Enantioselective Friedel-Crafts Research Articles

Enantioselective Friedel-Crafts Alkylation between Nitroalkenes and Indoles Catalyzed by Charge Activated Thiourea Organocatalysts.

A series of methylated and octylated pyridinium and quinolinium containing thiourea salts with a chiral 2-indanol substituent are reported. These organocatalysts are positively charged analogues of privileged bis(3,5-trifluoromethyl)phenyl substituted thioureas, and are found to be much more active catalysts despite the absence of an additional hydrogen bond donor or acceptor site (i.e., the presence of a heteroatom-hydrogen or heteroatom). Friedel-Crafts reactions of trans-β-nitorostyrenes with indoles are examined, and good yields and enantioselectivities are obtained. Mechanistic studies indicate that this is a second-order transformation under the employed conditions, and is consistent with the dimer of the thiourea being the active catalyst. Charged organocatalysts, consequently, represent an attractive design strategy for catalyst development.

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.

Highly Enantioselective Friedel–Crafts Reactions of Indoles with Isatins Catalyzed by Chiral Imidodiphosphoric Acids

AbstractA highly enantioselective Friedel–Crafts arylation of indoles with isatins catalyzed by H8‐1,1’‐bi‐2‐naphthol (BINOL) imidodiphosphoric acids is reported here. This reaction proceeds smoothly under mild conditions and afford a range of 3‐hydroxy‐3‐indolyloxindoles with high yields (<92 %) and excellent enantioselectivities (<99 % ee). To the best of our knowledge, this is the first example in which the highly enantioselective arylation of indoles with isatins has been catalyzed by a Brønsted acid.

Copper-Catalyzed Chemoselective and Enantioselective Friedel-Crafts 1,2-Addition of Pyrrole with β,γ-Unsaturated α-Ketoesters.

A Friedel-Crafts alkylation of pyrrole was developed to afford the β,γ-unsaturated α-hydroxy esters bearing a quaternary stereogenic center with good enantioselectivities and yields. This protocol represents the first report of 1,2-addition of Friedel-Crafts alkylation of pyrrole to β,γ-unsaturated α-ketoesters.

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.

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.

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.

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.

Bifunctional Amine‐Squaramide Catalyzed Friedel–Crafts Alkylation Based on ortho‐Quinone Methides in Oil‐Water Phases: Enantioselective Synthesis of Triarylmethanes

AbstractAn efficient enantioselective Friedel–Crafts alkylation reaction of electron‐rich β‐naphthol with in situ generated ortho‐quinone methides catalyzed by chiral bifunctional amine‐squaramide catalysts has been developed. The chiral triarylmethane derivatives were obtained in good to high yields (up to 97% yield) with high enantioselectivities (up to 97% ee) for most substrates under mild conditions. This study also revealed that the oil‐water biphase could significantly improve the efficiency of this catalytic system.magnified image

Cooperative Cation‐Binding Catalysis as an Efficient Approach for Enantioselective Friedel–Crafts Reaction of Indoles and Pyrrole

AbstractIn this study, we demonstrated the cooperative cation‐binding catalysis as an efficient approach for enantioselective Friedel–Crafts reaction of indoles and pyrroles. By using highly accessible chiral oligoethylene glycol (oligoEG) as the cation‐binding catalyst and KF as the base, a highly enantioselective Friedel–Crafts reaction of indoles, 4,7‐dihydroindoles, and pyrrole with bench‐stable α‐amidosulfones as in‐situ equivalents of sensitive imines was achieved. The scope of this new catalytic protocol was not limited to aromatic imines. Heteroaromatic and aliphatic substrates as well as α‐iminoethyl glyoxylate also afforded the desired products with excellent yields and ees. The enforced proximity of the catalyst and substrates in a chiral cage in situ formed by incorporation of the potassium salt enhanced the reactivity and efficiently transferred the stereochemical information, mimicking the action of enzymes.magnified image

A highly enantioselective Friedel-Crafts reaction of 3,5-dimethoxylphenol with nitroolefins mediated by a bifunctional quinine derived thiourea catalyst.

