Alkylation Of Indoles Research Articles

TiCl2(OTf)-SiO2: A solid stable lewis acid catalyst for Michael addition of α-Aminophosphonates, Amines, Indoles and Pyrrole

ABSTRACTTiCl2(OTf)-SiO2 is simply prepared by immobilization of TiCl3(OTf) on silica gel surface and introduced as a non-hygroscopic Lewis acid catalyst for C-N and C-C bond formation via Michael addition reaction. A variety of structurally diverse nitrogen nucleophiles including α-aminophosphonates, aliphatic and aromatic amines and imidazole were evaluated as Michael donors. Friedel–Crafts alkylation of indoles and pyrrole was also investigated through Michael addition reaction in the presence of TiCl2(OTf)-SiO2 as a catalyst. The reactions were conducted at room temperature or 60 °C under solvent-free conditions and the desired Michael adducts were obtained in high to excellent yields.

Rh-Catalyzed C-H bond alkylation of indoles with α,α-difluorovinyl tosylate via indolyl group migration.

Herein we demonstrate that an alkylation of indoles could be accessed through C-H bond functionalization with α,α-difluorovinyl tosylate. The key aspect for the effective alkylation is the influence of the fluorine substituents on the reactivity of the C[double bond, length as m-dash]C double bond, allowing regioselective insertion as well as an indolyl group shift process. Furthermore, the fluorides are removed through alcoholysis to furnish the alkylation product as a traceless auxiliary.

Regio- and stereospecific Friedel-Crafts alkylation of indoles with spiro-epoxyoxindoles.

A highly efficient strategy for the regio- and stereospecific Friedel-Crafts alkylation of indoles with spiro-epoxyoxindoles has been developed in the mixed solvents of HFIP/H2O (1 : 9) without the use of catalysts. This protocol provides an atomically economical, catalyst-free and simple route for the construction of synthetically useful 3-(3-indolyl)-oxindole-3-methanols in high yields. Starting from optically active spiro-epoxyoxindoles a variety of enantiospecific 3-(3-indolyl)-oxindole-3-methanols could be obtained in high yields with complete retention of enantioselectivity.

Ionic liquids vs. microporous solids as reusable reaction media for the catalytic C–H functionalization of indoles with alcohols

High performance reusable catalysts and reaction media are evaluated for the green alkylation of indoles with alcohols under mild and solvent-free conditions.

Friedel-Crafts alkylation reaction with fluorinated alcohols as hydrogen-bond donors and solvents.

An effective and clean FC alkylation of indoles and electron-rich arenes with β-nitroalkenes in HFIP was reported. The desired products are formed rapidly in excellent yields under mild conditions without the need for any additional catalysts or reagents. Further, this methodology can be applied to one-pot synthesis of biologically active tryptamine derivatives.

Visible‐Light‐Promoted Alkylation of Indoles with Tertiary Amines by the Oxidation of a sp3 C‐H Bond

AbstractA visible‐light driven reaction for the synthesis of 3‐arylmethyl indole derivatives using tertiary amines and indoles was first reported. Corresponding products were obtained with yields of up to 70%, and various functional groups on the indoles were well tolerated when Rose Bengal was used as a photosensitizer and air was used as a green oxidant under mild reaction conditions.magnified image

New thiourea organocatalysts and their application for the synthesis of 5-(1H-indol-3-yl)methyl-2,2-dimethyl-1,3-dioxane-4,6-diones a source of chiral 3-indoylmethyl ketenes

ABSTRACTThe stereoselective properties of modified thiourea organocatalysts were tested in the Friedel–Crafts alkylation of indole with 5-arylidene-2,2-dimethyl-1,3-dioxane-4,6-diones, which produces chiral 5-((1H-indol-3-yl)(aryl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-diones. Based on a tentative reaction mechanism for ((S)-N-benzyl-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N,3,3-trimethylbutanamide organocatalysts, modifications were applied in four selected regions. Systematic structure-stereoselectivity relationship study allowed designing the best efficient organocatalyst for the investigated Friedel–Crafts alkylation of indole with 5-arylidene-2,2-dimethyl-1,3-dioxane-4,6-diones.

