Microwave-assisted, rapid synthesis of 2-vinylquinolines and evaluation of their antimalarial activity

Article abstract of DOI:10.1016/j.tetlet.2019.05.054

A rapid and efficient synthesis of 2-vinylquinolines via trifluoromethanesulfonamide-mediated olefination of 2-methylquinoline and aldehyde under microwave irradiation is reported. Biological evaluation of these scaffolds demonstrates that 2-vinylquinolines 3x-3z possess excellent antimalarial activities against chloroquine-resistant Dd2 strain of Plasmodium falciparum (IC₅₀ < 100 nM).

Full text of DOI:10.1016/j.tetlet.2019.05.054

Accepted Manuscript
Microwave-assisted, rapid synthesis of 2-vinylquinolines and evaluation of their
antimalarial activity
Guang Huang, Claribel Murillo Solano, Yuxin Su, Nameer Ezzat, Shino Matsui,
Liuyu Huang, Debopam Chakrabarti, Yu Yuan
PII:
S0040-4039(19)30508-8
https://doi.org/10.1016/j.tetlet.2019.05.054
TETL 50826
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
2 May 2019
28 May 2019
Please cite this article as: Huang, G., Solano, C.M., Su, Y., Ezzat, N., Matsui, S., Huang, L., Chakrabarti, D., Yuan,
Y., Microwave-assisted, rapid synthesis of 2-vinylquinolines and evaluation of their antimalarial activity,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.05.054
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Microwave-assisted, rapid synthesis of 2-vinylquinolines and
evaluation of their antimalarial activity
a
Guang Huang a, 1, Claribel Murillo Solano b, 1, Yuxin Su c, d, 1, Nameer Ezzat , Shino
Matsui a, Liuyu Huang d, Debopam Chakrabarti b, *, Yu Yuan a, *
a Department of Chemistry, University of Central Florida, Orlando, FL, USA
b
Division of Molecular Microbiology, Burnett School of Biomedical Sciences,
University of Central Florida, Orlando, FL, USA
c.Academy of Military Medical Science, Beijing, China
d Chinese PLA Center for Disease Control and Prevention, Beijing, China
*Corresponding author.
E-mail address: Debopam.Chakrabarti@ucf.edu (D. Chakrabarti); Yu.Yuan@ucf.edu (Y.
Yuan).
1 These authors contribute equally to this work.
Abstract
A rapid and efficient synthesis of 2-vinylquinolines via trifluoromethanesulfonamide-
mediated olefination of 2-methylquinoline and aldehyde under microwave irradiation is
reported. Biological evaluation of these scaffolds demonstrates that 2-vinylquinolines 3x-
3z possess excellent antimalarial activities against chloroquine-resistant Dd2 strain of
Plasmodium falciparum (IC50 < 100 nM).
Keywords
2-vinylquinoline, 2-methylquinoline, olefination, microwave-assisted synthesis,
antimalarial
Introduction
Quinoline as a unique heterocyclic scaffold has found broad applications in medicinal
chemistry, as well as material science and agrochemical industries [1]. For example,
aminoquinolines such as chloroquine (CQ), amodiaquine (AQ) and piperaquine (PQ) are
clinical antimalarial drugs; hydroxyquinolines are excellent metal chelators as well as
important precursors for agrochemical production; and N-alkylated quinoline dyes are

