Visible-Light-Promoted Copper-Catalyzed Regioselective Benzylation of Pyridine N-Oxides versus Thermal Acylation Reaction with Toluene Derivatives

Article abstract of DOI:10.1002/ejoc.201701586

Copper-catalyzed visible light mediated direct C–H bond benzylation of pyridine N-oxides with toluene derivatives was accomplished by recent developments in photochemical carbon–carbon bond formation through a photo-induced bond-dissociation strategy. Thi

Full text of DOI:10.1002/ejoc.201701586

DOI: 10.1002/ejoc.201701586
Full Paper
Pyridine N-Oxides
Visible-Light-Promoted Copper-Catalyzed Regioselective
Benzylation of Pyridine N-Oxides versus Thermal Acylation
Reaction with Toluene Derivatives
Ebrahim Kianmehr*[a] and Maral Gholamhosseyni[a]
Abstract: Copper-catalyzed visible light mediated direct C–H and toluene derivatives. Furthermore, preliminary research indi-
bond benzylation of pyridine N-oxides with toluene derivatives cates that the acylation reaction can be carried out under ther-
was accomplished by recent developments in photochemical mal reaction conditions. This protocol provides easy access to
carbon–carbon bond formation through a photo-induced 2-benzyl and 2-acyl pyridine N-oxide derivatives in the presence
bond-dissociation strategy. This visible light driven protocol has of a copper catalyst.
been successfully applied to a broad scope of pyridine N-oxides
Introduction
Transition metal catalyzed cross-coupling reactions of two read-
ily accessible reagents has emerged as a straightforward and
economical strategies for new C–C bond construction.[1] Over
the past decades, the functionalization of C–H bonds through
Figure 1. Examples of bioactive 2-benzylpyridines.
a transition metal catalyzed approach has received much atten-
tion. This strategy is more appealing when it comes to choosing
starting materials without any requirements of pre-functionali-
zation. Cross-dehydrogenative coupling (CDC) reactions are
highly beneficial and avoid the need to prepare pre-functional-
ized molecules and make synthetic routes shorter, more effi-
cient and easier.[2] Oxidative coupling reactions have been suc-
cessfully applied to construct C–C bonds between Csp–H and
Csp–H,[3] Csp–H and Csp2–H,[4] Csp–H and Csp3–H,[5] Csp2–H
and Csp2–H,[6] Csp3–H and Csp2–H bonds.[7] Despite the signifi-
cant progress made in this area, the more challenging Csp3–H
and Csp2–H couplings through CDC reactions remain scarce.
2-Benzylpyridine unit is a significant building block found
in biologically active molecules, pharmaceuticals, and organic
functional materials,[8] for example α-(2-pyridine) benzyl
aryl ketones, compound 1, are potential hypocholesteremic
agents.[9] In particular, 2-benzylpridine compound 2 is used for
rat-selective induction of the mitochondrial permeability transi-
tion[10] (Figure 1).
and copper catalysts have been shown to be very effective for
functionalization of pyridine N-oxides.[12]
Synthesis of 2-benzylpyridines by direct arylation of benzylic
Csp3–H bond of 2-methylpyridine N-oxides was reported by
Fagnou in 2008 (Scheme 1).[13] In 2010, Liu and co-workers re-
ported cross-coupling of 2-(2-pyridyl)acetates with aryl halides
for the synthesis of 2-benzylpyridine derivatives.[14] Palladium-
catalyzed arylation of 2-methylpyridine with aryl halides was
reported by Knochel in 2011 for the synthesis of 2-benzyl-
pyridines.[15] In 2012, Pd-catalyzed benzylic cross-coupling
reactions of pyridine N-oxides with benzyl chloride in the pres-
ence of tBu3P–HBF4 and K2CO3 for the synthesis of the corre-
sponding 2-benzyl pyridine N-oxides was developed by Mai
(Scheme 1).[16] A copper-catalyzed regioselective cross-coupling
of N-tosylhydrazones with azine N-oxides to yield ortho-alkyl-
ated products was developed by Jain in 2016 (Scheme 1).[17] In
all of the above-mentioned methods, pre-functionalization of
the coupling partner of pyridine N-oxides is necessary. A palla-
dium-catalyzed benzylation of pyridine N-oxides was reported
by us recently (Scheme 1).[18] Visible-light provides a new ap-
proach for C–C,[19] C–N,[20] C–P,[21] C–S,[22] and C–Se[23] bond
formation through the generated radicals from visible light pro-
moted cleavage of weak bonds. Recently, light-promoted proce-
dures in the present of various photocatalysts emerged as one
of the most powerful C–H activation processes. In particular,
the visible light catalyzed CDC reaction has received much at-
tention because of its mild, clean, and eco-friendly properties.
Most C–H bond functionalization processes generally rely on
the strategies of directing group-assisted C–H bond activation,
which provides a unique approach to target molecules.[11] Pyr-
idine N-oxides often serve as important intermediates for the
activation and functionalization of the pyridine ring. Palladium
[a] School of Chemistry, College of Science, University of Tehran,
Tehran, Iran
E-mail: kianmehr@khayam.ut.ac.ir
http://schem.ut.ac.ir/en/~kianmehr
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201701586.
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Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
[mol-%]
Oxidant (equiv.)
Solvent
Yield
[%]
1
2
3
4
5
6
7
8
Cu(OAc)2 (15)
CuBr (15)
CuCl (15)
CuBr2 (15)
CuO (15)
Pd(OAc)2 (15)
PdCl2 (15)
CuO (20)
CuO (15)
CuO (15)
CuO (15)
CuO (15)
CuO (15)
CuO (15)
CuO (15)
CuO (15)
CuO (15)
CuO (15)
CuO (15)
CuO (15)
CuO (15)
CuO (15)
CuO (15)
K2S2O8 (1.25)
K2S2O8 (1.25)
K2S2O8 (1.25)
K2S2O8 (1.25)
K2S2O8 (1.25)
K2S2O8 (1.25)
K2S2O8 (1.25)
K2S2O8 (1.25)
K2S2O8 (1.25)
K2S2O8 (1.25)
K2S2O8 (1.25)
K2S2O8 (1.25)
K2S2O8 (1.25)
TBHP (2.0)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
DCE
25
31
70
41
81
24
28
79
0
11
25
0
0
0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
PhCl
DMSO
DMF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DTBP (2.0)
0
(NH4)2S2O8 (1.25)
Na2S2O8 (1.25)
K2S2O8 (0.75)
K2S2O8 (2.0)
K2S2O8 (1.25)
K2S2O8 (1.25)
K2S2O8 (1.25)
K2S2O8 (1.25)
68
53
33
80
79[b]
80[c]
78[d]
0e
Scheme 1. Different routes for benzylation of pyridine N-oxides.
As part of our ongoing interest to explore C–C bond forma-
tions through CDC reactions[24] herein we report an efficient
and highly regioselective procedure for the direct benzylation
of pyridine N-oxides with toluenes at room temperature in-
duced by visible light in the presence of a copper catalyst,
which is less expensive and more environmentally benign rela-
tive to palladium or rhodium complexes. The reaction repre-
sents a regioselective route towards synthesis of 2-benzylpyr-
idine N-oxide derivatives.
