Hydride Relay Exchange Mechanism for the Heterocyclic C–H Arylation of Benzofuran and Benzothiophene Catalyzed by Pd Complexes

Abstract

The mechanism and regioselectivity of the heterocyclic C–H arylation of benzofuran and benzothiophene catalyzed by Pd­(OAc)2 complexes were investigated using the density functional theory (DFT) method. The Pd(0)­L2(PhI) complex (L = HOAc) is proposed to be the catalytic species. Compared to the traditional Heck-type mechanism, concerted metalation-deprotonation (CMD) mechanism, and electrophilic aromatic substitution (SEAr) mechanism for the C–H arylation, a new hydride relay exchange mechanism was proposed for the benzoheterocyclic C–H arylation catalyzed by Pd complexes, which consists of two redox processes between Pd­(II) and Pd(0) species to complete the regioselective C–H activation. The calculated results indicate that the reaction along the hydride relay exchange mechanism is more favorable than those along other mechanisms, including the traditional Heck-type mechanism and the base-assisted anti-H elimination mechanism. This agrees well with the experimental results. Meanwhile, the origin for the regioselective C–H arylation was unveiled in which the α-C-H arylation products are major for the heterocyclic C–H arylation of benzofuran, but the β-C-H arylation products are major for that of benzothiophene. This study might provide a deep mechanistic understanding on the regioselective C–H activation and arylation of benzoheterocycle compounds catalyzed by transition-metal complexes.

Direct α-Arylation of Benzo[b]furans Catalyzed by a Pd3 Cluster

“…63,64,68,74−78 Furthermore, a kinetic isotope effect (KIE) study was conducted, and the small magnitude of KIE (1.17) showed that the cleavage of the C−H bond is unlikely to be involved in the rate-determining step (Scheme 3-iii). 63,64,68,74−78 Beyond the CMD mechanism, an S E Ar mechanism at the C-2 site of benzofuran followed by reductive elimination and rearomatization 58,74,79,80 or an electrophilic attack of cationic palladium followed by aryl ligand migration 78 seem more likely to be responsible for the reaction, which is consistent with the results of deuterium scrambling and the KIE studies. In addition, the Heck-type mechanism might also be possible, as demonstrated by many others.…”

“…In addition, the Heck-type mechanism might also be possible, as demonstrated by many others. 57,59,60,63,64,68,74 Finally, although we cannot rule out the possibility of the Pd 3 cluster acting as a reservoir to in situ generate some mononuclear Pd species or nanoparticles, the ultraviolet−visible (UV−vis) spectra of the solution in the reaction process (Scheme 3-iv) showed that the Pd 3 Cl absorption spectrum remained essentially unchanged over the reaction course, 31 indicating that the Pd 3 cluster core might not undergo substantial change or decomposition during catalysis.…”

“…We conducted a D/H exchange experiment. Deuterated substrate 1a-D was treated under the standard conditions (Scheme -ii), and no deuterium scrambling was observed in product 1a , suggesting that a reversible concerted metalation–deprotonation process is unlikely to occur in the reaction. ,,,− Furthermore, a kinetic isotope effect (KIE) study was conducted, and the small magnitude of KIE (1.17) showed that the cleavage of the C–H bond is unlikely to be involved in the rate-determining step (Scheme -iii). ,,,− Beyond the CMD mechanism, an S E Ar mechanism at the C-2 site of benzofuran followed by reductive elimination and rearomatization ,,, or an electrophilic attack of cationic palladium followed by aryl ligand migration seem more likely to be responsible for the reaction, which is consistent with the results of deuterium scrambling and the KIE studies. In addition, the Heck-type mechanism might also be possible, as demonstrated by many others. ,,,,,, Finally, although we cannot rule out the possibility of the Pd 3 cluster acting as a reservoir to in situ generate some mononuclear Pd species or nanoparticles, the ultraviolet–visible (UV–vis) spectra of the solution in the reaction process (Scheme -iv) showed that the Pd 3 Cl absorption spectrum remained essentially unchanged over the reaction course, indicating that the Pd 3 cluster core might not undergo substantial change or decomposition during catalysis.…”

“…A gram-scale experiment was performed, and product 3aa was obtained in good yield (Scheme i). According to the previous studies, ,,− several mechanisms, including the concerted metalation–deprotonation (CMD) mechanism, electrophilic aromatic substitution (SEAr) mechanism, Heck-type mechanism, and others, may be responsible for the C–H arylation of heteroarenes. Therefore, further studies were undertaken to shed light on the possible reaction mechanism of the current α-arylation of benzofurans.…”

Improved Elastic Image Pair Method for Finding Transition States

“…Transition metal catalysts are widely used in organic synthesis. − To evaluate the efficacy of the i-EIP method for transition metal-catalyzed reactions, five reactions were selected from a variety of published libraries − for use as a test set. The selected reactions contain different transition metal atoms, and the size of these reaction systems is relatively large.…”