Sulfated tungstate as hydroxyl group activator for preparation of benzyl, including p-methoxybenzyl ethers of alcohols and phenols

Article abstract of DOI:10.1080/00397911.2016.1230218

Sulfated tungstate was found to be an effective heterogeneous and reusable catalyst for hydroxy group activation–mediated preparation of benzylic ethers including p-methoxybenzylic ethers of a wide range of alcohols and phenols under mild reaction conditions.

Full text of DOI:10.1080/00397911.2016.1230218

Sulfated Tungstate as Hydroxyl Activator for Preparation of Benzyl, Including p-
Methoxybenzyl Ethers of Alcohols and Phenols
Kamlesh V. Katkar1, Sachin D. Veer1, Krishnacharya G. Akamanchi1
1Department of Pharmaceutical Sciences and Technology, Institute of Chemical
Technology, Matunga, Mumbai, India
Address Corresponding to K. G. Akamanchi, Department of Pharmaceutical Sciences
and Technology, Institute of Chemical Technology, Matunga, Mumbai 400 019, India E-
mail kg.akamanchi@ictmumbai.edu.in, kgap@reddifmail.com
Abstract
Sulfated tungstate was found to be an effective heterogeneous and reusable catalyst for
hydroxy group activation mediated preparation of benzylic ethers including p-
methoxybenzylic ethers of a wide range of alcohols and phenols under mild reaction
conditions.
Graphical Abstract
KEYWORDS: Unsymmetrical ethers, Sulfated tungstate, Heterogeneous catalysis,
Alcohols, PMB protection
1

INTRODUCTION
Activation of hydroxyl group has been recognized, by ACS Green Chemistry
Institute (GCI) and the global pharmaceutical corporations in its roundtable meeting held
in 2005, as one of the important and high priority areas of research to-wards developing
green processes for manufacture of active pharmaceutical ingredients.[1] Nucleophilic
substitution reactions, using alcohols and its modified or activated form or in presence of
activators, are fundamental reactions in organic chemistry and used extensively in
alkylation of alcohols and phenols forming ethers, for N-alkylation, S-alkylation, Ritter
reactions, C-alkylation and many more.[2] Classical approaches of activation of alcohols
is derivatizing it into a good leaving group by making its tosylate, mesalyte, or acetate
among others or converting it into a good leaving chloride, bromide, or iodide.[3] In-situ
derivatization is another approach to activate alcohols most prominent among them being
activation by using DMAD as in case of Mitsunobu reactions, diimide based coupling
agents, triphenylphosphine/halogen combination and others.[4] All these approaches,
though frequently used, require stoichiometric or more amount of reagents, may need
additional steps and represent very poor overall atom economy leading to generation of
large amount of effluents. To overcome these limitations alcohols are directly employed
for the reactions in presence of activators, such as Lewis and Bronsted acids, metal salts
and complexes.[5]
Many homogeneous catalysts such as ZnCl2,[6a] FeCl3,[6b] Yb(OTf)3,[6c]
CO2(CO)6-complex,[6d] PtCl2-AgSbF6,[6e] BiBr3,[6f] PdCl2,[6g] Gold,[6h] IrCl2-complex[6i]
NaHSO3[6j] and [(C6H6)(PCy3)(CO)RuH]+BF4−[6k] have been reported in the etherification
2

of alcohols. These catalysts have some drawbacks such as, they get deactivated by water
formed during the reaction, difficulties of catalyst recovery and are often very expensive.
Other heterogeneous catalysts such as, AlPW12O40,[7a] Cs2.5TPA/ZrO2,[7b] Silica supported
heteropoly acid[7c] and Ti4+-montmorillonite[7d] have also been found suitable. Benzylic,
particularly benzyl and p-methoxybenzyl ethers are amongst the most extensively used
protecting groups for alcoholic and phenolic groups in organic synthesis due to
compatibility with variety of transformations ease of formation and providing options for
removal under wide range of conditions including hydrogenolysis, acid catalyzed
hydrolysis and oxidative cleavage.[8a] Benzylic ethers are useful as intermediates in
synthesis of dyes, pharmaceuticals, agrochemicals and are also found as structural
moieties in pharmaceuticals such as atomoxetine and dulotextin.[8b]
The benzyl groups, such as p-methoxybenzyl (PMB), have been used extensively
as protecting groups in carbohydrate chemistry.[9a-b] The most commonly employed
methods for PMB protection of alcohols involve usage of p-methoxybenzyl chloride
(PMBCl) or p-methoxybenzyl bromide (PMBBr) in presence of strong base like NaH.[9c]
The main problem associated with this method is handling and storage of PMBCl and
PMBBr which are prone to decomposition and highly lachrymatory.[10] Additionally, this
protocol requires anhydrous, conditions and in some cases use of hazardous bases like
NaH, n-BuLi. In contrast p-methoxybenzyl alcohol is stable, easy to handle, totally
devoid of these issues.
Our research group has devoted particular attention towards development of environment
3

