Chemodivergent synthesis of N-(pyridin-2-yl)amides and 3-bromoimidazo[1,2-a]pyridines from α-bromoketones and 2-aminopyridines

N-(Pyridin-2-yl)amides and 3-bromoimidazo[1,2-a]pyridines were synthesized respectively from α-bromoketones and 2-aminopyridine under different reaction conditions. N-(Pyridin-2-yl)amides were formed in toluene via C–C bond cleavage promoted by I₂ and TBHP and the reaction conditions were mild and metal-free. Whereas 3-bromoimidazopyridines were obtained in ethyl acetate via one-pot tandem cyclization/bromination when only TBHP was added, the cyclization to form imidazopyridines was promoted by the further bromination, no base was needed, and the versatile 3-bromoimidazopyridines could be further transferred to other skeletons.

N-(Pyridin-2-yl)amides and 3-bromoimidazo[1,2-a]pyridines were synthesized respectively from α-bromoketones and 2-aminopyridine under different reaction conditions.     

DMAP-stabilized bis(silyl)silylenes as versatile synthons for organosilicon compounds

DMAP-stabilized silylenes 1a–c are obtained from the reductive debromination of the corresponding dibromosilanes in the presence of DMAP. Their distinctly different thermal isomerization reactions via C–H bond activation, dearomative ring expansion and silyl migration are discussed. Furthermore, complexes 1 dissociate at elevated temperatures, providing the corresponding free silylenes in situ, which are even capable of single-site activation of H₂. Additionally, a potassium-substituted silicon-centered radical 2 is isolated from overreduction of (^tBu₃Si)₂SiBr₂.

DMAP-stabilized silylenes 1a–c, which are convenient, room temperature stable synthetic equivalents for the corresponding highly reactive free bis(silyl)silylenes are reported.     

Rh(iii)-catalyzed synthesis of tetracyclic isoquinolinium salts via C–H activation and [4+2] annulation of 1-phenyl-3,4-dihydroisoquinolines and alkynes in ethanol

An efficient and convenient method to construct tetracyclic isoquinolinium salts via [Cp*RhCl₂]₂ catalyzed C–H activation and [4 + 2] annulation reactions in ethanol is described. This reaction is very fast and highly efficient in the green solvent ethanol. The reaction works with a broad substrate scope affording the products in good to excellent yields in a short time. Moreover, a ratio of S/C up to 10 000 could be achieved with gram scale synthesis.

An efficient method to construct tetracyclic isoquinolinium salts via C–H activation and [4 + 2] annulation reactions in ethanol is described.     

Rh(iii)-catalyzed spiroannulation of 3-arylquinoxalin-2(1H)-ones with alkynes: practical access to spiroquinoxalinones

The Rh(iii)-catalyzed synthesis of spiroquinoxalinone derivatives from 3-arylquinoxalin-2(1H)-ones and alkynes via a C–H functionalization/[3 + 2] annulation sequence has been developed. This method, featuring low catalyst loading, was amenable to Gram scale synthesis and tolerated a variety of functional groups and substitution patterns on the aryl rings, providing the target products in good to excellent yields.

The use of imines as a H acceptor for Rh(iii)-catalyzed spirocyclization of 3-arylquinoxalinones and alkynes via a C–H functionalization/[3 + 2] annulation sequence has been achieved.     

Catalysis with magnetically retrievable and recyclable nanoparticles layered with Pd(0) for C–C/C–O coupling in water

