Efficient tetrahydropyranylation of phenols and alcohols catalyzed by supported Mo and W Keggin heteropolyacids

Article abstract of DOI:10.1081/SCC-120018695

The protection of phenols as tetrahydropyranyl acetals is studied using supported Keggin heteropolyacids as catalysts, specifically molybdophosphoric or tungstophosphoric acids supported on silica. Phenol tetrahydropyranyl acetals are obtained in short times at room temperature with excellent yields. Protection of alcohols is also performed under mild conditions using both supported heteropolyacids, with yields ranging between good and quantitative. The reactions are clean and their workup is very simple. The use of these solid catalysts allows replacing the usual soluble inorganic acids, contributing to waste reduction.

Full text of DOI:10.1081/SCC-120018695

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Efficient Tetrahydropyranylation of Phenols and
Alcohols Catalyzed by Supported Mo and W Keggin
Heteropolyacids
G. P. Romanelli , P. G. Vázquez , L. R. Pizzio , C. V. Cáceres , M. N. Blanco & J. C.
Autino
To cite this article: G. P. Romanelli , P. G. Vázquez , L. R. Pizzio , C. V. Cáceres , M. N. Blanco
&
J. C. Autino (2003) Efficient Tetrahydropyranylation of Phenols and Alcohols Catalyzed by
Supported Mo and W Keggin Heteropolyacids, Synthetic Communications, 33:8, 1359-1365,
DOI: 10.1081/SCC-120018695
To link to this article: http://dx.doi.org/10.1081/SCC-120018695
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 8, pp. 1359–1365, 2003
Efficient Tetrahydropyranylation of Phenols
and Alcohols Catalyzed by Supported
Mo and W Keggin Heteropolyacids
1
,2
2
zquez, L.R.Pizzio,
2
G.P.Romanelli,
2
P.G.Va
´
ceres, M.N.Blanco, and J.C.Autino 1,*
2
C.V.Ca
´
1
LADECOR, Laboratorio de Estudio de Compuestos
Organicos, Departamento de Quımica,
Facultad de Ciencias Exactas, Universidad Nacional de
´
´
La Plata, La Plata, Argentina
2
CINDECA, Centro de Investigacio
´
n en Procesos
mica,
Catalıticos, Departamento de Quı
´
´
Facultad de Ciencias Exactas, Universidad Nacional de
La Plata – CONICET, La Plata, Argentina
ABSTRACT
The protection of phenols as tetrahydropyranyl acetals is studied
using supported Keggin heteropolyacids as catalysts, specifically
*Correspondence: J. C. Autino, LADECOR, Laboratorio de Estudio de
Compuestos Organicos, Departamento de Quımica, Facultad de Ciencias
´ ´
Exactas, Universidad Nacional de La Plata, Calles 47 y 115, B1900AJL La Plata,
Argentina; E-mail: jautino@quimica.unlp.edu.ar.
1
359
DOI: 10.1081/SCC-120018695
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1
360
Romanelli et al.
molybdophosphoric or tungstophosphoric acids supported on silica.
Phenol tetrahydropyranyl acetals are obtained in short times at
room temperature with excellent yields. Protection of alcohols is
also performed under mild conditions using both supported
heteropolyacids, with yields ranging between good and quantitative.
The reactions are clean and their workup is very simple. The use
of these solid catalysts allows replacing the usual soluble inorganic
acids, contributing to waste reduction.
Key Words: Protecting group; Tetrahydropyranyl; Heteropoly-
acids; Keggin catalyst; Alcohols; Phenols.
INTRODUCTION
Transformation of phenols and alcohols into their mixed acetals,
ketals, ethers, or esters, has been recognized as a useful method for
[
1]
hydroxyl group protection. Tetrahydropyranyl acetal is one of the most
common and useful derivatives for that protection, because of its ease
of formation, relative ease of removal, stability of the acetals to various
nonacidic reaction conditions and the reagent low cost. Introduction of
THP group on oxygen is usually carried out using a mineral acid as catalyst
[
1,2]
[3]
both in liquid phase
heterogeneous catalysts have been used, such as zinc chloride on alumina,
or adsorbed on a solid support. Besides, other
[
4]
[5]
[6]
vanadyl(IV) acetate, zirconium sulfophenyl phosphonate, etc. The
problems associated with both, the handling and the disposal of the
conventional inorganic acids e.g., sulfuric, hydrofluoric, boron trifluoride
have raised the interest in the development of alternative clean processes
using solid acid catalysts.
Keggin heteropolyacids (HPAs) are constituted by a close-packed
framework of metal-oxygen octahedra, MO (M ¼ Mo(VI), W(VI)) sur-
6
[
7]
rounding a central atom X (Si(IV), P(V)). These catalysts are stronger
acids than the conventional ones. Advantages of using supported HPAs
to be highlighted are their ease of recovery and recycling after carrying
out the liquid phase reactions, and the easier isolation of the products in
comparison with homogeneously catalyzed reactions. The preparation of
supported Keggin based catalysts from tungstophosphoric acid (TPA) and
[
8–10]
from molybdophosphoric acid (MPA) has been described elsewhere.
[
A variety of reactions have been reported to be catalyzed by HPAs.
7,11,12]
Tetrahydropyranylation of alcohols was carried out using homogeneous
catalysis by HPAs, and likewise was accomplished the protection of
unsubstituted phenol; however, tetrahydropyranylation of substituted

