Ligand-enabled, copper-promoted regio- and chemoselective hydroxylation of arenes, aryl halides, and aryl methyl ethers

Article abstract of DOI:10.1021/acs.joc.5b02302

We report here a practical method for the ortho C-H hydroxylation of benzamides with inexpensive copper(II) acetate monohydrate and a pyridine ligand. An intra- and intermolecular ligand combination was explored to achieve regio- and chemoselective hydroxylation. Interestingly, typical regiochemical scrambling associated with the C-H activation was further resolved by introducing a ligand-directed ortho hydroxylation of haloarenes and aryl methyl ethers.

Full text of DOI:10.1021/acs.joc.5b02302

Subscriber access provided by NEW MEXICO STATE UNIV
Article
A Ligand-Enabled, Copper-Promoted Regio- and Chemoselective
Hydroxylation of Arenes, Aryl Halides, and Aryl Methyl Ethers
Bijaya Kumar Singh, and Ranjan Jana
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02302 • Publication Date (Web): 13 Jan 2016
Downloaded from http://pubs.acs.org on January 14, 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 32
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
A Ligand-Enabled, Copper-Promoted Regio- and Chemoselective
Hydroxylation of Arenes, Aryl Halides, and Aryl Methyl Ethers
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
Bijaya Kumar Singh and Ranjan Jana*
Organic and Medicinal Chemistry Division, CSIRꢀIndian Institute of Chemical Biology,
4 Raja S. C. Mullick Road, Jadavpur, Kolkataꢀ700032, West Bengal, India
Academy of Scientific and Innovative Research, Kolkata
Fax: (+91) 33 2473 5197; Eꢀmail: rjana@iicb.res.in
Abstract: We report here a practical method for the ortho CꢀH hydroxylation of benzamides with
inexpensive copper(II) acetate monohydrate and pyridine ligand. An intraꢀ and intermolecular ligand
combination was explored to achieve regioꢀ and chemoselective hydroxylation. Interestingly, typical
regiochemical scrambling associated with the CꢀH activation was further resolved by introducing a
ligandꢀdirected ortho hydroxylation of haloarenes and aryl methyl ethers.
INTRODUCTION
A paradigm shift from “innate” to “guided” CꢀH activation has been observed in the last decades for
the development of high utility synthetic methods.1 The use of ligands to control reactivity and
selectivity in transition metal catalyzed CꢀH functionalization is emerging.2 While the intramolecular
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 32
1
2
3
4
5
6
7
8
9
ligands direct the site of CꢀH functionalization,3 the external ligands control the chemoꢀ,4 and
stereoselectivity5 of the transformations. Owing to their importance in pharmaceuticals, agrochemicals,
polymer, and materials industry, considerable attention has been dedicated to the synthesis of phenolic
compounds directly from hydrocarbons (Figure 1).6 Following the seminal report by Jintoku, Fujiwara,
and coꢀworkers, numerous noble metal such as Pd, and Ruꢀcatalyzed direct acetylation/hydroxylation of
arenes have been reported.7 However, expensive noble metal catalysts are not attractive to the largeꢀ
scale industrial processes. Alternatively, copper has attracted much attention due to earthꢀabundance,
lowꢀcost, and the distinct reactivity of copperꢀcontaining metalloenzymes toward oxidation.8 The Yu
group reported a copper(II) mediated ortho CꢀH acetoxylation/hydroxylation using a nonꢀremovable
pyridine moiety.9a and removable oxazolyamide group with moderate yields.9b A copper(II)ꢀmediated
ortho hydroxylation of arenes and heteroarene carboxylates using removable 2ꢀ(pyridineꢀ2ꢀyl)isopropyl
(PIP) ligand was reported by the Shi group.10 However this method is limited due to the use of
expensive directing group, super stoichiometric silver(I) salt and moisture sensitive
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
tetrabutylammonium salt. In recent years, a plethora of copperꢀcatalyzed/mediated C(sp2)ꢀH
functionalization using cheap and commercially available 8ꢀaminoquinoline has been reported.11 In fact,
a discrete example of copper(II)/silver(I)ꢀmediated C(sp2)ꢀH acetoxylation in moderate yield (40%)
using 8ꢀaminoquinoline was also reported by Kuninobu and Kanai group.11g
Figure 1. Biologically active salicylic acid derivatives
We report here a practical, operationally simple, and commercially available 8ꢀaminoquinolineꢀ
directed ortho hydroxylation of benzamides using inexpensive copper(II) acetate monohydrate and
pyridine ligand without any additional oxidants or additives. We also report for the first time, a highly
2
ACS Paragon Plus Environment

Page 3 of 32
The Journal of Organic Chemistry
1
2
3
4
ortho selective hydrolysis of bromo, chloro, and methoxy groups, keeping the other regioisomers intact
5
6
7
(Scheme 1).
8
9
Scheme 1. Regio and Chemoselective Hydroxylation
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
RESULTS AND DISCUSSION
Considering the ability of bidentate monoanionic ligands to stabilize higher oxidation states of metals,
we chose Daugulis’s 8ꢀaminoquinoline derived benzamide, 1a, as a model substrate for reaction
optimization.3a Heating a mixture of 1a with 1.0 equiv of copper(II) acetate monohydrate in acetonitrile
at 100 oC afforded 15% of the desired hydroxylation product. After rigorous screening, we found that
the hydroxylation product was formed almost quantitatively in DMSO. We also observed that
substitution on the benzamide has a prominent effect on chemoselectivity. Although, oꢀCF3 resulted in
hydroxylation product exclusively, the mꢀCF3 afforded a mixture of hydroxylation and homocoupling
product, and the pꢀCF3 provided homocoupling product exclusively. We hypothesized that
coordinatively unsaturated copper may undergo further intermolecular CꢀH insertion and reductive
elimination to form the homocoupling product. Therefore, addition of external ligands may stabilize the
monomeric species and facilitate intramolecular reductive elimination to provide acetoxylation product
first, which will hydrolyse in situ to provide phenolic compounds. Gratifyingly, using 1,10ꢀ
phenanthroline (2.0 equiv) hydroxylation product was formed almost quantitatively (entry 10, Table 1).
Considering the industrial viability, expensive 1,10ꢀphenanthroline was successfully replaced by cheap
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 32
1
2
3
4
5
6
7
8
9
and abundant pyridine ligand. The DMSO was found to be essential for this transformation and the
yield of the desired hydroxylation product was improved to some extent by using a mixture DMSO and
DMF (1:3) (entry 7 vs 8, Table 1). Finally, heating the reaction mixture with excess (10 equiv) pyridine
in a mixture of DMSO/DMF (1:3) at 100 oC afforded the desired hydroxylation product quantitatively
and selectively (entry, 13, Table 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
Table 1. Optimization of Reaction Conditionsa,b
R
QHN
O
O
NHQ
H
O
NHQ
OH
Cu(OAc)2 H2O
(1.0 equiv)
+
ligand, solvent
O
NHQ
100 o
C
R
R
R
1
2
3
entry
R
ligand
solvent
DMF
yield (%)
2/3c
1
2
3
4
5
6
7
H
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
0
ꢀ
H
H
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
15
99
80
70
65
85
>20:1
>20:1
>20:1
1:20
oꢀCF3
mꢀCF3
pꢀCF3
pꢀCF3
>1:20
7:1
1,10ꢀphen
(1.2 equiv)
1,10ꢀphen
(1.2 equiv)
1,10ꢀphen
(1.5 equiv)
1,10ꢀphen
(2.0 equiv)
pyridine
(2.0 equiv)
pyridine
(5.0 equiv)
pyridine
8
pꢀCF3
pꢀCF3
pꢀCF3
pꢀCF3
pꢀCF3
p-CF3
mꢀCF3
H
DMSO/
DMF (1:3)
DMSO/
DMF (1:3)
DMSO/
DMF (1:3)
DMSO/
DMF (1:3)
DMSO/
DMF (1:3)
DMSO/
DMF (1:3)
DMSO/
DMF (1:3)
DMSO/
88
91
96
85
90
96
98
99
10:1
20:1
9
10
11
12
13
14
15
>20:1
2:1
3:1
>20:1
>20:1
>20:1
(10 equiv)
pyridine
(10 equiv)
pyridine
(10 equiv)
DMF (1:3)
aAll reactions were carried out in 0.1 mmol scale, 0.1 M. bYields refer to here are overall isolated yields.
cProduct distribution was determined by 1H NMR of the crude product. Q = 8ꢀquinoline.
Under the optimized reaction conditions, we explored the substrate scope of CꢀH hydroxylation. A
wide variety of substituents at the para position such as alkyl, phenyl, alkoxy, trifluoromethyl, acyl,
4
ACS Paragon Plus Environment

Page 5 of 32
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
even halogens such as fluoro, chloro, bromo, and iodo were compatible under the reaction conditions
(Scheme 2). Various substituents at the ortho position such as trifluoromethyl, fluoro, nitro, methyl, and
thiomethyl were also intact (2fꢀ2j, Scheme 2). Interestingly, pyridylꢀ4ꢀcarboxamide afforded
hydroxylation product in high yield. Of note, in all cases the monohydroxylation products were formed
exclusively even with higher copper loading. The halogen substituents on the product could be useful
for further manipulations.
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 2. Scope of benzamides in C-H hydroxylationa,b
aConditions: Benzamides (0.2 mmol), Cu(OAc)2·H2O (0.2 mmol), pyridine (2.0 mmol), DMF/DMSO
(3:1, 2ml), 100 oC, 2 h. bYields refer to the average isolated yields of at least two experiments.
During the course of this study, we observed that the steric and electronic parameters of the meta
substitution play an important role in the product selectivity. For example, electron donating groups
such as methyl, methoxy, and even bromo led to the formation of both regioisomers of the
hydroxylation products (Scheme 3). Interestingly, the electron withdrawing trifluoromethyl group
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 32
1
2
3
4
5
6
7
8
9
provided a single hydroxylation product quantitatively. The bulky aryl substituents also afforded a
single isomer of the desired hydroxylation product at the sterically less hindered side.
Scheme 3. Regiochemical Scrambling in C-H Hydroxylation
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
H
O
O
OH
O
std. reaction
conditions
R
R
NHQ
R
NHQ
NHQ
+
C-H
hydroxylation
H
OH
2v-2aa
1v-1aa
2v'-2x'
R = Me, 94% yield, (2v:2v' = 60:40)
R = OMe, 70% yield (2w:2w' = 57:43)
R= Br, 88% yield (2x:2x' = 50:50)
R = CF3, 98% yield, 2y only
R = p-tolyl, 98% yield, 2z only
R = 2,4-difluorophenyl, 94% yield, 2aa only
Conditions: Benzamides (0.2 mmol), Cu(OAc)2·H2O (0.2 mmol), pyridine (2.0 mmol), DMF/DMSO
(3:1, 2ml), 100 oC, 2 h.
To overcome this regioselectivity issue, we introduced the concept of ligandꢀdirected CꢀX
hydroxylation. We observed that ortho chloroꢀ or bromoꢀ containing benzamides hydrolysed to the
corresponding phenol in preference to the CꢀH hydroxylation under the optimized reaction conditions.
However, ortho iodo resulted in a complex mixture of products. More interestingly, the ortho methoxy
group also hydrolysed to the corresponding phenol in high yield. Being encouraged by these
unprecedented results, we intended to extend this ligandꢀdirected CꢀX hydroxylation to the dihalo and
inexpensive polymethoxy benzamides. Contrary to the conventional CꢀX hydroxylation,12 it was
observed that chloro, bromo or methoxy groups were hydrolysed selectively at the ortho position while
the same functional groups at the meta and para position remain intact. This directed CꢀX hydroxylation
strategy could be a potential solution to the regiochemical scrambling as observed in CꢀH hydroxylation
(1vꢀ1x, Scheme 3 vs entries 7,8, Table 2). Particularly, 3ꢀbromobenzamide 1x furnished an inseparable
mixture of 2x and 2x’ (Scheme 3) which is not synthetically useful. But 2,5ꢀdibromo benzamide (entry
8, Table 2) afforded a single hydroxylation product in excellent yield. More interestingly, 2,3ꢀdichloro
and 2,4,5ꢀtrimethoxy benzamides provided hydroxylation selectively at the sterically more hindered
side (entry 6,11, Table 2) whereas in such situations, CꢀH hydroxylation occurs preferably at the less
hindered side.
6
ACS Paragon Plus Environment

