A Highly Efficient and Chemoselective Synthetic Protocol for Tetrahydropyranylation/Depyranylation of Alcohols and Phenols

Article abstract of DOI:10.1002/ejoc.200300429

Various alcohols and phenols can be converted efficiently to the corresponding tetrahydropyranyl (THP) ethers in good yields using catalytic amounts of bromodimethylsulfonium bromide (0.005-0.02 equivalent) at room temperature. On the other hand, various THP ethers can also be deprotected to the parent alcoholic or phenolic compounds in CH₂Cl₂/ MeOH (5:2) by employing 0.05 equivalent of the same catalyst. Some of the major advantages of this procedure are its mild conditions, that it is highly selective and efficient, high yielding, and cost-effective, that it needs no solvent and is compatible with the presence of other protecting groups. Furthermore, no brominations occur at a double or triple bond, at an allylic position or even at an aromatic ring. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300429

SHORT COMMUNICATION
A Highly Efficient and Chemoselective Synthetic Protocol for
Tetrahydropyranylation/Depyranylation of Alcohols and Phenols
Abu T. Khan,*[a] Ejabul Mondal,[a] Ballav M. Borah,[a] and Subrata Ghosh[a]
Dedicated to the late Mr. Gadadhar Mondal[‡]
Keywords: Protecting groups / Deprotecting groups / Hydroxyl compounds / Ethers / Catalysis / Alcohols
Various alcohols and phenols can be converted efficiently to
the corresponding tetrahydropyranyl (THP) ethers in good
yields using catalytic amounts of bromodimethylsulfonium
bromide (0.005−0.02 equivalent) at room temperature. On
the other hand, various THP ethers can also be deprotected
to the parent alcoholic or phenolic compounds in CH2Cl2/
MeOH (5:2) by employing 0.05 equivalent of the same cata-
lyst. Some of the major advantages of this procedure are its
mild conditions, that it is highly selective and efficient, high
yielding, and cost-effective, that it needs no solvent and is
compatible with the presence of other protecting groups.
Furthermore, no brominations occur at a double or triple
bond, at an allylic position or even at an aromatic ring.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
and deprotection of the hydroxy functionality as a THP
ether, which works under mild and economically cheaper
reaction conditions. As part of our research program to de-
velop new synthetic methodologies,[14] we conceived that
bromodimethylsulfonium bromide, which can generate HBr
in the reaction medium on reaction with alcohol, might be
a useful catalyst for tetrahydropyranylation and depyranyl-
ation of alcohols and phenols. The catalyst bromodimethyl-
sulfonium bromide has been utilized so far for the trans-
formation of alcohols to the corresponding bromides,[15]
oxidation of sulfides to disulfides,[16] deprotection of di-
thioacetals,[17] and preparation of α-bromoenones.[18] In this
communication, we report a simple and convenient syn-
thetic protocol for tetrahydropyranylation of alcohols and
phenols catalyzed by bromodimethylsulfonium bromide un-
der solvent-free conditions, and their depyranylation to the
corresponding parent compounds using the same catalyst
in CH2Cl2/MeOH (Scheme 1).
The protectionϪdeprotection of hydroxyl compounds as
tetrahydropyranyl (THP) ethers is one of the most fre-
quently employed transformations in multi-step organic
syntheses[1] because of their low cost, ease of preparation,
stability towards basic media and ease of removal of pro-
tecting groups at a later stage. Over the years, numerous
methods have been developed for the protection of hydroxyl
groups as THP ethers[2] and their deprotection,[3] but there
is still a need to find better alternatives that work under
mild conditions. Some of the recently used reagents that can
catalyze both tetrahydropyranylation and depyranylation
are ZrCl4,[4] I2,[5] LiBr,[6] acetonylphenylphosphonium bro-
mide,[7] TBATB,[8] aluminum chloride hexahydrate,[9] In-
(OTf)3,[10] dialkylimidazolium tetrachloroaluminates,[11]
and InCl3 immobilized in ionic liquids.[12] However, some of
the reported procedures have drawbacks, such as requiring
higher reaction temperatures, much longer reaction times
and the use of volatile organic solvents, being incompatible
with other acid-sensitive functional groups, and involving
expensive catalysts. In an endeavor to gradually change the
current working practices to greener alternatives and to
meet environmental demands,[13] there is a need for a sol-
vent-free and catalytically efficient alternative for protection
Scheme 1
[a]
Department of Chemistry, Indian Institute of Technology
Guwahati,
Results and Discussion
Guwahati 781 039, India
Fax: (internat.) ϩ91-361-2690762
E-mail: atk@postmark
As expected, a mixture of 1-decanol (5 mmol) and 3,4-
dihydro-2H-pyran (6 mmol) in the presence of bromodime-
[‡]
Teacher of A. T. K., for his constant moral support and
encouragement
Eur. J. Org. Chem. 2003, 4113Ϫ4117
DOI: 10.1002/ejoc.200300429
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4113

A. T. Khan, E. Mondal, B. M. Borah, S. Ghosh
SHORT COMMUNICATION
thylsulfonium bromide (0.05 mmol) at room temperature acetyl, benzoyl, benzyl, TBDPS, ester, thioketal, allyl, and
was converted smoothly to the corresponding tetrahydropy- isopropylidene were unaffected by the deprotection reaction
ranyl ether of 1-decanol within 5 min in 97% yield (run 1). conditions. Moreover, no brominations occurred at a
Similarly, a mixture of cetyl alcohol (5 mmol) and 3,4-di- double or triple bond or in the aromatic ring.
