Synergistic H4NI-AcOH Catalyzed Oxidation of the Csp3-H Bonds of Benzylpyridines with Molecular Oxygen

Article abstract of DOI:10.1021/acs.orglett.5b00602

The oxidation of benzylpyridines forming benzoylpyridines was achieved based on a synergistic H₄NI-AcOH catalyst and molecular oxygen in high yield under solvent-free conditions. This is the first nonmetallic catalytic system for this oxidation transformation using molecular oxygen as the oxidant. The catalytic system has a wide scope of substrates and excellent chemoselectivity, and this procedure can also be scaled up. The study of a preliminary reaction mechanism demonstrated that the oxidation of the C_sp³-H bonds of benzylpyridines was promoted by the pyridinium salts formed by AcOH and benzylpyridines. The synergistic effect of H₄NI-AcOH was also demonstrated by control experiments. (Figure Presented).

Full text of DOI:10.1021/acs.orglett.5b00602

Letter
pubs.acs.org/OrgLett
3
Synergistic H4NI−AcOH Catalyzed Oxidation of the Csp −H Bonds of
Benzylpyridines with Molecular Oxygen
Lanhui Ren,†,‡ Lianyue Wang,† Ying Lv,† Guosong Li,† and Shuang Gao*,†
†Dalian Institute of Chemical Physics, the Chinese Academy of Sciences and Dalian National Laboratory for Clean Energy, DNL 457
Zhongshan Road, Dalian, 116023, P. R. China
‡Graduate School of the Chinese Academy of Sciences, Beijing, 100049, P. R. China
S
* Supporting Information
ABSTRACT: The oxidation of benzylpyridines forming
benzoylpyridines was achieved based on a synergistic H4NI−
AcOH catalyst and molecular oxygen in high yield under
solvent-free conditions. This is the first nonmetallic catalytic
system for this oxidation transformation using molecular
oxygen as the oxidant. The catalytic system has a wide scope of
substrates and excellent chemoselectivity, and this procedure can also be scaled up. The study of a preliminary reaction
3
mechanism demonstrated that the oxidation of the Csp −H bonds of benzylpyridines was promoted by the pyridinium salts
formed by AcOH and benzylpyridines. The synergistic effect of H4NI−AcOH was also demonstrated by control experiments.
by chloroformates,8 Brønsted acid,9 benzyl bromide,10 etc.
3
he direct oxidation of the Csp −H bonds is one of the
Tmost useful and important transformations in organic Later, A. W. Lei and co-workers reported that the chloroacetate
chemistry.1 Benzoylpyridines are very useful intermediates in
can promote the selective oxidation of heterobenzylic
methylenes in the presence of a catalytic amount of copper
species using oxygen as the terminal oxidant.11 We envisioned
that a Brønsted acid, for example AcOH, can promote the
the synthesis of pharmaceuticals, such as arpromidine, phenir-
amine, chloropheniramine, triprolidine, doxylamine, etc.2 The
3
oxidation of the Csp −H bonds of benzylpyridines is an
3
oxidation of the Csp −H bonds of benzylpyridines by forming
attractive way to synthesize benzoylpyridines. Traditionally,
stoichiometric quantities of a hazardous oxidant such as
potassium permangante were used in this oxidation reaction
with large amounts of unwanted byproducts.3 During recent
decades, significant efforts have been made toward the
development of oxidative processes to obtain benzoylpyridines
from benzylpyridines utilizing transition metals as catalysts.4
However, the coordination between the N-heterocyclic
compound and the transition metal leads to the deactivation
of the catalyst and the poor chemoselectivity, and the metal
residue is also problematic. Nonmetallic catalysts are preferred
to solve the above problems. Although nonmetal-based
catalysts have been developed for this oxidation transformation
over the past decade, these protocols need a large excess of less
sustainable oxidants, such as peroxides.5 Molecular oxygen is a
convenient and green oxidant because water is the only
byproduct produced. However, dioxygen is inert.6 The
pyridinium salts (Scheme 1). Another key issue of the oxidation
Scheme 1. Process of the Oxidation of the Csp3−H Bonds of
Benzylpyridines with Molecular Oxygen
3
of Csp −H bonds of benzylpyridines with molecular oxygen is
the activation of molecular oxygen. In the process of the
3
oxidation of the Csp −H bonds of benzylpyridines with
3
molecular oxygen, benzylpyridiniums are changed into
corresponding free radical A, and then the free radical A reacts
with O2 forming the oxygen radical B (Scheme 1). So the
generation of the free radical A is very important for this
oxidation reaction. As we know, I2 is a radical initiator, and
iodide can be oxidized to I2 by molecular oxygen under acid
conditions. So we envisioned that iodide, for example KI, can
oxidation of the Csp −H bonds of benzylpyridines with
nonmetallic catalysts and molecular oxygen remains untouched,
and further research in this area is necessary.
