A Facile and General Oxidative Hydroxylation of Organoboron Compounds: Citric Acid as an Efficient Catalyst in Water to Access Phenolic and Alcoholic Motifs

An efficient and convenient method for the synthesis of phenols and aliphatic alcohols is described in this paper. The oxidative hydroxylation reaction of various organoboron compounds proceeded smoothly by employing H2O2 as the oxidant and citric acid as the catalyst in water at room temperature to produce phenols and aliphatic alcohols in satisfactory to excellent yields (up to 99% yield). Various synthetically useful functional groups, such as halogen atom, cyano, and nitro groups, remain intact during the oxidative hydroxylation. The developed catalytic system also could accommodate phenylboronic pinacol ester and potassium phenyltrifluoroborate to give the target product good yields.


Introduction
Phenols and aliphatic alcohols are widely recognized as privileged building blocks for the construction of sophisticated organic complexes such as polymers, pharmaceuticals, and natural products [1][2][3].Accordingly, the development of efficient and convenient methods for preparation has attracted considerable attention.Because of the unique properties of boronic acids, such as ready availability and stability in air and aqueous environments, the oxidative hydroxylation of boronic acids has become a straightforward and efficient avenue to access phenols and aliphatic alcohols.This process relies on the use of molecular oxygen (O 2 and air) [4][5][6][7][8][9][10] and stoichiometric oxidants such as hydrogen peroxide (H 2 O 2 ) [11][12][13][14][15][16][17][18], t-butylhydroperoxide (TBHP) [19], m-chloroperbenzoic acid (mCPBA) [20], hydroxylamine [21], N-oxides [22], hypervalent iodine [23], and sodium chlorite (NaClO 2 ) [24].In view of both the economy and the environment, molecular oxygen and H 2 O 2 are the ideal oxidants due to their low cost and lack of toxic byproducts.However, virtually all of the methods for the use of molecular oxygen were achieved using metal catalysts and relatively long reaction times.In general, metal catalysts are expensive, air or moisture sensitive, and can be a challenging task to remove; thus, from the practical viewpoint, metal-free processes are much more preferred in the pharmaceutical industry [14,22].Therefore, more benign, cost-effective, environmentally friendly metal-free procedures have emerged as beneficial alternatives.

