An Efficient Synthesis of Phenols via Oxidative Hydroxylation of Arylboronic Acids Using (NH4)2S2O8
A mild and efficient method for the ipso-hydroxylation of arylboronic acids to the corresponding phenols was developed using (NH4)2S2O8 as an oxidizing agent. The reactions were performed under metal-, ligand-, and base-free conditions.
Phenol and its derivatives are present in numerous natural products (e.g., aromatic steroids, cannabinoids, macrolides, quinines, terpenoids, lignans, and alkaloids) and serve as key synthetic intermediates for the construction of complex structures [1–5]. In medicinal chemistry, they are known to exhibit many pharmacological actions including antitumor, antiviral, antibacterial, cardioprotective, and antimutagenic activities [6–10]. The development of methods for accessing such structural motifs, therefore, remains an area of intensive research. In laboratory-scale synthesis, phenols are routinely prepared through the nucleophilic substitution of an activating aryl halide  in a copper-catalyzed transformation of a diazoarene  or through the Pd-catalyzed conversion of an aryl halide to a phenol using phosphine ligands . These methods, however, often suffer from several drawbacks, such as poor functional group compatibility, narrow substrate scope, harsh reaction conditions, and difficulties in obtaining the starting materials, which limit their utility and applicability. Phenols have been identified as by-products in many metal-catalyzed reactions of arylboronic acids ; however, only a few reports have described methodologies for the hydroxylation of arylboronic acids. Although the oxidation of arylboronic acid is not a popular or economical approach for preparing phenols, it provides access to phenols that may be difficult to obtain by other means .
In recent years, arylboronic acid derivatives have emerged as one of the most efficient and powerful synthetic precursors for facile regioselective functional group transformations . They are innocuous (generally nontoxic and stable to heat, air, and moisture) and available in a wide range of structures and often react under mild conditions with good functional group tolerance, making them an interesting and valuable potential precursor for phenols. The oxidation of arylboronic acids and their derivatives to phenols with alkaline hydrogen peroxide was first reported by Ainley and Challenger  and was later modified by Kuivila  and Simon et al. . Although this transformation is simple and green, when electron-deficient arylboronic acids and sensitive substituents are present, give low yields and alkaline hydrogen peroxide can lead to undesirable side reactions.
In this context, some reports have described the preparation of phenols from arylboronic acid using oxone [20, 21], Cu(OAc)2–H2O2 , NH2OH , H2O2-poly(N-vinylpyrrolidone) , CuSO4–phenanthroline , CuCl2–micellar systems , I2–H2O2 , photoredox catalysis , electrochemical reactions , N-oxides , Amberlite IR-120–H2O2 , Al2O3–H2O2 , MCPBA , and NaClO2 . Although these methods often provide good yields, in the majority of cases, these strategies have some disadvantages such as harsh reaction conditions, long time reactions, the use of transition metals with ligands or base, chlorinated organic solvents as reaction media, or expensive reagents. Thus the developments of protocols that are readily accessible, air and moisture stable, inexpensive, and environmentally acceptable and that can promote these reactions under mild reaction are still desirable.
The present study sought to develop an efficient conversion of substituted arylboronic acids to substituted phenols by an oxidative hydroxylation reaction using (NH4)2S2O8 under metal-, ligand-, and base-free conditions. Ammonium peroxodisulfate is an inexpensive easily available reagent, a “green” oxidizer that is widely used in industry for bleaching and waste water treatment. However, only scanty literature is available that describes its applications in organic synthesis. The compound has been used to accomplish certain oxidations of alkenes , benzyl alcohols , and substituted aromatics .
2. Materials and Methods
Arylboronic acids were obtained from Aldrich Chemical Co. Reagents and solvents were of the highest quality available and used as received. Flash chromatography purification was performed on silica gel 60 (230–400 mesh). All products are known compounds and were characterized by comparing the physical and NMR data to published information. NMR spectra were recorded at 200 and 400 MHz, chemical shift in ppm relative to TMS as an internal standard. Microwave heated reactions were performed in a CEM Discover reactor.
2.1. General Procedure for the Hydroxylation of Arylboronic Acid
To a solution of 50 mg arylboronic acid (0.41 mmol, 1.0 equiv.) in 3 cm3 MeOH : H2O (6 : 1) was added 2.5 equiv. NH4S2O8, and the mixture was stirred at 80°C for the time indicated in Scheme 1. The reaction progress was monitored by TLC, and the reaction was determined to have reached completion when the starting material had been completely consumed. The solvent was evaporated under reduced pressure and extracted with AcOEt. The organic phase was separated and dried over anhydrous Na2SO4. The solvent was removed under vacuum, and the compound was purified by column chromatography using hexane : AcOEt (9 : 1) as an eluent. All compounds were characterized by 1H NMR, 13C NMR, and MS and by comparison with the properties of known samples.
