Photochemical Aryl Radical Cyclizations to Give (E)-3-Ylideneoxindoles

(E)-3-Ylideneoxindoles are prepared in methanol in reasonable to good yields, as adducts of photochemical 5-exo-trig of aryl radicals, in contrast to previously reported analogous radical cyclizations initiated by tris(trimethylsilyl)silane and azo-initiators that gave reduced oxindole adducts.

As part of this collaboration we became interested in forming the oxindole skeleton in the absence of toxic and hazardous radical initiators or expensive metal catalysts [22][23][24]. In this article, an "initiator and metal-free" photochemical radical pathway giving non-reduced adducts, (E)-3-ylideneoxindoles, after 5-exo-trig cyclization is reported (Schemes 3 and 4).

Scheme 3. Preparation of 3-ylideneoxindole acetates.
The cyclization onto N,N-dimethylfumaramide 1f, and N-methyl sulfonylfumaramides 1b and 1c in acetonitrile gave 3-ylideneoxindoles 2f, 2b and 2c, as major products in low to moderate yields (26%-48%, Scheme 4). In these cases, there was no evidence of the photochemical cycloaddition. The yield for the N,N-dimethylfumaramide adduct 2f was marginally improved (to 54%) using methanol, but the yield of the N-methylsulfonylfumaramide 2c was reduced (to 24%). The instability of (E)-3-ylideneoxindole amides 2c and 2f was confirmed by subjecting them separately to UV-light (at 254 nm) for 3 h, which resulted in a complex intractable mixture of products.

Scheme 4. Preparation of 3-ylideneoxindole acetamides.
For N-methylsulfonylfumaramides 1b-1c the domino radical cyclization-Smiles rearrangement, which occurred with radical initiators, was not observed (Scheme 2) [21]. Column chromatography fractions from the irradiation of 1b were analyzed using ESI, and two major but unstable products with m/z 484.3 were observed, which proved difficult to rigorously purify and characterize due to conversion to the oxindole 2b. The mass fitted that of iodide adducts prior to HI-elimination to give 2b (Figure 1). The X-ray crystal of 2b confirmed the formation of the 5-exo-trig adduct and (E)-geometry about the 3-ylidene ( Figure 2) [25].

General
All chemicals were obtained from commercial sources and used without further purification. Thin layer chromatography (TLC) was performed on TLC silica gel 60 F254 plates. Dry vacuum column chromatography [26] was carried out on silica gel (Apollo Scientific ZEOprep 60/15-35 microns). Melting points were measured on a Stuart Scientific melting point apparatus SMP1. Infrared spectra were recorded using a Perkin-Elmer Spec 1 with ATR attached. 1 H-NMR spectra were recorded using a Joel GXFT 400 MHz instrument equipped with a DEC AXP 300 computer workstation. The chemical shifts were recorded in ppm relative to tetramethylsilane. 13 C-NMR data were collected at 100 MHz with complete proton decoupling. High resolution mass spectra (HRMS) were carried out using ESI time-of-flight mass spectrometer (TOFMS) in positive mode. The precision of all accurate mass measurements were better than 5 ppm. Photochemical reactions were carried out at 254 nm using a RPR-100 Rayonet photochemical reactor, encompassing sixteen mercury lamps.

Synthesis of Radical Precursors
The synthesis of radical precursors acetate 1a [20], and sulfonamides 1b and 1c [21] has been previously reported. -2-enoate (1d). 4-Methyl-morpholine (1.60 g, 15.9 mmol) was added to a suspension of fumaric acid monoethyl ester (2.30 g, 15.9 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (4.40 g, 15.9 mmol) in THF (50 mL) and the suspension was stirred at room temperature for 20 min. A solution of 2-iodo-p-toluidine (3.35 g, 14.4 mmol) in THF (5 mL) was added and the suspension was stirred overnight. The reaction mixture was diluted with water, extracted with diethyl ether washed with saturated NaHCO3, water, 2% hydrochloric acid, brine, dried (NaSO4), and evaporated. The residue was added to a mixture of sodium hydride (0.371 g, 15.4 mmol) in THF (25 mL), which was cooled to 0 °C. The solution was stirred for 30 min at 0 °C and at room temperature for another 30 min. Methyl iodide (2.74 g, 19.3 mmol) was added and the reaction was stirred for 2 h. The solvent was evaporated and the residue dissolved in ethyl acetate, washed with water, dried (MgSO4) and evaporated. The resulting crude was recrystallized from diethyl ether to give the title compound

Photochemical Radical Cyclizations
The o-iodoanilide derivative (0.5 mmol) in acetonitrile or methanol (29 mL) was irradiated in a cylindrical quartz tube at 254 nm for 3 h. The solution was evaporated to dryness and the residue washed with saturated NaHCO3 solution (20 mL), and extracted with dichloromethane (3 × 10 mL). The organic layers were combined, dried (Na2SO4), evaporated to dryness, and purified by dry vacuum column chromatography with gradient elution of petroleum ether and ethyl acetate.