Copper-Catalyzed N-Arylation of 2-Pyridones Employing Diaryliodonium Salts at Room Temperature

Article abstract of DOI:10.1021/acs.joc.6b01415

A new and mild synthetic approach for the N-arylation of 2-pyridones with diaryliodonium salts has been developed. Most reactions proceed readily at room temperature in the presence of 10 mol % of copper chloride. As a result, a wide range of N-arylpyridine-2-ones were synthesized in yields of 23% to 99%. With this method, an antifibrotic drug, Pirfenidone, was successfully synthesized in 99% yield within 30 min at room temperature.

Full text of DOI:10.1021/acs.joc.6b01415

Subscriber access provided by Northern Illinois University
Article
Copper-Catalyzed N-Arylation of 2-Pyridones
Employing Diaryliodonium Salts at Room Temperature
Seo-Hee Jung, Dan-Bi Sung, Cho-Hee Park, and Won-Suk Kim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01415 • Publication Date (Web): 02 Aug 2016
Downloaded from http://pubs.acs.org on August 3, 2016
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 19
The Journal of Organic Chemistry
1
2
3
4
5
6
Copper-Catalyzed N-Arylation of 2-Pyridones Employing Dia-
7
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
ryliodonium Salts at Room Temperature
SeoꢀHee Jung†, DanꢀBi Sung†, ChoꢀHee Park, and WonꢀSuk Kim*
Department of Chemistry and Nano Science, Ewha Womans University, Seoul 120ꢀ750, South Korea.
wonsukk@ewha.ac.kr
ABSTRACT: A new and mild synthetic approach for the Nꢀarylation of 2ꢀpyridones with diaryliodonium salts has been developed. Most
reactions proceed readily at room temperature in the presence of 10 mol % of copper chloride. As a result, a wide range of Nꢀaryl pyridineꢀ
2ꢀones were synthesized in yields of 23% to 99%. With this method, antifibrotic drug, Pirfenidone was successfully synthesized in 99%
yield within 30 min at room temperature.
INTRODUCTION
NꢀAryl pyridineꢀ2ꢀones are a ubiquitous moiety present in many bioactive compounds and pharmaceutical drugs
(Figure 1).1 Due to their intriguing biological activities such as antifibrotic, antiꢀinflammatory, anticonvulsant,
and sedative activities,2 several copperꢀcatalyzed coupling reactions for CꢀN bond formation between 2ꢀpyridones
and electrophiles such as aryl boronic acids,3 aryl stannanes,4 aryl bismuth,5 and aryl halides6 have been
previously reported (Scheme 1, eq 1). However, in general, copperꢀcatalyzed coupling reactions for this
transformation are relatively slow, requiring more than 12 h due to the low nucleophilicity of 2ꢀpyridones. In
particular, the Cuꢀcatalyzed Nꢀarylation of 2ꢀpyridones employing aryl halides is generally carried out at elevated
temperatures. Therefore, it is still required to develop a mild and expedient method for the preparation of Nꢀaryl
pyridine 2ꢀones.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 19
1
2
Figure 1. N-Aryl pyridine-2-ones containing Drugs.
3
4
5
6
7
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
More stable, electrophilic, and/or less toxic, compared to the corresponding B, Sn, and Bi electrophiles, diaꢀ
ryliodonium salts have been employed as arylating agents in many coupling reactions.7 In addition, the
electrophilicity of diaryliodonium salts can be increased in the presence of a Cu(I) catalyst by forming a reactive
arylꢀCu(III) intermediate.8 Recently, we demonstrated the use of diaryliodonium salts for the synthesis of Nꢀ
arylsulfonamides.9 This reaction was successfully carried out under copperꢀcatalyzed conditions at room
temperature. Thus, we hypothesized that the use of diaryliodonium salts could overcome the problems of the
current methods and permit the facile production of N-aryl pyridineꢀ2ꢀones at room temperature (Scheme 1, eq 2).
Furthermore, to the best of our knowledge, the Nꢀarylation of 2ꢀpyridones employing diaryliodonium salts has not
been reported.
With these considerations in mind, we report herein the preparation of Nꢀaryl pyridineꢀ2ꢀones using 2ꢀ
pyridones and diaryliodonium salts at room temperature.
Scheme 1. Synthetic Methods for N-Aryl pyridine-2-ones.
RESULTS AND DISCUSSION
Optimization of the Nꢀarylation of 2ꢀpyridones began at room temperature using 2ꢀhydroxypyridine 1 and
bis(4ꢀtertꢀbutyl)phenyl)iodonium triflate 2 (Table 1). Without a copper catalyst, only a low yield of the desired
product 3a was isolated after 24 h (Table 1, entries 1ꢀ2). However, when the reactions were conducted in the
presence of either CuI, CuBr, or CuBrꢀdimethylsulfide complex, the reactions went to completion within 10 min
2
ACS Paragon Plus Environment

Page 3 of 19
The Journal of Organic Chemistry
yielding product 3a in 96% yield (Table 1, entries 3, 4 and 6). Utilizing CuCl in toluene at room temperature furꢀ
nished a slightly higher 98% yield in 5 min (Table 1, entry 5). When Cu(II) catalysts such as CuCl2, CuBr2, CuO,
CuSO4, and Cu(OAc)2 were employed, prolonged reaction times and lower yields were observed (Table 1, entries
7ꢀ11). In particular, when the reaction was conducted with 5 mol % of CuCl, product 3a was obtained in a slightly
lower 96% yield in 5 min (Table 1, entry 12). Also, when bis(4ꢀ(tertꢀbutyl)phenyl)iodonium triflate 2 was utilized
as a limiting reagent, the desired product 3a was obtained in 89% yield in 15 min (Table 1, entry 13). Next, we
examined the solvent effects for Nꢀarylation of 2ꢀpyridone (Table 1, entries 14ꢀ15). When the reaction was carried
out in THF, no desired product was observed. However, utilizing CuCl in CH2Cl2 at room temperature provided
the desired product in 5 min in 95% yield. Furthermore, when different bases were employed, all proved inferior
to Et3N in terms of yield (Table 1, entries 16ꢀ22). Surprisingly, utilizing a bulky base such as DABCO furnished
the desired product 3a in 62% yield along with significant amounts of Oꢀarylated product 3aa (Table 1, entry 22).
1
2
3
4
5
6
7
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
Table 1. Optimization of the N-Arylation Reaction of 2-Pyridone 1 with Bis(4-(tert-butyl)phenyl)iodonium
Triflate 2
OTf
O
Cu cat.a
O
N
O
I
(10 mol %)
+
NH
t-Bu
N
t-Bu
t-Bu
t-Bu
solvent, base
1
2
3a
3aa
reaction
time
b
temp. (oC)
solvent
yield of
3a
(%)
entry
Cu cat.
base
1
2
3
no catalyst
no catalyst
CuI
Et3N
NaH
Et3N
Toluene
Toluene
Toluene
25
25
25
24 h
24 h
13
10
96
10 min
4
5
CuBr
CuCl
Et3N
Et3N
Toluene
Toluene
25
25
10 min
5 min
96
98
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
6
7
8
9
CuBr SMe2
CuCl2
25
25
25
25
10 min
24 h
96
27
76
90
CuBr2
24 h
CuO
24 h
CuSO4
Cu(OAc)2
10
11
25
25
24 h
24 h
33
10
12
13
14
15
CuCIc
CuCId
Et3N
Et3N
Toluene
Toluene
25
25
25
25
5 min
15 min
24 h
96
89
0
CuCI
CuCI
Et3N
Et3N
THF
CH2Cl2
5 min
95
16
CuCl
K2CO3
KOtBu
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
25
24 h
53
CuCl
CuCl
CuCl
17
18
19
20
21
22
25
25
24 h
41
93
DIPEA
Pyridine
K3PO4
5 min
25
24 h
14
CuCl
CuCl
25
25
24 h
70
94
Cs2CO3
DABCO
5 min
CuCl
25
15 min
62 (21)e
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 19
a
Reaction conditions: 0.25 mmol of 2ꢀhydroxypyridine, 0.325 mmol of bis(4ꢀ(tertꢀbutyl)phenyl)iodonium triflate, 0.50
1
2
mmol of base, solvent (0.1 M).
b
c
d
e
3
4
5
6
7
8
9
isolated yield.
5 mol % of CuCl.
0.25 mmol of bis(4ꢀ(tertꢀbutyl)phenyl)iodonium triflate, 0.325 mmol of 2ꢀhydroxypyridine.
Oꢀarylated product (3aa).
