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.     

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.     

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.     

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.     

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.     

Photoreaction of anthracenyl phosphine oxides: Usual reversible photo- and heat-induced emission switching,and unusual oxidative PC bond cleavage

Anthracenyl(diphenyl)phosphine oxide and dianthracenylphenylphosphine oxide as photoactive compounds have been synthesized. Anthracenyl group of these compounds indicate the multi-functional roles such as an emission component, a photodimerization component, and a leaving group. When the light irradiation was performed under an oxygen atmosphere, photo-oxidative PC bond cleavage to leave the antharacenyl group was observed. Moreover, phosphonyl radical was produced and then PP bond formation to form diphosphane was observed.     

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.     

Potentiometric and antimicrobial studies on the asymmetric Schiff bases and their binuclear Ni(II) and Fe(III) complexes; synthesis and characterization of the complexes

The protonation constants of two nitro-Schiff bases SB¹, SB² and three asymmetric tetradentate diimines H₂L¹, H₂L² and H₂L³ and the stability constants of their ML type binuclear Ni(II) and Fe(III) complexes have been determined potentiometrically. The asymmetric diimines are (2OH) RCHNC₆H₄CHNR′ (2OH) type compounds [where R = R′ = phenyl for H₂L¹; R = naphthyl, R′ = phenyl for H₂L² and R = R′ = naphthyl for H₂L³]. The effect of tautomeric forms on the acid-base properties of the diimines has been investigated and discussed. In addition, dimeric and binuclear Ni(II) and Fe(III) complexes of the diimines have been synthesized and characterized by physical and spectroscopic techniques. Also, in vitro antimicrobial activities of the diimines and the complexes have been evaluated against three bacteria: Micrococcus luteus (NRLL B-4375), Bacillus cereus (RSKK 863), Escherichia coli (ATCC 11230) and the fungus: Candida albicans (ATCC 10239).     

Stereoselective synthesis of novel functionalized cyclohexanone derivatives via the condensation of aromatic aldehydes with acetoacetamide and the influence of the ortho-effect and autocondensation

A simple, inexpensive and stereoselective synthesis of novel functionalized cyclohexanone derivatives via the reaction of acetoacetamide with aromatic aldehydes in ethanol at room temperature is described. Additionally, the presence of substituents such as NO₂ and Cl in the ortho-position of the aldehyde aromatic ring resulted in the formation of novel piperidines. The use of Lewis acids such as iron(III) chloride and bismuth(III) nitrate as catalysts led to autocondensation of acetoacetamide and the formation of 2,4-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide.     

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.     

Highly stereoselective and catalytic desulfitative CO and CI dienylation with sulfolenes: The importance of basic additives

Conjugated dienes and polyenes are central structural motifs of natural products, and key synthetic intermediates in organic synthesis and materials science. We describe herein a palladium-catalyzed dienylation of aryl, heteroaryl, and vinyl triflates, nonaflates and iodides that were previously identified as recalcitrant substrates for the sulfolene-mediated catalytic dienylation. The method has now been successfully expanded to CO and CI dienylation, demonstrating broad scope with respect to sulfonates, iodides and sulfolenes. The reactions proceed with high regio- and stereoselectivity, and efficiency that are strongly influenced by basic additives, whose influence on the reaction performance was systematically studied.     

DDQ-promoted C(sp3)H phosphorylation of cycloheptatriene

An efficient and convenient C(sp³)H phosphorylation has been achieved via the DDQ-promoted cross-dehydrogenative coupling between cycloheptatriene and P(O)H compounds at room temperature. This transformation provides a direct synthetic route to the construction of C(sp³)P bonds with good functional group compatibility, leading to the formation of cyclohepta-2,4,6-trien-1-ylphosphonates in up to 99% yield.     

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.     

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.     

Internal path investigation of the acting electrons during the photocatalysis of panchromatic ruthenium dyes in dye-sensitized solar cells

A series of heteroleptic Ru(II) complexes were theoretically investigated using time-dependent density functional theory. These dyes, including K8 and N3, are based on a common motif formed by Ru center, NCS, and polypyridyl ligands, but differ only by the nature of the added group in para position of each pyridyl. The presence of these ligands will enable the evaluation of the electronic effects ±I and ±M. This work focuses on the localization of the part, among the metal, the NCS, the polypyridyl ligands, and the added group R, which is most actively involved in the photocatalysis process. We dealt with both ground and excited states as well as the electronic transitions between them. To illustrate the effect of each functional group R on its photophysical properties, the geometries of five dyes were optimized in the molecular and univalent cationic states. All molecules are asymmetrical in shape with a distorted octahedral coordination of the RuN6 core. Atomic charge and spin density distributions show that a charge transfer process occurs from the NCS/Ru to polypyridyl ligand. Analysis of the electronic absorption spectra reveals that the band with the highest wavelength value is assigned to metal-to-ligand charge transfer transition. On the contrary, two other bands are assigned to multitransitions Ru/NCS to polypyridyl–π*. These attributions have been confirmed by the localization of all atoms intervening in them. We also introduced an adapted way to estimate the ionization probability values in each atomic center in the ground and first excited states. Phenomenal properties such as mobility, redox potential, electronic spectrum, ionization potential, and optical gap of the most efficient dye, which is the N3, fit well with experimental values.     

Hydroxyl radical formation upon dark oxidation of reduced iron minerals: Effects of iron species and environmental factors

Dark formation of hydroxyl radical upon oxidation of reduced iron minerals plays an important role in the degradation and transformation of organic and inorganic pollutants. Herein, we compared the hydroxyl radical formation from various reduced iron minerals at different redox conditions. OH production was generally observed from the oxidation of reduced iron minerals, following the order: mackinawite (FeS) > reduced nontronite (iron-bearing smectite clay) > pyrite (FeS₂) > siderite (FeCO₃). Structural Fe²⁺ and dissolved O₂ play critical roles in OH production from reduced iron minerals. OH production increases with decreasing pH, and Cl^? has little effect on this process. More importantly, dissolved organic matter significantly enhances OH production, especially under O₂ purging, highlighting the importance of this process in ambient environments. This sunlight-independent pathway in which OH forms during oxidation of reduced iron minerals is helpful for understanding the degradation and transformation of various inorganic and organic pollutants in the redox-fluctuation environments.     

Geometry,stability and aromaticity of β-diketiminate-coordinated alkaline-earth compounds

Alkaline-earth (Ae) metals have attracted a wealth of interdependent research from synthetic chemists. In Ae-catalyzed organometallic reactions, β-diketiminate is a typical ligand used to stabilize Ae catalysts by forming six-membered rings comprising Ae metals. Herein, studies focusing on the configuration of β-diketiminate-coordinated Ae compounds observed that the CC and CN bonds are homogeneous and unchanged. Furthermore, energetic studies observed that the formation of the Ae-incorporated six-membered rings results in enhanced stability of >20 kcal/mol. The nucleus-independent chemical shifts, anisotropy of the induced current density, and molecular orbital analyses demonstrated the non-aromaticity of the β-diketiminate-coordinated Ae compounds. The improved stability of these compounds can be explained by the delocalization of the π electrons derived from the β-diketiminate moiety.     

Mn(III)-mediated radical cascade reaction of boronic acids with isocyanides: Synthesis of diimide derivatives

A manganese(Ⅲ)-promoted oxidative radical cascade reaction of easily accessible arylboronic acids with isocyanides to construct diimide derivatives was studied. This protocol provides a new way to synthesis of acetyl diimide derivatives. New C-C, C-N and C=O bonds were formed in one step.