A switchable redox annulation of 2-nitroarylethanols affording N-heterocycles: photoexcited nitro as a multifunctional handle

Abstract

The efficient transformation of nitroaromatics to functional molecules such as N-heterocycles has been an attractive and significant topic in synthesis chemistry. Herein, a photoexcited nitro-induced strategy for switchable annulations of 2-nitroarylethanols was developed to construct N-heterocycles including indoles, N-hydroxyl oxindoles and N-H oxindoles. The metal- and photocatalyst-free reaction proceeds through intramolecular redox C-N coupling of branched hydroxyalkyl and nitro units, which is initiated by a double hydrogen atom abstraction (d-HAA) process. The key to the switchable reaction outcomes is the mediation of a diboron reagent by its favorable oxy-transfer reactivity to in situ generated nitroso species. The utility of this protocol was well demonstrated by broad substrate scope, excellent yields, functional group tolerance and wide applications. Finally, detailed mechanistic studies were performed, and kinetic isotope effect (KIE) experiments indicate that the homolysis of the C-H bond is involved in the rate-determining step.

Scheme 1. Research backgrounds and this work. ^a SET: single electron transfer.

Scheme 2. Substrate scope for the synthesis of indoles and other products. ^aStandard conditions: 0.2 mmol scale reaction in THF/MeOH (8/1, 0.45 mL), DIPEA (0.04 mmol, 20 mol%), B₂nep₂ (0.44 mmol, 2.2 equiv.), blue LED, N₂, rt, 12 h; isolated yields. ^bB₂(OH)₄ (0.44 mmol) instead of B₂nep₂. ^c Without the addition of DIPEA.

Scheme 3. Substrate scope for the synthesis of N-hydroxyl oxindoles and N-free oxindoles. ^a0.2 mmol scale reaction in THF/MeOH (8/1, 0.45 mL), a blue LED, N₂, rt, 6 h; isolated yields. ^b10 mmol scale. ^c5 mmol scale. ^dThe reaction was performed via a one-pot, two-step procedure (ESI 4.1†): 0.2 mmol scale reaction in THF/MeOH (8/1, 0.45 mL), blue LED, N₂, rt, 6 h; after 6 h, the solvent was evaporated and the subsequent reaction was performed in the same pot, B₂(OH)₄ (0.3 mmol, 1.5 equiv.), KOAc (0.4 mmol, 2.0 equiv.), MeOH (0.2 M), 50 °C, 2 h, isolated yields.

Scheme 4. Synthetic applications.

Scheme 5. Mechanistic studies. (A) Radical-quenching experiment for the synthesis of indole. (B) Annulation of o-nitrobenzylic ketone with an exogenetic H-donor. (C) HRMS analysis of the proposed intermediates.

Fig. 1. Light on–off experiments for the synthesis of N–OH oxindole (the reaction was performed in a sealed NMR tube and NMR yields were shown, ESI 5.3†).

Scheme 6. Kinetic isotope effect (KIE) experiments.

Scheme 7. Proposed mechanisms for the generation of indoles, N–OH oxindoles and N–H oxindoles.