2.2. General Procedure for the Hydroxylation of Arylboronic Acid under Microwave Irradiation
To a solution of 50 mg arylboronic acid (0.41 mmol, 1.0 equiv.) in 3 cm3 MeOH : H2O (6 : 1) was added 2.5 equiv. NH4S2O8, and the mixture was stirred at 105°C and 300 W for 15 min. The solvent was evaporated under reduced pressure and extracted with AcOEt. The organic phase was separated and dried over anhydrous Na2SO4. The solvent was removed under vacuum, and the compound was purified by column chromatography using hexane : AcOEt (9 : 1) as an eluent. All compounds were characterized by 1H NMR, 13C NMR, and MS and by comparison to the properties of known samples.
3. Results and Discussion
Our study began by optimizing the reaction conditions. The effectiveness of (NH4)2S2O8 toward oxidative hydroxylation was explored using phenylboronic acid 1a as a model substrate, Figure 1. Mixtures of 1a and (NH4)2S2O8 (1.0 equiv.) were prepared in several solvents by stirring at 0°C for 24 h. The phenol 2a was not obtained at all. In the same reaction at room temperature, only low yields of 2a were observed. Increasing the reaction temperature to 50°C or 80°C provided a range of yields, although the reaction did not reach completion. As shown in Table 1, the reaction proceeded in both protic and aprotic solvents, and the yield tended to vary with the solvent.
Several test reactions were carried out using different amounts of (NH4)2S2O8 to establish the optimal amount of catalyst required for this transformation. MeOH : H2O in a 6 : 1 ratio was employed as the solvent. It was found that 2.5 equiv. (Table 2, entry 4) was necessary to achieve the smooth oxidation of 1.0 equiv. of the substrate 1a. Essentially no product 2a was obtained from the reaction in the absence of (NH4)2S2O8 (Table 2, entry 1).
The scope and limitations of the current procedure were evaluated by treating a wide array of electronically diverse arylboronic acids with 2.5 equiv. (NH4)2S2O8 in MeOH : H2O (6 : 1) at 80°C. By using different arylboronic acid 1b–1k, the method proved to be compatible with a wide range of substrates and 1b–1k were converted into the corresponding products 2b–2k in good to excellent yields. In contrast with the traditional nucleophilic substitution of aryl halides, the method preferred to offer the electron-rich phenols easily.
Over the past 25 years, microwave chemistry techniques have been recognized as a powerful method for performing challenging reactions in short amounts of time with a high yield and high purity. We therefore focused on reducing the reaction time using microwave irradiation. Here also, we chose MeOH : H2O as our reaction medium because of its polarity, which is suitable for microwave heating. Using the established conditions, we irradiated the diverse arylboronic acid substrates (1 equiv.) in the presence of ammonium peroxodisulfate (2.5 equiv.) in MeOH : H2O (6 : 1, 3 mL) at 105°C, 300 W for 15 min. The Discover LabMate model reactor from CEM Corporation connected to an IR thermometer for temperature monitoring and control was used. The MW parameters were set at 105°C and 300 W power with a 15 min reaction time, excluding the time taken to reach the temperature (“ramp time”). The “ramp time” was approximately 1 min without the use of the “cooling mode” option. Then the power was zeroed and the irradiation was automatically applied periodically to keep the temperature stable at 105°C for the time of the reaction. Stirring was applied during MW irradiation. The results are summarized in Scheme 2.
We developed a mild, efficient, and comparatively cheap method for synthesizing phenols via oxidative hydroxylation of arylboronic acids using (NH4)2S2O8. The reaction was applied to arylboronic acids with either electron-withdrawing or electron-donating substituents. The substrates underwent an ipso-hydroxylation reaction in good yields (88–98%). The reactions were performed under metal-, ligand-, and base-free conditions. This transformation is broadly compatible with a variety of functional groups.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors thank the CIC-UMSNH for support of this work.
Supporting Information Available: Spectroscopic data (1H and 13C spectra) of all compounds isolated.
