Efficient deprotection of phenol methoxymethyl ethers using a solid acid catalyst with Wells-Dawson structure

Article abstract of DOI:10.3390/61201006

Deprotection of various phenols from their respective methoxymethyl ethers using an heteropolyacid catalyst was studied. The catalyst was the Wells-Dawson heteropolyacid, used both in bulk or supported on silica. Yields were high to quantitative after less than one hour reaction time and the catalyst was easily recoverable and reusable.

Full text of DOI:10.3390/61201006

Molecules 2001, 6, 1006-1011
molecules
ISSN 1420-3049
http://www.mdpi.org
Efficient Deprotection of Phenol Methoxymethyl Ethers Using a
†
Solid Acid Catalyst with Wells-Dawson Structure
1
,2,*
1
3
2
G. Romanelli , J.C. Autino , G. Baronetti and H. Thomas
1
Laboratorio de Estudio de Compuestos Orgánicos (LADECOR), Departamento de Química, Facultad de
Ciencias Exactas, Universidad Nacional de La Plata. Calles 47 y 115, (1900) La Plata, Argentina.
Centro de Investigación y Desarrollo en Procesos Catalíticos (CINDECA), Departamento de Química,
Facultad de Ciencias Exactas, Universidad Nacional de La Plata. Calle 47 Nº 257, (1900) La Plata,
Argentina.
2
3
†
Departamento de Ingeniería Química, Universidad de Buenos Aires. Pabellón de Industrias. (1428)
Ciudad Universitaria. Buenos Aires. Argentina.
This paper was presented at the Fifth Electronic Conference on Synthetic Organic Chemistry (ECSOC-
5), September 1-30, 2001 (Paper A0038).
*
Author to whom correspondence should be addressed; E-mail: gpr@dalton.quimica.unlp.edu.ar
Received: 27 October 2001 / Accepted: 2 November 2001 / Published: 30 November 2001
Abstract: Deprotection of various phenols from their respective methoxymethyl ethers
using an heteropolyacid catalyst was studied. The catalyst was the Wells-Dawson
heteropolyacid, used both in bulk or supported on silica. Yields were high to quantitative
after less than one hour reaction time and the catalyst was easily recoverable and
reusable.
Keywords: Protecting groups; methoxymethyl ethers; heteropolyacids; Well-Dawson
catalyst; phenols.

Molecules 2001, 6
1007
Introduction
Usually, the removal of methoxymethylene protective groups is carried out in liquid phase using
mainly sulphuric or hydrochloric acids as catalysts [1-3]. However, the problems associated with the
handling and disposal of the inorganic acids, and the environmental and potential hazards of the same
have raised interest in the development of an alternative process using solid acid catalysts. The use of
heteropolyoxoanions (HPAs) as catalysts is an interesting area that has widely been studied recently. The
6
+
6+
HPAs are composed of a close-packed framework of metal-oxygen octahedra, MO (M=Mo , W )
x
4
+
5+
surrounding a central atom, X (Si , P ). In particular, the Wells-Dawson acid structure (H P W O .aq.)
6
2
18 62
consists of two identical “half units” (P W ) linked through the oxygen atoms.
2
9
In this work, we present a deprotection study carried out using such a heteropolyacid (HPA) with
Wells-Dawson structure in organic solvents. The Wells-Dawson acid (WD) was tested using both bulk
solid samples and solid-supported ones using on large pore silica as the support.
Results and Discussion
The deprotection reaction was studied using compounds 1-9 as the substrates. Different reaction
conditions were checked, e.g. temperature, time, reaction solvent, concentration of the solution and
aggregation state of the catalyst. Concentration of the catalyst on the support and the molar ratio of WD to
substrate were also varied.
Reactions using bulk catalyst
When 1,2-dichloroethane was the solvent, the bulk catalyst did not dissolve, even at 80ºC. The
reaction is slow under these conditions and a maximum yield of 80% is reached in 5 hours. Secondary
products begin to appear at longer reaction times. On the other hand, the use of methanol as the solvent
allows the catalyst to dissolve, the reaction is fast and the yields are excellent, e.g. 98% within 45 min or
100% after 1 hr. reaction at 65ºC (Table 1).
Methanol is therefore a good solvent for the reaction, but it has the disadvantage that it dissolves the
WD off the silica when the supported catalyst was used. Consequently, we examined the use of mixtures
of solvents in which the catalyst is insoluble and small amounts (1 – 5%) of methanol. Yields are very
good using a 1,2-dichloroethane-methanol mixture. Among other potential solvents, THF was also
studied. Yields are low and reactions are slow when pure THF is used; however, addition of 1% methanol
rises the yield, being quantitative in 40 min. In all the experiments 1% catalyst (moles/ mole of substrate)
was used.

