Synthesis of ortho-arylated/benzylated arylacetamide derivatives: Pd(OAc)2-catalyzed bidentate ligand-aided arylation and benzylation of the γ-C[sbnd]H bond of arylacetamides

Article abstract of DOI:10.1016/j.tet.2016.08.026

In this paper, we report the Pd(OAc)₂/AgOAc, bidentate ligand-directed C[sbnd]H functionalization of the sp²γ-C[sbnd]H bond of arylacetamides. While, the bidentate ligand-directed site selective functionalization of the β-C[sbnd]H bond of aromatic carboxylic acid derivatives is well known, we herein, report our attempts on the Pd(II)-catalyzed, bidentate ligand-directed arylation, benzylation, alkylation, acetoxylation and hydroxylation of the sp²γ-C[sbnd]H bond of the arylacetamide systems. The arylation and benzylation of arylacetamides were successful; however, the alkylation and acetoxylation/hydroxylation of arylacetamides were not successful. Various ligands were screened to substantiate the need for the bidentate ligand in the arylation/benzylation of arylacetamides, and 8-aminoquinoline was found to be the best bidentate ligand. Several substituted aryl-/heteroaryl iodides, 4-nitrobenzyl bromide and arylacetamide substrates were used to examine their reactivity pattern and accomplish the substrate scope/generality. In general, the bidentate ligand 8-aminoquinoline-directed arylation of arylacetamides gave the corresponding ortho-diarylated arylacetamides and benzylation of arylacetamides gave the corresponding ortho-mono benzylated arylacetamides as the predominant compounds. Overall, this method has led to the synthesis of new ortho-substituted arylacetamides in good to high yields.

Full text of DOI:10.1016/j.tet.2016.08.026

Accepted Manuscript
Synthesis of ortho-arylated/benzylated arylacetamide derivatives: Pd(OAc) -
2
catalyzed bidentate ligand-aided arylation and benzylation of the γ-C–H bond of
arylacetamides
Narendra Bisht, Srinivasarao Arulananda Babu
PII:
S0040-4020(16)30791-8
10.1016/j.tet.2016.08.026
TET 28007
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 April 2016
Revised Date: 5 August 2016
Accepted Date: 9 August 2016
Please cite this article as: Bisht N, Babu SA, Synthesis of ortho-arylated/benzylated arylacetamide
derivatives: Pd(OAc) -catalyzed bidentate ligand-aided arylation and benzylation of the γ-C–H bond of
2
arylacetamides, Tetrahedron (2016), doi: 10.1016/j.tet.2016.08.026.
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Synthesis of Ortho-Arylated/Benzylated
Arylacetamide Derivatives: Pd(OAc)
Leave this area blank for abstract info.
2
-
Catalyzed Bidentate Ligand-Aided Arylation
and Benzylation of the γ-C-H Bond of
Arylacetamides
Narendra Bisht and Srinivasarao Arulananda Babu*
Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City, Sector 81, SAS
Nagar, Mohali, Manauli P.O., Punjab, 140306, India

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of Ortho-Arylated/Benzylated Arylacetamide Derivatives:
Pd(OAc) -Catalyzed Bidentate Ligand-Aided Arylation and Benzylation of
2
the γ-C-H Bond of Arylacetamides
Narendra Bisht and Srinivasarao Arulananda Babu∗
Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City, Sector 81, SAS Nagar, Mohali, Manauli
P.O., Punjab, 140306, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2
In this paper, we report the Pd(OAc) /AgOAc, bidentate ligand-directed C-H functionalization
2
of the sp γ-C-H bond of arylacetamides. While, the bidentate ligand-directed site selective
functionalization of the β-C-H bond of aromatic carboxylic acid derivatives is well known, we
herein, report our attempts on the Pd(II)-catalyzed, bidentate ligand-directed arylation,
2
Available online
benzylation, alkylation, acetoxylation and hydroxylation of the sp γ-C-H bond of the
arylacetamide systems. The arylation and benzylation of arylacetamides were successful;
however, the alkylation and acetoxylation/hydroxylation of arylacetamides were not successful.
Various ligands were screened to substantiate the need for the bidentate ligand in the
arylation/benzylation of arylacetamides, and 8-aminoquinoline was found to be the best
bidentate ligand. Several substituted aryl-/heteroaryl iodides, 4-nitrobenzyl bromide and
arylacetamide substrates were used to examine their reactivity pattern and accomplish the
substrate scope/generality. In general, the bidentate ligand 8-aminoquinoline-directed arylation
of arylacetamides gave the corresponding ortho-diarylated arylacetamides and benzylation of
arylacetamides gave the corresponding ortho-mono benzylated arylacetamides as the
predominant compounds. Overall, this method has led to the synthesis of new ortho-substituted
arylacetamides in good to high yields.
Keywords:
arylacetamides
arylacetic acid derivatives
γ-C-H activation
palladium
2
sp C-H functionalization
2
009 Elsevier Ltd. All rights reserved.
1. Introduction
In recent years, the transition metal-catalyzed C-H
activation/functionalization reaction has become a popular tool
1
-3
for forming the C-C bond. There exist several exceptional
reports dealing on the synthesis of biaryls via the direct
2
functionalization of the sp C-H bond of arenes and heteroarenes
1-4
without any directing groups.
Nevertheless, the transition
metal-catalyzed, directing group-enabled, site selective C-H
activation/functionalization reactions have been found to be
highly efficient and practically simple methods for synthesizing
1
-5
functionalized organic molecules. Functional groups, such as
ketone, amide, carbamate, carboxylic acid, aldehyde, ether, etc
were identified as weakly coordinating directing groups for
accomplishing
the
site
selective
C-H
1
-5
activation/functionalization. Along this line, since the seminal
work by Daugulis et al., bidentate ligands (e.g., 8-
6
aminoquinoline and picolinamide) were found to be very
2
3
2
3
efficient to accomplish the site selective sp and sp C-H
activation/functionalization of various aliphatic-, alicyclic- and
Scheme 1. Functionalization of sp and sp β-C-H bond.
1
-5
aromatic carboxamide derivatives (Scheme 1).
With regard to the site selectivity, in general, the C-H bond of
the β-position of aliphatic-, alicyclic- and aromatic carboxamide
—
——
∗
Corresponding author. Tel.: +91-172-2293165; fax: +91-172-2240266; e-mail: sababu@iisermohali.ac.in

ACCEPTED MANUSCRIPT
2
Tetrahedron
derivatives containing the bidentate ligands have been
arylacetic acid derivatives including arylacetamides are versatile
synthetic intermediates in synthetic organic chemistry and
3
d,5a,b,f,6
efficiently functionalized
bidentate ligand-directed arylation, alkylation, acetoxylation of
(Scheme 1). Accordingly, the
1
3,14
medicinal chemistry.
Hence, given the importance of the
C-H bond of the β-position of carboxamide derivatives have been
well explored. On the other hand, the functionalization of
arylacetic acid derivatives and in continuation of our interest on
1
-8
the bidentate ligand-enabled C-C bond construction via the C-H
8
remote C-H bond, (e.g., γ-C-H bond) of carboxylic acid
activation reactions, we envisaged the Pd(II)-catalyzed, 8-
9
-11
derivatives is relatively less explored.
Although, the ligand-
aminoquinoline-directed functionalization (arylation/alkylation)
2
directed functionalization (e.g., olefination, acetoxylation,
of the sp γ-C-H bond of the phenylacetamide systems and to
3
carbonylation, amidation, etc) of remote sp C-H bond (other than
assemble
derivatives (Scheme 2).
new
ortho-arylated/alkylated
arylacetamide
1
5
the β-C-H bond) of aliphatic carboxylic acids has met with some
9
notable success; the bidentate ligand-directed site selective
2
functionalization of remote sp C-H bond other than β-C-H bond
2. Results and Discussion
of aromatic carboxylic acid derivatives, (e.g., arylacetamides) has
1
0
not been explored well.
At the outset, we planned to attempt the Pd(II)-catalyzed
arylation of the γ-C-H bond of the phenylacetamide system. To
find out the optimized reaction conditions, we performed several
reactions comprising the Pd(II)-catalyzed, 8-aminoquinoline-
directed γ-C-H arylation of the substrate 1a (Table 1). The
reaction of 1a, 2a and AgOAc in the absence of any catalyst did
not give any C-H arylated product (entry 1, Table 1) and we also
Prior to this work and to the best of our knowledge, there exist
only two reports dealing on the bidentate ligand-directed
2
functionalization of the sp γ-C-H bond of the arylacetamide
1
0
systems. Chatani et al. reported the lactonization of the
2
arylacetamide system via the acetoxylation of the sp γ-C-H bond
10a
of the phenylacetamide system. Maiti et al. reported the Pd(II)-
2
catalyzed olefination of the sp γ-C-H bond of the
tested the reaction of 1a, 2a and 10 mol% of the Pd(OAc)
2
catalyst in the absence of any additive, and this reaction also did
1
0b
phenylacetamide system (Scheme 2).
not give any C-H arylated product, Then, the reaction of 1a (1
2
Scheme 2. Functionalization of the sp γ-C-H bond of the phenylacetamide systems.
It is worth to mention that the arylacetic acid derivatives are
imperative structural units commonly found in analgesics and
antiinflammatory drugs (e.g., ibuprofen, naproxen). Further,
equiv) with 2a (4 equiv) in the presence of the well-explored
5a,f,6
Pd(OAc) /AgOAc-catalytic system
gave the expected bis γ-C-
2
12
H arylated product 4a in high yield (85%, entry 2, Table 1).

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3
Table 1. Optimization reactions. γ-C-H Arylation of the phenylacetamide system 1a.
I
OMe
OMe
OMe
2
a
N
H
(0.48 mmol)
N
N
H
N
PdL (10 mol%)
H
N
2
N
O
additive
O
1
a
O
(0.3 mmol)
3a
4
a
(
0.12 mmol)
mono arylation
solvent (3 mL)
bis arylation
o
24 h, 80-110 C
OMe
o
entry PdL2
additive solvent (3 mL)
t ( C)
4a; yield (%) 3a; yield (%)
1
AgOAc
toluene
110
0
-
2
3
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
AgOAc
toluene
toluene
toluene
110
110
110
85
30
67
-
Ag2CO3
-
K2CO3
KOAc
-
-
5
Pd(OAc)2
toluene
110
0
6
7
8
9
1
Pd(OAc)2
PdCl2
PhI(OAc)2 toluene
110
110
110
110
110
0
-
AgOAc
toluene
toluene
toluene
toluene
25
46
0
-
Pd(CH3CN)2Cl2 AgOAc
-
-
Pd(TFA)2
Pd(PPh3)4
AgOAc
AgOAc
0
0
-
1
1
1
1
1
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
AgOAc
AgOAc
1,2-DCE
tBuOH
80
85
0
-
2
0
-
3
AgOAc
AgOAc
AgOAc
AgOAc
1,4-dioxane
tAmylOH
toluene
100
110
110
110
53
53
14
34
-
4
5a
-
25
25
1
6b
toluene
1
7c
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
AgOAc
AgOAc
AgOAc
toluene
toluene
toluene
110
110
110
53
-
-
1
8d
-
1
a
b
c
9e
37
36
1
2
Equiv (0.12 mmol) of 2a.
Equiv (0.24 mmol) of 2a.
3
0
1
Equiv (0.36 mmol) of 2a.
d
e
.1 Equiv (0.012 mmol) of AgOAc.
Equiv (0.12 mmol) of AgOAc.
We then carried out further optimization reactions to improve
the efficiency of the process and yield of the product 4a (Table
). Accordingly, the arylation of 1a with 2a in the presence of
mixtures of the reactions shown in Table 1 (entries 1-14). Our
8 5,6
previous experience and a survey of the literature indicated
that generally, 3-4 equivalents of aryl iodide are used for
obtaining the mono arylated products in high yields under the
palladium-catalyzed C-H arylation method. In the present case, it
seems that the bis arylation of 1a is a facile reaction and the
arylation of 1a with 4 equivalents 2a directly gave the bis
arylated product 4a in a maximum of 85% yield (entry 2, Table
1).
1
additives, such as, Ag CO or K CO gave the product 4a in 30
2
3
2
3
and 67% yields (entries 3 and 4, Table 1). The arylation of 1a
with 2a in the presence of additives, such as, KOAc or PhI(OAc)2
did not give the product 4a (entries 5 and 6, Table 1). The
arylation of 1a with 2a in the presence of the palladium catalysts
PdCl
yields, respectively (entries 7 and 8, Table 1). The arylation of 1a
with 2a in the presence of the palladium catalysts Pd(TFA) and
Pd(PPh ) did not give the product 4a (entries 9 and 10, Table 1).
2 3 2 2
and Pd(CH CN) Cl gave the product 4a in 25 and 46%
Then, we performed the arylation of 1a with fewer equivalents
of 2a to check whether we can obtain the mono arylation product.
The arylation of 1a with one equivalent of 2a gave the mono
arylated product 3a in 25% yield and bis arylated product 4a in
14% yield (entry 15, Table 1). A similar trend was observed
when the arylation of 1a was carried out with two equivalents of
2a and in this case, the compounds 4a and 3a were obtained in 34
and 25% yields, respectively (entry 16, Table 1). These two
reactions indicated that the bis arylation of 1a is a facile though
fewer equivalents of 2a were used. The arylation of 1a with three
equivalents of 2a gave the bis arylated product 4a in 53% yield
2
3
4
The arylation of 1a with 2a in solvents, such as, 1,2-DCE or tert-
butanol failed to give the product 4a (entries 11 and 12, Table 1).
However, the arylation of 1a with 2a in 1,4-dioxane or tert-
amylOH gave the product 4a in 53% yield (entries 13 and 14,
Table 1). In these reactions, the formation of the mono arylated
product 3a is also expected. However, we did not get any
characterizable amounts of the product 3a from the column
chromatographic purification of the respective crude reaction

