Mn(I)-Catalyzed Mechanochemical C–H Bond Activation: C-2 Selective Alkenylation of Indoles

Abstract

An efficient mechanochemical method for manganese-catalyzed regioselective C−H bond alkenylation of indoles with alkynes is developed. Recently, mechanochemical C−H bond activation has received due attention and the use of low-valent first-row transition metals in C−C cross-coupling via C−H activation under mechanochemical conditions is an additional feather to the cost-effectiveness of such useful synthetic protocols.The present method allows direct C-2 alkenylation of indoles in a mixer mill, employing a commercially available low-valent manganese catalyst, MnBr(CO) 5 , providing a sustainable route to hydroindolation on alkynes. The developed protocol is highly C-2-selective by the presence of a heteroaromatic N atom as a directing group (namely, pyridyl) and tolerant of structural variations with electron-rich and electron-deficient substituents both in the indoles and in the alkynes. Silica as the grinding media and the presence of a catalytic amount of acid and DIPEA as the base worked favorably to afford a variety of 2-alkenyl indoles in excellent yields at ambient conditions. The terminal alkynes offered better results than internal alkynes in terms of yields and reactivity. The scalability of the reaction was demonstrated by conducting the reactions in the gram scale. A short study indicated that a little tweak in conditions can be useful for double alkenylation to afford carbazole derivatives in moderate yields. A low E-factor along with a clean reaction profile, an easy experimental setup, the absence of an anhydrous condition, and being devoid of toxic organic solvents proclaims its advantage over the available conventional methods.

Mechanochemical-Cascaded C–N Cross-Coupling and Halogenation Using N-Bromo- and N-Chlorosuccinimide as Bifunctional Reagents

“…Furthermore, we have shown the calculation of the environmental impact factor ( E mw ) or E -factor based on the molecular weight (Table S4, Supporting Information). The E -factor calculation reveals that this mechanochemical method is superior to the existing methods …”

Mechanochemical C−X/C−H Functionalization: An Alternative Strategic Access to Pharmaceuticals

“…Indole scaffolds are prevalent in natural products, agrochemicals, and pharmaceutically relevant compounds, while C−H functionalization of indoles was one of the key strategies to access potential drug candidates with improved properties [106] . In recent years, significant advances have been made in the field of metal (Pd, Rh, Au, Co, and Mn) catalyzed mechanochemical C−H functionalization of indoles by the groups of Bolm, Yu & Su and Banerjee, enabling the use of various of different coupling partners such as acrylates, [103c] vinylethylene carbonate, [104a] 1,4,2‐dioxazol‐5‐ones, [105c] hypervalent alkynyl iodine reagents, [103g] iodoarenes [103h] and alkynes [104b] . Among which, highly chemo‐ and regio‐selective products could be produced by adjusting the catalytic systems under the mechanical impact.…”

Recent Advances in C—H Bond Functionalization under Mechanochemical Conditions

“…值得一提的是, 作者将机械力促进 C-H 键官 能化这一策略应用到药物分子的全合成中, 高效完成了 PLK4 抑制剂 CFI-400945 的中间体 [19] 和 HIF-1α 抑制剂 YC-1 [20] 的合成, 展现出机械化学在药物合成领域中的 应用潜力(Scheme 8). 同年, Banerjee 等 [21] 报道了机械力促进锰催化吲哚 与炔烃的 C-2 选择性烯基化反应(Scheme 9). 已报道溶 剂中进行的吲哚 C-H 烯基化反应一般以铑、钌、铼等 金属为催化剂 [16b,22] , 而以更廉价的锰金属为催化剂的 类似反应存在较大的底物类型限制问题, 比如反应只适 用于含给电子基团(EDG, Electron Donating Group)的端 炔烃(Terminal Alkynes).…”