Pd(OAc)2-Catalyzed, AgOAc-Promoted Z Selective Directed β-Arylation of Acrylamide Systems and Stereoselective Construction of Z-Cinnamamide Scaffolds

Article abstract of DOI:10.1021/acs.joc.5b02264

A Pd(OAc)₂-catalyzed, AgOAc-promoted and bidentate ligand-directed Z selective C-H activation, followed by the β-arylation of the C(sp²)-H bond of N-(quinolin-8-yl)acrylamide systems with aryl- and heteroaryl iodides, and a contemporary method for the construction of various Z-cinnamamides and β,β-diarylated acrylamides are reported. A plausible reaction mechanism comprising the bidentate ligand-aided, chelation-based C-H functionalization was proposed for the observed Z selective β-arylation of N-(quinolin-8-yl)acrylamide systems.

Full text of DOI:10.1021/acs.joc.5b02264

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Article
Pd(OAc)2-Catalyzed, AgOAc-Promoted Z Selective
Directed #-Arylation of Acrylamide Systems and
Stereoselective Construction of Z-Cinnamamide Scaffolds
Ramarao Parella , and Srinivasarao Arulananda Babu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02264 • Publication Date (Web): 30 Nov 2015
Downloaded from http://pubs.acs.org on November 30, 2015
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Pd(OAc)
2
ꢀCatalyzed, AgOAcꢀPromoted Z Selective Directed βꢀArylation of Acrylamide
Systems and Stereoselective Construction of ZꢀCinnamamide Scaffolds
Ramarao Parella and Srinivasarao Arulananda Babu*
Department of Chemical Sciences, Indian Institute of Science Education and Research
(IISER) Mohali, Manauli P.O., Sector 81, SAS Nagar, Mohali, Knowledge City, Punjab
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140306, India
sababu@iisermohali.ac.in
ABSTRACT:
A Pd(OAc) ꢀcatalyzed, AgOAcꢀpromoted and bidentate ligandꢀdirected Z selective CꢀH
2
2
activation followed by the βꢀarylation of C(sp )ꢀH bond of Nꢀ(quinolinꢀ8ꢀyl)acrylamide
systems with arylꢀ and heteroaryl iodides and a contemporary method for the construction of
various Zꢀcinnamamides and β, βꢀdiarylated acrylamides are reported. A plausible reaction
mechanism comprising the bidentate ligandꢀaided, chelationꢀbased CꢀH functionalization was
proposed for the observed Z selective βꢀarylation of Nꢀ(quinolinꢀ8ꢀyl)acrylamide systems.
INTRODUCTION
2
3
Transition metalꢀcatalyzed sp and sp CꢀH activation/functionalization reactions have
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ꢀ3
received substantial attention in recent years. Catalytic CꢀH activation/functionalization
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reactions considered as economical crossꢀcoupling methods, because, (a) it is a direct way for
forming the CꢀC bonds and generally, the prior preparation of organometallic reagents is not
required, and (b) in many cases, the suppression of waste/sideꢀproducts and usage of readily
available starting materials are possible. Amongst the transition metal catalysts, especially,
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the palladium catalysts are widely employed to perform the CꢀH functionalization reactions.
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While the unassisted CꢀH functionalization of organic molecules remains as a less explored
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area, the CꢀH functionalization of sp or sp CꢀH bonds of organic molecules directed by the
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ꢀ3
heteroatomꢀcontaining functional groups have been extensively studied. Particularly, the
recent studies by various research groups exposed the potential of the bidentate directing
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3
groups (e.g., 8ꢀaminoquinoline) in the research topic pertaining to the sp and sp CꢀH
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functionalization reactions.
Cinnamamide derivatives represent an important class of agrochemicals and several
cinnamamide derivatives (e.g., dimethomorph, flumorph and pyrimorph, Figure 1) exhibit
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b
4ꢀ7
herbicidal and fungicidal activities and a wide range of biological activities, such as,
antituberculosis, anticonvulsant, analgesic, antidepressant, antifungal and antiestrogenic
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agents) and function as mPTP inhibitors, KCNQ2 potassium channel openers and vanilloid
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receptorꢀ1 antagonists. Cinnamamide derivatives were also used as starting materials for
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assembling heterocyclic compounds (e.g. quinolones). Generally, cinnamamide derivatives
(βꢀarylated acrylamide derivatives) were prepared using the traditional synthetic methods or
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the celebrated Pdꢀcatalyzed MizorokiꢀHeck reaction of acrylic acidꢀbased substrates with a
suitable coupling partner. Apart from these methods, the βꢀarylated acrylic acid derivatives
were also assembled via the oxidative Heckꢀtype arylation tactic involving the reaction of
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acrylic acidꢀbased substrates with arenes or nucleophilic aryl metal reagents.
Usually, in
these reactions the corresponding βꢀarylated acrylic acid derivatives having the E geometry
were obtained as the major isomers. On the other hand, the exclusive preparation of βꢀ
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arylated acrylic acid derivatives including cinnamamides having the Z geometry under the
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traditional procedures is infrequently explored.
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Figure 1. Examples of cinnamamideꢀbased agrochemicals.
With regard to some of the notable methods dealing on the construction of βꢀarylated
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acrylamides having the Z geometry via the CꢀH functionalization;
Glorius’s group
P
*]ꢀcatalyzed CDC
10a
III
reported the Z selective βꢀarylation of the substrate 1a via the [Rh C
10d
reaction (Scheme 1). Ackermann’s group reported an attractive reaction involving an ironꢀ
catalyzed Z selective βꢀarylation of triazolyldimethylmethyl (TAM) amide (1b, Scheme 1).
10e
Recently, Ilies and Nakamura reported an interesting reaction involving the βꢀalkylation of
Nꢀ(quinolinꢀ8ꢀyl)acrylamide (1e) with alkyl tosylate in the presence of Fe(acac) /diphosphine
3
and ArZnBr as a base. In one of the reactions, the βꢀarylated acrylamide 4a (Z isomer) was
obtained along with the βꢀalkylated acrylamide product 3a (Scheme 1). Subsequently, Ilies
1
0f
and Nakamura reported the βꢀarylation of the substrate 1e with an organoborate reagent in
the presence of the iron and zinc catalysts, which afforded the corresponding βꢀarylated
acrylamides 5b / 4b (E/Z isomers, Scheme 1).
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Scheme 1. Pioneering Examples of Z Selective βꢀArylation of Acrylamide Systems and
Theme of This Work
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In continuation of our interest on the bidentate ligandꢀassisted CꢀH functionalization
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reactions, we envisaged Pd(OAc) ꢀcatalyzed AgOAcꢀmediated, bidentate ligand 8ꢀ
aminoquinolineꢀdirected, βꢀarylation of Nꢀ(quinolinꢀ8ꢀyl)acrylamide systems. To the best of
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our knowledge, the theme comprising Pd(OAc)
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ꢀcatalyzed, AgOAcꢀpromoted βꢀarylation of
Nꢀ(quinolinꢀ8ꢀyl)acrylamide systems has not been explored. Herein, we report the
stereoselective construction of various cinnamamide scaffolds having the Z geometry and β,
βꢀdiarylated acrylamides via the Pd(OAc) ꢀcatalyzed CꢀH activation followed by the βꢀ
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arylation of Nꢀ(quinolinꢀ8ꢀyl)acrylamides. This work demonstrates a contemporary route for
the βꢀarylation of acrylamide systems involving the straightforward experimental conditions,
in which commercially available arylꢀ or heteroaryl iodide is a coupling partner and
2 2
Pd(OAc) is a catalyst and AgOAc works as an additive to regenerate the Pd(OAc) catalyst.