Boosting Chemical Stability, Catalytic Activity, and Enantioselectivity of Metal-Organic Frameworks for Batch and Flow Reactions.

A key challenge in heterogeneous catalysis is the design and synthesis of heterogeneous catalysts featuring high catalytic activity, selectivity, and recyclability. Here we demonstrate that high-performance heterogeneous asymmetric catalysts can be engineered from a metal-organic framework (MOF) platform by using a ligand design strategy. Three porous chiral MOFs with the framework formula [Mn2L(H2O)2] are prepared from enantiopure phosphono-carboxylate ligands of 1,1'-biphenol that are functionalized with 3,5-bis(trifluoromethyl)-, bismethyl-, and bisfluoro-phenyl substituents at the 3,3'-position. For the first time, we show that not only chemical stability but also catalytic activity and stereoselectivity of the MOFs can be tuned by modifying the ligand structures. Particularly, the MOF incorporated with -CF3 groups on the pore walls exhibits enhanced tolerance to water, weak acid, and base compared with the MOFs with -F and -Me groups. Under both batch and flow reaction systems, the CF3-containing MOF demonstrated excellent reactivity, selectivity, and recyclability, affording high yields and enantioselectivities for alkylations of indoles and pyrrole with a range of ketoesters or nitroalkenes. In contrast, the corresponding homogeneous catalysts gave low enantioselectivity in catalyzing the tested reactions.

Secondary amine-catalyzed asymmetric formal aza [3 + 3] cycloaddition to construct enantioenriched piperidines derivatives

An amine-catalyzed asymmetric formal aza [3 + 3] cycloaddition of α,β-unsaturated aldehydes with N-Ts ketimines derived from both acyclic and cyclic ketones was developed, which was followed by an oxidation to afford chiral piperidine derivatives in good yields and excellent enantioselectivities (up to 99% ee). In addition, the corresponding cycloadduct piperidin-2-ols can be easily transformed to indolyl substituted chiral piperidine derivatives in good yields and excellent diastereoselectivities (>20:1) via Friedel-Crafts alkylation of indole in the presence of BF3·Et2O.

The Friedel–Crafts Reaction of Indoles with Michael Acceptors Catalyzed by Magnesium and Calcium Salts

Friedel–Crafts alkylation of indole and its derivatives with a variety of electron-deficient alkenes catalyzed by Mg and Ca salts has been studied. The dependence of the results on the nature of the starting olefins, substituents on indole, and Michael acceptors, as well as on the composition of the Lewis acid is discussed. High yields of the addition products were achieved in the addition of indole to β,γ-unsaturated α-keto esters and coumarin derivatives, some nitroolefins, and arylidenemalonates. Reactions involving arylidenemalonates were found to be the most versatile and smooth, the best yields reached 92%. Among the Mg and Ca salts tested, magnesium iodide (MgI2) proved to be the most appropriate catalyst in the addition to various unsaturated carbonyl compounds, while calcium triflimide [Ca(NTf2)2] efficiently catalyzed the addition to nitroolefins.

K2S2O8-Activated Friedel–Crafts Type Alkylation of Indoles with α-Amido Sulfones

A K2S2O8-activated regioselective alkylation of α-amido sulfones at the C-3 position of indoles is reported. The protocol developed herein provides an alternative new strategy to the previous approach by using Lewis acid, clay, and resin as catalyst for this Friedel–Crafts type alkylation of indoles with α-amido sulfones. The formed product bears a versatile transformable sulfone group and an amino group. The reaction condition is tolerant to a wide range of substrates, including a series of indoles with electron-withdrawing and electron-donating groups at different positions. Moreover, a variety of α-substituted phenylamido sulfones and some α-aliphatic amido sulfones also give the desired products in modest yield. Furthermore, a preliminary mechanism study was performed and the plausible reaction mechanism is discussed.

Friedel–Crafts Alkylation of Indoles with 3-Indolylmethanols

Friedel–Crafts Alkylation of Indoles with 3-Indolylmethanols

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.