E. Poupon and B. Nay, Biomimetic Organic Synthesis, Wiley-VCH, Weinheim, Germany, 2011.
Z. Rappoport, The Chemistry of Phenols, Wiley-VCH, Weinheim, Germany, 2003.
J. H. P. Tyman, Synthetic and Natural Phenols, Elsevier, New York, NY, USA, 1996.
M. Caricato, N. J. Leza, K. Roy et al., “A chiroptical probe for sensing metal ions in water,” European Journal of Organic Chemistry, vol. 2013, no. 27, pp. 6078–6083, 2013.View at: Publisher Site | Google Scholar
Y. Baudry, G. Bollot, V. Gorteau et al., “Molecular recognition by synthetic multifunctional pores in practice: are structural studies really helpful?” Advanced Functional Materials, vol. 16, no. 2, pp. 169–179, 2006.View at: Publisher Site | Google Scholar
R. W. Owen, A. Giacosa, W. E. Hull, R. Haubner, B. Spiegelhalder, and H. Bartsch, “The antioxidant/anticancer potential of phenolic compounds isolated from olive oil,” European Journal of Cancer, vol. 36, no. 10, pp. 1235–1247, 2000.View at: Publisher Site | Google Scholar
K. Likhitwitayawuid, B. Sritularak, K. Benchanak, V. Lipipun, J. Mathew, and R. F. Schinazi, “Phenolics with antiviral activity from Millettia erythrocalyx and Artocarpus lakoocha,” Natural Product Research, vol. 19, no. 2, pp. 177–182, 2005.View at: Publisher Site | Google Scholar
R. Puupponen-Pimiä, L. Nohynek, C. Meier et al., “Antimicrobial properties of phenolic compounds from berries,” Journal of Applied Microbiology, vol. 90, no. 4, pp. 494–507, 2001.View at: Publisher Site | Google Scholar
J. M. Wu, Z. R. Wang, T. C. Hsieh, J. L. Bruder, J. G. Zou, and Y. Z. Huang, “Mechanism of cardioprotection by resveratrol, a phenolic antioxidant present in red wine (review),” International Journal of Molecular Medicine, vol. 8, no. 1, pp. 3–17, 2001.View at: Google Scholar
E. González de Mejía, E. Castaño-Tostado, and G. Loarca-Piña, “Antimutagenic effects of natural phenolic compounds in beans,” Mutation Research, vol. 441, no. 1, pp. 1–9, 1999.View at: Google Scholar
A. Mehmood and N. E. Leadbeater, “Copper-catalyzed direct preparation of phenols from aryl halides,” Catalysis Communications, vol. 12, no. 1, pp. 64–66, 2010.View at: Publisher Site | Google Scholar
C. Hoarau and T. R. R. Pettus, “Strategies for the preparation of differentially protected ortho-prenylated phenols,” Synlett, no. 1, pp. 127–137, 2003.View at: Google Scholar
T. Schulz, C. Torborg, B. Schäffner et al., “Practical imidazole-based phosphine ligands for selective palladium-catalyzed hydroxylation of aryl halides,” Angewandte Chemie, vol. 48, no. 5, pp. 918–921, 2009.View at: Publisher Site | Google Scholar
H. Sakurai, H. Tsunoyama, and T. Tsukuda, “Oxidative homo-coupling of potassium aryltrifluoroborates catalyzed by gold nanocluster under aerobic conditions,” Journal of Organometallic Chemistry, vol. 692, no. 1–3, pp. 368–374, 2007.View at: Publisher Site | Google Scholar
R. Chen, H. Liu, X. Liu, and X. Chen, “An efficient synthesis of L-3,4,5-trioxygenated phenylalanine compounds from L-tyrosine,” Tetrahedron, vol. 69, no. 17, pp. 3565–3570, 2013.View at: Publisher Site | Google Scholar
