurs at the α-C–H bond exclusively (N-AcAlaOMe) or in competition with the side-chain functionalization (N-AcValOMe and N-AcLeuOMe). N-AcProOMe is smoothly and cleanly oxidized with high regioselectivity affording exclusively C-5 oxidation products. Remarkably, complex 1 is also able to catalyze the oxidation of the aromatic N-AcPheOMe. A marked preference for the aromatic ring hydroxylation over Cα–H and benzylic C–H oxidation was observed, leading to the clean formation of tyrosine and its phenolic isomers.

Amino acid derivatives are oxidized by the 1/H₂O₂ system. A marked preference for the aromatic over Cα–H and benzylic C–H oxidation is observed with phenylalanine.     

Mechanistic insights into rare-earth-catalysed C–H alkylation of sulfides: sulfide facilitating alkene insertion and beyond

The catalytic C–H alkylation with alkenes is of much interest and importance, as it offers a 100% atom efficient route for C–C bond construction. In the past decade, great progress in rare-earth catalysed C–H alkylation of various heteroatom-containing substrates with alkenes has been made. However, whether or how a heteroatom-containing substrate would influence the coordination or insertion of an alkene at the catalyst metal center remained elusive. In this work, the mechanism of Sc-catalysed C–H alkylation of sulfides with alkenes and dienes has been carefully examined by DFT calculations, which revealed that the alkene insertion could proceed via a sulfide-facilitated mechanism. It has been found that a similar mechanism may also work for the C–H alkylation of other heteroatom-containing substrates such as pyridine and anisole. Moreover, the substrate-facilitated alkene insertion mechanism and a substrate-free one could be switched by fine-tuning the sterics of catalysts and substrates. This work provides new insights into the role of heteroatom-containing substrates in alkene-insertion-involved reactions, and may help guide designing new catalysis systems.

The alkene insertion via the heteroatom-containing substrate facilitated mechanism were computationally revealed in rare-earth-catalyzed C–H alkylation of sulfides and other heteroatom-containing substrates such as pyridines and anisoles.     

Xylopins A–F,six rare guaiane dimers with three different connecting modes from Xylopia vielana

Six rare guaiane-type sesquiterpene dimers xylopins A–F, having three different connecting modes through two direct C–C bonds, were isolated from the roots of Xylopia vielana. Their absolute configurations were established by NOESY analysis, Cu Kα X-ray crystallography, and experimental and calculated electronic circular dichroism spectra. Flow cytometry demonstrated the fact that compound 6 arrested the cell cycle at G2 phase and concentration-dependently induced apoptosis of DU145 cells. Furthermore, the EPT2-TGC cell model, zebrafish study and western blot analysis illustrated compound 6 could induce apoptosis by efficiently inhibiting the Wnt/β-catenin signaling pathway via decreasing the expression of β-catenin.

Six rare guaiane-type sesquiterpene dimers xylopins A–F, having three different connecting modes through two direct C–C bonds, were isolated from the roots of Xylopia vielana.     

TBAI-assisted direct C–H activation of indoles with β-E-styrene sulfonyl hydrazides: a stereoselective access to 3-styryl thioindoles

The current work describes the challenging introduction of a vinyl sulfide group by simple C–H activation on a variety of substrates. The direct C–H activation of indoles with β-(E)-styrene sulfonyl hydrazides under the sulfenylation conditions, assisted by the iodic catalyst tert-butyl ammonium iodide (TBAI), afforded a series of (E)-styrylthioindoles. Accordingly, β-(E)-styrene sulfonyl hydrazides undergo radical cross-coupling reactions with a variety of substituted indoles to afford structurally diverse indole vinyl thioethers in moderate to high yields with E-stereoselectivity. This method is metal-catalyst-free and is valuable not only because of its novelty, but also for providing a convenient synthetic pathway to a variety of (E)-styrylthioindoles with retention of the configuration. The current study paves the way for the use of β-(E)-styrene sulfonyl hydrazides as a unique styryl mercaptan source in chemical synthesis.

