Asymmetric Friedel-Crafts Alkylation Research Articles

Enantioselective Friedel-Crafts alkylation of 1,3,5-trimethoxybenzene with trans-β-nitrostyrenes catalysed by [Cp*Rh{(R)-Prophos}(H2O)][SbF6]2 (Prophos = propane-1,2-diyl-bis(diphenylphosphane)

The aqua complex (SRh,RC)-[Cp*Rh{(R)-Prophos}(H2O)][SbF6]2 (Prophos = propane-1,2-diyl-bis(diphenylphosphane) catalyses the asymmetric Friedel-Crafts (FC) alkylation of 1,3,5-trimethoxybenzene with trans-β-nitrostyrenes. Only the monoalkylated adduct was obtained in all cases with enantioselectivities of up to 93/7 e.r. Solution NMR measurements have allowed us to detect and characterise catalytic intermediates such as metal-trans-β-nitrostyrene and metal‑aci-nitro complexes, as well as free aci‑nitro compound. Based on these studies, a Michael-type Friedel-Crafts mechanism is proposed.

Gold Catalysis, Asymmetric Friedel-Crafts Alkylation Cascade for One-Pot Synthesis of Chiral Dihydrocarbazoles and Dihydrodibenzofurans.

A one-pot gold-catalyzed acyl migration followed by ytterbium-catalyzed asymmetric Friedel-Crafts alkylation is disclosed, leading to the rapid synthesis of chiral dihydrocarbazoles and dihydrodibenzofuran in generally moderate to good overall yields with good to excellent enantioselectivities. The gold-catalyzed acyl migration of propargyl acetates generates α-ylidene-β-diketones with high E/Z ratios, which are then subjected to the ytterbium-catalyzed asymmetric Friedel-Crafts alkylation without any purification. Importantly, this protocol provides a new type of substrate for asymmetric Friedel-Crafts alkylation.

Naphthyridine–2NO, a new C2-symmetric rigid tetradentate bimetallic ligand and its application in asymmetric Friedel–Crafts alkylation

The development of a series of novel and easily accessed chiral naphthyridine-type binucleating ligands for asymmetric catalysis.

Asymmetric Hydrogenation of Tetrapyridine‐Type N‐Heteroarenes Using Phosphine‐Free Ruthenium Diamine Catalysts†

Comprehensive SummaryChiral ruthenium‐catalyzed enantioselective hydrogenation of tetrapyridine‐type N‐heteroarenes was firstly developed. The partial reduction of adjacent tetraheteroaromatic substrates proceeded smoothly in the presence of phosphine‐free chiral cationic ruthenium diamine complexes, affording unprecedented high reactivity, enantioselecitivity and diastereoselectivity (up to 93% yield, >99% ee and 92 : 8 dr). The potential application of chiral tetradentate pyridine‐amine products as chiral ligands has been demonstrated in the Cu‐catalyzed asymmetric Friedel–Crafts alkylation reaction between indoles and nitroalkenes.

Catalytic asymmetric Friedel–Crafts alkylation of unprotected indoles with nitroalkenes using a novel chiral Yb(OTf)3–pybox complex

Chiral chloro-indeno pybox has served as a new ligand for the Yb(OTf)3-catalyzed asymmetric Friedel–Crafts alkylation reaction of indoles with nitroalkenes. The tunable nature of pybox ligands enables the rational design of catalysts for optimal performance in terms of both activity and stereoselectivity in a Friedel–Crafts-type reaction. Good to excellent yields and enantioselectivities were obtained for a relatively wide range of substrates, including sterically hindered compounds, under optimized reaction conditions.

Catalytic Asymmetric Friedel–Crafts Alkylation of Indole via In Situ Generated Indol‐2‐one

AbstractAn asymmetric Friedel–Crafts alkylation of indole with in situ generated indol‐2‐one from functionalized 3‐bromooxinidole catalyzed by chiral N,N’‐dioxide/Ni(BF4)2 has been developed. This protocol provides an efficient route to stereoselective construction of a series of 3‐substituted 3’‐indolyloxindoles bearing a quaternary carbon center in excellent yields and enantioselectivities (up to 99 % ee). In addition, the conversion of the resulted 3‐substituted 3’‐indolyloxindole to the key intermediate for the formal synthesis of (+)‐folicanthine was also demonstrated.

Organocatalytic one-pot asymmetric synthesis of 6-trifluoromethyl-substituted 7,8-dihydrochromen-6-ol

A squaramide organocatalyst efficiently promoted the asymmetric Friedel–Crafts alkylation of α,β-unsaturated trifluoromethyl ketones with aromatic alcohols in a one-pot procedure, affording corresponding 6-trifluoromethyl-substituted 7,8-dihydrochromen-6-ol derivatives (up to 94% yield, 74% ee).

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.