ACCEPTED MANUSCRIPT
4
Tetrahedron
(
entry 17, Table 1). This reaction and the reaction of entry 2
electron withdrawing group at the para/meta position, which
afforded the products 4j-o in 50-70% yields, respectively (Table
2). In one of the case, the mono arylated product 3o (43%) was
also obtained along with the bis arylated product 4o (56%,
predominant product). Next, we performed the direct bis
arylation of the γ-C-H bond of the phenylacetamide system 1a
with heteroaryl iodides, which also gave the corresponding bis
arylated products 4p (44%) and 4q (70%). In an another reaction
comprising the γ-C-H arylation of the substrate 1a with 5-
iodoindole afforded only the mono arylated product 3r (44%) as
the predominant isomer and the corresponding bis arylated
product was not obtained in any characterizable amounts from
the column chromatographic purification of the crude reaction
mixture of this reaction. Presumably, since the indole unit is
relatively bigger and installation of a second indole moiety in 3r
seems to be difficult as it may result a steric crowding in the bis
arylated compound and hence, only the mono arylated product 3r
was obtained as the predominant isomer (Table 2).
(
Table 1) revealed that the second arylation of the product 3a is a
facile reaction and 3-4 equivalents of 2a are needed for obtaining
the bis γ-C-H arylated product 4a in high yield from the
phenylacetamide system 1a. Furthermore, we also performed the
arylation of 1a with 2a (4 equiv) in the presence of catalytic
amounts of AgOAc and this reaction gave an inseparable reaction
mixture containing the starting material as the predominant
compound (entry 18, Table 1). The arylation of 1a with 2a (4
equiv) in the presence of one equivalent of AgOAc instead of 2.5
equivalents of AgOAc (entry 2) gave the mono arylated product
3
a in 36% yield and the bis arylated product 4a in 37% yield
(
entry 19, Table 1).
Table 2. The Pd(II)-catalyzed synthesis of the ortho-arylated
arylacetamide derivatives 4a-q/3o,r.
N
Pd(OAc)2 (10 mol%)
N
Ar
+
Ar
I
HN
HN
2
AgOAc (0.3 mmol)
toluene (3 mL)
O
(0.48 mmol)
O
Ar
1
a
2
4 h, 110 o
C
(
0.12 mmol)
4a-q (bis arylation)
3
o,r (mono arylation)
OMe
Me
R
N
N
N
N
HN
HN
HN
HN
O
O
O
O
MeO
Me
R
4c; R = Et; 80%
4e; 81%
4
a; 85%
4b; 81%
t
4
d; R = Bu; 63%
O
CH3
Cl
H3C
N
O
CH3
CH3
Cl
N
N
N
Scheme 3. Bidentate ligands explored for the γ-C-H arylation
HN
HN
HN
HN
of the phenylacetamide system.
O
O
O
O
H3C
H3C
H3C
Cl
Having found the optimized reaction conditions for the bis
arylation of the γ-C-H bond of the phenylacetamide system 1a
containing 8-aminoquinoline as the directing group; then, we
wished to establish the efficiency of 8-aminoquinoline directing
group and find out the other suitable directing groups for the γ-C-
H arylation reactions. Accordingly, we performed the C-H
arylations of the substrates 1b-e (derived from the corresponding
bidentate ligands). The arylation of the substrates 1b-d failed to
afford the corresponding γ-C-H arylated products (Scheme 3).
However, the γ-C-H arylation of the substrate 1e (derived from
the bidentate ligand 2-(methylthio)aniline) with 2a successfully
afforded the mono arylated product 6a in 54% yield (Scheme 3).
Similarly, the mono arylated product 6b was obtained in 45%
yield from the γ-C-H arylation of the substrate 1e with the
corresponding aryl iodide compound (Scheme 3).
O
O
CH3
Cl
4g; 73%
4
h; 66%
4i; 45%
4
f; 63%
F
Cl
Br
NO2
N
N
N
N
HN
HN
HN
HN
O
O
O
O
NO2
F
Cl
Br
4
j; 64%
4k; 70%
4l; 58%
4m; 50%
COOMe
Ac
Ac
N
N
HN
HN
N
HN
O
O
O
Next, to expand the substrate scope and generality, we
performed the bis γ-C-H arylation of 1a with aryl iodides
containing an electron donating group at the para position, which
afforded the products 4a-d in 63-85% yields, respectively (Table
MeOOC 4n; 63%
Ac 4o; 56%
3
o; 43%
Br
N
N
S
N
HN
2
). The bis γ-C-H arylation of 1a with iodobenzene gave the
N
HN
HN
O
product 4e in 81% yield (Table 2). Then, the bis γ-C-H arylation
of 1a with di-substituted aryl iodides furnished the products 4f-i
in 45-73% yields, respectively (Table 2). Further, we performed
the direct bis arylation of 1a with aryl iodides containing an
O
O
N
S
4q; 70%
N
H
Br
4p; 44%
3r; 44%

ACCEPTED MANUSCRIPT
5
Table 3. The Pd(II)-catalyzed synthesis of the ortho-arylated
arylacetamide derivatives 7/8/9.
the yield of 11a we have carried out the benzylation of 1a by
using different reaction conditions (entries 2-9, Table 4).
However, we did not find any other suitable reaction conditions
for obtaining the product 11a in better yield than the initial
reaction (entry 1, Table 4). Similarly, the γ-C-H benzylation of
the phenylacetamide substrates 1f-h gave the mono benzylated
phenylacetamide systems 11b-d in 46-63% yields, respectively
(
Table 4). The reason for the formation of only mono benzylated
products 11a-d is not clear at this stage. Generally, the benzyl
bromide reagent is highly reactive and hence, it is assumed that
the benzyl bromide reagent might be decomposed or converted
1
6a,b
into 4-nitrobenzyl acetate under the experimental condition
and hence, the second benzylation of the substrates 11a-d did not
occur to afford the corresponding bis benzylated products (e.g.
12a).
Table 4. The Pd(II)-catalyzed synthesis of the ortho-
benzylated arylacetamide derivatives 11a-d.
4
(NO ) Bn Br
2
(
10, 0.48 mmol)
R1
N
R1
N
N
Pd(OAc)2 (10 mol%)
HN
HN
HN
+
AgOAc (0.15 mmol)
O
O
O
R1
12a
toluene (3 mL)
1
a
o
11a
2
4 h, 110 C
(0.12 mmol)
R1 = 4 (NO2) Bn
o
entry PdL2
additive
solvent (3 mL) t ( C)
yield (%)
1a
AgOAc
110
110
110
55
20
43
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
toluene
toluene
toluene
2
3
4
Ag2CO3
KOAc
Pd(OAc)2
PdCl2
PhI(OAc)2 toluene
110
0
5
6
7
8
9
AgOAc
toluene
toluene
tAmylOH
1,2-DCE
tBuOH
110
110
110
110
110
0
28
0
Pd(CH3CN)2Cl2 AgOAc
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
AgOAc
AgOAc
AgOAc
0
0
4
(NO2) Bn Br
(
10, 0.48 mmol)
Successively, to further extend the substrate scope of this
method, we performed the γ-C-H arylation of various
phenylacetamides containing different substituents in the aryl
ring. Accordingly, we synthesized the bis arylated products 7a-f
in 25-63% yields from their respective starting materials (Table
N
N
Pd(OAc)2 (10 mol%)
HN
HN
O
O
AgOAc (0.15 mmol)
toluene (3 mL)
R2
R2
2
1
1a-d
(
0.12 mmol)
a; R = H, 1f; R = Cl,
o
2
24 h, 110 C
1
3
). In some exceptional cases, the mono arylated products, such
1g
R = F, ; R = Br,
1h
2
2
;
NO2
as, 8e (34%) and 8f (36%) were also obtained along with their
corresponding bis arylated products 7e and 7f. Along this line,
we also obtained the mono arylated products 9a (52%) and 9b
N
N
2
HN
11b; R = F, 63%
(
75%) exclusively from their respective starting materials (Table
). In our further trials to extend the substrate scope, we did not
HN
2
1
1
1c; R = Cl, 46%
O
3
O
2
R2
1d; R = Br, 59%
get the arylated products 9c and 9d from the corresponding
thiophenylacetamide starting material 1k, which is structurally
similar to the phenylacetamide 1a. The reason for the failure of
the arylation of thiophenylacetamide 1k was not clear at this
stage.
Finally, we attempted the benzylation of the γ-C-H bond of the
phenylacetamide systems (Table 4). Fortunately, in an initial
trial, the benzylation of the γ-C-H bond of the phenylacetamide
system 1a successfully afforded the mono benzylated
phenylacetamide system 11a in 55% yield (Table 4). The column
chromatographic purification of the crude reaction mixture gave
only the product 11a and the bis benzylated compound 12a was
not obtained in any characterizable amounts. In order to improve
1
1a; 55%
NO2
NO2
a
The reaction was performed using 1a (0.12 mmol), 10 (0.48 mmol) and
AgOAc (0.15 mmol).
We also performed the double arylation of the γ-C-H bond of
the phenylacetamide system 1a with iodobenzene in a gram scale
and this reaction furnished the product 4e in 70% yield (Scheme
5). Then, we wished to remove the bidentate ligand (8-
aminoquinoline) from the representative γ-C-H arylated
arylacetamide system. Accordingly, we treated the bis arylated
arylacetamide system 4e with BF -OEt in MeOH, which
3
2

ACCEPTED MANUSCRIPT
6
Tetrahedron
1
13
successfully furnished the methyl ester of ortho-diarylated
IR spectra were recorded as KBr pellets or thin films. H/ C
NMR spectra of were recorded on 400 and 100 MHz
phenylacetic acid 13 after the removal of the bidentate ligand 8-
aminoquinoline in 66% yield (Scheme 4).
spectrometers,
respectively.
Column
chromatographic
purification of the crude reaction mixtures was performed using
silica gel (100-200 mesh). HRMS measurements were obtained
from QTOF mass analyzer using electrospray ionization (ESI)
technique. Reactions were carried out using anhydrous solvents
under a nitrogen atm and anhydrous solvents. Organic layers
after the work up procedure were dried using anhydrous sodium
sulphate. TLC analysis was carried out on silica gel and the
components were visualized by observation under iodine vapour.
Isolated yields of all the compounds are reported and yields of all
the reactions were not optimized. Carboxamide starting materials
a
The conversion of 4e to 13 was performed using 1.4 mmol of
9h, 10b, 18
were prepared by using the literature procedures.
4
e.
Characterization data of the arylated compounds, 4a, 4b, 4e, 4g,
1
5
4
k, 4l, 4o, 3o and 7a are reported in the literature.
Scheme 4. Gram scale reaction of the γ-C-H arylation of 1a
and the removal of the bidentate ligand 8-aminoquinoline.
3.2. Procedure for synthesis of phenylacetamides 1a-e and 1k.
Overall, while the arylation and benzylation of arylacetamides
were successful, our various attempts on the 8-aminoquinoline-
directed alkylation, acetoxylation and hydroxylation of
phenylacetamides were not successful (See the Supplementary
data). Apparently, the bidentate ligand 8-aminoquinoline seems
to be not assisting the C-O bond formation in the arylacetamide
A dry flask the corresponding containing amine (1 mmol) and
Et N (121 mg, 1.2 mmol) was stirred for 5-10 min under a
nitrogen atmosphere. Then, to the reaction flask anhydrous DCM
4 mL) was added followed by drop-wise addition of the
corresponding acid chloride. The resulting mixture was stirred at
rt for 12 h. After this period, the reaction mixture was diluted
with dichloromethane and washed with water and saturated
3
(
1
0a
system. Notably, Chatani’s group
was successful in
constructing the C-O in the phenylacetamide system by using a
less common bidentate ligand, quinolin-8-ylmethanamine
3
aqueous NaHCO solution (twice). The combined organic layers
were dried over anhydrous Na SO and then, the solvent was
2
4
(
Scheme 2). Different ligands were screened for performing the
evaporated in vacuo to afford
a crude reaction mixture.
arylation/benzylation of phenylacetamides and 8-aminoquinoline
was found to be best ligand. Various aryl iodides containing
electron- donating and withdrawing groups, heteroaryl iodides,
benzyl bromides and phenylacetamide starting materials were
used to examine their reactivity pattern. In general, the γ-C-H
arylation of arylacetamides with aryl iodides containing electron
donating groups gave ortho-diarylated arylacetamides as the
predominant compounds in high yields (Table 2). The γ-C-H
arylation of arylacetamides with aryl iodides containing electron
withdrawing groups gave ortho-diarylated arylacetamides as the
predominant compounds in moderate yields (Table 2).
Depending on the substituents in the aryl iodides and only in
specific cases the mono ortho-arylated arylacetamides were
obtained. The γ-C-H arylation of arylacetamides containing a
substituent at the meta position with aryl iodides gave only mono
ortho-arylated arylacetamides as the predominant compounds in
moderate to good yields (Table 3). Presumably, the installation of
a second aryl moiety may result a steric crowding in the bis
arylated compound and hence the arylation of arylacetamides
containing a substituent at the meta position gave only the mono
ortho-arylated arylacetamides. While, the γ-C-H benzylation of
arylacetamides gave only the mono ortho-benzylated
arylacetamides as the predominant compounds (Table 4), our
other trials to get the bis γ-C-H benzylated compounds were not
fruitful at this stage.
Purification of the crude reaction mixture by column
chromatography (silica gel, 100–200 mesh, (EtOAc/hexanes =
20:80) furnished the corresponding products 1a-e and 1k.
3.2.1. 2-Phenyl-N-(quinolin-8-yl)acetamide (1a): The resultant
crude mixture was purified by column chromatography
(
(
(
(
EtOAc:hexane = 20:80) to afford 1a as a dark brown color solid
o
449 mg, 68%); R
KBr): νmax 3345, 3055, 1681, 1527, 1265, 741 cm ; H NMR
f
(20% EtOAc/hexane) 0.5; mp: 91-93 C; IR
-1 1
400 MHz, CDCl
3
): δ
1.7 Hz), 8.71 (1 H, dd, J
8.3, J = 1.4 Hz), 7.55-7.51 (1 H, m), 7.49 (1 H, dd, J = 8.6, J
H
9.94 (1 H, br. s), 8.79 (1 H, dd, J
1
= 7.3, J
2
1
2
=
=
=
1
= 4.2, J = 1.7 Hz), 8.13 (1 H, dd, J
2
2
1
1.7 Hz), 7.46-7.40 (5 H, m), 7.38-7.33 (1 H, m), 3.92 (2 H, s);
13
C NMR (CDCl , 100 MHz): δ 169.5, 148.2, 138.4, 136.3,
3
C
1
4
2
34.7, 134.4, 129.6, 129.0, 127.9, 127.4, 121.6, 121.6, 116.4,
+
5.4; HRMS (ESI): MH , found 263.1177. C17
63.1184.
15 2
H N O requires
3.2.2. N-(2-Methylquinolin-8-yl)-2-phenylacetamide (1b): The
resultant crude mixture was purified by column chromatography
(EtOAc:hexane = 20:80) to afford 1b as a yellow color solid (480
o
mg, 86%); R (20% EtOAc/hexane) 0.5; mp: 86-88 C; IR (KBr):
f
-
1
1
νmax 3307, 3055, 1679, 1532, 1265, 740 cm ; H NMR (400
MHz, CDCl ): δH 9.97 (1 H, br. s), 8.73 (1 H, dd, J = 6.9, J =
3
1
2
2.0 Hz), 7.96 (1 H, d, J = 8.4 Hz), 7.48-7.44 (4 H, m), 7.44-7.40
3 H, m), 7.23 (1 H, d, J = 8.4 Hz) 3.93 (2 H, s), 2.55 (3 H, s);
(
13
In summary, we have revealed our investigations on the
Pd(II)-catalyzed, bidentate ligand-directed arylation and
C NMR (CDCl , 100 MHz): δ 169.5, 157.1, 137.8, 136.2,
3
C
134.7, 133.7, 129.9, 129.2, 127.5, 126.3, 125.9, 122.3, 121.4,
2
17
+
benzylation of the sp γ-C-H bond of arylacetamide derivatives.
116.0, 45.5, 25.0; HRMS (ESI): MH , found 277.1333.
Given the importance of the arylacetic acid derivatives in organic
synthesis and medicinal chemistry, this method has provided an
access to assemble new ortho-substituted arylacetamides.
C H N O requires 277.1341.
1
8
17
2
3.2.3. N-(2-Methoxyphenyl)-2-phenylacetamide (1c): The
resultant crude mixture was purified by column chromatography
(
(
(
(
EtOAc:hexane = 20:80) to afford 1c as an orange color solid
3
. Experimental Section
o
210 mg, 72%); R
KBr): νmax 3385, 3056, 1683, 1530, 1263, 750 cm ; H NMR
400 MHz, CDCl ): δ 8.42 (1 H, d, J = 6.8 Hz), 7.93 (1 H, br. s),
f
(20% EtOAc/hexane) 0.4; mp: 85-87 C; IR
-1 1
3
.1. General
3
H

