N-Bromosuccinimide (NBS): A mild and efficient catalyst for tetrahydropyranylation of alcohols and phenols under solvent-free conditions

Article abstract of DOI:10.1002/jccs.200700148

Different types of alcohols and phenols are tetrahydropyranylated in the presence of NBS catalyst in good to excellent yields under mild, neutral and solvent-free conditions.

Full text of DOI:10.1002/jccs.200700148

Journal of the Chinese Chemical Society, 2007, 54, 1029-1032
1029
N-Bromosuccinimide (NBS): a Mild and Efficient Catalyst for
Tetrahydropyranylation of Alcohols and Phenols under Solvent-Free
Conditions
Ardeshir Khazaei,a* Amin Rostamib and Ayeh Raiatzadeha
aDepartment of Chemistry, Faculty of Science, Bu-Ali Sina University, Hamedan, 6517838683, Iran
bDepartment of Chemistry, Faculty of Science, University of Kurdistan, Sanandaj, Iran
Different types of alcohols and phenols are tetrahydropyranylated in the presence of NBS catalyst in
good to excellent yields under mild, neutral and solvent-free conditions.
Keywords: N-Bromosuccinimide; Alcohols; Tetrahydropyranylation; Phenols; Solvent-free;
DHP.
INTRODUCTION
Protection of hydroxyl groups by their conversion to
plication of N-halo reagents in the transformation of or-
ganic functional groups,8 we have found that NBS is an in-
expensive, commercially available reagent. This reagent
has recently been used as an effective catalyst for acetaliza-
tion of carbonyl compounds,9a,b the conversion of alde-
hydes to 1,1-diacetates,9c and acylation of alcohols9d under
mild and nearly neutral reaction conditions. In this article
we wish to report a novel and efficient protocol for the
tetrahydropyranylation of a variety of alcohols and phenols
using dihydro-4H-pyran in the presence of a catalytic
amount of NBS at room temperature under solvent-free
conditions, as depicted in Scheme I.
the corresponding tetrahydropyranyl ethers (THP ethers) is
a common and extensively used transformation in organic
synthesis.1 This wide spread use is undoubtedly due to the
stability of the 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, carbo-
hydrate, and steroid chemistry.3 A variety of catalysts that
have been reported for this conversion include the use of
protic acids,4 Lewis acids,5 ionexchange resins,6 alumina
impregnated with ZnCl2,7a silica chloride,7b heteropoly
acids,7c ionic liquids,7d,e K-10 clay,7f I2,7g trichloroisocy-
anuric acid,7h polystyrene supported aluminum chloride,7i
PdCl2(CH3CN)27j and tetrabutylammonium bromide.7k Al-
though these methods are suitable for many synthetic con-
ditions, most of them have drawbacks such as harsh and
strong acidic conditions, expensive reagents, high tempera-
ture, special efforts required to prepare the catalyst, and
also volatile organic solvents or large amounts of solid sup-
ports are usually used, which would eventually result in the
generation of a large amount of toxic waste. Thus, it is in-
teresting to devise a solventless, neutral, inexpensive, mild
and catalytically efficient alternative for the protection of
hydroxyl functionality as THP ether.
Scheme I
(0.02-0.1 mmol)
NBS
+
RO
R
OH
,
O
Solvent-Free rt (1-9 h)
O
R=benzylic, linear, Cyclic, Aryl
We first examined the effect of different ratios of
ROH/DHP/catalyst. Ratios of 1:1.5:0.02 for alcohols and
1:3:0.1 for phenols gave the best result and furnished the
protected products in high yields (Table 1). Using this cata-
lyst, different kinds of alcohols (primary, secondary, ter-
tiary and benzylic) and phenols underwent tetrahydropyr-
anylation in good to excellent yields (Table 1). Due to the
nearly neutral nature of the reaction medium, no elimina-
tion by products were observed at all.
RESULTS AND DISCUSSION
Selectivity of a method is important in the multi-step
preparation of organic compounds and provides a broad
spectrum for its use in functional group transformation re-
During the course of our systematic study on the ap-

