Palladium-Catalysed Chemo- and Regioselective C–H Bond Acylation of Pyridine N-Oxides with Benzyl Halides and Alcohols

Article abstract of DOI:10.1002/ejoc.201700531

A palladium-catalysed method for the acylation of ortho C–H bonds of pyridine N-oxides using readily available benzyl halides and benzyl alcohols as the active acylating agents is described. This procedure provides a new approach to 2-acylpyridine N-oxides, which may be used as precursors for the synthesis of pharmaceuticals and agrochemicals.

Full text of DOI:10.1002/ejoc.201700531

DOI: 10.1002/ejoc.201700531
Full Paper
C–H Activation
Palladium-Catalysed Chemo- and Regioselective C–H Bond
Acylation of Pyridine N-Oxides with Benzyl Halides and
Alcohols
Ebrahim Kianmehr*[a] and Maral Gholamhosseyni[a]
Abstract: A palladium-catalysed method for the acylation of agents is described. This procedure provides a new approach
ortho C–H bonds of pyridine N-oxides using readily available to 2-acylpyridine N-oxides, which may be used as precursors for
benzyl halides and benzyl alcohols as the active acylating the synthesis of pharmaceuticals and agrochemicals.
Introduction
sequently, coupling reactions of pyridine N-oxides with aryl hal-
ides,[11] triflates,[12] and alkyl bromides[13] were developed using
various transition-metal catalysts and reaction conditions.
Oxidative cross-coupling reactions of pyridine N-oxides with
indoles,[14] thiophenes, furans,[15] and toluene derivatives[16]
have also been reported.
The acylation of pyridine N-oxide derivatives has rarely been
reported. In 2014, the acylation of pyridine N-oxides using α-
oxo carboxylic acids in the presence of a silver catalyst through
a decarboxylative process was described.[17] The reaction is not
regioselective, and acylation takes place at both the C-2 and
C-4 positions (Scheme 1). With this in mind, and in a continua-
tion of our interest in this area,[18] we report the palladium-
catalysed regioselective C–H bond acylation of pyridine
N-oxides using benzyl halides and alcohols as the acylating
agents (Scheme 1).
Pyridine N-oxides have found applications in a large number of
areas. They have been used to control the chirality in asymmet-
ric synthesis,[1] and they have also been found to act as inhibi-
tors of human severe acute respiratory syndrome (SARS), hu-
man immunodeficiency virus (HIV), and feline infectious perito-
nitis corona virus.[2] 2-Acylpyridine N-oxides are used as prochi-
ral ketones in the asymmetric Henry reaction[3] to give tertiary
nitro aldols,[4] which are building blocks for the synthesis of
pharmaceuticals and agrochemicals[5] (Figure 1, compound A).
They show excellent chelating properties in several asymmetric
metal-catalysed reactions,[6] and they have also been used as
precursors for the synthesis of norbormide (NRB; Figure 1, com-
pound B), which acts as a rat-selective toxicant,[7] vasocon-
strictor, and calcium-channel blocker.[8]
Figure 1. Examples of applications of 2-acylpyridine.
The direct functionalization of pyridine N-oxides has been
investigated, and it has been found to take place with complete
selectivity for the 2-position.[9] In 2005, the palladium-catalysed
arylation of pyridine N-oxides was reported by Fagnou.[10] Sub-
Scheme 1. Literature precedent for the acylation of pyridine N-oxides.
Results and Discussion
[a] School of Chemistry, College of Science, University of Tehran,
Tehran, Iran
Our initial investigation began with the coupling of pyridine N-
oxide (1a) with benzyl alcohol (2a) or benzyl chloride (2b) as
model reactions. Various conditions were screened to optimize
the reaction conditions (Table 1). A screening of catalysts re-
vealed that PdCl2 gave the best result when benzyl alcohol was
E-mail: kianmehr@khayam.ut.ac.ir
http://schem.ut.ac.ir/en/~kianmehr
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.201700531.
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used as the acylating agent; PdCl2(COD) (COD = 1,5-cyclooctadi-
The presence of alkyl groups at the para position of the
ene) gave the best result when benzyl chloride was used benzyl alcohols and halides resulted in better yields of the de-
(Table 1, Entries 1 and 2). Copper-based catalysts such as CuBr2 sired products (Table 2; 3b and 3g). Benzyl alcohols and halides
and Cu(OAc)2 were found to be inferior (Table 1, Entries 4–6). bearing electron-withdrawing groups such as CF3 or NO2 gave
The reaction was also tested with different catalyst loadings, the acylated products in poor to moderate yields. (Table 2; 3i,
and the results showed that 7 mol-% of the Pd catalyst was the 3j, and 3q). Pyridine N-oxides bearing electron-withdrawing
best choice for completing the reaction (Table 1, Entries 1, 2, groups such as nitro or methyl ketone groups reacted smoothly
and 7). Commonly used organic solvents were screened. Chloro- to give the corresponding 2-acylpyridine N-oxides in good
benzene gave the best yields for both acylating agents 2a and yields. Halogen groups on either the pyridine N-oxide or the
2b; solvents such as DMF, DMSO, and DCE (1,2-dichloroethane) acylating agent – the benzyl alcohol or halide – remained intact
gave moderate yields of the product, and CH3CN gave poor during the reactions; thus, they could be further transformed
results (Table 1, Entries 8–11). No reaction took place when H2O to give other important structures.
or AcOH were used as the solvent (Table 1, Entries 12 and 13).
The effectiveness of various oxidants was also examined. K2S2O8
was found to be more effective than other oxidants such as
(NH4)2S2O8, TBHP (tert-butyl hydroperoxide), and DTBP (di-tert-
butyl peroxide) (Table 1, Entries 14–16). The reaction tempera-
ture was also varied, and we found that the best results were
obtained at 130 °C (Table 1, Entries 1, 2, and 17). No reaction
occurred in the absence of catalyst or in the absence of oxidant
(Table 1, Entries 18 and 19).
