One-pot synthesis of 2-amino-3,4-dicyanopyridines from ketoximes and tetracyanoethylene via Cu(I)-catalyzed cyclization

A novel approach to 2-amino-3,4-dicyanopyridines has been discovered from Cu(I)-catalyzed cyclizations of simple and easily available ketoximes and tetracyanoethylene (TCNE). The complexed radical mechanism involves cleavage of several OH/NO/CH bonds, and new CC/CN bonds formation. A wide variety of substrates with different functional groups could be smoothly converted into the corresponding products in moderate yields.     

Reprint of: Acid-mediated four-component tandem cyclization: Access to multifused 1,3-benzoxazine frameworks

An acid-mediated multicomponent reaction has been developed for the direct synthesis of multifused 1,3-benzoxazine derivatives from simple and readily available arylglyoxal monohydrates and 2-aminobenzyl alcohols under mild conditions. This novel protocol is proposed to proceed through intramolecular poly-heterocyclizations, thus leading to the formation of three new rings and six new chemical bonds, including four CN and two CO bonds.     

Advances in amide and thioamide assisted C(sp3)H functionalization

CH activation is gaining substantial attention from synthetic and process chemists in recent years. Regio- and stereo-selective CH functionalization particularly facilitated by carboxylic acids and derivatives as directing groups has been progressing to an extent that this transformation could be conceived as one of the steps to assemble molecules in modern retrosynthetic analysis. This digest paper covers the most recent developments in C(sp³)H functionalization using carboxylic acid derivatives such as amides or thioamides as a directing group and highlights new reaction discoveries and applications. The content of this review is organized based on the types of directing groups and the mechanism by which the C(sp³)H bond is believed to be activated.     

Non-directed highly para-selective CH functionalization of TIPS-protected phenols promoted by a carboxylic acid ligand

Palladium-catalyzed non-directed CH functionalization provides an efficient approach for direct functionalization of arenes, but it usually suffers from poor site selectivity, limiting its wide application. Herein, it is reported for the first time that the carboxylic acid ligand of 3,5-dimethyladamantane-1-carboxylic acid (1-DMAdCO₂H) can affect the site selectivity during the CH activation step in palladium-catalyzed non-directed CH functionalization, leading to highly para-selective CH olefination of TIPS-protected phenols. This transformation displayed good generality in realizing various other para-selective CH functionalization reactions such as halogenation, and allylation reactions. A wide variety of phenol derivatives including bioactive molecules of triclosan, thymol, and propofol, were compatible substrates, leading to the corresponding para-selective products in moderate to good yields. A preliminary mechanism study revealed that the spatial repulsion factor between carboxylic acid ligand and bulky protecting group resulted in the selective CH activation at the less sterically hindered para-position. This new model non-directed para-selective CH functionalization can provide a straightforward route for remote site-selective CH activations.     

Effect of oxygen-containing functional groups on the wettability of coal through DFT and MD simulation

To investigate the wettability of different oxygen-containing functional group (OFG) surfaces, graphite substrates were used as a model for coal adsorbents. The substrates were modified with COOH, OH, CO, and OCH₃. The adsorption-diffusion behavior of H₂O molecules/water droplets on different OFG surfaces was investigated using molecular dynamics (MD) simulations with frontier orbital energy difference as a metric for different surface wettability degrees in quantum chemical analysis. The results indicated that the frontier orbital energy difference of the H₂O molecule was 3.480, 3.491, 3.631, and 3.680 eV for PhCOOH, PhOH, PhCO, and PhOCH₃, respectively. In addition, the equilibrium contact angle, interaction energy, and number of hydrogen bonds after the adsorption equilibrium of water droplets for COOH, OH, CO, and OCH₃ surfaces were 22.34°, ?5.03 kcal/mol, and 652; –23.72°, ?4.19 kcal/mol, and 450; 68.01°, ?0.79 kcal/ mol, and 61; 90.51°, ?0.50 kcal/mol, and 28, respectively. The smaller the energy difference between the frontier orbitals of the H₂O molecule and the OFG, the smaller the equilibrium contact angle between the water droplet and the OFG surface, the more hydrogen bonds were formed, and the larger the absolute value of the interaction energy, the better the wettability of the surface of the OFG. The order of wettability of the different OFG surfaces was COOH > OH > CO > OCH₃, which is consistent with the radial distribution function and the analysis results for the extended area, etc. The results of density functional theory (DFT) calculations and MD simulations exhibited identical patterns, indicating the reasonableness of the simulations. This study may serve as a reference for the suppression of hydrophilicity in low-order coal and the enhancement of the flotation effect.     

