Decarboxylative Arylation Research Articles

Recent Advances in the Transition-Metal-Free Arylation of Hetero­arenes

AbstractTransition-metal-free arylation reactions have attracted considerable attention for economic and environmental reasons over the past 40 years. In recent years, much effort has been made to develop efficient transition-metal-free approaches for the arylation of heteroarenes. Covering the literature from 2015 to early 2021, this review aims to provide a thorough overview of the synthetic and mechanistic aspects of these atom-economical and environmentally benign reactions.1 Introduction2 Arylation of Pre-functionalized Heteroarenes2.1 Arylation of Heteroaryl Halides2.2 Decarboxylative Arylation of Heteroarenes3 Direct C–H Arylation of Heteroarenes3.1 C(sp2)–H Arylation3.2 C(sp3)–H Arylation4 N-Arylation of Heteroarenes5 Summary and Outlook

Distinct roles of Ag(I) and Cu(II) as cocatalysts in the intramolecular cyclization of N-methyl-N-phenylanthranilic acid: A theoretical investigation

• The selectivity is controlled by the additive employed in this reaction. • The silver oxide promotes C(sp 3 )−H activation and C−O cyclization to provide 1,2-dihydro-(4H)−3,1-benzoxazin-4-one. • The copper acetate contributes to C(sp 2 )−H activation and decarboxylative arylation to afford carbazole. • The origins of the selectivity could be attributed to the cation-π interaction between Ag and the substrate arene ring. The mechanisms of the intramolecular cyclization of N-methyl-N-phenylanthranilic acid catalyzed by Pd(OAc) 2 were investigated by employing the density functional theory (DFT) calculations. The selectivity is controlled by the additive employed in this reaction. Silver oxide promotes C(sp 3 )−H activation and C−O cyclization to provide 1,2-dihydro-(4H)-3,1-benzoxazin-4-one, while copper acetate contributes to C(sp 2 )−H activation and decarboxylative arylation to afford carbazole. The origins of the selectivity could be attributed to the cation-π interaction between Ag and the substrate arene ring, which significantly lowers the activation energy for C(sp 3 )−H deprotonation. The distinct roles of Ag(I) and Cu(II) as cocatalysts were clarified through our calculations.

Acyl Radicals from α-Keto Acids: Metal-Free Visible-Light-Promoted Acylation of Heterocycles.

A general and metal-free visible-light-induced decarboxylative arylation procedure at room temperature was described for the construction of acylated heterocyclic derivatives, such as benzimidazo/indolo[2,1-a]isoquinolin-6(5H)-ones, aroylazaspiro[4.5]trienones, thioflavones, and so on. This practical arylation procedure was conducted by using 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN) as a photocatalyst under mild conditions, which avoided the use of an additional base, traditional heating, and metal reagents.

Aryl acyl peroxides for visible-light induced decarboxylative arylation of quinoxalin-2(1H)-ones under additive-, metal catalyst-, and external photosensitizer-free and ambient conditions

Aryl radicals were generated for the first time from aryl acyl peroxides in ethyl acetate under ambient conditions and visible-light illumination in the absence of any additive, metal catalyst, or external photosensitizer.

Direct Stereoselective β‐Arylation of Enol Ethers by a Decarboxylative Heck‐Type Reaction

Despite remarkable advances to promote regio‐ and stereoselective decarboxylative arylation of inactivated olefins with benzoic acid derivatives, methodologies involving hetero‐substituted alkenes are still lacking. Herein, PdII‐catalyzed decarboxylative Heck coupling of α‐alkoxyacrylates with (hetero)aryl carboxylic acids for the stereocontrolled production of (Z)‐β‐heteroarylated vinyl ethers is reported. This methodology offers a rational and step‐economical route to the synthesis of attractive β‐arylated α‐alkoxy α,β‐unsaturated carboxylates family which emerged as a relevant class of building blocks with different applications. Mechanistically, whereas electron rich benzoic acids undergo a PdII‐catalyzed decarboxylation, electron‐deficient substrates proceed through silver(I)‐mediated decarboxylation, explaining thus the formation of stereoisomers (E) and (Z) of β‐arylated vinyl ethers in presence of these latter.

Visible Light‐Catalyzed Decarboxylative Alkynylation of Arenediazonium Salts with Alkynyl Carboxylic Acids: Direct Access to Aryl Alkynes by Organic Photoredox Catalysis

AbstractA convenient method mediated by photoredox catalysis is developed for the direct construction of aryl alkynes. Readily available aromatic diazonium salts have been utilized as the aryl radical source to couple alkynyl carboxylic acids to feature the decarboxylative arylation. A wide range of substrates are amenable to this protocol with broad functional group tolerance, and diversely‐functionalized aryl alkynes could be synthesized under mild, neutral and transition metal‐free reaction conditions using visible light irradiation. Alongside synthetic sustainability associated with the photocatalytic and transition metal‐free operation, another key point of this method is that the organic dye catalyst acts as an excited‐state reductant, thus establishing the quenching cycle for radical addition and decarboxylative elimination.magnified image

