Arylation Of Indoles Research Articles

Rhodium-Catalyzed C-H Arylation of Indoles with Arylsilanes at Room Temperature.

The Cp*Rh-catalyzed C-H arylation of indoles with arylsilanes is developed. This C-H activation transformation allows for the Rh-catalyzed indole C2 arylation to overcome the limitations of requiring strong directing group assistance and high-temperature conditions, achieving a room-temperature transformation driven by a weak directing group. Cp*Rh/MeOH catalytic media are considered a key factor enabling this transformation to occur under mild conditions, and experimental studies and theoretical calculations were performed to rationalize the reaction mechanisms and the influence of methanol as a solvent in promoting the reaction.

Photoredox-catalyzed self-dimerization and cross-addition as well as Zn(OTf)2-mediated nucleophile coupling: A novel route to structurally diverse 2,2-disubstituted indolin-3-ones

An efficient protocol for the synthesis of 2,2-disubstituted indolin-3-ones from both 2-aryl and 2-alkyl indoles via photoredox-catalyzed self-dimerization and cross-addition as well as Zn(OTf)2-mediated nucleophile coupling is described. The photoredox reactions feature low catalyst loading, mild reaction conditions, and broad functional group tolerance, generating indolin-3-ones in moderate to excellent yields. The Zn(OTf)2-mediated transformation using indolin-3-one dimer as a newly active species provides a much gentle way to access structurally diverse indolin-3-ones.

Structural Reassignment of Covalent Organic Framework-Supported Palladium Species: Heterogenized Palladacycles as Efficient Catalysts for Sustainable C-H Activation.

Recent decades have witnessed remarkable progress in ligand-promoted C-H activation with palladium catalysts. While a number of transformations have been achieved with a fairly broad substrate scope, the general requirements for high palladium loadings and enormous challenges in catalyst recycling severely limit the practical applications of C-H activation methodologies in organic synthesis. Herein, we incorporate N,C-ligand-chelated palladacycles into rigid, porous, and crystalline covalent organic frameworks for the C-H arylation of indole and pyrrole derivatives. These heterogeneous palladium catalysts exhibit superior stability and recyclability compared to their homogeneous counterparts. We not only produce several highly reactive palladacycles embedded on new framework supports to facilitate C-H activation/C-C bond-forming reactions but also reassign heterogenized palladium species on frameworks containing a benzaldehyde-derived imine moiety as imine-based palladacycles via comprehensive characterization. Our findings provide guidance for the rational design of framework-supported metallacycles in the development of heterogeneous transition-metal catalysis.

CTAB-assisted synthesis of reduced graphene oxide supported Pd nanoparticles (Pd@rGO) as a sustainable heterogeneous catalyst for C-2 arylation of indoles with arylboronic acids

A series of Pd nanoparticles (NPs) incorporated in reduced graphene oxide (rGO), viz. Pd@rGO0.16, Pd@rGO0.32, Pd@rGO0.48, and Pd@rGO1 were synthesized employing water as a solvent. The subscript values correspond to the millimoles of cetyltrimethylammonium bromide (CTAB) utilized in the synthesis process. The quantity of CTAB was varied to finely tune both the morphology and size of the resulting nanoclusters. Transmission Electron Microscopy (TEM) analysis indicated that the average particle sizes of Pd@rGO0.16 and Pd@rGO0.32 fall in the range of 4.5–5.0 nm and 20–25 nm, respectively. On the other hand, particles were found to be agglomerated in Pd@rGO0.48 and Pd@rGO1. The Pd@rGO0.16 composite was exhaustively characterized by TEM, Scanning Electron Microcopy-Energy Dispersive X-ray analysis (SEM-EDX), powder X-ray diffraction(XRD), X-ray photoelectron spectroscopy (XPS), and inductively coupled plasma atomic emission spectroscopy (ICP-AES) measurements. ICP-AES analysis of Pd@rGO0.16 indicated that 0.01 g of Pd@rGO0.16 contains 0.09 mol% Pd. The catalytic potentiality of these NPs was investigated for direct C(sp[1])-H bond activation of various indoles with aryl boronic acids. Among the four composites, Pd@rGO0.16 exhibited the best activity for the abovementioned organic transformation. Different indoles with diverse electronic groups underwent coupling with aryl boronic acids giving up to 86 % product yield. It was retrievable for up to five consecutive catalytic cycles without compromising its catalytic activity.

Electrosynthesis of Spiro-indolenines via Dearomative Arylation of Indoles in Batch and Continuous Flow.

An electrosynthesis of spiro-indolenines in batch and continuous flow was achieved through dearomative arylation of indoles with good functional group compatibility. User-friendly undivided cells were used under catalyst- and oxidant-free conditions. Moreover, the use of a flow electrolysis cell gave high daily productivity and excellent scale-up potential under less supporting electrolyte and higher substrate concentration conditions.