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
With the optimized conditions in hand, we began to investigate the scope of the Cuꢀcatalyzed Nꢀarylation of
various 2ꢀpyridones with bis(4ꢀ(tertꢀbutyl)phenyl)iodonium triflate 2. As shown in Table 2, most 2ꢀpyridones
employed provided the desired products in goodꢀtoꢀexcellent yields within 1 h at room temperature. However,
when 2ꢀhydroxyquinoline was used as a coupling partner, the desired product 3d was obtained in 99% yield with
requiring a longer reaction time, 5 h. It is hypothesized that the increased reaction time is due to the steric hinꢀ
drance of 2ꢀhydroxyquinoline.6a In addition, previous studies have indicated that 2ꢀhydroxypyridine bearing a
strong electronꢀwithdrawing nitro group or containing substituents at the 6ꢀposition are able to impede Cuꢀ
catalyzed coupling reactions.3a, 6bꢀc Surprisingly, however, when either 2ꢀhydroxyꢀ5ꢀnitropyridine or 2ꢀhydroxyꢀ3ꢀ
methylꢀ5ꢀnitropyridine was respectively employed, the coupled product 3f and 3g were obtained in 86% and 87%
yield in only 5 min, presumably due to the increased electrophilicity of the diaryliodonium salts. Use of haloꢀ
substitutedꢀ2ꢀpyridones furnished the desired product 3h and 3i in excellent yields. Furthermore, other fused or
nonꢀfused nitrogen heterocycles proved effective coupling partners under the optimized conditions, furnishing the
desired products 3jꢀ3l in yields ranging from 65 to 82%. Next, we studied the use of 2ꢀhydroxyꢀ6ꢀsubstituted
pyridines which are known as unreactive coupling partners for the preparation of Nꢀaryl pyridineꢀ2ꢀones.3a, 6b Inꢀ
terestingly, the use of 2ꢀhydroxyꢀ6ꢀmethylpyridine gave a 1.5:1 ratio of Oꢀarylated product 3mm to Nꢀarylated
product 3m. When 2ꢀhydroxyꢀ6ꢀphenylpyridine was used, it showed less reactivity, but provided a 3:1 ratio of Oꢀ
arylated product 3nn to Nꢀarylated product 3n in 6 h. Presumably, bulky substituents at the 6ꢀposition of 2ꢀ
pyridones hindered coordination at the nitrogen and led to the formation of the Oꢀarylated product as the major
product.10
4
ACS Paragon Plus Environment

Page 5 of 19
The Journal of Organic Chemistry
1
2
3
Table 2. Cu-Catalyzed N-Arylation of Various 2-Pyridones 4 with Bis(4-(tert-butyl)phenyl)iodonium Tri-
4
5
6
flate 2
7
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
a Reaction conditions: 0.25 mmol of 2ꢀhydroxypyridine, 0.325 mmol of bis(4ꢀ(tertꢀbutyl)phenyl)iodonium triflate, 10 mol %
of CuCl, 0.50 mmol of Et3N, toluene (0.1 M).
b
1.5 equiv of bis(4ꢀ(tertꢀbutyl)phenyl)iodonium triflate.
Encouraged by these crossꢀcoupling results, our attention turned to the effect of the counteranions utilizing 3,5ꢀ
dibromoꢀ2ꢀhydroxypyridine 5 and various diphenyliodonium salts 6. As illustrated in Table 3, significant differꢀ
ences in the yield of 7a were observed. The reactions employing diphenyliodonium salts containing OTf, BF4, or
PF6 anions provided the coupled product 7a in excellent yields in a short time. However, the use of diphenylioꢀ
donium salts having anions OTs, Cl, and Br furnished a lower yield after 24 h.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 19
1
2
3
4
Table 3. Effect of the Counteranions for Cu-Catalyzed N-Arylation of 3,5-Dibromo-2-hydroxypyridine 5
5
6
7
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
a
Reaction conditions: 0.25 mmol of 3,5ꢀdibromoꢀ2ꢀhydroxypyridine, 0.325 mmol of diphenyliodonium salts, 10 mol % of
CuCl, 0.50 mmol of Et3N, toluene (0.1 M).
b
isolated yield.
To further investigate the scope of the Cuꢀcatalyzed Nꢀarylation of 2ꢀpyridones, various symmetrical and unꢀ
symmetrical diaryliodonium salts were utilized as a coupling partner under the optimized conditions (Table 4).
The use of 3,5ꢀdibromoꢀ2ꢀhydroxypyridine 5 and diaryliodonium salts containing electronꢀneutral, ꢀdonating, and
ꢀwithdrawing groups furnished the desired products 7aꢀ7j in moderate to excellent yields. In addition, to demonꢀ
strate the feasibility of the Cuꢀcatalyzed Nꢀarylation of 2ꢀpyridones, the coupling reaction was carried out on a
large scale (5.0 mmol), providing 7c in 99% yield in 5 min. When either the sterically bulky mesityl or trifluoroꢀ
methoxyꢀ and trifluoromethylꢀsubstituted iodonium salts were used, the reactions were sluggish at room temperaꢀ
o
ture. However, increasing the temperature from rt to 50 C, furnished full conversion and provided the desired
products 7d, 7e, and 7i in 54%, 61% and 53% yield, respectively. Utilizing haloꢀsubstituted iodonium triflates at
room temperature gave the coupled products 7fꢀ7h in excellent yields within 1 h. Particularly, when unsymmetric
mesityl iodonium triflates, used to transfer the other aryl or heteroaryl group selevtively,11 were employed at 50
oC, the desired products 7k and 7l were obtained in 23% and 73% yields along with the significant amounts of 7d.
6
ACS Paragon Plus Environment

Page 7 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
Table 4. Cu-Catalyzed N-Arylation of 3,5-Dibromo-2-hydroxypyridine 5 with Various Diaryliodonium
Salts 7
7
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
a
Reaction conditions: 0.25 mmol of 3,5ꢀdibromoꢀ2ꢀhydroxypyridine, 0.325 mmol of diaryliodonium salt, 10 mol % of
CuCl, 0.50 mmol of Et3N, toluene (0.1 M).
b
5.0 mmol of 3,5ꢀdibromoꢀ2ꢀhydroxypyridine, 6.5 mmol of bis(4ꢀtertꢀbutyl)phenyl)iodonium triflate.
c
The reaction was conducted at 50 oC.
d
1.5 equiv of diaryliodonium salt.
e
Yield of 7d.
Finally, encouraged by the feasibility of the Cuꢀcatalyzed Nꢀarylation of 2ꢀpyridones employing diaryliodoniꢀ
um salts, we next attempted to synthesize Pirfenidone 9, which has been a widely used antiꢀfibrotic agent for
idiopathic pulmonary fibrosis(IPF) (Scheme 2).12 Compound 9 was obtained in 99% isolated yield from 2ꢀ
hydroxyꢀ5ꢀmethylpyridine 8 and diphenyliodonium hexafluorophosphate in 30 min at room temperature. This
new and mild synthetic approach to Pirfenidone is meaningful compared to its previous preparations in terms of
yield, reaction time and temperature.5b, 13
Scheme 2. Synthesis of the Pirfenidone 9
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 19
1
2
3
4
5
6
7
8
CONCLUSION
9
In conclusion, we have described a new synthetic method for the preparation of Nꢀaryl pyridineꢀ2ꢀones employꢀ
ing 2ꢀpyridones and diaryliodonium salts. The reaction readily proceeds at room temperature, and large scale
preparation of 7c has been successfully conducted to demonstrate the feasibility of our method. The scope of this
method has been investigated employing various 2ꢀpyridones and diaryliodonium salts. In particular, 2ꢀ
hydroxypyridines bearing a nitro group proved the effective nucleophile under optimized condition using diaryliꢀ
odonium salts. In addition, it was found that 2ꢀhydroxypyridines containing substituents at the 6ꢀposition can be
used to give the Oꢀarylated product as the major product. Finally, antifibrotic drug, Pirfenidone was easily synꢀ
thesized in 99% yield in 30 min employing 2ꢀhydroxyꢀ5ꢀmethylpyridine and diphenyliodonium hexafluorophosꢀ
phate. Further applications and developments based on this method are currently ongoing in our laboratory.
