T. W. Green, P. G. M. Wuts, Protective Groups in Organic
Wiley-Interscience, New York, 1999, 76-86, 708-711.
|H2O:||pH < 1, 100°C||pH = 1, RT||pH = 4, RT||pH = 9, RT||pH = 12, RT||pH > 12, 100°C|
|Reduction:||H2 / Ni||H2 / Rh||Zn / HCl||Na / NH3||LiAlH4||NaBH4|
|Oxidation:||KMnO4||OsO4||CrO3 / Py||RCOOOH||I2, Br2, Cl2||MnO2 / CH2Cl2|
Benzyl ethers can by generated using the Williamson Ether Synthesis, for example, where initial deprotonation of the alcohol and subsequent reaction with benzyl bromide delivers the protected alcohol. Use of NaH as base for the deprotonation is convenient, but when selective substitution is needed - for example, protection of one hydroxyl group in diols or selective protection of a more accessible group - mild bases such as Ag2O allow a more selective reaction. For substrates that are not stable to basic conditions, the use of benzyl trichloroacetimidate allows protection under acidic conditions. As an example of a new benzylating reagent, 2-Benzyloxy-1-methylpyridinium triflate allows protection even under neutral conditions (see recent literature).
various protection and deprotection pathways
Deprotection is normally performed as palladium-catalyzed hydrogenation, delivering the alcohol and toluene. In the presence of other reducible groups, a hydrogen transfer source such as 1,4-cyclohexadiene can be used to limit the availability of hydrogen.
Cleavage of benzyl ethers is also possible using strong acids, but this method is limited to acid-insensitive substrates. Alternatively, oxidation to the benzoate allows a subsequent hydrolysis under basic conditions. Some substituted benzyl ethers enable more specific, high yielding deprotection methods. For example: p-methoxybenzyl ethers can also be cleaved using single electron oxidants such as DDQ, because the attached methoxy group stabilizes intermediates better due to resonance. Recently, a more reliable method for the use of DDQ with simple benzyl ethers has been reported using photoirradiation.
simplified mechanism for DDQ-induced deprotection (for full mechanism see: P. Kociensky, Protecting Groups, 3rd Edition, Thieme Verlag, Stuttgart 2006, 10.)
Another substituted version, the 2-nitrobenzyl group, has shown utility as a photoremovable protecting group, particularly in biochemical systems where chemical removal is impractical or impossible. This group can be removed by irradiation at 308 nm, and proceeds via oxidation of the benzylic position. (P. Kociensky, Protecting Groups, 3rd Edition, Thieme Verlag, Stuttgart 2006, 252.)
Protection of Hydroxyl Compounds
Inexpensive stable crystalline 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT) can be used as an acid-catalyzed O-benzylating reagent. The reaction of various functionalized alcohols with 0.4 equiv of TriBOT in the presence of trifluoromethanesulfonic acid afforded benzyl ethers in good yields. TriBOT, which is the formal trimerization of the smallest unit of benzyl imidate, offers high atom economy.
K. Yamada, H. Fujita, M. Kunishima, Org. Lett., 2012, 14, 5026-5029.
A fast, quantitative benzylation of hindered sugar hydroxyls with NaH/THF is possible in the presence of a catalytic amount of the quaternary ammonium salt IN(Bu)4. A sample procedure with catalyst produces quantitative yield after 10 - 165 min at r.t. versus 24 h at reflux with excess benzyl bromide and no catalyst.
S. Czernecki, C. Georgoulis, C. Provelenghiou, Tetrahedron Lett., 1976, 17, 3535-3536.
Treatment of a symmetrical diol with Ag2O and an alkyl halide gave the monoprotected derivative in very good yield.
A. Bouzide, G. Sauvé, Tetrahedron Lett., 1997, 38, 5945-5948.
Diarylborinic acid catalysis is an efficient and general method for selective acylation, sulfonylation, and alkylation of 1,2- and 1,3-diols. The efficiency, generality, and operational simplicity of this method are competitive with those of the broadly applied organotin-catalyzed reactions. A mechanism is suggested, in which a tetracoordinate borinate complex reacts with the electrophilic species in the turnover-limiting step of the catalytic cycle.
D. Lee, C. L. Williamson, L. Chan, M. S. Taylor, J. Am. Chem. Soc., 2012, 134, 8260-8267.
2-Benzyloxy-1-methylpyridinium triflate is a stable, neutral organic salt that converts alcohols into benzyl ethers upon warming. Benzylation of a wide range of alcohols occurs in very good yield.
K. W. C. Poon, G. B. Dudley, J. Org. Chem., 2006, 71, 3923-3927.
Various silyl ethers were readily and efficiently transformed into the corresponding alkyl ethers in high yields by the use of aldehydes combined with triethylsilane in the presence of a catalytic amount of iron(III) chloride.
K. Iwanami, K. Yano, T. Oriyama, Synthesis, 2005, 2669-2672.
A bench-stable chiral 9-hydroxy-9,10-boroxarophenanthrene catalyst is applied in a highly enantioselective desymmetrization of 2-aryl-1,3-diols using benzylic electrophiles under operationally simple, ambient conditions. Nucleophilic activation and discrimination of the enantiotopic hydroxy groups on the diol substrate occurs via a defined chairlike six-membered anionic complex.
C. D. Estrada, H. T. Ang, K.-M. Vetter, A. A. Ponich, D. G. Hall, J. Am. Chem. Soc., 2021, 143, 4162-4167.
Two methods are described for the regioselective displacement of the primary hydroxy group in methyl glycosides with iodide. Products of the first method employing triphenylphosphine and iodine need purification on a reverse phase column. A one-pot procedure via sulfonates and subsequent substitution with iodide and methods for the protection of the iodoglycosides are also described.
P. R. Skaanderup, C. S. Poulsen, L. Hyldtoft, M. R. Jørgensen, R. Madsen, Synthesis, 2002, 1721-1727.
A catalytic amount of Pd(η3-C3H5)Cp and DPEphos as ligand efficiently converted aryl benzyl carbonates into benzyl-protected phenols through a decarboxylative etherification. Alternatively, the nucleophilic substitution of benzyl methyl carbonates with phenols proceeded in the presence of the catalyst, yielding aryl benzyl ethers.
R. Kuwano, H. Kusano, Org. Lett., 2008, 10, 1795-1798.
Other Syntheses of Benzyl Ethers
Facile reductive etherification of carbonyl compounds can be conveniently performed by reaction with triethylsilane and alkoxytrimethylsilane catalyzed by iron(III) chloride. The corresponding alkyl ethers, including benzyl and allyl ethers, of the reduced alcohols were obtained in good to excellent yields under mild reaction conditions.
K. Iwanami, H. Seo, Y. Tobita, T. Oriyama, Synthesis, 2005, 183-186.
A regioselective reductive ring opening of benzylidene acetals in carbohydrate derivatives using triethylsilane and molecular iodine is fast and compatible with most of the functional groups encountered in oligosaccharide synthesis, and offers excellent yields. The reaction conditions are equally effective in thioglycosides.
R. Panchadhayee, A. K. Misra, Synlett, 2010, 1193-1196.
In situ generation of molecular hydrogen by addition of triethylsilane to palladium on charcoal results in rapid and efficient reduction of multiple bonds, azides, imines, and nitro groups, as well as deprotection of benzyl and allyl groups under mild, neutral conditions.
P. K. Mandal, J. S. McMurray, J. Org. Chem., 2007, 72, 6599-6601.
Transfer hydrogenation utilizing palladium on carbon and formic acid provides a fast and simple removal of O-benzyl groups from carbohydrate derivatives. However, when formic acid is the hydrogen donor, a large amount of palladium has to be used.
T. Bieg, W. Szeja, Synthesis, 1985, 76-77.
An efficient and convenient method allows the removal of benzyl ether protecting groups in the presence of other functionality. Varying the solvent allows the removal of trityl groups in the presence of benzyl ethers.
M. S. Congreve, E. C. Davison, M. A. M. Fuhry, A. B. Holmes, A. N. Payne, R. A. Robinson, S. E. Ward, Synlett, 1993, 663-664.
A chemoselective debenzylation of aryl benzyl ethers proceeds at low temperature with a combination of BCl3 and pentamethylbenzene as a cation scavenger in the presence of various functional groups.
K. Okano, K.-i. Okuyama, T. Fukuyama, H. Tokuyama, Synlett, 2008, 1977-1980.
The reaction of different protected alcohols, amines and amides with lithium and a catalytic amount of naphthalene in THF at low temperature leads to their deprotection under very mild reaction conditions, the process being in many cases chemoselective.
E. Alonso, D. J. Ramón, M. Yus, Tetrahedron, 1997, 53, 14355-14368.
Benzyl ether protective groups are oxidatively removed by ozone under relatively mild conditions. Reaction products are benzoic ester, benzoic acid, and the corresponding alcohol. Subsequent deacylation with sodium methoxide affords a convenient debenzylation technique which has been applied to various O-benzyl protected carbohydrates.
P. Angibeaud, J. Defaye, A. Gadelle, J.-P. Utille, Synthesis, 1985, 1123-1125.
The deprotection of benzyl ethers was effectively realized in the presence of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) in MeCN under photoirradiation using a long wavelength UV light.
M. A. Rahim, S. Matsumura, K. Toshima, Tetrahedron Lett., 2005, 46, 7307-7309.
Arylhydroxymethylphosphinic acid derivatives were prepared by a palladium(0) catalysed arylation of ethyl benzyloxymethylphosphinate with aryl halides followed by subsequent hydrogenolysis of the benzyl protecting group and hydrolysis of the ester function.
H.-J. Cristau, A. Hervé, F. Loiseau, D. Virieux, Synthesis, 2003, 2216-2220.
The ionic liquid [bmim][Br] confers high nucleophilicity on the bromide ion for the nucleophilic displacement of an alkyl group to regenerate a phenol from the corresponding aryl alkyl ether in good yield in the presence of p-toluenesulfonic acid. Dealkylation of various aryl alkyl ethers could also be achieved using stoichiometric amounts of concentrated hydrobromic acid in [bmim][BF4].
S. K. Boovanahalli, D. W. Kim, D. Y. Chi, J. Org. Chem., 2004, 69, 3340-3344.
Conversion of Benzyl Ethers to other Functional Groups
A counterattack protocol for differential acetylative cleavage of phenylmethyl ether allows the reuse of the phenylmethyl moiety as benzyl bromide, thus providing advantages in terms of waste minimization and atom economy. The applicability of this methodology has been extended for solid phase organic reactions with the feasibility of reuse of the solid support.
A. K. Chakraborti, S. V. Chankeshwara, J. Org. Chem., 2009, 74, 1367-1370.
A mild and high-yielding visible-light-promoted reaction of alkyl benzyl ethers provided alkyl esters or alkyl alcohols via radical chain reaction involving the homolytic cleavage of O-α-sp3 C-H bonds in the substrate as one of the propagation steps. α-Bromoethers are key intermediates in the transformation.
P. Lu, T. Hou, X. Gu, P. Li, Org. Lett., 2015, 17, 1954-1957.
Benzylic ethers are oxidatively cleaved by 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate in wet MeCN at room temperature to give the corresponding aromatic aldehydes and alcohols in high yield. Primary and secondary alkyl alcohols are further oxidized to give carboxylic acids and ketones, respectively.
P. P. Pradhan, J. M. Bobbitt, W. F. Bailey, J. Org. Chem., 2009, 74, 9501-9504.
Formation of a bromo radical through the oxidation of bromide under mild conditions enables an oxidative debenzylation of N-benzyl amides and O-benzyl ethers to provide the corresponding amides and carbonyl compounds in high yields.
K. Moriyama, Y. Nakamura, H. Togo, Org. Lett., 2014, 16, 3812-3815.
Benzyl Ethers in Multi-Step Syntheses
Ammonia, pyridine and ammonium acetate were extremely effective as inhibitors of Pd/C catalyzed benzyl ether hydrogenolysis. While olefin, Cbz, benzyl ester and azide functionalities were hydrogenated smoothly, benzyl ethers were not cleaved.
H. Sajiki, Tetrahedron Lett., 1995, 36, 3465-3468.