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.Facultad de Ciencias Exacta

Autino, Juan Carlos

Baronetti, Graciela T.

Romanelli, Gustavo Pablo

Thomas, Horacio J.

Molecules

Baronetti, Graciela Teresita

Thomas, Horacio Jorge

Servicio de Difusión de la Creación Intelectual

Molecules 2001, 6, 1006-1011moleculesISSN 1420-3049http://www.mdpi.orgEfficient Deprotection of Phenol Methoxymethyl Ethers Using aSolid Acid Catalyst with Wells-Dawson Structure†G. Romanelli1,2,*, J.C. Autino1, G. Baronetti 3 and H. Thomas2 1 Laboratorio de Estudio de Compuestos Orgánicos (LADECOR), Departamento de Química, Facultad deCiencias Exactas, Universidad Nacional de La Plata. Calles 47 y 115, (1900) La Plata, Argentina.2 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.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.arReceived: 27 October 2001 / Accepted: 2 November 2001 / Published: 30 November 2001Abstract: Deprotection of various phenols from their respective methoxymethyl ethersusing an heteropolyacid catalyst was studied. The catalyst was the Wells-Dawsonheteropolyacid, used both in bulk or supported on silica. Yields were high to quantitativeafter less than one hour reaction time and the catalyst was easily recoverable andreusable.Keywords: Protecting groups; methoxymethyl ethers; heteropolyacids; Well-Dawsoncatalyst; phenols.Molecules 2001, 6 1007IntroductionUsually, the removal of methoxymethylene protective groups is carried out in liquid phase usingmainly sulphuric or hydrochloric acids as catalysts [1-3]. However, the problems associated with thehandling and disposal of the inorganic acids, and the environmental and potential hazards of the samehave raised interest in the development of an alternative process using solid acid catalysts. The use ofheteropolyoxoanions (HPAs) as catalysts is an interesting area that has widely been studied recently. TheHPAs are composed of a close-packed framework of metal-oxygen octahedra, MOx (M=Mo6+, W6+)surrounding a central atom, X (Si4+, P5+). In particular, the Wells-Dawson acid structure (H6P2W18O62.aq.)consists of two identical “half units” (P2W9) linked through the oxygen atoms.In this work, we present a deprotection study carried out using such a heteropolyacid (HPA) withWells-Dawson structure in organic solvents. The Wells-Dawson acid (WD) was tested using both bulksolid samples and solid-supported ones using on large pore silica as the support.Results and DiscussionThe deprotection reaction was studied using compounds 1-9 as the substrates. Different reactionconditions were checked, e.g. temperature, time, reaction solvent, concentration of the solution andaggregation state of the catalyst. Concentration of the catalyst on the support and the molar ratio of WD tosubstrate were also varied.Reactions using bulk catalystWhen 1,2-dichloroethane was the solvent, the bulk catalyst did not dissolve, even at 80ºC. Thereaction is slow under these conditions and a maximum yield of 80% is reached in 5 hours. Secondaryproducts begin to appear at longer reaction times. On the other hand, the use of methanol as the solventallows the catalyst to dissolve, the reaction is fast and the yields are excellent, e.g. 98% within 45 min or100% 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 theWD off the silica when the supported catalyst was used. Consequently, we examined the use of mixturesof solvents in which the catalyst is insoluble and small amounts (1 – 5%) of methanol. Yields are verygood using a 1,2-dichloroethane-methanol mixture. Among other potential solvents, THF was alsostudied. Yields are low and reactions are slow when pure THF is used; however, addition of 1% methanolrises the yield, being quantitative in 40 min. In all the experiments 1% catalyst (moles/ mole of substrate)was used.Molecules 2001, 6 1008Scheme 1. Phenol methoxymethyl ether substrates.1 –  6   7 – 8         9Compound R1 R2 R31 OH Ac H2 H H H3 OCOC10H7-β Ac H4 OH COCH2COC10H7-β H5 CHO H OMe6 OMe H Pr i-7 α8 βTable 1. Deprotection of  1 using 1% of bulk Well-Dawson catalystRun Solvent T (ºC) t (min) % yield1 Cl2(CH2)2 80 300 802 MeOH 65 45 983 Cl2(CH2)2-MeOH 5% 70 45 954 Cl2(CH2)2-MeOH 1% 70 45 965 THF 70 180 536 THF-MeOH 1% 65 40 98Reactions using supported catalystIn 