Results
As a model reaction, we first investigated citric acid-catalyzed oxidative hydroxylation of phenylboronic acid (1a, 1 equiv.)under various conditions (Table 1).Given the fact that citric acid has good water solubility and boronic acids have high stability in aqueous environments, we reasoned that the oxidative hydroxylation of boronic acids to access phenolic and alcoholic motifs could be conducted in H 2 O instead of the organic solvents.Therefore, the reaction temperature was first screened using H 2 O 2 as the oxidant and H 2 O as the solvent.The results obtained indicated that room temperature with no extra energy consumption was the best reaction temperature (entry 3 vs.entries 1 and 2).The oxidant was subsequently investigated under room temperature conditions.Among the examined oxidants (H 2 O 2 , air, TPHP, di-t-butyl peroxide (DTBP), O 2 , sodium chlorite (NaClO 2 )), H 2 O 2 proved to be the best oxidant, providing the target product, phenol (3a), in 98% yield (entry 3 vs.entries 4-8).Decreased yields were observed when the loadings of oxidant H 2 O 2 and catalyst citric acid were reduced to 1.0 equivalent and 0.05 mol%, respectively (entries 9 and 11 vs. entry 3); on the other hand, quantitative yield was almost obtained even though the loadings of oxidant H 2 O 2 and catalyst citric acid increased to 3.0 equivalents and 0.20 mol%, respectively (entries 10 and 12 vs.entry 3).The results suggested that the target reaction was commendably accomplished using 2.0 equivalents of oxidant H 2 O 2 and 0.10 mol% of catalyst citric acid.Decreased yield was also obtained when the reaction time was shortened to 1 h from 2 h (entry 13 vs. entry 3).Moreover, the oxidative hydroxylation reaction of 1a was performed without citric acid and only provided 2a in 66% yield, suggesting that the presence of citric acid in the reaction system influenced the conversion efficiency significantly (entry 14 vs. entry 3).The influence of acid catalysts on oxidative hydroxylation was also investigated.Acetic acid and benzoic acid were not able to significantly improve the yield (entries 15 and 16 vs.entry 14), while tartaric acid and formic acid had some positive effect on this reaction, although it was not as good as citric acid (entries 17 and 18 vs.entry 3).Therefore, the subsequent oxidative hydroxylation reaction of various boronic acids with H 2 O 2 (2.0 equiv.) was performed in the presence of citric acid (0.1 mol%) in H 2 O (3 mL) at room temperature.Given the optimized reaction conditions, the scope and limitation of this reaction were explored, and the results are summarized in Scheme 1.The methyl (Me), cyclohexyl, and phenyl (Ph) linked on different positions of the benzene ring in substrate 1 did not influence the yield; the corresponding phenol products 2b-2e and 2t were obtained in 97-99% yields.Other electron-donating groups, such as methylthio (MeS), alkoxyl (MeO and n-C7H15O), phenoxyl (PhO), and diphenylamino (Ph2N), were also tolerated well in this oxidative hydroxylation reaction, providing the desired products 2f-2j in 61-94% yields, respectively.Reactions of boronic acid substrates 1 bearing electron-withdrawing group on the benzene ring, such as acetyl (Ac), cyano (CN), and nitro (NO2), were subsequently investigated under the optimized reaction conditions.The phenol products 2m-2o were obtained in good to excellent yields (80-94%).These results mentioned above indicated that the electron properties (electron donating or electron withdrawing) of substituents linked to the benzene ring did not influence the reactivities of 1. Notably, phenylboronic acid bearing a chloro substituent was successfully transformed to 3-chlorophenol (2l) in 98% yield.The functional groups, such as Cl, CN, and NO2, remained intact during the oxidative hydroxylation reaction, suggesting that further manipulation may produce additional useful compounds.The suitability of naphthalene-derived boronic acids 1p-1r in the current oxidative hydroxylation reaction was investigated, and excellent yields (91-98%) of the desired products 2p-2r were obtained, respectively.The desired products 2k and 2s were also obtained in 91% and 78% yields, respectively, from the reactions of benzo[d] [1,3]dioxol-5-ylboronic acid (1k) and (4-(9H-carbazol-9-yl)phenyl)boronic acid (1s).In general, this oxidative hydroxylation exhibits broad scope and proceeds efficiently with electron-poor and -rich arylboronic acids, even with significant steric hindrance.Given the optimized reaction conditions, the scope and limitation of this reaction were explored, and the results are summarized in Scheme 1.The methyl (Me), cyclohexyl, and phenyl (Ph) linked on different positions of the benzene ring in substrate 1 did not influence the yield; the corresponding phenol products 2b-2e and 2t were obtained in 97-99% yields.Other electron-donating groups, such as methylthio (MeS), alkoxyl (MeO and n-C 7 H 15 O), phenoxyl (PhO), and diphenylamino (Ph 2 N), were also tolerated well in this oxidative hydroxylation reaction, providing the desired products 2f-2j in 61-94% yields, respectively.Reactions of boronic acid substrates 1 bearing electron-withdrawing group on the benzene ring, such as acetyl (Ac), cyano (CN), and nitro (NO 2 ), were subsequently investigated under the optimized reaction conditions.The phenol products 2m-2o were obtained in good to excellent yields (80-94%).These results mentioned above indicated that the electron properties (electron donating or electron withdrawing) of substituents