A fast and practical approach to tetrahydropyranylation and depyranylation of alcohols using indium triflate

Article abstract of DOI:10.1016/S0040-4039(02)01864-6

Indium triflate-mediated tetrahydropyranylation of alcohols in dichloromethane and depyranylation of these products in aqueous methanol utilizing the same reagent but different molar ratio is described. In addition, indium triflate-promoted conversion of tetrahydropyran ethers to their corresponding acetates has also been described.

Full text of DOI:10.1016/S0040-4039(02)01864-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7975–7978
A fast and practical approach to tetrahydropyranylation and
depyranylation of alcohols using indium triflate
Tomoko Mineno*
Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, PO Box 1848, University,
MS 38677-1848, USA
Received 31 July 2002; accepted 26 August 2002
Abstract—Indium triflate-mediated tetrahydropyranylation of alcohols in dichloromethane and depyranylation of these products
in aqueous methanol utilizing the same reagent but different molar ratio is described. In addition, indium triflate-promoted
conversion of tetrahydropyran ethers to their corresponding acetates has also been described. © 2002 Elsevier Science Ltd. All
rights reserved.
The choice of the protection and deprotection strategy
in a synthetic sequence is inevitable, owing to chemose-
lective transformations in the presence of various func-
tional groups.1,2 Tetrahydropyran (THP) is an
attractive protecting group that is often used for protec-
tion of alcohol moieties due to its stability and compat-
ibility under various reaction conditions and reagents,
such as metal hydrides, alkyllithiums, Grignard
reagents, and catalytic hydrogenation. There are several
known methods for the tetrahydropyranylation and
depyranylation of alcohols.3 The most commonly used
reagents that can catalyze both transformations are
p-toluenesulfonic acid (PTSA),4,5 pyridinium p-toluene-
sulfonate (PPTS),6 NH4Cl,7 ZrCl4,8 I2,9,10 potassium
dodecatangestocobaltate trihydrate,11 LiBr,12 acetonyl-
trichloroethyl carbamates.16 In further extension to our
work, we have discovered that indium triflate
(In(OTf)3), which acts as Lewis acid catalyst for various
synthetic transformations,17 can affect the tetra-
hydropyranylation and depyranylation of alcohols
under different reaction conditions. The details of our
studies are presented herein.
The tetrahydropyranylation of various alcohols was
carried out using 0.005 equiv. of In(OTf)3 in
dichloromethane at 0°C (Eq. (1) and Table 1).18 As
evident from Table 1 the protection methodology was
successful over a range of functional groups furnishing
the protected alcohols in good yields. However, the
trichloroethanol derivative (entry 7) yielded the product
in only 33% yield. The possible reason ascribed to this
observation could be the inductive electron-withdraw-
ing effect of the trichloromethyl moiety. We extended
our method to investigate the protection of alcohols
that also possess silyl-protected alcohol moieties, such
as t-butyldiphenylsilyl (TBDPS) and t-butyldimethyl-
silyl (TBDMS) groups (entries 13 and 14). In both
cases, the THP protection was successful and gave
satisfactory yields without affecting silyloxy-protected
moieties.
triphenylphosphonium
butylammonium
tribromide.14
bromide,13
and
However,
tetra-
these
procedures have several drawbacks including elevated
reaction temperatures, longer reaction times, expensive
reagents. Despite a number of precedents, an efficient
and practical method for these transformations is
desired. During our endeavors to explore the utility of
indium and its salt, we have earlier reported a new,
mild, and chemoselective method for deprotection of
trichloroethoxycarbonyl and trichloroacetyl groups
using indium powder and aqueous NH4Cl in
methanol,15 as well as a mild method for deprotecting
(1)
Keywords: indium triflate; tetrahydropyranylation; depyranylation;
alcohols; acetylation.
* Present address: University of Notre Dame, Dept. of Chemistry and
Biochemistry, 251 Nieuwland Science Hall, Notre Dame, IN 46556,
USA. Tel: 1-574-631-5606; fax: 1-574-631-6652; e-mail: tmineno@
nd.edu
(2)
(3)
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01864-6

