Pd(II)-Catalyzed Pyridine N -Oxides Directed Arylation of Unactivated Csp3-H Bonds

Article abstract of DOI:10.1021/acs.joc.5b00489

A novel Pd(II)-catalyzed pyridine N-oxide directed remote arylation of unactivated C_sp³-H bonds in aliphatic amides with aryl iodides has been developed. This protocol allows installing various aryl groups at the β- or γ-C_sp³ atom of alkyl carboxylic acid amides. The key palladabicyclic intermediate of this transformation has been identified by HR-MS and ¹H NMR method. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b00489

Subscriber access provided by UNIV OF NEBRASKA - LINCOLN
Article
Pd(II)-Catalyzed Pyridine N-Oxide-Directed
Arylation of Unactivated Csp3-H bonds
Jianzhong Liu, Ying Xie, Wei Zeng, Dongen Lin, Yuanfu Deng, and Xiaoxia Lu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00489 • Publication Date (Web): 07 Apr 2015
Downloaded from http://pubs.acs.org on April 8, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Pd(II)-Catalyzed Pyridine N-Oxide-Directed Arylation of Unac-
9
tivated Csp3-H bonds
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Jianzhong Liu,† Ying Xie,‡ Wei Zeng,*,‡ Dongen Lin,‡ Yuanfu Deng,‡ and Xiaoxia Lu *,†
† Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
‡ School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510641, China
zengwei@scut.edu.cn (W. Zeng), luxx@cib.ac.cn (X. Lu)
ABSTRACT: A novel Pd(II)-catalyzed pyridine N-oxides directed remote arylation of unactivated Csp3-H bonds in aliphatic am-
ides with aryl iodides has been developed. This protocol allows installing various aryl groups at β- or γ-Csp3 atom of alkyl car-
1
boxylic acid amides. The key palladabicyclic intermediate of this transformation has been identified by HR-MS and H NMR
method.
INTRODUCTION
Heteroatom directed transition-metal-catalyzed C-H functionalization provides a concise access to the site-selectively
constructing carbon-carbon bonds. In the past decade, remarkable progress in this field has been achieved based on C(sp2)‒H
bond activation, which can occur due to that coordination-chelating interaction of metal catalysts with the π-electron system
from arenes or alkenes easily enable the Csp2-H functionalization.1 In comparison, transition metal-catalyzed unactivated Csp3-H
functionalization is quite difficult because of the possible β-H elimination from the metalated alkyl intermediates.2 Nevertheless,
Yu recently developed a novel mono-dentate amide directed Pd(II)-catalyzed Csp3-H bond arylation and alkylation in which the
β-carbon of amide was limited to tertiary or quaternary carbon atom.3 To surmount this limitation, and considering that the
high oxidation state of cyclometalated species could be possibly formed between heteroatom-containing bidentate group and
unbranched-chain-alkyl carbon atom in the absence of Thorpe-Ingold effect, and the corresponding bidentate coordination
would also further inhibit the β-H elimination by saturating the coordination sites on the metal atom, Daugulis, Chen, and Shi et
al therefore explored the effect of various bidentate directing groups on the unactivated Csp3-H bond functionalization, and
found 8-aminoquinoline,4 picolinamide,5 2-alkylthioaniline,6 and 2-(pyridine-2yl)isopropylamine7 could efficiently enhance the
unactivated Csp3-H bond arylation, alkylation and acetoxylation. However, albeit significant progress has been achieved in this
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 20
1
2
3
4
regard, developing novel bidentate directing groups is still important for exploring the potential novel C-H bond functionaliza-
tion reactions.
5
6
7
8
Recently, pyridine moiety has been widely employed as a directing group to enhance metal-catalyzed C-H bond activation, 8
but the pyridine N-oxides (PNO) directed remote Csp3-H functionalization was rarely reported. Nevertheless, Chang, Wu, Fu,
Hartwig groups, and Fagnou et al have recently realized Pd(II)-catalyzed the ortho C-H bond alkylation,9 alkenylation 10 and ary-
lation (Scheme 1a) 11 of PNO, respectively. More recently, Song and co-workers reported copper salts could efficiently promote
the PNO-directed Csp2-H bond aryloxylation and alkoxylation. 12 The above-mentioned works implied that PNO could be possi-
bly used as an attractive platform for remote Csp3-H functionalization. Encouraged by these works, we expect that a suitable
pyridine N-oxide-containing alkyl amides (A) may not only be employed as a bidetante functional group to form palladabicyclic
intermediuate (B), but also easily enable the Pd(II)→Pd(IV) process to occur due to that PNO (X-type ligand) can increase the
electron density at Pd(II) center, and finally lead to the remote Csp3-H functionalization (Scheme 1b).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. PNO-Directed Csp2-H and Csp3-H Functionaliza-
tion
2
a) Previous work about Pd(II)-catalyzed ortho Csp -H arylation of PNO
R
R
Pd(II)/Ar-X/oxidant
N
O
H
N
O
Ar
3
b) This work: PNO directed Pd(II)-catalyzed remote Csp -H arylation
R
R
R
R
O
X
Pd
(IV)
Ar
O
Pd(II)
Ar-X/oxidant
N
O
NH
N
O
NH
N
O
N
N
O
N
Pd
(II)
O
O
1
1
R
R
1
B
C
D
Ar
1
A
H
R
R
1
R
= alkyl and aryl
RESULTS AND DISCUSSION
To prove this hypothesis, we initially designed and made the N-(1-oxy-pyridin-2-yl)-propionamide 1a, and investigated the
halide substituting effect of phenyl halides (2a-2c) on the remote Csp3-H bond arylation in the presence of PdCl2 (10 mol %) and
Ag2CO3 (2.0 equiv), using p-xylene as solvent at 130 oC for 12 h (Table 1, entries 1-3). To our delight, we quickly found
13
iodobenzene 2c could furnish 50% yield of the desired monoarylation product 3-1a, in which the phenyl group was
incorporated into the beta- position of alkyl carboxylic acid amide 1a. Then, we employed 1a and iodobenzene 2c as model
substrates, and continued to screen various palladium catalysts to further improve the Csp3-H bond arylation yield. Among the
tested palladium catalysts (entries 3-8), Pd(OAc)2 could significantly increased the reaction yield from 50% to 78% (compare
entries 3-7 with 8). On the contrary, other palladium catalysts such as Pd(PPh3)4 and PdCl2(PhCN)2 etc. provided poorer yield,
and these palladium catalysts also simultaneously led to the formation 10-12% yield of the bisarylation product 3-aa (entries 5-7).
Subsequently, we investigated the effect of various additives on this transformation (entries 8-14), and found silver salts,
ACS Paragon Plus Environment

Page 3 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
especially for AgOAc, could effectively enhance the remote Csp3-H bond arylation, and provided 90% yield 3-1a (compare entry
8 with 15), other additives including K2CO3, NaOAc and Cu(OAc)2 etc. resulted in worse conversion (entries 9-14). Notably, em-
ploying polar aprotic solvent such as DMF and DMSO drastically decreased the reaction yields (compare entries 17-18 with 15-16);
and decreasing the reaction temperature also led to poorer conversion to some degree (compare entry 19 with 15). Finally, the
best yield of 3-1a (90%) could be achieved using Pd(OAc)2/AgOAc/p-xylene reaction system at 130 oC for 12 h (entry 15).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Optimization of the Reaction Parameters a
Pd catalysts
additives
X
O
O
O
+
+
N
N
N
O-
N
N
O-
N
p-xylene
130 oC, 12 h
H
H
O-
H
X = Cl,
X = Br,
X = I,
2a
2b
2c
Ph
Ph
Ph
1a
3-1a
3-aa
entry
1
Pd catalysts
PdCl2
Ar-X, 2
2a
2b
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
additives
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
CuOAc
Cu(OAc)2
K2CO3
yield (%)
8 b
2
PdCl2
10 b
3
PdCl2
50 b
4
Pd(TFA)2
Pd(PPh3)4
45 b
5
30 b /10 c
30 b/12 c
31 b /12 c
78 b
6
PdCl2(PhCN)2
PdCl2(CH3CN)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
7
8
9
20 b
10
11
12
13
14
15
16
17
18
19
trace b
trace
35 b
CuCl2
CuCl
Trace
30 b
NaOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
90 b
82 b, d
7 b, e
12 b, f
75 b, g
a Unless otherwise noted, the reactions were carried out using pyridine N-
oxide (1a) (0.10 mmol) and aryl halide (2) (0.15 mmol, 1.5 equiv) with
palladium catalyst (10 mol %) in the presence of additives (2.0 equiv) in p-
xylene (2.0 mL) at 130 ˚C under Ar for 12 h in a sealed reaction tube,
b
c
followed by flash chromatography on SiO2. Isolated yield for 3-1a.
Isolated yield for 3-aa. d Toluene was used as solvent. e DMF was used as
solvent. f DMSO was used as solvent. g 120 oC of reaction temperature.
With an optimized catalytic system in hand, we next investigated the scope of the current procedure by testing various io-
dobezene derivatives. As shown in Figure 1, aryl iodide substrates exhibited different reactivity which strongly depends on the
electronic effect of substituted groups from aryl iodides. For example, the substrates with electron-donating group and halide at
the 3 or 4-position of benzene ring provided moderate to excellent yield of arylation products (3-1a ∼ 3-1c, 3-1e ∼ 3-1k). On the
contrary, the electron-deficient 4-trifluoromethyl-phenyl iodide underwent obviously worse conversion and provided lower yield
of the Csp3-H bond arylation products (3-1l, 60% yield). Moreover, in comparison with para-substituted iodobezenes, ortho- or
meta-substituted substrates also obviously inhibited the transformation due to steric hindrance effect of substitutents (3-1c vs 3-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 20
1
2
3
4
1d; 3-1i vs 3-1j). Gratifyingly, the Csp3-H bond arylation between 3-iodothiophene and N-(1-oxy-pyridin-2-yl)-propionamide 1a
could also afford the corresponding mono- and bis- thiophenylation products 3-1m and 3-1n in an overall yield of 55% yield.
