aza-Friedel Crafts Reaction Research Articles

Asymmetric Aza Friedel-Crafts Reaction of 3,4-Dihydroisoquinolines with 1-Naphthols Catalyzed by Chiral Phosphoric Acids.

An efficient chiral phosphoric acid-catalyzed asymmetric aza Friedel-Crafts reaction of 3,4-dihydroisoquinolines and 1-naphthols is described. The reaction provides a general method for the synthesis of diverse chiral tetrahydroisoquinoline with 1-naphthol substituents at the C1-position in excellent yields and enantioselectivities. Based on the conducted mechanistic experiments, a plausible catalytic mechanism was proposed. Moreover, the practicability of the reaction is successfully demonstrated by its application on a gram scale.

Chiral phosphoric acid-catalyzed enantioselective synthesis of functionalized pyrrolinones containing a geminal diamine core via an aza-Friedel–Crafts reaction of newly developed pyrrolinone ketimines

A class of novel pyrrolinone ketimines was synthesized for the first time and applied to the asymmetric aza-Friedel–Crafts reaction with phenolic compounds.

Asymmetric para-Selective aza-Friedel–Crafts Reaction of Phenols Catalyzed by Bulky PyBidine-Ni(OAc)2

Asymmetric <i>para</i>-Selective aza-Friedel–Crafts Reaction of Phenols Catalyzed by Bulky PyBidine-Ni(OAc)₂

Recent advances in aza Friedel–Crafts reaction: strategies for achiral and stereoselective synthesis

The aza-Friedel–Crafts (aza-FC) reaction is a very powerful tool for forming C–C and C–N bonds, based on an acid-catalyzed addition of electron-rich aromatic compounds to imines.

Enantioselective synthesis of tryptanthrin derivatives enabled by an asymmetric aza-Friedel–Crafts reaction

A class of ketimines was first prepared and used in an asymmetric aza-Friedel–Crafts reaction for the highly enantioselective synthesis of tryptanthrin derivatives.

Chiral phosphoric acid-catalyzed enantioselective aza-Friedel-Crafts reaction of naphthols and electron-rich phenols with 2-aryl-3H-indol-3-ones.

The enantioselective aza-Friedel-Crafts reaction is one of the most straightforward and efficient strategies for constructing a new carbon-carbon bond bearing quaternary stereocenter in organic synthesis, but the catalytic asymmetric aza-Friedel-Crafts reaction of naphthols/phenols with cyclic-ketimines attached to a neutral functional group remains still relatively unexplored. Herein, a highly enantioselective aza-Friedel-Crafts reaction of cyclic-ketimines and naphthols/phenols has been realized using a chiral phosphoric acid catalyst. A variety of chiral aminonaphthols (chiral indolin-3-ones) containing a quaternary stereocenter at the C2 position were obtained with excellent outcomes (up to 97% yield, 98% ee). Moreover, the synthetic utility of the enantiomerically enriched chiral aminonaphthols was demonstrated in some efficient transformations. According to the experimental results, a possible transition state model has been proposed to rationalize the origin of asymmetric induction.

An enantioselective aza-Friedel-Crafts reaction of 5-aminoisoxazoles with isatin-derived N-Boc ketimines.

By employing a chiral phosphoric acid as a catalyst, an enantioselective aza-Friedel-Crafts reaction of 5-aminoisoxazoles with isatin-derived N-Boc ketimines was realized. The reaction provided a wide variety of novel 3-isoxazole 3-amino-oxindoles with good yields (up to 99%) and moderate to good enantioselectivities (up to 99%). The absolute configuration of one product was assigned by X-ray crystal structural analysis and a plausible reaction mechanism was proposed. In addition, a scale-up reaction was performed successfully. Finally, one product was subjected to Suzuki-Miyaura coupling with phenylboronic acid to afford the product in a moderate yield without erosion of the enantioselectivity.

Enantioselective Aza-Friedel-Crafts Reaction of Indoles and Pyrroles Catalyzed by Chiral C1-Symmetric Bis(phosphoric Acid).

A hydrogen bonding network in chiral Brønsted acid catalysts is important for the construction of a chiral cavity and the enhancement of catalytic activity. In this regard, we developed a highly enantioselective aza-Friedel-Crafts reaction of indoles and pyrroles with acyclic α-ketimino esters in the presence of a chiral C1-symmetric BINOL-derived bis(phosphoric acid) catalyst. The desired alkylation products with chiral quaternary carbon centers were obtained in high yields with high enantioselectivities on up to a 1.2-g scale with 0.2 mol % catalyst loading. Interestingly, the absolute configurations of the products from indoles and pyrroles were opposite even with the use of the same chiral catalyst. Moreover, preliminary mechanistic considerations disclosed that a unique hydrogen bonding network with or without π-π interactions among the catalyst and substrates might partially play a pivotal role.

