Synthesis and antimalarial activity of 1,4-disubstituted piperidine derivatives

Article abstract of DOI:10.3390/molecules25020299

In order to prepare, at low cost, new compounds active against Plasmodium falciparum, and with a less side-effects, we have designed and synthesized a library of 1,4-disubstituted piperidine derivatives from 4-aminopiperidine derivatives 6. The resulting compound library has been evaluated against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. The most active molecules—compounds 12d (13.64 nM (3D7)), 13b (4.19 nM (3D7) and 13.30 nM (W2)), and 12a (11.6 nM (W2))—were comparable to chloroquine (22.38 nM (3D7) and 134.12 nM (W2)).

Full text of DOI:10.3390/molecules25020299

molecules
Article
Synthesis and Antimalarial Activity of
1,4-Disubstituted Piperidine Derivatives
Rokhyatou Seck 1, Abdoulaye Gassama 1,*, Sandrine Cojean 2,3 and Christian Cavé 3,
*
1
Laboratoire de Chimie et Physique des Matériaux (LCPM), Université Assane SECK de Ziguinchor,
Ziguinchor BP 523, Senegal; seckrokhya@gmail.com
Centre National de Référence du Paludisme, Hôpital Bichat-Claude Bernard, APHP, 75018 Paris, France;
sandrine.cojean@u-psud.fr
Université Paris-Saclay, CNRS BioCIS, 92290 Châtenay-Malabry, France
Correspondence: agassama@univ-zig.sn (A.G.); christian.cave@u-psud.fr (C.C.)
2
3
*
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 17 December 2019; Accepted: 10 January 2020; Published: 11 January 2020
Abstract: In order to prepare, at low cost, new compounds active against Plasmodium falciparum, and
with a less side-effects, we have designed and synthesized a library of 1,4-disubstituted piperidine
derivatives from 4-aminopiperidine derivatives 6. The resulting compound library has been evaluated
against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. The most
active molecules—compounds 12d (13.64 nM (3D7)), 13b (4.19 nM (3D7) and 13.30 nM (W2)), and
12a (11.6 nM (W2))—were comparable to chloroquine (22.38 nM (3D7) and 134.12 nM (W2)).
Keywords: piperidine; reductive amination; reagent-based diversity; antimalarial; drug lead
1. Introduction
This year’s World Health Organization (WHO) report shows that after an unprecedented period of
success in global malaria control, progress has stalled [1]. In 2016, there were an estimated 216 million
cases of malaria, an increase of about 5 million cases over 2015. Deaths reached 445,000, a similar
number to the previous year.
Malaria-related mortality followed the same trend, i.e., a decline from 2010 to 2014, and then an
increase in 2015 and 2016. According to this report, it is in the WHO African region that the increase in
cases of malaria and associated deaths was the most significant. The African region still accounts for
some 90% of worldwide malaria cases and related deaths. Fifteen countries, all but one in sub-Saharan
Africa, account for 80% of the global burden of malaria.
One of the biggest challenges facing malaria chemotherapy is the rapid emergence of resistance
to existing antimalarial drugs [
2]. Chloroquine was replaced as first line therapy by the sulfonamide
antimalarials and, later on, artemisinin combination therapy (ACT), following the development of
widespread resistance against the drug by Plasmodium falciparum [3]. This challenge underscores the
need for the continued search for new antimalarials.
The 4-arylaminopiperidine is a structural moiety found in many alkaloids [
and pharmaceutical products such as fentanyl and structurally-related analgesic opioids or
H1-antihistamines agents such as bamipine [12 17] and neurokinin 1 (NK1) receptor antagonists [18 20].
26] have good selectivity and activity
4–11]
–
–
Studies have shown that compounds with piperidine rings [4,8,21–
for the P. falciparum strain.
Research is being pursued for the discovery of new antimalarials with less side effects, a faster
onset of action and a better rate of response [ 21 26]. In the process of searching for new small
molecules interacting with the P. falciparum strain, we have identified the target compounds with
4,8, –
A
Molecules 2020, 25, 299; doi:10.3390/molecules25020299
www.mdpi.com/journal/molecules

Molecules 2020, 25, 299
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various R1, R2 and R3 substituents (Figure 1). In this paper, we describe the synthesis of some new
derivatives with potential antimalarial properties.
Figure 1. target compounds A.
2. Results and Discussion
2.1. Chemistry
The key compound
Scheme 1 [27]. Thus, reductive amination [28
CH2Cl2, gave compounds 3a, b in 75–85% yield. Acylation of the sodium salts of
chlorides (85–90%). Final deprotection [32
in CH2Cl2 at 0 ◦C furnished compounds
trifluoroacetic acid at room temperature provided compounds 6a–b (50–95%) (Scheme 1).
6
has been synthesized through a three-step process according to the
31] of N-boc-piperidin-4-one ( ) with anilines 2a, b in
with phenoxyacetyl
33] of using
–
1
3
4
5
,
5
Scheme 1. Synthesis of compounds 6a–b.