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
8
ACS Paragon Plus Environment

Page 9 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
EXPERIMENTAL SECTION
General Considerations
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
Unless otherwise indicated, all chemical reagents were purchased from commercial suppliers and were used
without further purification. All reactions were carried out in ovenꢀdried glassware equipped with a magnetic stir
bar. Reactions were monitored by thin layer chromatography (TLC) with 0.25ꢀmm preꢀcoated silica gel plates
(Kieselgel 60F254). Products were detected by viewing under a UV light, by staining with an anisaldehyde soluꢀ
tion composed of acetic acid, sulfuric acid, and MeOH, or by staining with a KMnO4 solution composed of potasꢀ
sium carbonate, sodium hydroxide, and water. Flash column chromatography was performed on silica gel (70ꢀ230
mesh). Yields refer to chromatographically and spectroscopically pure compounds unless otherwise noted. 1H and
13C spectra were recorded on a 300 MHz NMR spectrometer. Chemical shifts are reported as δ values relative to
1
13
1
13
internal SiMe4 (δ 0.00 for H) or chloroform (δ 77.0 for C) or DMSOꢀd6 (δ 2.50 for H and δ 39.5 for C). IR
spectra were measured as neat oils and solids on a FTꢀIR spectrometer. HRMS data were obtained by electron
ionization with a doubleꢀfocusing highꢀresolution magnetic sector mass analyzer.
Preparation of 2-pyridones
4ꢀmethoxypyridinꢀ2(1H)ꢀone14a, 2ꢀmethylfuro[3,2ꢀc]pyridinꢀ4(5H)ꢀone14b, thieno[2,3ꢀc]pyridinꢀ7(6H)ꢀone14b were
prepared as according to cited literature procedures.
Preparation of diaryliodonium salts
Diphenyliodonium triflate,15a diphenyliodonium tetrafluoroborate,15b diꢀpꢀtolyliodonium triflate,15a bis(4ꢀ(tertꢀ
butyl)phenyl)iodonium triflate,15c dimesityliodonium triflate,15c bis(4ꢀ(trifluoromethoxy)phenyl)iodonium tetraꢀ
fluoroborate,15d bis(4ꢀfluorophenyl)iodonium triflate,15c bis(4ꢀchlorophenyl)iodonium triflate,15c bis(4ꢀ
bromophenyl)iodonium triflate,15c bis(3ꢀ(trifluoromethyl)phenyl)iodonium tetrafluoroborate,15b mesityl(4ꢀ
(methoxycarbonyl)phenyl)iodonium triflate,15e mesityl(2ꢀchloropyridinꢀ5ꢀyl)iodonium triflate15f and mesitꢀ
yl(thiophenꢀ3ꢀyl)iodonium triflate11d were prepared as according to cited literature procedures.
General procedure I for synthesis of N-Aryl pyridine-2-ones
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 19
A 10 mL round bottom flask was charged with diaryliodonium salts (0.325 mmol), CuCl (10 mol %), Et3N (0.5
mmol) and the corresponding pyridinꢀ2ꢀone (0.25 mmol). Toluene (2.5 mL) was then added to the flask. The
reaction mixture was stirred at room temperature under Ar. After completion of the reaction as monitored by TLC
analysis, the solvent was removed in vacuo and the residue was purified by flash column chromatography on
silica gel to obtain the desired product.
1
2
3
4
5
6
7
8
9
1-(4-(tert-butyl)phenyl)pyridin-2(1H)-one (3a) General procedure I was used employing bis(4ꢀ(tertꢀ
butyl)phenyl)iodonium triflate (0.325 mmol) and pyridinꢀ2(1H)ꢀone (0.25 mmol), and the reaction was completed
in 5 min. Flash chromatography on silica gel using hexane/ethyl acetate (2:1) provided pure 3a (55.7 mg, 0.245
mmol, 98%) as a white solid. m.p: 108ꢀ110 °C; Rf 0.15 (hexane/ethyl acetate=2:1); IR (neat) 2957, 1664, 1586,
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
1524, 1400, 1269, 1127, 838, 761, 592 cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.49 (d, J = 8.4 Hz, 2H), 7.41ꢀ7.27
13
(m, 4H), 6.65 (d, J = 9.3 Hz, 1H), 6.22 (t, J = 6.7 Hz, 1H), 1.35 (s, 9H); C NMR (75 MHz, CDCl3) δ 162.4,
151.3, 139.6, 138.2, 138.1, 126.2, 125.8, 121.7, 105.7, 34.6, 31.2; HRMSꢀEI: m/z 227.1310 [M+; calcd. for
C15H17NO+: 227.1310].
2-(4-(tert-butyl)phenoxy)pyridine (3aa) General procedure
I
was used employing bis(4ꢀ(tertꢀ
butyl)phenyl)iodonium triflate (0.325 mmol), DABCO (instead of Et3N) and pyridinꢀ2(1H)ꢀone (0.25 mmol), and
the reaction was completed in 15 min. Flash chromatography on silica gel using hexane/ethyl acetate (20:1ꢀ2:1)
provided pure 3a (35.2 mg, 0.155 mmol, 62%) as a white solid and 3aa (12.0 mg, 0.053 mmol, 21%) as a colorꢀ
less oil. Rf 0.64 (hexane/ethyl acetate=10:1); 1H NMR (300 MHz, CDCl3) δ 8.17 (dd, J = 4.8 Hz and J = 2.1 Hz,
1H), 7.57 (t, J = 7.2 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 9 Hz, 2H), 6.89 (t, J = 5.1 Hz, 1H), 6.84 (d, J
= 8.4 Hz, 1H), 1.31 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 163.6, 151.5, 147.4, 146.9, 139.0, 126.2, 120.2, 118.0,
111.1, 34.1, 31.2; Data are consistent with those reported in the literature.16
1-(4-(tert-butyl)phenyl)-5-methylpyridin-2(1H)-one (3b) General procedure I was used employing bis(4ꢀ(tertꢀ
butyl)phenyl)iodonium triflate (0.325 mmol) and 5ꢀmethylpyridinꢀ2(1H)ꢀone (0.25 mmol), and the reaction was
completed in 30 min. Flash chromatography on silica gel using hexane/ethyl acetate (2:1) provided pure 3b (59.1
mg, 0.245 mmol, 98%) as a white solid. m.p: 118ꢀ120 °C; Rf 0.13 (hexane/ethyl acetate=2:1); IR (neat) 3850,
3742, 2957, 2353, 1675, 1526, 1276, 829, 668 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.48 (dd, J = 2.0 Hz and J =
13
6.6 Hz, 2H), 7.32ꢀ7.22 (m, 3H), 7.11 (s, 1H), 6.60 (d, J = 9.3 Hz, 1H), 2.09 (s, 3H), 1.34 (s, 9H); C NMR (75
MHz, CDCl3) δ 161.7, 151.1, 142.3, 138.4, 135.5, 126.2, 125.9, 121.3, 114.6, 34.6, 31.2, 16.9; HRMSꢀEI: m/z
241.1465 [M+; calcd. for C16H19NO+: 241.1467].
1-(4-(tert-butyl)phenyl)-4-methoxypyridin-2(1H)-one (3c) General procedure I was used employing bis(4ꢀ(tertꢀ
butyl)phenyl)iodonium triflate (0.325 mmol) and 4ꢀmethoxypyridinꢀ2(1H)ꢀone (0.25 mmol), and the reaction was
completed in 30 min. Flash chromatography on silica gel using hexane/ethyl acetate (1:1) provided pure 3c (61.8
mg, 0.240 mmol, 96%) as a white solid. m.p: 118ꢀ120 °C; Rf 0.1 (hexane/ethyl acetate=2:1); IR (neat) 3444,
2960, 2348, 1659, 1482, 1347, 1233, 1026, 831, 618 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.48 (dd, J = 1.8 Hz and
10
ACS Paragon Plus Environment

Page 11 of 19
The Journal of Organic Chemistry
J = 6.6 Hz, 2H), 7.28 (dd, J = 2.1 Hz and J = 5.7 Hz, 2H), 7.21 (dd, J = 1.5 Hz and J = 6.6 Hz, 1H), 5.98ꢀ5.95 (m,
1
2
13
2H), 3.80 (s, 3H), 1.34 (s, 9H); C NMR (75 MHz, CDCl3) δ 168.1, 163.9, 151.1, 138.0, 137.8, 126.2, 126.0,
3
4
+
101.0, 97.5, 55.5, 34.6, 31.2; HRMSꢀEI: m/z 257.1415 [M+; calcd. for C16H19NO2 : 257.1416].