ACCEPTED MANUSCRIPT
7
7
.46-7.36 (5 H, m), 7.06 (1 H, td, J
1
= 7.7, J
2
= 1.4 Hz), 6.98 (1
3.3.1. 2-(4-Chlorophenyl)-N-(quinolin-8-yl)acetamide (1f):
H, td, J = 7.7, J = 1.4 Hz), 6.83 (1 H, d, J = 8.3 Hz), 3.81 (2 H,
The resultant crude mixture was purified by column
chromatography (EtOAc:hexane = 20:80) to afford 1f as a yellow
1
2
13
s), 3.73 (3 H, s); C NMR (CDCl
3
, 100 MHz): δ
C
169.4, 148.0,
1
1
C
34.6, 129.6, 129.5, 129.1, 128.6, 127.5, 127.2, 124.0, 121.1,
color solid (153 mg, 79%); R (20% EtOAc/hexane) 0.6; mp: 95-
97 C; IR (KBr): νmax 3343, 3054, 1682, 1527, 1265, 741 cm ; H
f
+
o
-1 1
19.7, 110.1, 55.7, 45.1; HRMS (ESI): MH , found 242.1174.
requires 242.1181.
15
H16NO
2
NMR (400 MHz, CDCl
m), 8.15 (1 H, dd, J = 8.3, J
(1 H, dd, J = 8.3, J
NMR (CDCl , 100 MHz): δ
133.3, 133.2, 130.9, 129.1, 127.9, 127.3, 121.8, 121.6, 116.4,
3
): δ
H
9.93 (1 H, br. s), 8.77-8.74 (2 H,
1
2
= 1.7 Hz), 7.56-7.50 (2 H, m), 7.44
= 4.2 Hz), 7.39 (4 H, s), 3.88 (2 H, s) ; C
168.9, 148.3, 138.4, 136.3, 134.2,
13
3.2.4. 2-Phenyl-N-(pyridin-2-yl)acetamide (1d): The resultant
1
2
crude mixture was purified by column chromatography
3
C
(
(
EtOAc:hexane = 20:80) to afford 1d as a pale yellow color solid
o
150 mg, 89%); R
+
f
(20% EtOAc/hexane) 0.3; mp: 115-117 C;
44.5; HRMS (ESI): MH , found 297.0788. C17
297.0795.
2
H14ClN O requires
-
1 1
IR (KBr): νmax 3233, 3053, 1650, 1578, 1291, 726 cm ; H NMR
(
(
=
1
4
2
400 MHz, CDCl ): δ 8.25-8.22 (2 H, m), 8.12 (1 H, br. s), 7.70
3
H
1 H, td, J
1
= 8.5, J
2
= 1.7 Hz), 7.42-7.34 (5 H, m), 7.04 (1 H, t, J
3.3.2. 2-(4-Fluorophenyl)-N-(quinolin-8-yl)acetamide (1g):
The resultant crude mixture was purified by column
chromatography (EtOAc:hexane = 20:80) to afford 1g as a
1
3
7.6 Hz), 3.77 (2 H, s); C NMR (CDCl , 100 MHz): δ 169.6,
3 C
51.6, 147.7, 138.4, 133.9, 129.5, 129.3, 127.7, 120.0, 114.0,
+
5.0; HRMS (ESI): MH , found 213.1022. C H N O requires
yellow color solid (197 mg, 23%); R (20% EtOAc/hexane) 0.5;
1
3
13
2
f
o
13.1028.
mp: 88-90 C; IR (KBr): νmax 3345, 3054, 1682, 1529, 1265, 741
cm ; H NMR (400 MHz, CDCl ): δ 9.93 (1 H, br. s), 8.78 (1 H,
-
1 1
3
H
3
.2.5. N-(2-(methylthio)phenyl)-2-phenylacetamide (1e): The
d, J = 7.2 Hz), 8.72 (1 H, d, J = 4.2 Hz), 8.11 (1 H, d, J = 8.2
Hz), 7.53-7.47 (2 H, m), 7.42-7.39 (3 H, m), 7.10 (2 H, t, J = 8.6
resultant crude mixture was purified by column chromatography
EtOAc:hexane = 20:80) to afford 1e as a colorless solid (449
1
3
(
Hz), 3.87 (2 H, s); C NMR (CDCl
3 C
, 100 MHz): δ 169.3, 162.2
o
mg, 87%); R
f
(20% EtOAc/hexane) 0.5; mp: 94-96 C; IR
(d, JC-F = 243.6 Hz), 148.2, 138.4, 136.3, 134.3, 131.2, (d, JC-F =
-
1
1
(
(
KBr): νmax 3311, 3055, 1683, 1517, 1265, 742 cm ; H NMR
400 MHz, CDCl ): δ 8.38 (2 H, d, J = 8.0 Hz), 7.46-7.35 (6 H,
8.0 Hz), 130.5 (d, JC-F = 3.1 Hz), 127.9, 127.3, 121.7, 121.6,
+
3
H
116.4, 115.8 (d, JC-F = 21.2 Hz), 44.3; HRMS (ESI): MH , found
m), 7.30 (1 H, t, J = 7.1 Hz), 7.03 (1 H, t, J = 6.7 Hz), 3.82 (2 H,
2
281.1082. C17H14FN O requires 281.1090.
13
s), 2.04 (3 H, s); C NMR (CDCl
3
C
, 100 MHz): δ 169.3, 138.5,
1
4
34.4, 133.6, 129.7, 129.3, 129.2, 127.8, 125.0, 124.3, 120.0,
5.4, 18.7;. HRMS (ESI): MH , found 258.0946. C15H16NOS
3.3.3. 2-(4-Bromophenyl)-N-(quinolin-8-yl)acetamide (1h):
The resultant crude mixture was purified by column
chromatography (EtOAc:hexane = 20:80) to afford 1h as a brown
+
requires 258.0953.
color solid (624 mg, 52%); R
f
(20% EtOAc/hexane) 0.6; mp:
o
3
.2.6. N-(Quinolin-8-yl)-2-(thiophen-2-yl)acetamide (1k): The
resultant crude mixture was purified by column chromatography
EtOAc:hexane = 20:80) to afford 1k as a brown solid (449 mg,
104-106 C; IR (KBr): ν 3342, 3054, 1682, 1527, 1265, 741
max
-
1 1
cm ; H NMR (400 MHz, CDCl
dd, J = 7.0, J = 2.0 Hz), 8.74 (1 H, dd, J
8.13 (1 H, dd, J = 8.3, J = 1.7 Hz), 7.55-7.48 (4 H, m), 7.42 (1
H, dd, J = 8.3, J = 4.2 Hz), 7.32 (2 H, d, J = 8.4 Hz), 3.85 (2 H,
s); C NMR (CDCl , 100 MHz): δ 168.8, 148.3, 138.3, 136.3,
134.2, 133.7, 132.0, 131.3, 127.9, 127.3, 121.8, 121.7, 121.4,
): δ
3 H
9.93 (1 H, br. s), 8.76 (1 H,
(
1
2
1
= 4.3, J = 1.7 Hz),
2
o
6
3
8%); R
339, 3054, 2308, 1527, 1265, 744 cm ; H NMR (400 MHz,
): δ 10.0 (1 H, br. s), 8.79 (1 H, dd, J = 7.1, J = 1.8 Hz),
.73 (1 H, dd, J = 4.2, J = 1.6 Hz), 8.13 (1 H, dd, J = 8.3, J
.6 Hz), 7.55-7.49 (2 H, m), 7.42 (1 H, dd, J = 8.3, J = 4.2 Hz),
.32 (1 H, dd, J = 5.1, J = 1.2 Hz), 7.14 (1 H, d, J = 3.4 Hz),
f
(20% EtOAc/hexane) 0.4; mp: 70-72 C; IR (KBr): νmax
1
2
-
1
1
1
2
1
3
CDCl
3
H
1
2
3
C
8
1
7
7
1
2
1
2
=
+
1
2
116.4, 44.5; HRMS (ESI): MH , found 341.0278. C17
requires 341.0290.
2
H14BrN O
1
2
1
3
.08 (1 H, dd, J = 5.2, J = 3.5 Hz), 4.12 (2 H, s); C NMR
1
2
(
CDCl
3
, 100 MHz): δ
C
168.3, 148.3, 138.5, 136.3, 135.3, 134.2,
3.3.4.
2-(3,4-Dimethoxyphenyl)-N-(quinolin-8-yl)acetamide
1
27.9, 127.5, 127.3, 125.6, 121.6, 116.4, 39.1;. HRMS (ESI):
(1i): The resultant crude mixture was purified by column
chromatography (EtOAc:hexane = 20:80) to afford 1i as a
+
MH , found 269.0742. C15
.3. Procedure for synthesis of phenylacetamides 1f-j.
A dry flask containing carboxylic acid (1 mmol) and SOCl
13 2
H N OS requires 269.0749.
colorless solid (218 mg, 45%); R
f
(20% EtOAc/hexane) 0.4; mp:
o
3
108-110 C; IR (KBr): νmax 3339, 3055, 1679, 1527, 1265, 743
-
1 1
cm ; H NMR (400 MHz, CDCl
dd, J = 7.3, J = 1.6 Hz), 8.70 (1 H, dd, J
8.12 (1 H, d, J = 8.3 Hz), 7.54-7.47 (2 H, m), 7.40 (1 H, dd, J
8.3, J = 4.2 Hz), 6.99-6.97 (2 H, m), 6.91 (1 H, d, J = 8.6 Hz),
3.93 (3 H, s), 3.91 (3 H, s), 3.84 (2 H, s); C NMR (CDCl
MHz): δ 169.8, 149.3, 148.4, 148.2, 138.5, 136.3, 134.4, 127.9,
3
): δ
H
9.97 (1 H, br. s), 8.77 (1 H,
2
(0.6
1
2
1
= 4.2, J = 1.5 Hz),
2
o
mL) was heated at 80 C for 4 h under a nitrogen atmosphere.
After the reaction period, the reaction mixture was concentrated
under reduced pressure to remove the volatiles and then, the
resultant crude reaction mixture was diluted with anhydrous
DCM (2 mL). The DCM solution of corresponding acid chloride
was slowly added to another RB flask containing the
1
=
2
1
3
3
, 100
C
127.3, 127.1, 121.8, 121.6, 121.6, 116.3, 112.5, 111.5, 56.0, 55.9,
+
45.0; HRMS (ESI): MH , found 323.1384. C H N O requires
1
9
19
2
3
corresponding amine (1 mmol), Et
3
N (111 mg, 1.1 mmol) and
323.1396.
DCM (4 mL) under a nitrogen atmosphere. The resulting mixture
was stirred at rt for 12 h. After this period, the reaction mixture
was diluted with dichloromethane and washed with water and
3.3.5. 2-(3-Chlorophenyl)-N-(quinolin-8-yl)acetamide (1j):
The resultant crude mixture was purified by column
chromatography (EtOAc:hexane = 20:80) to afford 1j as an
saturated aqueous NaHCO
organic layers were dried over anhydrous Na
3
solution (twice). The combined
SO and then, the
2
4
orange color solid (550 mg, 61%); R
f
(20% EtOAc/hexane) 0.6;
o
solvent was evaporated in vacuo to afford a crude reaction
mixture. Purification of the crude reaction mixture by column
chromatography (neutral alumina (EtOAc/hexanes = 25:75)
furnished the corresponding products 1f-j.
mp: 84-86 C; IR (KBr): νmax 3341, 3055, 1682, 1527, 1265, 741
-
1 1
cm ; H NMR (400 MHz, CDCl
dd, J = 7.0, J = 1.9 Hz), 8.74 (1 H, dd, J
8.12 (1 H, dd, J = 8.3, J = 1.6 Hz), 7.54-7.46 (3 H, m), 7.42 (1
H, dd, J = 8.3, J = 4.2 Hz), 7.34-7.31 (3 H, m), 3.87 (2 H, s);
C NMR (CDCl , 100 MHz): δ 168.6, 148.3, 138.4, 136.6,
): δ
3 H
9.96 (1 H, br. s), 8.76 (1 H,
1
2
1
= 4.2, J = 1.6 Hz),
2
1
2
1
2
13
3
C