5
6
7
8
Figure 1. Scope of Aryl Iodines a
O
O
Pd(OAc)2 (10 mol %)
AgOAc (2.0 equiv)
p-xylene, 130 oC, 12 h
N
O-
N
+
Ar
I
N
O-
N
9
H
H
Ar
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
1a
2
O
O
O
N
O-
N
H
N
O-
N
H
N
H
N
O-
Me
3-1a: 91%
3-1b: 90%
3-1c: 66%
OMe
O
O
O
N
O-
N
N
O-
N
Me
N
N
H
H
H
O-
3-1f: 47%
3-1d: 30%
3-1e: 68%
Ph
O
O
O
N
O-
N
H
N
O-
N
N
O-
N
H
H
3-1i: 80%
3-1h: 70%
3-1g: 72%
Br
Cl
F
O
O
O
N
O-
N
H
N
O-
N
Br
N
O-
N
H
H
3-1k: 52%
3-1j: 40%
3-1l: 60%
CF3
I
O
O
N
O
N
N
N
H
H
-
-
O
S
S
S
3-1n: 25%
3-1m: 30%
a
Unless otherwise noted, the reactions were carried out using
pyridine-N-oxide (1a) (0.10 mmol) and aryl iodides (2) (0.15 mmol,
1.5 equiv) with Pd(OAc)2 (10 mol %) in the presence of AgOAc
(2.0 equiv) in p-xylene (2.0 mL) at 130 ˚C under Ar for 12 h in a
b
sealed reaction tube, followed by flash chromatography on SiO2.
Isolated yield.
The scope of the procedure with regard to pyridine N-oxide-containing alkyl carboxylic acid amides was then explored with
iodobenzene 2c as an arylating agent. The results from Figure 2 demonstrated that most of alkyl carboxylic acid amides could be
installed one or two phenyl groups at the beta-Csp3 position; and also no significant electronic effect of the 5- substituted pyri-
dine N-oxides was found (3-2a, 3-2d ~ 3-2k). For example, the electron-rich 5-methyl-pyridine N-oxide gave the corresponding
mono- and bis-arylation product 3-2h and 3-2i in an overall yield of 65% yield; Similarly, electron-poor 5-trifluoromethyl-
pyridine N-oxide also furnished the mono- and bis-arylation pyridine N-oxide derivative 3-2j (30% yield) and 3-2k (28% yield) in
moderate overall yield. Unfortunately, 5-nitro-pyridine N-oxide just afforded 25% yield of 3-2l. It is worth to noting that beta-2,
2-dimethyl-propyl group substituted aliphatic amide could also be converted smoothly to more remote Csp3-H bond arylation
ACS Paragon Plus Environment

Page 5 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
and provided the corresponding γ-phenyl substituted product (3-2m) in 52% yield. Moreover, kinds of six-memebered, five-
memebered, four-memebered and three-memebered cycloalkyl substituted amides also allowed for this transformation, and
afforded the corresponding mono- or bis-arylation products (3-2n ~ 3-2s) in moderate overall yields. Among them, the structure
of 3-2q was already unambiguously assigned by its single crystal X-ray analysis [see Supporting Information (SI) for more details].
9
Figure 2. Scope of Pyridine N-Oxides a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
R1
O
Pd(OAc)2 (10 mol %)
AgOAc (2.0 equiv)
p-xylene, 130 oC, 12 h
R1
N
N
+
Ph
I
N
N
H
O-
H
O-
R4
R2
R3
Ph
1
2a
3
O
O
O
N
O-
N
Ph
N
O-
N
N
O-
N
H
Ph
H
H
Ph
N
Ph
3-2a: 75%
3-2b: 50%
3-2c: 40%
Cl
Cl
Br
Br
O
O
O
O
N
O-
N
H
N
O-
3-2d
N
H
N
N
O-
3-2g
N
H
H
O-
3-2f
Ph
Ph
Ph
Ph
Ph
Ph
3-2e
(3-2f + 3-2g = 59%, 3-2f/3-2g = 2.9:3)
(3-2d + 3-2e = 60%, 3-2d/3-2e = 1:1)
F3C
F3C
O
O
O
O
N
O-
N
N
O-
N
N
N
O-
N
O-
3-2k
N
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
3-2h
3-2j
3-2i
(3-2j + 3-2k = 58%, 3-2j/3-2k =15:14)
(3-2h + 3-2i = 65%, 3-2h/3-2i = 6:7)
O2N
O
Ph
O
O
O
N
N
N
O-
N
N
O-
N
N
O-
N
H
H
H
O-
H
Ph
Ph
Ph
Ph
3-2n
3-2o
Ph
3-2l: 25%
(3-2n + 3-2o = 30%, 3-2n/3-2o =1:1)
3-2m: 52%
O
O
O
O
Ph
N
N
N
N
N
N
N
N
H
H
H
H
-
-
-
-
O
O
O
O
Ph
Ph
Ph
Ph
3-2r
3-2q
(3-2q + 3-2r = 60%, 3-2q/3-2r = 1: 2)
3-2p: 60%
3-2s: 55%
a All reactions were carried out using pyridine-N-oxide (1) (0.10 mmol)
and aryl iodine (2a) (0.15 mmol, 1.5 equiv) with Pd(OAc)2 (10 mol %) in
the presence of AgOAc (2.0 equiv) in p-xylene (2.0 mL) at 130 ˚C under
Ar for 12 h in a sealed reaction tube, followed by flash chromatography
on SiO2; b Isolated yield.
Finally, the pyridine N-oxide directing group could be easily removed under base condition to provide the corresponding be-
ta-aryl substituted carboxylic acids which could be used for further synthetic transformations; three examples were shown in
Table 2.
Table 2. Removal of the PNO Directing Group a
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 20
1
2
3
4
O
O
NaOH (1.5 equiv)
HO
N
O
3
N
EtOH,
+
N
O
NH
2
H
-
o
-
Ar
R
85 C, 8 h
Ar
R
5
4
5
6
7
8
9
PNO-containing amides
3
entry
1
yield (%)
80%
β
-aryl carboxylic acids 4
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
HO
N
N
H
O-
4a
Ph
Ph
Ph
Ph
3-1a
O
O
N
O-
3-2a
N
H
HO
2
75%
78%
4b
3
a
All reactions were carried out using PNO-containing-amides (3) (0.10 mmol) and
NaOH (0.15 mmol, 1.5 equiv) in EtOH (2.0 mL) at 85 ˚C for 8 h, followed by flash
chromatography on SiO2. b Isolated yield.
To further investigate the primary reaction mechanism, several controlled experiments were carried out (Scheme 2). First, we
prepared N-pyridin-2-yl-propionamide (1n) and tried the Csp3-H bond arylation of 1n with iodobenzene (2c) under our standard
reaction conditions, and no desired product 3-2t was observed [Eq. (1)]. Moreover, N-methyl-N-(1-oxy-pyridin-2-yl)-
propionamide (1o) also could not furnish the corresponding arylation product (3-2u) possibly due to that amide N-H was
blocked by methyl group and could not form palladabicyclic species [Eq. (2)]. The above-mentioned results clearly indicated that
pyridine N-oxide and amide N-H group played a significant chelation-assisted directing role to form β-arylation products. Se-
o
cond, when the H/D exchange of N-(1-oxy-pyridin-2-yl)-propionamide (1a) was conducted in Pd(II)/AcOD system at 130 C for
24 h in absence of iodobenzene 2a, 85% deuterium incorporation was observed at the β-carbon atom of D-1a ([Eq. (3), see SI for
more details)], this experiment suggested that the Csp3-H insertion step was involved in the transformation under standard reac-
tion system. Finally, the intermolecular isotope effect (KH/KD = 2.0) suggested Csp3-H bond cleavage occurred in the rate-
limiting step [Eq. (4)] (see SI for more details).
Scheme 2. Preliminary Mechanistic Studies
ACS Paragon Plus Environment

Page 7 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
O
O
O
Pd(OAc)2 (10 mol %)
AgOAc (2.0 equiv)
p-xylene, 130 oC, 12 h
N
N
(1)
(2)
+
+
Ph
I
N
N
H
H
Ph
1n
2c
3-2t (not observed)
O
Pd(OAc)2 (10 mol %)
AgOAc (2.0 equiv)
p-xylene, 130 oC, 12 h
N
O
N
Ph
I
N
O
N
Me
Me
Ph
2c
3-2u (not observed)
1o
9
10
11
12
13
14
15
16
17
18
19
20
21
22
O
O
Pd(OAc)2 (10 mol %)
AgOAc (2.0 equiv)
p-xylene, 130 oC, 6 h
N
O
D-1a
N
+
(3)
(4)
N
N
H
AcOD
H
O
D
85% D
1a
O
O
D
Pd(OAc)2 (10 mol %)
AgOAc (2.0 equiv)
p-xylene, 130 oC, 12 h
N
O
D-3-1a
N
N
O
D-1a
N
H
+
Ph
I
H
D
Ph
D
KH/KD = 2.0
2c
D
D
From the above-mentioned experimental results, we proposed a possible mechanism that involved a Pd(II)/Pd(IV) redox pro-
cess (Figure 3). At first, the pyridine N‒O- and amide N-H group from substrate 3-1a coordinated to Pd(II) by abstracting a pro-
ton, followed by the cleavage of the β-Csp3-H bond via a concerted metalation-deprotonation (CMD) mechanism to form pal-
ladabicyclic intermediuate B, which was already identified by HR-MS and 1H NMR spectrum.14 Subsequently, oxidation addition
of the reactive palladium intermediate B to aryl iodine produce Pd(IV) intermediate C. Finally, Pd(IV) intermediate C could fur-
ther reductively eliminate to afford the corresponding β-Csp3-H bond arylation product 3-1a, followed by iodide exchange for
acetate by Ag+ completed the catalytic cycle.15
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. The Proposed Reaction Mechanism
O
O
N
O
N
H
3-1a
N
O
N
H
PdX2
1a
Ph
HX
X= OAc
HX
O
O
N
O
N
N
N
C
Pd
Ph
O
Pd
X
A
I
PhI
O
HX
N
O
N
Pd
B (Identified by HR-MS
and 1H NMR spectrum)
In summary, we have developed a novel pyridine N-oxides directed, palladium-catalyzed arylation of unactivated Csp3-H
bonds with aryl iodides. This protocol allows installing various aryl groups at β- or γ- Csp3 atom of alkyl carboxylic acid amides in
which the pyridine N-O- and amide N-H group was found to play a key chelation-assisted role to activate Csp3-H bond. A gen-
eral reaction mechanism has been proposed involving formation of palladabicyclic intermediate, which has been identified by
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 20
1
2
1
HR-MS and H NMR method. Further studies to explore other pyridine N-oxide directed, transition metal-catalyzed novel reac-
3
4
tions are now in progress
5
6
7
EXPERIMENTAL SECTION
8
9
General Information. All reactions were carried out in flame-dried sealed tubes with magnetic stirring. Unless otherwise
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
noted, all experiments were performed under argon atmosphere. Solvents were treated with 4 Å molecular sieves or sodium and
1
distilled prior to use. Flash chromatography was performed on silica gel (40~63 mm) by standard technique. H and 13C NMR
spectra were recorded on a 400 MHz NMR spectrometer (400 MHz for 1 H and 100 MHz for 13 C). Splitting patterns are designat-
ed as singlet (s), doublet (d), triplet (t), quartet (q). Splitting patterns that could not be interpreted or easily visualized are des-
ignated as multiple (m). Low resolution mass spectra were recorded using HPLC Mass Spectrometer. High resolution exact mass
measurements (HR-MS) were performed on a TOF spectrometer. Infrared spectra (IR) were reported as wavelength numbers
(cm-1). Infrared spectra were recorded by preparing a KBr pellet containing the title compound. Crystal data were obtained by
employing graphite monochromated Mo - Kα radiation (λ = 0.71073 Å) at 293 (2) K and operating in the φ-ω scan mode. The
structure was solved by direct methods SHELXS-97.
