Cupric sulfate pentahydrate (CuSO4·5H2O): A mild and efficient catalyst for tetrahydropyranylation/depyranylation of alcohols and phenols

Article abstract of DOI:10.1016/j.tetlet.2004.08.141

Various alcohols and phenols can be smoothly converted to the corresponding THP ethers using 20 mol % CuSO₄·5H₂O under mild reaction conditions at room temperature. Some of the major advantages of this procedure are nonaqueous work-up, very good yields, less expensive catalyst and compatibility with other protecting groups.

Full text of DOI:10.1016/j.tetlet.2004.08.141

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7891–7894
Cupric sulfate pentahydrate (CuSO4Æ5H2O): a mild and
efficient catalyst for tetrahydropyranylation/
depyranylation of alcohols and phenols
Abu T. Khan,* Lokman H. Choudhury and Subrata Ghosh
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
Received 22 July 2004; revised 15 August 2004; accepted 24 August 2004
Available online 11 September 2004
This paper is dedicated to Professor H. Ila on the occasion of her 60th birthday
Abstract—Various alcohols and phenols can be smoothly converted to the corresponding THP ethers using 20mol% CuSO4Æ5H2O
under mild reaction conditions at room temperature. Some of the major advantages of this procedure are nonaqueous work-up, very
good yields, less expensive catalyst and compatibility with other protecting groups.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The tetrahydropyranyl(THP) group is frequentyl used
for the protection of alcohols and phenols due to their
ease of preparation and stability under a wide variety
of reaction conditions such as with hydrides, alkylating
reagents, Grignard reagents and organometallic
reagents.1 In addition, they also serve as stable protect-
ing group in peptide, nucleoside and nucleotide, carbo-
hydrate and steroid chemistry. Tetrahydropyranylation
of alcohols can be accomplished by using p-TSA,2
use.4,8,9,14 There is a need for a greener catalytically
efficient method, which might work under mild and
economically cheaper conditions. As a part of our
ongoing research program to develop new synthetic
methodologies involving various new reagents,16,17 we
perceived that cupric sulfate pentahydrate, which is
readily available, might be a useful catalyst for tetra-
hydropyranylation because of its mild Lewis acidity.
In this paper we disclose that cupric sulfate pentahy-
drate can be used as an efficient catalyst for tetrahydro-
pyranylation/depyranylation of alcohols and phenols as
shown in Scheme 1.
BF3ÆOEt2 and PPTS.4 Some of the recently used
3
reagents that can catalyze both tetrahydropyranylation
and depyranylation are ZrCl4,5 I2,6 LiBr,7 acetonyltri-
phenylphosphonium bromide (ATPB),8 TBATB,9
aluminium
dialkylimidazolium
chloride
hexahydrate,10
In(OTf)3,11
InCl3
When a mixture of 1-hexadecanol 1a and 3,4-dihydro-
2H-pyran was treated with 20mol% of cupric sulfate
pentahydrate in acetonitrile as solvent, it was smoothly
converted to the corresponding THP ether 2a within
tetrachloroaluminates,12
immobilized in ionic liquids13 and bromodimethylsulfo-
nium bromide.14 On the other hand, many methods
have also been developed by using heterogeneous cata-
lysts, and these have been reviewed recently.15 However,
some of these procedures have some difficulties such as
requirement of much longer reaction times, incompati-
bility with other acid-sensitive functional groups,3,9,10,13
involvement of expensive and moisture sensitive cata-
lysts and some of them have to be prepared prior to
CuSO4. 5H2O
ROH
+
CH3CN / rt / 40 min-12 h
R
O
O
O
1
2
CuSO4. 5H2O
CH3OH/ rt / 2-6 h
CH3O
O
Keyword: Protection of hydroxylcompounds.
*
Corresponding author. Tel.: +91 361 2582305; fax: +91 361
2690762; e-mail: atk@postmark.net
Scheme 1. R = alkyl/aryl/sugar residue/nucleoside residue.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.141

