Synthesis of Spiro-Pyrrolidinyloxindoles by Oxidative Rearrangement of N-Acyltetrahydro-β-carbolines Using an Oxone/Aqueous Acetone Mixture

Abstract

Spiro-pyrrolidinyl-2-oxindoles were prepared by the oxidative rearrangement of N a -acetyl-1,2,3,4-tetrahydro-β-carbolines (THBC) using dimethyldioxirane generated in situ. The N aacetyl THBC substrates were obtained by Pictet-Spengler and acyl-Pictet-Spengler reactions of L-tryptophan methyl ester, followed by N a -acetylation. The stereoselectivity of the oxidative rearrangement was evaluated and 2D nuclear magnetic resonance (NMR) was used to determine the stereochemistry of the oxindole products relative to L-tryptophan. Density functional theory calculations were consistent with a face selective, substrate controlled, epoxidation of the indolic double bond. The calculations indicated that the resulting epoxide would readily rearrange at room temperature via a concerted ring opening/ring contraction process to give the 3-substituted-2-oxindole.

Green oxidation of indoles using halide catalysis

“…Therefore, it is not surprising that only a small number of oxidants have been identified for only one or two of the three major types of the indole oxidation (Fig. 1a): (i) oxidative rearrangement of tetrahydro-β-carbolines to spirooxindoles 8–14 , (ii) oxidation of C3-substituted indoles to 2-oxindoles 15 , and (iii) oxidative cleavage of C2,C3-disubstituted indoles to 2-keto acetanilides (Witkop oxidation) 16,17 . Although these oxidants under the optimized conditions could solve the chemo-selectivity and regio-selectivity with high yields, their environmental and/or health impacts were not addressed, which is contrary to the rising concept and awareness of Green Chemistry.

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Applications of Oxone® in Organic Synthesis: An Emerging Green Reagent of Modern Era

“…In this line, Marcal and Garden reported spiro‐pyrrolidinyloxindole derivatives by oxidative rearrangement of N ‐acyltetrahydro‐ β ‐carbolines (THBC) using in‐situ generated DMDO from oxone/aqueous acetone (Scheme 188). [438] As can be inspected from the Scheme 188, the authors have assembled diverse spirooxindole derivatives by employing the oxone as a key reagent. On the other hand, very recently, Zhao and Tong employed Achmatowicz rearrangement (AchR), a prevailing oxidative transformation for the synthesis of useful dihydropyranone acetals from furfuryl alcohols 609 which on subsequent o ‐glycosylation/[5+2]‐cycloadditiondeliver the pyrone derivatives 614 a – n in moderate to good yields using KBr/oxone (Scheme 189).…”

Green Selective Oxidation of Substituted Indoles Catalyzed by CuCl

“…In recent years, a large number of methods for the selective oxidation of indoles have developed to realize the activation of C–C bonds. Due to the advantages of its high atom economy, simple synthesis steps, and direct functionalization, these methods have attracted great attention from organic chemists . Witkop oxidation (Scheme a), a fundamental oxidative cleavage of C2–C3 double bond of indoles, is the most prevalent and general method for the oxidative cleavage of indoles to 2-ketoacetanilide derivatives, which are the key starting materials for the synthesis of different bioactive molecules and drugs .…”