On the basis of the above results and previous reports, a
plausible catalytic mechanism is shown in Scheme 2. Metalla-
tion of the pyridine N-oxide derivative with PdII generates inter-
mediate A. The benzyl alcohol or halide is oxidized with K2S2O8
to give the corresponding aldehyde.[19] Radical intermediate B
is generated in situ through hydrogen atom abstraction from
the aldehyde in the presence of a sulfate radical anion, which
is produced from K2S2O8 under the reaction conditions
(Scheme 2). PdII intermediate A reacts with acyl radical B to
Once the optimized conditions for the desired acylation reac- give PdIV intermediate C. This then undergoes reductive elimi-
tion were established, the scope of the reaction with regard to nation to produce the desired product and regenerate the PdII
different benzyl alcohols and halides as the acylating agents species.[20] To prove the role of K2S2O8 as a radical agent, a
was investigated. We found that a variety of benzyl alcohols control reaction was carried out using 2,6-di-tert-butyl-4-meth-
and halides with both electron-donating and electron-with- ylphenol (butylated hydroxytoluene, BHT) as a radical scaven-
drawing substituents on the aromatic ring were tolerated, and ger. When the reaction of 1a was carried out in the presence
moderate to good yields were obtained in most cases.
of BHT, none of the desired product 3a was observed.
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Oxidant
Solvent
Temp.
[°C]
Yield[b] with 2a
Yield[b] with 2b
[%]
[%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
PdCl2(COD)
PdCl2
Pd(OAc)2
CuCl
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
(NH4)S2O8
TBHP
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
DCE
DMF
DMSO
CH3CN
H2O
AcOH
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
100
130
130
63
72
18
11
69
32
70
10
23
31
2
0
0
30
0
0
65
57
21
trace
28
24
62
55
19
28
9
0
0
0
0
0
13
0
Cu(OAc)2
CuBr2
PdII[c,d]
PdII[c]
PdII[c]
PdII[c]
PdII[c]
PdII[c]
PdII[c]
PdII[c]
PdII[c]
PdII[c]
DTBP
PdII[c]
K2S2O8
K2S2O8
–
51
0
0
–
PdII[c]
0
[a] 1a (0.5 mmol), 2a (1.5 mmol), and solvent (2.0 mL) were stirred at 130 °C for 20 h. [b] Isolated yields of 3a. [c] PdCl2 was used with 2a, and PdCl2(COD)
was used with 2b. [d] 10 mol-% of catalyst was used.
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Table 2. Substrate scope.[a]
[a] 1a (0.5 mmol), 2a (1.5 mmol), Pd catalyst (7 mol-%), K2S2O8 (2.0 equiv.), chlorobenzene (2.0 mL), 130 °C, 20 h.
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mixture was cooled to room temperature. The mixture was diluted
with methanol and filtered, and the solvent was removed in vacuo.
The resulting residue was purified by column chromatography (n-
hexane/EtOAc/methanol, 1:1:0.1) to give the desired product.
2-Benzoylpyridine 1-Oxide (3a):[3] General procedure A was ap-
plied, using pyridine N-oxide (0.5 mmol, 47 mg), benzyl alcohol
(1.5 mmol, 0.15 mL), PdCl2 (6 mg, 7 mol-%), K2S2O8 (1 mmol,
270 mg), and chlorobenzene (2 mL). Also, general procedure B was
applied, using pyridine N-oxide (0.5 mmol, 47 mg), benzyl chloride
(1.5 mmol, 0.17 mL), PdCl2(COD) (8 mg, 7 mol-%), K2S2O8 (1 mmol,
270 mg), and chlorobenzene (2 mL). Purification by column chroma-
tography (silica gel; n-hexane/EtOAc/methanol, 1:1:0.1) gave the de-
sired product 3a (procedure A: 71 mg, 72 %; procedure B: 64 mg,
65 %) as a yellow solid. M.p. 85–87 °C. 1H NMR (500 MHz, CDCl3):
δ = 8.31 (d, J = 5.26 Hz, 1 H), 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): calcd. for C12H9NO2 [M]+
199.0624; found 199.0633.
2-(4-Methylbenzoyl)pyridine 1-Oxide (3b): General procedure A
was applied, using pyridine N-oxide (0.5 mmol, 47 mg), 4-methyl-
benzyl alcohol (2 mmol, 183 mg), PdCl2 (6 mg, 7 mol-%), K2S2O8
(1 mmol, 270 mg), and chlorobenzene (2 mL). Also, general proce-
dure B was applied, using pyridine N-oxide (0.5 mmol, 47 mg), 4-
methylbenzyl chloride (1.5 mmol, 0.20 mL), PdCl2(COD) (8 mg,
7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL).
Scheme 2. Plausible mechanism.
Conclusions
We have explored an efficient method for the ortho C–H bond Purification by column chromatography (silica gel; n-hexane/EtOAc/
methanol, 1:1:0.1) gave the desired product 3b (procedure A:
acylation of pyridine N-oxides with benzyl alcohols and halides
as aroyl surrogates. The reaction is applicable to numerous sub-
strates with good tolerance of various functional groups, and it
provides a straightforward route to 2-acylpyridine N-oxides
from accessible starting materials. The reaction products are
interesting compounds for research into pharmaceuticals and
agrochemicals.
83 mg, 78 %; procedure B: 75 mg, 71 %) as an off-white solid. M.p.
1
142–144 °C. H 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
73.43, H 5.24, N 6.54.
2-(4-Methoxybenzoyl)pyridine 1-Oxide (3c):[3] General proce-
dure A was applied, using pyridine N-oxide (0.5 mmol, 47 mg), 4-
methoxybenzyl alcohol (1.5 mmol, 200 mg), PdCl2 (6 mg, 7 mol-%),
K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL). Also, general
procedure B was applied, using pyridine N-oxide (0.5 mmol, 47 mg),
4-methoxybenzyl chloride (1.5 mmol, 0.20 mL), PdCl2(COD) (8 mg,
Experimental Section
General Remarks: Solvents, benzyl alcohols, benzyl halides, and
pyridine derivatives were purchased from Merck and Sigma. Other
reagents were purchased from commercial distributors and were
used without further purification. Pyridine N-oxide derivatives and
palladium catalysts were synthesized according to literature proce- 7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL).
dures. Analytical thin-layer chromatography (TLC) was carried out Purification by column chromatography (silica gel; n-hexane/EtOAc/
on precoated silica gel 60 F254 plates. Products were purified by
methanol, 1:1:0.1) gave the desired product 3c (procedure A: 86 mg,
preparative column chromatography on silica gel (0.063–0.200 mm, 76 %; procedure B: 79 mg, 70 %) as an off-white solid. M.p. 256–
1
Merck). 1H and 13C NMR spectra were recorded with Bruker DRX
600, 500, and 400 Avance instruments in CDCl3; chemical shifts are
reported on the δ scale in ppm; coupling constants (J) are reported
in Hz. Mass spectrometry was carried out with an Agilent 5975C VL
MSD instrument (ion source: EI+, 70 eV, 230 °C). High-resolution
mass spectra were recorded with a Kratos Concept IIH mass spec-
trometer.
