Categories: C-O Bond Formation >
Synthesis of Phenols
A copper-catalyzed synthesis of phenols with a traceless hydroxide surrogate under mild reaction conditions enables even a late-stage functional group transformation of druglike substrates.
P. S. Fier, K. M. Maloney, Org. Lett., 2017, 19, 3033-3036.
A flow protocol for the generation of phthaloyl peroxide in high purity (>95%) can be used to bypass the need to isolate and recrystallize phthaloyl peroxide, improving upon earlier batch procedures. The flow protocol for the formation of phthaloyl peroxide can be combined with arene hydroxylation reactions.
A. M. Eliasen, R. P. Thedford, K. R. Claussen, C. Yuan, D. Siegel, Org. Lett., 2014, 16, 3628-3631.
The direct and selective palladium-catalyzed synthesis of phenols from aryl halides and KOH has been achieved through the use of highly active monophosphine-based catalysts and the biphasic solvent system 1,4-dioxane/H2O.
K. W. Anderson, T. Ikawa, R. E. Tundel, S. L. Buchwald, J. Am. Chem. Soc., 2006, 128, 10694-10695.
The combination of a Ni catalyst and PhSiH3 promotes a highly efficient hydroxylation of (hetero)aryl halides using water as a hydroxyl source to provide diverse multifunctional pharmaceutically phenols and polyphenols.
L. Yang, Y. Yan, N. Cao, J. Hao, G. Li, W. Zhang, R. Cao, C. Wang, J. Xiao, D. Xue, Org. Lett., 2022, 24, 9431-9435.
An efficient microwave-assisted, palladium-catalyzed hydroxylation converts aryl and heteroaryl chlorides to phenols in the presence of a weak base carbonate. The reaction tolerates ketone, aldehyde, ester, nitrile, or amide functionalities.
C.-W. Yu, G. S. Chen, C.-W. Huang, J.-W. Chern, Org. Lett., 2012, 14, 3688-3691.
Boric acid, B(OH)3, is an efficient hydroxide reagent in a Pd-catalyzed conversion of (hetero)aryl halides to the corresponding phenols in very good yields under mild conditions. This transformation tolerates a broad range of functional groups.
Z.-Q. Song, D.-H. Wang, Org. Lett., 2020, 22, 8470-8474.
Catalytic amounts of Cu(acac)2 and N,N'-bis(4-hydroxyl-2,6-dimethylphenyl)oxalamide as ligand enable a powerful hydroxylation of (hetero)aryl halides to provide phenols and hydroxylated heteroarenes in very good yields. A wide range of (hetero)aryl chlorides bearing either electron-donating or -withdrawing groups can be converted at 130°C, whereas hydroxylations of bromides and iodides completed at lower temperatures.
S. Xia, L. Gan, K. Wang, Z. Li, D. Ma, J. Am. Chem. Soc., 2016, 138, 13493-13496.
CuI-nanoparticles catalyze a selective synthesis of phenols, anilines, and thiophenols from aryl halides in the absence of both ligands and organic solvents. Anilines were formed selectively with ammonia competing with hydroxylation and thiophenols were generated selectively with sulfur powder after subsequent reduction competing with hydroxylation and amination.
H.-J. Xu, Y.-F. Liang, Z.-Y. Cai, H.-X. Qi, C.-Y. Yang, Y.-S. Feng, J. Org. Chem., 2011, 76, 2296-2300.
A CuI/8-hydroxyquinoline-catalyzed direct hydroxylation of aryl iodides with KOH takes place at 100˚C in a mixed solvent system providing a broad range of phenols. Aryl bromides are less reactive under these reaction conditions.
S. Maurer, W. Liu, X. Zhang, Y. Jiang, D. Ma, Synlett, 2010, 976-978.
A facile, simple, and mild ligand-free copper-catalyzed reaction provides substituted phenols in good yields from aryl iodides via an O-arylsulfonate intermediate that is hydrolyzed. This protocol offers a wide substrate scope and functional group tolerance.
