Palladium-catalyzed Direct Arylation Research Articles

Mono or double Pd-catalyzed C-H bond functionalization for the annulative π-extension of 1,8-dibromonaphthalene: a one pot access to fluoranthene derivatives.

The Pd-catalyzed annulative π-extension of 1,8-dibromonaphthalene for the preparation of fluoranthenes in a single operation has been investigated. With specific arenes such as fluorobenzenes, the Pd-catalyzed double functionalization of C-H bonds yields the desired fluoranthenes. The reaction proceeds via a palladium-catalyzed direct intermolecular arylation, followed by a direct intramolecular arylation step. As the C-H bond activation of several benzene derivatives remains very challenging, the preparation of fluoranthenes from 1,8-dibromonaphthalene via Suzuki coupling followed by intramolecular C-H activation has also been investigated to provide a complementary method. Using the most appropriate synthetic route and substrates, it is possible to introduce the desired functional groups at positions 7-10 on fluoranthenes.

Mixed-Ligand Approach to Palladium-Catalyzed Direct Arylation of Heteroarenes with Aryl Chlorides: Controlling Reactivity of Catalytic Intermediates via Dynamic Ligand Exchange

Mixed-Ligand Approach to Palladium-Catalyzed Direct Arylation of Heteroarenes with Aryl Chlorides: Controlling Reactivity of Catalytic Intermediates via Dynamic Ligand Exchange

Palladium-Catalyzed Direct (Het)arylation Reactions of Benzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole and 4,8-Dibromobenzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole).

Palladium-catalyzed direct (het)arylation reactions of strongly electron-withdrawing tricyclic benzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole) and its 4,8-dibromo derivative were studied; the conditions for the selective formation of mono- and bis-aryl derivatives were found. The reaction of 4,8-dibromobenzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole) with thiophenes in the presence of palladium acetate as a catalyst and potassium pivalate as a base, depending on the conditions used, selectively gave both mono- and bis-thienylated benzo-bis-thiadiazoles in low to moderate yields; arenes were found to be inactive in these reactions. It was discovered that direct C-H arylation of benzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole with bromo(iodo)arenes and -thiophenes in the presence of Pd(OAc)2 and di-tert-butyl(methyl)phosphonium tetrafluoroborate salt is a powerful tool for the selective formation of 4-mono- and 4,8-di(het)arylated benzo-bis-thiadiazoles. Oxidative double C-H hetarylation of benzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole with thiophenes in the presence of Pd(OAc)2 and silver (I) oxide in DMSO was successfully employed to prepare bis-thienylbenzo-bis-thiadiazoles in moderate yields.

Ligandless Palladium-Catalyzed Direct C-5 Arylation of Azoles Promoted by Benzoic Acid in Anisole

The palladium-catalyzed direct arylation of azoles with (hetero)aryl halides is nowadays one of the most versatile and efficient procedures for the selective synthesis of heterobiaryls. Although this procedure is, due to its characteristics, also of great interest in the industrial field, the wide use of a reaction medium such as DMF or DMA, two polar aprotic solvents coded as dangerous according to environmental, health, safety (EHS) parameters, strongly limits its actual use. In contrast, the use of aromatic solvents as the reaction medium for direct arylations, although some of them show good EHS values, is poorly reported, probably due to their low solvent power against reagents and their potential involvement in undesired side reactions. In this paper we report an unprecedented selective C-5 arylation procedure involving anisole as an EHS green reaction solvent. In addition, the beneficial role of benzoic acid as an additive was also highlighted, a role that had never been previously described.

Practical and efficient total synthetic route of the resveratrol dimer (±)-ε-viniferin

A practical and efficient total synthetic route of the resveratrol dimer (±)-ε-viniferin (2) with benzyl as protecting group for phenols was achieved with high overall yield. The synthetic approach involved a palladium-catalyzed direct arylation, triethylsilane-mediated reduction of benzofuran, and selective debenzylation reaction. Selective debenzylation in the presence of reducible and acid-sensitive groups catalyzed using Pd/C and 1,4-cyclohexadiene was implemented to complete the total synthesis.