5
6
7
8
1-(4-(tert-butyl)phenyl)quinolin-2(1H)-one (3d) General procedure I was used employing bis(4ꢀ(tertꢀ
butyl)phenyl)iodonium triflate (0.375 mmol) and quinolinꢀ2(1H)ꢀone (0.25 mmol), and the reaction was completꢀ
ed in 5 h. Flash chromatography on silica gel using hexane/ethyl acetate (2:1) provided pure 3d (68.7 mg, 0.248
mmol, 99%) as a white solid. m.p: 156ꢀ158 °C; Rf 0.22 (hexane/ethyl acetate=2:1); IR (neat) 3442, 3049, 2957,
2349, 1657, 1590, 1450, 1249, 1118, 834, 753, 532 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J = 9.6 Hz, 1H),
7.61ꢀ7.55 (m, 3H), 7.32 (t, J = 7.9 Hz, 1H), 7.21ꢀ7.15 (m, 3H), 6.77 (d, J = 9.6 Hz, 1H), 6.67 (d, J = 8.7 Hz, 1H),
1.39 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 162.3, 151.6, 141.2, 139.6, 134.7, 130.0, 128.1, 128.0, 127.1, 122.13,
122.1, 120.2, 116.0, 34.7, 31.3; HRMSꢀEI: m/z 277.1464 [M+; calcd. for C19H19NO+: 277.1467].
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
Methyl 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (3e) General procedure I was used
employing bis(4ꢀ(tertꢀbutyl)phenyl)iodonium triflate (0.325 mmol) and methyl 6ꢀoxoꢀ1,6ꢀdihydropyridineꢀ3ꢀ
carboxylate (0.25 mmol), and the reaction was completed in 1 h. Flash chromatography on silica gel using hexꢀ
ane/ethyl acetate (3:1) provided pure 3e (69.9 mg, 0.245 mmol, 98%) as a white solid. m.p: 126ꢀ130 °C; Rf 0.36
1
(hexane/ethyl acetate=2:1); IR (neat) 3469, 3065, 2959, 1680, 1522, 1445, 1268, 1109, 841, 770, 635 cmꢀ1; H
NMR (300 MHz, CDCl3) δ 8.24 (dd, J = 0.6 Hz and J = 2.4 Hz, 1H), 7.91 (dd, J = 2.4 Hz and J = 9.6 Hz, 1H),
13
7.54ꢀ7.51 (m, 2H), 7.32ꢀ7.29 (m, 2H), 6.63 (dd, J = 0.6 Hz and J = 9.6 Hz, 1H), 3.86 (s, 3H), 1.36 (s, 9H); C
NMR (75 MHz, CDCl3) δ 164.5, 162.1, 152.0, 143.4, 138.6, 137.4, 126.3, 125.7, 120.4, 109.6, 51.9, 34.6, 31.1;
+
HRMSꢀEI: m/z 285.1362 [M+; calcd. for C17H19NO3 : 285.1365].
1-(4-(tert-butyl)phenyl)-5-nitropyridin-2(1H)-one (3f) General procedure I was used employing bis(4ꢀ(tertꢀ
butyl)phenyl)iodonium triflate (0.325 mmol) and 5ꢀnitropyridinꢀ2(1H)ꢀone (0.25 mmol), and the reaction was
completed in 5 min. Flash chromatography on silica gel using hexane/ethyl acetate (5:1) provided pure 3f (58.5
mg, 0.215 mmol, 86%) as a white solid. m.p: 182ꢀ185 °C; Rf 0.47 (hexane/ethyl acetate=2:1); IR (neat) 3073,
1
2958, 2349, 1682, 1509, 1339, 1272, 1109, 834, 753, 634 cmꢀ1; H NMR (300 MHz, CDCl3) δ 8.67 (d, J = 3.0
Hz, 1H), 8.16 (dd, J = 3.0 Hz and J = 10.2 Hz, 1H), 7.56 (d, J = 6.6 Hz, 2H), 7.32 (d, J = 6.6 Hz, 2H), 6.66 (d, J =
13
9.9 Hz, 1H), 1.37 (s, 9H); C NMR (75 MHz, CDCl3) δ 161.2, 153.0, 139.9, 136.6, 133.4, 130.9, 126.8, 125.6,
+
120.4, 34.9, 31.2; HRMSꢀEI: m/z 272.1162 [M+; calcd. for C15H16N2O3 : 272.1161].
1-(4-(tert-butyl)phenyl)-3-methyl-5-nitropyridin-2(1H)-one (3g) General procedure I was used employing
bis(4ꢀ(tertꢀbutyl)phenyl)iodonium triflate (0.325 mmol) and 3ꢀmethylꢀ5ꢀnitropyridinꢀ2(1H)ꢀone (0.25 mmol), and
the reaction was completed in 5 min. Flash chromatography on silica gel using hexane/ethyl acetate (9:1) providꢀ
ed pure 3g (62.3 mg, 0.218 mmol, 87%) as a white solid. m.p: 152ꢀ154 °C; Rf 0.66 (hexane/ethyl acetate=2:1); IR
1
(neat) 2958, 2349, 1671, 1510, 1341, 1267, 1118, 756, 676 cmꢀ1; H NMR (300 MHz, CDCl3) δ 8.57 (d, J = 2.7
Hz, 1H), 8.04 (dd, J = 1.2 Hz and J = 3.0 Hz, 1H), 7.54 (d, J = 6.9 Hz, 2H), 7.31 (d, J = 6.6 Hz, 2H), 2.25 (s, 3H),
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 19
13
1.36 (s, 9H); C NMR (75 MHz, CDCl3) δ 162.1, 152.8, 137.3, 137.0, 130.4, 130.3, 129.9, 126.6, 125.7, 34.8,
1
2
+
31.2, 17.6; HRMSꢀEI: m/z 286.1316 [M+; calcd. for C16H18N2O3 : 286.1317].
3
4
5
6
7
8
9
3-bromo-1-(4-(tert-butyl)phenyl)pyridin-2(1H)-one (3h) General procedure I was used employing bis(4ꢀ(tertꢀ
butyl)phenyl)iodonium triflate (0.325 mmol) and 3ꢀbromopyridinꢀ2(1H)ꢀone (0.25 mmol), and the reaction was
completed in 5 min. Flash chromatography on silica gel using hexane/ethyl acetate (5:1) provided pure 3h (68.9
mg, 0.225 mmol, 90%) as a white solid. m.p: 154ꢀ155 °C; Rf 0.43 (hexane/ethyl acetate=2:1); IR (neat) 3448,
2959, 2348, 1660, 1512, 1352, 1265, 1134, 1031, 839, 754, 613 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.79 (dd, J =
1.8 Hz and J = 7.2 Hz, 1H), 7.50ꢀ7.47 (m, 2H), 7.36 (dd, J = 2.1 Hz and J = 6.9 Hz, 1H), 7.31ꢀ7.26 (m, 2H), 6.14
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
13
(t, J = 7.0 Hz, 1H), 1.35 (s, 9H); C NMR (75 MHz, CDCl3) δ 158.6, 151.8, 141.7, 138.1, 137.6, 126.2, 125.7,
117.3, 105.7, 34.7, 31.2; HRMSꢀEI: m/z 305.0412 [M+; calcd. for C15H16BrNO+: 305.0415].
5-bromo-1-(4-(tert-butyl)phenyl)pyridin-2(1H)-one (3i) General procedure I was used employing bis(4ꢀ(tertꢀ
butyl)phenyl)iodonium triflate (0.325 mmol) and 5ꢀbromopyridinꢀ2(1H)ꢀone (0.25 mmol), and the reaction was
completed in 30 min. Flash chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure 3i (72.8
mg, 0.238 mmol, 95%) as a white solid. m.p: 118ꢀ120 °C; Rf 0.79 (hexane/ethyl acetate=2:1); IR (neat) 3058,
2959, 2349, 1670, 1588, 1516, 1272, 834, 743, 634 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.51ꢀ7.47 (m, 3H), 7.41
(dd, J = 2.7 Hz and J = 9.6 Hz, 1H) 7.31ꢀ7.25 (m, 2H), 6.57 (dd, J = 0.5 Hz and J = 9.6 Hz, 1H), 1.34 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ 160.8, 151.9, 142.7, 137.9, 137.4, 126.4, 125.7, 122.9, 97.9, 34.7, 31.2; HRMSꢀEI: m/z
305.0414 [M+; calcd. for C15H16BrNO+: 305.0415].
