Synthesis of 3,3-disubstituted oxindoles by organoselenium-induced radical cyclizations of N-arylacrylamides

Introduction

The prevalence of the oxindole ring system that represents a key structural component in natural products and pharmaceutical chemistry is well-established [1, 2]. Moreover, functionalized oxindoles have also found wide utility as versatile starting materials for the synthesis of a broad range of heterocyclic compounds. Accordingly, the search for sustainable and more efficient methods for the preparation of oxindoles is of constant interest [3, 4]. Among many different approaches to 3,3′-disubstituted oxindoles, radical-mediated cyclization of N-arylacrylamides has received much attention because of the potential application of the products of such reactions in pharmaceutical research. A wide range of function groups including trifluoromethyl [5], azide [6], diphenylphosphine oxide [7], carbonyl [8], nitro [9], substituted alkyl [10], trifluoromethylthio [11], sulfonyl [12], and aryl [13] have been introduced into oxindole frameworks through the radical cyclization strategy. To the best of our knowledge, a similar protocol using organoselenium derivatives as selenyl radicals is not well-documented.

The development of C-Se bond formation has emerged as a significant field of research in organic chemistry on account of organoselenium compounds as synthetic intermediates and discovery of their useful biological activities [14]. Thus, extensive studies have been focused on development of new synthetic strategies to introduce a selenium moiety into chemical structures [15]. The incorporation of selenium atom or selenium-containing functional groups can effectively modify the reactivity and physical, pharmacological, and toxicological properties of parent molecules. The methods used for incorporation of an organoselenium moiety into the organic structures are based on the use of electrophile [16], nucleophile [17, 18], or radical selenium species [19]. However, reports on the direct selenium-carbocyclization of N-arylacrylamides via a radical pathway to prepare selenium-containing oxindoles are quite rare. Following our research on the synthesis of oxindoles from arylacrylamides [20, 21], herein we wish to report an efficient tandem selenium-carbocyclization of arylacrylamides with N-(phenylseleno)phthalimide (N-PSP). The one-pot reactions generated the corresponding selenium-containing oxindoles in good yields.

These studies were initiated by screening for the optimal conditions for the selenium-carbocyclization of N-arylacrylamide 1a. When the reaction was carried out in the presence of K₂S₂O₈ (1.5 equiv) and diphenyl diselenide (0.5 equiv) in CH₃CN at 70°C for 2 h, the desired oxindole 2a was obtained in 35% isolated yield. In the absence of K₂S₂O₈, no reaction occurred. Using (NH₄)₂S₂O₈ instead of K₂S₂O₈ led to the increased yield of 44%. Changing the solvent to THF or DCE afforded only a trace amount of 2a. The yield was further improved to 67% when the reaction was conducted in DMSO. Screening of the selenium reagents showed that the use of N-PSP gave better results than diphenyl diselenide.

With the optimized reaction conditions in hand, we probed the reaction of a variety of N-arylacrylamides with N-PSP (Scheme 1). It was found that N-alkyl-substituted substrates, such as 1a–d are reactive. Subsequently, the effect of substituents at the N-aryl moiety was examined. Both electron-donating and electron-withdrawing groups located in the para or ortho position of the aromatic ring were found to be tolerated in this reaction, furnishing the corresponding oxindoles 2e–k in moderate to good yields. Moreover, 3,5-disubstituted N-arylacrylamide 1s was also transformed into the desired product 2s in 62% yield. The procedure seems sensitive to steric effects. Generally, substitutents in the para position on benzene are well tolerated. By contrast, the presence of ortho substituents on benzene reduces the yields. Finally, a variety of substituted N-PSP substrates reacted with N-arylacrylamide 1b smoothly to generate the desired products 2m–o.

Scheme 1

Experimental

Solvents were purified or dried in a standard manner. Reactions were monitored by TLC on silica gel plates (GF254). ¹H NMR spectra (400 MHz) and ¹³C NMR spectra (100 MHz) were measured in CDCl₃ with TMS as an internal standard.