RESULTS AND DISCUSSION
At the outset, to find out the best reaction conditions for achieving the Z selective βꢀ
arylation of the substrate 1e (derived from acryloyl chloride and Daugulis’s ligand), we
carried out several reactions comprising the bidentate ligand 8ꢀaminoquinolineꢀdirected CꢀH
activation followed by the βꢀarylation of the substrate 1e in the presence the Pd(OAc)2
catalyst (Table 1). The CꢀH arylation reaction of a mixture of 1e (1 equiv), iodobenzene (2b,
o
4
equiv), Pd(OAc)
2
catalyst (5 mol%) and AgOAc (additive, 2.2 equiv) in toluene at 110 C
afforded the mono βꢀarylated acrylamides 5b/4b (E/Z isomers) in 73% yield with E/Z ratio
:91 (entry 1, Table 1). Notably, this reaction afforded the βꢀarylated acrylamide 4b having
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the Z stereochemistry as the major isomer. The same reaction in the presence of 10 mol% of
the Pd(OAc) catalyst furnished the mono βꢀarylated acrylamides 5b/4b (E/Z isomers) with
2
slightly improved yield (87%) with E/Z ratio 11:89 (entry 2, Table 1). The Pdꢀcatalyzed
2 3
arylation of 1e with 2b in the presence of Ag CO instead of AgOAc gave the products 5b/4b
in only 36% yield (entry 3, Table 1). The arylation of 1e with iodobenzene (2b) in the
presence of other additives, such as, K CO or KOAc gave the products 5b/4b (E/Z isomers)
2
3
in low yields with poor E/Z selectivity (entries 4 and 5, Table 1). Usage of other palladium
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catalysts, such as, PdCl
products 5b/4b (E/Z isomers) in 32ꢀ58% yields with E/Z ratio up to 10:90 (entries 6ꢀ8, Table
). The reaction of substrate 1e with iodobenzene (2b) in other solvents, such as, 1,2ꢀDCE or
2 2 3 2 2 2
, Pd(TFA) and Pd(CH CN) Cl instead of Pd(OAc) gave the
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tertꢀbutanol or tertꢀamyl alcohol gave the products 5b/4b (E/Z isomers) in 44% (E/Z ratio =
2:98, entry 9, Table 1) and 36% (E/Z ratio = 17:83, entry 10, Table 1) and 63% yields (E/Z
ratio = 12:88, entry 11, Table 1), respectively. When compared to the reaction comprising the
arylation of substrate 1e with 4 equiv of iodobenzene (2b, entry 2), the yield of the products
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5b/4b (E/Z isomers) proportionately decreased in the reaction comprising the arylation of
substrate 1e with 3 or 2 or 1 equiv of iodobenzene (2b, entries 12ꢀ14, Table 1). The arylation
of 1e with the coupling partners other than iodobenzene (2b), such as, bromobenzene (2a) or
chlorobenzene (2c) was ineffective (entries 15 and 16, Table 1).
Next, to find out the other working directing groups, we performed the arylation of
the substrates 1hꢀj (which were derived from the corresponding bidentate ligands, Scheme 2)
using the Pd(OAc) /AgOAcꢀcatalytic system and the substrates 1hꢀj failed to afford the
2
corresponding βꢀarylated products (Scheme 2) under the optimized reaction conditions (entry
2
, Table 1) used for the substrate 1e. Further, we investigated the βꢀarylation of acrylamide
systems 1k and 1l (which were derived from 1ꢀnaphthylamine and αꢀmethylbenzylamine,
respectively). In contrast to the substrate 1e, the Pd(OAc) /AgOAcꢀcatalytic systemꢀbased
2
arylation of the substrates 1k and 1l directly gave the corresponding bis arylated products 7a
and 8a instead of any of the corresponding mono βꢀarylated products (7b or 8b, Scheme 2).
The Pdꢀcatalyzed arylation of the substrate 1k with 2 or 4 equiv of 4ꢀiodoanisole gave the bis
arylated product 7a in 17 and 49% yields (Scheme 2). Similarly, the Pdꢀcatalyzed arylation of
the substrate 1l with 4 equiv of 4ꢀiodoanisole gave the bis arylated product 8a in 52% yield
(Scheme 2).
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Table 1. Optimization of Reaction Conditions
Ph I (2b)
N
PdL (5-10 mol%)
N
N
2
O
O
O
+
additive (2.2 equiv)
N
H
N
H
N
H
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toluene (3 mL)
Ph
1e
Ph Ph
o
2
4 h, 80-110 C
5b / 4b (E : Z)
6
b
T ( C) yield (%)a
o
entry PdL (mol%)
additive
AgOAc
5b / 4b
E : Z
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5
b / 4b
Pd(OAc) (5)
1
2
110
73
9 : 91
Pd(OAc) (10)
2
2
AgOAc 110
87
11 : 89
Pd(OAc) (10)
Ag CO
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3
4
5
6
7
8
2
2
3
110
110
110
12 : 88
59 : 41
35 : 65
10 : 90
17 : 83
28 : 72
Pd(OAc) (10)
K CO
2 3
2
29
57
58
58
32
Pd(OAc) (10)
2
KOAc
PdCl (10)
2
AgOAc 110
AgOAc 110
AgOAc 110
AgOAc 80
AgOAc 85
Pd(TFA) (10)
2
Pd(CH CN) Cl (10)
3
2
2
9b
44
36
2 : 98
Pd(OAc) (10)
2
0c
1d
2e
1 f
4g
15h
1 i
17 : 83
Pd(OAc) (10)
1
1
2
Pd(OAc) (10)
2
AgOAc 105
63
12 : 88
Pd(OAc) (10)
1
2
AgOAc 110
AgOAc 110
73
55
10 : 90
11 : 89
Pd(OAc) (10)
3
2
Pd(OAc) (10)
1
2
AgOAc 110
37
10 : 90
Pd(OAc) (10)
2
AgOAc 110
AgOAc 110
0
0
-
-
Pd(OAc) (10)
6
2
a
The reactions were performed using 1e (0.25 mmol), 2b (4 equiv) and in these reactions, the
product 6b was not obtained in the column purification though traces of 6b seen in the crude
NMR of some cases. The E/Z ratios of diastereomers were determined from the NMR spectra
b
c
of the crude reaction mixtures. The reaction was performed in 1,2ꢀDCE. The reaction was
d
e
performed in tertꢀbutanol. The reaction was performed in tertꢀamyl alcohol. 3 Equiv of 2b
f
g
h
was used. 2 Equiv of 2b was used. 1 Equiv of 2b was used. In this reaction,
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i
bromobenzene (2a) was used instead of 2b. In this reaction, chlorobenzene (2c) was used
instead of 2b.
Scheme 2. Screening of Ligands and Conditions for the βꢀArylation of the Substrates
1hꢀl
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All the reactions were carried out using 0.25 mmol of 1k or 1l.
In an optimization reaction condition (entry 4, Table 1), the Pdꢀcatalyzed C(β)ꢀH
arylation of the substrate 1e with iodobenzene (2b) in the presence of K CO as an additive in
2
3
toluene furnished the products 5b/4b (E/Z isomers) with E/Z ratio 59:41. With an intention to
alter the E/Z ratio, we examined the reaction of the substrate 1e with iodobenzene (2b) in the
2 3
presence of K CO as an additive in tertꢀamyl alcohol, which afforded the product 5b (E
isomer) as the major isomer having the thermodynamically preferred E stereochemistry in
80% yield (5b/4b = E/Z = 92:8, Scheme 3). Along this line, the Pdꢀcatalyzed CꢀH arylation of
the substrate 1e with various aryl iodides in the presence of K CO in tertꢀamyl alcohol also
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gave the corresponding products 5a, 5cꢀg and 9 (E isomers) as the major isomers having the
thermodynamically preferred E stereochemistry (Scheme 3).
a,b
2 3
Scheme 3. PdꢀCatalyzed βꢀArylation of 1e and 1l in the presence of K CO
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a
The E/Z ratios of diastereomers were determined from the NMR spectra of the crude
b
reaction mixtures. All the reactions were carried out using 0.25 mmol of 1e or 1l. In some
case, the crude NMR revealed the presence of traces of the corresponding Z isomers and the
diꢀarylated compounds.
