N-substituted Indoles Research Articles

Copper-Catalyzed Aerobic Cross-Dehydrogenation Coupling of Indoles for Synthesis of 2,3'-Bisindoles.

2,3'-Bisindoles with C-C linkages have attracted interest in medicinal chemistry, yet their synthesis is intricate with many steps. Notably, direct C-H/C-H cross-coupling of non-directed heteroaromatics remains challenging, often requiring precious metals and oxidants to enhance coupling efficiency. Herein, we present a copper-catalyzed C-H/C-H cross-coupling method for N-substituted indoles without directing groups, facilitated by molecular oxygen under gentle conditions. It showed reasonable functional group compatibility and provided one-pot access to a variety of 2,3'-bisindoles derivatives in moderate to good yields.

Dearomative Cyclization/Spirocyclization via Electrochemical Reductive Hydroarylation of Nonactivated Arenes.

An electrochemical cyclization/spirocyclization hydroarylation via reductive dearomatization of a series of nonactivated arenes including N-substituted indoles, indole-3-carboxamide derivatives, and iodo-substituted benzamides is described. This protocol boasts high atom efficiency, broad substrate applicability, and excellent selectivity. Utilizing a simple undivided cell, various nonactivated arenes undergo cyclization/spirocyclization through the intramolecular addition of aryl radicals to an aromatic ring, yielding 50 indolines, spirocyclizative hydroarylation products, and phenanthridinones.

Selective N-functionalization of Arylhydrazines with Primary Alcohols and Acids under PPh3/DDQ System.

We present a PPh3/DDQ-mediated regiospecific selective N-functionalization of arylhydrazines with primary benzylic alcohols and aryl carboxylic acids for the synthesis of N1-benzyl arylhydrazines and N2-acyl arylhydrazines, respectively. This metal- and base-free approach features very short reaction times (about 10 min), broad substrate scope, good functional group tolerance, and mild reaction conditions. Furthermore, N1-benzlated products have also been successfully applied to the concise synthesis of N-substituted indoles and anticancer drug MDM2 inhibitor.

Heating conversion of indole-3-carbinol into N-substituted oligomers with anti-melanoma effect

Cruciferous vegetables (CVs) are globally consumed with some health benefits believed to arise from indole-3-carbinol (I3C), a labile phytochemical liberated from indole glucosinolates, but few reports describe the effect of cooking on I3C reactions. Here, we present heat-promoted direct conversions of I3C in broccoli florets into indole derivatives, which are unique in the N-indolylmethylation and -hydroxymethylation of indole nuclei by 3-methyleneindole and formaldehyde formed in situ from the I3C dehydration and the dimerization of I3C to 3,3′-diindolylmethane (DIM), respectively. Such N-substituted indoles were found in a range of 0.4–4.6 μg per gram of steamed broccoli florets, with a novel compound N-(indol-3-ylmethyl)-3,3′-diindolylmethane (DIM-1) bio-evaluated to inhibit A375 cells with an IC50 value of 1.87 μM. In aggregation, the investigation discloses the promoting effect of heating on the I3C transformation in CVs and identifies DIM-1 as an anti-cancer drug candidate, and thus updates the knowledge of I3C and bioactive derivatives thereof.

Nickel(II)-Catalyzed Formal [3+2] Cycloadditions between Indoles and Donor-Acceptor Cyclopropanes.

This article describes the development of a nickel-catalyzed regio- and diastereoselective formal [3+2] cycloaddition between N-substituted indoles and donor-acceptor cyclopropanes to synthesize cyclopenta[b]indoles. Optimized reaction conditions provide the desired nitrogen-containing cycloadducts in up to 93% yield and dr 8.6:1 with complete regioselectivity. The substrate scope showed high tolerance to various substituted indoles and cyclopropanes, resulting in the synthesis of six new cyclopenta[b]indoles and the isolation of five derivatives previously reported in the literature. In addition, a mechanistic proposal for the reaction was studied through online reaction monitoring by ESI-MS, allowing for the identification of the reactive intermediates in the Ni(II) catalyzed process. X-ray crystallography confirmed the structure and relative endo stereochemistry of the products. This method enables the fast and efficient construction of fused indolines from readily accessible starting materials.