3
A key issue of the oxidation of Csp −H bonds of pyridine
compounds is its low reactivity owing to the electron-
withdrawing N in the pyridine ring. To solve the problem,
pyridine N-oxides were developed to replace corresponding
pyridine compounds initially.7 In recent years, alternative
methods to activate the N-heterocyclic compounds were
established. The group of Y. G. Zhou reported that asymmetric
hydrogenation of N-heterocyclic compounds could be activated
3
be used in the oxidation of Csp −H bonds of benzylpyridines.
Received: February 27, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00602
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Organic Letters
Letter
According to the above analysis, we envisioned that the KI−
AcOH−O2 system can carry out the oxidation of 2-
benzylpyridine forming 2-benzoylpyridine. We made an
attempt to oxidize 2-benzylpyridine (0.5 mmol) with KI (0.5
mmol) and AcOH (0.5 mmol) and O2 (2 atm) in H2O (2.5
mL) at 100 °C for 24 h. We obtained the product 2a in 33%
yield and product 3a in 19% yield (Table 1, entry 1). When we
the H4NI and AcOH were tested, and a 92% isolated yield was
obtained when the amount of H4NI was 5 mol % and the
amount of AcOH was 10 mol % (Table 1, entries 15−17). The
reaction temperature was also studied. When the temperature
was decreased to 80 °C, the yield and chemoselectivity
decreased sharply (Table 1, entry 18). We tried to shorten
the reaction time, but a poor result was obtained (Table 1,
entry 19). The experiment with 5 mol % H4NI and 10 mol %
other acids such as methanesulfonic acid, TFA, and TsOH was
performed, and excellent results were obtained (Table 1, entries
20−22). These results suggested that the oxidation reaction
could occur smoothly in the presence of other Brønsted acids.
At last, we obtained the optimized catalytic system, viz., 5 mol
% H4NI as a catalyst, 10 mol % AcOH as a promoter, and 1 atm
of O2 as an oxidant under solvent-free conditions at 100 °C for
24 h.
a
Table 1. Optimization of the Reaction Conditions
k
entry
catalyst
additive
solvent
yield (%)
b
e
1
KI
KI
−
AcOH
−
H2O
H2O
H2O
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
2a: 33; 3a: 19
trace
b
2
Having identified the optimized reaction conditions, we
investigated the scope of the substrates. A variety of substituted
2- or 4-benzylpyridines which have electron-donating and
-withdrawing groups in the arene were subjected to our
oxidation protocol. The corresponding 2- or 4-benzoylpyridines
were obtained in moderate to good yields (Scheme 2, 2a−2q);
e
3
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
trace
4
KI
2a: 67
l
5
NaI
2a: 90 (94 )
l
6
H4NI
(CH3)4NI
LiI
2a: 93 (96 )
7
2a: 15
8
2a: 68; 3a: 20
l
9
ZnI2
2a: 91 (84 )
Scheme 2. Scope of Substrates of the Oxidation Protocol
(isolated yield)
10
11
12
AgI
trace
I2
2a: 89
CH3(Ph)3PI
H4NI
H4NI
2a: 79; 3a: 12
2a: 79
g
13
h
14
2a: 93
h
c
l
15
H4NI
2a: 91 (92 )
h
d
16
H4NI
2a: 80; 3a: 9
2a: 82; 3a: 10
2a: 40; 3a: 16
2a: 71; 3a: 18
2a: 97
h
c
f
17
H4NI
hi
,
c
18
19
20
21
22
H4NI
hj
,
c
H4NI
−
−
−
−
h
h
h
c
H4NI
methanesulfonic acid
c
H4NI
TFA
2a: 92
c
H4NI
TsOH
2a: 93
a
Reaction conditions: 1a (0.5 mmol), catalyst (10 mol %), AcOH (10
b
c
mol %), O2 (2 atm), 100 °C, 24 h. KI (0.5 mmol). Catalyst (5 mol
%). Catalyst (2 mol %). AcOH (0.5 mmol). AcOH (5 mol %). Air
(2 atm). O2 (1 atm). 80 °C. 16 h. GC-MS yield based on the
amount of 1a used. Isolated yield.
