Domino Grignard Addition and Oxidation for the One-Pot Synthesis of C2-Quaternary 2-Hydroxyindoxyls

Abstract

We herein delineate an unexplored reactivity of 3-hydroxyoxindoles toward Grignard addition enabling a rapid access to a broad range of unnatural C2-quaternary 2-hydroxyindoxyls in high yields. The reaction proceeds via a mechanistically intriguing one-pot 1,2-hydride shift followed by autoxidation pathway. The utility of this method is demonstrated by the synthesis of a new class of bis-indoxyl spirofuran derivatives.T he oxindole moiety is present in a large number of natural products and biologically active molecules. 1 The motif has also been used as a versatile synthetic intermediate for various organic transformations. 1,2 On the contrary, 2hydroxyindoxyl, a pseudooxindole moiety, has remained less explored. The indoxyl ring system bearing a C2-quaternary center is a privileged structural unit present in various natural products like brevianamide A and B, 3 rupicoline, 4 iboluteine, 5 austamide, 6 phytoaliexin, erucalexin, 7 and matemone, 8 as well as biologically active compounds (Figure 1). For instance, 2hydroxyindoxyl alkaloid melochicorin, isolated from the plant Melochia corchorifolia, 9 shows hepatoprotective and antioxidant activity. 10 While 3-substituted 3-hydroxy-2-oxindoles can be easily synthesized by reported methods, 11 the preparation of unnatural 2-substituted 2-hydroxyindoxyls remains a synthetic challenge. Until now, only a few convenient methods are available for the synthesis of pseudooxindole 2-hydroxyindoxyls. Generally, oxidation of indoles using m-CPBA, 12 monoperphthalic acid, 13 and DMDO 14 produces 2-hydroxyindoxyls as byproducts. Davis' reagent has been used to improve the yield of 2-hydroxyindoxyls. 15 Sakamoto et al. 16 reported oxidation of 2-substituted N-acylindoles by MoO 5 • HMPA to directly obtain 1-acetyl-2-hydroxyindoxyls. Later, Jimenez et al. used oxodiperoxo molybdenum complexes to improve the yield. 17 The oxidation of 2,3,6-trimethyl-4-(1H)quinolinone by NaOCl 18 and 2-methyl-3-phenylquinolinone by acidic potassium permanganate 19 has also been used to access the corresponding indoxyls. However, long reaction times and low yields render such approaches less attractive. Other reported approaches for the synthesis of 2-hydroxyindoxyls involve base-mediated ring contraction of 3-hydroxy-2,4(1H,3H)-quinolinediones, 20 acidic hydrolysis of a 3acetoxy-2-phenylindole precursor, 21 butyllithium-promoted tandem cyclization, and autoxidation of 2-(benzylamino)benzamide derivatives (Scheme 1). 22 Recently, Zhu and coworkers reported the synthesis of a 2-hydroxyindoxyl derivative by using a Cu(I)-catalyzed intramolecular C (sp3)−H amidation of 2-aminoacetophenone utilizing O 2 as the oxidant at high temperature (Scheme 1). 23 Later, Yang et al. developed an oxidative cyclization of 2-aminophenyl-1,3-dione using CAN and TEMPO as oxidants for the synthesis of 2hydroxyindoline-3-ones (Scheme 1). 24 Nevertheless, the synthesis of 2-hydroxyindoxyls from readily available starting materials with high flexibility in their substitution pattern is yet to be addressed. Therefore, an e...

Efficient Synthesis of Cyclohepta[b]indoles and Cyclohepta[b]indole‐Indoline Conjugates via RCM, Hydrogenation, and Acid‐Catalyzed Ring Expansion: A Biomimetic Approach

“…We were delighted to observe that the reaction between N‐methyl oxindole 2 a and 3‐butenylmagnesium bromide in anhydrous THF at room temperature resulted in the formation of 2‐allyl‐2‐(but‐3‐enyl)‐3‐oxindole derivative 3 a in 90 % yield following 1,2‐allyl shift (Scheme 2). [16e,17] We then explored the scope of this Grignard reaction to both electron rich and electron deficient N‐protected oxindoles 2 to obtain the corresponding 2‐allyl‐2‐(but‐3‐enyl)‐3‐oxindole derivatives 3 in acceptable yields.…”

“…Spirocyclohexene‐3‐oxindoles 4 could be derived from the RCM of 2‐allyl‐2‐(but‐3‐enyl)‐3‐oxindoles 3 . We anticipated that dialkene oxindoles 3 could be prepared by butenyl Grignard additions to the 3‐allyl‐3‐hydroxy‐2‐oxindole compounds 2 via our reported 1,2‐allyl shift pathway [16e,17] . Hydroxy oxindoles 2 could be synthesized from readily available isatin derivatives 1 via allyl metal addition (Scheme 1).…”

Facile access to 2-hydroxy-2-substituted indole-3-ones via a copper-catalyzed oxidative cyclization of 2-arylethynylanilines

“…Having successfully established the copper-catalyzed oxidative cyclization of 2-arylethynylanilines, we then turned our attention to the rearrangement of 2-hydroxy-2-substituted indol-3-ones into 3-hydroxy-3-substituted indol-2-ones 4. 11,17 As summarized in Scheme 3, this rearrangement reaction proceeded well with a variety of 2-hydroxy-2-substituted indol-3-ones, affording useful 3-hydroxy-3-substituted indol-2-ones in moderate to good yields.…”

“…16 Recently, Dash developed an elegant one-pot synthesis of C2-quaternary 2-hydroxyindoxyls via a domino Grignard addition and oxidation of 3-hydroxyoxindoles. 17 Ye described a controllable synthesis of C2-tertiary N -substituted 2-hydroxy-indol-3-ones by the visible-light-promoted 5 -endo-dig N -radical cyclization of o -ethynylanilines. 18 However, the majority of these approaches suffer from a narrow substrate scope, harsh conditions and/or low yields, which renders these approaches less efficient and attractive (Scheme 1).…”

Domino Relay Olefin Metathesis of Triallyl Oxindole and Indole Precursors to Access Cyclic Indoxyls and Carbazoles

“…[16] Metal-catalyzed [17] and metal-free [18] approaches, hypervalent iodine mediated strategies [19] and organocatalytic methods [20] have been reported for the construction of a wide range of spirocyclic and fused 3-oxindole derivatives. [21] Recently, we have utilized isatins for the facile synthesis of spirocyclic 3-oxindoles and spiro-furan indoxyls by ring-closing metathesis (RCM) [22] and Grignard reaction based [23] approaches.…”