7976
T. Mineno / Tetrahedron Letters 43 (2002) 7975–7978
Table 1. Indium triflate-catalyzed tetrahydropyranylation of alcoholsa
Subsequently, we discovered that depyranylation of
the THP ethers can be carried out to obtain the cor-
responding alcohols in good to excellent yields, using
the same catalyst but different molar ratio in aqueous
methanol at room temperature (Eq. (2) and Table
2).19 Compared to the protection, deprotection reac-
tions required 10 folds, or 0.05 equiv. of In(OTf)3
and extended reaction time for completion. Selective
deprotection was observed in entry 9, in which the
deprotection reaction proceeded without cleaving
TBDPS-protected alcohol unit. However, the
TBDMS-protected compound in entry 10 did not
undergo chemoselective deprotection. In general, the
TBDMS group is not as stable as the TBDPS in this
would be favored when there are more than one alco-
hol unit to manipulate by protection and deprotec-
tion.
In addition to these results, during our studies, we
also observed that In(OTf)3 promotes the acetylation
of THP ethers (Eq. (3) and Table 3).20 Earlier to this
report, the direct methods known to convert THP
ethers into acetate,21,22 generally require air sensitive
reagents and longer reaction periods. In contrast, the
method reported herein is fast and does not involve
any special reaction conditions or modifications.
Besides, this one step transformation can probably
confer a change of acid labile protecting group into a
base labile protecting group.
reaction condition. Selection of a TBDPS group

T. Mineno / Tetrahedron Letters 43 (2002) 7975–7978
Table 2. Indium triflate-catalyzed depyranylation of THP ethersa
7977
Table 3. Indium triflate-catalyzed acetylation of THP ethersa

7978
T. Mineno / Tetrahedron Letters 43 (2002) 7975–7978
In conclusion, we have established a simple and
efficient method for tetrahydropyranylation and
depyranylation of alcohols, as well as acetylation of
THP ethers, using catalytic amount of In(OTf)3. Since
the reactions described here are fast and practical, these
methodologies will be highly useful in the total synthe-
sis of natural products.
14. Naik, S.; Gopinath, R.; Patel, B. K. Tetrahedron Lett.
2001, 42, 7679–7681.
15. Valluri, M.; Mineno, T.; Hindupur, R. M.; Avery, M. A.
Tetrahedron Lett. 2001, 42, 7153–7154.
16. Mineno, T.; Choi, S.-R.; Avery, M. A. Synlett 2002,
883–886.
17. (a) Yadav, J. S.; Subba Reddy, B. V.; Srinivasa Rao, R.;
Veerendhar, G.; Nagaiah, K. Tetrahedron Lett. 2001, 42,
8067–8070; (b) Loh, T.-P.; Hu, Q.-Y.; Tan, K.-T.; Cheng,
H.-S. Org. Lett. 2001, 3, 2669–2672; (c) Prajapati, D.;
Laskar, D. D.; Sandhu, J. S. Tetrahedron Lett. 2000, 41,
8639–8643; (d) Gadhwal, S.; Sandhu, J. S. J. Chem. Soc.,
Perkin 1 2000, 2827–2829; (e) Chauhan, K. K.; Frost, C.
G.; Love, I.; Waite, D. Synlett 1999, 1743–1744; (f) Trost,
B. M.; Portnoy, M.; Kurihara, H. J. Am. Chem. Soc.
1997, 119, 836–837.
Acknowledgements
The author is grateful to Professor Mitchell A. Avery
for his profound support and suggestions.
References
18. General procedure for tetrahydropyranylation: Benzyl
alcohol (100 mg, 0.925 mmol, entry 1, Table 1) was
dissolved in dry CH2Cl2 (5 mL) under an argon atmo-
sphere at 0°C. Dihydropyran (92 mg, 1.11 mmol) and
In(OTf)3 (2.6 mg, 0.005 mmol) were added and stirred at
the same temperature for 30 min. The reaction mixture
was diluted with water and extracted with CH2Cl2 (3×10
mL). The combined organic layers were washed with
brine and dried over anhydrous Na2SO4. The mixture
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Purification by flash chromatography using hexanes/ethyl
acetate (9:1) furnished the THP ether of benzyl alcohol
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19. General procedure for depyranylation: Benzyl THP ether
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yielded the corresponding alcohol (52 mg, 93% yield).
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temperature for 10 min and then at rt for 1 h. The
reaction mixture was diluted with water and extracted
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were washed with brine and dried over anhydrous
Na2SO4. The mixture was filtered and concentrated by
rotary evaporation. Purification by flash chromatography
using hexanes/ethyl acetate (8:2) furnished benzyl acetate
(73 mg, 94% yield).
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