Page 7 of 32
The Journal of Organic Chemistry
1
2
3
4
Table 2. Scope of ortho CꢀX hydroxylationa,b
5
6
7
8
O
O
Cu(OAc)2 H2O (1.0 equiv)
pyridine (10.0 equiv)
DMF:DMSO (3:1)
110 oC, 12 h
N
N
H
H
N
N
X
OH
X
X
9
entry
substrate
O
product
O
yield (%)
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
2a
: X = Cl, 66
1ab
1ac
: X = Cl
: X = Br
: X = OMe
1
2
3
NHQ
NHQ
2a: X = Br, 80
c
1ad
2a
: X = OMe, 56
X
OH
X
O
X
O
c
2ab
2ac
: X = Cl, 62
1ae
1af
: X = Cl
: X = OMe
4
5
NHQ
NHQ
NHQ
: X = OMe, 0
X
OH
O
O
NHQ
1ag
: X = Cl
2ad
2w'
: X = Cl, 51
: X = OMe, 79
6
7
1ah: X = OMe
X
OH
X
X
O
O
Br
Br
NHQ
NHQ
1ai
2x
8
9
91
Br
OH
O
O
NHQ
NHQ
1aj
2ae
67
MeO
Br
OMe
MeO
OH
O
O
NHQ
NHQ
OH
10
11
1ak
2d
64
88
OMe
O
Br
O
NHQ
NHQ
OH
1al
2af
MeO
OMe
MeO
OMe
OMe
aConditions: Benzamides (0.2 mmol), Cu(OAc)2·H2O (0.2 mmol), pyridine (2.0 mmol), DMF/DMSO
(3:1, 2ml), 100 oC, 12 h. bYields refer to the average isolated yields of at least two experiments.
cUnreacted starting materials were recovered.
The Miura group reported a copperꢀmediated homocoupling of thiopheneꢀ2ꢀcarboxylates using 8ꢀ
aminoquinoline as directing group.13 We also examined the ligand directed dimerization of benzamides.
As expected, in the absence of pyridine the paraꢀsubstituted substrates afforded dimerization products
in good yields with minor hydroxylation products (Scheme 4).14
Scheme 4. Scope of Directed Homocoupling
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 32
1
2
3
4
5
6
7
8
9
R
O
NHQ
OH
QHN
O
O
NHQ
Cu(OAc)2 H2O (1.0 equiv)
+
DMSO
100 oC, 2 h
O
NHQ
R
R
R
3b:
3c:
3d:
R = Cl, 66%
R = Br, 68%
R = CF3, 65%
2c:
2d:
2o:
17%
15%
20%
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
To demonstrate the synthetic utility of the present protocol, the hydroxylation product 2aa was heated
in conc HCl to provide a nonꢀsteroidal antiꢀinflammatory drug (NSAID) diflunisal, 4a in excellent
yield. The 8ꢀaminoquinoline was also recovered in almost quantitative yield (Scheme 5).
Scheme 5. Synthesis of diflunisal
O
NHQ
OH
O
OH
OH
conc HCl
110 oC, 24 h
H2N
+
N
F
F
F
F
2aa
4a
4b,
94%
recovered
, 88%
Diflunisal
INVESTIGATION OF THE REACTION MECHANISM
We have performed several control experiments to clarify the mechanism of the hydroxylation
reaction (see Scheme 6). The kinetics of the hydroxylation reaction was measured with 1a and the
corresponding d5-1a. The high value of the intermolecular kinetic isotope effect (kH/kD = 3.6) indicates
that the reaction may involve a rateꢀlimiting concerted metalationꢀdeprotonation (CMD) (Eq 1, Scheme
6). In addition, 2,2,6,6ꢀtetramethylpiperidineꢀNꢀoxyl (TEMPO) has no significant effect on the reaction
outcome eliminating the radical pathway (Eq 2, Scheme 6). The OAc group was hydrolysed under the
reaction conditions but not during work up indicating that initially CꢀH acetoxylation occurs, and the
acetate is hydrolysed to the corresponding phenol in situ (Eq 3, Scheme 6). The 8ꢀaminoquinoline as
directing group is crucial for the chemoꢀ and regioselective hydroxylation under the present reaction
conditions since no hydroxylation product was obtained from the corresponding Nꢀphenylbenzamide or
2ꢀiodoꢀNꢀphenylbenzamide (Eq 4, 5, Scheme 6). Presumably, the directing group helps to bring copper
in close proximity to the CꢀX (X = Cl, Br, I) bonds for the oxidative addition. Subsequently, reductive
8
ACS Paragon Plus Environment

Page 9 of 32
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
elimination of the copper species results in the acetoxylation product which is hydrolysed in situ to
provide the desired hydroxylation product. From a control experiment it was evident that in the absence
of pyridine ligand no hydroxylation product from the corresponding aryl methyl ether was observed
which could be indicative for copper/pyridine mediated hydrolysis of the methyl ether. However, the
exact mechanism of methyl ether hydrolysis and dimerization is not clear at this moment.
Scheme 6. Control Experiments
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
CONCLUSION
In conclusion, we have developed a regioꢀ and chemoselective hydroxylation of benzamides combining
ligandꢀdirected and ligandꢀenabled strategy. The inherent regiochemical scrambling associated with Cꢀ
H bond activation was resolved via ligandꢀdirected ortho CꢀX (X = Cl, Br, OMe) bond hydroxylation.
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 32
1
2
3
4
5
6
7
8
9
The use of external ligand also enables a switch from homocoupling to hydroxylation product. An
inexpensive catalyst, reproducibility on gramꢀscale, removal and recovery of the directing group, etc.,
are the attractive features of the present protocol.
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
EXPERIMENTAL SECTION
General Information
Melting points were determined in open endꢀcapillary tubes and are uncorrected. TLC was performed
on silica gel plates (Merck silica gel 60, f254), and the spots were visualized with UV light (254 and
1
365 nm) and KMnO4 stain. H and 13C NMR spectra were recorded in CDCl3 or DMSOꢀd6 solvent
using TMS as the internal standard. HRMS (m/z) were measured using EI (magnetic sector, positive
ion) and ESI (QꢀTOF, positive ion) techniques. Infrared (IR) spectra were recorded on Fourier
transform infrared spectroscopy; only intense peaks were reported.
General Experimental Procedure for Amide Formation
The benzamides were prepared following the previous literature procedure:15 To a solution of N'ꢀ(3ꢀ
dimethylaminopropyl)ꢀNꢀethylcarbodimide, hydrochloride salt (EDC.HCl) (1.3 equiv.), 4ꢀN, Nꢀ
dimethylaminopyridine (DMAP) (0.1 equiv) and carboxylic acid (1.2 equiv) in CH2Cl2 (5.0 mL, for 1
mmol of 8ꢀaminoquinoline) was stirred under nitrogenatmosphere followed by 8ꢀaminoquinoline (720
mg, 5 mmol, 1.0 equiv) was added slowly at room temperature. The resulting reaction mixture was
stirred for overnight. After completion of reaction as indicated by TLC, the reaction mixture was
quenched with 1N HCl followed by extracted with CH2Cl2, brine solution. The organic layer was
separated and washed with saturated aqueous solution of NaHCO3 and brine. The organic layer was
dried over Na2SO4. Solvent was evaporated under vacuum. The crude residue was purified using
column chromatography on silica gel.
10
ACS Paragon Plus Environment

Page 11 of 32
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The benzamides (1a, 1b, 1d, 1f, 1h, 1i, 1k, 1y,1ab11i, 1c, 1l, 1s, 1t11d, 1e23, 1g21, 1o, 1ac22, 1q, 1r, 1v11l,
1w, 1x20, 1ad19,1ag11n, 1h7o,1aj11j, 1am17, 1ap16, 1aq18) were synthesized according to the above
general procedure and spectral data are consistent with the reported values.
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-(methylthio)-N-(quinolin-8-yl)benzamide, 1j. Column chromatography (SiO2, eluting with 9:1
1
hexane/ethyl acetate) afforded the desired product as a white solid, (1.29 g, 88%). H NMR (300 MHz,
CDCl3): δ 10.48 (s, 1H), 8.97 (dd, J = 7.2, 1.8 Hz, 1H), 8.80 (dd, J = 4.2, 1.8 Hz, 1H), 8.18 (dd, J = 8.4,
1.8 Hz, 1H), 7.77 (dd, J = 7.5, 1.2 Hz, 1H), 7.63ꢀ7.56 (m, 2H), 7.54ꢀ7.39 (m, 3H), 7.32ꢀ7.27(m, 1H),
2.51 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 166.5, 148.2, 138.7, 138.6, 136.3, 135.1, 134.6, 130.9,
128.1, 127.9, 127.4, 126.7, 124.9, 121.8, 121.6, 116.7, 16.5; HRMS (ESI, m/z) calcd. for
C17H14N2OSNa [M + Na]+: 317.0725; found: 317.0723.
2',4'-difluoro-N-(quinolin-8-yl)-[1,1'-biphenyl]-4-carboxamide,
yl)benzamide (327 mg, 1.0 mmol) was taken in an oven dried round bottom flask which was connected
through condenser under N2 atmosphere and dissolved with 3 ml DMF, then (2,4ꢀ
1m.
4ꢀbromoꢀNꢀ(quinolinꢀ8ꢀ
difluorophenyl)boronic acid (316 mg, 2.0 mmol, 2.0 equiv.) , K2CO3 (207 mg, 1.5 mmol, 1.5 equiv.),
Pd(PPh3)4 (57.8 mg, 0.05 equiv.) was added in it under nitrogen atmosphere at room temperature. Then,
o
it was stirred over night at 120 C. The reaction mixture was extracted with ethyl acetate and brine
solution. The desired organic phase was dried over Na2SO4, filtered and evaporated through vacuo. The
crude mixture was purified by Column chromatography (SiO2, eluting with 8:2 hexane/ethyl acetate)
1
afforded the desired product as a white solid, (306 mg, 85%). H NMR (300 MHz, CDCl3): δ 10.81 (s,
1H), 8.96 (d, J = 7.2 Hz, 1H), 8.87 (s, 1H), 8.22ꢀ8.16 (m, 3H), 7.71ꢀ7.44 (m, 6H), 7.04ꢀ6.93 (m, 2H);
13C NMR (75 MHz, CDCl3): δ 164.9, 148.3, 138.7, 138.4, 136.4, 134.3 (d, J = 18.0 Hz), 131.4, 131.3,
131.3, 129.2 (d, J = 3.0 Hz), 128.0, 127.5 (d, J = 6.0 Hz), 121.74, 121.69, 116.5, 111.8 (d, J = 25.5
Hz),104.6 (t, 25.5 Hz); HRMS (ESI, m/z) calcd. for C22H14F2N2ONa [M + Na]+: 383.0972; found:
383.0972.
4-acetyl-N-(quinolin-8-yl)benzamide, 1n. Column chromatography (SiO2, eluting with 7:3
1
hexane/ethyl acetate) afforded the desired product as a white solid, (1.16 g, 80%). H NMR (300 MHz,
CDCl3): δ 10.82 (s, 1H), 8.94 (dd, J = 6.9, 2.1 Hz, 1H), 8.87 (dd, J = 4.5, 1.8 Hz, 1H), 8.28ꢀ8.11 (m,
5H), 7.65ꢀ7.57 (m, 2H), 7.51 (dd, J = 8.4, 4.2 Hz, 1H), 2.69 (s, 3H); 13C NMR (75 MHz, CDCl3): δ
197.4, 164.3, 148.4, 139.3, 138.9, 138.7, 136.4, 134.2, 128.7, 128.0, 127.6, 127.4, 122.1, 121.8, 116.7,
26.9; HRMS (ESI, m/z) calcd. for C18H14N2O2Na [M + Na]+: 313.0953; found: 313.0936.
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 32
1
2
3
4-(pentyloxy)-N-(quinolin-8-yl)benzamide, 1p. Column chromatography (SiO2, eluting with 8:2
4
5
6
1
hexane/ethyl acetate) afforded the desired product as a white solid, (1.40 g, 84%). H NMR (300 MHz,
7
8
9
CDCl3): δ 10.68 (s, 1H), 8.91 (dd, J = 7.5, 0.9 Hz, 1H), 8.85 (dd, J = 4.2, 1.2 Hz, 1H), 8.18 (dd, J = 6.5,
1.2 Hz, 1H), 8.05 (d, J = 8.7 Hz, 2H), 7.62ꢀ7.54 (m, 2H), 7.51ꢀ7.45 (m, 1H), 7.02 (d, J = 8.7 Hz, 2H),
4.04 (t, J = 6.6 Hz, 2H), 1.88ꢀ1.79 (m, 2H), 1.52ꢀ1.35 (m, 4H), 0.95(t, J = 7.2 Hz, 3H); 13C NMR (75
MHz, CDCl3): δ 165.0, 162.1, 148.2, 138.7, 136.3, 134.8, 129.1, 128.0, 127.5, 127.1, 121.6, 121.3,
116.3, 114.4, 68.2, 28.8, 28.1, 22.4, 14.0; HRMS (ESI, m/z) calcd. for C21H22N2O2Na [M + Na]+:
357.1579; found: 357.1581.
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
4-pentyl-N-(quinolin-8-yl)benzamide, 1u. Column chromatography (SiO2, eluting with 9:1
1
hexane/ethyl acetate) afforded the desired product as a white solid, (1.37 g, 86%). H NMR (300 MHz,
CDCl3): δ 10.73 (s, 1H), 8.94 (dd, J = 7.2, 0.9 Hz, 1H), 8.85 (dd, J = 4.2, 1.2 Hz, 1H), 8.18 (dd, J = 8.4,
2.1 Hz, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.62ꢀ7.52 (m, 2H), 7.50ꢀ7.45 (m, 1H), 7.35 (d, J = 8.1 Hz, 2H),
13
2.70 (t, J = 7.5 Hz, 2H), 1.69ꢀ1.62 (m, 2H), 1.37ꢀ1.32 (m, 4H), 0.91 (t, J = 6.6 Hz, 3H); C NMR (75
MHz, CDCl3): δ 165.4, 148.2, 147.3, 138.7, 136.3, 134.7, 132.7, 132.5, 128.8, 127.9, 127.4, 127.34,
127.28, 121.6, 121.5, 116.4, 35.8, 31.42, 30.9, 22.5, 14.0; HRMS (ESI, m/z) calcd. for C21H22N2ONa
[M + Na]+: 341.1630; found: 341.1640.
4'-methyl-N-(quinolin-8-yl)-[1,
1'-biphenyl]-3-carboxamide,
1z.
3ꢀbromoꢀNꢀ(quinolinꢀ8ꢀ
yl)benzamide (327 mg, 1.0 mmol) was taken in an oven dried round bottom flask which was connected
through condenser under N2 atmosphere and dissolved with 3 ml DMF, then pꢀtolylboronic acid (272
mg, 2.0 mmol, 2.0 equiv.) , K2CO3 (207 mg, 1.5 mmol, 1.5 equiv.), Pd(PPh3)4 (57.8 mg, 0.05 equiv.)
was added in it under nitrogen atmosphere at room temperature. Then, it was stirred over night at 120
oC. The reaction mixture was extracted with ethyl acetate and brine solution. The desired organic phase
was dried over Na2SO4, filtered and evaporated through vacuo. The crude mixture was purified by
Column chromatography (SiO2, eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a
1
white solid, (284 mg, 84%). H NMR (300 MHz, CDCl3): δ 10.79 (s, 1H), 8.97 (d, J = 6.0 Hz, 1H), 8.85
(d, J = 3.9 Hz, 1H), 8.23 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.79 (d, J = 7.5 Hz,
1H), 7.63ꢀ7.54 (m, 5H), 7.48 (dd, J = 8.4, 4.2 Hz, 1H), 7.31 (d, J = 7.8 Hz, 2H), 2.43 (s, 3H); 13C NMR
(75 MHz, CDCl3): δ 165.3, 148.2, 141.6, 138.6, 137.5, 137.2, 136.2, 135.6, 134.4, 130.2, 129.5, 129.0,
127.8, 127.3, 126.9, 125.9, 125.4, 121.62, 121.55, 116.4, 21.0; HRMS (ESI, m/z) calcd. for
C23H18N2ONa [M + Na]+: 361.1317; found: 361.1317.
2',4'-difluoro-N-(quinolin-8-yl)-[1,1'-biphenyl]-3-carboxamide,
1aa.
3ꢀbromoꢀNꢀ(quinolinꢀ8ꢀ
yl)benzamide (327 mg, 1.0 mmol) was taken in an oven dried round bottom flask which was connected
12
ACS Paragon Plus Environment

Page 13 of 32
The Journal of Organic Chemistry
1
2
3
through condenser under N2 atmosphere
and dissolved with 3 ml DMF, then (2,4ꢀ
4
5
6
7
8
9
difluorophenyl)boronic acid (316 mg, 2.0 mmol, 2.0 equiv.) , K2CO3 (207 mg, 1.5 mmol, 1.5 equiv.),
Pd(PPh3)4 (57.8 mg, 0.05 equiv.) was added in it under nitrogen atmosphere at room temperature. Then,
o
it was stirred over night at 120 C. The reaction mixture was extracted with ethyl acetate and brine
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
solution. The desired organic phase was dried over Na2SO4, filtered and evaporated through vacuo. The
crude mixture was purified by Column chromatography (SiO2, eluting with 8:2 hexane/ethyl acetate)
1
afforded the desired product as a white solid, (293 mg, 82%). H NMR (300 MHz, CDCl3): δ 10.80 (s,
1H), 8.97 (dd, J = 7.2, 1.5 Hz, 1H), 8.88 (dd, J = 4.2, 1.5 Hz, 1H), 8.24ꢀ8.21 (m, 2H), 8.11ꢀ8.07 (m,
1H), 7.77ꢀ7.73 (m, 1H), 7.68ꢀ7.57 (m, 3H), 7.55ꢀ7.49 (m, 2H), 7.06ꢀ6.95 (m, 2H); 13C NMR (150 MHz,
CDCl3): δ 165.2, 162.6 (dd, J = 247.5, 11.9 Hz), 159.8 (dd, J = 249.0, 12.0 Hz), 148.3, 138.8, 136.4,
135.7 (d, J = 3.0 Hz), 134.5, 132.3 (d, J = 4.5 Hz), 131.5 (dd, J = 9.0, 4.5 Hz), 128.9, 128.0 (d, J = 1.5
Hz), 127.4, 126.3, 124.4 (dd, J = 13.5, 4.5 Hz), 121.8, 121.7, 116.6, 111.8 (dd, J = 21.0, 3.0 Hz), 104.5
(t, J = 25.5 Hz); HRMS (ESI, m/z) calcd. for C22H14F2N2ONa [M + Na]+: 383.0972; found: 383.0972.
2, 6-dichloro-N-(quinolin-8-yl)benzamide, 1ae. In an oven dried 100 ml round bottom (r.b.) flask, 2,
6ꢀdichlorobenzoic acid (764 mg, 4.0 mmol) was taken and 10 ml DCM and DMF (5 drops) were added
in it, ice bath was kept under r.b. flask, then oxyl chloride (0.4 ml, 4.8 mmol, 1.2 equiv.) was slowly
added, after completion of addition, the reaction mixture was stirred at room temperature for 3hrs. Then
the solvent and excess oxyl chloride was removed through vacuo, then, 15 ml DCM, Et3N (1.2 ml, 8.0
mmol, 2 equiv.) were added followed by 8ꢀaminoquinoline (692 mg, 4.8 mmol, 1.2 equiv.) at 0 oC, and
kept stirring over night at r.t. The reaction mixture was quenched with sat. aq. NaHCO3 and the organic
layer was separated and washed with 1N HCl aq. (50ml). Then the organic layer was dried over
Na2SO4, filtered and evaporated through vacuo. The desired crude was purified through Column
chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white
1
solid, (822 mg, 65%). H NMR (300 MHz, CDCl3): δ 10.05 (s, 1H), 8.97 (dd, J = 6.3, 2.7 Hz, 1H), 8.78
(dd, J = 3.6, 1.5 Hz, 1H), 8.20 (dd, J = 8.4, 1.8 Hz, 1H), 7.66ꢀ7.59 (m, 2H), 7.47 (dd, J = 8.4, 4.2 Hz,
1H), 7.43ꢀ7.40 (m, 2H), 7.37ꢀ7.31 (m, 1H); 13C NMR (75 MHz, CDCl3): δ 162.7, 148.4, 138.4, 136.4,
136.2, 134.0, 132.5, 130.9, 128.2, 128.0, 127.4, 122.5, 121.8, 117.2; HRMS (ESI, m/z) calcd. for
C16H10Cl2N2ONa [M + Na]+: 339.0068; found: 339.0068.
2,6-dimethoxy-N-(quinolin-8-yl)benzamide, 1af. In an oven dried 100 ml round bottom (r.b.) flask, 2,
6ꢀdimethoxybenzoic acid (728 mg, 4.0 mmol) was taken and 10 ml DCM and DMF (5 drops) were
added in it, ice bath was kept under r.b. flask, then oxyl chloride (0.4 ml, 4.8 mmol, 1.2 equiv.) was
slowly added, after completion of addition, the reaction mixture was stirred at room temperature for
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 32
1
2
3
3hrs. Then the solvent and excess oxyl chloride was removed through vacuo, then, 15 ml DCM, Et3N
(1.2 ml, 8.0 mmol, 2 equiv.) were added followed by 8ꢀaminoquinoline (692 mg, 4.8 mmol, 1.2 equiv.)
at 0 oC, and kept stirring over night at r.t. The reaction mixture was quenched with sat. aq. NaHCO3 and
the organic layer was separated and washed with 1N HCl aq. (50 ml). Then the organic layer was dried
over Na2SO4, filtered and evaporated through vacuo. The desired crude was purified through Column
chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate) afforded the desired product as a white
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
1
solid, (739 mg, 60%). H NMR (300 MHz, CDCl3): δ 10.07 (s, 1H), 9.04 (dd, J = 7.8, 1.5 Hz, 1H), 8.76
(dd, J = 4.2, 1.5 Hz, 1H), 8.16 (dd, J = 8.1, 1.5 Hz, 1H), 7.63ꢀ7.51 (m, 2H), 7.43 (dd, J = 8.4, 4.2 Hz,
1H), 7.35 (t, J = 8.4 Hz, 1H), 6.65 (d, J = 8.4 Hz, 2H), 3.85 (s, 6H); 13C NMR (75 MHz, CDCl3): δ
164.3, 157.7, 157.6, 148.0, 138.4, 136.2, 136.2, 134.9, 131.0, 127.9, 127.5, 121.5, 121.4, 116.7, 116.3,
104.05, 104.03, 55.99, 55.96; HRMS (ESI, m/z) calcd. for C18H16N2O3Na [M + Na]+: 331.1059; found:
331.1065.
2, 5-dibromo-N-(quinolin-8-yl)benzamide, 1ai. Column chromatography (SiO2, eluting with 8:2
1
hexane/ethyl acetate) afforded the desired product as a white solid, (1.85 g, 91%). H NMR (300 MHz,
CDCl3): δ 10.29 (s, 1H), 8.91 (dd, J = 6.0, 2.7 Hz, 1H), 8.80 (dd, J = 4.2, 1.5 Hz, 1H), 8.18 (dd, J = 8.4,
1.8 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.63ꢀ7.57 (m, 2H), 7.55ꢀ7.52 (m, 1H), 7.49ꢀ7.44 (m, 2H); 13C
NMR (75 MHz, CDCl3): δ 164.3, 148.4, 139.8, 138.5, 136.4, 135.0, 134.4, 134.0, 132.4, 128.0, 127.3,
122.4, 121.8, 121.6, 118.3, 117.0; HRMS (EI, m/z) calcd. for C16H10Br2N2O [M]+: 405. 9139; found:
405.9181.
4-bromo-2-methoxy-N-(quinolin-8-yl)benzamide, 1ak. Column chromatography (SiO2, eluting with
1
8:2 hexane/ethyl acetate) afforded the desired product as a white solid, (1.27 g, 71%). H NMR (300
MHz, CDCl3): δ 12.24 (s, 1H), 9.02 (dd, J = 8.1, 1.5 Hz, 1H), 8.87 (dd, J = 4.2, 1.5 Hz, 1H), 8.24ꢀ8.17
(m, 2H), 7.62ꢀ7.52 (m, 2H), 7.47 (dd, J = 8.4, 4.2 Hz, 1H), 7.31ꢀ7.28 (m, 1H), 7.23 (d, J = 1.5 Hz, 1H),
4.21 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 162.6, 157.9, 148.2, 139.1, 136.2, 135.5, 133.6, 128.0,
127.5, 127.1, 124.6, 121.7, 121.5, 121.3, 117.3, 115.1, 100.0, 56.5; HRMS (ESI, m/z) calcd. for
C17H13BrN2O2Na [M + Na]+: 379.0058; found: 379.0058.
2, 3, 4-trimethoxy-N-(quinolin-8-yl)benzamide, 1al. Column chromatography (SiO2, eluting with 7:3
hexane/ethyl acetate) afforded the desired product as a white solid, (1.28 g, 76%).
1H NMR (600 MHz,
CDCl3): δ 12.41 (s, 1H), 9.03 (dd, J = 3.9, 0.9 Hz, 1H), 8.91ꢀ8.90 (m, 1H), 8.19ꢀ8.17 (m, 1H), 8.11 (d, J
= 4.5 Hz, 1H), 7.60ꢀ7.57 (m, 1H), 7.53ꢀ7.51 (m, 1H), 7.48ꢀ7.46 (m, 1H), 6.85 (dd, J = 4.5, 0.3 Hz, 1H),
4.27 (s, 3H), 3.96 (s, 3H), 3.95 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 163.1, 156.8, 152.8, 148.2,
14
ACS Paragon Plus Environment