ACCEPTED MANUSCRIPT
8
Tetrahedron
1
36.3, 134.7, 134.2, 130.2, 129.7, 127.9, 127.8, 127.5, 127.3,
3.4.4. N-(Quinolin-8-yl)-2-(3,3'',4,4''-tetramethyl-[1,1':3',1''-
+
1
21.8, 121.7, 116.4, 44.7; HRMS (ESI): MH , found 297.0786.
O requires 297.0795.
terphenyl]-2'-yl)acetamide (4h): The resultant crude mixture
was purified by column chromatography (EtOAc:hexane =
C
17
H
14ClN
2
2
0:80) to afford 4h as a colorless solid (37 mg, 66%); R (20%
f
o
3
.4. General procedure for the Pd(II)-catalyzed arylation of
EtOAc/hexane) 0.7; mp: 99-101 C; IR (KBr): νmax 3349, 3054,
-1 1
phenylacetamides and preparation of the compounds 4a-
q/7a-f (bis arylation products), 3o,r/6a,b/8e,f/9a,b (mono
arylation products). An appropriate phenylacetamide (0.12
mmol, 1 equiv), an appropriate iodo compound (0.48 mmol, 4
1681, 1525, 1265, 741 cm ; H NMR (400 MHz, CDCl
9.38 (1 H, br. s), 8.71 (1 H, dd, J = 4.1, J = 1.3 Hz), 8.66 (1 H,
dd, J = 7.1, J = 1.5 Hz), 8.15 (1 H, d, J = 8.0 Hz), 7.53-7.47 (2
H, m,), 7.45-7.41 (2 H, m), 7.34 (2 H, d, J = 7.9 Hz), 7.20-7.18 (4
3 H
): δ
1
2
1
2
1
3
equiv), Pd(OAc)
2
(2.7 mg, 10 mol%), and AgOAc (50 mg, 0.3
H, m), 7.07 (2 H, d, J = 8.1 Hz), 3.82 (2 H, s), 2.10 (12 H, s);
C
mmol, 2.5 equiv) in anhydrous toluene (3 mL) was heated at 110
NMR (CDCl , 100 MHz): δ 170.3, 147.8, 143.8, 139.2, 138.2,
136.3, 136.1, 135.4, 134.7, 130.8, 130.6, 129.5, 129.4, 127.8,
3
C
o
C for 24 h under a nitrogen atmosphere. After the reaction
period, the solvent was evaporated in vacuo to afford a crude
reaction mixture. Purification of the crude reaction mixture by
column chromatography furnished the corresponding arylated
products 4a-q/7a-f (bis arylation products), 3o,r/6a,b/8e,f/9a,b
127.4, 126.8, 126.6, 121.4, 121.1, 116.0, 40.6, 19.6, 19.3; HRMS
+
(ESI): MH , found 471.2422. C33
H
31
N
2
O requires 471.2436.
3.4.5. N-(Quinolin-8-yl)-2-(3,3'',4,4''-tetrachloro-[1,1':3',1''-
terphenyl]-2'-yl)acetamide (4i): The resultant crude mixture
was purified by column chromatography (EtOAc:hexane =
(
mono arylation products) (see corresponding Tables/Schemes
for specific examples and reaction conditions).
2
0:80) to afford 4i as a yellow color solid (30 mg, 45%); R (20%
f
o
3
(
.4.1.
quinolin-8-yl)acetamide (4c): The resultant crude mixture was
purified by column chromatography (EtOAc:hexane = 20:80) to
afford 4c as a yellow color semi-solid (45 mg, 80%); R (20%
EtOAc/hexane) 0.7; IR (KBr): νmax 3349, 3054, 2305, 1682,
2-(4,4''-Diethyl-[1,1':3',1''-terphenyl]-2'-yl)-N-
EtOAc/hexane) 0.6; mp: 210-212 C; IR (KBr): νmax 3345, 3055,
-1 1
2305, 1422, 1265, 742 cm ; H NMR (400 MHz, CDCl
9.36 (1 H, br. s), 8.74 (1 H, dd, J = 4.2, J = 1.7 Hz), 8.61 (1 H, t,
J = 4.6 Hz), 8.17 (1 H, dd, J = 8.3, J = 1.7 Hz), 7.54-7.51 (4 H,
m), 7.48-7.42 (2 H, m), 7.36-7.29 (6 H, m), 3.73 (2 H, s);
NMR (CDCl , 100 MHz): δ 169.2, 148.3, 141.5, 141.2, 138.1,
3 H
): δ
1
2
f
1
2
1
3
C
-
1 1
1
8
1
7
265, 741 cm ; H NMR (400 MHz, CDCl
.68 (1 H, dd, J = 4.2, J = 1.7 Hz), 8.65 (1 H, dd, J
.8 Hz), 8.14 (1 H, dd, J = 8.3, J = 1.6 Hz), 7.53-7.49 (2 H, m),
.47-7.45 (1 H, m), 7.44-7.40 (2 H, m), 7.38-7.34 (1 H, m), 7.35
3
): δ
H
9.46 (1 H, br. s),
3
C
= 7.1, J
2
=
136.3, 134.0, 132.4, 131.8, 131.2, 130.7, 130.3, 130.0, 128.7,
1
2
1
127.9, 127.3, 127.3, 121.7, 121.6, 116.2, 40.2; HRMS (ESI):
1
2
+
MH , found 551.0263. C29
H19Cl
N
2
O requires 551.0251.
4
(
(
1
1
1
4
4 H, d, J = 8.1 Hz), 7.14 (4 H, d, J = 8.1 Hz), 3.83 (2 H, s), 2.54
13
4 H, q, J = 7.6 Hz), 1.13 (6 H, t, J = 7.6 Hz); C NMR (CDCl
3
,
3.4.6.
2-(4,4''-Difluoro-[1,1':3',1''-terphenyl]-2'-yl)-N-
00 MHz): δC 170.2, 147.9, 143.8, 143.0, 138.9, 138.3, 136.2,
(quinolin-8-yl)acetamide (4j): The resultant crude mixture was
purified by column chromatography (EtOAc:hexane = 20:80) to
afford 4j as a yellow color solid (35 mg, 64%); R
EtOAc/hexane) 0.5; mp: 116-118 C; IR (KBr): νmax 3345, 3055,
34.5, 130.7, 129.6, 129.2, 127.8, 127.7, 127.4, 127.0, 121.4,
+
21.2, 116.0, 40.5, 28.4, 15.3; HRMS (ESI): MH , found
f
(20%
o
71.2424. C33
31 2
H N O requires 471.2436.
-
1
1
1
681, 1525, 1262, 749 cm ; H NMR (400 MHz, CDCl
9.42 (1 H, br. s), 8.69 (1 H, dd, J = 4.2, J = 1.7 Hz), 8.63 (1 H,
dd, J = 5.8, J = 3.2 Hz), 8.16 (1 H, dd, J = 8.3, J = 1.6 Hz),
7.52-7.50 (2 H, m), 7.46-7.39 (6 H, m), 7.34 (2 H, d, J = 7.4 Hz),
3 H
): δ
3
.4.2. 2-(4,4''-Di-tert-butyl-[1,1':3',1''-terphenyl]-2'-yl)-N-
1
2
(
quinolin-8-yl)acetamide (4d): The resultant crude mixture was
purified by column chromatography (EtOAc:hexane = 20:80) to
afford 4d as a pale yellow solid (40 mg, 63%); R (20%
EtOAc/hexane) 0.7; mp: 161-163 C; IR (KBr): νmax 3353, 3054,
1
2
1
2
13
7.02-6.98 (4 H, m), 3.76 (2 H, s); C NMR (CDCl
3
, 100 MHz):
f
o
δ
C
169.7, 162.2 (d, JC-F = 244.6 Hz), 148.1, 142.9, 138.2, 137.4
-
1
1
2
9
1
987, 1422, 1265, 741 cm ; H NMR (400 MHz, CDCl3): δ
H
(d, JC-F = 3.1 Hz), 136.3, 134.2, 130.8 (d, JC-F = 8.7 Hz), 129.9,
127.9, 127.3, 127.1, 121.6, 121.5, 116.1, 115.3 (d, JC-F = 21.2
Hz), 40.3; HRMS (ESI): MH , found 451.1607. C29
requires 451.1622.
.45 (1 H, br. s), 8.67-8.64 (2 H, m), 8.13 (1 H, dd, J = 8.3, J =
1
2
+
.6 Hz), 7.53-7.46 (3 H, m), 7.44-7.40 (1 H, m), 7.39-7.37 (6 H,
H F N O
21 2 2
13
m), 7.32 (4 H, d, J = 8.5 Hz), 3.85 (2 H, s), 1.21 (18 H, s);
C
3 C
NMR (CDCl , 100 MHz): δ 170.3, 149.8, 148.0, 143.8, 138.7,
1
1
5
36.2, 134.5, 130.8, 129.6, 128.9, 127.8, 127.4, 127.0, 125.1,
21.5, 121.2, 116.0, 40.6, 34.4, 31.2; HRMS (ESI): MH , found
3.4.7.
2-(3,3''-Dinitro-[1,1':3',1''-terphenyl]-2'-yl)-N-
+
(quinolin-8-yl)acetamide (4m): The resultant crude mixture was
purified by column chromatography (EtOAc:hexane = 20:80) to
afford 4m as a brown color solid (30 mg, 50%); R
EtOAc/hexane) 0.3; mp: 97-99 C; IR (KBr): νmax 3340, 3054,
27.3045. C37
H
39
N
2
O requires 527.3062.
f
(20%
o
3
.4.3. 2-(2,6-Bis(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-
-
1
1
N-(quinolin-8-yl)acetamide (4f): The resultant crude mixture
was purified by column chromatography (EtOAc:hexane =
2987, 1422, 1265, 741 cm ; H NMR (400 MHz, CDCl
9.32 (1 H, br. s), 8.67 (1 H, dd, J = 4.2, J = 1.6 Hz), 8.56 (1 H,
dd, J = 5.6, J = 3.3 Hz), 8.35 (2 H, t, J = 1.9 Hz), 8.16 (1 H, dd,
= 8.3, J = 1.6 Hz), 8.10 (1 H, dd, J = 2.2, J = 0.9 Hz), 8.08 (1
H, dd, J = 2.1, J = 0.8 Hz), 7.83 (2 H, d, J = 7.6 Hz), 7.56-7.54
(1 H, m), 7.51-7.49 (3 H, m), 7.47-7.44 (2 H, m), 7.42 (2 H, d, J
3 H
): δ
1
2
2
0:80) to afford 4f as a yellow color solid (40 mg, 63%); R
f
(20%
1
2
o
EtOAc/hexane) 0.3; mp: 98-100 C; IR (KBr): νmax 3343, 3054,
2
9
J
1
2
1
2
-
1
1
986, 1680, 1265, 742 cm ; H NMR (400 MHz, CDCl ): δ
1
2
3
H
1 2
.46 (1 H, br. s), 8.69 (1 H, dd, J = 4.2, J = 1.7 Hz), 8.65 (1 H,
1
3
dd, J = 7.3, J = 1.6 Hz), 8.13 (1 H, dd, J = 8.3, J = 1.6 Hz),
3 C
= 7.6 Hz), 3.74 (2 H, s); C NMR (CDCl , 100 MHz): δ 168.7,
148.2, 148.1, 142.7, 141.6, 138.0, 136.4, 135.5, 133.7, 130.6,
130.4, 129.4, 127.8, 127.7, 127.3, 124.2, 122.5, 121.9, 121.7,
116.3, 40.1; HRMS (ESI): MH , found 505.1495. C29
requires 505.1512.
1
2
1
2
7
6
6
.53-7.46 (2 H, m), 7.44-7.39 (2 H, m), 7.32 (2 H, d, J = 7.1 Hz),
.94 (2 H, d, J = 2.0 Hz), 6.90 (2 H, dd, J = 8.6, J = 2.1 Hz),
1
2
1
3
+
.79 (2 H, d, J = 8.2 Hz), 4.12 (8 H, s), 3.87 (2 H, s); C NMR
, 100 MHz): δ 170.0, 148.0, 143.2, 143.1, 142.8, 138.3,
21 4 5
H N O
(
CDCl
3
C
1
1
36.1, 135.0, 134.5, 131.0, 129.6, 127.8, 127.4, 126.9, 122.4,
21.4, 121.2, 118.3, 117.0, 116.1, 64.2, 64.2, 40.4; HRMS (ESI):
3.4.8.
Dimethyl
2'-(2-oxo-2-(quinolin-8-ylamino)ethyl)-
+
MH , found 531.1904. C33
H
27
N
2
O
5
requires 531.1920.
[1,1':3',1''-terphenyl]-4,4''-dicarboxylate (4n): The resultant
crude mixture was purified by column chromatography
(
EtOAc:hexane = 20:80) to afford 4n as a yellow color solid (40