d
e
f
g
h
i
j
k
l
removed AcOH, we detected a trace amount of 2-
benzoylpyridine 2a (Table 1, entry 2). The oxidation reaction
could not occur without KI (Table 1, entry 3). KI and AcOH
were all necessary to achieve the oxidation reaction. We
thought that the hydrolysis of AcOH in H2O weakens the
activation to 2-benzylpyridine and the hydrogen bonds between
H2O solvent or 0.5 mmol AcOH and product 3a lead to the
poor chemoselectivity. So we removed the H2O solvent and
decreased the amount of AcOH to 0.05 mmol. We obtained the
product 2a as the only product in 67% yield (Table 1, entry 4).
Next, the type of iodide was studied. When the iodide was
chosen, H4NI, the oxidation reaction gave the best result
(Table 1, entries 4−12). Therefore, the H4NI was selected for
the next optimization study. Compared with pure O2, air which
is more easily available and environmentally friendly was
chosen as the oxidant, and we also obtained a good result
(Table 1, entry 13). Subsequently, we investigated the effect of
the pressure of O2 on the reaction. When the pressure of O2
was decreased to 1 atm, the result of the oxidation reaction was
also excellent (Table 1, entry 14). Next, different amounts of
thus, our oxidation protocol has a wide scope of substrates.
Para, meta, and ortho substitution of the arene group was
tolerated (Scheme 2, 2c−2e, 2h−2i). The substrates that
contain two chemically different benzylic positions were tested,
and the products 2f and 2g were obtained without byproducts
in good yields (Scheme 2, 2f, 2g). The substrate that contains a
thioether group that is sensitive to oxidation was also tested.
The thioether group was left untouched, and the corresponding
ketone product was obtained in 81% yield (Scheme 2, 2l). The
oxidation protocol showed good chemoselectivity.
B
DOI: 10.1021/acs.orglett.5b00602
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Organic Letters
Letter
Finally, the practical applicability of the oxidation protocol
was demonstrated. We used 2-(4-chlorobenzyl)pyridine as the
test substrate and worked on a gram scale. A 25 mmol (5.1 g)
reaction of 2-(4-chlorobenzyl)pyridine was performed with 5
mol % of H4NI as the catalyst, 10 mol % AcOH as the
promoter, and 6 atm O2 as the oxidant at 100 °C. The desired
product was obtained in 87% isolated yield within 96 h. This
result suggested that our oxidation protocol is a highly active,
selective, and practical process for the preparation of (4-
chlorophenyl)(pyridin-2-yl)methanone 2b.
characteristic of an organic radical with an absorption maximum
at g = 2.0026 (Figure 1). These EPR results demonstrated the
participation of organic radicals in our oxidation reaction
system.
To gain an insight into the mechanism for the oxidation of 2-
benzylpyridine to 2-benzoylpyridine, several control experi-
ments were performed. We thought that I2 was generated in
situ from the catalyst. So the experiment with 10 mol % I2 was
performed, and the 2-benzoylpyridine 2a was obtained in 65%
yield with poor chemoselectivity (Scheme 3A). Next, we
Scheme 3. Control Experiments
Figure 1. Eelectron paramagnetic resonance (EPR) spectra (X band,
9.3 GHz, 99.1 K).
On the basis of the above results and pertinent literature, we
proposed a possible reaction pathway (Scheme 4). Initially, 2-
Scheme 4. Possible Reaction Pathway
performed the experiment with 10 mol % I2 and 10 mol %
AcOH, and an excellent result was obtained (Scheme 3B).