[a] General reaction conditions: All reactions were irradiated for 24 h under
8 W blue LED strips by using 1a (1 equiv., 1 mmol), 2a (3 equiv., 3 mmol).
[b] Reaction time: 48 h. [c] Methylene blue (5 mol-%) was added. [d] Eosin Y
(5 mol-%) was added. [e] Reaction was performed in the dark.
toluene, which acted as both reactant and reaction medium
(Table 1, Entry 9). As shown in Table 1, a variety of oxidants,
such as tert-butyl hydroperoxide (TBHP) and di-tert-butyl perox-
ide (DTBP) were totally insufficient (Table 1, Entries 14 and 15).
To our delight oxidants such as K2S2O8, Na2S2O8, and
(NH4)2S2O8, were effective in this reaction and the best result
was obtained with potassium persulfate (Table 1, Entries 5, 16
and 17).
Results and Discussion
Our initial effort began with the reaction of pyridine N-oxide
(1a) with toluene (2a) in the presence of Cu(OAC)2 (15 mol-%)
and K2S2O8 under 8 W blue LED irradiation in acetonitrile.
Product formation was seen after 12 h. However, by increasing
The optimum amount of oxidant for the reaction was K2S2O8
the reaction time to 24 h, desired product 2-benzylpyridine-1- (1.25 equiv.). The reaction did not go to completion with less
oxide (3a) was obtained in 25 % yield (Table 1, Entry 1).
than 1.25 equiv. of K2S2O8, and an increased amount of oxidant
did not result in higher yields (Table 1, Entries 18 and 19). The
yield of the reaction was not improved by increasing the reac-
tion time beyond 24 h. (Table 1, Entry 20). Control experiments
revealed that light illumination in the presence of a photocata-
lyst, such as methylene blue and eosin Y, didn't affect the reac-
tion efficiency (Table 1, Entries 21 and 22). The reaction didn't
afford the desired product in the absence of light, which con-
firms the role of light in the reaction mechanism (Table 1, En-
try 23). Thus, the optimum reaction conditions involved irradiat-
ing the substrates under 8 W blue LED strips for 24 hours with
K2S2O8 (1.25 equiv.) and CuO (15 mol-%) in acetonitrile.
Optimization of the reaction conditions with respect to sol-
vent, catalyst, oxidant, and time was carried out. The use of
copper-based catalysts, such as CuCl and CuO, improved the
yield of the product up to 70 and 81 %, respectively (Table 1,
Entries 3 and 5). By changing the copper catalyst to Pd(OAc)2
and PdCl2 dropped the yield of 3a to 24 and 28 %, respectively
(Table 1, Entries 6 and 7). Furthermore, an increase in catalyst
loading to 20 mol-% did not improve the reaction efficiency
(Table 1, Entry 8). A variety of solvents were examined. As a
result, CH3CN, which gave the product in 81 % yield, was se-
lected as the best solvent among chlorobenzene, 1,2-dichloro-
ethane (DCE), dimethyl sulfoxide (DMSO) and dimethylform-
Once the optimized conditions for the desired benzylation
amide (DMF). Notably, the desired product was not observed in reaction were established, the scope of the reaction was investi-
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gated. A variety of combinations of substrates were examined, carboxylic acids, which leads to the formation of both C2- and
and the results are summarized in Table 2. Pyridine N-oxides C4-acylated products, has been reported recently.[27]
with both electron-donating and electron-withdrawing groups
reacted smoothly and resulted in the corresponding 2-benzyl
pyridine N-oxides in moderate to good yields. Pyridine N-oxides
with electron-donating groups gave higher yields (3e and 3m).
Table 3. Copper-catalyzed direct acylation reaction of pyridine N-oxides by
toluene derivatives.[a]
Table 2. Copper-catalyzed direct benzylation reactions of pyridine N-oxides
by toluene derivatives.[a]
[a] Reaction conditions: Pyridine N-oxides (1 equiv., 0.5 mmol), toluene deriv-
atives (3 equiv., 1.5 mmol), Cu(OAc)2 (15 mol-%), and K2S2O8 (2.5 equiv.,
1.25 mmol) in chlorobenzene (2.0 mL) at 135 °C for 24 h.
Based upon the above experimental results and previous re-
ports, a plausible mechanism is proposed and described in
Scheme 2.
Initially, a metallation reaction occurs preferentially at the C2-
position of the pyridine N-oxide derivatives that leads to the
formation of intermediate B. Radical intermediate A is gener-
ated in situ by hydrogen-atom abstraction from toluene or
benzaldehyde produced by toluene oxidation under the reac-
[a] Reaction conditions: Pyridine N-oxides (1 equiv., 1 mmol), toluene deriva-
tives (3 equiv., 3 mmol), CuO (15 mol-%), and K2S2O8 (1.25 equiv., 1.25 mmol)
in acetonitrile (2 mL) irradiated by 8 W blue LED strips for 24 h.
In the optimization study, we found that the visible light tion conditions[28] facilitated by the sulfate radical anion that is
irradiation was crucial for the benzylation reaction and, when produced from K2S2O8.[29] Next, coordination of copper com-
the reaction was performed under thermal conditions, the acyl- plex B with radical A gives intermediate C, which undergoes
ated product was obtained exclusively instead. A series of 2- reductive elimination to afford final product 3 or 4. To prove
acylated pyridine N-oxides, prepared by this procedure, are the radical mechanism, a control reaction that involves the use
shown in Table 3. 2-Acyl pyridine N-oxide derivatives are known of 2,6-di-tert-butyl-4-methylphenol as a radical scavenger was
to be important synthetic precursors for the preparation of performed. When 1a was treated in the presence of butylated
agrochemical[25] and pharmaceutical[26] products. A silver-cata- hydroxytoluene (1 equiv.) no desired product 3a (or 4a) was
lyzed decarboxylative acylation of pyridine N-oxides by α-oxo- observed.[30]
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Scheme 2. Plausible mechanism.
General Procedure for the Synthesis of 2-Benzyl pyridine
N-Oxides by Using Toluene as a Benzylation Agent: A 10 mL
microwave vial was charged with pyridine N-oxide derivatives
(1 equiv., 1 mmol), toluene derivatives (3 equiv., 3 mmol), K2S2O8
(1.25 equiv., 1.25 mmol), Cu catalyst (15 mol-%), and acetonitrile
(2 mL). The vial was irradiated with 8 W blue LED strips for 24 h.
After this time the reaction mixture was diluted with methanol and
filtered. The residue was purified by using column chromatography
(n-hexane/EtOAc/methanol, 1:1:0.1) to yield the desired products.
Conclusions
In conclusion, an efficient method for ortho C–H bond benzyl-
ation and acylation of pyridine N-oxides with methyl arenes has
been disclosed, that allows for synthesis of a broad range of
2-benzyl and 2-acyl pyridine N-oxides. We have established a
straightforward and versatile protocol that employed abun-
dantly available methyl arenes as a coupling partner and avoids
unproductive steps for pre-functionalization of starting materi-
als.