ACCEPTED MANUSCRIPT
9
o
mg, 63%); R
(
(
=
f
(20% EtOAc/hexane) 0.3; mp: 144-146 C; IR
7.46 (1 H, dd, J
1 2
= 7.7, J = 1.4 Hz), 7.43-7.28 (7 H, m), 7.06 (1
-
1
1
KBr): νmax 3343, 3055, 1721, 1422, 1265, 742 cm ; H NMR
400 MHz, CDCl ): δ 9.33 (1 H, br. s), 8.65 (1 H, dd, J = 4.1, J
1.6 Hz), 8.59 (1 H, dd, J = 5.8, J = 3.0 Hz), 8.14 (1 H, dd, J =
H, td, J = 7.6, J = 1.2 Hz), 6.93 (2 H, d, J = 8.8 Hz), 5.15 (1 H,
s), 3.82 (3 H, s), 2.04 (3 H, s); C NMR (CDCl , 100 MHz): δ
3 C
170.7, 158.9, 139.4, 138.6, 133.7, 131.1, 130.2, 129.3, 129.0,
1
2
1
3
3
H
1
2
1
2
1
8
.3, J
Hz), 7.51-7.49 (3 H, m), 7.42 (1 H, dd, J
.37 (2 H, d, J = 7.7 Hz), 3.85 (6 H, s), 3.75 (2 H, br. s);
NMR (CDCl , 100 MHz): δ 169.3, 166.8, 148.0, 146.1, 143.0,
38.1, 136.2, 134.2, 130.2, 129.7, 129.6, 129.4, 129.4, 129.1,
27.8, 127.4, 127.3, 121.5, 121.4, 116.1, 52.1, 40.1; HRMS
2
= 1.6 Hz), 7.98 (4 H, d, J = 8.2 Hz), 7.53 (4 H, d, J = 8.2
129.0, 127.5, 125.1, 124.4, 120.1, 114.4, 59.9, 55.4, 18.9; HRMS
+
1
= 8.3, J = 4.2 Hz),
2
(ESI): MNa , found 386.1190. C29
H
27NNaO
3
S requires 386.1191.
13
7
C
3
C
3.4.13. N-(2-(Methylthio)phenyl)-2-(3'-nitro-[1,1'-biphenyl]-2-
yl)acetamide (6b): The resultant crude mixture was purified by
column chromatography (EtOAc:hexane = 20:80) to afford 6b as
1
1
+
(
ESI): MH , found 531.1902. C33
H
27
N
2
O
5
requires 531.1920.
a pale yellow color solid (20 mg, 45%); R
f
(20% EtOAc/hexane)
): δ 8.61 (1 H, br. s), 8.40
3 H
o
0
.3; mp: 87-89 C; IR (KBr): νmax 3312, 3055, 1686, 1526, 1265,
-1 1
3
.4.9. 2-(2,6-Bis(5-bromopyridin-2-yl)phenyl)-N-(quinolin-8-
741 cm ; H NMR (400 MHz, CDCl
(1 H, dd, J = 8.2, J
= 7.5, J = 1.3 Hz), 7.76 (1 H, d, J = 7.8 Hz), 7.57 (1 H, t, J = 8.0
yl)acetamide (4p): The resultant crude mixture was purified by
column chromatography (EtOAc:hexane = 20:80) to afford 4p as
1
2 1
= 1.0 Hz), 8.27 (1 H, br. s), 8.19 (1 H, dd, J
2
a pale yellow color solid (30 mg, 44%); R
f
(20% EtOAc/hexane)
Hz), 7.48-7.38 (4 H, m), 7.35-7.31 (1 H, m), 7.09 (1 H, td, J =
1.2, J = 7.6 Hz), 5.25 (1 H, s), 2.09 (3 H, s); C NMR (CDCl3,
2
100 MHz): δ 168.9, 148.5, 141.1, 139.1, 137.7, 135.3, 133.5,
C
1
o
13
0
1
.4; mp: 209-211 C; IR (KBr): ν 3375, 3055, 2987, 1422,
265, 743 cm ; H NMR (400 MHz, CDCl
max
-
1 1
3
): δ
H
10.48 (1 H, br.
s), 8.82-8.79 (3 H, m), 8.59 (1 H, dd, J = 5.8, J = 3.3 Hz), 8.15
129.7, 129.5, 129.2, 129.0, 128.3, 125.4, 124.9, 124.2, 122.5,
120.3, 59.8, 18.9; HRMS (ESI): MH , found 379.1102.
C H N O S requires 379.1116.
21 19 2 3
1
2
+
(
1 H, dd, J
1
= 8.3, J
2
= 1.7 Hz), 7.88 (1 H, d, J = 2.4 Hz), 7.86 (1
= 8.3, J
, 100 MHz): δ 169.7,
H, d, J = 2.4 Hz), 7.52-7.48 (7 H, m), 7.45 (1 H, dd, J
1
2
=
1
3
4
1
1
.2 Hz), 4.15 (2 H, s); C NMR (CDCl
58.0, 150.2, 148.1, 141.1, 139.4, 136.2, 135.0, 131.5, 130.7,
28.0, 127.4, 127.3, 125.9, 121.5, 121.4, 119.6, 116.7, 39.3;
3
C
3.4.14. 2-(5'-Fluoro-4,4''-dimethoxy-[1,1':3',1''-terphenyl]-2'-
yl)-N-(quinolin-8-yl)acetamide (7b): The resultant crude
mixture was purified by column chromatography (EtOAc:hexane
+
HRMS (ESI): MNa , found 594.9766. C27
H18Br
2
N
4
NaO requires
5
94.9745.
= 20:80) to afford 7b as a pale yellow color solid (30 mg, 61%);
o
R
f
(20% EtOAc/hexane) 0.4; mp: 145-147 C; IR (KBr): νmax
-
1
1
3
.4.10.
2-(2,6-Di(thiophen-2-yl)phenyl)-N-(quinolin-8-
3345, 3055, 2305, 1514, 1265, 743 cm ; H NMR (400 MHz,
CDCl ): δ 9.43 (1 H, br. s), 8.71 (1 H, dd, J = 4.1, J = 1.9 Hz),
8.65 (1 H, dd, J = 6.4, J = 2.0 Hz), 8.15 (1 H, d, J = 8.2 Hz),
yl)acetamide (4q): The resultant crude mixture was purified by
column chromatography (EtOAc:hexane = 20:80) to afford 4q as
3
H
1
2
1
2
a yellow color solid (36 mg, 70%); R
f
(20% EtOAc/hexane) 0.2;
7.52-7.50 (2 H, m), 7.46-7.43 (1 H, m), 7.34 (4 H, d, J = 8.6 Hz),
o
mp: 144-146 C; IR (KBr): ν 3338, 3055, 1681, 1525, 1265,
7.07 (2 H, d, J = 9.1 Hz), 6.83 (4 H, d, J = 8.6 Hz), 3.75 (2 H, s),
max
-
1
1
13
7
(
42 cm ; H NMR (400 MHz, CDCl
1 H, dd, J = 7.3, J = 1.6 Hz), 8.67 (1 H, dd, J
Hz), 8.15 (1 H, dd, J = 8.3, J = 1.6 Hz), 7.57-7.53 (3 H, m),
.51 (1 H, dd, J = 8.3, J = 1.6 Hz), 7.47-7.41 (2 H, m), 7.29 (2
H, dd, J = 5.1, J = 1.1 Hz), 7.15 (2 H, dd, J = 3.5, J = 1.1 Hz),
.00-6.98 (2 H, m), 4.04 (2 H, br. s); C NMR (CDCl , 100
MHz): δ 170.0, 148.1, 141.9, 138.4, 136.5, 136.2, 134.5, 132.6,
3
): δ
H
9.73 (1 H, br. s), 8.76
3.68 (6 H, s); C NMR (CDCl
3
, 100 MHz): δ
C
170.0, 161.0 (d,
1
2
1
= 4.2, J = 1.7
2
J
C-F = 245.5 Hz), 159.0, 148.1, 145.4 (d, JC-F = 8.0 Hz), 138.2,
136.2, 134.4, 133.1, 133.1, 130.1, 127.8, 127.4, 127.2 (d, JC-F
3.0 Hz), 121.5, 121.3, 116.3 (d, JC-F = 20.6 Hz), 116.0, 113.7,
1
2
=
7
1
2
+
1
2
1
2
55.1, 39.8; HRMS (ESI): MH , found 493.1931. C31
requires 493.1927.
2 3
H26FN O
13
7
3
C
1
4
4
31.7, 127.9, 127.4, 127.3, 127.1, 126.0, 121.6, 121.5, 116.3,
3.4.15. 2-(5'-Bromo-4,4''-dimethoxy-[1,1':3',1''-terphenyl]-2'-
yl)-N-(quinolin-8-yl)acetamide (7c): The resultant crude
mixture was purified by column chromatography (EtOAc:hexane
20:80) to afford 7c as an orange color solid (35 mg, 63%); Rf
+
1.0; HRMS (ESI): MH , found 427.0924. C H N OS requires
2
5
19
2
2
27.0939.
=
o
3
.4.11.
2-(2-(1H-Indol-5-yl)phenyl)-N-(quinolin-8-
(20% EtOAc/hexane) 0.4; mp: 149-151 C; IR (KBr): νmax 3343,
-1 1
yl)acetamide (3r): The resultant crude mixture was purified by
column chromatography (EtOAc:hexane = 20:80) to afford 3r as
a brown color solid (20 mg, 44%); R
mp: 159-161 C; IR (KBr): νmax 3329, 3055, 1422, 1265, 896, 735
3053, 2926, 1682, 1264, 749 cm ; H NMR (400 MHz, CDCl
9.40 (1 H, br. s), 8.71 (1 H, dd, J = 4.2, J = 1.6 Hz), 8.64 (1
H, dd, J = 6.6, J = 2.4 Hz), 8.15 (1 H, dd, J = 8.3, J = 1.6 Hz),
7.51-7.49 (4 H, m,), 7.44 (1 H, dd, J = 8.3, J = 4.2 Hz), 7.33 (4
H, d, J = 8.7 Hz), 6.83 (4 H, d, J = 8.7 Hz), 3.74 (2 H, s), 3.66 (6
3
):
δ
H
1
2
f
(20% EtOAc/hexane) 0.4;
1
2
1
2
o
1
2
-
1 1
cm ; H NMR (400 MHz, CDCl
dd, J = 7.8, J = 0.8 Hz), 8.65 (1 H, dd, J
.23 (1 H, br. s), 8.13 (1 H, dd, J = 8.3, J
br. s), 7.58-7.56 (1 H, m), 7.53-7.49 (2 H, m), 7.46-7.38 (4 H, m),
3
): δ
H
9.75 (1 H, br. s), 8.74 (1 H,
= 4.2, J = 1.6 Hz),
= 1.6 Hz), 7.67 (1 H,
13
1
2
1
2
3 C
H, s); C NMR (CDCl , 100 MHz): δ 169.6, 159.0, 148.1,
8
1
2
145.3, 138.2, 136.2, 134.4, 132.6, 132.3, 130.5, 130.2, 127.8,
127.4, 121.6, 121.4, 120.6, 116.0, 113.8, 51.1, 40.0; HRMS
13
+
7
.25-7.22 (2 H, m), 6.51 (1 H, t, J = 2.1 Hz), 3.92 (2 H, s);
C
(ESI): MH , found 553.1105. C31
H26BrN
2
O
3
requires 553.1127.
NMR (CDCl , 100 MHz): δC 170.2, 148.0, 143.9, 138.4, 136.1,
3
1
1
1
35.0, 134.5, 132.8, 132.7, 131.1, 130.5, 127.9, 127.8, 127.5,
3.4.16. 2-(5'-Bromo-[1,1':3',1''-terphenyl]-2'-yl)-N-(quinolin-
8-yl)acetamide (7d): The resultant crude mixture was purified
by column chromatography (EtOAc:hexane = 20:80) to afford 7d
27.3, 127.2, 124.8, 123.6, 121.5, 121.4, 121.3, 116.3, 110.8,
+
02.8, 42.8; HRMS (ESI): MH , found 378.1594. C25
H
20
3
N O
requires 378.1606.
as a pale red color solid (25 mg, 51%); R (20% EtOAc/hexane)
f
o
0
.6; mp: 150-152 C; IR (KBr): νmax 3343, 3049, 1688, 1525,
-
1 1
3
(
.4.12.
methylthio)phenyl)acetamide (6a): The resultant crude
mixture was purified by column chromatography (EtOAc:hexane
2-(4'-Methoxy-[1,1'-biphenyl]-2-yl)-N-(2-
1422, 703 cm ; H NMR (400 MHz, CDCl
8.70 (1 H, dd, J = 4.2, J = 1.6 Hz), 8.60 (1 H, dd, J
2.6 Hz), 8.15 (1 H, dd, J = 8.3, J = 1.5 Hz), 7.54 (2 H, s), 7.51-
7.49 (2 H, m), 7.45-7.40 (5 H, m), 7.34-7.30 (4 H, m), 7.26 (2 H,
3
): δ
H
9.42 (1 H, br. s),
1
2
1
= 6.3, J
2
=
1
2
=
20:80) to afford (6a) as a pale yellow color solid (25 mg, 54%);
o
13
R
f
(20% EtOAc/hexane) 0.5; mp: 108-110 C; IR (KBr): νmax
3 C
t, J = 7.2 Hz), 3.73 (2 H, s); C NMR (CDCl , 100 MHz): δ
-
1
1
3
309, 3055, 2305, 1422, 1265, 741 cm ; H NMR (400 MHz,
169.3, 148.1, 145.7, 140.2, 138.2, 136.2, 134.3, 132.3, 129.8,
129.0, 128.4, 127.8, 127.7, 127.4, 121.6, 121.4, 120.7, 116.1,
CDCl ): δ 8.62 (1 H, br. s), 8.47 (1 H, dd, J = 8.2, J = 1.0 Hz),
3
H
1
2

