IBS-Catalyzed Regioselective Oxidation of Phenols to 1,2-Quinones with Oxone®

We have developed the first example of hypervalent iodine(V)-catalyzed regioselective oxidation of phenols to o-quinones. Various phenols could be oxidized to the corresponding o-quinones in good to excellent yields using catalytic amounts of sodium salts of 2-iodobenzenesulfonic acids (pre-IBSes) and stoichiometric amounts of Oxone® as a co-oxidant under mild conditions. The reaction rate of IBS-catalyzed oxidation under nonaqueous conditions was further accelerated in the presence of an inorganic base such as potassium carbonate (K2CO3), a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate (nBu4NHSO4), and a dehydrating agent such as anhydrous sodium sulfate (Na2SO4).

The hypervalent organoiodine(III or V)-catalyzed oxidation reactions with co-oxidants have also been extensively investigated over the past seven years [25][26][27][28][29]. From 2007 to 2009, Yakura and colleagues reported that p-alkoxyphenols or p-arylphenols were oxidized to the corresponding p-quinones or p-quinols, respectively, in excellent yields using catalytic amounts of 4-iodophenoxyacetic acid with Oxone ® (2KHSO 5 •KHSO 4 •K 2 SO 4 ) as a co-oxidant in aqueous acetonitrile [30][31][32]. To the best of our knowledge, however, there are no successful examples of a catalytic hypervalent iodine system for the regio-selective oxidation of phenols to o-quinones.
We recently reported a highly efficient and chemoselective oxidation of various alcohols to carbonyl compounds such as aldehydes, carboxylic acids, and ketones with powdered Oxone ® in the presence of catalytic amounts (1-5 mol%) of 2-iodobenzenesulfonic acids (pre-IBSes) or their sodium salts (1a-c) under nonaqueous conditions (Scheme 1a) [33][34][35][36]. 2-Iodoxybenzenesulfonic acids (IBSes) 2a-c as iodine(V), which are generated in situ from 1a-c and Oxone ® , serve as the actual catalysts for the oxidations (Scheme 1b) [33][34][35][36]. According to previous theoretical calculations [33], the relatively ionic character of the intramolecular hypervalent iodine-OSO 2 bond of IBS 2a lowers the twisting barrier of the alkoxyperiodinane intermediate. In fact, 2a shows much more catalytic activity than IBX [33]. The oxidation rate in 2a-catalyzed oxidation under nonaqueous conditions is further accelerated by the use of powdered Oxone ® due to its increased surface area. When Oxone ® is used under nonaqueous conditions, Oxone ® wastes can be removed by simple filtration. Furthermore, we developed the oxidative rearrangement of tertiary allylic alcohols to -disubstituted ,-unsaturated ketones with Oxone ® catalyzed by in situ-generated 5-Me-IBS (2b) (Scheme 1c) [37]. The addition of inorganic bases such as K 2 CO 3 , and a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate (nBu 4 NHSO 4 ), extended the substrate scope for oxidative rearrangement reactions. Recently, the IBS/Oxone ® catalytic oxidation system was applied to benzylic oxidation [38] and oxidation of fluorinated alcohols [39]. As part of our continuing interest in the IBS-catalyzed oxidation system, we report here the in situ-generated IBS-catalyzed regioselective oxidation of phenols to o-quinones with Oxone ® . Scheme 1. In situ generated IBS (2)-catalyzed selective oxidation of alcohols and oxidative rearrangement of tertiary allylic alcohols with powdered Oxone ® under non-aqueous conditions. Scheme 1. Cont.