Reaction pathway change on plasmonic Au nanoparticles studied by surface-enhanced Raman spectroscopy

Gold nanoparticles (Au NPs) are nanoscale sources of light and electrons, which are highly relevant for their extensive applications in the field of photocatalysis. Although a number of research works have been carried out on chemical reactions accelerated by the energetic hot electrons/holes, the possibility of reaction pathway change on the plasmonic Au surfaces has not been reported so far. In this proof-of-concept study, we find that Au NPs change the reaction pathway in photooxidation of alkyne under visible light irradiation. This reaction produces benzil (COCO) without the presence of Au NPs. In contrast, as indicated by surface-enhanced Raman spectroscopic (SERS) results, the CC triple bonds (CC) adsorbed on Au NPs are converted into carboxyl (COOH) and acyl chloride (COCl) groups. The plasmonic Au NPs not only provide energetic charge carriers but also activate the reactant molecules as conventional heterogeneous catalysts. This study discloses the second role of plasmonic NPs in photocatalysis and bridges the gap between plasmon-driven and conventional heterogeneous catalysis.     

Cobalt-catalyzed electrochemical CH/NH functionalization of N-(quinolin-8-yl)benzamide with isocyanides

An efficient synthesis of functionalized iminoisoindolinone derivatives has been achieved via a mild electrochemical oxidative CH/NH functionalization/intramolecular annulations with isocyanides in undivided cell equipped with a nickel cathode. In the presence of earth abundant cobalt catalyst, versatile iminoisoindolinone derivatives obtained in good yields and in a sustainable manner by using electricity as an oxidant in place of stoichiometric amount of silver and copper salts.     

Synthesis and properties of π-extended fluoranthene derivatives from 1,2-diarylacenaphthylene derivatives

Acenaphthylene units work as a useful platform for the synthesis of polycyclic aromatic hydrocarbons (PAH). Three 1,2-diarylacenaphthylene derivatives (9-phenanthryl, 7-t-butyl-2-pyrenyl and 2-naphthyl) were prepared by Suzuki-Miyaura coupling of 1,2-dibromoacenaphthylene with the corresponding boronic acids and ester. The Scholl reaction of the phenanthryl derivative affords a donor-acceptor type fluoranthene derivative possessing a hemi-coronene structure by forming two CC bonds between phenanthryl groups. The reaction of the pyrenyl derivative allows one CC bond formation to give a helicene-type fluoranthene derivative. The reaction of the naphthyl derivative provides an asymmetric fluroranthene derivative having an anthracene unit accompanied with one CC bonding reaction, while a photochemical cyclization followed by dehydroaromatization reaction of the compound gives a symmetric fluoranthene derivative with a [5]helicene structure.     

A Garratt-Braverman route to isoindolines and phthalans

Garratt-Braverman (GB) cyclization, two CC bond forming reaction in a single step, has been utilized to construct several isoindoline and phthalan derivatives. The precursors were the bispropargyl protected amines and ethers with one of the propargyl arm substituted with an alkene moiety. The GB cyclizations were generally carried out in presence of DBU in refluxing toluene. In case of the bispropargyl amine systems with the alkene arm substituted with electron withdrawing ester group, the cyclization occurred at room temperature. The yields of cyclization ranged from 64 to 86% which are acceptable considering the formation of two CC bonds. The protected isoindolines could be successfully deprotected by treatment with thiophenol in presence of triethyl amine and the corresponding free amines were isolated as the TFA salts.     

Synthesis of 2,3,5,6-tetrasubstituted pyridines via selective three-component reactions of aldehyde and two different enaminones

The three-component synthesis of structurally unsymmetrical pyridines with polysubstituted structure has been realized via the catalytic system consisting of CuI and KHSO₄. The employment of two different enaminones is the main factor allowing the successful [3+2+1] construction of the pyridine ring based on the formation of two CC and one CN bonds.     

Ru(II)-catalyzed regioselective C-7 hydroxymethylation of indolines with formaldehyde

A regioselective addition of C7H bonds of indolines to formaldehyde is reported to synthesize a variety of C-7 hydroxymethylated indolines via a Ru(II)-catalyzed CH activation. More importantly, a one-pot CH formylation procedure is also developed to synthesize valuable C7-formyl indoles.     

Palladium-catalyzed direct ortho CX bond construction via CH activation of azobenzenes: Synthesis of (E)-1,2-b(2,6-dibromo(chloro)-phenyl)diazene

A palladium-catalyzed direct CX bond formation of azobenzenes with 1,3-dibromo-5,5-dimethylhydantoin or trichloro isocyanuric acid via CH activation has been developed. The reaction could proceed smoothly under an air atmosphere at 110 °C in the presence of Pd(Ph₃P)₄ in DCE and 13 examples of products were obtained.     