Ionic liquid [Dabco-C8][FeCl4] as an efficient and recyclable catalyst for direct C3 alkylation of indoles with electron-deficient olefins

In this paper, a simple and highly efficient Friedel–Crafts Michael–type addition of indoles to electron-deficient olefins was achieved by a new magnetic ionic liquid catalyst ([Dabco-C8][FeCl4]). This catalyst system is applicable to a variety of electron-deficient olefins, including chalcones, enones, and nitro-olefins, and affords the corresponding 3-alkylindole derivatives in good to excellent yields under mild conditions within short times. The catalyst can be recycled four times without considerable activity loss.

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.

AlCl₃·6H₂O-Catalyzed Friedel-Crafts Alkylation of Indoles by the para-Quinone Methide Moiety of Celastrol.

A classical Friedel-Crafts alkylation of different indoles catalyzed by AlCl3·6H2O has been developed for a well-known important natural product, celastrol, resulting in a series of derivatives for further biological evaluation. The catalyst loading was reduced to 5 mol %, the reaction proceeds at ambient temperature and reaction time is only 3 h. The product yields range from 20% to 99%. A reaction mechanism is also proposed, based on our experiment results.

Efficient Catalytic Kinetic Resolution of Spiro-epoxyoxindoles with Concomitant Asymmetric Friedel-Crafts Alkylation of Indoles.

An efficient process involving the catalytic kinetic resolution of racemic spiro-epoxyoxindoles with the simultaneous enantioselective Friedel-Crafts alkylation of indoles has been realized using a chiral phosphoric acid catalyst. The reaction provides two useful intermediates in high yields and excellent enantioselectivities. Performing the catalysis on a gram scale led to (R)-3-(3-indolyl)-oxindole-3-methanol, which was used in the asymmetric formal total synthesis of (+)-gliocladin C. Notably, the enantiomers (S)-3-(3-indolyl)-oxindole-3-methanol can be obtained easily by the reaction of the resolved spiro-epoxyoxindole with indole.

Efficient Catalytic Kinetic Resolution of Spiro‐epoxyoxindoles with Concomitant Asymmetric Friedel–Crafts Alkylation of Indoles

AbstractAn efficient process involving the catalytic kinetic resolution of racemic spiro‐epoxyoxindoles with the simultaneous enantioselective Friedel–Crafts alkylation of indoles has been realized using a chiral phosphoric acid catalyst. The reaction provides two useful intermediates in high yields and excellent enantioselectivities. Performing the catalysis on a gram scale led to (R)‐3‐(3‐indolyl)‐oxindole‐3‐methanol, which was used in the asymmetric formal total synthesis of (+)‐gliocladin C. Notably, the enantiomers (S)‐3‐(3‐indolyl)‐oxindole‐3‐methanol can be obtained easily by the reaction of the resolved spiro‐epoxyoxindole with indole.

Design and Applications of N-tert-Butyl Sulfinyl Squaramide Catalysts.

A new chiral HBD system, N-tert-butyl sulfinyl squaramide, was designed and synthesized. The core N-tert-butyl sulfinyl squaramide with an 1-aminoindan-2-ol skeleton was found to be an efficient catalyst in the enantioselective Friedel-Crafts alkylation of indoles and acyl phosphonates.

Gold(I)-Mediated Thiourea Organocatalyst Activation: A Synergic Effect for Asymmetric Catalysis.

Several group 11 metal complexes with chiral thiourea organocatalysts have been prepared and tested as organocatalysts. The promising results on the influence of metal‐assisted thiourea organocatalysts in the asymmetric Friedel–Crafts alkylation of indole with nitrostyrene are described. Better results with the metal complexes have been achieved because of the cooperative effects between the chiral thiourea and the metal. The synergic effect between both species is higher than the effect promoted by each one separately, especially for gold(I). These outcomes are attributed to a pioneering gold(I) activation of the thiourea catalysts, affording a more acidic and rigid catalytic complex than that provided by the thiourea alone. Furthermore, the use of the gold–thiourea organocatalyst allows reducing the catalyst loading to 1–3 mol %. This contribution could become an important starting point for further investigations opening a new line of research overlooked so far in the literature.