Alkylation Of Indoles Research Articles

Tandem Friedel-Crafts-Alkylation-Enantioselective-Protonation by Artificial Enzyme Iminium Catalysis.

The incorporation of organocatalysts into protein scaffolds holds the promise of overcoming some of the limitations of this powerful catalytic approach. Previously, we showed that incorporation of the non‐canonical amino acid para‐aminophenylalanine into the non‐enzymatic protein scaffold LmrR forms a proficient and enantioselective artificial enzyme (LmrR_pAF) for the Friedel‐Crafts alkylation of indoles with enals. The unnatural aniline side‐chain is directly involved in catalysis, operating via a well‐known organocatalytic iminium‐based mechanism. In this study, we show that LmrR_pAF can enantioselectively form tertiary carbon centres not only during C−C bond formation, but also by enantioselective protonation, delivering a proton to one face of a prochiral enamine intermediate. The importance of various side‐chains in the pocket of LmrR is distinct from the Friedel‐Crafts reaction without enantioselective protonation, and two particularly important residues were probed by exhaustive mutagenesis.

Zn (II)/spiroQuinox catalyzed asymmetric Friedel–Crafts alkylation of indoles with cyclic N‐sulfonyl ketimino esters

Zinc complex of a new spiroQuinox ligand with a spirocarbon stereogenic center was examined for asymmetric Friedel–Crafts alkylation of indoles with cyclic N‐sulfonyl ketimino esters. This catalytic system provides a platform for facile synthesis of benzosultam derivatives functionalized with indole substituents, in high yield and excellent enantioselectivity.

Effects of Brønsted acid cocatalysts on the activities and selectivities of charge‐enhanced thiourea organocatalysts in Friedel–Crafts and oxa‐Pictet–Spengler reactions

AbstractCharge‐enhanced chiral thioureas were used in the organocatalysis of the Friedel–Crafts alkylation of indole with trans‐β‐nitrostyrene and the oxa‐Pictet–Spengler reaction of tryptophol and benzaldehyde. The effects of substoichiometric Brønsted acidic additives on the reaction conversions and enantiomeric ratios of these transformations were examined, and the role of these species in the mechanism of the latter reaction was explored using variable time normalization kinetics to elucidate the reaction order of the catalyst, cocatalyst, and reagents. A proposed pathway for the oxa‐Pictet–Spengler cyclization that involves matched and mismatched catalyst and cocatalyst pairs and an off‐cycle racemization of the latter species is provided.

HFIP as Protonation Reagent and Solvent for Regioselective Alkylation of Indoles with All-Carbon Centers

The regio- and chemoselective construction of indole bearing an all-carbon center at the C3-position, a versatile bioactive building block, by C(sp2)-C(sp3) formation with olefins has been achieved through utilization of hexafluoroisopropanol (HFIP) as the protonation reagent and solvent. The catalytic reactions are operationally simple and green compared with previous reports utilizing elaborated olefins and catalysts. This protocol allows for alkylation of a variety of substituted indoles with diverse of styrene type alkenes in excellent yields and with high selectivity. Application of this protocol to the synthesis of drug was pursued and with an improved yield in contrast to previous art. Catalytic kinetics and deuterium-labeling experiments suggest that the rate-determining step involves the protonation of olefin by HFIP to generate carbocation, followed by electrophilic addition to indole derivative.

NHPI-catalyzed electrochemical C–H alkylation of indoles with alcohols to access di(indolyl)methanes via radical coupling

The present indirect electrochemically mediated radical protocol outperforms the traditional Friedel–Crafts route with a broad substrate scope and functional group tolerance, as well as facile gram-scale synthesis without metal contamination.

Urea-engineering mediated hydrogen-bond donating Friedel–Crafts alkylation of indoles and nitroalkenes in a dual-functionalized microporous metal–organic framework with high recyclability and pore-fitting-induced size-selectivity

The impact of urea-engineering in the hydrogen-bond donating reaction of indole and nitroalkene under mild conditions is established in a dual-functionalized MOF that exhibits highly recyclable and pore-fitting-induced size-selective Friedel–Crafts alkylation.