versatile tools for biological studies. Among quinoline derivatives, 2-vinylquinolines
exhibit a wide range of pharmacological activities, as exemplified by antileishmanial
agent chimanine (A1) [2], anticancer compound A2 [3], integrase inhibitor FZ41 (A3) [4],
CysLT1 antagonist VUF 5017 (A4) [5] and antimalarial agent UCF 501 (A5) [6] (Fig. 1).
COOH
Br
OMe
OH
HOOC
N
N
Me
OH
N
FZ41
A3
chimanine
A1
A2
Me
OH
N
Me
Me
Me
O
O
N
Me
HN
MeO
N
COOH
N
VUF 5017
A4
UCF 501
A5
NO2
Fig. 1. Representative examples of bioactive 2-vinylquinolines.
Owing to their biological significance, the synthesis of 2-vinylquinolines has attracted
great attention from the chemistry community. The double bond is most conveniently
prepared from a Wittig reaction between 2-quinolinecarboxaldehydes and the
corresponding ylides (Scheme 1a) [7]. Nevertheless, the limited availability of 2-
quinolinecarboxaldehyde narrows the scope of this approach, and the stoichiometric
amount of phosphine oxide byproduct further complicates the purification. Alternatively,
treatment of quinoline N‑oxide with styrenes by reductive olefination or with boronic
acids via cross-coupling reaction can selectively afford trans-2-vinylquinolines (Scheme
1b) [8]. The downside of such transformations lies in the high cost of the metal catalyst
and the unsatisfactory yields. In addition, these olefination reactions also require long
reaction times and excessive amounts of the starting material.
From reagent cost and substrate availability perspectives, the most effective
methodology for the preparation of 2-vinylquinolines is the direct condensation of 2-
methylquinolines with proper aldehydes (Scheme 1c) [9]. However, this formal aldol-
type condensation requires long reaction time, high temperature or a metal catalyst,

furnishing 2-vinylquinolines in only modest isolated yields. To address this challenge,
many research groups have explored alternative imine surrogates and Mannich type
reactions (Scheme 1d). Wang and coworkers [10] reported N-bromosuccinimide (NBS)/
tert-butyl hydroperoxide (TBHP) mediated construction of 2-alkenlyquinoline through an
oxidative condensation-deamination process. Tian group [11] disclosed a related
olefination of secondary amines and 2-methylquinoline in the presence of 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ). Recently, Huang et al [12] developed an iron-
catalyzed synthesis of trans-2-vinylquinolines initiated by nucleophilic addition of 2-
methylquinolines to N-sulfonylaldimines. In addition, Wang [13] accomplished trans-
alkenylazaarene synthesis by reacting with in situ generated N-sulfonylaldimines. These
transformations greatly enriched the synthetic chemist’s toolbox, but rapid reactions
requiring no pre-formation of imines and organometallic catalysts are still highly
desirable.
Previous work:
(a)
+
+
Ph3P CHR
N
R
N
CHO
R2
R1
R1
R1
R
(b)
(c)
N
N
R2
R= H, BR2
ArCHO
O
R1
+
N
Ar
N
Me
R3
N
R1
R1
+
(d)
(e)
R2
N
R2
N
Me
This work:
R1
R2
R2
R1
MW, DMF, 140 oC
R3 CHO
+
N
R3
TfNH2, 20 min
N
Me
Scheme 1. Synthesis of 2-vinylquinolines
During the course of our investigation of 2-styrylquinolines as potential antimalarial

agents [6], we aimed to establish the preliminary structure–activity relationships (SARs)
at the C2 position by screening different arylvinyl groups. Herein, we report a rapid
synthesis of 2-vinylquinolines via trifluoromethanesulfonamide (TfNH2)-mediated
olefination under microwave irradiation (Scheme 1e) and the in vitro evaluation of these
compounds against Dd2 strain of Plasmodium falciparum.
Initially, the optimization was carried out using 2-methylquinoline 1a and
benzaldehyde 2a under microwave irradiation (Table 1). The additives played a crucial
role in the olefination reaction. For instance, the desired product was obtained in low
yields (13-30%) in the absence of any additive even with excess of aldehyde (Table 1,
entries 1-5); in contrast, the addition of sulfonamides significantly boosted the yield of 3a
(entries 6-11). Among the screened additives, TfNH2 was proved to be the most effective
(entries 8 and 11). Further investigation of solvents and additive stoichiometry revealed
that dimethylformamide (DMF) was the optimal solvent and 1.2 equivalents of TfNH2
provided the best yield of the 2-vinylquinoline (entry 12). The optimization of other
reaction parameters such as temperature and irradiation time quickly established that the
olefination reaction was best conducted at 140 ºC for 20 min (entry 16). No further
improvement was observed when higher temperature or shorter reaction time were
adopted (entries 14 and 17-20).
With the optimized conditions in hand, we investigated the generality of this
methodology (Table 2). The reaction of 6-methoxy-2-methylquinoline with different
aromatic aldehydes smoothly provided the desired products 3b-3e in excellent yields.
Aliphatic aldehydes (butyraldehyde and isovaleraldehyde) were valid substrates as well,
although the corresponding products 3f and 3g were isolated in moderate yields. We also
found that substitutions at the C4 position of the methylquinoline, including chloride,
aniline and aliphatic amines, were compatible with current microwave assisted conditions.
In general, chloro and phenylamino groups at the C4 position decreased the reaction
yields and alkyl amines retained the high yields of 2-vinylquinolines. The scope of
aldehydes was not limited to simple benzaldehydes and aliphatic aldehydes,
heteroaromatics aldehydes such as pyridinecarboxaldehyde and thiophenecarboxaldehyde
were also good substrates for the olefination. In line with the previous study [13], a
plausible mechanism for olefination is outlined in Scheme 2. Under our microwave

