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Article

Hydroxylation of Aryl Sulfonium Salts for Phenol Synthesis under Mild Reaction Conditions

by
Xuan-Bo Hu
1,
Qian-Qian Fu
1,
Xue-Ying Huang
1,
Xue-Qiang Chu
1,
Zhi-Liang Shen
1,*,
Chengping Miao
2,* and
Weiyi Chen
3,*
1
Technical Institute of Fluorochemistry (TIF), School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing 211816, China
2
College of Biological, Chemical Science and Engineering, Jiaxing University, 118 Jiahang Road, Jiaxing 314001, China
3
Soochow College, Soochow University, Suzhou 215006, China
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(4), 831; https://doi.org/10.3390/molecules29040831
Submission received: 11 January 2024 / Revised: 4 February 2024 / Accepted: 10 February 2024 / Published: 13 February 2024
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
Hydroxylation of aryl sulfonium salts could be realized by utilizing acetohydroxamic acid and oxime as hydroxylative agents in the presence of cesium carbonate as a base, leading to a variety of structurally diverse hydroxylated arenes in 47–95% yields. In addition, the reaction exhibited broad functionality tolerance, and a range of important functional groups (e.g., cyano, nitro, sulfonyl, formyl, keto, and ester) could be well amenable to the mild reaction conditions.

Graphical Abstract

1. Introduction

Phenols and their derivatives are not only important building blocks in modern organic synthesis, but also structural units which are ubiquitously present in natural products, biologically and pharmaceutically active molecules, and functional materials [1]. As a consequence, the development of effective methodologies for the preparation of phenols has attracted considerable attention from the synthetic community. In addition to the classic methods developed in order to access phenols by virtue of Sandmeyer reactions and direct arene oxidation [2,3,4,5,6,7,8,9,10], the transition-metal-catalyzed hydroxylation of aryl halides has also been proven to be one of the most efficient methods by which to synthesize phenol [11,12,13,14,15,16,17]. A range of hydroxide sources and their surrogates, such as alkali metal hydroxide (MOH) [18,19,20,21], water [22,23,24,25,26,27], boric acid [28], molecular oxygen [29,30], silanol [31], hydrogen peroxide [31], and nitrous oxide [32,33], have been revealed to be effective for the hydroxylation of aryl halides and its variants (Scheme 1a). In 2016 and 2017, the group of Fier and Maloney originally disclosed that benzaldoxime [34,35,36,37] and acetohydroxamic acid [38] could also function as effective hydroxylating agents for the conversion of aryl halides to phenols (Scheme 1b). In 2021, James et al. found that electron-rich pyrrole-based oxime is more efficient than benzaldoxime for the hydroxylation of aryl halides [39].
Recently, the development of alternative electrophiles [40,41,42,43,44,45,46,47] as substitutes for conventional aryl halides in hydroxylative reactions have aroused considerable attention in the field of synthetic organic chemistry (Scheme 1c) [48,49,50]. For instance, Cornella et al. have described how pyridinium salts generated in situ from the reaction of aminoheterocycles with pyrylium tetrafluoroborate salts could be converted into their hydroxylated analogue by utilizing acetohydroxamic acid as a hydroxyl source [48]. James et al. have demonstrated that nitroarenes could also be effectively transformed into phenols via a denitrative functionalization protocol that employs their previously developed pyrrole-based oxime as hydroxylating agent under transition-metal-free conditions [49]. Cheng and Ye have reported that aryl ammonium salts could also efficiently undergo hydroxylation by using benzaldoxime and acetohydroxamic acid as hydroxide surrogates [50]. In recent decades, readily accessible and shelf-stable organosulfonium salts have also been proven to be versatile electrophiles for undergoing a broad range of organic transformations [51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73]. Although the hydroxylation of aryl thianthrenium salts have been accomplished by using water as hydroxide source, the reaction should be conducted under photoredox conditions in the presence of Ir and Cu catalysts [74]. In the continuation of our efforts to develop efficient organic transformations with the use of alternative electrophiles [75,76,77,78,79,80,81,82,83,84] under mild reaction conditions, herein we report a hydroxylation of aryl sulfonium salts by using acetohydroxamic acid and oxime as hydroxylative agents, which enabled the efficient assembly of hydroxylated arenes in modest-to-good yields with good functional group compatibility (Scheme 1d).
Molecules 29 00831 sch001
Scheme 1. Hydroxylation of aryl halides and their counterparts. (a) Hydroxylation of aryl halides by using various hydroxide sources [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33]; (b) Hydroxylation of aryl halides by using oxime and acetohydroxamic acid [34,35,36,37,38,39]; (c) Hydroxylation of other aryl electrophiles by using oxime and hydroxamic acid [48,49,50]; (d) Hydroxylation of aryl sulfonium salts by using oxime and hydroxamic acid (this work).
Scheme 1. Hydroxylation of aryl halides and their counterparts. (a) Hydroxylation of aryl halides by using various hydroxide sources [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33]; (b) Hydroxylation of aryl halides by using oxime and acetohydroxamic acid [34,35,36,37,38,39]; (c) Hydroxylation of other aryl electrophiles by using oxime and hydroxamic acid [48,49,50]; (d) Hydroxylation of aryl sulfonium salts by using oxime and hydroxamic acid (this work).
Molecules 29 00831 sch001