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The alkylation of
3
with the acetyl chloride supplied compounds
7
in 85% yield. The condensation
of
7
with the phenol
8
gave compounds
9
(78–80%). Final deprotection [32
,
33] of
9 using trifluoroacetic
acid at room temperature provided compounds 6c
overall yields of compounds 6a–d.
–d (50–95%) (Scheme 2). The Table 1 gives the
Scheme 2. Synthesis of compound 6c and 6d.
Table 1. The products of the synthesis of 6 recorded.
Compounds R1 R2 Overall Yields %
6a
6b
6c
H
F
H
F
H
H
35
34
Cl 64
Cl 33
6d
Condensation of phenoxyacetyl chloride with compound 3a in the presence of triethylamine at
room temperature in acetone gave compounds 5a (55%) and 10 (30%) (Scheme 3). In this reaction we
used excess phenoxyacetyl chloride, and we think that this excess probably made the reaction medium
acidic which cause the cleavage of the N-Boc protective group. To avoid this side reaction, we used
NaH in CH2Cl2 which furnished compound 5a (Scheme 1).
Scheme 3. Synthesis of compounds 5a and 10.
A pharmaco-modulation has been achieved on the parent molecule
6 taking advantage of the
nucleophilicity of the piperidine nitrogen leading to compounds 17–34 in good yield. Thus, reductive

Molecules 2020, 25, 299
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amination [28
–
31] of
6
with benzaldehyde derivatives in 1,2-dichloroethane (ClCH2CH2Cl), gave
compounds A (Scheme 4) (Table 2).
R1
R1
O
R2
O
R2
O
N
NaBH(OAc)3/ AcOH
1.2 dichloroethane
O
N
N
H
O
R3
N
11
A
6a: R1= H, R2= H
6b: R1= F, R2= H
6c: R1= H, R2= Cl
6d: R2= F, R2= Cl
R3
R3= H, Cl, Br, 5*F
Scheme 4. Synthesis of target compounds A.
Table 2. The target compounds A.
Compounds R1 R2 R3
Time (h) Overall Yields %
12a
12b
12c
12d
13a
13b
13c
13d
14a
14c
14d
15a
16a
17a
17b
17c
17d
H
F
H
F
H
F
H
F
H
H
F
H
H
H
F
H
H
Cl
Cl
H
H
Cl
Cl
H
Cl
Cl
H
H
H
H
Cl
Cl
H
H
H
H
24
24
24
24
24
24
24
24
24
24
24
24
18
18
32
18
21
19
35
20
18
41
18
24
18
17
18
39
20
Br (o)
Br (o)
Br (o)
Br (o)
Cl (o)
Cl (o)
Cl (o)
OH (o), OH (p)
OH (o), OMe (o) 24
5xF (o,m,p)
5xF (o,m,p)
5xF (o,m,p)
5xF (o,m,p)
24
24
24
24
H
F
2.2. The Antimalarial Activity of Derivatives 6 and Target Compounds A
Studies have shown that compounds with piperidine rings [
4,
8,
21–
26] have good selectivity
and activity for the P. falciparum strain. This prompted us to assess their antiplasmodial activity
against the chloroquine-sensitive 3D7 and chloroquine-resistant W2 strains of P. falciparum as well as
their cytotoxic activity against HUVEC cells (Tables 3 and 4). Solutions of the 22 synthetic products
and the negative control (chloroquine (CQ)) were prepared by two-fold dilution, in a dose-titration
range of 0.098–100
(IC50 > 100). The compounds exhibited activities in the nanomolar range against both parasitic strains.
Their cytotoxicity against HUVEC ranged from CC50 0.052 0.004 to >100 mM, thus resulting in varied
µg/mL, to obtain 11 concentrations each, and all of them were inactive against W2
±
selectivity indexes (SI), 26 for 13b in the 3D7 strain and >11.3 for 14c in the W2 strain. Compared
with chloroquine (IC50 = 22.38 (3D7) and 134.12 (W2)), the compounds 13b (IC50 = 13.30 nM) and
12a (IC50 = 11.06 nM) showed a strong activity against W2. Molecules 13b (IC50 = 4.19 nM), 12d
(IC50 = 13.64 nM), 14d (IC50 = 14.85 nM) and 6b (IC50 = 17, 42 nM) had the highest activity against 3D7.
Interestingly, compounds 6c and 6d are inactive against both strains. However, after
pharmacomodulation on the nitrogen atom, their derivatives 12d, 14d, 17c, 13c and 14c showed
good activity against both strains.

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Compound 13b exhibits 5-fold more activity against strain 3D7 and 10-fold more against strain
W2 with very low cytotoxicity (CC50 = 112 nM), resulting in a high selectivity index (SI = 26.7 (3D7)
and 8.4 (W2), respectively) relative to chloroquine (CC50 = 37.56 nM, SI = 1.7 (3D7) and 0.3 (W2)).
