Synthesis and evaluation of antiplasmodial activity of 2,2,2-trifluoroethoxychalcones and 2-fluoroethoxy chalcones against plasmodium falciparum in culture

Article abstract of DOI:10.3390/molecules23051174

A new class of compounds comprising two series of chalcones with 2,2,2-trifluoroethoxy group and 2-fluoroethoxy groups were synthesized and screened for in vitro antiplasmodial activity against Plasmodium falciparum (3D7) using the [³H] hypoxanthine incorporation inhibition assay. Chalcones with 2,2,2-trifluoroethoxy groups substituted on the p- and m-positions of the 1-phenyl ring showed weak antiplasmodial activity, while compounds substituted on the o-position of the 1-phenyl ring displayed enhanced antiplasmodial activity, thus indicating that 2,2,2-trifluoroethoxy groups on the 1-phenyl ring of chalcones show position-dependent antiplasmodial activity. Of the 34 compounds synthesized, chalcones 3a and 3f exhibited significant inhibitory effects, with IC₅₀ values of 3.0 μg/mL and 2.2 μg/mL, respectively. Moreover, these compounds 3a and 3f showed profound antiplasmodial activity in combination with artemisinin in vitro. The most active molecules, 3a, and 3f, were further assessed for their cytotoxicity towards mammalian Vero cells and the selectivity index (SI) values are 8.6, and 8.2 respectively, being considered non-toxic. We also studied the antiplasmodial activity of 2-fluoroethoxychalcones to discern the effect of the number of fluorine atoms in the fluoroethoxy group. Our results showed that chalcones with 2-fluoroethoxy group on the 1-phenyl ring exhibited more enhanced inhibitory effects on the growth of parasites than their trifluoro analogues, which reveals that monofluoroethoxy group is generally more effective than trifluoroethoxy group in the inhibition of parasite growth. Thus o-2,2,2-trifluoroethoxychalcones (Series 3) and 2-fluoroethoxychalcones may serve as good antiplasmodial candidates for future further development.

Full text of DOI:10.3390/molecules23051174

molecules
Article
Synthesis and Evaluation of Antiplasmodial Activity
of 2,2,2-Trifluoroethoxychalcones and 2-Fluoroethoxy
Chalcones against Plasmodium falciparum in Culture
Kavita Devi 1, Vinoth Rajendran 2, Ayushee 3, T. M. Rangarajan 4, ID , Rishi Pal Singh 4,*,
*
Prahlad C. Ghosh 2 and Manjula Singh 5
1
Fluoroorganic Laboratory, Center for Fire, Explosive and Environment Safety, Delhi-110 054, India;
kavik188@gmail.com
Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi 110 021,
India; vinoth.avj@gmail.com (V.R.); pcghose@gmail.com (P.C.G.)
Department of Chemistry, Hansraj College, University of Delhi, Delhi 110 007, India;
ayusheesingh27@yahoo.in
Department of Chemistry, Sri Venkateswara College, University of Delhi, New Delhi 110 021, India
Department of Chemistry, Shivaji College, University of Delhi, New Delhi 110 027, India;
manjulasingh56@gmail.com
2
3
4
5
*
Correspondence: rangarajan93150@gmail.com (T.M.R.); rpsingh54@gmail.com (R.P.S.);
Tel.: +91-882-542-6596 (T.M.R.)
Academic Editor: Diego Muñoz-Torrero
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 2 April 2018; Accepted: 9 May 2018; Published: 14 May 2018
Abstract: A new class of compounds comprising two series of chalcones with 2,2,2-trifluoroethoxy
group and 2-fluoroethoxy groups were synthesized and screened for in vitro antiplasmodial activity
against Plasmodium falciparum (3D7) using the [3H] hypoxanthine incorporation inhibition assay.
Chalcones with 2,2,2-trifluoroethoxy groups substituted on the p- and m-positions of the 1-phenyl
ring showed weak antiplasmodial activity, while compounds substituted on the o-position of the
1-phenyl ring displayed enhanced antiplasmodial activity, thus indicating that 2,2,2-trifluoroethoxy
groups on the 1-phenyl ring of chalcones show position-dependent antiplasmodial activity. Of the
34 compounds synthesized, chalcones 3a and 3f exhibited significant inhibitory effects, with IC50
values of 3.0 µg/mL and 2.2 µg/mL, respectively. Moreover, these compounds 3a and 3f showed
profound antiplasmodial activity in combination with artemisinin in vitro. The most active molecules,
3a, and 3f, were further assessed for their cytotoxicity towards mammalian Vero cells and the
selectivity index (SI) values are 8.6, and 8.2 respectively, being considered non-toxic. We also studied
the antiplasmodial activity of 2-fluoroethoxychalcones to discern the effect of the number of fluorine
atoms in the fluoroethoxy group. Our results showed that chalcones with 2-fluoroethoxy group on
the 1-phenyl ring exhibited more enhanced inhibitory effects on the growth of parasites than their
trifluoro analogues, which reveals that monofluoroethoxy group is generally more effective than
trifluoroethoxy group in the inhibition of parasite growth. Thus o-2,2,2-trifluoroethoxychalcones
(Series 3) and 2-fluoroethoxychalcones may serve as good antiplasmodial candidates for future
further development.
Keywords: fluoroethoxychalcones; antiplasmodial activity; Plasmodium falciparum (3D7); artemisinin
combination therapy; cytotoxicity
Molecules 2018, 23, 1174; doi:10.3390/molecules23051174
www.mdpi.com/journal/molecules

Molecules 2018, 23, 1174
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1. Introduction
Chalcones (1,3-diaryl-2-propen-1-ones), or
α,β-unsaturated carbonyl compounds, the bioprecursors
of flavonoids, are an interesting class of compounds that engross medicinal [
and material chemists [ ] with their diverse applications. Considerable evidence has shown
that chalcones have immense chemotherapeutic importance, such as anti-inflammatory [ ],
antimicrobial [9,10], antileishmanial [11], anticancer [12,13], antimalarial [14–16] activities. Moreover,
radiolabeled chalcones have been used as PET imaging agents for in vivo imaging of the -amyloid
plaques of Alzheimer’s disease [17 18]. After the advent of licochalcone A with its antiplasmodial
activity [19], a large number ofnovel synthetic chalcone derivatives and chalcone hybrids have been
designed, synthesized and evaluated for their antiplasmodial activity [20 24]. Several reports suggest
1,2], synthetic [3],
4–6
7,8
β
,
–
that chalcones’ antiplasmodial potential is due the ability to inhibit both the plasmodial aspartate
protease and cysteine protease targets [24,25].
Malaria is a parasitic disease caused by Plasmodium, which is transmitted to human by female
anopheline mosquitoes and continues to be a major cause of the death, killing an estimated 1.5 to
2.7 million people per year [14,26,27]. The high mortality rate caused by P. falciparum strains
is compounded by the fact the parasite has shown clinical resistance to currently used first-line
antimalarial drugs like chloroquine and vaccines have proven ineffective. Even though Artemisinin is
currently considered to be an effective drug for treating chloroquine-resistant P. falciparum infections the
WHO has recommended artemisinin-based combination therapies (ACTs) due to the slow development
of clinical resistance to this compound. This averts or slows down the resistance developed by
P. falciparum to this compound. ACTs also mitigate the increasing demand for artemisinin, which is
isolated from the plant Artemisia annua, due to the unavailability of commercially viable synthesis.
Therefore, there is a state of emergency to develop new antimalarial agents or drug combinations
which are effective and cost-effective [15,16,28].
The use of fluorine or fluorine-containing functional groups in organic compounds has
shown spectacular growth in all branches of chemistry, such as medicinal chemistry [29–31],
agrochemistry [32], material sciences [33], etc. Substitution of fluorine or fluorine-containing
functional group in organic molecules exerts large electronic effects on neighboring carbon centers
and greatly affects the physico-chemical properties of the resulting molecules. Lipophilicity is an
important criterion for the molecules that increases fat solubility and bioavailability, and can be
increased by a strategic transformation of organic molecules into fluoroorganic molecules [29
Fluorine substitution at an appropriate site of the molecule can increase their biological half-life,
extended activity, and potency by altering the rate of drug metabolism [30 34]. Interestingly,
,30].
,
2,2,2-trifluoroethoxy group-containing molecules appear to be one of the most attractive fluoro
functionalities in pharmaceuticals, found in blockbuster drugs such as flecainide, lansoprazole,
MF-310, etc. [35,36].
Fluoroorganic compounds and chalcones alone exhibit broad ranges of applications [1–6,29–33,37].
Therefore, incorporation of fluorine or fluorine containing groups into chalcones would be expected to
have a strong effect on their physico-chemical properties which, in turn, could augment their biological
activities. Moreover, biological evaluations of fluorochalcones have not been fully explored, except
for some fluorochalcone derivatives, which have been reported for their anti-inflammatory [38
or anti-proliferative activity [40], or as inhibitors of monoamine oxidase-B [41 42]. Recently, we have
reported a novel methodology for the coupling of bromochalcones with alcohols and fluoroalcohols by
Pd/tBuXPhos catalyst systems [43 47]. Taking into consideration of the importance of fluoroethoxy
,39],
,
–
groups and chalcones in biological activity, we pleased to synthesize fluoroethoxy chalcones and
assess their antiplasmodial activity. Herein, we report the synthesis and antiplasmodial evaluation of
2,2,2-trifluoroethoxychalcones and 2-fluoroethoxychalcones on the growth of P. falciparum in culture.
The most active compounds, 3a and 3f, were further tested for hemolytic activity, cytotoxicity on Vero
cells and in combination with artemisinin as a partner antimalarial agent.

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2. Results and Discussion
2.1. Chemistry
A series of 2,2,2-trifluoroethoxychalcones 1a
–n,
2a–h,
2k
,
2m, and 3a
–j
were synthesized in poor
to excellent yields (40–94%) by base catalyzed Claisen
trifluoroethoxy)phenyl)ethanone (
trifluoroethoxy)phenyl)ethanone (
−
Schmidt condensation of 1-(4-(2,2,2-
), and 1-(2-(2,2,2-
1
), 1-(3-(2,2,2-trifluoroethoxy)phenyl)ethanone (
3
2
), with substituted benzaldehydes as shown in Scheme 1.
All the reactions were carried out at room temperature for 30 min, except in the case of
indole-2-carboxaldehyde which was the only aldehyde that required refluxing for 2 h as the reaction
did not proceed at room temperature and gave the product 1n in poor yield (40%).
Scheme 1. Synthesis of 2,2,2-trifluoroethoxychalcones.
Similarly, 2-fluoroethoxychalcones, in which 2-fluoroethoxy group is substituted on both
the 1-phenyl and 3-phenyl rings, were also synthesized in moderate to excellent yields (66–90%)
by the same method from the corresponding 1-(4-(2-fluoroethoxy)phenyl)ethanone (
fluoroethoxy)phenyl)ethanone ( ), and 1-(2-(2-trifluoroethoxy)phenyl)ethanone ( ), with substituted
benzaldehydes and 4-(2-fluoroethoxy)benzaldehyde ( ), 3-(2-fluoroethoxy)benzaldehyde ( ),
and 2-(2-fluoroethoxy)benzaldehyde ( ) with substituted acetophenones ix as shown in Scheme 2.
Of the 59 chalcones synthesized, 12 chalcones (compounds 1a 1e 4a 4e 4g 7i ii 7iv 7vii, and 8ii)
have already been reported [43 44] and the rest of the chalcones reported here are novel. All the
4), 1-(3-(2-
5
6
7
8
9
i–
,
–
g,
,
,
,
–
,
,
,
chalcones were characterized by 1H-, 13C- and 19F-NMR (NMR spectra of all the compounds can be
found in the supplementary materials), IR and HRMS analysis and the data were consistent with
the structure of the chalcones. The starting materials viz., ((2,2,2-trifluoroethoxy)phenyl)ethanones,
((2-fluoroethoxy)phenyl)ethanones, and 2-fluoroethoxy- benzaldehydes were synthesized by
nucleophilic displacement reactions of 2,2,2-trifluoroethyl-4-methylbenzenesulphonate and
2-fluoroethyl-4-methylbenzenesulphonate with the corresponding hydroxyacetophenones and
hydroxybenzaldehydes using sodium hydride base in dry DMF at 120 ◦C. The 2,2,2-trifluoroethyl-
4-methylbenzenesulphonate and 2-fluoroethyl-4-methylbenzene- sulphonate were synthesized from
the reaction of the corresponding fluoroalcohols with p-toluene-sulfonyl chloride in the presence of
potassium hydroxide solution in water at room temperature.
Scheme 2. Cont.

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Scheme 2. Synthesis of 2-fluoroethoxychalcones.
2.2. Antiplasmodial Activity of 2,2,2-Trifluoroethoxychalcones
Initially, we intended to investigate the effect of the position of the 2,2,2-trifluoroethoxy group on
the 1-phenyl ring of chalcones (Scheme 1) on the growth inhibition of P. falciparum (3D7) in culture.
The 50% inhibitory concentration (IC50) values on parasite growth for all compound series are given in
Table 1. The standard antimalarial drugs chloroquine (CQ) and artemisinin (ART) were used as positive
controls. In the first series of fourteen chalcone derivatives 1a–n, in which the 2,2,2-trifluoroethoxy
group has been incorporated at the p-position of the 1-phenyl ring of chalcones (Scheme 1 and
Table 1), showed very weak inhibitory effects on parasite growth, having IC50 values in the range
of 32 to >50
10 g/mL (27.3
2,2,2-trifluoroethoxy group has been incorporated at the m-position of the 1-phenyl ring of chalcones
(Scheme 1 and Table 1), six chalcones 2a 2h 2k, and 2m showed weak inhibitory effects with IC50
values of >46 g/mL on parasite growth and other three chalcones 2d showed moderate activity
towards the parasite with IC50 values of 23–11 g/mL. However, the chalcone 2g, was found to be
active against P. falciparum (3D7) parasite with an IC50 value of 6 g/mL (20 M). In the third series
of ten chalcone derivatives 3a , in which the 2,2,2-trifluoroethoxy group has been incorporated at
the o-position of the 1-phenyl ring (Scheme 1 and Table 1), only two chalcones, 3e and 3h, showed
weak activity and the other chalcones were found to display moderate (compounds 3b 3g, and 3j
g/mL and
µg/mL, except for the chalcone 1m which showed good activity with an IC50 value of
µ
µ
M). In the second series of ten chalcone derivatives 2a 2k, and 2m, in which
–h,
–c
,
,
µ
–f
µ
µ
µ
–
j
,
)
and good activities (compounds 3a, 3c, 3d, 3f, and 3i), with IC50 values less than 20 µ
10 µg/mL, respectively.
Table 1. In vitro antiplasmodial activity of 2,2,2-trifluoroethoxychalcones against P. falciparum (3D7).
P. falciparum (3D7)
No.
Yield (%) a
Chalcone
IC50 (µg/mL) b
IC50 (µM)
1
2
3
87
>50
>156.1
77
90
>50
41
>143.1
120.3

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Table 1. Cont.
P. falciparum (3D7)
IC50 (µM)
No.
Yield (%) a
Chalcone
IC50 (µg/mL) b
4
77
94
43
43
111.6
122.4
5
6
78
37
101.0
7
8
9
61
93
81
>50
38
>168.8
97.1
32
83.1
10
11
74
72
>50
40
>129.8
118.9
12
13
91
70
36
10
107.0
27.3

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Table 1. Cont.
P. falciparum (3D7)
IC50 (µM)
No.
Yield (%) a
Chalcone
IC50 (µg/mL) b
14
40
80
71
>50
>50
>50
>144.8
>156.1
>143.1
15
16
17
18
73
75
49
23
143.8
59.7
19
20
73
77
22
11
62.6
30.0
21
22
23
24
65
85
73
64
6
20.3
>127.8
142.7
125.6
>50
48
46

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Table 1. Cont.
P. falciparum (3D7)
IC50 (µM)
No.
Yield (%) a
Chalcone
IC50 (µg/mL) b
25
82
72
73
3
12.5
9
9.4
26
27
35.8
26.4
28
29
73
75
10
46
26.0
130.9
30
31
62
59
2.2
14
6.0
47.3
32
33
34
87
74
74
30
7
76.7
18.2
49.3
19
Chloroquine (CQ) c
0.010
0.021
0.031
0.074
Artemisinin (ART) c
a
b
Isolated yield;
IC50 (µg/mL): concentration corresponding to 50% growth inhibition of parasite;
c
Antimalarial control.

