Bioinspired and Ligand‐Regulated Unnatural Prenylation and Geranylation of Oxindoles with Isoprene under Pd Catalysis

Abstract

In nature, prenylation and geranylation are two important metabolic processes for the creation of hemiterpenoids and monoterpenoids under enzyme catalysis. Herein, we have demonstrated bioinspired unnatural prenylation and geranylation of oxindoles using the basic industrial feedstock isoprene through ligand regulation under Pd catalysis. Pentenylated oxindoles (with C 5 added) were attained with high selectivity when using a bisphosphine ligand, whereas upon switching to a monophosphine ligand, selectivity toward geranylated oxindoles (with C 10 added) was achieved. Moreover, the head-to-head product could be further isomerized to an internal skipped diene under PdÀ H catalysis. No stoichiometric by-product was formed in the process.

Theoretical Insight into the Palladium-Catalyzed Prenylation and Geranylation of Oxindoles with Isoprene

“…The calculated results for this process are shown in Figure a. The reaction occurs through TS1 , which has a relative high energy of 43.6 kcal/mol, making it inaccessible under the experimental reaction conditions (60 °C) . Moreover, this process is calculated to be endothermic by 36.0 kcal/mol, indicating that it is both kinetically and thermodynamically unfavorable.…”

“…The authors achieved distinctive formation of prenylated product P 1 and geranylated product P 2 by using different ligands. Notably, none of the potential additional products, including P 3 (3,4-addition product), P 4 (1,4-addition product with the nitrogen in oxindole as the active site), P 5 (C2′ in isoprene as the nucleophilic site), and P 6 (the nitrogen in oxindole as the active site), were observed in the experiment . This indicates excellent regioselectivity of the reaction.…”

“…In 2017, the same group successfully achieved the selective synthesis of prenylated products and geranylated products of oxindoles using Pd(0) catalysis, dimethylallyl alcohol carbonates as reagents, and introducing a protecting group on the nitrogen atom of oxindoles . Recently, Chen et al reported the palladium-catalyzed ligand-controlled selective prenylation and geranylation reactions of oxindoles with isoprene. A representative example of their reactions is depicted in Scheme .…”

“…Moreover, Chen’s group proposed the distinct ligand-controlled mechanisms for the formation of the pentenylation product P 1 and the geranylation product P 2 . When the bis-phosphine ligand, d­( i Pr)­pf (Scheme ), is utilized, it is suggested that the isoprene-coordinated Pd(0) species A undergoes oxidative addition with MeOH, forming a MeO–Pd­(II)–H species B .…”

Ligand-controlled regiodivergence in cobalt-catalyzed hydrosilylation of isoprene

“…Recently, we explored an iron-catalyzed regiodivergent hydrosilylation reaction of isoprene, where the regioselectivity could be efficiently regulated by the bidentate or tridentate nitrogen ligand, respectively. 12 g As an extension of our continuous research in regiodivergent catalysis, 14 herein we report a Co-catalyzed protocol for regio-controllable 4,1- and 2,1-hydrosilylation of isoprene by modifying the substituents in bidentate nitrogen ligands (Scheme 1c).…”