Cerium(IV) sulfate tetrahydrate: A catalytic and highly chemoselective deprotection of THP, MOM, and BOM ethers

Article abstract of DOI:10.1016/j.tetlet.2013.10.117

Tetrahydropyranyl (THP), methoxymethyl (MOM), and benzyloxymethyl (BOM) phenyl/alkyl ethers were efficiently cleaved to the corresponding parent hydroxyl compounds in good yields using catalytic amounts of Ce(SO ₄)₂·4H₂O by microwave-assisted or conventional heating in methanol solution. Intramolecular and competitive experiments demonstrated the chemoselective deprotection of THP ethers in the presence of triisopropylsilyl (TIPS) and tert-butyldiphenylsilyl (TBDPS) phenyl ethers.

Full text of DOI:10.1016/j.tetlet.2013.10.117

Tetrahedron Letters 54 (2013) 7164–7166
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cerium(IV) sulfate tetrahydrate: a catalytic and highly
chemoselective deprotection of THP, MOM, and BOM ethers
a,
⇑
a
a
b
Davir González-Calderón , Carlos A. González-González , Aydeé Fuentes-Benítez , Erick Cuevas-Yáñez ,
b
a,
⇑
David Corona-Becerril , Carlos González-Romero
a
Departamento de Química Orgánica, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón/Paseo Tollocan s/n, Toluca, Estado de México 50120, Mexico
Centro Conjunto de Investigación en Química Sustentable UAEM-UNAM, Toluca-Atlacomulco km. 14.5, San Cayetano, Toluca, Estado de México 50200, Mexico
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Tetrahydropyranyl (THP), methoxymethyl (MOM), and benzyloxymethyl (BOM) phenyl/alkyl ethers were
efficiently cleaved to the corresponding parent hydroxyl compounds in good yields using catalytic
Received 27 July 2013
Revised 18 October 2013
Accepted 21 October 2013
Available online 31 October 2013
amounts of Ce(SO
4
)
2 2
Á4H O by microwave-assisted or conventional heating in methanol solution. Intra-
molecular and competitive experiments demonstrated the chemoselective deprotection of THP ethers
in the presence of triisopropylsilyl (TIPS) and tert-butyldiphenylsilyl (TBDPS) phenyl ethers.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydropyranyl ethers
Methoxymethyl ethers
Benzyloxymethyl ethers
Alcohols
Cerium(IV) sulfate tetrahydrate
1
Tetrahydropyranyl (THP) ethers were one of the first generally
useful protecting groups for alcohols to be adopted and they are
decided to investigate the Ce(SO
pyranyl ether 1a in more detail.
4
)
2 2
Á4H O cleavage of tetrahydro-
2
still widely used today in multistep organic syntheses. The partic-
ular merits of THP group are its ease of introduction, the low cost of
dihydropyran, and its stability under a wide range of reaction con-
ditions. A drawback of THP group is the formation of an additional
stereocenter, therefore, methoxymethyl (MOM) and benzyloxym-
ethyl (BOM) ethers may be used instead THP of ethers.
Ce(SO ) 4H O
4 2 2
2
0 mol%
OTHP
OH
MeOH
MW or
1a
1
3
4
5
Several methods for THP, MOM, and BOM ether removal have
been reported. The most common methods involve acid hydroly-
sis; however, these methodologies are inappropriate in the case
of acid sensitive molecules. Thus, there is a need to develop new
alternatives to remove THP, MOM, and BOM ethers under mild
and preferably catalytic conditions. Recently, various inorganic
Table 1
Deprotection of THP ethers using 20 mol % Ce(SO
MW) or conventional heating (
4
)
2
Á4H
2
O in methanol by microwave
(
D)
Entry
Substrate
Alcohola
Yieldb,c (%)
MWd
De
6
salts have shown promise for THP ether cleavage, particularly,
7
cerium ammonium nitrate (CAN) are the unique cerium based
1
2
3
4
5
6
7
8
2a
3a
4a
5a
6a
7a
8a
9a
2
3
4
5
6
7
8
9
92
92
94
96
inorganic reagent reported for depyranylation, but their scope
and selectivity in the presence of silyl ethers have not been
explored.
During one of our current research programs, we observed that
menthol protected as THP ether 1a was cleaved within minutes
upon microwave heating in methanol containing cerium(IV) sul-
fate tetrahydrate. As a consequence of the above results, we
87
90
94
90
90
93
86
88
Trace
NR
Trace
NR
a
b
c
Confirmed by comparison with 1H NMR and 13C NMR with authentic sample.
Yields refer to chromatographically pure isolated compounds.
In some cases no reaction occurred (NR) or product yields were very low and ca.
⇑
Corresponding authors. Tel.: +52 722 217 5109x113; fax: +52 722 217 3890.
E-mail addresses: qfb_dgonzalez@yahoo.com.mx (D. González-Calderón), cgon-
90–95% of starting material was recovered.
d
1
6
30 °C, 20 min.
0 °C, 12 h.
e
zalezr@uaemex.mx (C. González-Romero).
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.117