Table 2. Generality of the Pd(II)ꢀCatalyzed Z Selective Mono βꢀArylation of 1e with
a
Various Aryl Iodides
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Next, the generality of this protocol comprising the Pd(OAc) ꢀcatalyzed, AgOAcꢀ
mediated Z selective βꢀarylation of Nꢀ(quinolinꢀ8ꢀyl)acrylamide (1e) was expanded by
performing the CꢀH arylation of the substrate 1e with a variety of aryl iodides (Table 2). The
Pd(OAc) /AgOAcꢀcatalytic systemꢀbased direct βꢀarylation of Nꢀ(quinolinꢀ8ꢀyl)acrylamide
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1e) with aryl iodides containing a substituent at the para or meta position (e.g., alkyl, OMe,
2
F, Cl and NO ) successfully afforded the corresponding mono βꢀarylated acrylamides 5aꢀ
f/4aꢀf and 5hꢀq/4hꢀq (E/Z isomers) in 32ꢀ88% yields with E/Z ratio up to 2:98. We also
performed the Pdꢀcatalyzed βꢀarylation of Nꢀ(quinolinꢀ8ꢀyl)acrylamide (1e) with a variety of
heteroaryl iodides, which gave the corresponding products 5rꢀt/4rꢀt (E/Z isomers) in 59ꢀ73%
yields with E/Z ratio up to 20:80. In general, the βꢀarylated acrylamides 5/4 (E/Z isomers)
were obtained in good to very good yields and good to high E/Z ratios. Specifically, the low
or moderate yield and E/Z ratio of the products 5o/4o, 5s/4s and 5t/4t (E/Z isomers) may be
related to the reactivity pattern of the corresponding aryl iodides. Although, a precise reason
is not clear for this, it is assumed that the corresponding aryl iodides have strong coordinating
moieties (e.g. 1ꢀidodoꢀ2,4ꢀdimethoxybenzene contains an ortho methoxy group and 2ꢀfluoroꢀ
5ꢀiodopyridine and 5ꢀbromoꢀ2ꢀiodopyridine are pyridine based aryl iodides) which might be
disturbing the Pdꢀcatalyzed reaction course. The E stereochemistry of the minor isomers 5
and the Z stereochemistry of the major isomers 4 (Scheme 3 and Table 2) were ascertained
based on the observed characteristic coupling constant values of the corresponding doublet
peaks of the olefin protons (J = ~12.5 Hz for the Z isomer (4aꢀf and 4hꢀt) and J = ~15.5 Hz
for the E isomer (5aꢀt)) and the Xꢀray structure of the representative Z isomer 4s.
Then, we envisioned to extend the substrate scope of this method dealing on the
Pd(OAc)
2
ꢀcatalyzed, AgOAcꢀmediated
Z
selective βꢀarylation of Nꢀ(quinolinꢀ8ꢀ
yl)acrylamide. In this regard, we planned to use various acrylamide substrates (as shown in
Table 3), such as, cyclic carboxamides 1m, 1n, βꢀalkylated compounds 1o, 1p having the E
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1
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2
2
2
2
2
2
2
2
2
3
3
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5
5
5
5
5
5
5
6
stereochemistry and mono βꢀarylated acrylamide systems 5a, 5b, 5j, 5k and 5r having the E
stereochemistry. Initially, we carried out the Pdꢀcatalyzed βꢀarylation of the cyclic
2
carboxamides 1m and 1n, which gave the corresponding sp C(β)ꢀH bond arylated cyclic
carboxamides 10aꢀc in 20ꢀ53% yields (Table 3). Next, we performed the Pdꢀcatalyzed βꢀ
arylation of the βꢀalkylated compound 1o having the E stereochemistry with various
iodobenzenes, which successfully gave the corresponding βꢀalkylated β′ꢀarylated acrylamides
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
10dꢀg in 50ꢀ57% yields. Along this line, the Pdꢀcatalyzed βꢀarylation of the βꢀalkylated
compound 1p having the E stereochemistry also gave the corresponding βꢀalkylated β′ꢀ
arylated acrylamides 10h and 10i in 80 and 63% yields, respectively (Table 3).
Successively, we were interested to perform the second arylation of the C(β)ꢀH bond
of the mono βꢀarylated acrylamide system 5 having the E stereochemistry (e.g., 5a, 5b, 5j, 5k
2
and 5r) via the Pd(OAc) ꢀcatalyzed, AgOAcꢀmediated and bidentate ligand 8ꢀ
aminoquinolineꢀdirected CꢀH activation approach (Table 4). Accordingly, we carried out the
Pdꢀcatalyzed Z selective C(β)ꢀH activation followed by arylation of the mono βꢀarylated
acrylamide 5b having the E stereochemistry with several arylꢀ and heteroaryl iodides, which
successfully afforded the corresponding β,β′ꢀdiarylated acrylamides 6bꢀl in 40ꢀ81% yields
(Table 4). Along this line, the Pdꢀcatalyzed Z selective CꢀH functionalization of other mono
βꢀarylated acrylamide systems 5a, 5j, 5k and 5r (E isomers) with various arylꢀ and heteroaryl
iodides gave the corresponding β,β′ꢀdiarylated acrylamides 6mꢀp in 51ꢀ61% yields (Table 4).
Next, we carried out the benzylation of the substrate 5b using benzyl bromides in the
2
presence of Pd(OAc) catalyst, which successfully furnished the corresponding benzylated
acrylamides 11aꢀc in 54ꢀ79% yields (Table 4). The stereochemistry of the products 6cꢀl and
11aꢀc were assigned based on the Xꢀray structure of the representative compound 6i. The Xꢀ
ray structure of the representative compound 6i confirmed that the Pdꢀcatalyzed CꢀH
arylation of the substrate 5b having the E stereochemistry was stereoselective and the
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stereochemistry of the phenyl group in the product 6i was found to be unchanged with respect
to the carboxamide group of the mono βꢀarylated acrylamide 5b.
a
Table 3. Construction of the βꢀArylated Carboxamides 10aꢀi
10
11
12
13
14
15
16
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19
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22
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39
40
41
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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2
2
2
2
2
2
2
2
2
3
3
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3
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3
4
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
The compounds 10a and 10b were obtained from the substrate 1m. The Compound 10c was
obtained from the substrate 1n. The compounds 10dꢀg were obtained from the substrate 1o.
b
The compounds 10h,i were obtained from the substrate 1p. In this case, 2 equiv of the
c
corresponding aryl iodide was used. In this case, 4 equiv of the corresponding aryl iodide
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
was used.
a
Table 4. Construction of the βꢀArylated Carboxamides 6 and 11
R1 I (2, 4 equiv)
N
N
O
O
Pd(OAc) (10 mol%)
2
N
H
N
H
R1
AgOAc (2.2 equiv)
toluene (3 mL)
Ar
Ar
o
2
4 h, 110 C
5
a / 5b / 5j / 5k / 5r
6 / 11 (%)
(
0.25 mmol)
2
6
6
6
6
6
b; R = H; 65
2
N
N
c; R = Cl; 53
N
O
O
O
2
d; R = OMe; 64
N
H
N
H
N
H
2
e; R = Me; 60
2
6i; 60
(X-ray)
f; R = Et; 47
2
R2
6g; R = NO2; 50
O
2
6j; 70
6
h; R = F; 40
NO2
O
N
N
O
O
N
O
2
3
6
m; R , R = OMe; 61 (36 h)
N
N
H
H
N
2
3
Me
H
6n; R , R = Cl; 51 (48 h)
2
3
6
o; R , R = Me; 55
S
R3
R2
6
k; 59 Me
6l; 81
N
N
O
N
O
O
N
H
N
H
N
H
4
11c; 56d
1
1a; R = CF ; 79
3
4
S
S
11b; R = NO ; 54
2
Cl
6p; 55 (36 h)
R4
a
The compounds 6bꢀl were obtained from the substrate 5b. The compounds 6m, 6n, 6o and
p were obtained from the corresponding starting compounds 5a, 5j, 5k, and 5r. The
6
compounds 11aꢀc were obtained from the reaction of the substrate 5b with the corresponding
benzyl bromides.
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Thenceforward, we wished to perform the Pd(II)ꢀcatalyzed second βꢀarylation of the mono βꢀ
arylated acrylamide compound mixture 5b / 4b (E/Z isomers, E/Z ratio 11:89), in which the Z
2
isomer is the major compound. Accordingly, the Pd(OAc) ꢀcatalyzed, AgOAcꢀpromoted βꢀ
arylation of 5b / 4b (E/Z isomers, E/Z ratio 11:89) with iodobenzene (2b) furnished the β,β′ꢀ
diarylated acrylamide 6b in 50% yield (Scheme 4). Similarly, the βꢀarylation of 5b / 4b (E/Z
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
isomers, E/Z ratio 11:89) with iodobenzene (2b) in the presence of the Pd(OAc)
2
catalyst and
K
2
CO as an additive also gave the β,β′ꢀdiarylated acrylamide 6b in 48% yield. In these cases,
3
the product 6b was obtained in moderate yield and we did not isolate any other
characterizable side product from the column chromatography purification. We expected that
these reactions either will not proceed or give very low yield of 6b with recovery the E
isomer 5b, however, the product 6b was obtained in moderate yields (48 and 50%,
respectively, Scheme 4), which indicated that we cannot ignore the occurrence of E/Z
isomerization under the experimental conditions (see Table S1 and Scheme S2 of the
Supporting Information for some other trial reactions involving E/Z isomerization under the
experimental conditions and the arylation of 5b / 4b (E/Z isomers) with iodoanisole instead of
2b). When compared to the results of Table 4, notably, the βꢀarylation of the mono βꢀarylated
acrylamide compound 5b (having the E geometry) containing the directing group under the
conventional MizorokiꢀHeck reaction conditions failed to afford the corresponding β, β′ꢀ
diarylated acrylamide 12a (Scheme 4).