Direct C–H activation of indoles with beta-(E)-styrene sulfonyl hydrazides assisted by TBAI afforded structurally diverse indole vinyl thioethers in moderate to high yields with E-stereoselectivity.     

Catalytic,selective, and stereocontrolled construction of C4 quaternary and homobenzylic dihydroisoquinolones by sp3 C–H benzylation

C1 benzylated isoquinoline derivatives constitute the core of benzylisoquinoline alkaloids (BIAs). However, their C4 congeners remain elusive. Here, we describe a diastereoselective, catalytic, and modular C(sp³)–C(sp³) coupling protocol wherein β-amino sp³ C–H bonds of readily affordable vicinally functionalized dihydroisoquinolones are replaced by sp³ C–benzyl bonds. The method provides expedient access to C4 quaternary and homobenzylic dihydroisoquinolones, which are attractive fragments for potential drug discovery.

A diastereoselective and catalytic C(sp³)–C(sp³) coupling protocol wherein β-amino sp³ C–H bonds are replaced by sp³ C–benzyl bonds, leading to C4 quaternary and homobenzylic dihydroisoquinolones, is described.     

Methods for direct C(sp2)–H bonds azidation

Direct functionalization of C–H bonds has attracted great attention in recent years from the perspectives of atom and step economy. In this context, a variety of processes have been developed for the construction of synthetically and biologically important organic azides through the oxidative C–H bonds azidation. In this review, we have summarized recent progress in the direct azidation of C(sp²)–H bonds. The review is divided into three major sections: (i) direct azidation of aromatic C–H bonds; (ii) direct azidation of olefinic C–H bonds; and (iii) direct azidation of aldehydic C–H bonds. Mechanistic aspects of the reactions are considered and discussed in detail.

Direct functionalization of C–H bonds has attracted great attention in recent years from the perspectives of atom and step economy.     

Highly economical and direct amination of sp3 carbon using low-cost nickel pincer catalyst

Developing more efficient routes to achieve C–N bond coupling is of great importance to industries ranging from products in pharmaceuticals and fertilizers to biomedical technologies and next-generation electroactive materials. Over the past decade, improvements in catalyst design have moved synthesis away from expensive metals to newer inexpensive C–N cross-coupling approaches via direct amine alkylation. For the first time, we report the use of an amide-based nickel pincer catalyst (1) for direct alkylation of amines via activation of sp³ C–H bonds. The reaction was accomplished using a 0.2 mol% catalyst and no additional activating agents other than the base. Upon optimization, it was determined that the ideal reaction conditions involved solvent dimethyl sulfoxide at 110 °C for 3 h. The catalyst demonstrated excellent reactivity in the formation of various imines, intramolecularly cyclized amines, and substituted amines with a turnover number (TON) as high as 183. Depending on the base used for the reaction and the starting amines, the catalyst demonstrated high selectivity towards the product formation. The exploration into the mechanism and kinetics of the reaction pathway suggested the C–H activation as the rate-limiting step, with the reaction second-order overall, holding first-order behavior towards the catalyst and toluene substrate.

Developing more efficient routes to achieve efficient C–N bond coupling is of great importance to industries ranging from products in pharmaceuticals and fertilizers to biomedical technologies and next-generation electroactive materials.     

An efficient access to β-ketosulfones via β-sulfonylvinylamines: metal–organic framework catalysis for the direct C–S coupling of sodium sulfinates with oxime acetates

A copper-based framework Cu₂(OBA)₂(BPY) was synthesized and used as a recyclable heterogeneous catalyst for the synthesis of β-sulfonylvinylamines from sodium sulfinates and oxime acetates via direct C–S coupling reaction. The transformation was remarkably affected by the solvent, and chlorobenzene emerged as the best option. This Cu-MOF displayed higher activity than numerous conventional homogeneous and MOF-based catalysts. The catalyst was reutilized many times in the synthesis of β-sulfonylvinylamines without considerably deteriorating in catalytic efficiency. These β-sulfonylvinylamines were readily converted to the corresponding β-ketosulfones via a hydrolysis step with aqueous HCl solution. To the best of our knowledge, this direct C–S coupling reaction to achieve β-sulfonylvinylamines was not previously conducted with a heterogeneous catalyst.

