Lithium triflate (LiOTf) catalyzed efficient and chemoselective tetrahydropyranylation of alcohols and phenols under mild and neutral reaction conditions

Article abstract of DOI:10.1016/S0040-4039(02)00892-4

Different types of alcohols and phenols were effectively converted to the corresponding THP ethers in the presence of DHP and a catalytic amount of lithium trifluoromethanesulfonate (LiOTf) in refluxing 1,2-dichloroethane under essentially neutral reaction conditions. The method also shows good chemoselectivity for mono-tetrahydropyranylation of symmetrical diols.

Full text of DOI:10.1016/S0040-4039(02)00892-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5353–5355
Lithium triflate (LiOTf) catalyzed efficient and chemoselective
tetrahydropyranylation of alcohols and phenols under mild and
neutral reaction conditions
Babak Karimi* and Jafar Maleki
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), P.O. Box 45195-159, Gava Zang, Zanjan,
Iran
Received 23 February 2002; revised 1 May 2002; accepted 10 May 2002
Abstract—Different types of alcohols and phenols were effectively converted to the corresponding THP ethers in the presence of
DHP and a catalytic amount of lithium trifluoromethanesulfonate (LiOTf) in refluxing 1,2-dichloroethane under essentially
neutral reaction conditions. The method also shows good chemoselectivity for mono-tetrahydropyranylation of symmetrical diols.
© 2002 Elsevier Science Ltd. All rights reserved.
Protection of hydroxy groups by their conversion to the
corresponding tetrahydropyranyl ethers (THP ethers) is
a common and widely used transformation in organic
synthesis.1 This wide use is undoubtedly due to the
stability of THP group against a wide range of strong
nucleophilic and basic reagents.2 THP groups are also
the protective groups of choice in peptide, nucleotide,
carbohydrate, and steroid chemistry.3 A variety of pro-
tonic as well as Lewis acid catalysts have been devel-
oped for tetrahydropyranylation of hydroxy functions
such as acidic Clay,3 PTSA,4 bis[trimethylsilyl]sulfate,5
trimethyliodosilane,6 CuCl2,7 DDQ,8 BF3·OEt2,9
Herein, we disclose a new mild and efficient protocol
for tetrahydropyranylation of a variety of alcohols and
phenols using dihydro-4H-pyran in the presence of a
catalytic amount of lithium triflate (LiOTf) under neu-
tral reaction conditions (Scheme 1).19
In a typical procedure,20 when the alcohols or phenols
were treated with DHP (1.2–1.7 equiv.) in the presence
of LiOTf (0.6–0.7 equiv.) in refluxing 1,2-
dichloroethane, the corresponding THP-ethers were
obtained in good to excellent yields (Table 1).
triphenylphosphine
hydrobromide,10
Ru(CH3)3-
The present protocol is quite general as a wide range of
structurally varied alcohols such as primary, secondary,
tertiary, benzylic, and allylic underwent tetra-
hydropyranylation in good to excellent yields. The
method was also found to be highly selective for mono-
tetrahydropyranylation of symmetrical diols (Table 2).
(triphos)](OTf)2,11 I2,12 and silica chloride,13 some sup-
ported reagents such as BF3·OEt2 and Al2(SO4)3 on
silica gel14 and ionic liquids.15 However, many of these
methods have drawbacks such as harsh and acidic
conditions. In our development of new methods for
functional group transformations we are especially
interested in developing the potential uses of various
types of neutral catalysts.16 Along this line, very
recently we have found that LiOTf is a good catalyst
for highly chemoselective dithioacetalization of car-
bonyl compounds16g and transdithioacetalization of
acetals and 1,1-diacetate16k under neutral reaction con-
ditions. LiOTf has also been shown to be a catalyst for
the chemoselective aminolysis of oxiranes17 and glyco-
sylation of nucleophiles18 under neutral conditions.
In conclusion, the present procedure of tetra-
hydropyranylation demonstrates the potential of LiOTf
as a neutral catalyst in organic synthesis. Mild and
neutral reaction conditions, simplicity of the procedure,
general applicability for primary through tertiary alco-
hols, and selective mono-tetrahydropyranylation of
diols offer significant improvements over many existing
procedures.
DHP (1.6-2 equiv.), LiOTf (0.6-0.7 equiv.)
R
OH
ClCH2CH2Cl, reflux, 2-6.5 h
RO
O
* Corresponding author.
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00892-4