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Among the third series of chalcones, the chalcones 3a
–
d,
3f, and 3i
–
j
possessing diverse
substituent(s) such as 4-methyl-, 4-dimethylamino-, 4-chloro-, 4-bromo-, 2,5-dimethoxy-, 2-bromo-,
and 3-bromo- on the 3-phenyl ring and a 2,2,2-trifluoroethoxy group on the o-position of the 1-phenyl
ring showed moderate to good antiplasmodial activities, whereas, the chalcones possessing the same
substituents on the 3-phenyl ring, and a 2,2,2-trifluoroethoxy group on the p-(the first series) and
m-positions (the second series) of the 1-phenyl ring (compounds 1a
weak antiplasmodial activities. Evidently, the chalcones with 2,2,2-trifluoroethoxy groups substituted
on the o-position of the 1-phenyl ring displayed enhanced antiplasmodial activity (compounds 3a
3f, and 3i ). Also, chalcone 2g, with 3-furyl ring and a 2,2,2-trifluoroethoxy group on the m-position of
–d, 1f, 1i–j; 2a–d, and 2f) showed
–d,
–
j
the 1-phenyl ring showed significant activity in comparison with those of 2,2,2-trifluoroethoxy group
on the p-(compound 1g) and o-(compound 3g) positions. This result indicates that the position of
2,2,2-trifluoroethoxy group on the 1-phenyl ring of chalcones plays an important role in the increase of
parasite killing i.e., a 2,2,2-trifluoroethoxy group on the o-position in the 1-phenyl ring of chalcones
exhibited an enhanced killing effect on parasites whereas, those on the m- and p-positions have
little-to-no influence on parasite killing. Therefore, the antiplasmodial activity of chalcones with
2,2,2-trifluoroethoxy groups substituted on the 1-phenyl ring is highly position-dependent, which is
graphically represented in Figure 1.
Figure 1. Results of in vitro antiplasmodial activity of some para-, meta-, and ortho-2,2,2-trifluoro
ethoxychalcones with common substituent; NS: not synthesized.
We further evaluated the stage-specific inhibitory effect of the most active chalcones 3a and
3f on the progression of developmental blood stages and survival of parasites. Parasites treated
with chalcones displayed altered phenotypes with distorted morphological appearance according to
microscopy studies as shown in Figure 2. Moreover, compounds 3a and 3f arrested the growth of
mature blood stages (trophozoite) of parasites, leading to cell death. The most active compounds,
3a and 3f were found to be non-hemolytic at their effective concentrations (<20 µg/mL) indicating the
non-toxicity towards the normal (uninfected) red blood cells.
Most importantly, identification ofnew synthetic derivatives as drug partners for standard
combination therapy with artemisinin is now recommended for the treatment of P. falciparum malaria
due to improved efficacy, fast action, and delaying the resistance development [15,16]. Therefore,
the effect of the most active molecules 3a and 3f in combination with artemisinin on the various blood
stages of parasites in culture were studied.
It is observed that chalcones 3a and 3f exhibited enhanced antiplasmodial activity with reduced
IC50 values, as shown in Table 2. The drug combination study was carried out at a fixed concentration
of artemisinin (5 ng/mL & 10 ng/mL) with varying concentrations of the chalcones 3a and 3f to find
out the 50% inhibition concentration of parasite growth.

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Figure 2. Effect of 2,2,2-trifluoroethoxychalcones (3a and 3f) upon treatment causes developmental
growth arrest of P. falciparum (3D7) on blood stages shown using Giemsa-stained light micrographs of
highly synchronized ring-stage parasites in comparison to untreated parasites.
It is important to note that the IC50 values of chalcones 3a and 3f alone were found to be 3.0
µg/mL
and 2.2 g/mL (Table 1) respectively, and the parasite killing effect of artemisinin at 5 ng/mL and 10
µ
ng/mL concentration was found to be 10–15% only. However, the combination study of chalcones 3a
and 3f at a fixed concentration of artemisinin showed enhanced antiplasmodial activity with reduced
IC50 values (Table 2). Therefore, the combined treatment of artemisinin with chalcones 3a and 3f
exhibited positive interactions with synergetic effect on the parasites.
Table 2. Effect on antiplasmodial activity of chalcones 3a and 3f with artemisinin against P. falciparum
(3D7) at two different concentrations.
P. falciparum 3D7 (CQ Sensitive)
Drug Combination
IC50 Values µg/mL
3a + Artemisinin 5 ng/mL
3a + Artemisinin 10 ng/mL
3f + Artemisinin 5 ng/mL
3f + Artemisinin 10 ng/mL
1.04
0.6
2.15
0.89
As a result, these active molecules may find an effective means as strong chemotherapeutic agent
in combination with other antimalarial drugs in combating clinical resistance against malaria infections.
2.3. Antiplasmodial Activity of 2-fluoroethoxychalcones
Due to fluorine’s baffling nature, the effects of fluorine substitution on chemical reactivities
and biological activities remains unpredictable [30,48]. Therefore, we attempted to explore the
effect of the number of fluorine atoms in the fluoroethoxy group and its position in chalcones on
antiplasmodial activity. Therefore, we synthesized a series of 2-fluoroethoxychalcone derivatives in
which a 2-fluoroethoxy group substituted in both the 1-phenyl ring and 3-phenyl ring of chalcones
(Scheme 2). The antiplasmodial activity results of these 2-fluoroethoxychalcones are given in Table 3.
All the chalcones with 2-fluoroethoxy groups on the 1-phenyl ring (compounds 4a
,
4e–
g,
5d
,
5k, and 6i
)
exhibited moderate to good antiplasmodial activity, with IC50 values ranging from 20
µg/mL to
6.5 µg/mL.

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Table 3. In vitro antiplasmodial activity of 2-fluoroethoxychalcones against P. falciparum (3D7).
P. falciparum (3D7)
IC50 (µM)
No.
Yield (%) a
Entry
IC50 (µg/mL) b
1
78
20
13
70.3
41.2
2
3
66
80
8
24.2
4
5
6
67
76
69
20
76.8
c
c
12
34.4
c
c
7
75
8
9
90
76
12
39.9
18.6
6.5
10
11
76
59
25
10
92.5
35.2

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Table 3. Cont.
P. falciparum (3D7)
IC50 (µM)
No.
Yield (%) a
Entry
IC50 (µg/mL) b
12
67
73
8
5
23.6
16.6
13
14
15
16
71
90
70
10
7
28.6
25.9
31.6
9
17
18
80
86
4.5
13.3
c
c
19
20
74
81
12.5
35.8
c
c
21
83
3.5
12.3

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Table 3. Cont.
P. falciparum (3D7)
IC50 (µM)
No.
Yield (%) a
Entry
IC50 (µg/mL) b
22
89
6
17.7
23
24
78
71
10
28.6
c
c
25
85
5
17.6
Chloroquine (CQ)d
Artemisinin (ART)d
0.010
0.021
0.031
0.074
a
Isolated yield; b IC50
(µ
g/mL): concentration corresponding to 50% growth inhibition of parasite; c Not tested; d
Antimalarial control.
Surprisingly, it is observed that 2-fluoroethoxychalcones 4a, 4e–g, 5d, 5k, and 6i showed enhanced
parasite-killing activity, relative to their 2,2,2-trifluroethoxy analogues, irrespective of the position of
the 2-fluoroethoxy group on the 1-phenyl ring (Figure 3).
70
60
50
50
48
50
40
30
20
10
0
43
37
32
23
20
20
13
12
12
11
8
7
6.5
NE
1i 4i
NE
2f 5f
1a 4a
1f 4f
1g 4g
2d 5d
1e 4e
2k 5k
3i 6i
Chalcones
Figure 3. Graphical representation for the comparison of antiplasmodial activity of some
2,2,2-trifluoroethoxychalcones and 2-fluoroethoxychalcones with some common substituents;
NE: not evaluated.

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As a result, the number of fluorine atoms on the ethoxy group in chalcones plays an important
role in their antiplasmodial activity. The chalcones, 4f, and 6i showed good antiplasmodial activity
with IC50 values of 8.0
9i iii 9v, and 9vii viii with 2-fluoroethoxy groups on the 3-phenyl ring showed moderate to good
antiplasmodial activity. Among these chalcones, the chalcones 7iv 8iii 9ii 9iii, and 9viii showed
significant antiplasmodial activities, with IC50 values of 3.5–6.0 g/mL. Of all 2-fluoro-ethoxychalcones,
µg/mL and 6.5 µg/mL, respectively. Similarly, chalcones 7i–iv, 7vii; 8i–v;
–
,
–
,
,
,
µ
only two, 8iii, and 9ii, were found to be most active towards P. falciparum parasite. Our result reveals
that 2-fluoroethoxy substitution in chalcone derivatives are more effective than 2,2,2-trifluoroethoxy
substitution, irrespective of the position, in inhibition of plasmodial growth.
Finally, the most active molecules 3a
cell lines (kidney cells of African green monkey) and the results are given in Table 4. The selectivity
index (SI) values for the most active molecules, 3a 3f 8iii, and 9ii were calculated using the formula of
, 3f, 8iii, and 9ii were studied for their cytotoxic effect in Vero
,
,
IC50 value fnormal cell line (Vero)/IC50 value P. falciparum (3D7), are 8.6, 8.2, 3.3 and 6.9, respectively.
The most active molecules showed minimal cytotoxic effect towards Vero cells at therapeutic dosages
with selective killing of parasites. Therefore, the active molecules are considered to be selective towards
the inhibition of parasites.
Table 4. Cytotoxic effect on Vero cells and selectivity index of most active molecules (3a, 3f, 8iii, and 9ii)
in vitro.
Cytotoxicity (Vero Cell)
Selectivity Index (SI)
Chalcone
µg/mL
µM
3a
3f
8iii
9ii
26
18
15
24
81.2
49.1
44.2
84.4
8.6
8.2
3.3
6.9
3. Experimental
3.1. General Information
All substituted benzaldehydes, substituted acetophenones, p-toluenesulphonyl chloride and
dry DMF were purchased from Spectrochem Pvt. Ltd. (Mumbai, India). 20-Hydroxy-, 30-hydroxy-,
0
and 4 -hydroxyacetophenones, 2-hydroxy-, 3-hydroxy-, and 4-hydroxybenzaldehydes were purchased
from Sigma Aldrich Chemicals pvt. Ltd. (Bangalore, India). Sodium hydride 60% dispersion in
mineral oil was purchased from Thermo Fisher Scientific India Pvt. Ltd. (Mumbai, India) and
purged withnitrogen after every use. Other common solvents & reagent were purchased from other
common suppliers. Other starting materials such as 2,2,2-trifluoroethyl-4-methylbenzenesulphonate,
2-fluoroethyl-4-methylbenzenesulphonate, 40-(2,2,2-trifluoroethoxy)-, 30-(2,2,2-trifluoroethoxy)-,
and 20-(2,2,2-trifluoroethoxy)acetophenones, 40-(2-fluoroethoxy)-, 30-(2-fluoroethoxy)-, and 20-(2-
fluoroethoxy)acetophenones, 4-(2-fluoroethoxy)benzaldehyde, 3-(2-fluoroethoxy)benzaldehyde,
and 2-(2-fluoroethoxy)benzaldehyde were synthesized in house and used for the preparation of
chalcones. The chalcones were prepared by a Claisen-Schmidt condensation reported elsewhere in
the literature. Reactions were monitored by thin layer chromatography (TLC) on pre-coated silica gel
plates (silica gel 60, F254, Merck, Darmstadt, Germany) and visualized under UV light.
3.2. Analytical Methods
NMR data were obtained on a Jeol 400 MHz spectrometers (Jeol USA, Inc., Peabody, MA, USA).
All compounds were characterized by 1H-, 13C-, 19F-NMR (at 399.78 MHz, 100.5 MHz, 376.17 MHz
respectively), IR and HRMS. All 1H- and 13C-NMR chemical shifts were reported in parts per million
(ppm) and were measured relative to TMS or residual deuterated CDCl3 as solvent. 19F-NMR signals
are reported in ppm units and were referenced to CFCl3 as external reference. FTIR spectra were