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Tetrahydropyranylation of Phenols and Alcohols
1361
[
12]
phenols was reported to proceed with low yields. The use of other acid
catalysts for achieving the protection of phenols has involved reaction
conditions such as e.g., stirring of a mixture of the reactants and a satu-
ꢀ
[13]
rated AcOEt solution of HCl for 24 h at 25 C.
RESULTS
We have found that tetrahydropyranylation can be accomplished
very easily and cleanly on phenols, as well as on naphthols (Table 1).
Toluene was used as solvent and both HPAs supported on silica, MPA/S
and TPA/S, were used as catalysts. Reactions were optimized by varying
reaction temperature, reaction time, MPA(TPA) content of the catalyst,
mole ratio MPA/S(TPA/S):ArOH, 3,4-dihydro-2H-pyran (DHP) excess
and solvent. Characteristic reaction conditions include short times and
room temperature. In all the experiments the desired products were
obtained free of secondary products and almost quantitatively, and start-
ing phenol was quantitatively recovered when the reaction was incomplete.
Optimized reaction conditions are showed in Table 1 and the structures
of the phenols are included in the Figure 1. Besides, we have applied the
same procedure for achieving the tetrahydropyranylation of some alcohols
in toluene, comparing catalysis by both supported HPAs (Table 2).
Table 1. Protection of phenols and naphthols as tetrahydropyranyl
a
acetals.
Mole ratio
DHP/phenol
b
Phenol
Catalyst
Time (h)
% Yield
1
1
1
2
2
3
4
5
6
7
8
MPA/S
TPA/S
1
1
1
5
2
1
1
2
2
1
1
2:1
2:1
5:1
2:1
5:1
2:1
2:1
2:1
2:1
2:1
2:1
93
93
96
75
97
89
93
90
89
92
89
MPA/S
MPA/S
MPA/S
MPA/S
MPA/S
MPA/S
MPA/S
MPA/S
MPA/S
a
ꢀ
Reactions were performed at 20 C in toluene, using 1% (mmol) of
[
14]
MPA (TPA) supported on silica and washed.
b
Yields were calculated from isolated products.