friendly and efficient protocols for organic transformations using sulfated tungstate[11a]
a
green, reusable, heterogeneous, mild acid catalyst. Also demonstrated its effective use as
catalyst in amide bond formation,[11a-b] Biginelli,[11c] Willgerodt-Kindler reactions,[11d]
Strecker synthesis,[11e] Kindler reaction,[11f] N-formylation,[11g] transamidation[11h] and
hydration of alkynes.[11i] Sulfated tungstate activates alcohols and assists in alkylation as
demonstrated by N-monoalkylation of primary amines.[11j] On the same track feasibility
of sulfated tungstate as catalyst, for etherification of wide range of alcohols and phenols
by nucleophilic displacement of benzylic hydroxyl group was tested and results are
presented in this paper.
RESULT AND DISCUSSION
Initial experiment was conducted by stirring a mixture of p- methoxybenzyl alcohol and
n-butanol in presence of sulfated tungstate at 80 °C; reaction proceeded well to offer
desired unsymmetrical ether 1-(butoxymethyl)-4-methoxybenzene A (92% yield),
showing >99% selectivity, without the formation of symmetric ethers (B and C) (Scheme
1). Further investigations were under taken with this as model reaction.
Reactions were carried out at different temperatures and the best results were obtained at
80 °C. Investigations were also carried out to optimise the catalyst quantity and the
results are depicted in (Table 1, entries 1-3). To optimise the catalyst amount, a set of
experiments were carried out with increasing amounts of catalyst in the range of 1-15
wt%. From the outcome, it was concluded that an amount of 10 wt% was optimum giving
4

maximum yield with absence of dibenzyl ether B further increase in quantity did not
show any beneficial results (Table 1, entries 4-8).
To optimise mole ratio of substrates, experiments, by varying ratios of substrates were
carried out and results are given in Table 2. The reaction with equimolar quantities of p-
methoxybenzyl alcohol and n-butanol shows 56% yield of 1-(butoxymethyl)-4-
methoxybenzene A but with formation of 44% dibenzyl ether B (Table 2, entry 1). With
further increase in mole ratio formation of B was reduced. At the mole ratio of 1:2.5
(Table 2, entry 4) formation of B was completely absent and with yield of 92% of A.
Hence for further studies this mole ratio was selected.
To access general applicability of this protocol for PMB benzylation of various alcohols
was carried out and the results are exemplified in Table 3.
Sulfated tungstate was found to be suitable and efficient for preparation of p-
methoxybenzlic ethers. p-Methoxybenzyl alcohol could react with primary, secondary
and tertiary alcohols, giving corresponding PMB ethers in high yields (Table 3, entries 1-
7). Similarly cyclic alcohols underwent reaction smoothly and gave the ether in high
yield without formation of cyclic olefins arising out of acid catalyst dehydration.
Otherwise under strong acidic condition dehydration is a competitive reaction (Table 3,
entries 8-9). Another noteworthy feature of this protocol is selective formation in mono-
PMB ether of diols a further useful for monoprotection of diols. In the case of 1,4
butane-diol and cis-2-butene-1,4-diol the mono-PMB protected products were obtained
5