Squaramide-catalysed asymmetric Friedel-Crafts alkylation of naphthol and unsaturated pyrazolones.

The first method for highly efficient asymmetric Michael-type Friedel-Crafts alkylation of naphthol and unsaturated pyrazolones has been accomplished under mild reaction conditions. In the presence of the chiral squaramide catalyst, a wide range of substrates are tolerated in excellent yields (up to 99%) with reasonable enantioselectivities (up to 96% ee).

Asymmetric Friedel–Crafts Alkylation of Indoles Catalyzed by Chiral Aziridine-Phosphines

Over the course of the present studies, a series of optically pure phosphines functionalized by chiral aziridines was synthesized in reasonable/good chemical yields. Their catalytic activity was checked in the enantioselective Friedel–Crafts alkylation of indoles by β-nitrostyrene in the presence of a copper(I) trifluoromethanesulfonate benzene complex. The corresponding Friedel–Crafts products were achieved efficiently in terms of chemical yield and enantioselectivity (up to 85% in some cases).

Asymmetric Ruthenium-Catalyzed Hydrogenation of Terpyridine-Type N-Heteroarenes: Direct Access to Chiral Tridentate Nitrogen Ligands.

The first enantioselective hydrogenation of terpyridine-type N-heteroarenes has been successfully developed by using Ru(diamine) complexes as catalysts, providing partially reduced chiral pyridine-amine-type products in high yield (up to 93%) with excellent diastereo- and enantioselectivity (up to 94:6 dl/meso, > 99% ee). These pyridine-amine-type compounds can be served as a new class of chiral multidentate nitrogen-donor ligands, which were successfully applied to the Cu-catalyzed asymmetric Friedel-Crafts alkylation reaction of indoles with nitroalkenes.

Re-Engineering Organocatalysts for Asymmetric Friedel-Crafts Alkylation of Indoles through Computational Studies.

The discovery of efficient organocatalysts is generally carried out by thorough experimental screening of different candidates. We recently reported an efficient organocatalyst for iminium-ion-based asymmetric Diels-Alder reactions following a rational design approach. This result encouraged us to test this optimal catalyst in the mechanistically related Friedel-Crafts alkylation of indoles, but to our surprise, almost null enantioselectivity was observed. The results did not significantly improve with structurally related catalysts, and a totally unexpected facial selectivity inversion was also noticed. Using DFT calculations by modeling the competing transition structures with ONIOM, we could unravel the origins of those findings, further employed to predict the most efficient catalyst for this new transformation. The computational results were validated experimentally (up to 92:8 er), providing another successful example of a general strategy to accelerate catalyst development which still remains underexplored.

Synthesis of Chiral Bis(3-indolyl)methanes Bearing a Trifluoromethylated All-Carbon Quaternary Stereocenter via Nickel-Catalyzed Asymmetric Friedel-Crafts Alkylation Reaction.

Bis(3-indolyl)methanes are well-known natural products with a broad range of important biological functions including cancer cell growth inhibition and antimicrobial activity. Incorporation of a trifluoromethyl group is known to have a profound effect on the parent compound's biological activities. Here, an efficient method for the synthesis of chiral trifluoromethylated bis(3-indolyl)methanes via a catalytic asymmetric Friedel-Crafts (F-C) alkylation reaction has been established. Both enantiomers of the catalysis products can be obtained by tuning the chiral substituents of the catalyst. With 5 mol % of the Ni(II)/(imidazoline-oxazoline) complex as the catalyst, the F-C reaction of indoles with β-CF3-β-(3-indolyl)nitroalkenes proceeded well to afford a series of chiral bis(3-indolyl)methanes bearing a trifluoromethylated all-carbon quaternary stereocenter in generally good yields with excellent enantioselectivities (up to 98% yield and 94% ee). Furthermore, by interchanging the indole moieties of the two reactants, indole vs β-CF3-β-(3-indolyl)nitroalkene in the F-C reaction, both enantiomers of a given trifluoromethylated bis(3-indolyl)methane were obtained with high enantioselectivities (89-94% ee) upon removal of the indole N-protecting group in the F-C products. The current work represents the first general catalytic enantioselective approach to the important class of trifluoromethylated bis(3-indolyl)methanes.

Brønsted Acid-Catalyzed Asymmetric Friedel-Crafts Alkylation of Indoles with Benzothiazole-Bearing Trifluoromethyl Ketone Hydrates.

An efficient Brønsted acid-catalyzed asymmetric Friedel-Crafts alkylation of indoles with benzothiazole-bearing trifluoromethyl ketone hydrates as electrophiles has been developed. The mild organocatalytic reactions proceeded well with low catalyst loading to afford a range of enantioenriched α-trifluoromethyl tertiary alcohols containing both benzothiazole and indole rings with excellent yields and enantioselectivities.

