Direct arylation of C(sp3)-H bonds in aliphatic amides with diaryliodonium salts in the presence of a nickel catalyst

Article abstract of DOI:10.1021/jo501691f

The Ni(II)-catalyzed direct arylation of C(sp³)-H (methyl and methylene) bonds in aliphatic amides containing an 8-aminoquinoline moiety as the directing group with diaryliodonium salts as coupling electrophiles is described. A wide variety of functional groups are tolerated in the reaction. The reaction represents the first example of the Ni-catalyzed direct arylation of C(sp³)-H bonds with diaryliodonium salts. (Chemical Equation Presented).

Full text of DOI:10.1021/jo501691f

Subscriber access provided by Umea University Library
Article
Direct Arylation of C(sp3)-H Bonds in Aliphatic Amides with
Diaryliodonium Salts in the presence of a Nickel Catalyst
Miki Iyanaga, Yoshinori Aihara, and Naoto Chatani
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501691f • Publication Date (Web): 27 Aug 2014
Downloaded from http://pubs.acs.org on August 30, 2014
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 20
The Journal of Organic Chemistry
1
2
3
4
5
Direct Arylation of C(sp3)-H Bonds in Aliphatic Amides with Diaryliodonium Salts in the
presence of a Nickel Catalyst
6
7
8
9
Miki Iyanaga, Yoshinori Aihara and Naoto Chatani*
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
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-
0871, Japan
chatani@chem.eng.osaka-u.ac.jp
ABSTRACT: The Ni(II)-catalyzed direct arylation of C(sp3)-H (methyl and methylene) bonds in
aliphatic amides containing an 8-aminoquinoline moiety as the directing group with diaryliodonium
salts as coupling electrophiles is described. A wide variety of functional groups are tolerated in the
reaction. The reaction represents the first example of the Ni-catalyzed direct arylation of C(sp3)-H
bonds with diaryliodonium salts.
INTRODUCTION
The transition metal catalyzed direct functionalization of C-H bonds has been extensively
studied as an alternative method to traditional cross coupling reactions.1 A wide variety of
electrophiles, such as halides, and nucleophiles, including organo-boron, zinc and Grignard
reagents have been utilized as coupling partners in the direct functionalization of C-H bonds. In
2005, Sanford and co-workers reported the first example of the Pd-catalyzed chelation-assisted
arylation of C-H bonds with diaryliodonium salts as electrophilic coupling partners.2 After this
successful example appeared in the literature, the utilization of diarylionium salts in the
functionalization of C-H bonds as coupling electrophiles has been of great interest, because the
reactions proceeded under relatively milder reaction conditions than reactions with aryl halides.
However, despite this progress, only palladium, platinum, and copper catalysts have been used in
the arylation of C-H bonds with diaryliodonium salts, and the most of arylation reactions in which
diarylionium salts are used involve the functionalization of C(sp2)-H bonds.3 We also recently
reported on the Ru(II)-catalyzed direct arylation of C-H bonds in 2-arylpyridines with
diaryliodonium salts.4 However, the direct arylation of C(sp3)-H bonds with diarylionium salts was
limited to only two examples, and both involved the use of a palladium complex as the catalyst.
Sanford and co-workers reported on the Pd-catalyzed arylation of benzyl C(sp3)-H bonds in 8-
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 20
1
2
3
4
5
6
7
8
9
methylquinoline,2 and Shi and co-workers developed the Pd-catalyzed aryltion of C(sp3)-H bonds
in aliphatic amides containing an 8-aminoquinoline moiety as the directing group.5 Herein, we
report on the Ni-catalyzed direct arylation of C(sp3)-H bonds in aliphatic amides with
diaryliodonium salts via the use of bidentate chelation assistance (eq. 1). This reaction represents
the first example of the Ni-catalyzed direct arylation of C(sp3)-H bonds with diaryliodonium salts.
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
The functionalization of C-H bonds by taking advantage of an 8-aminoquinoline directing
group has been extensively studied in recent years,6, 7 and this chelation-system has been found to
be applicable to the development of various functionalization of C(sp3)-H bonds in the presence of
transition metal complexes, such as palladium,8 ruthenium,9 copper,10 nickel,11 and iron.12 We
previously reported on the Ni-catalyzed arylation of C(sp3)-H bonds in aliphatic amides containing
an 8-aminoquinoline moiety with aryl iodides.11a Thus, in an initial attempt, we carried out the
reaction at the same reaction conditions as were used in a previously reported reaction.11a The
reaction of amide 1 (0.3 mmol) with the diaryliodonium salt 2b (0.36 mmol) in the presence of
Ni(OTf)2 (0.03 mmol) as a catalyst, MesCOOH (0.06 mmol) as a ligand and Na2CO3 (0.6 mmol) as
a base in DMF (0.6 mL) at 140 °C for 24 h gave the -arylation product 3a in 23% NMR yield
along with 74% of 1 being recovered. No evidence was found for the formation of the biarylated
product or any other product resulting from a reaction at the benzyl and phenyl C-H bonds.
Importantly, only a 4-methoxyphenyl group in 2b was introduced into the arylated product due to
the steric hindrance of the mesityl group. The use of 1,4-dioxane as the solvent instead of DMF
resulted in a dramatically improved yield of 3a to 81% (entry 2). The addition of a sterically bulky
carboxylic acid was required for the reaction to proceed efficiently when aryl iodides were used as
the coupling partner.11a In contrast to the previous reaction, the arylated product was obtained in
good yield even in the absence of a carboxylic acid (entry 6). Product yield is dependent on the
base used in the reaction. The use of Na2CO3 resulted in a high yield of product, but the use of
other bases resulted in almost no reaction (entry 6-11). MTHP (4-methyltetrahydro-2H-pyran),
2
ACS Paragon Plus Environment

Page 3 of 20
The Journal of Organic Chemistry
1
2
3
4
5
which has a higher boiling point (105 °C) and is a better solvent to dissolve organic compounds
than dioxane, was the solvent of choice (entry 12).
6
7
8
9
Table 1. Optimization of the Nickel-Catalyzed Direct Arylation of Aliphatic Amide 1 with
Diaryliodonium Salt 2a a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a Reaction conditions: amide 1 (0.3 mmol), diaryliodonium salt (0.36 mmol), Ni(OTf)2 (0.03 mmol),
ligand (0.06 mmol), base (0.6 mmol) in solvent (1.0 mL) at 140 °C for 24 h. b NMR yields. Values
in parenthesis are the isolated yields.
The effect of the directing group was examined. The formation of arylated products was not
observed at all when other directing groups, such as 4 or 5, or N-2-naphthylbenzamaide 6 or the
ester 7 were used. These results indicate the importance of a quinoline nitrogen and an NH bond.