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362
Romanelli et al.
1
2
3
Compound
R
R
R
1
2
3
4
5
6
H
NO
H
H
2
H
H
OMe
Cl
H
H
H
H
CHO
H
OMe
i-Pr
H
Me
7
8
a-Naphthol
b-Naphthol
Figure1. Phenolsubstratesforthe tetrahydropyranylationreaction.
a
Table 2. Protection of alcohols as tetrahydropyranyl acetals.
b
Compound
Alcohol
Benzyl
Benzyl
Catalyst
% Yield
9
9
MPA/S
TPA/S
MPA/S
TPA/S
MPA/S
TPA/S
MPA/S
TPA/S
MPA/S
TPA/S
98
97
1
1
1
1
1
1
1
1
0
0
1
1
2
2
3
3
2-Phenylethanol
2-Phenylethanol
3-Phenyl-1-propanol
3-Phenyl-1-propanol
1-Phenyl-2-propanol
1-Phenyl-2-propanol
2-Phenoxyethanol
2-Phenoxyethanol
97
100
89
88
94
93
96
97
a
ꢀ
Reactions were performed for 1 h at 20 C in toluene, using a
mole ratio alcohol:DHP (1:2) and 1% (mmol) of MPA (TPA)
[
14]
supported on silica and washed.
b
Yields were calculated from isolated products.
When unsubstituted phenol (1) was protected using a DHP:1 mole
ratio 1:1, toluene as solvent and 1% MPA/S as catalyst, a maximum yield
ꢀ
of 82% was attained at 1 h reaction at 15 C. A reaction time of 0.5 h was
insufficient, and reaction times exceeding 1 h gave a lower yield. Besides,

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Tetrahydropyranylation of Phenols and Alcohols
1363
no noticeable changes occur by increasing the amount of the catalyst to
ꢀ
5%, irrespective of the temperature. A 93% yield was obtained at 20 C
and 1 h reaction using both catalysts (MPA/S or TPA/S), mole ratio 2:1,
ꢀ
and toluene as solvent (Table 1). p-Nitrophenol (2) required 5 h at 20 C
for attain a maximum yield, however using four-fold molar excess DHP,
an excellent yield is achieved in 2 h. THP acetals of compounds 3–8 are
obtained in good yield in 1–2 h reaction (Table 1). Alcohols were
protected in good to quantitative yield irrespective of the used catalyst
(
microanalytical
Table 2). Obtained THP acetals were homogeneous by HPTLC and their
and spectral data agree with the expected values.
[15]
On reutilization of the catalyst once more, the results obtained in the
first use were reproduced, within the experimental error.
REPRESENTATIVE PROTECTION REACTION
Protection was carried out mixing the phenol (0.33 mmol) with the
[
14]
stated quantity of DHP (see Table 1), the supported catalyst
and
ꢀ
toluene (1 mL). The suspension was stirred at 15 or 20 C during the
stated time (Table 1) and then was stirred with 3 mL of toluene; the
catalyst was filtered off and then was washed twice with 1 mL portions
of toluene. The extract and washings were combined and the organic
phase was washed with 1 M NaOH, then it was dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo. The residue
was then subjected to a short column flash chromatography, eluting
the product with toluene. Protection of alcohols does not involve the
alkaline washing step.
ACKNOWLEDGMENTS
Financial support of Universidad Nacional de La Plata, CONICET
and Agencia Nacional de Promocion Cientıficay Tecnolo gica
´ ´ ´
(
Argentina) is gratefully acknowledged.
REFERENCES
1
. Greene, T.W.; Wuts, P.G.M. Protection for the hydroxyl group,
including 1,2- and 1,3-diols. In Protective Groups in Organic Synthesis;
Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols, 2nd
Ed.; Wiley: New York, 1991; 31–34.

