Electronic Control on Linear versus Branched Alkylation of 2‐/3‐Aroylbenzofurans with Acrylates: Combined DFT and Synthetic Studies

Abstract

Investigations on the factors that govern unusual branched alkylation of 2-aroylbenzofurans with acrylates by Ru-catalyzed carbonyl-directed C-H activation has been carried out by calculating the kinetics associated with the two key steps-the coordination of the acrylate with the intermediate ruthenacycle and the subsequent migratory insertion reaction-studied with the help of DFT calculations. Eight possible orientations for each mode of alkylation have been considered for the calculations. From these calculations, it has been understood that there is a synergistic operation of the steric and electronic effects favoring the branched alkylation. Further DFT investigations on the alkylation of the isomeric 3-aroylbenzofurans indicated a preference for the linear alkylation and this has been verified experimentally. Overall, the observed/calculated complementary selectivity in the alkylation of 2-/3-aroylbenzofurans with acrylates reveals that the substrate-dependent charge distribution of the Ru-C bond in the intermediate ruthenacycle is an important determining factor and thus the current work opens up a new domain of substrate design for controlling regioselectivity.

A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry

“…Recently, the group published a follow-up paper trying to elucidate via DFT calculations how the linear/branched selectivity was controlled. 89 They calculated transition states leading either to the linear or to the branched products, which are both feasible pathways. The transition state towards the branched product turned out to be significantly lower in energy, which goes in line with the experimental observations.…”

“…Furthermore, the method was extended to the C2-alkylation of 3-aryloxybenzofurans. 89 On this second type of substrates, the linear product was preferred with high selectivity (20/1) and no protocol for the branched products was disclosed ( Scheme 3B ).…”

Beyond Friedel and Crafts: Directed Alkylation of C−H Bonds in Arenes

“…(2)]: although the reaction was found to be efficient in both cases, double alkylation was observed in some cases and 2‐acylpyridine itself was found to be a poor substrate, certainly because of the formation of a chelate that inhibits the activation of the C−H bond . The reaction was also shown to be efficient with ferrocenylketones, 3‐aroylbenzofurans,, thioxanthones, as well as for the directed alkylation of ring C of aromatic diterpenoids and also found efficient applications in polymer science . Ethylene can be replaced by a combination of tetraethylammonium bromide and potassium hydroxide for the introduction of an ethyl group …”

Synthesis of β-anti-Substituted α-Amino Acids through Iridium-Catalyzed Alkylation/Chelation-Controlled Nucleophilic Addition

“…9 Although we were unable to clarify the underlying reason for this drop in the dr for these products, the roles of electronic and steric effects around the iridium center appear to be critical for the diastereoselectivity of the reaction. 3,12 After obtaining a variety of -substituted -amino acids from variously protected allylic carbonate esters, we decided to investigate the com- Dieses Dokument wurde zum persönlichen Gebrauch heruntergeladen. Vervielfältigung nur mit Zustimmung des Verlages.…”

“…9 Although we were unable to clarify the underlying reason for this drop in the dr for these products, the roles of electronic and steric effects around the iridium center appear to be critical for the diastereoselectivity of the reaction. 3 12 After obtaining a variety of β-substituted α-amino acids from variously protected allylic carbonate esters, we decided to investigate the compatibility of glycine derivatives in this allylation protocol. The reaction of methyl or ethyl glycinate with 2a afforded the products 3i and 3j in yields of 85 and 86%, respectively, with 8:1 dr and 99% ee.…”