D. González-Calderón et al. / Tetrahedron Letters 54 (2013) 7164–7166
7165
8
The optimized conditions for the microwave assisted cleavage
Table 3
Cleavage of THP phenyl ethers in the presence of silyl phenyl ethers by competition
experiments
of 1a were heating at 130 °C for 20 min in methanol containing
0 mol % CuSO O. With this catalyst concentration, cleavage
of 1a was slow at room temperature, but heating (conventional)
2
4
Á5H
2
Ph OTHP Ce(SO ) 4H O Ph OH
4
2
2
2
0 mol%
+
+
at 60 °C resulted in acceptable reaction rates, and a 12 h reaction
MeOH
MW or
9
Ph OR
Ph OR
period was adopted as the standard.
R= TIPS or TBDPS
Cleavage of a series of THP ethers was then examined under
these optimized conditions (Table 1). Our method demonstrated
that THP alkyl and aryl ethers were very efficiently cleaved in high
yields. Interestingly, when we studied the deprotection of TIPS (en-
try 7) and TBDPS (entry 8) ethers of phenols using our method,
these were cleaved in trace amounts or not at all.
Entry
Substrate
Producta (Yield %)b
MWd
Dc
1
2
6a + 8a
7a + 9a
6 (88) + 8a (94)
7 (90) + 9a (96)
6 (90) + 8a (95)
7 (93) + 9a (94)
a
b
c
Confirmed by comparison with 1H NMR and 13C NMR with authentic sample.
Yields refer to chromatographically pure isolated compounds.
OR
OR
OR
OR
OR Ph
60 °C, 12 h.
Ph
3
3
O
d
130 °C, 20 min.
a
R= THP
R= H
OR
2
2
a
R= THP
COEt
4
a
R= THP
R= H
4
R= H
5a R= THP
Table 4
5
R= H
O
H
OR
Deprotection of MOM and BOM alkyl/aryl ethers using 20 mol % Ce(SO
methanol by microwave (MW) or conventional heating (D)
4
)
2
Á4H
2
O in
OR
RO
OR
OR
O
H
OMe
9
9
a
R= TBDPS
R= H
OR
COOEt
a
NHCOCH3
OR
OR
OR Ph
7
7
R= THP
8a R= TIPS
6
6
a
R= THP
R= H
Ph
O
R= H
8
R= H
Ph
OMe
O
1
1
4a R= MOM
4b R= BOM
R= H
OR
1
1
5a R= MOM
3
O
5b R= BOM
16a R= MOM
4
R= H
16b R= BOM 17a R= MOM
6
R= H
17b R= BOM
1
7
R= H
OR
OR
OR1
Entry
Substrate
Producta
Yieldb (%)
OR2
MWc
Dd
Cl
OMe
OTIPS
OMe
OTBDPS
1
0a R1= TIPS, R2= THP
R1= TIPS, R2= H
1
2
3
4
5
6
7
8
14a
14b
15a
15b
16a
16b
17a
17b
3
3
4
4
6
6
17
17
87
86
90
85
87
90
80
82
84
90
88
86
85
85
90
87
1
0
12a R= THP
13a R= THP
1
2
R= H
13 R= H
1
1
1a R1= TBDPS, R2= THP
R1= TBDPS, R2= H
1
Data in Table 1 clearly indicate that selective cleavage of THP
ethers in the presence of silyl phenyl ethers should be possible. In-
deed, the results presented in Table 2 demonstrate that THP alkyl
ethers are cleanly and efficiently removed in the presence of phe-
a
b
c
1
H NMR and 13C NMR with authentic sample.
Confirmed by comparison with
Yields refer to chromatographically pure isolated compounds.
nolic TIPS (entries 1 and 2) or phenolic TBDPS (entries 3 and 4)
ethers within the same molecule.10
130 °C, 20 min.
6
d
0 °C, 12 h.
In addition, we carried out competition experiments to demon-
strate that phenolic THP protected species can be cleanly cleaved
in the presence of other phenols protected as TIPS (Table 3, entry
cleavage of MOM (entries 1 and 3) and BOM (entries 2 and 4)
ethers of alcohols as well as MOM (entries 5 and 7) and BOM (en-
tries 6 and 8) ethers of phenols in good yields.
The chemistry of Ce(IV) as a powerful one-electron oxidants in
organic synthesis is well known. The electron-transfer processes
by O/Ce(IV) in the deprotection of several protective groups have
been proposed and demonstrated previously. Therefore, herein
we propose a plausible mechanism (Scheme 1) for the removal of
the THP group from organic molecules by using Ce(SO
) or TBDPS (entry 2) ether.10
1
On the other hand, we decided to explore the scope of our
method in similar protecting groups such as methoxymethyl
MOM) and benzyloxymethyl (BOM) ethers. Table 4 shows the
1
1
(
1
2
13
Table 2
Chemoselectivity deprotection of THP alkyl ethers in the presence of TIPS and TBDPS
phenyl ethers
4
)
2
2
Á4H O.
OR
OR
Ce(SO ) 4H O
4
2
2
2
0 mol%
R
R
OTHP
OH
O
O
O
O
MeOH
MW or
R= TIPS or TBDPS
O
R
CeIII
Entry
Substrate
Producta
Yieldb (%)
CeIV
MWc
Dd
1
2
3
4
10a
12a
11a
13a
10
12
11
13
92
93
95
90
88
95
95
90
H
O
R
O
O
R
H
O
Me
a
b
c
Confirmed by comparison with 1H NMR and 13C NMR with authentic sample.
Yields refer to chromatographically pure isolated compounds.
O
Me
O
1
6
30 °C, 20 min.
0 °C, 12 h.
Scheme 1. An O/Ce redox cycle is a proposed plausible mechanism for the cleavage
d
of THP ethers.

