C3 Position Of Indoles Research Articles

An attempted oxidative coupling approach to the scholarinine A framework

In this manuscript, an oxidative carbon–carbon bond forming reaction to construct the framework of alkaloids such as scholarinine A is explored using a constrained substrate. Instead of the desired carbon–carbon bond formation between an indole C3 position and a malonate group, a competing carbon–nitrogen bond between the malonate and indole C3 position was observed to form. This work adds to the growing body of substrates for oxidative carbon–carbon bond formation and importantly, demonstrates that these reactions are challenging for some conformationally constrained substrates.

Cu(II)-Catalyzed H/D exchange of indole derivatives

Cu(OTf)2 was explored as an efficient catalyst for hydrogen deuterium (H/D) exchange of indole derivatives. The advantage of this reaction is that deuteration selectivity can be adjusted by changing reaction parameters. When the reaction was performed with 10 mol% of Cu(OTf)2 as a catalyst in dioxane at 80 °C, deuteration preferentially occurred at C3 position of indole with high atom% deuterium incorporation. Furthermore, per-deuterated indole derivatives could be achieved by performing the reaction with higher catalyst loading in toluene at 120 °C. Performing the reaction on a continuous flow reactor facilitates the scale-up process, affording deuterated products with a throughput of 3.9 g/h.

Diastereoselective Synthesis of Indoline- and Pyrrole-Embedded Tetracycles via an Unprecedented Dearomative Indole-C3-Alkylation/Aza-Friedel-Crafts Cascade Reaction.

Dearomative indole C3-alkylation─intramolecular iminium trapping cascade reaction of indole-C3-tethered nucleophiles is a well-known blueprint for accessing 2,3-fused indolines. In exploring this strategy, synthetic chemists have utilized diverse classes of electrophilic reagents. However, the tethered nucleophiles have mainly been limited to heteronucleophiles and enolates; exploitation of tethered arenes/heteroarenes remains unknown. We herein describe the first examples of pyrrole-intercepted dearomative indole C3-allylation and benzylation of indole-tethered pyrroles toward the synthesis of 2,3-cis-fused tetracyclic indolines featuring a C3 all-carbon quaternary stereocentre. Our methodology capitalizes on the capability of NaOtBu/Et3B combination to direct the intermolecular alkylation to take place regioselectively at the indole C3 position over the other reactive sites (indole N and C2 and pyrrole C2 positions) and leverages the high nucleophilicity of the pyrrole template for the concomitant aza-Friedel-Crafts ring closure that traditionally would require an additional acid-catalyzed synthetic step. This cascade reaction is accomplished with broad substrate scope and excellent yields and chemo-, regio-, and diastereoselectivities.

Ethylene tri-/tetramerization catalysts supported by diphosphinoindole ligands

A new class of diphosphinoindole ligands have been developed. Upon activation with MMAO-3A, Cr catalysts supported by these bisphosphine ligands are active for ethylene tri-/tetramerization. The best result was achieved by using the bisphosphine ligand containing a phenyl group at C3 position of indole, giving a high activity of up to 364 kg/(g Cr/h) with a total selectivity of up to 72% toward 1-hexene (23.5%) and 1-octene (48.4%). A representative chromium tetracarbonyl complex was synthesized and structurally characterized by single-crystal X-ray diffraction.

From C4 to C7: Innovative Strategies for Site-Selective Functionalization of Indole C-H Bonds.

The widespread presence of hydrocarbons makes C-H functionalization an attractive alternative to traditional cross-coupling methods. As indole is an important heteroarene in a plethora of natural products and pharmaceuticals, C-H functionalization of indole moieties has emerged as one of the most important topics in this field. Due to the presence of multiple C-H bonds in indoles, site selectivity is a long-standing challenge. Much effort has been devoted to the C-H functionalization of indoles at the C3 or C2 position, while accessing the benzene core (from C4 to C7) is considerably more challenging.This Account summarizes our recent efforts toward site-selective C-H functionalization of indoles at the benzene core based on innovative strategies. A common method to solve the issue involves the development of directing groups (DGs). Our early studies establish that the installation of the N-P(O)tBu2 group at the N position can produce C7 and C6 arylation products using palladium and copper catalysts, respectively. The developed system can also be extended to direct arylation of indoles at the C5 and C4 positions by installing a pivaloyl group at the C3 position. Further investigation of indoles bearing N-PtBu2 groups shows a more diverse reactivity for C-H functionalizations at the C7 position, including arylation, olefination, acylation, alkylation, silylation, and carbonylation with different coupling partners. Compared to the P(V) DG, the P(III) group can be easily attached to the indole substrates and detached from the products. However, these attractive reactions rely mostly on precious metal catalysts with ligands; this requirement can be a significant limitation, particularly for large-scale syntheses and the necessity of removal of toxic trace metals in pharmaceutical products. We have also uncovered a general strategy for chelation-assisted aromatic C-H borylation just using simple BBr3 under mild conditions, in which the installation of pivaloyl groups at the N1 or C3 position of indoles can selectively deliver the boron species to the unfavorable C7 or C4 positions and allow subsequent C-H borylation without any metal. This transition-metal-free strategy can be extended to synthesize C7 and C4 hydroxylated indoles by boron-mediated directed C-H hydroxylation under mild reaction conditions and with broad functional group compatibility.In this Account, we describe our contributions to this topic since 2015. These studies provide efficient and attractive methods for the divergent synthesis of valuable substituted indoles and insights into the exploration of new strategies for the site-selective C-H functionalization and directives for other important heteroarenes.