Substitution of the piperidine nitrogen atom with a pentafluorobenzyl moiety did not significantly
alter the activity of its derivative molecules against both strains. Indeed, the compounds 17b and 17d,
derived from 6b and 6d, respectively, remained inactive while the activity of 17a (37.63 nM (3D7) and
47.84 nM (W2)) and 17c (14.65 nM (3D7) and 36.88 nM (W2)) respectively, and 6a (34.46 nM (3D7) and
61.37 nM (W2)) and 6c (17.42 nM (3D7) and 30.35 nM (W2)) varied slightly.
Table 3. The antimalarial activity of compounds derivatives 6.
Plasmodium
falciparum 3D7
Strain
Plasmodium
falciparum W2
Strain
Selectivity
Index (3D7)
Selectivity
Index (W2)
HUVEC Cells
Compounds
IC50 ± SD (nM)
IC50 ± SD (nM)
CC50 nM ± SD
=CC50/IC50
=CC50/IC50
6a
6b
6c
34.46 ± 9.25
17.42 ± 7.7
>100
61.37 ± 11.12
30.35 ± 6.09
>100
nd
nd
>17.5
/
nd
>10.8
/
>100
/
6d
CQ
>100
22.38 ± 3.24
>100
134.12 ± 32.29
/
/
/
37.56 ± 1.24
1.7
0.3
Table 4. The antimalarial activity of the target compounds.
Plasmodium
falciparum 3D7
Strain
Plasmodium
falciparum W2
Strain
Selectivity
Index (3D7)
Selectivity
Index (W2)
HUVEC Cells
Compounds
IC50 ± SD (nM)
IC50 ± SD (nM)
CC50 nM ± SD
=CC50/IC50
=CC50/IC50
10
25.37 ± 2.88
36.9 ± 6.59
34.45 ± 7.36
>100
42.14 ± 6.73
11.06 ± 4.82
38.95 ± 3.66
>100
>100
>8.9
2.85
>6.9
/
nd
/
26.7
>4.4
/
2.5
>4.2
6.83
/
>5.3
5.7
>6.1
/
nd
/
8.4
>6.8
/
1.6
>11.3
4.3
/
12a
12b
12c
12d
13a
13b
13c
13d
14a
14c
14d
15a
16a
17a
17b
17c
17d
CQ
100 ± 0.008
>100
/
13.64 ± 2.47
166.87 ± 9.64
nd
/
>100
>100
4.19 ± 1.12
44.17 ± 3.9
>100
20.72 ± 7.69
50.33 ± 3.8
14.85 ± 4.48
>100
13.30 ± 2.01
28.57 ± 1.91
>100
32.33 ± 9.97
18.97 ± 7.30
23.45 ± 4.66
>100
112 ± 0.008
>100
/
52 ± 0.004
>100
100 ± 0.005
/
/
>100
>100
/
/
37.63 ± 7.85
47.84 ± 5.83
nd
/
nd
/
nd
/
nd
/
nd
/
nd
/
>100
>100
14.65 ±2.55
>100
22.38 ± 3.24
36.88 ± 2.99561
>100
134.12 ± 32.29
37.56 ± 1.24
1.7
0.3
3. Materials and Methods
3.1. Apparatus, Materials, and Analytical Reagents
All chemical reagents and anhydrous solvents were obtained from commercial sources and used
1
without further purification. The H- and 13C-NMR spectra were recorded in CDCl3 at ambient
temperature on an AMX 500 spectrometer (Bruker, Palaiseau, France). Some product structures
were confirmed by DEPT 135, HMQC and HMBC experiments. Chemical shifts are given in
δ
(ppm) and coupling constants J (Hz) relative to TMS used as internal standard; multiplicities were
recorded as s (singlet), d (doublet), dd (double doublet), t (triplet), dt (double triple), q (quartet) or

Molecules 2020, 25, 299
6 of 16
m (multiplet). Reactions involving anhydrous conditions were conducted in dry glassware under
a nitrogen atmosphere. The infrared spectra have been recorded on a model 842 spectrometer
(Perkin-Elmer, 842) using polystyrene as reference. The melting points have been measured on a
Tottoli S Bucchi device (Buchi, Rungis, France). Microanalysis have been done on a Perkin-Elmer
2400-CMN apparatus (Perkin ElmerVillebon-sur-Yvette, France). GC/MS conditions: Analyses were
performed using a 5890 gas chromatogram connected to a G 1019 A mass spectrometer (both from
Hewlett Packard, Alpharetta, GA, USA) operating in the electrospray ionization mode (ESI).
3.2. Chemistry
3.2.1. General procedure for the Synthesis of tert-Butyl 4-(phenylamino) Piperidine-1-carboxylates
3a–b
A solution of aniline (1 equiv) in 1,2-dichloroethane (100 mL) containing t-butyl-4-oxo-1-piperidine
carboxylate (1 equiv), sodium triacetoxyborohydride (1.5 equiv) and acetic acid (1.5 equiv) was stirred
for 24 h at 20 ◦C. 1N NaOH (50 mL, 50 mmol) and 50 mL of ethyl acetate were added. The phases were
separated and the aqueous layer was extracted with ethyl acetate (3x25 mL). The combined organic
layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was
purified by crystallization (ether petroleum/ethyl acetate (8:2)).
tert-Butyl 4-(phenylamino) piperidine-1-carboxylate (3a). Aniline (2.8 g, 30.11 mmol) in 1.2-dichloroethane
(100 mL) containing t-butyl-4-oxo-1-piperidine carboxylate (6 g, 30.11 mmol), sodium triacetoxyborohydride
(9.57 g, 45.1 mmol) and acetic acid (2.71 g, 45.16 mmol) gave compound 3a (7.07 g, 85%), m.p.: 105 ◦C.