B. Y.-H. Tan, Y.-C. Teo, Synlett, 2016, 27, 1814-1819.
Hydrogen peroxide as an eco-friendly oxidant provides hydroxylation products of arylboronic acids in an efficient manner under metal- and base-free aerobic in the presence of a room-temperature ionic liquid (RTIL).
E.-J. Shin, G.-T. Kown, S.-H. Kim, Synlett, 2019, 30, 1815-1819.
A mild and efficient protocol for the synthesis of phenols from arylboronic acids in the presence of tert-butyl hydroperoxide is promoted by KOH. Products were obtained in good to excellent yields within several minutes.
S. Guo, L. Lu, H. Cai, Synlett, 2013, 24, 1712-1714.
The use of aqueous hydrogen peroxide as oxidizing agent and molecular iodine as catalyst enables a mild and efficient methodology for the ipso-hydroxylation of arylboronic acids to phenols. The reactions were performed at room temperature in short reaction time under metal-, ligand- and base-free conditions.
A. Gogoi, U. Bora, Synlett, 2012, 23, 1079-1081.
A water-soluble photocatalyst promotes an aerobic oxidative hydroxylation of arylboronic acids to furnish phenols in excellent yields. This transformation uses visible-light irradiation under environmentally friendly conditions.
H.-Y. Xie, L.-S. Han, S. Huang, X. Lei, Y. Cheng, W. Zhao, H. Sun, X. Wen, Q.-L. Xu, J. Org. Chem., 2017, 82, 5236-5241.
A general and efficient aerobic oxidative hydroxylation of arylboronic acids promoted by benzoquinone provides phenols in very good yields. The main advantages of this protocol are the use of water as solvent in the presence of a catalytic amount of benzoquinone under metal-free conditions.
G. Chen, X. Zeng, X. Cui, Synthesis, 2014, 46, 263-268.
In a useful synthesis of phenols from arylboronic acids, hydrogen peroxide is generated in situ by aerobic photooxidation using visible-light irradiation and easily handled 2-chloroanthraquinone as an organocatalyst. The mild, metal- and base-free conditions enable an environmentally benign approach to the synthesis of phenols from arylboronic acids.
K. Matsui, T. Ishigami, T. Yamaguchi, E. Yamaguchi, N. Tada, T. Miura, A. Itoh, Synlett, 2014, 25, 2613-2616.
An efficient, fast and selective electrosynthesis of phenols and anilines from arylboronic acids in aqueous ammonia is achieved in an undivided cell. By simply changing the concentration of aqueous ammonia and the anode potential, good yields of phenols and anilines can be obtained chemoselectively.
H.-L. Qi, D.-S. Chen, J.-S. Ye, J.-M. Huang, J. Org. Chem., 2013, 78, 7482-7487.
The use of MCPBA achieves a mild and highly efficient synthesis of phenols from arylboronic acids in a aqueous solution at room temperature. Isotopical labeling studies show that the hydroxyl oxygen atom of the phenol might originate from the MCPBA.
D.-S. Chen, J.-M. Huang, Synlett, 2013, 24, 499-501.
The use of Oxone allows the conversion of various aryl-, heteroaryl-, alkenyl-, and alkyltrifluoroborates into the corresponding oxidized products in excellent yields. This method tolerates a broad range of functional groups, and in secondary alkyl substrates it was demonstrated to be completely stereospecific.
G. A. Molander, L. N. Cavalcanti, J. Org. Chem., 2011, 76, 623-630.
A Bi-catalyzed cross-coupling of arylboronic acids with perfluoroalkyl sulfonate salts enables the unusual construction of C(sp2)-O bonds using commercially available NaOTf and KONf as coupling partners. The reaction is based on a Bi(III)/Bi(V) redox cycle. An electron-deficient sulfone ligand proved to be key for the successful implementation of this protocol.
O. Planas, V. Peciukenas, J. Cornella, J. Am. Chem. Soc., 2020, 142, 11382-11387.
Aryl and heteroaryl boronic acids and boronate esters are within minutes transformed into the corresponding phenols in the presence of N-oxides in an open flask at ambient temperature. This transformation tolerates a wide variety of functional groups.
C. Zhu, R. Wang, J. R. Falck, Org. Lett., 2012, 14, 3494-3497.
A general and efficient copper-catalyzed oxidative hydroxylation of arylboronic acids at room temperature in water gives phenols in excellent yields.
J. Xu, X. Wang, C. Shao, D. Su, G. Cheng, Y. Hu, Org. Lett., 2010, 12, 1964-1967.
In a practical method for the synthesis of phenols from electron-deficient haloarenes and heteroarenes, the products are formed from acetohydroxamic acid as the hydroxide source via a novel SNAr reaction/Lossen rearrangement sequence. Notably, these reactions occur under mildly basic conditions, employ inexpensive and air-stable reagents, require no special handling, and form products in high yields in the presence of various functionality.
P. S. Fier, K. M. Maloney, Org. Lett., 2016, 18, 2244-2247.
For a selective hydroxylation of aryl iodides and aryl bromides with tetrabutylammonium hydroxide pentahydrate, a combination of copper(I) iodide and 8-hydroxyquinaldine in a mixture of dimethyl sulfoxide and water is used. The resulting phenols can be readily reacted with alkyl and allyl halides in situ to provide the corresponding alkyl or allyl aryl ethers in high yields.
R. Paul, M. A. Ali, T. Punniyamurthy, Synthesis, 2010, 4268-4272.
A Cu(OTf)2-mediated Chan-Lam reaction of carboxylic acids with arylboronic acids is a facile and practical methodology to access phenolic esters in good yields. The procedure tolerates various functional groups, such as methoxycarbonyl, acetoxy, free phenolic hydroxyl, vinyl, nitro, trifluoromethyl, methoxyl, bromo, chloro, iodo, and acetyl groups.
L. Zhang, G. Zhang, M. Zhang, J. Cheng, J. Org. Chem., 2010, 75, 7472-7474.
Desilylative acetoxylation of (trimethylsilyl)arenes can be performed in the presence of 5 mol % of Pd(OAc)2 and PhI(OCOCF3)2 (1.5 equiv) in AcOH at 80°C for 17 h providing acetoxyarenes in very good yields. The synthetic utility is demonstrated with a one-pot transformation of (trimethylsilyl)arenes to phenols by successive acetoxylation and hydrolysis.
K. Gondo, J. Oyamada, T. Kitamura, Org. Lett., 2015, 17, 4778-4781.
Various siletanes have been used as substrates for the oxidation of carbon-silicon bonds upon exposure to aqueous fluoride and peroxide. These tetraalkylsilanes offer a combination of stability and reactivity with many practical benefits, including compatibility with silicon protecting groups and electron-rich aromatic rings.
J. D. Sunderhaus, H. Lam, G. B. Dudley, Org. Lett., 2003, 8, 4571-4573.
Rapid, efficient methods enable the preparation of phenols from the oxidation of arylhydrosilanes. Electron-rich aromatics benefit from silane activation via oxidation to the methoxysilane using homogeneous or heterogeneous transition metal catalysis. A combination of these two oxidations into a streamlined flow procedure involves minimal processing of reaction intermediates.
E. J. Rayment, N. Summerhill, E. A. Anderson, J. Org. Chem., 2012, 77, 7052-7060.
An efficient and practical approach to prepare phenols from benzoic acids using simple organic reagents at room temperature is compatible with various functional groups and heterocycles and can be easily scaled up. Mechanistic investigations suggest that the key migration step involves a free carbocation instead of a radical intermediate.
W. Xiong, Q. Shi, W. H. Liu, J. Am. Chem. Soc., 2022, 144, 15894-15902.
In a I2-catalyzed direct conversion of cyclohexanones to substituted catechols under mild and simple conditions via multiple oxygenation and dehydrogenative aromatization processes, DMSO acts as the solvent, oxidant, and oxygen source. This metal-free and simple system provides highly valuable substituted catechols for drug discovery.
Y.-F. Liang, X. Li, X. Wang, M. Zou, C. Tang, Y. Liang, S. Song, N. Jiao, J. Am. Chem. Soc., 2016, 138, 12271-12277.
A bifunctional bidentate carboxyl-pyridone ligand enables a room-temperature Pd-catalyzed C-H hydroxylation of a broad range of benzoic and phenylacetic acids with aqueous hydrogen peroxide. The scalability of this methodology is demonstrated by a 1 mol scale reaction of ibuprofen using only a 1 mol % Pd catalyst loading.
Z. Li, H. S. Park, J. X. Qiao, K.-S. Yeung, J.-Q. Yu, J. Am. Chem. Soc., 2022, 144, 18109-18116.
Pd(II)-catalyzed ortho-hydroxylation of variously substituted benzoic acids under an athmospheric pressure of oxygen or air is achieved under nonacidic conditions. Labeling studies support a direct oxygenation of aryl C-H bonds with molecular oxygen.
Y.-H. Zhang, J.-Q. Yu, J. Am. Chem. Soc., 2009, 131, 14654-14655.
A Ru(II) catalyzed ortho-hydroxylation of ethyl benzoates with ester as a directing groups enables a facile synthesis of various multifunctionalized arenes from easily accessible substrates. Crucial factors in this transformation are both the TFA/TFAA cosolvent system and the oxidants. The reaction demonstrates excellent reactivity, good functional group tolerance, and high yields.
Y. Yang, Y. Lin, Y. Rao, Org. Lett., 2012, 14, 2874-2877.
Nitroarenes react with anions of tert-butyl and cumyl hydroperoxides in the presence of strong bases to form substituted o- and p-nitrophenols. The reaction usually proceeds in high yields and is of practical value as a method of synthesis and manufacturing of nitrophenols.
M. Makosza, K. Sienkiewicz, J. Org. Chem., 1998, 63, 4199-4208.
Various anilides have been directly ortho-acetoxylated with acetic acid as the acetate source and K2S2O8 as the oxidant in the presence of Pd(OAc)2 as catalyst. The amide group is an elegant directing group to convert aromatic sp2 C-H bonds into C-O bonds.
G.-W. Wang, T.-T. Yuan, X.-L. Wu, J. Org. Chem., 2008, 73, 4717-4720.
A palladium-catalyzed synthesis of aryl tert-butyl ethers from a variety of unactivated aryl bromides or chlorides is described. The ether products, which are precursors to phenols, are obtained in very good yield in the presence of air-stable dialkylphosphinobiphenyl ligands.
C. A. Parrish, S. L. Buchwald, J. Org. Chem., 2001, 66, 2498-2500.
Drawbacks associated with the classic Balz-Schiemann reaction are eliminated in a series of examples by conducting fluorodediazoniation in ionic liquid solvents.
K. K. Laali, V. J. Gettwert, J. Fluorine Chem., 2001, 107, 31-34.
Copper catalysis allows the direct oxygen-arylation of dialkyl phosphonates with diaryliodonium salts. This reaction proceeds with a wide range of phosphonates and phosphoramidates under mild conditions and gives mixed alkyl aryl phosphonates in very good yields and very good selectivity.
M. Fañanás-Mastral, B. L. Feringa, J. Am. Chem. Soc., 2014, 136, 9894-9897.
A convenient radical oxidative cyclization mediated by N-iodosuccinimide (NIS) enables the synthesis of a series of dibenzopyranones from a wide scope of 2-arylbenzoic acids. The methodology offers good functional group tolerance and mild reaction conditions without the use of transition metals.
P. Gao, Y. Wei, Synthesis, 2014, 46, 343-347.