2-Benzylpyridine 1-Oxide (3a): The general procedure was fol-
lowed by using pyridine N-oxide (1 mmol, 95 mg), K2S2O8
(1.25 mmol, 338 mg), CuO (12 mg, 15 mol-%), toluene (3 mmol,
0.32 mL), and acetonitrile (2 mL). Purification by column chromatog-
raphy (silica gel, n-hexane/EtOAc/methanol, 1:1:0.1) gave final prod-
Experimental Section
General Information: Solvents, copper catalyst, toluene and pyr-
idine derivatives were purchased from Merck and Sigma. Other rea-
gents were purchased from commercial distributors and used with-
out further purification. Pyridine N-oxides derivatives was synthe-
sized in accordance with the literature. Analytical thin layer chroma-
tography (TLC) was performed with pre-coated silica gel 60 F254
plates. The products were purified by preparative column chroma-
tography on silica gel (0.063–0.200 mm; Merck). 1H and 13C NMR
Spectra: were recorded with a Bruker 500 and 400 Advance instru-
ment in CDCl3. Mass spectrometry was obtained with an Agilent
5975C VL MSD (Ion source: EI+, 70 eV, 230 °C).
1
uct 3a (150 mg, 81 % yield) as a pale brown oil. H NMR (400 MHz,
CDCl3): δ = 8.33–8.31 (m, 1 H), 7.85 (d, J = 7.4 Hz, 1 H), 7.50 (t, J =
7.7 Hz, 1 H), 7.37 (d, J = 7.5 Hz, 2 H), 7.33–7.29 (m, 2 H), 7.19–7.16
(m, 1 H), 6.97 (d, J = 6.7 Hz, 1 H), 4.28 (s, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 152.0, 139.4, 136.2, 129.7, 129.3, 128.9, 127.1,
125.9, 123.6, 36.6 ppm. MS (EI): m/z (%) = 185 (26) [M]+, 168 (100),
154 (6), 139 (7), 106 (14), 91 (7), 78 (50), 65 (15), 51 (29). C12H11NO
(185.22): calcd. C 77.81, H 5.99, N 7.56; found C 77.98, H 5.96, N
7.58.
2-(3-Methylbenzyl) pyridine 1-Oxide (3b): The general procedure
was followed by using pyridine N-oxide (1 mmol, 95 mg), K2S2O8
(1.25 mmol, 338 mg), CuO (12 mg, 15 mol-%), m-xylene (3 mmol,
0.37 mL) and acetonitrile (2 mL). Purification by column chromatog-
raphy (silica gel, n-hexane/EtOAc/methanol, 1:1:0.1) gave final prod-
uct 3b (151 mg, 76 % yield) as a pale brown oil. 1H NMR (400 MHz,
CDCl3): δ = 8.35–8.33 (m, 1 H), 7.19–7.16 (m, 2 H), 7.14–7.07 (m, 4
H), 6.99–6.96 (m, 1 H), 4.26 (s, 2 H), 2.37 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 152.2, 139.4, 138.6, 136.1, 130.5, 128.8, 127.8,
126.7, 125.9, 123.5, 36.4, 21.4 ppm. MS (EI): m/z (%) = 199 (33) [M]+,
182 (96), 167 (100), 152 (7), 136 (6), 119 (14), 106 (14), 91 (35), 78
General Procedure for the Synthesis of 2-Acylated Pyridine N-
Oxides by Using Toluene as an Acylating Agent: A 10 mL micro-
wave vial was charged with pyridine N-oxide derivatives (1 equiv.,
0.5 mmol), toluene derivatives (3 equiv., 1.5 mmol), K2S2O8
(2.5 equiv., 1.25 mmol), Cu catalyst (15 mol-%), and chlorobenzene
(2 mL). The vial was then sealed and immersed in an oil bath at
135 °C for 24 h. After this time the reaction mixture was cooled to
room temperature and then diluted with methanol and filtered. The
residue was purified by using column chromatography (n-hexane/
EtOAc/methanol, 1:1:0.1) to yield the desired products.
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(37), 65 (28), 51 (33), 43 (33). C13H13NO (199.25): calcd. C 78.36, H 140 mg), K2S2O8 (1.25 mmol, 338 mg), CuO (12 mg, 15 mol-%), p-
6.58, N 7.03; found C 78.58.74, H 6.60, N 7.00.
Xylene (3 mmol, 0.37 mL), and acetonitrile (2 mL). Purification by
column chromatography (silica gel, n-hexane/EtOAc/methanol,
1:1:0.1) gave final product 3g (192 mg, 79 % yield) as a pale yellow
oil. 1H NMR (400 MHz, CDCl3): δ = 8.37 (d, J = 7.1 Hz, 1 H), 8.00 (dd,
J = 7.0 & J = 3.1 Hz, 1 H), 7.82 (d, J = 3.1 Hz, 1 H), 7.24 (d, J = 8.1 Hz,
2 H), 7.19 (d, J = 8.1 Hz, 2 H), 4.21 (s, 2 H), 2.41 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 152.2, 139.4, 138.6, 136.2, 130.5, 128.8,
127.8, 123.5, 119.12, 32.0, 22.7 ppm. MS (EI): m/z (%) = 244 (44)
[M]+, 227 (66), 211 (7), 197 (14), 181 (70), 169 (13), 154 (14), 136
(40), 127 (17), 119 (25), 110 (18), 97 (30), 85 (48), 71 (73), 57 (100),
43 (46). C13H12N2O3 (244.25): calcd. C 63.93, H 4.95, N 11.47; found
C 63.67, H 4.95, N 11.49.
2-(4-Methylbenzyl) pyridine 1-Oxide (3c): The general procedure
was followed by using pyridine N-oxide (1 mmol, 95 mg), K2S2O8
(1.25 mmol, 338 mg), CuO (12 mg, 15 mol-%), p-Xylene (3 mmol,
0.37 mL), and acetonitrile (2 mL). Purification by column chromatog-
raphy (silica gel, n-hexane/EtOAc/methanol, 1:1:0.1) gave final prod-
1
uct 3c (155 mg, 78 % yield) as a dark brown oil. H NMR (400 MHz,
CDCl3): δ = 8.32–8.30 (m, 1 H), 7.20–7.12 (m, 6 H), 7.97–6.95 (m, 1
H), 4.23 (s, 2 H), 2.37 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
152.2, 139.4, 136.7, 133.1, 129.6, 129.5, 125.7, 123.5, 36.1, 22.7 ppm.
MS (EI): m/z (%) = 199 (30) [M]+, 182 (100), 167 (96), 152 (7), 139
(7), 119 (8), 106 (30), 91 (21), 78 (74), 65 (20), 51 (25). C13H13NO
(199.25): calcd. C 78.36, H 6.58, N 7.03; found C 78.51, H 6.56, N
7.01.