Toward the Synthesis of a Belt-Shaped Cyclic π-Conjugated System Comprising para-Phenylene Framework and Amide Bridging Unit

Abstract Belt-shaped π-conjugated systems have been attracting more and more attention in recent years from the synthetic interest as well as their mysterious properties that linear counterparts do not have. In this paper, the stepwise condensation of 2-bromo-4-(octylamino)benzoic acid and subsequent macrocyclization was carried out to obtain a cyclic hexamer (c6mer). The palladium-catalyzed direct arylation was then performed to get the target belt-shaped molecule (b6mer) although the isolation of b6mer did not meet with success because of the contamination of structural defects. Theoretical calculation of b6mer indicated the strain energy of ca. 100.9 kcal·mol−1 and revealed the electronic transition from degenerate HOMO-1 and HOMO-2 orbitals to LUMO similar to that of parent cycloparaphenylene derivatives.

Synthesis of Quinoxaline-Linked Bis(Benzimidazolium) Salts and Their Catalytic Application in Palladium-Catalyzed Direct Arylation of Heteroarenes

Synthesis of Quinoxaline-Linked Bis(Benzimidazolium) Salts and Their Catalytic Application in Palladium-Catalyzed Direct Arylation of Heteroarenes

Regiocontrolled palladium-catalyzed direct C2-arylation of a difluorobenzo[d]imidazole

Conditions for the regioselective palladium-catalyzed direct arylation of a 6,7-difluorobenzo[d]imidazole using aryl bromides as the coupling partners are described. The site selectivity of the arylation was found to be in favor of the C2-carbon of the difluorobenzo[d]imidazole; whereas the difluoro-substituted ring remained untouched, even in the presence of an excess of aryl bromide. This method tolerates a variety of substituents at para-, meta- and ortho-positions on the aryl bromide and also N-containing heteroaryl bromides.

Palladium-Catalyzed Direct Arylation of 2-Pyridylmethyl Silanes with Aryl Bromides.

The first palladium-catalyzed direct arylation of 2-pyridylmethyl silanes with aryl bromides to generate a diverse array of aryl(2-pyridyl)-methyl silane derivatives has been developed. This protocol facilitates access to various kinds of heterocycle-containing silanes in good to excellent yields (40 examples, 66-97% yield) with good functional group tolerance. The scalability of this transformation is demonstrated.

Bayesian reaction optimization as a tool for chemical synthesis.

Reaction optimization is fundamental to synthetic chemistry, from optimizing the yield of industrial processes to selecting conditions for the preparation of medicinal candidates1. Likewise, parameter optimization is omnipresent in artificial intelligence, from tuning virtual personal assistants to training social media and product recommendation systems2. Owing to the high cost associated with carrying out experiments, scientists in both areas set numerous (hyper)parameter values by evaluating only a small subset of the possible configurations. Bayesian optimization, an iterative response surface-based global optimization algorithm, has demonstrated exceptional performance in the tuning of machine learning models3. Bayesian optimization has also been recently applied in chemistry4-9; however, its application and assessment for reaction optimization in synthetic chemistry has not been investigated. Here we report the development of a framework for Bayesian reaction optimization and an open-source software tool that allows chemists to easily integrate state-of-the-art optimization algorithms into their everyday laboratory practices. We collect a large benchmark dataset for a palladium-catalysed direct arylation reaction, perform a systematic study of Bayesian optimization compared to human decision-making in reaction optimization, and apply Bayesian optimization to two real-world optimization efforts (Mitsunobu and deoxyfluorination reactions). Benchmarking is accomplished via an online game that links the decisions made by expert chemists and engineers to real experiments run in the laboratory. Our findings demonstrate that Bayesian optimizationoutperforms human decisionmaking in both average optimization efficiency (number of experiments) and consistency (variance of outcome against initially available data). Overall, our studies suggest that adopting Bayesian optimization methods into everyday laboratory practices could facilitate more efficient synthesis of functional chemicals by enabling better-informed, data-driven decisions about which experiments to run.