General procedure for the synthesis of N-(1-oxy-pyridin-2-yl)-alkylamide substrates (1a-1n'). 16
General procedure：A mixture of SOCl2 (1.2 mmol, 1.2 equiv), triethylamine (1.0 mmol, 1 equiv ) and the corresponding acid (1
mmol, 1 equiv）in CHCl3 ( 20 ml ) was vigorously refluxed at 70 oC for 2 h. The mixture was concentrated in vacuo and the crude
product was submitted to the next reaction without purification. The solution of the above-mentioned crude product was added
in the mixture of triethylamine (1.0 mmol, 1 equiv ) and 2-aminopyridine（1 mmol, 1 equiv) in CHCl3 ( 20 ml ) at 0 oC and contin-
ued to be stirred for 8 h. Then the mixture was evaporated under reduced pressure, and the resulting mixture was dissolved in
the CHCl3 ( 15 mL ) and treated with the m-CPBA (1.3 mmol, 1.3 equiv) at room temperature for 3 h. Then the reaction mixture
was diluted with CHCl3 ( 20 mL ) and washed with saturated Na2CO 3 aqueous solution (3 × 40 mL) and saturated NaCl aqueous
solution (3 ×50 mL), respectively. The combined organic layers were dried over Na2SO4. After filtration and evaporation of the
solvents in vacuum, the crude product was purified through flash chromatography on silica gel with dichloromethane and
MeOH (v/v = 20:1 to 10:1) as the eluent to afford the desired pyridine N-oxides (1a-1n').
2-Propionamidopyridine 1-oxide (1a): Pale yellow solid；141 mg, 85% yield; mp: 95.0-96.5 °C. 1H NMR (400 MHz, CDCl3) δ 10.03
(s, 1H), 8.46 (d, J = 8.5 Hz, 1H), 8.24 (d, J = 6.5 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 6.99 (t, J = 7.0 Hz, 1H), 2.56 (q, J = 7.4 Hz, 2H), 1.28
(t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.6, 144.2, 137.0, 128.1, 118.4, 114.7, 30.9, 9.1; HR-MS (ESI) calcd for [M + 1]+:
C8H11N2O2: 167.0815, found: 167.0817; IR (KBr): 2979, 1702, 1568, 1507, 1426, 1210, 756 cm -1.
2-Butyramidopyridine 1-oxide (1b): Pale yellow solid; 140 mg, 78% yield; mp: 115.0-116.0 °C. 1H NMR (400 MHz, CDCl3) δ 10.01 (s,
1H), 8.46 (d, J = 8.5 Hz, 1H), 8.24 (d, J = 6.5 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 6.98 (t, J = 7.0 Hz, 1H), 2.50 (t, J = 7.4 Hz, 2H), 1.84 –
ACS Paragon Plus Environment

Page 9 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1.74 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.9, 144.2, 137.0, 128.2, 118.4, 114.7, 39.7, 18.6, 13.6; HR-MS (ESI)
calcd for [M + 1]+: C9H13N2O2: 181.0972, found: 181.0973; IR (KBr): 2965, 1704, 1569, 1508, 1427, 1148, 761 cm -1.
2-Isobutyramidopyridine 1-oxide (1c): Pale yellow solid; 135 mg, 75% yield; mp: 82.0-83.0 °C. 1H NMR (400 MHz, CDCl3) δ 10.14
(s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.27 (d, J = 6.4 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.00 (t, J = 6.9 Hz, 1H), 2.79 – 2.69 (m, 1H), 1.30 (d, J
= 6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 175.9, 144.3, 137.0, 128.2, 118.4, 114.7, 36.8, 19.3; HR-MS (ESI) calcd for [M + 1]+:
C9H13N2O2: 181.0972, found: 181.0971; IR (KBr): 2969, 1703, 1569, 1509, 1428, 1205, 759 cm -1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Pivalamidopyridine 1-oxide (1d): Pale yellow solid; 155 mg, 80% yield; mp: 90.8-92.9 °C. 1H NMR (400 MHz, CDCl3) δ 10.41 (s,
1H), 8.46 (d, J = 8.5 Hz, 1H), 8.25 (d, J = 6.5 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 6.98 (t, J = 7.0 Hz, 1H), 1.37 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 177.6, 144.5, 136.9, 128.1, 118.3, 114.6, 40.5, 27.4; HR-MS (ESI) calcd for [M + 1]+: C10H15N2O2: 195.0866, found: 195.0864; IR
(KBr): 2965, 1568, 1508, 1427, 1203, 761 cm -1.
1
5-Chloro-2-propionamidopyridine 1-oxide (1e): White solid; 150 mg, 75% yield; mp: 154.2-155.8 °C. H NMR (400 MHz, CDCl3)
δ9.89 (s, 1H), 8.35 (d, J = 9.1 Hz, 1H), 8.21 (s, 1H), 7.24 (d, J = 9.1 Hz, 1H), 2.50 (q, J = 7.4 Hz, 2H), 1.18 (t, J = 7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 172.6, 143.1, 136.1, 128.1, 124.8, 114.4, 30.8, 9.0; HR-MS (ESI) calcd for [M + 1]+: C8H10ClN2O2: 201.0425, found:
201.0425; IR (KBr): 2978, 1699, 1583, 1506, 1428, 1214, 848 cm -1.
1
5-Bromo-2-propionamidopyridine 1-oxide (1f): White solid; 171 mg, 70% yield; mp: 170.0-172.0 °C. H NMR (400 MHz, CDCl3) δ
9.93 (d, J = 44.8 Hz, 1H), 8.36 (d, J = 7.7 Hz, 2H), 7.43 (d, J = 9.1 Hz, 1H), 2.55 (q, J = 7.5 Hz, 2H), 1.26 (t, J = 7.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 172.5, 143.4, 138.1, 130.8, 114.7, 111.3, 77.4, 77.1, 76.8, 31.0, 9.1; HR-MS (ESI) calcd for [M + 1]+: C8H10BrN2O2:
244.9920, found: 244.9921; IR (KBr): 2975, 1698, 1564, 1503, 1469, 1248, 891 cm -1.
1
5-Methyl-2-propionamidopyridine 1-oxide (1g): Pale yellow solid; 144mg, 80% yield; mp: 113.0-114.5 °C. H NMR (400 MHz,
CDCl3) δ 10.00 (s, 1H), 8.34 (d, J = 8.6 Hz, 1H), 8.10 (s, 1H), 7.17 (d, J = 8.6 Hz, 1H), 2.56 (q, J = 7.5 Hz, 2H), 2.29 (s, 3H), 1.26 (t, J =
7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.5, 141.8, 136.6, 129.4, 128.7, 114.2, 30.8, 17.8, 9.1; HR-MS (ESI) calcd for [M + 1]+:
C9H13N2O2: 181.0972, found: 181.0973; IR (KBr): 2921, 1702, 1532, 1508, 1450, 1278, 951 cm -1.
1
5-Nitro-2-propionamidopyridine 1-oxide (1h): Yellow solid; 84 mg, 40% yield; mp: 123.5-125.0 °C. H NMR (400 MHz, DMSO) δ
10.88 (s, 1H), 9.19 (s, 1H), 8.49 (d, J = 9.4 Hz, 1H), 8.23 (d, J = 9.4 Hz, 1H), 2.69 (q, J = 7.3 Hz, 2H), 1.09 (t, J = 7.3 Hz, 3H); 13C NMR
(100 MHz, DMSO) δ 174.0, 166.5, 148.4, 139.4, 133.8, 122.4, 112.8, 29.79, 8.9; HR-MS (ESI) calcd for [M + 1]+: C8H10N3O4: 212.0666,
found: 212.0668; IR (KBr): 2965, 1704, 1574, 1520, 1427, 1209, 803 cm -1.
2-Propionamido-5-(trifluoromethyl)pyridine 1-oxide (1i): White solid; 125 mg, 50% yield; mp: 127.0-128.5 °C. 1H NMR (400 MHz,
13
CDCl3) δ 10.11 (s, 1H), 8.68 – 8.47 (m, 2H), 7.54 (d, J = 8.8 Hz, 1H), 2.61 (q, J = 7.4 Hz, 2H), 1.29 (t, J = 7.5 Hz, 3H); C NMR (100
MHz, CDCl3) δ 172.8, 146.4, 134.7, 124.4, 124.4, 123.4 (d, J = 271 Hz), 122.5 (q, J = 35.4 Hz), 122.1, 120.7, 114.2, 31.1, 8.9; HR-MS (ESI)
calcd for [M + Na]+: C9H9F3N2O2Na: 257.0506, found: 257.0502; IR (KBr): 2969, 1708, 1560, 1520, 1431, 1211, 790 cm -1.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 20
1
2
3
4
5
6
7
8
1
2-(3, 5, 5-Trimethylhexanamido)pyridine 1-oxide (1j): White solid; 175 mg, 70% yield; mp: 120.0-122.0 °C. H NMR (400 MHz,
CDCl3) δ 10.04 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.26 (d, J = 6.4 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 6.99 (t, J = 6.9 Hz, 1H), 2.53 (dd, J =
14.6, 5.9 Hz, 1H), 2.34 (dd, J = 14.5, 8.2 Hz, 1H), 2.25 – 2.15 (m, 1H), 1.32 (dd, J = 14.0, 3.2 Hz, 1H), 1.18 (dd, J = 14.0, 6.4 Hz, 1H), 1.05
(d, J = 6.5 Hz, 3H), 0.93 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.5, 144.2, 137.1, 128.3, 118.4, 114.7, 50.5, 47.5, 31.0, 29.9, 27.3, 22.6;
HR-MS (ESI) calcd for [M + 1]+: C14H23N2O2: 251.1754, found: 251.1755; IR (KBr): 2960, 1704, 1569, 1508, 1427, 1148, 761 cm -1.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2-(Cyclohexanecarboxamido)pyridine 1-oxide (1k): White solid; 167 mg, 76% yield; mp: 150.1-151.7 °C. H NMR (400 MHz,
CDCl3) δ 10.09 (s, 1H), 8.46 (d, J = 8.5 Hz, 1H), 8.24 (d, J = 6.4 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 6.97 (t, J = 7.0 Hz, 1H), 2.43 (t, J = 11.5
Hz, 1H), 2.02 (d, J = 12.8 Hz, 2H), 1.85 (d, J = 12.4 Hz, 2H), 1.72 (d, J = 10.8 Hz, 1H), 1.56 (q, J = 12.1 Hz, 2H), 1.41 – 1.21 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 175.0, 144.4, 137.0, 128.1, 118.3, 114.7, 77.1, 76.7, 46.5, 29.4, 25.6, 25.5; HR-MS (ESI) calcd for [M + 1]+:
C12H17N2O2: 221.1285, found: 221.1283; IR (KBr): 3060, 2935, 2854, 1707, 1519, 1504, 1429, 1156, 761 cm -1.
