Copper-Catalyzed Selective Electron Transfer Enables Switchable Divergent Synthesis of 3-Functionalized Oxindoles

Abstract

Oxidative rearrangement of 3-substituted indoles is a fundamental organic transformation for the synthesis of 2-oxindole scaffolds. However, this time-consuming and complex task produces a single type of product via two-electron oxidation using stoichiometric chemical oxidants. Herein, we report a unified and efficient copper-catalyzed selective single-electron transfer strategy for three oxidation reactions of 3-substituted indoles using air (O 2 ) as the terminal oxidant, providing a streamlined and practical synthetic approach to access 3-hydroxyl-, 3-alkoxyl-, and 3hygrogenous-2-oxindoles via a 3-radical-2-hydroxyl indoline intermediate. This copper catalysis protocol demonstrates high chemoselectivity, good functional group tolerance, and broad application potential in the modular synthesis of biologically 3-functionalized oxindole derivatives.

Late-Stage Chemo- and Enantioselective Oxidation of Indoles to C3-Monosubstituted Oxindoles

“…The observation illustrates that the hydrogen at C3 of oxindole originates from the C2 of starting indole, thereby confirming the involvement of a 2,3-hydride migration process during the reaction. , Third, oxindole 2e was subjected to the standard conditions in the presence of D 2 O, and no 3-deuterated [D]- 2e was generated even after a prolonged time period (Figure C). The result indicates that the keto–enol tautomerization, a common phenomenon in both enzymatic and chemical indole oxidation, should be prohibited under this mild and simple titanium-catalyzed oxidation system to guarantee excellent enantioselectivity. , A competitive deuterium kinetic isotope effect (KIE) study, using a mixture of 1e and [D]- 1e , gave a k H / k D value of 0.80 (Figure D). This inverse KIE is consistent with a sp 2 to sp 3 hybridization change during the addition of an electrophilic titanium-oxo species to the sp 2 center of the indole pyrrole as the rate-limiting step …”

“…This approach is particularly attractive if late-stage asymmetric transformation of the indole core into bioisosteric oxindoles could be achieved, which would facilitate the syntheses, discovery, and optimization of drug candidates . However, to our knowledge such a catalytic asymmetric transformation by either enzymatic or chemical protocol has never been reported, presumably owing to diverse indole oxidation pathways and difficulties in enantioselective manipulation of thermodynamically unstable oxidized intermediates (Scheme B). − Notably, even an effective catalytic nonasymmetric variant has remained undeveloped. , In this context, several heme enzymes catalyze oxidation of 3-substituted indole by O 2 or H 2 O 2 to generate a putative epoxyindole intermediate that undergoes 2,3-hydride migration to form monooxygenated oxindole with spontaneous keto–enol tautomerization in buffer . Moreover, considerable amounts of dioxygenated products, such as 2-ketoformanilide via C 2 –C 3 cleavage (Witkop oxidation) and 3-hydroxyl oxindole via overoxidation are also observed as major products. , …”

Direct organocatalytic transfer hydrogenation and C–H oxidation: high-yielding synthesis of 3-hydroxy-3-alkyloxindoles

“…14 Ren and co-workers reported the synthesis of 4x from 9, which involved two metal salts, a complex ligand, and a longer reaction time (40 h) with only 53% yield (Scheme 3A). 15 Following our three-step protocol, we synthesized medicinally important 4x using three simple steps starting from commercially available isatin with an overall yield of 73% (Scheme 3B). A Wittig reaction followed by Hantzsch ester mediated transfer hydrogenation of isatin furnished 2x with an overall 80% yield.…”

Copper/Iodine Co-catalyzed Oxygenative Transannulation of Tryptamines Enables Direct Synthesis of Donaxaridine and Its Derivatives

“…On the basis of the results described above and relevant previous research, − a possible reaction pathway is proposed in Scheme . First, the Cu II species oxidizes tryptamine 1a to form 3-radical iminium cation intermediate A .…”