Regioselective Synthesis of 2-Alkenylindoles and 2-Alkenylindole-3-carboxylates through the Cascade Reactions of N-Nitrosoanilines with Propargyl Alcohols

Abstract

In this paper, a novel and efficient synthesis of 2-alkenylindoles and 2-alkenylindole-3-carboxylates via the cascade reactions of N-nitrosoanilines with propargyl alcohols is presented. Mechanistically, the formation of the title compounds is triggered by a Rh(III)-catalyzed C(sp)-H alkenylation of N-nitrosoaniline with propargyl alcohol followed by the simultaneous intramolecular amination/cyclization, NO extrusion, and dehydration. With this method, a variety of diversely substituted 2-alkenylindole derivatives were prepared in good efficiency and exclusive site-selectivity. To the best of our knowledge, this is the first example in which the indoyl and the alkenyl units are formed sequentially in one pot from halide-free substrates through a redox neutral C-H bond activation. In addition, the utility of the 2-alkenylindole products thus obtained was remarkably showcased by their facile transformations into synthetically and biologically significant compounds such as 2-acylindole, benzocarbazole, indoloquinoline, pyridoindolone, cyclopentaindolone, and indenoindolone.

Rhodium(III)-Catalyzed Redox-Neutral [3+3] Annulation of N-nitrosoanilines with Cyclopropenones: A Traceless Approach to Quinolin-4(1H)-One Scaffolds

“…In 2013, Zhu's group reported the pioneering work of Rh(III)-catalyzed redox-neutral [3+2] annulation of N-nitrosoanilines with internal alkynes to form efficiently indole derivatives (Scheme 1b) [23][24][25][26][27][28]. Similarly, several formal [3+2] annulations between N-nitrosoanilines and diazo compounds [29] as well as propargyl alcohols [30] utilizing the N−nitroso group as an internal oxidant have been reported to prepare diversified indole scaffolds, in which the substrate involving the N−nitroso group seems to be an excellent synthon to build these intriguing privileged structures via a C-H bond activation and further annulation cascade. Therefore, in continuation of our recent efforts on transition-metal-catalyzed C-H annulations for the construction of heterocyclic scaffolds [31][32][33][34][35][36], we surprisingly found a new redox-neutral [3+3] annulation of N-nitrosoanilines with cyclopropenones [37][38][39] to generate a different substituted quinolin-4(1H)-one scaffold (Scheme 1c), which is a desirable privileged structure for further drug discovery.…”

Recent Advances and Strategies for the Transition‐Metal‐Catalyzed C−H Functionalization of N‐Nitrosoanilines

“…This was the first example of the sequential formation of indoles from alkenyl substrates under multi‐component reaction conditions using a redox‐neutral C−H bond activation process. Efficient screening of different metal catalysts and additives showed that the optimized conditions for the synthesis of indole 3‐carboxylate derivatives were [RhCp*Cl 2 ] 2 , AgSbF 6 , and Cu(OAc) 2 in dichloroethane (DCE) at 100 °C (Scheme 9, Part I) [18] . Also, the authors mentioned that if R 5 of propargyl alcohols is Ph group, then, the desired products were obtained by using AgOAc instead of Cu(OAc) 2 at 120 °C.…”

Propargylic Alcohols as Coupling Partners in Transition‐Metal‐Catalyzed Arene C−H Activation

“…Fan and group reported a method for the synthesis of 2-alkenylindole-3-carboxilates and 2-alkenyl indoles through the cascade reactions of N-nitroso aniline with propargyl alcohols. [18] The proposed mechanism is shown in Scheme 14. It is initiated by Rh(III)catalyzed CÀ H alkenylation, then followed by simultaneous intramolecular amination/cyclization, NO extrusion, and dehydration to yield title compounds.…”

“…Fan and group reported a method for the synthesis of 2‐alkenylindole‐3‐carboxilates and 2‐alkenyl indoles through the cascade reactions of N‐nitroso aniline with propargyl alcohols [18] . The proposed mechanism is shown in Scheme 14.…”