PNA as Hybrid Catalyst Scaffold Catalyzed Asymmetric Friedel–Crafts Alkylation

Double-stranded DNA can form efficient hybrid catalysts for asymmetric catalysis upon binding of small metal complexes, which has attracted significant interest. Catalytic microenvironment and chiral transfer are still a matter of concern. Here, we introduced peptide nucleic acid (PNA) chains to design oligo-dsPNA and hybrid PNA/DNA as chiral scaffolds to catalyze Friedel–Crafts reaction. Though with the same sequence as DNA control, dsPNA and hybrid duplexes are less suited for use in asymmetric catalysis due to ligand-Cu2+ complex does not form highly active and enantioselective hybrid catalysts with PNA-containing scaffolds. CD and UV titration assays indicated that the complex bound to suitable groove and the resulting preferential conformation are the key to catalytic performance, rather than just binding affinity. The negative charge of backbone and the resulting groove size of DNA are the key to act as a more active and highly selective catalyst than PNA.

Electrostatically Enhanced Phosphoric Acids and Their Applications in Asymmetric Friedel-Crafts Alkylations.

A series of electrostatically enhanced phosphoric acid catalysts were synthesized and studied. These compounds possess two positively charged N-octylpyridinium or triarylphosphonium ion centers at the 3,3'-positions of the (R)-BINOL backbone to enhance reactivity and provide needed steric bulk for enantioselective transformations. Catalytic activities for Friedel-Crafts alkylations of indoles with trans-β-nitrostyrenes were studied. Both types of catalysts accelerate reaction conversions relative to noncharged analogues, and good enantioselectivities up to 90% ee are observed with the phosphonium-ion-tagged phosphoric acids. This transformation also can be scaled up to synthetically useful amounts, affording >250 mg of product without losing any reactivity or selectivity.

Chiral Brønsted acid-catalyzed Friedel–Crafts reaction of 3-indolylsulfamidates with indoles: Synthesis of enantioenriched bisindolylmethane sulfamates

A Brønsted acid-catalyzed asymmetric Friedel–Crafts alkylation of 3-indolylsulfamidates with indoles has been established toward the efficient synthesis of biologically important bisindolylarylmethane derivatives containing the phenylsulfamate group. The reaction using chiral BINOL-derived phosphoric acid as the catalyst was tolerant to a diverse range of 3-indolylsulfamates and indoles, and provided for the first time bisindolylarylmethane sulfamate derivatives in good yields and with moderate to high enantioselectivities (up to 89% yield, 94:6 er). Moreover, some of these novel compounds were evaluated for their biological activities and confirmed to show bioactivity for preventing peripheral nerve degeneration.

Asymmetric Synthesis of β-Indolyl Cyclopentanones and Cyclopentylamides with an All-Carbon Quaternary Stereocenter via Chiral Phosphoric Acid Catalyzed Friedel-Crafts Alkylation Reactions.

The asymmetric Friedel-Crafts alkylation reactions of indoles with β-substituted cyclopentenimines enabled by chiral phosphoric acid catalysis has been developed, which affords adducts possessing an all-carbon stereocenter with high levels of enantioselectivities. Furthermore, the addition products could be readily converted into two types of useful but previously challenging chiral building blocks, such as β-alkyl-β-indolyl cyclopentanones and β-alkyl-β-indolyl cyclopentylamides, in one pot via in situ hydrolysis or reduction without erosion of chiral information.

Organocatalyzed Asymmetric Friedel‐Crafts Reactions: An Update

AbstractThe Friedel‐Crafts alkylation (F‐CA) reaction is a special kind of carbon−carbon bond formations, which is frequently being used for the formation of such bond in some aromatic rings in organic synthesis. Its asymmetric variant gives enantiorich products. Commonly, an in situ organocatalyzed asymmetric Friedel‐Crafts alkylation (AF‐CA) proceeds via generation of an enamine as an intermediate. The organocatalyzed‐AF‐CA was discovered and established in the mid‐1980s and reviewed comprehensively in 2010. In this report, we are trying to update the applications of novel organocatalysts in the AF‐CA as a versatile synthetic strategy, which is frequently used in the effective asymmetric synthesis of complex molecules, pharmaceutically important compounds and most importantly in the total synthesis of biologically active natural products.

A kinetic resolution strategy for the synthesis of chiral octahedral NHC-iridium(iii) catalysts.

The transmetalation reaction of a chiral-bidentate NHC-silver complex to racemic [Ir(μ-Cl)(ppy)2]2 operates with kinetic resolution leading to chiral octahedral NHC-iridium(iii) complexes and enantio-enriched bis-cyclometalated iridium(iii) complexes. The iridium(iii) complexes demonstrated efficient catalytic activities in intermolecular [2+2] photocycloaddition reactions and in asymmetric Friedel-Crafts alkylations, respectively.