Deprotection of benzyl and p-methoxybenzyl ethers by chlorosulfonyl isocyanate-sodium hydroxide

Article abstract of DOI:10.1016/S0040-4039(02)02648-5

CSI-NaOH procedure provided a new and mild methodology for the deprotection of benzyl and p-methoxybenzyl ethers without affecting the other functional groups under similar reaction conditions.

Full text of DOI:10.1016/S0040-4039(02)02648-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 733–735
Deprotection of benzyl and p-methoxybenzyl ethers by
chlorosulfonyl isocyanate–sodium hydroxide
a
b
a
a,
Ji Duck Kim, Gyoonhee Han, Ok Pyo Zee and Young Hoon Jung *
a
College of Pharmacy, Sungkyunkwan University, Suwon 440-746, South Korea
b
Korea Research Institute of Bioscience and Biotechnology, Taejon 305-333, South Korea
Received 22 October 2002; revised 19 November 2002; accepted 22 November 2002
Abstract—CSI–NaOH procedure provided a new and mild methodology for the deprotection of benzyl and p-methoxybenzyl
ethers without affecting the other functional groups under similar reaction conditions. © 2003 Elsevier Science Ltd. All rights
reserved.
8
Deprotection of the benzyl group has been widely used
in multi-step organic synthesis with a variety of reac1-
tion conditions, including catalytic hydrogenolysis,
tions. Herein, we now report the extension of CSI
under new reaction condition to the cleavage of various
benzyl and p-methoxybenzyl protecting groups of alco-
hols and phenols in the presence of other functional
groups (Scheme 1).
2
3
4
Lewis acids such as FeCl , MgBr or CrCl /LiI and
3
2
2
5
6
lithium naphthalenide, etc. However, these procedures
sometimes can be problematic with multifunctional
substrates, such as unsaturated bonds during
hydrogenolysis, an acid-labile moiety in Lewis acids,
and a easily reducible functional groups in lithium
naphthalenide. These facts prompt us to find a milder
and more widely applicable method for debenzylation.
Since we have developed the novel synthetic methods
for N-protected allylic amines from allyl ether using
Our initial studies examined the deprotection of satu-
rated benzyl ethers. The treatment of 2-phenylethyl
benzyl ether (1a) with chlorosulfonyl isocyanate and
Na CO in methylene chloride under reflux and then
with NaOH in methanol gave the corresponding alco-
hol in 82% yield in one pot.
2
3
9
7
chlorosulfonyl isocyanate (CSI) and investigated its
In the same way that other Lewis acids promote the
debenzylation reaction, CSI should also lead to the
activation of benzyl ether to form N-chlorosulfonyl-N-
benzylcarbamate, which was easily cleaved by NaOH to
form the alcohol (Scheme 1).
mechanism, we have found a novel technique for com-
paring directly the stability of carbocations in the solu-
tion phase and have established the stability order of
the various carbocations under our reaction condi-
The formation of N-chlorosulfonyl-N-benzylcarbamate
can be rationalized in terms of the abstraction of the
−
alkoxy moiety by CSI to give the ClSO –N -CO R
2
2
species and a more stable benzyl carbocation. The
nitrogen anion then attacks the benzyl carbocation to
form N-chlorosulfonyl-N-benzylcarbamate.
A wide
range of structurally varied benzyl ethers has been
subjected to cleavage with CSI to provide the corre-
sponding alcohols. The results are shown in Table 1.
Secondary alkyl benzyl ethers treated with the
described reaction conditions produced consistently
good yields of deprotected alcohols (entries 2 and 3).
Treatment of benzyl ethers in the presence of a double
bond with the same reaction conditions afforded the
corresponding deprotected alcohols in good yields with-
out affecting the double bond (entries 4–10).
Scheme 1.
*
Corresponding author. Tel.: +8231-290-7711; fax: +8231-290-5403;
e-mail: yhjung@skku.ac.kr
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02648-5

