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.     

Asymmetric Friedel–Crafts Alkylation of Electron‐Rich N‐Heterocycles with Nitroalkenes Catalyzed by Diphenylamine‐Tethered Bis(oxazoline) and Bis(thiazoline) ZnII Complexes

The asymmetric Friedel–Crafts alkylation of electron‐rich N‐containing heterocycles with nitroalkenes under catalysis of diphenylamine‐tethered bis(oxazoline) and bis(thiazoline)‐Zn^II complexes was investigated. In the reaction of indole derivatives, the complex of ligand 4 f with trans‐diphenyl substitutions afforded better results than previously published ligand 4 e with cis‐diphenyl substitutions. Excellent yields (up to greater than 99 %) and enantioselectivities (up to 97 %) were achieved in most cases. The complex of ligand 4 d bearing tert‐butyl groups gave the best results in the reactions of pyrrole. Moderate to good yields (up to 91 %) and enantioselectivities (up to 91 %) were achieved in most cases. The origin of the enantioselectivity was attributed to the NH–π interaction between the catalyst and the incoming aromatic system in the transition state. Such an interaction was confirmed through comparison of the enantioselectivity and the absolute configuration of the products in the reactions catalyzed by designed ligands.     

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.     

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.     

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.     

Brønsted Acid Catalyzed Friedel–Crafts‐Type Coupling and Dedinitrogenation Reactions of Vinyldiazo Compounds

The direct Friedel–Crafts‐type coupling and dedinitrogenation reactions of vinyldiazo compounds with aromatic compounds using a metal‐free strategy are described. This Brønsted acid catalyzed method is efficient for the formation of α‐diazo β‐carbocations (vinyldiazonium ions), vinyl carbocations, and allylic or homoallylic carbocation species via vinyldiazo compounds. By choosing suitable nucleophilic reagents to selectively capture these intermediates, both trisubstituted α,β‐unsaturated esters, β‐indole‐substituted diazo esters, and dienes are obtained with good to high yields and selectivity. Experimental insights implicate a reaction mechanism involving the selective protonation of vinyldiazo compounds and the subsequent release of dinitrogen to form vinyl cations that undergo intramolecular 1,3‐ and 1,4‐ hydride transfer processes as well as fragmentation.     

An Arylation Strategy to Propargylamines: Catalytic Asymmetric Friedel–Crafts‐type Arylation Reactions of C‐Alkynyl Imines

The first arylation strategy for the synthesis of enantioenriched propargylamines is disclosed. This approach, which is complementary to previous alkynylation and alkylation strategies, involves a C(sp²)?C(sp³) bond formation, and is based on the first asymmetric Friedel–Crafts‐type arylation reaction of C‐alkynyl imines. Asymmetric Friedel–Crafts reactions with electron‐deficient phenols, a longstanding unsolved challenge, have thus been realized for the first time, enabled by the combination of our recently introduced C‐alkynyl N‐Boc‐protected N,O‐acetals as electrophiles and chiral phosphoric acids as catalysts. The synthetic utility of the resulting structurally diverse and polyfunctional chiral propargylamines was demonstrated by a series of selective transformations, including controlled reduction of the alkynyl group and iterative cross‐couplings.     

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.