Nanoparticles layered with palladium(0) were prepared from nano-sized magnetic Fe₃O₄ by coating it with silica and then reacting sequentially with phenylselenyl chloride under an N₂ atmosphere and palladium(ii) chloride in water. The resulting Fe₃O₄@SiO₂@SePh@Pd(0) NPs are magnetically retrievable and the first example of NPs in which the outermost layer of Pd(0) is mainly held by selenium. The weight percentage of Pd in the NPs was found to be 1.96 by ICP-AES. The NPs were authenticated via TEM, SEM-EDX, XPS, and powder XRD and found to be efficient as catalysts for the C–O and C–C (Suzuki–Miyaura) coupling reactions of ArBr/Cl in water. The oxidation state of Pd in the NPs having size distribution from ∼12 to 18 nm was inferred as zero by XPS. They can be recycled more than seven times. The main features of the proposed protocols are their mild reaction conditions, simplicity, and efficiency as the catalyst can be separated easily from the reaction mixture by an external magnet and reused for a new reaction cycle. The optimum loading (in mol% of Pd) was found to be 0.1–1.0 and 0.01–1.0 for O-arylation and Suzuki–Miyaura coupling, respectively. For ArCl, the required amount of NPs was more as compared to that needed for ArBr. The nature of catalysis is largely heterogeneous.

Fe₃O₄@SiO₂@SePh@Pd(0) (Pd, 1.96%) as the first example of NPs having a Pd(0) layer held by selenium can execute C–C/C–O coupling in 2–6 h (80 °C).     

The C–H activated controlled mono- and di-olefination of arenes in ionic liquids at room temperature

In this study, controlled mono and di-olefination of arenes was first realized at room temperature via the C–H bond activation in ionic liquids, probably due to the positive effects of ionic liquids. It is an energy-saving routes in industrial production without the need for heating equipment. Different catalysts were screened, and it was found that [Ru(p-cymene)Cl₂]₂ generated mono-olefinated products predominantly while [Cp*RhCl₂]₂ selectively gave di-olefinated products. These catalysts ([BMIM]NTf₂ and [BMIM]PF₆) as green and recyclable reaction media are highly efficient under mild conditions. This reaction process can avoid any volatile and environmentally toxic organic solvents, and is much safer without the need for pressure-tight equipment. A wide substrate scope with good yields and satisfactory selectivity was achieved. The reactions can be scaled up to gram-scale. Furthermore, an expensive rhodium/ruthenium catalytic system was recycled for at least 6 times with consistently high catalytic activity, which was economical and environmental friendly from an industrial point of view. According to the mechanistic study, the C–H bond cleavage was probably achieved via the concerted metalation–deprotonation. This technique can be applied in the synthesis of various valuable unsaturated aromatic compounds and shows a great potential for industrial production.

The controlled mono- and di-olefination of arenes was first realized at room temperature through C–H bond activation in ionic liquids.     

The green synthesis of a palm empty fruit bunch-derived sulfonated carbon acid catalyst and its performance for cassava peel starch hydrolysis

A sulfonated carbon acid catalyst (C–SO₃H) was successfully generated from palm empty fruit bunch (PEFB) carbon via hydrothermal sulfonation via the addition of hydroxyethylsulfonic acid and citric acid. The C–SO₃H catalyst was identified as containing 1.75 mmol g⁻¹ of acid and 40.2% sulphur. The surface morphology of C–SO₃H shows pores on its surface and the crystalline index (CrI) of PEFB was decreased to 63.8% due to the change structure as it became carbon. The surface area of the carbon was increased significantly from 11.5 to 239.65 m² g⁻¹ after sulfonation via hydrothermal treatment. The identification of –SO₃H, COOH and –OH functional groups was achieved using Fourier-transform infrared spectroscopy. The optimal catalytic activity of C–SO₃H was achieved via hydrolysis reaction with a yield of 60.4% of total reducing sugar (TRS) using concentrations of 5% (w/v) of both C–SO₃H and cassava peel starch at 100 °C for 1 h. The stability of C–SO₃H shows good performance over five repeated uses, making it a good potential candidate as a green and sulfonated solid acid catalyst for use in a wide range of applications.

A sulfonated carbon acid catalyst (C–SO₃H) was successfully generated from palm empty fruit bunch (PEFB) carbon via hydrothermal sulfonation via the addition of hydroxyethylsulfonic acid and citric acid.     