Results and Discussion
Initially, we investigated the reactivity and regioselectivity of the oxidation of 1-naphthol (3a) using conventional hypervalent catalysts under non-aqueous conditions (Table 1). A mixture of 3a, powdered Oxone ® (2 equiv.) and nBu 4 NHSO 4 (10 mol%) as a solid-liquid phase transfer catalyst was heated in ethyl acetate at 40 °C in the presence of 5 mol% of iodobenzene or Yakura's pre-catalyst (4-iodophenoxyacetic acid, 6) [30−32] (entries 2 and 3). However only trace amounts of the desired products were detected, and more than 80% of 3a was recovered with small amounts of unidentified side-products. The reaction was somewhat messy, and more than 80% of 3a was recovered. Additionally, the use of pre-IBX (7) gave both 1,2-naphthoquinone (4a) and 1,4-naphthoquinone (5a) each in 5% yield, and 80% of 3a was recovered (entry 4). In sharp contrast, and to our delight, when pre-IBS (1a) was used, 3a was completely consumed in 11 h, and quinones 4a and 5a were obtained in respective yields of 64% and 5% together with highly polar compounds (entry 5). As expected from our previous works [33,37], the use of pre-5-Me-IBS (1b) or pre-4,5-Me 2 -IBS (1c) gave slightly better results, and the former gave the best results (entries 6 and 7). Interestingly, when the oxidation was conducted in aqueous acetonitrile, 5a was obtained selectively as a major product in 51% yield (entry 8). We found that the carbon(1)-carbon(2) bond of o-quinone 4a was oxidatively cleaved under identical aqueous conditions to highly polar compounds including trans-2-carboxycinnamic acid (8) [40] and other minor unidentified compounds (Scheme 2). These results indicated that non-aqueous conditions were essential for the preparation of o-quinones in high yields. According to our previous works, the selective oxidation of acid-sensitive alcohols could be achieved in the presence of anhydrous sodium sulfate as a dehydrating agent [33,37]. Additionally, the oxidation rate and selectivity could be further accelerated with the use of additional base to buffer the acidity of the reaction mixture [37]. Based on these previous findings, the reaction of 3a was carried out in the presence of 1 equiv. of potassium carbonate and anhydrous sodium sulfate under the modified conditions in entry 6. Thus, 4a was obtained in 78% yield after 1 h, when Oxone ® and K 2 CO 3 were sufficiently premixed in the presence of anhydrous Na 2 SO 4 in ethyl acetate at room temperature for 24 h before the addition of 2b, 3a, and nBu 4 NHSO 4 (entry 9). Notably, the use of nBu 4 NHSO 4 was essential for the present oxidation, since almost no reaction occurred in its absence (entry 10).  To explore the generality of the in situ-generated 5-Me-IBS-catalyzed oxidation of phenols with Oxone ® , various naphthols, phenanthrols, and phenols 3b-l were examined as substrates under the optimized conditions: powdered Oxone ® (2 equiv.) and potassium carbonate (1 equiv.) in ethyl acetate were vigorously stirred at room temperature for 24 h in the presence of anhydrous sodium sulfate, and then 1b (5 mol%), 3a and nBu 4 NHSO 4 (10 mol%) were added and the resulting mixture was heated to 40 °C ( Table 2). As expected, 4a was obtained in slightly better yield by the oxidation of 2-naphthol 3b than by the oxidation of 3a ( Table 2, entry 1 versus Table 1, entry 9). 4-Bromo-or chloro-substituted 1-naphthols 3c and 3d gave the corresponding o-quinones in high yields (entries 2 and 3). Notably, the desired 1,2-quinones were obtained as a major product under our catalytic conditions even with the oxidation of 4-methoxy-1-naphthol (3e) and 4-methoxyphenol (3j) (entries 4 and 9). Accordingly, the previous iodine(III)-mediated oxidation of para-alkoxy phenols gave 1,4-quinones exclusively [30][31][32].

