Simple, efficient, and selective deprotection of phenolic methoxymethyl ethers using silica-supported sodium hydrogen sulfate as a heterogeneous catalyst

Article abstract of DOI:10.1021/jo030088+

A simple and efficient method has been developed for chemoselective deprotection of phenolic methoxymethyl (MOM) ethers using silica-supported sodium hydrogen sulfate as a heterogeneous catalyst. The conversions occur at room temperature, and the yields of the deprotected phenols are excellent. The method is suitable for deprotection of phenolic MOM ethers of multifunctional bioactive natural products.

Full text of DOI:10.1021/jo030088+

SCHEME 1
Sim p le, Efficien t, a n d Selective
Dep r otection of P h en olic Meth oxym eth yl
Eth er s Usin g Silica -Su p p or ted Sod iu m
Hyd r ogen Su lfa te a s a Heter ogen eou s
Ca ta lyst1
catalysts have not been studied in detail to determine
their selectivity toward the deprotection of the MOM
ethers of aliphatic and aromatic hydroxyls. Some cata-
lysts showed similar roles toward the cleavage of the
MOM ethers of both the hydroxyls.8,9 Most of the cata-
lysts also work under homogeneous conditions, and so
handling and removal from the reaction mixture is
sometimes a problem. Recently, clay-catalyzed deprotec-
tion of phenolic MOM ethers has been reported.10 The
catalyst works only for ortho-substituted MOM-protected
phenols containing a heteroatom in this ortho position.
We have developed a simple and efficient procedure for
the cleavage of phenolic MOM ethers using NaHSO4‚SiO2
as a heterogeneous catalyst. Several phenolic MOM
ethers were deprotected to the corresponding phenols
(Scheme 1, Table 1) by applying this catalyst.
The deprotection occurred under mild reaction condi-
tions at room temperature. The conversion took a short
reaction time, and the yields of the regenerated phenols
were very high. The structures of all the products were
confirmed by their spectral (1H NMR and MS) data and
by direct comparison with authentic samples.
The catalyst, NaHSO4‚SiO2, can easily be prepared11
from the readily available reagents, NaHSO4 and silica
gel (finer than 200 mesh), but it should be properly
activated. Both the ingredients are inexpensive and
nonhazardous. Thus, on the basis of economic and
ecological considerations, the catalyst is highly valuable.
The experimental procedure is very simple, and as the
reaction is heterogeneous in nature, the catalyst can
easily be removed by filtration. We observed that NaH-
SO4 or silica gel alone could not deprotect the MOM ether
under similar experimental conditions.
The present deprotection method is associated with
high chemoselectivity. Phenolic MOM ethers can be
cleaved selectively in the presence of a wide range of
functional groups present in the phenols. Alkyl and
benzylic ethers were not cleaved. Acetate, ester, alde-
hydes, and OTs groups also remained unaffected. Thus,
if the phenolic compounds contain two hydroxyl groups,
one of them can be protected with a MOM and the other
with an ester group and subsequently they can be
deprotected in different stages of a synthetic sequence.
The method has efficiently been applied for deprotection
of phenolic MOM ethers of bioactive natural products
(entries t and x) containing various functionalities. An
interesting observation is that the catalyst showed very
weak activity toward the cleavage of MOM ethers of
aliphatic hydroxyl groups. The MOM-protected phenyl
methanol (entry m) and phenyl ethanol (entry n) under-
went ∼10% deprotection with the catalyst under the
present experimental conditions (1.5 h). If the time was
C. Ramesh, N. Ravindranath, and Biswanath Das*
Organic Chemistry Division-I, Indian Institute of Chemical
Technology, Hyderabad 500 007, India
biswanathdas@yahoo.com
Received March 12, 2003
Abstr a ct: A simple and efficient method has been devel-
oped for chemoselective deprotection of phenolic methoxy-
methyl (MOM) ethers using silica-supported sodium hydro-
gen sulfate as a heterogeneous catalyst. The conversions
occur at room temperature, and the yields of the deprotected
phenols are excellent. The method is suitable for deprotec-
tion of phenolic MOM ethers of multifunctional bioactive
natural products.
The protection and subsequent deprotection of a hy-
droxyl group is the usual practice in multistep transfor-
mations and synthesis of complex organic molecules.2 The
methoxymethyl (MOM) group is widely used as a hy-
droxy-protecting group because it can easily be intro-
duced and is stable under a variety of reaction conditions,
including strongly basic and weakly acidic media.2 MOM-
protected phenols also undergo ortho metalation ef-
ficiently.3 Recently, MOM-protected 2,2′-dihydroxynaph-
thalene has been suggested as the most effective synthone
for the synthesis of enantiopure 3,3′-derivatives through
directed ortho metalation.3b The cleavage of MOM ethers
can be carried out under strongly acidic conditions using
HCl,4 BBr3,5 p-TsOH, or pyridinium p-toluenesulfonate.6
However, these catalysts can also affect other acid-
sensitive groups. Mild Lewis acids (e.g., ZnBr2 and TiCl4)
cleave the MOM ethers very slowly in an aprotic environ-
ment.7 Different derivatives of boron bromide (Me2BBr,8a
(i-PrS)2BBr8b) and CBr4 have also been applied for
9
deprotection of MOM ethers. However, some of these
(1) Part 26 in the series “Studies on Novel Synthetic Methodologies”.
(2) (a) Kocienski, P. J . Protecting Groups; Thieme: Stuttgart, 1994.
(b) Green, T. W.; Wuts, P. G. M. Protecting Groups in Organic
Synthesis, 3rd ed.; J ohn Wiley and Sons: New York, 1999.
(3) (a) Alzer, J .; Nock, N.; Wasser, G.; Masciadri, R. Tetrahedron
Lett. 1996, 37, 857. (b) Borner, C.; Dennis, M. R.; Sinn, E.; Woodward,
S. Eur. J . Org. Chem. 2001, 2435.
(4) (a) Auerback, J .; Weinreb, S. M. J . Chem. Soc., Chem. Commum.
1974, 298. (b) Meyers, A. I.; Durandetta, J . L.; Munavu, R. J . Org.
Chem. 1975, 40, 2025.
(5) Kleczykowski, G. R.; Schlessinger, R. H. J . Am. Chem. Soc. 1978,
100, 1938.
(6) (a) Boehlow, T. R.; Harburn, J . J .; Spilling, C. D. J . Org. Chem.
2001, 66, 3111. (b) Monti, H.; Leandri, G.; Klos-Rinquet, M.; Corriol,
C. Synth. Commun. 1983, 13, 1021.
(7) Corey, E. J .; Gras, J .-L.; Ulrich, P. Tetrahedron Lett. 1976, 809.
(8) (a) Quindon, Y.; Morton, H. E.; Yoakim, C. Tetrahedron Lett.
1983, 24, 3969. (b) Corey, E. J .; Hua, D. H.; Seitz, S. P. Tetrahedron
Lett. 1984, 25, 3. (c) Boeckman, R. K., J r.; Potenza, J . C. Tetrahedron
Lett. 1985, 26, 1411.
(10) Deville, J . P.; Behar, V. J . Org. Chem. 2001, 66, 4097.
(11) Breton G. W. J . Org. Chem. 1997, 62, 8952.
(9) Lee, A. S.-Y.; Hu, Y.-J .; Chu, S.-F. Tetrahedron. 2001, 57, 2121.
10.1021/jo030088+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/08/2003
J . Org. Chem. 2003, 68, 7101-7103
7101