Page 15 of 32
The Journal of Organic Chemistry
1
2
3
141.8, 139.3, 136.2, 135.8, 128.1, 127.5, 127.1, 121.42, 121.41, 119.3, 117.4, 107.4, 62.0, 61.0, 56.0;
HRMS (ESI, m/z) calcd. for C19H19N2O4 [M + H ]+: 339.1345; found: 339.1345.
4
5
6
7
8
9
N-methyl-N-(quinolin-8-yl)benzamide, 1an. To a solution of Nꢀ(quinolinꢀ8ꢀyl)benzamide (248 mg,
1.0 mmol) in 3ml DMF was taken in a dried round bottom flask and sodium hydride (36 mg, 1.5 mmol,
1.5 equiv.) was added in it followed by methyl iodide(0.9 ml, 1.5 mmol, 1.5 equiv.) was slowly added at
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
0 C and it was stirred over night at r.t. The reaction mixture was extracted with ethyl acetate, brine
solution. The organic layer was separated, dried over Na2SO4, filtered and evaporated through vacuo.
The desired crude product was purified by Column chromatography (SiO2, eluting with 9:1
hexane/ethyl acetate) afforded the desired product as a white solid, (231 mg, 88%). This compound is
know11j. H NMR (300 MHz, CDCl3): δ 9.01 (dd, J = 4.2, 1.5 Hz, 1H), 8.14 (dd, J = 8.1, 1.5 Hz, 1H),
1
7.69 (dd, J = 7.2, 2.1 Hz, 1H), 7.44 (dd, J = 8.4, 4.2 Hz, 1H), 7.41ꢀ7.34 (m, 2H), 7.31ꢀ7.28 (m, 2H),
7.10ꢀ7.07 (m, 1H), 7.02ꢀ6.97 (m, 2H), 3.62 (s, 3H).
2-(quinolin-8-ylcarbamoyl) phenyl acetate, 1ao. To a solution of 2ꢀhydroxyꢀNꢀ(quinolinꢀ8ꢀ
yl)benzamide (264 mg, 1.0 mmol) in 3ml DCM was taken in a dried round bottom flask and Et3N (0.29
ml, 2.0 mmol, 2.0 equiv.) was added in it followed by acetyl chloride (0.1 ml, 1.5 mmol, 1.5 equiv.) was
slowly added at 0 oC and it was stirred over night at r.t. The reaction mixture was extracted with DCM,
brine solution. The organic layer was separated, dried over Na2SO4, filtered and evaporated through
vacuo. The desired crude product was purified by Column chromatography (SiO2, eluting with 9:1
hexane/ethyl acetate) afforded the desired product as a white solid, (225 mg, 85%). 1H NMR (300 MHz,
CDCl3): δ 10.99 (s, 1H), 9.01 (dd, J = 7.2, 2.1 Hz, 1H), 8.85 (dd, J = 4.2, 1.5 Hz, 1H), 8.22 (dd, J = 8.1,
1.5 Hz, 1H), 8.17 (dd, J = 8.1, 1.8 Hz, 1H), 7.62ꢀ7.55 (m, 3H), 7.50 (dd, J = 8.4, 4.2 Hz, 1H), 7.45ꢀ7.40
(m, 1H), 7.28ꢀ7.25 (m, 1H), 2.45 (s, 3H).
Spectral Data for 2a-d5 Compound. Column chromatography (SiO2, eluting with 9:1 hexane/ethyl
1
acetate) afforded the desired product as a white solid, (1.15 g, 91%). H NMR (300 MHz, CDCl3): δ 10.
76 (s, 1H), 8.95 (dd, J = 7.5, 1.2 Hz, 1H), 8.85 (dd, J = 4.2, 1.5 Hz, 1H), 8.19 (dd, J = 8.1, 1.2 Hz, 1H),
7.63ꢀ7.53 (m, 2H), 7.48 (dd, J = 8.4, 4.2 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 165.1, 148.0, 138.4,
136.1, 134.7, 134.3, 131.5, 131.1, 130.8, 128.4, 128.1, 127.7, 127.2, 127.0, 126.6, 126.3, 121.49,
121.46, 116.2; HRMS (ESI, m/z) calcd. for C16H7D5N2ONa [M + Na]+: 276.1161; found: 276.1167.
General Experimental Procedure for C-H Hydroxylation Reaction
In a 15 ml sealed tube, the substrate (0.2 mmol, 1 equiv), Cu(OAc)2.H2O (40 mg, 0.2 mmol, 1equiv),
Pyridine (10 equiv ) was added followed by solvent DMF:DMSO 2 ml (3:1). The tube was charged with
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 32
1
2
3
4
5
6
7
8
9
preheated oil bath at 100 OC for 2 hrs. The reaction mixture was diluted with ethyl acetate and quenched
with 20 ml saturated solution of Na2S2O3.5H2O or Na2S. Then, the aqueous phase was extracted with
ethyl acetate (2x10). The combined organic phase was washed with 1N HCl (50 ml) and collected
organic phase, then dried over Na2SO4 and concentrated under vacuum. The crude was purified by
column chromatography on silica gel with gradient of elution of pet ether and ethyl acetate to give the
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
desired hydroxylation product
.
2-Hydroxy-N-(quinolin-8-yl)benzamide, 2a, Scheme 2. Column chromatography (SiO2, eluting with
9:1 hexane/ethyl acetate) afforded the desired product as a white solid, (52 mg, 99%), mp 120 – 122 oC.
1H NMR (300 MHz, CDCl3): δ 12.33 (s, 1H), 11.00 (s, 1H), 8.90 (dd, J = 4.2, 1.2 Hz, 1H), 8.84 (dd, J =
5.7, 3.0 Hz, 1H), 8.22 (dd, J = 8.4, 1.5 Hz, 1H), 7.87 (dd, J = 7.2, 0.9 Hz, 1H), 7.64ꢀ7.58 (m, 2H), 7.54ꢀ
7.46 (m, 2H), 7.09ꢀ7.00 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 168.4, 162.1, 148.5, 138.8, 136.5,
134.6, 133.5, 128.0, 127.3, 126.1, 122.3, 121.9, 119.0, 118.8, 116.9, 115.2; IR (neat): υmax 3347, 1651,
1543, 1491; HRMS (ESI, m/z) calcd. for C16H12N2O2Na [M + Na]+: 287.0796; found: 287.0791.
4-fluoro-2-hydroxy-N-(quinolin-8-yl)benzamide, 2b, Scheme 2. Column chromatography (SiO2,
eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid, (54 mg, 95%), mp
o
1
147 – 149 C. H NMR (300 MHz, CDCl3): δ 12.65 (s, 1H), 10.88 (s, 1H), 8.88 (dd, J = 4.2, 1.5 Hz,
1H), 8.79 (dd, J = 5.1, 3.9 Hz, 1H), 8.21 (dd, J = 8.4, 1.8 Hz, 1H), 7.87ꢀ7.82 (m, 1H), 7.60ꢀ7.57 (m,
2H), 7.51 (dd, J = 8.4, 4.2 Hz, 1H), 6.77ꢀ6.69 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 167.7, 166.3 (d, J
= 252.0 Hz), 164.2 (d, J = 13.5 Hz), 148.4, 138.6, 136.4, 133.3, 127.91, 127.92 (d, J = 11.3 Hz), 127.2,
122.3, 121.8, 116.9, 111.8 (d, J = 3.0 Hz), 107.0 (d, J = 23.3 Hz), 105.3 (d, J = 24.0 Hz); IR (neat): υmax
3431, 3338, 3066, 1627, 1551; HRMS (ESI, m/z) calcd. for C16H11FN2O2Na[M + Na]+: 305.0702;
found: 305.0693.
4-chloro-2-hydroxy-N-(quinolin-8-yl)benzamide, 2c, Scheme 2. Column chromatography (SiO2,
eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid, (55 mg, 91%), mp
o
1
181 – 183 C. H NMR (300 MHz, CDCl3): δ 12.49 (s, 1H), 10.91 (s, 1H), 8.88 (dd, J = 4.2, 1.5 Hz,
1H), 8.80ꢀ 8.77 (m, 1H), 8.11 (dd, J = 8.1, 1.5 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.59ꢀ7.58 (m, 2H),
13
7.51 (dd, J = 8.4, 4.2 Hz, 1H), 7.06 (d, J = 2.1 Hz, 1H), 6.97 (dd, J = 8.4, 1.8 Hz, 1H); C NMR (150
MHz, CDCl3): δ 167.7, 162.8, 148.5, 140.1, 138.7, 136.5, 133.3, 127.3, 127.0, 122.5, 121.9, 119.5,
118.8, 117.0, 113.7; IR (neat): υmax 3418, 3334, 1641, 1546, 1491; HRMS (ESI, m/z) calcd. for
C16H11ClN2O2Na [M + Na]+: 321.0407; found: 321.0394.
16
ACS Paragon Plus Environment

Page 17 of 32
The Journal of Organic Chemistry
1
2
3
4-bromo-2-hydroxy-N-(quinolin-8-yl)benzamide, 2d, Scheme 2 and entry 10, Table 2. Column
chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white
solid, (64 mg, 93%), mp 191 – 193 oC. 1H NMR (300 MHz, CDCl3): δ 12.47 (s, 1H), 10.93 (s, 1H), 8.88
(dd, J = 4.2, 2.7 Hz, 1H), 8.82ꢀ8.76 (m, 1H), 8.21 (dd, J = 8.4, 1.5 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H),
7.61 (dd, J = 8.7, 4.5 Hz, 2H), 7.52 (dd, J = 8.4, 4.2 Hz, 1H), 7.24 (d, J = 1.5 Hz, 1H), 7.13 (dd, J = 8.7,
1.8 Hz, 1H); 13C NMR (150 MHz, CDCl3): δ 167.8, 162.7, 148.6, 138.7, 136.5, 133.3, 128.5, 128.0,
127.3, 127.0, 122.5, 122.4, 121.9, 117.1, 114.1; IR (neat): υmax 3401, 3333, 1640, 1545, 1487; HRMS
(ESI, m/z) calcd. for C16H12BrN2O2 [M + H]+: 343.0082; found: 343.0082.
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
2-hydroxy-4-iodo-N-(quinolin-8-yl)benzamide, 2e, Scheme 2
. Column chromatography (SiO2,
eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid, (69 mg, 88%), mp
o
1
185 – 187 C. H NMR (300 MHz, CDCl3): δ 12.38 (s, 1H), 10.94 (s, 1H), 8.88 (d, J = 4.2 Hz, 1H),
8.79 (dd, J = 8.7, 4.5 Hz, 1H), 8.21 (d, J = 8.1 Hz, 1H), 7.60ꢀ7.59 (m, 2H), 7.54ꢀ7.50 (m, 2H), 7.46 (s,
1H), 7.34 (dd, J = 8.4, 1.2 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 168.0, 162.2, 148.6, 138.7, 136.5,
133.3, 128.2, 128.03, 127.96, 127.3, 126.8, 122.5, 121.9, 117.0, 114.6, 101.0; IR (neat): υmax 3429,
3313, 3092, 1619, 1592, 1554; HRMS (ESI, m/z) calcd. for C16H11IN2O2Na [M + Na]+: 412.9763;
found: 412.9763.
2-hydroxy-N-(quinolin-8-yl)-6-(trifluoromethyl)benzamide, 2f, Scheme 2. Column chromatography
(SiO2, eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a white solid, (64 mg,
1
96%), mp 250 – 252 oC. H NMR (300 MHz, DMSOꢀd6): δ 10.74 (s, 1H), 10.19 (s, 1H), 8.87ꢀ8.85 (m,
1H), 8.73 (d, J = 7.5 Hz, 1H), 8.45 (dd, J = 8.1, 1.2 Hz, 1H), 7.75 (d, J = 7.8, 1H), 7.68ꢀ7.63 (m, 2H),
7.53 (t, J = 7.8, 1H), 7.27 (d, J = 7.2 Hz, 2H); 13C NMR (75 MHz, DMSOꢀd6): δ 163.8, 155.4, 149.5,
138.1, 137.2, 134.5, 131.4, 128.2, 127.9 , 127.5 (q, J = 5.6 Hz), 124.2 (q, J = 271.6 Hz), 123.4, 122.8,
120.8, 116.9 (q, J = 5.2 Hz), 116.7; IR (neat): υmax 3344, 3234, 1653, 1527, 1482; HRMS (EI, m/z)
calcd. for C17H11F3N2O2 [M]+: 332.0773; found: 332.0779.
2-fluoro-6-hydroxy-N-(quinolin-8-yl)benzamide, 2g, Scheme 2. Column chromatography (SiO2,
eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid, (51 mg, 90%), mp
o
1
115 – 118 C. H NMR (300 MHz, CDCl3): δ 13.19 ( s, 1H), 11.54 (d, J = 19.8 Hz, 1H), 8.89 (dd, J =
4.2, 1.5 Hz, 1H), 8.87 (dd, J = 3.6, 1.8 Hz, 1H), 8.19 (dd, J = 8.1, 1.5 Hz, 1H), 7.60ꢀ7.55 (m, 2H), 7.49
(dd, J = 8.4, 4.2 Hz, 1H), 7.41ꢀ7.34 (m, 1 H), 6.86 (d, J = 8.4 Hz, 1H), 6.76ꢀ6.69 (m, 1H); 13C NMR (75
MHz, CDCl3): δ 166.4 (d, J = 3.0 Hz), 164.0 (d, J = 3.8 Hz), 161.2 (d, J = 247.5 Hz), 148.7, 138.9,
136.3, 134.0, 133.9, 128.0, 127.2, 122.7, 121.8, 118.0, 114.7 (d, J = 1.5 Hz), 105.9 (d, J = 25.5 Hz),
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 32
1
2
3
104.6 (d, J = 12.7 Hz); IR (neat): υmax 3413, 3321, 1616, 1545, 1455; HRMS (EI, m/z) calcd. for
C16H11FN2O2 [M]+: 282.0805; found: 282.0804.
4
5
6
7
8
9
2-hydroxy-6-nitro-N-(quinolin-8-yl)benzamide, 2h, Scheme 2. Column chromatography (SiO2,
eluting with 6:4 hexane/ethyl acetate) afforded the desired product as a white solid, (50 mg, 80%), mp
252 – 254 oC. 1H NMR (300 MHz, DMSOꢀd6): δ 11.38 (s, 1H), 10.79 (s, 1H), 8.87 (d, J = 4.2 Hz, 1H),
8.72 (d, J = 7.5 Hz, 1H), 8.43 (d, J = 8.1 Hz, 1H), 7.74ꢀ7.71 (m, 1H), 7.65ꢀ7.60 (m, 2H), 7.57ꢀ7.52 (m,
2H), 7.39ꢀ7.33 (m, 1H); 13C NMR (150 MHz, CDCl3): δ 162.2, 156.1, 149.5, 149.0, 138.4, 137.1,
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
134.8, 131.8, 128.3, 127.5, 122.8, 122.7, 122.0, 119.0, 117.1, 115.1; IR (neat): υmax 3344, 3233, 1654,
1528, 1325; HRMS (EI, m/z) calcd. for C16H11N3O4 [M]+: 309.0750; found: 309.0744.
2-hydroxy-6-methyl-N-(quinolin-8-yl)benzamide, 2i, Scheme 2. Column chromatography (SiO2,
eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid, (43 mg, 78%), mp
o
1
198 – 200 C. H NMR (300 MHz, CDCl3): δ 10.91 (s, 1H), 10.62 (s, 1H), 8.90 (dd, J = 6.0, 3.0 Hz,
1H), 8.81 (dd, J = 4.2, 1.5 Hz, 1H), 8.20 (dd, J = 8.1, 1.5 Hz, 1H), 7.64ꢀ7.57 (m, 2H), 7.48 (dd, J = 8.4,
4.2 Hz, 1H), 7.31ꢀ7.26 (m, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H), 2.84 (s, 3H); 13C
NMR (75 MHz, CDCl3): δ 168.8, 160.4, 148.5, 138.7, 136.4, 136.0, 133.9, 132.5, 128.0, 127.3, 122.9,
122.4, 121.8, 118.5, 117.2, 115.7, 22.8; IR (neat): υmax 3359, 3197, 1646, 1521, 1480; HRMS (EI, m/z)
calcd. for C17H14N2O2 [M]+: 278.1055; found: 278.1053.
2-hydroxy-6-(methylthio)-N-(quinolin-8-yl)benzamide, 2j, Scheme 2. Column chromatography
(SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid, (34 mg,
1
54%), mp 144 – 146 oC. H NMR (300 MHz, CDCl3): δ 12.09 (s, 1H), 11.81 (s, 1H), 8.91ꢀ8.84 (m, 2H),
8.18 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 4.2 Hz, 2H), 7.47 (dd, J = 8.4, 4.2 Hz, 1H), 7.31ꢀ7.26 (m, 1H),
7.02 (d, J = 7.8, 1H), 6.93 (d, J = 8.4 Hz, 1H), 2.56 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 168.1, 162.0,
148.6, 139.3, 136.5, 136.2, 134.2, 132.5, 128.1, 127.2, 122.8, 122.0, 121.7, 118.2, 116.9, 18.9; IR
(neat): υmax 3336, 3166, 1634, 1528, 1429; HRMS (ESI, m/z) calcd. for C17H14N2O2SNa [M + Na]+:
333.0674; found: 333.0674.
2-hydroxy-N-(quinolin-8-yl)-1-naphthamide, 2k, Scheme 2. Column chromatography (SiO2, eluting
with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid, (54 mg, 85%), mp 118 –
1
120 oC. H NMR (300 MHz, CDCl3): δ 11.51 (s, 1H), 10.92 (s, 1H), 8.96 (dd, J = 7.2, 2.1 Hz, 1H), 8.75
(dd, J = 4.2, 1.5 Hz, 1H), 8.48 (d, J = 8.7 Hz, 1H), 8.21 (dd, J = 8.4, 1.5 Hz, 1H), 7.92ꢀ7.85 (m, 2H),
7.68ꢀ7.57 (m, 3H), 7.47 (dd, J = 8.4, 4.2 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.25ꢀ7.22 (m, J, 1H); 13C
NMR (75 MHz, CDCl3): δ 168.7, 160.2, 148.6, 136.4, 134.5, 134.0, 130.7, 129.4, 128.9, 128.4, 128.0,
18
ACS Paragon Plus Environment

Page 19 of 32
The Journal of Organic Chemistry
1
2
3
127.4, 123.7, 123.3, 122.4, 121.8, 119.4, 117.4, 110.5; IR (neat): υmax 3411, 3316, 2921, 1641, 1521,
1463; HRMS (ESI, m/z) calcd. for C20H14N2O2Na [M + Na]+: 337.0953; found: 337.0953.
4
5
6
7
8
9
3-hydroxy-N-(quinolin-8-yl)-[1,
1'-biphenyl]-4-carboxamide,
2I,
Scheme
2.
Column
chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white
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
1
solid, (67 mg, 98%), mp 138 – 140 C. H NMR (300 MHz, CDCl3): δ 12.41 (s, 1H), 11.02 (s, 1H),
8.92ꢀ8.90 (m, 1H), 8.87ꢀ8.84 (m, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.68ꢀ7.60 (m,
4H), 7.55ꢀ7.39 (m, 4H), 7.23ꢀ7.24 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 168.2, 162.3, 148.5, 147.3,
139.6, 138.7, 136.4, 133.6, 128.9, 128.3, 128.0, 127.3, 127.1, 126.5, 122.2, 121.8, 117.9, 116.9, 116.8,
113.9; IR (neat): υmax 3413, 3352, 1645, 1536, 1485; HRMS (ESI, m/z) calcd. for C22H16N2O2Na [M +
Na]+: 363.1109; found: 363.1110.
2', 4'-difluoro-3-hydroxy-N-(quinolin-8-yl)-[1, 1'-biphenyl]-4-carboxamide, 2m, Scheme 2. Column
chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate) afforded the desired product as a white
o
1
solid, (66 mg, 88%), mp 191 – 193 C. H NMR (300 MHz, CDCl3): δ 12.40 (s, 1H), 11.03 (s, 1H),
8.91ꢀ8.89 (m, 1H), 8.85 (dd, J = 5.7, 3.3 Hz, 1H), 8.24ꢀ8.21 (m, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.65ꢀ7.60
(m, 2H), 7.55ꢀ7.44 (m, 2H), 7.20 (d, J = 3.6 Hz, 1H), 7.16 (s, 1H), 7.02ꢀ6.91 (m, 2H); 13C NMR (75
MHz, CDCl3): δ 168.1, 162.0, 148.5, 141.2, 138.8, 136.5, 133.5, 131.3 (dd, J = 9.8, 4.5 Hz), 128.0,
127.3, 126.2, 122.4, 121.9, 119.7 (d, J = 3.0 Hz), 118.9 (d, J = 2.3 Hz), 116.9, 114.3, 111.8 (dd, J =
21.0, 3.8 Hz),104.6 (t, J = 25.5 Hz); IR (neat): υmax 3416, 3352, 1655, 1545, 1492; HRMS (EI, m/z)
calcd. for C22H14F2N2O2 [M]+: 376.1023; found: 376.1013.
4-acetyl-2-hydroxy-N-(quinolin-8-yl)benzamide, 2n, Scheme 2. Column chromatography (SiO2,
eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a white solid, (59 mg, 96%), mp
o
1
170 – 172 C. H NMR (300 MHz, CDCl3): δ 12.35 (s, 1H), 11.06 (s, 1H), 8.89 (dd, J = 4.5, 1.8 Hz,
1H), 8.81 (dd, J = 5.1, 3.9 Hz, 1H), 8.21 (dd, J = 8.4, 1.5 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.62ꢀ7.55
(m, 4H), 7.52 (dd, J = 8.4, 4.2 Hz, 1H), 2.63 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 197.4, 167.4, 162.0,
148.6, 141.5, 138.7, 136.5, 133.2, 127.9, 127.3, 126.4, 122.7, 122.0 119.0, 118.4, 118.1, 117.1, 26.9; IR
(neat): υmax 3348, 3310, 1685, 1655, 1546, 1496; HRMS (EI, m/z) calcd. for C18H14N2O3[M]+:
306.1004; found: 306.1004.
2-hydroxy-N-(quinolin-8-yl)-4-(trifluoromethyl)benzamide, 2o, Scheme 2. Column chromatography
(SiO2, eluting with 7:3 hexane/ethyl acetate) afforded the desired product as a white solid, (64 mg,
96%), mp 140 – 142 oC. 1H NMR (300 MHz, CDCl3): δ 12.47 (s, 1H), 11.07 (s, 1H), 8.91 (dd, J = 4.2,
1.5 Hz, 1H), 8.86ꢀ8.81 (m, 1H), 8.24 ( dd, J = 8.4, 1.2 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.64ꢀ7.59 (m,
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 32
1
2
3
4
5
6
7
8
9
2H), 7.55 (dd, J = 8.4, 4.2 Hz, 1H), 7.33 (s, 1H), 7.28ꢀ7.24 (m, 1H); 13C NMR (75 MHz, CDCl3): δ
167.3, 162.0, 148.6, 138.7, 136.6, 133.1, 129.0 (q, J = 271.0 Hz), 128.0, 126.8, 122.8, 122.0, 117.8,
117.2, 116.1 (q, J = 8.0 Hz), 115.3 (q, J = 3.7 Hz), 100.0; IR (neat): υmax 3418, 3337, 1652, 1548, 1422;
HRMS (EI, m/z) calcd. for C17H11F3N2O2 [M]+: 332.0773; found: 332.0767.
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-hydroxy-4-(pentyloxy)-N-(quinolin-8-yl)benzamide, 2p, Scheme 2. Column chromatography
(SiO2, eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a white solid, (52 mg,
1
74%), mp 85 ꢀ 87 oC. H NMR (300 MHz, CDCl3): δ 12.64 (s, 1H), 10.80 (s, 1H), 8.88 (dd, J = 4.2, 1.5
Hz, 1H), 8.80 (dd, J = 6.9, 2.1 Hz, 1H), 8.20 (dd, J = 8.4, 1.5 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.61ꢀ
7.53 (m, 2H), 7.50 (dd, J = 8.4, 4.2 Hz, 1H), 6.57ꢀ6.51 (m, 2H), 4.01 (t, J = 6.6 Hz, 2H), 1.86ꢀ1.58 (m,
2H), 1.50ꢀ1.34 (m, 4H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 168.4, 164.3, 148.4,
138.7, 136.4, 133.8, 128.0, 127.3, 121.8, 121.8, 116.6, 107.9, 107.8, 102.1, 68.2, 28.7, 28.1, 22.4, 14.02;
IR (neat): υmax 3446, 3368, 2929, 1646, 1543; HRMS (ESI, m/z) calcd. for C21H22N2O3Na [M + Na]+:
373.1528; found: 373.1528.
3-hydroxy-N-(quinolin-8-yl)isonicotinamide, 2q, Scheme 2
Column chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a
o
1
white solid, (38 mg, 72%), mp 190 – 192 C. H NMR (600 MHz, CDCl3): δ 11.90 (s, 1H), 11.16 (s,
1H), 8.94ꢀ8.92 (m, 1H), 8.87ꢀ8.84 (m, 1H), 8.57 (s, 1H), 8.35 (d, J = 5.4 Hz, 1H), 8.26 (d, J = 8.4 Hz,
1H), 7.68ꢀ7.64 (m, 3H), 7.28 (d, J = 3.2 Hz, 1H); 13C NMR (150 MHz, CDCl3): δ 166.6, 156.2, 148.7,
143.1, 140.2, 138.7, 136.6, 132.8, 128.0, 127.3, 123.1, 122.1, 120.5, 118.2, 117.4; IR (neat): υmax 3449,
3284, 1667, 1546, 1491, 1329; HRMS (ESI, m/z) calcd. for C15H11N3O2 [M ]+: 265.0851; found:
265.0830.
2-hydroxy-4-methyl-N-(quinolin-8-yl)benzamide, 2r, Scheme 2. Column chromatography (SiO2,
eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid, (54 mg, 97%), mp
o
1
158 – 160 C. H NMR (300 MHz, CDCl3): δ 12.29 (s, 1H), 10.89 (s, 1H), 8.87(dd, J = 4.2, 1.5 Hz,
1H), 8.80 (dd, J = 6.6, 2.7 Hz, 1H), 8.19 (dd, J = 8.4, 1.5 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.61ꢀ7.54
13
(m, 2H), 7.49 (dd, J = 8.4, 4.2 Hz, 1H), 6.86 (s, 1H), 6.81 (d, J = 8.4 Hz, 1H), 2.38 (s, 3H); C NMR
(150 MHz, CDCl3): δ 168.5, 162.1, 148.4, 145.7, 138.8, 136.4, 133.7, 128.0, 127.3, 125.9, 122.0, 121.8,
120.2, 118.9, 116.8, 112.6, 21.7; IR (neat): υmax 3446, 3341, 1641, 1541; HRMS (ESI, m/z) calcd. for
C17H14N2O2Na [M + Na]+: 301.0953; found: 301.0948.
4-(tert-butyl)-2-hydroxy-N-(quinolin-8-yl)benzamide, 2s, Scheme 2. Column chromatography (SiO2,
eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid, (57 mg, 87%), mp
20
ACS Paragon Plus Environment

Page 21 of 32
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
o
1
140 – 142 C. H NMR (300 MHz, CDCl3): δ 12.25 (s, 1H), 10.93 (s, 1H), 8.87 (dd, J = 4.2, 1.2 Hz,
1H), 8.82 (dd, J = 6.6, 2.4 Hz, 1H), 8.20 (dd, J = 8.4, 1.5 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.60ꢀ7.57
13
(m, 2H), 7.50 (dd, J = 8.4, 4.2 Hz, 1H), 7.07 (s, 1H), 7.04 (d, J = 1.8 Hz, 1H), 1.35 (s, 9H); C NMR
(75 MHz, CDCl3): δ 168.3, 161.9, 158.8, 148.4, 138.7, 136.4, 133.6, 127.9, 127.3, 125.7, 122.0, 121.8,
116.8, 116.7, 115.5, 112.5, 35.1, 30.9; IR (neat): υmax 3426, 3336, 2959, 1643, 1612, 1546; HRMS (ESI,
m/z) calcd. for C20H20N2O2Na [M + Na]+: 343.1422; found: 343.1422.
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
4-ethyl-2-hydroxy-N-(quinolin-8-yl)benzamide, 2t, Scheme 2. Column chromatography (SiO2,
eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid, (50 mg, 85%), mp
108 – 110 oC. 1H NMR (300 MHz, CDCl3): δ 12.30 (s, 1H), 10.90 (s, 1H), 8.87ꢀ8.86 (m, 1H), 8.80 (dd,
J = 6.3, 2.4 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 5.1, 1H), 7.60ꢀ7.54 (m, 2H), 7.49 (dd, J = 8.4,
4.2 Hz, 1H), 6.89 (s, 1H), 6.84 (d, J = 8.1 Hz, 1H), 2.67 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H);
13C NMR (75 MHz, CDCl3): δ 168.4, 162.2, 151.9, 148.4, 138.7, 136.4, 133.6, 127.9, 127.2, 126.0,
122.0, 121.8, 119.0, 117.6, 116.8, 112.7, 28.9, 14.9; IR (neat): υmax 3421, 3352, 2963, 1542, 1422;
HRMS (ESI, m/z) calcd. for C18H16N2O2 [M + Na]+: 315.1109; found: 315.1096.
2-hydroxy-4-pentyl-N-(quinolin-8-yl)benzamide, 2u, Scheme 2. Column chromatography (SiO2,
eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid, (61 mg, 91%), mp
96 – 98 oC. 1H NMR (300 MHz, CDCl3): δ12.29 (s, 1H), 10.92 (s, 1H), 8.89ꢀ8.88 (m, 1H), 8.82 (dd, J =
6.6, 2.4 Hz, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.77 (d, J =8.1 Hz, 1H), 7.62ꢀ7.56 (m, 2H), 7.50 (dd, J = 8.4,
4.2 Hz, 1H), 6.88ꢀ6.82 (m, 2H), 2.63 (t, J = 7.5 Hz, 2H), 1.68ꢀ1.61 (m, 2H), 1.36ꢀ1.34 (m, 4H), 0.93ꢀ
0.88 (m, 3H); 13C NMR (75 MHz, CDCl3): δ 168.5, 162.1, 150.7, 148.4, 138.7, 136.4, 133.7, 128.0,
127.3, 125.9, 122.0, 121.8, 119.6, 118.2, 116.8, 112.7, 35.9, 31.4, 30.4, 22.5, 14.0; IR (neat): υmax 3409,
3331, 2921, 1649, 1545; HRMS (ESI, m/z) calcd. for C21H22N2O2Na [M + Na]+: 357.1579; found:
357.1579.
2-hydroxy-5-methyl-N-(quinolin-8-yl)benzamide, 2v, Scheme 3. Column chromatography (SiO2,
eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid, (32 mg, 57%), mp
o
1
120 – 122 C. H NMR (300 MHz, CDCl3): δ 12.09 (s, 1H), 10.92 (s, 1H), 8.91 (dd, J = 4.2, 1.5 Hz,
1H), 8.84 (dd, J = 6.0, 3.0 Hz, 1H), 8.21 (dd, J = 8.4, 1.8 Hz, 1H), 7.63ꢀ7.57 (m, 3H), 7.52 (dd, J = 8.4,
13
4.2 Hz, 1H), 7.31ꢀ7.26 (m, 1H), 6.97 (d, J = 8.4 Hz, 1H), 2.42 (s, 3H); C NMR (75 MHz, CDCl3): δ
168.5, 159.9, 148.5, 138.8, 136.5, 135.6, 133.6, 128.2, 128.0, 127.3, 125.8, 122.2, 121.8, 118.6, 117.0,
114.8, 20.8; IR (neat): υmax 3912, 3342, 1641, 1544, 1486; HRMS (ESI, m/z) calcd. for C17H15N2O2 [M
+ H]+: 279.1134; found: 279.1147.
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 32
1
2
3
2-hydroxy-3-methyl-N-(quinolin-8-yl)benzamide, 2v’, Scheme 3. Column chromatography (SiO2,
4
5
6
7
8
9
eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a white solid, (21 mg, 37%), mp
o
1
153 – 155 C. H NMR (300 MHz, CDCl3): δ 12.55 (s, 1H), 10.96 (s, 1H), 8.88 (dd, J = 4.2, 1.8 Hz,
1H), 8.83 (dd, J = 6.3, 2.4 Hz, 1H), 8.19 (dd, J = 8.1, 1.2 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.62ꢀ7.55
(m, 2H), 7.49 (dd, J = 8.4, 4.2 Hz, 1H), 7.34 (d, J = 7.2 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 2.32 (s, 3H);
13C NMR (75 MHz, CDCl3): δ 168.9, 160.6, 148.5, 138.9, 136.4, 135.3, 133.8, 128.0, 127.8, 127.4,
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
123.6, 122.1, 121.8, 118.3, 116.9, 114.4, 15.8; IR (neat): υmax 3418, 3341, 1641, 1544, 1486
(ESI, m/z) calcd. for C17H14N2O2Na [M + Na]+: 301.0953 ; found: 301.0945.
; HRMS
2-hydroxy-5-methoxy-N-(quinolin-8-yl)benzamide, 2w, Scheme 3. Column chromatography (SiO2,
eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a white solid, (24 mg, 40%), mp
o
1
168 – 170 C. H NMR (300 MHz, CDCl3): δ 11.77 (s, 1H), 10.92 (s, 1H), 8.89 (dd, J = 4.2, 1.5 Hz,
1H), 8.83 (dd, J = 5.7, 3.6 Hz, 1H), 8.22 (dd, J = 8.4, 1.8 Hz, 1H), 7.64ꢀ7.59 (m, 2H), 7.52 (dd, J = 8.4,
4.2 Hz, 1H), 7.36 (d, J = 2.7 Hz, 1H), 7.14ꢀ7.10 (m, 1H), 7.01 (d, J = 9.0 Hz, 1H), 3.90 (s, 3H); 13C
NMR (75 MHz, CDCl3): δ 168.0, 156.1, 151.8, 148.5, 138.7, 136.4, 133.5, 127.9, 127.2, 122.2, 121.8,
121.0, 119.4, 116.9, 115.0, 110.5, 56.1; IR (neat): υmax 3443, 3345, 1649, 1546, 1493; HRMS (ESI, m/z)
calcd. for C17H14N2O3Na [M + Na]+: 317.0902; found: 317.0920.
2-hydroxy-3-methoxy-N-(quinolin-8-yl)benzamide, 2w’, Scheme 3 and entry 7, Table 2. Column
chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate) afforded the desired product as a white
o
1
solid, (18 mg, 30%), mp 132 – 134 C. H NMR (300 MHz, CDCl3): δ 12.24 (s, 1H), 11.07 (s, 1H),
8.89 (dd, J = 4.2, 1.5 Hz, 1H), 8.67ꢀ8.85 (m, 1H), 8.21 (dd, J = 8.4, 1.5 Hz, 1H), 7.64ꢀ7.59 (m, 2H),
7.53ꢀ7.49 (m, 2H), 7.07 (d, J = 7.2 Hz, 1H), 6.97 (t, J = 8.1 Hz, 1H), 3.95 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 168.2, 151.9, 149.1, 148.4, 138.7, 136.4, 133.6, 127.9, 127.2, 122.2, 121.8, 118.4, 117.7,
117.0, 115.5, 115.0, 56.1; IR (neat): υmax 3417, 3340, 1642, 1589, 1546, 1464; HRMS (ESI, m/z) calcd.
for C17H14N2O3Na [M + Na]+: 317.0902; found: 317.0905.
3-bromo-2-hydroxy-N-(quinolin-8-yl)benzamide compound with 5-bromo-2-hydroxy-N-(quinolin-
8-yl)benzamide (1:1), 2x:2x’, Scheme 3. Column chromatography (SiO2, eluting with 9:1 hexane/ethyl
o
1
acetate) afforded the desired product as a white solid, (61 mg, 88%), mp 128 – 130 C. H NMR (300
MHz, CDCl3): δ 13.09 (s, 1H), 12.28 (s, 1H), 11.01 (s, 1H), 10.86 (s, 1H), 8.91 (dd, J = 4.2, 1.5 Hz,
1H), 8.87 (dd, J = 4.2, 1.2 Hz, 1H), 8.80 (dd, J = 9.00, 4.5 Hz, 1H), 8.77ꢀ8.74 (m, 1H), 8.21 (dd, J = 7.2,
0.9 Hz, 2H), 7.90 (d, J = 2.1 Hz, 1H), 7.81 (dd, J = 7.8, 0.6 Hz, 1H), 7.74 (d, J = 7.4 Hz, 1H), 7.59ꢀ7.48
(m, 4H), 7.34ꢀ7.32 (m, 3H), 6.96ꢀ6.87 (m, 2H); 13C NMR (150 MHz, CDCl3): δ 167.6, 167.1, 161.1,
158.6, 148.7, 148.6, 138., 137.8, 137.3, 136.49, 136.46, 133.18, 133.17, 128.5, 127.9, 127.3, 127.2,
22
ACS Paragon Plus Environment

Page 23 of 32
The Journal of Organic Chemistry
1
2
3
125.2, 122.6, 122.6, 122.0, 121.9, 120.7, 119.6, 117.2, 117.1, 116.7, 116.2, 112.6, 110.5; IR (neat): υmax
3418, 3416, 3353, 3322, 1649, 1579, 1544, 1485, 1429, 1367; HRMS (EI, m/z) calcd. for
C16H11BrN2O2 [M]+: 343.9983; found: 343.9940.
4
5
6
7
8
9
2-hydroxy-N-(quinolin-8-yl)-5-(trifluoromethyl)benzamide, 2y, Scheme 3. Column chromatography
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
(SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid, (65 mg,
1
98%), mp 141 – 143 oC. H NMR (300 MHz, CDCl3): δ 12.72 (s, 1H), 11.00 (s, 1H), 8.91 (dd, J = 4.2,
1.5 Hz, 1H), 8.79 (dd, J = 5.4, 3.3 Hz, 1H), 8.22 (dd, J = 8.4, 1.5 Hz, 1H), 8.07 (s, 1H), 7.70 (dd, J =
8.7, 1.5 Hz, 1H), 7.61ꢀ7.60 (m, 2H), 7.53 (dd, J = 8.4, 4.2 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H); 13C NMR
(150 MHz, CDCl3): δ 167.4, 164.6, 148.8, 138.7, 136.5, 133.1, 131.1 (q, J = 3.3 Hz), 128.0, 127.2,
123.9 (q, J = 270.9 Hz), 123.6 (q, J = 3.0 Hz), 122.8, 122.0, 119.5 (q, J = 34.0 Hz), 117.2, 115.0; IR
(neat): υmax 3432, 3311, 1651, 1602, 1551; HRMS (EI, m/z) calcd. For C17H11F3N2O2 [M]+: 332.0773;
found: 332.0779.
4-hydroxy-4'-methyl-N-(quinolin-8-yl)-[1, 1'-biphenyl]-3-carboxamide, 2z, Scheme 3. Column
chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white
o
1
solid, (70 mg, 98%), mp 197 – 199 C. H NMR (300 MHz, CDCl3): δ 12.27 (s, 1H), 11.04 (s, 1H),
8.89ꢀ8.84 (m, 2H), 8.22 (dd, J = 8.4, 1.8 Hz, 1 H), 8.01 (d, J = 2.1 Hz, 1H), 7.69 (dd, J = 8.7, 2.4 Hz,
1H), 7.62ꢀ7.58 (m, 2H), 7.56ꢀ7.49 (m, 3H), 7.32 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 8.7 Hz, 1H), 2.44 (s,
3H); 13C NMR (75 MHz, CDCl3): δ 168.4, 161.3, 148.6, 138.7, 137.4, 136.9, 136.4, 133.5, 133.4,
132.3, 129.7, 128.0, 127.3, 126.7, 124.2, 122.4, 121.8, 119.1, 117.0, 115.3, 21.1; IR (neat): υmax 3425,
3313, 2922, 1643, 1544, 1463; HRMS (ESI, m/z) calcd. for C23H18N2O2Na [M + Na]+: 377.1266;
found: 377.1266.
2', 4'-difluoro-4-hydroxy-N-(quinolin-8-yl)-[1,1'-biphenyl]-3-carboxamide, 2aa, Scheme 3
Column chromatography (SiO2, eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a
o
1
white solid, (71 mg, 94%), mp 200 – 202 C. H NMR (300 MHz, CDCl3): δ 12.39 (s, 1H), 11.03 (s,
1H), 8.89 (dd, J = 4.2, 1.5 Hz, 1H), 8.86 (dd, J = 5.4, 3.3 Hz, 1H), 8.24 (dd, J = 8.4, 1.8 Hz, 1H), 7.99ꢀ
7.98 (m, 1H), 7.65ꢀ7.61 (m, 3H), 7.55ꢀ7.45 (m, 2H), 7.16 (d, J = 8.7 Hz, 1H), 7.07ꢀ6.96 (m, 2H); 13C
NMR (150 MHz, CDCl3): δ 168.2, 162.3 (dd, J = 247.5, 12.0 Hz), 161.7, 159.8 (dd, J = 247.5, 12.0
Hz), 148.6, 138.8, 136.5, 135.1 (d, J = 3.0 Hz), 133.4, 131.1 (dd, J = 9, 4.5 Hz), 128.0, 127.3, 126.4 (d,
J = 3.0 Hz), 125.8, 124.3 (dd, J = 13.5, 4.5 Hz), 122.4, 121.9, 119.0, 117.1, 115.3, 111.7 (dd, J = 21.0,
3.0 Hz), 104.5 (t, J = 27.0 Hz); IR (neat): υmax 3412, 3341, 1656, 1547, 1487, 1371; HRMS (ESI, m/z)
calcd. for C22H14F2N2O2Na [M + Na]+: 399.0921; found: 399.0921.
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 32
1
2
3
4
5
General Experimental Procedure for C-X Hydroxylation Reaction
6
7
8
9
In a 15 ml sealed tube, the substrate (0.2 mmol, 1 equiv), Cu(OAc)2.H2O (40 mg, 0.2 mmol, 1equiv),
Pyridine (10 equiv ) was added followed by solvent DMF:DMSO 4 ml (3:1). The tube was charged
O
with preheated oil bath at 110 C for 12 hrs. The reaction mixture was diluted with ethyl acetate and
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
quenched with 20 ml saturated solution of Na2S2O3.5H2O or Na2S. Then, the aqueous phase was
extracted with ethyl acetate (2x10). The combined organic phase was dried over Na2SO4 and
concentrated under vacuum. The crude was purified by column chromatography on silica gel with
gradient of elution of pet ether and ethyl acetate to give the desired hydroxylation product
.
2-chloro-6-hydroxy-N-(quinolin-8-yl)benzamide, 2ab, Table 2. Column chromatography (SiO2,
eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid, (37 mg, 62%), mp
o
1
208 – 210 C. H NMR (300 MHz, CDCl3): δ 12.15 (s, 1H), 11.68 (s, 1H), 8.91 (dd, J = 5.4, 3.9 Hz,
1H), 8.87 (dd, J = 4.2, 1.5 Hz, 1H), 8.21 (dd, J = 8.4, 1.8 Hz, 1H), 7.64ꢀ7.60 (m, 2H), 7.50 (dd, J = 8.4,
4.2 Hz, 1H), 7.31 (t, J = 8.1 Hz, 1H), 7.05ꢀ6.97 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 167.4, 163.6,
149.3, 139.6, 136.9, 134.6, 133.6, 131.8, 128.6, 127.8, 123.5, 122.5, 122.4, 118.6, 118.0; IR (neat): υmax
3436, 3344, 3149, 1650, 1593, 1524; HRMS (ESI, m/z) calcd. for C16H11ClN2O2Na[M + Na]+:
321.0407; found: 321.0444.
3-chloro-2-hydroxy-N-(quinolin-8-yl)benzamide, 2ad, Table 2. Column chromatography (SiO2,
eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid, (31 mg, 51%), mp
180 – 182 oC. 1H NMR (300 MHz, CDCl3): δ 12.99 (s, 1H), 11.05 (s, 1H), 8.90ꢀ8.78 (m, 2H), 8.23 (d, J
= 7.5 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 4.2, 1H), 7.57ꢀ7.46 (m, 3H), 6.98 (t, J = 7.8 Hz,
1H); 13C NMR (75 MHz, CDCl3): δ 167.8, 157.9, 148.6, 138.8, 136.5, 134.6, 133.3, 128.0, 127.3,
124.5, 123.4, 122.6, 122.0, 119.0, 117.2, 116.4; IR (neat): υmax 3449, 3333, 2923, 2852, 1649, 1544,
1433; HRMS (ESI, m/z) calcd. for C16H11ClN2O2Na [M + Na]+: 321.0407; found: 321.0408.
5-bromo-2-hydroxy-N-(quinolin-8-yl)benzamide, 2x, Scheme 3 and entry 8, Table 2. Column
chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a white
o
1
solid, (63 mg, 91%), mp 143 – 145 C. H NMR (300 MHz, CDCl3): δ 12.30 ( s, 1H), 10.90 (s, 1H),
8.93 (dd, J = 4.2, 1.5 Hz, 1H), 8.80 (dd, J = 5.4, 3.4 Hz , 1H), 8.23 (dd, J = 8.1, 1.2 Hz, 1H), 7.94 (d, J =
13
2.1 Hz, 1H), 7.63ꢀ7.52 (m, 4H), 6.97 (d, J = 9.0 Hz, 1H); C NMR (75 MHz, CDCl3): δ 167.1, 161.0,
148.7, 138.6, 137.3, 136.4, 133.2, 128.5, 127.9, 127.2, 122.6, 122.0, 120.7, 117.1, 116.6, 110.5; IR
(neat): υmax 3419, 3321, 1650, 1546, 1484; HRMS (ESI, m/z) calcd. for C16H11BrN2O2Na [M + Na]+:
364.9902; found: 364.9902.
24
ACS Paragon Plus Environment

Page 25 of 32
The Journal of Organic Chemistry
1
2
3
2-hydroxy-4-methoxy-N-(quinolin-8-yl)benzamide, 2ae, Table 2. Column chromatography (SiO2,
4
5
6
7
8
9
eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a white solid, (40 mg, 67%), mp
o
1
140 – 142 C. H NMR (300 MHz, CDCl3): δ 12.68 (s, 1H), 10.82 (s, 1H), 8.88 (dd, J = 4.2, 1.5 Hz,
1H), 8.81 (dd, J = 6.6, 2.4 Hz, 1H), 8.20 (dd, J = 8.4, 1.8 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.62ꢀ7.57
(m, 2H), 7.51 (dd, J = 8.4, 4.2 Hz, 1H), 6.59ꢀ6.53 (m, 2H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3): δ
168.3, 164.6, 164.3, 148.3, 138.7, 136.4, 133.7, 127.9, 127.33, 127.28, 121.8, 121.7, 116.6, 108.1,
107.4, 101.6, 55.4; IR (neat): υmax 3421, 3351, 1652, 1601, 1547; HRMS (ESI, m/z) calcd. for
C17H14N2O3Na[M + Na]+: 317.0902; found: 317.0919.
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-hydroxy-3, 4-dimethoxy-N-(quinolin-8-yl)benzamide, 2af, Table 2
. Column chromatography
(SiO2, eluting with 7:3 hexane/ethyl acetate) afforded the desired product as a white solid, (57 mg,
1
88%), mp 137 – 139 oC. H NMR (300 MHz, CDCl3): δ 12.11 (s, 1H), 10.93 (s, 1H), 8.87 (dd, J = 4.2,
1.5 Hz, 1H), 8.83 (dd, J = 6.6, 2.4 Hz, 1H), 8.20 (dd, J = 8.4, 1.5 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H),
7.59ꢀ7.55 (m, 2H), 7.50 (dd, J = 8.4, 4.2 Hz, 1H), 6.62 (d, J = 8.7Hz, 1H), 3.95 (s, 6H); 13C NMR (75
MHz, CDCl3): δ 167.9, 156.8, 155.8, 148.4, 138.7, 137.0, 136.4, 133.8, 127.9, 127.3, 122.2, 122.0,
121.7, 116.8, 110.2, 103.0, 60.7, 56.0; IR (neat): υmax 3432, 3344, 1640, 1544, 1498; HRMS (ESI, m/z)
calcd. for C18H16N2O4Na [M + Na]+: 347.1008; found: 347.1008.
General Experimental Procedure for Homocoupling Reaction
In a 15 ml sealed tube, the substrate (0.2 mmol, 1 equiv), Cu(OAc)2.H2O (40 mg, 0.2 mmol, 1equiv)
was added followed by 2 ml DMSO. The tube was charged with preheated oil bath at 100 OC for 2 hrs.
The reaction mixture was diluted with ethyl acetate and quenched with 30 ml saturated solution of
Na2S2O3.5H2O or Na2S. Then, the aqueous phase was extracted with ethyl acetate (2x10). The combined
organic phase was dried over Na2SO4 and concentrated under vacuum. The crude was purified by
column chromatography on silica gel with gradient of elution of pet ether and ethyl acetate to give
mixture of product i.e. homo coupling product (major) and hydroxylation product (minor).
5, 5'-Dichloro-N2, N2'-di(quinolin-8-yl)-[1,1'-biphenyl]-2,2'-dicarboxamide, 3b, Scheme 4. Column
chromatography (SiO2, eluting with 6:4 hexane/ethyl acetate) afforded the desired product as a white
1
solid, (37 mg, 66%), mp 143 – 145 oC. H NMR (300 MHz, CDCl3): δ 10.23 (s, 2H), 8.58 (dd, J = 5.4,
3.6 Hz, 2H), 8.48ꢀ8.47 (m, 2H), 7.90 (dd, J = 6.9, 1.2 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 1.5
Hz, 2H), 7.44 (dd, J = 8.1, 1.8 Hz, 2H), 7.29 (d, J = 4.2 Hz, 2H), 7.18ꢀ7.16 (m, 4H); 13C NMR (150
MHz, CDCl3): δ 165.8, 147.7, 140.4, 138.0, 136.7, 135.7, 134.6, 134.1, 130.7, 129.2, 128.4, 127.2,
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 32
1
2
3
126.8, 121.5, 121.3, 116.5; IR (neat): υmax 3425, 3327, 1671, 1526, 1482; HRMS (ESI, m/z) calcd. for
C32H20Cl2N4O2Na [M + Na]+: 585.0861; found: 585.0851.
4
5
6
7
8
9
5, 5'-Dibromo-N2, N2'-di(quinolin-8-yl)-[1,1'-biphenyl]-2,2'-dicarboxamide, 3c, Scheme 4. Column
chromatography (SiO2, eluting with 5:5 hexane/ethyl acetate) afforded the desired product as a white
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
1
solid, (45 mg, 68 %), mp 241 – 243 C. H NMR (300 MHz, CDCl3): δ 10.22 (s, 2H), 8.58ꢀ8.55 (m,
2H), 8.48 (dd, J = 4.2, 1.5 Hz, 2H), 7.91 (dd, J = 8.1, 1.5 Hz, 2H), 7.69ꢀ7.66 (m, 4H), 7.62ꢀ7.58 (m,
13
2H), 7.29 (d, J = 4.2 Hz, 2H), 7.16ꢀ7.15 (m, 4H); C NMR (150 MHz, CDCl3): δ 165.9, 147.7, 140.4,
137.9, 135.7, 135.1, 134.1, 133.6, 131.4, 129.2, 127.2, 126.8, 125.0, 121.5, 121.3, 116.4; IR (neat): υmax
3414, 3334, 1667, 1525, 1482; HRMS (ESI, m/z) calcd. for C32H20Br2N4O2Na [M + Na]+: 672.9851;
found: 672.9851.
N2, N2'-di(quinolin-8-yl)-5, 5'-bis(trifluoromethyl)-[1,1'-biphenyl]-2,2'-dicarboxamide, 3d,
Scheme 4. Column chromatography (SiO2, eluting with 4:6 hexane/ethyl acetate) afforded the desired
product as a white solid, (41 mg, 65%), mp 230 – 232 oC. 1H NMR (300 MHz, CDCl3): δ 10.28 (s, 2H),
8.53ꢀ8.51 (m, 2H), 8.47 (dd, J = 4.2, 1.2 Hz, 2H), 7.93ꢀ7.90 (m, 4H), 7.79ꢀ7.74 (m, 4H), 7.29 (dd, J =
8.4, 4.2 Hz, 2H), 7.14ꢀ7.12 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 165.6, 147.9, 139.6, 137.99, 137.96,
135.9, 133.9, 132.8 (q, J = 32.3 Hz), 128.3, 127.9, 127.3, 126.9, 125.5, 125.4, 121.8, 121.5, 116.7; IR
(neat): υmax 3401, 3308, 1923, 1677, 1536, 1483; HRMS (ESI, m/z) calcd. for C34H20F6N4O2Na [M +
Na]+: 653.1388; found: 653.1388.
Experimental Procedure for the Reaction in Gram-Scale
Nꢀ(quinolinꢀ8ꢀyl)benzamide (1.1 gm, 4.5 mmol) was taken in an oven dried round bottom flask which
was connected through condenser under N2 atmosphere and dissolved with DMF:DMSO 100 ml (3:1),
then Cu(OAc)2.H2O (899 mg, 4.5 mmol, 1 equiv), pyridine (3.6 ml, 10 equiv) was added in it and
o
stirred for 4 hrs at 100 C. The reaction mixture was diluted with ethyl acetate and quenched with 200
ml saturated solution of Na2S2O3.5H2O or Na2S. Then, the aqueous phase was extracted with ethyl
acetate (4x30). The combined organic phase was washed with 1N HCl (100 ml) and collected organic
phase, then dried over Na2SO4 and concentrated under vacuum. The crude was purified by column
chromatography on silica gel with gradient of elution of pet ether and ethyl acetate to give the desired
white hydroxylation product 1.08 gm (yield 91%).
Experimental Procedure for Deprotection of the Directing Group
2ꢀhydroxyꢀNꢀ(quinolinꢀ8ꢀyl)benzamide (40 mg, 0.15 mmol) was taken in an oven dried round bottom
flask which was connected through condenser under N2 atmosphere and 3 ml of 12 M HCl was added in
26
ACS Paragon Plus Environment