Figure 1. Ineffective Directing Groups
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 20
1
2
3
4
5
6
7
8
9
It is known that diaryliodonium salts undergo decomposition to give aryl iodides and aryl
triflates at high temperatures or under the basic conditions (eq. 2).13 In order to examine whether
diaryliodonium salts themselves can function as a coupling partner or not, we carried out the
reaction with an aryl iodide and an aryl triflate (Scheme 1). Mes-I (2-iodo-1,3,5-trimethylbenzene)
was formed in 52% yield in the reaction with the diaryliodonium salt 2a. This result suggests that
an aryl triflate might be generated during the reaction, as shown in equation 2. While the reaction
with an aryl iodide gave the arylated product 3a in 37% under the standard reaction conditions, the
reaction with aryl triflate resulted in no reaction. These results suggest that the main pathway to 3a
involves a reaction with the diaryliodonium salt 2a, but the possibility that the small amount of 3a
is produced by a reaction with aryl iodide generated via the decomposition of the diaryliodonium
salt cannot be completely excluded.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme. 1 The Reaction with Various Electrophiles
With the optimized reaction conditions in hand, we examined the scope of the reaction (Table
2). We examined the effect of the counter anion of the diaryliodonium salt. The reaction with a
triflate (OTf) or a chloride (Cl) salt gave the arylated product 3b, but tetrafluoroborates (BF4) and
hexafluorophosphates (PF6) as counter ions resulted in no reaction. A variety of diaryliodonium
triflates 2b-2k were applicable to the arylation reaction. The reaction shows a high functional group
compatibility, tolerating methoxy, ester and chloride groups. A mesityl group was not introduced
in all cases, due to steric hindrance. Electron donating aryl groups resulted in slightly higher yields
than electron withdrawing aryl groups.
4
ACS Paragon Plus Environment

Page 5 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
Table 2. Arylation of Aliphatic Amide 1 with Various Diaryliodonium Salts a
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: amide 1 (0.3 mmol), diaryliodonium salt (0.36 mmol), Ni(OTf)2 (0.03
mmol), Na2CO3 (0.6 mmol) in MTHP (1.0 mL) at 140 °C for 24 h. Values in parenthesis are the
yields of recovered starting amide. b NMR yields. c Purified by GPC.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 20
1
2
3
4
5
6
Table 3. The Nickel-Catalyzed Direct Arylation of Aliphatic Amides with Diaryliodonium
Salt 2a a
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: amide (0.3 mmol), diaryliodonium salt 2a (0.36 mmol), Ni(OTf)2 (0.03
b
mmol), Na2CO3 (0.6 mmol) in MTHP (1.0 mL) at 140 °C for 24 h. Values in parenthesis are the
isolated yields based on the reacted amide.
6
ACS Paragon Plus Environment

Page 7 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Table 3 shows the results for reactions of various aliphatic amides with the diaryliodonium
salt 2a. The reaction was sensitive to the structure of the amide used, and unreactive amides are
listed at the bottom of Table 3. Aliphatic amides possessing no hydrogen at the -position reacted
exclusively at the methyl group, and methylene and benzene C-H bonds were not arylated.
Although the reaction of 1-methylcyclohexanecarboxamide 13 resulted in selective mono-arylation
only at the methyl group, 1-methylcycloheptanecarboxamide 14 gave a mixture of mono-arylated
14a and di-arylated products 14b, the latter of which was produced by a reaction at the cyclic
methylene C-H bonds. This difference in reactivity as a function of ring size probably stemmed
from differences in the stability of the cyclometalated complexes between the cleavage of the
methyl C-H bond and the methylene C-H bond, as evidenced by B3LYP/SDD (Ni)/6-31G* (C, H,
O, N) calculations. The results show that the complex involving the activation of a methyl C-H
bond is 4.6 kJ/mol more stable than a complex involving the activation of a methylene C-H bond in
13 and the complex activated methylene C-H bond is 13.9 kJ/mol more stable in 14 (Figure 2).
When 1-phenylcyclobutanecarboxamide 15 and 1-phenylcyclopentanecarboxamide 16 were used,
the cleavage of -methylene C-H bonds was the predominant reaction and -benzenes C(sp2)-H
bonds were completely unreactive.
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
Figure 2. DFT Calculation of the Energy Difference in a Cyclometalated Complex
To obtain mechanistic insights into the reaction, the deuterated amide 9-d3 was reacted with
the diarylionium salt 2a for 12 h (Scheme 2). H/D exchange between the methyl C-H bonds and the
N-H bond occurred. The D content in the recovered amide decreased from >99% to 92%. But the
extent of H/D exchange in the present reaction is smaller than a previously reported reaction with
aryl iodides,11a because the efficiency of cleavage of C-H bonds depends on the nature of the
additive and solvent used, and in addition, the oxidative addition of the diaryliodonium salt is
irreversible and proceeds more smoothly than that of aryl iodides. H/D exchange was also observed
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 20
1
2
3
4
5
6
in the absence of the diaryliodonium salt. These results indicate that the cleavage of the C-H bond
is a reversible step, and that it occurs before the oxidative addition of the diaryliodonium salt.
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
Scheme 2. Deuterium Labeling Experiments
A competition experiment with electronically different diaryliodonium salts was carried out
to obtain additional mechanistic information (eq. 3). Electronically donating aryl groups facilitate
the reaction, and this tendency conforms to our previously reported reaction with aryl iodides.11a,14
Diaryliodonium salts are also known to function as aryl radical precursors.15 To investigate
the possibility that an aryl radical is involved in the present reaction, a radical trapping experiment
was carried out (eq. 4). The addition of TEMPO had no effect on the reaction, and the arylated
product was obtained in a moderate yield of 56%, and the by-product of the reaction resulting from
the reaction of TEMPO with an aryl radical was not formed.
8
ACS Paragon Plus Environment

Page 9 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
TEMPO
Ni(OTf)2
Na2CO3
1.2 equiv
10 mol%
2 equiv
O
O
OTf
Ph
Ph
Q
+
Ph
Ph
Q
I
N
N
Mes
(4)
H
H
MTHP 1 mL
140 °C, 24 h
Q = 8-quinolinyl
Ar
OMe
1.2 equiv
56% (38% SM)
NMR yields
Ar
O
10
11
12
13
14
15
16
17
18
N
not formed
A proposed mechanism for the reaction is shown in Scheme 3. Coordination of the amide to
the Ni center followed by ligand exchange gives the Ni complex 18, which undergoes reversible
cyclometalation to give 19, probably via a CMD mechanism. The oxidative addition of the
diaryliodonium salt with the concomitant generation of an Mes-I gives the high valent Ni(IV)
complex 20 stabilized by an 8-aminoquinoline moiety. The complex 20 undergoes reductive
elimination and protonation to afford the desired arylation product with the regeneration of Ni(II).
The competition experiment clearly shows that the electron donating aryl group facilitates the
reaction and the data from the deuterium experiments suggests that the cleavage of C-H bonds
proceeds in the absence of diaryliodonium salts. Based on these results, the rate determined step is
not likely to be the cleavage of the C-H bond or the oxidative addition of the diaryliodonium salt,
and is likely to be the reductive elimination step. The advantage of this reaction is that the reaction
proceeds in the absence of a carboxylic acid in contrast to the reaction with aryl iodides.11a In the
reaction with aryl iodides, one of the roles of the carboxylic acid is to accelerate the reductive
elimination to generate a cationic Ni(IV) intermediate, thus replacing the iodide with a carboxylate
from the Aryl-Ni(IV)-I complex. However the reaction with diaryliodonium salts directly forms the
cationic Ni(IV) intermediate 20 because the counter anion of diaryliodonium salt is a triflate.