Pd(0)-embedded-lignocellulosic nanomaterials: A bio-tailored reusable catalyst for selective C2–H arylation of free N–H indoles

Lignocellulose-a carbon-neutral renewable source has been utilized as a convenient support material for Pd nanoparticles, without disturbing its natural bio-structure. Herein, we demonstrated a green and rapid assessment of lignocellulosic nanomaterials derived from waste fibrous-feedstock of pomegranate peels using a simple extraction process in aqueous medium. The formation of lignocellulose bio-support has been authenticated by standard spectroscopic analyses. The newly developed features of Pd bio-nanomaterials were exhibited towards directing-group-free catalytic C2–H arylation of indoles with arylboronic acids. Access to vital C2-arylated indoles (62–91%) were achieved with high regioselectivity, reusability for at least five reaction cycles and admirable functionality tolerance of free N–H indole moieties. Further applicability of the catalyst was noted for selective double-functionalization of indole frameworks in a one-pot system.

On the Barton Copper-Catalyzed C3-Arylation of Indoles using Triarylbismuth bis(trifluoroacetate) Reagents.

We disclose herein our detailed investigation into the Barton copper-promoted C3-arylation of indoles using triarylbismuth bis(trifluoroacetates). The arylation of unsubstituted 1H-indole using Barton's conditions gave a low yield of the C3-arylated indole, along with small amounts of the product of double C2/C3-arylation and traces of the product of C2 arylation. On the contrary, the arylation of indoles blocked at the C2 position is highly efficient, affording the desired products of C3-arylation in good to excellent yields. The reaction operates under simple conditions, shows good substrate scope, excellent functional group compatibility, and allows the transfer of electron-neutral or deficient aryl groups. Computational studies propose a mechanism involving a trifluoroacetate-assisted C-H activation step.

Imine induced metal-free C–H arylation of indoles

A simple, mild, and metal- and extra-auxiliary group-free method for the direct arylation of indole-3-carbaldehydes induced by an in situ generated transient directing group was developed.

Arylation of indole at C2 catalyzed by palygorskite grafted covalent organic frameworks supported palladium catalyst

A heterogeneous palladium catalyst, palygorskite grafted covalent organic frameworks supported palladium (Pd-Pal/COF), was successfully prepared by a simple method. A series of C2 aromatic indole derivatives were synthesized under mild reaction conditions. Pd-Pal/COF catalyst can be reused at least 5 times with inappreciable metal leaching. Undoubtedly, facile synthesis, mild reaction conditions, a wide scope of reactants, and recyclability make the catalyst systems potentially useful in organic synthesis. For the synthesized heterogeneous catalysts, palygorskite as a matrix, the unique structure and good dispersion of palygorskite result in the excellent catalytic activity and good cycle stability of the Pd-Pal/COF catalyst, comparing with the traditional clay catalyst. The result further expands the application scope of clay in the catalytic field.

Synthesis of N-Vinyl Cinnamaldehyde Nitrones through Atropisomeric Quinoxaline-Derived N,N,O-Ligand-Promoted Chan-Lam Reaction.

A type of quinoxaline-derived tridentate N,N,O-ligand was synthesized in good to excellent yields over three steps through iodination of 2-aryl indoles, sequential Kornblum-type oxidation with DMSO, and capture by 1,2-diaminobenzenes. The prepared atropisomeric N,N,O-ligand was successfully applied in the synthesis of N-vinyl cinnamaldehyde nitrones as only Z-isomers in good yields through the Chan-Lam reaction. The method features an easily accessed tunable tridentate N,N,O-ligand, broad substrate scope, good functional group tolerance, and high Z-isomer for N-vinyl nitrones.

Atroposelective Direct C–H Arylation of Indoles

Atroposelective Direct C–H Arylation of Indoles

Diarylation of N- and O-nucleophiles through a metal-free cascade reaction

Diarylation of N- and O-nucleophiles through a metal-free cascade reaction

Copper‐Catalyzed N‐Arylation of Indoles and Anilines with Aryltrialkoxysilanes

AbstractHerein, we report an efficient copper‐catalyzed aerobic Chan‐Lam type N‐arylation of various indoles and anilines with structurally diverse aryltrialkoxysilanes under mild conditions. This silicon‐based protocol enables the efficient C−N cross‐coupling of indoles and anilines with user‐friendly organosilicon reagents by employing inexpensive and nontoxic Cu(OAc)2, which is efficient and practical without the addition of other ligands, bases, and metal oxidants. This transformation is compatible with a wide range of substrates, and typically proceeds with high efficiency as well as with good functional group compatibility. A plausible mechanism involving the formation of Cu(III) species in the reaction was tentatively proposed.

