Alkylation Of Indoles Research Articles

Friedel–Crafts Alkylation of Indoles with Nitroalkenes through Hydrogen‐Bond‐Donating Metal–Organic Framework

AbstractUrea‐derived hydrogen‐bond‐donating (HBD) catalysts are good catalysts for organic transformations. Usually, urea derivatives undergo self‐recognition and aggregation during homogeneous catalytic processes. To avoid this, a new approach involving the incorporation of urea moieties into metal–organic frameworks (MOFs) was recently developed. Herein, we synthesized a new porous, zinc‐based MOF by using ureylenic acid that acts as a hydrogen‐bond‐donating catalyst. According to our knowledge, the pores of this MOF are larger than those of other reported HBD‐derived MOFs and, as such, can accommodate large substrates that typically cannot access the pores of other HBD‐based MOFs for the Friedel–Crafts reaction.

Polymer-Supported Chiral-at-Metal Lewis Acid Catalysts

The covalent immobilization of a chiral-at-metal bis-cyclometalated iridium(III) catalyst on a solid support is reported, and its catalytic activity has been investigated. As a catalyst immobilization strategy, a catalyst precursor was tethered to polystyrene macrobeads through an ester or amide linkage and subsequently converted to the immobilized active chiral Lewis acid by treatment with a Bronsted acid. The amide-linked catalyst displays high robustness and can be recycled multiple times without deterioration of enantioselectivity and only a gradual loss of catalytic activity. Chiral Lewis acid activity was demonstrated as an example for the enantioselective Friedel–Crafts alkylation of indole with an α,β-unsaturated 2-acyl imidazole and for the enantioselective Diels–Alder reactions of an α,β-unsaturated 2-acyl imidazole with 2,3-dihydrofuran or isoprene.

Cu3(BTC)2 as a viable heterogeneous solid catalyst for Friedel-Crafts alkylation of indoles with nitroalkenes

In the present work, Friedel-Crafts alkylation reaction of indole with β-nitrostyrene is examined using a readily available copper based metal-organic frameworks (MOFs) namely, Cu3(BTC)2 (BTC: 1,3,5-benzenetricarboxylic acid) as solid catalyst under mild reaction conditions. Among the various catalysts screened for this reaction, Cu3(BTC)2 exhibits higher activity under the optimized reaction conditions. Besides the absence of leaching of active sites, it is also observed that the catalyst can be reused for four cycles with a minimal decrease in its activity. Cu3(BTC)2 is used as a catalyst to synthesise a series of heterocyclic compounds with different indole and β-nitrostyrene derivatives in moderate to high yields. The present catalytic system shows comparable activity against to recent reports but the advantage of Cu3(BTC)2 is that it does not require any post-functionalization and above all it can be readily synthesised, thus contributing to the synthesis of heterocyclic compounds with high biological interest.

Cobalt-catalysed reductive C-H alkylation of indoles using carboxylic acids and molecular hydrogen.

The direct CH-alkylation of indoles using carboxylic acids is presented for the first time. The catalytic system based on the combination of Co(acac)3 and 1,1,1-tris(diphenylphosphinomethyl)-ethane (Triphos, L1), in the presence of Al(OTf)3 as co-catalyst, is able to perform the reductive alkylation of 2-methyl-1H-indole with a wide range of carboxylic acids. The utility of the protocol was further demonstrated through the C3 alkylation of several substituted indole derivatives using acetic, phenylacetic or diphenylacetic acids. In addition, a careful selection of the reaction conditions allowed to perform the selective C3 alkenylation of some indole derivatives. Moreover, the alkenylation of C2 position of 3-methyl-1H-indole was also possible. Control experiments indicate that the aldehyde, in situ formed from the carboxylic acid hydrogenation, plays a central role in the overall process. This new protocol enables the direct functionalization of indoles with readily available and stable carboxylic acids using a non-precious metal based catalyst and hydrogen as reductant.

Green Chemistry: Comparison of Ionic Liquid vs Conventional Solvent for Indole Alkylation

A comparison of the effectiveness of two synthetic methods was done for a green chemistry method using an ionic liquid-based solvent relative to a conventional method using organic solvents for the N-alkylation of indole. The green method used potassium hydroxide in the ionic liquid, 1-butyl-3-methylimidazolium tetrafluoroborate, followed by addition of the alkyl halide. The conventional method used sodium hydride in dimethylformamide. Possible advantages of the green method would be the use of a non-volatile solvent, the possibility of recycling the solvent, and the use of a less reactive base. However, its reaction yield was lower than for the conventional method, the reagent expense was higher, and recycling and reuse of the ionic solvent require considerable amounts of conventional solvent to clean it up sufficiently for reuse. On a laboratory scale, the ionic liquid method yielded neither a “green” nor an efficiency advantage. It is possible that with optimization on an industrial scale involving solvent reclamation that the green method could realize its promise. KEYWORDS: Green Chemistry; Sustainable Chemistry; Ionic Liquids; N-alkylation; Indole; Solvent Recycling; Organic Chemistry; 1-Butyl-3-methylimidazolium Tetrafluoroborate; Synthesis

