Site-selective Arylation Research Articles

Nondirected, Site-Selective Arylation of Quinone Imine Ketals Derived from Arylamines: One-Pot Access to meta-Substituted Anilines.

Herein, we develop a metal-free, nondirected, site-selective, one-pot approach to meta-arylation of arylamines. This Brønsted acid-catalyzed, direct C-C bond formation offers a broad substrate scope and scalability and creates the ideal conditions for overriding the conventional site-selectivity to furnish meta-substituted anilines. Additionally, the protocol applies to the meta-allylation of anilines and has been extended to afford late-stage functionalization and synthesis of medicinally privileged arylated diamines and densely functionalized anilines. The control experiments and density functional theory studies provide evidence for the proposed mechanism and selectivity.

Pd-Catalyzed C-7 Arylation of Indolines with Aryltriazenes under Mild Conditions.

A palladium-catalyzed direct C-H arylation of indolines at C-7 position has been achieved at near-ambient temperature. The reaction was carried out with aryltriazene as a stable aryl source and electron shuttle to sustainably release aryl radical in situ under the action of promoter, and pyrimidine as a detachable directing group for the synthesis of 7-arylindolines under oxidant- and ligand-free conditions. Notably, this catalytic system can also be applied to the direct and site-selective arylation of tetrahydroquinolines (C-8) and carbazoles (C-1).

Site-Selective Arylation of Carboxamides from Unprotected Peptides.

The amidated peptides are an important class of biologically active compounds due to their unique biological properties and wide applications as potential peptide drugs and biomarkers. Despite the abundance of free amide motifs (Asn, Gln, and C-terminal amide) in native peptides, late-stage modification of the amide unit in naturally occurring peptides remains very rare because of the intrinsically weak nucleophilicity of amides and the interference of multiple competing nucleophilic residues, which generally lead to undesired side reactions. Herein, chemoselective arylation of amides in unprotected polypeptides has been developed under an air atmosphere to afford the N-aryl amide peptides bearing various functional motifs. Its success relies on the combination of gold catalysis and silver salt to differentiate the relative inert amide among a collection of reactive nucleophilic amino acid residues (e.g., -NH2, -OH, and -COOH), favoring the C-N bond coupling toward amides over other more nucleophilic groups. Experimental and DFT studies reveal a crucial role of the silver cation, which serves as a transient coordination mask of the more reactive reaction sites, overcoming the inherently low reactivity of amides. The excellent biocompatibility of this strategy has been applied to functionalize a wide range of peptide drugs and complex peptides. The application could be further extended to peptide labeling and peptide stapling.

A transition metal- and photosensitizer-free approach for site-selective (hetero)arylation of polychlorinated heteroarenes.

We have developed an effective photochemical method for site-selective (hetero)arylation of polychlorinated heteroarenes. This approach eliminates the need for transition metal catalysts and photosensitizers by relying on in situ formation of unconventional electron donor-acceptor (EDA) complexes between two substrates and a basic additive. Our protocol yields chlorine-containing biaryl heterocyclic compounds with high levels of site-selectivity, which are of significant importance in both synthetic and medicinal chemistry.

Synthesis of multisubstituted pyrroles by ligand-controlled site-selective arylation and their transformation into multiarylated pyrrolines and pyrrolidines

Multisubstituted pyrroles were prepared by Pd-catalyzed site-selective arylation of 2,5-disubstituted 1H-pyrroles with aryl chlorides, triflates, or nonaflates. Site-selectivity of the reaction was controlled using appropriate ligands, and 2,2,5-trisubstituted 2H-pyrroles were synthesized via dearomative C2-arylation. Moreover, 2,3,5-trisubstituted 1H-pyrroles were successfully fabricated by direct C3-arylation. These arylations can be applied to the pharmaceuticals bearing aryl chloride moieties. Additionally, 2,2,5-triaryl-2H-pyrroles were converted into multiarylated pyrrolines and pyrrolidines, which will be useful in synthetic and medicinal chemistry.

