Influence of the solvent and of the reaction concentration for palladium-catalysed direct arylation of heteroaromatics with 4-bromoacetophenone

International audienceThe solvent is certainly one of the main sources of wastes during palladium-catalysed direct arylation reactions. We found that such direct arylations of heteroaromatics can be performed using very high concentrations of reactants (0.5 M–5 M). However, the Pd catalyst precursor used must be adapted to both the solvent nature and the concentration of reactants. The reactions performed in DMA, NMP or DMF can be carried out in very concentrated reaction mixtures using 0.1 mol% Pd(OAc)2 catalyst without phosphine ligand. On the other hand, the reactions in CPME, pentan-1-ol or diethylcarbonate should be performed with a palladium catalyst associated with a phosphine ligand. These reaction conditions allow us to reduce the amount of wastes formed in the course of these couplings.Le solvant est certainement l’une des principales sources de déchets lors des réactions d’arylation directes d’hétéroaromatiques catalysées au palladium. Nous avons constaté que ces réactions peuvent être réalisées en utilisant des concentrations très élevées (0,5 M–5 M). Cependant, le catalyseur de palladium utilisé doit être adapté à la fois à la nature du solvant et à la concentration des réactifs. Les réactions effectuées dans le DMA, la NMP ou le DMF peuvent être réalisées dans des mélanges réactionnels très concentrés, en utilisant 0,1 mol % de Pd(OAc)2 sans addition de ligand de type phosphine. En revanche, les réactions dans le CPME, le pentan-1-ol ou le carbonate de diéthyle doivent être effectuée avec un catalyseur de palladium associé à un ligand phosphine. Ces conditions réactionnelles permettent de réduire la quantité de déchets formés au cours de ces couplages

Phosphine-free palladium-catalysed direct C2-arylation of benzothiophenes with aryl bromides

Copies of 1H and 13C NMR spectra of new compounds are available (attached file).International audienceLigand-free Pd(OAc)2 was found to catalyse very efficiently the direct C2-arylation of benzothiophene derivatives under low catalyst concentration. The reaction can be performed employing as little as 0.5-0.1 mol % catalyst with electron-deficient and some electron-rich aryl bromides. The presence of a methyl or a formyl substituent at C3 of benzothiophene has a minor influence on the reactivity, and even a bromo substituents at C3 is tolerated. A wide variety of functional groups on the aryl bromide, such as nitrile, nitro, acetyl, formyl, ester, chloro, fluoro or trifluoromethyl has been employed

Palladium-acetate catalyst for regioselective direct arylation at C2 of 3-furanyl or 3-thiophenyl acrylates with inhibition of Heck type reaction

International audiencePd(OAc)2/KOAc was found to be an efficient catalytic system for the direct arylation of thiophene and furan derivatives bearing an acrylate at C3. The selectivity of the reaction strongly depends on the nature of the coordinating base. Na2CO3 and Li2CO3 favours the Heck type reaction; whereas the use of KOAc or CsOAc promotes regioselective arylation at C2 of the heteroarene and inhibits the Heck type reaction. The direct arylation products were obtained in moderate to good yields using only 0.1 mol % of catalyst. Electron-withdrawing substituent on aryl bromide, such as acetyl, formyl, ester, nitrile or nitro, favours the reaction; whereas electron-donating ones are unfavourable

Palladium-catalysed synthesis of arylated heterocycles using green reactions conditions

Durant ma thèse, j ai recherché des conditions pour l'activation / fonctionnalisation de liaisons C-H pour l arylation d hétérocycles viables pour l industrie. Par rapport aux protocoles de couplage classiques tels que les réactions de Suzuki, Stille ou Negishi, la fonctionalisation de liaisons C-H fournit des procédures moins coûteuses et plus écologiques si elle tolère des groupements utiles en synthèse et si elle utilise des solvants peu ou non toxiques. Nous avons observé que le thiophène peut être arylé en C2 avec de nombreux bromures d'aryle en présence de seulement 0.2 mol% de Pd(OAc)2. Ensuite, nous avons démontré que des solvants de type alcool tels que le pentan-1-ol permet le couplage de thiazoles ou d imidazoles avec des bromures d aryle. Ce type de solvant est certainement plus viable pour l industrie que les solvants usuellement utilisés pour ces couplages tels que le DMF ou le DMAc. Nous avons ensuite montré que certains de ces couplages peuvent même être effectués sans aucun solvant. Finalement, nous avons démontré que de nombreuses fonctions sur des bromopyridines sont tolérées lors de ces couplages, permettant l accès à des pyridines arylées fonctionnelles utiles pour l industrie pharmaceutique en une étape.During my PhD, I searched for industrially viable conditions for activation / functionalization of CH bonds for the arylation of heterocycles. Compared to conventional coupling protocols such as Suzuki, Stille or Negishi reactions, the functionalization of CH bonds provides less costly and more environmentally friendly procedures if it tolerates synthetically useful functional groups and if it uses solvents with little or no toxicity. We observed that thiophene can be arylated at C2 with a wide scope of aryl bromides in the presence of only 0.2 mol% of Pd(OAc)2. Then, we demonstrated that alcoholic solvents such as pentan-1-ol allow the coupling of thiazoles or imidazoles with aryl bromides. This type of solvent is certainly more viable for the industry as the solvents commonly used for these couplings such as DMF or DMAc. We then showed that some of these couplings can even be performed without any solvent. Finally, we have shown that many functions on bromopyridines are tolerated in these couplings, enabling access to arylated functionalized pyridines useful for the pharmaceutical industry in one step.RENNES1-Bibl. électronique (352382106) / SudocSudocFranceF