In the Pdꢀcatalyzed MizorokiꢀHeck reactions of acrylic acidꢀbased substrates with a
suitable coupling partner, generally, the corresponding βꢀarylatedꢀ acrylic acid derivatives
having the E stereochemistry were obtained as the major isomers. The exclusive or
predominant formation of the βꢀarylated acrylic acid derivatives having the Z stereochemistry
under the traditional Pdꢀcatalyzed MizorokiꢀHeck reactions conditions is infrequently
9ꢀ11, 13ꢀ18
observed.
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1
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2
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2
2
2
2
2
2
2
3
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3
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4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
In the present work, the Pd(OAc)
2
ꢀcatalyzed, AgOAcꢀpromoted bidentate ligand 8ꢀ
aminoquinolineꢀdirected βꢀarylation of Nꢀ(quinolinꢀ8ꢀyl)acrylamide system 1e was found to
be stereoselective and afforded the mono βꢀarylated acrylamides 4aꢀf and 4hꢀt having the Z
stereochemistry as the predominant isomers (Tables 1 and 2). Similarly, based on the results
of Table 4, the βꢀarylation of Nꢀ(quinolinꢀ8ꢀyl)acrylamide system 5b having the Eꢀ
stereochemistry was stereoselective and the stereochemistry of the phenyl group in the Xꢀray
structure of the representative product 6i was found to be unchanged with respect to the
carboxamide group of 5b. The observed Z selective βꢀarylation of Nꢀ(quinolinꢀ8ꢀ
yl)acrylamide systems 1e and 5b linked with the bidentate ligand 8ꢀaminoquinoline can be
envisaged via the plausible chelationꢀbased reaction pathway in concurrence with the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
ꢀ3,13
generally accepted proposed Pd(II/IV) catalytic cycle mechanism
pertaining to the
Pd(OAc) /AgOAcꢀcatalytic systemꢀbased CꢀH activation of carboxamides aided by the
2
bidentate ligand (Scheme 5). The mechanism for the bidentate directing groupꢀaided
Pd(OAc) /AgOAcꢀcatalytic systemꢀbased CꢀH activation proposed to involve the following
2
13
steps; (a) an initial coordination of the directing group to the Pd(II) catalyst followed by the
activation of C(β)ꢀH bond generates the Pd(II) species 13b, (b) next, in the oxidative addition
step, oxidation of the Pd(II) species 13b produces the Pd(IV) species 13c in presence of an
aryl iodide, (c) next, AgOAc helps in the ligand exchange step to generate the Pd(IV) species
13d, and finally, the reductive elimination of the Pd(IV) species 13d yields the desired
product 4/6 along with the regeneration of the Pd(II) catalyst for the next cycle. It is also
worth to mention here that the Niꢀ or Feꢀcatalyzed bidentate ligandꢀassisted Z selective CꢀH
arylation of acrylamide system was also proposed to occur involving a similar type of
14,15
chelationꢀbased CꢀH functionalization mechanism.
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a
Scheme 4. PdꢀCatalyzed βꢀArylation of 5b / 4b
Ph I (2b, 4 equiv)
N
N
O
N
O
Pd(OAc) (15 mol%)
O
2
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
H
Ph
b / 4b
E/Z = 11:89)
N
H
N
H
AgOAc (2.2 equiv)
toluene (3 mL)
Ph
Ph
Ph
5b 4b
/
; (0%)b
5
(
o
6b; 50%
48 h, 110 C
Ph I (2b, 4 equiv)
N
O
N
N
O
O
Pd(OAc) (10 mol%)
2
+
N
H
N
H
K CO (4 equiv)
N
H
2
3
Ph
b / 4b
E/Z = 11:89)
t-AmylOH (3 mL)
Ph
Ph
Ph
5
b / 4b; (0%)b
5
(
o
4
8 h, 105 C
6b; 48%
4
-iodoanisole (0.83 mmol)
Pd(OAc) (4 mol%)
2
N
O
N
PPh (8 mol%)
3
O
Cs CO (0.5 mmol)
N
H
2
3
12a; (0%)c
N
H
Ph
DMF (1.5 mL)
Ph
C H -(p)-OMe
6
4
5
b / 4b
o
2
4 h, 120 C
(E/Z = 100:0)
4
-iodoanisole (0.25 mmol)
N
O
N
O
Pd(OAc) (2 mol%)
2
PPh (4 mol%)
N
H
12a; (0%)c
3
N
H
Ph
C H -(p)-OMe
6
4
Ph
TMED (2 equiv)
o
5
b / 4b
5 h, 120 C
(E/Z = 100:0)
a
All the reactions were carried out using 0.25 mmol of 5b / 4b (E/Z isomers, E/Z ratio
b
11:89). The crude NMR spectra revealed the presence of only traces of 5b / 4b apart from
c
the product 6b. The crude NMR spectra revealed the recovery of the starting material 5b
and the Heck product 12a was not detected.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Additionally, to support the role of the bidentate ligand, 8ꢀaminoquinoline and
proposed Pdꢀcatalyzed, AgOAcꢀmediated chelationꢀbased CꢀH functionalization
13
mechanism (Scheme 5), we carried out some control reactions by using the substrates 14a
and 14b. Unlike the substrate 1e (which is linked with the bidentate ligand 8ꢀaminoquinoline)
which gave the mono βꢀarylated acrylamides 4aꢀf and 4hꢀt having the Z stereochemistry as
the predominant isomers; the CꢀH arylation of the substrates 14a and 14b (under the similar
reaction conditions used for the CꢀH arylation of the substrate 1e) in the presence of the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
Pd(OAc) catalyst and AgOAc as an additive furnished the corresponding mono βꢀarylated
acrylamides 15a and 15b having the Eꢀstereochemistry as the predominant isomers (Scheme
16
6), plausibly, via the ligandꢀfree MizorokiꢀHeck reaction mechanism.
Scheme 5. Plausible Mechanism for the Z Selective CꢀH Arylation of 1e and 5
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Scheme 6. MizorokiꢀHeckꢀType βꢀArylation of 14a,b and 1e,l Under the
a
Pd(OAc)
2
2 2 3
/AgOAc and Pd(OAc) /K CO Systems, Respectively
R1
4
-iodoanisloe (4 equiv)
via
Heck
reaction
mechanism
R1
Pd(OAc) (10 mol%)
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
AgOAc (2.2 equiv)
toluene (3 mL),
MeO
1
t
1
4a; R = COO Bu
E-isomer
1
o
1
t
1
4b; R = Ph
110 C, 24 h
1
1
5a; R = COO Bu; 75%
(0.25 mmol)
1
5b; R = Ph; 76%
O
Ar I (4 equiv)
O
R
N
via
Heck
reaction
mechanism
Pd(OAc) (10 mol%)
2
R
N
H
H
K CO (1.0 mmol)
2 3
Ar
E-isomer
t-AmylOH (2 mL)
1
(
e, l
0.25 mmol)
o
2
4 h, 105 C
5a-g, 9
Ar
I
I
O
O
Pd OAc
Pd(OAc)2
I
O
O
Pd OAc
Ar
R1
R1
base
R1
e, l
AcO
+
1
I
Pd OAc
B
Ar
I
R1
a-g, 9
Pd OAc
Ar
5
R1
adapted from Yao's ligand-free Heck reaction mechanism
Furthermore, from the reactions shown in Scheme 3, it is also known that the
Pd(OAc) ꢀcatalyzed βꢀarylation of the substrate 1e (which is linked with the bidentate ligand
8ꢀaminoquinoline) and the substrate 1l (which is not linked with the bidentate ligand 8ꢀ
2
1
7
aminoquinoline) in the presence of K CO instead of AgOAc in tertꢀamyl alcohol afforded
2
3
the corresponding βꢀarylated acrylamides 5aꢀg and 9 having the Eꢀstereochemistry as the
predominant isomers, plausibly, via the ligandꢀfree MizorokiꢀHeck reaction mechanism
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
8
suggested by Yao (Scheme 6). Moreover, from the reactions shown in Scheme 4, the βꢀ
arylation of the mono βꢀarylated acrylamide compound 5b (which is linked with the bidentate
ligand 8ꢀaminoquinoline) under the conventional MizorokiꢀHeck reaction conditions failed to
afford the product 12a. From the above deliberations, it is proposed that the observed Z
selective βꢀarylation of Nꢀ(quinolinꢀ8ꢀyl)acrylamide systems 1e and 5b (which are linked
0
1
2
3
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6
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8
9
0
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8
9
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0
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7
8
9
0
2
with the bidentate ligand 8ꢀaminoquinoline) is apparently governed by the Pd(OAc) /AgOAcꢀ
catalytic system and the bidentate ligand 8ꢀaminoquinoline, which can be comprehended via
the plausible chelationꢀbased CꢀH activation reaction pathway (as shown in Scheme 5) rather
than via the Heckꢀtype reaction mechanism.
a
Scheme 7. Gram Scale Reaction and Ligand Removal
a
All the amide hydrolysis reactions were carried out using 0.25 mmol of substrates.