258 °C. H NMR (400 MHz, CDCl3): δ = 8.33 (br. s, 1 H), 7. 85 (d, J =
8.8 Hz, 2 H), 7.50–7.36 (m, 3 H), 6.98 (d, J = 8.8 Hz, 2 H), 3.91 (s, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 187.2, 164.7, 140.1, 134.4,
132.1, 128.0, 126.9, 126.8, 125.7, 114.4, 55.8 ppm. MS (EI): m/z (%) =
229 (22) [M]+, 212 (11), 185 (17), 135 (12), 126 (17), 106 (50), 92 (19),
78 (100), 69 (12), 63 (20), 51 (25), 43 (30). C13H11NO3 (229.23): calcd.
C 68.11, H 4.84, N 6.11; found C 68.35, H 4.81, N 6.14.
General Procedure for the Synthesis of 2-Acylated Pyridine N-
Oxides Using Benzyl Alcohols and Halides as Acylating Agents:
2-Benzoyl-4-nitropyridine 1-Oxide (3d): General procedure A was
applied, using 4-nitropyridine N-oxide (0.5 mmol, 70 mg), benzyl
A microwave vial (10 mL) was loaded with pyridine N-oxide deriva- alcohol (1.5 mmol, 0.15 mL), PdCl2 (6 mg, 7 mol-%), K2S2O8 (1 mmol,
tive (1 equiv., 0.5 mmol), acylating agent [procedure A: benzyl alco-
hol (3 equiv., 1.5 mmol); procedure B: benzyl chloride (3 equiv.,
1.5 mmol); procedure C: benzyl bromide (3 equiv., 1.5 mmol)],
K2S2O8 (2 equiv., 1 mmol), Pd catalyst (7 mol-%), and chlorobenzene
(2 mL). The vial was then sealed and immersed in an oil bath, which
270 mg), and chlorobenzene (2 mL). Also, general procedure B was
applied, using 4-nitropyridine N-oxide (0.5 mmol, 70 mg), benzyl
chloride (1.5 mmol, 0.17 mL), PdCl2(COD) (8 mg, 7 mol-%), K2S2O8
(1 mmol, 270 mg), and chlorobenzene (2 mL). Purification by col-
umn chromatography (silica gel; n-hexane/EtOAc/methanol, 1:1:0.1)
was preheated at 130 °C, for 20 h. After this time, the reaction gave the desired product 3d (procedure A: 79 mg, 65 %; proce-
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dure B: 74 mg, 61 %) as a white solid. M.p. 187–19 °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
dure B was applied, using pyridine N-oxide (0.5 mmol, 47 mg), 4-
chlorobenzyl chloride (1.5 mmol, 240 mg), PdCl2(COD) (8 mg, 7 mol-
%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL). Also, gen-
eral procedure C was applied, using pyridine N-oxide (0.5 mmol,
47 mg), 4-chlorobenzyl bromide (1.5 mmol, 308 mg), PdCl2(COD)
(EI): m/z (%) = 244 (15) [M]+, 215 (7), 168 (8), 139 (8), 122 (18), 115 (8 mg, 7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene
(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 59.17,
H 3.32, N 11.51.
(2 mL). Purification by column chromatography (silica gel; n-hexane/
EtOAc/methanol, 1:1:0.1) gave the desired product 3h (procedure A:
77 mg, 66 %; procedure B: 68 mg, 59 %; procedure C: 72 mg, 62 %)
as a white solid. M.p. 117–119 °C. 1H NMR (400 MHz, CDCl3): δ =
8.29 (d, J = 6.8 Hz, 1 H), 7.81 (d, J = 8.7 Hz, 2 H), 7.49–7.46 (m, 5 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 188.0, 140.6, 140.1, 133.5,
130.9, 130.6, 129.3, 127.3, 126.0, 125.9, 255 ppm. MS (EI): m/z (%) =
235 [M + 2]+, 233 (16) [M]+, 216 (17), 167 (25), 149 (44), 139 (11),
113 (17), 106 (74), 78 (100), 71 (18), 57 (29), 43 (22). C12H8ClNO2
(233.65): calcd. C 61.69, H 3.45, N 5.99; found C 61.88, H 3.48, N
6.03.
4-Acetyl-2-benzoylpyridine 1-Oxide (3e): General procedure A
was applied, using 4-acetylpyridine N-oxide (0.5 mmol, 68 mg),
benzyl alcohol (1.5 mmol, 0.15 mL), PdCl2 (6 mg, 7 mol-%), K2S2O8
(1 mmol, 270 mg), and chlorobenzene (2 mL). Also, general proce-
dure B was applied, using 4-acetylpyridine N-oxide (0.5 mmol,
68 mg), benzyl chloride (1.5 mmol, 0.17 mL), PdCl2(COD) (8 mg,
7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL).
Purification by column chromatography (silica gel; n-hexane/EtOAc/
methanol, 1:1:0.1) gave the desired product 3e (procedure A: 97 mg,
81 %; procedure B: 95 mg, 79 %) as a pale brown solid. M.p. 120–
122 °C. 1H 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, 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 69.56, H
4.65, N 5.85.
2-Chloro-6-[4-(trifluoromethyl)benzoyl]pyridine 1-Oxide (3i):
General procedure A was applied, using 2-chloropyridine N-oxide
(0.5 mmol, 64 mg), 4-(trifluoromethyl) benzyl alcohol (1.5 mmol,
0.20 mL), PdCl2 (6 mg, 7 mol-%), K2S2O8 (1 mmol, 270 mg), and
chlorobenzene (2 mL). Purification by column chromatography (sil-
ica gel; n-hexane/EtOAc/methanol, 1:1:0.1) gave the desired product
1
3i (67 mg, 45 %) as a black solid. M.p. 78–80 °C. H NMR (400 MHz,
CDCl3): δ = 7.62 (d, J = 8.1 Hz, 2 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.41–
7.35 (m, 1 H), 6.66 (d, J = 7.2 Hz, 1 H), 6.23 (td, J = 6.7, J = 1.2 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 194.3, 162.5, 144.5, 140.1,
139.7, 137.1, 132.4, 129.1, 127.8, 126.8, 125.90, 125.87, 125.83,
125.80, 123.3, 121.6, 106.5 ppm. MS (EI): m/z (%) = 302 (13) [M +
1]+, 301 (7) [M]+, 252 (49), 253 (51), 254 (14), 234 (7), 189 (3), 159
(100), 140 (7), 109 (37), 79 (25), 43 (7). C13H7ClF3NO2 (301.65): calcd.