Heterogeneously Organocatalytic, Enantioselective Friedel-Crafts Alkylation of Indole with 3,3,3-Trifluoropyruvate

Heterogeneously Organocatalytic, Enantioselective Friedel-Crafts Alkylation of Indole with 3,3,3-Trifluoropyruvate

Friedel–Crafts alkylation of indoles with β-nitroalkenes using ammonium niobium oxalate as a recyclable catalyst

ANO as an efficient (high TON) and recyclable catalyst for the Friedel–Crafts alkylation of indoles and nitroalkenes.

Construction of Chiral All‐Carbon Quaternary Stereocenters by Asymmetric Friedel−Crafts Reaction of Isatin Derivatives

Comprehensive SummaryUnder the catalysis of chiral Cu(II) complex, C2 and C3 alkylation of pyrrole and C3 alkylation of indole were realized simultaneously. The chiral oxindole skeleton with an all‐carbon quaternary stereogenic center at the C3‐position could be obtained exclusively with high yields (up to 95%) and excellent enantioselectivities (up to > 99%).

Rhodium(III)‐Catalyzed Direct C7‐Selective Alkenylation and Alkylation of Indoles with Maleimides

AbstractA versatile and efficient method for the coupling of maleimides and indoles at the C7‐position has been established under Rh(III) catalysis. The present protocol was compatible with various functional groups, diverse 3‐(indol‐7‐yl)maleimides and 3‐(indol‐7‐yl)succinimides were obtained in moderate to excellent yields by switching reaction conditions. Moreover, this method further highlights the unique practical application for the conjugation with pharmaceutically useful compounds and amino acid derivatives. To explore the mechanism of this transformation, deuteration studies and control experiments have been carried out.magnified image

Cobalt-Catalyzed Hydrogenative Transformation of Nitriles

Here, we report the transformation of nitrile compounds in a hydrogen atmosphere. Catalyzed by a cobalt/tetraphosphine complex, hydrogenative coupling of unprotected indoles with nitriles proceeds smoothly in a basic medium, yielding C3 alkylated indoles. In addition, the direct hydrogenation of nitriles under the same conditions yielded primary amines. Isotope labeling experiments, along with a series of control experiments, revealed a reaction pathway that involves nucleophilic addition of indoles and 1,4-reduction of a conjugate imine intermediate. Different from reductive alkylation of indoles under an acidic condition, E1cB elimination is believed to occur in this base-promoted hydrogenative coupling reaction.

Efficient synthesis of bis(indolyl)methanes by the alkylation of indoles with alcohols using heterogeneous CuFe2O4 catalyst

Bis(3-indolyl)methanes (BIM) are highly valuable and appear in the core structure of many natural products and pharmacologically active compounds (anticancer, anti-inflammatory, antiobesity, antimetastatic, antimicrobial, etc.). Herein, we have disclosed an air stable and highly efficient CuFe2O4 heterogeneous catalyst for alkylation of indoles with alcohols to give bis(3-indolyl)methanes in very good yields. The CuFe2O4 catalyst has been found to be magnetically recycled at least five times without losing significant catalytic activity.

Nickel‐Catalyzed C−H Bond Functionalization of Azoles and Indoles

Direct C-H functionalization of privileged and biologically relevant azoles and indoles represents an important chemical transformation in molecular science. Despite significant progress in the palladium-catalyzed regioselective C-H functionalization of azoles and indoles, the use of abundant and less expensive nickel catalyst is underdeveloped. In the recent past, the nickel-catalyzed regioselective C-H alkylation, arylation, alkenylation and alkynylation of azoles and indoles have been substantially explored, which can be applied to the complex organic molecule synthesis. In this Account, we summarize the developments in nickel-catalyzed regioselective functionalization of azoles and indoles with a considerable focus on the reaction mechanism.

