Copper-catalyzed selective oxygenation of methyl and benzyl substituents in pyridine with O2

Article abstract of DOI:10.1246/cl.161074

A selective oxygenation of picolines and their derivatives has been achieved by usingasimple copper salt as a catalyst and molecular oxygen as an oxidant, where the α-position of the alkyl substituent is selectively oxidized to give the corresponding aldehydes or ketones. Addition of a catalytic amount of water enhances the catalytic activity, which could be attributed to the role of the proton donor to activate the substrates.

Full text of DOI:10.1246/cl.161074

Advance Publication Cover Page
Copper-Catalyzed Selective Oxygenation of Methyl and Benzyl Substituents
in Pyridine with O2
Tsukasa Abe, Shinji Tanaka, Atsuko Ogawa, Masanori Tamura, Kazuhiko Sato,* and Shinobu Itoh*
Advance Publication on the web December 29, 2016
doi:10.1246/cl.161074
© 2016 The Chemical Society of Japan
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Publication manuscripts.

1
Copper-Catalyzed Selective Oxygenation of Methyl and Benzyl Substituents
in Pyridine with O2
Tsukasa Abe,1 Shinji Tanaka,2 Atsuko Ogawa,2 Masanori Tamura,2 Kazuhiko Sato,*2 and Shinobu Itoh*1
1 Department of Material and Life Science, Division of Advanced Science and Biotechnology, Graduate School of Engineering, Osaka
University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
2 Interdisciplinary Research Center for Catalytic Chemistry, National Institute of Advanced Industrial Science and Technology (AIST),
Central 5, 1-1-1 Higashi, Tsukuba 305-8565, Japan
(E-mail: k.sato@aist.go.jp)
A selective oxygenation of picolines and their derivatives
Copper salts have been widely used as catalysts for
oxidative transformations of organic substrates, and their
combination with O2 has been a central research topic in terms
of not only the bioinorganic chemistry8,9 but also green-
sustainable chemistry.10-12 Behavior of copper salts in solution
is not so simple,13-15 because activity of copper salts is highly
dependent on counter anions, additives, and solvents, and in
some cases, the formation of multi-nuclear copper species is
observed in solution.14 Maes et al. reported that the CuI-
catalyzed oxygenation of benzyl pyridines using O2 and acetic
acid,16 although the oxidation of picolines did not proceed
except for a substrate containing electron withdrawing
group.16b Lei et al. reported the oxygenation of alkyl pyridines
catalyzed by CuCl2·2H2O with O2 using an equimolar amount
of ethyl chloroacetate for the activation of substrates, even
though picolines were inert under their reaction conditions.17
Thus, elucidation of the roles of additives in the Cu-catalyzed
has been achieved by using a simple copper salt as a catalyst
and molecular oxygen as an oxidant, where the position of
the alkyl substituent is selectively oxidized to give the
corresponding aldehydes or ketones. Addition of a catalytic
amount of water enhances the catalytic activity, that could be
attributed to a role of proton donor to activate the substrates.
Molecular oxygen (O2) is the cheapest natural resource
for the synthesis of oxygen-containing chemical products, so
that direct conversion of bulk chemicals into value-added
chemicals by oxygenation using O2 is highly desired.1 Since
the auto-oxidation of organic compounds with O2 is generally
non-selective, a variety of catalysts that can control the
reactivity of active-oxygen species (AOS) has been developed
to achieve selective transformation reactions. The oxidation of
benzylic positions in heteroaromatic compounds is one of the
most powerful synthetic tools to obtain carbonyl containing
derivatives. In particular, pyridinecarbaldehyde and its
derivatives are useful intermediates for the synthesis of
pharmaceuticals, agrochemicals, and functional materials,2
because the formyl group can be easily converted into a variety
of functional groups.3,4 However, synthetic methods of
pyridinecarbaldehyde are limited, because the oxygenation of
methyl group of picolines with O2 easily leads to formation of
carboxylic acids via over-oxidation.5,6 The direct oxygenation
of picolines using hazardous oxidants such as tert-butyl
hydroperoxide and selenium oxide may not be desirable from
the viewpoint of safety and environmental issues.7
oxidation
reactions
is
a
key
for
accessing
pyridinecarbaldehydes and other valuable organic compounds
in cleaner and simpler way. Herein, we found that a simple
copper salt catalyzes the selective oxygenation of picolines to
pyridinecarbaldehyde under mild conditions with atmospheric
pressure of O2, where addition of a catalytic amount of water
enhances the catalytic activity. While preparation of our
manuscript, Wang et al. reported CuCl2·2H2O-catalyzed
oxygenation of some heteroaromatic compounds (mainly
quinoline derivatives) bearing methyl group(s) using O2.18 In
this study, we have mainly focused on the oxidation of
substituted pyridines and elucidation of the role of water as an
additive.
We first examined the catalytic oxidation of 4-picoline
(1a) under atmospheric pressure of O2 using various transition
metal salts and solvents (Table 1). Treatment of 1a (1.0 mmol)
with O2 in the presence of CuCl2•2H2O (0.10 mmol) in DMSO
(3 mL) at 100 ºC for 22 h gave 4-pyridinecarbaldehyde (2a) in
77% yield based on the substrate (Table 1, entry 2), whereas no
reaction took place in the absence of the catalyst (Table 1, entry
1). Other CuII salts such as Cu(OAc)2 and Cu(NO3)2·2H2O
were less effective (Table 1, entries 3 and 4).19 When the
reaction was carried out in the presence of CuI, which was an
optimized catalyst in the reported work by Maes et al.16b, the
conversion and the yield of 2a was only 34% and 12%,
respectively, in the present system (Table 1, entry 5). The
reaction with CuBr also gave a similar result (Table 1, entry 6).
For the solvent, aprotic polar solvents such as DMSO and DMF
were desirable as compared to 1,4-dioxane, CH3COOH, and
Accordingly,
conventional
methods
to
obtain
pyridinecarbaldehydes involve multi-step processes including
oxidation and reduction reactions as indicated in Scheme 1.
Scheme 1. Synthesis of pyridinecarbaldehydes from picolines