ACCEPTED MANUSCRIPT
10
Tetrahedron
H22BrN O
2
+
3
9.9; HRMS (ESI): MH , found 493.0899. C29
requires 493.0916.
3.4.21.
quinolin-8-yl)acetamide (9a): The resultant crude mixture was
purified by column chromatography (EtOAc:hexane = 20:80) to
afford 9a as a yellow color solid (20 mg, 52%); R (20%
EtOAc/hexane) 0.4; mp: 101-103 C; IR (KBr): νmax 3335, 3055,
2-(4'-Ethyl-4,5-dimethoxy-[1,1'-biphenyl]-2-yl)-N-
(
3
.4.17. 2-(4-Chloro-2,6-bis(2,3-dihydrobenzo[b][1,4]dioxin-6-
yl)phenyl)-N-(quinolin-8-yl)acetamide (7e): The resultant
crude mixture was purified by column chromatography
f
o
-
1
1
(
EtOAc:hexane = 20:80) to afford 7e as a colorless solid (32 mg,
2987, 1681, 1265, 741 cm ; H NMR (400 MHz, CDCl
9.85 (1 H, br. s), 8.75 (1 H, dd, J = 7.1, J = 1.8 Hz), 8.72 (1 H,
dd, J = 4.2, J = 1.6 Hz), 8.15 (1 H, dd, J = 8.3, J = 1.6 Hz),
7.55-7.49 (2 H, m), 7.44 (1 H, dd, J = 8.3, J = 4.2 Hz), 7.34 (2
3 H
): δ
o
5
7%); R
f
(20% EtOAc/hexane) 0.4; mp: 168-170 C; IR (KBr):
1
2
-
1
1
ν
max 3343, 3054, 1679, 1422, 1265, 742 cm ; H NMR (400
1
2
1
2
MHz, CDCl
3
): δ
.6 Hz), 8.63 (1 H, dd, J
.3, J = 1.6 Hz), 7.53-7.47 (2 H, m), 7.44 (1 H, dd J
H
9.42 (1 H, br. s), 8.73 (1 H, dd, J
1
= 4.2, J
2
=
=
=
1
2
1
8
4
1
= 7.0, J = 1.6 Hz), 8.15 (1 H, dd, J
2
1
H, d, J = 8.1 Hz), 7.23 (2 H, d, J = 8.1 Hz), 7.05 (1 H, s), 6.89 (1
H, s), 3.97 (3 H, s), 3.92 (3 H, s), 3.81 (2 H, s), 2.67 (2 H, q, J =
2
1
= 8.3, J
2
1
3
.3 Hz), 7.32 (2 H, s), 6.91-6.86 (4 H, m), 6.79 (2 H, d, J = 8.2
7.6 Hz), 1.26 (3 H, t, J = 7.6 Hz); C NMR (CDCl , 100 MHz):
3
1
3
Hz), 4.13-4.10 (8 H, m), 3.79 (2 H, s); C NMR (CDCl
3
, 100
C
δ 170.2, 148.5, 148.1, 148.0, 143.1, 138.5, 138.3, 136.2, 135.3,
MHz): δ 169.6, 148.1, 144.8, 143.2, 143.1, 138.2, 136.2, 134.4.
134.5, 129.4, 127.9, 127.4, 124.3, 121.6, 121.5, 116.3, 113.5,
113.2, 56.1, 56.0, 42.4, 28.5, 15.5; HRMS (ESI): MH , found
C
+
1
1
5
33.7, 132.3, 129.8, 129.4, 127.8, 127.5, 122.2, 121.5, 121.3,
18.1, 117.2, 116.2, 64.2, 64.2, 39.8; HRMS (ESI): MH , found
+
427.2009. C H N O requires 427.2022.
2
7
27
2
3
65.1553. C33
H
26ClN
2
O
5
requires 565.1530.
3.4.22.
2-(4-Chloro-4'-methoxy-[1,1'-biphenyl]-2-yl)-N-
3
.4.18.
2-(4-Chloro-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-
(quinolin-8-yl)acetamide (9b): The resultant crude mixture was
yl)phenyl)-N-(quinolin-8-yl)acetamide (8e): The resultant
purified by column chromatography (EtOAc:hexane = 20:80) to
crude mixture was purified by column chromatography
afford 9b as an orange color solid (30 mg, 75%); R
f
(20%
o
(
(
(
(
EtOAc:hexane = 20:80) to afford 8e as a pale yellow color solid
EtOAc/hexane) 0.4; mp: 118-120 C; IR (KBr): νmax 3338, 3055,
o
-1
1
15 mg, 34%); R
f
(20% EtOAc/hexane) 0.5; mp: 141-143 C; IR
2305, 1682, 1265, 741 cm ; H NMR (400 MHz, CDCl
9.76 (1 H, br. s), 8.75-8.71 (2 H, m), 8.16 (1 H, dd, J = 8.2, J
1.2 Hz), 7.55-7.52 (3 H, m), 7.45 (1 H, dd, J = 8.2, J
7.36 (1 H, dd, J = 8.2, J = 2.0 Hz), 7.31-7.26 (3 H, m), 6.91 (2
H, d, J = 8.6 Hz), 3.83 (2 H, s), 3.78 (3 H, s); C NMR (CDCl3,
100 MHz): δ 169.0, 159.0, 148.2, 140.9, 138.4, 136.3, 134.4,
3
): δ
H
-
1
1
KBr): νmax 3339, 3054, 2305, 1422, 1265, 743 cm ; H NMR
1
2
=
400 MHz, CDCl
3
): δ
H
9.72 (1 H, br. s), 8.75 (1 H, dd, J
1
= 4.2, J
2
1
2
= 4.3 Hz),
=
1.7 Hz), 8.71 (1 H, dd, J
1
= 6.6, J = 2.4 Hz), 8.15 (1 H, dd, J
2
1
=
1
2
1
3
8.3, J = 1.6 Hz), 7.53-7.43 (4 H, m), 7.38-7.34 (2 H, m), 6.91-
2
13
6.86 (3 H, m), 4.25-4.21 (4 H, m), 3.85 (2 H, s); C NMR
C
(
CDCl , 100 MHz): δ 169.3, 148.2, 148.2, 143.8, 143.4, 143.3,
38.3, 136.2, 134.3, 133.1, 132.9, 132.0, 131.1, 130.4, 130.4,
134.3, 133.3, 132.2, 131.8, 130.6, 130.3, 127.9, 127.5, 127.4,
121.7, 121.6, 116.4, 113.9, 55.2, 42.5; HRMS (ESI): MH , found
3
C
+
1
1
6
27.8, 127.8, 127.4, 122.3, 121.6, 118.1, 118.0, 117.4, 116.3,
403.1198. C H ClN O requires 403.1213.
2
4
20
2
2
+
4.4, 64.3, 42.0; (ESI): MH , found 431.1156. C25
H
20ClN
2
O
3
requires 431.1162.
3.5. General procedure for the Pd(II)-catalyzed benzylation
of phenylacetamides and preparation of the compounds 11a-
3
.4.19. 2-(4-Bromo-2,6-bis(2,3-dihydrobenzo[b][1,4]dioxin-6-
2
d. An appropriate phenylacetamide (0.12 mmol), Pd(OAc) (2.7
yl)phenyl)-N-(quinolin-8-yl)acetamide (7f): The resultant crude
mixture was purified by column chromatography (EtOAc:hexane
mg, 10 mol%), 4-nitrobenzyl bromide (103 mg, 0.48 mmol, 4
equiv) AgOAc (25 mg, 0.15 mmol, 1.2 equiv) in anhydrous
toluene (3 mL) was heated at 110 C for 24 h under a nitrogen
atmosphere. After the reaction period, the solvent was evaporated
in vacuo to afford a crude reaction mixture. Purification of the
crude reaction mixture by column chromatography furnished the
o
=
20:80) to afford 7f as a brown color solid (15 mg, 25%); R
f
o
(
20% EtOAc/hexane) 0.3; mp: 197-199 C; IR (KBr): νmax 3343,
-
1 1
3
057, 1682, 1423, 1265, 743 cm ; H NMR (400 MHz, CDCl ):
3
H 1 2
δ 9.42 (1 H, br. s), 8.73 (1 H, dd, J = 4.2, J = 1.6 Hz), 8.63 (1
H, dd, J = 7.0, J = 1.9 Hz), 8.15 (1 H, dd, J = 8.3, J = 1.6 Hz),
corresponding
benzylated
compounds
11a-d
(see
1
2
1
2
7
6
.51-7.47 (4 H, m), 7.44 (1 H, dd, J
1
= 8.3, J
2
= 4.2 Hz), 6.90-
Tables/Schemes for specific examples).
.85 (4 H, m), 6.78 (2 H, d, J = 8.2 Hz), 4.13-4.10 (8 H, m), 3.79
1
3
(
2 H, s); C NMR (CDCl
3
, 100 MHz): δ
43.2, 143.1, 138.2, 136.2, 134.4, 133.5, 132.3, 130.3, 127.8,
27.5, 122.2, 121.5, 121.2, 120.6, 118.1, 117.2, 116.2, 64.2, 64.2,
C
169.5, 148.1, 145.0,
3.5.1. 2-(2-(4-Nitrobenzyl)phenyl)-N-(quinolin-8-yl)acetamide
(11a): The resultant crude mixture was purified by column
chromatography (EtOAc:hexane = 20:80) to afford 11a as a
1
1
3
+
9.9; HRMS (ESI): MH , found 609.1002.
C
33
H
26BrN
2
O
5
brown color viscous liquid (26 mg, 55%);
R
f
(20%
requires 609.1025.
EtOAc/hexane) 0.3; IR (KBr): νmax 3341, 3055, 2987, 1522,
-
1 1
3 H
1265, 744 cm ; H NMR (400 MHz, CDCl ): δ 9.67 (1 H, br. s),
3
.4.20. 2-(4-Bromo-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-
8.64 (1 H, dd, J
8.14 (1 H, dd, J
1
= 4.2, J = 1.6 Hz), 8.58 (1 H, t, J = 4.7 Hz),
2
= 8.2, J = 1.6 Hz), 7.83 (2 H, d, J = 8.8 Hz),
2
yl)phenyl)-N-(quinolin-8-yl)acetamide (8f): The resultant crude
1
mixture was purified by column chromatography (EtOAc:hexane
7.49-7.46 (3 H, m), 7.44-7.40 (4 H, m), 7.24 (2 H, d, J = 8.8 Hz),
4.23 (2 H, s), 3.85 (2 H, s); C NMR (CDCl , 100 MHz): δ
3 C
13
=
20:80) to afford 8f as a brown color thick liquid (17 mg, 36%);
R (20% EtOAc/hexane) 0.4; IR (KBr): ν 3339, 3057, 2926,
168.7, 148.1, 147.7, 138.2, 138.0, 136.3, 133.9, 133.5, 131.8,
131.3, 129.4, 128.3, 128.0, 127.8, 127.2, 123.6, 123.5, 121.8,
121.6, 116.2, 43.1, 39.2; HRMS (ESI): MH , found 398.1491.
f
max
-
1 1
1
3 H
682, 1265, 743 cm ; H NMR (400 MHz, CDCl ): δ 9.72 (1 H,
+
br. s), 8.76 (1 H, dd, J = 4.2, J = 1.6 Hz), 8.71 (1 H, dd, J = 6.6,
1
2
1
J
2
= 2.4 Hz), 8.15 (1 H, dd, J
1
= 8.3, J
2
= 1.6 Hz), 7.53-7.50 (4 H,
C
24
H
20
N
3
O
3
requires 398.1505.
m), 7.45 (1 H, dd, J
1
= 8.3, J
2
= 4.2 Hz), 7.40 (1 H, d, J = 8.0 Hz),
= 8.3, J = 1.9 Hz), 4.25-
.21 (4 H, m), 3.84 (2 H, s); C NMR (CDCl , 100 MHz): δ
6
4
1
1
1
4
.91-6.87 (2 H, m), 6.84 (1 H, dd, J
1
2
3.5.2.
2-(4-Fluoro-2-(4-nitrobenzyl)phenyl)-N-(quinolin-8-
1
3
3
C
yl)acetamide (11b): The resultant crude mixture was purified by
column chromatography (EtOAc:hexane = 20:80) to afford 11b
69.2, 148.2, 144.1, 143.4, 143.3, 138.3, 136.3, 134.3, 133.3,
33.0, 132.2, 131.7, 130.7, 127.8, 127.3, 122.3, 121.6, 121.1,
18.1, 117.3, 116.3, 64.2, 64.3, 42.1; HRMS (ESI): MH , found
as a yellow color solid (26 mg, 63%); R
f
(20% EtOAc/hexane)
+
o
0.2; mp: 94-96 C; IR (KBr): νmax 3353, 3055, 1738, 1519, 1265,
-
1 1
75.0640. C25
H20BrN
2
O
3
requires 475.0657.
3 H
741 cm ; H NMR (400 MHz, CDCl ): δ 9.69 (1 H, br. s), 8.68

