Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5965–5967
New selective O-debenzylation of phenol with Mg/MeOH
Wei Huang,a Xu Zhang,a,b Hong Liu,a,* Jianhua Shena and Hualiang Jianga,c,
*
aThe Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Shanghai Institutes for Biological Sciences, and Graduate School, Chinese Academy of Sciences, Shanghai 201203, PR China
bSchool of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China
cSchool of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China
Received 7 April 2005; revised 3 June 2005; accepted 7 June 2005
Available online 18 July 2005
Abstract—Carboxylate-benzyl and nitro-benzyl groups used in phenols protection were selectively debenzylated with 3–25 equiv
of Mg in methanol at room temperature. Good yields of the desired phenols were obtained within 3–10 h from a wide variety of
O-(carboxylate-benzyl)- or O-(nitro-benzyl)-phenols. Selective O-debenzylation was possible in the presence of O-(carboxylate-
benzyl)- or O-(nitro-benzyl)-phenols with Mg/MeOH.
Ó 2005 Published by Elsevier Ltd.
O-Benzyl and N-benzyl groups are widely used in
protecting many functional groups such as alcohols,
phenols, acids, amines and amides. The commonly em-
ployed deprotecting methods include hydrogenolysis
with catalytic Pd/C,1 acid hydrolysis in refluxing trifluo-
roacetic acid (TFA),2 FeCl3,3 lithium naphthalenide.4
However, in many cases, clean benzyl group is not prop-
er for those chemicals with labile groups under these
debenzylation methods. Furthermore, in a lot of com-
plex syntheses, diversiform and selective deprotection
methods are required for more than two functional
groups. Therefore, the specific debenzylation methods
of various substituted benzyl groups have been reported
in order to develop milder debenzylation conditions.5–8
For example, 4-methoxylbenzyl (MB), 2,4-dimethoxyl-
benzyl (DMB) and 2,4,6-trimethylbenzyl groups with
increased acid sensitivity have been used in the selective
N-debenzylation with p-TsOH.5
reaction of the corresponding phenols with CO2-
Me(Et)-benzyl bromide or p-NO2-benzyl bromide in
the presence of potassium carbonate at rt in excellent
yields. O-Debenzylation of compounds 1a–k occurred
smoothly with good yields of the isolated phenols. Even
with the 2-(benzothiazole-2-yl)-O-(p-CO2Me-benzyl)-
phenol (1k), a 77% yield of the desired product was iso-
lated in spite of steric hindrance.
Using O-(p-CO2Me-benzyl)-phenol (1a) as a model
compound, we optimized the reaction conditions by
testing several parameters, such as different amounts
of Mg and MeOH, as well as reaction time. Compound
1a was separately debenzylated with 3, 6, 9 and 12 equiv
of Mg and different reaction times. After 4 and 3 h, the
conversion rate of 1a achieved 100% (yields 90% and
91%) using 9 and 12 equiv of Mg at room temperature.
But after 10 h, the reactions with lower amount of 3 or
6 equiv of Mg were incomplete with corresponding con-
version rate of 68% and 82% (yields 52% and 70%). This
indicates that optimization of the debenzylation condi-
tions by increasing the amount of Mg may be useful
than extending the reaction time. The optimum results
were usually obtained when 0.1 M of the starting mate-
rial was allowed to react with 3–25 equiv of Mg turning
in 0.5–5 mL of anhydrous methanol at room tempera-
ture for 3–10 h (Table 1). The products were obtained
by column chromatography with silica gel.
Here we report a novel, convenient and selective debenz-
ylation method with Mg/MeOH, an electron transfer
reagent, for O-(carboxylate-benzyl)- or O-(nitro-benz-
yl)-phenols. To date, there is no debenzylation agent
for these compounds. The application of this reagent
is summarized in Table 1. The O-(carboxylate-benzyl)-
or O-(nitro-benzyl)-phenols were synthesized by the
Keywords: Substituted benzyl; Phenol protecting group; Selective
O-debenzylation; Mg/MeOH.
When we applied this reagent to debenzylation of
p-CO2Me-benzyl, m-CO2Me(Et)-benzyl and p-NO2-
benzyl as protecting groups, good to excellent yields of
*
Corresponding authors. Tel.: +86 21 5080 6600x1210; fax: +86 21
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.06.046