Cu₂(OBA)₂(BPY) was used as catalyst for the synthesis of β-sulfonylvinylamines from sodium sulfinates and oxime acetates. These β-sulfonylvinylamines were readily converted to corresponding β-ketosulfones via a hydrolysis step.     

Transition-metal-catalyzed remote C–H functionalization of thioethers

In the last decade, transition-metal-catalyzed direct C–H bond functionalization has been recognized as one of most efficient approaches for the derivatization of thioethers. Within this category, both mono- and bidentate-directing group strategies achieved the remote C(sp²)–H and C(sp³)–H functionalization of thioethers, respectively. This review systematically introduces the major advances and their mechanisms in the field of transition-metal-catalyzed remote C–H functionalization of thioethers from 2010 to 2021.

This minireview systematically introduces the major advances and their mechanisms in the field of transition-metal-catalyzed remote C–H functionalization of thioethers.     

One-pot method for the synthesis of 1-aryl-2-aminoalkanol derivatives from the corresponding amides or nitriles

We have identified a novel one-pot method for the synthesis of β-amino alcohols, which is based on C–H bond hydroxylation at the benzylic α-carbon atom with a subsequent nitrile or amide functional group reduction. This cascade process uses molecular oxygen as an oxidant and sodium bis(2-methoxyethoxy)aluminum hydride as a reductant. The substrate scope was examined on 30 entries and, although the respective products were provided in moderate yields only, the above simple protocol may serve as a direct and powerful entry to the sterically congested 1,2-amino alcohols that are difficult to prepare by other routes. The plausible mechanistic rationale for the observed results is given and the reaction was applied to a synthesis of a potentially bioactive target.

A one-pot method for β-amino alcohol synthesis based on α-hydroxylation and subsequent amide or nitrile functional group reduction has been identified and examined.     

Copper-catalyzed aerobic decarboxylative coupling between cyclic α-amino acids and diverse C–H nucleophiles with low catalyst loading

An aerobic decarboxylative cross-coupling of α-amino acids with diverse C–H nucleophiles has been realized using Cu₂(OH)₂CO₃ (1 mol%) as the catalyst under air. This protocol enables highly efficient formation of various C(sp³)–C(sp³), C(sp³)–C(sp²) and C(sp³)–C(sp) bonds under simple conditions without the use of any ligand or extra oxidant, providing a practical approach to numerous nitrogen-containing compounds in good to excellent yields. The efficiency and practicability were also demonstrated by the gram-scale experiment and three-step synthesis of a Rad51 inhibitor.

An aerobic decarboxylative cross-coupling of α-amino acids was realized using 1 mol% Cu₂(OH)₂CO₃ catalyst under ligand free conditions.     

N-Fluorobenzenesulfonimide: a useful and versatile reagent for the direct fluorination and amination of (hetero)aromatic C–H bonds

This review updates recent advances and developments in the direct fluorination and amination of (hetero)aromatic C–H bonds utilizing N-fluorobenzenesulfonimide, classified according to the type of catalyst.

This review updates recent advances and developments in the direct fluorination and amination of (hetero)aromatic C–H bonds utilizing N-fluorobenzenesulfonimide, classified according to the type of catalyst.     

Graphene oxide-catalyzed trifluoromethylation of alkynes with quinoxalinones and Langlois' reagent

The direct C–H trifluoromethylation of alkynes and quinoxalinones has been achieved using a graphene oxide/Langlois'' reagent system. This multi-component tandem reaction using graphene oxide as the catalyst and Langlois'' reagent as the robust CF₃ radical source results in the formation of olefinic C–CF₃ to access a series of 3-trifluoroalkylated quinoxalin-2(1H)-ones.