5-(4-(tert-butyl)phenyl)-2-methylfuro[3,2-c]pyridin-4(5H)-one (3j) General procedure I was used employing
bis(4ꢀ(tertꢀbutyl)phenyl)iodonium triflate (0.325 mmol) and 2ꢀmethylfuro[3,2ꢀc]pyridinꢀ4(5H)ꢀone (0.25 mmol),
and the reaction was completed in 1 h. Flash chromatography on silica gel using hexane/ethyl acetate (2:1) proꢀ
vided pure 3j (45.7 mg, 0.162 mmol, 65%) as a white solid. m.p: 136ꢀ138 °C; Rf 0.23 (hexane/ethyl acetate=2:1);
IR (neat) 3458, 2959, 2349, 1660, 1512, 1265, 1032, 840, 754, 614 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.49 (d, J
= 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 7.2 Hz, 1H), 6.60 (s, 1H), 6.52 (d, J = 7.5 Hz, 1H), 2.43 (s,
13
3H), 1.36 (s, 9H); C NMR (75 MHz, CDCl3) δ 159.0, 158.6, 154.0, 151.0, 138.5, 133.6, 126.4, 126.1, 117.7,
+
103.3, 95.7, 34.6, 31.3, 13.7; HRMSꢀEI: m/z 281.1417 [M+; calcd. for C18H19NO2 : 281.1416].
6-(4-(tert-butyl)phenyl)thieno[2,3-c]pyridin-7(6H)-one (3k) General procedure I was used employing bis(4ꢀ
(tertꢀbutyl)phenyl)iodonium triflate (0.325 mmol) and thieno[2,3ꢀc]pyridinꢀ7(6H)ꢀone (0.25 mmol), and the reacꢀ
tion was completed in 20 min. Flash chromatography on silica gel using hexane/ethyl acetate (5:1) provided pure
3k (53.8 mg, 0.190 mmol, 76%) as a white solid. m.p: 168ꢀ172 °C; Rf 0.41 (hexane/ethyl acetate=2:1); IR (neat)
1
3099, 2954, 2350, 1650, 1404, 1274, 1136, 839, 768, 706, 575 cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.69 (d, J =
5.1 Hz, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.35ꢀ7.21 (m, 3H), 7.22 (d, J = 7.2 Hz, 1H), 6.73 (d, J = 7.2 Hz, 1H), 1.35
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 158.7, 151.0, 147.4, 138.2, 132.7, 131.1, 126.2, 126.1, 125.6, 124.5, 101.7,
34.6, 31.2; HRMSꢀEI: m/z 283.1028 [M+; calcd. for C17H17NOS+: 283.1031].
12
ACS Paragon Plus Environment

Page 13 of 19
The Journal of Organic Chemistry
2-(4-(tert-butyl)phenyl)pyridazin-3(2H)-one (3l) General procedure I was used employing bis(4ꢀ(tertꢀ
butyl)phenyl)iodonium triflate (0.325 mmol) and pyridazinꢀ3(2H)ꢀone (0.25 mmol), and the reaction was comꢀ
pleted in 1 h. Flash chromatography on silica gel using hexane/ethyl acetate (1:1) provided pure 3l (46.8 mg,
0.205 mmol, 82%) as a white solid. m.p: 140ꢀ141 °C; Rf 0.08 (hexane/ethyl acetate=2:1); IR (neat) 3443, 3068,
2956, 2349, 1662, 1583, 1511, 1357, 1139, 1031, 831, 599 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.87 (dd, J = 1.8
Hz and J = 3.9 Hz, 1H), 7.54ꢀ7.46 (m, 4H), 7.22 (dd, J = 3.6 Hz and J = 9.3 Hz, 1H), 7.05 (dd, J = 1.8 Hz and J =
1
2
3
4
5
6
7
8
9
13
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
9.6 Hz, 1H), 1.34 (s, 9H); C NMR (75 MHz, CDCl3) δ 160.1, 151.3, 138.8, 136.5, 131.1, 131.0, 125.8, 124.7,
34.6, 31.2; HRMSꢀEI: m/z 228.1265 [M+; calcd. for C14H16N2O+: 228.1263].
1-(4-(tert-butyl)phenyl)-6-methylpyridin-2(1H)-one (3m) and 2-(4-(tert-butyl)phenoxy)-6-methylpyridine
(3mm) General procedure I was used employing bis(4ꢀ(tertꢀbutyl)phenyl)iodonium triflate (0.325 mmol) and 6ꢀ
methylpyridinꢀ2(1H)ꢀone (0.25 mmol), and the reaction was completed in 3 h. Flash chromatography on silica gel
using hexane/ethyl acetate (20:1ꢀ2:1) provided pure 3m (19.3 mg, 0.080 mmol, 32%) as a white solid and 3mm
(29.6 mg, 0.123 mmol, 49%) as a colorless oil. [3m] m.p: 122ꢀ124 °C; Rf 0.1 (hexane/ethyl acetate=2:1); IR
(neat) 3074, 2960, 2350, 1662, 1577, 1460, 1258, 1146, 806, 600, 522 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.53ꢀ
7.49 (m, 2H), 7.29 (q, J = 6.7 Hz, 1H), 7.13ꢀ7.09 (m, 2H), 6.52 (dd, J = 0.6 Hz and J = 9.3 Hz, 1H), 6.09 (dd, J =
0.9 Hz and J = 6.9 Hz, 1H), 1.95 (s, 3H), 1.36 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 164.0, 151.4, 146.7, 139.4,
136.0, 127.0, 126.6, 118.3, 105.8, 34.6, 31.2, 21.5; HRMSꢀEI: m/z 241.1465 [M+; calcd. for C16H19NO+:
241.1467]. [3mm] Rf 0.64 (hexane/ethyl acetate=10:1); IR (neat) 3851, 3742, 3054, 2959, 2353, 1583, 1448,
1
1234, 1018, 791 cmꢀ1; H NMR (300 MHz, CDCl3) δ 7.50 (t, J = 7.8 Hz, 1H), 7.41ꢀ7.35 (m, 2H), 7.08ꢀ7.02 (m,
13
2H), 6.84 (d, J = 7.2 Hz, 1H), 6.53 (d, J = 8.4 Hz, 1H), 2.47 (s, 3H), 1.33 (s, 9H); C NMR (75 MHz, CDCl3) δ
163.4, 157.6, 152.1, 147.1, 139.4, 126.5, 120.1, 117.7, 107.1, 34.3, 31.4, 24.1; HRMSꢀEI: m/z 241.1463 [M+;
calcd. for C16H19NO+: 241.1467].
1-(4-(tert-butyl)phenyl)-6-phenylpyridin-2(1H)-one (3n) and 2-(4-(tert-butyl)phenoxy)-6-phenylpyridine
(3nn) General procedure I was used employing bis(4ꢀ(tertꢀbutyl)phenyl)iodonium triflate (0.375 mmol) and 6ꢀ
phenylpyridinꢀ2(1H)ꢀone (0.25 mmol), and the reaction was completed in 6 h. Flash chromatography on silica gel
using hexane/ethyl acetate (20:1ꢀ2:1) provided pure 3n (18.2 mg, 0.060 mmol, 24%) as a white solid and 3nn
(53.9 mg, 0.178 mmol, 71%) as a colorless oil. [3n] m.p: 144ꢀ148 °C; Rf 0.14 (hexane/ethyl acetate=2:1); IR
(neat) 3054, 2958, 2349, 1666, 1542, 1389, 1261, 1011, 759, 607 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.43 (q, J =
6.6 Hz, 1H), 7.27ꢀ7.22 (m, 2H), 7.18ꢀ7.09 (m, 3H), 7.07ꢀ7.03 (m, 2H), 6.99ꢀ6.96 (m, 2H), 6.68 (dd, J = 1.2 Hz
and J = 9.3 Hz, 1H), 6.25 (dd, J = 1.2 Hz and J = 6.9 Hz, 1H), 1.23 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 163.4,
150.8, 149.9, 139.3, 135.8, 135.6, 128.9, 128.3, 128.2, 127.7, 125.6, 120.0, 107.7, 34.5, 31.2; HRMSꢀEI: m/z
303.1620 [M+; calcd. for C21H21NO+: 303.1623]. [3nn] Rf 0.75 (hexane/ethyl acetate=10:1); IR (neat) 3435, 2348,
1636, 1440, 1242, 753, 539 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.95 (dd, J = 1.8 Hz and J = 8.1 Hz, 2H), 7.70 (t,
J = 8.1 Hz, 1H) 7.47ꢀ7.35 (m, 6H), 7.17ꢀ7.11 (m, 2H), 6.73 (d, J = 8.1 Hz, 1H), 1.35 (s, 9H); 13C NMR (75 MHz,
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 19
CDCl3) δ 163.6, 155.6, 151.8, 147.2, 140.0, 138.4, 129.0, 128.5, 126.8, 126.3, 120.4, 114.5, 109.0, 34.3, 31.4;
HRMSꢀEI: m/z 303.1625 [M+; calcd. for C21H21NO+: 303.1623].