1030 J. Chin. Chem. Soc., Vol. 54, No. 4, 2007
Khazaei et al.
Table 1. Tetrahydropyranylation of alcohols and phenols using DHP catalyzed with NBS at
room temperature under solvent-free conditions
Entry
ROH
Subst/DHP/NBS
Time (h)
Yield (%)a,b
1
2
3
4
5
PhCH2OH
1:1.5:0.02
1:1.5:0.02
1:1.5:0.02
1:1.5:0.02
1:1.5:0.05
2.5
3.5
2.5
1
95
78
90
95
85
4-(OMe)C6H4CH2OH
4-(CH3)C6H4CH2OH
4-(Br) C6H4CH2OH
4-(NO2)C6H4CH2OH
3.5
CH2CH2OH
6
1:1.5:0.02
5.5
95
7
8
9
CH3(CH2) 6CH2OH
PhCH(OH)CH3
1:1.5:0.02
1:1.5:0.02
1:1.5:0.02
6.5
4
83
95
90
PhCH(OH)Ph
OH
9
10
11
1:1.5:0.02
1:5:0.3
8
90
86
OH
4.5
12
13
14
15
16
17
18
19
4-(CH3)C6H4OH
C6H5OH
1:3:0.1
1:3:0.1
1:3:0.1
1:3:0.1
1:3:0.1
1:3:0.1
1:3:0.1
1:6:0.2
3.5
4
95
90
92
90
92
81
87
70
4-(Cl)C6H4OH
4-(MeO)C6H4OH
1-Naphthol
5-Indanol
4
4
6
4.5
2.5
5
2-Naphthol
Resorcin
a All products were characterized by comparison of their spectral data (1H-NMR, IR spectro-
scopies) and physical propertieswith those of authentic compounds.
b Isolated yields.
actions. Therefore, we tried several competitive reactions
under similar conditions in order show the scope and limi-
tation of this catalytic system. By this system, a primary
benzylic hydroxyl group can be protected in the presence of
a secondary benzylic alcohol with the ratio of 90:10 (Table
2, entry 1). A primary aliphatic alcohol was protected in the
presence of tertiary alcohols with the ratio of 100:0 (Table
2, entry 2). An unhindered phenolic group can be very se-
lectively protected in the presence of a hindered phenolic
functional group (Table 2, entry 3).
tetrahydropyranylation of alcohols and phenols using
DHP, we propose a mechanism in which the role of NBS
for the protection of hydroxyl groups as DHP ethers is by
the in situ generation of catalytic amounts of HBr (Scheme
II).
CONCLUSIONS
In conclusion, we have introduced a new, selective
and efficient catalytic system for the tetrahydropyranyla-
tion reactions under mild and solvent-free conditions. NBS
is a safe, commercially available, inexpensive industrial
chemical. Due to the catalytic nature of the reaction, ab-
sence of volatile solvent, its mildness, non-toxic nature,
neutrality of conditions, availability and the low cost of the
reagent, we predict that this method will find useful appli-
In order to illustrate the catalytic activity of NBS, we
compared our obtained results for the tetrahydropyranyla-
tion of benzyl alcohol (as a model of alcohols) and phenol
(as a model of phenols) with the best of the well-known
data from the literature (Table 3).
On the basis of a previously reported mechanism,7g
and our observation in during the course of reaction for the

Tetrahydropyranylation of Alcohols and Phenols
J. Chin. Chem. Soc., Vol. 54, No. 4, 2007 1031
Table 2. Competitive tetrahydropyranylation reactions of alcohols using DHP in the presence
of NBS under solvent-free conditions
CH2OH
Me
Me
CH2OTHP
OTHP
(90%)
(10%)
,
Cat. (0.02 mmol)
(1.5 mmol)
DHP
1
OH
,
3h
Solvent -free
Ph
Ph
Ph
Ph
OH
OTHP
(100%)
,
Cat. (0.02mmol)
(1.5 mmol)
DHP
2
OTHP
OH
,
7h
Solvent -free
(0%)
(100%)
H3C
OTHP
H3C
OH
,
Cat. (0.1mmol)
(3 mmol)
DHP
3
,
4h
Solvent -free
OTHP
CH(CH3)2
OH
(H3C)2HC
(H3C)2HC
CH(CH3)2
(0%)
The percentage of the product in the reaction mixture was determined by GC analysis.
Table 3. Comparison of the activity of various catalysts in the tetrahydropyranylation of benzyl alcohol and phenol
Entry Substrate
Reagent
Condition
Cat/DHP
0.02:1.5
Time (hrs) Yield (%)
Ref
1
Benzyl
alcohol
a) NBS
Solvent free, rt
2.5
95
This work
b) K5CoW12O40.3H2O
c) PdCl2(CH3CN)2
d) LiOTf
Acetone, H2O, Reflux
THF, rt
0.01:2
5 min
1
97
72
96
98
92
91
90
-
7c
0.1:1.1
0.6:1.6
0.03:1
7j
ClCH2CH2Cl, reflux
Et2O, rt
2.5
1.5
5
5c
e) Fe(ClO4)3
5h
f) TCCA
Solvent-free 60-70 °C
CH2Cl2, rt
0.1:1.4
0.039:1.1
0.1:3
7g
g) Silica sulfuric acid
30 min
4
4e
2
Phenol
a) NBS
Solvent free, rt
This work
b) K5CoW12O40.3H2Oa Acetone, H2O, Reflux
0.01:2
NR
NR
5.5
N.R
36
7c
7j
a
c) PdCl2(CH3CN)2
d) LiOTf
THF, rt
0.1:1.1
0.6:1.7
0.03:1
-
ClCH2CH2Cl, reflux
Et2O, rt
94
-
5c
5h
7g
4e
e) Fe(ClO4)3
f) TCCA
Solvent-free, 60-70 °C
CH2Cl2, rt
0.1:1.4
0.039:1.1
85
-
g) Silica sulfuric acid
NR
a The reaction with substituted phenols gave traces of the corresponding products.
cation for the protection of the alcohols and phenols in
modern synthetic chemistry.
ture of DHP (0.1262-0.2524 g, 1.5-3 mmols) and NBS
(0.00356-0.01780 g, 0.02-0.1 mmols). The mixture was
stirred at room temperature for the appropriate reaction
time (Table 1). After completion of the reaction (TLC), the
resulting mixture was passed through a short column of sil-
ica gel using a mixture of n-hexane/acetone (10:1) as eluent.
Evaporation of the solvent under reduced pressure gave the
desired compound in high purity.
EXPERIMENTAL
General procedure for tetrahydropyranylation of al-
cohols and phenols catalyzed by NBS
The alcohol or phenol (1 mmol) was added to a mix-

1032 J. Chin. Chem. Soc., Vol. 54, No. 4, 2007
Khazaei et al.
Scheme II Proposed mechanism for the NBS-cata-
lyzed tetrahydropyranylation of alcohols
and phenols
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ACKNOWLEDGMENT
We are thankful to the Bu-Ali Sina University Re-
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Received August 28, 2006.
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