1H-NMR (CDCl3): 1.3 (m, 2H, CH2); 1.49 (s, 9H, 3CH3); 2.0 (m, 2H, CH2); 2.9 (m, 2H, CH2); 3.3 (m, 1H,
CH); 3.7 (broadband, 1H, NH); 4.1 (m, 2H, CH2); 6.5–7.5 (m, 5H aromatic). 13C-NMR (CDCl3)
(3 CH3); 32.52 (2 CH2); 42.30 (2 CH2); 50.22 (CH); 79.72 (C); 113.42 (2 CHAr); 117.61 (CHAr);
129.49 (2
δ: 28.57
×
×
×
×
×
CHAr); 149.89 (C); 154.92 (C). MS (m/z): calcd. for C16H24N2O2 276.2 found 277.1 [M + 1];
IR cm−1: 1763.07 (CO carbamate); 1671.6 (CO, amide).
tert-Butyl 4-(3-fluorophenylamino) piperidine-1-carboxylate (3b). 3-Fluoroaniline (3.34 g, 30.11 mmol)
in 1,2-dichloroethane (100 mL) containing t-butyl-4-oxo-1-piperidine carboxylate (6 g, 30.11 mmol),
sodium triacetoxyborohydride (9.57 g, 45.1 mmol) and acetic acid (2.71 g, 45.16 mmol) gave compound
3b (6.58 g, 74%); m.p.: 114 ◦C. 1H-NMR (CDCl3): 1.3 (m, 2H, CH2); 1.49 (s, 9H, 3CH3); 2.0 (m, 2H,
CH2); 2.9 (m, 2H, CH2); 3,4 (m, 1H, CH); 3.8 broad band, 1H, NH); 4.1 (m, 2H, CH2); 6.5–7.5 (m, 4H
aromatic). 13C-NMR (CDCl3)
99.95 (d, J = 25.26 Hz, CHAr); 103.84 (d, J = 21.25 Hz, CHAr); 109.19 (d, J = 2.2 Hz, CHAr); 130.58 (d,
J = 10.30 Hz, CHAr); 148.73 (d, J = 10.55 Hz, C); 154.896 (C), 163.34 (d, J = 242.72 Hz, C). ESI (m/z) calcd
for C16H23FN2O2 294.2; found 294.1 [M + 1]; IR cm−1: 1760.07 (CO carbamate); 1670.6 (CO, amide).
δ: 28.56 (3
×
CH3); 32.36 (2
×
CH2); 42.73 (2 CH2); 50.26 (CH); 79.81 (C);
×
3.2.2. General Procedure for the Coupling with Phenoxyacetyl chloride: Synthesis of Compounds 5a
To an ice-cooled suspension of sodium hydride (60% in mineral oil, 2 equiv) in CH2Cl2 (10 mL)
was added dropwise a solution of compound (1 equiv), in CH2Cl2 (15 mL). After stirring 15 min
phenoxyacetyl chloride
(2 equiv) was added. The reaction mixture was stirred for 1 h at 0 ◦C, and the
temperature was raised to room temperature during 3 h. 20 mL of saturated solution of NaHCO3 was
carefully added. The aqueous layer was extracted with CH2Cl2 (3 20 mL). The combined organic
–b
3
4
×
phases were dried over MgSO4, and concentrated in vacuum. The crude product was purified by
crystallisation (ether petroleum/ethyl acetate (8:2)).
tert-Butyl 4-(2-phenoxy-N-phenylacetamido) piperidine-1-carboxylate (5a). Following the general procedure,
sodium hydride (60% in mineral oil, 0.723 g, 18.1 mmol) in CH2Cl2 (10 mL) was added dropwise a
solution of compound 3a (2.5 g, 9.05 mmol), in CH2Cl2 (15 mL). After stirring 15 min phenoxyacetyl
1
chloride (2.5 mL, 18.1 mmol) was added to give compound 5a (3.06 g, 82%). H-NMR (CDCl3): 1.25
(m, 2H, CH2); 1.4 (s, 9H); 1.8 (m, 2H, CH2); 2.9 (m, 2H, CH2); 4.1 (m, 2H, CH2); 4.25 (m, 2H, CH2); 4.8

Molecules 2020, 25, 299
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(m, 1H, CH); 6.7–7.5 (m, 10H aromatic). 13C-NMR (CDCl3)
δ
: 28.456 (3
×
CH3, C(CH3)3); 30.32 (2
×
CH2); 43.315 (2
×
CH2); 52.96 (CH); 66.7 (CH2); 79.73 (C); 114.8 (2
×
CHAr); 121.47 (CHAr); 129.34 (CH);
129.46 (2 CHAr); 129.88 (2
×
×
CHAr); 130.09 (2 CHAr); 136.89 (C); 154.63 (C); 158.14 (C); 167.6 (C). ESI
×
(m/z) calcd for C24H30N2O4 410, 2 found 411.1 [M + 1], IR cm−1: 1744.95 (CO carbamate); 1652.06 (CO,
amide).