H4NI was used in our optimized conditions, so we envisioned
that AcONH4 was produced in the oxidation process. The
experiment with 10 mol % I2 and 10 mol % AcONH4 was
performed, and the 2-benzoylpyridine 2a was obtained in 92%
yield (Scheme 3C). The oxidation reaction was promoted by
AcOH resulting from the hydrolysis (the byproduct of O2 is
H2O) of AcO−. For comparison, when we changed the
AcONH4 to H4NCl, the same poor result was obtained with
the experiment with only 10 mol % I2 (Scheme 3D). We
performed a labeling experiment with 18O2 as the oxidant, and
the 18O-labeled product 2a was obtained in 96% yield (Scheme
3E). This result demonstrated that the carbonyl oxygen atom of
the phenyl(pyridin-2-yl)methanone 2a originated from dioxy-
gen.
benzylpyridinium acetate C was formed by interaction between
the 2-benzylpyridine and AcOH, and the H4NI and AcOH were
oxidized to AcONH4 and I2. Then the 2-benzylpyridinium C
reacted with a iodine radical which was produed from I2 at high
temperature forming free radical D and HI which was oxidized
to I2 again. The free radical D captured O2 forming the free
radical E, and then the free radical E reacted with another 2-
benzylpyridinium acetate C forming intermediate F and free
radical D. The decomposition of intermediate F can afford
To confirm an organic radical species involved in the overall
process, electron paramagnetic resonance (EPR) experiments
were performed. When H4NI and AcOH were tested, no signals
were observed. The EPR spectrum of a mixture of 2-
benzylpyridine, H4NI, and AcOH displayed a resonance
C
DOI: 10.1021/acs.orglett.5b00602
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Plietker, B. ChemCatChem 2013, 5, 126. (i) Citterio, A.; Sebastiano,
R.; Carvayal, M. C. J. Org. Chem. 1991, 56, 5335.
(5) Zhang, J. T.; Wang, Z. T.; Wang, Y.; Wan, C. F.; Zheng, X. Q.;
Wang, Z. Y. Green Chem. 2009, 11, 1973.
(6) Wang, L. Y.; Li, J.; Yang, H.; Lv, Y.; Gao, S. J. Org. Chem. 2012,
77, 790.
product 2a and released an AcOH molecule. The 2-
benzylpyridinium acetate C was detected at m/z values of
229.1 with a clear spectrum by GC-MS.
In summary, we have reported for the first time that a
3
nonmetallic catalytic oxidation protocol of the Csp −H bonds of
benzylpyridines formed benzoylpyridine with the synergistic
H4NI−AcOH catalyst and molecular oxygen. AcOH promoted
this oxidation reaction by forming pyridinium salts. This
catalytic oxidation protocol has wide substrate scope and
excellent chemoselectivity, and this procedure can also be
scaled up. No organic solvent is needed in the oxidation
process, making it more environmentally friendly. Further
studies will be aimed at extending the substrate scope and
further investigating the reaction mechanism.
(7) (a) Fontenas, C.; Bejan, E.; Aït Haddou, H.; Balavoine, G. G. A.
Synth. Commun. 1995, 25, 629. (b) Wurz, R. P.; Lee, E. C.; Ruble, J.
C.; Fua, G. C. Adv. Synth. Catal. 2007, 349, 2345. (c) Johnson, S.;
Drowns, M.; Tatlock, J.; Linton, A.; Gonzalez, J.; Hoffman, R.; Jewell,
T.; Patel, L.; Blazel, J.; Tang, M.; Li, H. Synlett 2010, 5, 796.
(8) Lu, S. M.; Wang, Y. Q.; Han, X. W.; Zhou, Y. G. Angew. Chem.
2006, 118, 2318. Angew. Chem., Int. Ed. 2006, 45, 2260.
(9) (a) Guo, R. N.; Cai, X. F.; Shi, L.; Ye, Z. S.; Chen, M. W.; Zhou,
Y. G. Chem. Commun. 2013, 49, 8537. (b) Wang, D. S.; Chen, Q. A.;
Li, W.; Yu, C. B.; Zhou, Y. G.; Zhang, X. M. J. Am. Chem. Soc. 2010,
132, 8909.
