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

Abstract

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

The First Catalytic Direct C–H Arylation on C2 and C3 of Thiophene Ring Applied to Thieno-Pyridines, -Pyrimidines and -Pyrazines

“…One of the other possible options was to use aryl bromides [16,17]. The 2-phenylthieno[3,2b]pyridine 2 was chosen for these experiments and was reacted with various amounts of Pd(OAc) 2 , K 2 CO 3 , or KOAc as base, with or without ligands in different solvents.…”

Sustainable protocols for direct C–H bond arylation of (hetero)arenes

“…In 2014, they reported a systematic study of the impact of reaction medium in the Pd-catalyzed direct C-H arylation reaction of five-membered monocyclic heteroarenes, including N-methyl pyrrole, with 4-bromoacetophenone: although toxic DMF and DMA gave the best results, among sustainable solvents 1-pentanol afforded the corresponding α-arylated product with the best conversion by using Pd(OAc) 2 as the catalyst and KOAc as the base. 209 In a following publication, the use of 1-pentanol and 3-methyl-1-butanol as solvents was investigated in combination with recoverable Pd/C catalyst for direct C-H arylations of N-methyl pyrrole with several bromoarenes: only slightly lower yields were observed compared to the corresponding reactions in DMA, especially in the case of 3-methyl-1-butanol (see also section 2.1.2). 33 It is clear that the possibility of merging the use of a sustainable reaction medium with a recoverable and cheap catalyst in the same procedure is highly desirable in the context of Green Chemistry, although it is far from trivial.…”

“…It is worth emphasizing that Doucet's research group studied in detail the possibility of using other greener alcohols (i.e., 1-pentanol and 3-methyl-1-butanol) as solvents in the direct C-H arylation reactions of furans and benzofurans with aryl bromides, although they always showed modest results compared to DMA, NMP and DMF. 33,209 3.2.4. Direct C-H bond arylation of S-heteroarenes in alcohols.…”

“…as the base at 150 °C, affording the corresponding product 184 with a yield (76%) similar to that obtained by using traditional DMA (Scheme 73). 209 In 2018, they also showed that 3-methyl-1-butanol was in general less effective than other more traditional solvents in the reaction of 2-substituted thiophenes (bearing both electron-poor and electron-rich functionalities) with para-and ortho-functionalized aryl bromides. 33 Aryldiazonium tetrafluoroborates were successfully used as arylating agents in the C3-regioselective direct arylation of benzo [b]thiophenes, performed in methanol in the presence of Pd(OAc) 2 only (i.e., under ligand-free and base-free conditions), 167 or in ethanol by using PdO-Fe 3 O 4 as an easily removable catalyst.…”

“…In 2014, in a comparative study of solvent and concentration effects in direct C-H bond arylation reactions, they described the direct coupling of 1-methylpyrrole, ethyl 2-methylfuran-3-carboxylate and thiophene 2-carbonitrile with 4-bromo acetophenone, using [Pd(C 3 H 5 )Cl(dppb)] as homogeneous catalyst and potassium acetate as the base. 209 Despite the use of a environmentally friendly solvent, in this specific study Doucet and co-workers were mainly focused on the investigation of solvent and concentration effects, rather than on the concrete development of a sustainable synthetic protocol with broad applicability.…”