Synthesis and Conformational Analysis of Naphthoxazine-Fused Phenanthrene Derivatives.

The synthesis of new phenanthr[9,10-e][1,3]oxazines was achieved by the direct coupling of 9-phenanthrol with cyclic imines in the modified aza-Friedel–Crafts reaction followed by the ring closure of the resulting bifunctional aminophenanthrols with formaldehyde. Aminophenanthrol-type Mannich bases were synthesised and transformed to phenanthr[9,10-e][1,3]oxazines via [4 + 2] cycloaddition. Detailed NMR structural analyses of the new polyheterocycles as well as conformational studies including Density Functional Theory (DFT) modelling were performed. The relative stability of ortho-quinone methides (o-QMs) was calculated, the geometries obtained were compared with the experimentally determined NMR structures, and thereby, the regioselectivity of the reactions has been assigned.

Enantioselective and regioselective aza-Friedel-Crafts reaction of electron-rich phenols with isatin-derived ketimines.

An efficient asymmetric aza-Friedel-Crafts reaction of phenols with isatin-derived ketimines is described. The reaction, which was promoted by a Bi(OH)3/CPA system, gave a series of chiral 3-amino-2-oxindoles with high yields (up to 99%), excellent enantioselectivities (up to 99%) and moderate to very good regioselectivities (up to 25/1).

Design of Planar Chiral Phosphoric Acids with a [2.2]Paracyclophanyl Backbone as Organocatalysts for the Highly Enantioselective Aza-Friedel-Crafts Reaction.

A new type of robust planar chiral phosphoric acid bearing a [2.2]paracyclophane scaffold was synthesized and shown to be an optimal catalyst in asymmetric aza-Friedel-Crafts reactions for the first synthesis of enantioenriched styryl indolylmethanamine derivatives in good yields with excellent enantioselectivities (93->99% ee) under 0.5-1 mol % catalyst loading.

Facile synthesis of chiral ε-sultams via an organocatalytic aza-Friedel-Crafts reaction.

Chiral ε-sultams, with their unique strain cyclic structure, are a type of molecule with important biological activities. A facile enantioselective aza-Friedel-Crafts reaction of seven-membered cyclic N-sulfonylimines with naphthols was developed with a cinchona alkaloid-based bifunctional organocatalyst, giving chiral ε-sultams with an enantiomeric excess of up to 92%.

Chiral Pyrophosphoric Acid Catalysts for the para-Selective and Enantioselective Aza-Friedel–Crafts Reaction of Phenols

Chiral BINOL-derived pyrophosphoric acid catalysts were developed and used for the regio- and enantioselective aza-Friedel–Crafts reaction of phenols with aldimines. ortho/para-Directing phenols could react at the para-position selectively with moderate to good enantioselectivities. Moreover, the gram-scale transformation of a product into the key intermediate for the antifungal agent (R)-bifonazole was demonstrated.

Enantioselective aza-Friedel–Crafts reaction of cyclic ketimines with indoles using chiral imidazoline–phosphoric acid catalysts

An enantioselective aza-Friedel Crafts reaction of cyclic 4-aryl-3-oxo-1,2,5-thiadiazol-1,1-oxides as cyclic ketimines with indoles was developed. High enantioselectivities were observed for the reaction of various cyclic ketimines with indoles using chiral imidazoline-phosphoric acid catalysts. The obtained products can be converted to chiral α-amino amide and hydantoin.

Enantioselective aza-Friedel-Crafts reaction of furan with α-ketimino esters induced by a conjugated double hydrogen bond network of chiral bis(phosphoric acid) catalysts.

Chiral C 2- and C 1-symmetric BINOL-derived bis(phosphoric acid) catalysts, which have OP([double bond, length as m-dash]O)(OH)2/OP([double bond, length as m-dash]O)(OH)(OR) moieties at the 2,2'-positions, were developed and used for the enantioselective aza-Friedel-Crafts reaction of 2-methoxyfuran with α-ketimino esters for the first time. The intramolecular conjugated double hydrogen bond network is a key to increasing the Brønsted acidity and preventing deactivation of the catalysts. Highly functionalized α-amino acid derivatives with a chiral quaternary carbon center could be transformed into versatile optically active N- and O-heterocycles and an α-aryl-substituted serine.