D. G. Hall, Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials, vol. 1 and 2, Wiley-VCH, 2011.
A. D. Ainley and F. Challenger, “CCLXXX. Studies of the boron-carbon linkage. Part I: the oxidation and nitration of phenyl-boric acid,” Journal of the Chemical Society, pp. 2171–2180, 1930.View at: Publisher Site | Google Scholar
H. G. Kuivila, “Electrophilic displacement reactions. III: kinetics of the reaction between hydrogen peroxide and benzeneboronic acid,” Journal of the American Chemical Society, vol. 76, no. 3, pp. 870–874, 1954.View at: Google Scholar
J. Simon, S. Salzbrunn, G. K. Surya Prakash, N. A. Petasis, and G. A. Olah, “Regioselective conversion of arylboronic acids to phenols and subsequent coupling to symmetrical diaryl ethers,” Journal of Organic Chemistry, vol. 66, no. 2, pp. 633–634, 2001.View at: Publisher Site | Google Scholar
K. S. Webb and D. Levy, “A facile oxidation of boronic acids and boronic esters,” Tetrahedron Letters, vol. 36, no. 29, pp. 5117–5118, 1995.View at: Google Scholar
R. E. Maleczka Jr., F. Shi, D. Holmes, and M. R. Smith III, “Regioselective conversion of arylboronic acids to phenols and subsequent coupling to symmetrical diaryl ethers,” Journal of the American Chemical Society, vol. 125, no. 26, pp. 7792–7793, 2003.View at: Publisher Site | Google Scholar
E. Kianmehr, M. Yahyaee, and K. Tabatabai, “A mild conversion of arylboronic acids and their pinacolyl boronate esters into phenols using hydroxylamine,” Tetrahedron Letters, vol. 48, no. 15, pp. 2713–2715, 2007.View at: Publisher Site | Google Scholar
G. K. S. Prakash, S. Chacko, C. Panja et al., “Regioselective synthesis of phenols and halophenols from arylboronie acids using solid poly(N-vinylpyrrolidone)/hydrogen peroxide and poly(4-vinylpyridine) /hydrogen peroxide complexes,” Advanced Synthesis and Catalysis, vol. 351, no. 10, pp. 1567–1574, 2009.View at: Publisher Site | Google Scholar
J. Xu, X. Wang, C. Shao, D. Su, G. Cheng, and Y. Hu, “Highly efficient synthesis of phenols by copper-catalyzed oxidative hydroxylation of arylboronic acids at room temperature in water,” Organic Letters, vol. 12, no. 9, pp. 1964–1967, 2010.View at: Publisher Site | Google Scholar
K. Inamoto, K. Nozawa, M. Yonemoto, and Y. Kondo, “Micellar system in copper-catalysed hydroxylation of arylboronic acids: facile access to phenols,” Chemical Communications, vol. 47, no. 42, pp. 11775–11777, 2011.View at: Publisher Site | Google Scholar
A. Gogoi and U. Bora, “An iodine-promoted, mild and efficient method for the synthesis of phenols from arylboronic acids,” Synlett, vol. 23, no. 7, pp. 1079–1081, 2012.View at: Publisher Site | Google Scholar
Y. Q. Zou, J. R. Chen, X. P. Liu et al., “Highly efficient aerobic oxidative hydroxylation of arylboronic acids: photoredox catalysis using visible light,” Angewandte Chemie, vol. 51, no. 3, pp. 784–788, 2012.View at: Publisher Site | Google Scholar
H. Jiang, L. Lykke, S. U. Pedersen, W. J. Xiao, and K. A. Jørgensen, “A practical electromediated ipso-hydroxylation of aryl and alkyl boronic acids under an air atmosphere,” Chemical Communications, vol. 48, pp. 7203–7205, 2012.View at: Publisher Site | Google Scholar
C. Zhu, R. Wang, and J. R. Falck, “Mild and rapid hydroxylation of aryl/heteroaryl boronic acids and boronate esters with N-oxides,” Organic Letters, vol. 14, pp. 3494–3497, 2012.View at: Publisher Site | Google Scholar
N. Mulakayala, Ismail, K. M. Kumar et al., “Catalysis by Amberlite IR-120 resin: a rapid and green method for the synthesis of phenols from arylboronic acids under metal, ligand, and base-free conditions,” Tetrahedron Letters, vol. 53, no. 45, pp. 6004–6007, 2012.View at: Google Scholar
A. Gogoi and U. Bora, “A mild and efficient protocol for the ipso-hydroxylation of arylboronic acids,” Tetrahedron Letters, vol. 54, pp. 1821–1823, 2013.View at: Google Scholar
D. S. Chen and J. M. Huang, “A mild and highly efficient conversion of arylboronic acids into phenols by oxidation with MCPBA,” Synlett, vol. 24, no. 4, pp. 499–501, 2013.View at: Publisher Site | Google Scholar
P. Gogoi, P. Bezboruah, J. Gogoi, and R. C. Boruah, “ipso-Hydroxylation of arylboronic acids and boronate esters by using sodium chlorite as an oxidant in water,” European Journal of Organic Chemistry, vol. 2013, no. 32, pp. 7291–7294, 2013.View at: Publisher Site | Google Scholar
W. E. Fristad and J. R. Peterson, “Iron(II) catalyzed persulfate oxidation of alkenes to vicinal diacetates,” Tetrahedron Letters, vol. 24, no. 42, pp. 4547–4550, 1983.View at: Google Scholar
G. Gelbard, “Polymer-supported reagents,” in Handbook of Green Chemistry and Technology, J. H. Clark and D. Macquarrie, Eds., Blackwell Science, Oxford, UK, 2002.View at: Google Scholar
A. Clerici and O. Porta, “Oxidation of substituted aromatic compounds by peroxydisulphate. Homolytic benzylation and oxidative coupling reaction,” Journal of Chemistry, vol. 58, no. 19, pp. 2117–2119, 1980.View at: Google Scholar