7892
A. T. Khan et al. / Tetrahedron Letters 45 (2004) 7891–7894
40min in 90% yield. Similarly, 4-methoxybenzyl alcohol
1b was converted to the corresponding THP ether 2b
within 40min under identicalreaction conditions.
Although dichloromethane can also be used, we
employed acetonitrile as solvent because dichlorometh-
ane is a halogenated solvent and harmful. The tetra-
hydropyranylation could be achieved on a large scale
between 10 and 100mmol without any difficulty. Fol-
lowing the typical reaction procedure,18 various benz-
ylic, allylic and secondary alcohols 1c–i as well as
phenols 1j–k were smoothly transformed to the corre-
sponding THP ethers 2c–k, respectively, in very good
yields. Remarkably, various diols were transformed to
mono THP ethers 2l–n along with 5–8% di-THP ether
by using 20mol% catalyst instead of 40mol% catalyst.
The diols could be converted to the di-THP ethers
2o–p in good yields in a similar manner. In various sub-
strates containing other functionalgroups such as
acetyl, TBDMS and TBDPS ethers, isopropylidene
protected diols and benzyl ethers were smoothly con-
verted to the desired THP ethers 2q–w in good
yields as shown in Table 1. All the products were fully
Table 1. Tetrahydropyranylation of alcohols and phenols in presence of a catalytic amount of CuSO4Æ5H2O
Entry
a
Substrate 1
Time (min)
40
Product 2a
Yieldb (%)
90
n
n
OH
OTHP
n = 13
n = 13
MeO
MeO
b
c
40
40
89
91
OH
OTHP
OH
OTHP
Cl
Cl
d
e
45
40
92
90
OTHP
OH
OH
OH
OTHP
O
O
OTHP
f
55
60
87
89
g
HO
THPO
OH
OTHP
h
i
55
80
91
85
C8H17
C8H17
HO
Cl
THPO
Cl
j
95
90
45
87
89
70
OH
OTHP
k
l
OH
MeO
THPO
HO
OTHP
MeO
HO
OH
OH
OH
m
n
12 h
60
83c
55
HO
n
n
OTHP
n = 4
n = 4
OH
OH
OTHP
HO
HO
HO
HO
o
90
92
OTHP
THPO
n
THPO
THPO
n
OH
OTHP
p
q
12 h
40
93
84
n = 4
n = 4
HO
OAc
OAc
r
s
40
40
THPO
THPO
82
82
OTBDMS
OTBDPS
HO
HO
OTBDMS
OTBDPS