1
2-(Cyclopentanecarboxamido)pyridine 1-oxide (1l): White solid; 167 mg, 81% yield; mp: 141.1-142.2 °C. H NMR (400 MHz,
CDCl3) δ 10.06 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 6.3 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 6.98 (t, J = 6.9 Hz, 1H), 2.91 (q, J =
7.9 Hz, 1H), 2.00 (m, J = 11.4, 7.0 Hz, 2H), 1.95 – 1.86 (m, 2H), 1.78 (m, J = 6.0 Hz, 2H), 1.71 – 1.59 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 175.3, 144.3, 137.0, 128.3, 118.3, 114.7, 77.4, 77.1, 76.8, 47.1, 30.4, 25.9; HR-MS (ESI) calcd for [M + 1]+: C11H15N2O2: 207.1128,
found: 207.1130; IR (KBr): 2953, 1693, 1568, 1504, 1424, 1210, 726 cm -1.
2-(Cyclobutanecarboxamido)pyridine 1-oxide (1m): Pale yellow solid; 153 mg, 80% yield; mp: 155.3-156.8 °C. 1H NMR (400 MHz,
CDCl3) δ 9.89 (s, 1H), 8.39 (d, J = 8.5 Hz, 1H), 8.16 (d, J = 6.4 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 6.90 (t, J = 7.0 Hz, 1H), 3.27 (p, J = 8.4
Hz, 1H), 2.38 – 2.27 (m, 2H), 2.21 (m, J = 8.7 Hz, 2H), 2.02 – 1.80 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 173.8, 144.2, 137.0, 128.1,
118.3, 114.6, 40.9, 25.1, 18.0; HR-MS (ESI) calcd for [M + 1]+: C10H13N2O2: 193.0972, found: 193.0970; IR (KBr): 2987, 1695, 1568, 1510,
1427, 1207, 762 cm -1.
1
2-(Cyclopropanecarboxamido)pyridine 1-oxide (1n'): White solid; 124 mg, 70% yield; mp: 153.3-155.4 °C. H NMR (400 MHz,
CDCl3) δ 10.24 (s, 1H), 8.42 (d, J = 8.5 Hz, 1H), 8.24 (d, J = 6.4 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 6.97 (t, J = 7.0 Hz, 1H), 1.76 (m, J =
10.2, 5.9 Hz, 1H), 1.14 (d, J = 2.4 Hz,2H), 0.97 (d, J = 4.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 172.6, 144.2, 137.0, 128.1, 118.3, 114.7,
16.3, 9.1; HR-MS (ESI) calcd for [M + 1]+: C9H11N2O2: 179.0815, found: 179.0814; IR (KBr): 2922, 1691, 1565, 1511, 1429, 1161, 755 cm -1.
General procedure for Pd(II)-catalyzed C(sp3)-H bond arylation
To an oven-dried Schlenk tube, N-(1-oxy-pyridin-2-yl)-alkylamide substrate (1) (0.2 mmol, 33.2 mg), aryliodide (2) (0.3 mmol,
61.2 mg), Pd (OAc)2 (0.02 mmol, 4.5 mg), AgOAc (0.4 mmol, 66.4 mg) and p-xylene (2 mL) were added under Ar atmosphere.
o
The mixture was stirred at 130 C for 12 h. After cooling down to ambient temperature, the reaction mixture was then filtered
through a short plug of silica sand and further concentrated in vacuo. The crude products were purified through flash chroma-
tography on silica gel with ethyl acetate and petroleum (v/v = 1:1 to 4:1) as the eluent to afford the desired Csp3-H bond arylation
products.
ACS Paragon Plus Environment

Page 11 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2-(3-Phenylpropanamido)pyridine 1-oxide (3-1a): White solid; 44 mg, 91% yield; mp: 104.1-105.2 °C. 1H NMR (400 MHz, CDCl3)
δ 10.01 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 6.4 Hz, 1H), 7.36 – 7.28 (m, 3H), 7.24 – 7.19 (m, 3H), 6.98 (t, J = 6.9 Hz, 1H), 3.08
(t, J = 7.6 Hz, 2H), 2.85 (t, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 171.0, 144.1, 140.0, 137.1, 128.7, 128.3, 128.1, 126.5, 118.6, 114.8,
39.3, 30.9; HR-MS (ESI) calcd for [M + 1]+: C14H15N2O2: 243.1128, found: 243.1126; IR (KBr): 2923, 1703, 1568, 1506, 1426, 1207, 756
cm-1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(3,3-Diphenylpropanamido)pyridine 1-oxide (3-aa): White solid; mp: 110.1-112.2 °C. 1H NMR (400 MHz, CDCl3) δ 10.12 (s, 1H),
8.35 (d, J = 8.3 Hz, 1H), 8.14 (d, J = 6.3 Hz, 1H), 7.32 – 7.14 (m, 11H), 6.89 (t, J = 6.8 Hz, 1H), 4.69 (t, J = 7.7 Hz, 1H), 3.29 (d, J = 7.7
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.0, 144.0, 143.2, 137.0, 128.8, 128.1, 127.7, 126.7, 118.6, 114.9, 46.8, 43.9; HR-MS (ESI) calcd
for [M + 1]+: C20H19N2O2: 319.1441, found: 319.1438; IR (KBr): 2938, 1700, 1567, 1506, 1426, 1207, 760 cm -1.
1
2-(3-(4-Methoxyphenyl)propanamido)pyridine 1-oxide (3-1b): Pale yellow solid; 54 mg, 90% yield; mp: 108.1-109.2 °C. H NMR
(400 MHz, CDCl3) δ 10.02 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 6.4 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H),
7.00 –6.94 (t, 1H), 6.84 (d, J = 7.9 Hz, 2H), 3.78 (s, 2H), 3.01 (t, J = 7.6 Hz, 2H), 2.81 (t, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3)
δ171.1, 158.2, 144.1, 137.1, 132.0, 129.3, 128.5, 128.2, 118.6, 114.8, 114.1, 55.3, 39.7, 30.1; HR-MS (ESI) calcd for [M + 1]+: C15H17N2O3:
273.1234, found: 273.1236; IR (KBr): 2958, 1700, 1567, 1507, 1461, 1133, 758 cm -1.
2-(3-(m-Tolyl)propanamido)pyridine 1-oxide (3-1c): Pale yellow solid; 33 mg, 66% yield; mp: 102.1-103.2 °C. 1H NMR (400 MHz,
CDCl3) δ 10.06 (s, 1H), 8.48 (d, J = 8.5 Hz, 1H), 8.24 (d, J = 6.4 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.21 (t, J = 7.3 Hz, 1H), 7.07 (m, 3H),
6.99 (t, J = 7.0 Hz, 1H), 3.05 (t, J = 7.7 Hz, 2H), 2.86 (t, J = 7.6 Hz, 2H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.1, 144.1, 140.0,
138.2, 137.1, 129.1, 128.5, 128.2, 127.2, 125.3, 118.6, 114.8, 39.4, 30.8, 21.4; HR-MS (ESI) calcd for [M + 1]+: C15H17N2O2: 257.1285, found:
257.1285; IR (KBr): 2925, 1701, 1568, 1508, 1426, 1207, 759 cm -1.
2-(3-(o-Tolyl)propanamido)pyridine 1-oxide (3-1d): Pale yellow solid; 16 mg, 30% yield; mp: 106.1-106.2 °C. 1H NMR (400 MHz,
CDCl3) δ 10.05 (s, 1H), 8.46 (d, J = 8.5 Hz, 1H), 8.22 (d, J = 6.4 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.14 (dd, J = 9.9, 5.8 Hz, 4H), 6.98 (t,
J = 7.0 Hz, 1H), 3.09 – 3.04 (m, 2H), 2.83 – 2.78 (m, 2H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.2, 144.1, 138.2, 137.1, 136.0,
130.4, 128.5, 128.2, 126.6, 126.3, 118.6, 114.8, 38.0, 28.2, 19.3. HR-MS (ESI) calcd for [M + 1]+: C15H17N2O2: 257.1285, found: 257.1287; IR
(KBr): 2923, 1702, 1568, 1507, 1426, 1207, 757 cm -1
2-(3-([1,1'-Biphenyl]-4-yl)propanamido)pyridine 1-oxide (3-1e): Pale yellow solid; 42 mg, 68% yield; mp: 120.2-121.6 °C. 1H NMR
(400 MHz, CDCl3) δ 10.08 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 6.4 Hz, 1H), 7.55 (dd, J = 15.8, 7.7 Hz, 4H), 7.42 (t, J = 7.6 Hz,
2H), 7.32 (t, J = 8.0 Hz, 4H), 6.97 (t, J = 6.9 Hz, 1H), 3.11 (t, J = 7.6 Hz, 2H), 2.89 (t, J = 7.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
171.0, 140.9, 139.4, 139.1, 137.1, 128.8, 128.2, 127.4, 127.2, 127.0, 118.6, 114.8, 39.2, 30.5; HR-MS (ESI) calcd for [M + 1]+: C20H19N2O2:
319.1441, found: 319.1447; IR (KBr): 2934, 1705, 1572, 1507, 1434, 1212, 759 cm -1.
1
2-(3-(Naphthalen-1-yl)propanamido)pyridine 1-oxide (3-1f): Pale yellow solid; 27 mg, 47% yield; mp: 122.2-123.4 °C. H NMR
(400 MHz, CDCl3) δ 9.99 (s, 1H), 8.40 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 6.4 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 20
1
2
3
4
5
6
7
8
7.66 (d, J = 6.4 Hz, 1H), 7.44 (dt, J = 14.7, 7.1 Hz, 2H), 7.31 (s, 2H), 7.25 (t, J = 8.1 Hz, 1H), 6.87 (t, J = 7.0 Hz, 1H), 3.46 (t, J = 7.9 Hz,
2H), 2.90 (t, J = 7.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 171.2, 144.1, 137.1, 136.1, 134.0, 131.5, 129.0, 128.36, 127.3, 126.2, 126.1, 125.7,
125.6, 123.3, 118.6, 114.9, 38.54, 28.0; HR-MS (ESI) calcd for [M + 1]+: C18H17N2O2: 293.1285, found: 293.1287; IR (KBr): 2924, 1702,
1568, 1508, 1426, 1207, 757 cm -1.
