Chiral N,N′‐Dioxide–Scandium(III) Complex‐Catalyzed Asymmetric Friedel–Crafts Alkylation Reaction of ortho‐Hydroxybenzyl Alcohols with C3‐Substituted N‐Protected Indoles

The first Lewis acid catalyzed asymmetric Friedel–Crafts alkylation reaction of ortho‐hydroxybenzyl alcohols with C3‐substituted indoles is described. A chiral N,N′‐dioxide Sc(OTf)₃ complex served not only to promote formation of ortho‐quinone methides (o‐QMs) in situ but also induced the asymmetry of the reaction. This methodology enables a novel activation of ortho‐hydroxybenzyl alcohols, thus affording the desired chiral diarylindol‐2‐ylmethanes in up to 99 % yield and 99 % ee. A range of functional groups were also tolerated under the mild reaction conditions. Moreover, this strategy gives concise access to enantioenriched indole‐fused benzoxocines.     

Furanyl Alcohols as Alkylating Reagents in Friedel–Crafts Reaction of Arenes

Furanyl alcohols react with arenes by a variant of the Friedel–Crafts reaction to give benzyl furans with fairly satisfying yields. The reaction is mediated by Tf₂O and occurs with reduced times in the presence of Ph₃PO. Some prepared compounds exhibit a lignan‐like backbone.     

NIS‐Assisted Aza‐Friedel–Crafts Reaction with α‐Carbamoysulfides as Precursors of N‐Carbamoylimines

A general and practical N‐iodosuccinimide (NIS)‐promoted aza‐Friedel–Crafts reaction of various aromatic nucleophiles with N‐acylimines generated in situ from α‐amidosulfides to give a rapid access to highly functionalized amines is described. The newly developed methodology is very mild, fast, efficient, and complementary.     

Biaryl Synthesis by Ring‐Opening Friedel–Crafts Arylation of 1,4‐Epoxy‐1,4‐dihydronaphthalenes Catalyzed by Iron Trichloride

Biaryl and heterobiaryl compounds are important frameworks across a range of fields including pharmaceutical and functional material chemistries. We have accomplished the efficient synthesis of various naphthalene‐linked arenes and heteroarenes as biaryls and heterobiaryls by the FeCl₃‐catalyzed Friedel‐Crafts reactions accompanied by the ring‐opening of the 1,4‐epoxy moiety of 1,4‐epoxy‐1,4‐dihydronaphthalenes. Especially, it is noteworthy that 1‐silylated substrates were regioselectively transformed to the 3‐aryl‐1‐silylnaphthalenes and the double Friedel–Crafts reactions using thiophene derivatives could directly produce the corresponding bis‐naphthlated thiophene derivatives.     

Temperature Dual Enantioselective Control in a Rhodium‐Catalyzed Michael‐Type Friedel–Crafts Reaction: A Mechanistic Explanation

By changing the temperature from 283 to 233 K, the S (99 % ee) or R (96 % ee) enantiomer of the Friedel–Crafts (FC) adduct of the reaction between N‐methyl‐2‐methylindole and trans‐β‐nitrostyrene can be obtained by using (S_Rh,R_C)‐[(η⁵‐C₅Me₅)Rh{(R)‐Prophos}(H₂O)][SbF₆]₂ as the catalyst precursor. This catalytic system presents two other uncommon features: 1) The ee changes with reaction time showing trends that depend on the reaction temperature and 2) an increase in the catalyst loading results in a decrease in the ee of the S enantiomer. Detection and characterization of the intermediate metal–nitroalkene and metal–aci‐nitro complexes, the free aci‐nitro compound, and the FC adduct‐complex, together with solution NMR measurements, theoretical calculations, and kinetic studies have allowed us to propose two plausible alternative catalytic cycles. On the basis of these cycles, all the above‐mentioned observations can be rationalized. In particular, the reversibility of one of the cycles together with the kinetic resolution of the intermediate aci‐nitro complexes account for the high ee values achieved in both antipodes. On the other hand, the results of kinetic measurements explain the unusual effect of the increment in catalyst loading.     

Iron‐Catalyzed Friedel–Crafts Benzylation with Benzyl TMS Ethers at Room Temperature

Friedel–Crafts benzylations between unactivated arenes and benzyl alcohol derivatives are clean and straightforward processes to construct biologically useful di‐ and tri‐arylmethanes. We have established an efficient iron‐catalyzed Friedel–Crafts benzylation method at room temperature that uses benzyl TMS ethers as substrates, which are poorly reactive under common nucleophilic substitution conditions. The reaction seems to progress through iron‐catalyzed self‐condensation of the benzyl TMS ether to the corresponding dibenzylic ether. The use of excess arene relative to benzyl TMS ether produced mono‐benzylated arene (di‐ and tri‐arylmethane products), whereas the use of excess benzyl TMS ether versus arene provided bis‐benzylated arene (polyarylated products) in high yields and regioselectivities. In previous methods, the latter double Friedel–Crafts benzylations hardly proceed.     

Linking Conformational Flexibility and Kinetics: Catalytic 1,4‐Type Friedel–Crafts Reactions of Phenols Utilizing 1,3‐Diamine‐Tethered Guanidine/Bisthiourea Organocatalysts

Herein, we present details of our conformationally flexible, 1,3‐diamine‐tethered guanidine/bisthiourea organocatalysts for chemo‐, regio‐, and enantioselective 1,4‐type Friedel–Crafts reactions of phenols. These organocatalysts show a unique stereo‐discrimination governed by the differential activation entropy (ΔΔS^≠), rather than by the differential activation enthalpy (ΔΔH^≠). Extensive kinetic analyses using Eyring plots for a series of guanidine/bisthiourea organocatalysts revealed the key structural motif in the catalysts associated with a large magnitude of differential activation entropy (ΔΔS^≠). A plausible guanidine–thiourea cooperative mechanism for the enantioselective Friedel–Crafts reaction is proposed.     

9‐Membered Carbocycle Formation: Development of Distinct Friedel–Crafts Cyclizations and Application to a Scalable Total Synthesis of (±)‐Caraphenol A

Explorations into a series of different approaches for 9‐membered carbocycle formation have afforded the first reported example of a 9‐exo‐dig ring closure via a Au^III‐promoted reaction between an alkyne and an aryl ring as well as several additional, unique Friedel–Crafts‐type cyclizations. Analyses of the factors leading to the success of these transformations are provided, with the application of one of the developed 9‐membered ring closures affording an efficient and scalable synthesis of the bioactive resveratrol trimer caraphenol A. That synthesis proceeded with an average yield of 89 % per step (7.8 % overall yield) and has provided access to more than 600 mg of the target molecule.     

Asymmetric Friedel–Crafts Reaction of 4,7‐Dihydroindoles with Nitroolefins by Chiral Brønsted Acids under Low Catalyst Loading

Slowly does it! By adding the substrate by a syringe pump, a highly efficient Friedel–Crafts reaction of 4,7‐dihydroindoles with nitroolefins was realized with 0.5 mol % of a chiral phosphoric acid. The Friedel–Crafts alkylation, together with a subsequent oxidation of the product, led to 2‐substituted indoles in excellent enantiomeric excesses, which can be easily transformed to enantioenriched tetrahydro‐γ‐carbolines.