Multicomponent reaction comprising one-pot installation of bidentate directing group and Pd(II)-catalyzed direct β-arylation of C(sp3)[sbnd]H bond of aliphatic and alicyclic carboxamides

Article abstract of DOI:10.1016/j.tet.2016.08.010

In this paper, we report a step-economical one-pot multicomponent reaction protocol comprising the installation of the bidentate directing group (auxiliary) followed by Pd(II)-catalyzed sp³C[sbnd]H activation and β-arylation of various aliphatic/alicyclic carboxamides. Accordingly, the reaction of a mixture of an aliphatic/alicyclic acid chloride, bidentate directing auxiliary (e.g., 8-aminoquinoline) and an aryl iodide in the presence of the Pd(OAc)₂catalyst and Ag₂CO₃additive directly afforded the corresponding β-C[sbnd]H-arylated N-(quinolin-8-yl)carboxamide derivative. To demonstrate the efficiency of the process, various bidentate directing auxiliaries were used and 8-Aminoquinoline was found to be the best directing group for accomplishing the one-pot Pd(II)-catalyzed, sp³C[sbnd]H activation and β-arylation of aliphatic/alicyclic carboxamides. A variety of aliphatic/alicyclic acid chlorides and aryl iodides were used as the substrates and several β-C[sbnd]H arylated carboxamide derivatives were synthesized in moderate to high yields via the multicomponent reaction strategy.

Full text of DOI:10.1016/j.tet.2016.08.010

Accepted Manuscript
Multicomponent reaction comprising one-pot installation of bidentate directing group
3
and Pd(II)-catalyzed direct β-arylation of C(sp )-H bond of aliphatic and alicyclic
carboxamides
Sruthi Mohan, Bojan Gopalakrishnan, Srinivasarao Arulananda Babu
PII:
S0040-4020(16)30768-2
10.1016/j.tet.2016.08.010
TET 27991
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 April 2016
Revised Date: 9 July 2016
Accepted Date: 3 August 2016
Please cite this article as: Mohan S, Gopalakrishnan B, Babu SA, Multicomponent reaction comprising
3
one-pot installation of bidentate directing group and Pd(II)-catalyzed direct β-arylation of C(sp )-H bond
of aliphatic and alicyclic carboxamides, Tetrahedron (2016), doi: 10.1016/j.tet.2016.08.010.
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Multicomponent reaction comprising one-
pot installation of bidentate directing group
and Pd(II)-catalyzed direct β-arylation of
C(sp3)-H bonds of aliphatic and alicyclic
carboxamides
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Sruthi Mohan, Bojan Gopalakrishnan 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

1
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Tetrahedron
journal homepage: www.elsevier.com
Multicomponent reaction comprising one-pot installation of bidentate directing
group and Pd(II)-catalyzed direct β-arylation of C(sp3)-H bond of aliphatic and
alicyclic carboxamides
Sruthi Mohan, Bojan Gopalakrishnan 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
In this paper, we report a step-economical one-pot multicomponent reaction protocol comprising
the installation of the bidentate directing group (auxiliary) followed by Pd(II)-catalyzed sp3 C-H
activation and β-arylation of various aliphatic/alicyclic carboxamides. Accordingly, the reaction
of a mixture of an aliphatic/alicyclic acid chloride, bidentate directing auxiliary (e.g., 8-
aminoquinoline) and an aryl iodide in the presence of the Pd(OAc)2 catalyst and Ag2CO3
additive directly afforded the corresponding β-C-H-arylated N-(quinolin-8-yl)carboxamide
derivative. To demonstrate the efficiency of the process, various bidentate directing auxiliaries
were used and 8-Aminoquinoline was found to be the best directing group for accomplishing the
one-pot Pd(II)-catalyzed, sp3 C-H activation and β-arylation of aliphatic/alicyclic carboxamides.
A variety of aliphatic/alicyclic acid chlorides and aryl iodides were used as the substrates and
several β-C-H arylated carboxamide derivatives were synthesized in moderate to high yields via
the multicomponent reaction strategy.
Available online
Keywords:
carboxamides
C-H activation
multicomponent reaction
palladium
2009 Elsevier Ltd. All rights reserved
.
sp3 C-H arylation
While the functionalization of the sp2 C-H bonds of organic
molecules have been extensively studied;1-6 until the
contemporaneous reports by Daugulis7a,b and Yu,8 the site-
selective functionalization of the sp3 C-H bonds of organic
molecules was a challenging task. After the seminal report by
Daugulis7a that involved the bidentate directing auxiliary 8-
aminoquinoline-directed sp3 C-H activation and β-arylation of
carboxamides withy ArI;6 several research groups demonstrated
the Pd(II)-catalyzed site-selective C-H functionalization of
various alicyclic, aliphatic and aromatic carboxamides.9-11
Recently, the Pd(II)-catalyzed β-C-H arylation of carboxamides
was demonstrated by using ArBr as the arylating agent.7c
1. Introduction
The
transition
metal-catalyzed
C-H
activation/functionalization reaction involving the C-C bond
formation is one of the remarkable synthetic transformations.1-4
In general, the C-C bond formation via the C-H activation route
considered as step-economical transformation, in which (a) the
prior preparation of the organometallic reagents is not necessary,
and (b) the usage of readily available substrates and the
minimization of reagent wastage are feasible. The C-H activation
reactions were performed with or without the help of directing
groups.1-4 It is worth to mention here that the directing group-
based C–H functionalization have been found to be stereo- and
regioselective. A variety of functional groups/moieties (e.g.,
amides, pyridine, ketones, oximes, oxazolines, carboxylic acids,
amines, hydroxyls, esters, etc) were recognized as the directing
groups for achieving the site-selective C-H functionalization.1-6
The C-H activation reactions were studied by using several
transition metal catalysts (e.g. Pd-, Rh-, Ru-, Cu-, and Ir-based
catalysts) and amongst the transition metal catalysts, the
palladium catalysts are frequently used to accomplish the C-H
activation/functionalization reactions.
Although, the C-H activation/functionalization is considered
as a step-economical synthetic transformation; however, this
process is associated with some limitations. Some of the
limitations
are;
(a)
the
site-selective
C-H
activation/functionalization often needs a suitable directing
group, especially, the Pd-catalyzed functionalization of the sp3 C-
H bond attained popularity only due to the assistance provided by
the suitable directing groups1-7 (e.g., 8-aminoquinoline,7a,b 2-
(methylthio)aniline,7a,b
picolinamide,7a,b,9d
and
weakly
coordinating N-arylamide directing auxiliary system,8 2,3,5,6-
tetrafluoro-4-(trifluoromethyl)aniline), (b) the installation of a
suitable directing group in a substrate that is subjected to the C-H
———
Corresponding author. Tel.: +91-172-2293165; fax: +91-172-2240266; e-mail: sababu@iisermohali.ac.in

2
Tetrahedron
functionalization is an additional synthetic transformation, and
Ag2CO3-mediated sp3 C-H activation and β-arylation of various
ACCEPTED MANUSCRIPT
(c) additionally, the removal of the directing group from the
substrate that was subjected to the C-H functionalization is also
an additional synthetic transformation.1-7 In recent years,
synthetic chemists are involved in developing C-H activation
processes in which some of these limitations are avoided. Along
this direction, there have been some outstanding reports dealing
on the organocatalytic and oxidative C–H activation processes
that are step-economical and straightforward processes.1-6,12
It would be appreciated if the well-received concept
comprising the bidentate directing auxiliary-directed Pd-
catalyzed C-H functionalization of carboxamide is also made as
step-economical process.7 In this regard, recently, Wan et al.
reported13a the Pd(II)-catalyzed arylation of the sp2 C-H bonds of
aromatic carboxamides via the multicomponent reaction of
aromatic acid chloride, aryl iodide and 8-aminoquinoline.
aliphatic and alicyclic carboxamides (Scheme 1).
2. Results and Discussion
To begin the investigation on the one-pot multicomponent
reaction protocol comprising the installation of the bidentate
directing group followed by the Pd(II)-catalyzed, sp3 C-H
activation and β-arylation of carboxamides; initially we
performed various optimization reactions to find out the suitable
reaction conditions, which will give the sp3 C-H arylation product
in high yield (Table 1). Initially, we heated a mixture of 2a (1
equiv), 6a (1 equiv), 4a (4 equiv), Pd(OAc)2 catalyst (10 mol%)
o
and AgOAc additive in toluene at 110 C. This reaction afforded
the bis C-H arylated cyclobutane 7a in only 20% yield (entry 1,
Table 1). The same reaction in tert-butanol instead of toluene
also afforded the product 7a in only 20% yield (entry 2, Table 1).
Then, we performed the reaction of a mixture of the substrates
2a, 6a, 4a (8 equiv), Pd(OAc)2 catalyst (10 mol%) and Ag2CO3
additive in neat condition at 110 oC and this reaction afforded the
product 7a in an improved yield (58%, entry 3, Table 1).
Comprehending the importance of functionalization of the sp3
C–H bonds,1-6 development of a simple procedure for the
bidentate directing auxiliary-aided, Pd(II)-catalyzed sp3 C–H
activation/functionalization of carboxamides will be highly
appreciated. In continuation of our lab’s interest on the C-H
activation reactions,11 herein, we report
a
one-pot
multicomponent reaction protocol involving the installation of
the bidentate directing group followed by the Pd(II)-catalyzed,
Scheme 1. Bidentate directing auxiliary-directed sp3 C-H arylation and topic of this work.

3
ACCEPTED MANUSCRIPT
Table 1. Optimization of the reaction conditions. The Pd(II)-catalyzed multicomponent reaction of the substrates 2a, 6a and 4a
and the synthesis of 7a via direct C-H arylation of 3a.a
a The reaction period for all the reactions was 36 h, unless otherwise mentioned. Isolated yields of 7a are reported.
b The reaction period was 12 h. c The reaction period was 24 h.
an additive instead of Ag2CO3 failed to afford the product 7a
(entry 12, Table 1). Similarly, the Pd-catalyzed C–H arylation
reaction of a mixture of the substrates 2a, 6a, 4a (8 equiv) in the
presence of AgOAc and K2CO3 as the additives instead of only
Ag2CO3 failed to give the product 7a (entry 13, Table 1). In
another trial, the Pd-catalyzed C–H arylation reaction of a
mixture of the substrates 2a, 6a, 4a (4-8 equiv) in the presence of
Ag2CO3 and Cs2CO3 as the additives gave the product 7a in only
28% yield (entry 14, Table 1). The optimization reactions
revealed that the one-pot Pd(II)-catalyzed C–H arylation reaction
of a mixture of 8-aminoquinoline (2a), cyclobutanecarbonyl
chloride (6a) and PhI (4a) successfully afforded the C-H arylated
product 7a in high yield when Ag2CO3 was used as an additive
(entries 3-11, Table 1).
Having observed that the use of Ag2CO3 as an additive instead
of AgOAc improved the yield of the product 7a. Next, we heated
a mixture of the substrates 2a, 6a, PhI (4a, 4 equiv), Pd(OAc)2
catalyst (10 mol%) and Ag2CO3 additive in toluene solvent at 110
oC. This reaction gave the product 7a in 59% (entry 4, Table 1).
The same reaction in tert-amylOH solvent instead of toluene
afforded the product 7a in 66-72% (entries 5-7, Table 1). Then,
to further improve the yield of the product 7a, we tried the
reaction of a mixture of the substrates 2a, 6a, 4a (4 or 8 equiv),
Pd(OAc)2 catalyst (10 mol%) and Ag2CO3 additive in o-xylene at
o
130 C, which also afforded the product 7a in 62-82% yields
(entries 8 and 9, Table 1). Then, the reaction of a mixture of the
substrates 2a, 6a, 4a (4 or 6 equiv) and Ag2CO3 additive in the
presence of only 5 mol% of the Pd(OAc)2 catalyst gave the
product 7a in 54-75% yields (entries 10 and 11, Table 1). The
one-pot Pd-catalyzed C–H arylation reaction of a mixture of the
substrates 2a, 6a, PhI (4a, 4 equiv) in the presence of K2CO3 as

4
Tetrahedron
Table 2. Examination of the substAratCe sCcoEpeP. MTuEltDicoMmpAoneNntUreSacCtioRn-IbPasTed, Pd(II)-catalyzed, sp3 C-H
activation and β-arylation of cycloalkanecarboxamides.a
R
I
COCl
Pd(OAc)2 (5-10 mol%)
N
N
+
H
+
NH2
2a
N
Ag2CO3 (2 equiv)
o-xylene (2 mL)
130 oC, 36 h
R
O
6
4
(1 equiv,
0.4 mmol)
R
(1 equiv)
(4-6 equiv)
7
O2N
Cl
N
H
N
H
N
N
H
N
N
O
O
O
7a; (68%)b (82%)c (75%)d
NO2
7c; 83%
7b; 40%
Cl
MeOC
MeO
Me
N
H
N
H
N
H
N
N
N
O
O
O
7f
; 71%
7e; 80%
7e; (19%)e
COMe
OMe
N
7d
; 78%
Me
CF3
H
N
H
N
N
O
O
CF3
7h; 25%
7g; 80%
Cl Cl
Me
Me
S
N
N
H
H
N
H
N
N
N
S
O
O
O
Cl
Me
Me
7k
; 78%
7j; 60%
Cl
7i
; 71%
N
HN
O
N
O
N
O
MeO
HN
OMe
HN
MeOC
COMe
7n
; 40%
7m; 35%
7l
; 38%
a
Isolated yields of all the compounds are reported. Unless otherwise mentioned, all the reactions were
carried out by using 2a (0.4 mmol, 1 equiv), 6 (0.4 mmol, 1 equiv), ArI (0.24 mmol, 6 equiv), Pd(OAc)2 (10
mol%), Ag2CO3 (0.8 mmol, 2 equiv), o-xylene (2 mL) at 130 oC, 36 h.
b PhI (0.16 mmol, 4 equiv) and tamylOH (2 mL) at 80 oC.
c PhI (0.32 mmol, 8 equiv).
d Pd(OAc)2 (5 mol%), PhI (0.24 mmol, 6 equiv).
e
2a (0.4 mmol, 1 equiv), 6a (0.4 mmol, 1 equiv), 1-bromo-4-methoxybenzene (0.24 mmol, 6 equiv),
Pd(TFA)2 (5 mol%), PivOH (0.2 mmol, 0.5 equiv), K2CO3 (1.4 mmol, 3.5 equiv), tamylOH (2 mL) at 110 oC,
36 h.

5
It is assumed that Ag2CO3 is performing a dual role in the
multicomponent reaction-based, Pd(II)-catalyzed arylation of
C(sp3)-H bond of 3a. Firstly, perhaps, Ag2CO3 is acting as a mild
base to promote the formation of 3a from the reaction of 2a and
6a under the experimental condition. This assumption is
supported by the optimization reactions shown in Table 1 (entries
1 and 2). It is to be noted that our group11c and Baran9w reported
the C-H arylation of the pre-assembled substrate 3a (containing
the bidentate directing auxiliary) in the presence of the Pd(OAc)2
catalyst and AgOAc as an additive afforded the product 7a in
high yield. In the literature,14 the role of AgOAc in the Pd(OAc)2-
catalyzed C-H arylation reaction was well documented, that it
helps as an I¯ (iodide anion) scavenger to regenerate the Pd(II)-
catalyst in the proposed PdII-PdIV catalytic cycle.14 Consequently,
in the present work, if 3a has formed commendably from the
reaction of the substrates 2a and 6a without the assistance of any
base/promoter then, it is expected that the product 7a should have
formed in high yield in the reaction of a mixture of the substrates
2a, 6a and 4a in the presence of the Pd(OAc)2 catalyst and
AgOAc as an additive (entries 1 and 2, Table 1). However, in the
present case, the usage of AgOAc as an additive afforded the C-
H arylated product 7a only in 20% yield (entries 1 and 2, Table
1). On the other hand, the usage of Ag2CO3 as an additive
ACCEPTED MANUSCRIPT
afforded the C-H arylated product 7a in 54-82% yields (Table 1).
Secondly, the Ag+ salt (Ag2CO3) is believed to participate in the
ligand exchange step as an I¯ (iodide anion) scavenger7c,10s in the
generally accepted-proposed PdII-PdIV catalytic cycle mechanism
comprising the bidentate directing auxiliary-aided Pd(II)-
catalyzed sp3 C-H activation and β-arylation of carboxamides.14
Having done the optimization reactions (Table 1), next, we
wished to investigate the scope and generality of this one-pot
multicomponent reaction protocol comprising the installation of
the bidentate directing auxiliary followed by the Pd(II)-catalyzed,
sp3 C-H activation and β-arylation of methylene C-H bond of
cycloalkanecarboxamides. Accordingly, we carried out the
Pd(II)-catalyzed, Ag2CO3-mediated C-H arylation reaction
involving the substrates 6a, 2a and a variety of aryl iodides to
afford several bis arylated cyclobutanecarboxamides 7a-k (Table
2). The Pd(II)-catalyzed, Ag2CO3-mediated multicomponent
reaction involving the substrates 6a, 2a and aryl iodides
containing the electron-withdrawing and donating groups at the
para positon afforded the products 7b-g in low to high yields
(40-83%, Table 2).
COCl
p-anisoyl
Pd(OAc)2 (10 mol%)
I
SMe
MeS
+
+
H
NH2
Ag2CO3 (2 equiv)
o-xylene (2-3 mL)
130 oC, 36 h
N
OMe
p-anisoyl
2b
6a
(1 equiv)
4e
(6 equiv)
O
(0.4 mmol)
7p; complex mixture
COCl
+
p-anisoyl
Pd(OAc)2 (10 mol%)
I
NMe2
NH2
Me2N
H
+
Ag2CO3 (2 equiv)
o-xylene (2-3 mL)
130 oC, 36 h
N
OMe
p-anisoyl
2c
O
6a
(1 equiv)
4e
(0.4 mmol)
(6 equiv)
7q; 0%
PdCl2(MeCN)2
(10 mol%)
COCl
N
H
N
PhI(OAc)2
+
+
N
NH2
Cs2CO3 (4 equiv)
mesitylene (2-3 mL)
110 oC, 36 h
(2.5 equiv)
O
2a
6a
(1 equiv)
(0.4 mmol)
7a; 40%
nBu
Pd(PPh)3Cl2
(10 mol%)
COCl
+
N
H
nBu
I
N
N
+
nBu
O
NH2
K2CO3 (3.5 equiv)
tamylOH (2 mL)
120 oC, 36 h
(6 equiv)
2a
6a
(1 equiv)
7r; 0%
(0.4 mmol)
Pd(OAc)2
(5 mol%)
O
N
H
N
N
+
+
I
( )5
( )5
Cl
NH2
K2CO3 (3 equiv)
PivOH (20 mol%)
tamylOH (2 mL)
110 oC, 24 h
O
(1 equiv)
(4-6 equiv)
2a
7s; 15-25%
(0.4 mmol)
COCl
( )m
7t; m = 4; 45% (condition a)
7u; m = 1; 55% (condition a)
7u; m = 1; 60% (condition b)
conditions
a or b
+
+
I
( )m
N
N
H
N
NH2
(4-5 equiv)
6b
(1 equiv)
2a
O
( )m
(0.4 mmol)
o
Reagents and conditions: (a) PdCl2(MeCN)2 (10 mol%), Ag2CO3 (0.8 mmol, 2 equiv), neat, 100 C, 48 h. (b)
o
Pd(TFA)2 (10 mol %), Cs2CO3 (0.8 mmol, 2 equiv), neat, 100 C, 48 h. Isolated yields of all the compounds are
reported.
Scheme 2. Examination of other bidentate directing auxiliaries and trials on the multicomponent reaction-based,
Pd(II)-catalyzed C-H arylation/alkylation of carboxamides.

6
Tetrahedron
ACCEPTED MANUSCRIPT
The bis arylated cyclobutanecarboxamide 7g was obtained in
cyclohexanecarboxamides 7l13b (38%) and 7m13b (35%) in low
80% yield from the multicomponent C-H arylation protocol
involving the substrates 6a, 2a and the corresponding ArI (4g)
possessing a CF3 group at the meta positon of the aryl ring 4g
(Table 2). Then, the bis arylated cyclobutanecarboxamide 7h was
obtained in only 25% yield from the multicomponent C-H
arylation protocol involving the substrates 6a, 2a and 1-
iodonapthalene (4h, Table 2). While an exact reason for the low
yields of the products 7b and 7h is not known and we presume
that, the corresponding aryl iodides might be less reactive or the
corresponding the C-H arylation reactions might be slow
processes as the plausible reasons . Next, we carried out the
Pd(II)-catalyzed, Ag2CO3-mediated multicomponent reaction
involving the substrates 6a, 2a and di-substituted aryl iodides,
which furnished the corresponding products 7i (71%) and 7j
(60%) in moderate to good yields (Table 2). The multicomponent
C-H arylation protocol involving the substrates 6a, 2a and a
heteroaryl iodide, such as, 2-iodothiophene furnished the product
7k in 78% yield (Table 2).
yields (Table 2) along with traces of by-products which we could
not isolate in pure form to characterize. The low yields in these
cases may be due to the following reasons. It is assumed that the
C-H arylation in the cyclohexane system might be increasing the
steric crowding in the cyclohexane system and hence, the C-H
arylation process involving cyclohexane system seems to be a
relatively sluggish process. Then, we also performed the Pd(II)-
catalyzed, Ag2CO3-mediated multicomponent reaction involving
cyclopropanecarbonyl chloride (6a), 2a and 4-acetyl-1-
iodobenzne,
which
gave
the
bis
arylated
cyclopropanecarboxamide 7n in 40% yield (Table 2) as the
predominant product along with some minor by-products (<15%
yield), which we could not isolate in pure form. It is to be noted
that the Pd(II)-catalyzed C-H arylation of N-(quinolin-8-
yl)cyclopropanecarboxamide system was relatively facile when
AgOAc was used as an additive.11b However, the product 7n was
obtained in low yield in the present method, which requires the
usage of Ag2CO3 as an additive. While a clear reason for the low
yield of 7n is not clear at this stage, however, the C-H arylation
of cyclopropane system seems to be a sluggish reaction under the
present experimental condition (Table 2).
We also carried out the Pd(II)-catalyzed, Ag2CO3-mediated
multicomponent reaction involving cyclohexanecarbonyl
chloride, 2a and iodobenzene or p-anisoyl iodide, which
furnished
the
corresponding
bis
arylated
Table 3.13c Examination of the substrate scope. Multicomponent reaction-based, Pd(II)-catalyzed, sp3 C-H activation
and β-arylation of aliphatic carboxamides.a
a Isolated yields of all the compounds are reported.

7
ACCEPTED MANUSCRIPT
Table 4.13c Examination of the substrate scope. Multicomponent reaction-based Pd(II)-catalyzed, sp3 C-H activation and
β-arylation of aliphatic carboxamides.a
I
O
Pd(OAc)2 (10 mol%)
N
N
O
+
+
Cl
R1
HN
NH2
2a
Ag2CO3 (1.5 equiv)
o-xylene (2 mL)
130 oC, 12-24 h
R
1
4
(1 equiv,
0.4 mmol)
(1 equiv)
R
(4 equiv)
R1
5
N
O
N
O
N
O
N
O
HN
OMe
OMe
HN
Me
HN
HN
OMe
5q; 93%
5s; 95%
5p; 92%
5r; 97%
N
O
HN
OMe
N
O
N
O
N
O
HN
OMe
HN
OMe
HN
5t; 85%
5v
5v'
5u; 80%
5v + 5v' = (75%)
OMe
OMe
(5v; 17% & 5v'; 58%)
a All the reaction were performed for 12 h and the reaction time for the formation of 5v/5ʹ was 24 h. Isolated yields of all
the compounds are reported
Next, we intended to find out the feasibility of using other
bidentate directing auxiliaries, such as, 2-(methylthio)aniline (2b)
and N1,N1-dimethylethane-1,2-diamine (2c) in the one-pot
multicomponent reaction protocol comprising the installation of
the bidentate directing auxiliary followed by the Pd(II)-catalyzed,
sp3 C-H activation and β-arylation of carboxamides. The Pd(II)-
catalyzed, Ag2CO3-mediated multicomponent C-H arylation
protocol involving the substrate 6a, bidentate directing auxiliary
2b or 2c and p-anisoyl iodide failed to afford the corresponding
bis arylated cyclobutanecarboxamides 7p and 7q (Scheme 2).
Although these directing auxiliaries were already employed for
the Pd-catalyzed C-H arylation of cyclobutanecarboxamides and
found to be reasonably efficient directing auxiliaries;7,11c
however, in the present reactions comprising the one-pot
installation of the bidentate directing auxiliary followed by the C-
H arylation of cyclobutane failed to afford any product. Hence,
based on the reactions shown in Tables 1, 2 and Scheme 2, the
bidentate directing auxiliary 2a found to be efficient for
accomplishing the Pd(II)-catalyzed, multicomponent C(sp3)-H
arylation protocol. Quin et al. showed15 PhI(OAc)2 as the reagent
for the C-H arylation and we also carried out the Pd(II)-
catalyzed, multicomponent C-H arylation reaction involving 6a,
2a and PhI(OAc)2, which gave the product 7a in 40% (Scheme
2).
yields. It should be noted that generally the Pd(II)-catalyzed sp3
C-H alkylation is a challenging reaction5,6 and a literature survey
revealed that the Pd(II)-catalyzed sp3 C-H alkylation reactions
were carried out by using a mild base as an additive (e.g.,
K2CO3); thus, under this reaction conditions, we cannot ignore,
that a base-mediated N-alkylation of the bidentate directing
auxiliary 8-aminoquinoline (2a) might have occurred as a side-
reaction. Hence, this might be a reason for the observed low
yields of the C-H alkylated product 7s. However, to understand
whether the Pd(II)-catalyzed, multicomponent C-H alkylation
will be efficient or not, we performed the Pd(II)-catalyzed,
multicomponent sp2 C-H alkylation protocol involving the
substrates 6b, 2a and butyl iodide or heptyl iodide by using
Ag2CO3 or Cs2CO3 as the additives. Notably, these Pd(II)-
catalyzed, multicomponent sp2 C-H alkylation reactions were
successful and the corresponding products 7t (45%) and 7u
(60%) were obtained in satisfactory yields (Scheme 2).
n
n
Next, we wished to further elaborate the scope and generality
of this method by using aliphatic carbonyl chlorides as the
substrates
in
the
Pd(II)-catalyzed,
Ag2CO3-mediated
multicomponent-based C-H arylation reaction. Accordingly, we
carried out the Pd(II)-catalyzed, multicomponent C-H arylation
protocol involving the substrates 1a, 2a and aryl iodides
containing various substituents at the para/meta position or
disubstituted aryl iodides, which successfully furnished the
corresponding β-C-H arylated carboxamides 5a-o in good to high
yields (50-99%, Table 3). Afterwards, the generality of this
method was also tested by using other aliphatic carbonyl
chlorides as the substrates; accordingly, various β-C-H arylated
aliphatic carboxamides 5p-u were obtained in high yields (80-
From the literature reports, we perceived that the reagents and
reaction conditions required for the sp3 C-H arylation and
alkylation are different and the arylation of the sp3 C-H bond of
carboxamides relatively easier than the alkylation of the sp3 C-H
bond of carboxamides. Our trials on the Pd(II)-catalyzed,
multicomponent C-H alkylation protocol involving the substrates
6a, 2a and nbutyl iodide failed to afford the C-H alkylated
product 7r under the present experimental conditions (Scheme 2).
In the further trials, the Pd(II)-catalyzed, multicomponent C-H
97%,
Table
4).
Furthermore,
the
Pd(II)-catalyzed,
multicomponent C-H arylation protocol involving propionyl
chloride afforded the mono arylated carboxamide 5v and bis
arylated carboxamide 5v′ in 17 and 58% yields (Table 4).
n
alkylation reaction comprising propionyl chloride, 2a and octyl
iodide afforded the C-H alkylated product 7s in only 15-22%

8
Tetrahedron
ACCEPTED MANUSCRIPT
Successively, we wished to perform the Pd(II)-catalyzed,
(e.g., 8-aminoquinoline) and an aryl iodide in the presence of the
multicomponent C-H arylation protocol in a gram scale.
Accordingly the Pd(II)-catalyzed, multicomponent C-H arylation
protocol comprising the corresponding acid chlorides 6a/1a, 2a
and 4e gave the products 7e and 5b in 66 and 63% yields
(Scheme 3). In general, removal of the bidentate directing
auxiliaries has been successfully carried out by using the C-H
arylated carboxamides,5-7,11 which were isolated from the column
chromatographic purification process. In the present work we
Pd(OAc)2 catalyst and Ag2CO3 additive directly afforded the
corresponding β-C-H arylated carboxamide. To demonstrate the
efficiency of the process, various acid chlorides and aryl iodides
were used in the one-pot multicomponent process involving the
installation of the bidentate directing auxiliary followed by the
Pd(II)-catalyzed β-C-H arylation of carboxamides. The bidentate
directing auxiliary 8-aminoquinoline was found to be best
directing group that promoted the one-pot Pd(II)-catalyzed sp3 C-
H activation and β-arylation of aliphatic/alicyclic carboxamides.
Overall, we have shown a step-economical16 and straightforward
synthetic process for the synthesis of a variety of β-C-H arylated
carboxamide derivatives in moderate to high yields via the
multicomponent reaction method.17
have shown
a
step-economical Pd(II)-catalyzed, sp3 C-H
activation and β-arylation of carboxamides. Along this line, we
attempted to remove the directing group after the C-H arylation
reaction by avoiding the column chromatographic purification
step. Thus, by using the crude reaction mixture containing the C-
H arylated carboxamide, we directly performed the amide
hydrolysis reactions by using the standard reaction conditions
(Scheme 3) and the corresponding compounds 8a (40%), 8b
(52%) and 8c (59%) were obtained in satisfactory yields (Scheme
3).
3. Experimental Section
3.1. General. IR spectra of compounds were recorded as KBr
pellets or thin films. 1H and 13C NMR spectra of compounds were
recorded on 400 and 100 MHz spectrometers, respectively (using
TMS as an internal standard). Column chromatographic
purification of the crude reaction mixtures was performed using
silica gel (100-200 mesh). HRMS measurements of compounds
reported in this work were obtained from QTOF mass analyzer
In summary, we have shown a one-pot multicomponent
reaction method-based Pd(OAc)2-catalyzed, Ag2CO3–mediated
sp3 C-H activation and β-arylation of various aliphatic/alicyclic
carboxamides. The reaction of a mixture of an appropriate
aliphatic/alicyclic acid chloride, bidentate directing auxiliary
MeO
Pd(OAc)2
(10 mol%)
COCl
I
N
H
N
+
+
+
N
7e; 66%
NH2
2a
OMe
Ag2CO3 (2 equiv)
o-xylene (20 mL)
130 oC, 36 h
O
4e
6a
(1 equiv)
(1g, 7 mmol
1 equiv)
(8 equiv)
OMe
I
O
Pd(OAc)2 (10 mol%)
N
N
+
Cl
Me
NH2
OMe
HN
O
OMe
Ag2CO3 (1.5 equiv)
o-xylene (2 mL)
130 oC, 36 h
2a
4e
(4 equiv)
1a
(1 equiv)
(1g, 7 mmol
1 equiv)
5b; 63%
conventional way
Ar
I
R
ligand removal
column
purification
Pd(OAc)2
AgOAc
N
R
H
R1O
N
N
H
excess NaOH
(or)
excess
N
R
O
O
conditions
R
O
R = H / Ar
R1 = H, Me
pure sample
R = H / Ar
pure sample
BF3-OEt2 in MeOH
one-pot C-H arylation
Pd(OAc)2
I
solvent removal
under vacuum
BF3-OEt2
(1.5-2 mL)
N
O
MeO
O
O
(10 mol%)
HN
nPr Cl
1a
+
+
N
Ag2CO3 (1.5 equiv)
no column
purification
MeOH (4 mL)
48 h
NH2
4a
2a
o-xylene (2 mL)
130 oC, 12-15 h
8a
; 40%
crude reaction mixture
R2
R2
one-pot C-H arylation
Pd(OAc)2
I
solvent removal
under vacuum
NaOH
(13 mmol)
COCl
(10 mol%)
N
H
HO
+
N
+
N
Ag2CO3 (2 equiv)
no column
purification
EtOH (2.5 mL)
12-15 h
open flask
O
4
NH2
O
R2
o-xylene (2 mL)
130 oC, 36 h
2a
6c
R2
; R2 = Br; 52%
8c; R2 = Cl; 59%
R2
crude reaction mixture
8b
Scheme 3.a Gram scale reaction and removal of the bidentate directing auxiliary after the Pd(II)-catalyzed C-H arylation of
carboxamides. a Isolated yields of all the compounds are reported.

9
using electrospray ionization (ESI) technique. Reactions were
carried out using anhydrous solvents under a nitrogen atm and
anhydrous solvents were prepared by using standard procedures.
Organic layers after the work up procedure were dried using
anhydrous sodium sulphate. TLC analysis was carried out on
silica gel plates 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. The di-arylation products 7a-k were obtained as
single stereoisomers and the corresponding mono-arylation
products were not obtained from their respective reactions. The
all cis stereochemistry of compounds 7a-k11c and 7n11b was
assigned based on the similarity in the NMR pattern of the
compounds 7a-k and 7n obtained in this work with the previous
works involving the bidentate directing auxiliary 8-
3.2.3. 3-(3,4-Dichlorophenyl)-N-(quinolin-8-yl)butanamide
ACCEPTED MANUSCRIPT
(5n): Following the general procedure, 5n was obtained after
purification by silica gel column chromatography (EtOAc :
Hexane = 5 : 95) as a pale yellow color solid (71 mg, 50%); Rf =
o
0.4 (EtOAc : Hexane = 15 : 85); mp 85-87 C; IR (DCM): υmax
3412, 2965, 1684, 1526, 1485, 1325, 1122, 1039, 825 cm-1; H
1
NMR (400 MHz, CDCl3): δH 9.70 (1 H, s), 8.79 (1 H, dd, J1 = 4.0
Hz, J2 = 1.6 Hz), 8.74 (1 H, dd, J1 = 6.8 Hz, J2 = 2 Hz), 8.16 (1
H, dd, J1 = 8.4 Hz, J2 = 1.6 Hz), 7.56–7.44 (4 H, m), 7.35 (1 H, d,
J = 8.4 Hz), 7.17 (1 H, dd, J1 = 8.4 Hz, J2 = 2.4 Hz), 3.51–3.46 (1
H, m), 2.88–2.76 (2 H, m), 1.41 (3 H, d, J = 6.8 Hz) ; 13C NMR
(100 MHz, CDCl3): δC 169.6, 148.2, 146.2, 138.2, 136.4, 134.2,
132.5, 130.5, 130.3, 128.9, 127.9, 127.3, 126.6, 121.6, 116.5,
46.5, 36.2, 21.7; HRMS (ESI): MH+, found 359.0706.
C19H17Cl2N2O requires 359.0718.
aminoquinoline-directed
C-H
arylation
of
cyclopropanecarboxamides11b and cyclobutanecarboxamides.11c
Compounds 7a-k,11c 7m,7 7s,7 5a-e,10s 5g-i,10s 5k-m,7c 5o,7c 5u,7c
5v,19 5v′,7c 8a,18 and 8b,c11c are reported in the literature and the
characterization of the known compounds was carried out by
comparing the data with the literature data.
3.2.4.
3-(4-Methoxyphenyl)-N-(quinolin-8-yl)hexanamide
(5p): Following the general procedure, 5p was obtained after
purification by silica gel column chromatography (EtOAc :
Hexane = 7 : 93) as a red color solid (128 mg, 92%); Rf = 0.40
(EtOAc : Hexane = 15 : 85); mp 85-87 oC; IR (DCM): υmax 3355,
1
2956, 1683, 1525, 1485, 1325, 1248, 1035 cm-1; H NMR (400
MHz, CDCl3): δH 9.69 (1 H, s), 8.77-8.75 (2 H, m), 8.13 (1 H, d,
J = 8.0 Hz), 7.54–7.42 (3 H, m), 7.23 (2 H, d, J = 8.4 Hz), 6.85 (2
H, d, J = 8.4 Hz), 3.75 (3 H, s), 3.31–3.27 (1 H, m), 2.85–2.82 (2
H, m), 1.79–1.66 (2 H, m), 1.29–1.22 (2 H, m), 0.89 (3 H, t, J =
7.2 Hz); 13C NMR (100 MHz, CDCl3): δC 170.6, 158.1, 148.0,
138.3, 136.3, 136.3, 134.5, 128.5, 127.9, 127.4, 121.5, 121.4,
116.4, 113.9, 55.2, 46.2, 41.6, 38.6, 20.6, 14.0; HRMS (ESI):
MH+, found 349.1906. C22H25N2O2 requires 349.1916.
3.2. General procedure for the multicomponent reaction
comprising one-pot installation of bidentate directing group
and Pd(II)-catalyzed direct β-arylation of C(sp3)-H bond of
aliphatic and alicyclic carboxamides:
A mixture of 8-
aminoquinoline (0.4 mmol), an appropriate carbonyl chloride
(0.4 mmol), an appropriate aryl iodide (0.16-0.24 mmol, 4-6
equiv), Pd(OAc)2 (10 mol%) and Ag2CO3 (0.6-0.8 mmol, 1.5-2
equiv) was heated in o-xylene (2 mL) at 110 oC for an
appropriate reaction period (12-36 h). Then, reaction mixture was
cooled to rt and the solvent evaporated in vacuo to give the crude
product, which was purified by chromatography to give the
corresponding C-H arylated products (see the respective Tables1-
4 /Scheme 2 for the specific entries and reaction conditions).
3.2.5. N-(Quinolin-8-yl)-3-(p-tolyl)hexanamide (5q): Following
the general procedure, 5q was obtained after purification by silica
gel column chromatography (EtOAc : Hexane = 5 : 95) as a pale
yellow color semi-solid (123 mg, 93%); Rf = 0.4 (EtOAc :
Hexane = 15 : 85); IR (DCM): υmax 3356, 2956, 1688, 1525,
1
1485, 1325, 1160, 1114, 825 cm-1; H NMR (400 MHz, CDCl3):
3.2.1. 3-(4-Acetylphenyl)-N-(quinolin-8-yl)butanamide (5f):
Following the general procedure, 5f was obtained after
purification by silica gel column chromatography (EtOAc :
Hexane = 20 : 80) as a brown color semi-solid (131 mg, 99%); Rf
= 0.1 (EtOAc : Hexane = 15 : 85); IR (DCM): υmax 3349, 2964,
δH 9.72 (1 H, s), 8.79–8.77 (2 H, m), 8.14 (1 H, dd, J1 = 8.4 Hz,
J2 = 1.6 Hz), 7.54–7.43 (3 H, m), 7.21 (2 H, d, J = 8.0 Hz), 7.13
(2 H, d, J = 8.0 Hz), 3.33–3.30 (1 H, m), 2.86 (2 H, d, J = 6.8
Hz), 2.31 (3 H, s), 1.80–1.68 (2 H, m), 1.29–1.22 (2 H, m), 0.89
(3 H, t, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3): δC 170.6,
148.0, 141.3, 138.3, 136.3, 135.8, 134.5, 129.2, 127.9, 127.4,
127.4, 121.5, 121.3, 116.4, 46.0, 42.0, 38.5, 21.1, 20.6, 14.1;
HRMS (ESI): MH+, found 333.1960. C22H25N2O requires
333.1967.
1
1682, 1525, 1486, 1325, 1164, 1014, 827 cm-1; H NMR (400
MHz, CDCl3): δH 9.74 (1 H, s), 8.77-8.74 (2 H, m), 8.15 (1 H, dd,
J1 = 8.4 Hz, J2 = 1.6 Hz), 7.91 (2 H, d, J = 8.4 Hz), 7.5–7.43 (5 H,
m), 3.62–3.56 (1 H, m), 2.92–2.80 (2 H, m), 2.56 (3 H, s), 1.44 (3
H, d, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3): δC 197.9, 169.8,
151.6, 148.1, 138.2, 136.4, 135.5, 134.2, 128.8, 127.9, 127.4,
127.2, 121.6, 121.6, 116.5, 46.3, 36.9, 26.6, 21.7; HRMS (ESI):
MH+, found 333.1588. C21H21N2O2 requires 333.1603.
3.2.6.
3-(4-Methoxyphenyl)-N-(quinolin-8-yl)heptanamide
(5r): Following the general1 procedure, 5r was obtained after
purification by silica gel column chromatography (EtOAc :
Hexane = 5 : 95) as a pale yellow color solid (140 mg, 97%); Rf
= 0.4 (EtOAc : Hexane = 15 : 85); mp 89-91 oC; IR (DCM): υmax
3.2.2. 3-(3-Nitrophenyl)-N-(quinolin-8-yl)butanamide (5j):
Following the general procedure, 5j was obtained after
purification by silica gel column chromatography (EtOAc :
Hexane = 7 : 93) as a brown color semi-solid (115 mg, 86%); Rf
= 0.4 (EtOAc : Hexane = 15 : 85); IR (DCM): υmax 3348, 2965,
1
3356, 2929, 1682, 1525, 1486, 1325, 1247, 1036 cm-1; H NMR
(400 MHz, CDCl3): δH 9.68 (1 H, s), 8.77–8.74 (2 H, m), 8.15 (1
H, d, J = 8.0 Hz), 7.54–7.43 (3 H, m), 7.23 (2 H, d, J = 8.4 Hz),
6.85 (2 H, d, J = 8.8 Hz), 3.76 (3 H, s), 3.28–3.24 (1 H, m), 2.85–
2.81 (2 H, m), 1.80–1.67 (2 H, m), 1.32–1.17 (4 H, m), 0.90–0.83
(3 H, m); 13C NMR (100 MHz, CDCl3): δC 170.6, 158.0, 148.0,
138.3, 136.4, 136.3, 134.4, 128.4, 127.8, 127.4, 121.5, 121.3,
116.4, 113.9, 55.2, 46.2, 41.8, 36.1, 29.7, 22.7, 14.0; HRMS
(ESI): MH+, found 363.2082. C23H27N2O2 requires 363.2073.
1
1682, 1531, 1486, 1350, 1164, 1031, 826 cm-1; H NMR (400
MHz, CDCl3): δH 9.75 (1 H, s), 8.76 (1 H, dd, J1 = 4.0 Hz, J2 =
1.2 Hz), 8.72 (1 H, dd, J1 = 6.4 Hz, J2 = 2.8 Hz), 8.23 (1 H, s),
8.14 (1 H, dd, J1 = 8.4 Hz, J2 = 1.6 Hz), 8.04 (1 H, dd, J1 = 8.0
Hz, J2 = 1.6 Hz), 7.67 (1 H, d, J = 7.6 Hz), 7.51–7.43 (4 H, m),
3.68–3.63 (1 H, m), 2.95–2.84 (2 H, m), 1.47 (3 H, d, J = 6.8
Hz); 13C NMR (100 MHz, CDCl3): δC 169.4, 148.5, 148.2, 148.0,
138.2, 136.4, 134.1, 133.7, 129.5, 127.9, 127.3, 121.7, 121.6,
121.6, 116.5, 46.2, 36.5, 21.7; HRMS (ESI): MH+, found
336.1333. C19H18N3O3 requires 336.1348.
3.2.7.
3-(4-Methoxyphenyl)-N-(quinolin-8-yl)nonanamide
(5s): Following the general1 procedure, 5s was obtained after
purification by silica gel column chromatography (EtOAc :
Hexane = 7 : 93) as a pale yellow color solid (148 mg, 95%); Rf

