Ferric perchlorate as an efficient and useful catalyst for the selective benzylation and methylation of alcohols with benzyl chloride and methyl iodide

Article abstract of DOI:10.1007/s00706-008-0054-x

A mild and efficient method was developed for selective benzylation and methylation of hydroxyl compounds in the presence of a catalytic amount of ferric perchlorate. We showed that ferric perchlorate was very effective in selectively promoting the benzylation and methylation of primary aliphatic and benzylic alcohols versus secondary aliphatic alcohols and phenolic hydroxy groups. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-008-0054-x

Monatsh Chem (2009) 140:181–184
DOI 10.1007/s00706-008-0054-x
ORIGINAL PAPER
Ferric perchlorate as an efficient and useful catalyst
for the selective benzylation and methylation of alcohols
with benzyl chloride and methyl iodide
Farahnaz K. Behbahani Æ Majid M. Heravi Æ
Hossien A. Oskooie
Received: 6 August 2008 / Accepted: 15 August 2008 / Published online: 7 October 2008
Ó Springer-Verlag 2008
Abstract A mild and efficient method was developed for
selective benzylation and methylation of hydroxyl com-
pounds in the presence of a catalytic amount of ferric
perchlorate. We showed that ferric perchlorate was very
effective in selectively promoting the benzylation and
methylation of primary aliphatic and benzylic alcohols
versus secondary aliphatic alcohols and phenolic hydroxy
groups.
stable methyl ether to the more elaborate, substituted trityl
ethers developed for use in nucleotide synthesis. Ethers are
formed and removed under a wide variety of conditions.
There have been many reports on the formation of the ether
linkage, but a few are presented from hydroxyl compounds
and halides [1]. Numerous methods are available for pro-
tecting an alcohol moiety. Conversion into corresponding
ethers has been recognized as a common and useful method
for the protection of hydroxyl groups. Most commonly
used protecting groups are the tetrahydropyranyl (THP), t-
butyldimethylsilyl (TBDMS), and benzyl (Bn) groups.
Benzyl ethers are widely utilized as alcohol protecting
groups. They are easily installed, but with poor selectivity
between primary and secondary alcohol groups [2, 3], e.g.,
in carbohydrates, are stable to a wide range of reagents, and
are readily removed in the presence of many common
functionalities via catalytic hydrogenolysis, dissolving
metals, or Lewis/Brønsted acids [4]. In other words,
selectivity of reaction pathways is extremely important in
organic reactions, such as etherification [5–7].
Keywords Benzylation Á Hydroxy compounds Á
Alcohols Á Ferric perchlorate Á Etherification Á Methylation
Introduction
Hydroxyl groups are present in a number of compounds of
biological and synthetic interest, including nucleosides,
carbohydrates, steroids, macrolides, polyethers, and the
side chain of some amino acids. In some oxidation reac-
tions, such as acylation, halogenation with phosphorus,
hydrogen halides, or dehydration of these compounds, a
hydroxyl group must be protected. In polyfunctional mol-
ecules, selective protection becomes an issue that has been
addressed by the development of a number of new meth-
ods. Ethers are among the most used protective groups in
organic synthesis and vary from the simplest, the most
Recently, we have reported etherification of allylic and
benzylic alcohols with aliphatic alcohols in the presence of
ferric perchlorate [8] and the ability of ferric perchlorate as
a catalyst for some kinds of transformations in organic
synthesis [9–12]. In continuation of our works to develop
new synthetic methodologies [13–23], we wish to report an
effective, inexpensive, and selective benzylation and
methylation of hydroxyl groups using ferric perchlorate
(Scheme 1).
M. M. Heravi (&) Á H. A. Oskooie
Department of Chemistry, School of Sciences,
Azzahra University, Vanak, Tehran, Iran
e-mail: mmh1331@yahoo.com
Results and discussion
F. K. Behbahani
Department of Chemistry, School of Sciences,
Islamic Azad University, Karaj branch, Karaj, Iran
e-mail: farahnazkargar@yahoo.com
Initially, a systematic study was carried out for catalytic
evaluation of ferric perchlorate for benzylation and
123

182
F. K. Behbahani et al.
Scheme 1
BnCl
MeI
1
R OBn
Fe(ClO )
4 3
1
R OH
1
R OMe
OH
OH
4a-4c, BnCl or MeI (1 eq.)
OBn
OBn
OMe
2
2
or
R
R
0.5-1 h
5a-5c
6a-6c
OH
4a, BnCl or MeI (2 eq.)
Fe(ClO )
OMe
4 3
OH
or
2
OMe
OBn
R
0.5-24 h
7
8
4a-c
4b, 4c, BnCl or MeI (2 eq.)
5b, 5c
or 6b, 6c
0.5-24 h
methylation of benzyl alcohol with benzyl chloride and
methyl iodide without catalyst. These reactions did not
proceed at all.
benzylic ethers on primary alcohol groups were selectively
formed from dihydroxy alcohols. It is noteworthy that,
when the benzylation and methylation reactions were car-
ried out with an excess of halide, the same ether products
were synthesized (Scheme 1, Table 2).
When a mixture of the benzyl alcohol and the benzyl
chloride is heated at 100 °C in the presence of catalytic
amount 5 mol% of ferric perchlorate, evolution of hydro-
gen halide occurred immediately, and a high yield (90%) of
the corresponding ether was obtained (entry 1, Table 1).
The high yields of the products, solvent-free and simple
reaction procedure make this method attractive for the
syntheses of benzylic ethers.
A plausible mechanism for this transformation is shown
in Scheme 2. In view of this, ferric perchlorate-activated
methyl iodide and then the alcohol oxygen lone pair attack
the activated methyl, followed by abstraction of the proton
providing the methyl ether (Scheme 2a). The same mech-
anism is suggested for benzylation of alcohols. In this case,
it is possible that the stable benzyl cation is formed, and
then the alcohol is collapsed by the benzyl cation yielding
the benzyl ether (Scheme 2b).
We also found that a catalytic amount of ferric per-
chlorate (5 mol%) is able to promote quantitative
methylation of alcohols using methyl iodide at room tem-
perature, without solvent and in dichloromethane (entries
3, 4, 6; Table 2) in high yields.
However, most of the alcohols studied here were con-
verted into their corresponding alkylation of alcohols in
good yields using this catalyst. Etherification was com-
pleted within 25–120 min (Tables 1, 2).
Conclusion
Ferric perchlorate acts as an efficient catalyst for the
alkylation of alcohols with benzyl and methyl halides. The
significant features of this method include operational
simplicity, inexpensive reagents, no need for any additive
to promote the reaction, high yields of products, and the
use of relatively non-toxic reagents and solvents.
In the presence of our system catalyst, phenolic hydroxy
groups did not react at all. When cyclic secondary alcohols,
such as cyclohexanol, were reacted with benzyl chloride,
the expected benzylic ethers were formed. In the end,
Table 1 Benzylation and methylation of alcohols 1a–j with benzyl chloride and methyl iodide
Alcohol 1
Time/min (2x)
BnCl ether (yield%) 23
Time/min (29)
MeI Ether (yield%) 33
BnOH (1a)
60
60
BnOBn 2a (90)
60
120
45
BnOMe 3a (90)
2-ClC6H4CH2OH (1b)
4-MeOC6H4CH2OH (1c)
4-MeC6H4CH2OH (1d)
Me3COH (1j)
2-ClC6H4CH2OBn 2b (91)
4-MeOC6H4CH2OBn 2c (89)
4-MeC6H4CH2OBn 2d (91)
Me3COBn 2j (89)
2-ClC6H4CH2OMe 3b (91)
4-MeOC6H4CH2OMe 3c (93)
4-MeC6H4CH2OMe 3d (88)
Me3COMe 3j (82)
30
30
60
120
120
123

Ferric perchlorate as an efficient and useful catalyst for the selective benzylation and methylation of alcohols
183
Table 2 Benzylation and methylation of glycols 4a–c with one or two equivalents of benzyl chloride and methyl iodide
Glycol 4
Time (h)
BnCl ether (yield%) 53 and 73
Time (h)
MeI ether (yield%)
69 and 89
Using 1 equiv. of BnCl or MeI
HO(CH2)2OH (4a)
0.5
1.0
0.5
HO(CH2)2OBn 5a (92)
1.5
1.2
1.2
HO(CH2)2OMe 6a (88)
MeCH(OH)CH2OH (4b)
n-PrCH(OH)CH2OH (4c)
Using 2 equiv. of BnCl or MeI
HO(CH2)2OH (4a)
MeCH(OH)CH2OBn 5b (84)
n-PrCH(OH)CH2OBn 4c (85)
MeCH(OH)CH2OMe 6b (83)
n-PrCH(OH)CH2OMe 6c (91)
0.5
24
24
BnO(CH2)2OBn 7 (90)
1.5
24
24
MeO(CH2)2OMe 8 (90)
MeCH(OH)CH2OH (4b)
n-PrCH(OH)CH2OH (4c)
MeCH(OH)CH2OBn 5b (82)
n-PrCH(OH)CH2OBn 4c (87)
MeCH(OH)CH2OMe 6b (85)
n-PrCH(OH)CH2OMe 6c (90)
of alcohols under solvent-free and reflux conditions, even
in large amounts.
Fe(ClO )
I---
ROHMe
H
+
4 3
ROH
Fe(ClO )
Me-I
+
4 3
Preparation of methyl ethers with ferric perchlorate:
general procedure
-H
(a)
ROMe
This was done as in the above procedure, but these reac-
tions were completed at room temperature and entries 3, 4,
and 6 were carried out in CH2Cl2.
Cl---
Fe(ClO )
Fe(ClO )
4 3
CH Cl
CH
4 3
2
References
ROH
CH OR
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Experimental
Preparation of benzyl ethers with ferric perchlorate:
general procedure
Benzyl chloride (1 mmol), 1 mmol alcohol, and 25 mg
Fe(ClO4)3 (0.05 mmol) were mixed in a one neck flask at
100 °C for 0.5–2.0 h (Table 1). The progress of the reac-
tion was monitored by TLC. After completion of the
reaction, the mixture was diluted with 10 cm3 H2O, and
10 cm3 CH2Cl2 was added to the reaction mixture. The
organic layer was concentrated, and the product was
purified by short-column chromatography to give the
benzyl ether in high yield. The identity of the products was
consistent with the data reported previously [24].
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large-scale preparations, we set up a reaction with 4.32 g
benzyl alcohol (40 mmol), 4.6 cm3 benzyl chloride
(40 mmol), and 1.0 g Fe(ClO4)3 (2.0 mmol) in a round
flask, and then stirred and heated it for 1.0 h under reflux
condition. The reaction was carried out without explosion
or fire. Thus, Fe(ClO4)3 could be used for the benzylation
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123