2-Benzylquinoline 1-Oxide (3h): The general procedure was fol-
lowed by using quinoline N-oxide (1 mmol, 145 mg), K2S2O8
(1.25 mmol, 338 mg), CuO (12 mg, 15 mol-%), toluene (3 mmol,
0.32 mL), and acetonitrile (2 mL). Purification by column chromatog-
raphy (silica gel, n-hexane/EtOAc/methanol, 1:1:0.1) gave final prod-
uct 3h (183 mg, 78 % yield) as a pale yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 7.85 (d, J = 8.2 Hz, 1 H), 7.60 (d, J = 7.9 Hz, 1 H), 7.55
(td, J = 8.2 Hz & j = 1.8 Hz, 2 H), 7.47–7.32 (m, 4 H), 7.26 (t, J =
7.7 Hz, 2 H), 6.75 (d, J = 8.1 Hz, 1 H), 4.47 (s, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 152.0, 140.1, 139.4, 136.2, 135.0, 134.3, 129.7,
129.3, 128.9, 127.1, 125.9, 125.7, 123.6, 36.6 ppm. MS (EI): m/z (%) =
235 (15) [M]+, 145 (100), 128 (10), 117 (70), 105 (7), 90 (40), 77 (14),
63 (21), 51 (15), 41 (7). C16H13NO (235.28): calcd. C 81.68, H 5.57, N
5.95; found C 81.42, H 5.59, N 5.92.
2-(3-Methylbenzyl)-4-nitropyridine 1-Oxide (3d): The general
procedure was followed by using 4-nitropyridine N-oxide (1 mmol,
140 mg), K2S2O8 (1.25 mmol, 338 mg), CuO (12 mg, 15 mol-%), m-
Xylene (3 mmol, 0.37 mL), and acetonitrile (2 mL). Purification by
column chromatography (silica gel, n-hexane/EtOAc/methanol,
1:1:0.1) gave final product 3d (183 mg, 75 % yield) as a pale yellow
solid. M.p. 143–145 °C. 1H NMR (400 MHz, CDCl3): δ = 8.36 (d, J =
7.1 Hz, 1 H), 8.02 (dd, J = 7.1,& J = 3.2 Hz, 1 H), 7.83 (d, J = 3.1 Hz,
1 H), 7.45 (t, J = 7.6 Hz, 1 H), 7.32 (d, J = 7.6 Hz, 1 H), 7.18 (d, J =
7.6 Hz, 1 H), 7.11 (s, 1 H), 4.21 (s, 2 H), 2.40 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 153.8, 140.1, 139.0, 134.4, 130.3, 129.6, 129.1,
128.6, 126.6, 120.1, 118.1, 36.6, 21.4 ppm. MS (EI): m/z (%) = 244
(23) [M]+, 227 (48), 197 (11), 181 (100), 166 (15), 154 (18), 139 (16),
128 (11), 115 (12), 105 (12), 91 (18), 77 (20), 63 (13), 51 (21), 41 (12).
5-Acetyl-2-(4-methylbenzyl) pyridine 1-Oxide (3i): The general
procedure was followed by using 3-acetylpyridine N-oxide (1 mmol,
137 mg), K2S2O8 (1.25 mmol, 338 mg), CuO (12 mg, 15 mol-%), p-
Xylene (3 mmol, 0.37 mL), and acetonitrile (2 mL). Purification by
column chromatography (silica gel, n-hexane/EtOAc/methanol,
1:1:0.1) gave final product 3i (164 mg, 68 % yield) as a pale yellow
oil. 1H NMR (400 MHz, CDCl3): δ = 8.84 (d, J = 1.6 Hz, 1 H), 7.66 (dd,
J = 8.0 & J = 1.7 Hz, 1 H), 7.21 (d, J = 8.1 Hz, 2 H), 7.19 (d, J = 7.8 Hz,
2 H), 7.07 (d, J = 7.9 Hz, 1 H) 4.27 (s, 2 H), 2.60 (s, 3 H), 2.39 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 193.9, 156.3, 139.7, 137.1,
132.3, 129.7, 129.6, 127.9, 125.6, 124.3, 36.4, 26.7, 21.1 ppm. MS (EI):
m/z (%) = 241 (25) [M]+, 224 (100), 209 (45), 194 (7), 180 (21), 166
(23), 152 (5), 139 (5), 120 (5), 105 (7), 91 (8), 77 (9), 63 (7), 43 (45).
C13H12N2O3 (244.25): calcd. C 63.93, H 4.95, N 11.47; found C 63.78,
H 4.96, N 11.51.
2-Benzyl-6-methylpyridine 1-Oxide (3e): The general procedure
was followed by using 2-methylpyridine N-oxide (1 mmol, 109 mg),
K2S2O8 (1.25 mmol, 338 mg), CuO (12 mg, 15 mol-%), toluene
(3 mmol, 0.32 mL), and acetonitrile (2 mL). Purification by column
chromatography (silica gel, n-hexane/EtOAc/methanol, 1:1:0.1) gave
final product 3e (169 mg, 85 % yield) as a light brown solid. M.p.
168–170 °C. 1H NMR (400 MHz, CDCl3): δ = 7.42–7.34 (m, 2 H), 7.33–
7.25 (m, 3 H), 7.17 (d, J = 7.6 Hz, 1 H), 7.07 (t, J = 7.8 Hz, 1 H), 6.84
(d, J = 6.8 Hz, 1 H), 4.30 (s, 2 H), 2.58 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 151.9, 149.0, 136.8, 129.8, 128.8, 126.9, 124.7,
124.0, 123.4, 37.1, 18.4 ppm. MS (EI): m/z (%) = 199 (33) [M]+, 182
(100), 167 (48), 154 (7), 139 (7), 128 (6), 115 (7), 106 (7), 91 (10), 77
(15), 65 (16), 51 (15), 41 (7). C13H13NO (199.25): calcd. C 78.36, H
6.58, N 7.03; found C 78.11, H 6.60, N 7.05.
C15H15NO2 (241.29): calcd. C 74.67, H 6.27, N 5.81; found C 74.83, H
6.24, N 5.83.
2-Methyl-6-(4-methylbenzyl) pyridine 1-Oxide (3j): The general
procedure was followed by using 2-methylpyridine N-oxide
(1 mmol, 109 mg), K2S2O8 (1.25 mmol, 338 mg), CuO (12 mg,
15 mol-%), p-Xylene (3 mmol, 0.37 mL), and acetonitrile (2 mL).
Purification by column chromatography (silica gel, n-hexane/EtOAc/
methanol, 1:1:0.1) gave final product 3j (155 mg, 73 % yield) as a
4-Acetyl-2-(4-methylbenzyl) pyridine 1-Oxide (3f): The general
procedure was followed by using 4-acetylpyridine N-oxide (1 mmol,
137 mg), K2S2O8 (1.25 mmol, 338 mg), CuO (12 mg, 15 mol-%), p-
Xylene (3 mmol, 0.37 mL), and acetonitrile (2 mL). Purification by
column chromatography (silica gel, n-hexane/EtOAc/methanol,
1:1:0.1) gave final product 3f (154 mg, 64 % yield) as a pale yellow
oil. 1H NMR (400 MHz, CDCl3): δ = 8.34 (d, J = 6.6 Hz, 1 H), 7.68 (dd,
J = 6.5 & J = 2.3 Hz, 1 H), 7.55 (d, J = 2.3 Hz, 1 H), 7.22 (d, J = 7.9 Hz,
2 H), 7.19 (d, J = 8.0 Hz, 2 H), 4.23 (s, 2 H), 2.51 (s, 3 H), 2.38 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 194.3, 152.6, 139.7, 137.0,
132.4, 129.7, 129.4, 127.9, 124.6, 122.3, 36.1, 26.3, 21.2 ppm. MS (EI):
m/z (%) = 241 (22) [M]+, 224 (100), 209 (29), 194 (7), 181 (15), 166
(14), 152 (7), 139 (7), 120 (14), 105 (13), 91 (15), 77 (13), 65 (9), 53
(9), 43 (28). C15H15NO2 (241.29): calcd. C 74.67, H 6.27, N 5.81; found
C 74.39, H 6.25, N 5.78.
