Synthesis of Indoles through Domino Reactions of 2‐Fluorotoluenes and Nitriles

Abstract

Indoles are essential heterocycles in medicinal chemistry,a nd therefore,n ovel and efficient approaches to their synthesis are in high demand. Among indoles,2 -aryl indoles have been described as privileged scaffolds.Advanced herein is astraightforward, practical, and transition-metal-free assembly of 2-aryl indoles.Simply combining readily available 2-fluorotoluenes,n itriles,L iN(SiMe 3 ) 2 ,a nd CsF enables the generation of adiverse arrayofindoles (38 examples,48-92 % yield). Ar ange of substituents can be introduced into each position of the indole backbone (C4 to C7, and aryl groups at C2), providing handles for further elaboration.Scheme 1. Transition-metal-free synthesis of indoles.

Synthesis of densely substituted pyridine derivatives from nitriles by a non-classical [4+2] cycloaddition/1,5-hydrogen shift strategy

“…Based on the above investigation and literature reports, [82][83][84][85][86][87][88][89][90] a possible mechanism is proposed in Fig. 5.…”

“…The resulting alkenyl-metal species C undergoes protonation and 1,5-hydrogen shift process to deliver the desired 3a. Alternatively, the reaction could proceed by either protonation or silylation of intermediate B with HN(SiMe 3 ) 2 from the initial deprotonation equilibrium, generating imine D. 82 In the presence of Li/KN(SiMe 3 ) 2 , the imine D would undergo a reversible addition, silyl migration, and elimination pathway to release nitrogen-exchanged intermediate F, 91,92 followed by the further silyl transfer and cyclization to give nitrogen-exchanged intermediate G.…”

“…[65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81] The di culty level of these reactions increases drastically when substrates with weakly acidic C(sp 3 )-H (especially for pKa > 40 in DMSO) bond are utilized, and the methods in this eld are rarely developed. 82 To address these challenges, a non-classical [4 + 2] cycloaddition along with 1,5-hydrogen shift strategy is proposed (Fig. 2C).…”

Applications of Ethynylanilines as Substrates for Construction of Indoles and Indole‐Substituted Derivatives

“…Hidetoshi Tokuyama et al [15] have reported cascade process for construction of N-linked indoles 108 (scheme 36) on 3aposition of pyrroloindoline 105. [56] In this process Bromopyrroloindoline 105 undergo silver catalysed one-pot amination with 2-ethynyl anilines 106 through 5-endo-dig cyclization in the presense of DTPB as an oxidant in dichloromethane solvent. The bromo group and alkyne moiety are activated by AgNTf 2 as α-Lewis acid and π-Lewis acid respectively.…”

Selective Quadruple C(sp3)-F Functionalization of Polyfluoroalkyl Ketones

“…To our delight, the proposed tandem strategy could be successfully realized to afford C-N bond-forming (Bariwal and Van der Eycken, 2013) product 3a in 74% NMR yield (70% isolated yield; Table 1, entry 1). Notably, the excellent performance of the reaction required the simultaneous use of cobalt salt, additive TBAB, and base (Mao et al, 2019;Xue et al, 2015) (Table 1, entries 2-4), as the reaction proceeded with reduced efficiency in the absence of any of them. It is noteworthy that decreasing reaction temperature even to room temperature still gave the same good yield of the product 3a (Table 1, entry 5).…”