Selective Construction of C-S/S-N Bonds from N-Substituted O-Thiocarbamates and Indoles under Transition-Metal-Free Conditions.

A method for the selective construction of S-N/C(sp2)-S bonds using N-substituted O-thiocarbamates and indoles as substrates is reported. This protocol features good atom utilization, mild conditions, short reaction time, and wide substrate scope, which can provide a convenient path for the functionalization of indoles. In addition, the reaction could be scaled up on gram scale, showing potential application value in industry synthesis.

Photochemically Mediated Ring Expansion of Indoles and Pyrroles with Chlorodiazirines: Synthetic Methodology and Thermal Hazard Assessment.

We demonstrate that arylchlorodiazirines serve as photo-activated halocarbene precursors for the selective one-carbon ring expansion of N-substituted pyrroles and indoles to the corresponding pyridinium and quinolinium salts. Preliminary investigations indicate that the same strategy also enables the conversion of N-substituted pyrazoles to pyrimidinium salts. The N-substituent of the substrate plays an essential role in: (1) increasing substrate scope by preventing product degradation, (2) enhancing yields by suppressing co-product inhibition, and (3) activating the azinium products towards subsequent synthetic manipulations. This latter point is illustrated by subjecting the quinolinium salts to four complementary partial reductions, which provide concise access to ring-expanded products with different degrees of increased C(sp3 ) character. Thermal analysis of the diazirines by differential scanning calorimetry (DSC) provides detailed insight into their energetic properties, and highlights the safety benefits of photolyzing-rather than thermolyzing-these reagents.

Theoretical Investigation on the Mechanistic Pathways of Cp*Cobalt(III)- Catalyzed Transformation of N-Substituted Carbamoyl Indoles to Pyrroloindolone Derivatives

Aim: A theoretical study on the Cp*cobalt(III) catalyzed C-H functionalization transformation of N-substituted carbamoyl indoles with alkyne derivatives to pyrroloindolone derivatives has been performed using DFT method. Background: Indole skeleton is an important part for developing regioselective C-H bond functionalisation reactions. Pyrrolo[1,2-a]indole bearing a 6-5-5 tricyclic skeleton (Scheme-1) is an important structural component found in many biologically active natural products and pharmaceuticals, (such as antitumor mitomycin C, antimalarial flinderole B etc.).Thus C−H activation process has great demand methods for efficiently synthesizing a pyrrolo[1,2-a]indole unit from readily available starting materials. One such attractive report was published by Matsunaga & Kanai et.al., Which shows pyrroloindolone derivatives can be synthesized (Scheme-2) through Cp*Co(III) catalysed C-H alkenylation and annulations from N-substituted carbamoyl indoles. Objective: Our current project deals with the determination of the rate determining step of the reaction, to determine the energetically favourable pathway. Investigation of the actual reason behind the regioselectivity of the products whether it is steric or electronic effects of the substituents. Method: The geometry optimization and energy calculations of all the systems were carried out with the Gaussian 09 software. Construction of trial geometries, monitoring the progress of calculations and visualization of the final output were done by several graphical user interface softwares like Gauss View, Molden etc. Geometry optimization of all species is performed using M06-2X functional in DFT method as a method for performing optimization of structures. 6-31G (d, p) basis set was employed for all non-metal atoms and the LANL2DZ basis set was employed for cobalt. To find out the geometries of several transition structures on the potential energy surface (PES) of the reaction pathway, relaxed scan method was used. Result: DFT study on a reaction of carbamoyl indoles with alkyne derivatives by activate Co(III)Cp* catalytic condition is done here. The target scheme followed the energetics of two possible pathways. The initial step of the reaction is the alkyne insertion step which needs 21.27 kcal mol-1 amount of energy. In the first case the final annulated product has been generated through a carbon-carbon bond formation, proton transfer and demetallation processes in path-a. The global activation barrier has been found to be quite high (30.17 kcal mol-1). However the study of the second pathway, which generated the simple alkenylated product through the proto-demetalation process in path-b, reveals a more reliable activation barrier (21.27 kcal mol-1). Conclusion: Comparison of the energy requirement clearly reveals that the formation of the final product should go through favourable simple alkenylation process that is path-b for dimethyl amine. Due to lower energy barrier the simple alkenylation pathway (i.e Path-b) is more favourable one. Initial alkyne addition step is the rate determining step. The regioselectivity of the alkyne addition is purely governed by the steric crowding around the substrate. Thus the favourable mode of alkyne addition has lower energy barrier due to lesser steric interactions. This theoretical investigation may guide the future researchers for developing some other economical route for generating similar derivatives.