Blue LED-Mediated N-H Insertion of Indoles into Aryldiazoesters at Room Temperature in Batch and Flow: Reaction Kinetics, Density Functional Theory, and Mechanistic Study.

Mild blue light-mediated N-H insertion of indole and its derivatives into aryldiazoesters has been reported in a batch and flow strategy to afford the corresponding N-alkylated product in moderate-to-excellent yield. Detailed high-performance liquid chromatography-based reaction kinetics measurements, control experiments, and kinetic isotope effect reveal that 3-substituted indoles with electron-withdrawing groups such as -CN and -CHO facilitated the product formation, whereas the electron-donating group retarded the process. The neutral indole performed in between them. Furthermore, Hammett plot and density functional theory-based transition-state optimization studies showed substantial correlation of the electronic nature of the substituents at the C3 position of indoles with the rate of the N-H insertion reaction. The strategy was utilized to synthesize a key intermediate for the natural product (-)-psychotrimine.

Rhodium(III)‐Catalyzed C−H Benzylation of Indole's C3 Position with Aza‐o‐Quinone Methides

AbstractIn this paper, we report an example of indole's site selective C3 benzylation process through a rhodium(III)‐catalyzed indole's C2 activation relay using aza‐o‐QM as a functionalization reagent, affording the desired products in good yields under mild conditions. The plausible reaction mechanism is proposed on the basis of control and deuterium labeling experiments and the further transformation has been also described.magnified image

Iridium-Catalyzed Enantioselective Intermolecular Indole C2-Allylation.

The enantioselective intermolecular C2‐allylation of 3‐substituted indoles is reported for the first time. This directing group‐free approach relies on a chiral Ir‐(P, olefin) complex and Mg(ClO4)2 Lewis acid catalyst system to promote allylic substitution, providing the C2‐allylated products in typically high yields (40–99 %) and enantioselectivities (83–99 % ee) with excellent regiocontrol. Experimental studies and DFT calculations suggest that the reaction proceeds via direct C2‐allylation, rather than C3‐allylation followed by in situ migration. Steric congestion at the indole‐C3 position and improved π–π stacking interactions have been identified as major contributors to the C2‐selectivity.

Atroposelective Haloamidation of Indoles with Amino Acid Derivatives and Hypohalides.

An atroposelective coupling of indoles with chiral amino acid-based sulfonamides mediated by hypohalides is described. A series of 2-amido-3-haloindoles with a C-N chiral axis are delivered using this strategy. The C3 halogen atoms can facilitate further transformation. Various functionalities, such as carbonyl, phosphine, aryl, and alkenyl groups, can be introduced into the C3 position of indoles. These structurally diverse and axially chiral indole derivatives can find further synthetic utilities. It can be exemplified with an axially chiral phosphine, which serves as a ligand in Pd-catalyzed cross couplings.

Iron-Catalyzed C–H Sulfonylmethylation of Indoles in Water–PEG400

An iron-catalyzed C–H sulfonylmethylation of indoles in water–PEG400 has been developed using p-toluenesulfonylmethyl isocyanide. This protocol enables direct regioselective construction of Csp2–Csp3 bond at the C3 position of indoles with a broad range of substrate compatibility in moderate to good yields, which is cost-effective and environmentally friendly.

Activation Relay on Rhodium-Catalyzed C-H Aminomethylation in Cooperation with Photoredox Catalysis.

A site selective C-H aminomethylation at indole's C3 position has been achieved by merging rhodium(III)-catalyzed C-H activation and photoredox catalysis in a one-pot manner. An investigation of the mechanistic insights rationalized the essence of the activation relay and the combination mode.