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. Sincethe solvents checked showed no substantial differences, we did not study further the use of the chlorinatedone. Formation of various by-products was observed when the reactions were carried out at a temperatureof 75ºC or higher. The use of WD(20)/SiO2 catalyst, or use of greater percentages of catalyst (in moleswith respect to the substrate) affords similar yields to those obtained with the WD(60)/SiO2 catalystOR3R1CH2OMeNOOHMeOO CH2OMeCH2OMeR2Molecules 2001, 6 1009[Table 2, runs 11 and 13 vs. 3]. The yields obtained were similar, regardless of whether WD,WD(20)/SiO2 or WD(60)/SiO2 were used [Table 1, run 6, vs. Table 2, run 13]. However, use of thesupported 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 catalystsRun Substrate Catalyst Catalyst  (mol %) Solvent T (ºC) t (min) Dilution % yield1 1 b 1 c 80 30 --- 702 1 b 1 c 70 45 --- 953 1 b 1 d 70 45 --- 1004 1 b 1 d 50 105 --- 975 1 b 1 d 75 45 --- 706 1 b 1 d 65 90 x 2 1007 1 b 1 d 65 120 x 4 958 1 b 1 d 65 45 x 1/2 909 1 b 5 d 65 60 --- 9910 1 b 10 d 65 45 --- 9511 1 a 1 d 65 50 --- 10012 1 a 1 d 70 40 --- 9013 1 a 5 d 65 55 --- 9514 2 b 1 d 65 60 --- 10015 2 a 1 d 65 55 --- 10016 2 a 1 d 65 45 x 1/2 9017 3 b 1 d 65 60 --- 10018 3 a 1 d 65 60 --- 9519 4 b 1 d 65 60 --- 8520 4 a 1 d 65 60 --- 8021 5 b 1 d 65 60 --- 9522 6 b 1 d 65 60 --- 9023 7 b 1 d 65 60 --- 9224 8 b 1 d 65 60 --- 9525 9 b 1 d 65 60 --- 72a) WD(20)/SiO2; b) WD(60)/SiO2; c) Cl2(CH2)2-MeOH 1%;  d) THF-MeOH 1%;Molecules 2001, 6 1010ConclusionsThe MOM-ether deprotection reactions performed using Wells-Dawson catalysts were clean, theirworkup was very simple and the yields ranged were good to excellent. The use of these solid catalystsallows replacement of the usual soluble inorganic acids. It also contributes to waste reduction.AcknowledgementsFinancial support from CONICET (Argentina), and Universidad Nacional de La Plata is gratefullyacknowledged.ExperimentalGeneralMethoxymethyl ethers 1, 2, 5-8 were obtained by refluxing the appropriate phenol with ClCH2OCH3,in the presence of anhydrous K2CO3 and acetone for 3-6 hours, depending on the starting phenol.Acylation of 1 gave 3 [4] and Baker-Venkataraman rearrangement of 3 gave 4 [4]. The 2-quinolone 9 wasprepared as already described [5]. Purification of the MOM-ethers was accomplished by flash columnchromatography on silica gel. Structure and substitution patterns of the starting MOM-compounds isshown in Scheme 1. Reaction products were characterised by GC-MS (their spectra were in agreementwith the expected ones in all cases) and by comparison of their TLC with authentic samples.The Wells-Dawson acid (H6P2W18O62.aq.) was prepared as described elsewhere [6] from an aqueoussolution of α/β K6P2W18O62·10H2O salt, which was treated with ether and concentrated (37%) HClsolution.Silica-supported Wells-Dawson acids (WD) were prepared by wet impregnation of Grace Davisonsilica (Grade 59, specific area= 250 m2/g) with an aqueous solution of the synthesised WD acid. Twocatalysts containing 20 and 60 wt% of WD were prepared (WD(20)/SiO2 and WD(60)/SiO2, respectively).After impregnation, samples were dried at room temperature in a vacuum-dessicator for 8 h.Typical procedureIn a deprotection experiment, 40 – 60 mg of substrate were dissolved in 1.0 mL of solvent (see Table2) 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. Thereaction mixture was filtered; the filtrate was concentrated and subjected to flash column chromatographyon silica.  In all the experiments, the desired products were obtained with high selectivity, and the startingmaterial could be quantitatively recovered. The results are collected in the Tables.Molecules 2001, 6 1011References1. Yardley, J.P.; Fletcher III, H. Synthesis 1976, 244.2. Wiesner, K. Pure Appl. Chem., 1979, 51, 689.3. Fieser, L. F. Fieser, M. Reagents for Organic Synthesis, J. Wiley and Sons, Inc.: New York, NY.1967, 1, 132.4. Jios, J. L.; Autino, J. C.; Pomilio, A. B. An. Asoc. Quim. Argent. 1995, 83, 183.5. Corral, R. A.; Orazi, O. O.; Autino, J. C. Tetrahedron Lett. 1983, 2359.6. Baronetti, G.T.; Briand, L.; Sedran, U.; Thomas, H. Appl. Catal. A: General 1998, 172, 265.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.

