Simple and facile tetrahydropyranylation of alcohols by use of catalytic amounts of benzyltriphenylphosphonium tribromide

Article abstract of DOI:10.1080/00397910500297297

An efficient and mild system for protection of a variety of alcohols with 3,4-dihydro-2H-pyran (DHP) in the presence of catalytic amounts of benzyltriphenyl-phosphonium tribromide (BTPTB) (1) gives the corresponding tetrahydropyan ethers (ROTHP) in dichloromethane. The experimental procedure is simple, and the products are straightforwardly isolated in high to excellent yields. Copyright Taylor & Francis, Inc.

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Simple and Facile
Tetrahydropyranylation
of Alcohols by use of
Catalytic Amounts of
Benzyltriphenylphosphonium
Tribromide
A. R. Hajipour a , S. A. Pourmousavi b & A. E. Ruoho
c
a Pharmaceutical Research Laboratory, College
of Chemistry , Isfahan University of Technology ,
Isfahan, Iran
b Department of Pharmacology , University of
Wisconsin Medical School , Madison, Wisconsin, USA
c Department of Pharmacology , University of
Wisconsin, Medical School , Madison, Wisconsin, USA
Published online: 22 Aug 2006.
To cite this article: A. R. Hajipour , S. A. Pourmousavi & A. E. Ruoho (2005) Simple
and Facile Tetrahydropyranylation of Alcohols by use of Catalytic Amounts of
Benzyltriphenylphosphonium Tribromide, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 35:22, 2889-2894
To link to this article: http://dx.doi.org/10.1080/00397910500297297

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Synthetic Communicationsw, 35: 2889–2894, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500297297
Simple and Facile Tetrahydropyranylation
of Alcohols by use of Catalytic Amounts of
Benzyltriphenylphosphonium Tribromide
A. R. Hajipour
Pharmaceutical Research Laboratory, College of Chemistry, Isfahan
University of Technology, Isfahan, Iran and Department of
Pharmacology, University of Wisconsin Medical School, Madison,
Wisconsin, USA
S. A. Pourmousavi
Pharmaceutical Research Laboratory, College of Chemistry, Isfahan
University of Technology, Isfahan, Iran
A. E. Ruoho
Department of Pharmacology, University of Wisconsin, Medical School ,
Madison, Wisconsin , USA
Abstract: An efficient and mild system for protection of a variety of alcohols with
3,4-dihydro-2H-pyran (DHP) in the presence of catalytic amounts of benzyltriphenyl-
phosphonium tribromide (BTPTB) (1) gives the corresponding tetrahydropyan ethers
(ROTHP) in dichloromethane. The experimental procedure is simple, and the
products are straightforwardly isolated in high to excellent yields.
Keywords: Protection, DHP, BTPTPB, phosphonium salt, tribromide
INTRODUCTION
Protection of the hydroxy group by 3,4-dihydro-2H-pyran is frequently used for
natural products in modern synthesis.[1] Because tetrahydropyan ethers are stable
Received in the UK November 1, 2004
Address correspondence to A. R. Hajipour, Pharmaceutical Research Laboratory,
College of Chemistry, Isfahan University of Technology, Isfahan 84156, Iran.
E-mail: haji@cc.iut.ac.ir
2889

2890
A. R. Hajipour, S. A. Pourmousavi, and A. E. Ruoho
in the presence of strong bases or nucleophiles such as Grignard reagents, organo
lithium compounds, metal hydrides, alkylating and acylating reagents, and
oxidizing compounds, tetrahydropyranylation is used to protect hydroxy groups
in multistep synthesis.[2] A number of methods, mostly acidcatalyzes, have
reported for the preparation of tetrahydropyranylated alcohols.[3–14] Unfortu-
nately most of the reported methods suffer from at least one of the following dis-
advantages: 1) high cost of preparations, 2) long reaction times, 3) hygroscopisity,
4) high acidity, 5) instability, 6) no selectivity, 7) photosensitivity, 8) dangerous
procedures for their preparation, and 9) tedious workup procedures. Therefore,
there is a need to introduce an alternative method for the tetrahydropyranylation
of alcohols under mild and less acidic conditions. Recently we have reported the
synthesis of benzyltriphenylphosphonium tribromide (1) as an efficient and mild
reagent for bromination of aromatic compounds.[15] In the course of our studies on
quaternary amine and phospine[16] here, we introduce an efficient, mild, and rapid
method for selective tetrahydropyranylation of alcohols to the corresponding tet-
rahydropan ethers (ROTHP) ethers with 3,4-dihydro-2H-pyran (DHP) in the
presence of catalytic amounts of benzyltriphenylphosphonium tribromide
(BTPTB) (1).
Tetrahydropyranylation did not occur when the reaction were performed in
the absence of (1). The reactions may occur by in situ formation of HBr from
interaction of alcohol with (1).[17] This catalytic amount of HBr is sufficient
to catalyze protection of alcohol through the following mechanism (Scheme 1).
A variety of alcohols, when treated with 3,4-dihydro-2H-pyran at room
temperature in presence of catalyst (1) (2.5% using alcohol), produced the
corresponding tetrahydropyranyl ethers in high yields (75–97%). The process
was found to be useful for protecting aliphatic, benzylic, and allylic alcohols
within a short time (5–20 min) and with a small quantity of catalyst. The
tolerance of various protecting groups under the reaction conditions has been
examined by reacting substrates bearing substituents, such as nitro, alkene,
and OMe, and the reaction conditions were compatible in the protection
stage. This method was found to be highly selective for monotetrahydropyrany-
lation of symmetric diols. When we used this process for tetrahydropyranyla-
tion of optically pure l-menthol, tetrahydropyranylation occurred without
Scheme 1.

