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. 2022 Jun 13;13(27):8180-8186.
doi: 10.1039/d2sc01827f. eCollection 2022 Jul 13.

Electrochemical synthesis of N, N'-disubstituted indazolin-3-ones via an intramolecular anodic dehydrogenative N-N coupling reaction

Jessica C Bieniek  1 , Michele Grünewald  1 , Johannes Winter  1 , Dieter Schollmeyer  1 , Siegfried R Waldvogel  1
Affiliations

Electrochemical synthesis of N, N'-disubstituted indazolin-3-ones via an intramolecular anodic dehydrogenative N-N coupling reaction

Jessica C Bieniek et al. Chem Sci. .

Abstract

The use of electricity as a traceless oxidant enables a sustainable and novel approach to N,N'-disubstituted indazolin-3-ones by an intramolecular anodic dehydrogenative N-N coupling reaction. This method is characterized by mild reaction conditions, an easy experimental setup, excellent scalability, and a high atom economy. It was used to synthesize various indazolin-3-one derivatives in yields up to 78%, applying inexpensive and sustainable electrode materials and a low supporting electrolyte concentration. Mechanistic studies, based on cyclic voltammetry experiments, revealed a biradical pathway. Furthermore, the access to single 2-aryl substituted indazolin-3-ones by cleavage of the protecting group could be demonstrated.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. Biologically active substances bearing an indazolin-3-one motif.
Scheme 2
Scheme 2. Photochemical and electrochemical approaches to indazolin-3-ones (Ar = aryl; s.m. = starting material; s.e. = supporting electrolyte).
Fig. 1
Fig. 1. Modelled yield plots, predicted using the response optimizer based on DoE optimization experiments. Undivided 5 mL Teflon™ screening cells, CGr electrodes, and NBu4PF6 in HFIP. Screened parameters: starting material concentration c(5a), NBu4PF6 concentration c(NBu4PF6), temperature T, stirring velocity vstirr, current density j, applied molar charge Qmol. (a) Central composite design based on a 26–2 fractional factorial design. (b) Modelled 1H NMR yield with 1,3,5-trimethoxybenzene as the internal standard. (c) Predicted values leading to the maximal yield of 6a. (d) Central composite design based on a 23 full factorial design.
Scheme 3
Scheme 3. Reaction scope. Undivided 5 mL Teflon™ screening cell, substrate (0.3 mmol), HFIP (5 mL). (a) Scale-up experiment in a 60 mL beaker-type glass cell, substrate (3.0 mmol), HFIP (50 mL). (b) Qmol = 3.3 F. (c) Qmol = 4.5 F. (d) j = 2.5 mA cm−2, Qmol = 4.0 F. (e) Qmol = 3.5 F. (f) Qmol = 3.1 F. (g) Qmol = 3.5 F. (h) Qmol = 6.0 F. (i) Cathode: platinum wire.
Scheme 4
Scheme 4. Proposed mechanism for the electrochemical synthesis of indazolin-3-ones based on CV studies and scope. Blue pathway: indazolin-3-one formation via biradical N–N bond linkage. Red pathway: benzoxazole formation as a side reaction through the previously reported cationic mechanism. Deprotonation steps occur via solvent molecules, releasing the protons at the cathode, resulting in hydrogen formation as the counter reaction.
Scheme 5
Scheme 5. Deprotection of 6a yielding single substituted indazolin-3-one 8. Reaction conditions: NaOH, EtOH, 80 °C, 3 h.
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