Direct Decarboxylative Allylation and Arylation of Aliphatic Carboxylic Acids Using Flavin‐Mediated Photoredox Catalysis

We describe herein a direct decarboxylative allylation of aliphatic carboxylic acids with allylsulfones using visible light and riboflavin tetraacetate (RFTA) as photocatalyst. The reaction proceeds at room temperature tolerating a wide range of functionalities, avoiding the use of external bases or additives. Mechanistic studies support that alkyl radicals are involved in the reaction and that a true photocatalytic cycle is operating. It is proposed that the carboxylic acid is deprotonated by [RFTA]·–, and the corresponding carboxylate acts as a reductive quencher of RFTA*, which after decarboxylation produces the alkyl radical. The methodology was adapted to prepare benzothiazoles substituted at C2, by reacting some carboxylic acids with 2‐(phenylsulfonyl)benzothiazole. The number of carboxylic acids suitable for this arylation was lower than for the allylation and this different reactivity was briefly commented.

On-DNA Decarboxylative Arylation: Merging Photoredox with Nickel Catalysis in Water.

A new catalytic manifold that merges photoredox with nickel catalysis in aqueous solution is presented. Specifically, the combination of a highly active, yet air-stable, nickel precatalyst with a new electron-deficient pyridyl carboxamidine ligand was key to the development of a water-compatible nickel catalysis platform, which is a crucial requirement for the preparation of DNA-encoded libraries (DELs). Together with an iridium-based photocatalyst and a powerful light source, this dual catalysis approach enabled the efficient decarboxylative arylation of α-amino acids with DNA-tagged aryl halides. This C(sp2)-C(sp3) coupling tolerates a wide variety of functional groups on both the amino acid and the aryl halide substrates. Due to the mild and DNA-compatible reaction conditions, the presented transformation holds great potential for the construction of DELs. This was further evidenced by showing that well plate-compatible LED arrays can serve as competent light sources to facilitate parallel synthesis. Lastly, we demonstrate that this procedure can serve as a blueprint toward the adaptation of other established nickel metallaphotoredox transformations to the idiosyncratic requirements of a DEL.

Controllable C–H Cyclization of N-Alkyl-N-arylanthranilic Acids

Key words chemoselective C–H activation - decarboxylative arylation - carbazole synthesis

3-Amino-fluorene-2,4-dicarbonitriles (AFDCs) as Photocatalysts for the Decarboxylative Arylation of α-Amino Acids and α-Oxy Acids with Arylnitriles.

1-(4-(9 H-Carbazol-9-yl)phenyl)-3-amino-9 H-fluorene-2,4-dicarbonitrile as a new photocatalyst for the decarboxylative cross-coupling reaction of α-amino acids or α-oxy carboxylic acids with arylnitriles is described. This light-driven reaction enables a variety of benzylic amines and ethers to be prepared from readily available starting materials under mild conditions.

Decarboxylative Arylation of Pyridine 1‐Oxides and Anilides with Benzoic Acid via Palladium‐Catalyzed C–H Functionalization

A novel method for the palladium‐catalyzed decarboxylative ortho C–H bond arylation of pyridine 1‐oxides and anilides with benzoic acids as aryl sources is described. The established methodology provides a direct approach for the synthesis of 2‐arylpyridine 1‐oxides and 2‐aryl anilides in good isolated yields.

Transition-Metal-Free Decarboxylative Arylation of 2-Picolinic Acids with Arenes under Air Conditions.

A facile, transition-metal-free, and direct decarboxylative arylation of 2-picolinic acids with simple arenes is described. The oxidative decarboxylative arylation of 2-picolinic acids with arenes proceeds readily via N-chloro carbene intermediates to afford 2-arylpyridines in satisfactory to good yields under transition-metal-free conditions. This new type of decarboxylative arylation is operationally simple and scalable and exhibits high functional-group tolerance. Various synthetically useful functional groups, such as halogen atoms, methoxycarbonyl, and nitro, remain intact during the decarboxylative arylation of 2-picolinic acids.

Decarboxylative Arylation of α,β‐Unsaturated Carboxylic Acids Using Aryl Triazenes by Copper/Ionic Liquid Combination in PEG‐400

A practical method for the construction of stilbene derivatives has been developed via catalytic cross‐coupling of cinnamic acids with aryl triazenes. The methodology offers high stereoselectivity and is endowed with broad substrate scope, high yield, and significant functional group tolerance.