C 51.76, H 2.34, N 4.64; found C 51.52, H 2.36, N 4.68.
2-Benzoyl-6-cyanopyridine 1-Oxide (3f): General procedure A
was applied, using 2-cyanopyridine N-oxide (0.5 mmol, 60 mg),
benzyl alcohol (1.5 mmol, 0.15 mL), PdCl2 (6 mg, 7 mol-%), K2S2O8
(1 mmol, 270 mg), and chlorobenzene (2 mL). Also, general proce-
dure B was applied, using 2-cyanopyridine N-oxide (0.5 mmol,
60 mg), benzyl chloride (1.5 mmol, 0.17 mL), PdCl2(COD) (8 mg,
7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL).
Purification by column chromatography (silica gel; n-hexane/EtOAc/
methanol, 1:1:0.1) gave the desired product 3f (procedure A: 76 mg,
68 %; procedure B: 68 mg, 61 %) as a white solid. M.p. 100–102 °C.
1H 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).
2-[4-(Trifluoromethyl)benzoyl]pyridine 1-Oxide (3j): General
procedure A was applied, using pyridine N-oxide (0.5 mmol, 47 mg),
4-(trifluoromethyl)benzyl alcohol (1.5 mmol, 0.20 mL), PdCl2 (6 mg,
7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL).
Purification by column chromatography (silica gel; n-hexane/EtOAc/
methanol, 1:1:0.1) gave the desired product 3j (45 mg, 38 %) as an
off-white solid. M.p. 111–113 °C. 1H NMR (400 MHz, CDCl3): δ = 8.50
(d, J = 6.1 Hz, 1 H), 8.22 (d, J = 8.2 Hz, 2 H), 7.98 (d, J = 8.1 Hz, 2
H), 7.80–7.73 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 188.2,
152.3, 137.9, 135.7, 134.88, 133.6, 131.1, 130.8, 130.5, 130.1, 128.8,
125.59, 125.55, 125.52, 125.48, 125.35, 124.79 ppm. MS (EI): m/z
(%) = 267 (13) [M]+, 238 (35), 223 (14), 190 (100), 173 (88), 145 (47),
125 (14), 95 (14), 75 (15), 50 (14). C13H8F3NO2 (267.20): calcd. C
58.43, H 3.02, N 5.24; found C 58.22, H 3.05, N 5.21.
C13H8N2O2 (224.21): calcd. C 69.64, H 3.60, N 12.49; found C 69.87,
H 3.63, N 72.45.
2-[4-(tert-Butyl)benzoyl]pyridine 1-Oxide (3 g): General proce-
dure A was applied, using pyridine N-oxide (0.5 mmol, 47 mg), 4-
tert-Butylbenzyl alcohol (1.5 mmol, 0.26 mL), PdCl2 (6 mg, 7 mol-%),
K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL). Purification
by column chromatography (silica gel; n-hexane/EtOAc/methanol,
1:1:0.1) gave the desired product 3g (108 mg, 85 %) as a pale yellow
solid. M.p. 130–132 °C. 1H NMR (400 MHz, CDCl3): δ = 8.30 (d, J =
4.9 Hz, 1 H), 7.81 (d, J = 8.6 Hz, 2 H), 7.52 (d, J = 8.6 Hz, 2 H), 7.46–
7.42 (m, 3 H), 1.35 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
188.7, 158.1, 147.6, 140.0, 132.4, 129.4, 126.9, 125.9, 125.7 125.6,
34.6, 30.7 ppm. MS (EI): m/z (%) = 255 (17) [M]+, 240 (45), 224 (11),
211 (17), 196 (31), 182 (17), 163 (26), 106 (77), 78 (100), 51 (14), 41
(11). C16H17NO2 (255.31): calcd. C 75.27, H 6.71, N 5.49; found C
75.07, H 6.66, N 5.44.
2-Benzoyl-6-chloropyridine 1-Oxide (3k): General procedure A
was applied, using 2-chloropyridine N-oxide (0.5 mmol, 64 mg),
benzyl alcohol (1.5 mmol, 0.15 mL), PdCl2 (6 mg, 7 mol-%), K2S2O8
(1 mmol, 270 mg), and chlorobenzene (2 mL). Also, general proce-
dure B was applied, using 2-chloropyridine N-oxide (0.5 mmol,
64 mg), benzyl chloride (2 mmol, 0.17 mL), PdCl2(COD) (8 mg,
7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL).
Purification by column chromatography (silica gel; n-hexane/EtOAc/
methanol, 1:1:0.1) gave the desired product 3k (procedure A: 79 mg,
1
68 %; procedure B: 76 mg, 66 %) as a black solid. M.p. 55–57 °C. H
NMR (400 MHz, CDCl3): δ = 7.36–7.29 (m, 6 H), 6.63 (d, J = 7.4 Hz,
1 H), 6.14 (td, J = 6.9, J = 1.3 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 190.1, 162.8, 139.3, 137.3, 136.4, 128.7, 128.1, 128.0,
120.9, 107.0 ppm. MS (EI): m/z (%) = 235 (6) [M + 2]+, 233 (18) [M]+,
218 (10), 184 (80), 185 (85), 186 (20), 156 (3), 128 (3), 91 (100), 65
2-(4-Chlorobenzoyl)pyridine 1-Oxide (3h):[3] General procedure A
was applied, using pyridine N-oxide (0.5 mmol, 47 mg), 4-chloro-
benzyl alcohol (1.5 mmol, 214 mg), PdCl2 (6 mg, 7 mol-%), K2S2O8 (22), 41 (3). C12H8ClNO2 (233.65): calcd. C 61.69, H 3.45, N 5.99;
(1 mmol, 270 mg), and chlorobenzene (2 mL). Also, general proce- found C 61.51, H 3.42, N 6.03.