1
2
3
4
5
6
7
8
9
3,5-dibromo-1-phenylpyridin-2(1H)-one (7a) General procedure I was used employing diphenyliodonium tetraꢀ
fluoroborate (0.325 mmol) and 3,5ꢀdibromopyridinꢀ2(1H)ꢀone (0.25 mmol), and the reaction was completed in 10
min. Flash chromatography on silica gel using hexane/ethyl acetate (5:1) provided pure 7a (78.1 mg, 0.237 mmol,
95%) as a white solid. m.p: 122ꢀ124 °C; Rf 0.4 (hexane/ethyl acetate=2:1); IR(neat) 3850, 3741, 3061, 2353,
1665, 1589, 1504, 1338, 1259, 857, 709 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J = 2.4 Hz, 1H), 7.51ꢀ7.42
(m, 4H), 7.37ꢀ7.34 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 157.3, 144.1, 140.0, 137.1, 129.4, 129.1, 126.2, 118.3,
96.9; HRMSꢀEI: m/z 326.8893 [M+; calcd. for C11H7Br2NO+: 326.8894].
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
3,5-dibromo-1-(p-tolyl)pyridin-2(1H)-one (7b) General procedure I was used employing diꢀpꢀtolyliodonium
triflate (0.325 mmol) and 3,5ꢀdibromopyridinꢀ2(1H)ꢀone (0.25 mmol), and the reaction was completed in 5 min.
Flash chromatography on silica gel using hexane/ethyl acetate (9:1) provided pure 7b (83.2 mg, 0.243 mmol,
97%) as a white solid. m.p: 134ꢀ136 °C; Rf 0.62 (hexane/ethyl acetate=2:1); IR(neat) 3447, 2348, 1664, 1592,
1509, 1261, 845, 748 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.86 (d, J = 2.4 Hz, 1H), 7.48 (d, J = 2.7 Hz, 1H), 7.30ꢀ
7.21 (m, 4H), 2.40 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 157.4, 144.0, 139.2, 137.6, 137.3, 130.0, 125.9, 118.3,
96.7, 21.1; HRMSꢀEI: m/z 340.9052 [M+; calcd. for C12H9Br2NO+: 340.9051].
3,5-dibromo-1-(4-(tert-butyl)phenyl)pyridin-2(1H)-one (7c) General procedure I was used employing bis(4ꢀ
(tertꢀbutyl)phenyl)iodonium triflate (0.325 mmol) and 3,5ꢀdibromopyridinꢀ2(1H)ꢀone (0.25 mmol), and the reacꢀ
tion was completed in 5 min. Flash chromatography on silica gel using hexane/ethyl acetate (10:1) provided pure
7c (94.3 mg, 0.245 mmol, 98%) as a white solid. For the large scale synthesis, general procedure I was used
employing bis(4ꢀ(tertꢀbutyl)phenyl)iodonium triflate (6.5 mmol) and 3,5ꢀdibromopyridinꢀ2(1H)ꢀone (5.0 mmol),
and the reaction was completed in 5 min as 99% yield (4.96 mmol, 1.91 g). m.p: 132ꢀ134 °C; Rf 0.78 (hexꢀ
1
ane/ethyl acetate=2:1); IR (neat) 3058, 2959, 2414, 1668, 1509, 1353, 1260, 1106, 850, 751, 544 cmꢀ1; H NMR
(300 MHz, CDCl3) δ 7.86 (d, J = 2.7 Hz, 1H), 7.51ꢀ7.48 (m, 3H), 7.28 (d, J = 9.0 Hz, 2H), 1.34 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 157.5, 152.3, 144.0, 137.5, 137.3, 126.4, 125.6, 118.3, 96.8, 34.8, 31.2; HRMSꢀEI: m/z
382.9521 [M+; calcd. for C15H15Br2NO+: 382.9520].
3,5-dibromo-1-mesitylpyridin-2(1H)-one (7d) General procedure I was used employing dimesityliodonium
triflate (0.325 mmol) and 3,5ꢀdibromopyridinꢀ2(1H)ꢀone (0.25 mmol) at 50 °C, and the reaction was completed in
5 h . Flash chromatography on silica gel using hexane/ethyl acetate (7:1) provided pure 7d (50.1 mg, 0.135 mmol,
54%) as a white solid. m.p: 128ꢀ130 °C; Rf 0.56 (hexane/ethyl acetate=2:1); IR(neat) 3854, 3742, 2354, 1664,
1264, 859, 756, 680 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 2.7 Hz, 1H), 7.26 (d, J = 2.7 Hz, 1H), 6.97
(s, 2H), 2.31 (s, 3H), 2.05 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 156.8, 144.3, 139.2, 137.2, 136.1, 134.0, 129.4,
118.6, 96.9, 21.0, 17.6; HRMSꢀEI: m/z 368.9362 [M+; calcd. for C14H13Br2NO+: 368.9364].
14
ACS Paragon Plus Environment

Page 15 of 19
The Journal of Organic Chemistry
3,5-dibromo-1-(4-(trifluoromethoxy)phenyl)pyridin-2(1H)-one (7e) General procedure I was used employing
bis(4ꢀ(trifluoromethoxy)phenyl)iodonium tetrafluoroborate (0.325 mmol) and 3,5ꢀdibromopyridinꢀ2(1H)ꢀone
(0.25 mmol) at 50 °C, and the reaction was completed in 6 h. Flash chromatography on silica gel using hexꢀ
ane/ethyl acetate (10:1) provided pure 7e (63.0 mg, 0.153 mmol, 61%) as a white solid. m.p: 104ꢀ106 °C; Rf 0.8
1
2
3
4
5
6
7
1
(hexane/ethyl acetate=2:1); IR(neat) 3851, 3741, 3447, 2353, 1662, 1516, 1258, 852, 751, 670 cmꢀ1; H NMR
8
9
(300 MHz, CDCl3) δ 7.88 (d, J = 2.7 Hz, 1H), 7.49 (d, J = 2.7 Hz, 1H), 7.46ꢀ7.40 (m, 2H), 7.34 (d, J = 8.4 Hz,
13
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
2H); C NMR (75 MHz, CDCl3) δ 157.2, 149.2 (d, J = 1.8 Hz) 144.4, 138.2, 136.6, 128.0, 121.8, 120.3 (q, J =
+
256.7Hz), 118.5, 97.3; HRMSꢀEI: m/z 410.8718 [M+; calcd. for C12H6Br2F3NO2 : 410.8717].
3,5-dibromo-1-(4-fluorophenyl)pyridin-2(1H)-one (7f) General procedure I was used employing bis(4ꢀ
fluorophenyl)iodonium triflate (0.325 mmol) and 3,5ꢀdibromopyridinꢀ2(1H)ꢀone (0.25 mmol), and the reaction
was completed in 1 h. Flash chromatography on silica gel using hexane/ethyl acetate (5:1) provided pure 7f (73.7
mg, 0.212 mmol, 85%) as a white solid. m.p: 148ꢀ150 °C; Rf 0.44 (hexane/ethyl acetate= 2:1); IR(neat) 3851,
3742, 3434, 2353, 1656, 1511, 1222, 833, 677, 517 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J = 2.7 Hz, 1H),
7.48 (d, J = 2.4 Hz, 1H), 7.38ꢀ7.32 (m, 2H), 7.17 (t, J = 8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 162.4 (d, J =
248.3 Hz) 157.3 144.2, 136.9, 135.9, 128.1 (d, J = 8.8 Hz), 118.3, 116.4 (d, J = 23 Hz), 97.1; HRMSꢀEI: m/z
344.8802 [M+; calcd for C11H6Br2FNO+: 344.8800].
3,5-dibromo-1-(4-chlorophenyl)pyridin-2(1H)-one (7g) General procedure I was used employing bis(4ꢀ
chlorophenyl)iodonium triflate (0.325 mmol) and 3,5ꢀdibromopyridinꢀ2(1H)ꢀone (0.25 mmol), and the reaction
was completed in 1 h. Flash chromatography on silica gel using hexane/ethyl acetate (6:1) provided pure 7g (84.5
mg, 0.233 mmol, 93%) as a white solid. m.p: 160ꢀ162 °C; Rf 0.5 (hexane/ethyl acetate=2:1); IR(neat) 3852, 3743,
1
2354, 1651, 1566, 1234, 1085, 833, 733; H NMR (300 MHz, CDCl3) δ 7.87 (d, J = 2.4 Hz, 1H), 7.47ꢀ7.44 (m,
13
3H), 7.33ꢀ7.29 (m, 2H); C NMR (75 MHz, CDCl3) δ 157.2, 144.3, 138.3, 136.6, 135.1, 129.6, 127.6, 118.4,
97.2; HRMSꢀEI: m/z 360.8505 [M+; calcd. for C11H6Br2ClNO+: 360.8505].