Molecules 2001, 6
1008
Scheme 1. Phenol methoxymethyl ether substrates.
CH OMe
2
O
CH OMe
2
OH
O CH OMe
R3
2
O
R1
N
Me
O
R2
1
– 6
7 – 8
9
1
2
3
Compound
R
R
R
H
1
2
3
4
5
6
OH
H
Ac
H
H
OCOC10
OH
H
7
-β
Ac
H
COCH
COC10
H
7
-β
H
2
CHO
OMe
H
H
OMe
i-
Pr
7
α
β
8
Table 1. Deprotection of 1 using 1% of bulk Well-Dawson catalyst
Run
Solvent
T (ºC)
80
t (min)
300
45
% yield
80
1
2
3
4
5
6
Cl (CH )
2
2 2
MeOH
65
98
Cl (CH ) -MeOH 5%
70
45
95
2
2 2
Cl (CH ) -MeOH 1%
70
45
96
2
2 2
THF
THF-MeOH 1%
70
180
40
53
65
98
Reactions using supported catalyst
In view of the results obtained when bulk catalyst and different solvents were employed (see Table 1),
in all the experiments involving supported catalysts, solvents with 1% added methanol were used. Since
the solvents checked showed no substantial differences, we did not study further the use of the chlorinated
one. Formation of various by-products was observed when the reactions were carried out at a temperature
of 75ºC or higher. The use of WD(20)/SiO catalyst, or use of greater percentages of catalyst (in moles
2
with respect to the substrate) affords similar yields to those obtained with the WD(60)/SiO catalyst
2

Molecules 2001, 6
1009
[
Table 2, runs 11 and 13 vs. 3]. The yields obtained were similar, regardless of whether WD,
WD(20)/SiO or WD(60)/SiO were used [Table 1, run 6, vs. Table 2, run 13]. However, use of the
2
2
supported ones allows for the easy separation and recovery of the catalyst for its immediate reutilization,
without any lowering of its catalytic activity. Dilution turns the reaction slower [Table 2, runs 6, 7, 8 vs.
3], and raising the quantity of catalyst used have not a substantial effect [Table 2, runs 9 and 10 vs. 3].
Deprotection of compounds 2-9 was performed using standard reaction conditions to give clean reactions,
with yields higher than 90% in most of the examples. Optimised results are included in Table 2.
Table 2. Deprotection using supported Well-Dawson catalysts
Run
1
Substrate Catalyst Catalyst (mol %) Solvent T (ºC) t (min) Dilution % yield
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
3
3
4
4
5
6
7
8
9
b
b
b
b
b
b
b
b
b
b
a
a
a
b
a
a
b
a
b
a
b
b
b
b
b
1
1
1
1
1
1
1
1
5
10
1
1
5
1
1
1
1
1
1
1
1
1
1
1
1
c
c
80
70
70
50
75
65
65
65
65
65
65
70
65
65
65
65
65
65
65
65
65
65
65
65
65
30
45
45
105
45
90
120
45
60
45
50
40
55
60
55
45
60
60
60
60
60
60
60
60
60
---
---
70
95
2
3
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
---
100
97
4
---
5
---
70
6
x 2
x 4
x 1/2
---
100
95
7
8
90
9
99
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
---
95
---
100
90
---
---
95
---
100
100
90
---
x 1/2
---
100
95
---
---
85
---
80
---
95
---
90
---
92
---
95
---
72
a) WD(20)/SiO ; b) WD(60)/SiO ; c) Cl (CH ) -MeOH 1%; d) THF-MeOH 1%;
2
2
2
2 2

Molecules 2001, 6
1010
Conclusions
The MOM-ether deprotection reactions performed using Wells-Dawson catalysts were clean, their
workup was very simple and the yields ranged were good to excellent. The use of these solid catalysts
allows replacement of the usual soluble inorganic acids. It also contributes to waste reduction.
Acknowledgements
Financial support from CONICET (Argentina), and Universidad Nacional de La Plata is gratefully
acknowledged.
Experimental
General
Methoxymethyl ethers 1, 2, 5-8 were obtained by refluxing the appropriate phenol with ClCH OCH ,
2
3
in the presence of anhydrous K CO and acetone for 3-6 hours, depending on the starting phenol.
2
3
Acylation of 1 gave 3 [4] and Baker-Venkataraman rearrangement of 3 gave 4 [4]. The 2-quinolone 9 was
prepared as already described [5]. Purification of the MOM-ethers was accomplished by flash column
chromatography on silica gel. Structure and substitution patterns of the starting MOM-compounds is
shown in Scheme 1. Reaction products were characterised by GC-MS (their spectra were in agreement
with the expected ones in all cases) and by comparison of their TLC with authentic samples.
The Wells-Dawson acid (H P W O .aq.) was prepared as described elsewhere [6] from an aqueous
6
2
18 62
solution of α/β K P W O ·10H O salt, which was treated with ether and concentrated (37%) HCl
6
2
18 62
2
solution.
Silica-supported Wells-Dawson acids (WD) were prepared by wet impregnation of Grace Davison
2
silica (Grade 59, specific area= 250 m /g) with an aqueous solution of the synthesised WD acid. Two
catalysts containing 20 and 60 wt% of WD were prepared (WD(20)/SiO and WD(60)/SiO , respectively).
2
2
After impregnation, samples were dried at room temperature in a vacuum-dessicator for 8 h.
Typical procedure
In a deprotection experiment, 40 – 60 mg of substrate were dissolved in 1.0 mL of solvent (see Table
2) and the catalyst was added to the solution. The mixture was then stirred at the indicated temperature,
and reactions were assumed complete when the TLC analysis did not show any starting material. The
reaction mixture was filtered; the filtrate was concentrated and subjected to flash column chromatography
on silica. In all the experiments, the desired products were obtained with high selectivity, and the starting
material could be quantitatively recovered. The results are collected in the Tables.

Molecules 2001, 6
1011
References
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2
3
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967, 1, 132.
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6
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Sample Availability: Samples of compounds 1 and 3 are available from MDPI.
2001 by MDPI (http://www.mdpi.org). Reproduction is permitted for non commercial purposes.
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