8,8′-(Benzo[c][1,2,5]thiadiazole-4,7-diyl)bis(quinolin-4(1H)-one): a twisted photosensitizer with AIE properties

A new benzothiadiazole (BTZ) luminogen is prepared via the Suzuki–Miyaura Pd-catalysed C–C cross-coupling of 8-iodoquinolin-4(1H)-one and a BTZ bispinacol boronic ester. The rapid reaction (5 min) affords the air-, thermo-, and photostable product in 97% yield as a yellow precipitate that can be isolated by filtration. The luminogen exhibits aggregated-induced emission (AIE) properties, which are attributed to its photoactive BTZ core and nonplanar geometry. It also behaves as a molecular heterogeneous photosensitizer for the production of singlet oxygen under continuous flow conditions.

A new benzothiadiazole (BTZ) luminogen is prepared via the Suzuki–Miyaura Pd-catalysed C–C cross-coupling of 8-iodoquinolin-4(1H)-one and a BTZ bispinacol boronic ester.     

Nickel(ii)-catalyzed reductive silylation of alkenyl methyl ethers for the synthesis of alkyl silanes

A new one pot protocol has been developed for the reductive silylation of alkenyl methyl ethers using Et₃Si–BPin and HSiEt₃ with nickel(ii) catalyst. Styrene type methyl ethers, multi-substituted vinyl methyl ethers, heterocycles and unconjugated vinyl ethers are all tolerated to form alkyl silanes. Mechanistic study reveals that it is a cascade of a C–O bond silylation and vinyl double bond hydrogenation process. Internal nucleophilic substitution or oxidative addition pathways were both acceptable for C–O bond cleavage. The acquired intermediate alkenyl silanes then proceeded through an unconventional reduction process thus providing alkyl silanes.

A Ni(ii)-catalyzed tandem reaction including vinyl C–O bond silylation and olefin hydrogenation has been developed providing structurally diversified alkyl silanes.     

Iodine-mediated C–N and N–N bond formation: a facile one-pot synthetic approach to 1,2,3-triazoles under metal-free and azide-free conditions

A novel strategy towards the synthesis of 1,4-disubstituted 1,2,3-triazoles via C–N and N–N bond formation has been demonstrated under transition metal-free and azide-free conditions. These 1,2,3-triazoles were obtained in a regioselective manner from commercially available anilines, aryl alkenes/aryl alkynes and N-tosylhydrazines using I₂ under O₂ atmosphere. Broad substrate scope, milder reaction conditions, good to moderate yields and clean protocol are the notable features of the method. Moreover, this protocol is amenable for the generation of a library of medicinally important key building blocks.

A novel strategy towards the synthesis of 1,4-disubstituted 1,2,3-triazoles via C–N and N–N bond formation has been demonstrated under transition metal-free and azide-free conditions.     

Phenanthroline-based microporous organic polymer as a platform for an immobilized palladium catalyst for organic transformations

Porous organic polymers have attracted significant attention owing to their large specific surface area, excellent chemical and thermal stability, and controllable skeletons. phenanthroline-based microporous organic polymer (Phen-MOP) has been synthesized via a cost-effective method based on the Scholl reaction. The Phen-MOP polymer exhibits high surface area and good stability. Owing to the phenanthroline skeleton embedding into the microporous polymer framework, the Phen-MOP can serve as a platform to support a transition metal catalyst. After being post-modified with palladium acetate, the synthesized Phen-Pd-MOP framework can serve as a highly efficient heterogeneous catalyst for the Suzuki–Miyaura coupling reaction and the Heck coupling reaction. Moreover, the Phen-Pd-MOP catalyst could be reused at least 10–12 times without any significant loss of the catalytic activity.

Phenanthroline-based microporous organic polymer (Phen-MOP) is synthesized via a cost-effective method based on the Scholl reaction. After post-modification with Pd(OAc)₂, the synthesized Phen-Pd-MOP is a highly efficient heterogeneous catalyst for C–C coupling reactions.     

Oxidative radical coupling of hydroquinones and thiols using chromic acid: one-pot synthesis of quinonyl alkyl/aryl thioethers

An efficient, simple and practical protocol for one-pot sequential oxidative radical C–H/S–H cross-coupling of thiols with hydroquinones (HQs) and oxidation leading to the formation of quinonyl alkyl/aryl thioethers using H₂CrO₄ was developed. This cross-coupling of thiyl and aryl radicals offers mono thioethers in good to moderate yield and works well with a wide variety of thiols. Similarly, this method works well for coupling of 2-amino thiophenol and HQs to form phenothiazine-3-ones 5a–c. C–S bond formation via thioether synthesis was observed using a chromium reagent for the first time. Theoretical studies on the pharmacokinetic properties of compounds 5a–c revealed that due to drug-like properties, compound 5b strongly binds with Alzheimer''s disease (AD) associated AChE target sites.

Oxidative radical C–H/S–H cross coupling of hydroquinones and thiols and oxidation to quinone using a H₂CrO₄ system was developed.     

Catalyzed M–C coupling reactions in the synthesis of σ-(pyridylethynyl)dicarbonylcyclopentadienyliron complexes

The reactions between terminal ethynylpyridines, (trimethylsilyl)ethynylpyridines and cyclopentadienyliron dicarbonyl iodide were studied under Pd/Cu-catalyzed conditions to develop a synthetic approach to the σ-alkynyl iron complexes Cp(CO)₂Fe–C C–R (R = ortho-, meta-, para-pyridyl). Depending on the catalyst and reagents used, the yields of the desired σ-pyridylethynyl complexes varied from 40 to 95%. In some cases the reactions with ortho-ethynylpyridine gave as byproduct the unexpected binuclear FePd μ-pyridylvinylidene complex [Cp(CO)Fe{μ₂-η¹(C_α):η¹(C_α)-κ¹(N)-C_α C_β(H)(o-C₅H₄N)}(μ-CO)PdI]. The conditions, catalysts, and reagents that provide the highest yields of the desired σ-pyridylethynyl iron compounds were determined. The methods developed allowed the synthesis of the corresponding σ-4-benzothiadiazolylethynyl complex Cp(CO)₂Fe–C C–(4-C₆H₃N₂S) as well. Eventually, synthetic approaches to σ-alkynyl iron complexes of the type Cp(CO)₂Fe–C C–R (R = ortho-, meta-, para-pyridyl, 4-benzothiadiazol-2,1,3-yl) based on the Pd/Cu-catalyzed cross-coupling reactions were elaborated.

Two approaches were developed for the synthesis of iron σ-pyridylethynyl complexes based on Pd/Cu- and Pd-catalyzed Fe–C coupling reactions.     

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.     

Ruthenium-catalyzed decarboxylative C–S cross-coupling of carbonothioate: synthesis of allyl(aryl)sulfide

A novel ruthenium-catalyzed decarboxylative cross-coupling of carbonothioate is disclosed. This method provides straightforward access to the corresponding allyl(aryl)sulfide derivatives in generally good to excellent yields under mild conditions and features a broad substrate scope, wide group tolerance and in particular, no need to use halocarbon precursors.

A method for the construction of a C–S bond via the ruthenium-catalyzed decarboxylative cross-coupling of carbonothioate under mild conditions is described.     

Chemoselective and one-pot synthesis of novel coumarin-based cyclopenta[c]pyrans via base-mediated reaction of α,β-unsaturated coumarins and β-ketodinitriles

In this paper, the base-mediated cascade reactions of 4-chloro-3-vinyl coumarins with β-ketodinitriles were demonstrated, allowing the efficient synthesis of coumarin-based cyclopenta[c]pyran-7-carbonitriles with interesting chemoselectivity. These transformations include the domino-style formation of C–C/C–C/C–O bonds through a base-mediated nucleophilic substitution, Michael addition, tautomerization, O-cyclization, elimination, and aromatization. The presented synthetic strategy has many advantages such as simple and readily available starting materials, green solvent, highly chemoselective route, synthetically useful yields, and easy purification of products by washing them with EtOH (96%), described as GAP (Group-Assistant-Purification) chemistry.