1
pale yellow oil. H NMR (400 MHz, CDCl3): δ = 7.21–7.12 (m, 5 H),
7.06 (t, J = 7.7 Hz, 1 H), 6.84 (d, J = 7.7 Hz, 1 H), 4.25 (s, 2 H), 2.58
(s, 3 H), 2.36 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.1,
148.9, 137.3, 135.2, 129.7, 129.5, 127.9, 123.9, 123.3, 43.6, 21.1,
18.4 ppm. MS (EI): m/z (%) = 213 (25) [M]+, 196 (100), 181 (95), 163
(30), 120 (25), 105 (45), 91 (27), 77 (25), 65 (20), 51 (8), 43 (35).
C14H15NO (213.27): calcd. C 78.84, H 7.09, N 6.57; found C 78.18, H
7.11, N 6.54.
2-(4-Methylbenzyl) quinoline 1-Oxide (3k): The general proce-
dure was followed by using quinoline N-oxide (1 mmol, 145 mg),
K2S2O8 (1.25 mmol, 338 mg), CuO (12 mg, 15 mol-%), p-Xylene
(3 mmol, 0.37 mL), and acetonitrile (2 mL). Purification by column
chromatography (silica gel, n-hexane/EtOAc/methanol, 1:1:0.1) gave
final product 3k (177 mg, 71 % yield) as a brown solid. M.p. 81–
2-(4-Methylbenzyl)-4-nitropyridine 1-Oxide (3g): The general
procedure was followed by using 4-nitropyridine N-oxide (1 mmol,
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1
84 °C. H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 8.1 Hz, 1 H), 7.59
(100), 167 (42), 152 (7), 106 (9), 91 (10), 77 (15), 65 (16), 51 (15), 41
(7). C13H13NO (199.25): calcd. C 78.36, H 6.58, N 7.03; found C 78.53,
H 6.55, N 7.01.
(d, J = 7.8 Hz, 1 H), 7.53 (t, J = 7.9 Hz, 1 H), 7.43–7.31 (m, 3 H), 7.20
(d, J = 8.1 Hz, 2 H), 7.16 (d, J = 8.2 Hz, 2 H), 4.40 (s, 2 H), 2.36 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 141.1, 138.4, 138.3, 137.3,
135.2, 130.7, 129.4, 128.8, 128.7, 127.9, 122.7, 111.9, 116.1, 43.5,
23.3 ppm. MS (EI): m/z (%) = 249 (10) [M]+, 219 (15), 163 (59), 149
(23), 120 (35), 106 (100), 91 (29), 77 (25), 65 (14), 51 (14), 43 (59).
C17H15NO (249.31): calcd. C 81.90, H 6.06, N 5.62; found C 81.65, H
6.04, N 5.63.
2-Benzyl-3,5-dimethylpyridine 1-Oxide (3p): The general proce-
dure was followed by using 3,5-dimethylpyridine N-oxide (1 mmol,
123 mg), K2S2O8 (1.25 mmol, 338 mg), CuO (12 mg, 15 mol-%),
toluene (3 mmol, 0.32 mL), and acetonitrile (2 mL). Purification by
column chromatography (silica gel, n-hexane/EtOAc/methanol,
1:1:0.1) gave final product 3p (127 mg, 60 % yield) as a brown oil.
1H NMR (400 MHz, CDCl3): δ = 8.04 (s, 1 H), 7.28–7.16 (m, 5 H), 6.92
(s, 1 H), 4.36 (s, 2 H), 2.27 (s, 3 H), 2.23 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 147.2, 137.3, 137.0, 135.2, 133.4, 129.7, 128.5,
128.2, 126.5, 32.3, 19.1, 17.9 ppm. MS (EI): m/z (%) = 213 (29) [M]+,
196 (100), 181 (40), 162 (7), 152 (7), 120 (10), 106 (10), 91 (9), 77
(14), 59 (13), 51 (9), 43 (15). C14H15NO (213.27): calcd. C 78.84, H
7.09, N 6.57; found C 78.71, H 7.07, N 6.60.
2-(3-Methoxybenzyl) pyridine 1-Oxide (3l): The general proce-
dure was followed by using pyridine N-oxide (1 mmol, 95 mg),
K2S2O8 (1.25 mmol, 338 mg), CuO (12 mg, 15 mol-%), 3-methylanisol
(3 mmol, 0.38 mL), and acetonitrile (2 mL). Purification by column
chromatography (silica gel, n-hexane/EtOAc/methanol, 1:1:0.1) gave
final product 3l (161 mg, 75 % yield) as a brown oil. 1H NMR
(400 MHz, CDCl3): δ = 8.33 (d, J = 7.7 Hz, 1 H), 7.35–7.29 (m, 2 H),
7.18 (t, J = 5.2 Hz, 2 H), 6.98 (t, J = 5.6 Hz, 1 H), 6.90–6.88 (m, 1 H),
6.86 (s, 1 H), 4.27 (s, 2 H), 3.83 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 151.9,139.4, 137.8, 129.9, 125.8, 125.6, 123.6, 122.1,
115.5, 112.4, 55.2, 36.6 ppm. MS (EI): m/z (%) = 215 (28) [M]+, 198
(100), 183 (63), 167 (15), 154 (28), 117 (9), 92 (9), 78 (21), 65 (10), 51
(13), 41 (7). C13H13NO2 (215.25): calcd. C 72.54, H 6.09, N 6.51; found
C 72.27, H 6.08, N 6.53.
2-Benzoylpyridine 1-Oxide (4a):[31] The general procedure was
followed by using pyridine N-oxide (0.5 mmol, 47 mg), K2S2O8
(1.25 mmol, 338 mg), Cu(OAc)2 (14 mg, 15 mol-%), toluene
(1.5 mmol, 0.16 mL), and chlorobenzene (2 mL). Purification by col-
umn chromatography (silica gel, n-hexane/EtOAc/methanol, 1:1:0.1)
gave final product 4a (74 mg, 75 % yield) as a yellow solid. M.p.
1
85–87 °C. H NMR (500 MHz, CDCl3): δ = 8.31 (d, J = 5.26 Hz, 1 H),
2-Benzyl-6-ethylpyridine 1-Oxide (3m): The general procedure
was followed by using 2-ethylpyridine N-oxide (1 mmol, 123 mg),
K2S2O8 (1.25 mmol, 338 mg), CuO (12 mg, 15 mol-%), toluene
(3 mmol, 0.32 mL), and acetonitrile (2 mL). Purification by column
chromatography (silica gel, n-hexane/EtOAc/methanol, 1:1:0.1) gave
7.89 (d, J = 7.26 Hz, 2 H), 7.87 (t, J = 7.36 Hz, 1 H), 7.65 (t, J =
7.64 Hz, 2 H), 7.52–7.45 (m, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 189.2, 147.2, 140.1, 134.3, 129.3, 128.9, 128.4, 127.0, 126.04,
125.8 ppm. HRMS (EI): m/z calcd. for C12H9NO2 [M]+ 199.0624; found
199.0633.