Enantioselective Aza-Friedel–Crafts Reaction of Indoles with Ketimines Catalyzed by Chiral Potassium Binaphthyldisulfonates

The enantioselective aza-Friedel–Crafts reaction of indoles with low-reactive ketimines has been developed in the presence of a chiral monopotassium binaphthyldisulfonate as a strong Bronsted acid catalyst. A broad substrate scope was achieved, and the corresponding 3-indolylmethanamines with a chiral quaternary carbon center were obtained in high yields with high enantioselectivities. The addition of a catalytic amount of acetic acid considerably promoted the reaction, and a gram-scale reaction could be achieved with reduced catalyst loading.

Unveiling Mechanism of a Quinine-Squaramide Catalyzed Enantioselective Aza-Friedel-Crafts Reaction between Cyclic Trifluoromethyl Ketimine and Naphthol: A DFT Study.

A mechanism study of quinine-squaramide catalyzed enantioselective aza-Friedel-Crafts (aza-F-C) reaction is described using density functional theory (DFT). The most favorable pathway is obtained through the discussions of four possible modes of hydrogen bond interactions, in which the nucleophile is activated by the squaramide N-H groups (N-Ha and N-Hb) and the electrophile binds to the protonated amine by hydrogen bonding. Meanwhile, we have also studied the energy barrier of the stereocontrolling transition states that might play a role of stereoselectivity. In addition, noncovalent interaction (NCI) analyses show a series of favorable cooperative noncovalent interactions, including N-H···O and C-H···F hydrogen-bonding, and π···π interactions. The strong interactions and lower barrier were found for TS3R, indicating the preference for the R-configuration adduct, which is in good agreement with the experimental observations.

Chiral Brønsted Acid Catalyzed Enantioselective aza-Friedel-Crafts Reaction of Cyclic α-Diaryl N-Acyl Imines with Indoles.

Asymmetric addition of indoles to cyclic α-diaryl-substituted N-acyl imines, which are generated in situ from 3-aryl 3-hydroxyisoindolinones, is described. The transformation proceeds smoothly with a broad range of indoles and isoindolinone alcohols using a SPINOL-derived chiral Brønsted acid catalyst to afford α-tetrasubstituted (3-indolyl)(diaryl)methanamines in excellent yields and enantioselectivities (up to 98% yield, up to >99:1 e.r.). The origin of stereochemical induction is supported by DFT calculations and experimental data.

From Technical Efficiency to Economic Efficiency: Development of Aza-Friedel–Crafts Reaction Using Phosphoric Acid Immobilized in Glycerol as a Sustainable Approach

The search for sustainable and practical synthetic methodology with high levels of technical efficiency is a highly topical subject that would contribute to developing recycling economy and saving resources. Green synthetic science has been firmly established and has provided essential design criteria for the development of a sustainable approach to high added value molecules and drug discovery, and the further development of sustainable manufacturing processes of medicines with new optimality principles for economic efficiency. In this study, a green atom economical aza-Friedel–Crafts reaction catalyzed by phosphoric acid immobilized in glycerol has been developed. This protocol provides a sustainable approach for the preparation of pyrrolyl and trifluoromethyl dihydrobenzoxazinones in excellent yields with remarkable features, such as bio-renewable glycerol as a cheap, safe and green solvent, easy product separation and catalytic system recycling under mild conditions. Furthermore, the preliminary biological activity of these products was evaluated in glioma (C6) and melanoma (B16BL6) tumor cell lines by using adriamycin as a positive control with the thiazoyl blue tetrazolium bromide (MTT) assay. The result suggests that product 5n shows promising cancer growth inhibition of glioma and melanoma, and is a promising lead compound for further investigation as anti-glioma and anti-melanoma agents.

Sc(OTf)3-Catalyzed Aza-Friedel–Crafts Reaction of Electron-Rich Arenes with Isatin-Derived Ketimines: Access to 3-Amino-3-Aryl-2-Oxindoles

A Sc(OTf)3-catalyzed aza-Friedel–Crafts reaction of electron-rich arenes with isatin-derived ketimines is disclosed, providing biologically interesting 3-amino-3-aryl-2-oxindoles in moderate to good yields with broad substrate scope. This reaction can be easily scaled up, and the Boc protecting group could be readily removed under mild reaction conditions to afford the free amine.