hydro-2H-pyran (DHP) (6 mmol) provided the correspond-
The formation of the product can be explained as follows.
ing THP ether within 15 min in 98% yield (run 2) under It has been shown that bromodimethylsulfonium bromide
identical reaction conditions. Using the above typical pro- can generate HBr on reaction with alcohol.[14] We believe
cedure, various secondary alcohols (runs 3Ϫ8) were trans- that in situ-generated HBr catalyzes the conversion of hy-
formed easily to the corresponding THP ethers in good droxyl compounds into the corresponding tetrahydropy-
yields. Interestingly, mono protection of an alcoholic hy- ranyl ethers (Scheme 2). We have observed that the pH of
droxyl group is possible in the presence of a phenolic OH the solution was ca. 2Ϫ3 while the reaction was proceeding.
group (run 9) and other alcoholic OH group (run 10) if
Similarly, the deprotection of THP ethers can be ex-
10% of the starting material is left unchanged. The conver- plained by the fact that bromodimethylsulfonium bromide
sion (run 1) is more efficient in terms of yield and reaction generates HBr on reaction with methanol, which is utilized
time than another recently reported procedure.[8] Moreover, for cleavage of THP ethers to the corresponding hydroxyl
a wide variety of protected alcoholic compounds were compounds.
transformed to the corresponding THP ethers under ident-
ical reaction conditions using the same catalyst (runs
11Ϫ15). It should be noted that various other protecting
groups such as acetyl, benzoyl, trityl, ester and TBDPS
Conclusion
groups remain unaffected during the reaction. In addition,
We have demonstrated a simple and convenient method
various double bonded and triple bonded substrates also
for preparation of tetrahydropyranyl (THP) ethers from the
provided the corresponding THP ethers under identical re-
corresponding alcohols and phenols under solvent-free con-
ditions as well as deprotection to the parent hydroxyl com-
pounds chemoselectively using the same catalyst by tuning
action conditions (runs 16Ϫ20). Importantly, no bromin-
ations took place at the double or triple bonds. It is worth
mentioning that geraniol was smoothly transformed to the
the amount of reagent and the reaction conditions. In ad-
corresponding THP ether at a much faster rate than it was
dition, this method is very simple and mild, easy to handle,
by a recently reported procedure,[9] which also shows the
and compatible with the presence of a large number of
efficiency of our protocol. Subsequently, various phenolic
other protecting groups. It is noteworthy that no bromin-
compounds were converted into the corresponding THP
ations take place at double or triple bonds, or even in aro-
ethers (runs 21Ϫ24) using the same catalyst without sol-
matic rings. Because of its operational simplicity, generality,
vent. It is noteworthy that no brominations take place in
and efficacy, this method is expected to have wide applica-
the aromatic ring even for an electron-rich aromatic sub-
bility for the conversion of various hydroxyl compounds to
strate (run 24) and that there is no cleavage of the dithioace-
the corresponding tetrahydropyranyl (THP) ethers and
tal group (run 23). Remarkably, a highly acid-sensitive sub-
vice-versa.
strate can be protected to the corresponding THP ethers
using the same catalyst (runs 25 and 26). Furthermore, vari-
ous carbohydrate and nucleosidic compounds were trans-
Experimental Section
formed smoothly to the corresponding THP ethers (runs
27Ϫ32) by the same reaction procedure. The results are
summarized in Table 1. The products were fully charac-
General Procedure for Tetrahydropyranylation: Bromodimethylsul-
fonium bromide (0.011 g, 0.05 mmol) was added to a mixture of 1-
decanol (0.790 g, 5 mmol, run 1) and 3,4-dihydro-2H-pyran
(0.550 mL, 6 mmol) and the resulting mixture was stirred at room
temperature. The reaction was complete within 5 min as monitored
by TLC and it was neutralized by addition of saturated NaHCO3
solution (2Ϫ3 drops). The mixture was extracted with CH2Cl2 (2
ϫ 15 mL) and the combined organic extracts were washed with
1
terized by IR, H NMR, and 13C NMR spectroscopy and
by elemental analyses. It is worth mentioning that benzyl,
isopropylidene, and a thio group at the anomeric position
were unaffected by the experimental conditions.