1
final product 3m (183 mg, 86 % yield) as a pale yellow oil. H NMR
2-(4-Methylbenzoyl) pyridine 1-Oxide (4b):[31] The general proce-
dure was followed by using pyridine N-oxide (0.5 mmol, 47 mg),
K2S2O8 (1.25 mmol, 338 mg), Cu(OAc)2 (14 mg, 15 mol-%), p-Xylene
(1.5 mmol, 0.18 mL), and chlorobenzene (2 mL). Purification by col-
umn chromatography (silica gel, n-hexane/EtOAc/methanol, 1:1:0.1)
gave final product 4b (83 mg, 78 % yield) as an off-white solid. M.p.
142–144 °C. 1H NMR (400 MHz, CDCl3): δ = 8.09 (br. s, 1 H), 7.79 (d,
J = 6.3 Hz, 2 H), 7.63–7.46 (m, 3 H), 7.32 (d, J = 6.7 Hz, 2 H), 2.45 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 188.2, 155.1, 145.6, 140.1,
135.1, 132.4, 129.7, 129.6, 128.5, 122.1, 21.5 ppm. MS (EI): m/z (%) =
213 (17) [M]+, 196 (11), 169 (46), 106 (92), 91 (40), 78 (100), 65 (31),
51 (31). C13H11NO2 (213.23): calcd. C 73.23, H 5.20, N 6.57; found C
73.46, H 5.21, N 6.54.
(400 MHz, CDCl3): δ = 7.41–7.31 (m,4 H), δ = 7.18–7.10 (m,3 H), 6.83
(dd, J = 7.6,& J = 2.0 Hz, 1 H), 4.30 (s, 2 H), 3.02 (q, J = 7.5 Hz, 2 H),
1.35 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.6,
151.8, 136.8, 129.8, 128.8, 127.9, 126.9, 124.8, 123.1, 37.1, 24.1,
10.7 ppm. MS (EI): m/z (%) = 213 (30) [M]+, 196 (100), 181 (42), 167
(21), 149 (15), 106 (25), 91 (21), 77 (20), 65 (15), 43 (16). C14H15NO
(213.27): calcd. C 78.84, H 7.09, N 6.57; found C 78.94, H 7.12, N
6.54.
2-Ethyl-6-(4-methylbenzyl) pyridine 1-Oxide (3n): The general
procedure was followed by using 2-ethylpyridine N-oxide (1 mmol,
123 mg), K2S2O8 (1.25 mmol, 338 mg), CuO (12 mg, 15 mol-%), p-
Xylene (3 mmol, 0.37 mL), and acetonitrile (2 mL). Purification by
column chromatography (silica gel, n-hexane/EtOAc/methanol,
1:1:0.1) gave final product 3n (179 mg, 79 % yield) as a dark brown
solid. M.p. 43–44 °C. 1H NMR (400 MHz, CDCl3): δ = 7.19 (d, J =
7.7 Hz, 2 H), 7.16–7.10 (m, 4 H), 6.83 (dd, J = 7.3, 2.4 Hz, 1 H), 4.23
(s, 2 H), 3.00 (q, J = 7.4 Hz, 2 H), 2.38 (s, 3 H), 1.34 (t, J = 7.5 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.6, 152.1, 136.5, 133.6,
129.5, 129.4, 127.9, 125.1, 123.0, 43.5, 23.3, 21.1, 10.7 ppm. MS (EI):
m/z (%) = 228 (33) [M + 1+], 227 (18) [M]+, 210 (51), 195 (20), 180
(10), 163 (74), 148 (15), 120 (51), 106 (100), 91 (33), 77 (19), 65 (15),
43 (53). C15H17NO (227.30): calcd. C 79.26, H 7.54, N 6.16; found C
79.09, H 7.56, N 6.18.
2-(2-Methoxybenzoyl) pyridine 1-Oxide (4c): The general proce-
dure was followed by using pyridine N-oxide (0.5 mmol, 47 mg),
K2S2O8 (1.25 mmol, 338 mg), Cu(OAc)2 (14 mg, 15 mol-%), 2-methyl-
anisole (1.5 mmol, 0.19 mL), and chlorobenzene (2 mL). Purification
by column chromatography (silica gel, n-hexane/EtOAc/methanol,
1:1:0.1) gave final product 4c (87 mg, 76 % yield) as a brown solid.
1
M.p. 267–269 °C. H NMR (400 MHz, CDCl3): δ = 7.97 (d, J = 7.5 Hz,
1 H), 7.70–7.33 (m, 5 H), 7.12 (t, J = 7.5 Hz, 1 H), 6.94 (d, J = 8.3 Hz,
1 H), 3.67 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 186.2, 159.7,
151.1, 138.4, 135.9, 135.2, 130.8, 128.1, 127.5, 125.2, 121.4, 111.7,
56.4 ppm. MS (EI): m/z (%) = 229 (10) [M]+, 198 (88), 170 (18), 135
(14), 106 (66), 78 (100), 51 (29). C13H11NO3 (229.23): calcd. C 68.11,
H 4.84, N 6.11; found C 68.27, H 4.83, N 6.13.
2-Benzyl-3-methylpyridine 1-Oxide (3o): The general procedure
was followed by using 3-methylpyridine N-oxide (1 mmol, 109 mg),
K2S2O8 (1.25 mmol, 338 mg), CuO (12 mg, 15 mol-%), toluene
(3 mmol, 0.32 mL), and acetonitrile (2 mL). Purification by column
chromatography (silica gel, n-hexane/EtOAc/methanol, 1:1:0.1) gave
final product 3o (155 mg, 78 % yield) as a brown oil. 1H NMR
(400 MHz, CDCl3): δ = 8.22 (d, J = 7.2 Hz, 1 H), 7.33–7.20 (m, 5 H),
7.10 (d, J = 7.4 Hz, 2 H), 4.44 (s, 2 H), 2.36 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 150.3, 137.5, 136.7, 135.9, 129.6, 128.6, 128.3,
127.8, 126.6, 32.7, 19.3 ppm. MS (EI): m/z (%) = 199 (28) [M]+, 182
2-(3-Methylbenzoyl)-4-nitropyridine 1-Oxide (4d): The general
procedure was followed by using 4-nitropyridine N-oxide (0.5 mmol,
70 mg), K2S2O8 (1.25 mmol, 338 mg), Cu(OAc)2 (14 mg, 15 mol-%),
m-Xylene (1.5 mmol, 0.18 mL), and chlorobenzene (2 mL). Purifica-
tion by column chromatography (silica gel, n-hexane/EtOAc/meth-
anol, 1:1:0.1) gave final product 4d (89 mg, 69 % yield) as an orange
solid. M.p. 144–146 °C. 1H NMR (400 MHz, CDCl3): δ = 8.40 (d, J =
Eur. J. Org. Chem. 2018, 1559–1566
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7.2 Hz, 1 H), 8.31 (d, J = 3.2 Hz, 1 H), 8.07 (dd, J = 7.2, 3.2 Hz, 1 H),
7.61 (s, 1 H), 7.46 (t, J = 7.6 Hz, 1 H), 7.43–7.33 (m, 2 H), 2.48 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 184.2, 150.6, 141.4, 138.5,
136.0, 131.6, 129.6, 128.6, 126.2, 121.7, 118.5, 29.7 ppm. MS (EI): m/z
(%) = 258 (7) [M]+, 241 (10), 230 (33), 214 (9), 201 (21), 181 (28), 154
(45), 139 (28), 123 (46), 105 (13), 91 (65), 77 (66), 57 (63), 43 (100).
