Tandem Pd-Catalyzed Cyclization/Coupling of Non-Terminal Acetylenic Activated Methylenes with (Hetero)Aryl Bromides

Abstract

We report a new method for a tandem Pd-catalyzed intramolecular addition of active methylene compounds to internal alkynes followed by coupling with aryl and heteroaryl bromides. Highly substituted vinylidenecyclopentanes were obtained with good yields, complete selectivity, and excellent functional group tolerance. A plausible mechanism, supported by DFT calculations, involves the oxidative addition of bromoarene to Pd(0), followed by cyclization and reductive elimination. The excellent regio- and stereoselectivity arises from the 5-exo-dig intramolecular addition of the enol form of the substrate to alkyne activated by the π-acidic Pd(II) center, postulated as the rate-determining step.

Controllable Access to Furans and Dihydrofurans through Cyclization/Coupling of Internal Acetylenic β‐Ketoesters with Aryl Bromides

“…A competition reaction of bromobenzene with an equimolar mixture of 60 and 1 revealed 2.5‐fold faster reaction of ketoester bearing terminal, compared to Me‐capped alkyne moiety (Scheme 3). In related Pd‐ or Au‐promoted 5‐exo‐dig carbocyclizations of acetylenic ketoesters, steric hindrance on the alkyne fragment played a much more dramatic role, where internal alkynes remained intact in competition experiments [9b–c] …”

Recent Progress in Pd-Catalyzed Tandem Processes

“…The mechanism involving oxidative addition, cyclization, and reductive elimination was also confirmed by the computational study. The rate-and configuration-determining step was found to be the 5-exo-dig intramolecular nucleophilic addition of the enol intermediate to the alkyne activated via coordination with Pd(II) [87].…”

“…As a result, the optimum parameters were chosen (catalyst Pd(OAc) 2 ; solvent NMA; additive CH 3 CO 2 H; temperature ≥ 80 • C; and, optionally, AgCF 3 CO 2 ), which provided the yields of target products of up to 86%. A novel procedure for the tandem intramolecular addition of active methylene compounds to internal alkynes, followed by coupling with aryl and heteroaryl bromides, was described by Błocka et al [87] (Figure 34). As a catalyst, third-generation (G3) Buchwald palladium precatalysts in combination with diphenyl-2-pyridylphosphine (DPPPY) ligand was used.…”

Tandem Pd-catalyzed annulation/coupling of acetylenic enamines with aryl triflates

“…3,4 Palladium, 1 d ,5 also featuring carbophilic Lewis acidity, can enable a tandem process involving cyclization followed by cross coupling, producing additional molecular complexity in one synthetic step through construction of two new C–C bonds. 6 On the other hand, cyclization of unactivated ketones is considerably more challenging due to unfavorable enolization granting another active nucleophilic species (Scheme 1b). 7 Rare strategies for reaching this goal rely either on dual activation of a ketone and a C–C unsaturated moiety 8 or prior conversion of a ketone into its nucleophilic surrogate ( e.g.…”