Copper(II) bromide as an efficient catalyst for acetal to bisarylmethyl ether interconversion

Article abstract of DOI:10.1016/j.tetlet.2014.10.115

Transprotection of acetals to bis(methoxyphenyl)methyl (BMPM) ethers can be efficiently achieved in the presence of copper dibromide as catalyst in acetonitrile at room temperature. Acetals are conveniently and selectively converted to the corresponding m

Full text of DOI:10.1016/j.tetlet.2014.10.115

Accepted Manuscript
Copper(II) bromide as efficient catalyst for acetal to bisarylmethyl ether inter-
conversion
Rofia Mezaache, Hassina Harkat, J. Obszynski, Abdelhamid Benkouider,
Aurélien Blanc, Jean-Marc Weibel, Patrick Pale
PII:
S0040-4039(14)01821-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.115
TETL 45344
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 August 2014
20 October 2014
21 October 2014
Please cite this article as: Mezaache, R., Harkat, H., Obszynski, J., Benkouider, A., Blanc, A., Weibel, J-M., Pale,
P., Copper(II) bromide as efficient catalyst for acetal to bisarylmethyl ether interconversion, Tetrahedron Letters
(2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.10.115
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Graphical Abstract
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Copper(II) bromide as efficient catalyst for
acetal to bisarylmethyl ether interconversion.
R. Mezaache, H. Harkat, J. Obszynski, A. Benkouider,
A. Blanc, J.-M. Weibel,* P. Pale*
Dept de pharmacie, Faculté de médecine, Université de
Batna, Batna, Algeria, and Laboratoire de synthèse,
réactivité organiques et de catalyse, Institut de Chimie,
UMR7177-CNRS, Université de Strasbourg, 67070
Strasbourg, France.
Acetals are conveniently and regioselectively
transformed into monoprotected diols in the presence
of bis(methoxyphenyl)methyl cation source and
copper bromide in acetonitrile. The new reagent
BMPMOiPr proved to be the most efficient for
transprotection with 1,3-dioxolanes and 1,3-dioxanes.

Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
Copper(II) bromide as efficient catalyst for acetal to
bisarylmethyl ether interconversion.
Rofia Mezaache,a,b Hassina Harkat,a,b J. Obszynski,b Abdelhamid Benkouider,a Aurélien Blanc,b
Jean-Marc Weibelb* and Patrick Paleb*
a Département de Pharmacie, Faculté de Médecine, Université de Batna, Batna 05000, Algeria
b Laboratoire de synthèse, réactivité organiques, et de catalyse, Institut de Chimie, UMR7177-CNRS, Université de Strasbourg, 4 Rue
Blaise Pascal, 67070 Strasbourg, France
Abstract: — Transprotection of acetals to bis(methoxyphenyl)methyl (BMPM) ethers can be efficiently achieved in the presence of copper
dibromide as catalyst in acetonitrile at room temperature. Acetals are conveniently and selectively converted to the corresponding mono-
protected diol with bis(methoxyphenyl)methyl isopropyl ether (BMPMOiPr) as reagent. This new practical reagent allows the BMPM
transfert to 1,3-dioxolanes or 1,3-dioxanes under copper catalysis. The reaction conditions are also very mild and tolerant to various
functional groups, including other protecting groups.
Keywords— protecting group; transprotection, acetal, alcohol; copper, bis(methoxyphenyl)methyl;
© 2014 Elsevier Science. All rights reserved
Acetal is the most common functional group in Nature, due
to its ubiquitous presence as glycosidic linkage in
carbohydrates and most glycoconjugates, the most
abundant natural products on Earth.1 Other natural
products, such as ionophore antibiotics2 and some
pheromones,3 also contain such motif, mostly as spiroketal.
Acetals are also common protecting groups in organic
synthesis.4
Despite their interest, acetal protecting groups sometimes
require to be exchanged by another group, especially in
total synthesis due to compatibility reasons,5 and more
recently, for the valorization of glycerol from biomass as
gasoline or diesel additives.6 Classically achieved through
Scheme 1. Diarylmethyl derivatives as protecting group: Palladium and
copper-promoted protection or deprotection of alcohols (eq.1); copper-
deprotection and reprotection, such sequence would be
more convenient by direct exchange. Although valuable,
such transprotections, converting one protecting group to
another, usually from a different orthogonal set, are
surprisingly scarce.4a
promoted transprotection of silyl ethers (eq. 2) and the present
transprotection of acetal (eq. 3).
Following our work on diarylmethyl ethers15 as alcohol
protecting groups revealing their orthogonal protection and
deprotection compared to classical benzyl-type groups
using palladium(II) salts16 or copper(II) bromide17 as
catalysts (Scheme 1, equation 1), we recently showed that
copper(II) bromide can catalyze the interconversion of silyl
ethers to bis(methoxyphenyl)methyl (BMPM) ethers
(Scheme 1, equation 2).18 We now report the
transprotection of acetonides and related acetals to our
Known transprotections include the transformation of enol
ethers into ketals7 or thioketals,8 the conversions of silyl or
THP ethers into benzyl ethers or esters,9 including
11
acetates,10 alkyl ethers to esters,10a,
thioesters into
thioethers or thioketals,12 allyl carbamates into amides,13 N-
Fmoc into S-fluorenylmethyl in cysteine and peptides.14
———
* Corresponding author. Tel.: +33 368 85 15 xx; fax: +33 368 85 xx xx; e-mail: jmweibel@unistra.fr.
* Corresponding author. Tel.: +33 368 85 15 17; e-mail: ppale@unistra.fr.