in good yield (Table 3, entries 10-11). PMB protection also showed good results in case
of allylic alcohols (Table 3, entry 12) and 1-pentyn-4-ol (Table 3, entry 14) giving high
yield without effecting triple bond, thus showing chemoselectivity.
To test the general applicability of the protocol experiments were performed using
different benzylic alcohols and results are given in Table 4.
It can be seen that, various benzylic alcohols on reaction with n-butanol offered high
yields of corresponding benzylic ethers (Table 4, entries 1-5). Various substituted benzyl
alcohols such as p-chloro- and p-hydroxybenzyl alcohols with electron-donating groups
at the para-position, also gave good yield (Table 4, entries 3-5). Vanillyl butyl ether,
commonly used as warming agents and in fragrances could also be synthesized in high
yield (Table 4, entry 5). It is note worthy that under the reaction conditions p-hydroxy
groups remained unreacted thus showing chemoselectivity. The protocol can also be
extended to preparation of secondary benzylic ethers of variety of alcohols. Thus α-
methyl, α-phenylbenyl, ethers of variety of alcohols could be prepared in high yields
(Table 4, entries 6-13). It is to be emphasised here that under the reaction condition,
none of the α-methylbenzyl alcohols underwent dehydration to form styrenes (Table 4,
entries 6-9). Therefore, sulfated tungstate appears to be very mild catalyst for preparation
of benzylic (primary and secondary) ethers of alcohols.
Different phenols were also screened for preparation of their PMB ethers but under
slightly modified reaction conditions of using 1:1 ratio of phenols and p-methoxybenzyl
6

alcohol in toluene as solvent. The results are given in Table 5. PMB etherification of all
the phenols could be performed in moderate to good yield (Table 5, entries 1–8) without
formation of dibenzyl ether B. This observation is attributed to higher reactivity of
phenols. In case of p-hydroxyphenol, mono-PMB ether was obtained in good yield with
small amount of di-PMB, ether (Table 5, entry 6).
Reusability study was performed by following standard protocol, catalyst recovered
simply by filtration of reaction mass, followed by washing with ethyl acetate and drying
at 100 oC, and found that the catalyst was stable and reusable four times without
significant loss of catalytic activity and yield dropped marginally from 92% to 88% with
respect to fresh and fourth recycle respectively, the results are compiled in Table 6.
Catalyst leaching experiment was performed by heating catalyst alone in n-butanol at 80
oC for 2h. Catalyst was filtered and to the filtrate p-methoxybenzyl alcohol was added
and heated at 80 0C for 5h. There was no reaction. The workup of the reaction mixture is
simple, convenient and user friendly. Thus protocol developed represents improved and
cost effective methodology for etherification.
In Conclusion, It is established that sulfated tungstate is a mild, efficient, selective,
recyclable, solvent free and user-friendly catalyst for preparation of benzylic including p-
methoxybenzylic ethers of a variety of alcohols and phenols under solvent free conditions
that scores very high on eco-friendliness. This method may attract attention, especially
7

for p-methoxybenzyl protection of alcohols and phenols using p-methoxybenzyl alcohol,
a stable and safe reagent.
EXPERIMENTAL
Preparation Of Sulfated Tungstate
Sulfated tungstate was prepared as described in reference [11a]
General Procedure For Sulfated Tungstate Mediated Synthesis Of 1-
(Butoxymethyl)-4-Methoxybenzene (Table 3 Entry 4)
Sulfated tungstate (10 wt%) was added to a mixture of p-methoxybenzyl alcohol (1g,
7.25mmol) and n-butanol (1.34g, 18.11mmol) the reaction mixture was stirred at 80 °C
for 1h. The progress of the reaction was monitored by TLC. After completion of the
reaction, the reaction mixture was diluted with EtOAc (15ml) and filtered to recover the
catalyst. Organic layer was concentrated under reduced pressure, residue obtained was
purified by chromatography on silica gel (#60-120) with n-hexane-EtOAc (90 : 10) as
eluent to get pure p-methoxybenzyl ether as colourless oil.
Yield: 92%, Colorless liquid; bp: 260-262°C (lit6j 262-263°C); ); Rf 0.75 (n-
hexane/EtOAc, 90:10); IR 2931, 2863, 1229, 1098 cm-1; 1H NMR (400 MHz; CDCl3;
Me4Si): δ = 7.27-7.24 (d, J=8.64 Hz, 2H), 6.89-6.86 (d, J=8.64 Hz, 2H), 4.43 (s, 2H),
3.80 (s, 3H), 3.45-3.41 (t, 2H), 1.64-1.59 (m, 2H), 1.41-1.35 (m, 2H), 0.90-0.84 (t, 3H).
8

All the products were known compounds and were characterized by IR, 1H NMR spectral
data, boiling points and compared with reported values.
SUPPORTING INFORMATION
Experimental method, 1H NMR, IR and MP for this article can accessed in the
publisher’s website.
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Table 1. Optimization of Reaction Conditionsa
Entry Sulfated
tungstate (wt%)
15
Temp
Time
[h]
1
Yield of Ab
Yield of Bc
1
2
3
4
5
6
7
8
100
80
60
80
80
80
80
80
65
94
50
NR
18
46
92
94
35
00
00
NR
12
10
00
00
15
15
-
2
12
12
8
2
5
8
10
15
1
1
aReaction condition: p-methoxybenzyl alcohol (1g, 7.25 mmol), n-butanol (1.34g, 18.11
mmol) at 80 °C.
bIsolated yield, cGC analysis.
12