7
166
D. González-Calderón et al. / Tetrahedron Letters 54 (2013) 7164–7166
An essential step in depyranylation reaction involves oxidation of
tetrahydropyranyl ether to give the corresponding radical cation
3rd ed.; John Wiley & Sons: New York; (c) Wang, Y. G.; Wu, X. X.; Jiang, Z. Y.
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IV
III
while the reduction of Ce –Ce takes place. Radical cations then
undergo fragmentation to give an alkoxy radical. Then, reduction
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IV
III
of alkoxy radical to alkoxide allows regeneration of Ce from Ce .
Finally, protonation of alkoxide by methanol produces free alcohol.
In conclusion, we report that catalytic cerium(IV) sulfate tetra-
hydrate in methanol solution, affects the efficient, facile, mild, and
selective deprotection of THP, MOM, and BOM ethers. Furthermore,
we demonstrated that THP ethers are efficiently cleaved in the
presence of phenols protected as triisopropylsilyl or tert-butyldi-
phenylsilyl ethers. The noteworthy feature of this deprotection
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2758.
method, in addition to its selectivity, is that Ce(SO
ily available, easily handled, and of relatively low toxicity.
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)
2
Á4H
2
O is read-
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Acknowledgements
(
e) Namboodiri, V. V.; Varma, R. S. Tetrahedron Lett. 2002, 43, 1143–1146; (f)
Davis, K. J.; Bhalerao, U. T.; Vittal-Rao, B. Synth. Commun. 2000, 30, 2301–2308;
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Financial support from UAEMéx (Project No. 2441) and CONA-
CyT (postgraduate scholarship) is gratefully acknowledged. The
authors would like to thank the referee and Joseph M. Muchowski
7
8
.
.
(
visiting professor, Facultad de Química, UNAM) for their valuable
comments and suggestions; M.N. Zavala-Segovia, L. Triana-Cruz
CCIQS UAEMéx–UNAM) for the technical support. Special thanks
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Microwave Irradiation Procedure: A 10-mL reaction vessel was charged with a
(
magnetic stir bar, 0.4 mmol of THP ether and 20 mol % Ce(SO
4
)
2
Á4H
2
O in 2 mL
to SIGNA and Dr. Luis D. Miranda (UNAM) for their valuable
assistance.
of MeOH. A septum cap was affixed; the vessel was placed in the microwave
cavity of an Anton-Paar microwave equipment. The stirring reaction mixture
was irradiated at 130 °C for 20 min. After cooling to room temperature, TLC
indicated the disappearance of starting material. The solid cerium sulfate was
filtered off and the solvent was removed under reduced pressure. Column
chromatography afforded pure alcohol. All products were spectrally identical
with authentic alcohols.
Supplementary data
Supplementary data (characterization data of all compounds
9
.
Conventional Heating Procedure: A 10-mL round-bottom flask was equipped
with a magnetic stir bar and a reflux condenser. Then were added 0.4 mmol of
1
13
and copies of H NMR and C NMR spectra) associated with this
article can be found, in the online version, at http://dx.doi.org/
THP ether and 20 mol % Ce(SO
4
)
2
Á4H
2
O in 2 mL of MeOH. The reaction mixture
was stirred at 60 °C for 12 h. After cooling to room temperature, TLC indicated
the disappearance of starting material. The solid cerium sulfate was filtered off
and the solvent was removed under reduced pressure. Column
chromatography afforded pure alcohol. All products were spectrally identical
with authentic alcohols.
1
0.1016/j.tetlet.2013.10.117.
References and notes
1
1
1
1
0. During the experiments, we test the possible chemoselective cleavage of THP
ethers in presence of tert-butyldimethylsilyl (TBDMS) ethers but these were
unsuccessful.
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