Protonation and Sequential Microsolvation of 5-Hydroxyindole: Infrared Photodissociation Spectra of 5HIH+–Ln with L = Ar and N2 (n ≤ 3)

Protonation and solvation of functionalized heterocyclic aromatic molecules, which often occur as biomolecular building blocks, are important processes in (bio-)organic biochemistry. Herein, we study the protonation and microsolvation mechanisms of 5-hydroxyindole (5HI, 1 H-indol-5-ol, C8H7NO), the chromophore of serotonin, produced by electron and and chemical ionization using infrared photodissociation (IRPD) spectroscopy of mass-selected cold 5HIH+-L n clusters (L = Ar/N2, n ≤ 3) and dispersion-corrected density functional theory calculations (B3LYP-D3/aug-cc-pVTZ). Isomer-selective OH and NH stretch frequencies in the spectral range 3000-3800 cm-1 reveal the coexistence of at least four protonated species: the most stable syn (cis) isomer protonated at the C3 position of indole, both syn- and anti-rotamers protonated at C4 of the phenol ring, and the drastically less stable O-protonated isomer (Δ E0 = 117.1 kJ/mol) stabilized by kinetic trapping. Manipulation of the IRPD conditions (fragmentation channels) facilitates the spectroscopic isolation of O-protonated species. Upon protonation, the acidity of the OH group increases in the order 5HIH+(C3), 5HIH+(C4), and 5HIH+(O), while the acidity of the NH group decreases along this series, strongly affecting the microsolvation motifs of the individual isomers. Comparison of 5HIH+-L to the corresponding neutral and radical cation clusters reveals the impact of both protonation and ionization on the interaction with nonpolar ligands. Furthermore, our results are compared to protonated phenol, for which similar gas-phase protonation mechanisms have been found. Comparison of 5HIH+-L with the corresponding clusters of protonated phenol illustrates the effects of functional substitution and addition of aromatic rings on intermolecular potential.

Weak Directing Group Steered Formal Oxidative [2+2+2]-Cyclization for Selective Benzannulation of Indoles.

A double C-H activation and double insertion process to achieve the synthesis benzo[e]indole frameworks has been disclosed. This type of benzannulation is directed by a trifluoromethylketone moiety, which is easy to install on the indole C3-position. Overall the reaction takes places as an oxidative cyclization of two alkynes with the C4-C5 position of indole.

Catalytic Synthesis of 3-Thioindoles Using Bunte Salts as Sulfur Sources under Metal-Free Conditions.

An efficient catalytic method for the synthesis of 3-thioindoles has been successfully developed, which uses odorless, stable, readily available crystalline Bunte salts as the sulfenylating agents, iodine as nonmetallic catalyst, and DMSO as both the oxidant and solvent. This method is practical and environmentally benign in terms of sulfur sources, catalyst, and solvent. The catalytic reaction is selective at the C3 position of indoles and compatible with a wide range of substrates, giving the desired products in good to excellent yields.

Intramolecular dearomative oxidative coupling of indoles: a unified strategy for the total synthesis of indoline alkaloids.

Indole alkaloids, one of the largest classes of alkaloids, serve as an important and rich source of pharmaceuticals and have inspired synthetic chemists to develop novel chemical transformations and synthetic strategies. Many biologically active natural products contain challenging indoline scaffolds, which feature a C3 all-carbon quaternary stereocenter that is often surrounded by a complicated polycyclic ring system. The creation of this quaternary stereocenter creates an inherent synthetic challenge because the substituents on the carbon center cause high steric repulsion. In addition, the presence of nitrogen atoms within the surrounding polycyclic rings can lead to synthetic difficulties. Oxidative coupling between two sp(3)-hybridized carbon anions provides a unique and powerful method for building C-C single bonds, especially for generating a C-C bond that joins one or two vicinal quaternary stereocenters. Although chemists have known of this transformation for a long time, they have only applied this reaction in total synthesis of complex natural products during the past decade. The progress of this class of reaction depends on the use of indole moieties as coupling partners. In this Account, we summarize our recent efforts to develop iodine-mediated intramolecular dearomative oxidative coupling (IDOC) reactions of indoles as part of a unified strategy for the total synthesis of three classes of indoline alkaloids. We categorized these IDOC reactions into three types based on their mode of connection to the indole moiety. In type I, the carboanion nucleophile was tethered to the indole at the C3 position. This reaction enabled the assembly of skeleton A, which features a spiro ring at the C3 position of the indole. We demonstrated the efficiency of this method by quickly assembling two classes of tetracyclic compounds and completing the total synthesis of (-)-communesins F, A, and B. For the type II IDOC reactions, the carboanion nucleophile residing at the C2 position of the indole formed a quaternary center at the C3 position of indole to produce skeleton B. We applied this IDOC reaction to synthesize two akuammiline alkaloids, vincorine and aspidophylline A. Type III IDOC reactions employed substrates with a preinstalled ring at the C2 and C3 positions of the indole. These transformations proceeded smoothly to afford polycyclic ring system C, which we used in the first enantioselective total synthesis of Kopsia alkaloid methyl N-decarbomethoxychanofruticosinate. These results further demonstrate how new chemical strategies and reactions facilitate both the first total syntheses of natural products and the discovery of more efficient synthetic routes.