A. T. Khan et al. / Tetrahedron Letters 45 (2004) 7891–7894
7893
Table 1 (continued)
Entry
t
Substrate 1
Time (min)
50
Product 2a
Yieldb (%)
85
O
O
O
O
OTHP
OH
OH
O
OTHP
O
O
O
u
v
85
90
83
81
O
O
O
O
O
O
OBn
O
OBn
HO
BnO
BnO
THPO
BnO
BnO
O
OMe
OMe
O
O
N
N
O
O
N
O
O
N
HO
THPO
w
45
90
O
O
O
O
a All products were characterized by IR, 1H NMR and elemental analysis.
b Isolated yields.
c Yield based on starting material recovery.
Table 2. Tetrahydropyranylation of 4-methoxybenzyl alcohol 1b using
various forms of cupric sulfatea
Acknowledgements
A.T.K. thanks the DST, New Delhi for a financial grant
(Grant No SP/S1/G-35/98), L.H.C. and S.G. are grateful
to IITG for their research fellowships. The authors are
also grateful to the referee for his valuable comments
and suggestions.
Run
Catalyst
Conversion (%)
Time (min/[h])
1
2
3
4
CuSO4Æ5H2
CuSO4
O
100
80
90
0
45
[3]
CuSO4ÆSiO2
SiO2
[2.5]
[3]
a Reactions were monitored by GC.
References and notes
1
characterized by IR, H NMR spectroscopy and by ele-
mentalanayl ses. The most interesting feature is that the
THP ether 2a undergoes cleavage within 5h using same
catalyst (20mol%) in methanol in 85% yield.19 Other
THP ethers 2b, 2c, 2f and 2k were converted to the
respective hydroxylcompounds 1b, 1c, 1f and 1k within
2–6h in 80–85% yields under identical reaction
conditions.
1. Greene, T. W.; Wuts, P. G. M. Protective Groups
in Organic Synthesis, 3rd ed.; John Wiley & Sons: New
York, 1999; p 49.
2. (a) Corey, E. J.; Niwa, H.; Knolle, J. J. Am. Chem. Soc.
1978, 100, 1942; (b) Bernady, K. F.; Floyd, M. B.; Poletto,
J. F.; Weiss, M. J. J. Org. Chem. 1979, 44, 1438.
3. Alper, H.; Dinkes, L. Synthesis 1972, 81.
4. Miyashita, M.; Yoshikoshi, A.; Grieco, P. A. J. Org.
Chem. 1977, 42, 3772.
5. Rezai, N.; Meybodi, F. A.; Salehi, P. Synth. Commun.
2000, 30, 1799.
6. Deka, N.; Sarma, J. C. Synth. Commun. 2000, 30, 4435.
7. Reddy, M. A.; Reddy, L. R.; Bhanumathi, N.; Rao, K. R.
Synth. Commun. 2000, 30, 4323.
8. Hon, Y.-S.; Lee, C.-F. Tetrahedron Lett. 1999, 40, 2389.
9. Naik, S.; Gopinath, R.; Patel, B. K. Tetrahedron Lett.
2001, 42, 7679.
10. Namboodiri, V. V.; Varma, R. S. Tetrahedron Lett. 2002,
43, 1143.
11. Mineno, T. Tetrahedron Lett. 2002, 43, 7975.
12. Namboodiri, V. V.; Verma, R. S. Chem. Commun. 2002,
342.
13. Yadav, J. S.; Subba Reddy, B. V.; Gnaneshwar, D. New J.
Chem. 2003, 202.
14. Khan, A. T.; Mondal, E.; Borah, B. M.; Ghosh, S. Eur. J.
Org. Chem. 2003, 4113.
15. Sartori, G.; Ballini, R.; Bigi, F.; Bosica, G.; Maggi, R.;
Righi, P. Chem. Rev. 2004, 104, 199.
The tetrahydropyranylation of 4-methoxybenzyl alcohol
1b was investigated with the various forms of cupric sul-
fate to find out the relative efficiencies (Table 2). Cupric
sulfate pentahydrate showed the highest catalytic activ-
ity in terms of reaction time and yield.
In summary, the present methodology demonstrates Cu-
SO4Æ5H2O as an effective catalyst for tetrahydropyranyl-
ation/depyranylation of alcohols and phenols. The main
advantages of our protocol are: mild, clean, environ-
mentally benign reaction conditions as well as good
yields. In addition, our methodology might be useful
for the substrates containing acid-sensitive protecting
groups because of the almost neutral reaction condi-
tions. Furthermore, this method is also expected to have
better applicability in organic synthesis due to the
low cost of the reagent. We believe this protocol will
be
methodologies.
a
usefuladdition to the modern synthetic
16. Khan, A. T.; Mondal, E.; Ghosh, S.; Islam, S. Eur. J. Org.
Chem. 2004, 22, 2002.

7894
A. T. Khan et al. / Tetrahedron Letters 45 (2004) 7891–7894
17. Khan, A. T.; Ghosh, S.; Choudhury, L. H. Eur. J. Org.
Chem. 2004, 2198.
J = 6.6Hz), 1.22–1.32 (m, 26H), 1.47–1.81 (m, 8H), 3.32–
3.38 (m, 1H), 3.44–3.49 (m, 1H), 3.65–3.73 (m, 1H), 3.81–
3.87 (m, 1H), 4.54 (m, 1H). Elemental analysis: calcd for,
C21H42O2 (326.56); C 77.24, H 12.96, found C 77.08, H
12.87.
18. Typicalprocedure of protection: Into a mixture of 3,4-
dihydro-2H-pyran (1.1mmol) and alcohol or phenol
(1mmol) in acetonitrile (2mL) was added cupric sulfate
pentahydrate (0.05g, 0.2mmol) at room temperature and
the mixture stirred untilcompeltion of the reaction was
ascertained by the disappearance of the alcohol spot on
TLC. The product was isolated in almost pure form from
the reaction mixture by simply filtering through a What-
man 42 filter paper without aqueous work-up. The pure
product was obtained from the reaction mixture by
passing it through a short column of basic alumina.
Compound 2a: IR (Neat): 2919, 2854, 1469, 1354, 1228,
1122, 1071, 1037; 1H NMR (CDCl3): 0.85 (t, 3H,
19. Typicalprocedure of deprotection: To a soul tion of THP
ether 2a (0.325g, 1mmol) in methanol (5mL) was added
cupric sulfate pentahydrate (0.05g, 0.2mmol) and the
mixture stirred at room temp. The reaction was completed
within 5h and the solid cupric sulfate was filtered off. The
solid residue was washed with dry methanol (2 · 5mL).
After concentration of the combined filtrate, the crude
residue was purified through a short silica gel column.
The desired cetylaclohol 1a was obtained 0.206g in 85%
yield.