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2-Chloro-6-(2,4-dichlorobenzoyl)pyridine 1-Oxide (3l): General
procedure A was applied, using 2-chloropyridine N-oxide (0.5 mmol,
64 mg), 2,6-dichlorobenzyl alcohol (1.5 mmol, 260 mg), PdCl2 (6 mg,
7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL).
Purification by column chromatography (silica gel; n-hexane/EtOAc/
J = 8.4 Hz, 2 H), 7.33–7.29 (m, 1 H), 7.26 (d, J = 8.2 Hz, 2 H), 6.63 (d,
J = 7.5 Hz, 1 H), 6.18–6.14 (td, J = 6.8, J = 1.2 Hz, 1 H), 1.32 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 189.6, 162.2, 145.05, 139.4,
137.2, 133.2, 128.0, 125.8, 121.2, 106.1, 34.2, 31.6 ppm. MS (EI): m/z
(%) = 292 (11) [M + 2]+, 290 (21) [M]+, 240 (22), 241 (85), 242 (15),
methanol, 1:1:0.1) gave the desired product 3l (80 mg, 53 %) as a 196 (3), 168 (3), 147 (100), 117 (40), 91 (22), 65 (3), 41 (7).
black solid. M.p. 64–66 °C. 1H NMR (500 MHz, CDCl3): δ = 7.41 (d,
J = 6.4 Hz, 1 H), 7.37–7.26 (m, 2 H), 7.23 (d, J = 6.7 Hz, 1 H), 6.63 (d,
J = 7.1 Hz, 1 H), 6.19 (t, J = 6.7 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 195.5, 162.4, 145.0, 139.8, 137.5, 134.5, 134.1, 132.4,
131.2, 129.4, 121.4, 107.0 ppm. MS (EI): m/z (%) = 302 (21) [M]+, 253
(7), 218 (100), 219 (35), 220 (80), 183 (11), 159 (88), 123 (55), 109
(11), 89 (18), 79 (11), 63 (11), 51 (11). C12H6Cl3NO2 (302.54): calcd. C
47.64, H 2.00, N 4.63; found C 47.46, H 2.03, N 4.67.
C16H16ClNO2 (289.76): calcd. C 66.32, H 5.57, N 4.83; found C 66.49,
H 5.61, N 4.86.
2-Cyano-6-(4-methylbenzoyl)pyridine 1-Oxide (3p): General pro-
cedure A was applied, using 2-cyanopyridine N-oxide (0.5 mmol,
60 mg), 4-methylbenzyl alcohol (1.5 mmol, 183 mg), PdCl2 (6 mg,
7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL).
Also, general procedure B was applied, using 2-cyanopyridine N-
oxide (0.5 mmol, 60 mg), 4-methylbenzyl chloride (1.5 mmol,
0.20 mL), PdCl2(COD) (8 mg, 7 mol-%), K2S2O8 (1 mmol, 270 mg),
and chlorobenzene (2 mL). Purification by column chromatography
(silica gel; n-hexane/EtOAc/methanol, 1:1:0.1) gave the desired
product 3p (procedure A: 81 mg, 68 %; procedure B: 75 mg, 63 %)
as an off-white solid. M.p. 98–100 °C. 1H 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), 7.15 (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 70.41, H 4.25, N 11.73.
2-Chloro-6-(4-chlorobenzoyl)pyridine 1-Oxide (3m): General pro-
cedure A was applied, using 2-chloropyridine N-oxide (0.5 mmol,
64 mg), 4-chlorobenzyl alcohol (1.5 mmol, 214 mg), PdCl2 (6 mg,
7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL).
Also, general procedure B was applied, using 2-chloropyridine N-
oxide (0.5 mmol, 64 mg), 4-chlorobenzyl chloride (1.5 mmol,
240 mg), PdCl2(COD) (8 mg, 7 mol-%), K2S2O8 (1 mmol, 270 mg),
and chlorobenzene (2 mL). Also, general procedure C was applied,
using 2-chloropyridine N-oxide (0.5 mmol, 64 mg), 4-chlorobenzyl
bromide (1.5 mmol, 308 mg), PdCl2(COD) (8 mg, 7 mol-%), K2S2O8
(1 mmol, 270 mg), and chlorobenzene (2 mL). Purification by col-
umn chromatography (silica gel; n-hexane/EtOAc/methanol, 1:1:0.1)
gave the desired product 3m (procedure A: 80 mg, 60 %; proce-
dure B: 76 mg, 57 %; procedure C: 79 mg, 59 %) as a black solid.
M.p. 76–78 °C. 1H NMR (400 MHz, CDCl3): δ = 7.30–7.25 (m, 3 H),
7.37–7.32 (m, 2 H), 6.64 (d, J = 7.4 Hz, 1 H), 6.20–6.17 (td, J = 6.8,
J = 1.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 192.4, 162.8,
139.6, 137.1, 134.9, 134.0, 129.5, 129.1, 121.4, 106.0 ppm. MS (EI):
m/z (%) = 270 (6) [M + 2]+, 268 (18) [M]+, 253 (2), 218 (20), 219 (61),
220 (20), 183 (2), 149 (3), 125 (100), 99 (22), 79 (29), 57 (44).
C12H7Cl2NO2 (268.09): calcd. C 53.76, H 2.63, N 5.22; found C 53.59,
H 2.65, N 5.19.
2-Cyano-6-(4-nitrobenzoyl)pyridine 1-Oxide (3q): General proce-
dure A was applied, using 2-cyanopyridine N-oxide (0.5 mmol,
60 mg), 4-nitrobenzyl alcohol (1.5 mmol, 230 mg), PdCl2 (6 mg,
7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL).
Also, general procedure B was applied, using 2-cyanopyridine N-
oxide (0.5 mmol, 60 mg), 4-nitrolbenzyl chloride (1.5 mmol,
260 mg), PdCl2(COD) (8 mg, 7 mol-%), K2S2O8 (1 mmol, 270 mg),
and chlorobenzene (2 mL). Purification by column chromatography
(silica gel; n-hexane/EtOAc/methanol, 1:1:0.1) gave the desired
product 3q (procedure A: 64 mg, 48 %; procedure B: 57 mg, 43 %)
as a brown solid. M.p. 110–112 °C. 1H 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
(18), 92 (25), 77 (35), 69 (11), 57 (14), 43 (14). C13H7N3O4 (269.21):
calcd. C 58.00, H 2.62, N 15.61; found C 58.18, H 2.60, N 15.64.