Next, we searched for suitable reaction conditions for de-
protection of THP ethers to the parent hydroxyl com-
pounds. The THP ether of cetyl alcohol was deprotected water (10 mL), brine (10 mL), and dried with Na2SO4. The organic
layer was concentrated in vacuo and the crude residue was purified
through a short alumina column. The pure product was obtained
(1.170 g) in 97% yield as a colorless liquid. Spectroscopic data of
THP ether of p-allyloxybenzyl alcohol: 1H NMR (400 MHz,
CDCl3): δ ϭ 1.46Ϫ1.86 (m, 6 H, CH2), 3.46Ϫ3.50 (m, 1 H, OCH2),
3.82Ϫ3.92 (m, 1 H, OCH2), 4.49 (s, 2 H, OCH2), 4.65Ϫ4.70 (m, 3
H, OCH2, OCHO-), 5.24 (dd, J ϭ 1.4, J ϭ 10.5 Hz, 1 H, CHϭ
CH2), 5.37 (dd, J ϭ 1.7, J ϭ 17.3 Hz, 1 H, CHϭCH2), 5.97Ϫ6.06
(m, 1 H, CHϭCH2), 6.86 (d, J ϭ 8.5 Hz, 2 H, ArH), 7.24 (d, J ϭ
8.3 Hz, 2 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 19.35,
smoothly to the parent cetyl alcohol within 30 min on treat-
ment with 0.05 equivalents of bromodimethylsulfonium
bromide in dichloromethane/methanol at room temperature
(run 1). Similarly, we successfully converted various THP
ethers to the parent hydroxyl compounds under identical
reaction conditions (runs 2Ϫ18). The results are summar-
ized in Table 2 and the products were characterized by IR,
1H NMR, 13C NMR spectroscopy, and elemental analyses,
as well as by comparison with the authentic compounds.
We also observed that various protecting groups such as 25.39, 30.53, 62.08, 68.44, 68.76, 97.44, 114.54 (2 C), 117.58, 129.41
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Efficient and Chemoselective Synthetic Protocol for Tetrahydropyranylation
SHORT COMMUNICATION
Table 1. Protection of various hydroxyl compounds to the corresponding tetrahydropyranyl ethers using catalytic amount of bromodi-
methylsulfonium bromide
1
[a] All final products were characterized by IR, H NMR, 13C NMR spectroscopy, and elemental analysis. [b] Isolated yield. [c] Reaction
was carried out by keeping 10% starting material unchanged.
Eur. J. Org. Chem. 2003, 4113Ϫ4117
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A. T. Khan, E. Mondal, B. M. Borah, S. Ghosh
SHORT COMMUNICATION
Table 2. Deprotection of various tetrahydropyranyl ethers to the
corresponding hydroxyl compounds using catalytic amount of
bromodimethylsulfonium bromide in dry dichloromethane/
methanol
Scheme 2. Proposed mechanism of protection
(2 C), 130.42, 133.23, 158.07 ppm. C15H20O3 (248.32): calcd. C
72.55, H 8.12; found: C 72.38, H 8.01%.
General Procedure for Depyranylation: Bromodimethylsulfonium
bromide (0.056 g, 0.25 mmol) was added to a well-stirred solution
of the THP ether of 2-phenylethanol (1.060 g, 5 mmol, run 2) in
CH2Cl2/MeOH (5:2; 10 mL) at room temperature. The reaction
was complete within 25 min as monitored by TLC. The mixture
was neutralized with saturated NaHCO3 solution and extracted
with CH2Cl2 (2 ϫ 10 mL). The combined organic extracts were
washed with water (10 mL), brine (10 mL), and dried with Na2SO4.
The organic layer was concentrated in vacuo and finally purified
by silica-gel column chromatography. The pure product was ob-
tained in 97% yield. Spectroscopic data of p-allyloxybenzyl alcohol:
1H NMR (400 MHz, CDCl3): δ ϭ 1.80 (br. s, 1 H, OH, D2O ex-
changeable), 4.38Ϫ4.40 (m, 2 H, OCH2), 4.45 (s, 2 H, OCH2), 5.15
(dd, J ϭ 1.4, J ϭ 10.5 Hz, 1 H, CHϭCH2), 5.28 (dd, J ϭ 1.5, J ϭ
17.8 Hz, 1 H, CHϭCH2), 5.86Ϫ5.96 (m, 1 H, CHϭCH2), 6.76 (d,
J ϭ 8.0 Hz, 2 H, ArH), 7.12 (d, J ϭ 8.3 Hz, 2 H, ArH) ppm.
C10H12O2 (164.20): calcd. C 73.15, H 7.37; found: C 72.87, H
7.28%.
Acknowledgments
A. T. K. thanks the Department of Science and Technology (DST),
New Delhi for a financial grant (Grant No. SP/S1/G-35/98). E. M.
is grateful to the CSIR for a senior research fellowship, and S. G.
to IITG for his fellowship.
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Efficient and Chemoselective Synthetic Protocol for Tetrahydropyranylation
SHORT COMMUNICATION
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