ACCEPTED MANUSCRIPT
1
1
(
1 H, dd, J
1
= 4.2, J
2
= 1.6 Hz), 8.59 (1 H, dd, J
1
= 5.7, J
2
= 3.3
This work was funded by IISER Mohali. The authors thank
Hz), 8.16 (1 H, dd, J = 8.3, J = 1.7 Hz), 7.88 (2 H, d, J = 8.8
the NMR and HRMS facilities of IISER Mohali. N. B. thanks
UGC, New Delhi, for providing JRF and SRF fellowships.
1
2
Hz), 7.49-7.42 (4 H, m), 7.25 (2 H, d, J = 8.8 Hz), 7.11 (1 H, td,
J = 8.3, J = 2.3 Hz), 6.96 (1 H, dd, J = 9.4, J = 2.7 Hz), 4.20 (2
1
2
1
2
13
H, s), 3.83 (2 H, s); C NMR (CDCl
= 1.0 Hz), 162.4 (d, JC-F = 245.6 Hz), 148.2, 146.7, 146.3, 140.4
d, JC-F = 7.3 Hz), 138.2, 136.4, 133.8, 133.3 (d, JC-F = 8.1 Hz),
3
, 100 MHz): δ
C
168.4 (d, JC-
References and notes
F
1
.
(a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529; (b) For a themed
issue on C-H activation reactions, see: C–H Functionalisation in
organic synthesis; Chem. Soc. Rev. 2011, 40, 1845; (c) Kakiuchi,
F.; Murai, S. Acc. Chem. Res. 2002, 35, 826.
(
1
1
3
29.5, 129.3 (d, JC-F = 3.5 Hz), 127.8, 127.2, 123.6, 121.9, 121.6,
18.0 (d, JC-F = 21.5 Hz), 116.2, 114.7 (d, JC-F = 21.0 Hz), 42.3,
+
9.2, 39.1; HRMS (ESI): MH , found 416.1395. C24
H
19FN
3
O
3
requires 416.1410.
2. (a) Shilov, A. E.; Shul’pin, G. B. Chem. Rev. 1997, 97, 2879; (b)
Kakiuchi, F.; Chatani, N. Adv. Synth. Catal. 2003, 345, 1077; (c)
Satoh, T.; Miura, T. Chem. Lett. 2007, 36, 200; (d) Kakiuchi, F.;
Kochi, T. Synthesis 2008, 3013; (e) Daugulis, O.; Do, H.-Q.;
Shabashov, D. Acc. Chem. Res. 2009, 42, 1074; (f) Chen, X.;
Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem. Int. Ed.
2009, 48, 5094; (g) Zhang, M. Adv. Synth. Catal. 2009, 351, 2243;
(h) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147; (i)
Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936; (j)
White, M. C. Synlett 2012, 23, 2746; (k) Kuhl, N.; Hopkinson, M.
N.; Wencel-Delord, J.; Glorius, F. Angew. Chem. Int. Ed. 2012,
3
.5.3. 2-(4-Chloro-2-(4-nitrobenzyl)phenyl)-N-(quinolin-8-
yl)acetamide (11c): The resultant crude mixture was purified by
column chromatography (EtOAc:hexane = 20:80) to afford 11c
as a colorless solid (20 mg, 46%); R
f
(20% EtOAc/hexane) 0.3;
o
mp: 134-136 C; IR (KBr): ν 3339, 3055, 1682, 1523, 1265,
max
-
1 1
7
44 cm ; H NMR (400 MHz, CDCl
3 H
): δ 9.68 (1 H, br. s), 8.69
(
1 H, dd, J = 4.2, J = 1.6 Hz), 8.57 (1 H, dd, J = 6.1, J = 2.9
1
2
1
2
Hz), 8.16 (1 H, dd, J
Hz), 7.49-7.44 (3 H, m), 7.41-7.40 (2 H, m), 7.26-7.24 (3 H, m),
1 2
= 8.3, J = 1.7 Hz), 7.89 (2 H, d, J = 8.8
5
1, 10236; (l) Li, B.-J.; Shi, Z. -J. Chem. Soc. Rev. 2012, 41, 5588;
(m) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Itami, Angew.
Chem. Int. Ed. 2012, 51, 8960; (n) Chen, D. Y.-K.; Youn, S. W.
Chem. Eur. J. 2012, 18, 9452; (o) Colby, D. A.; Tsai, A. S.;
Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814; (p)
Giri, R.; Thapa, S.; Kafle, A. Adv. Synth. Catal. 2014, 356, 1395.
(a) Nithiy, N.; Rosa, D.; Orellana, A. Synthesis 2013, 45, 3199; (b)
Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013, 42, 5744; (c) Wang,
C.; Huang, Y. Synlett 2013, 24, 145; (d) Corbet, M.; De Campo, F.
Angew. Chem. Int. Ed. 2013, 52, 9896; (e) Liu, Y.-J.; Xu, H.;
Kong, W.-J.; Shang, M.; Dai, H.-X. Yu, J.-Q. Nature, 2014, 515,
13
4
1
1
1
3 C
.20 (2 H, s), 3.81 (2 H, s); C NMR (CDCl , 100 MHz): δ
68.1, 148.2, 146.7, 146.4, 139.9, 138.2, 136.4, 133.9, 133.8,
33.0, 132.1, 131.0, 129.4, 128.0, 127.8, 127.2, 123.7, 122.0,
+
21.7, 116.2, 42.4, 39.0; HRMS (ESI): MH , found 432.1099.
3
.
C
24
H
19ClN
3
O
3
requires 432.1115.
3
.5.4.
2-(4-Bromo-2-(4-nitrobenzyl)phenyl)-N-(quinolin-8-
yl)acetamide (11d): The resultant crude mixture was purified by
column chromatography (EtOAc:hexane = 20:80) to afford 11d
as a yellow color solid (25 mg, 59%); R
3
2
89; (f) Miura, M.; Satoh, T.; Hirano, K. Bull. Chem. Soc. Jpn.
014, 87, 751; (g) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C.
f
(20% EtOAc/hexane)
Adv. Synth. Catal. 2014, 356, 17; (h) Wencel-Delord, J.; Colobert,
F. Synlett 2015, 26, 2644; (i) Wang, K.; Hu, F.; Zhang, Y.; Wang,
J. Sci. China Chem. 2015, 58, 1252; (j) Yang, L.; Huang, H.
Chem. Rev. 2015, 115, 3468; (k) Shaikh, T. M.; Hong, F.-E. J.
Organomet. Chem. 2016, 801, 139; (l) McMurray, L.; O’Hara, F.;
Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885; (m) Davies, H. M.
L.; Jin, Q.; Ren, P.; Kovalevsky, A. Y. J. Org. Chem. 2002, 67,
4165; (n) Chen, K.; Zhang, S.-Q.; Jiang, H.-Z.; Xu, J.-W.; Shi, B.-
F. Chem. Eur. J. 2015, 21, 3264; (o) Rousseaux, S.; Davi, M.;
Sofack-Kreutzer, J.; Pierre, C.; Kefalidis, C. E.; Clot, E.; Fagnou,
K.; Baudoin, O. J. Am. Chem. Soc. 2010, 132, 10706; (p)
Subramanian, P.; Rudolf, G. C.; Kaliappan, K. P. Chem. Eur. J.
o
0
1
8
2
.2; mp: 139-141 C; IR (KBr): ν 3339, 3054, 1681, 1523,
max
-
1 1
265, 741 cm ; H NMR (400 MHz, CDCl
.70 (1 H, dd, J = 4.1, J = 1.4 Hz), 8.57 (1 H, dd, J
.7 Hz), 8.16 (1 H, dd, J = 8.3, J = 1.4 Hz), 7.89 (2 H, d, J = 8.6
= 8.0, J = 1.8 Hz), 7.49-7.44 (3 H, m),
.40 (1 H, d, J = 1.6 Hz), 7.35 (1 H, d, J = 8.1 Hz), 7.25 (2 H, d,
3
): δ
H
9.68 (1 H, br. s),
1
2
1
= 6.2, J
2
=
1
2
Hz), 7.55 (1 H, dd, J
7
1
2
1
3
J = 8.1 Hz), 4.20 (2 H, s), 3.80 (2 H, s); C NMR (CDCl
3
, 100
MHz): δ 168.0, 148.2, 146.7, 140.2, 138.1, 136.4, 133.9, 133.7,
C
1
1
33.3, 132.6, 131.0, 129.4, 127.8, 127.3, 123.7, 122.0, 122.0,
21.7, 116.2, 42.4, 39.0; HRMS (ESI): MH , found 476.0595.
+
2
016, 11, 168.
24 3 3
C H19BrN O requires 476.0610.
4
.
(a) Zhang, F.; Spring, D. R. Chem. Soc. Rev. 2014, 43, 6906; (b)
Ros, A.; Fernández, R.; Lassaletta, J. M. Chem. Soc. Rev. 2014,
4
3, 3229; (c) Bheeter, C. B.; Chen, L.; Soulé, J.-F.; Doucet, H.
3
.6. Procedure for the preparation of the compound 13: To
dry flask was added the compound 4e (1.4 mmol) dissolved in
MeOH (4 mL) and then, BF3·Et O (0.5 mL) was added slowly
and the reaction mixture was heated at 90 °C for 24 h. After this
period, the reaction mixture was neutralized with NEt and the
Catal. Sci. Technol. 2016, 6, 2005; (d) Yadav, M. R.; Rit, R. K.;
Majji, S.; Sahoo, A. K. Asian. J. Org. Chem. 2015, 4, 846; (e)
Song, G.; Li, X. Acc. Chem. Res. 2015, 48, 1007; (f) Shin, K.;
Kim, H.; Chang, S. Acc. Chem. Res. 2015, 48, 1040; (g) Yoshikai,
N. ChemCatChem 2015, 7, 732; (h) Su, B.; Cao, Z.-C.; Shi, Z.-J.
Acc. Chem. Res. 2015, 48, 886; (i) Yuan, K.; Soulé, J.-F.; Doucet,
H. ACS Catal. 2015, 5, 978; (j) Yang, J. Org. Biomol. Chem.
2
3
solvent was evaporated in vacuo to afford a crude reaction
mixture. Purification of the crude reaction mixture by column
chromatography furnished the compound 13.
2
3
015, 13, 1930; (k) Hussain, I.; Singh, T. Adv. Synth. Catal. 2014,
56, 1661; (l) Martin, N.; Pierre, C.; Davi, M.; Jazzar, R.;
Baudoin, O. Chem. Eur. J. 2012, 18, 4480; (m) Murakami, R.;
Tsunoda, K.; Iwai, T.; Sawamura, M. Chem. Eur. J. 2014, 20,
13127; (n) Singh, P. P.; Gudup, S.; Aruri, H.; Singh, U.; Ambala,
S.; Yadav, M.; Sawant, S. D.; Vishwakarma, R. A. Org. Biomol.
Chem. 2012, 10, 1587; (o) Pandit, R. P.; Lee, Y. R. Adv. Synth.
Catal. 2014, 356, 3171; (p) Saget, T.; Perez, D.; Cramer, N. Org.
Lett. 2013, 15, 1354.
(a) Rouquet, G.; Chatani, N. Angew. Chem. Int. Ed. 2013, 52,
11726; (b) Zhang, M.; Zhang, Y.; Jie, X.; Zhao, H.; Li, G.; Su, W.
Org. Chem. Front. 2014, 1, 843; (c) De Sarkar, S.; Liu, W.;
Kozhushkov, S. I.; Ackermann, L. Adv. Synth. Catal. 2014, 356,
3
.6.1. Methyl 2-([1,1':3',1''-terphenyl]-2'-yl)acetate (13): The
resultant crude mixture was purified by column chromatography
EtOAc:hexane = 20:80) to afford 13 as a viscous liquid (28 mg,
(
6
2
7
6%); R (20% EtOAc/hexane) 0.8; IR (KBr): ν 3412, 3053,
f max
-1 1
926, 1740, 1523, 1264 cm ; H NMR (400 MHz, CDCl
3 H
): δ
.45-7.34 (11 H, m), 7.30 (2 H, d, J = 7.4 Hz), 3.53 (2 H, s), 3.45
5
6
.
.
1
3
(
3 H, s); C NMR (CDCl
3 C
, 100 MHz): δ 172.6, 143.4, 141.6,
1
30.0, 129.3, 129.2, 128.2, 127.2, 126.8, 51.7, 36.9; HRMS
+
(
19 2
ESI): MH , found 303.1374. C21H O requires 303.1385.
1
461; (d) Castro, L. C. M.; Chatani, N. Chem. Lett. 2015, 44, 410;
(e) Huang, Z.; Lim, H. N.; Mo, F.; Young, M. C.; Dong, G. Chem.
Soc. Rev. 2015, 44, 7764; (f) Yang, X.; Shan, G.; Wang, L.; Rao,
Y. Tetrahedron. Lett. 2016, 57, 819.
For initial reports dealing on the bidentate-ligand directed C-H
functionalization reactions, see: (a) Zaitsev, V. G.; Shabashov, D.;
Acknowledgments