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2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
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3
. McOmie,J.F.W.Protectivegroups.Adv.Org.Chem.1963,3,191–294.
. Heravi, M.M.; Ajami, D.; Ghassemzadeh, M. Solvent free
tetrahydropyranylation of alcohols and phenols over sulfuric
acid adsorbed on silica gel. Synth. Commun. 1999, 29 (6), 1013–
1016.
4
. Ranu, B.C.; Saha, M.A. Simple, efficient, and selective method for
tetrahydropyranylation of alcohols on a solid phase of alumina
impregnated with zinc chloride. J. Org. Chem. 1994, 59, 8269–8270.
. Choudary, B.M.; Neeraja, V.; Lakshmi Kantam, M. Vanadyl(IV)
acetate: a mild and efficient heterogeneous catalyst for the tetra-
hydropyranylation of alcohols, thiols and phenols. J. Mol. Catal.
A—Chemical 2001, 175, 169–172.
5
6
. Curini,M.;Epifano,F.;Marcotullio,M.C.;Rosati,O.;Costantino,U.
Zirconium sulfophenyl phosphonate as a heterogeneous catalyst in
tetrahydropyranylation of alcohols and phenols. Tetrahedron Lett.
1998, 39, 8159–8162.
7
8
9
. Kozhevnikov, I.V. Heteropoly acids and related compounds as
catalysts for fine chemical synthesis. Catal. Rev. Sci. Engin. 1995,
37 (2), 311–352.
. Pizzio, L.R.; Ca
´
ceres, C.V.; Blanco, M.N. Acid catalysts prepared
by impregnation of tungstophosphoric acid solutions on different
supports. Appl. Catal. A 1998, 167 (2), 283–294.
. Va
on supported 12-molybdophosphoric acid. Catal. Lett. 1999, 60,
05–215.
zquez, P.G.; Blanco, M.N.; Caceres, C.V. Catalysts based
´ ´
2
1
0. The silica-supported MPA or TPA based catalysts were prepared
by means of the pore filling impregnation technique. Solutions of
H PMo O Án H O (MPA) or H PW O Án H O (TPA) in ethanol-
3
12 40
2
3
12 40
2
water were used with the necessary concentration in order to obtain
a content of 0.3 g MPA(TPA)/g catalyst. The support was SiO2
Grace (S). Then, the catalysts were dried at room temperature for
ꢀ
2
4 h and calcined at 250 C for 1 h.
1
1
1. Okuhara, T.; Mizuno, N.; Misono, M. Catalytic chemistry of
heteropoly compounds. Adv. Catal. 1996, 41, 113–252.
´ ´
2. Molnar, A.; Beregszaszi, T. Mild and efficient tetrahydropyranyla-
tion and deprotection of alcohols catalyzed by heteropoly acids.
Tetrahedron Lett. 1996, 37 (47), 8597–8600.
1
3. Grant, H.N.; Prelog, V.; Sneeden, R.P.A. Synthese eines 1-oxaphe-
nalen-derivates mit dem chromophoren system des biflorins. Helv.
Chim. Acta 1963, 46, 415–421.
14. The used catalysts, MPA and TPA both supported on silica, were
prior to the reaction, washed with toluene three times during 24 h

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Tetrahydropyranylation of Phenols and Alcohols
1365
each, with continuous stirring. The final content of HPA showed to
be 0.3 mg MPA(TPA)/mg of catalyst.
5. Analytical data for selected acetals: 1—THP: Calcd. for C H O :
1
1
1
14
2
C, 74.13, H, 7.92. Found: C, 74.01, H, 7.90. 2—THP: Calcd. for
C H NO : C, 59.19, H, 5.87, N, 6.27. Found: C, 59.23, H, 5.85, N,
1
1
13
4
6.24. 4—THP: Calcd. for C H O : C, 69.21, H, 7.74. Found:
C, 69.16, H, 7.72. 5—THP: Calcd. for C H O : C, 76.87,
12 16 3
1
5
22
2
H, 9.48. Found: C, 76.81, H, 9.44. 8—THP: Calcd. for C H O :
1
5
16
2
C, 78.92, H, 7.06. Found: C, 78.87, H, 7.03. 10—THP: Calcd. for
C H O : C, 75.69, H, 8.80. Found: C, 75.62, H, 8.78. 11—THP:
Calcd. for C H O : C, 76.32, H, 9.15. Found: C, 76.25, H, 9.12.
1
3
18
2
1
4
20
2
13—THP: Calcd. for C H O : C, 70.24, H, 8.16. Found: C, 70.19,
H, 8.12.
13 18 3
Received in the USA June 15, 2002

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