Facile Tetrahydropyranylation of Alcohols and Phenols Using Anhydrous Calcium Chloride under Mild and Neutral Conditions

Article abstract of DOI:10.1007/s00706-002-0468-9

Treatment of 3,4-dihydro-2H-pyran with various alcohols and phenols in the presence of a catalytic amount of anhydrous calcium chloride in dichloromethane furnished tetrahydropyranyl ethers under almost neutral conditions.

Full text of DOI:10.1007/s00706-002-0468-9

Monatshefte f u r Chemie 134, 425±428 ꢀ2003)
DOI 10.1007/s00706-002-0468-9
Facile Tetrahydropyranylation of Alcohols
and Phenols Using Anhydrous Calcium
Chloride under Mild and Neutral Conditions
Ã
Lavkumar S. Uppalla, and Suresh V. Patil
Babasaheb P. Bandgar , VaibhavS. Sada va rte,
Organic Chemistry Research Laboratory, School of Chemical Sciences,
Swami Ramanand Teerth Marathwada University, Nanded-431606, India
Received January 25, 2002; accepted ꢀrevised) March 20, 2002
Published online December 19, 2002 # Springer-Verlag 2002
Summary. Treatment of 3,4-dihydro-2H-pyran with various alcohols and phenols in the presence of a
catalytic amount of anhydrous calcium chloride in dichloromethane furnished tetrahydropyranyl ethers
under almost neutral conditions.
Keywords. Tetrahydropyranylation; THP ethers; Alcohols and phenols; Anhydrous CaCl2.
Introduction
The tetrahydropyranyl moiety ꢀTHP) is one of the most widely used protective
groups employed in organic synthesis because of its low cost, the convenient pre-
paration, its stability towards most non-acidic reagents, and the ease with which it
can be removed. Although a number of methods are reported in the literature [1],
some of these procedures suffer from using strongly acidic or expensive reagents.
In addition to the well known protic and Lewis acids, other reagents and catalysts,
such as iodotrimethylsilane [2], triphenylphosphine hydrobromide [3], montmo-
rillonite clay [4], Envirocat EPZG [5], lithium perchlorate [6], and iodine [7] have
been used to effect tetrahydropyranylation of alcohols. In spite of several efforts,
the methods available for selective protection of alcohols as THP ethers and their
deprotection without affecting acid and base sensitive functionalities present else-
where in the molecule are limited [1]. Consequently, there is still a need to develop
mild and ef®cient methods for tetrahydropyranylation of alcohols and phenols.
We now report anhydrous calcium chloride as a mild and inexpensive catalyst
for the tetrahydropyranylation of alcohols and phenols under neutral conditions
ꢀ
Scheme 1).
à Corresponding author. E-mail: bandgar_bp@yahoo.com

4
26B. P. Bandgar et al.
Scheme 1
Results and Discussion
Treatment of 3,4-dihydro-2H-pyran with benzyl alcohol ꢀ1a) in dichloromethane
in the presence of anhydrous calcium chloride for 1.5 h at ambient temperature
afforded 2-benzyl tetrahydropyranyl ether 2a in 89% yield. The reaction was
extended to a variety of alcohols ꢀprimary, secondary, tertiary, allylic, benzylic, pro-
pargylic) and phenols which also underwent facile tetrahydropyranylation with
anhydrous CaCl in CH Cl at ambient temperature, affording the corresponding
2
2
2
tetrahydropyranyl ethers 2a±2t in good to excellent yields. Even otherwise less re-
active tertiary alcohols gave the corresponding THP ethers 2i, j in good yield. It
is worth commenting that sensitive functional groups such as CˆC ꢀ1c, g), CꢀC
ꢀ
ꢀ
1h, j), methoxy ꢀ1l), acetal ꢀ1m), thioacetal ꢀ1n), TMS ꢀ1o), TBDMS ꢀ1p), epoxide
1q), acetyl ꢀ1r), or methylenedioxy ꢀ1t) remained intact under these neutral and
mild reaction conditions ꢀTable 1). When tetrahydropyranylation of alcohols was
tried without anhydrous calcium chloride, it resulted in isolation of unreacted
alcohols even after stirring for extended periods ꢀ12 h). Attempts to remove the
Table 1. Tetrahydropyranylation of alcohols and phenols using anhydrous CaCl2
a,b
Yield=%
c
Substrate ꢀ1)
Product ꢀ2)
t=h
Ref.
a
b
c
1.5
2
89
92
78
[2, 4]
[2, 4]
[2, 4]
2.5
d
e
2
2
85
85
[2, 4]
[2, 4]
f
2.5
3
83
67
[2, 4]
g
[2, 4]
ꢀcontinued)