tert-Butyl 4-(N-(3-fluorophenyl)-2-phenoxyacetamido) piperidine-1-carboxylate (5b). Following the general
procedure, sodium hydride (60% in mineral oil, 0.677 g, 16.93 mmol) in CH2Cl2 (10 mL) was added
dropwise a solution of compound 3b (2.49 g, 8.46 mmol), in CH2Cl2 (15 mL). After stirring 15 min
1
phenoxyacetyl chloride (2.88 g, 16.93 mmol) was added to give compound 5b (2.34 g, 65%). H-NMR
(CDCl3): 1.25 (m, 2H, CH2); 1.4 (s, 9H, 3
4.30 (s, 2H, CH2); 4.75 (m, H, CH); 6.7–7.6 (m, 9 H aromatic). 13C-NMR (CDCl3)
C(CH3)3); 30.284 (2 CH2); 43.16 (2
CH2); 53.188 (CH); 66.82 (CH2); 79.81 (C); 114.76 (2× CHAr);
116.53 (d, J = 20.74 Hz, CHAr); 117.63 (d, J = 21.49 Hz, CHAr); 121.60 (CHAr); 125.97 (d, J = 3.14 Hz,
CHAr); 129.50 (2 CHAr);130.92 (d, J = 7.3 Hz, CHAr); 138.52 (d, J = 9.17 Hz, C); 154.58 (C); 157.97 (C);
×
CH3); 1.8 (d, 2H, CH2); 2.8 (m, 2H, CH2); 4.15 (m, 2H, CH2);
δ: 28.44 (3× CH3,
×
×
×
161.91 (d, J = 250.14 Hz, C); 167.19 (C). ESI (m/z): calcd for C24H29FN2O4 428.2, found 429.0 [M + 1]; IR
cm−1: 1745.07 (CO carbamate); 1660.6 (CO, amide).
3.2.3. General Procedure for the Coupling with Chloroacetyl chloride: Synthesis of Compounds 7a
–b
One equiv of compound was dissolved in 25 mL of CH2Cl2, 2 equiv. of potassium carbonate
3
were added and the mixture was cooled to 0 ◦C. Two equiv. of chloroacetyl chloride were added to 0 ◦C,
and the mixture was stirred overnight. The reaction was quenched by addition of a saturated solution
of NaHCO3 (25 mL), the aqueous phase was decanted and extracted twice with 15 mL of CH2Cl2.
Combined organic phases were washed with water and brine, dried over MgSO4 and concentrated in
vacuum. The crude product was purified by crystallisation (ether petroleum/ethyl acetate (8:2)).
tert-Butyl-4-(2-chloro-N-phenylacetamido) piperidine-1-carboxylate (7a). Following the general procedure,
2.5 g (9.03 mmol) of compound 3a were dissolved in 25 mL of CH2Cl2, 2.5 g (18.06 mmol) of potassium
carbonate were added and the mixture was cooled to 0 ◦C. 2.04 g (18.06 mmol) of chloroacetyl chloride
were added, and the mixture was stirred overnight to afford 7a as a white solid (2.55 g, 80%), m.p.:
110 ◦C. 1H-NMR (CDCl3, 500 MHz): 1.25 (m, 2H, CH2); 1.4 (s, 9 H, 3
2H, CH2); 2.8 (m, 2H, CH2); 4.1 (m, 2H, CH2); 4.75 (m, 1H, CH); 7–7.5 (m, 5H aromatic). 13C-NMR
(125 MHz, CDCl3) : 28.485 (C(CH3)3); 30.32 (2 CH2); 42.55 (CH2); 43.41 (2 CH2); 53.5 (CH); 79.8 (C);
129.47 (2
×
CH3); 1.8 (m, 2H, CH2); 3.7 (s,
δ
×
×
×
CHAr); 129.9 (CHAr); 130.2 (2 CH); 137.3 (C); 154.64 (C); 166.04 (C). ESI (m/z): calcd for
×
C18H25ClN2O3 352.2, found 353.0 [M + 1]; IR cm−1: 1730.5 (CO carbamate); 1699.03 (CO, amide).
tert-Butyl 4-(2-chloro-N-(3-fluorophenyl) acetamido)piperidine-1-carboxylate (7b). Following the general
procedure, 2.5 g (8.46 mmol) of compound 3b were dissolved in 25 mL of CH2Cl2, then 2.34 g
(16.93 mmol) of potassium carbonate were added and the mixture was cooled to 0 ◦C. Chloroacetyl
chloride (1.91 g◦, 18.06 mmol) was added, and the mixture was stirred overnight to afford 7b (2.66 g,
1
85%), m.p.: 90 C. H-NMR (CDCl3, 500 MHz): 1.25 (m, 2H, CH2); 1.4 (s, 9 H, 3CH3); 1.8 (m, 2H,
CH2); 3.7 (s, 2H, CH2); 2.8 (m, 2H, CH2); 4.1 (m, 2H, CH2); 4.75 (m, 1H, CH); 7–7.5 (m, 5H aromatic).