Page 27 of 32
The Journal of Organic Chemistry
1
2
3
4
o
it. Then, it was stirred for 24 hrs at 110 C followed by cooling. EtOAc (15 ml) and saturated aq.
5
6
7
8
NaHCO3 (50 ml) were added. The aqueous layer was extracted with EtOAc (2 x5 ml). The combined
organic layers were washed with brine (10 ml), dried over MgSO4, filtered and concentrated in in vacuo
to afford the 8ꢀaminoquinoline (yellow solid, 21 mg, 97 %). Then 1 M HCl was added in aqueous layer
until pH 4. The aqueous layer was extracted with EtOAC (2 x 5 ml). The combined organic layers were
washed with brine (10 ml), dried over MgSO4, filtered and concentrated in in vacuo. The residue was
purified by column chromatograpy on silica gel to afford the desired carboxylic acid (white solid, 20
mg, 96%).
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
2-hydroxybenzoic acid, Column chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate)
o
1
afforded the desired product as a white solid, (20 mg, 96%), mp 155 – 157 C. H NMR (300 MHz,
CDCl3): δ 10.39 (s, 1H), 7.96 (dd, J = 8.1, 1.8 Hz, 1H), 7.58ꢀ7.52 (m, 1H), 7.05ꢀ6.94 (m, 2H); 13C NMR
(150 MHz, CDCl3): δ 173.9, 162.2, 136.8, 130.8, 119.5, 117.8, 111.2; IR (neat): υmax 3428, 3238, 2857,
1659, 1611, 1442, 1296, 1246; HRMS (EI, m/z) calcd. for C7H6O3 [M]+: 138.0317; found: 138.0285.
Quinolin-8-amine, 4b, Scheme 5: 1H NMR (300 MHz, CDCl3): δ 8.78 (dd, J = 4.2, 1.8 Hz, 1H), 8.08
(dd, J = 8.4, 1.8 Hz, 1H), 7.40ꢀ7.32 (m, 2H), 7.18ꢀ7.15 (m, 1H), 6.95 (dd, J = 7.5, 1.2 Hz, 1H), 4.99 (s,
2H)
Experimental Procedure for the Synthesis of Diflunisal:
Step 1. Experimental Procedure for Synthesis of 2',4'-difluoro-4-hydroxy-N-(quinolin-8-yl)-[1,1'-
biphenyl]-3-carboxamide, 2aa from 1aa
2',4'ꢀdifluoroꢀNꢀ(quinolinꢀ8ꢀyl)ꢀ[1,1'ꢀbiphenyl]ꢀ3ꢀcarboxamide, yy (144 mg, 0.4 mmol) was taken in an
oven dried round bottom flask which was connected through condenser under N2 atmosphere and
dissolved with DMF:DMSO 8 ml (3:1), then Cu(OAc)2.H2O (80 mg, 0.4 mmol, 1 equiv), pyridine (0.3
ml, 10 equiv) was added in it and stirred for 2 hrs at 100 oC. The reaction mixture was diluted with ethyl
acetate and quenched with 50 ml saturated solution of Na2S2O3.5H2O or Na2S. Then, the aqueous phase
was extracted with ethyl acetate (2x30). The combined organic phase was washed with 1N HCl (50 ml)
and collected organic phase, then dried over Na2SO4 and concentrated under vacuum. The crude was
purified by column chromatography on silica gel with gradient of elution of pet ether and ethyl acetate
to give the desired white hydroxylation product 141 mg (yield 94%).
Step 2. Deprotection of 2aa to Diflunisal, 4aa
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 32
1
2
3
2',4'ꢀdifluoroꢀ4ꢀhydroxyꢀNꢀ(quinolinꢀ8ꢀyl)ꢀ[1,1'ꢀbiphenyl]ꢀ3ꢀcarboxamide (57 mg, 0.15 mmol) was
taken in an oven dried round bottom flask which was connected through condenser under N2
atmosphere and 3 ml of 12 M HCl was added in it. Then, it was stirred for 24 hrs at 110 oC followed by
cooling. EtOAc (15 ml) and saturated aq. NaHCO3 (50 ml) were added. The aqueous layer was
extracted with EtOAc (2 x5 ml). The combined organic layers were washed with brine (10 ml), dried
over MgSO4, filtered and concentrated in in vacuo to afford the 8ꢀaminoquinoline (yellow solid, 20 mg,
94 %). Then 1 M HCl was added in aqueous layer until pH 4. The aqueous layer was extracted with
EtOAC (2 x 5 ml). The combined organic layers were washed with brine (10 ml), dried over MgSO4,
filtered and concentrated in in vacuo. The residue was purified by column chromatograpy on silica gel
to afford the desired drug molecule diflunisal (white solid, 33 mg, 88%).
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
o
1
mp 210 – 212 C. H NMR (600 MHz, DMSOꢀd6): δ 7.89 (s, 1H), 7.56ꢀ7.52 (m, 2H), 7.35ꢀ7.31 (m,
1H), 7.17ꢀ7.14 (m, 2H), 6.95 (d, J = 4.5 Hz, 1H); 13C NMR (150 MHz, DMSOꢀd6): 171.8, 162.0, 161.7
(dd, J = 244.5, 12.0 Hz), 159.4 (dd, J = 246.0, 12.0 Hz), 134.9, 131.9 (dd, J = 9.0, 4.5 Hz), 130.72,
130.70, 124.8, 124.4, 117.6, 112.5 (d, J = 4.5 Hz), 112.3 (d, J = 4.5 Hz), 104.9 (t, J = 22.5 Hz); IR
(neat): υmax 3447, 2925, 2855, 1673, 1486, 1448, 1245; HRMS (EI, m/z) calcd. for C13H8F2O3 [M]+:
250.0442; found: 250.0447.
Spectral Data for 2a-d4 Compound, Column chromatography (SiO2, eluting with 9:1 hexane/ethyl
o
1
acetate) afforded the desired product as a white solid, (49 mg, 91%), mp 132 – 134 C. H NMR (300
MHz, CDCl3): δ 12.31 (s, 1H), 10.99 (s, 1H), 8.89 (dd, J = 4.2, 1.5 Hz, 1H), 8.87ꢀ8.82 (m, 1H), 8.21
(dd, J = 8.1, 1.2 Hz, 1H), 7.61ꢀ7.57 (m, 2H), 7.52 (dd, J = 8.4, 4.2 Hz, 1H); 13C NMR (75 MHz,
CDCl3): δ 168.4, 162.0, 148.5, 138.7, 136.4, 133.5, 128.0, 127.3, 122.2, 121.9, 116.9, 115.1; IR (neat):
υmax 3411, 3348, 1647, 1541, 1487; HRMS (ESI, m/z) calcd. for C16H8D4N2O2Na [M + Na]+: 291.1048;
found: 291.1038.
ASSOCIATED CONTENT
Supporting Information
Mechanistic, spectral, and crystallographic data. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: rjana@iicb.res.in
ACKNOWLEDGMENT
28
ACS Paragon Plus Environment

Page 29 of 32
The Journal of Organic Chemistry
1
2
3
This work was supported by Ramanujan fellowship, award no. SR/S2/RJNꢀ97/2012, DST, Govt. of
India. BKS thanks UGC for his fellowship. We thank RN for analyzing crystal structures.
4
5
6
7
8
9
References:
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) For reviews, see: (a) BrÜckl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Acc. Chem. Res. 2012, 45,
826ꢀ839. For selected examples, see: (b) Narayan, A. R. H.; JiménezꢀOsés, G.; Liu, P.; Negretti, S.;
Zhao, W.; Gilbert, M. M.; Ramabhadran, R. O.; Yang, Y.ꢀF.; Furan, L. R.; Li, Z.; Podust, L. M.;
Montgomery, J.; Houk, K. N.; Sherman, D. H. Nat. Chem. 2015, 7, 653ꢀ660.
(2) For reviews, see: (a) Engle, K. M.; Yu, J.ꢀQ. J. Org. Chem. 2013, 78, 8927ꢀ8955. For selected
examples, see: (b) Xu, H.; Shang, M.; Dai, H.ꢀX.; Yu, J.ꢀQ. Org. Lett. 2015, 17, 3830ꢀ3833. (c)
Wodrich, M. D.; Ye, B.; Gonthier, J. F.; Corminboeuf, C.; Cramer, N. Chem. Eur. J. 2014, 20, 15409ꢀ
15418. (d) Millet, A.; Larini, P.; Clot, E.; Baudoin, O. Chem. Sci. 2013, 4, 2241ꢀ2247; (e) Tang, S.ꢀY.;
Guo, Q.ꢀX.; Fu, Y. Chem. Eur. J. 2011, 17, 13866ꢀ13876.
(3) For reviews, see: (a) Daugulis, O.; Roane, J.; Tran, L. D. Acc. Chem. Res. 2015, 48, 1053ꢀ1064. (b)
Rouquet, G.; Chatani, N. Angew. Chem. Int. Ed. 2013, 52, 11726ꢀ11743. (c) Engle, K. M.; Mei, T.ꢀS.;
Wasa, M.; Yu, J.ꢀQ. Acc. Chem. Res. 2012, 45, 788ꢀ802. (d) Lyons, T. W.; Sanford, M. S. Chem. Rev.
2010, 110, 1147ꢀ1169. For selected examples, see: (e) Shang, M.; Wang, H.ꢀL.; Sun, S.ꢀZ.; Dai, H.ꢀX.;
Yu, J.ꢀQ. J. Am. Chem. Soc. 2014, 136, 11590ꢀ11593. (f) Liu, Y.ꢀJ.; Xu, H.; Kong, W.ꢀJ.; Shang, M.;
Dai, H.ꢀX.; Yu, J.ꢀQ. Nature, 2014, 515, 389ꢀ393. (g) Tran, L. D.; Roane, J.; Daugulis, O. Angew.
Chem. Int. Ed. 2013, 52, 6043ꢀ6046 (h) Zaitsev, V.G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154ꢀ13155.
(4) (a) Chen, G.; Shigenari, T.; Jain, P.; Zhang, Z.; Jin, Z.; He, J.; Li, S.; Mapelli, C.; Miller, M. M.;
Poss, M. A.; Scola, P. M.; Yeung, K.ꢀS.; Yu, J.ꢀQ. J. Am. Chem. Soc. 2015, 137, 3338ꢀ3351. (b) Li, S.;
Chen, G.; Feng, C.ꢀG.; Gong, W.; Yu, J.ꢀQ. J. Am. Chem. Soc. 2014, 136, 5267ꢀ5270. (c) He, J.; Li, S.;
Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.; Homs, A.; Yu, J.ꢀQ. Science, 2014, 343, 1216ꢀ1220.
29
ACS Paragon Plus Environment