(10) (a) Ye, Z. S.; Chen, M. W.; Chen, Q. A.; Duan, L.; Shi, Y.; Zhou,
Y. G. Angew. Chem. 2012, 124, 10328. Angew. Chem., Int. Ed. 2012, 51,
10181. (b) Ye, Z. S.; Guo, R. N.; Cai, X. F.; Chen, M. W.; Shi, L.;
Zhou, Y. G. Angew. Chem. 2013, 125, 3773. Angew. Chem., Int. Ed.
2013, 52, 3685. (c) Huang, W. X.; Yu, C. B.; Shi, L.; Zhou, Y. G. Org.
Lett. 2014, 16, 3324.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) Liu, J. M.; Zhang, X.; Yi, H.; Liu, C.; Liu, R.; Zhang, H.; Zhuo,
K. L.; Lei, A. W. Angew. Chem. 2015, 127, 1277. Angew. Chem., Int. Ed.
2015, 54, 1261.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sgao@dicp.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Nos. 2009CB623505
and 21403219).
REFERENCES
■
(1) (a) Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski,
M. C. Chem. Rev. 2013, 113, 6234. (b) Shi, Z.; Zhang, C.; Tang, C.;
Jiao, N. Chem. Soc. Rev. 2012, 41, 3381. (c) Campbell, A. N.; Stahl, S.
S. Acc. Chem. Res. 2012, 45, 851. (d) Liu, C.; Zhang, H.; Shi, W.; Lei,
A. Chem. Rev. 2011, 111, 1780. (e) Punniyamurthy, T.; Velusamy, S.;
Iqbal, J. Chem. Rev. 2005, 105, 2329. (f) Shi, Z. J.; Sun, C. L.; Li, B. J.
Chem. Rev. 2011, 111, 1293.
(2) (a) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D.
Pharmaceutical Substances, 4th ed.; Georg Thieme, Stuttgart, 2001.
(b) Reis, D. C.; Pinto, M. C. X.; Souza-Fagundes, E. M.; Wardell, S. M.
S. V.; Wardell, J. L.; Beraldo, H. Eur. J. Med. Chem. 2010, 45, 3904.
(c) Guyton, A. C.; Hall, J. E. Textbook of Medical Physiology, 11th ed.;
Elsevier Saunders: Philadelphia, 2005. (d) Easmon, J.; Heinisch, G.;
̈
Purstinger, G.; Langer, T.; Osterreicher, J. K. J. Med. Chem. 1997, 40,
4420.
̈
(3) (a) Crook, K. E.; Mcelval, S. M.; Mceivain, S. M. J. Am. Chem.
Soc. 1930, 52, 4006. (b) Huntress, E. H.; Walter, H. C. J. Am. Chem.
Soc. 1948, 70, 3702. (c) Stevens, J. I.; Sumrell, G.; Ham, G. E. J. Org.
Chem. 1957, 22, 1724.
(4) (a) Akhlaghinia, B.; Ebrahimabadi, H.; Goharshadi, E. K.; Samiee,
S.; Rezazadeh, S. J. Mol. Catal. A: Chem. 2012, 357, 67. (b) Itoh, M.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2014, 16, 2050. (c) Kappe,
C. O.; Pieber, B. Green Chem. 2013, 15, 320. (d) Maes, B. U. W.;
Houwer, J. D.; Tehrani, K. A. Angew. Chem. 2012, 124, 2799. Angew.
Chem., Int. Ed. 2012, 51, 2745. (e) Dong, J. J.; Unjaroen, D.; Mecozzi,
F.; Harvey, E. C.; Saisaha, P.; Pijper, D.; de Boer, J. W.; Alsters, P.;
Feringa, B. L.; Browne, W. R. ChemSusChem 2013, 6, 1774.
(f) Nakanishi, M.; Bolm, C. Adv. Synth. Catal. 2007, 349, 861.
(g) Nawratil, S.; Grypioti, M.; Menendez, C.; Mallet-Ladeira, S.;
Lherbet, C.; Baltas, M. Eur. J. Org. Chem. 2014, 654. (h) Hsu, S. F.;
D
DOI: 10.1021/acs.orglett.5b00602
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