Electrophile, Substrate Functionality, and Catalyst Effects in the Synthesis of α‐Mono and Di‐Substituted Benzylamines via Visible‐Light Photoredox Catalysis in Flow

AbstractWe report herein the facile and one‐pot synthesis of α‐mono‐ and di‐substituted benzylamines from cheap and readily available α‐amino acids, via photocatalytic decarboxylative arylation in flow. This enables to access intermediates and building blocks that are difficult to obtain via other synthetic routes, but are key for the manufacture of pharmaceuticals, agrochemicals, and fine chemicals. The optimal decarboxylative conditions were identified through a high‐throughput evaluation of catalysts, organic or inorganic bases, ligands, and reaction parameters (i. e., contact time, temperatures, and photoelectron power). The reaction turned out to be electronically controlled as the yields increased with increasing electron‐density on the aryl moiety. The results were correlated with the redox properties of the photocatalysts, deriving catalyst structure‐performance relationships which can facilitate the future identification of even better materials. In addition, compared to traditional batch chemistry, the use of a flow protocol led to quicker reactions (30 min instead of 12–72 h) and ensured more predictable reaction scale‐ups.

Decarboxylative arylation of substituted pyrroles N-protected with 2-(trimethylsilyl)ethoxymethyl (SEM)

Palladium-catalyzed decarboxylative arylation is reported using pyrroles N-protected with the 2-(trimethylsilyl)ethoxymethyl (SEM) group and featuring 2-, 3-, and 4-substituents about the pyrrolic framework. In contrast to N-protected pyrroles previously used in decarboxylative arylation, the use of SEM allows deprotection under mild conditions.

Palladium (II) Acetate/Base‐Catalyzed Intermolecular Coupling of Imidazo[1, 2‐a]pyridine Esters with Aryl Halides

AbstractThe combination of Cs2CO3 and Pd(OAc)2 enables the coupling of imidazo[1, 2‐a]pyridine esters and aryl halides, allowing an easy access to generate 3‐aryl imidazo[1, 2‐a]pyridine. The reaction pathway involves a Cs2CO3‐mediated ester hydrolysis followed by a palladium (II) acetate‐catalyzed decarboxylative arylation. The method is comparable with direct arylation of imidazo[1, 2‐a]pyridine and aryl halides. The synthetic utility of this relay reaction resulted in the generation of novel GABAA ligand and potent kinase inhibitor in high overall yields.

Photoredox Iridium–Nickel Dual-Catalyzed Decarboxylative Arylation Cross-Coupling: From Batch to Continuous Flow via Self-Optimizing Segmented Flow Reactor

Photoredox decarboxylative cross-coupling via iridium–nickel dual catalysis has emerged as a valuable method for C(sp2)–C(sp3) bond formation. Herein we describe the application of a segmented flow (“microslug”) reactor equipped with a newly designed photochemistry module for material-efficient reaction screening and optimization. Through the deployment of a self-optimizing algorithm, optimal flow conditions for the model reaction were rapidly developed, simultaneously accounting for the effects of continuous variables (temperature and time) and discrete variables (base and catalyst). Temperature was found to be a critical parameter with regard to reaction rates and hence productivity in subsequent scale-up in flow. The optimized conditions identified at microscale were found to directly transfer to a Vapourtec UV-150 continuous flow photoreactor, enabling predictable scale-up operation at a scale of hundreds of milligrams per hour. This optimization approach was then expanded to other halide coupling par...

Abnormal NHC supported palladacycles: Regioselective arylation of heteroarenes via decarboxylation

We report synthesis of two new palladium(II) complexes of abnormal N-heterocyclic carbene ligands. The catalytic activity of these palladium(II) complexes was examined for the decarboxylative arylation of N-methylindole-carboxylic acids. An exclusive regioselectivity and very good yields were obtained with a variety of aryl halide partners.

Nickel-Catalyzed Oxidative Decarboxylative (Hetero)Arylation of Unactivated C–H Bonds: Ni and Ag Synergy

Oxidative decarboxylative arylation reactions are potentially attractive routes to generate biaryl structures from simple and readily available precursors; yet, they are underutilized, because of limitations in the carboxylic acid scope. Here, we report a nickel catalyst system that enables the selective decarboxylative arylation of unactivated C–H bonds with a broad scope of (hetero)aromatic carboxylate coupling partners. Preliminary mechanistic insights suggest that the efficiency and selectivity of this protocol originate from cooperation between Ni and Ag.

Palladium-catalyzed highly regioselective and stereoselective decarboxylative arylation of unactivated olefins with aryl carboxylic acids

Palladium(II)-catalyzed highly regioselective and stereoselective decarboxylative arylation of unactivated olefins with aryl carboxylic acids has been developed. This method is applicable to a variety of unactivated olefins, including allylamides, long chain functionalized olefins and purely aliphatic olefins, leads to the formation of linear E-configured products in high yields. Both electron-rich and electron-deficient aryl carboxylic acids are suitable arylation reagents. It was found that the choice of solvent, catalyst precursor and oxidant had an important influence on reaction efficiency. As a co-solvent and ligand, DMSO is critical to catalysis. This chemistry expands the scope of decarboxylative arylation of olefins with aryl carboxylic acids, and provides a rapid access to useful linear arylation products of unactivated olefins.