Molecules 2018, 23, 1174
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recorded on a model RXI (Perkin-Elmer, Waltham, MA, USA) or model alphaT (Bruker, Billerica, MA,
USA, untry) spectrometer, using KBr pellets and KBr films (DCM solvent) methods. HRMS (ESI)
measurements were performed on an 1969A TOF (MS ES+) mass spectrometer (Agilent, Santa Clara,
CA, USA) and an Orbitrap Elite Hybrid Ion Trap-Orbitrap Mass Spectrometer (Thermo Scientific,
Waltham, MA, USA). Yields refer to isolated compounds.
3.3. Biological Evaluation
3.3.1. In Vitro Culture of Plasmodium falciparum
We have tested a series of fluoroethoxychalcone derivatives against drug-susceptible P. falciparum
(3D7) obtained from National Institute of Malaria Research (NIMR, New Delhi, India). The strain
of P. falciparum was maintained by serial passages in human red blood cells (RBCs) cultured at
4–5% hematocrit in RPMI-1640 medium supplemented with 0.5% AlbuMAX II (complete RPMI) and
incubated at 37 ◦C under the atmosphere of mixed gases (5% CO2, 5% O2, and 90% N2). The whole
blood was collected from the Rotary Blood Bank (New Delhi, India). RBCs were separated under
sterile conditions by centrifugation to remove plasma and peripheral blood mononuclear cells (PBCs)
using Histopaque 1077 solution. The levels of parasitemia were routinely monitored by thin blood
smear and staining with 5% Giemsa solution.
3.3.2. Evaluation of In Vitro Antiplasmodial Activity
In vitro antiplasmodial activity was determined based on the [3H]-hypoxanthine incorporation
inhibition assay. The level of radiolabelled precursor [3H]-hypoxanthine incorporation in the nucleic
acid of parasites was used as direct measurement for determining the inhibitory growth concentration
of parasites. Stock solutions of test compounds (chalcones) and artemisinin were dissolved in
100% DMSO and chloroquine diphosphate in sterile distilled water. The final concentration of DMSO
is 0.4% (vehicle control) was found to be non-toxic to parasites. Briefly, different concentrations of test
compounds ranging from 50 µg/mL to 0.1 µg/mL were serially diluted (2-fold dilution) and added to
P. falciparum infected asynchronous erythrocyte suspension (4% final hematocrit and 2% parasitemia)
in a 96-well micro dilution plate along with an untreated control. In another set, different concentration
of standard antimalarial drugs chloroquine diphosphate (CQ) and artemisinin (ART) were added to
infected erythrocyte suspension as positive control. After 30 h of incubation period at 37 ◦C, 20
µL
of 0.2 µ
Ci/well of [3H]-hypoxanthine (American Radiolabeled Chemicals, Inc., ST. Louis, MO, USA
specific activity 25 Ci/mmol) was added to each well containing infected erythrocytes. After additional
18 h of incubation, the cells were harvested onto a glass-fiber filter mat (Whatman GF/A) using a
semi-automated 96 well cell harvester (Skatron, Norway, MI, USA). The dried paper discs were placed
in 5 mL toluene based scintillation cocktail and radioactive count was measured in a TriCarb 2900TR
liquid scintillation analyzer beta-counter (PerkinElmer, Waltham, MA, USA). The 50% inhibitory
concentration (IC50) values were determined by plotting the drug concentration versus the percent cell
viability of the parasite after 48 h of incubation of growth assay period. All data points were collected
in triplicate for each experiment conducted independently.
3.3.3. Assessment of In Vitro Hemolytic Activity
The hemolytic activity was measured at different concentrations for highly potent
2,2,2-trifluoroethoxychalcones, 3a, and 3f, and 2-fluroethoxychalcones, 6i
, 7iv, 8iii, 9ii, 9iii, and 9viii,
in normal and infected erythrocytes by measuring the lysis of RBCs in culture medium at absorbance
of 405 nm. Briefly, a series of concentrations 50
µ
g/mL
−
0.1
µ
g/mL were added to normal erythrocytes
◦
at 4% hematocrit in a 96-well plate for 48 h incubation period at 37 C. After incubation, the plate was
spun down and absorbance of supernatant was measured using spectrophotometric microplate reader
(infinite 200 pro, Tecan trading AG, Switzerland). By mixing the erythrocytes with sterile distilled

Molecules 2018, 23, 1174
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water (for 100% hemolysis) and PBS alone (for baseline values) served as positive and negative
controls, respectively.
3.3.4. Assessment of In Vitro Cytotoxicity on Vero Cells
The cytotoxic effect of most potent molecules (3a
cells using MTT assay. In Brief, exponentially growing Vero cells were seeded in 96 well plates at
a cell density of 1 L DMEM medium, 24 h prior to the experiment. Cells
104 cells/well in 200
, 3f, 8iii, and 9ii) was evaluated against Vero
×
µ
were incubated with different concentrations of◦compounds (100
µ
g/mL to 0.78
µ
g/mL) two-fold
dilution and incubated further for 48 h at 37 C, followed by incubating with 10
µL of 3-(4,5-
dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) MTT reagent (5 mg/mL) for additional 3 h
at 37 ◦C. The presence of formazan crystals were solubilized using 100
L DMSO and the absorbance
µ
of each well optical density was measured using a microplate reader (BioRad, CA, USA) at 570 nm.
The 50% inhibitory concentration (IC50 value) was determined by plotting the drug concentration
versus the percentage cell viability of 48 h of a growth assay period. The relative cell viability (%)
compared with control cells were calculated as follows:
Abs(sample) − (Abs blank)
Cell viability (%) =
× 100,
(1)
Abs(control) − (Abs blank)
3.4. General Procedure for Fluoroethoxylation of Hydroxyacetophenones and Benzaldehydes
A round bottom flask was charged with sodium hydride (1.2 eq.). The appropriate
hydroxyacetophenone or hydroxybenzaldehyde (1 eq.) in DMF (100 mL) was added dropwise over
10 min at rt. Then 2,2,2-trifluoroethyl-4-methylbenzenesulphonate (1.2 eq.) in DMF (50 mL) was added
dropwise. The reaction mixture was then allowed to reflux at 130 ◦C for 15 h. After completion of
reaction, monitored by TLC, the reaction mixture was poured into water and extracted with ethyl
acetate. The extract was washed with water, brine solution and finally dried over sodium sulfate and
evaporated to dryness. The crude reaction mixture was purified by column chromatography (silica gel
60–200 mesh) to afford desired compounds.
◦
◦
1-(4-(2,2,2-Trifluoroethoxy)phenyl)ethanone (
1
) [49]. White solid, Yield: 75%, m.p. 67–68 C (lit. 67–68 C);
3
1H-NMR (CDCl3)
δ
(ppm): 2.57 (s, 3H), 4.42 (q, 2H, J = 8.0 Hz), 6.98–7.00 (m, 2H), 7.97 (d, 2H,
3J = 8.8 Hz).
◦ ◦
2) [49]. White solid, Yield: 71%, m.p. 66–68 C (lit. 67–68 C);
1-(3-(2,2,2-Trifluoroethoxy)phenyl)ethanone (
1H-NMR (CDCl3) (ppm): 2.61 (s, 3H), 4.41 (q, 2H, 3J = 8.0 Hz), 7.17–7.19 (m, 1H), 7.41–7.45 (m, 1H),
δ
7.51–7.52 (m, 1H), 7.63–7.65 (m, 1H)
1-(2-(2,2,2-Trifluoroethoxy)phenyl)ethanone (3 δ (ppm):
) [50]. Yellow liquid, Yield: 68%, 1H-NMR (CDCl3)
2.63 (s, 3H), 4.45 (q, 2H, 3J = 7.9 Hz), 6.88–6.90 (m, 1H), 7.10–7.14 (m, 1H), 7.47–7.52 (m, 1H), 7.79–7.81
(m, 1H)
1-(4-(2-Fluoroethoxy)phenyl)ethanone (
1H-NMR (CDCl3)
4
) [46]. Yellow solid, Yield: 75%, m.p. 52–54 ◦C (lit. 51–55 ◦C);
3
δ
(ppm): 2.56 (s, 3H), 4.28 (dt, 2H, 3JH-H = 3.9 Hz, JH-F = 27.5 Hz), 4.78 (dt, 2H,
3JH-H = 4.2 Hz, 2JH-F = 47.5 Hz), 6.95–6.97 (m, 2H), 7.93–7.95 (m, 2H)
◦
1
1-(3-(2-Fluoroethoxy)phenyl)ethanone (
δ
5
)
.
White solid, Yield: 69%, m.p. 66–68 C; H-NMR (CDCl3)
3
3
3
(ppm): 2.60 (s, 3H), 4.27 (dt, 2H, JH-H = 3.90 Hz, JH-F = 27.90 Hz), 4.78 (dt, 2H, JH-H = 4.1 Hz,
2JH-F = 47.9 Hz), 7.14–7.17 (m, 1H), 7.37–7.41 (m, 1H), 7.50 (s, 1H), 7.56–7.58 (m, 1H); 13C-NMR (CDCl3)
2
1
δ
(ppm): 26.86, 67.38 (d, JC-F = 20.2 Hz), 81.91 (d, JC-F = 171.1 Hz), 113.04, 120.41, 121.85, 129.86,
138.61, 158.76, 198.00; HRMS (ESI) calcd. for C10H11FO2: [M + H]+ 183.0821; Found: 183.0818.
1-(2-(2-Fluoroethoxy)phenyl)ethanone) (
6
)
.
Yellow liquid, Yield: 64%, 1H-NMR (CDCl3)
δ
(ppm): 2.66
(s, 3H), 4.32 (dt, 2H, 3JH-H = 4.1 Hz, JH-F = 27.8 Hz), 4.81 (dt, 2H, 3JH-H = 4.7 Hz, JH-F = 46.5 Hz),
3
2
6.92–6.94 (m, 1H), 7.02–7.06 (m, 1H), 7.44–7.48 (m, 1H), 7.75–7.78 (m, 1H); 13C-NMR (CDCl3)
δ (ppm):

Molecules 2018, 23, 1174
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2
1
32.14, 67.73 (d, JC-F = 20.1 Hz), 81.66 (d, JC-F = 171.6 Hz), 112.49, 121.42, 128.73, 130.75, 133.79,
157.77, 199.94; HRMS(ESI) calcd. for C10H11FO2: [M + H]+ 183.08213 and [M + Na]+ 205.06408; Found:
183.0813 and 205.0634.
4-(2-Fluoroethoxy)benzaldehyde (7 δ (ppm):
) [46]. Yellow liquid, Yield: 77%, 1H-NMR (CDCl3)
4.30 (dt, 2H, 3JH-H = 4.0 Hz, 3JH-F = 28.3 Hz), 4.79 (dt, 2H, 3JH-H = 3.9 Hz, 2JH-F = 47.5 Hz), 7.02–7.05 (m,
2H), 7.84–7.86 (m, 2H), 9.90 (s, 1H)
1
3-(2-Fluoroethoxy)benzaldehyde (
8
)
.
Yellow oil, Yield: 71%, H-NMR (CDCl3)
δ
(ppm): 4.28 (dt, 2H,
3JH-H = 4.0 Hz, 3JH-F = 28 Hz), 4.78 (dt, 2H, 3JH-H = 4.0 Hz, 2JH-F = 47.5 Hz), 7.22–7.24 (m, 1H), 7.40–7.41
(m, 1H), 7.45–7.51 (m, 2H), 9.98 (s, 1H); 13C-NMR (CDCl3) (ppm): 67.43 (d, 2JC-F = 20.7 Hz), 81.83
δ
(d, 1JC-F = 170.9 Hz), 112.60, 122.32, 124.34, 130.36, 137.92, 159.11, 192.14; 19F-NMR (CDCl3)
−223.44 to −223.84 (m, 1F).
δ
(ppm):
◦
◦
2-(2-Fluoroethoxy)benzaldehyde (
1H-NMR (CDCl3)
9
) [51]. Yellow solid, Yield: 69%, m.p. 37–38 C (lit. 37.5–38 C);
δ
(ppm): 4.35 (dt, 2H, 3JH-H = 3.9 Hz, 3JH-F = 27.9 Hz), 4.82 (dt, 2H, 3JH-H = 3.7 Hz,
2JH-F = 47.8 Hz), 6.97–6.99 (m, 1H), 7.05–7.09 (m, 1H), 7.55 (t, 1H, 3J = 8.0 Hz), 7.86 (d, 1H, 3J = 7.8 Hz),
10.54 (s, 1H).
3.5. General Procedure for the Preparation of Fluoroethoxychalcones
An aqueous solution of KOH (1.2 eq.) was added at room temperature to a solution of the
appropriate acetophenone (1.0 eq.), and benzaldehyde (1.2 eq.) in ethanol (10 mL). The reaction
mixture was then stirred for 30 min. After completion of reaction, the reaction was judged by TLC.
The reaction mixture was filtered through a Buckner funnel under vacuum. The solid was washed
several times with a 1:1 ethanol-water mixture. The solid was finally dried under vacuum. The crude
product was further purified by column chromatography or recrystallization.
(E)-3-(4-Methylphenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1a) [43]. Yellow crystalline solid,
Yield: 87%, m.p. 148–150 ◦C (lit. 148–151 ◦C); 1H-NMR (CDCl3)
δ (ppm): 2.40 (s, 3H), 4.44 (q, 2H,
3J = 8.0 Hz), 7.03 (d, 2H, 3J = 8.7 Hz), 7.23 (d, 2H, 3J = 8.8 Hz) 7.48 (d, 1H, 3J = 15.2 Hz), 7.55 (d, 2H,
3J = 8.4 Hz), 7.80 (d, 1H, 3J = 15.6 Hz), 8.06 (d, 2H, 3J = 8.8 Hz).
(E)-3-(4-(Dimethylamino)phenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1b
77%, m.p. 130–135 ◦C; 1H-NMR (CDCl3) (ppm): 3.05 (s, 6H), 4.43 (q, 2H, 3J = 8.0 Hz), 6.70 (d, 2H,
3J = 8.4 Hz), 7.02 (d, 2H, 3J = 9.1 Hz), 7.33 (d, 1H, 3J = 15.2 Hz), 7.55 (d, 2H, 3J = 8.4 Hz), 7.79 (d, 1H,
3J = 15.2 Hz), 8.04 (d, 2H, 3J = 9.1 Hz); 13C-NMR (CDCl3) (ppm): 40.26, 65.65 (q, 2JC-F = 36.2 Hz),
111.92, 114.53, 116.43, 122.71, 130.54, 130.75, 133.63, 145.75, 152.14, 160.36, 188.95; 19F-NMR (CDCl3)
). Yellow solid, Yield:
δ
δ
δ
(ppm):
−
73.7(t, 3F,3J = 8.7 Hz); IR (KBr)
ν: 3070, 2909, 1650, 1585, 1528, 1371, 1343, 1287, 1231, 1162,
1069, 1027, 969, 808, 676; HRMS (ESI) calcd. for C19H18F3NO2: [M + H]+ 350.1368 and [M + Na]+
372.1187; Found: 350.1366 and 372.1163.
(E)-3-(4-Chlorophenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1c
90%, m.p. 139–140 ◦C; 1H-NMR (CDCl3) (ppm): 4.44 (q, 2H, 3J = 8.0 Hz), 7.04 (d, 2H, 3J = 8.8 Hz),
7.40 (d, 2H, 3J = 8.4 Hz), 7.49 (d, 1H, 3J = 15.4 Hz), 7.58 (d, 2H, 3J = 8.4 Hz), 7.76 (d, 1H, 3J = 15.4 Hz),
8.05 (d, 2H, 3J = 8.8 Hz); 13C-NMR (CDCl3) (ppm): 65.70 (q, 2JC-F = 36.7 Hz), 114.79, 122.16, 129.41,
129.72, 131.06, 132.70, 133.54, 136.57, 143.23, 160.95, 188.50; 19F-NMR (CDCl3)
(ppm): 73.67 (t, 3F,
3J = 8.6 Hz); IR (KBr)
: 3066, 2947, 2815, 1663, 1609, 1510, 1490, 1406, 1343, 1293, 1162, 1029, 972, 811,
692, 657; HRMS (ESI) calc. for C17H12ClF3O2: [M + H]+ 341.0056; Found: 341.056.
). Pale yellow solid, Yield:
δ
δ
δ
−
ν
(E)-3-(4-Bromophenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1d). Pale yellow solid, Yield:
77%, m.p. 145–146 ◦C; 1H-NMR (CDCl3)
δ
(ppm): 4.44 (q, 2H, 3J = 8.0 Hz), 7.04 (d, 2H, 3J = 9.1 Hz),
7.49–7.57 (m, 5H), 7.74 (m, 1H), 8.05 (d, 2H, J = 9.1 Hz); 13C-NMR (CDCl3)
δ (ppm): 65.70 (q,
3
2JC-F = 36.6 Hz), 114.79, 122.25, 124.93, 129.92, 131.06, 132.37, 132.68, 133.96, 143.30, 160.95, 188.49;
19F-NMR (CDCl3) 73.67 (t, 3F, 3J = 8.7 Hz); IR (KBr)
(ppm): : 2946, 2812, 1668, 1609, 1511, 1487,
δ
−
ν