13C-NMR (125 MHz, CDCl3)
δ
: 28.44 (3
×
CH3); 30.27 (2
×
CH2); 42.26 (CH2); 42.97 (2 CH2); 53.69
×
(CH); 79.878 (C); 116.72 (d, J = 20.74 Hz, CHAr); 117.79 (d, J = 21.49 Hz, CHAr); 126.14 (CHAr); 131.08
(d, J = 9.17 Hz, CHAr); 138.8 (d, J = 9.17 Hz, C); 154.58 (C); 161.926 (C); 163.92 (d, J = 234,80 Hz, C). ESI
(m/z): calcd for C18H24ClFN2O3 370.1 found 371.0 [M + 1]; IR cm−1: 1730.5 (CO carbamate); 1699.08
(CO, amide).
3.2.4. General Procedure for Synthesis of Compounds 9a–b
To a mixed solution of acetonitrile/acetone (50/50) were added 1 equiv of compound 7; 1 equiv of
2-chlorophenol and 2 equiv of potassium carbonate. After 12 h of stirring under reflux the mixture
was concentrated in vacuum. The residual was dissolved in 15 mL of ethyl acetate and (1N) of NaOH

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(15 mL), the aqueous phase was decanted and extracted twice with 15 mL of ethyl acetate. Combined
organic phases were washed with water and brine, dried over MgSO4 and concentrated in vacuum.
The crude product was purified by crystallisation (ether petroleum/ethyl acetate (8:2)).
tert-Butyl 4-(2-(2-chlorophenoxy)-N-phenylacetamido) piperidine-1-carboxylate (9a). Following the general
procedure, 2.83 g (8.04 mmol) of compound
(16.09 mmol) of potassium carbonate. (3.57 g, 99%); m.p.: 123 ◦C; 1H-NMR (CDCl3, 600 MHz): 1.3
(m, 2H, CH2); 1.5 (s, 9H, 3 CH3); 1.80 (m, 2H, CH2); 2.85 (m, 2H, CH2); 4.12 (m, 1H, CH); 4.33 (s,
2H, CH2); 4.76 (m, H, CH); 6.4–7.5 (m, 9H aromatic). 13C-NMR (150 MHz, CDCl3)
: 28.46(3 CH3);
29.83 (2 CH2); 42.75 (2 CH2) 53.04 (CH); 67.62 (CH2); 79.78 (C); 113.95 (2 CHAr); 122.27 (2 CHAr);
7; 1.032 g (8.04 mmol) of 2-chlorophenol and 2.22 g
×
δ
×
×
×
×
×
123.27 (C); 127.61 (CHAr); 129.45(CHAr); 129.97 (CHAr); 130.14 (CHAr); 130.45 (CHAr); 136.64 (C);
153.9 (C); 154.64 (C); 166.84 (C). ESI (m/z): calcd for C24H29ClN2O4 444.1, found 445.0 [M + 1]; IR cm−1
:
1727.5 (CO carbamate); 1693.33 (CO, amide).
tert-Butyl 4-(2-(2-chlorophenoxy)-N-(3-fluorophenyl) acetamido) piperidine-1-carboxylate (9b). Following the
general procedure, 1.80 g (4.87 mmol) of compound 7; 0.626 g (4.87 mmol) of 2-chlorophenol and 1.34
g (9.75 mmol) of potassium carbonate were reacted to give 9b (2.01 g, 89%); m.p.: 125◦C; 1H-NMR
(CDCl3, 500 MHz): 1.18 (m, 2H, CH2); 1.21 (s, 9H, 3CH3); 1.74 (m, 2H, CH2); 2.71 (t, J = 12 Hz, 2H,
CH2); 4.06 (m, 2H, CH2); 4.31 (s, 2H, CH2); 4.67 (m, 1H, CH) 6.4–7.5 (m, 8H aromatic). 13C-NMR (125
MHz, CDCl3)
δ
: 27.12 (2
×
CH2); 28.36 (3CH3); 30.21 (2 CH2); 53.32 (CH); 67.75 (CH2); 79.75 (C); 114.0
×
(CHAr); 116.43 (d, J = 31.25 Hz, CHAr); 117.40 (d, J = 26.25 Hz, CHAr); 122.36 (CHAr); 123.27 (C);
125.94 (CHAr); 127.55 (CHAr); 130.52 (CHAr); 130.84 (d, J = 11.25 Hz, CHAr); 138.20 (d, J = 20 Hz, C);
153.69 (C); 154.51 (C); 161.41 (d, J = 281.25 Hz, C); 166.60 (C). ESI (m/z): calcd for C24H28ClFN2O4 462.2,
found 463.0 [M + 1]; IR cm−1: 1727.5 (CO carbamate); 1693.33 (CO, amide).