Diarylation of N- and O-nucleophiles through a metal-free cascade reaction

Diarylation of N- and O-nucleophiles through a metal-free cascade reaction

Palladium-Catalyzed Site-Selective Arylation of α,β-Unsaturated Carbonyl Compounds through a Ligand-Controlled Strategy

AbstractPalladium-catalyzed direct arylation of α,β-unsaturated carbonyl compounds is an efficient and attractive strategy to access arylated α,β-unsaturated carbonyl compounds through the construction of carbon–carbon bonds. This reaction has several challenges, especially in terms of the control of regioselectivity between α- and γ-arylation and the selectivity for monoarylation and multiple arylation. Herein, we discuss the recent development of γ-arylation of α,β-unsaturated carbonyl compounds and present the ligand-controlled, site-selective α- and γ-arylation of α,β-unsaturated carbonyl ketones with (hetero)aryl halides. The site selectivity of the reaction is switchable by simply changing the phosphine ligand.1 Introduction2 Reaction Development and Mechanistic Investigation3 Conclusion and Outlook

Site-Selective Synthesis of 3,17-Diaryl-1,3,5,16-estratetraenes

A straightforward, site-selective arylation of the bis(triflate) of estrone by Suzuki–Miyaura reactions has been developed. Monoarylation occurs selectively at the D-ring with good to excellent yield. Such products were exemplarily employed for the synthesis of estrones containing two different aryl substituents.

Directing Effects on the Copper-Catalyzed Site-Selective Arylation of Indoles.

Different site selectivities have been reported for indoles with different directing groups in copper-catalyzed site-selective C-H arylations. Computational and mass spectrometric studies have been conducted in an effort to understand the origin of site selectivity and the effects of the directing groups. A Heck-like mechanism involving a four-membered ring is found in all three of the cases studied. For N-acetyl indole with a weak directing group, a neutral Heck-like mechanism is controlled by an electronic effect resulting in C2 site selectivity. In contrast, indole with a N-P(O) tBu2 group and N-benzyl-3-pivaloyl indole prefer a cationic Heck-like reaction in which a favorable six-membered chelation between the directing group and the CuIII center determines the C6 and C5 site selectivities.

Direct Pd(II)-Catalyzed Site-Selective C5-Arylation of 2-Pyridone Using Aryl Iodides.

A straightforward Pd(II)-catalyzed general strategy was developed for the C5-selective arylation of the 2-pyridone core with easily available aryl iodides. The transformation was highly regioselective and accomplished with a wide scope and functional group tolerance. Silver nitrate played a crucial role in this direct site-selective arylation. The method was extended to synthesize biologically active molecules.

Palladium-catalyzed site-selective arylation of aliphatic ketones enabled by a transient ligand.

Transition metal-catalyzed direct C-H bond functionalization enabled by transient ligands has become an attractive topic. Here we report a palladium-catalyzed site-selective arylation of β-C(sp3)-H bonds in aliphatic ketones with β-alanine as the transient ligand.

Cover Feature: Programmed Site‐Selective Palladium‐Catalyzed Arylation of Thieno[3,2‐b]thiophene (Chem. Asian J. 21/2017)

Cover Feature: Programmed Site‐Selective Palladium‐Catalyzed Arylation of Thieno[3,2<i>‐b</i>]thiophene (Chem. Asian J. 21/2017)

Auxiliary‐Directed C(sp3)−H Arylation by Synergistic Photoredox and Palladium Catalysis

Herein we describe the auxiliary-directed arylation of unactivated C(sp3 )-H bonds with aryldiazonium salts, which proceeds under synergistic photoredox and palladium catalysis. The site-selective arylation of aliphatic amides with α-quaternary centres is achieved with high selectivity for β-methyl C(sp3 )-H bonds. This operationally simple method is compatible with carbocyclic amides, a range of aryldiazonium salts and proceeds at ambient conditions.

Regiocontrolled Direct C−H Arylation of Indoles at the C4 and C5 Positions

An effective and practical strategy has been established for the direct and site-selective arylation of indoles at the C4 and C5 positions with the aid of a readily accessible, cheap, and removable pivaloyl directing group at the C3 position. This transformation shows good functional-group tolerance and could serve as a powerful synthetic tool for the synthesis of medicinally relevant compounds. This method and those developed in previous research together enable the regiocontrolled direct arylation of indole at each C-H bond without prefunctionalization of the reactive sites.