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
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 20
1
2
3
4
5
6
O
N
O
Na2CO3
+
N
H
N
H
N
NiX2
Ar
7
HX
NaX + NaHCO3
8
9
O
O
N
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
N
N
Ni
X
N
18
Ni
H
Ar
OTf
21
Na2CO3
NaHCO3 + NaX
O
O
N
Ni
N
N
Ni
N
Ar
20
19
OTf
Mes
HX = NaHCO3, H2O, amide
I
OTf
Ar
I
Mes
Scheme 3. Proposed Mechanism
CONCLUSIONS
We report herein on the development of the Ni(II)-catalyzed direct arylation of C(sp3)-H
bonds (methyl and methylene) in aliphatic amides with diaryliodonium salts, taking advantage of a
bidentate chelation assistance. The reaction represents the first example of the Ni-catalyzed
functionalization of C-H bonds with diaryliodonium salts. The reaction is sensitive to the nature of
bases used in the reaction. The reaction shows high functional group compatibility. The cleavage of
C-H bonds is reversible. The 8-aminoquinoline directing group is easily removed and converted to
more useful functional groups.16
EXPERIMENTAL SECTION
General Comments
1H NMR and C NMR spectra were recorded were recorded at 400 and 100 MHz in CDCl3 with
13
tetramethylsilane as the internal standard. Data are reported as follows: chemical shift in ppm,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, and m = multiplet),
coupling constant (Hz), and integration. For Infrared spectra (IR), absorptions are reported in
reciprocal centimeters with the following relative intensities: s (strong), m (medium), or w (weak).
Mass spectra were obtained with ionization voltages of 70 eV. High resolution mass spectra
(HRMS) were obtained by EI using a double focusing mass spectrometer. Analytical gas
chromatography (GC) was carried out with a flame ionization detector. Column chromatography
10
ACS Paragon Plus Environment

Page 11 of 20
The Journal of Organic Chemistry
1
2
3
4
5
was performed with SiO2 (Silicycle SiliaFlash F60 (230-400 mesh)). Some compounds were
purified by gel permeation chromatography (GPC).
6
7
8
Synthesis of the Starting Amides.
All amides containing an 8-aminoquinoline moiety were prepared by the reaction of the
corresponding acid chlorides with 8-aminoquinoline. 11a,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
Synthesis of the Diaryliodonium Salts.
4-Methoxyphenyl(mesityl)iodonium trifluoromethanesulfonate 2a was prepared by Gaunt’s
method.18
4-Methylphenyl(mesityl)iodonium
trifluoromethanesulfonate
2h
and
3-
Methylphenyl(mesityl)iodonium trifluoromethanesulfonate 2i were prepared by Olofsson’s
method.19 The other diaryliodonium triflate salts (Ar1Ar2IOTf) were prepared by MacMillan’s
method.20 Diphenyliodonium tetrafluoroborate 8c was prepared by Ochiai’s method.21
General Procedure for the Arylation of Aliphatic Amide with Diaryliodonium Salts.
To an oven-dried 5 mL screw-capped vial in a glove box, 2,2-diphenyl-N-(quinolin-8-
yl)propanamide
1
(106
mg,
0.3
mmol),
4-methoxyphenyl(mesityl)iodonium
trifluoromethanesulfonate 2a (181 mg, 0.36 mmol), Ni(OTf)2 (10.6 mg, 0.03 mmol), Na2CO3 (64
mg, 0.6 mmol) and 4-methyltetrahydropyrane (1 mL) were added. The mixture was stirred for 24 h
at 140 °C. The resulting mixture was filtered through a celite pad and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc= 10/1) to
afford the desired arylated product 3a (99 mg, 72%) as a white solid.
3-(4-Methoxyphenyl)-2,2-diphenyl-N-(quinolin-8-yl)propanamide (3a). Rf 0.18 (hexane/EtOAc
= 10/1). White solid. Yield: 99 mg, 72%. Mp =164 °C. 1H NMR (CDCl3, 399.78 MHz) 3.68 (s, 3H),
3.85 (s, 2H), 6.56 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H), 7.54-7.32 (m, 7H), 7.36-7.38 (m,
4H), 7.42 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 8.52 (dd, J = 4.0,
1.2 Hz, 1H), 8.78 (dd, J = 8.0, 1.2 Hz, 1H), 10.22 (brs, 1H); 13C NMR (CDCl3, 100.53 MHz) 43.6,
55.0, 64.5, 112.8, 116.0, 121.3, 121.4, 127.0, 127.3, 127.8, 128.0, 129.7, 129.8, 132.2, 134.7, 136.0,
138.7, 142.4, 148.1, 157.9, 172.2; HRMS Calcd for C31H26N2O2: 458.1994; Found: 458.1995.
2,2,3-Triphenyl-N-(quinolin-8-yl)propanamide (3b). Rf 0.31 (hexane/EtOAc = 10/1). Off white
solid. Yield: 87 mg, 68%. Mp = 135-136 °C. 1H NMR (CDCl3, 399.78 MHz) 3.92 (s, 2H), 6.83 (d,
J = 6.8 Hz, 2H), 6.99-7.08 (m, 3H), 7.25-7.31 (m, 7H), 7.36-7.39 (m, 4H), 7.42 (d, J = 8.0 Hz, 1H),
8.04 (dd, J = 8.0, 1.4 Hz, 1H), 8.52 (dd, J = 4.2, 1.4 Hz, 1H), 8.79 (d, J = 8.0 Hz, 1H), 10.24 (brs,
13
1H); C NMR (CDCl3, 100.53 MHz) 44.4, 64.4, 116.0, 121.3, 121.4, 126.0, 127.0, 127.0, 127.4,
127.7, 128.0, 129.7, 131.2, 134.6, 135.9, 137.9, 138.6, 142.2, 148.1, 172.1; IR (neat) 3330 w, 3027
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 20
1
2
3
4
5
w, 1678 m, 1522 s, 1483 m; MS m/z (relative intensity, %) 428 (M+, 5), 220 (20), 172 (11), 171
(100), 144 (7); HRMS Calcd for C30H24N2O:428.1889; Found: 428.1891.
6
7
8
9
2,2-Diphenyl-N-(quinolin-8-yl)-3-(4-(trifluoromethyl)phenyl)propanamide (3c). Rf 0.25
1
(hexane/EtOAc = 10/1). Yield: 97 mg, 65%. White solid. Mp = 165 °C. H NMR (CDCl3, 399.78
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
MHz) 3.95 (s, 2H), 6.94 (d, J = 8.4 Hz, 2H), 7.27-7.32 (m, 9H), 7.33-7.39 (m, 4H), 7.44 (d, J = 8.4
Hz, 1H) 7.51 (t, J = 8.0 Hz, 1H), 8.06 (dd, J = 8.2, 1.4 Hz, 1H), 8.53 (dd, J = 4.0, 1.4 Hz, 1H), 8.76
(dd, J = 7.8, 1.4 Hz, 1H), 10.24 (brs, 1H); 13C NMR (CDCl3, 100.53 MHz) 44.3, 64.4, 116.0, 121.5
(d, 2.81 Hz), 124.1 (d, 3.82 Hz), 124.3 (q, 271 Hz), 127.2, 127.3, 127.7, 127.8, 128.0, 128.2, 128.32,
128.7, 129.5, 131.5, 134.5, 136.0, 138.6, 141.6, 141.9, 142.3, 148.1, 171.7; IR (neat) 3329 w, 3058
w, 1680 m, 1522 s, 1484 m; MS m/z (relative intensity, %) 496 (M+, 5), 220 (22), 172 (11), 171
(100), 144 (4); HRMS Calcd for C31H23F3N2O:496.1762; Found: 496.1765.