2
Tetrahedron Letters
recently introduced bis(methoxyphenyl)methyl (BMPM)
ethers (Scheme 1, equation 3).
1 was submitted to various BMPM derivatives in the
presence of copper dibromide (Table 1).
The results gained from our preceding investigations with
silyl ethers18 suggested a mechanism involving the transient
formation of an ion pair with a hydroxycuprate and a
bisbenzhydryl-type carbocation (A in Scheme 2), the latter
acting as Lewis acid toward the oxygen atom of a silyl
ether ultimately leading to transprotection. If true, this
suggests to use this ion pair toward acetals (Scheme 2).
Indeed, interaction and ligation of the bisbenzhydryl-type
carbocation to one acetal oxygen would give the oxonium
species B, in which the acetal would be broken and one
oxygen would be already converted to ether. Hydroxide ion
transfer from the hydroxycuprate anion would then
generate the corresponding ether hemiacetal C, giving the
transprotected product, while regenerating the copper
catalyst. Furthermore, the size of the bisbenzhydryl moiety
could lead to regioselective opening of the acetal, as in the
well known reductive opening of acetals, especially in
carbohydrate chemistry,19 and impede the further protection
of the so-formed hydroxy group.
Scheme 3. Lewis acid-promoted dissociation of diaryl ethers.
Table 1. Screening of conditions for the acetal to BMPM ether
interconversion.a
Entry
Reagent
Time Conv.
Yield(%)c
2:3
72
(h)
8
(%)b
1
2
3
4
5
6
BMPMOH
(BMPM)2Od
BMPMOAc
BMPMOMe
BMPMOiPr
85
3:1
4.5
48
6.5
4.5
4
100
50
100
1:1
32
1:0
50
46
4:1
100
0
88
3:1
e
BMPMOiPr
-
without CuBr2
Scheme 2. Proposed mechanism for the Cu(II)-catalyzed interconversion
a) [BMPM-OR]= 1.1 M, [Acetal]= 1 M, [Cu2+]= 0.1 M; b) based on the
recovered starting materials; c) cumulative isolated yield of 2 and 3,
without taking into account conversion; d) 0.55 equiv was used; e) starting
material recovered.
of acetals into BMPM ethers.
To explore this chemistry, we submitted acetonides derived
from glycerol to the best conditions achieved for the
transprotection from silyl to diarylmethyl ethers, i.e. with
copper(II) bromide (10 mol%) in acetonitrile at room
temperature.18 As shown in our earlier work in this area,
As expected, BMPM-OH gave transprotection products in
high yield, although the conversion was not complete even
after 8 h (entry 1). As anticipated (see above), the
monoether 2 was selectively produced. The multiplicity of
bis(methoxyphenyl)methanol
(BMPM-OH)
partly
dimerized in this reaction, but the so-formed ether
(BMPM)2O disappeared during the reaction course,
probably being in equilibrium with the ion pair already
mentioned (Scheme 3; R=H). The latter can be a source of
the bisbenzhydryl-type carbocation and thus used as
reagent. On the other hand, this equilibrium could be
controled and even suppressed depending on the leaving
group ability of the OR moiety (Scheme 3) if diarylmethyl
ethers or esters are used as reagent. Therefore, we first
examined the importance of the BMPM sources. The
acetonide of glycerol monoprotected with a pivaloyl group
1
the hydrogen atom of the hydroxyl group in H NMR in
deutered benzene (doublet at 2.35 ppm) allowed to
unambiguously determine the structure of compound 2.
However, and quite surprisingly, 2 was also accompanied
by the corresponding diether 3 in which the acetal was fully
replaced by two ethers. The latter was caracterized by the
1
presence in H NMR spectra of two methine hydrogens
from both benzhydryl moiety (5.71 and 5.25 ppm in C6D6).
The in situ formation of (BMPM)2O (see scheme 3) also
led to the concomitant formation of water, leading to 10%
of 2,3-dihydroxypropyl pivalate through
a
more
conventional mechanism (entry 1).20 Starting from the

Tetrahedron Letters
3
dimer mentioned above (BMPM)2O, both compounds 2 and
3 were equally produced. Interestingly from a mechanism
point of view (see below), the reaction was rather fast and
very efficient, with an almost quantitative transprotection
(entry 2). On the other hand, the BMPM acetate led to the
sole formation of the monoether 2 but with half conversion
despite a very long reaction time (entry 3). Surprisingly,
simple BMPM ethers proved effective and selective, but to
various extends depending on their ether moiety. With the
methoxy BMPM, only half conversion could be achieved
after 6.5h, but a good selectivity in favor of 2 was observed
(entry 4). In sharp contrast, the isopropoxy BMPM rapidly
and almost quantitatively provided the monoether 2 as the
main product, still with the diether 3 but with a good
selectivity in favor of the former (entry 5). Control
experiment without copper salt did not lead to any
transformation and only the starting materials were
recovered (entry 6).
noticing that different functional groups have been
introduced in the selected acetals in order to look at their
compatibility with the reaction conditions.
Table 2. Screening of catalysts for the acetal-to-BMPM ether
interconversion.a
Entry
R
Cat.
Time Yield Yield Yield Yield
(h) 1(%)b 2(%)b 3(%)b 4(%)b
1c
2 c
3 c
4 c
5 c
6
BMPM
FeCl3
Sc(OTf)3
InCl3
1
1.5
4
10
25
15
30
10
0
61
44
38
44
48
53
30
36
58
13
58
0
16
22
40
14
35
47
16
18
18
13
18
0
11
6
"
"
5
"
AuCl
2.5
24
4.5
7
8
Copper bromide (II) proved to be the most efficient catalyst
for the protection and deprotection of alcohol as
diarylmethylethers, as well as for the interconversion of
silyl to diarylmethyl ethers.17-18 To be sure that this catalyst
was also the best for the present acetal-to-BMPM ether
interconversion, we screened several other metal salts as
catalysts with the two best BMPM reagents identified
above (Table 2). Except palladium salts, the examined Sc,
Fe, Au, In catalysts also led to the mono- and diether 2 and
3 (entries 1-11 and 13 vs entry 12). Oxophilic catalysts
such as iron, scandium or indium salts did not lead to full
conversion, except copper salts (entries 1-5 and 7-12 vs
entries 6 and 13).21 The less oxophilic gold salts gave
variable results, but less effective than those achieved with
copper salts. Copper(II) bromide proved to be again the
best catalyst for the transprotection of acetal to BMPM
ethers.
"
NaAuCl4
CuBr2
7
"
0
7 c
8 c
9
iPr
"
FeCl3
15
10
10
18
10
90
0
4
Sc(OTf)3
InCl3
6.5
5.5
8
6
"
11
n.d.d
7
10
11 c
12
13
14
"
AuCl
"
NaAuCl4
7
"
Pd(MeCN)2Cl2 72
10
0
"
"
CuBr2
CuBr2
THF
4.5
64
63
24
20
12
5
5
15
16
"
"
CuBr2
dioxane
CuBr2
DCE
24
24
65
35
12
38
5
8
9
12
Solvents were also briefly screened. Performing the
reaction in the less coordinating THF did not change much
the outcome but led to longer reaction time (entry 14 vs
13). Surprisingly, in dioxane, the reaction turned out to be
very slow, and even after a day, the starting acetal 1 was
still the major compound together with the monoether 2
(entry 15 vs 13). In a non-coordinating solvent such as
dichloroethane, the reaction still proceeded but as expected,
slowly although less than in dioxane (entry 16 vs 15).
Despite a modest conversion, the monoether 2 was strongly
favored under these conditions.
a) [(BMPM)2O]= 1 M or [BMPM-OiPr]= 1.1 M, [Acetal]= 1 M, [Cu2+]=
0.1 M, in acetonitrile unless otherwise noted; b) Isolated yield, without
taking into account conversion; c) dichloroethane as solvent; d) n.d. for
not determined.
We first examined the role of the acetal nature in the
outcome of this transformation, since it has been showed
that ring and substituent sizes of acetal affect their
hydrolysis.22 A series of monopivaloyl glycerol, protected
with acetals of various sizes, was prepared and engaged in
the CuBr2-catalyzed transprotection. Increasing the size,
from dimethyl to diethyl, led to substantial decrease in
reactivity, with a significantly lower conversion (~ 25%)
and thus lower yields, but also in selectivity with an equal
amount of mono and diBMPM ethers formed (entry 2 vs 1).
Increasing rigidity with cyclohexylidene acetal also led to
some decrease in reactivity and selectivity, but to a less
extend (entry 3). Lowering the size did not increase
reactivity nor selectivity (entries 4-5), while the simplest
acetal seemed too fragile and only led to decomposition
under the reaction conditions (entry 6). Surprisingly,
The product of deacetalization, diol 4, could also be
detected in small amounts (≤ 12%) in most cases, except
with copper salts in acetonitrile (Table 2, entries 1-5 vs 6).
These observations tend to support a direct transprotection
for the copper-catalyzed version.
With these results in hand, we then briefly examined the
scope and limitation(s) of this copper-catalyzed
transprotection (Table 3). Various acetals were thus
prepared and submitted to the best conditions we found, i.e.
with BMPM-OiPr as reagent and with 10 mol% of copper
dibromide in acetonitrile at room temperature. It is worth