9
2-(3-(4-Fluorophenyl)propanamido)pyridine 1-oxide (3-1g): Pale yellow solid; 38 mg, 72% yield; mp: 120.2-121.6 °C. 1H NMR (400
MHz, CDCl3) δ 10.04 (s, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 6.2 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.19 (t, J = 6.2 Hz, 2H), 6.98 (t,
J = 8.0 Hz, 3H), 3.04 (t, J = 7.5 Hz, 2H), 2.83 (t, J = 7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.8, 162.8 (d, J = 236.7 Hz), 129.8 (d,
J = 7.9 Hz), 129.7, 128.2, 118.6, 115.5 (d, J =21.3 Hz), 115.3, 114.8, 39.3, 30.0; HR-MS (ESI) calcd for [M + 1]+: C14H14FN2O2: 261.1034,
found: 261.1034; IR (KBr): 2921, 1702, 1568, 1508, 1426, 1214, 759 cm -1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2-(3-(4-Chlorophenyl)propanamido)pyridine 1-oxide (3-1h): Pale yellow solid; 38 mg,70% yield; mp: 119.2-120.2 °C. H NMR (400
MHz, CDCl3) δ 10.07 (s, 1H), 8.44 (d, J = 8.5 Hz, 1H), 8.22 (d, J = 6.4 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 7.8 Hz, 2H), 7.18 (d,
J = 7.8 Hz, 2H), 6.98 (t, J = 7.0 Hz, 1H), 3.05 (t, J = 7.5 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.7, 144.0,
138.5, 137.1, 132.2, 129.7, 128.7, 128.2, 118.7, 114.8, 39.0, 30.1; HR-MS (ESI) calcd for [M + 1]+: C14H14ClN2O2: 277.0738, found: 277.0737;
IR (KBr): 2965, 1691, 1555, 1509, 1430, 1079, 714 cm -1.
1
2-(3-(4-Bromophenyl)propanamido)pyridine 1-oxide (3-1i): Pale yellow solid; 51 mg, 80% yield; mp: 94.2-95.3 °C. H NMR (400
MHz, CDCl3) δ 10.07 (s, 1H), 8.43 (d, J = 8.5 Hz, 1H), 8.21 (d, J = 6.5 Hz, 1H), 7.41 (d, J = 7.8 Hz, 2H), 7.33 (t, J = 8.0 Hz, 1H), 7.11 (d, J
= 7.8 Hz, 2H), 6.98 (t, J = 7.0 Hz, 1H), 3.02 (t, J = 7.5 Hz, 2H), 2.83 (t, J = 7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.7, 144.0,
139.1, 137.1, 131.7, 130.1, 128.2, 120.2, 118.7, 114.8, 38.9, 30.2; HR-MS (ESI) calcd for [M + 1]+: C14H14BrN2O2: 321.0233, found: 321.0232;
IR (KBr): 2922, 1700, 1567, 1508, 1425, 1206, 758 cm -1.
1
2-(3-(2-Bromophenyl)propanamido)pyridine 1-oxide (3-1j): Pale yellow solid; 25 mg, 40% yield; mp: 93.2-94.7 °C. H NMR (400
MHz, CDCl3) δ 10.07 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 6.4 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.37 – 7.21 (m, 3H), 7.09 (t, J =
7.5 Hz, 1H), 6.98 (t, J = 6.9 Hz, 1H), 3.18 (t, J = 7.7 Hz, 2H), 2.87 (t, J = 7.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.7, 144.1, 139.3,
137.1, 133.0, 130.6, 128.3, 128.2, 127.7, 124.4, 118.6, 114.8, 77.4, 77.1, 76.7, 37.5, 31.4; HR-MS (ESI) calcd for [M + 1]+: C14H14BrN2O2:
321.0233, found: 321.0232; IR (KBr): 2922, 1702, 1568, 1507, 1426, 1206, 755 cm -1.
1
2-(3-(4-Iodophenyl)propanamido)pyridine 1-oxide (3-1k): Pale yellow solid; 38 mg, 52% yield; mp: 101.1-102.5 °C. H NMR (400
MHz, CDCl3) δ 10.05 (s, 1H), 8.44 (d, J = 8.5 Hz, 1H), 8.23 (d, J = 6.1 Hz, 1H), 7.61 (d, J = 7.9 Hz, 2H), 7.34 (t, J = 8.0 Hz, 1H), 7.00 (d,
J = 7.7 Hz, 3H), 3.01 (t, J = 7.4 Hz, 2H), 2.83 (t, J = 7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.6, 144.0, 139.7, 137.7, 137.1, 130.4,
128.4, 118.7, 114.8, 91.6, 38.9, 30.3; HR-MS (ESI) calcd for [M + 1]+: C14H14IN2O2: 369.0095, found: 369.0094; IR (KBr): 2922, 1701,
1568, 1508, 1425, 1206, 760 cm -1.
1
2-(3-(4-(Trifluoromethyl)phenyl)propanamido)pyridine 1-oxide (3-1l): Pale yellow solid; 37 mg, 60% yield; mp: 96.2-96.3 °C. H
NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 8.45 (d, J = 8.5 Hz, 1H), 8.22 (d, J = 6.4 Hz, 1H), 7.56 (d, J = 7.8 Hz, 2H), 7.35 (m, J = 13.8,
ACS Paragon Plus Environment

Page 13 of 20
The Journal of Organic Chemistry
1
2
3
4
5
7.8 Hz, 3H), 6.99 (t, J = 7.0 Hz, 1H), 3.14 (t, J = 7.5 Hz, 2H), 2.89 (t, J = 7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.5, 144.2, 144.0,
137.1, 128.7, 128.3, 125.6, 125.5 (d, J = 24.4 Hz), 118.7, 114.8, 38.6, 30.5; HR-MS(ESI) calcd for [M+1]+: C15H14F3N2O2: 311.1002, found:
311.1004; IR(KBr): 3230, 2923, 1706, 1570, 1513, 1424, 1107, 755 cm -1.
6
7
8
9
2-(3-(Thiophen-3-yl)propanamido)pyridine 1-oxide (3-1m): Pale yellow solid; 15 mg, 30 % yield; mp: 100.2-101.5 °C. 1H NMR (400
MHz, CDCl3) δ 10.03 (s, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.22 (d, J = 6.4 Hz, 1H), 7.33 (t, J = 8.1 Hz, 1H), 7.26 (s, 1H), 7.04 (s, 1H), 6.98
(d, J = 3.5 Hz, 2H), 3.10 (t, J = 7.5 Hz, 2H), 2.85 (t, J = 7.5 Hz, 32H); 13C NMR (100 MHz, CDCl3) δ 170.9, 144.1, 140.2, 137.1, 128.2,
127.9, 126.0, 121.0, 118.6, 114.8, 38.6, 25.4; HR-MS (ESI) calcd for [M + 1]+: C12H13N2O2S: 249.0692, found: 249.0694; IR (KBr): 2920,
1701, 1568, 1507, 1426, 1207, 758 cm -1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2-(3,3-Di(thiophen-3-yl)propanamido)pyridine 1-oxide (3-1n): Pale yellow solid; 17 mg, 25% yield; mp: 112.2-113.5 °C. H NMR
(400 MHz, CDCl3) δ 10.03 (s, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 6.4 Hz, 1H), 7.29 (t, J = 6.0 Hz, 1H), 7.26 (t, J = 3.6 Hz, 2H),
7.05 (s, 2H), 6.95 (t, J = 7.5 Hz, 3H), 4.84 (t, J = 7.5 Hz, 1H), 3.20 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 169.8, 144.0,
143.6, 137.02, 128.1, 127.2, 126.2, 121.0, 118.7, 114.8, 44.7, 38.3; HR-MS (ESI) calcd for [M + 1]+: C16H15N2O2S2: 331.0569, found: 331.0572;
IR (KBr): 3223, 2923, 1702, 1569, 1507, 1427, 1262, 749 cm -1.
2-(3-Phenylbutanamido)pyridine 1-oxide(3-2a): Pale yellow solid; 38 mg, 75% yield, mp: 110.2-111.5 °C. 1H NMR (400 MHz, CDCl3)
δ 10.02 (s, 1H), 8.43 (d, J = 8.5 Hz, 1H), 8.19 (d, J = 9.6 Hz, 1H), 7.35 – 7.25 (m, 5H), 7.21 (t, J = 6.9 Hz, 1H), 6.95 (t, J = 7.0 Hz, 1H),
3.42 (h, J = 7.1 Hz, 1H), 2.86 (dd, J = 15.0, 6.9 Hz, 1H), 2.76 (dd, J = 15.0, 8.0 Hz, 1H), 1.37 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 170.6, 145.3, 144.1, 137.0, 128.7, 128.2, 126.7, 126.6, 118.5, 114.8, 46.3, 36.6, 21.9; HR-MS (ESI) calcd for [M + 1]+: C15H17N2O2:
257.1285, found: 257.1285; IR (KBr): 3231, 2963, 1701, 1568, 1506, 1425, 1208, 760 cm -1.
1
2-(2-Benzyl-3-phenylpropanamido)pyridine 1-oxide (3-2b): Pale yellow solid; 33 mg, 50% yield; mp: 123.4-124.6 °C. H NMR (400
MHz, CDCl3) δ 9.63 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 6.4 Hz, 1H), 7.18 (dd, J = 12.6, 7.2 Hz, 5H), 7.10 (d, J = 7.1 Hz, 6H),
6.83 (t, J = 7.0 Hz, 1H), 3.05 – 2.92 (m, 3H), 2.81 (dd, J = 12.7, 4.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 173.6, 143.8, 138.6, 137.0,
128.8, 128.6, 128.0, 126.7, 118.5, 114.7, 53.0, 38.5; HR-MS (ESI) calcd for [M + 1]+: C21H21N2O2: 333.1598, found: 333.1598; IR (KBr):
3224, 2960, 1704, 1566, 1504, 1427, 1206, 757 cm -1.