Finally, we carried out the Pd(II)ꢀcatalyzed βꢀarylation of acrylamide 1e with
iodobenzene (2b) in a gram scale, which furnished the products 5b / 4b in 62% yield (E/Z
ratio 20:80, Scheme 7). Then, we planned to remove the bidentate ligand (8ꢀaminoquinoline)
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from the representative βꢀarylated acrylamide systems 5b / 4b (E/Z isomers, E/Z ratio 11:89)
1
2d,e
and 6b. Accordingly, the TfOHꢀmediated hydrolysis
of the representative carboxamides
o
5
b / 4b (E/Z isomers, E/Z ratio 11:89) at 100 C afforded the thermodynamically preferred Eꢀ
cinnamic acid 16a instead of the Z cinnamic acid under the experimental condition. Similarly,
the TfOHꢀmediated hydrolysis hydrolysis of the carboxamide 6b afforded the carboxylic acid
10
11
12
13
14
15
16
17
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19
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22
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16b in 53% yield (Scheme 7). We also tried the removal of the bidentate ligand (8ꢀ
aminoquinoline) from the βꢀarylated acrylamides 5b / 4b (E/Z isomers, E/Z ratio 11:89) using
a variety of other amide hydrolysis reaction conditions to get the Z cinnamic acid, however,
our efforts to get the Z cinnamic acid from the βꢀarylated acrylamides 5b / 4b (E/Z isomers,
E/Z ratio 11:89) were not fruitful (see the Supporting Information for the additional reactions
1ꢀ3,12
tried in this regard). Notably, a survey of the literature works
revealed that the removal of
the bidentate ligand (8ꢀaminoquinoline) from carboxamides after the CꢀH functionalization
reaction needs to be carried out by using relatively strong acidic or basic reaction conditions
and under heating conditions. In concurrence with the literature reports dealing on the cisꢀ
1
9ꢀ21
trans isomerization of cinnamic acid under thermal conditions
and considering the
reaction conditions worked (Scheme 7) to remove the bidentate ligand (8ꢀaminoquinoline),
the cis-trans isomerization was unavoidable in the present work. However, we will continue
to find out a suitable condition for removing of the bidentate ligand (8ꢀaminoquinoline) from
the βꢀarylated acrylamides 5b / 4b (E/Z isomers, E/Z ratio 11:89) to get the Z cinnamic acid.
CONCLUSION
2
In summary we have shown a contemporary method comprising Pd(OAc) ꢀcatalyzed,
AgOAcꢀpromoted and bidentate ligandꢀdirected Z selective CꢀH activation followed by the
arylation of C(β)ꢀH bond of Nꢀ(quinolinꢀ8ꢀyl)acrylamide systems with arylꢀ and heteroaryl
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5
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5
5
5
5
5
6
iodides. This method provided an easy access to mono Z cinnamamide derivatives and β, βꢀ
diarylated acrylamides. The observed Z selective βꢀarylation of Nꢀ(quinolinꢀ8ꢀyl)acrylamide
systems was explicated via a plausible chelationꢀbased CꢀH activation reaction pathway.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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8
9
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9
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9
0
EXPERIMENTAL SECTION
General. Melting points are uncorrected. IR spectra of compounds were recorded as
1
13
1
thin films or KBr pellets. H and C{ H} NMR spectra of compounds were recorded on 400
MHz and 100 MHz spectrometers respectively. HRMS measurements were obtained from
TOF mass analyzer using electrospray ionization (ESI). Column chromatography was carried
out using silica gel 100ꢀ200 mesh. Reactions were performed in anhydrous solvent under a
nitrogen atmosphere. Isolated yields of all the compounds were reported and yields were not
optimized. Amides (starting materials) used in the Pdꢀcatalyzed CꢀH arylation reactions were
prepared (from their corresponding acid chlorides and amines) by using the standard
literature procedures. The Heckꢀtype reactions involving the formation of 11b shown in
Scheme 4 were performed by using the standard literature procedures. The E/Z ratios of
diastereomers (E/Z isomers) were determined from the NMR spectra of the crude reaction
mixtures. In the cases of the Tables 1 and 2 and Schemes 3 and 6 the total isolated yields
diastereomers (E/Z isomers) were reported. In general, the E/Z isomers are separable and the
following points are with regard to Tables 1 and 2 and Scheme 3; after the Pd(II)ꢀcatalyzed
mono CꢀH arylation of the corresponding acrylamide systems, the purification of the crude
reaction mixture afforded the respective diastereomers (E/Z isomers) as a mixture since the
f
corresponding diastereomers (E/Z isomers) had similar R values. Then, the respective
diastereomers (E/Z isomers) were again subjected to the column chromatographic purification
to get the pure major and minor isomers. In most of the cases, the purification of the crude
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reaction mixtures gave only the major diastereomers in pure form and the corresponding
minor isomers could not be completely separated from their respective major isomers.
Additionally (except the reactions that gave very high E/Z ratio), the complete isolation of the
corresponding major diastereomers also was not possible and only a few fractions of the
corresponding major diastereomers were obtained, which were used to characterize the
corresponding major isomers. In some cases, the major diastereomers were isolated with
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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28
29
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32
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10e,f
22b
22c
22e
22a
traces of the corresponding minor diastereomers. Compounds 1e,
1i, 1j, 1k, 1l,
10f
10b
10f
10e
22d
23a
23b
1
m, 1n, 5b, 4a, 16a (commercial chemical), 16b, 15a and 15b are reported
in the literature.
General procedure for the βꢀarylation of acrylamides and preparation of 5aꢀf / 5hꢀt / 4aꢀ
f / 4hꢀt / 6bꢀp 7a / 8a / 10aꢀi / 11aꢀc / 15a,b using the Pd(OAc)
2
and AgOAc catalytic
(5ꢀ15 mol%, 2.8ꢀ8.4
system. An appropriate acrylamide (1.0 equiv, 0.25 mmol), Pd(OAc)
2
mg, 0.0125ꢀ0.0375 mmol), an appropriate aryl iodide (4.0 equiv, 1.0 mmol) and AgOAc
o
(91.8 mg, 0.55 mmol) in anhydrous toluene (3 mL) was heated at 110 C for 24ꢀ48 h under
nitrogen atmosphere. After the reaction period, the reaction mixture was concentrated in
vacuum and purification of the resulting reaction mixture through column chromatography
furnished the corresponding arylated acrylamides 5aꢀf / 5hꢀt / 4aꢀf / 4hꢀt / 6bꢀp 7a / 8a / 10aꢀ
i / 11aꢀc / 15a,b (see the respective Tables/Schemes for specific examples).
General procedure for the preparation of 5aꢀg / 4aꢀg / 6b / 9 using the Pd(OAc)
2
and
K CO catalytic system. An appropriate acrylamide (1.0 equiv, 0.25 mmol), Pd(OAc) (10
2
3
2
2 3
mol%, 5.6 mg, 0.025 mmol), an appropriate aryl iodide (4.0 equiv, 1.0 mmol) K CO (4.0
o
equiv, 138.2 mg, 1 mmol) in anhydrous t-AmylOH (2 mL) was heated at 105 C, for 24 h
under nitrogen atmosphere. After the reaction period, the reaction mixture was concentrated
in vacuum and purification of the resulting reaction mixture by column chromatography
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1
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1
1
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2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
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4
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5
5
5
5
5
5
6
furnished the corresponding arylated acrylamides 5aꢀg / 4aꢀg / 6b / 9 (see the respective
Tables/Schemes for specific examples).