Donor–Acceptor Polymers Containing 4,8-Dithienylbenzo[1,2-b:4,5-b′]dithiophene via Highly Selective Direct Arylation Polymerization

While palladium-catalyzed direct arylation polymerization (DArP) is an easy and safe method to synthesize semiconducting polymers with alternating donor–acceptor units (DA polymers), branching and cross-linking defects arising from unintended side reactions are common. When these polymers are used as electronic materials in organic solar cells (OSCs) and similar devices, these defects may adversely affect device performance. We have recently shown that the side reactions can be inhibited by the simultaneous presence of two ligands, P(2-MeOC6H4)3 and N,N,N′,N′-tetramethylethylenediamine (TMEDA). In this study, an efficient donor polymer for OSCs (P1), based on 4,8-dithienylbenzo[1,2-b:4,5-b′]dithiophene (DTBDT) units, was prepared with this mixed-ligand method. The DA polymer is found to exhibit a well-controlled structure, with homocoupling defects of 2.0%, compared to 14.8% observed in the Migita–Stille product (P2). The power conversion efficiency (PCE) was 9.9% when P1 was used, compared to 9.8% for P2 in bulk-heterojunction-type OSC with a nonfullerene acceptor. This demonstrates the effectiveness of the DArP method as a clean and safe alternative method to synthesize DTBDT-based DA polymers for OSCs.

Palladium-catalyzed direct Hiyama arylation of quinoxalin-2(1H)-ones with aryl siloxanes in water

An efficient method for palladium-catalyzed direct Hiyama coupling of various quinoxalin-2(1H)-ones with aryl siloxanes has been developed. The protocol provides a convenient access to a variety of useful C3-arylated 1-methylquinoxalin-2(1H)-one derivatives in reasonable yields by using low cost water as a solvent and oxygen as an oxidant.

Regiocontrolled synthesis of ester-functionalized polythiophenes via direct arylation polycondensation

A series of ester-functionalized polythiophenes (P3OETs) with precisely controlled head-to-tail (HT) ratios was synthesized via palladium-catalyzed direct arylation polycondensation (DArP). The ionization potentials and optical bandgaps of P3OETs decreased as their HT ratios increased because of the increased backbone coplanarity and extensive π-electron delocalization. The method of precisely controlling the regioregularity and HT ratio can contribute to the design of new polythiophene derivatives with enhanced electronic functionality. A series of ester-functionalized polythiophenes (P3OETs) with precisely controlled head-to-tail (HT) ratios was synthesized via palladium-catalyzed direct arylation polycondensation (DArP). The ionization potentials and optical bandgaps of P3OETs decreased as their HT ratios increased because of the increased backbone coplanarity and extensive π-electron delocalization. The method of precisely controlling the regioregularity and HT ratio can contribute to the design of new polythiophene derivatives with enhanced electronic functionality.

Efficient synthesis of mono- and bis-arylated ethylenedioxy thiophene-based functional π-conjugated molecules via clay-supported palladium-catalysed direct arylation reactions

An active Pd catalyst was prepared by the modification of montmorillonite clay. The catalyst was found to be effective for the synthesis of ethylenedioxy thiophene-based π-conjugated molecules. The reaction proceeded through clay-supported Pd-catalysed direct C–H bond activation (arylation) mechanism. Preparation, characterization and application of the catalysts are reported. The products were analysed with LCMS, and comparison with reported spectral data (FT-IR, 1H NMR). Reusability of clay-supported palladium catalyst towards direct arylation reaction was tested for three reaction cycles without a significant loss of catalytic activity.

How To Make Nitroaromatic Compounds Glow: Next-Generation Large X-Shaped, Centrosymmetric Diketopyrrolopyrroles.

Red‐emissive π‐expanded diketopyrrolopyrroles (DPPs) with fluorescence reaching λ=750 nm can be easily synthesized by a three‐step strategy involving the preparation of diketopyrrolopyrrole followed by N‐arylation and subsequent intramolecular palladium‐catalyzed direct arylation. Comprehensive spectroscopic assays combined with first‐principles calculations corroborated that both N‐arylated and fused DPPs reach a locally excited (S1) state after excitation, followed by internal conversion to states with solvent and structural relaxation, before eventually undergoing intersystem crossing. Only the structurally relaxed state is fluorescent, with lifetimes in the range of several nanoseconds and tens of picoseconds in nonpolar and polar solvents, respectively. The lifetimes correlate with the fluorescence quantum yields, which range from 6 % to 88 % in nonpolar solvents and from 0.4 % and 3.2 % in polar solvents. A very inefficient (T1) population is responsible for fluorescence quantum yields as high as 88 % for the fully fused DPP in polar solvents.

Aqueous Palladium-Catalyzed Direct Arylation Polymerization of 2-Bromothiophene Derivatives.