C13H10N2O4 (258.23): calcd. C 60.47, H 3.90, N 10.85; found C 60.63,
H 3.92, N 10.88.
2-Benzoyl-4-nitropyridine 1-Oxide (4e):[31] The general procedure
was followed by using 4-nitropyridine N-oxide (0.5 mmol, 70 mg),
K2S2O8 (1.25 mmol, 338 mg), Cu(OAc)2 (14 mg, 15 mol-%), toluene
(1.5 mmol, 0.16 mL), and chlorobenzene (2 mL). Purification by col-
umn chromatography (silica gel, n-hexane/EtOAc/methanol, 1:1:0.1)
gave final product 4e (79 mg, 65 % yield) as a white solid. M.p. 187–
189 °C. 1H NMR (500 MHz, CDCl3): δ = 8.36 (d, J = 7.5 Hz, 1 H), 8.27
(d, J = 3.0 Hz, 1 H), 8.02 (dd, J = 7.0 & J = 3.0 Hz, 1 H), 7.79 (dd, J =
7.1 & J = 2.0 Hz, 2 H), 7.80–7.51 (m, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 185.8, 141.4, 133.6, 130.8, 130.6, 129.1, 128.9, 128.7,
121.6, 118.5 ppm. MS (EI): m/z (%) = 244 (15) [M]+, 215 (7), 168 (8),
139 (8), 122 (18), 115 (22), 105 (44), 77 (96), 69 (8), 63 (22), 57 (23),
51 (100), 45 (44). C12H8N2O4 (244.20): calcd. C 59.02, H 3.30, N 11.47;
found C 59.26, H 3.32, N 11.43.
129.2, 128.7, 125.3, 119.7, 29.4 ppm. MS (EI): m/z (%) = 242 (14) [M
+ 1]+, 241 (3) [M]+, 224 (100), 180 (8), 141 (9), 122 (49), 103 (44), 77
(70), 51 (40). C14H11NO3 (241.24): calcd. C 69.70, H 4.60, N 5.81;
found C 69.48, H 4.62, N 5.83.
5-Acetyl-2-benzoylpyridine 1-Oxide (4i):[31] The general proce-
dure was followed by using 3-acetylpyridine N-oxide (0.5 mmol,
68 mg), K2S2O8 (1.25 mmol, 338 mg), Cu(OAc)2 (14 mg, 15 mol-%),
toluene (1.5 mmol, 0.16 mL), and chlorobenzene (2 mL). Purification
by column chromatography (silica gel, n-hexane/EtOAc/methanol,
1:1:0.1) gave final product 4i (82 mg, 68 % yield) as a pale yellow
solid. M.p. 95–97 °C. 1H NMR (400 MHz, CDCl3): δ = 8.80 (s, 1 H),
8.38 (d, J = 7.9 Hz, 1 H), 7.89 (t, J = 7.4 Hz, 1 H), 7.68 (dd, J = 8.0 &
J = 2.4 Hz, 1 H), 7.48 (d, J = 7.4 Hz, 2 H), 7.37 (t, J = 7.3 Hz, 2 H),
2.62 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 191.0, 186.0,
163.2, 147.9, 134.1, 131.5, 129.2, 128.8, 128.5, 127.1, 125.9, 29.7 ppm.
MS (EI): m/z (%) = 242 (26) [M + 1]+, 241 (6) [M]+, 225 (100), 180
(18), 153 (77), 131 (65), 103 (65), 77 (55), 51 (29). C14H11NO3 (241.24):
calcd. C 69.70, H 4.60, N 5.81; found C 69.94, H 4.63, N 5.84.
2-Cyano-6-(4-methylbenzoyl) pyridine 1-Oxide (4j):[31] The gen-
eral procedure was followed by using 2-cyanopyridine N-oxide
(0.5 mmol, 60 mg), K2S2O8 (1.25 mmol, 338 mg), Cu(OAc)2 (14 mg,
15 mol-%), p-Xylene (1.5 mmol, 0.18 mL), and chlorobenzene (2 mL).
Purification by column chromatography (silica gel, n-hexane/EtOAc/
methanol, 1:1:0.1) gave final product 4j (82 mg, 69 % yield) as an
4-Acetyl-2-(4-methylbenzoyl) pyridine 1-Oxide (4f):[31] The gen-
eral procedure was followed by using 4-acetylpyridine N-oxide
(0.5 mmol, 68 mg), K2S2O8 (1.25 mmol, 338 mg), Cu(OAc)2 (14 mg,
15 mol-%), p-Xylene (1.5 mmol, 0.18 mL), and chlorobenzene (2 mL).
Purification by column chromatography (silica gel, n-hexane/EtOAc/
methanol, 1:1:0.1) gave final product 4f (100 mg, 79 % yield) as a
1
off-white solid. M.p. 98–100 °C. H NMR (500 MHz, CDCl3): δ = 8.47
(dd, J = 7.8 &, J = 1.9 Hz, 1 H), 8.26 (d, J = 7.4 Hz, 1 H), 7.46 (t, J =
7.7 Hz, 1 H), 7.27 (d, J = 7.2 Hz, 2 H), 7.1 5 (d, J = 7.6 Hz, 2 H), 2.33
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 188.2, 159.8, 140.6,
137.1, 134.8, 129.4, 129.0, 127.7, 127.3, 127.2, 116.0, 21.1 ppm. MS
(EI): m/z (%) = 239 (27) [M + 1]+, 238 (6) [M]+, 225 (91), 167 (7), 149
(10), 135 (20), 119 (18), 106 (74), 91 (27), 78 (100), 65 (11), 57 (14),
43 (14). C14H10N2O2 (238.24): calcd. C 70.58, H 4.23, N 11.76; found
C 70.77, H 4.21, N 11.81.
1
light brown solid. M.p. 125–127 °C. H NMR (400 MHz, CDCl3): δ =
8.24 (d, J = 7.2 Hz, 1 H), 7.92 (d, J = 7.1 Hz, 1 H), 7.35 (d, J = 8.0 Hz,2
H), 7.24 (d, J = 8.2 Hz,2 H), 7.18 (s, 1 H), 2.66 (s, 3 H), 2.4 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 193.2, 189.8, 163.0, 139.5, 129.9,
129.5, 128.8, 128.7, 127.9, 126.5, 126.4, 29.7, 21.3 ppm. MS (EI): m/z
(%) = 257 (9) [M + 2]+, 256 (7) [M + 1]+, 255 (9) [M]+, 243 (39), 208
(3), 149 (36), 105 (100), 77 (18), 43 (22). C15H13NO3 (255.27): calcd.
