Abstract
Accessing fascinating organic and biological significant indolines via dearomatization of indoles represents one of the most efficient approaches. However, it has been difficult for the dearomatization of the electron deficient indoles. Here we report the studies leading to developing a photoredox mediated Giese-type transformation strategy for the dearomatization of the indoles. The reaction has been implemented for chemoselectively breaking indolyl C=C bonds embedded in the aromatic system. The synthetic power of this strategy has been demonstrated by using structurally diverse indoles bearing common electron-withdrawing groups including (thio)ester, amide, ketone, nitrile and even aromatics at either C2 or C3 positions and ubiquitous carboxylic acids as radical coupling partner with high trans-stereoselectivity (>20:1 dr). This manifold can also be applied to other aromatic heterocycles including pyrroles, benzofurans and benzothiophenes. Furthermore, enantioselective dearomatization of indoles has been achieved by a chiral camphorsultam auxiliary with high diastereoselectivity.
Highlights
Accessing fascinating organic and biological significant indolines via dearomatization of indoles represents one of the most efficient approaches
Single-electron transfer (SET) involved oxidation-induced C–H functionalization of the nucleophilic indoles has been elegantly realized as powerful alternatives for indole dearomatization[17], mild, green visible light photocatalytic and electrochemical methods (Fig. 1a)[3,15,18,19,20,21,22,23,24,25,26,27,28,29]
It is believed that the carboxylate 2a can be selectively oxidized by the photocatalyst (PC, Ir [dF(CF3)ppy]2(dtbpy))PF6) to give the corresponding radical while the oxidation of the C2=C3 π bond is difficult because the E1/2* is +1.21 V50 of the PC and 2a salt Eox is around +1.00 V56 while the Eox of the indole methyl ester 1a is +1.94 V
Summary
Accessing fascinating organic and biological significant indolines via dearomatization of indoles represents one of the most efficient approaches. The reactivity has dictated indole dearomatization methodology development[1,2,3,4,5,6,7,8] since Woodward’s pioneering study using a Pictet-Spengler type reaction to break the aromatic tryptamine in total synthesis of strychnine in 195416 This important array of reactivity from the intrinsically nucleophilic indoles upon activation by various tailored electrophiles has become a powerful manifold for the synthesis of structurally diverse indolines as it enables regioselective reactivity, facile ring formation, and efficient skeleton rearrangement[1,2,3,4,5,6,7,8]. The original conditions using stoichiometric amounts of trialkyl tin reagents have motivated organic chemists to develop more practical protocols
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