Molecules 2018, 23, 1174
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1349, 1305, 1293, 1254, 1180, 1161, 1079, 1028, 972, 808, 687; HRMS (ESI) calc. for C17H12BrF3O2:
[M + H]+ 385.0051; Found: 385.0037.
(E)-3-(3-Nitrophenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1e) [43]. Yellow solid, Yield: 94%,
m.p. 169–171 ◦C (lit. 168–171 ◦C); 1H-NMR (CDCl3)
δ
(ppm): 4.46 (q, 2H,3J = 7.9 Hz), 7.07 (d, 2H,
3J = 9.1 Hz), 7.62 (d, 1H, 3J = 15.9 Hz), 7.84 (d, 1H, 3J = 15.9 Hz) 7.92 (d, 1H, 3J = 7.6 Hz), 8.09 (d, 2H,
3J = 8.5 Hz), 8.26 (d, 1H, 3J = 8.5 Hz), 8.52 (s, 1H).
(E)-3-(2,5-Dimethoxyphenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1f) [43]. Yellow solid, Yield:
78%, m.p. 98–99 ◦C (lit. 97–99 ◦C); 1H-NMR (CDCl3)
δ (ppm): 3.82 (s, 3H), 3.87 (s, 3H), 4.44 (q, 2H,
3J = 7.9 Hz), 6.87–6.89 (m, 1H), 6.93–6.96 (m, 1H), 7.03 (d, 2H, 3J = 8.8 Hz), 7.16–7.17 (m, 1H), 7.57 (d,
1H, 3J = 15.9 Hz), 8.04–8.09 (m, 3H).
(E)-3-(Furan-2-yl)-1-(4-(2,2,2-◦trifluoroethoxy)phenyl)prop-2-en-1-one (1g) [43]. Light yellow crystalline
◦
solid, Yield: 61%, m.p. 94–96 C (lit. 94.5–96.5 C); 1H-NMR (CDCl3) (ppm): 4.43 (q, 2H, 3J = 8.0 Hz),
δ
6.52 (m, 1H), 6.72 (d, 1H, 3J = 3.5 Hz), 7.03 (d, 2H, 3J = 8.7 Hz), 7.45 (d, 1H, 3J = 15.3 Hz), 7.52 (s, 1H),
7.59 (d, 1H, 3J = 15.3 Hz), 8.07 (d, 2H, 3J = 8.7 Hz).
(E)-3-(5-Bromothiophen-2-yl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1h). Pale yellow solid,
◦
Yield: 93%, yield, m.p. 93–94 C; 1H-NMR (CDCl3)
δ
(ppm): 4.44 (q, 2H, 3J = 8.0 Hz), 7.03 (d, 2H,
3J = 8.7 Hz), 7.06 (d, 1H, J = 4.2 Hz), 7.10 (d, 1H, J = 4.2 Hz), 7.21 (d, 1H, J = 15.6 Hz), 7.81 (d,
3
3
3
3
3
2
1H, J = 15.6 Hz), 8.02 (d, 2H, J = 8.7 Hz); 13C-NMR (CDCl3)
δ (ppm): 65.71 (q, JC-F = 36.0 Hz),
114.80, 116.48, 120.69, 130.96, 131.51, 132.49, 132.60, 136.20, 142.12, 160.96, 187.84; 19F-NMR (CDCl3)
δ
(ppm):
−
73.68 (t, 3F, 3J = 7.6 Hz); IR (KBr)
ν: 3068, 2829, 1648, 1605, 1510, 1422, 1353, 1294, 1249, 1168,
1159, 1069, 1028, 972, 826, 796, 675 cm−1; HRMS (ESI) calcd. for C15H10BrF3O2S: [M + H]+ 390.9615;
Found: 390.9608.
(E)-3-(2-Bromophenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1i
)
.
Pale yellow solid, Yield: 81%,
(ppm): 4.43 (q, 2H, 3J = 7.9 Hz), 7.02 (d, 2H, 3J = 8.5 Hz), 7.24 (m,
1H), 7.34 (m, 1H), 7.39 (d, 1H, 3J = 15.7 Hz), 7.63 (d, 1H, 3J = 7.3 Hz), 7.71 (d, 1H,3J = 7.6 Hz), 8.04 (d,
2H, 3J = 8.5 Hz), 8.12 (d, 1H, 3J = 15.7 Hz); 13C-NMR (CDCl3) (ppm): 65.69 (q, 2JC-F = 36.1 Hz), 114.77,
123.20 (q, 1JC-F = 277.60 Hz), 124.88, 125.99, 127.85, 128.02, 131.21, 131.45, 132.55, 133.72, 135.25, 143.11,
◦
m.p. 107–108 C; 1H-NMR (CDCl3)
δ
δ
160.94, 188.78; 19F-NMR (CDCl3)
δ
(ppm):
−
73.67 (t, 3F, 3J = 7.7 Hz); IR (KBr)
ν: 3072, 2952, 2821, 1660,
1607, 1511, 1463, 1435, 1344, 1299, 1220, 1184, 1076, 1027, 970, 865, 830, 757, 739, 688, 657 cm−1; HRMS
(ESI) calcd. for C17H12BrF3O2: [M + H]+ 385.0051; Found: 385.0051.
(E)-3-(3-Bromophenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1j
)
.
Pale yellow solid, Yield: 74%,
(ppm): 4.45 (q, 2H, 3J = 7.9 Hz), 7.04 (d, 2H, 3J = 8.9 Hz), 7.28–7.32
(m, 1H), 7.50–7.55 (m, 3H), 7.73 (m, 1H), 7.80 (s, 1H), 8.07 (d, 2H,3J = 8.9 Hz); 13C-NMR (CDCl3)
(ppm): 65.70 (q, 2JC-F = 36.4 Hz), 114.80, 122.95, 123.24, 127.43, 130.63, 130.90, 131.11, 132.57, 133.38,
137.17, 142.87, 161.01, 188.32; 19F-NMR (CDCl3) 73.63 (t, 3F, 3J = 8.8 Hz); IR (KBr)
(ppm): : 3064,
◦
m.p. 104–106 C; 1H-NMR (CDCl3)
δ
δ
δ
−
ν
2948, 2894, 2361, 1663, 1611, 1511, 1418, 1341, 1255, 1220, 1182, 1127, 1078, 1030, 971, 830, 780, 669,
661 cm−1; HRMS (ESI) calcd. for C17H12BrF3O2: [M + H]+ 385.0051; Found: 385.0019.
(E)-3-(4-Methox◦yphenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1k
). Yellow solid, Yield: 72%,
(ppm): 3.86 (s, 3H), 4.44 (q, 2H, J = 7.9 Hz), 6.94 (d, 2H,
1
3
m.p. 100–102 C; H-NMR (CDCl3)
δ
3J = 8.8 Hz), 7.03 (d, 2H, 3J = 8.8 Hz),7.41 (d, 1H, 3J = 15.9 Hz), 7.61 (d, 2H, 3J = 8.8 Hz), 7.79 (d, 1H,
3J = 15.9 Hz), 8.05 (d, 2H, 3J = 8.8 Hz); 13C-NMR (CDCl3) (ppm): 55.56, 65.69 (q, 2JC-F = 35.9 Hz),
114.57, 114.67, 119.41, 127.77, 130.36, 130.93, 133.15, 144.61, 160.68, 161.82, 188.85; 19F-NMR (CDCl3)
δ
δ
(ppm):
−
73.69 (t, 3F, 3J = 7.7 Hz); IR (KBr)
ν: 3042, 3073, 2957, 2839, 1657, 1603, 1572, 1510, 1423, 1344,
1295, 1249, 1168, 1033, 976, 813, 680 cm−1; HRMS(ESI) calcd. for C18H15F3O3: [M + H]+ 337.1051 and
[M + Na]+ 359.0871; Found: 37.1051 and 359.0864.
(E)-3-(3-Methoxyphenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1l
). Pale yellow solid, Yield:
91%, m.p. 78–80 ◦C; 1H-NMR (CDCl3) (ppm): 3.86 (s, 3H), 4.44 (q, 2H, 3J = 7.9 Hz), 6.96–6.98 (m,
δ

Molecules 2018, 23, 1174
18 of 28
3
3
1H), 7.04 (d, 2H, J = 8.7 Hz), 7.15–7.16 (m, 1H), 7.23 (s, 1H), 7.34 (t, 1H, J = 8.2 Hz), 7.54 (d, 1H,
3J = 15.7 Hz), 7.77 (d, 1H, 3J = 15.7 Hz), 8.06 (d, 2H, 3J = 8.7 Hz); 13C-NMR (CDCl3)
65.63 (q, 2JC-F = 39.0 Hz), 113.63, 114.73, 116.37, 121.21, 122.06, 130.12, 131.07, 132.82, 136.41, 144.68,
δ (ppm): 55.51,
160.09, 160.84, 188.82; 19F-NMR (CDCl3)
δ
(ppm):
−
73.66 (t, 3F, 3J = 8.8 Hz); IR (KBr)
ν: 3079, 3004,
2941, 2833, 1650, 1606, 1510, 1426, 1314, 1264, 1217, 1158, 1026, 978, 818, 677 cm−1; HRMS (ESI) Calc.
for C18H15F3O3: [M + H]+ 337.1051 and [M + Na]+ 359.0871; Found: 337.1048 and 359.0865.
(E)-3-(3,4-Dimethoxyphenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1m
)
.
Yellow solid, Yield:
70%, m.p. 116–118 ◦C; 1H-NMR (CDCl3)
δ
(ppm): 3.94 (s, 3H), 3.96 (s, 3H), 4.44 (q, 2H, 3J = 7.9 Hz),
6.90 (d, 1H, 3J = 8.9 Hz), 7.04 (d, 2H, 3J = 8.7 Hz), 7.16 (d, 1H, 3J = 1.9 Hz), 7.24 (dd, 1H, 3J = 8.3 Hz,
4J = 1.9 Hz) 7.38 (d, 1H, 3J = 15.7 Hz), 7.77 (d, 1H, 3J = 15.7 Hz), 8.05 (d, 2H, 3J = 8.7 Hz); 13C-NMR
(CDCl3)
133.10, 144.95, 149.39, 151.58, 160.70, 188.89; 19F-NMR (CDCl3)
(KBr)
δ
(ppm): 56.12, 56.15, 65.69 (q, 2JC-F = 36.0 Hz), 110.23, 111.26, 119.69, 123.28, 128.00, 130.96,
δ
(ppm):
−
73.67 (t, 3F, 3J= 7.6 Hz); IR
ν
: 3079, 3003, 2941, 2833, 1651, 1606, 1590, 1510, 1425, 1361, 1236, 1217, 1180, 1141, 978, 817, 791,
677 cm−1; HRMS (ESI) calcd. for C19H17F3O4: [M + H]+ 367.1157 and [M + Na]+ 389.0977; Found:
367.1157 and 389.0987.
(E)-3-(1H-Indol-2-yl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1n
194–195 ◦C; 1H-NMR (CDCl3) (ppm): 4.44 (q, 2H, 3J = 8.0 Hz), 7.05 (d, 2H, 3J = 8.0 Hz), 7.31–7.33 (m,
2H), 7.45–7.47 (m, 1H), 7.57–7.62 (m, 2H), 8.03 (dd, 1H, 3J = 6.7 Hz, 4J = 3.0 Hz), 8.09–8.13 (m, 3H), 8.61
(s, 1H); 13C-NMR (CDCl3) (ppm): 65.68 (q, 2JC-F
35.9), 112.14, 114.64, 117.50, 120.84, 121.92, 123.72,
125.48, 130.46, 130.80, 133.55, 137.38, 138.83, 160.47, 189.26; 19F-NMR (CDCl3)
(ppm): 73.68 (t, 3F,
3J = 8.7 Hz); IR (KBr) : 3219, 2929, 1647, 1604, 1587, 1554, 1365, 1246, 1170, 1041, 815, 735, 677 cm−1
HRMS (ESI) calcd. for C19H14F3NO2: [M + H]+ 346.1055; Found: 346.1051.
). Yellow solid, Yield: 40%, m.p.
δ
δ
=
δ
−
ν
;
(E)-3-(4-Methyl◦phenyl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2a
)
.
Yellow solid, Yield: 80%,
1
3
m.p. 107–108 C; H-NMR (CDCl3)
δ (ppm): 2.42 (s, 3H), 4.45 (q, 2H, J = 8.1 Hz), 7.20 (dd, 1H,
3J = 8.2 Hz, 4J = 2.5 Hz), 7.24–7.27 (m, 2H), 7.46–7.50 (m, 2H), 7.56–7.58 (m, 3H), 7.72 (d, 1H, 3J = 8.0 Hz),
7.83 (d, 1H, 3J = 15.6 Hz); 13C-NMR (CDCl3) (ppm): 21.70, 65.99 (q, 2JC-F = 36.1 Hz), 113.82, 120.10,
120.79, 122.84, 128.72, 129.90, 130.10, 132.12, 140.13, 141.50, 145.62, 157.76, 189.88; 19F-NMR (CDCl3)
δ
δ
(ppm):
−
73.7 (t, 3F, 3J = 7.8 Hz); IR (KBr)
ν: 3083, 3049, 2360, 1658, 1595, 1580, 1454, 1325, 1305, 1247,
1161, 1076, 1041, 967, 812, 800, 741, 674 cm−1; HRMS (ESI) Calc. for C18H15F3O2: [M + H]+ 321.1124;
Found: 321.1093.
(E)-3-(4-(Dimethylamino)phenyl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2b
)
.
Yellow solid,
◦
1
3
Yield: 71%, m.p. 134–136 C; H-NMR (CDCl3)
δ
(ppm): 3.05 (s, 6H), 4.44 (q, 2H, J = 8.1 Hz),
6.69 (d, 2H, 3J = 9.2 Hz), 7.16 (dd, 1H, 3J= 8.3 Hz, 4J = 2.5 Hz), 7.30 (d, 1H, 3J = 15.6 Hz), 7.44 (t, 1H,
3J = 7.9 Hz), 7.54–7.57 (m, 3H), 7.69 (d, 1H, 3J = 7.9 Hz), 7.81 (d, 1H, 3J = 15.6 Hz); 13C-NMR (CDCl3)
δ
(ppm): 40.27, 66.00 (q, 2JC-F = 35.8 Hz), 111.96, 113.69, 116.56, 119.62, 122.61, 122.67, 129.93, 130.71,
140.92, 146.54, 152.30, 157.69, 189.86; 19F-NMR (CDCl3)
δ
(ppm):
−
73.71 (t, 3F, 3J = 7.6Hz); HRMS (ESI
calc. for C19H18F3NO2: [M + H]+ 350.1368; Found: 350.1362.
(E)-3-(4-Chlorophenyl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2c
)
.
Yellow solid, Yield: 73%,
◦
1
3
3
m.p. 117–118 C; H-NMR (CDCl3)
δ
(ppm): 4.44 (q, 2H, J = 8.1 Hz), 7.20 (dd, 1H, J = 8.8 Hz,
4J = 2.7 Hz) 7.40–7.42 (m, 2H), 7.46–7.50 (m, 2H), 7.58–7.60 (m, 3H), 7.70 (d, 1H, 3J = 7.9 Hz), 7.78 (d,
1H, 3J = 15.7 Hz); 13C-NMR (CDCl3) (ppm): 65.99 (q, 2JC-F = 35.8 Hz), 113.90, 120.31, 122.17, 122.86,
129.45, 129.81, 130.19, 133.34, 136.80, 139.80, 143.97, 157.82, 189.50; 19F-NMR (CDCl3)
(ppm): 73.76
δ
δ
−
(t, 3F, 3J = 8.7 Hz); IR (KBr)
ν: 3104, 3081, 2945, 2360, 1664, 1610, 1581, 1490, 1451, 1295, 1273, 1250, 1170,
1152, 1045, 973, 914, 868, 821, 789, 690 cm−1; HRMS (ESI) calc. for C17H12ClF3O2: [M + H]+ 341.0556
and [M + Na]+ 363.0376; Found: 341.0555 and 363.0375.
(E)-3-(4-Bromophenyl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2d
75%, m.p. 125–126 ◦C; 1H-NMR (CDCl3) (ppm): 4.44 (q, 2H, 3J = 8.0 Hz), 7.20 (dd, 1H, 3J = 8.4 Hz,
4J = 2.7 Hz), 7.45–7.58 (m, 7H), 7.70 (d, 1H, 3J = 8.4 Hz), 7.76 (d, 1H, 3J = 15.6 Hz); 13C-NMR (CDCl3)
). Pale yellow solid, Yield:
δ
δ

