C–H Alkenylation of Heteroarenes: Mechanism, Rate, and Selectivity Changes Enabled by Thioether Ligands

Abstract

Thioether ancillary ligands have been identified that can greatly accelerate the C-H alkenylation of O-, S-, and N-heteroarenes. Kinetic data suggest thioether-Pd-catalyzed reactions can be as much as 800× faster than classic ligandless systems. Furthermore, mechanistic studies revealed C-H bond cleavage as the turnover-limiting step, and that rate acceleration upon thioether coordination is correlated to a change from a neutral to a cationic pathway for this key step. The formation of a cationic, low-coordinate catalytic intermediate in these reactions may also account for unusual catalyst-controlled site selectivity wherein C-H alkenylation of five-atom heteroarenes can occur under electronic control with thioether ligands even when this necessarily involves reaction at a more hindered C-H bond. The thioether effect also enables short reaction times under mild conditions for many O-, S-, and N-heteroarenes (55 examples), including examples of late-stage drug derivatization.

Base‐Assisted C−H Bond Cleavage in Cross‐Coupling: Recent Insights into Mechanism, Speciation, and Cooperativity

“…[71b] Kinetic studies indicated the presence of 56 led to an acceleration of turnover-limiting activation of the heteroarene substrate by standard CMD. DFT calculations on the two competing standard CMD pathways involving the typically proposed intermediate, ( t Bu 3 P)Pd(Ph) (k 2 -OAc) (54), and the in situ generated metallocycle 56 supported the latter as being more reactive by ΔΔG � = 6 kcal/ mol. Based on these observations, a catalytic process was proposed in which the palladacycle promotes standard CMD to generate 57 followed by Pd-to-Pd transmetalation with the OA complex (53/54) to give diarylÀ Pd species 55 that generates product through CÀ C reductive elimination (Figure 28).…”

“…The highest selectivity was observed for Pd catalysts coordinated by anionic thioethers L2 or L3, which are particularly reactive toward CÀ H alkenylation with electronrich heteroarenes. [54] This switch in substrate preference could be indicative of a change in the nature of the transition state of CÀ H cleavage; while tempting to attribute the electrophilic reactivity in the CÀ H alkenylation reactions to a step-wise S E Ar type pathway, it was shown for the thioetherÀ Pd cases that CÀ H cleavage is turnover-limiting. It should be noted that the turnover-limiting step of CÀ H alkenylation has not been established for cases employing pyridine-or DAF-coordinated Pd(OAc) 2 .…”

“…Ligand effect on competitive CÀ H alkenylation between a more or less electron-rich thiophene under otherwise identical reaction conditions. [54] AMLA and CMD models share a number of similarities, particularly in the general constitution of atoms in the CÀ H cleavage transition state, the former model originated from studies of complexes exhibiting electrophilic reactivity patterns while the latter did not. The direct arylation reactions studied by Fagnou to develop the CMD model were shown to occur through rate-limiting CÀ H cleavage, in most cases, yet the site selectivity for these reactions routinely strays from S E Ar type reactivity patterns favoring instead more electronpoor (hetero)arenes or sites with more acidic CÀ H bonds.…”

“…Proposed catalytic mechanisms through (a) a neutral pathway for benzene CÀ H acetoxylation using pyridine-coordinated Pd(OAc) 2 or (b) a cation pathway for heteroarene CÀ H alkenylation using thioether-coordinated Pd(OAc) 2 [54][55]. (c) Off-cycle catalytic intermediates identified in these studies are also noted.…”

Aerobic Oxidative Functionalization of Indoles

“…[18] In the studies on the thioether ligand-promoted CÀ H alkenylation of heteroarenes, Carrow and co-workers also disclosed feasible aerobic examples of indole functionalization (Scheme 7, conditions D). [19] For selective indole C2 alkenylation, the strategy of directing CÀ H activation could be used. In this regard, earlier works focused on the palladium-catalyzed oxidative Heck reactions, in which Cu(OAc) 2 was generally used as the terminal electron acceptor.…”