2-Chloro-6-(4-methylbenzoyl)pyridine 1-Oxide (3n): General pro-
cedure A was applied, using 2-chloropyridine N-oxide (0.5 mmol,
64 mg), 4-methylbenzyl alcohol (1.5 mmol, 183 mg), PdCl2 (6 mg,
7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL).
Also, general procedure B was applied, using 2-chloropyridine N-
oxide (0.5 mmol, 64 mg), 4-methylbenzyl chloride (1.5 mmol,
0.20 mL), PdCl2(COD) (8 mg, 7 mol-%), K2S2O8 (1 mmol, 270 mg),
and chlorobenzene (2 mL). Purification by column chromatography
(silica gel; n-hexane/EtOAc/methanol, 1:1:0.1) gave the desired
product 3n (procedure A: 87 mg, 71 %; procedure B: 86 mg, 70 %)
as a black solid. M.p. 33–35 °C. 1H NMR (400 MHz, CDCl3): δ = 7.34–
7.26 (m, 1 H), 7. 23 (d, J = 8.1 Hz, 2 H), 7.17 (d, J = 8.0 Hz, 2 H), 6.63
(d, J = 7.3 Hz, 1 H), 6.17–6.13 (td, J = 6.7, J = 1.0 Hz, 1 H), 2.35 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 188.6, 163.0, 139.5, 137.9,
137.1, 133.2, 129.4, 128.1, 121.1, 106.2, 21.3 ppm. MS (EI): m/z (%) =
247 (19) [M]+, 198 (24), 199 (81), 200 (10), 167 (7), 149 (11), 119 (11),
105 (100), 98 (7), 91 (11), 79 (25), 65 (7), 57 (7), 51 (11), 43 (7).
C13H10ClNO2 (247.68): calcd. C 63.04, H 4.07, N 5.66; found C 63.28,
H 4.11, N 5.62.
5-Acetyl-2-benzoylpyridine 1-Oxide (3r): General procedure A
was applied, using 3-acetylpyridine N-oxide (0.5 mmol, 68 mg),
benzyl alcohol (1.5 mmol, 0.15 mL), PdCl2 (6 mg, 7 mol-%), K2S2O8
(1 mmol, 270 mg), and chlorobenzene (2 mL). Also, general proce-
dure B was applied, using 3-acetylpyridine N-oxide (0.5 mmol,
68 mg), benzyl chloride (1.5 mmol, 0.17 mL), PdCl2(COD) (8 mg,
7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL).
Purification by column chromatography (silica gel; n-hexane/EtOAc/
methanol, 1:1:0.1) gave the desired product 3r (procedure A:
106 mg, 88 %; procedure B: 97 mg, 81 %) as a pale yellow solid.
1
M.p. 95–97 °C. H NMR (400 MHz, CDCl3): δ = 8.80 (s, 1 H), 8.38 (d,
2-[4-(tert-Butyl)benzoyl]-6-chloropyridine 1-Oxide (3o): General
procedure A was applied, using 2-chloropyridine N-oxide (0.5 mmol,
64 mg), 4-tert-butylbenzyl alcohol (1.5 mmol, 0.26 mL), PdCl2 (6 mg,
7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL).
Purification by column chromatography (silica gel; n-hexane/EtOAc/
methanol, 1:1:0.1) gave the desired product 3o (105 mg, 73 %) as a
black solid. M.p. 122–124 °C. 1H NMR (400 MHz, CDCl3): δ = 7.38 (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 69.83, H 4.63, N 5.77.
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5-Acetyl-2-(4-chlorobenzoyl)pyridine 1-Oxide (3s): General pro-
cedure A was applied, using 3-acetylpyridine N-oxide (0.5 mmol,
68 mg), 4-chlorobenzyl alcohol (2 mmol, 214 mg), PdCl2 (6 mg,
7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL).
Also, general procedure B was applied, using 3-acetylpyridine N-
oxide (0.5 mmol, 68 mg), 4-chlorobenzyl chloride (1.5 mmol,
241 mg), PdCl2(COD) (8 mg, 7 mol-%), K2S2O8 (1 mmol, 270 mg),
and chlorobenzene (2 mL). Also, general procedure C was applied,
using 3-acetylpyridine N-oxide (0.5 mmol, 68 mg), 4-chlorobenzyl
bromide (2 mmol, 308 mg), PdCl2(COD) (8 mg, 7 mol-%), K2S2O8
(1 mmol, 270 mg), and chlorobenzene (2 mL). Purification by col-
benzyl chloride (1.5 mmol, 0.18 mL), PdCl2(COD) (8 mg, 7 mol-%),
K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL). Also, general
procedure C was applied, using pyridine N-oxide (0.5 mmol, 47 mg),
4-fluorobenzyl bromide (1.5 mmol, 0.19 mL), PdCl2(COD) (8 mg,
7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL).
Purification by column chromatography (silica gel; n-hexane/EtOAc/
methanol, 1:1:0.1) gave the desired product 3v (procedure B: 56 mg,
52 %; procedure C: 59 mg, 55 %) as a pale yellow oil. 1H NMR
(500 MHz, CDCl3): δ = 8.25 (d, J = 5.21 Hz, 1 H), 7.86 (dd, J = 7.3,
J = 5.2 Hz, 2 H), 7.45–7.39 (m, 3 H), 7.26–7.12 (m, 2 H) ppm. 13C
NMR (150 MHz, CDCl3): δ = 187.1, 167.4, 165.5, 140.3, 132.8, 132.3,
umn chromatography (silica gel; n-hexane/EtOAc/methanol, 1:1:0.1) 132.2, 127.3, 126.0, 116.4, 116.2 ppm. HRMS (EI): calcd. for
gave the desired product 3s (procedure A: 105 mg, 77 %; proce-
C12H8FNO2 [M]+ 217.0535; found 217.0539.
