Oxidative Arylation Research Articles

Hypervalent iodine-mediated oxidative alkene arylation: a thorough analysis

A hypervalent iodine (HVI)-mediated, oxidative alkene arylation reaction has been developed. Both Koser’s reagent (PhI(OH)OTs) and (diacetoxyiodo)toluene (TolI(OAc)2) were equally viable as oxidants, which reacted with ortho-vinylbiphenyl derivatives to produce tri-, tetra-, and pentacyclic polycyclic aromatic hydrocarbons in yields up to 97%. Comparison of this stoichiometric reaction with a previously reported catalytic process showed that these protocols were largely complementary, and that they likely operate via the same general mechanistic sequence involving vinyliodonium salts decomposing into vinylene phenonium ions. Various mechanistic control experiments were conducted, which ruled out epoxides as intermediates, and which showed that E- and Z-alkene geometry in 10-substituted ortho-vinylbiphenyls had no impact on the ensuing isomeric product distributions. These experiments strongly supported the formation of E-vinyliodonium ions as initial reaction intermediates, and while the occurrence of 1,2-phenyl shift products was a common phenomenon, we concluded that alkyl substitution on the ortho-vinylbiphenyl was a requirement for this alternate pathway to occur.

Iodine-Promoted Controlled and Selective Oxidation of (Aryl)(Heteroaryl)Methanes.

The development of direct and controlled oxidation of C(sp3)-H bonds is of great importance. Herein, an iodine-catalyzed controlled oxidation of (aryl)(heteroaryl)methanes to (aryl)(heteroaryl)methanols is disclosed under metal-free reaction conditions. A catalytic system comprised of iodine/silyl chloride with HI as an additive in the presence of dimethyl sulfoxide selectively oxidizes the C(sp3)-H bonds without being overoxidized to corresponding ketones. Therapeutically important aryl heteroaryl methanol derivatives were obtained in good yields. The preliminary mechanistic investigation proves that the primary source of oxygen is DMSO.

Synthesis, crystal structure, spectral characterization, theoretical studies, and investigation of catalytic activity in selective oxidation of sulfides by oxo-peroxo tungsten(VI) Schiff base complex

A novel oxo–peroxo tungsten(VI) Schiff base complex, [WO(O2)L(CH3OH)], a homogeneous catalyst for sulfoxidation was synthesized by treating WO3 in the presence of H2O2 with a dibasic tridentate (ONO) Schiff base ligand. The complex was characterized by FT–IR, 1H NMR, and 13C NMR spectroscopy. Moreover, the structure of the crystalline tungsten(VI) complex was further investigated by single crystal X-ray diffraction analysis (SC-XRD). The crystal structure analysis revealed that the complex is hepta-coordinated, and metal ion is surrounded by ONO set of the coordinated doubly deprotonated ligand to adopt a distorted pentagonal–bipyramidal geometry. The theoratical calculations of the geometrical parameters, frontier molecular orbitals (FMOs), molecular electrostatic potential (MEP), and natural bond orbital (NBO) analysis of the synthesized compounds utilizing DFT at the B3LYP level of theory at the Def2-TZVP basis set revealed that the predicted data match the experimental results. The main purpose of the current study is to employ the synthesized W complex for its homogeneous catalytic effectiveness for the oxidation of aryl and alkyl sulfides in ethanol by using 30% aqueous H2O2.

Metal-free oxidative formal C(sp2)-H arylation of cyclopentene-1,3-diones with β-naphthols.

An efficient, mild, and transition-metal free formal C(sp2)-H arylation of prochiral 2,2-disubstituted cyclopentene-1,3-diones is reported. This oxidative arylation with β-naphthols proceeds via base-mediated C-Michael addition followed by aerial oxygen insertion and a subsequent α-hydroperoxy elimination sequence. This operationally simple and environmentally benign transformation is highly scalable and does not require any pre-functionalization. Moreover, this reaction affords excellent yields of α-substituted β-naphthols bearing all-carbon quaternary centers.

Copper-catalyzed multiple oxidation and cycloaddition of aryl-alkyl ketones (alcohols) for the synthesis of 4-acyl- and 4-diketo-1,2,3-triazoles.

A Cu/TEMPO-catalyzed tandem multiple oxidative dehydrogenation and cycloaddition has been developed, which affords 4-acyl-1,2,3-triazoles and 4-diketo-1,2,3-triazoles from readily-available aryl-alkyl ketones (or alcohols) and different organic azides. Moreover, the reaction used environmentally friendly dimethyl carbonate (DMC) as the solvent and air as the oxidant, and H2O was the only by-product, so it provides a green and practical synthetic method for 1,2,3-triazoles.

Cu-catalyzed oxidative denitrogenation of 3-aminoindazoles for the synthesis of isoquinolinones.

A Cu-catalyzed oxidative dual arylation of active alkenes via the cleavage of two C-N bonds of 3-aminoindazoles is presented for constructing isoquinolinones. Importantly, 3-aminoindazoles are used as efficient arylating agents through a radical process. This method has a good substrate scope and functional group compatibility.

Metal-Free Oxidative Radical Arylation of Styrene with Anilines to Access 2-Arylacetophenones and Selective Oxidation of Amine

Metal-Free Oxidative Radical Arylation of Styrene with Anilines to Access 2-Arylacetophenones and Selective Oxidation of Amine

Palladium-catalyzed oxidative Heck reaction of non-activated alkenes directed by fluorinated alcohol.

A novel, Pd-catalyzed oxidative Heck reaction of non-activated alkenes synergistically directed by bifunctional groups has been developed firstly by using O2 as a green oxidant, yielding the oxidative Heck products with excellent yields in a regio- and stereoselective manner. This bifunctional synergistic activation mechanism was demonstrated by experimental analysis and detailed computational studies, wherein the hydroxyl group directs the migratory insertion of the alkenes and the trifluoromethyl group facilitates the subsequent β-H elimination and reductive elimination. Moreover, a pesticidal active compound was synthesized using the bifunctional synergistically directed C-H arylation as the key step, which demonstrated its synthetic utility.

Synthesis of Conjugated Polymers via Transition Metal Catalysed C-H Bond Activation.

Transition metal catalysed C-H bond activation chemistry has emerged as an exciting and promising approach in organic synthesis. This allows us to synthesize a wider range of functional molecules and conjugated polymers in a more convenient and more atom economical way. The formation of C-C bonds in the construction of pi-conjugated systems, particularly for conjugated polymers, has benefited much from the advances in C-H bond activation chemistry. Compared to conventional transition-metal catalysed cross-coupling polymerization such as Suzuki and Stille cross-coupling, pre-functionalization of aromatic monomers, such as halogenation, borylation and stannylation, is no longer required for direct arylation polymerization (DArP), which involve C-H/C-X cross-coupling, and oxidative direct arylation polymerization (Ox-DArP), which involves C-H/C-H cross-coupling protocols driven by the activation of monomers' C(sp2 )-H bonds. Furthermore, poly(annulation) via C-H bond activation chemistry leads to the formation of unique pi-conjugated moieties as part of the polymeric backbone. This review thus summarises advances to date in the synthesis of conjugated polymers utilizing transition metal catalysed C-H bond activation chemistry. A variety of conjugated polymers via DArP including poly(thiophene), thieno[3,4-c]pyrrole-4,6-dione)-containing, fluorenyl-containing, benzothiadiazole-containing and diketopyrrolopyrrole-containing copolymers, were summarized. Conjugated polymers obtained through Ox-DArP were outlined and compared. Furthermore, poly(annulation) using transition metal catalysed C-H bond activation chemistry was also reviewed. In the last part of this review, difficulties and perspective to make use of transition metal catalysed C-H activation polymerization to prepare conjugated polymers were discussed and commented.

Intramolecular oxidative rearrangement: I2/TBHP/DMSO-mediated metal free facile access to quinoxalinone derivatives

Iodine/TBHP/DMSO mediated oxidative rearrangement of 3-styrylquinoxalin-2(1H)-one led to the formation of 3-aroylquinoxalin-2(1H)-ones in good to high yields via Kornblum oxidation. This methodology proceeds under mild conditions via oxidative aryl migration, followed by CC bond cleavage and does not make use of any metal.

Catalyst-Controlled Regioselectivity in Pd-Catalyzed Aerobic Oxidative Arylation of Indoles.

Pd-catalyzed C-H arylation of heteorarenes is an important and widely studied synthetic transformation; however, the regioselectivity is often substrate-controlled. Here, we report catalyst-controlled regioselectivity in the Pd-catalyzed oxidative coupling of N-(phenylsulfonyl)indoles and aryl boronic acids using O2 as the oxidant. Both C2- and C3-arylated indoles are obtained in good yield with >10:1 selectivity. A switch from C2 to C3 regioselectivity is achieved by including 4,5-diazafluoren-9-one or 2,2'-bipyrimidine as an ancillary ligand to a "ligand-free" Pd(OTs)2 catalyst system. Density functional theory calculations indicate that the switch in selectivity arises from a change in the mechanism, from a C2-selective oxidative-Heck pathway to a C3-selective C-H activation/reductive elimination pathway.

Selective construction of fused heterocycles by mild oxidative C-H functionalization using non-metallic catalysis

Summary Under non-metallic catalysis and conditions with no external energy input, there remain to date significant unmet challenges in precise C-H functionalization with controllable sites and numbers. Here, by establishing a hierarchical, porous, low N-doped graphitic carbon/hexafluoroisopropanol (HFIP) catalyst system, we report selective construction of structurally novel π-extended N,O-heterocycles from tetrahydroquinoxalines and 2-naphthols via oxidative aryl C-H bifunctionalization at room temperature. There is good substrate and functional group compatibility, as well as excellent step and atom efficiency, and the reaction uses an accessible catalyst and a naturally abundant oxidant. Mechanistic study reveals that the in situ-formed catalyst-O2 species stabilized by HFIP enables a decent substrate oxidation to match the coupling processes. The work highlights the potential practicality of a strategy merging suitable carbon material and HFIP in further development of oxidative transformations under sustainable catalysis.

Electrochemical gold redox catalysis for selective oxidative arylation

The combination of ArB(OH)2 transmetallation with cationic gold(I) [LAu]+ and electrochemical anodic oxidation (EAO) approach was successfully developed for the preparation of AuIII-Ar intermediate for the first time. This in-situ generated aryl gold intermediate gave rapid and controllable transmetallation with ArB(OH)2 or alkyne followed by reductive elimination to generate either di-aryl coupling or sp2-sp Sonogashira-type coupling products under mild conditions with no need of external oxidants, which significantly extended the versatility of electrochemical approach in promoting gold redox catalysis.

Cu-Catalyzed Oxidative Dual Arylation of Active Alkenes: Preparation of Cyanoarylated Oxindoles through Denitrogenation of 3-Aminoindazoles.

A novel and mild Cu-catalyzed oxidative dual arylation of carbon-carbon double bonds in acrylamides with 3-aminoindazoles is proposed for the synthesis of cyanoarylated oxindoles. Notably, 3-aminoindazoles are employed as efficient arylating agents via the cleavage of two C-N bonds. This oxidative dual arylation of active alkenes involves a radical process and undergoes a sequence of 3-aminoindazole oxidation, two-C-N-bond cleavage, cyanoaryl radical addition, and intramolecular cyclization.

Rational design and synthesis of 6-aryl-6H-benzo[c]chromenes as non-steroidal progesterone receptor antagonists for use against cancers

Progesterone receptor (PR) antagonists have been found to be effective for treating certain human cancers. However, the steroidal structure of PR antagonists could bind to other hormone receptors, thus leading to serious side effects. On the other hand, non-steroidal PR antagonists have rarely been evaluated for their anti-cancer efficacy. Therefore, identifying novel non-steroidal PR antagonists possessing potent anti-cancer efficacy would be an attractive project to pursue. In this study, we presented a new metal-free oxidative CH arylation method to rapidly synthesize a series of 6-aryl-6H-benzo[c]chromene derivatives. Multiple cancer cell lines were used for their anti-cancer activity screening. An extensive analysis of structure–activity relationships (SAR) of the derivatives revealed that compounds 32 and 34 markedly inhibited the proliferation of MCF-7 cells with IC50 values of 6.32 ± 0.52 μM and 5.71 ± 0.49 μM, respectively. Further investigation indicated that derivatives 32 and 34 could elevate the expression of p21 and decrease the expressions of CDK4 and cyclin D1, leading to cell cycle arrest at G0/G1 phase. In addition, derivatives 32 and 34 could induce apoptosis of MCF-7 cells in both dose- and time-dependent manners by activation of p53 pathway, i.e., activation of Cleaved Caspase-3, p53 and P-p53 as well as elevation of the Bax/Bcl-2 ratio. Docking of derivatives 32 and 34 into a PR homology model exhibited potent PR antagonistic activity indicating the 6-aryl-6H-benzo[c]chromene derivatives are promising PR antagonists. We envisioned that derivatives 32 and 34 might be potential anti-cancer drug candidates as novel therapeutic treatment for breast cancer.

Recent Advances in Asymmetric Functionalization of Olefins Induced by Chiral Hypervalent Iodine Reagents

The functionalization of olefins induced by chiral hypervalent iodine reagents is a basic method for obtaining enantiomerically enriched chiral molecules and biologically active natural products. It is one of the new and promising fields in asymmetric synthesis. Throughout the past 20 years development in this area, on the one hand, stereoselective functionalizations of alkenes such as disulfonyloxylation, diacetoxylation, dihalogenation, diamination, hydroxylation-sulfonyloxylation and halogenation-alkylation and carbonylation have been successfully achieved with chiral hypervalent iodine reagents through intermolecular reactions, in which various functionalized products were enantioselectively obtained. On the other hand, many of hetero-cyclic compounds such as γ-butyrolactones, chromans, isochromans, oxazolidinones, piperidines, pyrrolidines and aziridines can be synthesized by intramolecular oxidative lactonization, etherification, amidation, arylation and other reactions, in which hypervalent iodine reagents can provide efficient methods for the synthesis of chiral heterocyclic compounds. In addition, various functionalization reactions of olefins mediated by chiral hypervalent iodine reagents can afford target compounds with excellent yield and enantioselectivity. Thus, this methodology has also been used in the total synthesis of natural products. The functionalization of olefins induced by chiral hypervalent iodine reagents and their applications in the total synthesis of natural products are reviewed.

Copper Catalyzed Oxidative Arylation of Tertiary Carbon Centers.

We describe herein a Cu(OTf)2 catalyzed oxidative arylation of a tertiary carbon-containing substrate including aryl malononitriles, 3-aryl benzofuran-2-ones, and 3-aryl oxindoles. In some cases, the nitrile groups of the aryl malononitriles undergo further reactions leading to lactones or imines. These reaction conditions are applicable for a range of arenes, including phenols, anilines, anisoles, and heteroarenes. Mechanistic studies support the formation of a cationic intermediate via a two-electron oxidation.

Room Temperature Oxidative C−H Functionalization for Selective Construction of Fused Heterocycles by a Low N-Doped Graphitic Carbon/HFIP Catalyst System

Under metal-free catalysis and external energy input-free conditions, there remain to date significant unmet challenges in precise C−H functionalization with controllable sites and numbers. Here, by establishing a low N-doped hierarchical porous graphitic carbon/hexafluoroisopropanol (HFIP) catalyst system, we demonstrate, for the first time, a direct construction of structurally novel π-extended N,O-heterocycles from tetrahydroquinoxalines and 2-naphthols via selective oxidative aryl C−H bifunctionalization at room temperature, proceeding with the striking features of good substrate and functional group compatibility, excellent step and atom-efficiency, and the use of easily accessible and reusable catalyst and naturally abundant oxidant. Mechanistic study reveals that the in situ formed catalyst-O2 species stabilized by HFIP enables a decent oxidation of substrates to match the coupling processes. The work highlights the potential practicality of the strategy merging suitable carbon material and hexafluoroisopropanol in further development of oxidative C−H functionalization reactions under sustainable catalysis.

Palladium‐Catalyzed Oxidative Arylation of 1H‐Indazoles with Arenes

A simple method for the direct Pd(OAc)2‐catalyzed oxidative arylation of inactivated 1H‐indazole derivatives with simple arenes is reported. This method exhibits good reaction efficiency and good functional‐group tolerance. Using the developed method, 28 arylated products were prepared in yields up to 80 %.

Iodine- and TBHP-Promoted Acylation of Benzothiazoles under Metal-Free Conditions

A simple protocol for the synthesis of 2-acylbenzothiazoles using aryl ketones and benzothiazoles in the presence of I2 and TBHP is described. Acylation of the benzothiazoles is achieved through a sequence involving oxidation of the aryl ketone to an aryl glyoxal, ring-opening of the benzothiazole followed by condensation of the amino group with the aryl glyoxal, cyclization and oxidation. The method avoids the use of metals and toxic solvents. In addition, this protocol has the advantage of broad scope and provides good to excellent product yields.