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.     

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.     

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.     

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.     

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.     

Synthesis of triphenylene derivatives by Pd-catalyzed Suzuki coupling/intramolecular CH activation between arylboronic acids and dibromobiphenyls

An efficient and regioselective synthesis of functionalized triphenylenes via palladium-catalyzed Suzuki-Miyaura coupling and subsequent intramolecular CH activation between arylboronic acids and dibromobiphenyls was developed. This methodology showed excellent atomic economy and regiospecificity as well as synthetic feasibility of unsymmetrical triphenylenes.     

Synthesis of 2-substituted indoles by iridium (III)-catalyzed CH functionalization of N-phenylpyridin-2-amines

A highly regioselective synthesis of 2-substituted indoles was realized through Ir(III)-catalyzed CH functionalization of N-phenylpyridin-2-amines followed by the reaction with sulfoxonium ylides and intramolecular cyclization under mild conditions. The reaction completed with broad range of substrate scopes and gave various 2-substituted indoles in up to 98% yields.     

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.     

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.     

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.     

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.     

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.     

An ab initio study of the valence tautomerism of type B mesoionic rings

The MP2 calculated Gibbs free energies of a series of type B mesoionic rings and their acyclic valence tautomers suggest that in the gas phase the relative stability of the mesoionic ring increases with single bond strength (SS > RNNR > OO). Inclusion of aqueous solvation in the calculations further favours the stability of the mesoionic ring by ～10–15 kcal mol^?1. Replacement of CR groups at ring positions by nitrogen atoms results in a significant increase in the relative stability of the mesoionic ring. Calculations of aromatic stabilization energy (ASE), together with the Bird aromaticity index (I₅), suggest that aromaticity decreases with aza substitution and the increase in relative stability is attributable to charge stabilisation by the electronegative nitrogen atoms, which more than compensates for any loss of aromaticity.     

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).     

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.     

Facile one-pot synthesis of novel highly functionalized dihydro-1H-pyrrole derivatives catalyzed by molecular iodine

An efficient, environmentally benign and molecular iodine promoted protocol was described for cascade synthesis of two kinds of novel dihydro-1H-pyrrole derivatives, 5 and 7. Compounds 5 were prepared via four-component reaction between diethyl acetylenedicarboxylate (DEAD), aromatic amines and phenylglyoxal monohydrate catalyzed by 10 mol% of iodine in ethanol at room temperature. In addition, using same reaction conditions, a three-component reaction between (E)-N-methyl-1-(methylthio)-2-nitroethenamine (NMSM), aromatic amines and arylglyoxal monohydrate was performed to access product 7. These transformations apparently proceed through an imine intermediate followed by iodine induced Mannich reaction and subsequent intra-molecular cyclization sequences. The protocol involves the formation of CN, CC and OH bonds leading to the preparation of a hexa substituted five membered ring with two stereo centres. The syntheses avoid the use of traditional column chromatography and recrystallization purification methods and, hence, follow the group-assisted purification (GAP) chemistry process.     

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.