Asymmetric Friedel-Crafts Alkylation Of Indoles Research Articles

Asymmetric Friedel-Crafts Alkylation of Indoles with Trifluoromethyl Pyruvate Catalyzed by a Dinuclear Zinc Catalyst.

A bimetallic cooperative catalysis model has been reported for the asymmetric Friedel-Crafts (F-C) alkylation of indoles with trifluoromethyl pyruvates using Trost's intramolecular dinuclear zinc complex as the catalyst. This dinuclear zinc catalyst was prepared in situ by reacting the chiral ligand (S,S)-L2b with 2 equiv of ZnEt2. A series of trifluoromethyl alcohol and indole-containing biological compounds were formed in moderate to good yields (up to 95%) with good enantioselectivity (up to 88% enantiomeric excess (ee)) in the presence of 10 mol % catalyst under mild conditions. A synergistic transition state model was proposed to explain the origin of the asymmetric induction.

Ammonium chiral borate salt catalyzed asymmetric Friedel-Crafts alkylation of indoles with α,β-disubstituted enals

In the presence of a catalytic amount of ammonium chiral borate salt, asymmetric Friedel-Crafts alkylation of indoles with α,β-disubstituted enals proceeded to give the corresponding 1,4-addition products with moderate enantioselectivities.

Fiaud's Acid: A Brønsted Acid Catalyst for Enantioselective Friedel-Crafts Alkylation of Indoles with 2-Alkene-1,4-diones.

Fiaud's acid (trans-1-hydroxy-2,5-diphenylphospholane 1-oxide), a phospholane-based phosphinic acid, is introduced as an efficient chiral Brønsted acid catalyst that mediates the asymmetric Friedel-Crafts alkylation of indoles with 2-butene-1,4-diones. With a catalyst loading of 10 mol %, the reaction proceeded smoothly to afford 2-(indol-3-yl)butane-1,4-diones in high yield (up to 82%) and high enantioselectivity (up to 91% ee, one such product showed enhanced ee of 98% after recrystallization). The reaction conditions are sufficiently mild to tolerate sensitive functionality at room temperature and are therefore suitable for the synthesis of complex targets.

Chiral Sulfonimide as a Brønsted Acid Organocatalyst for Asymmetric Friedel–Crafts Alkylation of Indoles with Imines

Binaphthyl-based chiral sulfonimide (CSI) is demonstrated for the first time to be an efficient, strong Brønsted acid in asymmetric organocatalysis. A series of CSIs were synthesized and screened in the asymmetric Friedel-Crafts alkylation of indoles with imines. Good to excellent yields and enantioselectivities have been achieved. It was proved that it was crucial to wash the CSI catalyst with HCl before use.

ChemInform Abstract: Synthesis of Tridentate Ligands Based on Chiral Diamines and Their Application to Enantioselective Friedel—Crafts Alkylation of Indoles with Nitroalkenes.

A new type of chiral tridentate ligands were prepared and their Zn complexes were examined for the asymmetric Friedel-Crafts alkylation of indoles with nitroalkenes, which gave rise to good yields and moderate enantioselectivities.

Synthesis of Tridentate Ligands Based on Chiral Diamines and Their Application to Enantioselective Friedel‐Crafts Alkylation of Indoles with Nitroalkenes

AbstractA new type of chiral tridentate ligands were prepared and their Zn complexes were examined for the asymmetric Friedel‐Crafts alkylation of indoles with nitroalkenes, which gave rise to good yields and moderate enantioselectivities.

Asymmetric Friedel-Crafts Alkylation of Indoles: The Control of Enantio- and Regioselectivity

The asymmetric Friedel-Crafts reaction of indoles isa synthetic methodology that enables direct access to the enantiopure indolederivatives. In this review, work mainly carried out by You andhis co-workers on the regio- and enantioselective synthesis of indolederivatives will be discussed. Chiral Bronsted acids oriridium complexes promote highly enantioselective Friedel-Craftsreactions of indoles and 4,7-dihydroindoles starting with various electrophilicreagents, such as imines, N-tosyl-substitutedamines, β,γ-unsaturated α-keto esters,nitro-substituted olefins, aldehydes, and allyl carbonates. Thesemethodologies can be used to readily prepare diverse enantioenrichedindoles, such as indol-3-ylmethanamines, indol-2-ylmethanamines,unsymmetrical arylbis(indol-3-yl)methanes, 9-indol-3-ylfluorenes,tetrahydropyrano[3,4- B]indoles,tetrahydro-γ-carbolines, and tetrahydro-β-carbolines. 1 Introduction 2 Asymmetric Friedel-Crafts Alkylation of Indoles atthe -3-Position 2.1 Chiral Phosphoric Acids and Their Activation Mode 2.2 Asymmetric Friedel-Crafts Alkylation of Indoleswith -Imines 2.3 Asymmetric Friedel-Crafts Alkylation of Indoleswith N-Tosyl-Substituted Amines 2.4 Tandem Friedel-Crafts Alkylation of Indoles withAldehydes and Alcohols 2.5 Iridium-Catalyzed Asymmetric Friedel-Crafts Allylic Alkylationof Indoles 3 Asymmetric Friedel-Crafts Alkylation of Indoles atthe 2-Position 3.1 Asymmetric Friedel-Crafts Alkylation of 4,7-Dihydro-indoleswith Imines 3.2 Asymmetric Friedel-Crafts Alkylation of 4,7-Dihydro-indoleswith Keto Esters 3.3 Asymmetric Friedel-Crafts Alkylation of 4,7-Dihydro-indoleswith Nitro-Substituted Olefins 4 Sequential Catalysis for the Enantioselective Synthesis of PolycyclicIndoles 5 Conclusion and Outlook

