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.     

Conformationally Constrained Cyclic Peptides: Powerful Scaffolds for Asymmetric Catalysis

Cyclic peptides containing a disulfide bridge were identified as a simple and versatile coordination sphere for asymmetric catalysis. Upon complexation with Cu²⁺ ions they catalyze Diels–Alder and Friedel–Crafts reactions with high enantioselectivities of up to 99 % ee and 86 % ee, respectively. Moreover, the peptides ligands were systematically optimized with the assistance of “Alanine Scanning”. This biomolecular design could greatly expand the choice of peptide scaffolds for artificial metallopeptide catalysts.     

Bioinspired Total Synthesis of the Dimeric Indole Alkaloid (+)‐Haplophytine by Direct Coupling and Late‐Stage Oxidative Rearrangement

A bioinspired convergent total synthesis of (+)‐haplophytine, a dimeric indole alkaloid with diazabicyclo[3.3.1]nonane and hexacyclic aspidosperma segments, is described. This synthesis involves the direct coupling of the two segments in a AgNTf₂‐mediated Friedel–Crafts reaction and construction of the diazabicyclo[3.3.1]nonane skeleton through late‐stage chemoselective aerobic oxidation of the 1,2‐diaminoethene moiety and a sequential semipinacol‐type rearrangement.     

Lewis Acid Catalyzed Cascade Reactions of 1,6‐Diynes and 1,6‐Enynes with Vinylidenecyclopropanes

Cascade reactions : Lewis acid catalyzed cascade reactions of 1,6‐diynes and 1,6‐enynes with arylvinylidenecyclopropanes produce polycyclic compounds and isopropylidene‐3,3‐diarylcyclobut‐1‐enylmethyl derivatives (see scheme) in good to high yields along with a PtCl₂‐catalyzed cyclization and a Cu(OAc)₂ ? H₂O‐catalyzed Eglinton coupling reaction.

     

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.     

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.     

Structures of the Intermediate Complexes in Friedel-Crafts Acylations

Addition compounds of Lewis acids MX_n and acyl halides R? COX occur as intermediates in Friedel-Crafts acylations. IR and NMR studies on these intermediates have indicated the probable existence of structural isomers. In X-ray structural analysis, it is possible to distinguish two forms, i.e. the molecular form, in which the compounds are present as donor-acceptor complexes R? CXO→MX_n, and the ionic form, in which they can be formulated as oxocarbenium salts [R? CO]⁺[MX_n+1]^?. The compounds of the donor-acceptor type R? CXO→MX_n are characterized by the formation of a coordinate oxygen-metal bond; the transfer of electrons from the oxygen to the metal of the acceptor is always due to a weak donor-acceptor interaction. The positive charge of the aryloxocarbenium ions is partly delocalized over the aromatic nucleus. The positive charge in alkyloxocarbenium ions, on the other hand, is essentially localized on the carbon atom of the carbonyl group, as is confirmed by electron density distribution calculations.     

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.     

Anilines as C‐Nucleophiles in Ir‐Catalyzed Intramolecular Asymmetric Allylic Substitution Reactions

Anilines generally act as N‐nucleophiles in transition‐metal‐catalyzed allylic substitution reactions. In this paper, a highly enantioselective intramolecular Friedel–Crafts‐type allylic alkylation of aniline derivatives was realized by using an iridium catalyst derived from [Ir(cod)Cl]₂ and (R _a)‐BHPphos. Various tetrahydroisoquinilin‐5‐amines were obtained in moderate to good yields, excellent enantioselectivity and regioselectivity under mild reaction conditions. BHPphos=N ‐benzhydryl‐N ‐phenyldinaphthophosphoramidite.     

Evidence for Endocyclic Cleavage of Conformationally Restricted Glycopyranosides

2,3‐trans‐carbamate‐ and ‐carbonate‐carrying pyranosides were very easily anomerised from the β to the α direction in the presence of a Lewis acid compared to other pyranosides. This reaction is caused by endocyclic cleavage of the pyranosides. Evidence for endocyclic cleavage of conformationally restricted pyranosides in the chair form was obtained by intra‐ and intermolecular Friedel–Crafts reactions, chloride addition, and reduction of the generated cation. On the other hand, pyranosides with the distorted conformation were never cleaved in an endocyclic manner.     

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.     

A Highly Efficient Friedel–Crafts Reaction of 3‐Hydroxyoxindoles and Aromatic Compounds to 3,3‐Diaryl and 3‐Alkyl‐3‐aryloxindoles Catalyzed by Hg(ClO4)2⋅3 H2O

We report a highly efficient Friedel–Crafts reaction of 3‐alkyl or 3‐aryl 3‐hydroxyoxindoles with a variety of aromatic and heteroaromatic compounds to unsymmetrical 3,3‐diaryloxindoles or 3‐alkyl‐3‐aryloxindoles, which are interesting medicinal targets and useful building blocks for the synthesis of natural products. Hg(ClO₄)₂ ? 3 H₂O was identified as a powerful catalyst for this reaction, and is significantly more efficient than other screened metal perchlorate hydrates and Brønsted acids such as HOTf and HClO₄. The high catalytic property of Hg(ClO₄)₂ ? 3 H₂O originates from the unprecedented dual activation effects of aromatic mercuration, which could generate a strong protic acid to facilitate the generation of a carbocation at the C3‐position of oxindoles and simultaneously form the more reactive nucleophilic reaction partner.