Benzyl ethers
Bn-OR
T. W. Green, P. G. M. Wuts, Protective Groups in Organic
Synthesis,
Wiley-Interscience, New York, 1999, 76-86, 708-711.
Stability
| H2O: | pH < 1, 100°C | pH = 1, RT | pH = 4, RT | pH = 9, RT | pH = 12, RT | pH > 12, 100°C |
| Bases: | LDA | NEt3, Py | t-BuOK | Others: | DCC | SOCl2 |
| Nucleophiles: | RLi | RMgX | RCuLi | Enolates | NH3, RNH2 | NaOCH3 |
| Electrophiles: | RCOCl | RCHO | CH3I | Others: | :CCl2 | Bu3SnH |
| Reduction: | H2 / Ni | H2 / Rh | Zn / HCl | Na / NH3 | LiAlH4 | NaBH4 |
| Oxidation: | KMnO4 | OsO4 | CrO3 / Py | RCOOOH | I2, Br2, Cl2 | MnO2 / CH2Cl2 |
General
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
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.
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.
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 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.
Deprotection
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, 6556-6561.
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.
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.
