BiBr3, an efficient catalyst for the benzylation of alcohols: 2-Phenyl- 2-propyl, a new benzyl-type protecting group

Article abstract of DOI:10.1016/S0040-4039(00)00304-X

The benzylation of aliphatic alcohols with various benzylic alcohols has been achieved in the presence of BiBr₃ under mild conditions. 2- Phenylpropan-2-ol proved to be the most efficient and can be considered as a novel protecting group. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00304-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2891–2894
BiBr3, an efficient catalyst for the benzylation of alcohols:
2-phenyl-2-propyl, a new benzyl-type protecting group
Bernard Boyer,∗ El-Mehdi Keramane, Jean-Pierre Roque and André A. Pavia
Département de Chimie Organique Fine, Université Montpellier II, Place E. Bataillon, 34095 Montpellier Cedex 5, France
Received 20 December 1999; accepted 16 February 2000
Abstract
The benzylation of aliphatic alcohols with various benzylic alcohols has been achieved in the presence of BiBr3
under mild conditions. 2-Phenylpropan-2-ol proved to be the most efficient and can be considered as a novel
protecting group. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: bismuth; alcohols; benzylic ethers; protection.
Numerous methods are available for protecting an alcohol moiety.1 Conversion into the corresponding
ethers has been recognized as a common and useful method for the protection of hydroxyl groups. Most
commonly used are the tetrahydropyranyl (THP), 1-ethoxyethyl (EE), t-butyldimethylsilyl (TBDMS),
benzyl (Bn) derivatives, etc. The experimental conditions used for benzylation being rather drastic (BnBr,
DMSO, KOH), the need for a milder method is very important.
In the course of our ongoing research using bismuth(III) halides2,3 as reagents for halogenation
reactions, we recently reported a new, simple and efficient BiBr3-promoted etherification that allows the
synthesis of symmetrical benzylic ethers from benzylic alcohols.2 This reaction is specific to benzylic
alcohols. Several attempts with aliphatic alcohols proved unsuccessful. This difference of reactivity
prompted us to examine the possibility of using this method to protect aliphatic alcohols as benzylic
ethers.
The potential of this approach was demonstrated by the synthesis of a series of alkyl–benzyl ethers
from various benzylic alcohols (benzyl alcohol (Bn-OH), 1-phenylethanol (Pe-OH) and 2-phenylpropan-
2-ol (Pp-OH)) in the presence of BiBr3 as catalyst.
Bismuth(III) salts as catalysts are attracting the attention of an increasing number of chemists in
various domains.4 To the best of our knowledge, the results reported here are the first examples of the
use of BiBr3 to promote the formation of benzylic ethers. The reaction is described in Scheme 1 and the
results are summarized in Table 1.
∗
Corresponding author. Fax: (33) 04 67 14 38 88; e-mail: bboyer@univ-montp2.fr (B. Boyer)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00304-X
tetl 16584

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Scheme 1.
Table 1
Protection of alcohols as benzyl-type ethers using BiBr3 as catalyst in CCl4 at 25°Ca

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As shown in Table 1, various aliphatic alcohols were reacted with either benzyl, 1-phenylethyl and
2-phenyl-2-propyl alcohols in the presence of BiBr3 in CCl4 at room temperature to provide the expected
ethers (ROBn, ROPe or ROPp). According to the experimental conditions used,5 it was expected that a
complex would first form between ROH and BiBr3 due to the weak Lewis acid character of the latter.6
The data reported in Table 1 call for the following remarks:
(i) all the alcohols studied were converted in good yields into their corresponding benzylic ethers under
conditions milder (room temperature, neutral medium) and cheaper than those usually described in
the literature;1
(ii) etherifications were completed within 5–60 min, 5–120 min and 2–96 h for, respectively, 2-
phenylpropan-2-ol, 1-phenylethanol and benzyl alcohol;
(iii) whatever the aliphatic alcohol, the reactivity of Pp-OH was significantly higher than Pe-OH and
especially higher than Bn-OH. For example (Table 1, entry 2), under identical conditions, Pp-OH
gave a 95% yield of ether after 5 min, while Pe-OH afforded nearly the same yield after 20 min.
In contrast, benzyl alcohol displayed a substantially lower reactivity. Completion of the reaction
required much longer reaction times, i.e. up to 90 h.
It appears that the formation of benzylic ethers by the method reported here is more convenient than
the usual O-benzylation. However, for the 2-phenyl-2-propyl and 1-phenylethyl protecting groups to find
wide applications in organic synthesis, they must be easily cleaved under mild conditions.
In this respect, ethers 1–10 were submitted to hydrogenolysis in the presence of ammonium formate
and 10% Pd/C in ethanol at 50°C. The results are given in Table 2.
Table 2
Deprotection of benzylic ethers (ROBn and ROPe) using ammonium formate and 10% Pd/C
It can be seen that ethers deriving from 1-phenylethanol (1–4) and 2-phenylpropan-2-ol (7–10) were as
easy to cleave as those derived from benzyl alcohol. All the reactions mentioned above were completed
in a short time (2–2 h 45 min). However, owing to the tertiary nature of the 2-phenyl-2-propyl group, we
anticipated that this group could also be easily cleaved under acidic conditions, in contrast to conventional
benzyl ethers.
Compounds 1–10 were, therefore, submitted to acidolysis on treatment with 50% trifluoroacetic acid
(5 mol. equiv.) in CH2Cl2 at room temperature.
As expected, benzyl and 1-phenylethyl ethers proved much more stable under these conditions than
those derived from 2-phenylpropan-2-ol. For instance, no cleavage of ethers 1–6 was detected within

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48 h. In contrast, ethers 7–10 derived from 2-phenylpropan-2-ol were cleaved under the same acidic
conditions within 4 h.
Consequently, the 2-phenyl-2-propyl group provides a novel useful method for the protection of
hydroxyl groups. It can be removed in experimental conditions affecting neither benzyl nor phenylethyl
ethers. In addition, it is usable with substrate-possessing unsaturated functions that would have been
affected by hydrogenolysis.
In summary, our procedure, based on the utilization of BiBr3, provides a new simple, efficient and
useful alternative for the preparation of benzylic ethers; in particular, those derived from 1-phenylethanol
and 2-phenylpropan-2-ol. The advantages of this procedure are mainly: (i) the mild conditions; (ii) easy
work-up; (iii) very good yields; and (iv) fast reaction times.
References
1. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; 2nd ed.; John Wiley & Sons: New York, 1991. (b)
Schelhaas, M.; Waldmann, H. Angew. Chem., Int. Ed. Engl. 1996, 35, 2056. (c) Kocienski, P. J. Protecting Groups; Enders,
D.; Noyori, R.; Trost, B. M., Eds.; Georg Thieme Verlag: New York, 1994. (d) Hon, Y. S.; Lee, C. F. Tetrahedron Lett. 1999,
40, 2389, and references cited therein. (e) Nishiyama, Y.; Kurita, K. Tetrahedron Lett. 1999, 40, 927, and references cited
therein.
2. Boyer, B.; Keramane, E. M.; Montero, J. L.; Roque, J. P. Synth. Commun. 1998, 28, 1737.
3. Boyer, B.; Keramane, E. M.; Arpin, S.; Montero, J. L.; Roque, J. P. Tetrahedron 1999, 55, 1971.
4. Suzuki, H.; Ikegami, T.; Matano, Y. Synthesis 1997, 249.
5. Benzylation of alcohols. General procedure: A mixture of ROH (1.25 mmol), BiBr3 (1.25 mmol) in CCl4 (3 ml) at room
temperature was stirred vigorously for 15 min (1 to 2 min for tertiary alcohols). To this stirred suspension, a solution of R0OH
(1.25 mmol) in CCl4 (2 ml) was slowly added and the stirring continued. On completion (GC and TLC monitoring), the
reaction mixture was filtered and the solvent was removed under reduced pressure to provide the product, which was purified
on a silica gel chromatography with dichloromethane.
6. Répichet, S.; Le Roux, C.; Hernandez, P.; Dubac, J. J. Org. Chem. 1999, 64, 6479, and references cited therein.