2
toluene (Table 1, entries 7-11), and almost no reaction took
place in pyridine (Table 1, entry 11). As the result, DMSO was
the best solvent among the solvents examined. The yield of 2a
was decreased at the elevated temperature, whereas the
catalytic activity was significantly suppressed at a lower
corresponding ketones (2f and 2g) in 33% and 96% yields,
respectively (Table 2, entries 5 and 6). In contrast to the
case of 2-methylpyridine (1b), 2-benzylpyridine (1h) was
efficiently oxygenated to the ketone product (2h) in a high
yield (Table 2, entry 7). Since an equimolar amount of
acetic acid (for 1g and 1h) was required for the efficient
oxygenation of those substrates in the reported work,16b our
simple catalytic system without such additives has some
advantages.
o
temperature (80 C) (Table 1, entries 2 and 12-14). The best
result was obtained, when the reaction time was elongated to
45 h at 100 oC (Table 1, entry 15). 2a was formed efficiently
even when the loading of the catalyst was reduced to 5 mol%,
yet further reduction of the catalyst amount led to a low
conversion of the substrate (Table 1, entries 16 and 17). 2a was
formed in 68% yield even under atmospheric pressure of air,
but no reaction took place under N2 (Table 1, entries 18 and 19).
a
Table 2. Oxygenation of Picoline and Its Derivatives with O2
Conv.
(%)b
Yield
(%)b
entry
substrate
product
a
Table 1. Oxygenation of 4-Picoline with O2
1
37
6
22
<1
2b
2c
1b
1c
2
3
Conv.
[%]b
<1
83
5
Yield
[%]b
<1
77
2
entry
Catalyst
Solvent
1
2
none
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
98
(58)
98
82
CuCl2·2H2O
Cu(OAc)2
3
2d
2e
3e
1d
1e
4
Cu(NO3)2·2H2O
CuI
13
34
5
12
12
1
5
2e: 14
3e: 24
6
CuBr
4
7
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
73
16
16
18
<1
87
96
11
95
88
27
76
<1
71
4
8
CH3COOH
1,4-dioxane
Toluene
Pyridine
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
9
<1
<1
<1
31
88
9
10
11
12c
13d
14e
15f
16f,g
17f,h
18i
19j
5
6
97
97
33
1f
2f
96
(83)
95
88
26
68
<1
1g
2g
81
(69)
7
99
a Reaction conditions: 4-picoline (1.0 mmol), catalyst (0.10 mmol), solvent
(3 mL), O2 balloon (1 atm) at 100 ºC for 22 h. b Determined by GC-FID
analysis using biphenyl as an internal standard. Averages of two runs are
shown. c at 140 oC. d at 120 oC. e at 80 oC. f 45 h. g catalyst (0.050 mmol).
h catalyst (0.010 mmol). i under Air. j under N2.
1h
2h
aReaction conditions: substrates (1.0 mmol), CuCl2•2H2O (0.10 mmol),
DMSO (3.0 mL), O2 balloon (1 atm) at 100 ºC for 45 h. bDetermined by
GC-FID analysis using biphenyl or nitrobenzene as an internal standard.
Yields of isolated products were shown in parentheses.
In Table 2 is shown the substrate scope under the
optimized reaction conditions. 2-Picoline (1b) was also
oxygenated to 2-pyridinecarbaldehyde (2b), but its yield was
significantly lower as 22% (Table 2, entry 1), and 3-picoline
(1c) was not converted to 3-pyridinecarboaldehyde (3b) under
this reaction condition (Table 2, entry 2). In the case of 3,4-
lutidine (1d), selective oxygenation took place only at the 4-
position to give 4-formyl-3-methylpyridine (2d) in 98% yield
(Table 2, entry 3). Similarly, oxygenation of 4-methy group
was favored in 2,4-lutidine (1e) to give 4-formyl-2-
methylpyridine (2e) (14%) together with 2,4-diformylpyridine
(3e: 24%) (entry 4). For 4-ethylpyridine (1f) and 4-
In order to get insight into the reaction mechanism, we
attempted to isolate a copper species involved in the catalytic
oxygenation reaction. Treatment of 4-picoline (1a) (1.0 mmol)
with CuCl2•2H2O (0.10 mmol) in DMF (3.0 mL) under aerobic
conditions at room temperature gave trans-CuCl2(4-pic)2(4: 4-
pic = 4-picoline) quantitatively based on the copper metal
source.20,21 The X-ray crystallographic analysis of 4 showed an
ideal square planar geometry (4 = 0),22 where two Cl atoms and
two 4-picoline occupied the trans-positions, respectively
(Figure S1). Formation of 4 in solution can be monitored by
UV-vis: DMF solution of isolated 4 displayed a similar
spectrum as that of reaction mixture at a lower temperature
under catalytic condition (Figure S3 and S4). In addition, 4
benzylpyridine (1g), the -position (the carbon directly
attached to the pyridine ring) was oxygenated to give the