1
2-(2,2-Dimethyl-3-phenylpropanamido)pyridine 1-oxide (3-2c): Pale yellow solid; 22 mg, 40% yield; mp: 104.6-104.8 °C. H NMR
(400 MHz, CDCl3) δ 10.34 (s, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 6.3 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.21 (t, J = 7.9 Hz, 3H),
7.13 (d, J = 6.8 Hz, 2H), 6.97 (t, J = 6.9 Hz, 1H), 2.97 (s, 2H), 1.35 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 137.2, 137.0, 130.2, 128.1, 126.7,
118.5, 114.6, 46.5, 45.2, 24.9; HR-MS (ESI) calcd for [M + 1]+: C16H19N2O2: 271.1141, found: 271.1143; IR (KBr): 3257, 2963, 1691, 1566,
1506, 1424, 1203, 762 cm-1.
5-Chloro-2-(3-phenylpropanamido)pyridine 1-oxide (3-2d): Pale yellow solid; 17 mg, 30% yield; mp: 165.2-166.5 °C. 1H NMR (400
MHz, CDCl3) δ 9.84 (s, 1H), 8.42 (d, J = 9.0 Hz, 1H), 8.25 (s, 1H), 7.30 (t, J = 7.4 Hz, 3H), 7.24 – 7.19 (m, 3H), 3.06 (t, J = 7.6 Hz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 20
1
2
2H), 2.84 (t, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.9, 142.9, 139.9, 136.2, 128.7, 128.3, 128.1, 126.5, 125.2, 114.5, 39.3, 30.9;
3
4
HR-MS (ESI) calcd for [M + 1]+: C14H14ClN2O2: 277.0738, found: 277.0740; IR (KBr): 2958, 1687, 1570, 1506, 1432, 1212, 769 cm -1.
5
6
7
8
o
1
5-Chloro-2-(3, 3-diphenylpropanamido)pyridine 1-oxide (3-2e): Pale yellow; 21 mg, 30% yield; mp: 171..2-172.7 C. H NMR (400
MHz, CDCl3) δ 9.86 (s, 1H), 8.33 (d, J = 9.2 Hz, 1H), 8.20 (s, 1H), 7.27 (t, J = 6.3 Hz, 11H), 7.19 (t, J = 6.6 Hz, 2H), 4.67 (t, J = 7.8 Hz,
1H), 3.27 (d, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 169.8, 143.0, 136.1, 128.8, 128.1, 127.6, 126.8, 125.2, 46.9, 44.0; HR-MS (ESI)
calcd for [M + 1]+: C20H18ClN2O2: 353.1051, found: 353.1048; IR (KBr): 3201, 2958, 1703, 1557, 1505, 1450, 1213, 749 cm -1.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-Bromo-2-(3-phenylpropanamido)pyridine 1-oxide (3-2f): Pale yellow solid; 19 mg, 29% yield; mp: 189.4-190.8 °C. 1H NMR (400
MHz, CDCl3) δ 9.83 (s, 1H), 8.37 (d, J = 9.3 Hz, 2H), 7.44 (d, J = 9.0 Hz, 1H), 7.33 – 7.27 (m, 2H), 7.23 (d, J = 7.3 Hz, 3H), 3.06 (t, J =
7.5 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.9, 139.8, 138.1, 130.8, 128.7, 128.3, 126.6, 114.8, 111.5, 39.3, 30.8;
HR-MS (ESI) calcd for [M + 1]+: C14H14BrN2O2: 321.0233, found: 321.0222; IR (KBr): 3228, 2959, 1701, 1556, 1502, 1378, 1210, 752 cm -1.
1
5-Bromo-2-(3,3-diphenylpropanamido)pyridine 1-oxide ( 3-2g): Pale yellow solid; 24 mg, 30% yield; mp: 196.4-197.5 °C. H NMR
(400 MHz, CDCl3) δ 9.87 (s, 1H), 8.35 – 8.28 (m, 2H), 7.40 (d, J = 9.1 Hz, 1H), 7.35 – 7.27 (m, 9H), 7.23 (d, J = 6.8 Hz, 2H), 4.70 (t, J
= 7.8 Hz, 1H), 3.29 (d, J = 7.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 169.8, 143.0, 138.0, 130.7, 128.8, 127.6, 126.8, 114.8, 111.5, 46.9,
44.0; HR-MS (ESI) calcd for [M + Na]+: C20H17BrN2NaO2: 419.0371, found: 419.0366; IR (KBr): 2922, 1701,1555, 1500, 1382, 1079, 698
cm -1.
1
5-Methyl-2-(3-phenylpropanamido)pyridine 1-oxide (3-2h): Pale yellow solid; 15 mg, 30% yield; mp: 127.2-128.7 °C. H NMR (400
MHz, CDCl3) δ 9.94 (s, 1H), 8.33 (d, J = 8.6 Hz, 1H), 8.05 (s, 1H), 7.32 – 7.26 (m, 2H), 7.25 – 7.20 (m, 3H), 7.14 (d, J = 8.5 Hz, 1H),
3.06 (t, J = 7.6 Hz, 2H), 2.83 (t, J = 7.6 Hz, 2H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.8, 141.8, 140.1, 136.7, 129.4, 129.0,
128.6, 128.3, 126.4, 114.3, 39.3, 31.0, 17.9; HR-MS (ESI) calcd for [M + 1]+: C15H17N2O2: 257.1285, found: 257.1283; IR (KBr): 3209, 2924,
1695, 1576, 1531, 1452, 1113, 764 cm -1.
2-(3,3-Diphenylpropanamido)-5-methylpyridine 1-oxide (3-2i): Pale yellow solid; 23 mg, 35% yield; mp: 134.2-136.1 °C. 1H NMR
(400 MHz, CDCl3) δ 9.95 (s, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.01 (s, 1H), 7.28 (d, J = 4.0 Hz, 9H), 7.19 (dd, J = 8.1, 3.8 Hz, 2H), 7.08 (d,
J = 8.7 Hz, 1H), 4.69 (t, J = 7.7 Hz, 1H), 3.26 (d, J = 7.8 Hz, 2H), 2.23 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 169.7, 143.2, 141.7, 136.6,
129.3, 129.0, 128.7, 127.7, 126.7, 114.3, 46.9, 43.9, 17.8; HR-MS (ESI) calcd for [M + 1]+: C21H21N2O2: 333.1598, found: 333.1595; IR (KBr):
2923, 1691, 1523, 1508, 1448, 1148, 699 cm -1.
1
2-(3-Phenylpropanamido)-5-(trifluoromethyl)pyridine 1-oxide (3-2j): Pale yellow solid; 20 mg, 30% yield; mp: 135.7-136.9 °C. H
NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 8.61 (d, J = 8.8 Hz, 1H), 8.54 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.37 – 7.20 (m, 5H), 3.10 (t, J =
7.4 Hz, 2H), 2.91 (t, J = 7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 171.2, 146.3, 139.7, 134.7, 128.7 (d, J = 43.6 Hz), 128.3, 126.6, 124.6,
123.3, 122.6 (q, J = 15.1 Hz), 122.3, 120.6, 114.4, 39.3, 30.7; HR-MS (ESI) calcd for [M + Na]+: C15H13F3N2O2Na: 333.0814, found:
333.0819; IR (KBr): 2931, 1698, 1526, 1510, 1448, 1138, 701 cm -1.
ACS Paragon Plus Environment

Page 15 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2-(3,3-Diphenylpropanamido)-5-(trifluoromethyl)pyridine 1-oxide (3-2k): Pale yellow solid; 23 mg, 28% yield; mp: 147.3-148.8
°C. 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.50 (d, J = 12.2 Hz, 2H), 7.47 (t, J = 8.2 Hz, 1H), 7.33 – 7.16 (m, 10H), 4.68 (t, J = 7.7
Hz, 1H), 3.32 (d, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.2, 146.2, 142.9, 134.7, 129.1, 128.8 (d, J = 43.6 Hz), 128.5, 128.4,
128.3, 127.6, 126.9, 124.7, 124.6, 123.3 (q, J = 35.4Hz), 122.7, 122.3, 120.6, 114.5, 46.9, 44.0; HR-MS (ESI) calcd for [M + Na]+:
C21H17F3N2O2Na: 409.1135, found: 409.1138; IR (KBr): 2935, 1694, 1536, 1512, 1450, 1148, 701 cm -1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2-(3, 3-Diphenylpropanamido)-5-nitropyridine 1-oxide (3-2l): Pale yellow solid; 18 mg, 25% yield; mp: 145.1-146.7 °C. H NMR
(400 MHz, CDCl3) δ 10.17 (s, 1H), 9.10 (s, 1H), 8.55 (d, J = 9.3 Hz, 1H), 8.10 (d, J = 9.3 Hz, 1H), 7.35 – 7.28 (m, 8H), 7.24 (d, J = 6.1
Hz, 2H), 4.70 (t, J = 7.6 Hz, 1H), 3.36 (d, J = 7.6 Hz, 2H), 1.63 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.2, 142.7, 133.5, 128.87, 127.6,
127.0, 122.7, 112.8, 46.9, 44.2; HR-MS (ESI) calcd for [M + 1]+: C20H18N3O4: 364.1292, found: 364.1293; IR (KBr): 2960, 1713, 1570, 1517,
1452, 1348, 1116, 700 cm -1.
2-(3-Benzyl-5, 5-dimethylhexanamido)pyridine 1-oxide (3-2m): Pale yellow solid; 34 mg, 52% yield; mp: 132.4-133.9 °C. 1H NMR
(400 MHz, CDCl3) δ 9.90 (s, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 6.3 Hz, 1H), 7.33 – 7.28 (t, 1H), 7.25 (d, J = 7.5 Hz, 2H), 7.21 (d,
J = 7.2 Hz, 2H), 7.15 (t, J = 7.0 Hz, 1H), 6.96 (t, J = 6.9 Hz, 1H), 2.75 (dd, J = 13.3, 6.2 Hz, 1H), 2.62 (dd, J = 13.2, 7.9 Hz, 1H), 2.46 (t, J
= 5.9 Hz, 2H), 2.43 – 2.33 (m, 1H), 1.38 (dd, J = 14.1, 3.0 Hz, 1H), 1.32 – 1.24 (dd, 1H), 0.88 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.4,
144.1, 140.2, 137.0, 129.4, 128.3, 128.1, 126.1, 118.4, 114.7, 47.3, 44.2, 42.8, 33.8, 31.1, 29.8; HR-MS (ESI) calcd for [M + 1]+: C20H27N2O2:
327.2067, found: 327.2068; IR (KBr): 2957, 1701, 1567, 1508, 1424, 1127, 759 cm -1.