Diethylzinc-Promoted Synthesis of Trifluromethyl-Containing Tryptamine Analogues from Indoles and 2-Trifluromethyl-N-(4-Toluenesulfonyl)-Aziridine

Incorporation of fluorine atoms into biologically active organic molecules often causes enhancement of activity, stability, and solubility, as well as reduction of toxicity. Tryptamine derivatives are known for important medicines concerning our mental health. Therefore, fluorinated tryptamine derivatives could be promising medicinal candidates for pharmaceutical chemistry. We have already reported the regioselective ring-opening reaction of 2-CF3-N-Ts-aziridine (Ts=4-toluenesulfonyl) with some nucleophiles. If this ring-opening reaction proceeds smoothly at the C3 position of indoles, it could provide a solution for the synthesis of CF3-containing tryptamine analogues. We examined the diethylzinc-promoted direct C3 alkylation of indoles with 2-CF3-N-Ts-aziridine under basic conditions. We have developed the synthesis of CF3-tryptamine from 2-CF3-N-Ts-aziridines and indoles by using diethylzinc as a base with excellent yields and complete regioselectivity.

Mechanistic Studies for Synthesis of Bis(indolyl)methanes: Pd-Catalyzed C–H Activation of Indole–Carboxylic Acids with Benzyl Alcohols in Water

A method for synthesis without protecting groups of bis(indolyl)methanes by the (η3-benzyl)palladium system generated from a palladium catalyst and benzyl alcohol in water is developed. This domino protocol involves C3–H bond activation/benzylation of indole–carboxylic acids and benzylic C–H functionalization. Mechanistic studies indicate that the (η3-benzyl)palladium(II) complex, which is formed via oxidative addition of benzyl alcohol 2 to a Pd(0) species, activates the C–H bond at the C3-position of indole 1. Notably, water plays an important role in our catalytic system for sp3 C–O bond activation and stabilization of OH− by hydration for the smooth generation of the activated Pd(II) cation species, as well as for nucleophilic attack of indoles to hydrated benzyl alcohols.

Metal-free catalyzed oxidative trimerization of indoles by using TEMPO in air: a biomimetic approach to 2-(1H-indol-3-yl)-2,3′-biindolin-3-ones

A simple, convenient and efficient metal-free catalyzed oxidative trimeric reaction of indoles toward a variety of 2-(1H-indol-3-yl)-2,3'-biindolin-3-one derivatives in moderate to excellent yields has been developed. This transformation proceeds via a tandem oxidative homocoupling reaction by using TEMPO in air as an environmentally benign oxidant. This methodology provides an alternative approach for the direct generation of all-carbon quaternary centers at the C3 position of indoles.

Discovery and optimization of indole and 7-azaindoles as Rho kinase (ROCK) inhibitors (Part-II)

Therapeutic interventions with Rho kinase (ROCK) inhibitors may effectively treat several disorders such as hypertension, stroke, cancer, and glaucoma. Herein we disclose the optimization and biological evaluation of potent novel ROCK inhibitors based on substituted indole and 7-azaindole core scaffolds. Substitutions on the indole C3 position and on the indole NH and/or amide NH positions all yielded potent and selective ROCK inhibitors (25, 42, and 50). Improvement of aqueous solubility and tailoring of in vitro and in vivo DMPK properties could be achieved through these substitutions.

Formal Homo‐Nazarov and Other Cyclization Reactions of Activated Cyclopropanes

The Nazarov cyclization of divinyl ketones gives access to cyclopentenones. Replacing one of the vinyl groups by a cyclopropane leads to a formal homo-Nazarov process for the synthesis of cyclohexenones. In contrast to the Nazarov reaction, the cyclization of vinyl-cyclopropyl ketones is a stepwise process, often requiring harsh conditions. Herein, we describe two different approaches for further polarization of the three-membered ring of vinyl-cyclopropyl ketones to allow the formal homo-Nazarov reaction under mild catalytic conditions. In the first approach, the introduction of an ester group α to the carbonyl on the cyclopropane gave a more than tenfold increase in reaction rate, allowing us to extend the scope of the reaction to non-electron-rich aryl donor substituents in the β position to the carbonyl on the cyclopropane. In this case, a proof of principle for asymmetric induction could be achieved using chiral Lewis acid catalysts. In the second approach, heteroatoms, especially nitrogen, were introduced β to the carbonyl on the cyclopropane. In this case, the reaction was especially successful when the vinyl group was replaced by an indole heterocycle. With a free indole, the formal homo-Nazarov cyclization on the C3 position of indole was observed using a copper catalyst. In contrast, a new cyclization reaction on the N1 position was observed with Brønsted acid catalysts. Both reactions were applied to the synthesis of natural alkaloids. Preliminary investigations on the rationalization of the observed regioselectivity are also reported.