3
itself decomposed at 100 ºC for 22 hours to give 4-
pyridinecarbaldehyde (2a) in a 31% yield based on 4, and
catalytic oxidation of 1a using 4 as a catalyst afforded 2a in
72% yield (Scheme S1). These results clearly indicated that 4
is involved as an intermediate in this catalytic system.
In summary, we have developed a direct and selective
oxygenation reaction of picolines to the corresponding
aldehydes catalyzed by a simple copper salt using atmospheric
pressure of O2 as an oxidant. The use of hydrated copper salts
(CuCl2·2H2O) is key for the high product yield because water
worked as a source of proton that activates the substrate at the
initial stage of catalytic cycle. Further investigations of the
scope of the copper-catalyzed oxygenation protocol as well as
the mechanistic study are underway.
T.A. thanks JSPS for a Research Fellowship for young
scientists. S.T. acknowledges financial support by Grant-in-
Aid for Scientific Research on Innovative Areas (JSPS
KAKENHI Grant Number 16H01044 in Precisely Designed
Catalysts with Customized Scaffolding).
Concerning the reaction mechanism, Maes and co-
workers propose that CuII species initially reacts with an
enamine form of substrate that is generated by acid-catalyzed
imine-enamine tautomerization.16a To check the possibility of
such a tautomerization of the substrate as the key factor in our
catalysis as well, we conducted the catalytic reaction in the
presence of acetic acid as additive. In fact, the yield of 2a was
slightly increased by the addition of 1 eq of acetic acid (Scheme
2(a)). Thus, it could be concluded that the acid-catalyzed
tautomerization of 1a is also involved as a key step in our
catalytic reaction. Nonetheless, the reaction proceeded quite
smoothly even in the absence of acetic acid (Scheme 2(a)).
Then, the next question is what is the proton source for the
tautomerization in the absence of acetic acid. A possible proton
source is H2O, which is derived from the catalyst and/or the
solvent. Considering that CuCl2·2H2O in polar solvent forms a
4-O bridged cluster in the presence of base,14a such a
transformation of Cu species accompanies the generation of
proton. To confirm this hypothesis, we carried out the catalytic
reaction under anhydrous condition using anhydrous CuCl2 and
molecular sieve MS4A (Scheme 2(b)). In this case, the
catalytic reaction was suppressed almost completely. In
addition, the catalytic reaction with NEt3 gave 2a in a low yield
(Scheme 2(a)), and the incorporation of D in methyl group of
4-picoline was detected in a label experiment using D2O as the
additive under Ar (Scheme 3(a)). These results clearly indicate
that a small amount of water acts as the proton source to
promote the tautomerization of 1a at the initial stage of
catalytic cycle (Scheme 3(b)).
References and Notes
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Scheme 2. Additive effect on oxidation of 1a using CuCl2·2H2O (a) and
CuCl2 (b) as a catalyst.
18 G. Zheng, H. Liu, M. Wang, Chin. J. Chem. 2016, 34, 519.
19 Other 3d transition metal chloride salts with hydrated water such as
FeCl3·6H2O, FeCl2·4H2O, NiCl2·6H2O, MnCl2·4H2O, and
CoCl2·6H2O were not effective under the present reaction conditions
(Table S1).
20 K. Satoh, T. Suzuki, K. Sawada, J. Chem. Research (S) 1988, 66.
21 [CuCl(dmf)(2-pic)]2(-Cl)2 (5: 2-pic = 2-picoline) was formed when
2-picoline (1b) was used instead of 4-picoline (1a). The molecular
structure and the crystallographic data of 5 are presented in Figure S2,
Tables S2, and Table S3 of supporting information.
22 L. Yang, D. R. Powell, R. P. Houser, Dalton Trans. 2007, 955.
Scheme 3. (a) Incorporation of D in 4-picoline using D2O as additive, and
(b) tautomerization of 4-picoline catalyzed by acid.