Nꢀ(2ꢀMethylquinolinꢀ8ꢀyl)acrylamide (1h): Compound 1h was obtained after purification
by column chromatography on silica gel (EtOAc:Hexanes = 30:70) as a yellow colour liquid;
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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2
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4
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6
7
8
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3
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7
8
9
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2
3
4
5
6
7
8
9
0
ꢀ1 1
Yield: 75% (159 mg); IR (DCM): 3338, 1713, 1529, 1222, 737 cm ; H NMR (400 MHz,
CDCl ): δ 9.92 (br. s, 1H ), 8.78 (dd, 1H, J = 7.3 Hz, J = 1.6 Hz), 7.87 (d, 1H, J = 8.4 Hz),
.40ꢀ7.32 (m, 2H), 7.17 (d, 1H, J = 8.4 Hz), 6.52ꢀ6.41 (m, 2H), 5.77 (dd, 1H, J = 8.6 Hz, J
3
1
2
7
2
1
1
2
=
1
3
1
.9 Hz), 2.64 (s, 3H); C{ H} NMR (100 MHz, CDCl
3
): δ 163.5, 157.2, 137.6, 136.3, 133.6,
+
31.9, 127.2, 126.1, 125.9, 122.4, 121.6, 116.6, 25.2; HRMS (ESI): m/z [M + H] calcd for
C H N O: 213.1028; found 213.1025.
13
13
2
(E)ꢀNꢀ(Quinolinꢀ8ꢀyl)hexꢀ2ꢀenamide (1o): Compound 1o was obtained after purification by
column chromatography on neutral alumina (EtOAc:Hexanes = 20:80) as a brown colour
ꢀ1
1
liquid; Yield: 54% (130 mg); IR (DCM): 3351, 1682, 1530, 1486, 1385, 791 cm ; H NMR
(
400 MHz, CDCl ): δ 9.85 (br. s, 1H), 8.87 (dd, 1H, J = 7.5 Hz, J = 1.5 Hz), 8.81 (dd, 1H, J
3
1
2
1
= 4.2 Hz, J
2
1 2
= 1.7 Hz), 8.16 (dd, 1H, J = 8.2 Hz, J = 1.6 Hz), 7.56 (t, 1H, J = 8.2 Hz), 7.50
(
dd, 1H, J
1
= 8.2 Hz, J
= 7.0 Hz), 6.19 (td, 1H, J
.5 Hz), 1.60ꢀ1.52 (m, 2H), 0.99 (t, 3H, J = 7.3 Hz); C{ H} NMR (100 MHz, CDCl
2
= 1.5 Hz), 7.45 (dd, 1H, J
1
= 8.3 Hz, J
2
= 2.5 Hz), 7.08 (td, 1H, J
1
=
=
1
1
1
5.2 Hz, J
2
1
= 15.2 Hz, J
2
= 1.5 Hz), 2.28 (dq, 2H, J
1
= 7.2 Hz, J
2
13
1
3
): δ
64.4, 148.1, 146.2, 138.4, 136.4, 134.7, 127.9, 127.5, 124.7, 121.6, 121.5, 116.7, 34.2, 21.5,
+
13.8; HRMS (ESI): m/z [M + H] calcd for C H N O: 241.1341; found 241.1334.
15
17
2
(E)ꢀNꢀ(Quinolinꢀ8ꢀyl)pentꢀ2ꢀenamide (1p): Compound 1p was obtained after purification
by column chromatography on neutral alumina (EtOAc:Hexanes = 20:80) as a yellow colour
ꢀ1
1
liquid; Yield: 57% (130 mg); IR (DCM): 3350, 1684, 1527, 1485, 1327, 971 cm ; H NMR
(
400 MHz, CDCl ): δ 9.85 (br. s, 1H ), 8.86 (dd, 1H, J = 7.5 Hz, J = 1.4 Hz), 8.81 (dd, 1H,
3
1
2
J
1
= 4.2 Hz, J
2
= 1.6 Hz), 8.15 (dd, 1H, J
1
= 8.3 Hz, J
2
= 1.7 Hz), 7.55 (t, 1H, J = 8.1 Hz), 7.49
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(dd, 1H, J
5.2 Hz, J
J = 7.4 Hz); C{ H} NMR (100 MHz, CDCl
1
= 8.3 Hz, J
2
= 1.4 Hz), 7.44 (dd, 1H, J = 8.2 Hz, J
1
2 1
= 4.2 Hz), 7.13 (td, 1H, J =
1
2
= 6.4 Hz), 6.19 (td, 1H, J
1
= 15.2 Hz, J = 1.7 Hz), 2.36ꢀ2.29 (m, 2H), 1.50 (t, 3H,
2
13
1
3
): δ 164.4, 148.1, 147.6, 138.4, 136.4, 134.7,
+
127.9, 127.5, 123.7, 121.6, 121.4, 116.7, 25.3, 12.5; HRMS (ESI): m/z [M + H] calcd for
10
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13
14
15
16
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18
19
20
21
22
23
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29
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C H N O: 227.1184; found 227.1180.
14
15
2
1
0e
(Z)ꢀ3ꢀ(4ꢀMethoxyphenyl)ꢀNꢀ(quinolinꢀ8ꢀyl)acrylamide (4a): Compound 4a was obtained
after purification by column chromatography on silica gel (EtOAc:Hexanes = 27:73) as a
brown colour liquid; Yield: 74% (56 mg), (E:Z = 24:76); IR (DCM): 3412, 1713, 1362, 1222,
ꢀ1 1
7
37 cm ; H NMR (400 MHz, CDCl ): δ 9.94 (br. s, 1H), 8.88 (dd, 1H, J = 7.4 Hz, J = 1.3
3
1
2
Hz), 8.68 (dd, 1H, J
1
= 4.2 Hz, J
2
= 1.7 Hz), 8.15 (dd, 1H, J
1
= 8.2 Hz, J
= 1.5 Hz), 7.43 (dd, 1H,
2
= 4.2 Hz), 6.90 (d, 1H, J = 12.5 Hz) 6.87 (d, 2H, J = 8.9 Hz), 6.18 (d, 1H, J =
2
= 1.6 Hz), 7.69 (d,
2H, J = 8.9 Hz), 7.57 (t, 1H, J = 8.2 Hz), 7.52 (dd, 1H, J
= 8.4 Hz, J
2.5 Hz), 3.80 (s, 3H); C{ H} NMR (100 MHz, CDCl
1 2
= 8.3 Hz, J
J
1
13
1
1
1
3
): δ 165.2, 160.2, 148.0, 139.3,
38.4, 136.2, 134.6, 131.6, 127.9, 127.5, 127.4, 122.3, 121.5, 121.5, 116.6, 113.7, 55.3;
+
HRMS (ESI): m/z [M + H] calcd for C H N O : 305.1290; found 305.1280.
1
9
17
2
2
(E)ꢀ3ꢀ(4ꢀMethoxyphenyl)ꢀNꢀ(quinolinꢀ8ꢀyl)acrylamide (5a): Compound 5a was obtained
after purification by column chromatography on neutral alumina (EtOAc:Hexanes = 20:80)
o
as a colourless solid; Yield: 57% (44 mg), (E:Z = 95:5); mp 116ꢀ118 C; IR (KBr): 2922,
ꢀ1 1
1
602, 1525, 1381, 1033 cm ; H NMR (400 MHz, CDCl ): δ 9.99 (br. s, 1H), 8.93 (dd, 1H,
3
J
1
= 7.5 Hz, J
2
= 1.4 Hz), 8.85 (dd, 1H, J
1
= 4.2 Hz, J
2
= 1.6 Hz), 8.20 (dd, 1H, J
= 8.2 Hz, J
= 4.2 Hz), 6.95 (d, 2H, J = 8.3 Hz), 6.70 (d, 1H, J = 15.5
): δ 164.6, 161.1, 148.1, 141.8, 138.5,
1
= 8.3 Hz, J
2
= 1.6 Hz), 7.80 (d, 1H, J = 15.5 Hz), 7.62ꢀ7.58 (m, 3H), 7.54 (dd, 1H, J
1
2
= 1.4
Hz), 7.49 (dd, 1H, J
1
= 8.3 Hz, J
2
13
1
Hz), 3.87 (s, 3H); C{ H} NMR (100 MHz, CDCl
3
136.5, 134.8, 129.7, 128.0, 127.5, 121.7, 121.5, 119.1, 116.8, 114.3, 55.4; HRMS (ESI): m/z
+
[M + H] calcd for C H N O : 305.1290; found 305.1277.