ACCEPTED MANUSCRIPT
12
Tetrahedron
Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154; (b)
9884; (k) Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Angew. Chem. Int. Ed.
Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965.
For selected recent articles dealing on the bidentate-ligand
directed C-H functionalization reactions, see: (a) Gutekunst, W.
R.; Baran, P. S. J. Org. Chem. 2014, 79, 2430 and references cited
therein; (b) Ano, Y.; Tobisu, M.; Chatani, N. Org. Lett. 2012, 14,
2008, 47, 6452.
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.
12. For selected reports, see: (a) Brune, K.; Hinz, B. Arthritis &
Rheumatism, 2004, 50, 2391; (b) Hinz, B.; Dorn, C. P.; Shen, T.
Y.; Brune, K. Anti-inflammatory–Antirheumatic Drugs. Ullmann's
Encyclopedia of Industrial Chemistry, 2000; (c) Hata, A. N.;
Lybrand, T. P.; Marnett, L. J.; Breyer, R. M. Mol Pharmacol
2005, 67, 640; (d) Friderichs, E.; Christoph, T.; Buschmann, H.
Analgesics and Antipyretics, 2. Nonsteroidal Anti-inflammatory
Drugs. Ullmann's Encyclopedia of Industrial Chemistry, 2011; (e)
Dörwald, F. Z. Arylacetic, Benzoic, and Related Carboxylic Acids
(NSAIDS), in Lead Optimization for Medicinal Chemists:
Pharmacokinetic Properties of Functional Groups and Organic
Compounds, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim,
Germany, 2012.
3
5
54; (c) Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2013, 135,
308; (d) He, G.; Chen, G. Angew. Chem. Int. Ed. 2011, 50, 5192;
(
(
e) Chen, K.; Shi, B.-F. Angew. Chem. Int. Ed. 2014, 53, 11950;
f) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8,
3
391; (g) Wang, B.; Nack, W. A.; He, G.; Zhang, S.-Y.; Chen, G.
Chem. Sci. 2014, 5, 3952; (h) Affron, D. P.; Bull, J. A. Eur. J.
Org. Chem. 2016, 139; (i) Feng, R.; Wang, B.; Liu, Y.; Liu, Z.;
Zhang, Y. Eur. J. Org. Chem. 2015, 142; (j) Nadres, E. T.; Santos,
G. I. F.; Shabashov, D.; Daugulis, O. J. Org. Chem. 2013, 78,
9
689; (k) Shang, R.; Ilies, L.; Asako, S.; Nakamura, E. J. Am.
13. For selected patents/articles revealing the importance of
arylacetamides, see: (a) Cassayre, J. Y.; El Qacemi, M. WO
2013135674 A1 (2013); (b) Aay, N.; Aoyama, R. G.; Arcalas, A.
Chan, W. K. V.; Du, H.; Kearney, P.; Koltun, E. S.; Nachtigall, J.
A.; Pack, M.; Richards, S. J. WO 2010091164 A1 (2010); (c) Le
Bourdonnec, B.; Ajello, C. W.; Seida, P. R.; Susnow, R. G.;
Cassel, J. A.; Belanger, S.; Stabley, G. J.; DeHaven, R. N.;
DeHaven-Hudkins, D. L.; Dolle, R. E. Bioorg. Med. Chem. Lett.
2005, 15, 2647.
Chem. Soc. 2014, 136, 14349; (l) Kanyiva, K. S.; Kuninobu, Y.;
Kanai, M. Org. Lett. 2014, 16, 1968; (m) Han, J.; Liu, P.; Wang,
C.; Wang, Q.; Zhang, J.; Zhao, Y.; Shi, D.; Huang, Z.; Zhao, Y.
Org. Lett. 2014, 16, 5682; (n) Reddy, M. D.; Watkins, E. B. J.
Org. Chem. 2015, 80, 11447; (o) Luo, F.; Yang, J.; Li, Z.; Xiang,
H.; Zhou, X. Adv. Synth. Catal. 2016, 358, 887; (p) Nack, W. A.;
Wang, B.; Wu, X.; Jiao, R.; He, G.; Chen, G. Org. Chem. Front.
2
016, 3, 561; (q) Cheng, X.; Chen, Z.; Gao, Y.; Xue, F.; Jiang, C.
Org. Biomol. Chem. 2016, 14, 3298; (r) Tang, H.; Huang, X.-R.;
Yao, J.; Chen, H. J. Org. Chem. 2015, 80, 4672; (s) Hoshiya, N.;
Takenaka, K.; Shuto, S.; Uenishi, J. Org. Lett. 2016, 18, 48; (t)
Zhang, S.-K.; Yang, X.-Y.; Zhao, X.-M.; Li, P.-X.; Niu, J.-L.;
Song, M.-P. Organometallics 2015, 34, 4331; (u) Rodríguez, N.;
Romero-Revilla, J. A.; Fernández-Ibáñez, M. Á.; Carretero, J. C.
Chem. Sci. 2013, 4, 175; (v) Li, M.; Dong, J.; Huang, X.; Li, K.;
Wu, Q.; Song, F.; You, J. Chem. Commun., 2014, 50, 3944.
14. For selected papers dealing on the intramolecular cyclization of
2
arylacetic acid systems via the sp γ-C-H bond functionalization
and related reactions, see: (a) Yang, M.; Jiang, X.; Shi, W.-J.; Zhu,
Q.-L.; Shi, Z.-J. Org. Lett 2013, 15, 690; (b) Cheng, X.-F.; Li, Y.;
Su, Y.-M.; Yin, F.; Wang, J.-Y.; Sheng, J.; Vora, H. U.; Wang,
X.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 1236; (c) Wasa, M.;
Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14058; (d) Bera, M.;
Modak, A.; Patra, T. ; Maji, A.; Maiti, D. Org. Lett. 2014, 16,
5760; (e) Rit, R. K.; Yadav, M. R.; Sahoo, A. K. Org. Lett. 2014,
16, 968.
8
.
(a) Parella, R.; Gopalakrishnan, B.; Babu, S. A. Org. Lett. 2013,
1
5, 3238; (b) Parella, R.; Gopalakrishnan, B.; Babu, S. A. J. Org.
Chem. 2013, 78, 11911; (c) Parella, R.; Babu, S. A. J. Org. Chem.
15. While we finalized this manuscript for submission, we came to
know that Wan et al. also done a parallel investigation and
reported a similar theme as a communication involving the Pd(II)-
catalyzed arylation of γ-C-H bond of phenylacetamides, see: Liu,
Y.; Huang, B.; Cao, X.; Wan, J.-P. ChemCatChem 2016, 8, 1470.
While nine of the examples (4a, 4b, 4e, 4g, 4k, 4l, 4o, 3o and 7a)
are common between this work and Wan’s work, in the present
work, we were involved to realize the Pd(II)-catalyzed
functionalization of γ-C-H bond of the arylacetamide systems
2
8
015, 80, 2339; (d) Parella, R.; Babu, S. A. J. Org. Chem. 2015,
0, 12379; (e) Gopalakrishnan, B.; Babu, S. A.; Padmavathi, R.
Tetrahedron 2015, 71, 8333; (f) Padmavathi, R.; Sankar, R.;
Gopalakrishnan, B.; Parella, R.; Babu, S. A. Eur. J. Org. Chem.
2
015, 3727; (g) Parella, R.; Babu, S. A. Synlett 2014, 25, 1395; (h)
Rajkumar, V.; Naveen; Babu, S. A. ChemistrySelect 2016, 1,
1
2
207; (i) Mohan, S.; Gopalakrishnan, B. Babu, S. A. Tetrahedron
016, http://dx.doi.org/10.1016/j.tet.2016.08.010.
9
.
For selected articles dealing on the ligand-directed
functionalization of the sp γ-C-H bond, see: (a) Seki, A.;
including,
arylation,
benzylation,
alkylation
and
3
2
acetoxylation/hydroxylation of the sp γ-C-H bond of
arylacetamides. The arylation and benzylation of the γ-C-H bond
of the arylacetamide systems were successful; however, the
alkylation and acetoxylation/hydroxylation of the γ-C-H bond of
the arylacetamide systems were not successful in our hand.
Various ligands were screened to substantiate the need for the
bidentate ligand in the Pd(II)-catalyzed arylation/benzylation of
phenylacetamides. Several substituted aryl-/heteroaryl iodides,
benzyl bromide and phenylacetamide substrates were used to
examine their reactivity pattern and accomplish the substrate
Takahashi, Y.; Miyake, T. Tetrahedron Lett. 2014, 55, 2838; (b)
Pasunooti, K. K.; Banerjee, B.; Yap, T.; Jiang, Y.; Liu, C.-F. Org.
Lett. 2015, 17, 6094; (c) Jiang, H.; He, J.; Liu, T.; Yu, J.-Q. J. Am.
Chem. Soc. 2016, 138, 2055; (d) Li, S.; Chen, G.; Feng, C.-G.;
Gong, W.; Yu, J.-Q. J. Am. Chem. Soc. 2014, 136, 5267; (e) He,
G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012,
1
34, 3; (f) Poveda, A.; Alonso, I.; Fernández-Ibáñez, M. Á. Chem.
Sci. 2014, 5, 3873; (g) Fan, M.; Ma, D. Angew. Chem. Int. Ed.
013, 52, 12152; (h) He, G.; Zhang, S.-Y.; Nack, W. A.; Li, Q.;
Chen, G. Angew. Chem. Int. Ed. 2013, 52, 11124.
2
scope/generality. We have also shown
a gram scale γ-C-H
2
1
1
0. (a) For the ligand-directed acetoxylation/lactonization of the sp γ-
arylation of the arylacetamide system and the removal of the
bidentate ligand after the γ-C-H arylation of the arylacetamide
system.
C-H bond of arylacetamide, see: Uemura, T.; Igarashi, T.;
Noguchi, M.; Shibata, K.; Chatani, N. Chem. Lett. 2015, 44, 621;
2
(
b) For the ligand-directed olefination of the sp γ-C-H bond of
16. (a) In some of the reactions, we have isolated the 4-nitrobenzyl
acetate after the C-H benzylation reaction. (b) To find out a reason
for the formation of only mono benzylation product and to obtain
the bis benzylated compound we have tried the benzylation of 1a
by adding a total of 0.48 mmol 4-nitrobenzyl bromide in small
amounts (0.12 mmol) after every 6 h. This reaction gave only the
compound 11a in 17% yield. Then, we have tried the benzylation
of 1a by using excess of 4-nitrobenzyl bromide (0.96 mmol). This
reaction also gave only the mono benzylated compound 11a in
decreased yield 20% yield and there might be of an over-reaction,
which could be a reason for the decreased yield this reaction.
17. (a) The observed ortho selective functionalization of the γ-C-H
bond of the phenylacetamide system linked with the bidentate
ligand (e.g., 8-aminoquinoline) can be exemplified via the
plausible chelation-assisted reaction pathway in concurrence with
the generally accepted proposed Pd(II/IV) catalytic cycle
arylacetamide, see: Deb, A.; Bag, S.; Kancherla, R.; Maiti, D. J.
Am. Chem. Soc. 2014, 136, 13602.
1. For selected papers dealing on the ligand-directed, C-O and C-N
bond formation based on functionalization of the remote C-H
bond of alkyl/benzyl amine systems, see; (a) Gou, F.-R.; Wang,
X.-C.; Huo, P.-F.; Bi, H.-P.; Guan, Z.-H.; Liang, Y.-M. Org. Lett.
2
009, 11, 5726; (b) Ye, X.; He, Z.; Ahmed, T.; Weise, K.;
Akhmedov, N. G.; Petersen, J. L.; Shi, X. Chem. Sci. 2013, 4,
712; (c) Li, Q.; Zhang, S.-Y.; He, G.; Nack, W. A.; Chen, G.
3
Adv. Synth. Catal. 2014, 356, 1544; (d) Zhang, S.-Y.; He, G.;
Zhao, Y.; Wright, K.; Nack, W. A.; Chen, G. J. Am. Chem. Soc.
2
012, 134, 7313; (e) Ju, L.; Yao, J.-Z.; Wu, Z.-H.; Liu, Z.-X.;
Zhang, Y.-H. J. Org. Chem. 2013, 78, 10821; (f) Vickers, C. J.;
Mei, T.-S.; Yu, J.-Q. Org. Lett. 2010, 12, 2511; (g) Wang, C.;
Han, J.; Zhao, Y. Synlett 2015, 26, 997; (h) Takamatsu, K.;
Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2015, 80, 3242; (i)
Nadres, E. T.; Daugulis, O. J. Am. Chem. Soc. 2012, 134, 7; (j)
Wang, C.; Chen, C.; Zhang, J.; Han, J.; Wang, Q.; Guo, K.; Liu,
P.; Guan, M.; Yao, Y.; Zhao, Y. Angew. Chem. Int. Ed. 2014, 53,
2
mechanism involving the Pd(OAc) /AgOAc catalytic system. (see
the Supplementary data); (b) Topczewski, J. J.; Sanford, M. S.
Chem. Sci. 2015, 6, 70; (c) Rit, R. K.; Yadav, M. R.; Ghosh, K.;
Sahoo, A. K. Tetrahedron 2015, 71, 4450. (d) See refs ; (e)
Furthermore, we also attempted the
2
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ACCEPTED MANUSCRIPT
1
3
alkylation/hydroxylation/acetoxylation of the γ-C-H bond of the
phenylacetamide system 1a by using the standard reaction
conditions reported in the literature. Unfortunately, these reactions
failed
to
afford
the
corresponding
products
γ-C-H
the
alkylated/hydroxylated/acetoxylated
Supplementary data).
(see
1
8. (a) Shao, J.; Huang, X.; Wang, S.; Liu, B.; Xu, B. Tetrahedron
012, 68, 573; (b) Shugrue, C. R.; Miller, S. J. Angew. Chem. Int.
2
Ed. 2015, 54, 11173; (c) Sun, J.; Tan, Q.; Yang, W.; Liu, B.; Xu,
B. Adv. Synth. Catal. 2014, 356, 388; (d) Li, G.; Gerritz, S. W.;
Kakarla, R. J. Comb. Chem. 2007, 9, 745; (e) Dong, Y.; Liu, B.;
Chen, P.; Liu, Q.; Wang M. Angew. Chem. Int. Ed. 2014, 53,
3
442; (f) Ramesh, P.; Fadnavis, N. W. Chem. Lett. 2015, 44, 138.
ꢀ
Supplementary data
1
13
Supplementary data (copy of H, C NMR Charts of compounds and
unsuccessful trials on the γ-C-H acetoxylation/hydroxylation/alkylation and
proposed mechanism for the γ-C-H arylation) associated with this article can
be found in the online version.