4
Tetrahedron Letters
shifting from 1,3-dioxolane to 1,3-dioxane restored
reactivity and seemed to increase the selectivity, but in
favor of the diBMPM ether (entry 7 vs 5).
Table 3. Screening of conditions for the acetal to BMPM ether
interconversion.a
To check the latter point and to invert the reaction course,
we investigated the reactivity of benzylidene acetals and
acetonide derived from carbohydrates (entries 9-11). It is
worth noting that such compounds already exhibit an acetal
moiety, potentially leading to competition and opening of
the carbohydrate ring. Rewardingly, not only the
carbohydrate moiety was preserved but the regioselectivity
of the acetal opening was very good and even excellent
starting from acetonides. Mostly or almost exclusively was
the 6-O-monoBMPM product formed, as expected from
steric constrain in such 4,6-O-benzylidene acetal derived
from glucose (entry 11 vs 9, 10).
Entry
Acetal
mono
Time
(h)
Yield
(%)b
BMPM
mono:di
88
1
2
3
4.5
4
3:1
70c
From these results, we can confirm the proposed
mechanism (see Scheme 2). Copper(II) bromide acts as
Lewis acid and, upon coordination to the BMPM reagent,
provides dimethoxybenzhydryl carbocation and a cuprate,
The carbocation could then be trapped by the oxygen atom
of the acetal, leading to acetal opening and ultimately to
transprotection. Such mechanism also allows to explain the
regioselectivity usually observed, based on steric grounds
(Scheme 4).
1:1
"
5
78
2:1
4
5
"
"
9
9
75c
1.5:1
50d
1.5:1
6
7
8
"
24
6
tracese
-
61c
1:4
7
75
Scheme 4. Rational for the observed regioselectivity in the present CuII-
1.4:1
catalyzed transprotection of acetals.
In summary, we have showed that transprotection of acetals
to bis(methoxyphenyl)methyl (BMPM) ethers can be
efficiently achieved in the presence of copper dibromide as
catalyst at room temperature. Starting from disymmetric
acetals, the reaction mostly provides the monoBMPM
ether. Furthermore, the reaction is regioselective, producing
the less crowdy monoBMPM ether. The reaction conditions
are also very mild and tolerant to various functional groups,
including other protecting groups.
9
7
7
55c
6:1
10
11
51c
6:1
4.5
4
40d
19:1
52 f
"
42:1
Copper(II) salts are cheap and non toxic Lewis acids; it is
thus worth to develop new applications of copper salts in
organic synthesis.23 The present interconversion of acetals
to BMPM ethers offers a new tool to the chemist palette.
a) [BMPM-OR]= 1.1 M, [Acetal]= 1 M, [Cu2+]= 0.1 M; b) Isolated yield;
c) 15-25% of starting material recovered; d) 30% of starting material
recovered; e) degradation occurred; f) performed in THF.
Further works are now in progress to further explore the
scope of this reaction and to extend its application to
organic synthesis.
Acknowledgments
The authors thank the "CNRS" and the French Ministry of
Research for financial support, as well as the CMEP-Tassili
exchange program for support to RM. HH thanks the
University of Batna for financial support. JO thanks the
FRC for a PhD fellowship.

Tetrahedron Letters
5
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Typical procedure: To a solution of acetal (1 mmol) and
BMPMOiPr (316 mg, 1.1 mmol) in dry acetonitrile (1 mL) was
added in one portion dried copper dibromide (22.5 mg, 0.1 mmol).
The resulting green solution was magnetically stirred under argon
at room temperature for 4.5 hours. The reaction mixture was
concentrated under vacuum and then diluted with ether (15 mL)
and water (15 mL). After partitioning, the aqueous layer was
extracted three times with ether (15 mL) and the combined
organic layers were dried over Na2SO4. After ether evaporation,
the residue was then purified by flash chromatography over silica
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