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

SEDICI - Repositorio de la UNLP

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†
G. Romanelli1,2,*, J.C. Autino1, G. Baronetti 3 and H. Thomas2
 
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.
2 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.
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
HPAs are composed of a close-packed framework of metal-oxygen octahedra, MOx (M=Mo6+, W6+)
surrounding a central atom, X (Si4+, P5+). In particular, the Wells-Dawson acid structure (H6P2W18O62.aq.)
consists of two identical “half units” (P2W9) linked through the oxygen atoms.
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.
1 –  6   7 – 8         9
Compound R1 R2 R3
1 OH Ac H
2 H H H
3 OCOC10H7-β Ac H
4 OH COCH2COC10H7-β H
5 CHO H OMe
6 OMe H Pr i-
7 α
8 β
Table 1. Deprotection of  1 using 1% of bulk Well-Dawson catalyst
Run Solvent T (ºC) t (min) % yield
1 Cl2(CH2)2 80 300 80
2 MeOH 65 45 98
3 Cl2(CH2)2-MeOH 5% 70 45 95
4 Cl2(CH2)2-MeOH 1% 70 45 96
5 THF 70 180 53
6 THF-MeOH 1% 65 40 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)/SiO2 catalyst, or use of greater percentages of catalyst (in moles
with respect to the substrate) affords similar yields to those obtained with the WD(60)/SiO2 catalyst
O
R3
R1
CH2OMe
N
O
OH
Me
O
O CH2OMe
CH2OMe
R2
Molecules 2001, 6 1009
[Table 2, runs 11 and 13 vs. 3]. The yields obtained were similar, regardless of whether WD,
WD(20)/SiO2 or WD(60)/SiO2 were used [Table 1, run 6, vs. Table 2, run 13]. However, use of the
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 Substrate Catalyst Catalyst  (mol %) Solvent T (ºC) t (min) Dilution % yield
1 1 b 1 c 80 30 --- 70
2 1 b 1 c 70 45 --- 95
3 1 b 1 d 70 45 --- 100
4 1 b 1 d 50 105 --- 97
5 1 b 1 d 75 45 --- 70
6 1 b 1 d 65 90 x 2 100
7 1 b 1 d 65 120 x 4 95
8 1 b 1 d 65 45 x 1/2 90
9 1 b 5 d 65 60 --- 99
10 1 b 10 d 65 45 --- 95
11 1 a 1 d 65 50 --- 100
12 1 a 1 d 70 40 --- 90
13 1 a 5 d 65 55 --- 95
14 2 b 1 d 65 60 --- 100
15 2 a 1 d 65 55 --- 100
16 2 a 1 d 65 45 x 1/2 90
17 3 b 1 d 65 60 --- 100
18 3 a 1 d 65 60 --- 95
19 4 b 1 d 65 60 --- 85
20 4 a 1 d 65 60 --- 80
21 5 b 1 d 65 60 --- 95
22 6 b 1 d 65 60 --- 90
23 7 b 1 d 65 60 --- 92
24 8 b 1 d 65 60 --- 95
25 9 b 1 d 65 60 --- 72
a) WD(20)/SiO2; b) WD(60)/SiO2; c) Cl2(CH2)2-MeOH 1%;  d) THF-MeOH 1%;
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 ClCH2OCH3,
in the presence of anhydrous K2CO3 and acetone for 3-6 hours, depending on the starting phenol.
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 (H6P2W18O62.aq.) was prepared as described elsewhere [6] from an aqueous
solution of α/β K6P2W18O62·10H2O salt, which was treated with ether and concentrated (37%) HCl
solution.
Silica-supported Wells-Dawson acids (WD) were prepared by wet impregnation of Grace Davison
silica (Grade 59, specific area= 250 m2/g) with an aqueous solution of the synthesised WD acid. Two
catalysts containing 20 and 60 wt% of WD were prepared (WD(20)/SiO2 and WD(60)/SiO2, respectively).
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
1. Yardley, J.P.; Fletcher III, H. Synthesis 1976, 244.
2. Wiesner, K. Pure Appl. Chem., 1979, 51, 689.
3. Fieser, L. F. Fieser, M. Reagents for Organic Synthesis, J. Wiley and Sons, Inc.: New York, NY.
1967, 1, 132.
4. Jios, J. L.; Autino, J. C.; Pomilio, A. B. An. Asoc. Quim. Argent. 1995, 83, 183.
5. Corral, R. A.; Orazi, O. O.; Autino, J. C. Tetrahedron Lett. 1983, 2359.
6. Baronetti, G.T.; Briand, L.; Sedran, U.; Thomas, H. Appl. Catal. A: General 1998, 172, 265.
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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Efficient deprotection of phenol methoxymethyl ethers using a solid acid catalyst with Wells-Dawson structure

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