linked to the benzene ring did not influence the reactivities of 1. Notably, phenylboronic acid bearing a chloro substituent was successfully transformed to 3-chlorophenol (2l) in 98% yield.The functional groups, such as Cl, CN, and NO 2 , remained intact during the oxidative hydroxylation reaction, suggesting that further manipulation may produce additional useful compounds.The suitability of naphthalene-derived boronic acids 1p-1r in the current oxidative hydroxylation reaction was investigated, and excellent yields (91-98%) of the desired products 2p-2r were obtained, respectively.The desired products 2k and 2s were also obtained in 91% and 78% yields, respectively, from the reactions of benzo[d] [1,3]dioxol-5-ylboronic acid (1k) and (4-(9H-carbazol-9-yl)phenyl)boronic acid (1s).In general, this oxidative hydroxylation exhibits broad scope and proceeds efficiently with electron-poor and -rich arylboronic acids, even with significant steric hindrance.Encouraged by these results, we next explored the scope of this reaction with respect to alkylboronic acids.As shown in Scheme 2, various alkylboronic acids 3a-3e were smoothly converted into the desired products 4a-4e in good to excellent yields (84-90%).Notably, aliphatic alcohols are generally susceptible to oxidation conditions and could be readily transformed into the corresponding aldehydes or ketones.Advantageously, alcohols are able to survive under our organocatalytic oxidation conditions.Encouraged by these results, we next explored the scope of this reaction with respect to alkylboronic acids.As shown in Scheme 2, various alkylboronic acids 3a-3e were smoothly converted into the desired products 4a-4e in good to excellent yields (84-90%).Notably, aliphatic alcohols are generally susceptible to oxidation conditions and could be readily transformed into the corresponding aldehydes or ketones.Advantageously, alcohols are able to survive under our organocatalytic oxidation conditions.
Continuous substrate extension studies showed that the potassium phenyltrifluoroborate (5) and phenylboronic pinacol ester (6) could be used as a phenyl source to synthesize phenol under the standard conditions (Scheme 3, (1) and ( 2)).Large-scale synthesis of phenol (2a) was performed under optimal reaction conditions to demonstrate the synthetic practicality and utilization of the new methodology further (Scheme 3, (3)).As expected, the desired products 2a were obtained in excellent yield when the reaction of 1a was conducted on a 20.0 mmol scale.The yield is comparable to that obtained in the small-scale experiment.Continuous substrate extension studies showed that the potassium phenyltrifluoroborate ( 5) and phenylboronic pinacol ester (6) could be used as a phenyl source to synthesize phenol under the standard conditions (Scheme 3, ( 1) and ( 2)).Large-scale synthesis of phenol (2a) was performed under optimal reaction conditions to demonstrate the synthetic practicality and utilization of the new methodology further (Scheme 3, (3)).As expected, the desired products 2a were obtained in excellent yield when the reaction of 1a was conducted on a 20.0 mmol scale.The yield is comparable to that obtained in the smallscale experiment.Based on the experimental results and previous reports [11][12][13][14]28,29], a plausible reaction mechanism for the current oxidative hydroxylation is depicted in Scheme 4. Initially, the citric acid-activated H2O2 species A was generated in situ through a hydrogen bond.The activated H2O2 species then underwent nucleophilic attack on boronic acid 1 to form a key intermediate, boron peroxo complex B, followed by phenyl migration in the  Continuous substrate extension studies showed that the potassium phenyltrifluoroborate ( 5) and phenylboronic pinacol ester (6) could be used as a phenyl source to synthesize phenol under the standard conditions (Scheme 3, ( 1) and ( 2)).Large-scale synthesis of phenol (2a) was performed under optimal reaction conditions to demonstrate the synthetic practicality and utilization of the new methodology further (Scheme 3, (3)).As expected, the desired products 2a were obtained in excellent yield when the reaction of 1a was conducted on a 20.0 mmol scale.The yield is comparable to that obtained in the smallscale experiment.Based on the experimental results and previous reports [11][12][13][14]28,29], a plausible reaction mechanism for the current oxidative hydroxylation is depicted in Scheme 4. Initially, the citric acid-activated H2O2 species A was generated in situ through a hydrogen bond.The activated H2O2 species then underwent nucleophilic attack on boronic acid 1 to form a key intermediate, boron peroxo complex B, followed by phenyl migration in the Scheme 3. Substrate extension studies and large-scale synthesis.
Based on the experimental results and previous reports [11][12][13][14]28,29], a plausible reaction mechanism for the current oxidative hydroxylation is depicted in Scheme 4. Initially, the citric acid-activated H 2 O 2 species A was generated in situ through a hydrogen bond.The activated H 2 O 2 species then underwent nucleophilic attack on boronic acid 1 to form a key intermediate, boron peroxo complex B, followed by phenyl migration in the form of C to a peroxygen atom to generate boron phenoxide D. Finally, the hydrolysis of D occurred to yield the target product 2.
form of C to a peroxygen atom to generate boron phenoxide D. Finally, the hydrolysis of D occurred to yield the target product 2. Scheme 4. The plausible reaction mechanism.