Molecules 2018, 23, 1174
19 of 28
(ppm): 66.64 (q, 2JC-F = 36.5 Hz), 113.96, 120.32, 122.39, 122.88, 125.19, 130.01, 130.20, 132.41, 133.79,
139.90, 144.03, 157.84, 189.75; 19F-NMR (CDCl3) 73.7 (t, 3F, 3J = 7.7 Hz); IR (KBr)
(ppm): : 3076,
δ
−
ν
2945, 2360, 1667, 1599, 1486, 1450, 1401, 1314, 1295, 1170, 1152, 1080, 1045, 973, 867, 816, 788, 688 cm−1
HRMS (ESI) calc. for C17H12BrF3O2: [M + H]+ 385.0051 and [M + Na]+ 406.9871; Found: 385.0054 and
406.9879.
;
(E)-3-(3-Nitrophenyl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2e
)
.
Brown solid, Yield: 73%, m.p.
(ppm): 4.45 (q, 2H, 3J = 8.0 Hz), 7.23 (dd, 1H, 3J = 8.5 Hz, 4J = 3.0 Hz), 7.50
(t, 1H, 3J = 8.1 Hz), 7.59–7.65 (m, 3H), 7.74 (d, 1H, 3J = 7.8 Hz), 7.85 (m, 1H), 7.93 (d, 1H, 3J = 7.2 Hz), 8.27
(dd, 3J = 8.0 Hz, 4J = 2.7 Hz), 8.51–8.8.52 (m, 1H); 13C-NMR (CDCl3) (ppm): 66.01 (q, 2JC-F = 35.2 Hz),
113.95, 120.67, 122.58, 122.98, 124.36, 130.25, 130.34, 134.51, 136.62, 139.33, 142.28, 148.89, 157.91, 188.96;
◦
78–80 C; 1H-NMR (CDCl3)
δ
δ
19F-NMR (CDCl3)
δ
(ppm):
−
73.39 (t, 3F, 3J = 8.8 Hz); IR (KBr)
ν: 3074, 2869, 2360, 1662, 1591, 528,
1444, 1357, 1309,1272, 1248, 1173, 1158, 1083, 1068, 974, 911, 857, 795, 780, 740, 675 cm−1; HRMS (ESI)
calc. for C17H12F3NO4: [M + H]+ 352.0797; Found: 352.0789.
(E)-3-(2,5-Dimethoxyphenyl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2f
77%, m.p. 72–74 ◦C; 1H-NMR (CDCl3) (ppm): 3.83 (s, 3H), 3.88 (s, 3H), 4.44 (q, 2H, 3J = 8.1 Hz), 6.89
(m, 1H), 6.94–6.97 (m,1H), 7.16–7.18 (m, 1H), 7.20 (d, 1H, 4J = 2.7 Hz), 7.46 (t, 1H, 3J = 8.0 Hz), 7.53–7.57
(m, 2H), 7.69 (d, 1H, 3J = 8.4 Hz), 8.09 (d, 1H, 3J = 16 Hz); 13C-NMR (CDCl3)
(ppm): 56.01, 56.25,
66.05 (q, 2JC-F = 35.90 Hz), 112.64, 113.90, 113.99, 117.60, 120.10, 122.01, 122.96, 124.49, 130.06, 140.25,
140.86, 153.56, 153.70, 157.77, 190.40; 19F-NMR (CDCl3) 73.7 (t, 3F, 3J = 7.7 Hz); IR (KBr)
(ppm):
: 2948, 2838, 2357, 1659, 1587, 1494, 1442, 1323, 1248, 1172, 1123, 1047, 985, 974, 848, 791, 693 cm−1
HRMS (ESI) calc. for C19H17F3O4: [M + H]+ 367.1157; Found: 367.1158.
). Yellow solid, Yield:
δ
δ
δ
−
ν
;
(E)-3-(Furan-2-yl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2g
)
.
Brown viscous liquid, Yield:
65%, 1H-NMR (CDCl3) δ (ppm): 4.39 (q, 2H, 3J = 7.90 Hz), 6.44–6.45 (m, 1H), 6.64 (d, 1H, 3J = 3.5 Hz),
6.9 (d, 1H, 3J = 8.4 Hz), 7.09–7.13 (m,1H), 7.21–7.22 (m, 1H), 7.36–7.46 (m, 3H), 7.64 (d, 1H, 3J = 8.0 Hz);
13C-NMR (CDCl3)
δ
(ppm): 65.58 (q, 2H, 3J = 36.2 Hz,) 112.94, 113.61, 116.87, 118.98, 120.29, 122.83,
130.14, 131.26, 139.89, 145.29, 157.76, 189.14; 19F-NMR (CDCl3)
: 3126, 1688, 1586, 1486, 1442, 1401, 1250, 1169, 1069, 1016, 973, 858, 789, 734, 680 cm−1; HRMS (ESI)
calc. for C15H11F3O3: [M + H]+ 297.0739; Found: 297.0730.
δ
(ppm):
−
73.71 (t, 3J = 8.7 Hz); IR (KBr)
ν
(E)-3-(5-Bromothiophen-2-yl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2h). Yellow solid, Yield:
◦
1
3
85%, m.p. 103–105 C; H-NMR (CDCl3)
δ
(ppm): 4.44 (q, 2H, J = 8.1 Hz), 7.07 (m, 1H), 7.12 (m,
3
1H), 7.17–7.21 (m, 2H), 7.45–7.48 (m, 1H), 7.54–7.55 (m, 1H), 7.66 (d, 1H, J = 7.6 Hz), 7.83 (d, 1H,
3J = 15.7 Hz); 13C-NMR (CDCl3)
δ
(ppm): 65.94 (q, JC-F = 36.1 Hz), 113.65, 116.90, 120.35, 120.59,
2
121.94, 122.74, 130.19, 131.55, 132.84, 136.85, 139.65, 141.89, 157.78, 188.82; 19F-NMR (CDCl3)
δ (ppm):
−
73.75 (t, 3F, 3J = 8.8 Hz); IR (KBr)
ν: 3073, 2941, 1658, 1579, 1488, 1423, 1346, 1264, 1247, 1162, 1070,
1057, 970, 917, 854, 814, 783, 716, 697 cm−1; HRMS (ESI) calc. for C15H10BrF3O2S: [M + H]+ 390.9615;
Found: 390.961.
(E)-3-(4-Methoxyphenyl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2k
)
.
Yellow solid, Yield: 73%,
(ppm): 3.86 (s, 3H) 4.44 (q, 2H, 3J = 8.0 Hz), 6.94 (d, 2H, 3J = 8.3 Hz),
7.18 (dd, 1H, 3J = 8.6 Hz, 4J = 2.6 Hz),7.38 (d, 1H, 3J = 15.6 Hz),7.46 (t, 1H, 3J = 8.2 Hz), 7.56–7.57 (m,
1H), 7.61 (d, 2H, 3J = 8.4 Hz), 7.70 (d, 1H, 3J = 8.0 Hz), 7.80 (d, 1H, 3J = 15.6 Hz); 13C-NMR (CDCl3)
(ppm): 55.57, 65.95 (q, 2JC-F = 35.40), 113.75, 114.59, 119.43, 119.98, 122.77, 127.57, 130.07, 130.51, 140.27,
145.38, 157.73, 161.98, 189.81; 19F-NMR (CDCl3) 73.7 (t, 3F, 3J = 8.8 Hz); IR (KBr)
(ppm): : 3075,
◦
m.p. 79–82 C; 1H-NMR (CDCl3)
δ
δ
δ
−
ν
3014, 2941, 2843, 1655, 1587, 1573, 1442, 1342, 1287, 1245, 1187, 1156, 1056, 1027, 972, 921, 872, 824, 798,
788, 669 cm−1; HRMS (ESI) calc. for C18H15F3O3: [M + H]+ 337.1052; Found: 337.1048.
(E)-3-(3,4-Dimethoxyphenyl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2m
)
.
Yellow solid, Yield:
(ppm): 3.94 (s, 3H), 3.96 (s, 3H), 4.44 (q, 2H, J = 8.1 Hz), 6.91 (d, 1H,
3J = 8.0 Hz), 7.17–7.18 (m,1H), 7.19–7.24 (dd, 1H),7.36 (d, 1H, 3J = 15.6 Hz), 7.47 (t, 1H, 3J = 8.0 Hz), 7.57
(s, 1H), 7.70 (d, 1H, 3J = 8.0 Hz), 7.78 (d, 1H, 3J = 15.6 Hz); 13C-NMR (CDCl3)
(ppm): 55.94, 56.11,
1
3
64%, H-NMR (CDCl3)
δ
δ

Molecules 2018, 23, 1174
20 of 28
65.94 (q, 2JC-F = 36.1 Hz), 110.14, 111.20, 113.85, 119.68, 119.89, 122.78, 123.53, 127.80, 130.06, 140.23,
145.73, 149.37, 151.71, 157.72, 189.85; 19F-NMR (CDCl3)
δ
(ppm):
−
73.75 (t, 3F, 3J = 8.8 Hz); IR (KBr)
ν:
3128, 2840, 1656, 1576, 1517, 1421, 1256, 1165, 1080, 1026, 977, 919, 785, 724, 679 cm−1; HRMS (ESI) Calc.
for C19H17F3O4: [M + H]+ 367.1157 and [M + Na]+ 389.0977; Found: 367.1154 and 389.0979.
(E)-3-(4-Methylphenyl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3a
)
.
Pale yellow solid, Yield:
(ppm): 2.38 (s, 3H), 4.44 (q, 2H, 3J = 8.0 Hz), 6.96 (d, 1H,
3J = 8.0 Hz), 7.15–7.17 (m, 1H), 7.20 (d, 2H, 3J = 8.0 Hz), 7.38 (m, 1H), 7.49 (d, 2H, 3J = 7.6 Hz), 7.64
◦
82%, m.p. 80–82 C; 1H-NMR (CDCl3)
δ
(m, 1H), 7.70 (d, 1H, 3J = 7.8 Hz), 7.78 (d, 1H, 3J = 7.8 Hz); 13C-NMR (CDCl3)
δ (ppm): 21.66, 66.53
(q, 2JC-F = 35.8 Hz), 113.21, 123.05, 125.55, 128.65, 129.78, 130.36, 131.19, 132.27, 133.02, 141.11, 144.30,
3
155.60, 192.08; 19F-NMR (CDCl3)
δ
(ppm):
−
73.51 (t, 3F, J = 8.8 Hz); IR (KBr)
ν
: 3115.70, 1648.15,
1604.14, 1484.69, 1449.97, 1403.88, 1330.59, 1265.53, 1163.65, 119.59, 978, 813.90, 761.55, 682.04 cm−1
HRMS (ESI) calc. for C18H15F3O2: [M + H]+ 321.1102; Found: 321.1095.
;
(E)-3-(4-(Dimethylamino)phenyl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3b
)
.
Yellow solid, Yield:
(ppm): 3.05 (s, 6H), 4.44 (q, 2H, 3J = 8.1 Hz), 6.69–6.71 (m, 2H),
7.14–7.17 (m, 1H), 7.28–7.32 (m,1H), 7.44 (t, 1H), 7.54–7.57 (m, 3H), 7.68–7.70 (m, 1H), 7.79–7.83 (m,
1H); 13C-NMR (CDCl3) (ppm): 40.27, 65.65 (q, 2JC-F = 36.20 Hz), 111.93, 114.53, 116.43, 121.87, 122.72,
124.63, 130.54, 130.75, 133.63, 145.75, 152.14, 160.36, 188.96; 19F-NMR (CDCl3)
(ppm): 74.19 (t, 3F,
3J = 7.6 Hz); IR (KBr)
: 2821, 2359, 1646, 1599, 1520, 1484, 1447, 1339, 1266, 1233, 1162, 1064, 1025, 970,
861, 815, 767, 753, 676 cm−1; HRMS (ESI) calc. for C19H18F3NO2: [M + H]+ 350.1368; Found: 350.1366.
◦
72%, m.p. 64–66 C; 1H-NMR (CDCl3)
δ
δ
δ
−
ν
(E)-3-(4-Chlorophenyl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3c
)
.
Yellow solid, Yield: 73%,
◦
1
3
3
m.p. 61–63 C; H-NMR (CDCl3)
δ
(ppm): 4.45 (q, 2H, J = 8.0 Hz), 6.95 (d, 1H, J = 8.4 Hz), 7.17
3
3
(t, 1H, J = 7.7 Hz), 7.36–7.40 (m, 3H), 7.49–7.53 (m, 3H), 7.62 (m, 1H), 7.73 (dd, 1H, J = 7.6 Hz,
4J = 1.9 Hz); 13C-NMR (CDCl3)
δ
(ppm): 66.37 (q, 2JC-F = 36.0 Hz), 112.94, 123.10, 126.91, 129.32, 129.73,
(ppm): 73.70 (t, 3F,
129.91, 131.40, 133.42, 133.58, 136.41, 142.31, 155.69, 191.49; 19F-NMR (CDCl3)
δ
−
3J = 7.6 Hz); IR (KBr)
ν: 2884, 2361, 1651, 1602, 1588, 1485, 1447, 1330, 1260, 1227, 1196, 1069, 1024,
979, 863, 821, 769, 693 cm−1; HRMS (ESI) calc. for C17H12ClF3O2: [M + H]+ 341.0556 and [M + Na]+
363.0376;Found: 341.0545 and 363.0363.
(E)-3-(4-Bro◦mophenyl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3d
). Yellow solid, Yield: 73%,
m.p. 68–71 C; 1H-NMR (CDCl3)
δ
(ppm): 4.45 (q, 2H, 3J = 8.0 Hz), 6.95 (d, 1H, 3J = 8.0 Hz), 7.17 (t, 1H,
3J = 7.4 Hz), 7.43 (d, 1H, 3J = 15.9 Hz), 7.45 (d, 2H, 3J = 8.0 Hz), 7.53 (d, 2H, 3J = 8.5 Hz), 7.61 (d, 1H,
3J = 15.9 Hz), 7.73 (d, 1H, 3J = 7.9 Hz); 13C-NMR (CDCl3) (ppm): 66.34 (q, 2JC-F = 35.1 Hz), 112.89,
123.09, 124.62, 124.78, 126.98, 129.92, 131.40, 132.27, 133.44, 133.99, 142.33, 155.68, 191.46; 19F-NMR
δ
(CDCl3)
δ
(ppm):
−
73.54 (t, 3F, 3J = 7.6 Hz); IR (KBr)
ν: 2855, 2361, 1652, 1603, 1586, 1486, 1450, 1329,
1276, 1198, 1071, 1022, 819, 764, 692 cm−1; HRMS (ESI) calc. for C17H12BrF3O2: [M + H]+ 385.0051;
Found: 385.0042.
(E)-3-(3-Nitrophenyl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3e
170–172 ◦C; 1H-NMR (CDCl3) (ppm): 4.48 (q, 2H, 3J = 7.9 Hz), 6.96 (d, 1H, 3J = 8.4 Hz), 7.17–7.21
(m, 1H), 7.53–7.61 (m, 3H), 7.69–7.72 (m, 1H), 7.78 (dd, 1H, J = 7.7 Hz, J = 1.9 Hz), 7.89 (d, 1H,
3J = 8.1 Hz), 8.24 (d, 1H, 3J = 8.8 Hz), 8.46 (s, 1H); 13C-NMR (CDCl3) (ppm): 66.21 (q, 2JC-F = 35.7 Hz),
112.66, 122.72, 123.14, 124.64, 129.04, 129.33, 130.06, 131.59, 133.92, 134.12, 136.91, 140.25, 148.87, 155.83,
). Brown solid, Yield: 75%, m.p.
δ
3
4
δ
190.86; 19F-NMR (CDCl3)
δ
(ppm):
−
73.67 (t, 3F, 3J = 8.7 Hz); IR (KBr)
ν: 3113, 3093, 2954, 2359, 1651,
1604, 1527, 1487, 1448, 1331, 1271, 1230, 1061, 1021, 979, 865, 769, 747, 670 cm−1; HRMS (ESI) calc. for
C17H12F3NO4: [M + H]+ 352.0796 and [M + Na]+ 374.0616; Found: 352.0798 and 374.0616.
(E)-3-(2,5-Dimethoxyphenyl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3f
62%, 77–79 ◦C; 1H-NMR (CDCl3) (ppm): 3.79 (s, 3H), 3.82 (s, 3H), 4.43 (q, 2H, 3J = 8.1 Hz), 6.83–6.86
(m, 1H), 6.91–6.96 (m, 2H), 7.11–7.17 (m, 2H), 7.39–7.43 (m, 1H), 7.46–7.50 (m, 1H), 7.69 (dd, 1H,
3J = 7.7 Hz, 4J = 2.1 Hz), 8.02 (d, 1H, 3J = 16.0 Hz); 13C-NMR (CDCl3)
(ppm): 55.84, 56.24, 66.64 (q,
2JC-F = 35.8 Hz), 112.38, 112.69, 113.39, 118.18, 123.08, 124.51, 126.82, 130.61, 131.20, 132.91, 139.20,
). Yellow solid, Yield:
δ
δ