Tetrahydropyranylation of Alcohols
2891
Table 1. Tetrahydropyranylation of alcohols (2) by (1)a,b
Time
(min)
Yield
(%)c
Entry
Substrate 2
Product 3
Ref.
18
2a
5
5
5
95
97
95
2b
2c
1
19
2d
7
90
20
2e
2f
7
10
5
87
89
97
21
20
1
2g
2h
2i
15
10
90
95
20
21
2j
20
80
20
2k
2l
20
15
85
85
22
20
(continued)

2892
A. R. Hajipour, S. A. Pourmousavi, and A. E. Ruoho
Table 1. Continued
Time
(min)
Yield
(%)c
Entry
Substrate 2
Product 3
Ref.
1
2m
10
10
75
85
2n
23
2o
10
92
18
2p
2q
2r
2s
CH3(CH2)3OH
CH3(CH2)5OH
CH3(CH2)6OH
CH3(CH2)7OH
(CH3)2CHCH2OH
(CH3)2CH(CH2)2OH
HO(CH2)5OH
CH3(CH2)3OTHP
CH3(CH2)5OTHP
CH3(CH2)6OTHP
CH3(CH2)7OTHP
(CH3)2CHCH2OTHP
(CH3)2CH(CH2)2OTHP
HO(CH2)5OTHP
10
10
10
12
10
8
90
95
97
90
92
95
90
93
90
24
25
20
18
18
21
26
18
25
2t
2u
2v
2w
2x
8
CH3CH(OH)CH3
(CH3)3COH
CH3CH(OTHP)CH3
(CH3)3COTHP
5
15
aSubstrate/DHP/1 (1 : 1.1 : 0.025).
bConfirmed by comparison with authentic samples.
cYield of isolated pure products.
racemization of product. Even the otherwise less reactive and bulky t-butyl
alcohol satisfactory protected without any dehydration (Table 1).
In conclusion we report an efficient and mild process for tetrahydropyrany-
lation of alcohols to the corresponding THP ether in high yields and short
reaction times. The method is a mild process for protection of aliphatic,
benzylic, cyclic, allylic, and optically pure alcohols, and the pure product was
straightforwardly isolated, without any purification. In this method strong
acids were not used, and epimerization of optical pure alcohols did not occur.
EXPERIMENTAL
The reagent (1) was prepared according to our previously reported pro-
cedures.[15] Yields refer to isolated pure products. The protection products
1
were characterized by comparison of their spectral (IR, H NMR) data with
the authentic samples.[1,18–26] All 1H NMR spectra were recorded at

Tetrahydropyranylation of Alcohols
2893
90 MHz in CDCl3 or CCl4 relative to TMS (0.00 ppm), and IR spectra were
recorded on Shimadzu 435 IR spectrometer.
Protection of Benzyl Alcohol (2a) with Reagent (1) to Benzyl
Tetrahydropyranyl Ether (3a)
A solution of benzyl alcohol (3 mmol, 0.324 g) (2a) and reagent (1)
(0.075 mmol, 0.044 g) in CH2Cl2 (5 ml) was stirred at room temperature.
After 10 min, a solution of 3,4-dihydro-2H-pyran (3.3 mmol, 0.277 g) in
CH2Cl2 (2 ml) was added dropwise to the solution. When TLC showed
complete disappearance of benzyl alcohol (5 min), the solvent was evaporated
and residue was extracted with n-hexane (4 Â 5 ml). The combined organic
layer was evaporated under vacuum to give pure benzyl tetrahydropyranyl
ether (3a) as a colorless liquid in 95% yield (0.56 g).
ACKNOWLEDGMENT
We gratefully acknowledge the funding support received for this project from
the Isfahan University of Technology (IUT), Iran (A.R. H.) and Grant GM
33138 (A.E.R.) from the National Institutes of Health, USA. Further
financial support from the Center of Excellency in Chemistry Research
(IUT) is gratefully acknowledged.
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