Aqueous palladium-catalyzed direct arylation polymerization (DArP) of 2-bromothiophene derivatives 6-(2-(2-bromothiophen-3-yl)ethoxy)hexyl trimethylammonium bromide (T1) and 4-(2-(2-bromothien-3-yl)ethoxy)butylsulfonate (T2) is achieved. The supporting ligand, triphenylphosphine-3,3',3''-trisulfonic acid trisodium salt (m-TPPTs), facilitates DArP of both derivatives; however, its separation from the polymers by dialysis is difficult due to its strong aggregation in water and N,N-dimethylacetamide (DMAc). This is supported by dynamic light scattering, gel permeation chromatography (GPC), and single-crystal X-ray crystallography. Pyrimidine-Pd(OAc)2 is utilized in the DArP of T1 to afford PT1 without ligand contamination. Density functional theory calculations to determine the coordinating capability of the carboxylate/pivalic acid/water to palladium indicate the viability of implementing DArP in water. Finally, polyelectrolyte molecular-weight overestimation by GPC in water is attributed to the polyelectrolyte effect. Aggregation of the conjugated polyelectrolytes leads to a contracted hydrodynamic volume, and the molecular weight and dispersity assessed by GPC in DMAc significantly deviate from the actual values. An objective approach to evaluate the molecular weight for conjugated polyelectrolytes requires further development.

Mixed-Ligand Approach to Palladium-Catalyzed Direct Arylation Polymerization: Synthesis of Donor–Acceptor Polymers Containing Unsubstituted Bithiophene Units

The combined use of P(2-MeOC6H4)3 (L1) and TMEDA as ligands effectively prevents defect formation in palladium-catalyzed direct arylation polymerization (DArP) to give donor–acceptor type alternati...

Reactivity of N-methyl-N-(polyfluorobenzyl)acetamides and N-methyl-N-(polyfluorobenzyl)benzamides in Pd-catalyzed C–H bond arylation

Abstract The influence of fluoro substituents on the aryl group of N-methyl-N-benzylacetamides and N-methyl-N-benzylbenzamides on the regioselectivity of palladium-catalyzed direct arylations was studied. With these (poly)fluoro-substituted tertiary benzamides, the arylations proceed very regioselectively at the C–H bond flanked by two fluoro substituents using 2.5 mol% of air-stable palladium catalysts and PivOK/N,N-dimethylacetamide (DMA) as the reaction conditions. For these reactions, a variety of substituents on the aryl bromide, such as ester, propionyl, acetyl, formyl, nitro, nitrile, methoxy, or methyl, was tolerated. Nitrogen-containing heteroaryl bromides were also successfully used. These results reveal that under our reaction conditions, fluoro substituents act as better directing groups than amides in palladium-catalyzed direct arylations.

Palladium-Catalyzed C12-Selective Direct Arylation of [1,2-c]Quinazolin-6(5H)-ones

A straightforward approach to the synthesis of the challenging 12-arylindolo[1,2-c]quinazolin-6(5H)-ones through the palladium-catalyzed direct arylation of N-benzyl and NH-free [1,2-c]quinazolin-6(5H)-ones with aryl halides is described.

Synthesis of π-conjugated network polymers based on triphenylamine (TPA) and tetraphenylethylene (TPE) as building blocks via direct Pd-catalyzed reactions and their application in CO2 capture and explosive detection.

In this study, we report the synthesis of π-conjugated network polymers via palladium-catalyzed direct arylation polycondensation of triphenylamine (TPA) and tetraphenylethylene (TPE) with different active substrates. Moreover, six conjugated porous polymers were obtained (named as TPA-TPA-MA, TPA-PB-MA, TPA-TFB-MA, TPA-TPE-MA, TPE-PB-MA, and TPE-TFB-MA). Then, the fluorescence properties in the solid and dispersed states, the corresponding microporous structures, and the Brunauer–Emmett–Teller (BET) surface areas of all polymers were well studied. Among the obtained materials, TPA-PB-MA possessed not only largest BET surface area (686 m2 g−1) and largest pore volume (0.716 cm3 g−1), but also the smallest pore size of 0.823 nm. These properties are very beneficial for the application of TPA-PB-MA in CO2 storage and PA sensing. At 1 bar, TPA-PB-MA demonstrated the significant CO2 uptake of 2.70 and 1.35 mmol g−1 at 273 and 298 K, respectively. Furthermore, TPA-PB-MA was most sensitive and selective towards PA recognition. The KSV constant was measured as 4.0 × 104 M−1.