A useful enantioselective Friedel-Crafts reaction of 3,5-dimethoxylphenol with nitroolefins catalyzed by a bifunctional quinine derived thiourea catalyst 9 was developed. The Michael addition products could be obtained in good to high yields (68-92%) and with excellent enantioselectivities (89-98% ee). Such a reaction is exceptionally attractive in virtue of its simple protocol, ready availability of the starting materials, and practical applications of the products.

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.

Organocatalytic Enantioselective Synthesis of α-Hydroxyketones through a Friedel-Crafts Reaction of Naphthols and Activated Phenols with Aryl- and Alkylglyoxal Hydrates.

An efficient organocatalytic asymmetric synthesis of α-hydroxyketones has been developed. Quinine-derived thiourea catalyzed the enantioselective Friedel-Crafts alkylation of naphthols and activated phenols with aryl- and alkylglyoxal hydrates, providing the corresponding chiral α-hydroxyketones with high yields (up to 97%) and excellent enantioselectivities (up to 99% ee).

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.

Construction of Furan Derivatives with a Trifluoromethyl Stereogenic Center: Enantioselective Friedel-Crafts Alkylations via Formal Trienamine Catalysis.

An asymmetric Friedel-Crafts alkylation reaction of 2-furfuryl ketones with β-trifluoromethyl enones has been developed via formal trienamine catalysis of a bifunctional primary amine-thiourea substance derived from L-tert-leucine, delivering the furan derivatives incorporating a stereogenic trifluoromethyl (CF3) group in good to high yields with excellent enantioselectivity.

ChemInform Abstract: Catalytic Enantioselective Friedel—Crafts Reactions of Naphthols and Electron‐Rich Phenols

AbstractReview: [61 refs.

Enantioselective and Regiodivergent Functionalization of N‐Allylcarbamates by Mechanistically Divergent Multicatalysis

A pair of mechanistically divergent multicatalytic reaction sequences has been developed consisting of nickel-catalyzed isomerization of N-allylcarbamates and subsequent phosphoric-acid-catalyzed enantioselective functionalization of the resulting intermediates. By appropriate selection of reaction partners, in situ generated imines and ene-carbamates are mechanistically partitioned to yield opposing functionalized products. Formal α-functionalization to give protected α-arylamines is achieved upon enantioselective Friedel-Crafts reaction with arene nucleophiles, whereas formal β-functionalization is achieved upon reaction with diarylimine electrophiles in an enantioselective Povarov-[4+2] cycloaddition.

Asymmetric Assisted Tandem Catalysis: Hydroamination followed by Asymmetric Friedel–Crafts Reaction from a Single Chiral N,N,N′,N′‐Tetradentate Pyridylmethylamine‐Based Ligand

AbstractWith the rising interest in asymmetric catalysis promoted by earth‐abundant elements, a chiral ligand will undoubtedly be the most valuable unit of the catalyst. The first proof of concept of the use of a multitask chiral ligand in an asymmetric assisted tandem catalysis protocol that successively combines metallo‐ and organocatalytic processes is reported herein. In this protocol, the chiral ligand of the newly designed rare‐earth catalyst of the first reaction is converted into a novel chiral organocatalyst for the second transformation by the simple addition of HCl. The observation of some enantioinduction in the tandem sequence—alkyne hydroamination followed by enantioselective Friedel–Crafts alkylation—confirms the relay of the chiral N,N,N′,N′‐tetradentate ligand and the importance of its pyridylmethylamine scaffold.

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: Enantioselective Friedel—Crafts Alkylation Reactions of 3‐Substituted Indoles with Electron‐Deficient Alkenes.

Highly enantioselective Friedel–Crafts C2-alkylation reactions of 3-substituted indoles with α,β-unsaturated esters and nitroalkenes were developed using chiral Lewis acids as catalysts, which afforded chiral indole derivatives bearing C2-benzylic stereogenic centers in good to excellent yields (up to 99%) and enantioselectivities (up to 96% ee).