Methyl
4-(3-oxo-2,2-diphenyl-3-(quinolin-8-ylamino)propyl)benzoate
(3d).
Rf
0.09
1
(hexane/EtOAc = 10/1). White solid. Yield: 90 mg, 62%. Mp = 169-170 °C. H NMR (CDCl3,
399.78 MHz) 3.83 (s, 3H), 3.95 (s, 2H), 6.91 (d, J = 7.6 Hz, 2H), 7.24-7.32 (m, 7H), 7.37-7.39 (m,
4H), 7.43 (d, J = 8.4 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.68 (d, J = 7.6 Hz, 2H), 8.04 (d, J = 8.4 Hz,
13
1H), 8.52 (d, J = 4.4 Hz, 1H), 8.76 (d, J = 7.6 Hz, 1H), 10.24 (brs, 1H); C NMR (CDCl3, 100.53
MHz) 44.5, 51.9, 64.4, 116.0, 121.4, 127.2, 127.2, 127.8, 128.2, 128.6, 128.7, 129.5, 131.2, 134.5,
136.0, 138.6, 141.9, 143.7, 148.1, 167.2, 171.7; IR (neat) 3330 w, 2950 w, 1717 m, 1679 m, 1522 s,
1484 m; MS m/z (relative intensity, %) 487 (M+, 2), 220 (23), 172 (11), 171 (100), 144 (6); HRMS
Calcd for C32H26N2O3: 486.1943; Found: 486.1940.
3-(4-Acetylphenyl)-2,2-diphenyl-N-(quinolin-8-yl)propanamide (3e). Rf 0.11 (hexane/EtOAc =
1
10/1). Pale yellow solid. Yield: 80 mg, 57%. Mp = 179-180 °C. H NMR (CDCl3, 399.78 MHz)
2.50 (s, 3H), 3.96 (s, 2H), 6.93 (d, J = 8.4 Hz, 2H), 7.26-7.34 (m, 7H), 7.36-7.41 (m, 4H), 7.45 (dd,
J = 8.0, 1.4 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2 H), 8.06 (dd, J = 8.2, 1.4 Hz,
1H), 8.53 (dd, J = 4.0, 1.2 Hz, 1H), 8.76 (dd, J = 7.6, 1.0 Hz, 1H), 10.23 (brs, 1H); 13C NMR
(CDCl3, 100.53 MHz) 26.5, 44.5, 64.4, 116.0, 121.5, 127.2, 127.2, 127.4, 127.8, 128.2, 128.5,
129.5, 131.4, 134.5, 134.9, 136.0, 138.6, 142.0, 144.0, 148.1, 171.7, 198.2; IR (neat) 3330 w, 3019
w, 1679 s, 1604 w, 1523 s, 1423 m; MS m/z (relative intensity, %) 471 (M+, 2), 220 (23), 172 (12),
171 (100), 144 (5) HRMS Calcd for C32H26N2O2: 470.1994; Found: 470.1996.
3-(4-Nitrophenyl)-2,2-diphenyl-N-(quinolin-8-yl)propanamide (3f). Rf 0.2 (hexane/EtOAc =
10/1). Pale yellow solid. Yield: 61 mg, 43%. Mp = 210 °C. 1H NMR (CDCl3, 399.78 MHz) 3.99 (s,
2H), 7.01 (d, J = 8.4 Hz, 2H), 7.27-7.33 (m, 7H), 7.36-7.40 (m, 4H), 7.45 (dd, J = 8.2 , 1.2 Hz, 1H),
7.51 (t, J = 8.0 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 8.07 (dd, J = 8.0, 1.2 Hz, 1H), 8.54 (dd, J = 4.2,
12
ACS Paragon Plus Environment

Page 13 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
13
1.2 Hz, 1H) 8.74 (dd, J = 8.0, 1.2 Hz, 1H), 10.23 (brs, 1H); C NMR (CDCl3, 100.53 MHz) 44.4,
64.4, 116.0, 121.5, 121.6, 122.4, 127.2, 127.5, 128.4, 129.4, 132.0, 134.4, 136.0, 138.6, 141.7,
146.3, 146.3, 148.2, 171.4; IR(neat) 3328 w, 3059 w, 1680 m, 1520 s, 1485 m; MS m/z (relative
intensity, %) 473 (M+, 5), 220 (23), 172 (12), 171 (100); HRMS Calcd for C30H23N3O3:473.1739;
Found: 473.1737.
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-(4-Chlorophenyl)-2,2-diphenyl-N-(quinolin-8-yl)propanamide (3g). Rf 0.26 (hexane/EtOAc =
1
10/1). Pale yellow solid. Yield: 79 mg, 57%. Mp = 178-179 °C. H NMR (CDCl3, 399.78 MHz)
3.86 (s, 2H), 6.76 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 7.28-7.32 (m, 7H), 7.33-7.38 (m,
4H), 7.44 (d, J = 8.4 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 8.05 (dd, J = 8.2, 1.4 Hz, 1H), 8.53 (dd, J =
13
4.0, 1.4 Hz, 1H), 8.75 (dd, J = 7.6, 1.4 Hz, 1H), 10.23 (brs, 1H); C NMR (CDCl3, 100.53 MHz)
43.8, 64.4, 116.0, 121.4, 121.4, 127.2, 127.2, 127.4, 127.8, 128.2, 129.6, 131.9, 132.5, 134.5, 136.0,
136.4, 138.6, 142.0, 148.1, 171.8; IR (neat) 3330 w, 3020 w, 1679 m, 1522 s, 1485 s; MS m/z
(relative intensity, %) 462 (M+, 5), 220 (24), 172 (11), 171 (100), 144 (9); HRMS Calcd for
C30H23ClN2O: 462.1499; Found: 462.1501.
2,2-Diphenyl-N-(quinolin-8-yl)-3-(p-tolyl)propanamide (3h). Rf 0.26 (hexane/EtOAc = 10/1).
Off white solid. Yield: 93 mg, 70%. Mp = 150-151 °C. 1H NMR (CDCl3, 399.78 MHz) 2.20 (s, 3H),
3.87 (s, 2H), 6.70 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 8.0 Hz, 2H), 7.28-7.31 (m, 7H), 7.36-7.42 (m,
5H), 7.49 (t, J = 8.0 Hz, 1H), 8.03 (dd, J = 8.4, 1.2 Hz, 1H), 8.51 (dd, J = 2.4, 1.2 Hz, 1H), 8.78 (dd,
J = 8.0, 1.2 Hz, 1H), 10.23 (brs, 1H); 13C NMR (CDCl3, 100.53 MHz) 21.0, 44.0, 64.3, 116.0,
121.3, 121.4, 127.0, 127.2, 127.7, 128.0, 128.1, 129.7, 131.1, 134.6, 134.6, 135.5, 135.9, 138.6,
142.3, 148.0, 172.2; IR (neat) 3331 w, 3020 w, 1679 m, 1521 s, 1483 m; MS m/z (relative
intensity, %) 442 (M+, 16), 220 (21), 172 (12), 171 (100), 144 (21); HRMS Calcd for C31H26N2O:
442.2045; Found: 442.2044.