Montmorillonite K10 catalyzed facile synthesis of N-substituted indoles from primary amines and Morita–Baylis–Hillman acetate of cyclohexenone

Transition metal- and base-free synthesis of N-substituted indoles from primary amines and MBH acetate of cyclohexenone is developed.

Nickel-Catalyzed Direct Synthesis of N-Substituted Indoles from Amino Alcohols and Alcohols.

A one-pot cascade approach for the synthesis of N-substituted indoles from amino alcohols and alcohols under additive and base-free conditions with the liberation of water as the only stoichiometric byproduct is reported. The commercially available bench-stable Ni(OTf)2 salt in combination with 1,2-bis(dicyclohexylphosphino)ethane (dcype) is very effective for this unprecedented catalytic transformation. A broad range of substrates including aromatic and aliphatic primary alcohols, cyclic and acyclic secondary alcohols, and various substituted 2-aminophenyl ethyl alcohols are employed in the reaction conditions to provide a diverse range of N-alkylated indoles. Mechanistic studies revealed that the reaction proceeds through tandem N-alkylation via hydrogen autotransfer followed by the cyclization of N-alkylated alcohol intermediate.

Hypervalent Iodine(III)-Mediated Umpolung Dialkoxylation of N-Substituted Indoles.

Herein, we report dialkoxylation of N-substituted indoles through a hypervalent iodine-mediated umpolung strategy, affording trans-2,3-dimethoxyindolines with up to 95% yield. In addition, C5-selective bromination of 2,3-dialkoxyindoline via NBS-mediated rearomatization was achieved. DFT calculation of the sequence of electrophilic addition and nucleophilic substitution pathway of N-substituted indoles has also been investigated.

Visible-light-induced indole synthesis via intramolecular C-N bond formation: desulfonylative C(sp2)-H functionalization.

Despite significant advances made on the synthesis of indole derivatives through photochemical strategies during the past several years, the requirement of equivalent amounts of oxidants, bases or other additional additives has limited their practical applications in the synthesis of natural products and pharmaceuticals as environment-friendly processes. Herein, we report LED visible-light-induced redox neutral desulfonylative C(sp2)-H functionalization for the synthesis of N-substituted indoles with a broad scope through γ-fragmentation under mild conditions in the absence of any additional additive. The reaction mechanism paradigm has been investigated on the basis of deuterium labeling experiments, kinetic analysis, Hammett plotting analysis and DFT calculations.

Environmentally Friendly Protocol for 2,3-Difunctionlization of Indole Derivatives.

Environmentally friendly and highly regioselective C-3 dichlorination and C-2 oxidation of N-substituted indoles have been established using NaCl as a chlorine source and H2O as an oxygen source. A series of 3,3-dichloro-2-oxindoles were obtained in moderate to excellent yields. The gram-scale synthesis and derivatization reaction were explored. The possible mechanism for this reaction was elucidated.