General Information
Unless otherwise noted, all reactions were carried out in oven-dried 25 mL Schlenk tubes under a nitrogen atmosphere.An IKA plate was used as the heat source.All reagents and solvents were of pure analytical grade.Thin-layer chromatography (TLC) was performed on HSGF254 silica gel, pre-coated on glass-backed plates coated with 0.2 mm silica and revealed with a UV lamp (λmax = 254 nm).The products were purified by flash column chromatography on silica gel 200-300 mesh. 1 H and 13 C NMR spectra were recorded on a Varian Inova-500 spectrometer (500 MHz for 1 H, 126 MHz for 13 C) and a Bruker Avance NEO 600M NMR Spectrometer (600 MHz for 1 H, 151 MHz for 13 C) using CDCl3 as the solvent with tetramethylsilane (TMS) as the internal standard at room temperature.The chemical shifts are reported in ppm downfield (δ) from TMS, and the coupling constants J are given in Hz.The peak patterns are indicated as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; q, quartet; p, quintet; h, sextet; m, multiplet (see Supplementary Materials).High-resolution mass spectra were recorded on either a Q-TOF mass spectrometer or an LTQ Orbitrap XL mass spectrometer.

General Information
Unless otherwise noted, all reactions were carried out in oven-dried 25 mL Schlenk tubes under a nitrogen atmosphere.An IKA plate was used as the heat source.All reagents and solvents were of pure analytical grade.Thin-layer chromatography (TLC) was performed on HSGF254 silica gel, pre-coated on glass-backed plates coated with 0.2 mm silica and revealed with a UV lamp (λ max = 254 nm).The products were purified by flash column chromatography on silica gel 200-300 mesh. 1 H and 13 C NMR spectra were recorded on a Varian Inova-500 spectrometer (500 MHz for 1 H, 126 MHz for 13 C) and a Bruker Avance NEO 600M NMR Spectrometer (600 MHz for 1 H, 151 MHz for 13 C) using CDCl 3 as the solvent with tetramethylsilane (TMS) as the internal standard at room temperature.The chemical shifts are reported in ppm downfield (δ) from TMS, and the coupling constants J are given in Hz.The peak patterns are indicated as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; q, quartet; p, quintet; h, sextet; m, multiplet (see Supplementary Materials).High-resolution mass spectra were recorded on either a Q-TOF mass spectrometer or an LTQ Orbitrap XL mass spectrometer.

The Typical Procedure for the Oxidative Hydroxylation of Alkylboronic Acids
A mixture of alkylboronic acids 3 (1.0 mmol) and citric acid (0.2 mg, 0.001 mmol, 0.1 mol%) in H 2 O (3 mL) was added into a Schlenk flask (25 mL).Then, 30% aqueous H 2 O 2 (227 µL, 2.0 equiv.) was added and stirred at room temperature under an air atmosphere for 2 h.After the reaction was finished, the reaction mixture was diluted with water and then extracted with ethyl acetate.The combined organic layer was dried on sodium sulfate and filtered.Then, the solvent evaporated under reduced pressure and the residue was purified by column chromatography (petroleum ether/ethyl acetate 5:1 to 4:1) to provide the product 4.

Substrate Extension Studies
Potassium phenyltrifluoroborate (5) (184.0 mg, 1.0 mmol, 1.0 equiv.)or a phenylboronic pinacol ester (6), 30% aqueous H 2 O 2 (227 µL, 2.0 equiv.),citric acid (0.2 mg, 0.001 mmol, 0.1 mol%), and water (3 mL) under an air atmosphere were added to an oven-dried 25 mL Schlenk tube equipped with a magnetic stir bar.The reaction mixture was stirred at room temperature for 2 h.After the reaction was finished, the reaction mixture was diluted with water and then extracted with ethyl acetate.The combined organic layer was dried on sodium sulfate and filtered.Then, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (petroleum ether/ethyl acetate 5:1) to afford the desired product 2a as a light pink solid.

Large-Scale Synthesis
Phenylboronic acid (1a) (2.44 g, 20.0 mmol, 1.0 equiv.),30% aqueous H 2 O 2 (4.5 mL, 2.0 equiv.),citric acid (3.8 mg, 0.02 mmol, 0.1 mol%), and water (60 mL) were added to an oven-dried 250 mL round-bottom flask equipped with a magnetic stir bar under an air atmosphere.The reaction mixture was stirred at room temperature for 2 h.After the reaction was finished, the reaction mixture was diluted with water and then extracted with ethyl acetate.The combined organic layer was dried on sodium sulfate and filtered.Then, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate 5:1) to afford the desired product 2a.

Conclusions
In summary, employing a citric acid-catalyzed transition metal-free strategy, we have successfully developed a facile, convenient, and alternative method to achieve the oxidative hydroxylation of organoboron compounds.Advantageously, alcohols can survive under our organocatalytic oxidation conditions.The oxidative hydroxylation reaction of various aromatic and aliphatic boric acids proceeded smoothly by employing H 2 O 2 as a green oxidant in an aqueous environment at room temperature to produce phenols and aliphatic alcohols in satisfactory to excellent yields (up to 99% yield).Notably, the catalyst citric acid is nontoxic, low-cost, biodegradable, and environmentally benign, and the loading was only 0.1 mol%.The readily available starting materials, the mild and green reaction conditions, and the experimental simplicity make the present methodology highly useful in the synthesis of phenols and aliphatic alcohols.Based on the significance of both environmental protection and resource conservation, we believe that this methodology using natural substances as catalysts and H 2 O as a solvent at room temperature could be of interest to organic chemists.

Scheme 3 .
Scheme 3. Substrate extension studies and large-scale synthesis.

Scheme 3 .
Scheme 3. Substrate extension studies and large-scale synthesis.

Table 1 .
Optimization of reaction conditions a .

Table 1 .
Optimization of reaction conditions a .