1
9
17
2
2
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1
0f
(Z)ꢀ3ꢀPhenylꢀNꢀ(quinolinꢀ8ꢀyl)acrylamide (4b):
Compound 4b was obtained after
purification by column chromatography on silica gel (EtOAc:Hexanes = 25:75) as a brown
colour liquid; Yield: 87% (59 mg), (E:Z = 11:89); IR (DCM): 3342, 176, 1523, 1484, 790
ꢀ1 1
cm ; H NMR (400 MHz, CDCl ): δ 9.92 (br. s, 1H), 8.86 (dd, 1H, J = 7.5 Hz, J = 1.3 Hz),
3
1
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8.62 (dd, 1H, J = 4.2 Hz, J = 1.6 Hz), 8.14 (dd, 1H, J = 8.1 Hz, J = 1.6 Hz), 7.64ꢀ7.62 (m,
1
2
1
2
2H), 7.56 (t, 1H, J = 8.1 Hz), 7.51 (dd, 1H, J
1
= 8.3 Hz, J
2
1
= 1.6 Hz), 7.41 (dd, 1H, J = 8.2
2
Hz, J = 4.2 Hz), 7.35ꢀ7.28 (m, 3H), 7.01 (d, 1H, J = 12.5 Hz), 6.30 (d, 1H, J = 12.5 Hz);
1
3
1
C{ H} NMR (100 MHz, CDCl
3
): δ 164.9, 148.0, 139.0, 138.4, 136.2, 135.0, 134.4, 129.4,
+
1
28.7, 128.3, 127.9, 127.4, 124.7, 121.6, 121.5, 116.6; HRMS (ESI): m/z [M + H] calcd for
C H N O: 275.1184; found 275.1171.
18
15
2
1
0f
Nꢀ(Quinolinꢀ8ꢀyl)cinnamamide (5b): Compound 5b was obtained after purification by
column chromatography on silica gel (EtOAc:Hexanes = 30:70) as a pale yellow colour solid;
o
Yield: 80% (55 mg), (E:Z = 92:8); mp 117ꢀ119 C; IR (KBr): 3346, 1629, 1526, 1259, 825
ꢀ1 1
cm ; H NMR (400 MHz, CDCl ): δ 10.04 (br. s, 1H), 8.94 (dd, 1H, J = 7.5 Hz, J = 1.4
3
1
2
Hz), 8.86 (dd, 1H, J
1
= 4.2 Hz, J
2
= 1.6 Hz), 8.20 (dd, 1H, J
1
= 8.3 Hz, J
2
= 1.6 Hz), 7.85 (d,
1
H, J = 15.5 Hz), 7.65ꢀ7.63 (m, 2H), 7.59 (t, 1H, J = 7.6 Hz), 7.55 (dd, 1H, J
1
= 8.3 Hz, J
2
=
1
.5 Hz), 7.50 (dd, 1H, J = 8.3 Hz, J = 4.2 Hz), 7.46ꢀ7.41 (m, 3H), 6.83 (d, 1H, J = 15.5 Hz);
1 2
1
3
1
C{ H} NMR (100 MHz, CDCl
3
): δ 164.2, 148.2, 142.1, 138.5, 136.5, 134.8, 134.6, 129.9,
+
1
28.9, 128.1, 128.0, 127.5, 121.7, 121.5, 116.9; HRMS (ESI): m/z [M + H] calcd for
C H N O: 275.1184; found 275.1170.
18
15
2
(Z)ꢀ3ꢀ(4ꢀEthylphenyl)ꢀNꢀ(quinolinꢀ8ꢀyl)acrylamide (4c): Compound 4c was obtained after
purification by column chromatography on silica gel (EtOAc:Hexanes = 30:70) as a brown
colour liquid; Yield: 67% (50 mg), (E:Z = 10:90); IR (DCM): 3344, 1713, 1363, 1270, 530
ꢀ1 1
cm ; H NMR (400 MHz, CDCl ): δ 9.94 (br. s, 1H), 8.88 (dd, 1H, J = 7.5 Hz, J = 0.96
3
1
2
= 1.6 Hz), 7.59 (d,
26
Hz), 8.64 (dd, 1H, J
1
= 4.2 Hz, J
2
= 1.6 Hz), 8.13 (dd, 1H, J
1
= 8.3 Hz, J
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2H, J = 8.1 Hz), 7.55 (d, 1H, J = 7.7 Hz), 7.51 (dd, 1H, J
1 2
= 8.3 Hz, J = 1.4 Hz), 7.40 (dd,
1
H, J = 8.3 Hz, J = 4.2 Hz), 7.16 (d, 2H, J = 8.1 Hz), 6.96 (d, 1H, J = 12.5 Hz), 6.25 (d, 1H,
1
2
13
1
J = 12.5 Hz), 2.63 (q, 2H, J = 7.2 Hz), 1.20 (t, 3H, J = 7.6 Hz); C{ H} NMR (100 MHz,
CDCl ): δ 165.1, 147.9, 145.2, 139.3, 138.4, 136.2, 134.5, 132.3, 129.7, 127.9, 127.8, 127.4,
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
123.7, 121.6, 121.5, 116.6, 28.7, 15.4; HRMS (ESI): m/z [M + H] calcd for C H N O:
20
19
2
303.1497; found 303.1488.
(
E)ꢀ3ꢀ(4ꢀEthylphenyl)ꢀNꢀ(quinolinꢀ8ꢀyl)acrylamide (5c): Compound 5c was obtained after
purification by column chromatography on silica gel (EtOAc:Hexanes = 30:70) as a
o
colourless solid; Yield: 73% (55 mg), (E:Z = 85:15); mp 125ꢀ127 C; IR (KBr): 3348, 1675,
ꢀ1 1
1
526, 1485, 825 cm ; H NMR (400 MHz, CDCl
Hz, J = 1.4 Hz), 8.86 (dd, 1H, J = 4.2 Hz, J = 1.6 Hz), 8.20 (dd, 1H, J
Hz), 7.84 (d, 1H, J = 15.6 Hz), 7.62ꢀ7.53 (m, 4H), 7.49 (dd, 1H, J
3
): δ 10.02 (br. s, 1H), 8.94 (dd, 1H, J
1
= 7.5
= 1.6
2
1
2
1
= 8.2 Hz, J
2
1
2
= 8.2 Hz, J = 4.2 Hz),
7
.27 (d, 2H, J = 8.1 Hz), 6.80 (d, 1H, J = 15.6 Hz), 2.71 (q, 2H, J = 7.6 Hz), 1.29 (t, 3H, J =
13
1
7
.6 Hz); C{ H} NMR (100 MHz, CDCl ): δ 164.4, 148.1, 146.6, 142.1, 138.5, 136.5, 134.7,
3
132.3, 128.4, 128.2, 128.0, 127.5, 121.7, 121.6, 120.5, 116.8, 28.8, 15.4; HRMS (ESI): m/z
+
[
M + H] calcd for C20
H
19
N
2
O: 303.1497; found 303.1488.
(
Z)ꢀ3ꢀ(4ꢀIsopropylphenyl)ꢀNꢀ(quinolinꢀ8ꢀyl)acrylamide (4d): Compound 4d was obtained
after purification by column chromatography on silica (EtOAc:Hexanes = 25:75) as
colourless liquid; Yield: 82% (65 mg), (E/Z = 2:98); IR (DCM): 3345, 1675, 1524, 1484, 890
ꢀ1 1
cm ; H NMR (400 MHz, CDCl
Hz), 8.63 (dd, 1H, J = 4.2 Hz, J
H, J = 8.2 Hz), 7.55 (d, 1H, J = 7.7 Hz), 7.51 (dd, 1H, J
H, J = 8.2 Hz, J = 4.2 Hz), 7.19 (d, 2H, J = 8.2 Hz), 6.96 (d, 1H, J = 12.5 Hz), 6.24 (d, 1H,
3
): δ 9.94 (br. s, 1H), 8.87 (dd, 1H, J
= 1.6 Hz), 8.13 (dd, 1H, J = 8.3 Hz, J
= 8.2 Hz, J = 1.4 Hz), 7.40 (dd,
1
= 7.5 Hz, J
2
= 0.96
1
2
1
2
= 1.6 Hz), 7.60 (d,
2
1
1
2
1
2
1
3
1
J = 12.5 Hz), 2.91ꢀ2.84 (m, 1H), 1.21 (d, 6H, J = 6.9 Hz); C{ H} NMR (100 MHz, CDCl ):
3
δ 165.1, 149.8, 147.9, 139.2, 138.4, 136.2, 134.5, 132.4, 129.7, 127.9, 127.4, 126.4, 123.7,
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
121.5, 121.5, 116.5, 34.0, 23.8; HRMS (ESI): m/z [M + H] calcd for C21
H
21
N
2
O: 317.1654;
found 317.1657.