3.2.5. General Procedure for Deprotection: Synthesis of 6a–b
One equiv of compound
5 was dissolved in 15 mL of CH2Cl2, and 13 equiv of trifluoroacetic acid
were added. After 2 h of stirring at room temperature, the reaction mixture was concentrated under
vacuum. The residue was dissolved in 5 mL of ethyl acetate then neutralized with NaHCO3 (5%). The
aqueous layer was extracted with ethyl acetate (4x5mL). The combined organic phases were dried
over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by
crystallisation (ether petroleum/ethyl acetate (8:2)).
2-Phenoxy-N-Phenyl-N-(piperidin-4-yl) acetamide (6a). Following the general procedure, 3.06 g (7.48 mmol)
of compound 5a were dissolved in 15 mL of CH2Cl2, then 7.49 mL (97.24 mmol) of trifluoroacetic acid
◦
1
were added to produce compound 6a (1.15 g, 50%); m.p.: 59 C. H-NMR (CDCl3, 600 MHz): 1.5
(m, 2H, CH2); 1.9 (m, 2H, CH2); 2.7 (m, 2H, CH2); 3.4 (m, 2H, CH2); 3.4 (broad, 1H, NH); 4.6 (s, 2H,
O-CH2); 4.75 (m, 1H, CH), 6.5–7.7 (m, 10H aromatic). 13C-NMR (150 MHz, CDCl3)
δ
: 30 (2
×
CH2);
45.06 (2× CH2); 52.15 (CH); 66.74 (CH2); 114.76 (2
×
CHAr); 121.53 (CHAr); 129.17 (CHAr); 129.46
CHAr); 130.17 (CHAr); 136.63 (C); 158.07 (C); 167.48 (C). ESI
(2× CHAr); 129.50 (CHAr); 130.00 (2
×
(m/z): calcd for C19H22N2O2 310.2, found 311.0 [M + 1]; IR cm−1: 3443 (NH), 1691.33 (CO).
N-(3-Fluorophenyl)-2-phenoxy-N-(piperidin-4-yl) acetamide (6b). Following the general procedure, 4.65 g
(10.87 mmol) of compound 5b were dissolved in 15 mL of CH2Cl2, 10.81 mL (141.31 mmol) of
trifluoroacetique acid were added. (2.5 g, 70%); m.p.: 200 ◦C; 1H-NMR (CDCl3, 500 MHz): 1.3 (m,
2H, CH2); 1.80 (m, 2H, CH2); 2.85 (m, 2H, CH2); 3.7 (broad, 1H, NH); 4.06 (m, 2H, CH2); 4.31 (m, 2H,
CH2); 4.67 (m, 1H, CH) 6.4–7.5 (m, 9H aromatic). 13C-NMR (125 MHz, CDCl3)
(2× CH2); 51.11 (CH); 66.69 (CH2); 114.74 (2 CHAr); 117.34 (d, J = 50.53 Hz, CHAr); 121.97 (CHAr);
129.68 (2 CHAr); 129.86 (CHAr); 131.71 (CHAr); 138.23 (C); 153.69 (C); 164.11–161.27 (C); 168.211 (C).
ESI (m/z): calcd for C19H21FN2O2 328.2; found 329.166 [M + 1]; IR cm−1: 3445 (NH), 1693.01 (CO).
δ: 27.14 (2
×
CH2); 43.99
×
×
2-(2-Chlorophenoxy)-N-Phenyl-N-(piperidin-4-yl) acetamide (6c). Compound (3.90 g, 8.78 mmol) was
9
dissolved in 15 mL of CH2Cl2, then 8.73 mL (114.14 mmol) of trifluoroacetic acid were added, to give

Molecules 2020, 25, 299
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6c (3.02 g, 95%); m.p.: 161 ◦C; 1H-NMR (CDCl3, 600 MHz): 1.70 (m, 2H, CH2); 1.93 (broad, 1H, NH);
2.06 (m, 2H, CH2); 2.97 (m, 2H, CH2); 3.38 (m, 2H, CH2); 4.37 (s, 2H, CH2); 4.77 (m, 1H, CH); 6.5–7.5 (m,
9H Ar). 13C-NMR (150 MHz, CDCl3)
δ
: 27.12 (2
×
CH2); 43.55 (2
×
CH2); 50.68 (CH); 67.53 (CH2); 114.01
CHAr); 129.84 (CHAr); 130.24 (CHAr);
(2×
CHAr); 122.27 (CHAr); 123.27 (C); 127.55 (CHAr); 129.55(2
×
130.55 (CHAr); 135.76 (C); 153.67 (C); 167.27 (C). ESI (m/z): calcd for C19H21ClN2O2 344.1; found 345.13
[M + 1]; IR cm−1: 3445 (NH), 1691.33 (CO).