Direct Experimental Evidence for the Priority of Flexible Ligand Skeleton in Asymmetric Friedel-Crafts Alkylation of Indole with Nitroalkenes

Abstract: Direct experimental evidence for the priority of flexible ligand skeleton in asymmetric Friedel-Crafts alkylation was obtained through XRD analysis of flexible ligand/ZnCl 2 complex, as well as synthesis of dihydroacridine-linked bis(oxazoline) ligands with planar rigid scaffold. A transition state model without NH …  interaction was proposed for the rigid ligands to interpret the inversion of absolute configuration. Keywords: Rigid scaffold, flexible scaffold, diphenylamine, dihydroacridine, bis(oxazoline), Friedel-Crafts alkylation. INTRODUCTION Since the pioneering reports on oxazolines [1], chiral bis(oxazoline) ligands have been extensively developed by chemists in the fields of coordination chemistry, synthetic chemistry, and catalysis [2]. Large number of ligands with diverse scaffolds have been synthesized from commercially available amino alcohols and carboxylic acids/aldehydes through facile procedures, which illustrates their great potency in application. Some ligand scaffolds stand out from vast reports and gain broad applications in different asymmetric transformations [3], while most ligand scaffolds give satisfying results only in specific cases. Such a situation makes the design of novel ligands for designated reactions a difficult and unprofitable work. In recent years, some groups dedicated to the research on the relationship of ligand structure and enantioselectivity, especially the tuning of electronic effect and rigidity of ligand scaffold. Compared with the encouraging results achieved in the former case [4], much less attention has been paid on the tuning of rigidity [5]. Herein, we would like to document our recent progress on this subject. Diphenylamine-linked bis(oxazoline) ligands

AgAsF6/Sm(OTf)3 Promoted Reversal of Enantioselectivity for the Asymmetric Friedel−Crafts Alkylations of Indoles with β,γ-Unsaturated α-Ketoesters

The first example of central metal controlled reversal of enantioselectivity in asymmetric Friedel-Crafts alkylation of indoles and beta,gamma-unsaturated alpha-ketoesters has been developed. Using the same chiral starting material derived N,N'-dioxides 1a and 1b as ligands, various indole esters 4 were obtained in good to excellent yields and enantioselectivities. The reaction also featured mild reaction conditions and remarkably low catalyst loading (down to 0.01 mol %).

Modification of diphenylamine-linked bis(oxazoline) ligands: Tuning of electronic effect and rigidity of ligand skeleton

The electronic effect of diphenylamine-linked bis(oxazoline) ligands was tuned through introduction of electron-withdrawing bromo and nitro substituents onto the 4 and 4′ position. The variation of the NH bond acidity was determined by the different chemical shifts of NH. The catalytic activity and enantioselectivity of the modified ligands were tested in the asymmetric Friedel-Crafts alkylation of indole with β-nitrostyrene. The effect of ligand skeleton rigidity was also investigated through the synthesis of iminodibenzyl-linked bis(oxazoline) ligands and evaluation of their catalytic activity in Friedel-Crafts alkylation.

Asymmetric Friedel-Crafts alkylation of indole with chalcones catalyzed by chiral phosphoric acids.

The reaction of indole with chalcones, to give Michael-type adducts, was found to occur with good efficiency (up to 98% yield) and moderate enantioselectivity (up to 52% e.e.) in the presence of a chiral BINOL-based phosphoric acid. Furthermore, the alkylation products can be obtained in much higher e.e.s after one only crystallization.

Enantioselective Friedel–Crafts Alkylation of Indoles with Alkylidene Malonates Catalyzed by N,N′‐Dioxide–Scandium(III) Complexes: Asymmetric Synthesis of β‐Carbolines

An efficient catalytic asymmetric Friedel-Crafts alkylation of indoles with alkylidene malonates has been developed by using a chiral N,N'-dioxide-Sc(OTf)(3) complex as the catalyst (see scheme). Some optically active intermediates containing the indole skeleton have been synthesized, such as indolepropionic acid, tryptamines, and beta-carbolines. The coordination between the scandium atom and the chiral N,N'-dioxide compound has been revealed by X-ray structure analysis.

Remarkable Effect of N-Substituent on Enantioselective Ruthenium-Catalyzed Propargylation of Indoles with Propargylic Alcohols

Ruthenium-catalyzed enantioselective propargylation of indoles with propargylic alcohols affords the corresponding beta-propargylated indoles in good yields with a high enantioselectivity (up to 95% ee). A remarkable effect of the nature of the N-substituent of indoles is observed for the enantioselectivity of the propargylated indoles. The preparative method described in this paper may provide a novel protocol for asymmetric Friedel-Crafts alkylation of indoles using propargylic alcohols as a new type of electrophiles.

Organocatalytic Asymmetric Friedel-Crafts Alkylation of Indoles with Enones

Melchiorre and co-workers reported an efficient asymmetric organocatalytic alkylation of indoles 1 with simple α,β-unsaturated ketones 2, giving access to a broad range of highly enantio­enriched β-indolyl ketones 3. The reaction is catalyzed by amine salt 4, in which both the cation and anion are chiral, through iminium ion catalysis, and tolerates steric and electronic demands of the β-olefin substitutent as well as aromatic ketones. The methodology can also be applied to substituted indoles without affecting the effi­ciency of the system. However, substitution on the indolic nitrogen leads to a strong decrease of the reactivity and has a detrimental effect on the ­selectivity.