(
E)ꢀ3ꢀ(4ꢀIsopropylphenyl)ꢀNꢀ(quinolinꢀ8ꢀyl)acrylamide (5d): Compound 5d was obtained
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
after purification by column chromatography on silica (EtOAc:Hexanes = 25:75) as a
o
colourless solid; Yield: 82% (65 mg), (E/Z = 95:5); mp 136ꢀ138 C; IR (KBr): 3278, 1655,
ꢀ1 1
1618, 1544, 763 cm ; H NMR (400 MHz, CDCl
Hz, J = 1.2 Hz), 8.85 (dd, 1H, J = 4.2 Hz, J = 1.6 Hz), 8.18 (dd, 1H, J
Hz), 7.84 (d, 1H, J = 15.5 Hz), 7.61ꢀ7.56 (m, 3H), 7.53 (dd, 1H, J
3
): δ 10.02 (br. s, 1H), 8.95 (dd, 1H, J
1
= 7.5
= 1.6
2
1
2
1
= 8.3 Hz, J
2
1
2
= 8.2 Hz, J = 1.2 Hz),
7
.48 (dd, 1H, J = 8.3 Hz, J = 4.2 Hz), 7.30 (d, 2H, J = 8.3 Hz), 6.79 (d, 1H, J = 15.5 Hz),
1 2
13
1
3
3
.0ꢀ2.93 (m, 1H), 1.30 (d, 6H, J = 6.9 Hz); C{ H} NMR (100 MHz, CDCl ): δ 164.4, 151.2,
148.1, 142.2, 138.4, 136.5, 134.7, 132.4, 128.2, 128.0, 127.5, 127.0, 121.7, 121.6, 120.5,
+
1
16.8, 34.1, 23.8; HRMS (ESI): m/z [M + H] calcd for C21
H
21
N
2
O: 317.1654; found
317.1662.
(
Z)ꢀ3ꢀ(3,5ꢀDichlorophenyl)ꢀNꢀ(quinolinꢀ8ꢀyl)acrylamide (4e): Compound 4e was obtained
after purification by column chromatography on silica (EtOAc:Hexanes = 25:75) as a pale
o
yellow colour solid; Yield: 76% (65 mg), (E/Z = 2:98); mp 67ꢀ69 C; IR (KBr): 3340, 1676,
ꢀ1 1
1
558, 1485, 1329, 790 cm ; H NMR (400 MHz, CDCl
7.0 Hz, J = 2.0 Hz), 8.68 (dd, 1H, J = 4.2 Hz, J = 1.7 Hz), 8.13 (dd, 1H, J
.7 Hz), 7.56ꢀ7.50 (m, 4H), 7.41 (dd, 1H, J = 8.3 Hz, J = 4.2 Hz), 7.26ꢀ7.25 (m, 1H), 6.83
3
): δ 9.87 (br. s, 1H), 8.79 (dd, 1H, J
1
=
2
1
2
1
= 8.3 Hz, J =
2
1
1
2
13
1
3
(d, 1H, J = 12.5 Hz), 6.35 (d, 1H, J = 12.5 Hz); C{ H} NMR (100 MHz, CDCl ): δ 163.6,
148.1, 138.3, 137.9, 136.5, 136.3, 134.8, 134.1, 128.5, 127.9, 127.7, 127.4, 126.9, 122.0,
+
1
21.7, 116.8; HRMS (ESI): m/z [M + H] calcd for C18
H13Cl
2
N
2
O: 343.0405; found
343.0403.
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(E)ꢀ3ꢀ(3,5ꢀDichlorophenyl)ꢀNꢀ(quinolinꢀ8ꢀyl)acrylamide (5e): Compound 5e was obtained
after purification by column chromatography on neutral alumina (EtOAc:Hexanes = 20:80)
o
as a colourless solid; Yield: 56% (48 mg), (E:Z = 95:5); mp 148ꢀ150 C; IR (KBr): 2922,
ꢀ1 1
1
738, 1357, 1217, 786 cm ; H NMR (400 MHz, CDCl ): δ 10.08 (br. s, 1H), 8.90 (dd, 1H,
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
J = 7.2 Hz, J = 1.8 Hz), 8.85 (dd, 1H, J = 4.2 Hz, J = 1.6 Hz), 8.21 (dd, 1H, J = 8.3 Hz, J
1
2
1
2
1
2
=
1.6 Hz), 7.70 (d, 1H, J = 15.5 Hz), 7.62ꢀ7.55 (m, 2H), 7.50 (dd, 1H, J
1
= 8.3 Hz, J
2
= 4.2
13
1
Hz), 7.48 (d, 2H, J = 1.8 Hz), 7.38 (t, 1H, J = 1.8 Hz), 6.83 (d, 1H, J = 15.5 Hz); C{ H}
NMR (100 MHz, CDCl
3
): δ 163.1, 148.3, 139.2, 138.4, 137.8, 136.5, 135.5, 134.3, 129.5,
+
1
28.0, 127.5, 126.2, 124.2, 122.1, 121.8, 117.0; HRMS (ESI): m/z [M + H] calcd for
C H Cl N O: 343.0405; found 343.0394.
18
13
2
2
(Z)ꢀ3ꢀ(3ꢀNitrophenyl)ꢀNꢀ(quinolinꢀ8ꢀyl)acrylamide (4f): Compound 4f was obtained after
purification by column chromatography on silica gel (EtOAc:Hexanes = 30:70) as a yellow
o
colour solid; Yield: 88% (70 mg), (E:Z = 8:92); mp 150ꢀ152 C; IR (KBr): 3410, 1713, 1363,
ꢀ1 1
1
222, 738 cm ; H NMR (400 MHz, CDCl ): δ 9.95 (br. s, 1H), 8.82 (dd, 1H, J = 6.1 Hz, J
3
1
2
= 2.9 Hz), 8.70 (dd, 1H, J
1
= 4.2 Hz, J
2
= 1.7 Hz), 8.50 (br. s, 1H), 8.17 (dd, 2H, J
1
= 8.2 Hz,
2
J = 1.7 Hz), 8.02 (d, 1H, J = 7.8 Hz), 7.58ꢀ7.53 (m, 2H), 7.50 (t, 1H, J = 8.0 Hz), 7.46 (dd,
13
1
1H, J
1 2
= 8.3 Hz, J = 4.2 Hz), 7.02 (d, 1H, J = 12.4 Hz), 6.46 (d, 1H, J = 12.4 Hz); C{ H}
NMR (100 MHz, CDCl
3
): δ 163.5, 148.2, 148.1, 138.3, 137.3, 136.6, 136.4, 135.4, 134.0,
+
129.1, 127.9, 127.4, 126.8, 124.5, 123.3, 122.1, 121.7, 116.9; HRMS (ESI): m/z [M + H]
calcd for C H N O : 320.1035; found 320.1020.
18
14
3
3
(E)ꢀ3ꢀ(3ꢀNitrophenyl)ꢀNꢀ(quinolinꢀ8ꢀyl)acrylamide (5f): Compound 5f was obtained after
purification by column chromatography on neutral alumina (EtOAc:Hexanes = 20:80) as a
o
colourless solid; Yield: 59% (47 mg), (E:Z = 95:5); mp 199ꢀ201 C; IR (KBr): 2922, 1677,
ꢀ1 1
1
526, 1485, 1350, 1168 cm ; H NMR (400 MHz, CDCl ): δ 10.13 (br. s, 1H), 8.91 (dd, 1H,
3
J
1
= 7.0 Hz, J
2
= 2.0 Hz), 8.87 (dd, 1H, J
1
= 4.2 Hz, J
2
= 1.7 Hz), 8.50 (t, 1H, J = 1.8 Hz),
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