a
TABLE 1. Dep r otection of MOM Eth er s Usin g Na HSO4‚SiO2
7102 J . Org. Chem., Vol. 68, No. 18, 2003

Ta ble 1. (Con tin u ed )
a
All products were characterized from their spectral (1H NMR and MS) data and by comparison with authentic samples.
SCHEME 2
phenolic methoxymethyl ethers using NaHSO4‚SiO2 as
a heterogeneous catalyst at room temperature. The
operational simplicity, shorter reaction times, application
of an inexpensive and nontoxic catalyst, excellent yields,
and high chemoselectivity are the great advantages of
the present procedure. The method has been found to be
suitable for deprotection of phenolic MOM ethers of
multifunctional bioactive compounds. The procedure can
also be extended for deprotection of phenolic MEM ethers
and the MOM esters of both the aliphatic and aromatic
acids. We feel that the present process will find important
applications in synthetic organic chemistry.
increased, the deprotection was increased somewhat
more. TBDBS ether (entry r) of p-nitrophenol also
underwent a small degree of deprotection (5%) after
treatment with the catalyst for 1.5 h. However, phenolic
MEM (methoxyethoxymethyl) ethers could be deprotected
with equal activity. Thus, MEM ethers (entry p) of
p-nitrophenol afforded the corresponding phenol with a
yield of 99% in the presence of NaHSO4‚SiO2 at room
temperature for 1.5 h.
The method has also been extended for the cleavage
of MOM esters of carboxylic acids (Scheme 2). However,
in this case the MOM esters of both the aliphatic and
aromatic acids were equally deprotected. As for an
example, the MOM esters of benzoic and phenylacetic
acids could be converted quantitatively into the corre-
sponding acids using NaHSO4‚SiO2 at room temperature
for 1.5 h.
Typ ica l Exp er im en ta l P r oced u r e
To a stirred solution of the MOM ether of p-nitrophenol (183
mg, 1 mmol) in DCM (10 mL) was added activated (while hot)
NaHSO4‚SiO2 (200 mg) (the catalyst was kept in an oven at 120
°C for 48 h before using it) at room temperature. After comple-
tion of the reaction (monitored by TLC, 1 h) the catalyst was
filtered off and washed with DCM (2 × 5 mL). The filtrate and
washings were combined, and the solvents were removed under
vacuum to give pure p-nitrophenol (139 mg, 1 mmol, 100%) as
a solid.
Ack n ow led gm en t. The authors thank UGC New
Delhi for financial assistance.
In conclusion, we have developed an exceedingly mild,
simple, and efficient methodology for the deprotection of
J O030088+
J . Org. Chem, Vol. 68, No. 18, 2003 7103