2. Results

Initially, we sought to optimize the reaction conditions for the hydroxylation of (4-cyanophenyl)dimethylsulfonium-trifluoromethanesulfonate (1a) by using N-hydroxyacetamide (2a) as a hydroxylating agent [38] in the co-existence of various bases and solvents. Among the different organic bases and inorganic bases surveyed and outlined in Table 1 (entries 1–11), Cs2CO3 emerged as the base of choice (entry 8), leading to the corresponding phenol 3a in 66% NMR yield when the reaction was carried out in DMSO (1 mL) at 80 °C for 18 h. Subsequent screening of other reaction media, including DMF, 1,4-dioxane, NMP, MeCN, toluene, THF, and H2O (entries 12–18), did not further enhance the reaction performance. Conducting the reaction at different temperatures (60 °C and 100 °C, entries 19–20) also made no significant difference. Gratifyingly, the NMR yield of product 3a could be further improved to 81% by using 2 mL DMSO as solvent (entry 21). In addition, evaluation of other reaction parameters, including the amount of Cs2CO3 (3 equiv. or 7 equiv., entries 22–23), reaction time (12 h or 24 h, entries 24–25), equivalents of N-hydroxyacetamide 2a (2 equiv. or 4 equiv., entries 26–27), and the amount of DMSO (4 mL, entry 28), were performed. However, in most cases, variation of the reaction conditions either led to decreased product yield or produced a comparable result to that of entry 21.
Under the above established reaction conditions, we investigated an array of aryl sulfonium salts for this hydroxylation reaction by utilizing acetohydroxamic acid 2a as the hydroxylating agent. As summarized in Table 2, aryl sulfonium salts 1a–k, containing an electron-withdrawing group in the aryl ring, efficiently took part in the hydroxylation to give the corresponding phenols at moderate-to-high yields. More significantly, important functional groups, including cyano, nitro, sulfonyl, formyl, keto, and ester, could be well compatible with the established conditions, which could be retained for downstream derivatization. However, when (4-chlorophenyl)dimethylsulfonium triflate containing a chloro atom in the phenyl ring was used as a substrate, no desired hydroxylative product was obtained, presumably because of its relatively low reactivity as compared with aryl sulfonium salt bearing an electron-withdrawing group in the phenyl ring. In addition, and analogous to a previous report of Fier and Maloney in which the hydroxylation only worked with an electron-poor aryl halide [38], the present reaction also could not be applied to less reactive aryl sulfonium salts derived from an electron-rich aryl ring which bears an electron-donating substituent.
In addition to acetohydroxamic acid 2a, we also investigated the hydroxylation of aryl sulfonium salt 1a by employing benzaldoxime [34,35,36,37,39] (1.3 equiv.) as a hydroxylative reagent. In the beginning, we also optimized the reaction conditions. As outlined in Table 3, the reaction of aryl sulfonium salt 1a with benzaldehyde oxime (2b) proceeded smoothly in the presence of Cs2CO3 in DMSO at 80 °C for 4 h to give the hydroxylated product 3a in 58% NMR yield (entry 1). Ensuing screening of reaction solvent (entries 2–7) revealed that DMF served as the more appropriate solvent of the reaction, which slightly improved the reaction efficiency and gave rise to the corresponding product 3a in 67% NMR yield (entry 7). Next, a variety of bases were also examined in the hydroxylating reaction (entries 8–19). However, Cs2CO3 was still the optimal base for the transformation. Pleasingly, by increasing the amount of 2b to 1.5 equivalents, NMR yield of the product could be increased to 74% (entry 20).
Apart from benzaldehyde oxime (2b), a variety of oximes 2 were also evaluated as hydroxide surrogates (Table 4). Of the various oximes 2b–g studied, oxime 2g, derived from pyrrole [39], was found to be the most suitable hydroxylating reagent for the reaction, affording the expected product 3a in 89% NMR yield.
With the establishment of the optimized reaction conditions, substrate scope of aryl sulfonium salts 1 was investigated with the use of oxime 2g as the hydroxylating agent. As listed in Table 5, a variety of aryl sulfonium salts 1a–k possessing an electron-poor phenyl ring could be amenable to the reaction, leading to the corresponding hydroxylated arenes in 47–95% yields. Analogously, the reactions proceeded with tolerances to a plethora of important functionalities, such as CN, NO2, SO2Me, CHO, COR, and COOR. Additionally, aryl sulfonium salts containing electron-donating group in the aryl ring were proven to be inappropriate for the current hydroxylation reaction, which is similar to reports in the literature [38,39,49,50].
Finally, the scalability of the reactions was also investigated. As illustrated in Scheme 2, 3 mmol scale reaction of aryl sulfonium salt 1a with both 2a and 2g worked equally well under the optimized reaction conditions, producing the anticipated product 3a in 73% and 75% yields, respectively.
Based on previous reports [34,38,50], possible mechanisms for these two hydroxylative reactions have been tentatively proposed. As shown in Figure 1a, for the reaction of aryl sulfonium salt with aldehyde oxime, the reaction possibly proceeds via the nucleophilic substitution of the aldehyde oxime with the sulfonium salt under the action of base to give intermediate A, accompanied by the generation of dimethyl sulfide as a byproduct. Next, a base-mediated deprotonation of intermediate A, followed by fragmentation and subsequent protonation, affords the corresponding phenol as the final product and aryl nitrile as a byproduct. With regard to hydroxylation employing acetohydroxamic acid as hydroxide source (Figure 1b), the reaction presumably occurs through a similar base-facilitated nucleophilic substitution of acetohydroxamic acid with aryl sulfonium salt to produce intermediate B, along with the formation of Me2S as a byproduct. Subsequently, a Lossen rearrangement takes place to yield the desired phenol after acidific workup.

