A mild and selective cleavage of p-methoxybenzyl Ethers by CBr4-MeOH

Article abstract of DOI:10.1246/cl.2000.566

p-Methoxybenzyl ethers were selectively deprotected to the corresponding alcohols and phenols in high yields by CBr₄ in refluxing methanol under neutral reaction conditions.

Full text of DOI:10.1246/cl.2000.566

566
Chemistry Letters 2000
A Mild and Selective Cleavage of p-Methoxybenzyl Ethers by CBr4-MeOH
J. S. Yadav* and B.V. Subba Reddy
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500 007, India
(Received January 24, 2000; CL-000083))
p-Methoxybenzyl ethers were selectively deprotected to
the corresponding alcohols and phenols in high yields by CBr4
in refluxing methanol under neutral reaction conditions.
Selective protection and deprotection of hydroxyl group is
an important process in multi-step synthesis of complex natural
products.1 Among various hydroxyl protecting groups, the p-
methoxybenzyl (PMB) ether is one of the most commonly used
due to its stability towards a variety of reaction conditions and
it can be removed selectively in the presence of benzyl ethers
under mild conditions. Different methods are available for the
selective removal of PMB group, which include Lewis acid
catalysed cleavage by TMSCl-SnCl2-anisole,2 AlCl3-EtSH,3
Me2BBr,4 BF3·Et2O-NaCNBH3,5 MgBr2-Me2S6 and
CeCl3·7H2O-NaI7 as well as oxidative cleavage8 by DDQ, CAN
and I2-MeOH. Also, the cleavage of p-methoxybenzyl ether
has been achieved by 10% solution of trifluoroacetic acid in
dichloromethane.9 However, inspite of their potential utility,
some of these methods suffer from drawbacks like the use of
heavy metals, lack of selectivity, unsatisfactory yields, expen-
sive reagents and the use of strong oxidants. Although, the
cleavage of p-methoxybenzyl ether has been reported by I2-
MeOH, the method involves longer reaction times resulting in
moderate yields of the products. Moreover, iodine is hazardous
and is not chemoselective in the presence of other functional
groups present in the substrate. Consequently, the development
of new methods with more efficacy, convenient procedures and
better yeilds is desirable. Although the use of CBr4 as catalyst
and reagent for various transformations10 is reported, it has not
been used for the deprotection of PMB ethers.
Herein, we report a new and efficient method for the selec-
tive removal of PMB group from the alcohols and phenols in
the presence of benzyl ether and other functional groups. The
deprotection proceeds smoothly by the treatment of the ether
with a catalytic amount of CBr4 in methanol at reflux tempera-
ture.
Thus, p-methoxybenzyl ethers were cleaved selectively in
the presence of other protecting groups like O-allyl, OBn, OPh,
OMe, OBz, BOC, CBz and acetonide in the substrate. The
results are summarised in the table. The advantage of the use of
CBr4 in methanol lies in its simplicity. Among various solvents
studied, methanol is found to be more effective for this cleav-
age. The occurance of this cleavage may be attributed to the in
situ formation of HBr itself by the reaction of CBr4 with
MeOH. To confirm the effect of the solvent the reactions were
also carried out in refluxing acetonitrile in the presence of CBr4
Copyright © 2000 The Chemical Society of Japan

Chemistry Letters 2000
567
which resulted in low to moderate yields of the products after a
long reaction time. When the reactions were carried out with
10% CBr4 the cleavage requires longer reaction times and
anhydrous conditions to achieve comparable yields with 20%
CBr4. Neither expensive reagents nor overly acidic conditions
are employed. Further, no precautions need to be taken to
exclude moisture or oxygen from the reaction mixture. The
method is compatible with other functional groups like nitro,
cyano, olefinic, ester and cyclopropyl moieties in the molecule.
If an oxirane ring is present in the substrate, a competitive reac-
tion of nucleophilic ring opening of epoxide was observed
along with the cleavage of PMB group. Further, the carbohy-
drate derivative entry(s) which contains an isopropylidine
group, benzyl ether and glycosidic bond are unaffected under
the present reaction conditions. However the deprotection is
slow by CBr4 in refluxing acetonitrile, various functional
groups like acetates, THP ethers, epoxides and primary iso-
propylidine groups are unaffected.
The procedure for deprotection of PMB group is very sim-
ple. A mixture of ether (5 mmol) and CBr4 (1 mmol) in distilled
methanol (15 mL) was refluxed for an appropriate time as
required to complete the reaction. After complete conversion as
indicated by TLC, the reaction mass was cooled to room tem-
perature and diluted with water and extracted twice with ether
(2 × 20 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4 and concentrated in vacuo
to yield crude product, which was purified by column chro-
matography on silica gel (Aldrich, 100–200 mesh, ethyl acetate:
hexane, 1:9) to afford pure alcohol.
makes it a useful addition to the existing methods.
BVS thanks CSIR, New Delhi for the award of fellowship.
References and Notes
1
a) T. W. Greene and P. G. M. Wuts, "Protective Groups in
Organic Synthesis", 3rd ed, John Wiley & Sons, New York
(1999). b) P. J. Kocienski, "Protecting Groups". Georg,
Thieme Verlag, Stuttgart, New York (1994).
2
3
4
T. Akiyama, H. Shima, and S. Ozaki, Synlett, 1992, 415.
A. Bouzide and G. Sauve, Synlett, 1997, 1153.
N. Hebert, A. Beck, R. B. Lennox, and G. Just, J. Org.
Chem., 57, 1777 (1992).
5
6
7
8
A. Srikrishna, R. Viswajanani, J.A. Sattigeri, and D.
Vijaykumar, J. Org. Chem., 60, 5961 (1995).
T. Onoda, R. Shirai, and S. Iwasaki, Tetrahdron Lett., 38,
1443 (1997).
A. Cappa, E. Marcantoni, and E. Torregiani, J. Org.
Chem., 64, 5696 (1999).
a) K. Horita, T. Yoshioka, T. Tanaka, Y. Oikawa, and O.
Yonemitsu, Tetrahedron, 42, 3021 (1986). b) S.
Chandrasekhar, G. Sumithra, and J. S. Yadav, Tetrahedron
Lett., 37, 1645 (1996). c) R. Johansson and B. Saumelsson,
J. Chem. Soc., Perkin Trans 1, 1984, 2371. d) A. R. Vaino
and W. A. Szarek, Synlett, 1995, 1157.
9
L. Yan, and D. Kahne, Synlett, 1995, 523.
10 a) E. J. Corey and P. L. Fuchs, Tetrahedron Lett., 1972,
3769. b) A. Wagner, M. P. Heitz, and C. Mioskowski,
Tetrahedron Lett., 31, 3141 (1990). c) A.-S. -Y. Lee, F.-Y.
Su, and Y.-C. Liao, Tetrahedron Lett., 40, 1323 (1999). d)
C. Johnstone, W. J. Kerr, and J. S. Scott, J. Chem. Soc.,
Chem. Commun., 1996, 341.
In conclusion, the letter describes a mild and efficient pro-
cedure for the selective removal of PMB ether group in the
presence of benzyl ether using CBr4 in refluxing methanol. The
adopted procedure is simple, inexpensive, high yielding which
IICT Communication No. 4471.