1
2-(2-Phenylcyclohexanecarboxamido)pyridine 1-oxide (3-2n): Pale yellow solid; 9 mg, 15% yield; mp: 161.3-163.0 °C. H NMR
(400 MHz, CDCl3) δ 9.76 (s, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 6.5 Hz, 1H), 7.23 (d, J = 3.2 Hz, 4H), 7.19 (t, J = 8.2 Hz, 1H), 7.15
– 7.10 (m, 1H), 6.87 (t, J = 7.0 Hz, 1H), 2.92 (t, J = 11.3 Hz, 1H), 2.68 (t, J = 11.4 Hz, 1H), 2.12 (d, J = 13.2 Hz, 1H), 1.91 (dd, J = 26.7, 12.3
Hz, 4H), 1.72 (dd, J = 24.3, 12.1 Hz, 1H), 1.55 – 1.50 (m, 1H), 1.48 – 1.40 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 173.9, 144.2, 136.9,
128.6, 128.0, 127.2, 126.6, 118.3, 114.6, 53.4, 46.5, 34.3, 30.8, 26.1, 25.4; HR-MS (ESI) calcd for [M + 1]+: C18H21N2O2: 297.1598, found:
297.1597; IR (KBr): 2925, 1699, 1567, 1506, 1425, 1207, 757, 699 cm -1.
2-(2,6-Diphenylcyclohexanecarboxamido)pyridine 1-oxide (3-2o): Pale yellow solid; 12 mg, 15% yield; mp: 162.3-163.5 °C. 1H NMR
(400 MHz, CDCl3) δ 9.75 (s, 1H), 8.09 (t, J = 6.9 Hz, 2H), 7.42 – 7.36 (m, 4H), 7.32 (t, J = 7.3 Hz, 2H), 7.26 (t, J = 7.3 Hz, 2H), 7.20
(t, J = 7.0 Hz, 2H), 7.13 (t, J = 8.0 Hz, 1H), 6.82 (t, J = 7.0 Hz, 1H), 3.57 (dd, J = 12.9, 6.9 Hz, 2H), 3.41 – 3.35 (m, 1H), 2.23 (d, J = 11.8
Hz, 2H), 2.01 (dt, J = 20.1, 10.3 Hz, 2H), 1.80 (t, J = 10.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 171.9, 144.8, 143.9, 142.6, 136.8, 128.7,
128.6, 128.3, 127.9, 127.4, 126.6, 126.4, 118.1, 114.5, 54.7, 42.8, 40.5, 32.4, 30.3, 21.4; HR-MS (ESI) calcd for [M + 1]+: C24H25N2O2:
373.1911, found: 373.1907; IR (KBr): 2959, 1705, 1567, 1502, 1424, 1206, 756, 699 cm -1.
1
2-(2-Phenylcyclopentanecarboxamido)pyridine 1-oxide (3-2p): Pale yellow solid; 34 mg, 60% yield; mp: 154.2-156.1 °C. H NMR
(400 MHz, CDCl3) δ 9.56 (s, 1H), 8.11 (t, J = 8.8 Hz, 2H), 7.23 (d, J = 7.5 Hz, 2H), 7.17 (t, J = 7.6 Hz, 3H), 7.07 (t, J = 7.2 Hz, 1H), 6.85
(t, J = 7.0 Hz, 1H), 3.52 (dd, J = 16.9, 8.5 Hz, 1H), 3.25 (dd, J = 14.3, 7.6 Hz, 1H), 2.32 – 2.19 (m, 2H), 2.13 (dd, J = 18.8, 13.1 Hz, 3H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 20
1
2
3
4
5
6
1.82 (dd, J = 18.7, 10.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 173.3, 143.8, 140.7, 136.8, 128.2, 127.9, 127.8, 126.6, 118.1, 114.3, 52.8, 49.9,
31.2, 28.6, 24.7; HR-MS (ESI) calcd for [M + 1]+: C17H19N2O2: 283.1441, found: 283.1443; IR (KBr): 2932, 1708, 1567, 1506, 1425, 1308,
699 cm -1.
7
8
9
2-(2-Phenylcyclobutanecarboxamido)pyridine 1-oxide (3-2q): Pale yellow solid; 11 mg, 20% yield; mp: 163.2-163.5 °C. 1H NMR
(400 MHz, CDCl3) δ 9.57 (s, 1H), 8.12 (dd, J = 11.7, 7.7 Hz, 2H), 7.25 (d, J = 7.6 Hz, 3H), 7.19 (dd, J = 16.2, 8.1 Hz, 2H), 7.08 (t, J = 7.0
Hz, 1H), 6.86 (t, J = 6.8 Hz, 1H), 4.08 (q, J = 8.7 Hz, 1H), 3.70 (d, J = 4.1 Hz, 1H), 2.67 (dt, J = 17.5, 8.9 Hz, 1H), 2.60 – 2.51 (m, 1H),
2.40 (dd, J = 23.7, 13.5 Hz, 1H), 2.29 (dd, J = 18.6, 8.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 171.7, 140.0, 136.8, 128.3, 127.9, 127.3,
126.7, 118.1, 114.3, 47.6, 43.3, 24.5, 20.2; HR-MS (ESI) calcd for [M + 1]+: C16H17N2O2: 269.1285, found: 269.1286; IR (KBr): 2923, 1698,
1567, 1505, 1425, 1311, 761, 699 cm -1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(2,4-Diphenylcyclobutanecarboxamido)pyridine 1-oxide (3-2r): Pale yellow solid; 28 mg, 40% yield; mp: 170.1-171.5 °C. 1H NMR
(400 MHz, CDCl3) δ 9.69 (s, 1H), 8.06 (d, J = 6.4 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.30 – 7.19 (m, 8H), 7.12 (t, J = 6.3 Hz, 2H), 7.03
(t, J = 8.0 Hz, 1H), 6.78 (t, J = 7.0 Hz, 1H), 4.05 (dd, J = 17.6, 7.3 Hz, 4H), 3.45 (q, J = 10.4 Hz, 1H), 2.73 – 2.62 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 169.5, 143.7, 140.0, 136.7, 128.2, 127.9, 126.8, 126.3, 118.1, 114.5, 54.5, 38.9, 29.3; HR-MS (ESI) calcd for [M + 1]+:
C22H21N2O2: 345.1598, found: 345.1597; IR (KBr): 3272, 2938, 1700, 1567, 1506, 1425, 1208, 763, 697 cm -1.
1
2-(2-Phenylcyclopropanecarboxamido)pyridine 1-oxide (3-2s): Pale yellow solid; 28 mg, 55% yield; mp: 160.4-162.3 °C. H NMR
(400 MHz, CDCl3) δ 10.15 (s, 1H), 8.18 (d, J = 6.7 Hz, 2H), 7.27 (dd, J = 13.2, 6.8 Hz, 4H), 7.18 (d, J = 10.0 Hz, 2H), 6.89 (t, J = 7.0 Hz,
1H), 2.68 (dd, J = 16.9, 8.6 Hz, 1H), 2.26 (dd, J = 14.5, 7.7 Hz, 1H), 1.95 – 1.85 (m, 1H), 1.46 (dd, J = 13.4, 8.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 168.4, 144.1, 136.9, 135.8, 129.2, 128.1, 128.1, 126.8, 118.1, 114.6, 27.0, 25.0, 11.4; HR-MS (ESI) calcd for [M + 1]+:
C15H15N2O2: 255.1228, found: 255.1227; IR (KBr): 3203, 2924, 1691, 1567, 1508, 1425, 1209, 1136, 754, 695 cm -1.
Several examples about removal of the Pyridine N-Oxide group of 3
NaOH (0.30 mmol, 1.5 eqiv) was added to a solution of arylation product 3 (0.20 mmol, 1.0 equiv) in EtOH (2.0 mL), and the
mixture was stirred at 85 oC for 8 h. After the solvent was removed in vacuo, the resulting residue was dissolved in aq. HCl solu-
tion (1.0 M, 3.0 mL) and extracted with CH2Cl2 (3 × 10 mL), and then combined organic layers were washed with brine and dried
over MgSO4. The corresponding crude products were purified through flash chromatography on silica gel to provide the desired
products.
o
3-Phenylpropanoic acid (4a): 17 White solid; mp: 45-47.5 C; 24 mg, 80% yield. 1H NMR (400 MHz, CDCl3) δ 7.29 (t, J = 6.8 Hz,
2H), 7.20 (d, J = 6.8 Hz, 3H), 2.95 (t, J = 7.6 Hz, 2H), 2.68 (t, J = 7.7 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 179.4, 140.2, 128.6, 128.3,
126.4, 35.7, 30.6; LR- MS (ESI) m/z 151.1 [M + H]+. IR (KBr) 3060, 1699, 1304, 1221, 696 cm -1.
o
1
3-Phenylbutanoic acid (4b): 18 Light yellow solid; mp: 35-37 C; 25 mg, 75% yield. H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 7.3
Hz, 2H), 7.25 – 7.18 (m, 3H), 3.26 (dt, J = 13.9, 7.0 Hz, 1H), 2.67 (dd, J = 15.5, 6.7 Hz, 1H), 2.57 (dd, J = 15.4, 8.3 Hz, 1H), 1.31 (d, J =
ACS Paragon Plus Environment

Page 17 of 20
The Journal of Organic Chemistry
1
2
3
6.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 178.6, 145.5, 128.6, 126.7, 126.5, 42.6, 36.2, 21.9; MS (ESI) m/z 165.1 [M + H]+; IR (KBr)
3030, 1604, 1453,1297, 700 cm -1.
4
5
6
7
8
2, 4-Diphenylcyclobutanecarboxylic acid (4c): 19 Light yellow solid; mp: 171-173 °C; 39 mg, 78% yield. 1H NMR (400 MHz, CDCl3)
δ 7.30 (s, 8H), 7.22 (d, J = 6.0 Hz, 2H), 3.78 (q, J = 9.3 Hz, 2H), 3.31 (t, J = 9.5 Hz, 1H), 2.78 (q, J = 8.8 Hz, 1H), 2.31 (q, J = 10.4 Hz,
1H); 13C NMR (101 MHz, CDCl3) δ 179.8, 142.7, 128.6, 126.7, 126.6, 52.4, 39.5, 32.7; MS (ESI) m/z 253.1 [M + H]+; IR (KBr) 3015, 1623,
1456,1260, 696 cm -1.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Mechanistic studies for Pd(II)-catalyzed C(sp3)-H bond arylation
2-(N-Methylpropionamido)pyridine 1-oxide (1o): A mixture of 2-propionamidopyridine 1-oxide (0.5 mmol, 83 mg), K2CO3 (1.0
mmol, 138 mg) and methyl iodide (0.75 mmol, 106 mg) in CH3CN (5 mL) was stirred at 85 °C for 3 h. After the reaction mixture
was then filtrated, the corresponding filtrate was concentrated and purified by silica gel chromatography to give the desired
product (1o) as pale yellow oil (54 mg, 60% yield). 1H NMR (400 MHz, CDCl3) δ 8.29 (dd, J = 33.1, 6.1 Hz, 1H), 7.41 – 7.28 (m, 3H),
3.24 (s, 3H), 2.15 (q, J = 7.3 Hz, 2H), 1.10 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 174.1, 148.8, 140.5, 126.2, 126.1, 125.1, 34.2,
26.9, 9.0; HR-MS (ESI) calcd for [M + Na]+: C9H12N2NaO2: 203. 0791, found: 203.0791; IR (KBr): 2980, 1700, 1570, 1507, 1432, 1209,
761 cm -1.