3,5-dibromo-1-(4-bromophenyl)pyridin-2(1H)-one (7h) General procedure I was used employing bis(4ꢀ
bromophenyl)iodonium triflate (0.325 mmol) and 3,5ꢀdibromopyridinꢀ2(1H)ꢀone (0.25 mmol), and the reaction
was completed in 30 min. Flash chromatography on silica gel using hexane/ethyl acetate (9:1) provided pure 7h
(91.8 mg, 0.225 mmol, 90%) as a white solid. m.p: 160ꢀ162 °C; Rf 0.6 (hexane/ethyl acetate=2:1); IR(neat) 3854,
3742, 2354, 1659, 1252, 836, 673 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J = 2.7 Hz, 1H), 7.63 (d, J = 9.0
13
Hz, 2H), 7.46 (d, J = 2.7 Hz, 1H), 7.26 (d, J = 9.0 Hz, 2H); C NMR (75 MHz, CDCl3) δ 157.2, 144.3, 138.9,
136.5, 132.7, 127.9, 123.2, 118.5, 97.3; HRMSꢀEI: m/z 404.8002 [M+; calcd. for C11H6Br3NO+: 404.7999].
3,5-dibromo-1-(3-(trifluoromethyl)phenyl)pyridin-2(1H)-one (7i) General procedure I was used employing
bis(3ꢀ(trifluoromethyl)phenyl)iodonium tetrafluoroborate (0.375 mmol) and 3,5ꢀdibromopyridinꢀ2(1H)ꢀone (0.25
mmol) at 50 ℃, and the reaction was completed in 3 h. Flash chromatography on silica gel using hexane/ethyl
acetate (9:1) provided pure 7i (52.6 mg, 0.132 mmol, 53%) as a white solid. m.p: 128ꢀ130 °C; Rf 0.67 (hexꢀ
ane/ethyl acetate=2:1); IR(neat) 3852, 3740, 3445, 2353, 1651, 1542, 1329, 1128, 667 cmꢀ1; 1H NMR (300 MHz,
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 19
13
CDCl3) δ 7.90 (d, J = 2.4 Hz, 1H), 7.75ꢀ7.57 (m, 4H), 7.50 (d, J = 2.7 Hz, 1H); C NMR (75 MHz, CDCl3) δ
157.2, 144.5, 140.3, 136.3, 132.1 (q, J = 33.1 Hz), 130.2, 129.8, 126.0 (d, J = 3.6 Hz), 123.5 (d, J = 3.8 Hz),
123.2 (d, J = 271.1 Hz), 118.5, 97.6; HRMSꢀEI: m/z 394.8769 [M+; calcd. for C12H6Br2F3NO+: 394.8768].
1
2
3
4
5
6
7
8
Methyl 4-(3,5-dibromo-2-oxopyridin-1(2H)-yl)benzoate (7j) General procedure I was used employing mesitꢀ
yl(4ꢀ(methoxycarbonyl)phenyl)iodonium triflate (0.325 mmol) and 3,5ꢀdibromopyridinꢀ2(1H)ꢀone (0.25 mmol),
and the reaction was completed in 6 h. Flash chromatography on silica gel using hexane/ethyl acetate (3:1) proꢀ
vided pure 7j (62.9 mg, 0.163 mmol, 65%) as a pale yellow solid. m.p: 183ꢀ185 °C; Rf 0.3 (hexane/ethyl aceꢀ
tate=2:1); IR(neat) 3854, 3743, 2354, 1659, 1561, 1281, 1105, 862, 723 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.17
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
13
(dd, J = 1.8 Hz and J = 6.9 Hz, 2H), 7.89 (d, J = 2.4 Hz, 1H), 7.51ꢀ7.46 (m, 3H), 3.95 (s, 3H); C NMR (75
MHz, CDCl3) δ 165.8, 157.1, 144.4, 143.5, 136.3, 130.83, 130.77, 126.3, 118.6, 97.5, 52.5; HRMSꢀEI: m/z
+
384.8948 [M+; calcd. for C13H9Br2NO3 : 384.8949].
3,5-dibromo-6'-chloro-2H-[1,3'-bipyridin]-2-one (7k) General procedure I was used employing mesityl(2ꢀ
chloropyridinꢀ5ꢀyl)iodonium triflate (0.325 mmol) and 3,5ꢀdibromopyridinꢀ2(1H)ꢀone (0.25 mmol) at 50 ℃, and
the reaction was completed in 1 h. Flash chromatography on silica gel using hexane/ethyl acetate (7:1−3:1) proꢀ
vided pure 7k (21.0 mg, 0.058 mmol, 23%) as a white solid and 7d (59.3 mg, 0.160 mmol, 64%) as a white solid.
1
m.p: 168ꢀ172 °C; Rf 0.36 (hexane/ethyl acetate=2:1); IR(neat) 3851, 3738, 3445, 2353, 1643, 751, 665 cmꢀ1; H
NMR (300 MHz, DMSOꢀd6) δ 8.57 (d, J = 2.6 Hz, 1H), 8.28 (d, J = 2.5 Hz, 1H), 8.18 (d, J = 2.6 Hz, 1H), 8.06
13
(dd, J = 2.8 Hz and J = 8.5 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H); C NMR (75 MHz, DMSOꢀd6) δ 157.2, 150.4,
148.5, 145.4, 139.1, 138.8, 136.5, 125.0, 116.8, 97.1; HRMSꢀEI: m/z 361.8456 [M+; calcd. for C10H5Br2ClN2O+:
361.8457].
3,5-dibromo-1-(thiophen-3-yl)pyridin-2(1H)-one (7l) General procedure I was used employing mesitꢀ
yl(thiophenꢀ3ꢀyl)iodonium triflate (0.325 mmol) and 3,5ꢀdibromopyridinꢀ2(1H)ꢀone (0.25 mmol), and the reacꢀ
tion was completed in 1 h. Flash chromatography on silica gel using hexane/ethyl acetate (9:1−7:1) provided pure
7l (61.1 mg, 0.182 mmol, 73%) as a pale yellow solid and 7d (11.1 mg, 0.030 mmol, 12%) as a white solid. m.p:
138ꢀ140 °C; Rf 0.67 (hexane/ethyl acetate=2:1); IR(neat) 3854, 3742, 2354, 1660, 1589, 1403, 1264, 859, 727
cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.84 (s, 1H), 7.59 (s, 1H), 7.47 (s, 1H), 7.38 (s, 1H), 7.22 (d, J = 4.5 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 156.8, 143.7, 137.4, 136.6, 125.9, 124.3, 120.4, 118.2, 97.0; HRMSꢀEI: m/z
332.8459 [M+; calcd. for C9H5Br2NOS+: 332.8459].
Procedure for synthesis of Pirfenidone 9 (5-methyl-1-phenylpyridine-2-(1H)-one)
A 10 mL round bottom flask was charged with diphenyliodonium hexafluorophosphate (0.325 mmol), CuCl (10
mol %), Et3N (0.5 mmol) and 5ꢀmethylpyridinꢀ2(1H)ꢀone (0.25 mmol). Toluene (2.5 mL) was then added to the
flask. The reaction mixture was stirred at room temperature under Ar. After 30 min, the solvent was removed in
vacuo and the residue was purified by flash column chromatography on silica gel using dichloroꢀ
16
ACS Paragon Plus Environment

Page 17 of 19
The Journal of Organic Chemistry
methane/methanol (30:1) provided pure Pirfenidone 9 (45.8 mg, 0.247 mmol, 99%) as a white solid. Rf 0.08
(hexane/ethyl acetate=2:1); 1H NMR (300 MHz, CDCl3) δ 7.50ꢀ7.44 (m, 2H), 7.43ꢀ7.35 (m, 3H), 7.26 (dd, J = 2.8
Hz and J = 9.3 Hz, 1H), 7.12ꢀ7.10 (m, 1H), 6.60 (d, J = 9.6 Hz, 1H), 2.10 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
161.6, 142.5, 141.0, 135.2, 129.2, 128.2, 126.5, 121.4, 114.7, 16.9; Data are consistent with those reported in the
literature.5b
1
2
3
4
5
6
7
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
ASSOCIATED CONTENT
Supporting Information
Copies of 1H and 13C spectra for all novel compounds prepared. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: wonsukk@ewha.ac.kr
Author Contributions
† S.ꢀH. Jung and D.ꢀB. Sung contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) (NRFꢀ
2015R1A1A1A05001334) and the New & Renewable Energy of the Korea Institute of Energy Technology Evaluation and Planning
(KETEP) grant (No. 20133030000210).
REFERENCES
(1) (a) Scudi, J. V.; Reisner, D. B.; Childress, S. J.; Walter, L. US2947755, 1960. (b) Young, S. D.; Anthony, N. J.;
Gomez, R. P.; Tran, L. O. WO9828980, 1998. (c) Moffat, D. C. F. WIPO, WO2007129036 A1, 2007. (d) Lv, Z.;
Sheng, C.; Wang, T.; Zhang, Y.; Liu, J.; Feng, J.; Sung, H.; Zhong, H.; Niu, C.; Li, K. J. Med. Chem. 2010, 53, 660ꢀ
668. (e) Hibi, S.; Ueno, K.; Nagato, S.; Kawano, K.; Ito, K.; Norimine, Y.; Takenaka, O.; Hanada, T.; Yonaga, M. J.
Med. Chem. 2012, 55, 10584ꢀ10600.
(2) (a) Azima, H.; Arthurs D.; Silver, A. Am. J. Psychiarty 1961, 118, 159ꢀ160. (b) Nakazato, H.; Oku, H.; Yamane, S.;
Tsuruta, Y.; Suzuki, R. Eur. J. Pharmacol. 2002, 446, 177ꢀ185. (c) Azuma, A. Expert Rev. Respir. Med. 2010, 4,
301ꢀ310. (d) Cho, M.; Kopp, J. B. Expert Opin. Investig. Drugs. 2010, 19, 275ꢀ283. (e) Schaefer. C. J.; Ruhrmund,
D. W.; Pan, L.; Seiwert, S. D.; Kossen, K. Eur. Respir. Rev. 2011, 20, 85ꢀ97.(f) Hoppner, A. C.; Fauser S.; Kerling
F. Epileptic Disord. 2013, 15, 362ꢀ364. (g) Dirani, M.; Nasreddine, W.; Abdulla, F.; Beydoun, A. Epilepsy Behav.
Case Rep. 2014, 2, 164ꢀ166.
(3) (a) Mederski, W. W. K. R.; Lefort, M.; Germann, M.; Kux, D. Tetrahedron 1999, 55, 12757ꢀ12770. (b) Lam, Y. S.
P.; Clark, C. G.; Sauber, S.; Adams, J.; Averill, K. M.; Chan, D. M. T.; Combs, A. Synlett 2000, 674ꢀ676. (c) Lam,
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 19
Y. S. P.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415ꢀ3418. (d) McElhinꢀ
ny, C. J.; Carroll, F. I.; Lewin, A. H. Synthesis 2012, 57ꢀ62. (e) Chen, T.; Luo, Y.; Hu, Y.; Yang, B. Lu, W. Eur. J.
Me. Chem. 2013, 64, 613ꢀ620.
1
2
3
4
5
6
7
8
(4) (a) Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G. Tetrahedron Lett. 2002, 43, 3091ꢀ3094. (b) Tsou, H.ꢀR.; Liu,
X.; Brinberg, G.; Kaplan, J.; Otteng, M.; Tran, T.; Kutterer, K.; Tang, Z.; Suayan, R. Zask, A.; Ravi, M.; Bretz, A.;
Grillo, M.; McGinnis, J. P.; Rabindran, S. K.; AyralꢀKaloustian, S.; Mansour, T. S. J. Med. Chem. 2009, 52, 2289ꢀ
2310.
(5) (a) Ikegai, K.; Nagata, Y.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2006, 79, 761ꢀ767. (b) Crifar, C.; Petiot, P.; Ahmad,
T. Gagnon, A. Chem. Eur. J. 2014, 20, 2755ꢀ2760.
9
(6) (a) Sugahara, M.; Ukita, T. Chem. Pharm. Bull. 1997, 45, 719ꢀ721. (b) Li, C. S.; Dixon, D. D. Tetrahedron Lett.
2004, 45, 4257ꢀ4260. (c) Altman, R. A.; Buchwald, S. L. Org Lett. 2007, 9, 643ꢀ646 and references cited therein.
(7) For a recent review, see: (a) Yosimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116, 3328ꢀ3435. (b) Aradi, K.; Tóth,
B. L.; Tolnai, G. L.; Novák, Z. Synlett 2016, 27, 1456ꢀ1485. (c) Olofsson, B. Top. Curr. Chem. 2016, 373, 135ꢀ166
and references cited therein.
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
(8) (a) Hickman, A. J.; Sanford, M. S. Nature 2012, 484, 177ꢀ185. (b) Casitas, A.; Ribas, X. Chem. Sci. 2013, 4, 2301ꢀ
2318.
(9) Moon, S.ꢀY.; Koh, M.; Rathwell, K.; Jung, S.ꢀH.; Kim, W.ꢀS. Tetrahedron 2015, 71, 1566ꢀ1573.
(10)Chen, T.; Huang, Q.; Luo, Y.; Hu, Y.; Lu, W. Tetrahedron Lett. 2013, 54, 1401ꢀ1404.
(11)(a) Kalayani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330ꢀ7331. (b) Kuriyaꢀ
ma, M.; Hamaguchi, N.; Onomura, O. Chem. - Eur. J. 2012, 18, 1591ꢀ1594. (c) Malmgren, J.; Santoro, S.; Jalalian,
N.; Himo, F.; Olofsson, B. Chem. Eur. J. 2013, 19, 10334ꢀ10342. (d) Collins, B. S. L.; Suero, M. G.; Gaunt, M. J.
Angew. Chem. Int. Ed. 2013, 52, 5799ꢀ5802.
(12)(a) Raghu, G.; Johnson, W. C.; Lockhart, D.; Mageto, Y. Am. J. Respir. Crit. Care. Med. 1999, 159, 1061ꢀ1069. (b)
Dosanjh, A. Eur. J. Pharmacol. 2006, 536, 219ꢀ222. (c) du Bois, R. M. Nature Rev. Drug. Discov. 2010, 9, 129ꢀ140.
(d) Richeldi, L.; Yasothan U. Kirkpatrick, P. Nature Rev. Drug. Discov. 2011, 10, 489ꢀ490.
(13)(a) Abd El Kader, K. F.; El Bialy, S. A. A.; ElꢀAshmawy, M. B.; Boykin, D. W. Heterocycl. Commun. 2012, 18,
193ꢀ197. (b) Taniguchi, T.; Hayashi, K.; Morizawa, Y. WO03014087, 2003. (c) Gant, T. G.; Sarshar, S.
WO2008157786, 2008.
(14)(a) Sieburth, S. M.; Lin, C. H.; Rucando, D. J. Org. Chem. 1999, 64, 950ꢀ953. (b) Li, L.; Degardin, M.; Lavergne,
T.; Malyshev, D. A.; Dhami, K.; Ordoukhanian, P.; Romesberg, F. E. J. Am. Chem. Soc. 2014, 136, 826ꢀ829.
(15)(a) Bielawski, M.; Olofsson, B. Chem. Commun. 2007, 2521ꢀ2523. (b) Bielawski, M.; Aili, D.; Olofsson, B. J. Org.
Chem. 2008, 73, 4602ꢀ4607. (c) Bielawski, M.; Zhu, M.; Olofsson, B. Adv. Synth. Catal. 2007, 349, 2610ꢀ2618. (d)
Monastyrskyi, A.; Namelikonda, N. K.; Manetsch, R. J. Org. Chem. 2015, 80, 2513ꢀ2520. (e) Bedford, R. B.;
Webster, R. L.; Mitchell, C. J. Org. Biomol. Chem. 2009, 7, 4853ꢀ4857. (f) Nikolaienko, P.; Yildiz, T.; Ruepin, M.
Eur. J. Org. Chem. 2013, 15, 5134ꢀ5137.
(16)Londregan, A. T. ; Jennings, S. ; Wei, L. Org. Lett. 2011, 13, 1840ꢀ1843.
18
ACS Paragon Plus Environment

Page 19 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
Table of Contents Graphic
7
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
19
ACS Paragon Plus Environment