3. Materials and Methods

3.1. General Information

Unless otherwise specified, the reagents were purchased from commercial suppliers and used without further purification. All reactions were conducted under N2 atmosphere using undistilled solvent. Analytical thin layer chromatography (TLC) was performed using silica gel plate (0.2 mm thickness). Subsequent to elution, plates were visualized using UV radiation (254 nm). Flash chromatography was performed using Merck silica gel (200–300 mesh) for column chromatography with freshly distilled solvents. IR spectra were recorded on an FT-IR spectrophotometer using KBr optics. 1H and 13C NMR spectra were recorded in CDCl3 and DMSO-d6 on Bruker Avance or Jeol 400 MHz spectrometers. The chemical shifts (δ) are reported in ppm and coupling constants (J) in Hz. NMR splitting patterns are designated as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), doublet of doublets (dd), doublet of triplets (dt), doublet of quartets (dq), triplet of doublets (td), triplet of triplets (tt), quartet of doublets (qd), doublet of doublet of doublets (ddd), etc. Tetramethylsilane (TMS) served as internal standard for 1H and 13C NMR analysis. High resolution mass spectra (HRMS) were obtained via a Waters Q-TOF Premier Spectrometer (ESI source).

3.2. Experimental

3.2.1. General Procedure for the Synthesis of Aryl Sulfonium Salts 1a–k

A 50 mL single-neck round-bottom flask was sequentially charged with aryl thioether (20 mmol, 1.0 equiv.), DCE (20 mL), and MeOTf (3938.4 mg, 24 mmol, 1.2 equiv.). The reaction mixture was vigorously stirred at room temperature for 12 h. Then, solvent was evaporated and the residual was purified through silica gel column chromatography using petroleum ether and EtOAc as eluent to afford the analytically pure product of aryl sulfonium salts 1a–k. Spectral data of these compounds are in accordance with those previously documented [62,63,64,65].

3.2.2. General Procedure for the Synthesis of Oximes 2b–g

A 250 mL round-bottom flask was sequentially charged with aryl aldehyde (20.0 mmol, 1 equiv.), MeOH (100 mL), Na2CO3 (2.54 g, 24 mmol, 1.2 equiv.), and NH2OH∙HCl (1.67 g, 24 mmol, 1.2 equiv.). The reaction mixture was then heated to reflux and stirred for 2 h. The reaction was allowed to cool to room temperature and MeOH was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and H2O (50 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (50 mL × 2). The organic extracts were combined, washed with brine (50 mL), and dried over Na2SO4. The extracts were concentrated under reduced pressure to afford the crude product, which was purified via silica gel column chromatography (using EtOAc/petroleum ether + 3% Et3N as eluents) to afford the analytically pure oximes 2b–g. Spectral data of the products are in accordance with those previously documented [39].

3.2.3. General Procedure for the Reaction of Aryl Sulfonium Salt with Acetohydroxamic Acid

To an oven-dried Schlenk tube equipped with a magnetic stir bar was sequentially added aryl sulfonium salt 1 (0.5 mmol, 1 equiv.), acetohydroxamic acid 2a (112.6 mg, 1.5 mmol, 3 equiv.), and Cs2CO3 (814.6 mg, 2.5 mmol, 5 equiv.). Then, dry DMSO (2 mL) was added into the tube by syringe. The reaction mixture was stirred at 80 °C for 18 h before quenching with aqueous hydrochloric acid (6 mmol, 6 mL, 1 M in water) and extracting with EtOAc (20 mL × 3). The organic layers were combined, washed with brine, and dried over Na2SO4. The extracts were concentrated under reduced pressure to afford the crude product, which was further purified via silica gel column chromatography (using EtOAc/petroleum ether as eluents) to yield the analytically pure product 3.

3.2.4. General Procedure for the Reaction of Aryl Sulfonium Salt with Oxime

To an oven-dried Schlenk tube equipped with a magnetic stir bar was sequentially added aryl sulfonium salt 1 (0.5 mmol, 1 equiv.), oxime 2g (93.1 mg, 0.75 mmol, 1.5 equiv.), and Cs2CO3 (814.6 mg, 2.5 mmol, 5 equiv.). Then dry DMF (2 mL) was added into the tube by syringe. The reaction mixture was stirred at 80 °C for 4 h before quenching with aqueous hydrochloric acid (6 mmol, 6 mL, 1 M in water) and extracting with EtOAc (20 mL × 3). The organic layers were combined, washed with brine, and dried over Na2SO4. The extracts were concentrated under reduced pressure to afford the crude product, which was further purified through silica gel column chromatography (using EtOAc/petroleum ether as eluents) to yield the analytically pure product 3.

3.2.5. Scale-Up Reaction of Sulfonium Salt 1a with Acetohydroxamic Acid 2a

To an oven-dried Schlenk tube equipped with a magnetic stir bar was sequentially added aryl sulfonium salt 1a (940.0 mg, 3 mmol, 1 equiv.), acetohydroxamic acid 2a (1013.4 mg, 9 mmol, 3 equiv.), and Cs2CO3 (7331.4 mg, 15 mmol, 5 equiv.). Then dry DMSO (12 mL) was added into the tube by syringe. The reaction mixture was stirred at 80 °C for 18 h before quenching with aqueous hydrochloric acid (36 mmol, 36 mL, 1 M in water) and extracting with EtOAc (80 mL × 3). The organic layers were combined, washed with brine, and dried over Na2SO4. The extracts were concentrated under reduced pressure to afford the crude product, which was further purified through silica gel column chromatography (using EtOAc/petroleum ether as eluents) to yield the analytically pure product 3a in 73% yield (262.9 mg).

3.2.6. Scale-Up Reaction of Sulfonium Salt 1a with Oxime 2g

To an oven-dried Schlenk tube equipped with a magnetic stir bar was sequentially added aryl sulfonium salt 1a (940.0 mg, 3 mmol, 1 equiv.), oxime 2g (419.0 mg, 4.5 mmol, 1.5 equiv.), and Cs2CO3 (7331.4 mg, 15 mmol, 5 equiv.). Then, dry DMSO (12 mL) was added into the tube by syringe. The reaction mixture was stirred at 80 °C for 4 h before quenching with aqueous hydrochloric acid (36 mmol, 36 mL, 1 M in water) and extracting with EtOAc (80 mL × 3). The organic layers were combined, washed with brine, and dried over Na2SO4. The extracts were concentrated under reduced pressure to afford the crude product, which was further purified through silica gel column chromatography (using EtOAc/petroleum ether as eluents) to yield the analytically pure product 3a in 75% yield (270.1 mg).
4-Hydroxybenzonitrile (3a). Purification of this product was performed via silica gel column chromatography employing petroleum ether and ethyl acetate as eluant (petroleum ether/EtOAc = 15:1) with a yield = 86%, 51.4 mg using 2a as hydroxylating agent and a yield = 87%, 51.8 mg using 2g as hydroxylating agent. White solid. 1H NMR (400 MHz, CDCl3): δ 7.57–7.51 (m, 2H), 7.18 (brs, 1H), 6.97–6.90 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 160.4, 134.3, 119.3, 116.5, 102.6 ppm. IR (KBr, neat): ν = 3292, 2927, 2856, 1610, 1586, 1508, 1286, 1166, 835, 700, 458 cm−1. HRMS (ESI, m/z): calculated for C7H6NO [M + H]+ 120.0444, found: 120.0442. Spectral data of the product are in accordance with previously documented data [85].
4-Hydroxy-2-methylbenzonitrile (3b). Purification of this product was performed via silica gel column chromatography employing petroleum ether and ethyl acetate as eluant (petroleum ether/EtOAc = 20:1) with a yield = 49%, 32.9 mg using 2a as hydroxylating agent and a yield = 59%, 39.5 mg using 2g as hydroxylating agent. Yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.48 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H), 6.74 (dd, J = 8.4, 2.5 Hz, 1H), 6.47 (brs, 1H), 2.48 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 159.9, 144.5, 134.5, 118.6, 117.2, 113.8, 103.8, 20.5 ppm. IR (KBr, neat): ν = 3300, 2921, 2225, 1616, 1576, 1498, 1303, 1231, 1163, 1098 cm−1. HRMS (ESI, m/z): calculated for C8H8KNO [M+K]+ 172.0159, found: 172.0170. Spectral data of the product are in accordance with previously documented data [24].
4-Nitrophenol (3c). Purification of this product was performed via silica gel column chromatography employing petroleum ether and ethyl acetate as eluant (petroleum ether/EtOAc = 20:1) with a yield = 95%, 66.3 mg using 2a as hydroxylating agent and a yield = 95%, 66.1 mg using 2g as hydroxylating agent. Yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.21–8.13 (m, 2H), 6.98–6.91 (m, 2H), 6.64 (brs, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 161.7, 141.4, 126.3, 115.8 ppm. IR (KBr, neat): ν = 3337, 2962, 2360, 2342, 1592, 1498, 1339, 1289, 1262, 1112 cm−1. HRMS (ESI, m/z): calculated for C6H6NO3 [M + H]+ 140.0342, found: 140.0353. Spectral data of the product are in accordance with previously documented data [85].
3-Methyl-4-nitrophenol (3d). Purification of this product was performed via silica gel column chromatography employing petroleum ether and ethyl acetate as eluant (petroleum ether/EtOAc = 20:1) with a yield = 79%, 60.5 mg using 2a as hydroxylating agent and a yield = 55%, 42.4 mg using 2g as hydroxylating agent. White solid. 1H NMR (400 MHz, DMSO-d6): δ 10.79 (brs, 1H), 8.00–7.95 (m, 1H), 6.79–6.74 (m, 2H), 2.49 (s, 3H) ppm. 13C NMR (100 MHz, DMSO-d6): δ 162.7, 140.9, 137.3, 128.3, 119.2, 114.3, 21.5 ppm. IR (KBr, neat): ν = 3301, 3090, 2929, 1589, 1507, 1477, 1458, 1317, 1260, 1077 cm−1. HRMS (ESI, m/z): calculated for C7H8NO3 [M + H]+ 154.0499, found: 154.0498. Spectral data of the product are in accordance with previously documented data [86].
4-(Methylsulfonyl)phenol (3e). Purification of this product was performed via silica gel column chromatography employing petroleum ether and ethyl acetate as eluant (petroleum ether/EtOAc = 5:1) with a yield = 81%, 70.1 mg using 2a as hydroxylating agent and a yield = 79%, 68.3 mg using 2g as hydroxylating agent. Yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.78–7.65 (m, 3H), 7.00–6.92 (m, 2H), 3.06 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 161.4, 130.6, 129.6, 116.2, 44.9 ppm. IR (KBr, neat): ν = 3375, 3017, 2918, 1588, 1502, 1447, 1302, 1283, 1144, 1090 cm−1. HRMS (ESI, m/z): calculated for C7H9O3S [M + H]+ 173.0267, found: 173.0266. Spectral data of the product are in accordance with previously documented data [24].
4-Hydroxybenzaldehyde (3f). Purification of this product was performed via silica gel column chromatography employing petroleum ether and ethyl acetate as eluant (petroleum ether/EtOAc = 20:1) with a yield = 61%, 37.3 mg using 2a as hydroxylating agent and a yield = 52%, 31.8 mg using 2g as hydroxylating agent. White solid. 1H NMR (400 MHz, CDCl3): δ 9.84 (s, 1H), 7.86–7.78 (m, 2H), 7.38 (brs, 1H), 7.04–6.97 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 191.9, 162.4, 132.8, 129.3, 116.1 ppm. IR (KBr, neat): ν = 3167, 2878, 1668, 1599, 1453, 1316, 1287, 1218, 1161, 834 cm−1. HRMS (ESI, m/z): calculated for C7H7O2 [M + H]+ 123.0441, found: 123.0453. Spectral data of the product are in accordance with previously documented data [87].
(4-Hydroxyphenyl)(phenyl)methanone (3g). Purification of this product was performed via silica gel column chromatography employing petroleum ether and ethyl acetate as eluant (petroleum ether/EtOAc = 20:1) with a yield = 56%, 55.9 mg using 2a as hydroxylating agent) and a yield = 53%, 52.8 mg using 2g as hydroxylating agent. Yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.82–7.73 (m, 4H), 7.65 (brs, 1H), 7.61–7.55 (m, 1H), 7.52–7.44 (m, 2H), 6.99–6.91 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 196.8, 160.8, 138.0, 133.1, 132.2, 129.8, 129.5, 128.3, 115.4 ppm. IR (KBr, neat): ν = 3150, 2346, 1634, 1602, 1559, 1507, 1313, 1288, 1232, 1148 cm−1. HRMS (ESI, m/z): calculated for C13H11O2 [M + H]+ 199.0754, found: 199.0765. Spectral data of the product are in accordance with previously documented data [24].
2-Hydroxyanthracene-9,10-dione (3h). Purification of this product was performed via silica gel column chromatography employing petroleum ether and ethyl acetate as eluant (petroleum ether/EtOAc = 20:1) with a yield = 73%, 81.8 mg using 2a as hydroxylating agent and a yield = 68%, 76.5 mg using 2g as hydroxylating agent. Yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.17–8.14 (m, 2H), 8.08 (d, J = 8.5 Hz, 1H), 7.93–7.85 (m, 2H), 7.49 (d, J = 2.5 Hz, 1H), 7.24 (dd, J = 8.5, 2.6 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 183.0, 181.5, 163.6, 135.6, 134.9, 134.4, 133.6, 133.5, 130.3, 127.03, 127.01, 125.6, 122.0, 112.7 ppm. IR (KBr, neat): ν = 3357, 2960, 2255, 1671, 1581, 1450, 1342, 1304, 1022, 997 cm−1. HRMS (ESI, m/z): calculated for C14H9O3 [M + H]+ 225.0546, found: 225.0551. Spectral data of the product are in accordance with previously documented data [88].
1-(4-Hydroxyphenyl)ethan-1-one (3i). Purification of this product was performed via silica gel column chromatography employing petroleum ether and ethyl acetate as eluant (petroleum ether/EtOAc = 20:1) with a yield = 51%, 34.7 mg using 2a as hydroxylating agent and a yield = 60%, 41.0 mg using 2g as hydroxylating agent. White solid. 1H NMR (400 MHz, CDCl3): δ 8.15 (brs, 1H), 7.95–7.88 (m, 2H), 6.97–6.92 (m, 2H), 2.58 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 199.0, 161.7, 131.3, 129.3, 115.6, 26.3 ppm. IR (KBr, neat): ν = 3306, 2995, 2926, 1663, 1603, 1577, 1512, 1357, 1279, 1219, 1166 cm−1. HRMS (ESI, m/z): calculated for C8H9O2 [M + H]+ 137.0597, found: 137.0594. Spectral data of the product are in accordance with previously documented data [85].
Methyl 4-hydroxybenzoate (3j). Purification of this product was performed via silica gel column chromatography employing petroleum ether and ethyl acetate as eluant (petroleum ether/EtOAc = 20:1) with a yield = 54%, 41.1 mg using 2a as hydroxylating agent and a yield = 47%, 35.8 mg using 2g as hydroxylating agent. White solid. 1H NMR (400 MHz, CDCl3): δ 7.97–7.91 (m, 2H), 7.15 (brs, 1H), 6.93–6.87 (m, 2H), 3.90 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 167.8, 160.6, 132.0, 121.9, 115.3, 52.2 ppm. IR (KBr, neat): ν = 3307, 2962, 1683, 1607, 1588, 1515, 1435, 1278, 1163, 1106 cm−1. HRMS (ESI, m/z): calculated for C8H9O3 [M + H]+ 153.0546, found: 153.0549. Spectral data of the product are in accordance with previously documented data [85].
5-Hydroxyisobenzofuran-1(3H)-one (3k). Purification of this product was performed via silica gel column chromatography employing petroleum ether and ethyl acetate as eluant (petroleum ether/EtOAc = 20:1) with a yield = 70%, 52.8 mg using 2a as hydroxylating agent and a yield = 60%, 45.1 mg using 2g as hydroxylating agent. Yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.67 (brs, 1H), 7.70–7.60 (m, 1H), 6.98–6.89 (m, 2H), 5.26 (s, 2H) ppm. 13C NMR (100 MHz, DMSO-d6): δ 171.0, 163.6, 150.8, 127.2, 117.6, 116.1, 108.9, 69.6 ppm. IR (KBr, neat): ν = 3270, 2962, 2925, 1718, 1603, 1467, 1434, 1346, 1273, 1097 cm−1. HRMS (ESI, m/z): calculated for C8H7O3 [M + H]+ 151.0390, found: 151.0399. Spectral data of the product are in accordance with previously documented data [32].

4. Conclusions

In conclusion, the hydroxylation of aryl sulfonium salts by utilizing acetohydroxamic acid and oxime as hydroxylating reagents was developed. The reactions proceeded effectively with the aid of cesium carbonate to afford a series of hydroxylated arenes in moderate-to-high yields with broad functional group compatibility. In addition, the hydroxylation could be subjected to scale-up synthesis, leading to the desired phenol in a good yield.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29040831/s1.

Author Contributions

Synthesis and characterization, X.-B.H., Q.-Q.F. and X.-Y.H.; methodology and project administration, X.-Q.C.; writing—original draft preparation, and supervision, Z.-L.S.; writing—review and editing, and funding acquisition, Z.-L.S., C.M. and W.C. All authors have read and agreed to the published version of the manuscript.

Funding

We gratefully acknowledge the financial support from Nanjing Tech University (Start-up Grant No. 39837118), Jiaxing University, and Soochow University.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 29 00831 sch002
Scheme 2. Scale-up synthesis.
Scheme 2. Scale-up synthesis.
Molecules 29 00831 sch002
Molecules 29 00831 g001
Figure 1. Tentatively proposed mechanisms. (a) When using aldehyde oxime as hydroxylative source; (b) When using acetohydroxamic acid as hydroxylative source.
Figure 1. Tentatively proposed mechanisms. (a) When using aldehyde oxime as hydroxylative source; (b) When using acetohydroxamic acid as hydroxylative source.
Molecules 29 00831 g001
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 29 00831 i001
Entry2a (x equiv.)Base
(y equiv.)		Solvent
(z mL)		Temp.
(°C)		Time (h)Yield (%) b
13 equiv.DBU (5 equiv.)DMSO (1 mL)80 °C18 h9
23 equiv.DABCO (5 equiv.)DMSO (1 mL)80 °C18 h<5
33 equiv.CsF (5 equiv.)DMSO (1 mL)80 °C18 h31
43 equiv.NaOAc (5 equiv.)DMSO (1 mL)80 °C18 h<5
53 equiv.K3PO4 (5 equiv.)DMSO (1 mL)80 °C18 h27
63 equiv.Na2CO3 (5 equiv.)DMSO (1 mL)80 °C18 h10
73 equiv.K2CO3 (5 equiv.)DMSO (1 mL)80 °C18 h52
83 equiv.Cs2CO3 (5 equiv.)DMSO (1 mL)80 °C18 h66
93 equiv.KOH (5 equiv.)DMSO (1 mL)80 °C18 h40
103 equiv.tBuOK (5 equiv.)DMSO (1 mL)80 °C18 h6
113 equiv.LDA (5 equiv.)DMSO (1 mL)80 °C18 h11
123 equiv.Cs2CO3 (5 equiv.)DMF (1 mL)80 °C18 h53
133 equiv.Cs2CO3 (5 equiv.)1,4-dioxane (1 mL)80 °C18 h11
143 equiv.Cs2CO3 (5 equiv.)NMP (1 mL)80 °C18 h56
153 equiv.Cs2CO3 (5 equiv.)MeCN (1 mL)80 °C18 h24
163 equiv.Cs2CO3 (5 equiv.)toluene (1 mL)80 °C18 h6
173 equiv.Cs2CO3 (5 equiv.)THF (1 mL)80 °C18 h5
183 equiv.Cs2CO3 (5 equiv.)H2O (1 mL)80 °C18 h<5
193 equiv.Cs2CO3 (5 equiv.)DMSO (1 mL)60 °C18 h66
203 equiv.Cs2CO3 (5 equiv.)DMSO (1 mL)100 °C18 h69
213 equiv.Cs2CO3 (5 equiv.)DMSO (2 mL)80 °C18 h81 (86) c
223 equiv.Cs2CO3 (3 equiv.)DMSO (2 mL)80 °C18 h78
233 equiv.Cs2CO3 (7 equiv.)DMSO (2 mL)80 °C18 h81
243 equiv.Cs2CO3 (5 equiv.)DMSO (2 mL)80 °C12 h80
253 equiv.Cs2CO3 (5 equiv.)DMSO (2 mL)80 °C24 h82
262 equiv.Cs2CO3 (5 equiv.)DMSO (2 mL)80 °C18 h69
274 equiv.Cs2CO3 (5 equiv.)DMSO (2 mL)80 °C18 h79
283 equiv.Cs2CO3 (5 equiv.)DMSO (4 mL)80 °C18 h86
a Unless otherwise specified, the reactions were conducted at 80 °C for 18 h by employing 1a (0.5 mmol, 1 equiv.), 2a (3 equiv.), and base (5 equiv.) in solvent (1 mL). b NMR yield determined by employing 4-methoxyanisole as internal standard. c Isolated yield.
Table 2. Substrate scope of aryl sulfonium salt a.
Table 2. Substrate scope of aryl sulfonium salt a.
Molecules 29 00831 i002
EntryProductYield (%) b
1Molecules 29 00831 i0033a86
2Molecules 29 00831 i0043b49
3Molecules 29 00831 i0053c95
4Molecules 29 00831 i0063d79
5Molecules 29 00831 i0073e81
6Molecules 29 00831 i0083f61
7Molecules 29 00831 i0093g56
8Molecules 29 00831 i0103h73
9Molecules 29 00831 i0113i51
10Molecules 29 00831 i0123j54
11Molecules 29 00831 i0133k70
a The reactions were conducted at 80 °C for 18 h by employing aryl sulfonium salt 1a–k (0.5 mmol), acetohydroxamic acid 2a (1.5 mmol), and Cs2CO3 (2.5 mmol) in DMSO (2 mL). b Isolated yield.
Table 3. Optimization of reaction conditions a.
Table 3. Optimization of reaction conditions a.
Molecules 29 00831 i014
EntryBaseSolventYield (%) b
1Cs2CO3DMSO58
2Cs2CO3NMP63
3Cs2CO3MeCN62
4Cs2CO31,4-dioxane54
5Cs2CO3toluene15
6Cs2CO3THF56
7Cs2CO3DMF67
8DBUDMF16
9DABCODMF<5
10DIPEADMF<5
11CsFDMF57
12NaOAcDMF<5
13K3PO4DMF56
14NaHCO3DMF<5
15KHCO3DMF22
16Na2CO3DMF<5
17K2CO3DMF47
18tBuOKDMF66
19LDADMF58
20Cs2CO3DMF74 c (70) d
a Unless otherwise specified, the reactions were conducted at 80 °C for 4 h by employing 1a (0.5 mmol, 1 equiv.), 2b (1.3 equiv.), and base (5 equiv.) in solvent (2 mL). b NMR yield determined by employing 4-methoxyanisole as internal standard. c Using 1.5 equiv. of 2b. d Isolated yield.
Table 4. Screening of various oximes a.
Table 4. Screening of various oximes a.
Molecules 29 00831 i015
EntryOximeYield (%) b
1Molecules 29 00831 i0162b74
2Molecules 29 00831 i0172c41
3Molecules 29 00831 i0182d82
4Molecules 29 00831 i0192e45
5Molecules 29 00831 i0202f38
6Molecules 29 00831 i0212g89 (87) c
a The reactions were conducted at 80 °C for 4 h by employing 1a (0.5 mmol, 1 equiv.), 2b–g (1.5 equiv.), and Cs2CO3 (5 equiv.) in DMF (2 mL). b NMR yield determined by employing 4-methoxyanisole as internal standard. c Isolated yield.
Table 5. Substrate scope of aryl sulfonium salt a.
Table 5. Substrate scope of aryl sulfonium salt a.
Molecules 29 00831 i022
EntryProductYield (%) b
1Molecules 29 00831 i0233a87
2Molecules 29 00831 i0243b59
3Molecules 29 00831 i0253c95
4Molecules 29 00831 i0263d55
5Molecules 29 00831 i0273e79
6Molecules 29 00831 i0283f52
7Molecules 29 00831 i0293g53
8Molecules 29 00831 i0303h68
9Molecules 29 00831 i0313i60
10Molecules 29 00831 i0323j47
11Molecules 29 00831 i0333k60
a The reactions were conducted at 80 °C for 4 h by employing aryl sulfonium salt 1a–k (0.5 mmol), 2g (0.75 mmol), and Cs2CO3 (2.5 mmol) in DMF (2 mL). b Isolated yield.
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MDPI and ACS Style

Hu, X.-B.; Fu, Q.-Q.; Huang, X.-Y.; Chu, X.-Q.; Shen, Z.-L.; Miao, C.; Chen, W. Hydroxylation of Aryl Sulfonium Salts for Phenol Synthesis under Mild Reaction Conditions. Molecules 2024, 29, 831. https://doi.org/10.3390/molecules29040831

AMA Style

Hu X-B, Fu Q-Q, Huang X-Y, Chu X-Q, Shen Z-L, Miao C, Chen W. Hydroxylation of Aryl Sulfonium Salts for Phenol Synthesis under Mild Reaction Conditions. Molecules. 2024; 29(4):831. https://doi.org/10.3390/molecules29040831

Chicago/Turabian Style

Hu, Xuan-Bo, Qian-Qian Fu, Xue-Ying Huang, Xue-Qiang Chu, Zhi-Liang Shen, Chengping Miao, and Weiyi Chen. 2024. "Hydroxylation of Aryl Sulfonium Salts for Phenol Synthesis under Mild Reaction Conditions" Molecules 29, no. 4: 831. https://doi.org/10.3390/molecules29040831

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