2,2-Diphenyl-N-(quinolin-8-yl)-3-(m-tolyl)propanamide (3i). Rf 0.26 (hexane/EtOAc = 10/1).
1
Off white solid. Yield: 66 mg, 50%. Mp = 164 °C. H NMR (CDCl3, 399.78 MHz) 2.08 (s, 3H),
3.87 (s, 2H), 6.50 (s, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.85-6.93 (m, 2H), 7.28-7.31 (m, 7H), 7.36-7.39
(m, 4H), 7.42 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 8.04 (dd, J = 8.4, 1.6 Hz, 1H), 8.52 (dd, J
= 4.0, 1.6 Hz, 1H), 8.78 (dd, J = 8.0, 1.6 Hz, 1H), 10.24 (brs, 1H); 13C NMR (CDCl3, 100.53 MHz)
21.2, 44.3, 64.4, 116.0, 121.3, 121.4, 126.7, 127.0, 127.2, 127.2, 127.4, 127.8, 128.0, 128.0, 129.7,
132.2, 134.7, 136.0, 136.7, 137.6, 138.7, 142.3, 148.1, 172.1; IR (neat) 3331 w, 3056 w, 1681 m,
1523 s, 1485 m; MS m/z (relative intensity, %) 442 (M+, 6), 220 (20), 172 (11), 171 (100), 144
(11); HRMS Calcd for C31H26N2O: 442.2045; Found: 442.2048.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 20
1
2
3
4
5
6
7
8
9
2-(4-Methoxybenzyl)-2-phenyl-N-(quinolin-8-yl)heptanamide (9a). Rf 0.26 (hexane/EtOAc =
10/1). White solid. Yield: 79 mg, 58%. Mp = 144 °C. 1H NMR (CDCl3, 399.78 MHz) 0.83 (t, J =
6.4 Hz, 3H), 1.26-1.55 (m, 6H), 2.01 (t, J = 8.0, 2H), 3.35 (d, J = 14.0 Hz, 1H), 3.51 (d, J = 13.6 Hz,
1H), 3.72 (s, 3H), 6.63 (s, 4H), 7.25-7.36 (m, 6H), 7.46 (d, J = 8.0, 1H), 7.54 (t, J = 8.4 Hz, 1H),
8.08 (d, J = 8.4 Hz, 1H), 8.58 (dd, J = 4.0, 1.2 Hz, 1H), 8.78 (d, J = 7.6 Hz, 1H), 9.81 (brs, 1H); 13C
NMR (CDCl3, 100.53 MHz) 14.0, 22.4, 24.1, 32.3, 34.0, 40.8, 55.1, 56.6, 113.0, 116.0, 21.01,
121.4, 127.0, 127.3, 127.7, 127.8, 128.4, 129.3, 131.2, 134.7, 138.6, 143.0, 148.1, 158.0, 174.7;
HRMS Calcd for C30H32N2O2: 452.2464; Found: 452.2469.
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-Butyl-2-(4-methoxybenzyl)-N-(quinolin-8-yl)hexanamide (10a). Rf 0.28 (hexane/EtOAc =
10/1). Pale brown solid. Yield: 26 mg, 21%. Mp =97-98 °C. 1H NMR (CDCl3, 399.78 MHz) 0.92 (t,
J = 6.8 Hz, 6H), 1.32-1.38 (m, 8H), 1.59-1.80 (m, 4H), 3.01 (s, 2H), 3.68 (s, 3H), 6.70 (d, J = 8.8
Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 7.42 (dd, J = 8.4, 4.0, 1H), 7.48-7.57 (m, 2H), 8.14 (dd, J = 8.4,
13
1.6 Hz, 1H), 8.74 (dd, J = 4.4, 1.6 Hz, 1H), 8.82 (dd, J = 8.0, 1.6 Hz, 1H), 10.15 (brs, 1H); C
NMR (CDCl3, 100.53 MHz) 14.0, 23.2, 26.2, 34.3, 40.2, 51.6, 55.0, 113.3, 116.2, 121.1, 121.4,
127.4, 127.9, 129.8, 130.9, 134.4, 136.2, 138.7, 148.1, 158.0, 175.4; HRMS Calcd for C27H34N2O2:
418.2620; Found: 418.2617.
2-Benzyl-2-(4-methoxybenzyl)-N-(quinolin-8-yl)butanamide (11a). Rf 0.23 (hexane/EtOAc =
10/1). Pale brown solid. Yield: 55 mg, 43%. Mp =97-98 °C. 1H NMR (CDCl3, 399.78 MHz) 1.18 (t,
J = 7.2 Hz, 3H), 1.75 (q, J = 7.2 Hz, 2H), 2.95 (dd, J = 20.8, 13.6 Hz, 2H), 3.29 (dd, J = 25.6,14.0
Hz, 2H), 3.64 (s, 3H), 6.66 (d, J = 8.0 Hz, 2H), 7.07-7.21 (m, 7H), 7.36 (dd, J = 8.4, 4.0 Hz,1H),
7.47 (d, J = 8.4 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.60 (dd, J = 4.0, 1.2 Hz,
1H), 8.86 (dd, J = 8.0, 1.2 Hz, 1H), 9.95 (brs, 1H); 13C NMR (CDCl3, 100.53 MHz) 8.7, 23.8, 40.9,
41.5, 53.3, 55.0, 113.4, 116.2, 121.3, 121.4, 126.2, 127.3, 127.8, 128.0, 129.5, 130.1, 131.0, 134.2,
136.0, 137.7, 138.6, 148.0, 158.0, 174.6; HRMS Calcd for C28H28N2O2: 424.2151; Found:
424.2145.
3-(4-Methoxyphenyl)-2-methyl-2-phenyl-N-(quinolin-8-yl)propanamide
(12a).
Rf 0.11
1
(hexane/EtOAc = 10/1). White solid. Yield: 45 mg, 38%. Mp =136 °C. H NMR (CDCl3, 399.78
MHz) 1.68 (s, 3H), 3.34 (d, J = 13.6 Hz, 1H), 3.56 (d, J = 13.6 Hz, 1H), 3.71 (s, 3H), 6.66 (d, J =
8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 7.27-7.38 (m, 4H), 7.43-7.45 (m, 3H), 7.52 (t, J = 8.4 Hz, 1H),
8.06 (dd, J = 8.4, 1.6 Hz, 1H), 8.57 (dd, J = 4.0, 1.6 Hz, 1H), 8.80 (d, J = 8.0 Hz, 1H), 9.89 (brs,
1H); 13C NMR (CDCl3, 100.53 MHz) 22.8, 44.3, 52.9, 55.0, 113.0, 116.0, 121.2, 121.4, 127.1,
127.2, 127.3, 127.8, 128.5, 129.5, 131.5, 134.6, 136.0, 138.6, 143.1, 148.1, 158.0, 175.1; HRMS
Calcd for C26H24N2O2: 396.1838; Found: 396.1838.