Site‐Selective N‐1 and C‐3 Heteroarylation of Indole with Heteroarylnitriles by Organocatalysis under Visible Light

Site-selective N-1 and C-3 arylation of indole has been sought after because of the prevalent application of arylindoles and the intricate reactivities associated with the multiple sites of the N-unsubstituted indole. Represented herein is the first regioselective heteroarylation of indole via a radical-radical cross-coupling by visible-light irradiation. Steady and time-resolved spectroscopic and computational studies revealed that the hydrogen-bonding interaction of organic base and its conjugated acid, namely with indole and heteroarylnitrile, determined the reaction pathway, which underwent either proton-coupled electron-transfer or energy-transfer for the subsequent radical-radical cross-coupling, leading to the regioselective formation of C-3 and N-1 heteroarylation of indoles, respectively. The parallel methodologies for regioisomeric N-1 and C-3 heteroaryl indoles with good functional group compatibility could be applied to large-scale synthesis and late-stage derivatization of bioactive compounds under extremely mild reaction conditions.

Site‐Selective N‐1 and C‐3 Heteroarylation of Indole with Heteroarylnitriles by Organocatalysis under Visible Light

AbstractSite‐selective N‐1 and C‐3 arylation of indole has been sought after because of the prevalent application of arylindoles and the intricate reactivities associated with the multiple sites of the N‐unsubstituted indole. Represented herein is the first regioselective heteroarylation of indole via a radical–radical cross‐coupling by visible‐light irradiation. Steady and time‐resolved spectroscopic and computational studies revealed that the hydrogen‐bonding interaction of organic base and its conjugated acid, namely with indole and heteroarylnitrile, determined the reaction pathway, which underwent either proton‐coupled electron‐transfer or energy‐transfer for the subsequent radical–radical cross‐coupling, leading to the regioselective formation of C‐3 and N‐1 heteroarylation of indoles, respectively. The parallel methodologies for regioisomeric N‐1 and C‐3 heteroaryl indoles with good functional group compatibility could be applied to large‐scale synthesis and late‐stage derivatization of bioactive compounds under extremely mild reaction conditions.

Cobalt-Catalyzed Enantioselective C-H Arylation of Indoles.

Atropoisomeric (hetero)biaryls are scaffolds with increasing importance in the pharmaceutical and agrochemical industries. Although it is the most obvious disconnection to construct such compounds, the direct enantioselective C-H arylation through the concomitant induction of the chiral information remains extremely challenging and uncommon. Herein, the unprecedented earth-abundant 3d-metal-catalyzed atroposelective direct arylation is reported, furnishing rare atropoisomeric C2-arylated indoles. Kinetic studies and DFT computation revealed an uncommon mechanism for this asymmetric transformation, with the oxidative addition being the rate- and enantio-determining step. Excellent stereoselectivities were reached (up to 96% ee), while using an unusual N-heterocyclic carbene ligand bearing an essential remote substituent. Attractive dispersion interactions along with positive C-H---π interactions exerted by the ligand were identified as key factors to guarantee the excellent enantioselection.

Solvent-controlled regioselective arylation of indoles and mechanistic explorations

A new reaction for the regioselective arylation of indoles at C2 or C3 positions achieved by adjusting the solvent and with P(O)tBu2 as an auxiliary group is reported. And the experimental results and DFT confirmed the process.

Ligand-controlled regiodivergent direct arylation of indoles via oxidative boron Heck reaction

Ligand-controlled direct arylation of indoles via Pd(ii) catalyzed oxidative boron Heck reaction under aerobic conditions is reported.

The solvent-controlled Rh(III)-catalyzed switchable [4+2] annulation of 2-arylIndoles with iodonium ylides.

Highly selective and switchable [4+2] annulations of 2-arylindoles with iodonium ylides were achieved by performing solvent-controlled Rh(III)-catalyzed C-H activations. When using DCM as a solvent, the C-H functionalization of 2-arylindoles with iodonium ylides selectively delivered indolo[2,1-a]isoquinoline derivatives. In contrast, the same catalytic system with a polar HFIP solvent predominately provided benzo[a]carbazole moieties.

Late-Stage C–H Arylation of Azepinoindole via Pd/Cu Catalysis: A Step Efficient and Convergent Synthesis of Rucaparib

AbstractThe C–H arylation of indoles holds the promise to shorten synthetic routes in the production of pharmaceuticals. However, late-stage C–H activation reactions often rely on the presence of protecting groups or stoichiometric metal additives. The regiospecific C–H arylation of a highly functionalized azepino[5,3,4-cd]indole scaffold lacking directing groups via Pd(II) and Cu(II) co-catalysis is reported. The direct C–H coupling was demonstrated in the convergent synthesis of rucaparib, an FDA approved anticancer drug.