Scheme 4. Possible mechanism for the IBS-catalyzed oxidation of phenols.
While, the reason for the para-selective oxidation of 3l is not yet clear, a plausible mechanism is depicted in Scheme 5. The peroxo-IBS complex 12 might be generated reversibly in situ from IBS and ammonium Oxone ® . Electrophilic aromatic oxidation at the highly nucleophilic carbon(4) position of 3l with 12 gives 13, which easily tautomerizes to IBS-hydroquinone complex 14. Finally, the oxidation of hydroquinone gives 1,4-quinone 5l and iodine(III) 9. Notably, 5l was also obtained by the oxidation of 3l with only Oxone ® (Scheme 3) [41]. The reactivity of Oxone ® should be accelerated by complexation with IBS [42]. Thus, the oxidation was faster and the chemical yield of 5l was higher in the presence of IBS (Scheme 3).

Scheme 5.
Possible mechanism for the para-selective oxidation of 3l.

General
Infrared (IR) spectra were recorded on a Jasco FT/IR 460 plus spectrometer. 1 H-NMR spectra (400 MHz) and 13 C-NMR spectra (100 MHz) were measured on a Jeol ECS-400 spectrometer at ambient temperature. Data were recorded as follows: chemical shift in ppm from internal tetramethylsilane on the  scale, multiplicity (s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet), coupling constant (Hz), integration, and assignment. Chemical shifts were recorded in ppm from the resonance of the solvent used as the internal standard (deuterochloroform at 77.0 ppm). For thin-layer chromatography (TLC) analysis throughout this work, Merck precoated TLC plates (silica gel 60 GF 254 0.25 mm) were used. The products were purified by column chromatography on silica gel (E. Merck Art. 9385). High-resolution mass spectral analysis (HRMS) and elemental analysis were performed at the Chemical Instrument Center, Nagoya University. Pre-catalysts 1a-c were prepared according to known procedures [33]. Additionally, 1a and 1b (as potassium salts) are also commercially available from Junsei Chemical Japan, TCI and Sigma-Aldrich. Starting materials 3d [43], 3f [44], 3g [24], and 3l [45] were prepared according to known procedures. In experiments that required solvents, ethyl acetate, acetonitrile, and nitromethane were purchased from Wako Pure Chemical Industries, Ltd. in "anhydrous" form and used without any purification. Other simple chemicals were analytical-grade and obtained commercially.

General Procedure for the Oxidation Phenol to Quinone
A mixture of powdered Oxone ® (1.2 g, 2.0 mmol), potassium carbonate (0.14 g, 1.0 mmol) and anhydrous sodium sulfate (1.0 g, dried by a heat-gun under vacuum before use), in ethyl acetate (4.0 mL) was vigorously stirred at room temperature for 24 h. To the resulting mixture were added 3 (1.0 mmol), nBu 4 NHSO 4 (34 mg, 0.10 mmol), 1b (17 mg, 0.050 mmol), and EtOAc (6.0 mL), and the resulting mixture was stirred vigorously at 40 °C. The reaction was monitored by TLC analysis. After the reaction was completed, the reaction mixture was cooled to room temperature and the solids were filtered-off and washed with EtOAc. The filtrate was washed with water, and the aqueous layers were extracted with EtOAc. The combined organic layers were washed by water and brine, and dried over anhydrous Na 2 SO 4 . The solvents were removed under vacuo, and the residue was purified by column chromatography on silica gel (hexane-EtOAc as eluent) to give the corresponding quinones 4 or 5. 3-Methoxy-1,4-naphthoquinone (5l) [53]. Yellow solid; TLC, R f = 0.46 (hexane-EtOAc = 1:1); 1 H-NMR (CDCl 3 )  3.90 (s, 3H), 6.17 (s, 1H); 13

Conclusions
We have demonstrated the in situ-generated IBS-catalyzed regioselective oxidation of phenols to o-quinones with Oxone ® . The reaction rate is accelerated with the use of inorganic bases such as K 2 CO 3 , a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate (nBu 4 NHSO 4 ), and dehydrating agent such as Na 2 SO 4 . Various phenols are oxidized to the corresponding o-quinones in good to excellent yields. To the best of our knowledge, this is the first example of the hypervalent iodine-catalyzed oxidation of phenols to o-quinones.