Green Oxidation of Indoles using halide Catalysis

Oxone-Halide is a green catalysis system that can replace many widely used oxidants such as NBS, NCS, t-BuOCl, and m-CPBA.

Go to the profile of Rongbiao Tong
Oct 29, 2019

Background and Challenge: Chemical oxidation of indoles is a fundamental organic transformation to deliver a diverse array of versatile nitrogen-containing compounds, in particular 2-oxindoles, which have been used widely in organic synthesis and drug discovery. The electron-rich property of indoles allows the oxidation to occur under many oxidation conditions. However, a mixture of oxidation products is usually observed due to the competing oxidation of nitrogen, C2 and C3 as well as potential rearrangement and over-oxidation. The challenging chemo- and regioselectivity requires not only a site-selective oxidant but also suitable substitutions at C2 and/or C3 as well as the protecting group on the nitrogen. Therefore, it is not surprising that only a small number of oxidants (Fig 1a) have been identified for only one or two of the three major types of the indole oxidation: (i) oxidative rearrangement of tetrahydro-β-carbolines to spirooxindoles, (ii) oxidation of C3-substituted indoles to 2-oxindoles, and (iii) oxidative cleavage of C2,C3-disubstituted indoles to 2-keto acetanilides (Witkop oxidation). Although these oxidants under the optimized conditions could solve the chemo- and regioselectivity with high yields, their environmental and/or health impacts were not addressed. Herein, we reports a general green oxidation of indoles using halide catalysis (Fig.1b) 

Fig.1 Oxidation of Indoles. (a) Prior methods for oxidation of Indoles. (b) Our green oxidation of indoles using halide catalysis.

On the basis of our previous work on the development of mild green oxone-halide protocols for halonium-mediated oxidations,1-6 we strongly believe that the halogenating species generated in situ from oxone and catalytic amount of halide in a low concentration is able to oxidize various indoles in a chemo- and regioselective way. Our study support this idea: oxone-halide is an effective green catalysis system that can replace many widely used oxidants including organic halogenating agents (NBS, NCS, t-BuOCl etc) or peracids (m-CPBA) and achieve three major types of indole oxidations. We propose a hypothetic mechanism to explain the divergent pathways for these three oxidation processes (Fig. 2). As compared to prior methods, this protocol is usually more efficient and selective partly due to the in situ generated halenium ion (X+) catalyst that has the appropriate concentration and reactivity towards the C2-C3 double bond of indoles and thus significantly suppressed other competing oxidations/rearrangements. Additionally, no need to protect the indole nitrogen is advantageous since most previous methods required to mask the indole nitrogen with electron-withdrawing groups (e.g., N-Ts, N-Boc, N-Ac etc) for better chemo- and regioselectivity. Achieving this oxone-halide oxidation of indoles is believed to be a milestone in the indole oxidation for its low-cost, safe/simple operation (open flask), and most importantly its greenness in several aspects of the 12 Green Chemistry Principles including (1) preventing waste, (2) less hazardous chemical synthesis, (3) safer chemicals, and (4) using catalysis. We believed that this oxone-halide system might be used for other types of indole oxidation that were not explored in this article. 

Fig.2 Hypothetic mechanism responsible for the oxone-halide oxidation of indoles.

1. Ren, J. & Tong, R. Convenient in situ generation of various dichlorinating agents from oxone and chloride: diastereoselective dichlorination of allylic and homoallylic alcohol derivatives. Org. Biomol. Chem. 11, 4312-4315 (2013).

2. Li, Z. & Tong, R. Catalytic Environmentally Friendly Protocol for Achmatowicz Rearrangement. J. Org. Chem. 81, 4847-4855 (2016).

3. Xu, J. & Tong, R. An environmentally friendly protocol for oxidative halocyclization of tryptamine and tryptophol derivatives. Green Chem. 19, 2952-2956 (2017).

4. Zhao, G. & Tong, R. A Solvent-free Catalytic Protocol for Achmatowicz Rearrangement. Green Chem. 21, 64-68 (2019).

5. Zhao, G.; Tong, R. Silica gel enables Achmatowicz rearrangement using KBr/Oxone under “anhydrous” condition for one-pot functionalization. Tetrahedron 75, 1669-1675 (2019).

6. Zhao, G.; Liang, L.; Wen, C. H. E. & Tong, R. Efficient in situ Generation of Nitrile Oxides from NaCl-Oxone Oxidation of Various Aldoximes and their 1,3-Dipolar Cycloaddition. Org. Lett. 21, 315-319 (2019).

Go to the profile of Rongbiao Tong

Rongbiao Tong

Associate Professor, HKUST

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