Molecules 2018, 23, 1174
21 of 28
153.43, 153.69, 155.63, 192.34; 19F-NMR (CDCl3)
δ
(ppm):
−
73.45 (t, 3F, 3J = 8.8 Hz); IR (KBr)
ν
: 2942,
2836, 2358, 1657, 1601, 1587, 1497, 1338, 1220, 1164, 1043, 978, 863, 820, 751, 680 cm−1; HRMS (ESI) calc.
for C19H17F3O4: [M + H]+ 367.1157; Found: 367.1132.
(E)-3-(◦Furan-2-yl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3g
). Brown solid, Yield: 59%, m.p.
72–74 C, 1H-NMR (CDCl3) (ppm): 4.44 (q, 2H, 3J = 7.9 Hz), 6.48–6.50 (m, 1H), 6.69 (d, 1H, 3J = 3.5 Hz),
δ
6.95 (d, 1H, 3J = 8.4 Hz), 7.14–7.18 (m, 1H), 7.27–7.31 (m, 1H), 7.41–7.51 (m, 3H), 7.69 (d, 1H, 3J = 8 Hz);
13C-NMR (CDCl3) (ppm): 66.63 (q, 2JC-F = 36.0 Hz), 112.68, 113.41, 115.88, 123.05, 124.17, 130.15, 130.27,
131.11, 133.08, 145.17, 151.79, 155.73, 191.56; 19F-NMR (CDCl3) 73.54 (t, 3F, 3J = 8.7 Hz); IR
(ppm):
(KBr) : 3040, 2901, 2360, 2342, 1645, 1603, 1587, 1487, 1449, 1330, 1295, 1206, 1016, 969, 868, 771, 746,
675 cm−1; HRMS (ESI) calc. for C15H11F3O3: [M + H]+ 297.0738; Found: 297.0735.
δ
δ
−
ν
(E)-3-(5-Bromothio◦phen-2-yl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3h
). Yellow solid, Yield:
87%, m.p. 94–95 C; 1H-NMR (CDCl3)
δ
(ppm): 4.45 (q, 2H, 3J = 8.0 Hz), 6.94 (d, 1H, 3J = 8.4 Hz),
7.03–7.07 (m, 2H), 7.14–7.18 (m, 2H), 7.48–7.53 (m, 1H), 7.67–7.73 (m, 2H); 13C-NMR (CDCl3)
δ
(ppm):
66.64 (q, JC-F = 36.3 Hz), 113.00, 116.60, 123.08, 123.23 (q, JC-F = 279.6 Hz), 125.52, 129.83, 131.39,
132.20, 133.41, 135.25, 142.20, 142.60, 155.73, 190.75; 19F-NMR (CDCl3) 73.3 (t, 3F, 3J = 7.5 Hz);
(ppm):
IR (KBr) : 3096, 2361, 1645, 1580, 1597, 1568, 1427, 1347, 1296, 1270, 1170, 1159, 1023, 979, 966, 867, 773,
675 cm−1; HRMS (ESI) calc. for C18H15F3O2: [M + H]+ 321.1102; Found: 321.1093.
2
1
δ
−
ν
(E)-3-(2-Bromophenyl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3i Pale yellow solid, Yield: 74%,
(ppm): 4.45 (q, 2H, 3J = 8.0 Hz), 6.96 (d, 1H, 3J = 8.4 Hz), 7.18 (t, 1H,
3J = 7.8 Hz), 7.20–7.23 (m, 1H), 7.32–7.37 (m, 2H), 7.49–7.54 (m, 1H), 7.61 (d, 1H, 3J = 7.4 Hz), 7.70–7.74
).
◦
m.p. 76–77 C; 1H-NMR (CDCl3)
δ
3
2
(m, 2H), 8.02 (d, 1H, J = 15.7 Hz); 13C-NMR (CDCl3)
δ (ppm): 66.47 (q, JC-F = 35.9 Hz), 113.03,
121.86, 123.12, 126.17, 127.83, 127.88, 128.99, 129.89, 131.37, 131.41, 133.36, 133.59, 142.33, 155.68, 191.73;
19F-NMR (CDCl3)
δ
(ppm):
−
73.48 (t, 3F, 3J = 6.5 Hz); IR (KBr)
ν: 3060, 2902, 2342, 1646, 1604, 1486,
1450, 1329, 1278, 1201, 1149, 1120, 1023, 970, 864, 753, 693 cm−1; HRMS (ESI) calc. for C17H12BrF3O2:
[M + H]+ 385.0051 and [M + Na]+ 406.9871; Found: 385.0042 and 406.9854.
(E)-3-(3-Bromophenyl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3j
m.p. 97–98 ◦C; 1H-NMR (CDCl3) (ppm): 4.47 (q, 2H, 3J = 7.9 Hz), 6.96 (d, 1H, 3J = 8.4 Hz), 7.17–7.21
(m, 1H), 7.27–7.30 (m, 2H), 7.43–7.47 (m, 1H), 7.52 (d, 2H, 3J = 8.4 Hz), 7.58–7.62 (m, 1H), 7.73–7.76
(m, 2H); 13C-NMR (CDCl3) (ppm): 66.36 (q, 2JC-F = 36.1 Hz), 112.90, 123.08, 127.14, 127.67, 129.76,
130.51, 131.20, 131.40, 133.23, 133.52, 137.20, 141.90, 155.72, 191.33; 19F-NMR (CDCl3)
(ppm): 73.49
). Yellow solid, Yield: 74%,
δ
δ
δ
−
(t, 3F, 3J = 7.7 Hz); IR (KBr)
ν: 3039, 2870, 2361, 2343, 1647, 1605, 1588, 1451, 1325, 1289, 1266, 1119, 1056,
1024, 969, 865, 767, 667 cm−1; HRMS (ESI) calc. for C17H12BrF3O2: [M + H]+ 385.0051 and [M + Na]+
406.9871; Found: 385.0057 and 406.9874.
(E)-1-(4-(2-Fluoroethoxy)phenyl)-3-(4-methylphenyl)-prop-2-en-1-one (4a) [44]. Yellow solid, Yield: 78%,
3
m.p. 110.1–110.7 ◦C; 1H-NMR (CDCl3)
δ
(ppm): 2.39 (s, 3H), 4.30 (dt, 2H, JH-H = 3.8 Hz,
3JH-F = 28.1 Hz), 4.80 (dt, 2H, JH-H = 4.1 Hz, JH-F = 47.2 Hz), 7.00–7.02 (m, 2H), 7.22–7.24 (m,
3
2
2H), 7.48–7.56 (m, 3H), 7.77–7.81(m,1H), 8.04(d, 2H, J = 8.4 Hz).
(E)-1-(4-(2-Fluoroethoxy)phenyl)-3-(3-ni◦trophenyl)prop-2-en-1-one (4e) [44]. Pale yellow solid, Yield:
◦
1
3
66%, m.p. 116–118 C (lit. 115–117 C); H-NMR (CDCl3)
δ (ppm): 4.32 (dt, 2H, JH-H = 4.0 Hz,
3JH-F = 27.1 Hz,), 4.81 (dt, 2H, 3JH-H = 3.9 Hz,2JH-F = 47.1 Hz,), 7.04 (m, 2H), 7.60–7.69 (m, 2H), 7.81–7.85
(m, 1H), 7.91 (d, 1H, 3J = 7.7 Hz), 8.08 (d, 2H, 3J = 8.7 Hz), 8.25 (d, 1H, 3J = 8.0 Hz), 8.52 (s, 1H).
(E)-3-(2,5-Dimethoxyphenyl)-1-(4-(2-fluoroethoxy)phenyl)prop-2-en-1-one (4f). Yellow solid, Yield: 80%,
◦
◦
1
m.p. 76–77 C (lit. 75–77 C); H-NMR (CDCl3)
δ
(ppm): 3.82 (s, 3H), 3.87 (s, 3H), 4.30 (dt, 2H,
3JH-H = 4.9 Hz, JH-F = 25.6 Hz), 4.80 (dt, 2H, JH-H = 4.7 Hz, JH-F = 46.4 Hz), 6.87–6.89 (m, 1H),
3
3
2
6.92–6.95 (m, 1H), 7.01 (d, 2H, 3J = 8.8 Hz), 7.16–7.17 (m, 1H), 7.57–7.61 (m, 1H), 8.02–8.09 (m, 3H);
13C-NMR (CDCl3) (ppm): 55.99, 56.26, 67.31 (d, 2JC-F = 20.7 Hz), 81.82 (d, 1JC-F = 170.9 Hz), 112.57,
δ
113.92, 114.45, 117.13, 123.03, 124.78, 131.01, 131.43, 131.97, 139.67, 153.42, 153.62, 162.15, 189.46;