conditions, TfNH2 is optimal for in situ aldimine formation and facilitates the subsequent
elimination.
Table 1
Optimization of reaction conditions
CHO
N
N
Me
3a
1a
2a
entry
1
solvent
DMF
additive
-
equiv. a t (oC)
time (min) yield (%) b
3
130
130
130
130
130
130
130
130
130
130
130
130
130
130
140
140
140
150
160
160
30
30
30
30
30
30
30
30
30
30
30
30
30
20
30
20
10
20
20
10
19
30
13
26
22
45
72
81
64
82
89
92
83
73
86
93
82
84
75
83
2
DMF
-
5
3
1,4-dioxane
xylene
DMSO
xylene
xylene
xylene
DMF
-
5
4
-
5
5
-
5
6
carzenide
p-TsNH2
TfNH2
carzenide
p-TsNH2
TfNH2
TfNH2
TfNH2
TfNH2
TfNH2
TfNH2
TfNH2
TfNH2
TfNH2
TfNH2
3
7
3
8
3
9
3
10
11
12
13
14
15
16
17
18
19
20
DMF
3
DMF
3
DMF
1.2
1
DMF
DMF
1.2
1.2
1.2
1.2
1.2
1.2
1.2
DMF
DMF
DMF
DMF
DMF
DMF
a Represents the amount of benzaldehyde 2a
b Isolated yield

Table 2
Substrate scope of olefination under microwave irradiation.
R2
N
R2
R1
R1
TfNH2, MW
R3CHO
140 oC, DMF
2
R3
N
Me
1
3
Cl
N
MeO
MeO
N
N
R
R
3b
3c
3d
3e
: R = phenyl, 95% yield
3a
: 93% yield
3h
3i
: R = 4-nitrophenyl, 51% yield
: R = 4-pyridyl, 43% yield
: R = 4-dimethylaminophenyl, 94% yield
: R = 4-nitrophenyl, 91% yield
: R = 4-pyridyl, 87% yield
3f
3g
: R = propyl, 54% yield
: R = isobutyl, 60% yield
O
N
Ph
Cy
HN
N
NH
MeO
MeO
MeO
R
N
R
N
R
3l
3m
3n
3o
: R = 4-nitrophenyl, 91% yield
: R = 4-pyridyl, 85% yield
: R = 4-nitrophenyl, 93% yield
: R = 4-pyridyl, 87% yield
3j
: R = 4-nitrophenyl, 55% yield
3k
: R = 4-pyridyl, 48% yield
N
N
N
N
MeO
MeO
MeO
N
R
N
R
N
R
3r
: R = 4-nitrophenyl, 91% yield
3s
3t
3u
: R = 4-nitrophenyl, 84% yield
: R = 4-pyridyl, 87% yield
3p
3q
: R = 4-nitrophenyl, 90% yield
: R = 4-pyridyl, 88% yield
: R = 4-pyridyl, 85% yield
C2H4OH
N
Me
N
HN
Me
R
N
N
MeO
N
R
3x
3y
3z
: R = 4-pyridyl, 83% yield
: R = 2-thienyl, 88% yield
: R = 4-bromophenyl, 92% yield
3v
: R = 4-nitrophenyl, 83% yield
3w
: R = 4-pyridyl, 80% yield