dure B: 100 mg, 73 %; procedure C: 101 mg, 74 %) as an off-white
solid. M.p. 119–121 °C. H NMR (400 MHz, CDCl3): δ = 8.81 (s, 1 H),
2-Cyano-6-(4-fluorobenzoyl)pyridine 1-Oxide (3w): General pro-
cedure B was applied, using 2-cyanopyridine N-oxide (0.5 mmol,
60 mg), 4-fluorobenzyl chloride (1.5 mmol, 0.18 mL), PdCl2(COD)
(8 mg, 7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene
(2 mL). Also, general procedure C was applied, using 2-cyanopyr-
idine N-oxide (0.5 mmol, 60 mg), 4-fluorobenzyl bromide (1.5 mmol,
0.19 mL), PdCl2(COD) (8 mg, 7 mol-%), K2S2O8 (1 mmol, 270 mg),
and chlorobenzene (2 mL). Purification by column chromatography
(silica gel; n-hexane/EtOAc/methanol, 1:1:0.1) gave the desired
product 3w (procedure B: 38 mg, 32 %; procedure C: 42 mg, 35 %)
as a white solid. M.p. 140–142 °C. 1H NMR (600 MHz, CDCl3): δ =
7.81 (dd, J = 8.4, J = 5.4 Hz, 2 H), 7.20–7.17 (m, 2 H), 7.13–7.10 (m,
3 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 188.9, 168.4, 165.9, 133.34,
133.3, 132.73, 132.7, 129.8, 129.75, 115.8, 115.7, 115.5 ppm. MS (EI):
m/z (%) = 242 (13) [M]+, 139 (77), 123 (100), 95 (77), 75 (66), 69 (11),
57 (7), 50 (10), 44 (13). C13H7FN2O2 (242.20): calcd. C 64.47, H 2.91,
N 11.57; found C 64.63, H 2.93, N 11.53.
1
7.91 (d, J = 8.3 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 7.46 (d, J = 8.4 Hz,
2 H), 7.40 (d, J = 8.0 Hz, 2 H), 2.48 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 191.3, 186.0, 175.1, 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 (%) = 277 (6) [M
+ 2]+, 275 (18) [M]+, 259 (22), 242 (7), 224 (14), 165 (62), 153 (29),
137 (51), 125 (62), 111 (22), 101 (98), 89 (22), 75 (80), 63 (100), 51
(85), 43 (40). C14H10ClNO3 (275.69): calcd. C 60.99, H 3.66, N 5.08;
found C 60.70, H 3.68, N 5.11.
5-Acetyl-2-(4-methylbenzoyl)pyridine 1-Oxide (3t): General pro-
cedure A was applied, using 3-acetylpyridine N-oxide (0.5 mmol,
68 mg), 4-methylbenzyl alcohol (1.5 mmol, 183 mg), PdCl2 (6 mg,
7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL).
Also, general procedure B was applied, using 3-acetylpyridine N-
oxide (0.5 mmol, 68 mg), 4-methybenzyl chloride (1.5 mmol,
0.20 mL), PdCl2(COD) (8 mg, 7 mol-%), K2S2O8 (1 mmol, 270 mg),
and chlorobenzene (2 mL). Purification by column chromatography
(silica gel; n-hexane/EtOAc/methanol, 1:1:0.1) gave the desired
product 3t (procedure A: 102 mg, 80 %; procedure B: 98 mg, 77 %)
as a brown solid. M.p. 185–187 °C. 1H NMR (400 MHz, CDCl3): δ =
8. 81 (s, 1 H), 8.38 (d, J = 8.5 Hz, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.34
(d, J = 8.0 Hz, 2 H), 7.19 (d, J = 7.8 Hz, 2 H), 2.54 (s, 3 H), 2.37 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 193.6, 189.7, 163.2, 147.8,
142.7, 140.3, 130.0, 129.5, 129.2, 128.7, 127.1, 29.7, 21.1 ppm. MS
(EI): m/z (%) = 256 (35) [M + 1]+, 255 (10) [M]+, 243 (74), 222 (37),
208 (11), 194 (12), 153 (77), 122 (33), 105 (100), 91 (22), 77 (22), 63
(21), 53 (21), 43 (22). C15H13NO3 (255.27): calcd. C 70.58, H 5.13, N
5.49; found C 70.77, H 5.09, N 5.43.
4-Acetyl-2-(4-fluorobenzoyl)pyridine 1-Oxide (3x): General pro-
cedure B was applied, using 4-acetylpyridine N-oxide (0.5 mmol,
68 mg), 4-fluorobenzyl chloride (1.5 mmol, 0.18 mL), PdCl2(COD)
(8 mg, 7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene
(2 mL). Also, general procedure C was applied, using 4-acetylpyr-
idine N-oxide (0.5 mmol, 68 mg), 4-fluorobenzyl bromide (1.5 mmol,
0.19 mL), PdCl2(COD) (8 mg, 7 mol-%), K2S2O8 (1 mmol, 270 mg),
and chlorobenzene (2 mL). Purification by column chromatography
(silica gel; n-hexane/EtOAc/methanol, 1:1:0.1) gave the desired
product 3x (procedure B: 60 mg, 46 %; procedure C: 62 mg, 48 %)
as a white solid. M.p. 108–110 °C. 1H NMR (600 MHz, CDCl3): δ =
8.28 (d, J = 6.0 Hz, 1 H), 8.07 (dd, J = 8.7, J = 5.3 Hz, 1 H), 7.90 (d,
J = 6.24 Hz, 2 H), 7.85 (s, 1 H), 7.62 (dd, J = 8.6, J = 5.5 Hz, 2 H), 2.6
(s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 190.2, 185.3, 166.9,
165.3, 163.7, 145.6, 139.8, 132.8, 132.7, 130.8, 130.7, 125.2, 29.7 ppm.
MS (EI): m/z (%) = 261 (16) [M + 2]+, 259 (6) [M]+, 227 (92), 198 (9),
170 (7), 149 (100), 121 (59), 101 (77), 78 (48), 51 (77). C14H10FNO3
(259.23): calcd. C 64.86, H 3.89, N 5.40; found C 64.68, H 3.86, N
5.43.
4-Acetyl-2-(4-methylbenzoyl)pyridine 1-Oxide (3u): General pro-
cedure A was applied, using 4-acetylpyridine N-oxide (0.5 mmol,
68 mg), 4-methylbenzyl alcohol (1.5 mmol, 183 mg), PdCl2 (6 mg,
7 mol-%), K2S2O8 (1 mmol, 270 mg), and chlorobenzene (2 mL).