C 70.58, H 5.13, N 5.49; found C 70.39, H 5.11, N 5.51.
2-Benzoyl-6-cyanopyridine 1-Oxide (4k):[31] The general proce-
dure was followed by using 2-cyanopyridine N-oxide (0.5 mmol,
60 mg), K2S2O8 (1.25 mmol, 338 mg), Cu(OAc)2 (14 mg, 15 mol-%),
toluene (1.5 mmol, 0.16 mL), and chlorobenzene (2 mL). Purification
by column chromatography (silica gel, n-hexane/EtOAc/methanol,
1:1:0.1) gave final product 4k (75 mg, 67 % yield) as a white solid.
4-Acetyl-2-(3-methylbenzoyl)pyridine 1-Oxide (4g): The general
procedure was followed by using 4-acetylpyridine N-oxide
(0.5 mmol, 68 mg), K2S2O8 (1.25 mmol, 338 mg), Cu(OAc)2 (14 mg,
15 mol-%), m-Xylene (1.5 mmol, 0.18 mL), and chlorobenzene
(2 mL). Purification by column chromatography (silica gel, n-hexane/
EtOAc/methanol, 1:1:0.1) gave final product 4g (90 mg, 71 % yield)
1
M.p. 100–102 °C. H NMR (500 MHz, CDCl3): δ = 7.79 (d, J = 7.0 Hz,
2 H), 7.96–7.59 (m, 1 H), 7.50–7.35 (m, 2 H), 7.46–7.42 (m, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 188.7, 156.7, 133.5, 132.1, 130.6,
130.1, 128.9, 128.7, 128.4, 127.4; 114.7 ppm. MS (EI): m/z (%) = 226
(15) [M + 2]+, 211 (14), 196 (25), 183 (37), 121 (51), 105 (80), 77
(100), 51 (74). C13H8N2O2 (224.22): calcd. C 69.64, H 3.60, N 12.49;
found C 69.39, H 3.58, N 12.46.
1
as a pale yellow solid. M.p. 121–123 °C. H NMR (400 MHz, CDCl3):
δ = 8.32 (d, J = 7.2 Hz, 1 H), 7.95 (d, J = 7.2 Hz, 1 H), 7.88 (s, 1 H),
7.56 (d, J = 7.9 Hz, 1 H), 7.49 (d, J = 8.2 Hz, 1 H), 7.44 (s, 1 H), 7.37
(t, J = 7.8 Hz, 1 H), 2.52 (s, 3 H), 2.44 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 190.2, 185.6, 147.1, 139.6, 138.9, 135.5, 133.8, 132.2,
129.3, 129.1, 126.1, 125.3, 119.5, 29.72, 21.35 ppm. MS (EI): m/z (%) =
256 (9) [M + 1]+, 255 (7) [M]+, 241 (33), 224 (100), 209 (32), 194 (15),
180 (33), 167 (16), 149 (16), 115 (33), 105 (16), 91 (33), 71 (32), 57
(45), 43 (78). C15H13NO3 (255.27): calcd. C 70.58, H 5.13, N 5.49;
found C 70.76, H 5.14, N 5.48.
2-Cyano-6-(3-methylbenzoyl) pyridine 1-Oxide (4l): The general
procedure was followed by using 2-cyanopyridine N-oxide
(0.5 mmol, 60 mg), K2S2O8 (1.25 mmol, 338 mg), Cu(OAc)2 (14 mg,
15 mol-%), m-Xylene (1.5 mmol, 0.18 mL), and chlorobenzene
(2 mL). Purification by column chromatography (silica gel, n-hexane/
EtOAc/methanol, 1:1:0.1) gave final product 4l (78 mg, 66 % yield)
as a light brown solid. M.p. 74–76 °C. 1H NMR (400 MHz, CDCl3): δ =
8.61 (d, J = 7.3 Hz, 1 H), 8.23 (d, J = 7.9 Hz, 1 H), 7.89 (td, J = 7.7,
1.6 Hz, 1 H), 7.75–7.51 (m, 2 H), 7.51–7.42 (m, 1 H), 7.29 (s, 1 H),
2.42 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 189.6, 169.9, 148.4,
138.5, 137.3, 133.4, 132.7, 128.5, 128.1, 126.5, 124.3, 122.5, 21.4 ppm.
MS (EI): m/z (%) = 238 (6) [M]+, 135 (70), 119 (100), 106 (10), 91 (90),
79 (48), 65 (33), 44 (30). C14H10N2O2 (238.24): calcd. C 70.58, H 4.23,
N 11.67; found C 70.44, H 4.25, N 11.70.
4-Acetyl-2-benzoylpyridine 1-Oxide (4h):[31] The general proce-
dure was followed by using 4-acetylpyridine N-oxide (0.5 mmol,
68 mg), K2S2O8 (1.25 mmol, 338 mg), Cu(OAc)2 (14 mg, 15 mol-%),
toluene (1.5 mmol, 0.16 mL), and chlorobenzene (2 mL). Purification
by column chromatography (silica gel, n-hexane/EtOAc/methanol,
1:1:0.1) gave final product 4h (80 mg, 67 % yield) as a light brown
1
solid. M.p. 120–122 °C; H NMR (400 MHz, CDCl3): δ = 8.33 (d, J =
7.9 Hz, 1 H), 7.95 (d, J = 7.8 Hz, 2 H), 7.91 (s, 1 H), 7.69 (dd, J = 8.0 &
J = 2.2 Hz, 1 H), 7.50–7.45 (m, 3 H), 2.65 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 194.0, 186.2, 146.8, 143.8, 139.7, 134.4, 131.3,
2-Cyano-6-(4-nitrobenzoyl) pyridine 1-Oxide (4m):[31] The gen-
eral procedure was followed by using 2-cyanopyridine N-oxide
Eur. J. Org. Chem. 2018, 1559–1566
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© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
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15 mol-%), 4–nitrotoluene (1.5 mmol, 0.19 mL), and chlorobenzene
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EtOAc/methanol, 1:1:0.1) gave final product 4m (75 mg, 56 % yield)
1
as a brown solid. M.p. 110–112 °C. H NMR (500 MHz, CDCl3): δ =
8.46 (d, J = 7.6 Hz, 1 H), 8.24 (d, J = 7.2 Hz, 1 H), 7.44 (t, J = 7.1 Hz,
1 H), 7.31 (d, J = 7.1 Hz, 2 H), 6.87 (d, J = 6.9 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 190.1, 166.8, 162.6, 149.5, 148.3, 137.3, 129.3,
126.52, 122.5, 114.5, 113.8 ppm. MS (EI): m/z (%) = 271 (22) [M +
2]+, 269 (5) [M]+, 256 (5), 241 (11), 151 (74), 135 (100), 121 (35), 107
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Acknowledgments
We gratefully acknowledge the financial support from the Re-
search Council of the University of Tehran and the Iran National
Science Foundation (INSF, No. 96008622).
Keywords: Synthetic methods · Homogeneous catalysis ·
Benzylation · Acylation · C–H activation
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Received: November 15, 2017
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© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim