Palladium on Carbon-Catalyzed Chemoselective Oxygen Oxidation of Aromatic Acetals

Article abstract of DOI:10.1021/acs.orglett.6b02833

The development of an unprecedented chemoselective transformation has contributed to forming a novel synthetic process for target molecules. Chemoselective oxidation of aromatic acetals has been accomplished using a reusable palladium on carbon catalyst under atmospheric oxygen conditions to form ester derivatives with tolerance of aliphatic acetals and ketals.

Full text of DOI:10.1021/acs.orglett.6b02833

Letter
pubs.acs.org/OrgLett
Palladium on Carbon-Catalyzed Chemoselective Oxygen Oxidation
of Aromatic Acetals
Naoki Yasukawa, Shota Asai, Maho Kato, Yasunari Monguchi, Hironao Sajiki,* and Yoshinari Sawama*
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4-Daigaku-nishi, Gifu 501-1196, Japan
S
* Supporting Information
ABSTRACT: The development of an unprecedented chemoselective trans-
formation has contributed to forming a novel synthetic process for target
molecules. Chemoselective oxidation of aromatic acetals has been accomplished
using a reusable palladium on carbon catalyst under atmospheric oxygen
conditions to form ester derivatives with tolerance of aliphatic acetals and ketals.
irect transformation methods that display novel chemo-
selectivity are crucially important to synthesize target
been reported. We now report a novel chemoselective oxygen
oxidation of aromatic cyclic acetals 1 bearing benzylic C−H
bonds into hydroxyalkyl ester derivatives 4 in the presence of
aliphatic acetals 2 or ketals 3 using reusable Pd/C as a catalyst
(Scheme 1).
D
molecules in fewer steps. Acetals and ketals are widely utilized
as protected carbonyl compounds and generally transformed
into various functionalities via the acid-mediated formation of
oxonium ion intermediates.1 Nevertheless ketals preferentially
undergo various transformations such as deprotection in the
presence of acetals because of the added stability of their
oxonium ion intermediates.1 Fujioka and Kita have also
pioneered the chemoselective transformation of acetals via
the specific formation of pyridinium-type salts mediated by
stoichiometic silyl triflates and an adequate pyridine derivative.2
Significantly, this method tolerates ketals, permitting the
efficient synthesis of target molecules in fewer steps. Never-
theless, a catalytic method with the ability to distinguish
between acetals and ketals has not been accomplished, and the
development of an unprecedented chemoselective trans-
formation of aromatic versus aliphatic acetals is still challenging.
On the other hand, various oxidative cleavages of cyclic acetals
into hydroxyalkyl esters have been widely developed using
stoichiometric oxidants [tert-butyl hydroperoxide (TBHP) with
transition metals,3 TBHP/pyridinium dichromate,4 TBHP/
iodine(III) compound,5 o-iodoxybenzoic acid/Et4NBr,6 PhI-
(OAc)2/LiBr,7 KMnO4,8 ozone,9 oxone,10 N-hydroxyphthali-
mide,11 NaOCl,12 electrophilic halogens,13 m-chloroperoxyben-
zoic acid,14 dimethyldioxirane,15 and hydrogen peroxide16]
because of the utility of the generated hydroxyalkyl esters as
synthetic precursors, such as in cross-linking of polyesters17 and
the site-selecitve Diels−Alder reaction.18 Additionally, the
hydroxyalkyl ester moiety is known to be a useful structural
unit of an active hypolipidemic agent.19 The clean oxidation of
cyclic acetals under atmospheric molecular oxygen conditions is
particularly attractive from the viewpoint of environmental and
economic considerations.20 However, these reaction conditions
never control the chemoselectivity between aromatic and
aliphatic cyclic acetals, which are equally oxidized to the
corresponding hydroxyalkyl esters. Furthermore, the heteroge-
neously catalyzed method and the chemoselective oxidation of
an acetal function in the presence of acid-labile ketals have not
Scheme 1. Palladium on Carbon-Catalyzed Chemoselective
Oxygen Oxidation of Aromatic Acetals 1 to Hydroxylalkyl
Esters 4
We initially investigated the catalyst and solvent efficiencies
of the oxidation of five-membered cyclic acetal 1a derived from
benzaldehyde and ethylene glycol as an aromatic acetal using 5
mol % catalyst under atmospheric oxygen at 80 °C for 6 h
(Table 1). The desired benzoic acid hydroxyethyl ester (4a)
was obtained using either 10% Pd/C or 10% Pt/C in MeOH in
high yield (entries 1 and 2), while Rh/C, Ru/C, and Au/C
were inefficient (entries 3−5). Ethylene glycol was also an
efficient solvent, giving 4a in 85% yield (entry 6). Because some
reactions in MeOH using other substrates (as shown in Table
2) gave the corresponding aromatic aldehyde dimethyl acetals
as byproducts by transacetalization, ethylene glycol proved to
be a better solvent. i-PrOH and THF were inadequate solvents
(entries 7 and 8), and the reaction in H2O gave benzoic acid via
hydrolysis of 4a (entry 9). The 20-fold scale-up reaction of 1a
(5 mmol) under the optimized reaction conditions using 10%
Pd/C in ethylene glycol (entry 6) could also be successfully
performed to give 4a in 84% yield (entry 10). Reuse of the
catalyst is important from the viewpoint of green sustainable
chemistry and cost performance. The 10% Pd/C can be reused
several times after simple filtration, a wash with H2O and
Received: September 20, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02833
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Table 1. Catalyst and Solvent Effects
Table 2. Scope of Substrates
yield (%)
SM (1a)
entry
catalyst
solvent
MeOH
4a
1
2
3
4
5
6
7
8
9
10% Pd/C
10% Pt/C
10% Rh/C
10% Ru/C
10% Au/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
0
0
88
70
0
MeOH
MeOH
16
2
MeOH
0
MeOH
3
4
(CH2OH)2
i-PrOH
0
85
37
43
0
53
45
0
THF
H2O
a
10
bc
,
(CH2OH)2
(CH2OH)2
(CH2OH)2
(CH2OH)2
(CH2OH)2
(CH2OH)2
(CH2OH)2
(CH2OH)2
(CH2OH)2
0
84
82
84
69
86
31
84
82
86
11
12
13
14
15
16
17
18
0
bd
,
0
e
f
17
0
g
h
i
51
0
4
j
0
a
b
5 mmol of 1a was used. 10% Pd/C was reused after simple filtration,
washing with H2O and MeOH, and drying in vacuo. In each run, 95−
c
99% of the Pd/C could be recovered. Second use of 10% Pd/C after
d
the reaction in entry 6. Third use of 10% Pd/C after the reaction in
e
f
g
h
i
entry 11. For 1 h. For 3 h. At room temperature. At 60 °C. Under
j
air. 1 mol % of 10% Pd/C was used.
MeOH, and drying (entries 11 and 12). During the present
oxidation, no Pd leaching into the reaction solution was
observed by inductively coupled plasma−optical emission
spectrometry (ICP-OES) analysis (see the Supporting In-
formation). Further experiments revealed that the oxidation
using 10% Pd/C (5 mol %) in ethylene glycol was complete
within 3 h (entry 6 vs entries 13 and 14) and could effectively
proceed even at 60 °C (entry 6 vs entries 15 and 16). The
desired oxidation could be performed under air (entry 17), and
a decrease in the catalyst loading to 1 mol % did not influence
the reaction efficiency, giving 4a in good yield (entry 18).21
The scope of substrates bearing a benzylic C−H bond was
next investigated (Table 2). Various aromatic five-membered
cyclic acetals 1b−h bearing electron-donating or electron-
withdrawing groups at the para position of each aromatic
nucleus efficiently underwent oxygen oxidation to give the
corresponding esters 4b−h in good to excellent yields (entries
1−7). Substrate 1i bearing an aromatic bromide moiety could
also be oxidized into the corresponding ester product 4i in
good yield, but a small amount of debrominated product 4a
was obtained (entry 8). Moreover, 1j and 1k bearing a methoxy
group at the meta and ortho positions, respectively, were
converted into the desired ester products in efficient yields
(entries 9 and 10). The oxidation of 1l derived from
cinnamaldehyde also proceeded effectively to provide α,β-
unsaturated ester 4l (entry 11). Naphthalene derivative 1m
could also be transformed into the corresponding ester 4m
(entry 12). Furthermore, the present oxidation method was
applicable to other types of aromatic cyclic acetals bearing 1,3-
dioxane (1n), 4,4,5,5-tetramethyldioxolane (1o), and unsym-
metrical dioxolanes derived from benzaldehyde (1p and 1q) to
a
b
Recovered yield of the starting material. At 120 °C (the reaction
c
hardly proceeded at 80 °C). The formation of an inseparable reduced
product of the olefin moiety was observed. See the Supporting
Information. Substrates were completely consumed except for entries
4 and 8. Bz: benzoyl.
d
give the corresponding esters in good yields (entries 13−16).