R2
N
R2
N
R1
R1
TfNH2
R3CHO
R3
MW, DMF
2
Me
3
1
TfNH2
R1
R2
R2
R2
R1
R1
Tf
HN
N
H
R3
N
7
R3
N
H
6
4
N
Tf
TfNH2
N
R3CHO
Tf
2
R3
5
Scheme 2. Plausible mechanism for formation of 2-vinylquinoline 3
The newly synthesized compounds 3a–3z were evaluated for their in vitro antimalarial
activity against chloroquine-resistant Plasmodium falciparum Dd2 strain by SYBR green
I-based DNA quantification assay, using chloroquine as a positive control. As shown in
Table 3, compounds 3a-3h exhibited low activity against Dd2 strain (IC50 > 10 μM).
Attachment of phenylamino or cyclohexylamino groups at the C4 position improved
antimalarial activity to the low micromolar range. For instance, compound 3l (IC50 =
0.168 ± 0.001 μM) and 3m (IC50 = 0.227 ± 0.020 μM) showed comparable activity to
chloroquine (IC50 = 0.172 μM). Other simple amino groups incorporated into the C4
position, such as morpholinyl and piperidyl groups abolished antiplasmodial activity, as
demonstrated by compounds 3n-3p (IC50 > 10 μM), whereas analogues with pyrrolyl, 1-
methylpiperidyl, N-(2-hydroxyethyl) piperidyl and dimethylamino groups at C4 position
exhibited good activity against Dd2 strains with IC50 values ranging from 0.367 ± 0.052
to 0.672 ± 0.011 μM, except for compound 3w. In particular, compounds 3x-3z were
found to be more potent than chloroquine toward Dd2 strain (IC50 < 0.1 μM). It is worth
noting that 1l, an aminoquinoline without a vinyl group (IC50 = 5.516 ± 0.571 μM) is
significantly less potent than 3x, 3y and 3z, indicating that alkene motifs at the C2
position are vital to the antimalarial potency of aminoquinolines.

Table 3
In vitro antimalarial activity of 3a–3z against Dd2 strain
Compd.
Dd2 IC50 (μM) a
>10.0 b
Compd.
3o
Dd2 IC50 (μM) a
>10.0 b
3a
3b
>10.0 b
3p
>10.0 b
3c
>10.0 b
3q
4.895 ± 1.043
0.493 ± 0.092
0.367 ± 0.052
0.452 ± 0.087
0.610 ± 0.069
0.672 ± 0.011
>10.0 b
3d
>10.0 b
3r
3e
>10.0 b
3s
3f
>10.0 b
3t
3g
>10.0 b
3u
3h
>10.0 b
3v
3i
2.540 ± 0.434
0.509 ± 0.052
0.965 ± 0.167
0.171 ± 0.001
0.277 ± 0.020
>10.0 b
3w
3x
3j
0.033 ± 0.007
0.096 ± 0.005
0.040 ± 0.010
5.516 ± 0.571
0.172
3k
3y
3l
3z
c
3m
1l
3n
Chloroquine
aValues are mean of n ≥ 3.
b>IC50 value is above the highest concentration used in the assay.
c see supplemental data for structure.
Conclusions
In summary, we have explored the chemical space at quinoline’s C2 position with
various vinyl substituents. Access to such scaffolds is achieved by a rapid olefination
reaction mediated by TfNH2 under microwave irradiation. Compared to previous
approaches, our current method demonstrates broad substrate scope, mild conditions and
superior reaction kinetics. With this method, we have prepared a diverse range of
vinylquinoline analogues, some of which exhibit excellent antimalarial activity. Further
medicinal chemistry optimizations are currently underway to identify potent candidates
for the treatment of malaria infection.
Acknowledgment

This work is supported by the University of Central Florida and NIH/NIAID AI117298.
Supplementary data
Supplementary data associated with this article can be found.
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


Direct olefination of 2-methylquinoline under microwave irradiation
Broad substrate scope, excellent reaction kinetics
Potent antimalarial activity against chloroquine-resistant strain