H/D exchange of N-(1-oxy-pyridin-2-yl)-propionamide (1a): To an oven-dried Schlenk tube, N-(1-oxy-pyridin-2-yl)-
propionamide (1a) (0.2 mmol, 33.2 mg), AcOD (1.0 mL), Pd (OAc)2 (0.02 mmol, 4.5 mg), AgOAc (0.4 mmol, 66.4 mg) and p-
xylene (2.0 mL) were added. The mixture was stirred at 130 °C for 6 h, then cooled down to room temperature and filtered
through a short plug of silica sand. The corresponding filtrate was further concentrated in vacuo and purified through flash
chromatography on silica gel with ethyl acetate/petroleum (v/v = 1/2) as the eluent to afford the desired product D-1a (60% yield)
as pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 6.4 Hz, 1H), 7.35 (t, J = 8.0 Hz,
1H), 6.99 (t, J = 6.7 Hz, 1H), 2.55 (s, 1H), 2.04 (s, 0.45 H); HR-MS (ESI) calcd for [M + 1]+: C8H8D3N2O2: 170.1003, found: 170.1002.
Kinetic isotope effect of this transformation: Parallel Individual Reactions of 1a and D-1a: The mixture of Pd (OAc)2 (0.02 mmol,
4.5 mg), AgOAc (0.4 mmol, 66.4 mg ), PhI(0.3 mmol, 61.0 mg), 2-propionamidopyridine 1-oxide (1a) (0.2 mmol, 33.2 mg) or the
o
isotopically-labeled substrate D-1a (0.2 mmol, 33.8 mg) in p-xylene (2.0 mL) was heated at 130 C in a tube under Ar atomo-
sphere. Then aliquots (0.5 mL) of the reaction solution were taken at 80 minutes intervals. Each aliquot was removed the solvent
1
1
under reduced pressure and analyzed by H NMR. The H NMR raw data of the reactions of 1a and D-1a was displayed (see SI,
Figure 1 and figure 2). Comparison of the reaction progress in the early stage (0–320 min) indicated that the corresponding KIE
value is 2.0 (see SI, Figure 3).
ACKNOWLEDGMENTS
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 20
1
2
3
4
We thank the NSFC (No. 21372085 and 21272229), West Light Foundation of CAS (No. Y3C1011100) and GNSF
(No.10351064101000000) for financial support.
5
6
7
Supporting Information
8
9
Details for experiments conditions, copies of 1 H and 13 C NMR spectra for all isolated compounds, and single crystal data of 3-
2q. This material is available free of charge via the Internet at http://pubs.acs.org.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
REFERENCES
(1) For selected reviews, see: (a) Ackermann, L. Acc. Chem. Res. 2014, 47, 281; (b) Ritleng, V.; Sirlin, C.; Pfeffer, M.; Chem. Rev. 2002, 102, 1731;
(c) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879; (d) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651; (e) Cai, X.;
Xie, B. Synthesis 2015, 47, 737 and references herein.
(2) For selected examples and reviews, see: (a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685;
(b) Chaumontet, M.; Piccardi, R.; Audic, N.; Hitce, J.; Peglion, J. L.; Clot, E.; Baudoin, O. J. Am. Chem. Soc. 2008, 130, 15157; (c) Lafrance, M.;
Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 14570; (d) Giri, R.; maugel, N.; Li, J. J.; Wang, D. H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.
Q. J. Am. Chem. Soc. 2007, 129, 3510; (e) Polukeev, A. V.; Marcos, R.; Ahlquist, M. S. G.; Wendt, O. F. Chem. Sci. 2015, 6, 2060; (f) Mukai, C.; Ohta,
Y.; Oura, Y.; Kawaguchi, Y.; Inagaki, F. J. Am. Chem. Soc. 2012, 134, 19580; (g) Whited, M. T.; Grubbs, R. H. Acc. Chem. Res. 2009, 42, 1607; (h)
Girard, S. A.; Knauber, T.; Li, C. J. Angew. Chem., Int. Ed. 2014, 53, 74.
(3) (a) Wang, D. H.; Wasa, M.; Giri, R.; Yu, J. –Q. J. Am. Chem. Soc. 2008, 130, 7190; (b) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010,
132, 3680; (c) Wasa, M.; Engle, K. M.; Yu, J. Q. J. Am. Chem. Soc. 2009, 131, 9886.
(4) (a) Shang, R.; Ilies, L.; Matsumoto, A.; Nakamura, E. J. Am. Chem. Soc. 2013, 135, 6030; (b) Nadres, E. T.; Santos, G. I. F.; Shabashov, D.;
Daugulis, O. J. Org. Chem. 2013, 78, 9689; (c) Pan, F.; Shen, P. X.; Zhang, L. S.; Wang, X.; Shi, Z. J. Org. Lett. 2013, 15, 4758; (d) Wei, Y.; Tang, H.;
Cong, X.; Rao, B.; Wu, C.; Zeng, X. Org. Lett. 2014, 16, 2248.
(5) (a) Zhang, S. –Y.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Chen, G. J. Am. Chem. Soc. 2013, 135, 2124; (b) He, G.; Chen, G. Angew. Chem., Int. Ed.
2011, 50, 5192; (c) Cheng, T.; Yin, W.; Zhang, Y.; Zhang, Y.; Huang, Y. Org. Biomol. Chem. 2014, 12, 1405; (d) Ju, L.; Yao, J.; Wu, Z.; Liu, Z.; Zhang, Y.
J. Org. Chem. 2013, 78, 10821.
(6) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965.
(7) Zhang, Q.; Chen, K.; Rao, W.; Zhang, Y.; Chen, F. J.; Shi, B. –F. Angew. Chem. Int. Ed. 2013, 52, 13588.
(8) For selected examples, see: (a) Li, C.; Yano, T.; Ishida, N.; Murakami, M. Angew. Chem., Int. Ed. 2013, 52, 9801; (b) Hull, K. L.; Lanni, E. L.;
Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 14047; (c) Oi, S.; Fukita, S.; Inoue, Y. Chem. Commun. 1998, 22, 2439; (d) Liang, LB.; Fu, SM.; Lin, D.;
Zhang, XQ.; Deng, YF.; Jiang, HF.; Zeng, W. J. Org. Chem. 2014, 79, 7492; (e) Shibata, T.; Takayasu, S.; Yuzawa, S.; Otani, T. Org. Lett. 2012, 14,
5106; (f) Tsai, C. C.; Shih, W. C.; Fang, C. H.; Li, C. Y.; Ong, T. G.; Yap, G. P. A. J. Am. Chem. Soc. 2010, 132, 11887; (g) Karthikeyan, I.; Sekar, G. Eur.
J. Org. Chem. 2014, 36, 8055; (h) Xie, Y.; Chen, T.; Fu, S.; Li, X.; Deng, Y.; Jiang, H.; Zeng, W. Chem. Commun. 2014, 50, 10699; (i) Li, MY.; Xie, Y.;
Ye, Y.; Zou, Y.; Jiang, HF.; Zeng, W. Org. Lett. 2014, 16, 6232.
(9) Xiao, B.; Liu, Z. J.; Liu, L.; Fu, Y. J. Am. Chem. Soc. 2013, 135, 616.
ACS Paragon Plus Environment

Page 19 of 20
The Journal of Organic Chemistry
1
(10) (a) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254; (b) Wu, J.; Cui, X.; Chen, L.; Jiang, G.; Wu, Y. J. Am. Chem. Soc.
2009, 131, 13888.
2
3
4
5
6
7
8
(11) (a) Tan, Y.; Barrios-Landeros, F.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 3683; (b) Duric, S.; Sypaseuth, F. D.; Hoof, S.; Svensson, E.;
Tzschucke, C. C. Chem-Eur. J. 2013, 19, 17456; (c) Campeau, L. C.; Stuart, D. R.; Leclerc, J. P.; Bertrand-Laperle, M.; Villemure, E.; Sun, H. Y.;
Lasserre, S.; Guimond, N.; Lecavallier, M.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 3291..
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(12) (a) Hao, X. Q.; Chen, L. J.; Ren, B.; Li, L. Y.; Yang, X. Y.; Gong, J. F.; Niu, J. L.; Song, M. P. Org. Lett. 2014, 16, 1104; (b) Zhang, L. B.; Hao, X.
Q.; Zhang, S. K.; Liu, K.; Ren, B.; Gong, J. F.; Niu, J. L.; Song, M. P. J. Org. Chem. 2014, 79, 10399.
(13) It is also worth to note that employing phenylboronic acid as aryl sources instead of iodobenzene 2c could not lead to the formation of
desired arylation products including 3-1a and 3-aa.
(14) For the corresponding HR-MS and 1H NMR spectrum about Pd(II) intermediate B, please see SI for more details.
(15) For selected references on the palladium-catalyzed arylation of C-H bonds by the use of a combination of aryl iodides and silver salts, see:
a) Chiong, H. A.; Pham, Q. –N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879; b) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154.
(16) (a) García-Barrantes, P. M.; Feliciano, A. S. Eur. J. Med. Chem. 2013, 70, 548. (b) Aksinenko, A.Y.; Sokolov, V. B. J. Fluo. Chem. 2012, 137,
105. (c) Kokatla, H. P.; Lakshman, M. K. J. Org. Chem. 2011, 76, 7842.
(17) Wang, C. Y.; Song, R. J.; Wei, W. T.; Fan, j. H.; Li. J. H.; Chem. Commun. 2015, 51, 2361.
(18) Hay, D. A.; Brennan, P.E. J. Am. Chem. Soc. 2014, 136, 9308.
(19) Stoermer, R.; Stroh, H.; Albert, H. Ber. Dtsch. Chem. Ges. 1935, 68B, 2102.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 20
1
2
Graphic Abstract
3
4
5
6
7
O
Pd(OAc)2 (10 mol %)
O
R3
O
R3
R3
AgOAc (2.0 equiv)
p-xylene, 130 oC, 12 h
Ar
I
+
N
O-
N
N
N
N
O-
N
H
R1
R2
H
H
R2
O-
R1
R1
Ar
R2
26 examples
Ar
R1 = R2 = H, alkyl, aryl
R1
R
2 = H
tBuCH ,
=
2
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment