Bidentate ligand 8-aminoquinoline-aided Pd-catalyzed diastereoselective β-arylation of the prochiral secondary sp3 C-H bonds of 2-phenylbutanamides and related aliphatic carboxamides

Article abstract of DOI:10.1016/j.tet.2015.08.049

Investigations on the Pd-catalyzed 8-aminoquinoline-aided diastereoselective β-arylation of the prochiral 2° sp³ C-H bonds of various aliphatic carboxamides having substituents at the α- or γ-positions are reported. The Pd-catalyzed β-arylation of the 2° sp³ C-H bonds of racemic 2-phenylbutanamides with aryl iodides gave the arylated products (±)-3a-l (anti isomers) with moderate to good diastereoselectivities (dr up to 86:14). Next, the Pd-catalyzed β-arylation of various γ-substituted aliphatic carboxamides with aryl iodides furnished the corresponding C-H arylated products with poor diastereoselectivities. Then, the arylation of the C(β)-H bonds of 2-ethyl-N-(quinolin-8-yl)butanamide possessing two prochiral centers with aryl iodides successfully furnished the bis arylated products meso-8eA-hA and (±)-8eB-hB (diastereomers). The arylation of (S)-2-phenylbutanamide also gave the corresponding enantiomerically enriched compounds 10a-c (anti isomers). The stereochemistry of the products (±)-3a-l (major isomers), meso-8eA-hA (major isomers), (±)-8eB-hB (minor isomers) and enantiomerically enriched compounds 10a-c (major isomers) were assigned based on the X-ray structures of the major isomers 3b,c,e,l, 8eA, 10c and minor isomers 8eB and 8fB. The limitations and outcome of the stereocontrol in the Pd-catalyzed C-H arylation reactions involving aliphatic carboxamides are illustrated.

Full text of DOI:10.1016/j.tet.2015.08.049

Tetrahedron 71 (2015) 8333e8349
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Bidentate ligand 8-aminoquinoline-aided Pd-catalyzed
diastereoselective b-arylation of the prochiral secondary sp CeH
3
bonds of 2-phenylbutanamides and related aliphatic carboxamides
*
Bojan Gopalakrishnan, Srinivasarao Arulananda Babu , Rayavarapu Padmavathi
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
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 June 2015
Received in revised form 17 August 2015
Accepted 20 August 2015
Available online 22 August 2015
Investigations on the Pd-catalyzed 8-aminoquinoline-aided diastereoselective
b
-arylation of the pro-
- or -positions
-arylation of the 2 sp CeH bonds of racemic 2-phenylbutanamides
with aryl iodides gave the arylated products (ꢁ)-3ael (anti isomers) with moderate to good diaster-
eoselectivities (dr up to 86:14). Next, the Pd-catalyzed -arylation of various -substituted aliphatic
carboxamides with aryl iodides furnished the corresponding CeH arylated products with poor diaster-
eoselectivities. Then, the arylation of the C( )-H bonds of 2-ethyl-N-(quinolin-8-yl)butanamide pos-
sessing two prochiral centers with aryl iodides successfully furnished the bis arylated products meso-
eAehA and (ꢁ)-8eBehB (diastereomers). The arylation of (S)-2-phenylbutanamide also gave the cor-
ꢀ
3
chiral 2 sp CeH bonds of various aliphatic carboxamides having substituents at the
a
g
ꢀ
3
are reported. The Pd-catalyzed
b
b
g
Keywords:
b
Aliphatic carboxamides
CeH activation/arylation
Diastereoselectivity
Palladium
8
responding enantiomerically enriched compounds 10aec (anti isomers). The stereochemistry of the
products (ꢁ)-3ael (major isomers), meso-8eAehA (major isomers), (ꢁ)-8eBehB (minor isomers) and
enantiomerically enriched compounds 10aec (major isomers) were assigned based on the X-ray struc-
tures of the major isomers 3b,c,e,l, 8eA, 10c and minor isomers 8eB and 8fB. The limitations and outcome
of the stereocontrol in the Pd-catalyzed CeH arylation reactions involving aliphatic carboxamides are
illustrated.
3
sp CeH functionalization
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
task. Consequently, the direct functionalization of the sp3 CeH
bonds of organic compounds has been considered as one of the
1
e14
Transition metal-catalyzed CeH activation/functionalization
reactions have emerged as a powerful carbon-carbon bond forming
tactics.1 Especially, the directing group based CeH activation/
functionalization strategy has emerged as a robust method to
important research areas.
In 2005, Daugulis reported a seminal
work on the use of the bidentate directing group for the Pd-
e3
3
catalyzed arylation of non-acidic sp CeH bonds of various car-
1
a,b,11a
boxamide substrates.
Concomitantly, Yu’s group reported the
1
e3
functionalize organic compounds.
In the past two decades, by
pioneering works and demonstrated the Pd-catalyzed arylation of
3
exercising the directing group-aided CeH activation tactics, nu-
non-acidic sp CeH bonds directed by pyridyl, carboxyl, and acidic
2
3a,b,10
merous reactions comprising the functionalization of the sp CeH
N-arylamide groups.
Later, Chen’s group revealed the Pd-
1e8
3
bonds of organic molecules have been reported.
Apart from the
catalyzed arylation of the non-acidic sp CeH bonds directed by
a picolyl group.
Based on the inspiring works of the Daugulis,
and other research groups;
arylation of the sp b-CeH bonds or remote sp CeH bonds of
14a
well-known CeH functionalization protocols encompassing, (a) the
benzylic CeH bonds,5f and (b) the sp CeH bonds of the
3
a
-position
1b,11a
Yu,3a,b Shi,11q
14a
4e14
next to a heteroatom or diazocarbonyl compound-based CeH in-
Chen
the direct and selective
2
a,g,5gej
3
3
sertion reactions;
in general, the functionalization of non-
acidic/unactivated sp3 CeH bonds is considered as a challenging
carboxamide substrates can be achieved by using an appropriate
directing group (e.g., 8-aminoquinoline, 2-(methylthio)aniline,
2,3,5,6-tetrafluoro-4-(trifluoromethyl)-aniline and 2-picolyl de-
rivative). Correspondingly, the directing group-aided Pd-catalyzed
functionalization strategy has been successfully demonstrated by
*
Corresponding author. Tel.: þ91 172 2293165; fax: þ91 172 2240266; e-mail
address: sababu@iisermohali.ac.in (S.A. Babu).
http://dx.doi.org/10.1016/j.tet.2015.08.049
0
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

8334
B. Gopalakrishnan et al. / Tetrahedron 71 (2015) 8333e8349
using several aliphatic carboxamide systems, amino acid de-
CeH bonds of simple aliphatic carboxamides having substituents at
the - or -positions.
In continuation of our interest on the Pd-catalyzed CeH func-
tionalization reactions, herein, we report Pd(OAc) -catalyzed
bidentate ligand 8-aminoquinoline-directed diastereoselective
4
e14
rivatives, carbocyclic and saturated heterocyclic systems.
a
g
3
Thedirectinggroup-aidedPd-catalyzedarylationofthesp
b-CeH
3
bonds or remote sp CeH bonds of cyclic carboxamide systems pro-
vides an easy method to create two or three stereocenters. Along this
line, the diastereoselective CeH arylation of the carbocyclic systems,
2
b
-
ꢀ
3
arylation of the prochiral 2 sp CeH bonds of aliphatic carbox-
amide substrates and the construction of aliphatic carboxamides
1
2aec
11hej,12d
such as cyclopropane,
s,
cyclobutane,
medium-sized ring-
11a,b
12e
and norbornane framework, and saturated heterocyclic sys-
possessing vicinal stereocenters (Scheme 2). Representative liter-
tems (e.g., tetrahydropyran, proline,11c,l tetrahydrofuran, and 1,4-
11e
13
ature methods
2a,15c
dealing with the construction of b-aryl 2-
13
benzodioxane ) have been successfully demonstrated.
phenylbutyric acid derivatives possessing vicinal stereocenters
are shown in Scheme 3. Davies’s group reported the Rh-catalyzed
intermolecular CeH insertion method and Baba’s group revealed
Notably, there have been several reports dealing on the directing
3
group-aided selective arylation of the prochiral sp
b- (or) g-CeH
bonds or remote sp3 CeH bonds of enantiomerically pure amino
acid systems. This process has led to the diastereoselective con-
struction of two vicinal stereocenters on the backbone of various
amino acid derivatives.14 With regard to the diastereoselective
the InCl
allyl alcohol for the construction of
derivatives. Nonetheless, the present work reveals a contemporary
method in which the stereoselective synthesis of several -aryl 2-
-catalyzed addition of enolate with methyl ether of styr-
3
b
-aryl 2-phenylbutyric acid
b
ꢀ
3
arylation of the prochiral 2 sp CeH bonds of the simple aliphatic
phenylbutyric acid derivatives can be accomplished by using a va-
riety of aryl iodides (Scheme 2).
10
carboxylic acid systems; in 2012, Yu’s group demonstrated three
reactions comprising the Pd(TFA) -catalyzed arylation of the pro-
chiral sp3
-CeH bonds of three aliphatic carboxamide systems
2
b
using 1-iodo-4-methylbenzene (Scheme 1). In these cases, the
weakly coordinating N-arylamide ligand system (assembled from
the carboxylic acid and 2,3,5,6-tetrafluoro-4-(trifluoromethyl)ani-
line) directed the Pd-catalyzed CeH activation along with an ex-
ternal ligand (2-isobutoxyquinoline). The stereochemistry of the
products obtained in the Pd-catalyzed CeH arylation reactions
10
shown in Scheme 1 were unknown.
-arylation of the prochiral 2 sp3 CeH
ꢀ
Scheme 2. This work. 8-Aminoquinoline-aided b
bonds of aliphatic carboxamides.
Scheme 3. Representative literature methods dealing with the construction of
-phenylbutyric acid derivatives.
b-aryl
2
2. Results and discussion
To explore the bidentate ligand-aided Pd-catalyzed diaster-
ꢀ
3
eoselective
phatic carboxamides, at first we assembled the racemic compound
a by linking 2-phenylbutanoyl chloride with bidentate ligand 8-
b-arylation of the prochiral 2 sp CeH bonds of ali-
1
11a
aminoquinoline (Daugulis’s auxiliary).
Then, to find out the
best reaction conditions, we performed the optimization reactions
ꢀ
-arylation of the prochiral 2 sp3 CeH bonds of
b
as shown in Table 1. A mixture of substrate 1a, 1-iodo-4-
Scheme 1. Available examples on the
aliphatic carboxamides and amino acids.
methoxybenzene (2a) and an additive AgOAc in the presence of
1
0
ꢀ
Apart from the three reactions reported by the Yu’s group, and
5 mol % of Pd(OAc)
reaction gave the CeH arylated product 3a/3a (racemic com-
2
catalyst was heated at 110 C for 24 h. This
14
0
the CeH arylation reactions of amino acid systems and cyclic
compounds;1
1aej,12
to the best of our knowledge, the diaster-
pounds) possessing two vicinal stereocenters in 82% yield with
0
oselective CeH arylation reactions involving simple aliphatic car-
good diastereoselectivity (dr¼78:22, 3a (anti)/3a (syn); entry 1,
1
e3,8
boxamides are less explored.
catalyzed diastereoselective
Hence, we investigated the Pd-
Table 1). Next, the Pd-catalyzed CeH arylation of 1a in toluene at
ꢀ
3
ꢀ 0
110 C for 24 h gave the diastereomers 3a/3a with an improved
b
-arylation of the prochiral 2 sp

B. Gopalakrishnan et al. / Tetrahedron 71 (2015) 8333e8349
8335
Table 1
-arylation of the prochiral 2 sp3 CeH bonds of (ꢁ)-1a
ꢀ
a
Optimization of reaction conditions. Diastereoselective
b
Entry
Catalyst
Solvent
Additive
Yield (%)
dr¼anti/syn
1
2
3
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
Neat
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
82
89
66
71
85
67
61
57
64
55
44
0
78:22
86:14
75:25
75:25
75:25
70:30
66:34
75:25
80:20
77:23
75:25
d
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
Dioxane
DMSO
Toluene
Toluene
Toluene
Toluene
b
c
4
5
6
7
8
9
Pd(MeCN)
Pd(acac)
PdCI
Pd(TFA)
2 2
CI
2
2
2
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
10
11
12
13
14
15
2
2
2
2
2
2
Ag
Ag
2
2
CO
O
3
0
0
7
d
Oxone
d
K
2
S
2
O
8
67:33
a
b
c
All the reactions were carried out using (ꢁ)-1a (0.25 mmol) and 2a (1 mmol, 4 equiv) in a solvent (3 mL).
In this case, 0.5 mmol (2 equiv) of 1-iodo-4-methoxybenzene (2a) was used.
In this case, 0.75 mmol (3 equiv) of 1-iodo-4-methoxybenzene (2a) was used. The total yield of both the diastereomers is reported. The ratios of diastereomers were
determined from the NMR spectra of the crude reaction mixtures.
yield and diastereoselectivity (89%, dr 86:14, entry 2, Table 1).
catalyzed CeH arylation of (ꢁ)-1a with 1-bromo-4-
methoxybenzene (2aA) gave the product (ꢁ)-3a in 68% yield with
good diastereoselectivity (dr 75:25, Scheme 4). Similarly, the Pd-
catalyzed CeH arylation of (ꢁ)-1a with 6-bromo-2,3-
dihydrobenzo[b][1,4]dioxine (2kA) afforded the CeH arylated
product (ꢁ)-3k in only 33% yield with moderate diaster-
eoselectivity (dr 70:30, Scheme 4).
When the CeH arylation of 1a was performed with 2 or 3 equiv of
0
2
a, the diastereomers 3a/3a were obtained in moderate yields (66
and 71%, dr 75:25, entries 3 and 4, Table 1). The CeH arylation of 1a
with 2a in the presence of other palladium catalysts, such as
Pd(MeCN)
2
Cl
2
, Pd(acac)
2
, PdCl
2
and Pd(TFA)
2
also gave the di-
0
astereomers 3a/3a in 57e85% yields (dr up to 75:25, entries 5e8,
Table 1). Further, the Pd-catalyzed CeH arylation of 1a with 2a in
other solvents, such as DMF, 1,4-dioxane, and DMSO gave the di-
The stereochemistry of all the major isomers (ꢁ)-3ael was
assigned based on the following discussion. In all the reactions, we
tried to isolate both major and minor isomer in pure forms from the
column chromatography purification. In majority of the trials, the
major diastereomers were successfully isolated in pure forms.
Representatively, the major isomers (ꢁ)-3b,c,e,l were recrystallized
to obtain the single crystals, which were subjected to the X-ray
structure analysis. The X-ray structure analysis of the major isomers
(ꢁ)-3b,c,e,l unambiguously revealed that the major diastereomers
formed in the CeH arylation of (ꢁ)-1a were having the anti ste-
0
astereomers 3a/3a in moderate yields (44e64%, dr up to 80:20,
entries 9e11, Table 1). Finally, we also performed the Pd-catalyzed
CeH arylation of 1a with 2a in the presence of other silver salts or
additives instead of AgOAc and these reactions were ineffective
(
entries 12e15, Table 1).
Then, the generality and scope of this work involving Pd-
ꢀ
3
catalyzed diastereoselective
b-arylation of the prochiral 2 sp
CeH bond of carboxamide substrate (ꢁ)-1a were investigated by
1
using a variety of aryl iodides (Table 2). By using the optimized
reochemistry (Fig. 1). Furthermore, upon analyzing the H NMR
reaction conditions (entry 2, Table 1), we performed the Pd(OAc)
catalyzed
including electron-donating group or electron-withdrawing group
2
-
spectra, we found a typical pattern in the chemical shift values for
the doublet peaks of the methyl protons present in the CeH ary-
lated products (ꢁ)-3. Characteristically, the methyl protons of the
major diastereomers (ꢁ)-3ael (anti isomers) appeared as doublet
b
-arylation of substrate (ꢁ)-1a with several aryl iodides
at the para or meta position of the aryl moiety. Accordingly, a vari-
ety of
b
-arylated 2-phenyl-butanamides (ꢁ)-3beh (anti isomers)
at d 1.10e1.25 ppm. On the other hand, the methyl protons of the
0
0
possessing two vicinal stereocenters were obtained in 62e91%
minor compounds (ꢁ)-3a el (syn isomers) appeared as doublet at
yields with good to very good diastereoselectivities (dr up to 81:19,
d 1.51e1.64 ppm. Accordingly, the stereochemistry of all the major
Table 2). Afterwards, we performed the Pd-catalyzed
b
-arylation of
compounds (ꢁ)-3ael (anti isomers) and minor compounds
0
0
(
ꢁ)-1a with various disubstituted aryl iodides, which gave the re-
(ꢁ)-3a el (syn isomers) were assigned on the basis of the X-ray
structures of the compounds (ꢁ)-3b,c,e,l coupled with the simi-
larity in their NMR spectral pattern.
spective
b
-arylated 2-phenyl-butanamides (ꢁ)-3iek (anti isomers)
in 65e93% yields with moderate to very good diastereoselectivities
dr up to 80:20, Table 2). Along this line, the Pd-catalyzed -aryla-
tion of the prochiral sp CeH bond of (ꢁ)-1a with hetero aryl iodide
e.g., 2-iodothiophene) furnished the product (ꢁ)-3l (anti isomer)
in 90% yield with good diastereoselectivity (dr 77:23, Table 2).
We also carried out the
-arylation of (ꢁ)-1a by using aryl
bromides instead of aryl iodides (Scheme 4). Accordingly, the Pd-
(
b
Next, to find out the other working bidentate ligands, we pre-
pared a series of 2-phenyl-butanamide substrates (ꢁ)-1bee by
linking 2-phenylbutanoyl chloride with various bidentate ligands,
such as 2-picolyl amine, 2-aminopyridine, N,N-dimethylethylene
diamine and 2-(methylthio)aniline (Scheme 4). Then, we per-
3
(
b
2
formed the Pd(OAc) ecatalyzed CeH arylation reactions of

8336
B. Gopalakrishnan et al. / Tetrahedron 71 (2015) 8333e8349
Table 2
Synthesis of
a
b-arylated-2-phenylbutanamides (ꢁ)-3aem from the diastereoselective CeH-arylation of (ꢁ)-1a
a
All the reactions were carried out using (±)-1a (0.25 mmol) and 2 (1 mmol, 4 equiv) in toluene (3 mL). The total yield of both the diastereomers is reported.
The ratios of diastereomers were determined from the NMR spectra of the crude reaction mixtures.
ꢀ
substrates (ꢁ)-1bee with aryl iodides in toluene at 110 C for 24 h.
arylation reaction of (ꢁ)-1f with aryl iodides, such as 2-
iodothiphene and 1-bromo-4-iodobenzene, which afforded the
corresponding products (ꢁ)-6a (84%, dr 52:48) and (ꢁ)-6b (40%, dr
67:33) with poor diastereoselectivities. Similarly, the Pd-catalyzed
Unfortunately, in these reactions we did not get any of the corre-
sponding
Supplementary data for the details).
b-arylated 2-phenyl-butanamides 4/5 (See the
Subsequently, we planned to explore the bidentate ligand-
b
-arylation of (ꢁ)-1f with 1-chloro-4-iodobenzene and 1,2-
directed Pd-catalyzed diastereoselective
b
-arylation of the prochi-
ral 2 sp CeH bonds of other simple aliphatic carboxamide sub-
strates having a substituent at the -position (Scheme 5). In this
dichloro-4-iodobenzene gave the corresponding products (ꢁ)-6c
(53%, dr 70:30) and (ꢁ)-6d (68%, dr 54:46) with poor diaster-
ꢀ
3
g
eoselectivities. Furthermore, the Pd-catalyzed
b-arylation of (ꢁ)-1g
regard, we assembled the substrates (ꢁ)-1f and (ꢁ)-1g by linking
with aryl iodides, such as 1-bromo-4-iodobenzene and 1-iodo-4-
methoxybenzene also furnished the respective products (ꢁ)-6e
(50% dr 77:23) and (ꢁ)-6f (57%, dr 65:35, Scheme 5).
the respective acid chlorides with the bidentate ligand 8-
aminoquinoline. At first, we attempted the Pd-catalyzed
b-

B. Gopalakrishnan et al. / Tetrahedron 71 (2015) 8333e8349
8337
a
The reaction was carried out using (±)-1a (0.25 mmol) and aryl halide (1
mmol, 4 equiv).
Scheme 4. The Pd-catalyzed
ineffective directing groups.
b-arylation of substrate (ꢁ)-1a with aryl bromides and
a
The reaction was carried out using (±)-1f or (±)-1g (0.25 mmol) and aryl
halide (1 mmol, 4 equiv).
The observed anti stereochemistry of (ꢁ)-3ael can be compre-
17a
Scheme 5. The bidentate ligand-aided Pd-catalyzed
b
-arylation of aliphatic carbox-
hended via the plausible reaction pathway (Scheme 6)
in con-
15a,16a
amides (ꢁ)-1f and (ꢁ)-1g.
currence with the literature mechanism pertaining to the bidentate
3
ligand-aided Pd-catalyzed sp CeH activation of aliphatic carbox-
amides.11a,b
the aliphatic carboxamide is activated. In the present study, when
Accordingly, in the present study, the CeH activation of
compared to the substrate (ꢁ)-1a, which has a substituent at the
a
-
-
one of the diastereotopic protons of 7a (produced from 1a) gener-
ates the proposed metallocycle TS 7b. Upon the reaction of 7b with
an aryl iodide generates the proposed TS 7c, from which the pro-
posed CeH arylated TS 7d is formed. Subsequently, the product 3
with anti stereochemistry and the catalyst is regenerated from 7d.
On the other hand, the formation of the products (ꢁ)-6aef with
position, the substrates (ꢁ)-1f,g are having a substituent at the
g
position. Further, the aliphatic carboxamide chains in the sub-
strates (ꢁ)-1f,g are highly flexible due to the free rotation. By
considering the above mentioned points, the observed poor dia-
stereoselectivities of the products (ꢁ)-6aef may be rationalized
based on the following two the reasons; (a) the substituent at the g-
poor diastereoselectivities is not surprising to us. According to the
literature mechanism1
1a,b
position in 1f,g has not helped and provided the rigidity to the
proposed TS (see the plausible TS 7e and 7f, Scheme 6), and (b) the
characteristically, only the b-CeH bond of
aliphatic chain after the
of the ring of the proposed metallocycle TS 7e,f.
g-carbon and the g-substituent are not part
16a
We examined the Pd-catalyzed 8-aminoquinoline-aided dia-
3
stereoselective sp CeH arylation of aliphatic carboxamides pos-
sessing the bulky substituents at both the
Scheme 7). In this regard, initially, we carried out the CeH aryla-
tion reaction of (ꢁ)-1h with 2a; this reaction failed to afford the
corresponding
-arylated product (ꢁ)-8a and presumably, the
presence of the bulky tertiary butyl group at the -position might
have hindered the -CeH arylation. Then, we prepared the sub-
a- and b-positions
(
b
a
b
strate (ꢁ)-1iA having an ester group (COOEt) at the
a
b
-position in-
-arylation of
stead of the tertiary butyl group. The Pd-catalyzed
substrate (ꢁ)-1iA with aryl iodides, such as 2-iodothiphene and 1-
iodo-4-methoxybenzene, gave the corresponding products (ꢁ)-8b
16b
and (ꢁ)-8c in 65 and 50% yields (Scheme 7). Unlike in substrate
(
ꢁ)-1h, the presence of an ester (COOEt) moiety at the
a
-position of
ꢀ
substrate (ꢁ)-1iA did not hinder the
b-arylation of the prochiral 2
3
sp CeH bond of substrate (ꢁ)-1iA. Disappointingly, the respective
products (ꢁ)-8b and (ꢁ)-8c were obtained as diastereomers with
dr 1:1 and perhaps, this could be because of the reasons; (a) there is
only a slight difference between the two structurally similar aryl
groups present at the
contain an acidic proton at the
figurationally stable under the experimental condition.
b
-carbon, and (b) the compounds 8b and 8c
a
-carbon, which may be not con-
Fig. 1. X-ray structures of the major diastereomers (ꢁ)-3b,c,e,l (anti isomers).

8338
B. Gopalakrishnan et al. / Tetrahedron 71 (2015) 8333e8349
Successively, we planned to examine the Pd-catalyzed 8-
aminoquinoline-aided double CeH arylation of a suitable sub-
3
strate containing two sp prochiral centers. We assembled sub-
strate 1iB by linking 2-ethylbutanoyl chloride with 8-
aminoquinoline. Then, to find out the best reaction conditions
and to obtain the double CeH arylated product from substrate 1iB,
we performed the optimization reactions as shown in Table 3,
which comprises of the Pd-catalyzed CeH arylation of 1iB with 2a.
The reaction of a mixture of 1iB, 2a and AgOAc in the presence of
5
2
mol % of Pd(OAc) catalyst furnished the double CeH arylated
product 8eA (meso) and (ꢁ)-8eB in 8% yield with low diaster-
eoselectivity (dr 65:35, entry 1, Table 3). Then, to improve the yield
we performed the double CeH arylation of 1iB by using different
reaction conditions. However, our attempts were not fruitful and
the diastereomers 8eA (meso) and (ꢁ)-8eB were obtained without
any further improvement in the overall yield (entries 2e4, Table 3).
Later, we performed the double CeH arylation of substrate 1iB with
2
a (6 mmol) by using Ag
2 3
CO as an additive and 15 mol % of
ꢀ
Pd(TFA) catalyst in DCE at 120 C for 36 h. This reaction success-
2
fully afforded the double CeH arylated products meso-8eA (40%,
major isomer) and (ꢁ)-8eB (22%, minor isomer) in good yields
(
total yield¼62%, dr 70:30, entry 5, Table 3). Subsequently, by fol-
lowing this reaction condition, we performed the double CeH
arylation reaction of 1iB with different aryl iodides, such as iodo-
benzene, 4-bromoiodobenzene and 4-chloroiodobenzene, which
commendably afforded the corresponding compounds 8fAehA
Scheme 6. Proposed reaction pathway17a in concurrence with the literature11a,b and
plausible TS for the observed stereoselectivity.
(
8
meso) and (ꢁ)-8fBehB in good yields (Table 4). The diastereomers
fAehA (meso) and (ꢁ)-8fBehB were isolated in pure forms and
characterized based on the NMR and HRMS analysis. The stereo-
chemistry of the compounds meso-8eAehA (major isomers) and
(
ꢁ)-8eBehB (minor isomers) was assigned based on the single
18
crystal X-ray structures (Fig. 2) of 8eA (meso, major isomer),
ꢁ)-8eB (minor isomer) and (ꢁ)-8fB (minor isomer) and the sim-
(
16c
ilarity in their NMR spectral pattern.
Characteristically, the formation of two diastereomers meso-
eAehA and (ꢁ)-8eBehB can be rationalized based on the pro-
8
posed reaction pathway shown in Scheme 8. The substrate 1iB has
ꢀ
two chemically equivalent 2 prochiral centers. The arylation of
these centers could have occurred stepwise and perhaps not si-
multaneously. Our efforts to isolate the mono arylated product
(
ꢁ)-8d (structure of one of the diastereomers) was not fruitful as
only traces of (ꢁ)-8d was present in the crude reaction mixture.
Further, in all the reactions, which were performed to optimize the
reaction conditions, we isolated only the double CeH arylated
products meso-8eA and (ꢁ)-8eB in pure forms (Table 3). We believe
that the direct double CeH arylation reaction seems to be a facile
reaction and even by reducing the concentration of the aryl iodide
2
a, we did not get the mono arylated product (ꢁ)-8d in our hand.
Actually, the mono CeH arylated product (ꢁ)-8d contains two
)eHa and C(
b
)eH bonds and as a result, the
b
diastereotopic C(
second CeH arylation of these diastereotopic C(b)eH and C(b)eH
b
a
b
bonds led to the formation of the corresponding diastereomers
meso-8eA (R*, S*) and (ꢁ)-8eB (S*, S*). These deliberation accounts
for the formation of two diastereomers meso-8eA (R*, S*) and
(
ꢁ)-8eB (S*, S*) from the second CeH arylation of the mono ary-
lated compound (ꢁ)-8d. Obviously, we cannot ignore the instance
that at first, the mono arylated product also could have formed as
0
the diastereomers (ꢁ)-8d and (ꢁ)-8d from the starting material
1
iB (Scheme 8). Hence, by considering this instance, it is proposed
0
that the respective diastereomers (ꢁ)-8d and (ꢁ)-8d in-
dependently underwent the subsequent second CeH arylation and
gave the corresponding pair of diastereomers (Scheme 8). Accord-
ingly, the diastereomers 8eA (R*, S*) and 8eB (S*, S*) were formed
from the second CeH arylation of an intermediate substrate (ꢁ)-8d
a
The reaction was carried out using (±)-1h or (±)-1iA (0.25 mmol) and aryl
halide (1 mmol, 4 equiv).
0
0
Scheme 7. Bidentate ligand-directed Pd-catalyzed
amides (ꢁ)-1h and (ꢁ)-1iA.
b-arylation of aliphatic carbox-
and the diastereomers 8eA (S*, R*) and 8eB (R*, R*) were formed
15a,16b
0
from the second arylation of an intermediate substrate (ꢁ)-8d .

B. Gopalakrishnan et al. / Tetrahedron 71 (2015) 8333e8349
8339
Table 3
-arylation of the prochiral 2 sp3 CeH bonds of aliphatic carboxamide 1iB
ꢀ
Bidentate ligand-aided Pd-catalyzed double b
Entry
2a (x mmol)
PdX
2
(y mol %)
AgOAc (equiv/mmol)
t (h)
Yield (%)
ꢁ)-8d
(
(ꢁ)-8e (dr)
1
2
3
4
5
1
1
1
1.5
6
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
(5)
2.2/0.55
2.2/0.55
3.2/0.8
3.2/0.8
36
24
36
36
36
Traces
Traces
Traces
Traces
Traces
8 (65:35)
(10)
(10)
(10)
(15)
19 (62:38)
b
16(ꢂ)
b
19(ꢂ)
a
Pd(TFA)
2
3/3
62 (70:30)
a
ꢀ
2 2 3 2 4
This reaction was performed using 1iB (1 mmol), Pd(TFA) (15 mol %), Ag CO (3 mmol, 3 equiv), K HPO (1.2 mmol, 1.2 equiv) in DCE (10 mL) at 120 C for 36 h. The total
yield of both the diastereomers is reported. The ratios of diastereomers were determined from the NMR spectra of the crude reaction mixtures.
b
The dr was not determined in this case.
0
Basically, 8eA (R, S) and 8eA (S, R) are meso compounds and 8eB (S,
major isomers (ꢁ)-3d and (ꢁ)-3c (diastereomers with anti ster-
17d
0
S) and 8eB (R, R) are a pair of enantiomers. Since the diastereomers
eochemistry).
The hydrolysis of (ꢁ)-3d under the well-known
0
(
ꢁ)-8d and (ꢁ)-8d are not enantiomerically enriched compounds,
amide hydrolysis reaction conditions involving the standard re-
agents, such as HCl or NaOH failed in our hand and we did not get
eventually, the Pd-catalyzed second CeH arylation of the two di-
0
17b
astereomers (ꢁ)-8d and (ꢁ)-8d afforded the corresponding meso
the corresponding carboxylic acid (ꢁ)-11 (Scheme 9).
With
0
0
compound 8eA/8eA and racemic compound 8eB/8eB (Scheme 8).
further trials, we found that the hydrolysis of the major isomer
(ꢁ)-3d underwent in the presence of triflic acid (TfOH) and gave
the carboxylic acid (ꢁ)-11. Similarly, the amide hydrolysis of the
major isomer (ꢁ)-3c in the presence of triflic acid (TfOH) also gave
the corresponding carboxylic acid (ꢁ)-12.
We wished to expand the usefulness of this protocol by syn-
thesizing enantiomerically enriched
nolin-8-yl)butanamides through the Pd-catalyzed CeH arylation
reaction. At first, we assembled the enantiomerically enriched
substrate 1j (Table 5) by linking the enantiomerically enriched 2-
phenylbutanoyl chloride with 8-aminoquinoline. Then, we per-
b-arylated 2-phenyl-N-(qui-
3. Summary
2
formed the Pd(OAc) -catalyzed b-arylation of the enantiomerically
enriched substrate 1j (with ee 78%) with different aryl iodides,
which gave the corresponding products 10aec (anti, major di-
astereomers) in 68e93% yields with good diastereoselectivities and
In summary, we have shown our explorations on the Pd-
catalyzed 8-aminoquinoline-aided diastereoselective
b
-arylation
of the prochiral 2 sp CeH bonds of various racemic aliphatic
carboxamides. The Pd-catalyzed -arylation of racemic 2-
phenylbutanamide with a variety of aryl iodides gave several
arylated products possessing two vicinal stereocenters in moderate
to very high yields with dr up to 86:14. It is a limitation that the
ꢀ
3
19
ee up to 78% for the anti diastereomers (Table 5). In all these re-
actions, we tried to obtain the major and minor isomers in pure
forms from the column chromatography purification. However, in
majority of the cases, only the major diastereomers (anti isomers)
were isolated in pure forms and the minor isomers could not be
isolated in pure forms. The anti stereochemistry of the major
compounds 10aec (2S,3R, anti isomer) were assigned on the basis
b
b
-
b
-
ꢀ
3
arylation of the prochiral 2 sp CeH bonds of aliphatic carbox-
amides having a substituent at the -position gave the -arylated
products with poor diastereoselectivities. The -arylation of the
prochiral 2 sp CeH bonds of an aliphatic carboxamide having
a bulky tertiary butyl substituent at the -position did not give any
products. On the other hand, the -arylation of the prochiral 2 sp
CeH bond of an aliphatic carboxamide having an ester group
COOEt) substituent at the -position gave the product with poor
g
b
b
18
of the X-ray structures of the major isomers 3b,c,e,l (racemic
compounds) and the major isomer 10c (enantiomerically enriched
compound) coupled with the similarity in their NMR pattern.
Furthermore, we performed the amide hydrolysis reactions to
remove the 8-aminoquinoline ligand by using the representative
3
ꢀ
a
ꢀ
3
b
(
a

8340
B. Gopalakrishnan et al. / Tetrahedron 71 (2015) 8333e8349
Table 4
Investigation on the Pd-catalyzed 8-aminoquinoline-aided diastereoselective double
b
-arylation of the sp3 CeH bonds of aliphatic carboxamide (ꢁ)-1iBa
a
Isolated yields of individual diastereomers were given and the ratios of diastereomers were determined from the NMR spectra of the crude
reaction mixtures.
diastereoselectivities. Notably, the Pd-catalyzed 8-aminoquinoline
phenylbutanamides. Overall, the present work reveals a contem-
porary method for the stereoselective synthesis of several -ary-
ligand-aided double CeH arylation of 2-ethyl-N-(quinolin-8-yl)
b
ꢀ
3
butanamide possessing two chemically equivalent 2 sp prochiral
lated aliphatic carboxamides via the CeH arylation method. The
stereochemistry of the representative diastereomers was un-
ambiguously established and we have also demonstrated the out-
come of the stereocontrol and limitations in the Pd-catalyzed CeH
activation process involving aliphatic carboxamides.
centers resulted the corresponding double CeH arylated products
as diastereomers. Furthermore, the Pd-catalyzed
of (S)-2-phenylbutanamide with different aryl iodides gave
the corresponding enantiomerically enriched -arylated 2-
b-arylation
b
Fig. 2. X-ray structures of meso-8eA (major isomer), (ꢁ)-8eB (minor isomer), (ꢁ)-8fB (minor isomer) and 10c (enantiomerically enriched, major isomer).

B. Gopalakrishnan et al. / Tetrahedron 71 (2015) 8333e8349
8341
17c
Scheme 8. Formation of diastereomers meso-8eA (major isomer (R*, S*)) and (ꢁ)-8eB (minor isomer (S*, S*)).
4
4
. Experimental section
.1. General
Melting points are uncorrected. IR spectra of all the compounds
1
13
were recorded as KBr pellets or thin films. H and C NMR spectra
of all the compounds were recorded on 400 MHz and 100 MHz
spectrometers, respectively, using TMS as an internal standard.
Column chromatography was carried out using silica gel
(
100e200 mesh). HRMS measurements reported in this work were
obtained from TOF mass analyzer using electrospray ionization
ESI). All the reactions were performed using anhydrous solvents
under nitrogen. Organic layers after the work up procedure were
dried using anhydrous Na SO . Thin layer chromatography analysis
TLC) was performed on silica gel plates and components were
(
2
4
(
visualized by observation under iodine vapour. In the cases of the
Tables 1e3, 5 and Schemes 4, 5 and 7 the total isolated yields di-
astereomers were reported. In the case of Table 4, the isolated
yields of individual diastereomers were reported. Yields of all the
reactions were not optimized. The diastereomeric ratios were ob-
1
tained from the integration of the H NMR signal corresponding to
1
same proton of the major and minor isomers in H NMR spectra of
the respective crude reaction mixtures. After the Pd-catalyzed CeH
arylation reaction, the purification of the crude reaction mixture
gave the corresponding diastereomers as a mixture since the cor-
f
responding diastereomers had the same R values (at this stage, the
total isolated yield of the corresponding diastereomers was calcu-
lated). Then, the corresponding diastereomers were again sub-
jected to the column chromatographic purification to obtain the
major and minor isomers in pure forms. In majority of the cases, the
column chromatographic purification of the crude reaction
a
The reaction was carried out using 0.25 mmol of (±)-3d or (±)-3c.
Scheme 9. Removal of the 8-aminoquinoline ligand and synthesis of carboxylic acids
1 and 12.
1

8342
B. Gopalakrishnan et al. / Tetrahedron 71 (2015) 8333e8349
Table 5
4.2.1. (ꢁ)-2-Phenyl-N-(quinolin-8-yl)butanamide (1a). Following
the general procedure, 1a (203 mg, 70%) was obtained after purifi-
Synthesis of enantiomerically enriched b-arylated 10aec from the Pd-catalyzed b-
arylation of 1ja
cation bycolumn chromatography on silica gel as a colourless solid; R
f
ꢀ
(
10% EtOAc/Hexanes) 0.48; mp 99e101 C; IR (KBr)
n
max 3343, 2964,
9.98 (1H, br s),
¼4.2, J ¼1.6 Hz), 7.85
¼1.6 Hz), 7.55 (2H, d, J¼7.2 Hz), 7.43e7.37 (3H, m),
.30e7.26 (2H, m), 7.18 (1H, dd, J ¼4.2 Hz), 3.66 (1H, t,
¼8.3, J
J¼7.6 Hz), 2.46e2.35 (1H, m), 2.07e1.96 (1H, m),1.02 (3H, t, J¼7.4 Hz);
ꢂ1
1
2
8
630, 1678, 1532 cm ; H NMR (400 MHz, CDCl
.87 (1H, dd, J ¼1.1 Hz), 8.62 (dd, 1H, J
¼7.7 Hz, J
¼8.3, J
3 H
) d
1
2
1
2
(1H, dd, J
1
2
7
1
2
13
3 C
C NMR (100 MHz, CDCl ) d 172.1, 148.1, 140.0, 138.2, 136.1, 134.5,
1
28.9, 128.1, 127.7, 127.4, 127.2, 121.5, 121.5, 116.3, 56.7, 26.8, 12.5;
þ
HRMS: m/z [MþH] , found 291.1494, C19
19 2
H N O requires 291.1497.
4
.2.2. (ꢁ)-2-Phenyl-N-(pyridin-2-ylmethyl)butanamide
1b). Following the general procedure, 1b (107 mg, 42%) was ob-
tained after purification by column chromatography on neutral
alumina as a brown color liquid; R (20% EtOAc/Hexanes) 0.1; IR
(
f
ꢂ1
1
(
(
thin film)
400 MHz, CDCl
¼7.7, J ¼1.8 Hz), 7.36e7.23 (5H, m), 7.16e7.13 (2H, m), 6.95 (1H, br
s), 4.55 (1H, dd, J ¼5.3 Hz), 4.45 (1H, dd, J ¼16.3, J ¼5.1 Hz),
¼16.2, J
.36 (1H, t, J¼7.6 Hz), 2.26e2.15 (1H, m), 1.89e1.78 (1H, m), 0.89
n
max 3278, 2960, 2929, 1658, 1528, 1170 cm ; H NMR
3
): 8.46 (1H, dd, J ¼1.7 Hz), 7.60 (1H, td,
d
H
1
¼5.8, J
2
J
1
2
1
2
1
2
3
(
1
1
3
3H, t, J¼7.4 Hz); C NMR (100 MHz, CDCl
3 C
) d 173.7, 156.7, 148.9,
40.0, 136.8, 128.7, 128.0, 127.1, 122.3, 122.0, 55.1, 44.5, 26.5, 12.4;
þ
HRMS: m/z [MþH] , found 255.1509, C16
H
19
N
2
O requires 255.1497.
4
.2.3. (ꢁ)-2-Phenyl-N-(pyridin-2-yl)butanamide
(1c). Following
the general procedure, 1c (150 mg, 63%) was obtained after puri-
fication by column chromatography on Alumina gel as colourless
a
The reaction was carried out using 1j (0.25 mmol) and aryl halide (1 mmol,
equiv). The total yield of both the diastereomers is reported. The ratios of
liquid; R
2874, 1693, 1523, 1433, 1296 cm
.61 (1H, br s), 8.27 (1H, d, J¼8.4 Hz), 8.23 (1H, dd, J
.72e7.68 (1H, m), 7.35e7.25 (5H m), 7.04e7.00 (1H, m), 3.41 (1H, t,
J¼7.5 Hz), 2.31e2.20 (1H, m), 1.92e1.81 (1H, m), 0.92 (3H, t,
f
(20% EtOAc/Hexanes) 0.1; IR (thin film)
n
max 3299, 2965,
H NMR (400 MHz, CDCl
¼4.9, J ¼1.0 Hz)
ꢂ1
1
4
;
3 H
) d
diastereomers were determined from the NMR spectra of crude reaction
mixtures and ee was determined from the HPLC analysis.
8
7
1
2
1
5b
13
mixtures gave only the corresponding major diastereomers in pure
forms and the corresponding minor isomers could not be separated
from the corresponding major isomers. Additionally, in none of the
case (except Table 4 compounds), the complete isolation of the
corresponding major isomer also was possible and only a few
fractions of the corresponding major isomers were obtained, which
were used to characterize the respective major isomer. In some
cases, the products were isolated as a mixture of inseparable di-
astereomers. The HPLC analyses were performed using AD-H
J¼7.4 Hz); C NMR (100 MHz, CDCl )
3 C
d 172.3, 151.6, 147.6, 139.2,
138.5, 128.9, 127.9, 127.5, 119.8, 114.3, 56.1, 26.4, 12.3; HRMS: m/z
þ
[MþH] , found 241.1350, C15H17N O requires 241.1341.
2
4.2.4. (ꢁ)-N-(2-(Dimethylamino)ethyl)-2-phenylbutanamide
(1d). Following the general procedure,1d (59 mg, 25%) was obtained
after purification by column chromatography on neutral alumina as
a brown colour liquid; R (10% EtOAc/Hexanes) 0.1; IR (thin film)
3292, 3063, 1809, 1658, 1649, 1552 cm ; H NMR (400 MHz, CDCl )
f
n
max
ꢂ1
1
3
(
0.46 cm IDR, 25 cm length) as a chiral column (eluents, flow
H
d 7.32e7.22 (5H, m), 6.44 (1H, br s), 3.39e3.31 (1H, m), 3.27e3.20
rate, detection method are listed on the HPLC charts, see the
Supplementary data).
(2H, m), 2.43e2.32 (2H, m), 2.18 (6H, s), 2.14e2.11 (1H, m),1.84e1.73
13
(1H, m), 0.88 (3H, t, J¼7.4 Hz); C NMR (100 MHz, CDCl3)
C
d 173.8,
1
40.3, 128.6, 127.9, 127.0, 57.8, 55.1, 44.9, 36.7, 26.5, 12.3; HRMS: m/z
þ
23 2
[MþH] , found 235.1803, C14H N O requires 235.1810.
4
.2. General procedure for the synthesis of the carboxamides
(
± ±-1aeh, 1iB and 1j-(S±
4.2.5. (ꢁ)-N-(2-(Methylthio)phenyl)-2-phenylbutanamide
1e). Following the general procedure, 1e (214 mg, 75%) was ob-
(
The corresponding carboxylic acid (1.5 mmol) was dissolved in
tained after purification by column chromatography on Alumina as
ꢀ
SOCl
2
(4 mmol) and stirred for 24 h at rt under nitrogen. After this
a colourless solid; R
(KBr) max 3278, 2960, 2929, 1658, 1528, 1170 cm
(400 MHz, CDCl
8.41 (1H, br s), 8.38 (1H, d, J¼8.3 Hz), 7.46e7.38
(5H, m), 7.34e7.28 (2H, m), 7.02 (1H, td, J ¼1.2 Hz), 3.53 (1H,
¼7.6, J
dd, J ¼7.0 Hz), 2.41e2.32 (1H, m), 2.03 (3H, s), 2.02e1.92
¼8.3, J
f
(10% EtOAc/Hexanes) 0.60; mp 60e62 C; IR
ꢂ1
1
period, the reaction mixture was concentrated in vacuum and di-
luted with anhydrous DCM (3 mL) under nitrogen. Then, the DCM
solution of acid chloride was added to another RB flask containing
n
; H NMR
3 H
) d
1
2
the corresponding auxiliary (amine, 1 mmol) and Et
3
N (1.1 mmol)
1
2
ꢀ
13
in anhydrous DCM (2 mL) at 0 C. Then, reaction mixture was
stirred at rt for 10 min and then, the reaction mixture was refluxed
for 12 h. After this period, the reaction mixture was diluted with
DCM (5 mL) and washed with water followed by saturated aqueous
(1H, m), 0.99 (3H, t, J¼7.4 Hz); C NMR (100 MHz, CDCl
3 C
) d 171.9,
139.4, 138.8, 133.7, 129.3, 129.1, 128.2, 127.6, 124.9, 124.1, 120.2, 56.5,
þ
25.7, 18.8, 12.4; HRMS: m/z [MþH] , found 286.1259, C17
H20NOS
requires 286.1266.
NaHCO
anhydrous Na
3
solution. The combined organic layers were dried over
SO , concentrated in vacuum and purification of the
2
4
4.2.6. (ꢁ)-4-Methyl-N-(quinolin-8-yl)nonanamide (1f). Following
the general procedure, 1f (235 mg, 79%) was obtained after puri-
fication by column chromatography on silica gel as a colourless
resulting reaction mixture by column chromatography (EtOAc/
Hexanes¼15:85) furnished the corresponding carboxamides
(ꢁ)-1aeh, 1iB and 1j-(S).
f
liquid; R (15% EtOAc/Hexanes) 0.55; IR (thin film) nmax 3356, 2925,

B. Gopalakrishnan et al. / Tetrahedron 71 (2015) 8333e8349
8343
2
8
859,1688, 1526 cmꢂ1; 1H NMR (400 MHz, CDCl
.84e8.80 (2H, m), 8.18 (1H, dd, J ¼1.6 Hz), 7.58e7.49 (2H,
¼8.2, J
¼8.2, J ¼4.2 Hz), 2.66e2.52 (2H, m), 1.93e1.85
3
)
d
H
9.84 (1H, br s),
3
Et N (1.1 mmol) dissolved in anhydrous DCM (5 mL) under nitrogen
1
2
atmosphere. The reaction mixture was stirred for 10 min and then,
refluxed for 20 h. After the reaction period, the reaction mixture
was extracted with DCM and washed with water followed by sat-
m), 7.47 (1H, dd, J
1
2
(
0
1
1H, m), 1.70e1.54 (2H, m), 1.41e1.17 (8H, m), 0.97 (3H, d, J¼6.6 Hz),
13
.90 (3H, t, J¼7.1 Hz); C NMR (100 MHz, CDCl
3
)
d
C
172.2, 148.1,
urated NaHCO
over anhydrous Na
3
solution. The collected organic layers were dried
SO , concentrated under vacuum and purifi-
38.3, 136.4, 134.6, 127.9, 127.5, 121.6, 121.3, 116.4, 36.8, 36.0, 32.6,
2
4
þ
3
2
2.6, 32.2, 26.7, 22.7, 19.5, 14.1; HRMS: m/z [MþH] , found
cation of the crude reaction mixture by column chromatography
(EtOAc/Hexanes¼20:80) furnished the product 1i.
99.2131, C19
H N
27 2
O requires 299.2123.
4
.2.7. (ꢁ)-4-Ethyl-N-(quinolin-8-yl)octanamide (1g). Following the
4.3.2. Ethyl 3-oxo-3-(quinolin-8-ylamino)propanoate (1i). Follow
ing the general procedure, 1i (183 mg, 71%) was obtained after
purification by column chromatography on silica gel as a pale yel-
general procedure,1g (247 mg, 83%) was obtained after purification
by column chromatography on silica gel as a colourless liquid; R
f
ꢀ
(
15% EtOAc/Hexanes) 0.53; IR (thin film)
n
max 3356, 2956, 2863,
9.83 (1H, br s),
low solid; R
n
f
(20% EtOAc/Hexanes) 0.50; mp 98e100 C; IR (KBr)
ꢂ1
1
ꢂ1 1
1688, 1527 cm
;
H NMR (400 MHz, CDCl
3
)
d
H
max 3312, 2984, 2938, 1739, 1486, 1534 cm ; H NMR (400 MHz,
CDCl 10.75 (1H, br s), 8.69 (1H, dd, J ¼1.7 Hz), 8.66 (1H,
¼4.2, J
dd, J ¼2.4 Hz), 7.95 (1H, dd, J ¼8.3, J ¼1.7 Hz), 7.37e7.31
¼6.6, J
(2H, m), 7.26 (1H, dd, J ¼4.2 Hz), 4.18 (2H, q, J¼7.2 Hz), 3.59
¼8.2, J
8
.82e8.80 (2H, m), 8.16 (1H, dd, J
1
¼8.3, J
2
¼1.5 Hz), 7.56e7.44 (3H,
3
)
d
H
1
2
m), 2.58e2.54 (2H, m), 1.84e1.78 (2H, m), 1.41e1.31 (9H, m), 0.92
1
2
1
2
13
(
1
6H, t, J¼7.2 Hz); C NMR (100 MHz, CDCl
3
)
d
C
172.2, 148.1, 138.3,
1
2
1
3
36.4, 134.6, 127.9, 127.5, 121.6, 121.3, 116.4, 38.5, 35.6, 32.6, 28.9,
(2H, s), 1.21 (3H, t, J¼7.2 Hz); C NMR (100 MHz, CDCl
3 C
) d 168.4,
þ
2
C
8.9, 25.7, 23.1, 14.2, 10.8; HRMS: m/z [MþH] , found 299.2128,
163.5, 148.4, 138.4, 136.1, 134.2, 127.8, 127.0, 122.0, 121.5, 116.7, 61.7,
þ
H N
19 27 2
O requires 299.2123.
43.6, 14.0; HRMS: m/z [MþH] , found 259.1095, C14
15 2 3
H N O re-
quires 259.1083.
4
.2.8. (ꢁ)-2-Benzyl-3,3-dimethyl-N-(quinolin-8-yl)butanamide
(1h). Following the general procedure, 1h (315 mg, 95%) was ob-
4.3.3. Procedure for the preparation of ethyl 2-benzyl-3-oxo-3-(qui-
nolin-8-ylamino)propanoate (ꢁ)-1iA from 1i. Benzyl bromide
(1.2 mmol) was added to a solution of ethyl 3-oxo-3-(quinolin-8-
ylamino)propanoate (1i, 1 mmol) dissolved in dry THF (5 mL).
tained after purification by column chromatography on silica gel as
ꢀ
a colourless solid; R
f
(15% EtOAc/Hexanes) 0.47; mp 104e106 C; IR
ꢂ1
1
(
KBr)
CDCl
dd, J
J¼8.3 Hz), 7.44 (1H, dd, J
¼4.2 Hz), 7.30 (2H, d, J¼7.1 Hz), 7.21 (2H, t, J¼7.4 Hz), 7.09 (1H, t,
J¼7.3 Hz), 3.25 (1H, dd, J ¼13.3, J ¼11.6 Hz), 2.96 (1H, dd, J ¼13.3,
¼2.4 Hz), 2.53 (1H, dd, J ¼11.5, J
100 MHz, CDCl 172.8, 148.0, 140.9, 138.3, 136.2, 134.3, 128.8,
28.4, 127.8, 127.3, 126.0, 121.4, 121.3, 116.4, 62.1, 34.4, 33.8, 28.2;
n
max 3364, 2961, 2896, 1677, 1524 cm ; H NMR (400 MHz,
9.56 (1H, br s), 8.81 (1H, dd, J ¼1.3 Hz), 8.71 (1H,
¼7.6, J
¼1.6 Hz), 8.07 (1H, dd, J ¼8.3, J ¼1.7 Hz), 7.51 (1H, t,
¼8.2, J ¼1.3 Hz), 7.36 (1H, dd, J ¼8.2,
3
)
d
H
1
2
2 3
Next, to this reaction mixture K CO (3 mmol) was added under
1
¼4.2, J
2
1
2
nitrogen at rt and then, the reaction mixture was refluxed for 20 h.
After the reaction period, the reaction mixture was filtered to de-
cant the inorganic salts, and then, the organic layers were con-
centrated under vacuum, purification of the crude reaction mixture
by column chromatography (EtOAc/Hexanes¼30:70) furnished the
product (ꢁ)-1iA.
1
2
1
J
2
1
2
1
13
J
2
1
2
¼2.6 Hz), 1.22 (9H, s); C NMR
(
3 C
) d
1
þ
HRMS: m/z [MþH] , found 333.1966, C22
25
H N
2
O requires 333.1970.
4.3.4. (ꢁ)-Ethyl 2-benzyl-3-oxo-3-(quinolin-8-ylamino)propanoate
(1iA). Following the general procedure, 1iA (174 mg, 50%) was
4
.2.9. (S)-2-Phenyl-N-(quinolin-8-yl)butanamide
(1j). Following
obtained after purification by column chromatography on silica gel
ꢀ
the general procedure, 1j (ee 78%) (168 mg, 58%) was obtained after
purification by column chromatography on silica gel as a pale yel-
low solid; R
3
9
as a pale yellow solid; R
IR (KBr) max 3323, 2963, 2913, 1731, 1672, 1527 cm
(400 MHz, CDCl 10.59 (1H, br s), 8.86 (1H, dd, J
¼4.2, J
8.79 (1H, dd, J ¼3.1 Hz), 8.18 (1H, dd, J ¼8.3, J
¼5.9, J
7.58e7.53 (2H, m), 7.48 (1H, dd, J ¼4.2 Hz), 7.33e7.21 (5H,
¼8.2, J
m), 4.23 (2H, q, J¼7.2 Hz), 3.88 (1H, dd, J ¼8.8, J ¼6.6 Hz),
3.50e3.38 (2H, m), 1.24 (3H, t, J¼7.1 Hz); C NMR (100 MHz, CDCl
170.3, 166.0, 148.4, 138.6, 138.1, 136.3, 134.3, 129.0, 128.6, 127.9,
f
(20% EtOAc/Hexanes) 0.45; mp 73e75 C;
ꢂ1
1
n
;
H NMR
¼1.7 Hz),
¼1.7 Hz),
ꢀ
f
(20% EtOAc/Hexanes) 0.51; mp 82e84 C; IR (KBr)
n
max
3
)
d
H
1
2
ꢂ1
1
349, 2964, 2871, 1693, 1523 cm ; H NMR (400 MHz, CDCl
.95 (1H, br s), 8.81 (1H, dd, J ¼1.4 Hz), 8.76 (1H, dd, J ¼4.2,
¼7.4, J
¼1.6 Hz), 8.12 (1H, dd, J ¼8.2, J ¼1.6 Hz), 7.54e7.46 (4H, m),
3
)
d
H
1
2
1
2
1
2
1
1
2
J
2
1
2
1
2
13
7
2
.44e7.38 (3H, m), 7.30 (1H, t, J¼7.3 Hz), 3.66 (1H, t, J¼7.6 Hz),
3
)
13
.43e2.32 (1H, m), 2.06e1.95 (1H, m), 1.03 (3H, t, J¼7.4 Hz);
C
d
C
NMR (100 MHz, CDCl
3
)
d
C
172.2, 148.1, 139.9, 138.4, 136.2, 134.5,
127.3, 126.8, 122.0, 121.7, 116.8, 61.8, 56.7, 35.9, 14.0; HRMS: m/z
þ
128.9, 128.1, 127.8, 127.3, 127.3, 121.5, 121.5, 116.3, 56.8, 26.7, 12.5;
[MþH] , found 349.1556, C21
21 2 3
H N O requires 349.1552.
þ
HRMS: m/z [MþH] , found 291.1497, C19
19 2
H N O requires 291.1497.
4.2.10. 2-Ethyl-N-(quinolin-8-yl)butanamide (1iB). Following the
4.4. General procedure for the b-arylation of aliphatic car-
general procedure, 1iB (208 mg, 86%) was obtained after purifica-
boxamides and the preparation of the racemic compounds
3ael, 4aec, 5a, 6aef, 8aec, 8eAehA, 8eBehB and enantio-
merically enriched 10aec
tion by column chromatography on silica gel as a colourless solid; R
f
ꢀ
(
2
8
15% EtOAc/Hexanes) 0.58; mp 58e60 C; IR (KBr)
n
max 3356, 2962,
9.88 (1H, br s),
¼4.2, J ¼1.6 Hz), 8.11
¼1.5 Hz), 7.54e7.45 (2H, m), 7.41 (1H, dd, J ¼8.2,
¼4.2 Hz), 2.35e2.29 (1H, m),1.88e1.79 (2H, m),1.70e1.60 (2H, m),
ꢂ1
1
631, 1687, 1524 cm ; H NMR (400 MHz, CDCl
.87 (1H, dd, J ¼1.3 Hz), 8.80 (1H, dd, J
¼7.5, J
¼8.3, J
3 H
) d
1
2
1
2
A mixture of the corresponding carboxamide ((ꢁ)-1aeh or
(
1H, dd, J
1
2
1
(ꢁ)-1iA or 1iB or 1j-(S)) (0.25 mmol), Pd(OAc)
2
(2.8 mg, 5 mol %),
J
2
aryl iodide (1.0 mmol, 4 equiv) and AgOAc (92 mg, 0.55 mmol,
1
3
ꢀ
1
1
.01 (6H, t, J¼7.5 Hz); C NMR (100 MHz, CDCl
3
)
d
C
174.8, 148.2,
2.2 equiv) in anhydrous toluene (3 mL) was heated at 110 C for
38.4, 136.3, 134.5, 127.9, 127.4, 121.6, 121.4, 116.4, 52.6, 25.9, 12.1;
24e70 h (see the respective Tables/Schemes for the reaction time
for the specific examples) under nitrogen atmosphere. After the
reaction period, the reaction mixture was concentrated in vacuum
and purification of the resulting reaction mixture by silica gel col-
þ
19 2
HRMS: m/z [MþH] , found 243.1466, C15H N O requires 243.1497.
4
.3. Procedures for the preparation of 1iA
umn chromatography furnished the corresponding b-CeH arylated
4
.3.1. Procedure for the preparation of ethyl 3-oxo-3-(quinolin-8-
racemic compounds 3ael, 4aec, 5a, 6aef, 8aec, 8eAehA, 8eBehB
and enantiomerically enriched 10aec (see Tables/Schemes for the
reaction conditions for the specific examples).
ylamino)propanoate 1i. Ethylmalonyl chloride (1 mmol)) was
added dropwise to the mixture of 8-aminoquinoline (1 mmol) and

8344
B. Gopalakrishnan et al. / Tetrahedron 71 (2015) 8333e8349
4
.4.1. (2R*,3S*)-3-(4-Methoxyphenyl)-2-phenyl-N-(quinolin-8-yl)bu-
dd, J
1
¼4.3, J
2
¼1.7 Hz), 8.58 (1H, t, J¼4.6 Hz), 8.10 (1H, dd, J ¼8.2,
1
tanamide (3a). Following the general procedure, 3a (89 mg, 90%)
was obtained after purification by column chromatography on sil-
ica gel as a colourless solid; R
J
2
¼1.7 Hz), 7.62 (2H, d, J¼7.1 Hz), 7.43e7.29 (10H, m), 3.81 (1H, d,
13
J¼10.9 Hz), 3.77e3.68 (1H, m), 1.11 (3H, d, J¼6.9 Hz); C NMR
f
(10% EtOAc/Hexanes) 0.44; mp
(100 MHz, CDCl 170.6, 148.1, 144.3, 138.3, 138.2, 136.3, 134.2,
3 C
) d
ꢀ
ꢂ1 1
9
6e98 C; IR (KBr)
n
max 3328, 2959, 2927,1683, 1525 cm ; H NMR
9.69 (1H, br s), 8.75 (1H, dd, J ¼1.7 Hz),
¼4.2, J
¼6.8, J ¼2.2 Hz), 8.05 (1H, dd, J ¼8.2, J ¼1.6 Hz), 7.65
131.6, 129.2, 128.8, 128.5, 127.8, 127.6, 127.2, 121.5, 121.4, 120.1, 116.3,
þ
(
400 MHz, CDCl
3
)
d
H
1
2
62.5, 42.4, 20.1; HRMS: m/z [MþH] , found 445.0917, C25
2
H22BrN O
8
.61 (1H, dd, J
1
2
1
2
requires 445.0915. The NMR spectra of this compound contain
traces of the corresponding minor isomer.
(
2H, d, J¼7.1 Hz), 7.43e7.36 (7H, m), 7.33e7.29 (1H, m), 6.80 (2H, d,
J¼8.7 Hz), 3.82 (1H, d, J¼10.9 Hz), 3.77e3.71 (1H, m), 3.68 (3H, s),
13
1
1
.13 (3H, d, J¼6.9 Hz); C NMR (100 MHz, CDCl
3
)
d
C
171.0, 158.0,
4.4.6. (2R*,3S*)-3-(4-Nitrophenyl)-2-phenyl-N-(quinolin-8-yl)buta-
namide (3f). Following the general procedure, 3f (82 mg, 80%) was
obtained as a mixture of diastereomers after purification by column
chromatography on silica gel as a pale yellow solid; R
Hexanes) 0.20; mp 142e144 C; IR (KBr)
1679, 1526, 1482 cm ; H NMR (400 MHz, CDCl
8.73 (1H, dd, J ¼4.3, J ¼1.6 Hz), 8.54 (1H, dd, J ¼5.5, J
(2H, d, J¼8.8 Hz), 8.08 (1H, dd, J ¼8.3, J
m), 3.90e3.82 (2H, m), 1.16 (3H, d, J¼6.6 Hz); C NMR (100 MHz,
CDCl 170.6, 170.1, 153.2, 152.0, 148.3, 148.1, 146.6, 146.3, 138.3,
138.1, 137.8, 137.6, 136.4, 136.3, 134.3, 134.0, 129.0, 128.7, 128.6,
128.4, 128.4, 128.2, 127.9, 127.9, 127.8, 127.4, 127.3, 127.2, 123.8,
123.4, 121.9, 121.7, 121.7, 121.6, 116.6, 116.4, 62.1, 61.9, 43.7, 43.0,
48.0, 138.8, 138.2, 137.3, 136.2, 134.4, 128.7, 128.6, 128.3, 127.7,
127.4, 127.2, 121.4, 121.2, 116.3, 113.8, 63.1, 55.1, 42.1, 20.3; HRMS: m/
þ
z [MþH] , found 397.1913, C26
25
H N
2
O
2
requires 397.1916.
f
(20% EtOAc/
ꢀ
n
max 3333, 2968, 2929,
9.70 (1H, br s),
¼3.6 Hz), 8.12
¼1.7 Hz), 7.65e7.11 (10H,
ꢂ1
1
4
.4.2. (2R*,3S*)-2,3-Diphenyl-N-(quinolin-8-yl)butanamide
3 H
) d
(3b). Following the general procedure, 3b (83 mg, 91%) was ob-
1
2
1
2
tained after purification by column chromatography on silica gel as
1
2
ꢀ
13
a pale yellow solid; R
IR (KBr) max 3339, 2968, 2924, 1680, 1522 cm
400 MHz, CDCl 9.70 (1H, br s), 8.75 (1H, dd, J
¼4.2, J
¼8.3, J ¼1.7 Hz), 7.66
f
(10% EtOAc/Hexanes) 0.46; mp 149e151 C;
ꢂ1
1
n
;
H NMR
¼1.6 Hz),
3 C
) d
(
8
3
)
d
H
1
2
.59 (1H, dd, J
1
¼6.6, J
2
¼2.4 Hz), 8.05 (1H, dd, J
1
2
(
(
2H, d, J¼7.1 Hz), 7.47 (2H, d, J¼7.1 Hz), 7.43e7.25 (8H, m), 7.13e7.08
1H, m), 3.89 (1H, d, J¼10.9 Hz), 3.83e3.73 (1H, m), 1.15 (3H, d,
þ
20.9, 19.8; HRMS: m/z [MþH] , found 412.1641, C25
22 3 3
H N O re-
13
J¼7.0 Hz); C NMR (100 MHz, CDCl
3
)
d
C
170.9, 148.0, 145.2, 138.7,
quires 412.1661. The compound 3f was isolated as a mixture of
1
1
38.2, 136.2, 134.3, 128.8, 128.6, 128.5, 127.7, 127.5, 127.4, 127.2,
diastereomers and the H NMR data given here for the major iso-
mer and the C NMR values are given for both the diastereomers.
þ
13
1
3
26.4,121.4, 121.3, 116.3, 62.7, 43.0, 20.3; HRMS: m/z [MþH] , found
67.1821, C25 O requires 367.1810. The NMR spectra of this
compound contain traces of the corresponding minor isomer.
23 2
H N
4.4.7. (2R*,3S*)-3-(4-Acetylphenyl)-2-phenyl-N-(quinolin-8-yl)buta-
namide (3g). Following the general procedure, 3g (91 mg, 89%) was
obtained after purification by column chromatography on silica gel
4
.4.3. (2R*,3S*)-3-(4-Ethylphenyl)-2-phenyl-N-(quinolin-8-yl)buta-
namide (3c). Following the general procedure, 3c (88 mg, 90%) was
obtained after purification by column chromatography on silica gel
(EtOAc:Hexanes¼20:80) as a colourless solid; R
f
(20% EtOAc/Hex-
ꢀ
anes) 0.18; mp 145e147 C; IR (KBr)
n
max 3339, 2963, 2924, 1677,
9.70 (1H, br s), 8.73
¼3.6 Hz), 8.05 (1H,
¼1.7 Hz), 7.86 (2H, d, J¼8.4 Hz), 7.65 (2H, d, J¼7.1 Hz),
7.55 (2H, d, J¼8.4 Hz), 7.44e7.29 (6H, m), 3.91 (1H, d, J¼10.9 Hz),
ꢂ1
1
as
a
pale yellow solid;
R
f
(10% EtOAc/Hexanes) 0.45; mp
1603, 1525 cm ; H NMR (400 MHz, CDCl
(1H, dd, J ¼1.7 Hz), 8.56 (dd, 1H, J ¼5.4, J
¼4.3, J
dd, J
¼8.2, J
3 H
) d
ꢀ
ꢂ1 1
122e124 C; IR (KBr)
n
max 3338, 2966, 2925, 1676, 1524 cm
9.67 (1H, br s), 8.74 (1H, dd, J
¼7.2, J ¼1.8 Hz), 8.03 (1H, dd, J
;
H
1
2
1
2
NMR (400 MHz, CDCl
3
)
d
H
1
¼4.3,
1
2
J
J
2
¼1.7 Hz), 8.60 (1H, dd, J
1
2
1
¼8.2,
13
2
¼1.7 Hz), 7.66 (2H, d, J¼7.1 Hz), 7.44e7.29 (8H, m), 7.09 (2H, d,
3.86e3.78 (1H, m), 2.48 (3H, s), 1.15 (3H, d, J¼6.8 Hz); C NMR
(100 MHz, CDCl 197.9, 170.5, 151.1, 148.0, 138.2, 138.1, 136.2,
J¼8.1 Hz), 3.87 (1H, d, J¼10.9 Hz), 3.79e3.71 (1H, m), 2.50 (2H, q,
3 C
) d
13
J¼7.6 Hz), 1.14 (3H, d, J¼6.9 Hz), 1.08 (3H, t, J¼7.6 Hz); C NMR
100 MHz, CDCl 171.0, 147.9, 142.4, 142.1, 138.8, 138.2, 136.1,
34.4, 128.7, 128.6, 128.0, 127.7, 127.4, 127.2, 127.2, 121.4, 121.2, 116.2,
135.4, 134.1, 128.9, 128.7, 128.5, 127.7, 127.7, 127.7, 127.2, 121.5, 121.4,
þ
(
3
)
d
C
116.3, 62.2, 43.0, 26.5, 20.0; HRMS: m/z [MþH] , found 409.1916,
1
6
C
27 25 2 2
C H N O requires 409.1916. The NMR spectra of this compound
þ
2.9, 42.6, 28.3, 20.3, 15.3; HRMS: m/z [MþH] , found 395.2123,
contain traces of the corresponding minor isomer.
27 27 2
H N O requires 395.2123.
4.4.8. (2R*,3S*)-3-(3-Nitrophenyl)-2-phenyl-N-(quinolin-8-yl)buta-
4
.4.4. (2R*,3S*)-2-Phenyl-N-(quinolin-8-yl)-3-(p-tolyl)butanamide
namide (3h). Following the general procedure, 3h (64 mg, 62%) was
obtained as a mixture of diastereomers after purification by column
(3d). Following the general procedure, 3d (85 mg, 89%) was ob-
tained after purification by column chromatography on silica gel as
chromatography on silica gel as a yellow solid; R
f
(20% EtOAc/
ꢀ
ꢀ
a colourless solid; R
f
(10% EtOAc/Hexanes) 0.44; mp 179e181 C; IR
Hexanes) 0.20; mp 157e159 C; IR (KBr)
n
max 3332, 2968, 2870,
9.69 (1H, br s), 8.72
¼4.2 Hz), 8.36 (1H,
¼1.6 Hz), 7.97e7.93 (1H, m),
7.79e7.77 (1H, m), 7.65 (2H, d, J¼7.1 Hz), 7.57e7.10 (7H, m),
ꢂ1
1
ꢂ1 1
(
KBr)
CDCl
dd, J
n
max 3350, 2970, 2922, 1677, 1526 cm ; H NMR (400 MHz,
9.69 (1H, br s), 8.76 (1H, dd, J ¼1.7 Hz), 8.60 (1H,
¼4.2, J
¼8.3, J ¼1.7 Hz), 7.64 (2H, d,
1680, 1526 cm ; H NMR (400 MHz, CDCl
(1H, dd, J ¼1.6 Hz), 8.52 (1H, dd, J ¼5.0, J
¼4.2, J
t, J¼1.9 Hz), 8.07 (1H, dd, J ¼8.3, J
3 H
) d
3
)
d
H
1
2
1
2
1
2
1
¼6.2, J
2
¼2.8 Hz), 8.08 (1H, dd, J
1
2
1
2
J¼7.1 Hz), 7.44e7.38 (5H, m), 7.33 (2H, d, J¼8.1 Hz), 7.31e7.29 (1H,
m), 7.06 (2H, d, J¼7.8 Hz), 3.85 (1H, d, J¼10.9 Hz), 3.76e3.68 (1H,
13
3.93e3.83 (2H, m),1.18 (3H, d, J¼6.5 Hz); C NMR (100 MHz, CDCl
3
)
13
m), 2.20 (3H, s), 1.12 (3H, d, J¼7.0 Hz); C NMR (100 MHz, CDCl
3
)
d
C
d
C
170.6, 170.1, 148.4, 148.3, 148.1, 147.4, 146.3, 138.3, 138.1, 137.8,
170.9, 147.9, 142.2, 138.8, 138.2, 136.2, 135.8, 134.4, 129.2, 128.7,
137.7, 136.4, 136.2, 134.6, 134.6, 134.3, 134.0, 129.3, 129.0, 128.9,
128.6, 128.5, 128.3, 127.9, 127.8, 127.7, 127.4, 127.3, 127.1, 122.4, 121.9,
1
28.6, 127.7, 127.4, 127.2, 127.2, 121.4, 121.2, 116.3, 62.8, 42.5, 21.0,
þ
2
3
0.4; HRMS: m/z [MþH] , found 381.1967, C26
H
25
N
2
O requires
121.8, 121.7, 121.7, 121.6, 121.6, 121.4, 116.6, 116.3, 62.3, 62.1, 43.5,
þ
81.1967.
42.8, 21.0, 19.9; HRMS: m/z [MþH] , found 412.1646, C25
22 3 3
H N O
requires 412.1661. The compound 3h was isolated as a mixture of
1
4
.4.5. (2R*,3S*)-3-(4-Bromophenyl)-2-phenyl-N-(quinolin-8-yl)bu-
diastereomers and the H NMR data given here for the major iso-
13
tanamide (3e). Following the general procedure, 3e (85 mg, 77%)
was obtained after purification by column chromatography on sil-
mer and the C NMR values are given for both the diastereomers.
ica gel (EtOAc:Hexanes¼20:80) as a colourless solid; R
f
(20% EtOAc/
max 3341, 2971, 2927, 1676,
4.4.9. (2R*,3S*)-3-(3,4-Dimethylphenyl)-2-phenyl-N-(quinolin-8-yl)
butanamide (3i). Following the general procedure, 3i (75 mg, 76%)
was obtained after purification by column chromatography on
ꢀ
Hexanes) 0.67; mp 172e174 C; IR (KBr)
n
ꢂ1
1
1
3 H
524 cm ; H NMR (400 MHz, CDCl ) d 9.68 (1H, br s), 8.76 (1H,

B. Gopalakrishnan et al. / Tetrahedron 71 (2015) 8333e8349
8345
ꢂ1
silica gel as a brown colour solid; R
f
(20% EtOAc/Hexanes) 0.43; mp
2924, 2857, 1686, 1526 cm ; 1H NMR (400 MHz, CDCl
3
)
d
H
9.77
¼6.9,
ꢀ
ꢂ1 1
;
1
43e145 C; IR (KBr)
n
max 3347, 2964, 2923, 1683, 1525 cm
9.68 (1H, br s), 8.75 (1H, dd, J
¼7.1, J ¼1.9 Hz), 8.05 (1H, dd, J
H
(1H, br s), 8.80 (1H, dd, J
¼2.2 Hz), 8.15 (1H, dd, J
(1H, dd, J
¼8.2, J
(1H, m), 6.89 (1H, dd, J
(1H, dd, J ¼5 Hz), 2.86 (1H, dd, J
¼14.8, J
1.90e1.83 (1H, m), 1.53e1.13 (8H, m), 1.02 (3H, d, J¼6.8 Hz),
1
¼4.2, J
2
¼1.8 Hz), 8.73 (1H, dd, J
1
NMR (400 MHz, CDCl
3
)
d
H
1
¼4.2,
J
2
1
¼8.3, J ¼1.6 Hz), 7.54e7.49 (2H, m), 7.46
2
J
J
2
¼1.6 Hz), 8.60 (1H, dd, J
1
2
1
¼8.2,
1
2
¼4.2 Hz), 7.12 (1H, dd, J
1
¼5.1, J
¼3.5 Hz), 3.68e3.63 (1H, m), 3.02
¼14.7, J ¼9.7 Hz),
2
¼1.2 Hz), 6.93e6.91
2
¼1.4 Hz), 7.66 (2H, d, J¼7.4 Hz), 7.43e7.29 (6H, m), 7.22e7.18 (2H,
1
¼5.0, J
2
m), 7.00 (1H, d, J¼7.7 Hz), 3.87 (1H, d, J¼10.9 Hz), 3.73e3.66 (1H,
1
2
1
2
13
m), 2.17 (3H, s), 2.08 (3H, s), 1.12 (3H, d, J¼7.0 Hz); C NMR
100 MHz, CDCl 171.1, 147.9, 142.6, 138.9, 138.2, 136.4, 136.1,
34.5,134.4,129.7, 128.7, 128.7,128.6,127.7,127.4,127.2,124.5,121.4,
13
(
1
3
)
d
C
3 C
0.92e0.85 (3H, m); C NMR (100 MHz, CDCl ) d 170.3,148.0,146.8,
138.3,136.3,134.4,127.9,127.4,126.4,124.9, 123.1,121.5,121.4,116.4,
þ
þ
1
21.1, 116.3, 62.7, 42.6, 20.5, 19.8, 19.3; HRMS (ESI): m/z [MþH] ,
found 395.2108, C27 O requires 395.2123. The NMR spectra of
this compound contain traces of the corresponding minor isomer.
43.1, 42.4, 38.9, 33.8, 32.0, 27.0, 22.7, 17.1, 14.1; HRMS: m/z [MþH] ,
H N
27 2
29 2
found 381.1992, C23H N OS requires 381.2000. The compound 6a
was isolated as a mixture of diastereomers and the NMR data given
here for the major.
4
.4.10. (2R*,3S*)-3-(3,4-Difluorophenyl)-2-phenyl-N-(quinolin-8-yl)
butanamide (3j). Following the general procedure, 3j (94 mg, 93%)
was obtained after purification by column chromatography on sil-
4.4.14. 3-(4-Bromophenyl)-4-methyl-N-(quinolin-8-yl)nonanamide
(6b). Following the general procedure, 6b (45 mg, 40%) was ob-
tained after purification by column chromatography on silica gel
ica gel (EtOAc:Hexanes¼10:90) as a colourless solid; R
f
(10% EtOAc/
ꢀ
Hexanes) 0.67; mp 182e184 C; IR (KBr)
n
max 3339, 2970, 2924,
9.69 (1H, br s), 8.75
¼3.5 Hz), 8.08 (1H,
¼1.7 Hz), 7.63 (2H, d, J¼7.1 Hz), 7.46e7.25 (7H, m),
.18e7.14 (1H, m), 7.05e6.98 (1H, m), 3.78 (1H, d, J¼10.8 Hz),
(EtOAc:Hexanes¼20:80) as a pale yellow liquid; R
Hexanes) 0.44; IR (thin film) max 3351, 2926, 1686, 1525,
H NMR (400 MHz, CDCl 9.64 (1H, br s), 8.78
¼4.2, J ¼1.7 Hz), 8.66 (1H, dd, J ¼6.0, J ¼3.0 Hz), 8.15
¼8.3, J ¼1.6 Hz), 7.52e7.48 (2H, m), 7.46 (1H, dd, J ¼8.3,
¼4.2 Hz), 7.39 (2H, d, J¼8.4 Hz), 7.17 (2H, d, J¼8.4 Hz), 3.25e3.19
(1H, m), 3.02 (1H, dd, J ¼4.8 Hz), 2.82 (1H, dd, J ¼14.8,
¼14.8, J
¼10.2 Hz), 1.83e1.77 (1H, m), 1.39e1.14 (8H, m), 0.99 (3H, d,
f
(20% EtOAc/
ꢂ1
1
1
(
674, 1524 cm ; H NMR (400 MHz, CDCl
1H, dd, J ¼1.7 Hz), 8.58 (1H, dd, J
¼4.2, J
dd, J
¼8.3, J
3
)
d
H
n
ꢂ1
1
1
2
1
¼5.5, J
2
1484 cm
;
3 H
) d
1
2
(1H, dd, J
1
2
1
2
7
3
(1H, dd, J
1
2
1
13
.75e3.69 (1H, m),1.11 (3H, d, J¼6.5 Hz); C NMR (100 MHz, CDCl
170.4, 151.5 (d, 1CeF¼246.0,
CeF¼12.7 Hz), 150.3 (dd,
2CeF¼12.7 Hz), 149.0 (dd, J1CeF¼245.0, J2CeF¼12.7 Hz), 148.1, 142.3
t, JCeF¼4.1 Hz), 138.2, 138.1, 136.3, 134.1, 128.9, 128.5, 127.8, 127.7,
27.2, 123.5 (dd, 2CeF¼3.5 Hz), 121.5, 117.1 (d,
1CeF¼5.9,
CeF¼16.8 Hz), 116.4, 116.1 (d, JCeF¼16.9 Hz), 62.7, 42.3, 20.0; HRMS:
3
)
J
2
d
C
J
J
1
2
1
J
(
J
2
13
J¼6.7 Hz), 0.86 (3H, t, J¼6.9 Hz); C NMR (100 MHz, CDCl
3 C
) d
1
J
J
170.4, 148.0, 142.4, 138.2, 136.3, 134.3, 131.4, 130.0, 127.9, 127.3,
J
121.6, 121.4, 120.0, 116.4, 47.3, 41.2, 38.1, 33.9, 32.0, 26.8, 22.6,
þ
þ
m/z [MþH] , found 403.1629, C25
H
21
F
2
N
2
O requires 403.1622.
17.0, 14.1; HRMS: m/z [MþH] , found 453.1541, C25
2
H30BrN O re-
quires 453.1542. The characterization data corresponds to the
major isomer and the H NMR spectrum of this compound
1
4
.4.11. (2R*,3S*)-3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-2-phenyl-
N-(quinolin-8-yl)butanamide (3k). Following the general pro-
cedure, 3k (69 mg, 65%) was obtained after purification by column
showed the presence of traces of the corresponding minor
isomer.
chromatography on silica gel as a pale yellow colour solid; R
f
(20%
ꢀ
EtOAc/Hexanes) 0.21; mp 161e163 C; IR (KBr)
n
max 3323, 2960,
9.69 (1H, br s),
¼1.9 Hz), 8.06
¼1.6 Hz), 7.63 (2H, d, J¼7.1 Hz), 7.44e7.37 (5H, m),
4.4.15. 3-(4-Chlorophenyl)-4-methyl-N-(quinolin-8-yl)nonanamide
(6c). Following the general procedure, 6c (54 mg, 53%) was ob-
tained after purification by column chromatography on silica gel
ꢂ1
1
2
8
924, 1688, 1525 cm ; H NMR (400 MHz, CDCl
.75 (1H, dd, J ¼1.7 Hz), 8.62 (1H, dd, J ¼7.1, J
¼4.2, J
¼8.2, J
3 H
) d
1
2
1
2
(
1H, dd, J
1
2
(EtOAc:Hexanes¼20:80) as a pale yellow liquid; R
Hexanes) 0.42; IR (thin film) max 3352, 2926, 2857, 1687, 1526,
1486 cm ; H NMR (400 MHz, CDCl 9.65 (1H, br s), 8.78 (1H,
dd, J ¼2.9 Hz), 8.15 (1H, dd,
¼6.1, J
¼1.6 Hz), 7.51e7.48 (2H, m), 7.45 (1H, dd, J ¼8.3,
¼4.2 Hz), 7.26e7.21 (4H, m), 3.26e3.21 (1H, m), 3.02 (1H, dd,
¼14.8, J ¼4.8 Hz), 2.82 (1H, dd, J ¼14.8, J ¼10.2 Hz),1.83e1.76 (1H,
f
(20% EtOAc/
7.33e7.29 (1H, m), 6.96e6.92 (2H, m), 6.74 (1H, d, J¼8.2 Hz),
4
n
ꢂ1
1
.16e4.09 (4H, m), 3.79 (1H, d, J¼10.9 Hz), 3.70e3.62 (1H, m), 1.09
3 H
) d
13
(
3H, d, J¼7.0 Hz); C NMR (100 MHz, CDCl
3
)
d
C
170.9, 148.0, 143.3,
1
¼4.2, J
2
¼1.7 Hz), 8.66 (1H, dd, J
1
2
141.9, 138.7, 138.7, 138.2, 136.2, 134.4, 128.7, 128.6, 127.7, 127.4, 127.2,
J
1
J
2
J
1
¼8.2, J
2
1
1
21.4, 121.2, 120.5, 117.1, 116.3, 115.9, 64.3, 64.2, 62.9, 42.2, 20.4;
þ
HRMS: m/z [MþH] , found 425.1868,
C
27
H
25
N
2
O
3
requires
2
1
2
4
25.1865.
m), 1.39e1.15 (8H, m), 1.00 (3H, d, J¼6.7 Hz), 0.86 (3H, t, J¼6.8 Hz);
13
3 C
C NMR (100 MHz, CDCl ) d 170.5, 148.0, 141.8, 138.2, 136.3, 134.3,
4
.4.12. (2R*,3S*)-2-Phenyl-N-(quinolin-8-yl)-3-(thiophen-2-yl)buta-
131.9, 129.6, 128.4, 127.9, 127.3, 121.6, 121.4, 116.4, 47.2, 41.3, 38.2,
þ
namide (3l). Following the general procedure, 3l (83 mg, 90%) was
obtained after purification by column chromatography on silica gel
33.9, 32.0, 26.8, 22.6, 17.0, 14.1; HRMS: m/z [MþH] , found
2
409.2066, C25H30ClN O requires 409.2047. The characterization
ꢀ
as a colourless solid; R
IR (KBr)
CDCl
dd, J
J¼7.7 Hz), 7.48e7.37 (5H, m), 7.34e7.30 (1H, m), 7.08 (1H, d,
J¼5.1 Hz), 7.05 (1H, d, J¼3.4 Hz), 6.85 (1H, dd, J ¼5.0, J ¼3.5 Hz),
.18e4.10 (1H, m), 3.82 (1H, d, J¼10.6 Hz), 1.22 (3H, d, J¼7.0 Hz);
NMR (100 MHz, CDCl 170.8, 148.9, 148.0, 138.2, 138.2, 136.2,
34.4, 128.8, 128.5, 127.8, 127.6, 127.3, 126.6, 124.3, 123.0, 121.5,
f
(15% EtOAc/Hexanes) 0.45; mp 161e163 C;
data corresponds to the major isomer.
ꢂ1
1
n
max 3347, 2970, 2925,1679,1525 cm ; H NMR (400 MHz,
9.78 (1H, br s), 8.76 (1H, dd, J ¼1.6 Hz), 8.69 (1H,
¼4.2, J
¼7.2, J ¼1.7 Hz), 8.09 (1H, dd, J ¼8.3, J ¼1.6 Hz), 7.61 (2H, d,
3
)
d
H
1
2
4.4.16. 3-(3,4-Dichlorophenyl)-4-methyl-N-(quinolin-8-yl)non-
anamide (6d). Following the general procedure, 6d (75 mg, 68%)
was obtained after purification by column chromatography on sil-
1
2
1
2
1
2
ica gel as a pale yellow liquid; R
film) max 3349, 2927, 2857, 1687, 1526, 1484 cm
(400 MHz, CDCl 9.64 (1H, br s), 8.79 (1H, dd, J
¼4.2, J
8.65 (1H, dd, J ¼3.2 Hz), 8.15 (1H, dd, J ¼8.3, J
¼5.8, J
7.52e7.48 (2H, m), 7.46 (1H, dd, J ¼4.2 Hz), 7.40 (1H, d,
¼8.3, J
J¼2.0 Hz), 7.31 (1H, d, J¼8.3 Hz), 7.12 (1H, dd, J ¼8.3, J ¼2.1 Hz),
.25e3.19 (1H, m), 3.02 (1H, dd, J ¼4.6 Hz), 2.80 (1H, dd,
¼14.9, J
¼14.9, J ¼10.3 Hz), 1.84e1.75 (1H, m), 1.38e1.16 (8H, m), 1.00 (3H,
f
(20% EtOAc/Hexanes) 0.40; IR (thin
13
ꢂ1
1
4
C
n
;
H NMR
¼1.6 Hz),
¼1.7 Hz),
3
)
d
C
3
)
d
H
1
2
1
1
2
1
2
þ
1
C
21.4, 116.4, 63.8, 38.2, 21.1; HRMS: m/z [MþH] , found 373.1377,
1
2
23 21
H N
2
OS requires 373.1375.
1
2
3
1
2
4
.4.13. 4-Methyl-N-(quinolin-8-yl)-3-(thiophen-2-yl)nonanamide
J
1
2
13
(6a). Following the general procedure, 6a (80 mg, 84%) was ob-
d, J¼6.7 Hz), 0.86 (3H, t, J¼6.8 Hz); C NMR (100 MHz, CDCl
3 C
) d
tained as a mixture of diastereomers after purification by column
chromatography on silica gel (EtOAc:Hexanes¼20:80) as a colour-
170.1, 148.1, 143.9, 138.2, 136.3, 134.2, 132.3, 130.2, 130.1, 130.1, 127.9,
127.3, 121.6, 121.5, 116.4, 47.1, 41.0, 38.1, 34.0, 32.0, 26.7, 22.6, 16.9,
þ
less semi solid; R
f
(20% EtOAc/Hexanes) 0.47; IR (KBr)
n
max 3352,
14.1; HRMS: m/z [MþH] , found 443.1676, C25
2 2
H29Cl N O requires

8346
B. Gopalakrishnan et al. / Tetrahedron 71 (2015) 8333e8349
ꢀ
4
43.1657. The characterization data corresponds to the major
0.18; mp 73e75 C; IR (KBr)
n
max 3326, 2981, 2930, 1733, 1690,
10.43 (1H, br s), 8.89 (1H,
¼7.0, J ¼2.0 Hz), 8.16 (1H, dd,
ꢂ1
1
isomer.
1527 cm ; H NMR (400 MHz, CDCl
dd, J ¼4.2, J ¼1.7 Hz), 8.60 (1H, dd, J
¼8.3, J ¼1.7 Hz), 7.50e7.47 (3H, m), 7.42 (2H, d, J¼7.2 Hz),
3 H
) d
1
2
1
2
4
(
.4.17. 3-(4-Bromophenyl)-4-ethyl-N-(quinolin-8-yl)octanamide
6e). Following the general procedure, 6e (56 mg, 50%) was obtained
after purification by column chromatography on silica gel
J
1
2
7.34e7.29 (4H, m), 7.23e7.22 (1H, m), 6.74 (2H, d, J¼8.8 Hz), 4.91
(1H, d, J¼12.2 Hz), 4.46 (1H, d, J¼12.2 Hz), 4.06 (2H, q, J¼7.2 Hz),
13
(
EtOAc:Hexanes¼20:80) as a pale yellow liquid; R
f
(20% EtOAc/
3.66 (3H, s), 1.04 (3H, t, J¼7.2 Hz); C NMR (100 MHz, CDCl
3 C
) d
ꢂ1
Hexanes) 0.43; IR (thin film)
n
max 3352, 2928,1686,1525,1484 cm
;
169.4, 164.8, 158.3, 148.4, 141.8, 138.5, 136.2, 134.1, 133.2, 128.9,
1
H NMR (400 MHz, CDCl
3
)
d
H
9.64 (1H, br s), 8.78 (1H, dd, J
¼6.1, J ¼2.9 Hz), 8.15 (1H, dd, J
¼1.6 Hz), 7.51e7.48 (2H, m), 7.46 (1H, dd, J ¼8.3, J
1
¼4.2,
128.6, 127.8, 127.2, 126.8, 123.4, 121.8, 121.6, 116.7, 114.1, 61.7, 61.1,
þ
J
J
2
¼1.6 Hz), 8.66 (1H, dd, J
1
2
1
¼8.3,
55.1, 51.7, 13.8; HRMS: m/z [MþH] , found 455.1965, C28
27 2 4
H N O
2
1
2
¼4.2 Hz), 7.39
requires 455.1971.
(
(
(
2H, d, J¼8.4 Hz), 7.18 (2H, d, J¼8.4 Hz), 3.42e3.35 (1H, m), 3.04e2.97
1H, m), 2.86e2.79 (1H, m),1.61e1.57 (1H, m) 1.47e1.08 (8H, m), 0.96
4. 4. 21. (2R*, 3S*)-3-(4-Methoxyphenyl)-2-((R*)-1-(4-
methoxyphenyl)-ethyl)-N-(quinolin-8-yl)butanamide (8eA). Follow-
ing the general procedure, 8eA (181 mg, 40% meso (major) isomer)
was obtained after purification by column chromatography on sil-
ica gel as a colourless solid; R
143e145 C; IR (KBr)
13
3H, t, J¼7.4 Hz), 0.92e0.84 (3H, m); C NMR (100 MHz, CDCl
3 C
) d
1
70.4, 148.0, 142.2, 138.2, 136.3, 134.3, 131.4, 130.1, 127.9, 127.3, 121.5,
121.4, 120.0, 116.4, 44.3, 43.8, 41.4, 29.8, 29.2, 23.0, 22.7, 14.1, 11.1;
þ
HRMS: m/z [MþH] , found 453.1555,
25 2
C H30BrN O
requires
f
(10% EtOAc/Hexanes) 0.10; mp
ꢀ
ꢂ1 1
;
4
53.1542. The characterization data corresponds to the major isomer.
n
max 3357, 2962, 2932, 1684, 1524 cm
9.37 (1H, br s), 8.70 (1H, dd, J
¼6.8, J ¼1.8 Hz), 8.07 (1H, dd, J
H
NMR (400 MHz, CDCl
3
)
d
H
1
¼4.2,
4
.4.18. 4-Ethyl-3-(4-methoxyphenyl)-N-(quinolin-8-yl)octanamide
J
J
2
¼1.6 Hz), 8.55 (1H, dd, J
1
2
1
¼8.2,
(
6f). Following the general procedure, 6f (57 mg, 57%) was ob-
tained after purification by column chromatography on silica gel
EtOAc:Hexanes¼20:80) as a colourless liquid; R (20% EtOAc/
Hexanes) 0.44; IR (thin film) max 3355, 2927, 1686, 1523,
177 cm ; H NMR (400 MHz, CDCl 9.64 (1H, br s), 8.76 (1H,
dd, J ¼2.0 Hz), 8.13 (1H, dd,
¼6.9, J
2
¼1.4 Hz), 7.44e7.37 (3H, m), 7.28 (4H, d, J¼8.6 Hz), 6.74 (4H, d,
J¼8.6 Hz), 3.66 (6H, s), 3.33e3.26 (2H, m), 3.01 (1H, t, J¼7.8 Hz), 1.55
1
3
(
f
(6H, d, J¼7.0 Hz); C NMR (100 MHz, CDCl
3 C
) d 171.2, 158.0, 147.8,
n
138.2, 136.1, 136.1, 134.2, 129.0, 127.7, 127.3, 121.4, 120.9, 116.0, 113.5,
ꢂ1
1
þ
1
3
)
d
H
62.7, 55.0, 39.0, 21.2; HRMS: m/z [MþH] , found 455.2345,
1
¼4.2, J
2
¼1.7 Hz), 8.68 (1H, dd, J
1
2
29 31 2 3
C H N O requires 455.2335.
J
J
1
¼8.3, J
2
¼1.6 Hz), 7.51e7.47 (2H, m), 7.44 (1H, dd, J ¼8.3,
1
2
¼4.2 Hz), 7.21 (2H, d, J¼8.6 Hz), 6.81 (2H, d, J¼8.6 Hz), 3.73 (3H, s),
4.4.22. (S*)-3-(4-Methoxyphenyl)-2-((S*)-1-(4-methoxyphenyl)
ethyl)-N-(quinolin-8-yl)butanamide (8eB). Following the general
procedure, 8eB (100 mg, 22%, minor isomer) was obtained after
3
.40e3.32 (1H, m), 3.03e2.96 (1H, m), 2.87e2.80 (1H, m),
1
.60e1.55 (1H, m), 1.46e1.08 (8H, m), 0.91 (3H, t, J¼6.8 Hz), 0.88
13
(
3H, t, J¼7.3 Hz); C NMR (100 MHz, CDCl
3
)
d
C
171.0, 157.9, 147.9,
purification by column chromatography on silica gel as a colourless
ꢀ
138.3, 136.2, 135.1, 134.5, 129.2, 127.8, 127.4, 121.5, 121.2, 116.3, 113.6,
solid; R
f
(15% EtOAc/Hexanes) 0.11; mp 157e159 C; IR (KBr)
n
max
ꢂ1
1
5
5.1, 44.5, 43.7, 42.1, 29.5, 29.3, 29.0, 23.1, 23.1, 14.1, 11.3; HRMS: m/z
3355, 2963, 2834, 1683, 1524 cm ; H NMR (400 MHz, CDCl
9.14 (1H, br s), 8.66e8.63 (2H, m), 8.09 (1H, dd, J ¼1.6 Hz),
¼8.3, J
7.50e7.42 (2H, m), 7.38 (1H, dd, J
¼4.2 Hz), 7.22 (2H, d,
3 H
) d
þ
[
MþH] , found 405.2541, C26
H N
33 2
O
2
requires 405.2542. This
1
2
compound was isolated as a mixture of diastereomers. The NMR
spectra of this compound correspond to mixture of diastereomers
1
¼8.2, J
2
J¼8.7 Hz), 7.16 (2H, d, J¼8.7 Hz), 6.77 (2H, d, J¼8.7 Hz), 6.72 (2H, d,
J¼8.7 Hz), 3.66 (3H, s), 3.66 (3H, s), 3.33e3.25 (2H, m), 2.92 (1H, t,
13
and the C NMR data given here corresponds to the major isomer.
13
J¼7.8 Hz), 1.44 (3H, d, J¼7.0 Hz), 1.43 (3H, d, J¼7.0 Hz); C NMR
4
.4.19. Ethyl 3-oxo-2-(phenyl(thiophen-2-yl)methyl)-3-(quinolin-8-
ylamino)propanoate (8b). Following the general procedure, 8b
70 mg, 65%) was obtained as a mixture of diastereomers after
3 C
(100 MHz, CDCl ) d 171.5, 158.1, 157.9, 147.7, 138.2, 137.3, 136.5,
136.0, 134.3, 128.9, 128.5, 127.7, 127.3, 121.3, 121.1, 116.2, 113.9, 113.4,
þ
(
62.6, 55.1, 55.0, 39.4, 38.9, 20.4, 17.7; HRMS: m/z [MþH] , found
purification by column chromatography on silica gel as a colourless
solid; R
31 2 3
455.2343, C29H N O requires 455.2335.
ꢀ
f
(25% EtOAc/Hexanes) 0.23; mp 103e105 C; IR (KBr)
n
max
ꢂ1
1
3
328, 2979, 1729, 1684, 1529, 1485 cm ; H NMR (400 MHz, CDCl
10.45 (1H, br s), 10.36 (1H, br s) , 8.90e8.88 (1H, 1H , m), 8.70
1H, dd, J ¼2.8 Hz), 8.54 (1H, dd, J ¼7.4, J ¼1.6 Hz) , 8.16
¼6.2, J
1H, 1H , td, J ¼1.7 Hz), 7.53e7.43 (5H, 5H , m), 7.38e7.34
¼8.2, J
1H, 1H , m), 7.29e7.19 (2H, 2H , m), 7.09e7.02 (2H, 2H , m), 6.95
1H, dd, J ¼3.5 Hz), 6.82 (1H, dd, J ¼5.1, J ¼3.5 Hz) , 5.25 (1H,
¼5.1, J
, 4.45 (1H, d, J¼11.9 Hz), 4.43
, d, J¼12.0 Hz), 4.21e4.15 (2H , m), 4.05e3.99 (2H, q,
J¼7.1 Hz), 1.17 (3H, t, J¼7.1 Hz) , 1.00 (3H, t, J¼7.2 Hz); C NMR
100 MHz, CDCl 169.0, 168.5, 164.4, 164.0, 148.5, 148.4, 145.0,
44.7, 141.0, 140.6, 138.5, 138.4, 136.3, 136.3, 134.1, 133.9, 128.7,
28.7,128.0,127.8, 127.8, 127.4, 127.3,127.2, 126.8,126.6, 125.1, 124.7,
24.7, 124.6, 122.0, 122.0, 121.7, 121.7, 116.8, 116.7, 62.3, 62.2, 62.0,
3
)
4.4.23. (2R*,3S*)-3-Phenyl-2-((R*)-1-phenylethyl)-N-(quinolin-8-yl)
butanamide (8fA). Following the general procedure, 8fA (197 mg,
50%, meso (major) isomer) was obtained after purification by col-
umn chromatography on silica gel (EtOAc:Hexanes¼10:90) as
d
H
*
*
(
(
(
(
1
2
1
2
*
*
1
2
*
*
*
*
a colourless liquid; R
3357, 3027, 2965, 1687, 1523 cm
9.41 (1H, br s), 8.71 (1H, dd, J
¼4.2, J
8.09 (1H, dd, J ¼1.0 Hz), 7.42e7.35 (5H, m), 7.32e7.26 (1H,
¼8.3, J
m), 7.24e7.15 (5H, m), 7.10 (2H, t, J¼7.6 Hz), 3.37e3.31 (2H, m), 3.09
f max
(10% EtOAc/Hexanes) 0.12; IR (thin film) n
ꢂ1
1
1
2
1
2
*
;
H NMR (400 MHz, CDCl
3 H
) d
d, J¼12.0 Hz), 5.24 (1H, d, J¼12.0 Hz)
*
1
2
¼1.6 Hz), 8.52e8.50 (1H, m),
(
1H, 1H
*
*
1
2
13
*
13
(
1
1
1
3
)
d
C
(1H, t, J¼7.8 Hz),1.57 (6H, d, J¼7.0 Hz); C NMR (100 MHz, CDCl
3 C
) d
171.0, 147.8, 144.2, 138.3, 136.1, 134.1, 128.2, 128.1, 127.7, 127.3, 126.3,
þ
121.4, 120.9, 116.0, 62.2, 39.9, 21.0; HRMS: m/z [MþH] , found
27 2
395.2127, C27H N O requires 395.2123.
þ
6
C
1.8, 47.6, 47.5, 13.9, 13.7; HRMS: m/z [MþH] , found 431.1435,
H
25 23
N
2
O
3
S requires 431.1429. This compound was isolated as
4.4.24. (S*)-3-Phenyl-2-((S*)-1-phenylethyl)-N-(quinolin-8-yl)buta-
namide (8fB). Following the general procedure, 8fB (82 mg, 21%,
minor isomer) was obtained after purification by column chroma-
1
a mixture of diastereomers. Represents the H NMR data of the
corresponding other diastereomer. The C NMR data given here for
both the diastereomers.
*
13
tography on silica gel (EtOAc:Hexanes¼10:90) as a colourless solid;
ꢀ
R
f
(10% EtOAc/Hexanes) 0.10; mp 142e144 C; IR (KBr)
n
max 3356,
9.20
¼1.6 Hz),
¼4.2 Hz), 7.33e7.23
(6H, m), 7.18 (2H, t, J¼7.4 Hz), 7.13 (1H, t, J¼7.3 Hz), 7.07 (1H, t,
ꢂ1
1
4
.4.20. Ethyl 3-(4-methoxyphenyl)-3-phenyl-2-(quinolin-8-
ylcarbamoyl)propanoate (8c). Following the general procedure, 8c
56 mg, 50%) was obtained after purification by column chroma-
tography on silica gel as a pale yellow solid; R (20% EtOAc/Hexanes)
3059, 3027, 1683, 1524 cm
(1H, br s), 8.66e8.64 (2H, m), 8.08 (1H, dd, J
7.50e7.42 (2H, m), 7.38 (1H, dd, J
¼8.2 Hz, J
;
H NMR (400 MHz, CDCl
3 H
) d
1
¼8.2, J
2
(
1
2
f

B. Gopalakrishnan et al. / Tetrahedron 71 (2015) 8333e8349
8347
J¼7.2 Hz), 3.40e3.30 (2H, m), 3.03 (1H, t, J¼7.8 Hz), 1.48 (3H, d,
the anti (major) isomer) was obtained after purification by column
13
J¼7.0 Hz), 1.46 (3H, d, J¼7.0 Hz); C NMR (100 MHz, CDCl
3
)
d
C
171.3,
chromatography on silica gel as a colourless solid; R
f
(10% EtOAc/
ꢀ
147.8,145.3,144.4,138.2,136.0,134.2,128.6,128.1,128.0,127.7,127.7,
Hexanes) 0.48; mp 153e155 C; IR (KBr)
n
max 3343, 2965, 2925,
9.70 (1H, br s), 8.75
¼2.6 Hz), 8.06 (1H,
¼1.6 Hz), 7.66 (2H, d, J¼7.1 Hz), 7.47 (2H, d, J¼7.0 Hz),
7.43e7.37 (5H, m), 7.34e7.25 (3H, m), 7.13e7.09 (1H, m), 3.88 (1H, d,
ꢂ1
1
1
27.3, 126.4, 126.3, 121.3, 121.1, 116.2, 62.1, 40.3, 40.0, 20.3, 17.8;
1680, 1525 cm ; H NMR (400 MHz, CDCl
(1H, dd, J ¼1.7 Hz), 8.59 (1H, dd, J ¼6.4, J
¼4.3, J
dd, J
¼8.2, J
3 H
) d
þ
HRMS: m/z [MþH] , found 395.2126, C27
H N
27 2
O requires 395.2123.
1
2
1
2
1
2
4
.4.25. (2R*,3S*)-3-(4-Bromophenyl)-2-((R*)-1-(4-bromophenyl)
13
ethyl)-N-(quinolin-8-yl)butanamide (8gA). Following the general
procedure, 8gA (231 mg, 42%, meso (major) isomer) was obtained
J¼10.9 Hz), 3.81e3.73 (1H, m), 1.15 (3H, d, J¼6.9 Hz); C NMR
(100 MHz, CDCl 170.9, 148.0, 145.2, 138.7, 138.2, 136.2, 134.3,
3 C
) d
after purification by column chromatography on silica gel as a pale
128.8, 128.6, 128.5, 127.7, 127.5, 127.4, 127.2, 126.4,121.4, 121.2, 116.3,
ꢀ
þ
yellow solid; R
f
(10% EtOAc/Hexanes) 0.70; mp 152e154 C; IR (KBr)
62.7, 43.0, 20.3; HRMS: m/z [MþH] , found 367.1813, C25
23 2
H N O
ꢂ1
1
n
max 3350, 2967, 2931, 1686, 1524 cm ; H NMR (400 MHz, CDCl
9.41 (1H, br s), 8.74 (1H, dd, J ¼1.7 Hz), 8.49 (1H, dd,
¼4.2, J
¼5.6, J ¼3.4 Hz), 8.11 (1H, dd, J ¼8.2, J ¼1.6 Hz), 7.45e7.42 (3H,
m), 7.31 (4H, d, J¼8.5 Hz), 7.22 (4H, d, J¼8.5 Hz), 3.30e3.23 (2H, m),
3
)
requires 367.1810. The characterization data corresponds the anti
d
H
1
2
(major) isomer.
J
1
2
1
2
4.4.30. (2S,3R)-2-phenyl-N-(quinolin-8-yl)-3-(thiophen-2-yl)buta-
namide (10b). Following the general procedure,10b (80 mg, 86%, ee
75% for the anti (major) isomer) was obtained after purification by
13
3
CDCl
.00 (1H, t, J¼7.9 Hz), 1.52 (6H, d, J¼7.0 Hz); C NMR (100 MHz,
3
)
d
C
170.4, 148.1, 142.9, 138.2, 136.2, 133.8, 131.3, 129.9, 127.8,
þ
1
27.3, 121.6, 121.4, 120.3, 116.2, 61.8, 39.4, 20.9; HRMS: m/z [MþH] ,
column chromatography on silica gel as a pale yellow solid; R
f
(15%
ꢀ
found 551.0311, C27
H25Br
2
N
2
O requires 551.0334.
EtOAc/Hexanes) 0.46; mp 130e132 C; IR (KBr)
n
max 3345, 2966,
9.78 (1H, br s),
¼2.0 Hz), 8.09
¼1.7 Hz), 7.61 (2H, d, J¼7.0 Hz), 7.48e7.38 (5H, m),
7.34e7.29 (1H, m), 7.08 (1H, dd, J ¼1.1 Hz), 7.04e7.03 (1H,
¼5.1, J
m), 6.84 (1H, dd, J ¼3.5 Hz), 4.18e4.10 (1H, m), 3.81 (1H, d,
¼5.1, J
ꢂ1
1
2
923,1682,1524 cm ; H NMR (400 MHz, CDCl
8.76 (1H, dd, J ¼1.7 Hz), 8.70 (1H, dd, J ¼7.0, J
¼4.2, J
(1H, dd, J
¼8.3, J
3 H
) d
4
(
8
.4.26. (S*)-3-(4-Bromophenyl)-2-((S*)-1-(4-bromophenyl)ethyl)-N-
quinolin-8-yl)butanamide (8gB). Following the general procedure,
gB (88 mg, 16%, minor isomer) was obtained after purification by
1
2
1
2
1
2
1
2
column chromatography on silica gel as a pale yellow solid; R
f
(10%
1
2
ꢀ
13
EtOAc/Hexanes) 0.80; mp 148e150 C; IR (KBr)
n
max 3347, 2967,
9.09 (1H, br s),
¼2.9 Hz), 8.11
¼1.6 Hz), 7.49e7.45 (2H, m), 7.42 (1H, dd, J ¼8.3,
¼4.2 Hz), 7.19e7.15 (8H, m), 3.34e3.27 (2H, m), 2.90 (1H, dd,
J¼10.6 Hz), 1.22 (3H, d, J¼7.0 Hz); C NMR (100 MHz, CDCl
3 C
) d
ꢂ1
1
2
8
917, 1683, 1524 cm ; H NMR (400 MHz, CDCl
.66 (1H, dd, J ¼1.6 Hz), 8.57 (1H, dd, J ¼6.0, J
¼4.2, J
¼8.2, J
3
)
d
H
170.8, 148.9, 148.0, 138.3, 138.2, 136.2, 134.4, 128.8, 128.5, 127.8,
1
2
1
2
127.6, 127.3, 126.6, 124.3, 123.1, 121.5, 121.4, 116.4, 63.8, 38.2, 21.1;
þ
(
1H, dd, J
1
2
1
HRMS: m/z [MþH] , found 373.1369 C23
21 2
H N OS requires 373.1375.
J
J
2
The characterization data corresponds the anti (major) isomer.
1
3
1
¼8.5, J
2
¼7.1 Hz), 1.43 (3H, d, J¼7.0 Hz), 1.42 (3H, d, J¼7.0 Hz);
170.5, 148.0, 143.4, 142.9, 138.0, 136.1,
33.8, 132.1, 132.0,129.3, 128.9,128.7, 128.2,127.7, 127.2, 121.5, 121.4,
C
NMR (100 MHz, CDCl
1
3
)
d
C
4.4.31. (2S,3R)-3-(4-Methoxyphenyl)-2-phenyl-N-(quinolin-8-yl)bu-
tanamide (10c). Following the general procedure, 10c (92 mg, 93%,
ee 73% for the anti (major) isomer) was obtained after purification
þ
116.3, 61.9, 39.5, 39.2, 20.1, 16.9; HRMS: m/z [MþH] , found
5
51.0313, C27
H
25Br
2
N
2
O requires 551.0334.
by column chromatography on silica gel as a colourless solid; R
f
ꢀ
(
10% EtOAc/Hexanes) 0.45; mp 153e155 C; IR (KBr)
n
max 3351,
ꢂ1
1
4
.4.27. (2R*,3S*)-3-(4-Chlorophenyl)-2-((R*)-1-(4-chlorophenyl)
2961, 2927, 1685, 1522 cm
(1H, br s), 8.74 (1H, dd, J
;
H NMR (400 MHz, CDCl
¼4.2, J ¼1.6 Hz), 8.61 (1H, dd, J
¼8.3, J ¼1.6 Hz), 7.63 (2H, d, J¼7.2 Hz),
3
)
d
H
9.67
ethyl)-N-(quinolin-8-yl)butanamide (8hA). Following the general
procedure, 8hA (250 mg, 54%, meso (major) isomer) was obtained
after purification by column chromatography on silica gel as a col-
1
2
1
¼6.1,
J
2
¼3.0 Hz), 8.08 (1H, dd, J
1
2
7.43e7.29 (8H, m), 6.78 (2H, d, J¼8.7 Hz), 3.81 (1H, d, J¼10.9 Hz),
ꢀ
13
ourless solid; R
f
(10% EtOAc/Hexanes) 0.70; mp 108e110 C; IR
3.74e3.69 (1H, m), 3.68 (3H, s), 1.12 (3H, d, J¼6.9 Hz); C NMR
ꢂ1
1
(
KBr)
CDCl
dd, J
3H, m), 7.27 (4H, d, J¼8.5 Hz), 7.15 (4H, d, J¼8.5 Hz), 3.31e3.23 (2H,
n
max 3350, 2967, 2931, 1685, 1524 cm ; H NMR (400 MHz,
9.39 (1H, br s), 8.73 (1H, dd, J ¼1.6 Hz), 8.48 (1H,
¼4.2, J
¼2.9 Hz), 8.12 (1H, dd, J ¼8.3, J ¼1.7 Hz), 7.45e7.42
3 C
(100 MHz, CDCl ) d 171.1, 158.0, 147.8, 138.8, 137.9, 137.3, 136.4,
3
)
d
H
1
2
134.3, 128.7, 128.6, 128.3, 127.8, 127.4, 127.3, 121.4, 121.3, 116.5,
þ
1
¼6.0, J
2
1
2
113.9, 63.0, 55.1, 42.2, 20.3; HRMS: m/z [MþH] , found 397.1924,
(
26 25 2 2
C H N O requires 397.1916. The characterization data corre-
13
m), 2.99 (1H, t, J¼7.9 Hz), 1.52 (6H, d, J¼7.0 Hz); C NMR (100 MHz,
sponds the anti (major) isomer.
CDCl
3
)
d
C
170.4, 148.0, 142.3, 138.2, 136.2, 133.8, 132.1, 129.5, 128.3,
þ
1
27.8, 127.3, 121.5, 121.3, 116.1, 62.0, 39.3, 20.9; HRMS: m/z [MþH] ,
4.5. General procedure for the hydrolysis of carboxamides
(± ±-3c and (± ±-3d and the preparation of carboxylic acids (± ±-11
and (± ±-12
2 2
found 463.1341, C27H25Cl N O requires 463.1344.
4
(
8
.4.28. (S*)-3-(4-Chlorophenyl)-2-((S*)-1-(4-chlorophenyl)ethyl)-N-
quinolin-8-yl)butanamide (8hB). Following the general procedure,
hB (106 mg, 23%, minor isomer) was obtained after purification by
To a round bottom flask (with a capacity of 25 mL) molded with
a Liebig condenser (approximate length¼15 cm) sealed at the top
portion and having a J Young air inlet valve at the side of the round
bottom flask, was sequentially added a solution of carboxamide
column chromatography on silica gel as a colourless solid; R
f
(10%
ꢀ
EtOAc/Hexanes) 0.60; mp 165e167 C; IR (KBr)
n
max 3347, 2977,
9.09 (1H, br s),
¼2.9 Hz), 8.12
¼1.6 Hz), 7.48e7.46 (2H, m), 7.42 (1H, dd, J ¼8.3,
¼4.2 Hz), 7.19e7.15 (8H, m), 3.36e3.28 (2H, m), 2.90 (1H, dd,
ꢂ1
1
17d
17d
1
8
(
683, 1524, 1487 cm ; H NMR (400 MHz, CDCl
.66 (1H, dd, J ¼1.7 Hz), 8.57 (1H, dd, J ¼6.1, J
¼4.2, J
1H, dd, J
¼8.2, J
3
)
d
H
(ꢁ)-3c
or (ꢁ)-3d
(0.25 mmol) dissolved in a mixture of tolu-
SO H (0.5 mL) with the help
1
2
1
2
ene (3 mL) and water (0.5 mL) and CF
3
3
1
2
1
of syringes. Next, the air inlet was closed and the reaction mixture
ꢀ
J
J
2
was heated at 100 C and chilled water was circulated in the outer
1
3
1
¼8.5, J
2
¼7.1 Hz), 1.43 (3H, d, J¼7.0 Hz), 1.42 (3H, d, J¼7.0 Hz);
170.5, 148.0, 143.4, 142.9, 138.0, 136.1,
33.8, 132.1, 132.0, 129.3, 128.9, 128.7, 128.2, 127.7, 127.1, 121.5, 121.5,
C
glass tube of the condenser. The reaction mixture was heated for
12 h, then, the reaction mixture was transferred into a separating
funnel with the help of a syringe. The reaction mixture was diluted
3 C
NMR (100 MHz, CDCl ) d
1
þ
1
4
16.3, 61.9, 39.5, 39.2, 20.1, 16.9; HRMS: m/z [MþH] , found
2 3
with ethyl acetate and extracted with saturated aqueous Na CO
63.1340, C27
H
25Cl
2
N
2
O requires 463.1344.
solution (20 mLꢃ2). Then, the combined aqueous layers were
acidified with 1 N HCl (15 mLꢃ2) to get pHw2. Then, the aqueous
layers were extracted using ethyl acetate (10 mLꢃ2) and the com-
4
.4.29. (2S,3R)-2,3-Diphenyl-N-(quinolin-8-yl)butanamide
(10a). Following the general procedure, 10a (62 mg, 68%, ee 78% for
2 4
bined organic layers were dried over anhydrous Na SO and

8348
B. Gopalakrishnan et al. / Tetrahedron 71 (2015) 8333e8349
evaporation in vacuum afforded the corresponding carboxylic acid
ꢁ)-11 or (ꢁ)-12.
103, 2861; (h) Satoh, T.; Miura, T. Chem. Lett. 2007, 36, 200; (i) Miura, M.; Satoh,
T.; Hirano, K. Bull. Chem. Soc. Jpn. 2014, 87, 751.
(
. For selected reviews/articles on sp2 and sp3 CeH activation reactions, see; (a)
3
Engle, K. M.; Yu, J.-Q. J. Org. Chem. 2013, 78, 8927; (b) Chen, X.; Engle, K. M.;
Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094; (c) Li, B.-J.; Shi, Z.-J.
Chem. Soc. Rev. 2012, 41, 5588; (d) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011,
4
.5.1. (2R*,3S*)-2-Phenyl-3-(p-tolyl)butanoic acid (11).17d Following
the general procedure, (ꢁ)-11 (59 mg, 93%) was obtained after the
111, 1293; (e) For a themed issue on CeH activation reactions, see: CeH
work up procedure (the crude material was almost pure; purity of
Functionalization in organic synthesisChem. Soc. Rev. 2011, 40, 1845; (f) Davies,
H. M. L.; Du Bois, J.; Yu, J.-Q. Chem. Soc. Rev. 2011, 40, 1855; (g) Arockiam, P. B.;
Bruneau, C.; Dixneu, P. H. Chem. Rev. 2012, 112, 5879; (h) Colby, D. A.; Bergman,
R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624; (j) Hartwig, J. F. Acc. Chem. Res.
ꢀ
the compound >95%) as a colourless solid; mp 172e174 C; IR (KBr)
ꢂ1
1
n
max 3418, 1714, 1661, 1025, 999 cm
CDCl 7.43 (2H, d, J¼7.1 Hz), 7.31e7.18 (5H, m), 7.05
þDMSO-d
2H, d, J¼7.8 Hz), 3.64 (1H, d, J¼11.3 Hz), 3.41e3.33 (1H, m), 2.26 (3H,
;
H NMR (400 MHz,
3
6 H
) d
2012, 45, 864; (k) Corbet, M.; De Campo, F. Angew. Chem., Int. Ed. 2013, 52, 9896;
(
(l) Padmavathi, R.; Sankar, R.; Gopalakrishnan, B.; Parella, R.; Babu, S. A. Eur. J.
Org. Chem. 2015, 3727.
1
3
s) 0.94 (3H, d, J¼7.0 Hz); C NMR (100 MHz, CDCl
3
þDMSO-d
6 C
) d
4
. For selected articles on sp3 CeH activation reactions, see; (a) Giri, R.; Maugel,
N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am. Chem.
Soc. 2007, 129, 3510; (b) He, G.; Zhang, S.-Y.; Nack, W. A.; Li, Q.; Chen, G. Angew.
Chem., Int. Ed. 2013, 52, 11124; (c) Feng, Y.; Wang, Y.; Landgraf, B.; Liu, S.; Chen,
G. Org. Lett. 2010, 12, 3414; (d) Anas, S.; Cordi, A.; Kagan, H. B. Chem. Commun.
1
2
2
75.0, 142.3, 138.1, 135.7, 129.0, 128.6, 128.5, 127.4, 127.3, 59.4, 42.7,
þ
1.0, 20.4; HRMS: m/z [MꢂH] , found 253.1211, C17
17 2
H O requires
53.1229.
2
011, 11483; (e) Prokopcov ꢀa , H.; Bergman, S. D.; Aelvoet, K.; Smout, V.; Her-
4
.5.2. (2R*,3S*)-3-(4-Ethylphenyl)-2-phenylbutanoic acid (12).17d
Following the general procedure, the compound (ꢁ)-12 (62 mg,
3%) was obtained after the work up procedure (the crude material
rebout, W.; Van der Veken, B.; Meerpoel, L.; Maes, B. U. W. Chem.dEur. J. 2010,
16, 13063; (f) Larionov, E.; Nakanishi, M.; Katayev, D.; Besnard, C.; K
u€ ndig, E. P.
Chem. Sci. 2013, 4, 1995; (g) Stowers, K. J.; Kubota, A.; Sanford, M. S. Chem. Sci.
9
2012, 3, 3192; (h) Ye, X.; He, Z.; Ahmed, T.; Weise, K.; Akhmedov, N. G.; Pe-
was almost pure; purity of the compound >95%) as a colourless
tersen, J. L.; Shi, X. Chem. Sci. 2013, 4, 3712; (i) Chen, F.-J.; Zhao, S.; Hu, F.; Chen,
K.; Zhang, Q.; Zhang, S.-Q.; Shi, B.-F. Chem. Sci. 2013, 4, 4187; (j) Desai, L. V.;
Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542; (k) Tang, H.; Huang,
X.-R.; Yao, J.; Chen, H. J. Org. Chem. 2015, 80, 4672; (l) Wang, M.; Yang, Y.; Fan, Z.;
Cheng, Z.; Zhu, W.; Zhang, A. Chem. Commun. 2015, 3219; (m) Gou, Q.; Zhang,
Z.-F.; Liu, Z.-C.; Qin, J. J. Org. Chem. 2015, 80, 3176.
ꢀ
ꢂ1
;
solid; mp 99e101 C; IR (KBr)
n
max 3418,1714,1661,1025, 999 cm
1
H NMR (400 MHz, CD
3
OD)
d
H
7.50 (2H, d, J¼7.0 Hz), 7.38 (2H, t,
J¼7.5 Hz), 7.33e7.30 (1H, m), 7.27 (2H, d, J¼8.1 Hz), 7.15 (2H, d,
J¼8.2 Hz), 3.76 (1H, d, J¼11.5 Hz), 3.45e3.37 (1H, m), 2.62 (2H, q,
5. For selected articles on sp3 CeH activation reactions, see; (a) Tsukano, C.;
Okuno, M.; Takemoto, Y. Chem. Lett. 2013, 42, 753; (b) 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; (c) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am.
Chem. Soc. 2006, 128, 12634; (d) Shan, G.; Yang, X.; Zong, Y.; Rao, Y. Angew.
Chem., Int. Ed. 2013, 52, 13606; (e) Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am.
Chem. Soc. 2008, 130, 7190; For a representative paper dealing on benzylic
system, see; (f) Cao, X.; Yang, W.; Liu, C.; Wei, F.; Wu, K.; Sun, W.; Song, J.; Xie,
L.; Huang, W. Org. Lett. 2013, 15, 3102; For representative papers dealing on
13
J¼7.6 Hz), 1.23 (3H, t, J¼7.6 Hz), 0.97 (3H, d, J¼7.0 Hz); C NMR
(
100 MHz, CD
3
OD)
d
C
175.5, 142.4, 142.2, 138.3, 128.3, 128.3, 127.4,
þ
1
27.2, 127.1, 59.4, 42.7, 28.1, 19.4, 14.9; MS: m/z 268 ([M] , 1), 266
þ
þ
þ
þ
(
[M ꢂH
2
] , 8), 265 ([M e H
3
] , 88%).
Acknowledgements
functionalization of sp3 CeH bonds in the
a-position to a heteroatom, see; (g)
This work was funded by IISER Mohali. We thank the NMR, X-
ray and HRMS facilities of IISER Mohali. We also thank the single
crystal X-ray facility of the Department of Chemical Sciences, IISER-
Mohali. B.G. thanks Department of Science and Technology (DST),
New Delhi, for providing Innovation in Science Pursuit for Inspired
Research (INSPIRE) Senior Research fellowship. R. P. thanks IISER
Mohali for providing project assistant fellowship.
Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063;
(h) Wei, W.-T.; Song, R.-J.; Li, J.-H. Adv. Synth. Catal. 2014, 356, 1703; (i) Singh, P.
P.; Gudup, S.; Aruri, H.; Singh, U.; Ambala, S.; Yadav, M.; Sawant, S. D.; Vish-
wakarma, R. A. Org. Biomol. Chem. 2012, 10, 1587; (j) Pandit, R. P.; Lee, Y. R. Adv.
Synth. Catal. 2014, 356, 3171.
6. For selected articles on sp3 CeH activation reactions, see; (a) Zhang, S.-Y.; He,
G.; Zhao, Y.; Wright, K.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2012, 134, 7313;
(b) Ren, Z.; Mo, F.; Dong, G. J. Am. Chem. Soc. 2012, 134, 16991; (c) He, G.; Zhao,
Y.; Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012, 134, 3; (d) Bhakuni, B. S.;
Yadav, A.; Kumar, S.; Patel, S.; Sharma, S.; Kumar, S. J. Org. Chem. 2014, 79, 2944;
(
(
e) Kumar, N. Y. P.; Jeyachandran, R.; Ackermann, L. J. Org. Chem. 2013, 78, 4145;
f) Basl eꢀ , O.; Li, C.-J. Org. Lett. 2008, 10, 3661; (g) Watanabe, T.; Oishi, S.; Fujii, N.;
Supplementary data
Ohno, H. Org. Lett. 2008, 10, 1759; (h) Saget, T.; Perez, D.; Cramer, N. Org. Lett.
2013, 15, 1354; (i) Wertjes, W. C.; Wolfe, L. C.; Waller, P. J.; Kalyani, D. Org. Lett.
Supplementary data (Copy of 1H, 13C NMR charts of all the
compounds and X-ray (ORTEP diagram) structure of the com-
pounds (ꢁ)-3b, (ꢁ)-3c, (ꢁ)-3e, (ꢁ)-3l, 10c (enantiomerically
enriched compound), meso-8eA, (ꢁ)-8eB and (ꢁ)-8fB) associated
with this article can be found in the online version, at http://
dx.doi.org/10.1016/j.tet.2015.08.049.
2013, 15, 5986; (j) Wasa, M.; Yu, J.-Q. Tetrahedron 2010, 66, 4811; (k) Martin, N.;
Pierre, C.; Davi, M.; Jazzar, R.; Baudoin, O. Chem.dEur. J. 2012, 18, 4480; (l)
Murakami, R.; Tsunoda, K.; Iwai, T.; Sawamura, M. Chem.dEur. J. 2014, 20,
13127; (m) Sun, W.-W.; Cao, P.; Mei, R.-Q.; Li, Y.; Ma, Y.-L.; Wu, B. Org. Lett. 2014,
16, 480; (n) Aspin, S.; Goutierre, A.-S.; Larini, P.; Jazzar, R.; Baudoin, O. Angew.
Chem., Int. Ed. 2012, 51, 10808.
7
. For selected articles on sp3 CeH activation reactions, see; (a) Ano, Y.; Tobisu, M.;
Chatani, N. J. Am. Chem. Soc. 2011, 133, 12984; (b) Zhang, Q.; Chen, K.; Rao, W.;
Zhang, Y.; Chen, F.-J.; Shi, B.-F. Angew. Chem., Int. Ed. 2013, 52, 13588; (c) Zhu, R.-
Y.; He, J.; Wang, X.-C.; Yu, J.-Q. J. Am. Chem. Soc. 2014, 136, 13194; (d) Zhang, S.-
Y.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Chen, G. J. Am. Chem. Soc. 2013, 135, 2124;
References and notes
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2
G. Angew. Chem., Int. Ed. 1992, 31, 1023.
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(
. For selected reviews on Pd-catalyzed sp3 CeH activation reactions, see. (a)
8
9
Dastbaravardeh, N.; Christakakou, M.; Haider, M.; Schn u€ rch, M. Synthesis 2014,
Shul’pin, G. B. Chem. Rev. 1997, 97, 2879; (o) Mousseau, J. J.; Charette, A. B.
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Davies, H. M. L.; Jin, Q.; Ren, P.; Kovalevsky, A. Y. J. Org. Chem. 2002, 67, 4165; (b)
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2006; (d) Chen, K.; Zhang, S.-Q.; Jiang, H.-Z.; Xu, J.-W.; Shi, B.-F. Chem.dEur. J.
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B. Gopalakrishnan et al. / Tetrahedron 71 (2015) 8333e8349
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15. (a) The total yield of both the diastereomers is reported. The ratio of di-
astereomers was determined from the NMR spectra of the crude reaction
mixture; (b) See the Supplementary data file for the HPLC profile; (c) Nishi-
moto, Y.; Saito, T.; Yasuda, M.; Baba, A. Tetrahedron 2009, 65, 5462.
2
2
1
0. For a paper on ligand-enabled Pd-catalyzed diastereoselective arylation of
16. (a) In these cases, the products (ꢁ)-6aef were isolated as mixture of di-
astereomers and our efforts to separate the major and minor isomer in pure
form were not fruitful, hence we could not predict the stereochemistry of the
products (ꢁ)-6aef; (b) The respective products (ꢁ)-8b and (ꢁ)-8c were ob-
tained as diastereomers (dr 1:1); (c) In addition to the unambiguous assign-
ment of the stereochemistry of the corresponding diastereomers meso-8eAehA
(major isomers) and (ꢁ)-8eBehB (minor isomers) based on the single crystal
X-ray structure analysis (Fig. 2) of the diastereomers meso-8eA (major isomer),
(ꢁ)-8eB (minor isomer) and (ꢁ)-8fB (minor isomer); the NMR spectral pattern
of the respective series of the major diastereomers meso-8eAehA and minor
diastereomers (ꢁ)-8eBehB were compared. Typically, since the major di-
astereomers 8eAehA have a molecular symmetry (absolute configuration,
3S*,2R*), only half of the required 13C NMR signals were present in the C NMR
spectra of the corresponding major diastereomers meso-8eAehA. On the other
hand, the minor diastereomers (ꢁ)-8eBehB (absolute configuration, 3S*,2S*)
are structurally unsymmetrical and do not have a molecular symmetry. Hence,
all the required 13C NMR signals were present in the C NMR spectra of the
corresponding minor diastereomers (ꢁ)-8eBehB.
prochiral sp3 CeH bonds of aliphatic chains, see Wasa, M.; Chan, K. S. L.; Zhang,
X.-G.; He, J.; Miura, M.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134, 18570.
11. Directing group-enabled Pd-catalyzed diastereoselective arylation of prochiral
3
sp CeH bonds of aliphatic cyclic systems, see. (a) Zaitsev, V. G.; Shabashov, D.;
Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154; (b) Shabashov, D.; Daugulis, O. J.
Am. Chem. Soc. 2010, 132, 3965; (c) Feng, R.; Wang, B.; Liu, Y.; Liu, Z.; Zhang, Y.
Eur. J. Org. Chem. 2015, 142; (d) Xiao, K.-J.; Lin, D. W.; Miura, M.; Zhu, R.-Y.; Gong,
W.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2014, 136, 8138; (e) He, J.; Wasa, M.;
Chan, K. S. L.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 3387; (f) Kubota, A.; Sanford,
M. S. Synthesis 2011, 2579; (g) Wei, Y.; Tang, H.; Cong, X.; Rao, B.; Wu, C.; Zeng,
X. Org. Lett. 2014, 16, 2248; (h) Gutekunst, W. R.; Baran, P. S. J. Am. Chem. Soc.
13
2
011, 133, 19076; (i) Gutekunst, W. R.; Baran, P. S. J. Org. Chem. 2014, 79, 2430; (j)
Gutekunst, W. R.; Gianatassio, R.; Baran, P. S. Angew. Chem., Int. Ed. 2012, 51,
507; (k) Ting, C. P.; Maimone, T. J. Angew. Chem., Int. Ed. 2014, 53, 3115; (l)
7
Affron, D. P.; Davis, O. A.; Bull, J. A. Org. Lett. 2014, 16, 4956; (m) Wasa, M.; Engle,
K. M.; Lin, D. W.; Yoo, E. J.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 19598; (n) Nadres,
E. T.; Santos, G. I. F.; Shabashov, D.; Daugulis, O. J. Org. Chem. 2013, 78, 9689; (o)
Pan, F.; Shen, P.-X.; Zhang, L.-S.; Wang, X.; Shi, Z.-J. Org. Lett. 2013, 15, 4758; (p)
Seki, A.; Takahashi, Y.; Miyake, T. Tetrahedron Lett. 2014, 55, 2838; (q) Zhang, Q.;
Yin, X.-S.; Zhao, S.; Fanga, S.-L.; Shi, B.-F. Chem. Commun. 2014, 8353.
13
17. (a) In Scheme 6 the structure of one of the plausible conformers 1a,j, 3/10 and
7aed is drawn just for understanding the observed anti stereochemistry of
(ꢁ)-3ael. However, considering the free CeC bond rotation, there will be more
than one conformers of 1a,j, 3/10 and 7aee; (b) The anti stereochemistry of the
compounds (ꢁ)-11 and (ꢁ)-12 was assigned based on the their corresponding
starting materials. Further, since the amide hydrolysis has been carried out
under acidic condition the possibility of epimerization under acidic condition
was ignored in concurrence with our previous experience, see Ref. 13; (c) In
Scheme 8 the structure of one of the plausible conformers is drawn just for
understanding the observed stereocontrol and the stereochemistry of meso-8eA
(major isomer), (ꢁ)-8eB (minor isomer). However, considering the free CeC
bond rotation, there will be more than one conformers; (d) The starting ma-
terials (ꢁ)-3c or (ꢁ)-3d used for the hydrolysis contained traces of the corre-
sponding minor isomers and the NMR spectra of compounds 12 and 11 contains
traces of impurity peaks and presumably, these traces of impurity peaks be
associated to the minor isomers. Further, the carboxylic acids 11 and 12 ob-
tained in the work up procedure were almost pure (the purity of these com-
pounds >95%).
1
2. (a) Roman, D. S.; Charette, A. B. Org. Lett. 2013, 15, 4394; (b) Hoshiya, N.; Ko-
bayashi, T.; Arisawa, M.; Shuto, S. Org. Lett. 2013, 15, 6202; (c) Parella, R.; Go-
palakrishnan, B.; Babu, S. A. Org. Lett. 2013, 15, 3238; (d) Parella, R.;
Gopalakrishnan, B.; Babu, S. A. J. Org. Chem. 2013, 78, 11911; (e) Parella, R.; Babu,
S. A. Synlett 2014, 1395.
13. For paper on CeH functionalization of THF and 1,4-benzodioxane system, see
Parella, R.; Babu, S. A. J. Org. Chem. 2015, 80, 2339.
14. Directing group-enabled Pd-catalyzed diastereoselective arylation of primary
3
and secondary prochiral sp CeH bonds of amino acid systems, see; (a) He, G.;
Chen, G. Angew. Chem., Int. Ed. 2011, 50, 5192; (b) Wang, B.; Nack, W. A.; He, G.;
Zhang, S.-Y.; Chen, G. Chem. Sci. 2014, 5, 3952; (c) Zhang, S.-Y.; Li, Q.; He, G.;
Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2013, 135, 12135; (d) Chen, K.; Shi, B.-F.
Angew. Chem., Int. Ed. 2014, 53, 11950; (e) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J.
Org. Lett. 2006, 8, 3391; (f) Rodríguez, N.; Romero-Revilla, J. A.; Fern aꢀ ndez-
Ib aꢀ n~ ez, M. A.; Carretero, J. C. Chem. Sci. 2013, 4, 175; (g) Tran, L. D.; Daugulis, O.
ꢀ
Angew. Chem., Int. Ed. 2012, 51, 5188; (h) He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza,
B. N.; Spangler, J. E.; Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216; (i) Noisier, A. F.
M.; Brimble, M. A. Chem. Rev. 2014, 114, 8775; (j) Feng, Y.; Chen, G. Angew. Chem.
18. CCDC-1061839 (for (ꢁ)-3b), 1061840 (for (ꢁ)-3c), 1061841 (for (ꢁ)-3e), 1061842
(for (ꢁ)-3l), 1061846 (for enantiomerically enriched compound 10c), 1061843
(for meso-8eA), 1061844 (for (ꢁ)-8eB), and 1061845 (for (ꢁ)-8fB) contain the
supplementary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
19. The reaction involving the CeH arylation of 1j indicated that the ee values were
not changed during the course of the reaction (as both starting material 1j and
product 10a (anti, major diastereomer) have the ee value about 78%) and hence,
the configuration at the stereocenter was conserved in the products 10aec.
,
Int. Ed. 2010, 49, 958; (k) Chen, K.; Hu, F.; Zhang, S.-Q.; Shi, B.-F. Chem. Sci. 2013,
4
2
2
2
, 3906; (l) Chen, K.; Zhang, S.-Q.; Xu, J.-W.; Hu, F.; Shi, B.-F. Chem. Commun.
014, 13924; (m) Gong, W.; Zhang, G.; Liu, T.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc.
014, 136, 16940; (n) Poveda, A.; Alonso, I.; Fern ꢀa ndez-Ib aꢀ n~ ez, M. A. Chem. Sci.
ꢀ
014, 5, 3873; (o) Chen, G.; Shigenari, T.; Jain, P.; Zhang, Z.; Jin, Z.; He, J.; Li, S.;
Mapelli, C.; Miller, M. M.; Poss, M. A.; Scola, P. M.; Yeung, K.-S.; Yu, J.-Q. J. Am.
Chem. Soc. 2015, 137, 3338.