Palladium-Catalyzed Site-Selective Arylation of γ-Vinyl-γ-Lactone

Palladium-Catalyzed Site-Selective Arylation of γ-Vinyl-γ-Lactone

Pd-Catalyzed Site-Selective Mono-allylic Substitution and Bis-arylation by Directed Allylic C-H Activation: Synthesis of anti-γ-(Aryl,Styryl)-β-hydroxy Acids and Highly Substituted Tetrahydrofurans.

An efficient palladium-catalyzed site-selective arylation of γ-vinyl-γ-lactone by aryl boronic acid has been developed. γ-Vinyl-γ-lactone 1a has been contemplated as allyl electrophile donor for allylic arylation via π-allyl palladium intermediate using 1.5 equiv of aryl boronic acid 2. Using 3.0 equiv of the latter resulted in mono-arylation by allylic substitution and subsequent site-selective second arylation by directed allylic C-H activation giving stereoselectively anti-γ-(aryl,styryl)-β-hydroxy acids. Presence of O2 was crucial for the second arylation via Pd(II) catalysis. Thus, a good synergy of dual catalysis by Pd(0) and Pd(II) was observed. This methodology has been elaborated to synthesize highly substituted tetrahydrofurans including aryl-Hagen's gland lactone analogues via intramolecular iodoetherification.

Cu-Catalyzed Direct C6-Arylation of Indoles.

The first example of direct and site-selective arylation of indoles at the C6 position has been reported. The key to this high regioselectivity is the appropriate choice of the N-P(O)(t)Bu2 directing group and the use of diaryliodonium triflate salts as the coupling partners in the presence of catalytic CuO. The protocol is distinguished by mild reaction system that avoids ligand and additives, exhibiting wide scope of indole and arene coupling components without compromising its efficiency and scalability, thus representing a significant advancement in the implementation of regioselective direct arylation of indoles.

Catalytic C(sp(3) )-H Arylation of Free Primary Amines with an exo Directing Group Generated In Situ.

Herein, we report the palladium-catalyzed direct arylation of unactivated aliphatic C-H bonds in free primary amines. This method takes advantage of an exo-imine-type directing group (DG) that can be generated and removed in situ. A range of unprotected aliphatic amines are suitable substrates, undergoing site-selective arylation at the γ-position. Methyl as well as cyclic and acyclic methylene groups can be activated. Furthermore, when aniline-derived substrates were used, preliminary success with δ-C-H arylation was achieved. The feasibility of using the DG component in a catalytic fashion was also demonstrated.

Positional Selectivity in C-H Functionalizations of 2-Benzylfurans with Bimetallic Catalysts.

Metal-catalyzed carbon-carbon bond-forming reactions are a mainstay in the synthesis of pharmaceutical agents. A long-standing problem plaguing the field of transition metal catalyzed C-H functionalization chemistry is control of selectivity among inequivalent C-H bonds in organic reactants. Herein we advance an approach to direct site selectivity in the arylation of 2-benzylfurans founded on the idea that modulation of cooperativity in bimetallic catalysts can enable navigation of selectivity. The bimetallic catalysts introduced herein exert a high degree of control, leading to divergent site-selective arylation reactions of both sp(2) and sp(3) C-H bonds of 2-benzylfurans. It is proposed that the selectivity is governed by cation-π interactions, which can be modulated by choice of base and accompanying additives [MN(SiMe3)2, M = K or Li·12-crown-4].

Site-selective synthesis of arylated pyridines by Suzuki–Miyaura reactions of 2,3,5,6-tetrachloropyridine

Site-selective arylation of commercially available 2,3,5,6-tetrachloropyridine has been accomplished, using the Suzuki–Miyaura reaction. The reaction conditions were thoroughly optimized, allowing the selective synthesis of mono-, di-, tri- and tetraarylated pyridines in good to quantitative yields. In addition, we studied the electrochemical properties of selected tetraarylpyridines by DPV-measurements.