14
ACS Paragon Plus Environment

Page 15 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1-(4-Methoxybenzyl)-N-(quinolin-8-yl)cyclohexanecarboxamide (13a). Rf 0.23 (hexane/EtOAc
= 10/1). Colorless oil. Yield: 29 mg, 25%. 1H NMR (CDCl3, 399.78 MHz) 1.32-1.75 (m, 8H), 2.22-
2.25 (m, 2H), 2.90 (s, 2H), 3.61 (s, 3H), 6.61 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 7.40 (dd,
J = 8.4, 4.0 Hz, 1H), 7.47 (dd, J = 8.0, 4.0, 1H), 7.54 (t, J = 8.4 Hz, 1H), 8.12 (dd, J = 8.4, 2.0 Hz,
1H), 8.69 (dd, J = 4.0, 2.0 Hz, 1H), 8.80 (dd, J = 8.0, 1.6 Hz, 1H), 10.00 (brs, 1H); 13C NMR
(CDCl3, 100.53 MHz) 23.1, 25.9, 34.1, 46.4, 49.6, 55.0, 113.2, 116.3, 121.1, 121.4, 127.4, 127.8,
129.1, 131.0, 134.5, 136.1, 138.7, 148.0, 158.1, 174.7; HRMS Calcd for C24H26N2O2: 374.1990;
Found: 374.1994.
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-(4-Methoxybenzyl)-N-(quinolin-8-yl)cycloheptanecarboxamide (14a). Rf 0.34 (hexane/EtOAc
1
= 5/1). Pale yellow oil. Yield: 33 mg, 28%. H NMR (CDCl3, 399.78 MHz) 1.58-1.78 (m, 10 H),
2.22-2.28 (m, 2H), 2.93 (s, 2H), 3.63 (s, 3H), 6.63 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H),
7.41 (dd, J = 8.4, 4.0 Hz, 1H), 7.48 (dd, J = 8.4, 1.6 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 8.13 (dd, J =
8.0, 1.6 Hz, 1H), 8.71 (dd, J = 4.0, 1.6 Hz, 1H), 8.82 (dd, J = 8.0, 1.2 Hz, 1H), 10.02 (brs, 1H); 13C
NMR (CDCl3, 100.53 MHz) 23.5, 30.0, 36.1, 46.9, 52.5, 55.0, 113.2, 116.2, 121.1, 121.4, 127.4,
127.8, 129.7, 131.0, 134.6, 136.1, 138.7, 148.0, 158.1, 175.9; HRMS Calcd for C25H28N2O2:
388.2152; Found: 388.2152.
1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)-N-(quinolin-8-yl)cycloheptanecarboxamide (14b).
1
Rf 0.23 (hexane/EtOAc = 5/1). White solid. Yield: 16 mg, 11%. Mp =79-80 °C. H NMR (CDCl3,
399.78 MHz) 1.44-1.68 (m, 5H), 1.92-1.95 (m, 3H), 2.31-2.49 (m, 3H), 2.79 (t, J = 10.0 Hz, 1H),
2.98 (d, J = 13.6 Hz, 1H), 3.11 (d, J = 14.0 Hz, 1H), 3.64 (s, 3H), 3.82 (s, 3H), 6.60 (d, J = 8.0 Hz,
1H), 6.86 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.41 (dd, J = 8.0,
4.0 Hz, 1H), 7.48-7.56 (m, 2H), 8.13 (d, J = 8.4 Hz, 1H), 8.72 (d, J = 4.4 Hz, 1H), 8.80 (d, J = 7.2
13
Hz, 1H), 10.12 (brs, 1H); C NMR (CDCl3, 100.53 MHz) 23.8, 31.1, 35.7, 40.1, 40.7, 43.8, 45.8,
51.9, 55.0, 55.2, 113.4, 113.8, 116.3, 121.2, 121.4, 127.4 (two overlapping peaks), 127.8, 129.5,
131.0, 134.5, 136.2, 142.0, 148.1, 157.6, 158.1, 175.9; HRMS Calcd for C32H34N2O3: 494.2569;
Found: 494.2568.
2-(4-Methoxyphenyl)-1-phenyl-N-(quinolin-8-yl)cyclobutanecarboxamide (15a). Rf 0.31
1
(hexane/EtOAc = 5/1). White solid. Yield: 43 mg, 35%. Mp =128 °C. H NMR (CDCl3, 399.78
MHz) 2.26-2.37 (m, 2H), 2.70-2.78 (m, 1H), 3.27 (t, J = 7.6 Hz, 1H), 3.48 (s, 3H), 4.28 (t, J = 7.6
Hz, 1H), 6.57 (d, J = 2H), 7.23 (dd, J = 8.4, 4.0 Hz, 1H), 7.29-7.46 (m, 7H), 7.53 (d, J = 8.0 Hz,
2H), 7.96 (dd, J = 8.4, 1.6 Hz, 1H), 8.37 (dd, J = 4.0, 1.6 Hz, 1H), 8.57 (dd, J = 8.0, 1.6 Hz, 1H),
13
9.27 (brs, 1H); C NMR (CDCl3, 100.53 MHz) 24.6, 29.0, 49.8, 55.0, 61.4, 113.5, 115.6, 120.9,
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 20
1
2
3
4
5
6
121.0, 126.3, 126.9, 127.0, 129.0, 129.2, 132.6, 134.5, 135.6, 138.4, 146.0, 147.6, 158.4, 171.5;
HRMS Calcd for C27H24N2O2: 408.1838; Found: 408.1835.
7
8
9
2,4-Bis(4-methoxyphenyl)-1-phenyl-N-(quinolin-8-yl)cyclobutanecarboxamide (15b). Rf 0.20
(hexane/EtOAc = 5/1). White solid. Yield: 8 mg, 5%.Mp =87 °C. 1H NMR (CDCl3, 399.78 MHz)
2.72 (q, 8.0 Hz, 1H), 3.49 (q, J = 10.4 Hz, 1H), 3.69 (s, 6H), 4.09 (dd, J = 10.8, 8.0 Hz, 1H), 6.78 (d,
J = 8.8 Hz, 4H), 7.20 (dd, J = 8.0, 4.0 Hz, 1H), 7.27-7.34 (m, 2H), 7.43-7.48 (m, 5H), 7.34 (t, J =
7.6 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 8.31 (dd, J = 4.4, 1.6 Hz, 1H),
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
8.44 (dd, J = 7.6, 1.6 Hz, 1H), 9.38 (brs, 1H); C NMR (CDCl3, 100.53 MHz) 30.8, 47.2, 55.1,
67.6, 113.4, 115.9, 120.9, 121.0, 127.1, 127.3, 127.5, 129.1, 129.6, 132.6, 134.3, 135.7, 138.5,
145.1, 147.6, 158.1, 169.6; HRMS Calcd for C34H30N2O3: 514.2256; Found: 514.2253.