In this paper, the base-mediated cascade reactions of 4-chloro-3-vinyl coumarins with β-ketodinitriles were demonstrated, allowing the efficient synthesis of coumarin-based cyclopenta[c]pyran-7-carbonitriles with interesting chemoselectivity.     

Metal-free site-selective C–H cyanoalkylation of 8-aminoquinoline and aniline-derived amides with azobisisobutyronitrile

Using K₂S₂O₈, an efficient and metal-free site-selective C–H cyanoalkylation of 8-aminoquinoline and aniline-derived amides with AIBN (azobisisobutyronitrile) was developed. Without any catalyst, various substrates and functional groups were compatible to afford corresponding products in moderate to high yields. A mechanism study displayed that a radical–radical coupling process was involved via the N-centered radical generation and delocalization of aryl amides.

An efficient metal-free cyanoalkylation of 8-aminoquinoline and aniline-derived amides was achieved in the presence of K₂S₂O₈. The method showed good substrate tolerance and also suitable for bromination and dimerization reactions.     

The molecular mechanism of P450-catalyzed amination of the pyrrolidine derivative of lidocaine: insights from multiscale simulations

Nitrogen heterocycles are key and prevalent motifs in drugs. Evolved variants of cytochrome P450_BM3 (CYP102A1) from Bacillus megaterium employ high-valent oxo-iron(iv) species to catalyze the synthesis of imidazolidine-4-ones via an intramolecular C–H amination. Herein, we use multi-scale simulations, including classical molecular dynamics (MD) simulations, quantum mechanical/molecular mechanical (QM/MM) calculations and QM calculations, to reveal the molecular mechanism of the intramolecular C–H amination of the pyrrolidine derivative of lidocaine bearing cyclic amino moieties catalyzed by the variant RP/FV/EV of P450_BM3, which bears five mutations compared to wild type. Our calculations show that overall catalysis includes both the enzymatic transformation in P450 and non-enzymatic transformation in water solution. The enzymatic transformation involves the exclusive hydroxylation of the C–H bond of the pyrrolidine derivative of lidocaine, leading to the hydroxylated intermediate, during which the substrate radical would be bypassed. The following dehydration and C–N coupling reactions are found to be much favored in aqueous situation compared to that in the non-polar protein environment. The present findings expand our understanding of the P450-catalyzed C(sp₃)–H amination reaction.

Nitrogen heterocycles are key and prevalent motifs in drugs.     

Direct synthesis of 2-oxo-acetamidines from methyl ketones,aromatic amines and DMF via copper-catalyzed C(sp3)–H amidination

A convenient method for the synthesis of 2-oxo-acetamidines from methyl ketones using aromatic amines and DMF as nitrogen sources is reported via copper-catalyzed C(sp³)–H amidination. Various methyl ketones react readily with aromatic amines and DMF, producing 2-oxo-acetamidines in yields of 47 to 92%. This protocol features the simultaneous formation of C–N and C N bonds using DMF and aromatic amines as two different nitrogen sources. It thus provides an efficient approach to construct acyclic amidines via three C(sp³)–H bond amidination. Based on the preliminary experiments, a plausible mechanism of this transformation is disclosed.

A convenient method for the synthesis of 2-oxo-acetamidines from methyl ketones using aromatic amines and DMF as nitrogen sources is reported via copper-catalyzed C(sp³)–H amidination.     

Palladium-catalysed difluoroolefination of benzyl tosylates toward the synthesis of gem-difluoro-2-trifluromethyl styrene derivatives

We have presented an efficient method to access gem-difluoro-2-trifluromethyl styrene derivatives via palladium catalysis. This method features mild reaction conditions, broad substrate scope and good product yields. Moreover, gram–scale reactions demonstrated the robustness and potential of this method. Control experiments revealed that the –CF₃ group was essential to the success of this transformation. Finally, the practicality of this method was successfully proven by three synthetic applications.

We presented an efficient method to access gem-difluoro-2-trifluromethyl styrene derivatives via palladium catalysis, which features mild reaction conditions and broad substrate scope.