Synthesis of heteroarenes dyads from heteroarenes and heteroarylsulfonyl chlorides via Pd-catalyzed desulfitative C-H bond heteroarylations

International audienceWe report herein on the palladium-catalyzed direct heteroarylation of heteroarenes (e.g., pyrroles, furans, and thiophenes) in which heteroarylsulfonyl chlorides are used as coupling partners through a desulfitative cross-coupling. These C-H bond functionalizations occurred at the α-position in the case of pyrrole and furan derivs., while in the case of thiophenes the C-H bonds at the β-position have been heteroarylated. This methodol. represents a very simple route to heteroaryl dyads. Moreover, some examples of heteroaryl triads have been synthesized via iterative C-H bond arylations

Palladium-catalyzed direct desulfitative C2 arylations of 3-halo-: N -protected indoles using (hetero)arenesulfonyl chlorides

International audienceThe direct arylation of N-protected 3-haloindole derivatives with benzenesulfonyl chlorides as coupling partners using 5 mol% of bis(acetonitrile)dichloropalladium(ii) catalyst and lithium carbonate as a base in 1,4-dioxane was investigated. We demonstrated that both iodo and chloro substituents at the indolyl C3 position act as temporary blocking groups allowing the formation of 2-arylindoles through a direct desulfitative arylation, followed by in situ dehalogenation. While, from 3-bromoindole derivatives, 2-aryl-3-bromoindoles were obtained without debromination, and could be converted into 2,3-diarylindoles through a second palladium coupling. This method allows one to prepare in a few steps a very wide variety of indole derivatives, which are of interest in the synthesis of bioactive molecules

sp3–sp3 carbon–carbon bonds formation using 2-alkylazoles and a bromoacrylate as the reaction partners

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Palladium-catalyzed non-directed C–H bond arylation of difluorobenzenes and dichlorobenzenes bearing benzoxazole or benzothiazole

International audienceWe report, herein, on palladium-catalyzed direct arylation of difluorobenzenes and dichlorobenzenes bearing benzoxazole or benzothiazole moieties, which don't act as directing groups. With moderate electron-withdrawing substituents on the aryl bromides as coupling partners, the reaction proceeds nicely using phosphine-free PdCl2 catalyst, and potassium pivalate/dimethylacetamide (PivOK/DMA) as catalytic system. The reaction was regioselective and occurred at the less hindered ortho-positions of fluorine or chlorine atom

Synthesis of Symmetrical and Unsymmetrical 1,3-Diheteroarylbenzenes Through Palladium-Catalyzed Direct Arylation of Benzene-1,3-disulfonyl Dichloride and 3-Bromobenzenesulfonyl Chlorides

International audienceThe palladium-catalyzed synthesis of unsymmetrical 1,3-diheteroarylbenzenes was investigated. The first synthetic pathway relies on the desymmetrization of benzene-1,3-disulfonyl dichloride through two successive palladium-catalyzed direct desulfitative arylations with two different heteroarenes. The second strategy employs the orthogonal functionalization of 3-bromobenzenesulfonylchloride using an iterative C–H bond arylation sequence, namely, palladium-catalyzed direct desulfitative arylation followed by a palladium-catalyzed direct arylation step using aryl bromide as the coupling partner. The synthesis of symmetrical 1,3-diheteroarylbenzenes was also investigate

Conditions for the Palladium-Catalysed Direct 2-Arylation of 3-Bromobenzo[b]thiophene Tolerant of the Benzothienyl Carbon-Bromine Bond

International audiencePhosphine-free palladium(II) acetate catalyst was found to promote the direct 2-arylation of 3-bromobenzo[b]thiophene without cleavage of the benzothienyl carbon-bromine bond, allowing the synthesis of 2-aryl-3-bromobenzo[b]thiophenes in only one step. The best results were generally obtained using a low loading of the palladium catalyst (0.5 mol%), quite low reaction temps. (80-120 °C) and short reaction times (0.5-2 h). The reaction proceeds with electron-deficient para-, meta- and ortho-substituted aryl bromides and also with heteroaryl bromides. The benzothienyl carbon-bromine bond has been profitably employed for further palladium-catalyzed functionalisations. This strategy allows the straightforward synthesis of 2,3-di(hetero)arylated benzo[b]thiophenes with two different (hetero)aryl units via sequential catalytic arylations