The direct C–H trifluoromethylation of alkynes and quinoxalinones using a graphene oxide/Langlois'' reagent system.     

Synthesis of 1-(β-coumarinyl)-1-(β-indolyl)trifluoroethanols through regioselective Friedel–Crafts alkylation of indoles with β-(trifluoroacetyl)coumarins catalyzed by Sc(OTf)3

A highly efficient Friedel–Crafts alkylation of indole derivatives with β-(trifluoroacetyl)coumarins using Sc(OTf)₃ as a catalyst has been developed, which gives regioselective 1,2-adducts to afford 1-(β-coumarinyl)-1-(β-indolyl)trifluoroethanols. A series of tertiary trifluoroethanols containing different indole and coumarin groups were synthesized in moderate to excellent yields (up to 95%) in the presence of 5 mol% catalyst in a short time (only 2 minutes at least). A mechanism of the reaction, in which the trace amount of water plays the role of proton transfer in catalyzing circulation was proposed and confirmed.

A Friedel–Crafts alkylation of indoles with β-(trifluoroacetyl)coumarins catalyzed by Sc(OTf)₃ to afford 1-(β-coumarinyl)-1-(β-indolyl)trifluoroethanols in a short time and high yield was developed.     

The Reformatsky analogous reaction for the synthesis of novel β-thioxoesters via using aroyl isothiocyanates under solvent-free ball milling and conventional conditions

The classical Reformatsky reaction, initially described in 1887, is considered one of the most useful ways of forming C–C bonds. The target of this work includes improving the Reformatsky reaction between aroyl isothiocyanates and α-haloesters using metallic zinc to form β-thioxoesters (3–11). In this procedure, a new metal-mediated carbon–carbon linkage is formed with the formation of an organozinc halide and decomposition due to the presence of dilute acid, affording a good yield of the desired product via conventional techniques and ball milling. The Reformatsky reaction requires no solvent and no inert gases.

The Reformatsky analogous reaction between aroyl isothiocyanates and α-haloesters using metallic zinc to form β-thioxoesters via ball milling and conventional techniques.     

Progress and recent trends in the direct selenocyanation of (hetero)aromatic C–H bonds

This review covers recent advances in the direct selenocyanation of (hetero)aromatic C–H bonds with an emphasis on the reaction mechanisms. This novel approach is an effective means of preparing a variety of aromatic and heteroaromatic selenocyanates, which are extremely versatile synthetic precursors of selenium-containing compounds, such as selenols, seleninic acids, selenides, diselenides, and trifluoromethyl selenides.

Concise overview on the synthesis of biologically and synthetically important aromatic and heteroaromatic selenocyanates through the direct selenocyanation of (hetero)aromatic C–H bonds with an emphasis on the reaction mechanisms.     

Cross-dehydrogenative coupling reactions between arenes (C–H) and carboxylic acids (O–H): a straightforward and environmentally benign access to O-aryl esters

Transition-metal catalyzed cross-dehydrogenative-coupling reactions encompass highly versatile and atom economical methods for the construction of various carbon–carbon and carbon–heteroatom bonds by combining two C(X)–H (X = heteroatom) bonds. Along this line, direct acyloxylation of C–H bonds with carboxylic acids has emerged as a powerful and green approach for the synthesis of structurally diverse esters. In this focus-review we will describe recent progress in direct esterification of aromatic C–H bonds with special emphasis on the mechanistic features of the reactions. Literature has been surveyed until the end of February 2019.

Transition-metal catalyzed cross-dehydrogenative-coupling encompass atom economical methods for the construction of various carbon–carbon and carbon–heteroatom bonds by combining two C(X)–H (X = heteroatom) bonds.