Synthesis of N-Substituted Indoles via Aqueous Ring-Closing Metathesis

We report herein the synthesis of N-substituted indoles resulting from the ring-closing metathesis of indole precursors bearing N-terminal alkenes. The aqueous metathesis of the indole precursors gave good yields of N-substituted indoles (up to 72%) with commercial metathesis catalysts and with artificial metalloenzymes based on the biotin-streptavidin technology. Strikingly, the yield of the N-acetylindole increases in presence of a second metathesis substrate.

Formal oxo- and aza-[3 + 2] reactions of α-enaminones and quinones: a double divergent process and the roles of chiral phosphoric acid and molecular sieves.

A double divergent process has been developed for the reaction of α-enaminones with quinones through facile manipulation of catalyst and additive, leading to structurally completely different products. The two divergent processes, which involve formal aza- and oxo-[3 + 2] cycloaddition reactions, are mediated by chiral phosphoric acid and molecular sieves, respectively. While inclusion of phosphoric acid in the reaction switched the reaction pathway to favor the efficient formation of a wide range of N-substituted indoles, addition of 4 Å molecular sieves to the reaction switched the reaction pathway again, leading to enantioselective synthesis of 2,3-dihydrobenzofurans in excellent yields and enantioselectivities under mild conditions. Studies in this work suggest that the chiral phosphoric acid acts to lower the transition state energy and promote the formation of amide intermediate for the formal aza-[3 + 2] cycloaddition and the molecular sieves serve to facilitate proton transfer for oxo-[3 + 2] cycloaddition. The reactivity of α-enaminones is also disclosed in this work.

Synthesis, Characterization and Catalytic Application of Starch Supported Cuprous Iodide Nanoparticles

The starch supported cuprous iodide nanoparticles (CuI-NPs@Starch) were synthesized in aqueous medium and characterized by transmission electron microscopy, scanning electron microscopy, X-ray powder diffraction, energy-dispersive X-ray spectroscopy and atomic absorption spectra analysis. The newly synthesized CuI NPs on starch have been demonstrated first time as an efficient catalyst for the regioselective 3-allylation reaction of N-substituted indoles as well as ring-substituted indoles using various allyl alcohols under moisture and air insensitive conditions.

N-Iodosuccinimide-Mediated Oxidative Coupling of Indoles and Phenols: A Synthetic Study toward the Benzofuroindoline Moiety of Bipleiophylline

We report our efforts to apply an N-iodosuccinimide-mediated dearomative oxidative coupling of indoles and phenols to benzo­furoindoline-containing polycyclic scaffolds related to the natural product bipleiophylline. Suitable conditions from N-substituted indoles are developed and applied to the synthesis of a hexacyclic model starting from a tetracyclic ABCE precursor.

Iron-Catalyzed C3-Formylation of Indoles with Formaldehyde and Aqueous Ammonia under Air

An efficient iron-catalyzed C3-selective formylation of free (N–H) or N-substituted indoles was developed by employing formaldehyde and aqueous ammonia, with air as the oxidant. This new method gave 3-formylindoles in moderate to excellent yields with fairly short reaction times. Moreover, this procedure for catalytic formylation of indoles can be applied to gram-scale syntheses.

Enantioselective Dearomative Difunctionalization of Indoles by Palladium-Catalyzed Heck/Sonogashira Sequence.

Palladium-catalyzed enantioselective dearomative arylalkynylation of N-substituted indoles, through a Heck/Sonogashira sequence, was established using a new BINOL-based phosphoramidite as the chiral ligand. A wide range of 2,3-disubstituted indolines, bearing vicinal quaternary and tertiary stereocenters, were efficiently constructed in one step with excellent enantioselectivities (up to 97 % ee) and diastereoselectivities (>20:1).

Iodine-catalyzed C3-formylation of indoles using hexamethylenetetramine and air

Abstract An efficient iodine-catalyzed chemoselective 3-formylation of free (N–H) and N-substituted indoles was achieved by using hexamethylenetetramine (HMTA) in the presence of activated carbon under air atmosphere. This new method could provide 3-formylindoles in moderate to excellent yields with fairly short reaction times. Moreover, this catalytic formylation of indoles procedure can be applied to gram-scale synthesis.