Tetrahydropyranylation Catalyzed by CaCl2
427
Table 1 ꢀcontinued)
a,b
Yield=%
c
Substrate ꢀ1)
Product ꢀ2)
t=h
Ref.
h
i
1.5
75
[2, 4]
[2, 4]
4.5
2
80
80
j
[2, 4]
k
l
1
89
87
[2, 4]
[2, 4]
0.5
m
1
87
[2, 4]
n
o
p
q
r
1.5
2
95
91
94
84
93
88
[2, 4]
[2, 4]
[2, 4]
[2, 4]
[2, 4]
[2, 4]
[2, 4]
1.5
3
3
s
2.5
1.5
t
93
a
b
Yields of pure isolated products; products characterized by spectroscopic data; references for
c
spectroscopic data of products

4
28
B. P. Bandgar et al.: Tetrahydropyranylation Catalyzed by CaCl2
ꢁ
THP group using the same catalyst in methanol at 25 C or re¯ux temperature
ꢁ
ꢀ
65 C) failed.
Attempts to effect tetrahydropyranylation of alcohols using catalysts such as
NaCl, KCl, or CoCl failed. However, Lewis acids such as ZnCl and LiCl are
2
2
useful to some extent as catalysts for the preparation of THP ethers. Considering
recently reported results on the tetrahydropyranylation of alcohols using lithium
perchlorate [6], the present protocol is superior in terms of cost, yields, and reac-
tion times. t-Butanol in diethyl ether with lithium perchlorate as catalyst afforded
the corresponding THP ether in 56% yield within a period of 17 h, whereas the
THP ether of the same alcohol was obtained in 80% yield in 4.5 h using anhydrous
calcium chloride. In this case, the advantage lies in the neutral reaction conditions
which restrict dehydration of the alcohol as compared to the weakly acidic con-
ditions of lithium perchlorate in diethyl ether. Benzyl alcohol and cyclohexanol
gave the corresponding THP ethers in excellent yields in 1.5 h and 2.5 h with CaCl2,
whereas the lithium perchlorate pathway required 12 h for the same reaction.
In conclusion, anhydrous calcium chloride has been found to be an excellent
inexpensive catalyst for the protection of alcohols and phenols as THP ethers under
neutral and mild conditions ꢀroom temperature).
Experimental
1
IR spectra were recorded on a Bomem MB-104 FTIR spectrometer, H NMR spectra on a Bruker AC-
3
00 F NMR spectrometer operating at 300 MHz using CDCl as solvent and TMS as internal standard.
3
General procedure for the preparation of THP ethers
ꢁ
A mixture of 3,4-dihydro-2H-pyran ꢀ7mmol) and 5 mmol of alcohol was stirred at 25 C in the
3
presence of 1 mmol anhydrous CaCl in 5 cm CH Cl . After completion of the reaction ꢀTLC), the
2
2
2
3
catalyst was ®ltered off and washed with 3Â5 cm CH Cl . The solvent was removed under vacuum,
2
2
and the product was further puri®ed by column chromatography on silica gel ꢀhexane:ethyl
acetate ˆ 9:1). The products were identi®ed by TLC, elemental analyses, and spectroscopic data [2, 4].
Acknowledgments
V. S. Sadavarte thanks CSIR, New Delhi, for a junior research fellowship. S. V. Patil thanks UGC,
New Delhi, for a teacher fellowship.
References
[
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[
[
[
[
[
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