Chiral phosphoric acid catalyzed aza-Friedel-Crafts alkylation of indoles with cyclic aryl α-ketimino esters

A highly enantioselective aza-Friedel-Crafts alkylation of indoles with cyclic aryl α-ketimino esters catalyzed by a chiral phosphoric acid has been developed, the corresponding α,α-disubstituted unnatural α-amino ester derivatives were obtained in moderate to high yields (67–85%) with high enantioselectivities (up to 93% ee) under mild reaction conditions.

ChemInform Abstract: Palladium‐Catalyzed Dearomative Allylic Alkylation of Indoles with Alkynes to Synthesize Indolenines with C3‐Quarternary Centers.

A palladium-catalyzed dearomative allylic alkylation of indoles with alkynes to construct indolenines with C3-quarternary centers was reported. The in situ formed arylallene intermediate omitted the need to install leaving groups on the allylic compounds and employ extra oxidants to oxidize the allylic C–H bonds. The reaction exhibited good functional group tolerance and high atom economy. Moreover, the reaction was further expanded to synthesize pyrroloindolines and furanoindolines.

Polystyrene-supported cu(II)-R-Box as recyclable catalyst in asymmetric Friedel–Crafts reaction

The complex of copper(II) trifluoromethanesulfonate with chiral isopropyl bis(oxazoline) ligand (i-Pr-Box) was immobilized on accessible and inexpensive Merrifield resin according to a “click” procedure. The resulting catalyst showed high efficiency and recyclability in the asymmetric Friedel–Crafts alkylation of indole and its derivatives. The catalyst can be recycled five times without appreciable loss in activity and enantioselectivity.

Lewis Acid Catalyzed Friedel–Crafts Alkylation of Indoles and Other­ Electron-Rich Aromatic Compounds with Ethyl 2-(Diethoxyphosphoryl)acrylate and Tetraethyl Ethene-1,1-diylbis(phosphonate)

Friedel–Crafts alkylation of indoles and other electron-rich aromatic compounds with ethyl 2-(diethoxyphosphoryl)acrylate and tetraethyl ethene-1,1-diylbis(phosphonate) was carried out in the presence of 5 mol% Cu(ClO4)2·6H2O/2,2′-Bipy complex as a catalyst in acetonitrile at room temperature to afford a broad series of heteroaryl- and aryl-substituted 2-(diethoxyphosphoryl)propionates and ethyl-1,1-diylbis(phosphonates) in 58–96% yield.

ChemInform Abstract: Cu(I)‐Catalyzed Enantioselective Friedel—Crafts Alkylation of Indoles with 2‐Aryl‐N‐sulfonylaziridines as Alkylating Agents.

AbstractThe scalable procedure provides tryptamine derivatives in high yields and with high enantioselectivities.

Restricted Conformation of a Hydrogen Bond Mediated Catalyst Enables the Highly Efficient Enantioselective Construction of an All-Carbon Quaternary Stereocenter

A highly active catalyst for the enantioselective Friedel–Crafts alkylation of indoles with β,β-disubstituted nitroalkenes is reported, allowing catalyst loadings down to 0.05 mol % for this challenging transformation, providing useful synthetic building blocks with an all-carbon quaternary stereocenter. The catalyst is based on a bis-cyclometalated iridium(III) complex as a structural template, and through the ligand sphere it forms hydrogen bonds with the two substrates. Starting from a previous design (Angew. Chem. Int. Ed. 2013, 52, 14021), the catalyst was rendered C2-symmetrical in order to maximize the atom economy of this catalyst scaffold (two catalytic centers per iridium complex), and, most importantly, rational design was applied to restrict the conformational freedom of a key hydrogen bond acceptor, being responsible for activating the indole nucleophile and bringing it in an ideal position for the presumed ternary transition state.

Synthesis of Magnetic Nanoparticles and Polymer Supported Imidazolidinone Catalysts for Enantioselective Friedel‐Crafts Alkylation of Indoles

AbstractThe copper catalyzed Huisgen cycloaddition has been used for the immobilization of enantiopure tbutyl‐imidazolidin‐4‐one on magnetic nanoparticles (MNP‐A, MNP‐B) at two different anchoring sites and a Merrifield resin support (PS). The obtained catalysts have been characterized by FTIR, elemental analysis, XRD and TEM. These catalysts have been used in alkylation of indoles with α,β‐unsaturated aldehydes affording the desired products in high yields with excellent enantioselectivities. MNP‐A with the magnetic nano‐functionalization at the amide nitrogen (N3) position shows relatively lower catalytic efficiency compared to MNP‐B with nanoparticles anchored at the O‐aryl residue. The PS, owing to its high loading of the catalyst, shows higher catalytic activity than MNP‐A and MNP‐B but the magnetic nanocatalysts show higher recycling efficiency than the PS as they can be easily separated from the reaction medium through simple magnetic decantation.