Enantioselective Friedel-Crafts alkylation of indole with nitroalkenes in the presence of bifunctional squaramide organocatalysts

A series of chiral bifunctional quinine and 2-aminoDMAP based squaramide organocatalysts are evaluated in Friedel-Crafts alkylation of indoles with nitroolefins. These 3-substituted indole derivatives are synthesized in the presence of sterically encumbered tert-butyl squaramide/quinine with high enantioselectivity (up to >99% ee) and moderate chemical yields (up to 80%) by representing as chiral precursors for very important biologically active molecules. Besides, this asymmetric transformation provides a very simple, efficient, clean and environmental friendly route. In addition, this process has very mild reaction conditions such as ambient temperature and usage of only 2 mol% catalyst loading compared to previous studies in literature.

Theoretical studies on the mechanism of Pd2+-catalyzed regioselective C-H alkylation of indole with MesICH2CF3OTf.

The reaction mechanism of Pd2+-catalyzed regioselective C-H alkylation of indole with MesICH2CF3OTf has been investigated by the density functional theory calculations. The reaction mechanism mainly contains four steps: C-H activation, oxidative addition, reductive elimination, and ligands substitution. From our calculations, we find that the C-H activation step was realized by the acetate anion (-OAc) assisted concerted metalation deprotonation (CMD) process and the transition state of C-H activation process is a square planar configuration. Moreover, the calculation results suggest that the regioselectivity of C-H bond alkylation of indole with MesICH2CF3OTf can be ascribed to the different stability of the CMD transition states in C-H activation step and the relative stabilities of deprotonated intermediates.

Ruthenium(II)-carboxylate-catalyzed C4/C6–H dual alkylations of indoles

Position-selective functionalizations of specific C–H bonds are in high demand. Especially, the selectivity beyond the traditional C2- and C3-manifold is highly challenging. Herein, we disclose site-selective C4/C6–H double alkylations of indoles accomplished by arene-ligand-free ruthenium(II)-carboxylate catalysis. Base-assisted C2–H ruthenation enabled the C4/C6–H dialkylations with ample substrate scope. The robust C4/C6–H alkylations were demonstrated by gram-scale syntheses and late-stage diversifications. Mechanistic studies unraveled the unique features of ruthenium(II)-catalyzed C4/C6–H indole functionalizations.

Rhodium(II)-Catalyzed Regioselective Remote C–H Alkylation of Protic Indoles

Control of regioselectivity that defies the intrinsic reactivity of arene C–H bonds remains a formidable challenge. In this work, dimeric Rh(II) complexes have been applied as an efficient catalyst...

Rhodium(I)‐Catalyzed C2‐Selective Decarbonylative C−H Alkylation of Indoles with Alkyl Carboxylic Acids and Anhydrides

AbstractA Rh(I)‐catalyzed chelation‐assisted C2‐selective C−H decarbonylative alkylation of indoles with readily available, cheap, safe and structurally diverse alkyl carboxylic acids or anhydrides has been developed. A wide variety of primary and secondary alkyl carboxylic acids and differently substituted indoles are compatible with this transformation, allowing facile synthesis of various C2‐alkylated indoles with high efficiency and broad tolerance of diverse functional groups. The reaction proceeds in the absence of any external oxidant, and the presence of readily installable and removable N‐pyrimidyl directing group is critical for catalysis. The process is convenient and scalable, and avoids the use of a dried solvent and an inert atmosphere. Moreover, selective C7‐alkylation and C2, C7‐dialkylation have also been achieved by slightly modifying the reaction conditions.

Efficient copper-catalyzed synthesis of C3-alkylated indoles from indoles and alcohols

A highly efficient copper(II) catalyst system for alkylation of indoles with alcohols via hydrogen borrowing method has been developed to afford C3-alkylated indoles in good to excellent yields. Cu(OAc)2 in the combination with dppm ligand has been found to be the most suitable catalyst system for this alkylation reaction.

Facile access to bis(indolyl)methanes by copper-catalysed alkylation of indoles using alcohols under air

Bis(3-indolyl)methanes (BIM) are important and present in the structure of many alkaloid and bioactive compounds (anti-inflammatory, anticancer, antiobesity, antimicrobial, etc.). Herein, we have reported an air stable and convenient Cu(OAc)2 catalyst for alkylation of indoles with alcohols to give bis(3-indolyl)methanes in very good yields.