However, regiocontrolled cleavage of the unsymmetrical
dioxolanes 1p and 1q was extremely difficult, and mixtures of
regioisomers (4pa/4pb and 4qa/4qb) were obtained (entries
15 and 16).
B
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It is noteworthy that a ketal (2a) and an aliphatic acetal (3a)
did not undergo the present oxidation and remained unchanged
(eq 1). Since the reaction of 1a was completely inhibited by the
during the oxidation of 1a to 4a (entry 3). The aliphatic
aldehyde dimethyl acetal 3b was transformed into the five-
membered cyclic acetal 3a by transacetalization with ethylene
glycol (entry 4). The present chemoselectivities could be
realized by the use of substrates bearing an aromatic acetal and
an aliphatic acetal or ketal in the same molecule, as the aromatic
acetal moieties in 1r and 1s were selectively transformed into
the corresponding ester products 4r and 4s in good yields with
tolerance of the ketal and aliphatic acetal units (entries 5 and
6).
The obtained hydroxyalkyl ester 4a effectively underwent
esterification (acetylation or acryloylation) to give 5 or 6 as
unsymmetrical compounds bearing an ethylene glycol as the
basic framework structure (eq 3). The acrylated product can be
addition of 7,7,8,8-tetracyanoquinodimethane (TCNQ) or
tetracyanoethylene (TCNE) as a radical scavenger (eq 2), the
present oxidation of aromatic acetals probably proceeds via a
benzylic radical intermediate, which is known to be
comparatively stable, formed by C−H activation of the benzylic
C−H bonds.20b−e The detailed elucidation of the reaction
mechanism is under investigation.
Encouraged by the unprecedented chemoselectivities shown
in eq 1, we carried out the selective oxidation of aromatic
acetals in the presence of aliphatic acetals or ketals (Table 3).
The Pd/C-catalyzed oxygen oxidation of 1a to give 4a could be
selectively performed without any transformation of the
aromatic and aliphatic cyclic ketals 2a and 2b (entries 1 and
2). The aliphatic cyclic acetal 3a was perfectly unchanged
Table 3. Chemoselective Reaction of Aromatic Acetals
a useful backbone for constructing valuable functional materials,
such as the dendritic polyethylene−cationic poly(p-phenylene
ethynylene) polyvalent nanocarrier22 and a biorenewable
alternative for the glassy end blocks of the triblock copolymer.23
Furthermore, transesterification using methanol and amidation
using morpholine under basic conditions provided the
corresponding methyl ester 7 and morpholine amide 8,24
respectively (eq 3). These reactions could be performed under
basic conditions, which are inactive toward ketals.1 Namely, the
aromatic acetal moiety of 1t could be chemoselectively
transformed into a ketone (9) by consecutive Pd/C-catalyzed
oxygen oxidation, amidation using morpholine, and methyl-
ation24 using a Grignard reagent without the chemical
conversion of the coexisting ketal moiety in the same molecule
(eq 4). This type of transformation has never been
accomplished as a general synthetic procedure via the acid-
mediated transformation of acetals because ketals are
preferentially deprotected into ketones under acidic con-
ditions.1
We have developed an unprecedented catalytic and chemo-
selective transformation of aromatic cyclic acetals into the
corresponding hydroxyalkyl ester derivatives in the presence of
aliphatic cyclic acetals or ketals. The present mild and neutral
oxidation method using oxygen as a clean oxidant and a
C
DOI: 10.1021/acs.orglett.6b02833
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Organic Letters
Letter
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reusable heterogeneous Pd/C catalyst is valuable from the
viewpoint of green sustainable chemistry and provides a novel
synthetic process.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02833.
Typical procedures and spectroscopic data for the
products (PDF)
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5642.
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Tada, N.; Miura, T.; Itoh, A. Tetrahedron Lett. 2015, 56, 1973−1975.
(b) Karimi, B.; Rajabi, J. Synthesis 2003, 2373−2377. (c) Karimi, B.;
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: sajiki@gifu-pu.ac.jp.
*E-mail: sawama@gifu-pu.ac.jp.
Notes
The authors declare no competing financial interest.
(21) Other side products were not isolated.
(22) Zhang, L.; Huang, H.; Xu, N.; Yin, Q. J. Mater. Chem. B 2014, 2,
ACKNOWLEDGMENTS
■
4935−4942.
We thank the N. E. Chemcat Corporation for the kind gift of
the catalysts and Nissan Chemical Industries, Ltd. for the
important suggestion of the application of this method and the
ICP-OES measurements.
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Chem. Phys. 2016, 217, 292−303.
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