Also, general procedure B was applied, using 4-acetylpyridine N-
oxide (0.5 mmol, 68 mg), 4-methybenzyl chloride (1.5 mmol,
0.20 mL), PdCl2(COD) (8 mg, 7 mol-%), K2S2O8 (1 mmol, 270 mg),
and chlorobenzene (2 mL). Purification by column chromatography
(silica gel; n-hexane/EtOAc/methanol, 1:1:0.1) gave the desired
product 3u (procedure A: 105 mg, 83 %; procedure B: 102 mg, 80 %)
Acknowledgments
1
as a pale brown solid. M.p. 125–127 °C. H NMR (400 MHz, CDCl3):
We gratefully acknowledge the financial support from the Re-
search Council of the University of Tehran and the Iran National
Science Foundation (INSF).
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]+, 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 70.76, H 5.16, N 5.50.
Keywords: Pyridine N-oxides · Nitrogen heterocycles · Cross-
coupling · Benzylic compounds · Acylation · C-H activation
2-(4-Fluorobenzoyl)pyridine 1-Oxide (3v): General procedure B
was applied, using pyridine N-oxide (0.5 mmol, 47 mg), 4-fluoro-
[1] G. Chelucci, G. Murineddu, G. A. Pinna, Tetrahedron: Asymmetry 2004, 15,
1373.
Eur. J. Org. Chem. 2017, 4786–4793
www.eurjoc.org
4792
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[2] a) M. Stevens, C. Pannecouque, E. De Clercq, J. Balzarini, J. Antimicrob.
Agents Chemother. 2003, 47, 2951; b) J. Balzarini, E. Keyaerts, L. Vijgen, F.
Vandermeer, M. Stevens, E. De Clereq, H. Egberink, M. V. Ranst, J. Anti-
microb. Chemother. 2006, 57, 472; c) J. Balzarini, M. Stevens, E. De Clercq,
D. Schols, J. Antimicrob. Chemother. 2005, 55, 135.
[8] D. Rennison, S. Bova, M. Cavalli, F. Ricchelli, A. Zulian, B. Hopkins, M. A.
Brimble, Bioorg. Med. Chem. 2007, 15, 2963.
[9] G. Yan, A. J. Borah, M. Yang, Adv. Synth. Catal. 2014, 356, 2375.
[10] L.-C. Campeau, S. Rousseaux, K. Fagnou, J. Am. Chem. Soc. 2005, 127,
18020.
[3] M. Holmquist, G. Blay, M. C. Muñoz, J. R. Pedro, Org. Lett. 2014, 16, 1204.
[4] a) F. A. Luzzio, Tetrahedron 2001, 57, 915; b) N. Ono, The Nitro Group in
Organic Synthesis, Wiley-VCH, New York, 2001.
[11] H.-Q. Do, R. M. K. Khan, O. Daugulis, J. Am. Chem. Soc. 2008, 130, 15185.
[12] D. J. Schipper, M. El-Salfiti, C. J. Whipp, K. Fagnou, Tetrahedron 2009, 65,
497.
[5] a) V. Farina, J. T. Reeves, C. H. Senanayake, J. J. Song, Chem. Rev. 2006,
106, 2734; b) T.-X. Metro, A. Cochi, D. Gomez Pardo, J. Cossy, J. Org. Chem.
2011, 76, 2594; c) A. Cochi, T.-X. Metro, D. Gomez Pardo, J. Cossy, Org.
Lett. 2010, 12, 3693; d) L. Liu, S. L. Zhang, F. Xue, G. S. Lou, H. Y. Zhang,
S. C. Ma, W. H. Duan, W. Wang, Chem. Eur. J. 2011, 17, 7791.
[6] a) S. Barroso, G. Blay, J. R. Pedro, Org. Lett. 2007, 9, 1983; b) A. Landa, A.
Minnkila, G. Blay, K. A. Jørgensen, Chem. Eur. J. 2006, 12, 3472; c) S.
Barroso, G. Blay, M. C. Muñoz, J. R. Pedro, Adv. Synth. Catal. 2009, 351,
107; d) A. Landa, B. Richter, R. L. Johansen, A. Minkkila, K. A. Jørgensen,
J. Org. Chem. 2007, 72, 240; e) P. K. Singh, V. K. Singh, Org. Lett. 2008,
10, 4121; f) S. Barroso, G. Blay, M. C. Muñoz, J. R. Pedro, Org. Lett. 2011,
13, 402; g) P. K. Singh, V. K. Singh, Org. Lett. 2010, 12, 80; h) S. K. Ray, S.
Rout, V. K. Singh, Org. Biomol. Chem. 2013, 11, 2412; i) A. Livieri, M.
Boiocchi, G. Desimoni, G. Faita, Chem. Eur. J. 2012, 18, 11662; j) A. Livieri,
M. Boiocchi, G. Desimoni, G. Faita, Chem. Eur. J. 2011, 17, 516.
[13] B. Xiao, Z.-J. Liu, L. Liu, Y. Fu, J. Am. Chem. Soc. 2013, 135, 616.
[14] X. Gong, G. Song, H. Zhang, X. Li, Org. Lett. 2011, 13, 1766.
[15] P. Xi, F. Yang, S. Qin, D. Zhao, J. Lan, G. Gao, C. Hu, J. You, J. Am. Chem.
Soc. 2010, 132, 1822.
[16] E. Kianmehr, N. Faghih, K. M. Khan, Org. Lett. 2015, 17, 414.
[17] R. Suresh, R. S. Kumaran, V. Senthilkumar, S. Muthusubramanian, RSC Adv.
2014, 4, 31685.
[18] E. Kianmehr, S. Kazemi, A. Foroumadi, Tetrahedron 2014, 70, 349.
[19] a) I. Mohammadpoor-Baltork, A. R. Hajipour, H. Mohammadi, Bull. Chem.
Soc. Jpn. 1998, 71, 1649; b) B. L. Gadilohar, H. S. Kumbhar, G. S. Shankar-
ling, New J. Chem. 2015, 39, 4647.
[20] a) G. Zhang, S. Sun, F. Yang, Q. Zhang, J. Kang, Y. Wu, Y. Wu, Adv. Synth.
Catal. 2015, 357, 443; b) F. Luo, J. Yang, Z. Li, H. Xia, X. Zhou, Eur. J. Chem.
2015, 2463.
[7] M. Jay-Smith, E. C. Murphy, L. Shapiro, C. T. Eason, M. A. Brimble, D.
Rennison, Tetrahedron 2016, 72, 5331.
Received: April 16, 2017
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