7
34
J. D. Kim et al. / Tetrahedron Letters 44 (2003) 733–735
1
5
Table 1. Results of the deprotection of benzyl ethers
(2,3-dichloro-5,6-dicyanobenzoquinone, ceric ammo-
16 17
nium nitrate ), trifluoroacetic acid, and clay-sup-
1
8
ported ammonium nitrate-irradiation. Many of these
procedures sometimes have one or more problems, for
example, use of a heavy metal, a side reaction, low
yield, or the cost of the reagent. Especially, DDQ is
inclined to overoxidize allylic p-methoxybenzyl ether to
19
an unsaturated ketone. These problems led us to find
a mild and efficient methodology for cleavage of PMB
ethers.
We examined the cleavage of p-methoxybenzyl pro-
tected alcohols and phenols in the presence of a double
bond under the CSI–NaOH reaction conditions used in
the deprotection of benzyl ethers. The results of depro-
tection of PMB ethers using CSI–NaOH are summa-
rized in Table 3. In the case of cleavage of
PMB-protected allyl alcohols, the similar results were
obtained at lower temperature (−78°C) than the case of
benzyl protected alcohols (entries 1–3). However,
entries 4 and 5 reveal that the yield was highly
increased and the reaction occurred rapidly in the case
of cleavage of PMB-protected phenols compared to the
case of benzyl protected phenols. Also, we tried to find
appropriate reaction conditions for the selective cleav-
age of benzyl- and p-methoxybenzyl-protected alcohols.
Table 2. Results of the deprotection of benzyl ethers
Next, we examined the deprotection of benzyl ethers in
the presence of other functional groups as shown in
Table 2. 3-Benzyloxypropanol (1k) was treated with
CSI–NaOH to give the corresponding alcohol in 87%
yield in one pot. Benzyl ethers in the presence of cyclic
ether, silyl ether, ester or nitro group also produced the
corresponding deprotected alcohols in moderate yields
without affecting these functional groups (entries 3–6).
Unfortunately, in the case of entries 7 and 8, the
aromatic benzyl ethers gave poor yields in deprotection
under our reaction condition.
The p-methoxybenzyl (PMB) group is one of the most
useful groups for alcohol protection, and there are
various methods for selectively removing the PMB
group which include Lewis acid-catalyzed cleavage
1
0
11
(
TMSCl–SnCl –anisole,
Me BBr,
BF ·OEt –
2
2
3 2
1
2
13
14
NaCNBH3, AlCl –EtSH, CeCl –NaI), oxidation
3
3

J. D. Kim et al. / Tetrahedron Letters 44 (2003) 733–735
735
Table 3. Results of the deprotection of p-methoxybenzyl
ethers
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. General procedure for the deprotection of benzyl ether by
CSI–NaOH. A suspension of Na CO3 (22.5 mmol) in
2
anhydrous CH Cl (40 mL) was added CSI (15 mmol),
2
2
and benzyl ether (10 mmol) was added under N . The
2
reaction mixture was stirred under reflux for 20 h and
cooled to 0°C. MeOH (40 mL) and NaOH (50 mmol)
were added and stirred at rt for 1 h. The reaction mixture
Entries 6 and 7 showed that the p-methoxybenzyl
group was cleaved selectively without affecting the ben-
zyl group at −78°C. This phenomenon is quite different
from the result of debenzylation by catalytic
was concentrated and dissolved in H O. The solution was
2
neutralized with 1N HCl and extracted with EtOAc. The
1
f
hydrogenolysis.
organic layer was washed with H O and brine, dried over
2
MgSO4 and concentrated in vacuo. The residue was
purified by column chromatography (hexane/EtOAc) or
distillation to afford the alcohol.
In conclusion, we have developed a new and mild
methodology for the deprotection of benzyl and p-
methoxybenzyl without affecting the other functional
groups using CSI–NaOH reaction conditions. The use
of the CSI–NaOH procedure for cleavage of benzyl and
p-methoxybenzyl ethers, both or selectively, in the pres-
ence of other various functional groups is in progress.
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Acknowledgements
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This study was supported by a grant of the Korea
Health 21 R&D Project, Ministry of Health & Welfare,
Republic of Korea (00-PJ2-PG1-CD02-0007). We wish
to thank Professor Kiyoshi Tomioka at Kyoto Univer-
sity for helpful discussions.
1
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