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B. Karimi, J. Maleki / Tetrahedron Letters 43 (2002) 5353–5355
Table 1. Tetrahydropyranylation of alcohols and phenols
using DHP in the presence of LiOTf in refluxing 1,2-
dichloroethane
Acknowledgements
The authors acknowledge the Institute for Advanced
Studies in Basic Sciences Research Council for support
of this work.
Entry Alcohol
Subst/DHP/ Time Yielda
LiOTf
(h)
(%)
1
2
3
4
5
6
7
8
9
PhCH2OH
1:1.6:0.6
1:1.6:0.7
1:1.6:0.6
1:2:0.6
1:1.6:0.6
1:1.7:0.6
1:1.7:0.7
1:2:0.7
2.5
2.5
3
96
90
92
91
95
94
96
95
86b
4-BrC6H4CH2OH
4-NO2C6H4CH2OH
4-i-PrC6H4CH2OH
4-ClC6H4CH2OH
Ph(CH2)2OH
References
2
2.25
2.5
2.5
4
1. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2nd ed.; Wiley: New York, 1991; pp.
31–34; (b) Kocienski In Protecting Groups; Enders, R.;
Trost, B. M., Eds.; Thieme: Stuttgart, 1994.
2. Katritzky, A. R.; Rees, C. W.; Meth-Cohn, O. Compre-
hensive Organic Functional Group Transformations; Perga-
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Ph(CH2)3OH
Ph2CHOH
1:3:0.7
4
HO
OH
10
1:1.7:0.7
4
84
3. Hoyer, S.; Laszlo, P. Synthesis 1986, 655.
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89c
89
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Tetrahedron Lett. 1988, 29, 4583.
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1777 and references cited therein.
14. (a) Ranu, B. C.; Saha, M. J. Org. Chem. 1994, 59, 8269;
(b) Nishiguchi, T.; Kawamine, K. J. Chem. Soc., Chem.
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OH
13
14
15
16
17
18
4-BrC6H4OH
4-FC6H4OH
4-MeC6H4OH
4-OHC6H4CHO
1-Naphthol
1:1.6:0.6
1:1.7:0.6
1:1.7:0.6
1:1.7:0.6
1:1.7:0.6
1:1.6:0.6
5
6
5.5
6.5
6
96
93
94
91
91
92
2-Naphthol
6
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a Isolated yield.
16. (a) Karimi, B.; Ebrahimian, G. R.; Seradj, H. Org. Lett.
1999, 1, 1737; (b) Karimi, B.; Miri-Ashtiani, A. Chem.
Lett. 1999, 1199; (c) Karimi, B.; Seradj, H. Synlett 2000,
641; (d) Karimi, B.; Seradj, H.; Ebrahimian, G. R. Syn-
lett 1999, 1456; (e) Karimi, B.; Seradj, H.; Tabaei, M. H.
Synlett 2000, 1798; (f) Karimi, B.; Golshani, B. J. Org.
Chem. 2000, 65, 7228; (g) Firouzabadi, H.; Karimi, B.;
Eslami, S. Tetrahedron Lett. 1999, 40, 4055; (h) Firouza-
badi, H.; Iranpoor, N.; Karimi, B. Synthesis 1999, 58; (i)
Karimi, B.; Seradj, H. Synlett 2001, 519; (j) Karimi, B.;
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19. Lithium trifluoromethanesulfonate was purchased from
Aldrich. A 0.1 M solution of the salt in deionized water
showed a pH of 6.6–6.8.
b Yield refers to isolated pure bis-THP ether.
c No elimination products were observed.
Table 2. Chemoselective mono-tetrahydropyranylation of
symmetrical diols in the presence of LiOTf
Entry Alcohol
Subst/DHP/ Time (h) Yielda,b
LiOTf
(%)
1
1:1:0.6
5.5
5.5
83 (93)
HO
OH
OH
OH
2
1:1:0.6
87 (95)
20. A typical procedure is as follows: To a stirred mixture of
the alcohol (10 mmol) and 3,4-dihydro-2H-pyran (16–20
mmol) in dichloroethane (50 mL), anhydrous LiOTf (6–7
mmol) was added. The mixture was heated at reflux while
stirring was continued, and the progress of the reaction
a Conversion based on NMR and GC.
b The numbers in parentheses refer to selective formation of mono-
THP ethers evaluated from NMR spectra.

B. Karimi, J. Maleki / Tetrahedron Letters 43 (2002) 5353–5355
5355
tion of the solvent under reduced pressure gave almost
pure product. Further purification was achieved by vacu-
um distillation (Table 1). All of the products are known
and gave satisfactory physical data compared with those
of authentic samples.
was followed by TLC. After completion of the reaction,
CHCl3 (100 mL) was added and the mixture was washed
successively with 10% NaOH solution (2×25 mL), brine
(15 mL), and water (15 mL). The organic layer was
separated and dried over anhydrous Na2SO4. Evapora-