2-(4-Methoxyphenyl)-1-phenyl-N-(quinolin-8-yl)cyclopentanecarboxamide (16a). Rf 0.23
1
(hexane/EtOAc = 5/1). White solid. Yield: 47 mg, 37%. Mp =130 °C. H NMR (CDCl3, 399.78
MHz) 1.74-1.81 (m, 1H), 2.14-2.33 (m, 4H), 3.40-3.11 (m, 1H), 3.54 (s, 3H), 3.92 (t, J = 8.0 Hz,
1H), 6.54 (d, J = 8.8 Hz, 2H), 7.23-7.31 (m, 4H), 7.33-7.44 (m, 4H), 7.62 (d, J = 8.8 Hz, 2H), 7.97
(dd, J = 8.0, 1.6 Hz, 1H), 8.39 (dd, J = 4.4, 1.6 Hz, 1H), 8.56 (dd, J = 8.0, 1.6 Hz, 1H), 9.35 (brs,
1H); 13C NMR (CDCl3, 100.53 MHz) 22.5, 33.3, 38.3, 52.8, 54.9, 65.0, 113.3, 115.7, 120.9, 121.1,
126.9, 127.2, 127.5, 128.7, 130.0, 134.1, 134.5, 138.4, 144.1, 147.7, 158.0, 173.4; HRMS Calcd for
C28H26N2O2: 422.1994; Found: 422.1992.
2,5-Bis(4-methoxyphenyl)-1-phenyl-N-(quinolin-8-yl)cyclopentanecarboxamide (16b). Rf 0.23
(hexane/EtOAc = 5/1). White solid. Yield: 24 mg, 15%. Mp =130 °C. 1H NMR (CDCl3, 399.78
MHz) 2.31-2.38 (m, 2H), 2.81-2.86 (m, 2H), 3.57 (s, 6H), 3.74-3.78 (m, 2H), 6.57 (d, J = 8.8 Hz,
4H), 7.16 (dd, J = 8.4, 4.0 Hz, 1H), 7.23 (d, J = 8.4 Hz, 4H), 7.26-7.33 (m, 5H), 7.37 (dd, J = 8.0,
1.6 Hz, 1H), 7.95 (dd, J = 8.0, 1.6 Hz, 1H), 8.16 (dd, J = 4.0, 1.6 Hz, 1H), 8.76 (dd, J = 7.2, 1.6 Hz,
1H), 9.14 (brs, 1H); 13C NMR (CDCl3, 100.53 MHz) 30.7, 54.9, 56.8, 69.2, 113.0, 115.8, 120.9,
121.0, 127.0, 127.1, 127.5, 128.0, 129.3, 130.8, 132.3, 134.5, 135.4, 138.5, 140.5, 147.5, 158.1,
171.5; HRMS Calcd for C35H32N2O3: 528.2413; Found: 528.2414.
2-Cyclohexyl-3-(4-methoxyphenyl)-N-(quinolin-8-yl)propanamide
(17a).
Rf
0.23
(hexane/EtOAc = 5/1). Pale yellow oil. Yield: 55 mg, 47%. 1H NMR (CDCl3, 399.78 MHz) 1.34-
1.31 (m, 5H), 1.64-1.87 (m, 5H), 2.04 (d, J = 8.4 Hz, 1H), 2.46-2.52 (m, 1H), 2.92-3.04 m, 2H),
3.64 (s, 3H), 6.69 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.36 (dd, J = 8.4, 4.0 Hz, 1H), 7.41-
7.50 (m, 2H), 8.07 (dd, J = 8.4, 1.2 Hz, 1H), 8.70 (dd, J = 4.0, 2.0 Hz, 1H), 8.76 (d, J = 8.0 Hz, 1H),
13
9.52 (brs, 1H); C NMR (CDCl3, 100.53 MHz) 26.39 (t, J = 5.7 Hz), 30.9, 31.1, 35.1, 40.7, 55.1,
16
ACS Paragon Plus Environment

Page 17 of 20
The Journal of Organic Chemistry
1
2
3
4
5
58.1, 113.7, 116.3, 121.2, 121.4, 127.3, 127.8, 129.8, 132.3, 134.3, 136.2, 138.3, 148.0, 157.8,
173.4; HRMS Calcd for C25H28N2O2: 388.2151; Found: 388.2153.
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
Experimental procedures and characterization data of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org/.
AUTHOR INFORMATION
Corresponding Author
*E-mail: chatani@chem.eng.osaka-u.ac.jp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported, in part, by a Grant-in-Aid for Scientific Research on Innovative Areas
"Molecular Activation Directed toward Straightforward Synthesis" from Monbusho (The Ministry
of Education, Culture, Sports, Science and Technology), and by JST Strategic Basic Research
Programs “Advanced Catalytic Transformation Program for Carbon Utilization (ACT-C)” from
Japan Science and Technology Agency. Y.A. expresses his special thanks for JSPS Research
Fellowship for Young Scientists. MTHP (4-methyltetrahydro-2H-pyran) was supplied by Kuraray
Co. Ltd.
REFERENCES
(1)
For recent reviews on functionalization of C-H bonds, see: (a) Godula, K.; Samaes, D.
Sience 2006, 312, 67. (b) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013. (c) Daugulis, O.; Do, H.-
Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (d) Colby, D. A.; Bergman, R. G.; Ellman, J. A.
Chem. Rev. 2010, 110, 624. (e) Sehnal, P.; Taylor, R. J. K.; Fairlamb, I. J. S. Chem. Rev. 2010, 110,
824. (f) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (g) Xu, L.-M.; Li, B.-J., Yang,
Z.; Shi, Z.-J. Chem. Soc. Rev. 2010, 39, 712. (h) Ackermann, L. Chem. Commun. 2010, 46, 4866.
(i) Wasa, M.; Engle, K. M.; Yu, J.-Q. Isr. J. Chem. 2010, 50, 605. (j) Chen, D. Y.-K.; Youn, S. W.
Chem. Eur. J. 2012, 18, 9452. (k) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem. Int.
Ed. 2012, 51, 8960. (l) Kuhl, N.; Hoplinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 20
1
2
3
4
5
6
7
8
9
Int. Ed. 2012, 51, 10236. (m) Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013, 42, 5744. (n) Wencel-
Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369. (o) Gao, K. Yoshikai, N. Acc. Chem. Res. 2014, 47,
1208. (p) Sarkar, S. D.; Liu, W.; Kozhushkov, S. I.; Ackermann, L. Adv. Synth. Catal. 2014, 356,
1461.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2)
(3)
Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330.
For selected studies on catalytic arylation of C-H bonds with diarylionium salts: (a) Phipps,
R. J.; Grismster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172. (b) Deprez, N. R.; Sanford,
M. S. J. Am. Chem. Soc. 2009, 131, 11234. (c) Phipps, R. J.; Gaunt, M. J.; Science 2009, 323, 1593.
(d) Xiao, B.; Fu, Y.; Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am. Chem. Soc. 2010, 132, 468.
(e) Bedford, R. B.; Mitchell, C. J.; Webster, R. L.; Chem. Commun. 2010, 46, 3095. (f) Wagner, A.
M.; Sanford, M. S. Org. Lett. 2011, 13, 288. (g) Hickman, A. J.; Sanford, M. S. ACS Catal. 2011, 1,
170. (h) Duong, H. A.; Gilligan, R. E.; Cooke, M. L.; Phipps, R. J.; Gaunt, M. J. Angew. Chem. Int.
Ed. 2011, 50, 463. (i) Phipps, R. J.; McMurray, L.; Ritter, S.; Duong, H. A.; Gaunt, M. J. J. Am.
Chem. Soc. 2012, 134, 10773. (j) Gigant, N.; Chausset-Boissarie, L.; Belhomme, M.-C.; Poisson,
T.; Pannecoucke, X.; Gillaizeau, I. Org. Lett. 2013, 15, 278. (k) Storr, T. E.; Greaney, M. F. Org.
Lett. 2013, 15, 1410. (l) Chan, L. Y.; Cheong, L. Kim. S.; Org. Lett. 2013, 15, 2186. (m) Guo, F.;
Han, J.; Mao, S.; Li, J.; Geng, X.; Yu, J.; Wang, L. RSC Adv. 2013, 3, 6267. (n) Wu, Z.; Chen, S.;
Hu, C.; Li, Z.; Xiang, H.; Zhou, X. ChemCatChem, 2013, 5, 2839. (o) Wagner, A. M.; Hickman, A.
J.; Sanford, M. S. J. Am. Chem. Soc. 2013, 135, 15710.
(4)
48.
(5)
(6)
(7)
Ho, J. S.; Castro, L. C. M.; Aihara, Y.; Tobisu, M.; Chatani, N. Asian J. Org. Chem. 2014, 3,
Pan, F.; Shen, P.-X.; Zhang, L.-S.; Wang, X.; Shi, Z.-J. Org. Lett. 2013, 15, 4758.
Zaitsev, V.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154.
For recent reviews on functionalization of C-H bonds utilizing a bidentate-chelation
assistance, see: (a) Corbet, M.; De Campo, F. Angew. Chem. Int. Ed. 2013, 52, 9896. (b) Rouquet,
G.; Chatani, N. Angew. Chem. Int. Ed. 2013, 52, 11726.
(8)
(a) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391. (b) Shabashov, D.;
Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965. (c) Feng, Y.; Chen, G. Angew. Chem. Int. Ed.
2010, 49, 958. (d) Feng, Y.; Wang, Y.; Landgraf, B.; Liu, S.; Chen, G. Org. Lett. 2010, 12, 3414.
(e) Ano, Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 12984. (f) Tran, L. D.; Daugulis,
O. Angew. Chem. Int. Ed. 2012, 51, 5188. (g) Gutekunst, W. R.; Gianatassio, R.; Baran, P. S.
Angew. Chem. Int. Ed. 2012, 51, 7507. (h) Zhang, S.-Y.; Li, Q.; He, G.; Nack, W. A.; Chen, G. J.
Am. Chem. Soc. 2013, 135, 12135. (i) Chen, K.; Hu, F.; Zhang, S.-Q.; Shi, B.-F. Chem. Sci. 2013, 4,
18
ACS Paragon Plus Environment

Page 19 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3906. (j)Nadres, E. T.; Santos, G. I.; Shabashov, D.; Daugulis, O. J. Org. Chem. 2013, 78, 9689.
(k)Parella, R.; Gopalakrishnan, B.; Babu, S. A. J. Org. Chem. 2013, 78, 11911. (l) Parella, R.;
Gopalakrishnan, B.; Babu, S. A. Org. Lett. 2013, 15, 3283. (m) Hoshiya, N.; Kobayashi, T.;
Arisawa, M.; Shuto, S. Org. Lett. 2013, 15, 6202. (n) Al-Amin, M.; Arisawa, M.; Shuto, S.; Ano,
Y.; Tobisu, M.; Chatani, N. Adv. Synth. Catal. 2014, 356, 1631. (o) Kanyiva, K. S.; Kuninobu, Y.;
Kanai, M. Org. Lett. 2014, 16, 1968. (p) Wei, Y.; Tang, H.; Cong, X.; Rao, B.; Wu, C.; Zeng, X.
Org. Lett. 2014, 16, 2248.
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)
(a) Hasegawa, N.; Charra, V.; Inoue, S.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2011,
133, 8070. (b) Hasegawa, N.; Shibata, K.; Charra, V.; Inoue, S.; Fukumoto, Y.; Chatani, N.
Tetrahedron 2013, 69, 4466.
(10) (a) Wang, Z.; Ni, J.; Kuninobu, Y.; Kanai, M. Angew. Chem. Int. Ed. 2014, 53, 3496. (b)
Wu, X.; Zhao, Y.; Zhang, G.; Ge, H. Angew. Chem. Int. Ed. 2014, 53, 3706.
(11) (a) Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2014, 136, 898. (b) Wu, X.; Zhao, Y.; Ge, H.
J. Am. Chem. Soc. 2014, 136, 1789. (c) Li, M.; Dong, J.; Huang, X.; Li, K.; Wu, Q.; Song, F.; You,
J. Chem. Commun. 2014, 50, 3944. (d) Wu, X.; Zhao, Y.; Ge, H. Chem. Eur. J. 2014, 20, 9530.
(12) (a) Shang, R.; Ilies, L.; Matsumoto, A.; Nakamura, E. J. Am. Chem. Soc. 2013, 135, 6030.
(b) Asako, S.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2013, 135, 17755.
(13) (a) Beringer, F. M.; Bodlaender, P. J. Org. Chem. 1969, 34, 1981. (b) Kaźmierczak, P.;
Skulski, L. Synthesis 1995, 1027. (c) McEwen, W. E.; DeMassa, J. W. Heteroatom Chem. 1996, 7,
349. (d) Wang, B.; Graskemper, J. W.; Qin, L.; DiMango, S. G. Angew. Chem. Int. Ed. 2010, 49,
4079. (e) Wang, B.; Qin, L.; Neumann, K. D.; Uppaluri, S, Cerny, R. L.; DiMango, S. G. Org. Lett.
2010, 12, 3352. (f) Kasahara, T.; Jang, Y. J.; Racicot, L.; Panagopoulos, D.; Liang, S. H.; Ciufolini,
M. A. Angew. Chem. Int. Ed. 2014, 53, ASAP. (DOI: 10.1002/anie.201405594).
(14) Yokota, A.; Aihara, Y.; Chatani.N. J. Org. Chem. in press. (DOI: 10.1021/jo501697n)
(15) (a) Neufeldt, S. R.; Sanford, M. S. Adv. Synth. Catal. 2012, 354, 3517. (b) Liu, Y.-X.; Xue,
D.; Wang, J.-D.; Zhao, C.-J.; Zou, Q.-Z.; Wang, C.; Xia, J. Synlett 2013, 24, 507. (c) Tobisu, M.;
Furukawa, T.; Chatani, N. Chem. Lett. 2013, 42, 1203.
(16) (a) Rouquet, G.; Chatani, N. Chem. Sci. 2013, 4, 2201. (b) Nishino, M.; Hirano, K.; Satoh,
T.; Miura, M. Angew. Chem. Int. Ed. 2014, 52, 4457. (c) Tran, L. D.; Roante, J. Daugulis, O.
Angew. Chem. Int. Ed. 2013, 52, 6043. See also ref 8f, 8g, 10a, and 10b.
(17) (a) Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2013, 135, 5308. (b) Aihara, Y.; Chatani, N.
Chem. Sci. 2012, 4, 664.
(18) Bigot, A.; Williamson, A. E.; Gaunt, M. J. J. Am. Chem. Soc. 2011, 133, 13778.
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 20
1
2
3
4
5
6
7
8
(19) Biielawski, M.; Olofsson, B. Chem. Commun. 2007, 2521.
(20) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133, 4260.
(21) Chen, D. W.; Ochiai, M. J. Org. Chem. 1999, 64, 6804.
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 of Contents
**********************************
20
ACS Paragon Plus Environment