Palladium-Catalyzed Oxidative Direct C3- and C7-Alkenylations of Indazoles: Application to the Synthesis of Gamendazole

Abstract

The first palladium-catalyzed oxidative alkenylation of (1H)- and (2H)-indazole derivatives with various olefins is described. The use of Pd(OAc)2 as the catalyst and Ag2CO3 as the oxidant promoted the selective C3-monoalkenylation of (1H)-indazoles and (2H)-indazoles, affording the desired products in good yields. An original oxidative C7-alkenylation of 3-substituted (1H)-indazoles was also developed. The oxidative alkenylation of (1H)-indazole was successfully applied to the total synthesis of the drug candidate gamendazole in a step- and atom-economical fashion.

Oxidative Alkenylation of Fused Bicyclic Heterocycles

“…Recently, some of us [90] reported the first example of palladium-catalyzed oxidative C3-alkenylation of (1H)-and (2H)-indazole derivatives 100 and 101 with various olefins. The reaction was conducted at 120°C in dioxane for 18 h, using Pd(OAc) 2 as catalyst and Ag 2 CO 3 as oxidant in the presence of 1 equiv.…”

Palladium Catalyzed Direct Alkenylation of Dihydropyrrolo[2,1‐a]isoquinolines through the Oxidative Heck Reaction

“…Recently, the groups of Hong,[7a] Ge,[7b] Joo, Kazzouli, Guillaumet, and Gallagher et al have paid much attention on extension of this palladium catalyzed direct modification strategy of N‐heterocycle for modifying other privileged frameworks. More nitrogen‐containing heterocycles other than indoles and pyrroles, such as imidazole, benzoimidazole, pyrido[1,2‐ a ]pyrimidine, indazole, and quinolin‐4(1H)‐one, have been applied in oxidative Heck reaction for modifications .…”

Metal‐Free Regioselective Dual C‐H Functionalization in a Cascade Fashion: Access to Isocryptolepine Alkaloid Analogues

“…Notably, C3‐functionalization of 2 H ‐indazoles like direct arylation, Heck and cross‐coupling reactions have been reported more recently. In spite of these developments, there has been a rare precedence of direct C−H activation leading to annulated indazoles (Scheme , eq.…”