Molecules 2018, 23, 1174
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19F-NMR (CDCl3)
δ
(ppm):
−
223.52 to
−
223.92 (m, 1F); IR (KBr)
ν
: 2946, 2838, 1656, 1607, 1598, 1572,
1496, 1453, 1427, 1341, 1318, 1281, 1249, 1185, 1116, 1073, 1052, 974, 950 cm−1; HRMS (ESI) calcd. for
C19H19FO4: [M + H]+ 331.1346 and [M + Na]+ 353.1165; Found: 331.1359 and 353.1171.
(E)-1-(4-(2-Fluoroethoxy)phenyl)-3-(furan-2-yl)prop-2-en-1-one (4g) [44]. Brown solid, Yield: 67%, m.p.
◦
1
3
3
75–76 C; H-NMR (CDCl3)
δ (ppm): 4.30 (dt, 2H, JH-H = 4.1 Hz, JH-F = 26.9 Hz), 4.79 (dt, 2H,
3JH-H = 3.5 Hz, 2JH-F = 48.0 Hz), 6.51 (dd, 1H, 3J = 3.1 Hz, 3J = 1.7 Hz), 6.7 (d, 1H, 3J = 3.9 Hz), 6.99–7.02
(m, 2H), 7.44–7.60 (m, 3H), 8.04–8.06 (m, 2H).
(E)-3-(2-Bromophenyl)-1-(4-(2-fluoroethoxy)phenyl)prop-2-en-1-one (4i
)
.
Pale yellow solid, Yield: 76%,
◦
1
3
3
m.p. 115–116 C; H-NMR (CDCl3)
δ
(ppm): 4.31 (dt, 2H, JH-H = 3.8 Hz, JH-F = 28.3 Hz), 4.80
3
2
3
(dt, 2H, JH-H = 4.0 Hz, JH- F = 47.5 Hz), 7.02 (d, 2H, J = 8.8 Hz), 7.32–7.45 (m, 3H), 7.64 (d, 1H,
3J = 8.1 Hz), 7.72–7.74 (m, 1H), 8.03–8.06 (m, 2H), 8.10–8.14 (m, 1H); 13C-NMR (CDCl3)
(d, 2JC-F = 20.6 Hz), 81.77 (d, 1JC-F = 172.1 Hz), 114.57, 122.78, 125.03, 125.95, 127.82, 128.00, 131.17,
131.33, 133.68, 135.37, 142.69, 162.42; 19F-NMR (CDCl3)
(ppm): 223.50 to 223.90 (m, 1F); IR (KBr)
δ (ppm): 67.35
δ
−
−
ν
: 3696, 3311, 2360, 1657, 1599, 1575, 1509, 1464, 1368, 1332, 1316, 1273, 1222, 1187, 1092, 1017, 918,
886, 829, 757, 740, 671, 647, 579, 509 cm−1; HRMS (ESI) calcd. for C17H14BrFO2: [M + H]+ 349.0239;
Found: 349.0233.
(E)-3-(4-Bromophenyl)-1-(3-(2-fluoroethoxy)phenyl)prop-2-en-1-one (5d
)
.
Yellow solid, Yield: 69%, m.p.
◦
1
3
3
122–124 C; H-NMR (CDCl3)
δ
(ppm): 4.30 (dt, 2H, JH-H = 4.0 Hz, JH-F = 27.9 Hz), 4.8 (dt, 2H,
3JH-H = 4.1 Hz, JH-F = 47.4 Hz), 7.17–7.19 (m,1H), 7.43 (t, 1H, J = 8.0 Hz), 7.48–7.57 (m, 6H),
2
3
7.62–7.64 (m, 1H), 7.72–7.76 (m, 1H); 13C-NMR (CDCl3)
1JC-F = 171.3 Hz), 113.65, 120.19, 121.75, 122.53, 125.03, 127.64, 129.97, 132.37, 133.86, 139.55, 143.67,
158.90, 189.88; 19F-NMR (CDCl3)
(ppm): 223.49 to 223.89 (m, 1F); IR (KBr) : 2968, 1660, 1597,
δ
(ppm): 67.45 (d, 2JC-F = 20.60 Hz), 81.90 (d,
δ
−
−
ν
1577, 1459, 1486, 1443, 1313, 1181, 1113, 1072, 1049, 1007, 975, 945, 893, 876, 834, 819, 793, 770, 691,
678, 612, 491 cm−1; HRMS (ESI) calcd. for C17H14BrFO2 : [M + H]+ 349.0239 and [M + Na]+ 371.0059;
Found: 349.0233 and 371.0059.
(E)-3-(2,5-Dimethoxyphenyl)-1-(3-(2-fluoroethoxy)phenyl)prop-2-en-1-one (5f
75%, 1H-NMR (CDCl3) (ppm): 3.82 (s, 3H), 3.87 (s, 3H), 4.30 (dt, 2H, 3JH-H = 4.2 Hz, 3JH-F = 27.9 Hz),
4.79 (dt, 2H, 3JH-H = 4.4 Hz, 2JH-F = 47.0 Hz), 6.86–6.89 (m, 1H), 6.94–6.97 (m, 1H), 7.12–7.18 (m, 2H),
7.42 (t, 1H, 3J = 8.0 Hz), 7.54–7.58 (m, 2H), 7.62–7.64 (m, 1H), 8.07–8.10 (m, 1H); 13C-NMR (CDCl3)
(ppm): 56.01, 56.26, 67.44 (d, 2JC-F = 20.1 Hz), 81.97 (d, 1JC-F = 171.20 Hz), 112.62, 113.62, 113.85, 117.51,
119.97, 121.86, 123.15, 124.58, 129.82, 140.04, 140.52, 153.52, 153.66, 158.81, 190.81; 19F-NMR (CDCl3)
). Yellow viscous solid, Yield:
δ
δ
δ
(ppm):
−
223.46 to
−
223.86 (m, 1F); IR (KBr) ν: 2952, 2836, 2066, 1866, 1660, 1585, 1495, 1438, 1326, 1259,
1180, 1118, 1046, 990, 946, 859, 865, 747, 710, 612, 564 cm−1; HRMS (ESI) calcd. for C19H19FO4:[M + H]+
331.1346 and [M + Na]+ 353.1165; Found: 331.1338 and 353.1157.
(E)-1-(3-(2-Fluoroethoxy)phenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (5k
m.p. 104–105 ◦C; 1H-NMR (CDCl3) (ppm): 3.86 (s, 3H), 4.30 (dt, 2H, 3JH-H = 4.1 Hz,3JH-F = 28.4 Hz,),
4.79 (dt, 2H, 3JH-H = 3.9 Hz, 2JH-F = 47.2 Hz), 6.93–6.95(m, 2H), 7.15–7.17 (m, 1H), 7.38–7.44(m, 2H),
7.56–7.64 (m, 4H), 7.77–7.81(m, 1H); 13C-NMR (CDCl3) (ppm): 55.57, 67.41 (d, 2JC-F = 20.2 Hz), 81.97
(d, 1JC-F = 170.9 Hz), 113.55, 114.57, 119.76, 119.86, 121.67, 127.69, 129.82, 130.44, 140.08, 145.04, 158.83,
161.88, 190.26; 19F-NMR (CDCl3)
(ppm): 223.51 to 223.91 (m, 1F); IR (KBr) : 2972, 1657, 1594,
). Pale yellow solid, Yield: 90%,
δ
δ
δ
−
−
ν
1575, 1511, 1486, 1418, 1326, 1309, 1286, 1254, 1182, 1172, 1112, 1074, 1046, 1030, 976, 890, 875, 830, 793,
739, 680, 536, 516 cm−1; HRMS (ESI) calcd. for C18H17FO3 :[M + H]+ 301.1240 and [M + Na]+ 323.1059;
Found: 301.1233 and 323.1050.
(E)-3-(2-Bromophenyl)-1-(2-(2-fluoroethoxy)phenyl)prop-2-en-1-one (6i
)
.
Yellow solid, Yield: 76%, m.p.
◦
1
3
3
86–88 C; H-NMR (CDCl3)
δ
(ppm): 4.33 (dt, 2H, JH-H = 3.7 Hz, JH-F = 28.6 Hz), 4.76 (dt, 2H,
3JH-H = 4.0 Hz, 2JH-F = 47.5 Hz), 6.96–6.98 (m, 1H), 7.08–7.11 (m, 1H), 7.19–7.24 (m, 1H), 7.30–7.34 (m,
1H), 7.46–7.50 (m, 2H), 7.60–7.62 (m, 1H), 7.71–7.78 (m, 2H), 8.01–8.05 (m, 1H); 13C-NMR (CDCl3)
δ
2
1
(ppm): 67.91 (d, JC-F = 19.7 Hz), 81.77 (d, JC-F = 171.40 Hz), 112.60, 121.75, 126.14, 127.82, 127.96,

Molecules 2018, 23, 1174
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127.98, 129.43, 131.17, 131.21, 133.43, 133.54, 135.22, 141.21, 157.17, 192.15; 19F-NMR (CDCl3)
δ
(ppm):
−
222.76 to 223.16 (m, 1F); IR (KBr) ν: 3331, 2893, 1646, 1606, 1484, 1464, 1450, 1329, 1281, 1262, 1166,
1119, 1064, 1042, 1026, 975, 922, 880, 814, 756, 670, 648, 616, 578, 530, 467, 446 cm−1; HRMS (ESI) calcd.
for C17H14BrFO2: [M + H]+ 349.0239 and [M + Na]+ 371.0059; Found: 349.0243 and 371.0057.
◦
(E)-3-(4-(2-Fluoroethoxy)phenyl)-1-phenylprop-2-en-1-one (7i) [44]. Yellow solid, Yield: 76%, m.p. 79–80 C
(lit. 78–80 ◦C); 1H-NMR (CDCl3) (ppm): 4.27 (dt, 2H, 3JH-H = 4.2 Hz, 3JH-F = 27.6 Hz), 4.79 (dt, 2H,
δ
3JH-H = 3.8 Hz, 2JH-F = 47.6 Hz), 6.96–6.98 (m, 2H), 7.41–7.45 (m, 1H), 7.49–7.52 (m, 2H), 7.56–7.58 (m,
1H), 7.61–7.63 (m, 2H), 7.77–7.81 (m, 1H), 8.00–8.02 (m, 2H).
(E)-3-(4-(2◦-Fluoroethoxy)ph◦enyl)-1-(3-nitrophenyl)prop-2-en-1-one (7ii) [44]. Pale yellow solid, Yield: 59%,
1
3
122–124 C (lit. 122–124 C); H-NMR (CDCl3)
δ (ppm): 2.44 (s, 3H), 4.27 (dt, 2H, JH-H = 4.1 Hz,
3JH-F = 27.5 Hz), 4.78 (dt, 2H, 3JH-H = 4.2 Hz, 2JH-F = 47.4 Hz), 6.96 (d, 2H, 3J = 8.9 Hz), 7.30 (d, 2H,
3J = 8.0 Hz), 7.42–7.45 (m, 1H), 7.60–7.62 (m, 2H), 7.76–7.80 (m, 1H), 7.92–7.94 (m, 2H).
(E)-1-(2,4-Dichlorophenyl)-3-(4-(2-fluoroethoxy)phenyl)prop-2-en-1-one (7iii
m.p. 85–87 ◦C; 1H-NMR (CDCl3) (ppm): 4.26 (dt, 2H, 3JH-H = 4.2 Hz, 3JH-F = 27.6 Hz), 4.78 (dt, 2H,
3JH-H = 4.1 Hz, 2JH-F = 47.4 Hz), 6.94–6.97 (m, 2H), 7.01 (s, 1H), 7.33–7.36 (m, 1H), 7.39–7.41 (m, 1H),
7.43–7.48 (m, 2H), 7.52–7.54 (m, 2H); 13C-NMR (CDCl3) (ppm): 67.27 (d, 2JC-F = 21.20 Hz), 81.76 (d,
1JC-F = 171.5 Hz), 115.22, 124.17, 127.39, 127.64, 130.29, 130.47, 130.67, 132.42, 136.84, 137.80, 146.52,
160.98, 192.82; 19F-NMR (CDCl3)
223.52 (m, 1F); IR (KBr) : 3072, 2968, 1897,
). Pale yellow solid, Yield: 67%,
δ
δ
δ
(ppm): −223.92 to
−
ν
1731, 1660, 1592, 1572,1516, 1456, 1427, 1374, 1337, 1296, 1253, 1267, 1208, 1180, 1048, 1025, 984, 921, 885,
863, 793, 682, 579, 519 cm−1; HRMS (ESI) calcd. for C17H13Cl2FO2: [M + H]+ 339.0355 and [M + Na]+
361.0174; Found: 339.0342 and 361.0155.
(E)-3-(4-(2-Fluoroethoxy)phenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (7iv) [44]. Yellow solid, Yield: 73%,
m.p. 88–89 ◦C (lit. 87–89 ◦C); 1H-NMR (CDCl3)
δ
(ppm): 3.89 (s, 3H), 4.42 (dt, 2H, 3JH-H = 3.9 Hz,
3JH-F = 28.2 Hz), 4.77 (dt, 2H, 3JH-H = 4.0 Hz, 2JH-F = 47.6 Hz), 6.93 (d, 2H, 3J = 8.7 Hz), 6.98–7.05 (m,
2H), 7.22–7.25 (m, 1H), 7.46 (t, 1H, 3J = 8.0 Hz), 7.52–7.55 (m, 2H), 7.58–7.60 (m, 2H).
(E)-1-(2-Bromophenyl)-3-(4-(2-fluoroethoxy)phenyl)prop-2-en-1-one (7vii) [44]. Yellow solid, Yield: 71%,
1
3
m.p. 107–108 ◦C (lit. 107–109 ◦C); H-NMR (CDCl3)
δ
(ppm): 4.27 (dt, 2H, JH-H = 4.1 Hz,
3JH-F = 27.7 Hz), 4.78 (dt, 2H, JH-H = 3.9 Hz, JH-F = 46.4 Hz), 6.97 (d, 2H, J = 7.5 Hz), 7.17 (m,
3
2
3
2H), 7.38–7.42 (m, 1H), 7.60–7.62 (m, 2H), 7.77–7.81 (m, 1H), 8.03–8.07 (m, 2H).
(E)-3-(3-(2-Fluoroethoxy)phenyl)-1-(4-methylphenyl)-prop-2-en-1-one (8ii) [44]. Yellow solid, Yield: 70%,
◦
◦
1
3
m.p. 81–82 C (lit. 80–82 C); H-NMR (CDCl3)
δ (ppm): 2.5 (s, 3H), 4.33 (dt, 2H, JH-H = 3.9 Hz,
3JH-F = 28.1 Hz), 4.85 (dt, 2H, 3JH-H = 3.7 Hz, 2JH-F = 47.7 Hz), 7.04–7.06 (m, 1H), 7.32–7.43 (m, 4H),
7.58–7.60 (m, 1H), 7.80–7.84 (m, 1H), 7.99–8.01 (m, 2H).
(E)-1-(2,4-Dichlorophenyl)-3-(3-(2-fluoroethoxy)phenyl)prop-2-en-1-one (8iii
)
.
Pale yellow solid, Yield: 80%,
(ppm): 4.28 (dt, 2H, 3JH-H = 4.2 Hz, 3JH-F = 27.6 Hz), 4.76 (dt, 2H,
3JH-H = 4.4 Hz, 2JH-F = 47.9 Hz), 6.91–6.93 (m, 1H), 7.01–7.04 (m, 1H), 7.24–7.28 (m, 1H), 7.33–7.48 (m,
4H), 7.58 (d, 1H, 3J = 7.4 Hz), 7.82–7.86 (m, 1H); 13C-NMR (CDCl3) (ppm): 67.87 (d, 2JC-F = 20.6 Hz),
81.71 (d, 1JC-F = 171.5 Hz), 112.59, 121.74, 123.91, 126.82, 127.30, 129.85, 130.28, 130.69, 132.40, 132.57,
136.89, 137.76, 142.10, 157.74, 193.12; 19F-NMR (CDCl3)
(ppm): 223.56 to 223.95 (m, 1F); IR (KBr)
◦
m.p. 101–102 C; 1H-NMR (CDCl3)
δ
δ
δ
−
−
ν:
2966, 1671, 1600, 1572, 1493, 1450, 1372, 1320, 1280, 1248, 1203, 1130, 1073, 1041, 1016, 987, 928, 887, 824,
762, 745, 575 cm−1; HRMS (ESI) calcd. for C17H13Cl2FO2: [M + H]+ 339.0355 and [M + Na]+ 361.0174;
Found: 339.0350 and 361.0164.
(E)-3-(3-(2-Fluoroethoxy)phenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (8iv). Pale yellow paste, Yield: 86%,
3
1H-NMR (CDCl3)
δ
(ppm): 3.89 (s, 3H), 4.28 (dt, 2H, 3JH-H = 4.3 Hz, JH-F = 26.9 Hz), 4.78 (dt, 2H,
3JH-H = 5.1 Hz, 2JH-F = 45.7 Hz), 6.90–6.92 (m, 1H), 6.98–7.05 (m, 3H), 7.34 (t, 3J = 7.8 Hz), 7.43–7.48
(m, 2H), 7.61 (d, 2H, J = 8.0 Hz), 7.94–7.98 (m, 1H); 13C-NMR (CDCl3)
δ (ppm): 55.81, 67.78 (d,
3
2JC-F = 20.7 Hz), 81.80 (d, 1JC-F = 171.8 Hz), 111.67, 112.44, 120.75, 121.56, 124.68, 128.02, 129.36, 129.65,

Molecules 2018, 23, 1174
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130.46, 131.54, 132.77, 138.77, 157.56, 158.17, 193.78; 19F-NMR (CDCl3)
1F); IR (KBr) ν: 2962, 1658, 1604, 1485, 1438, 1403, 1281, 1246, 1179, 1163, 1114, 1055, 1028, 982, 886, 761,
678, 655 cm−1; HRMS (ESI) calcd. for C18H17FO3: [M + H]+ 301.1240 and [M + Na]+ 323.1059; Found:
301.1206 and 323.1029.
δ
(ppm):
−
223.45 to
−
223.85 (m,
(E)-1-(4-Bromophenyl)-3-(3-(2-fluoroethoxy)phenyl)prop-2-en-1-one (8v
)
.
Yellow solid, Yield: 74%, m.p.
◦
3
122–123 C; 1H-NMR (CDCl3)
δ
(ppm): 4.33 (dt, 2H, 3JH-H = 4.0 Hz, JH-F = 27.9 Hz), 4.85 (dt, 2H,
2
3JH-H = 3.9 Hz, JH-F = 47.7 Hz), 7.05–7.08 (m, 1H), 7.32–7.34 (m, 2H), 7.40–7.44 (m, 1H), 7.50–7.54
(m, 1H), 7.71–7.73 (m, 2H),7.82–7.86 (m, 1H), 7.94–7.96 (m, 2H); 13C-NMR (CDCl3)
2JC-F = 20.8 Hz), 81.97 (d, 1JC-F = 170.50 Hz), 114.43, 117.08, 121.96, 122.01, 128.13, 130.17, 130.27, 132.10,
δ (ppm): 67.38 (d,
136.31, 136.95, 145.21, 158.95, 189.44; 19F-NMR (CDCl3)
δ
(ppm):
−
223.19 to
−
223.59 (m, 1F); IR (KBr) ν:
2928, 1659, 1604, 1491, 1310, 1262, 1213, 1178, 1048, 1027, 990, 883, 824, 778, 755, 666, 467 cm−1; HRMS
(ESI) calcd. for C17H14BrFO2: [M + H]+ 349.0239; Found: 349.0232.
(E)-3-(3-(2-Fluoroethoxy)phenyl)-1-(3-methylphenyl)-prop-2-en-1-one (8ix). Pale yellow solid, Yield: 90%,
◦
m.p. 82–84 C; 1H-NMR (CDCl3) (ppm): 2.44 (s, 3H), 4.27 (dt, 2H, 3JH-H = 27.8 Hz, 3JH-F = 3.9 Hz), 4.79
δ
(dt, 2H, 3JH-H = 47.3 Hz, 2JH-F = 4.0 Hz), 6.98–7.00 (m,1H), 7.20 (s, 1H), 7.28–7.37 (m, 3H), 7.50–7.54 (m,
1H), 7.74–7.78 (m, 1H), 7.93–7.95 (m, 2H); 13C-NMR (CDCl3) (ppm): 21.82, 67.39 (d, 2JC-F = 20.4 Hz),
81.99 (d, 1JC-F = 171.90 Hz), 114.33, 116.82, 121.86, 122.71, 128.81, 129.50, 130.19, 135.70, 136.69, 143.88,
144.18, 158.95, 190.09; 19F-NMR (CDCl3)
(ppm): 223.48 to 223.88 (m, 1F); IR (KBr) : 3055, 2920,
δ
δ
−
−
ν
1658, 1600, 1576, 1494, 1439, 1372, 1311, 1205, 1182, 1096, 1078, 1055, 1030, 1016, 994, 884, 848 cm−1
HRMS (ESI) calcd. for C18H17FO2: [M + H]+ 285.1291 and [M + Na]+ 307.1110; Found: 285.1286
and 307.1104
;
(E)-3-(2-(2-Fluoroethoxy)phenyl)-1-phenylprop-2-en-1-one (9i). Pale yellow viscous liquid, Yield: 81%,
1H-NMR (CDCl3)
δ
(ppm): 4.33 (dt, 2H, 3JH-H = 3.9 Hz, 3JH-F = 27.5 Hz), 4.85 (dt, 2H, 3JH-H = 4.2 Hz,
2JH-F = 47.5 Hz), 6.93–6.95 (m, 1H), 7.02–7.06 (m, 1H), 7.37 (t, 1H, J = 8.3 Hz), 7.48–7.52 (m, 2H),
3
7.56–7.58 (m, 1H), 7.62–7.64 (m, 1H), 7.76–7.80 (m, 1H), 8.04–8.09 (m, 2H); 13C-NMR (CDCl3)
δ
(ppm):
67.68 (d, JC-F = 21.2 Hz), 81.87 (d, JC-F = 171.70 Hz), 112.36, 121.65, 123.68, 128.35, 128.71, 130.58,
131.70, 132.79, 133.09, 138.55, 140.49, 157.83, 191.21; 19F-NMR (CDCl3)
(ppm): 223.86 to 223.46 (m,
2
1
δ
−
−
1F); IR (KBr) ν: 2958, 2360, 1661, 1600, 1573, 1488, 1448, 1334, 1279, 1248, 1215, 1180, 1112, 1052, 1017,
927, 886, 753, 734, 694, 578 cm−1; HRMS (ESI) calcd. for C17H15FO2: [M + H]+ 271.1134 and [M + Na]+
293.0954 ; Found: 271.1131 and 293.0945.
(E)-3-(2-(2-Fluoroethoxy)phenyl)-1-(4-methylphenyl)-prop-2-en-1-one (9ii). Yellow viscous liquid, Yield:
◦
83%, m.p. 69–70 C; 1H-NMR (CDCl3) (ppm): 2.43 (s, 3H), 4.33 (dt, 2H, 3JH-H = 4.2 Hz, 3JH-F = 27.5 Hz),
δ
4.85 (dt, 2H, 3JH-H = 4.0 Hz, 2JH-F = 47.4 Hz), 6.93–6.95 (m, 1H), 7.02–7.06 (m, 1H), 7.29–7.31 (m, 2H),
7.34–7.38 (m, 1H), 7.62–7.64 (m, 1H), 7.77–7.80 (m, 1H), 7.95–7.97 (m, 2H), 8.04–8.08 (m, 1H); 13C-NMR
(CDCl3)
124.59, 128.84, 129.42, 130.55, 131.55, 135.98, 140.02, 143.59, 157.79, 190.69; 19F-NMR (CDCl3)
δ
(ppm): 21.81, 67.67 (d, 2JC-F = 20.6 Hz), 81.88(d, 1JC-F = 171.90 Hz), 112.34, 121.62, 123.73,
δ
(ppm):
−
223.82 to
−
223.43 (m, 1F); IR (KBr) ν: 2860, 2361, 1659, 1598, 1490, 1449, 1280, 1251, 1181, 1126, 1040,
930, 884, 742, 572, 474 cm−1; HRMS (ESI) calcd. for C18H17FO2: [M + H]+ 285.1291 and [M + Na]+
307.1110 ; Found: 285.1288 and 307.1105.
(E)-1-(2,4-Di◦chlorophenyl)-3-(2-(2-fluoroethoxy)phenyl)prop-2-en-1-one (9iii). Yellow solid, Yield: 89%,
1
3
3
m.p. 93–94 C; H-NMR (CDCl3)
δ (ppm): 4.28 (dt, 2H, JH-H = 4.3 Hz, JH-F = 27.7 Hz), 4.77 (dt,
2H, 3JH-H = 4.2 Hz, 2JH-F = 47.0 Hz), 6.92 (m, 1H), 7.01–7.04 (m, 1H), 7.24 (s,1H), 7.28–7.48 (m, 4H),
7.57–7.59 (m, 1H), 7.84 (d, 1H, 3J = 16.5 Hz); 13C-NMR (CDCl3) (ppm): 67.86 (d, 2JC-F = 20.6 Hz),
81.71 (d, 1JC-F = 171.80 Hz), 112.58, 112.74,123.90, 126.82, 127.30, 129.86, 130.28, 130.69, 132.40, 132.57,
136.90, 137.76, 142.11, 157.74, 193.13; 19F-NMR (CDCl3)
(ppm): 223.85 to 223.46 (m, 1F); IR (KBr)
δ
δ
−
−
ν:
2966, 1671, 1600, 1584, 1572, 1493, 1450, 1371, 1334, 1320, 1280, 1247, 1202, 1167, 1130, 1111, 1072, 1042,
1016, 987, 928, 886, 824, 790, 762, 745, 609, 575, 520, 454 cm−1; HRMS (ESI) calcd. for C17H13Cl2FO2 :
[M + H]+ 339.0355; Found: 339.0344.

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(E)-1-(4-Bromophenyl)-3-(2-(2-fluoroethoxy)phenyl)prop-2-en-1-one (9v). Pale yellow solid, Yield: 78%,
m.p. 84–86 ◦C; 1H-NMR (CDCl3) (ppm): 4.33 (dt, 2H, 3JH-H = 6.2 Hz, 3JH-F = 23.0 Hz), 4.86 (dt, 2H,
3JH-H = 3.7 Hz, 2JH-F = 48.5 Hz), 6.93–6.95 (m, 1H), 7.02–7.06 (m, 1H), 7.36–7.40 (m, 1H), 7.57–7.65 (m,
3H), 7.74–7.78 (m, 1H), 7.83–7.85 (m, 1H), 7.90–7.93 (m, 1H), 8.03–8.07 (m, 1H); 13C-NMR (CDCl3)
δ
δ
2
1
(ppm): 67.60 (d, JC-F = 20.7 Hz), 81.86 (d, JC-F = 171.30 Hz), 112.34, 121.67, 123.16, 124.26, 129.88,
130.24, 130.95, 131.89, 131.99, 137.27, 141.12, 157.91, 190.08; 19F-NMR (CDCl3)
(ppm): 223.51 to
223.91 (m, 1F); IR (KBr) ν: 2960, 1919, 1684, 1657, 1600, 1571, 1490, 1448, 1394, 1333, 1274, 1252, 1205,
1177, 1128, 1064, 1008, 983, 930, 884, 822, 740, 667, 608, 580, 540, 468 cm−1; HRMS (ESI) calcd. for
C17H14BrFO2: [M + H]+ 349.0239 and [M + Na]+ 371.0053; Found: 349.0230 and 371.0044.
δ
−
−
(E)-3-(2-(2-Fluoroethoxy)phenyl)-1-(4-fluorophenyl)prop-2-en-1-one (9vii). Yellow solid, Yield: 71%, m.p.
◦
1
3
3
44–45 C; H-NMR (CDCl3)
δ (ppm): 4.33 (dt, 2H, JH-H = 4.3 Hz, JH-F = 27.6 Hz), 4.86 (dt, 2H,
3JH-H = 3.9 Hz, JH-F = 47.5 Hz), 6.93–6.95 (m, 1H), 7.02–7.06 (m, 1H), 7.10–7.19 (m, 2H), 7.36–7.40
2
(m, 1H), 7.60–7.62 (m, 1H), 7.76–7.80 (m, 1H), 8.03–8.10 (m, 2H); 13C-NMR (CDCl3)
2JC-F = 20.6 Hz), 81.87 (d, 1JC-F = 172.4), 112.35, 115.69, 115.90, 121.67, 123.34, 130.88, 130.96, 131.05,
131.24, 131.33, 131.79, 140.79, 189.77; 19F-NMR (CDCl3)
(ppm): 105.71 to 105.78 (m, 1H) and
223.46 to
223.86 (m, 1H); HRMS (ESI) calcd. for C17H14F2O2: [M + H]+ 289.1040 and [M + Na]+
311.0860; Found: 289.1025 and 311.0843.
δ (ppm): 67.66 (d,
δ
−
−
−
−
(E)-3-(2-(2-Fluoroethoxy)phenyl)-1-(2-methylphenyl)-prop-2-en-1-one (9viii). Pale yellow viscous liquid,
1
3
3
Yield: 85%, H-NMR (CDCl3)
δ (ppm): 2.46 (s, 3H), 4.27 (dt, 2H, JH-H = 4.0 Hz, JH-F = 27.1 Hz),
4.75 (dt, 2H, 3JH-H = 4.1 Hz, 2JH-F = 48.1 Hz), 6.90–6.92 (m, 1H), 7.00–7.04 (m, 1H), 7.25–7.29 (m, 3H),
7.34–7.39 (m, 2H), 7.52–7.54 (m, 1H), 7.58–7.60 (m, 1H), 7.83 (d, 1H, 3J =16.4 Hz); 13C-NMR (CDCl3)
δ
(ppm): 20.49, 67.79 (d, 2JC-F = 20.40 Hz), 81.75 (d, 1JC-F = 172.6 Hz), 112.48, 121.67, 124.27, 125.54,
127.70, 128.43, 129.53, 130.52, 131.39, 131.92, 137.16, 139.34, 141.36, 15s7.54, 197.15; 19F-NMR (CDCl3)
δ
(ppm):
−
223.53 to
−
223.93 (m, 1F); IR (KBr) ν: 3707, 3314, 2869, 1636, 1600, 1489, 1459, 1390, 1310, 1276,
1245, 1168, 1112, 1064, 994, 922, 882, 748, 607, 458 cm−1; HRMS (ESI) calcd. for C18H17FO2: [M + H]+
285.1291 and [M + Na]+ 307.1110; Found: 285.1286 and 307.1102.
4. Conclusions
In summary, we have reported the synthesis of a series of 2,2,2-trifluoroethoxy- and
2-fluoroethoxychalcones and their in vitro antiplasmodial evaluation against P. falciparum (3D7).
It was found for the first time that 2,2,2-trifluoroethoxychalcones exhibited position-dependent
antiplasmodial activity and the compounds 3a and 3f exhibited good activity with negligible toxic
effects on normal erythrocytes and mammalian cells. The influence of the number of fluorine atoms on
antiplasmodial activity was also demonstrated with 2-fluoroethoxychalcones. The results showed that
chalcones with 2,2,2-trifluoroethoxy groups on the o-position of the 1-phenyl ring and 2-fluoroethoxy
chalcones could be considered as viable alternatives to current drugs of future interest. Based on
this result, a detailed study on the antiplasmodial activity of 2,2,2-trifluoroethoxychalcones in which
the 2,2,2-trifluoroethoxy group is substituted on the 3-phenyl ring and 2-fluoroethoxychalcones will
be undertaken.
Supplementary Materials: Supplementary materials are available online.
Author Contributions: T.M.R., R.P.S., and P.C.G. conceived and planned the experiments; K.D. and Ayushee
performed the synthetic work and M.S. and R.P.S. compiled the supporting data. V.R. performed the biological
works. V.R. and P.C.G. compiled and interpreted the activity data. T.M.R., R.P.S., and V.R. wrote the manuscript.
Acknowledgments: Authors are grateful to Defense R & D Organization (DRDO) for financial assistance.
Authors also acknowledge Director, CFEES, DRDO and Principal, Sri Venkateswara College, University of Delhi,
for their encouraging support throughout this work. We thank to USIC-University of Delhi for analytical support.
Conflicts of Interest: The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are not available from the authors.
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