Table 2. Mole ratio studya
Entry p-methoxybenzyl alcohol : n-butanol (mmol) Yield of Ab
Yield of Bb
(%)
(%)
44
1
2
3
4
1 : 1
56
76
90
92
1: 1.5
1: 2.0
1: 2.5
24
Trace
00
aReaction was performed with appropriate mmol scale with 10 wt% of catalyst for 1h at
80 °C, bIsolated yield.
13

Table 3. Synthesis of p-methoxybenzylic ether of different classes of alcohols by sulfated
tungstatea
Yieldb
R
Entry
Product
Time
(h)
1
2
3
CH3
2
2
80
85
90
CH3CH2
CH3(CH2)2
1.5
4
5
CH3(CH2)3
CH3(CH2)4
(CH3)2CH
(CH3)3C
1
1
2
1
2
92
87
88
85
88
6
7
8
cyclo-C5H9
cyclo-C6H11
2
2
83
9
80c
10
HO-CH2(CH2)3
83c
85
11
12
HO-CH2CH=CHCH2
CH2=CHCH2
3
2
13
14
CH2=CH(CH2)9
2
2
87
80
CH≡C(CH2)3
aReaction conditions: p-methoxybenzyl alcohol (1.0 equiv), alcohols (2.5 equiv) at 80 °C,
solvent free. bIsolated yield, cno disubstituted product observed (by GC). All products are
1
known and were identified by their boiling point, IR and HNMR spectra according to
literature.
14

Table 4. Etherification of different classes of benzalic alcohols by sulfated tungstatea
R1
R2
Entry
Product
Time (h) Yieldb
1
2
C6H4CH2
CH3(CH2)3
CH3(CH2)3
2
2
88
90
p-CH3C6H4CH2
3
4
5
p-ClC6H4CH2
p-HOC6H4CH2
CH3(CH2)3
CH3(CH2)3
3.5
3.5
3
82
80
83
p-HO,m-OCH3C6H3CH2 CH3(CH2)3
6
7
8
9
Ph(CH)CH3
Ph(CH)CH3
CH3(CH2)2
CH3(CH2)3
CH3(CH2)3
CH3(CH2)3
2
2
2
3
88
90
87
82
p-CH3Ph(CH)CH3
p-ClPh(CH)CH3
Ph(CH)Ph
10
11
12
13
14
CH3CH2
CH3(CH2)2
CH3(CH2)3
CH2C≡CH
CH3(CH2)3
2
2
2
2
2
81
86
89
85
82
Ph(CH)Ph
Ph(CH)Ph
Ph(CH)Ph
PhCH=CHCH2
15

aReaction conditions: benzylic alcohol (1.0 equiv), alcohols (2.5 equiv) at temperature 80
b
°C, solvent free. Isolated yield. All products are known and were identified by their
boiling point, IR and 1H-NMR spectra according to literature.
16

Table 5. PMB protection of hydroxy groups in the presence of sulfated tungstatea
Yieldb
90
R
Entry
1
Product
Time
(h)
1.5
2
3
2
85
86
2
4
2
4
85
78
5c
6c
7c
4
5
72
70
8c
3
80
aReaction conditions: p-methoxybenzyl alcohol (1.0 equiv), alcohols (1.0 equiv) at 80 °C,
b
c
solvent free. Isolated yield, toluene as solvent. All products are known and were
identified by their melting point, IR and 1H-NMR spectra according to literature
17

Table 6. Reusability studya
Run no.b
% Yield of 1-(butoxymethyl)-4-
methoxybenzene
Fresh
92
91
91
90
88
First Recycle
Second Recycle
Third Recycle
Fourth Recycle
aReaction condition: p-methoxybenzyl alcohol (1 g, 7.25 mmol), n-butanol (11.34g,
b
18.11 mmol) at 80 0C, 1h. Loss of catalyst (<5%) during handling.
18

Scheme 1. Etherification of n-butanol with p-methoxybenzyl alcohol Ratio of
A:B:C=>99:<1:<1
19