10
Tetrahedron
ACCEPTED MANUSCRIPT
o
1
= 0.4 (EtOAc : Hexane = 15 : 85); mp 75-77 C; IR (DCM):
1677, 1522, 1480, 1325, 1262, 1113 cm-1; H NMR (400 MHz,
υmax 3356, 2928, 1683, 1520, 1486, 1325, 1247, 1036 cm-1; H
NMR (400 MHz, CDCl3): δH 9.68 (1 H, s), 8.78–8.75 (2 H, m),
8.14 (1 H, d, J = 8.4 Hz), 7.54–7.43 (3 H, m), 7.23 (2 H, d, J =
8.8 Hz), 6.85 (2 H, d, J = 8.8 Hz), 3.76 (3 H, s), 3.28–3.25 (1 H,
m), 2.85–2.81 (2 H, m), 1.79–1.67 (2 H, m), 1.28–1.22 (8 H, m),
0.85 (3 H, t, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3): δC 170.6,
158.0, 148.0, 138.3, 136.4, 136.3, 134.5, 128.4, 127.9, 127.4,
121.5, 121.3, 116.4, 113.9, 55.2, 46.2, 41.9, 36.4, 31.8, 29.3,
27.4, 22.6, 14.1; HRMS (ESI): MH+, found 391.2379.
C25H31N2O2 requires 391.2386.
CDCl3): δH 9.96 (1 H, br. s), 9.02 (1 H, dd, J1 = 7.6 Hz, J2 = 1.6
Hz), 8.75 (1 H, dd, J1 = 4.4 Hz, J2 = 2.0 Hz), 8.21 (1 H, dd, J1 =
8.0 Hz, J2 = 1.6 Hz), 7.66-7.58 (2 H, m), 7.46 (1 H, dd, J1 = 8.4
Hz, J2 = 4.4 Hz), 7.33 (1 H, d, J = 7.2 Hz), 7.18 (2 H, d, J = 8.0
Hz), 2.73 (4 H, t, J = 8.0 Hz), 1.73-1.65 (4 H, m), 1.30-1.12 (16
H, m), 0.79-0.75 (6 H, m); 13C NMR (100 MHz, CDCl3): δC
168.9, 148.2, 139.5, 138.5, 137.5, 136.3, 134.5, 129.0, 128.0,
127.5, 126.7, 121.8, 121.6, 116.7, 33.5, 31.7, 31.6, 29.6, 29.0,
22.6, 14.0; HRMS (ESI): MH+, found 445.3236. C30H41N2O
requires 445.3219.
1
3.2.8. 3-(4-Methoxyphenyl)-N-(quinolin-8-yl)dodecanamide
(5t): Following the general1 procedure, 5t was obtained after
purification by silica gel column chromatography (EtOAc :
Hexane = 7 : 93) as a pale yellow color solid (147 mg, 85%); Rf
= 0.4 (EtOAc : Hexane = 15 : 85); mp 56-58 oC; IR (DCM): υmax
3.2.12.
2,6-Dibutyl-N-(quinolin-8-yl)benzamide
(7u):
Following the general procedure, 7u was obtained after
purification by silica gel column chromatography (EtOAc :
Hexane = 2 : 98) as a brown color semi-solid (69 mg, 55%); Rf =
0.8 (EtOAc : Hexane = 15 : 85); IR (DCM): υma1x 3347, 2927,
2858, 1676, 1522, 1482, 1325, 1262, 1126, cm-1; H NMR (400
MHz, CDCl3): δH 9.95 (1 H, br. s), 9.01 (1 H, dd, J1 = 7.6 Hz, J2
= 1.2 Hz), 8.75 (1 H, dd, J1 = 4.4 Hz, J2 = 1.6 Hz), 8.20 (1 H, dd,
J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 7.67-7.58 (2 H, m), 7.47 (1 H, dd,
J1 = 8.0 Hz, J2 = 4.0 Hz), 7.38 (1 H, d, J = 8.0 Hz), 7.18 (2 H, d, J
= 7.6 Hz), 2.73 (4 H, t, J = 8.0 Hz), 1.73-1.65 (4 H, m), 1.34-1.28
(4 H, m), 0.84-0.80 (6 H, m); 13C NMR (100 MHz, CDCl3): δC
168.9, 148.2, 139.5, 138.5, 137.5, 136.3, 134.5, 128.9, 128.0,
127.5, 126.7, 121.9, 121.7, 116.8, 33.8, 33.2, 22.7, 13.9; HRMS
(ESI): MH+, found 316.2265. C24H29N2O requires 316.2280.
1
3356, 2926, 1683, 1520, 1486, 1325, 1248, 1037 cm-1; H NMR
(400 MHz, CDCl3): δH 9.68 (1 H, s), 8.77–8.75 (2 H, m), 8.13 (1
H, d, J = 8.4 Hz), 7.51–7.43 (3 H, m), 7.23 (2 H, d, J = 8.8 Hz),
6.85 (2 H, d, J = 8.8 Hz), 3.76 (3 H, s), 3.30–3.25 (1 H, m), 2.85–
2.81 (2 H, m), 1.80–1.67 (2 H, m), 1.30–1.22 (14 H, m), 0.89 (3
H, t, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3): δC 170.6, 158.0,
148.0, 138.3, 136.4, 136.3, 134.5, 128.4, 127.9, 127.4, 121.5,
121.3, 116.4, 113.9, 55.1, 46.2, 41.9, 36.4, 31.9, 29.6, 29.6, 29.6,
29.3, 27.5, 22.7, 14.2; HRMS (ESI): MH+, found 433.2838.
C28H37N2O2 requires 433.2855.
3.2.2. General procedure for the synthesis of 8a-c: After
performing the corresponding C-H arylation reactions, the
reaction mixtures were cooled to rt and the solvent evaporated in
vacuo to give the crude products, which were subjected to the
amide hydrolysis reaction by using the standard literature
procedures.5-7
3.2.9. 2,6-Diphenyl-N-(quinolin-8-yl)cyclohexanecarboxamide
(7l): Following the general procedure, 7l was obtained after
purification by silica gel column chromatography (EtOAc :
Hexane = 4 : 96) as a colorless solid (61 mg, 38%); Rf = 0.5
o
(EtOAc : Hexane = 15 : 85); mp 176-178 C; IR (DCM): υmax
1
3357, 2929, 2247, 1682, 1520, 1486, 1324, 1165 cm-1; H NMR
(400 MHz, CDCl3): δH 8.66 (1 H, br. s), 8.54 (1 H, dd, J1 = 7.6
Hz, J2 = 1.2 Hz), 8.45 (1 H, dd, J1 = 4.4 Hz, J2 = 1.6 Hz), 7.99 (1
H, dd, J1 = 8.4 Hz, J2 = 1.6 Hz), 7.44–7.34 (6 H, m), 7.28 (1 H,
dd, J1 = 8.4 Hz, J2 = 4.0 Hz), 7.13 (4 H, t, J = 7.6 Hz), 6.98–6.94
(2 H, m), 3.22–3.18 (3 H, m), 2.87–2.77 (2 H, m), 2.30–2.24 (1
H, m), 1.86–1.82 (2 H, m), 1.70–1.67 (1 H, m); 13C NMR (100
MHz, CDCl3): δC 171.0, 147.4, 144.1, 1378.0, 135.7, 134.1,
128.2, 127.5, 127.4, 127.0, 126.3, 121.1, 120.9, 115.9, 59.9, 47.9,
26.6, 25.6; HRMS (ESI): MH+, found 407.2130. C28H27N2O
requires 407.2123.
Acknowledgments
This work was funded by IISER Mohali. The authors thank
the NMR and HRMS facilities of IISER Mohali. S. M. thanks
Department of Science and Technology (DST), New Delhi, for
providing Innovation in Science Pursuit for Inspired Research
(INSPIRE) fellowship. B.G. thanks Department of Science and
Technology (DST), New Delhi, for providing Innovation in
Science Pursuit for Inspired Research (INSPIRE) Senior
Research fellowship.
3.2.10.
2,3-Bis(4-acetylphenyl)-N-(quinolin-8-
yl)cyclopropanecarboxamide (7n): Following the general
procedure, 7n was obtained after purification by silica gel
column chromatography (EtOAc : Hexane = 5 : 95) as a yellow
color solid (71 mg, 40%); Rf = 0.4 (EtOAc : Hexane = 15 : 85);
References and notes
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o
mp 83-85 C; IR (DCM): υmax 3346, 3053, 1682, 1525, 1486,
1
1325, 1162 cm-1; H NMR (400 MHz, CDCl3): δH 10.0 (1 H, s),
8.71 (1 H, dd, J1 = 4.0 Hz, J2 = 1.6 Hz), 8.61 (1 H, dd, J1 = 6.8
Hz, J2 = 2.4 Hz), 8.14 (1 H, dd, J1 = 8.4 Hz, J2 = 1.6 Hz), 7.80 (4
H, d, J = 8.4 Hz), 7.47–7.42 (3 H, m), 7.35 (4 H, d, J = 8.4 Hz),
3.16 (2 H, d, J = 9.2 Hz), 2.91 (1 H, t, J = 9.2 Hz), 2.55 (6 H, s);
13C NMR (100 MHz, CDCl3): δC 198.0, 166.2, 148.0, 139.9,
138.1, 136.4, 135.3, 134.3, 131.2, 127.9, 127.6, 127.3, 121.6,
121.5, 116.5, 29.9, 29.4, 26.6; HRMS (ESI): MH+, found
449.1848. C29H25N2O3 requires 449.1865.
3.2.11.
2,6-Diheptyl-N-(quinolin-8-yl)benzamide
(7t):
2. (a) For a themed issue on C-H activation reactions, see: C–H
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Following the general procedure, 7t was obtained after
purification by silica gel column chromatography (EtOAc :
Hexane = 2 : 98) as a brown color semi-solid (80 mg, 45%); Rf =
0.8 (EtOAc : Hexane = 15 : 85); IR (DCM υmax 3348, 2925, 2855,

11
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12
Tetrahedron
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ACCEPTED MANUSCRIPT
2015, 5, 46192; (b) The all cis stereochemistry of
compound 7m was assigned based on the similarity in
the NMR pattern of the compound 7m obtained in this
work with the previous work reported by Daugulis et al.
(see ref.7b) involving the bidentate directing auxiliary 8-
aminoquinoline-directed C-H arylation of pre-
assembled cyclohexanecarboxamide. Then, in analogy
to the stereochemistry of 7m, the all cis stereochemistry
of the compound 7l was assigned. (c) With regard to the
products reported in Tables 3 and 4; except for 5v/5ʹ, the
other corresponding C-H arylation reactions of the
respective starting materials afforded only the
corresponding mono arylation products 5a-u as single
compounds. We did not observe the formation any of
the corresponding di-arylation products.
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Supplementary data
Supplementary data (copy of 1H, 13C NMR Charts of compounds)
associated with this article can be found, in the online version.