Highly Efficient Tetranuclear ZnII2LnIII2 Catalysts for the Friedel–Crafts Alkylation of Indoles and Nitrostyrenes

We demonstrate for the first time the high efficacy of tetranuclear ZnII2LnIII2 coordination clusters (CCs) as catalysts for the Friedel–Crafts (FC) alkylation of indoles with a range of trans-β-nitrostyrenes. The reaction proceeds in good to excellent yields (76%–99%) at room temperature with catalyst loadings as low as 1.0 mol %.

Metal‐Templated Asymmetric Catalysis: (Z)‐1‐Bromo‐1‐Nitrostyrenes as Versatile Substrates for Friedel–Crafts Alkylation of Indoles

AbstractAn asymmetric Friedel–Crafts alkylation of indoles with (Z)‐1‐bromo‐1‐nitrostyrenes, which is efficiently catalyzed by a number of hydrogen bond interactions with the ligand sphere of bis‐cyclometalated iridium complexes, has been reported. The proposed transition state exploits a hydrogen bond network, which is illustrated by the co‐crystal structure of a model catalyst with an analog of the nitro substrate. The bromo functional group not only plays an important role for achieving a high asymmetric induction but also affords chiral indole‐containing products, which can be readily converted to a range of useful intermediates for the creation of chiral indole building blocks.

ChemInform Abstract: Friedel—Crafts Alkylation of Indoles with p‐Quinols: The Role of Hydrogen Bonding of Water for the Desymmetrization of the Cyclohexadienone System.

Abstract5‐Indolyl substituted 4‐hydroxy‐4‐methyl‐2‐cyclohexanone systems are prepared in a high π‐facial diastereoselective manner.

Unified Strategy for Nickel-Catalyzed C-2 Alkylation of Indoles through Chelation Assistance

A nickel-catalyzed direct C-2 alkylation of indoles through monodentate-chelation assistance has been described. This reaction proceeds via an unusual strategy by the use of a well-designed and defined (quinolinyl)amido–nickel catalyst, [{κN,κN,κN-Et2NCH2C(O)(μ-N)C9H6N}Ni(OAc)], providing a solution to the limitations associated with bidentate-chelate auxiliaries. The method allows coupling of indoles with various unactivated primary and secondary alkyl halides with ample substrate scope. This uniquely strategized alkylation proceeded through crucial C–H activation and via an alkyl radical intermediate. The reaction by this approach represents a rare example of Ni-catalyzed monodentate-chelate-assisted C–H functionalization.

Palladium-Catalyzed Dearomative Allylic Alkylation of Indoles with Alkynes To Synthesize Indolenines with C3-Quarternary Centers.

A palladium-catalyzed dearomative allylic alkylation of indoles with alkynes to construct indolenines with C3-quarternary centers was reported. The in situ formed arylallene intermediate omitted the need to install leaving groups on the allylic compounds and employ extra oxidants to oxidize the allylic C-H bonds. The reaction exhibited good functional group tolerance and high atom economy. Moreover, the reaction was further expanded to synthesize pyrroloindolines and furanoindolines.

ChemInform Abstract: Polystyrene or Magnetic Nanoparticles as Support in Enantioselective Organocatalysis? A Case Study in Friedel—Crafts Chemistry.

AbstractThe efficiency of the second‐generation MacMillan organocatalyst onto slightly cross‐linked polystyrene or iron oxide magnetic nanoparticles is evaluated in the enantioselective Friedel—Crafts alkylation of indoles with α,β‐unsaturated aldehydes.

ChemInform Abstract: Easy Access to a Library of Alkylindoles: Reductive Alkylation of Indoles with Carbonyl Compounds and Hydrosilanes under Indium Catalysis.

AbstractVarious functionalized indoles are alkylated with a diverse range of alkyl, aryl or hetaryl aldehydes or ketones following a practical and scalable one or two step procedure.

ChemInform Abstract: Observations Concerning the Synthesis of Tryptamine Homologues and Branched Tryptamine Derivatives via the Borrowing Hydrogen Process: Synthesis of Psilocin, Bufotenin, and Serotonin.

AbstractThe selective indole alkylation reaction applying the Ir‐catalyzed‐borrowing hydrogen methodology and using amino alcohols (II), (V), (VII) as suitable nitrogen‐containing electrophiles is reported.