A synthesis of cephalostatin 1

A synthesis of cephalostatin 1 from hecogenin is described in detail. The gram-scale synthesis of south part features a Baeyer–Villiger oxidation of hecogenin to 16,20-diol, a selective oxidation of C16OH with Dess–Martin periodinane, a Rh(I)-catalyzed C15C16 double bond shift to C14C15 position, and a Hg(OAc)₂-mediated spiroketal formation from cyclic enol ethers with alkenyl side chain at 2-position. Key transformations in the synthesis of north part, also on gram scale, include an abnormal Baeyer–Villiger oxidation of hecogenin to the corresponding dinorcholanic lactone, where a catalytic amount of iodine acts as a traceless and catalytic switch, an umpolung of steroidal 22-aldehyde to forge C22C23 bond with good stereochemical control, a cascade spiroketal-forming process to establish DEF rings in one operation, and a selective oxidation of C3OH. There are also other noteworthy transformations that, although not used in our final route, are valuable and could be applied to other syntheses, including: intra- or intermolecular S_N2′ processes of C14-heteroatom-substituted C15C16 alkenes, an unprecedented rearrangement of β-adduct of D-ring dienes and singlet oxygen, a chelation-controlled methylallylation of C23 aldehyde, and so on.     

Rhodium-catalyzed CH activation/cyclization of enaminones with sulfoxonium ylides toward polysubstituted naphthalenes

A rhodium-catalyzed ortho-CH functionalization and annulation between enaminones and sulfoxonium ylides was developed, affording a series of multi-substituted naphthalenes in good to moderate yields with excellent functional group compatibility. The procedure featured with enaminone acting as both a directing and cyclization bifunctional group, and the application of sulfoxonium ylide in CH functionalization.     

Photogenerated electrophilic radicals for the umpolung of enolate chemistry

The use of enolate chemistry is the election choice when a CC bond formation is required exploiting the acidity of carbonyl derivatives in the α position. However, a reversed-polarity equivalent of enolate chemistry is emerging making use of electrophilic radicals having a radical site in place of a negative charge in the same α position. Visible light photoredox catalysis is becoming the ideal tool for the generation of these radicals thus allowing their wide application in several synthetic routes. Aim of this review is to collect recent examples of the chemistry of photogenerated electrophilic radicals for the forging of new CC or other CY bonds.     

Silica supported potassium oxide catalyst for dehydration of 2-picolinamide to form 2-cyanopyridine

The dehydration of 2-picolinamide to produce 2-cyanopyridine was investigated thoroughly using silica supported potassium oxide as a heterogeneous catalyst. Both large specific surface area and pore size of SiO_2 (B) contributed to the favorable catalytic performance for the synthesis of 2-CP. In addition, the yield of 2-CP showed the linear relationship with the amounts of medium basicity of the catalysts,demonstrating that medium basic sites were the active sites of silica supported potassium oxide catalysts. The catalysts were further characterized by XRD and FT-IR to clarify the active species. The results indicated the Si—O—K group produced by the reaction of K_2CO_3 with Si—OH was the active species, which was further evidenced by the adjustment of the amount of Si—OH by silylation and hydroxylation procedure.     

I2/TBHP mediated multiple CH bonds functionalization of azaarenes with methylarenes to synthesize iodoisoquinolinones via iodination/N-benzylation/amidation sequence

An oxidative multi-functionalization of azaarenes with benzylic CH bonds of methylarenes via iodination/N-benzylation/amidation cascade, to produce N-benzyl-4-iodoisoquinolin-1(2H)-ones and N-benzyl-3-iodoquinolin-2(1H)-ones is developed. The molecular iodine plays a triple role in activating benzylic sp³ CH bond of methylbenzenes, accelerating the oxidation process and serving as iodination reagent. This reaction utilizes cheap and readily available azaarenes and methylarenes as starting materials and proceeds under metal-free conditions to construct C-I, CN and CO bonds consecutively and afford iodo(iso)quinolinones efficiently.     

Recent advances in the diversification of chromones and flavones by direct CH bond activation or functionalization

Chromone and flavone are both central backbones of natural products and clinical medicines. Synthesis of diversely functionalized chromones and flavones constitutes significant research contents of the modern synthetic science because abundant molecular libraries of such types are crucial in providing candidate compounds for the discovery of new pharmaceuticals and functional materials. The direct CH bond activation or functionalization on these heterocyclic backbones provides highly powerful tools for the rapid accesses to densely functionalized chromone and flavone derivatives. Considering the importance of the functionalized chromone and flavone compounds as well as the notable advances in the synthesis of such products by direct CH activation or functionalization, we review herein the research advances in the CH bond activation and functionalization reactions of chromone and flavones, in hope of showing the current states and promise of the research domain.     

Total synthesis of penta-Me amurensin H and diptoindonesin G featuring a Rh-catalyzed carboacylation/aromatization cascade enabled by CC activation

Oligostilbenoids represented a family of natural products, which contained one or several multifused benzofuran substructures and displayed promising biological activities towards cancer as well as immunological therapeutic targets. A convergent-divergent strategy featuring Rh-catalyzed carboacylation/aromatization cascade reaction based on CC activation of benzocyclbutenones had been conceived. penta-Methyl amurensin H and diptoindolnesin G were successfully synthesized without any protecting groups, constituting a new entry towards oligostilbenoids’ natural product synthesis. The synthesis completed within 10 steps for both natural products, suggesting conciseness and efficacy of the CC activation in complex natural product synthesis.