2-(2-Chlorophenoxy)-N-(3-fluorophenyl)-N-(piperidin-4-yl) acetamide (6d). Following the general procedure,
1.99 g (4.327 mmol) of compound 9 were dissolved in 15 mL of CH2Cl2, and 4.30 mL (56.25 mmol) of
trifluoroacetic acid were added to afford 6d (2.4 g 60%); m.p.: 140◦C; 1H-NMR (CDCl3, 600 MHz): 1.40
(m, 2H, CH2); 2.06 (m, 2H, CH2); 2.7 (broad band, 1H, NH) 2.97 (m, 2H, CH2); 3.2 (m, 2H, CH2); 4.37 (s,
2H, CH2); 4.77 (m, 1H, CH); 6.5–7.5 (m, 8H aromatic). 13C-NMR (150 MHz, CDCl3)
δ
: 30.9 (2× CH2);
45.7 (2
×
CH2); 53.11 (CH); 67.79 (CH2); 114.05 (CHAr); 116.55 (d, J = 24.9 Hz, CHAr); 117.74 (d,
J = 106.5 Hz, CHAr); 122.447 (CHAr); 123.27 (CHAr); 126.068 (d, J = 3.75 Hz, CHAr); 127.673 (CHAr);
130.619 (CHAr); 131.958 (d, J = 10.95 Hz, CHAr); 138.292 (C); 153.780 (C); 161.963 (d, J = 298.5 Hz,
C); 166.60 (C). ESI (m/z): calcd for C19H20ClFN2O2 362.1; found 363.12 [M + 1]; IR cm−1: 3445 (NH),
1691.33 (CO).
3.2.6. General Procedure for Synthesis of Target Compounds A
A solution of benzaldehyde derivatives (1 equiv) in 1,2-dichloroethane containing compound
6
(1 equiv), sodium triacetoxyborohydride (1.5 equiv) and acetic acid (1.5 equiv) was stirred for 24 h
at 20 ◦C. 1N NaOH (15 mL) and 15 mL of ethyl acetate were added. The phases were separated and
the aqueous layer was extracted with ethyl acetate (3
dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by
×
15 mL). The combined organic layers were
chromatography on silica gel (petroleum ether/EtOAc (8:2)).
N-(1-Benzylpiperidin-4-yl)-2-phenoxy-N-phenylacetamide (12a). Following the general procedure for
reductive amination, using benzaldehyde derivative 11 (R3 = H) (34 mg, 0.322 mmol); compound 6a
(100 mg, 0.322 mmol); sodium triacetoxyborohydride (102 mg, 0.4838 mmol) and acetic acid (29 mg,
0.4838 mmol) in 1,2-dichloroethane (5 mL) give compound 12a (0.1291 g, 52%); m.p. 89 ◦C. 1H-NMR
(CDCl3, 600 MHz): 1.32 (m, 2H, CH2); 1.74 (m, 2H, CH2); 2.06 (m, 2H, CH2); 2.83 (m, 2H, CH2); 3.42
(s, 2H, CH2); 4.15 (s, 2H, CH2); 4.62 (m, H, CH); 6.68–7.38 (m, 15H aromatic); 13C-NMR (150 MHz,
CDCl3)
δ
: 32.17 (2
×
CH2); 43.72 (2
×
CH2); 52.84 (CH); 62.89 (CH2); 66.73 (CH2); 114.74 (4
×
CHAr);
CHAr);
121.32 (CHAr); 128.25 (CHAr); 129.08 (CHAr); 129.34 (4
135.30 (C) 136.69 (C); 158.14 (C); 167.25 (C). ESI (m/z): calcd for C26H28N2O2 400.02; found 401.22
[M + 1]; IR cm−1: 1680 (CO).
×
CHAr); 129.68 (2 CHAr); 130.14 (2
×
×
N-(1-Benzylpiperidin-4-yl)-N-(3-fluorophenyl)-2-phenoxyacetamide (12b). Following the general procedure,
benzaldehyde derivative 11 (R3 = H(o)) (48.4 mg, 0.457 mmol); compound 6b (150 mg, 0.457 mmol);
sodium triacetoxyborohydride (145.3 mg, 0.6855 mmol) and acetic acid (41.6 mg, 0.6855 mmol)◦in
◦
1.2-dichloroethane (5 mL) was stirred for 24 h at 20 C to furnish 12b (0.103 g, 54%); m.p.: 90 C.
1H-NMR (CDCl3, 500 MHz): 1.36 (m, 2H, CH2); 1.83 (m, 2H, CH2); 2.15 (m, 2H, CH2); 2.94 (m, 2H, CH2);
3.50 (s, 2H, CH2,); 4.30 (s, 2H, CH2); 4.67 (m, H, CH); 6.78–7.47 (m, 14H aromatic). 13C-NMR (125 MHz,
CDCl3)
δ
: 30.26 (2
×
CH2); 43.72 (2
×
CH2); 52.84 (CH); 62.80 (CH2); 66.81 (CH2); 114.73 (4× CHAr);
CHAr); 126.03 (CHAr); 127.16 (C); 128.24 (2× CHAr); 129.16
117.50 (d, J = 22 Hz, CHAr); 121.47 (2
×
(CHAr); 129.40 (2 CHAr); 130.66 (CHAr); 138.67 (C); 157.99 (C); 161.59 (d, J = 251 Hz, C); 167.06 (C).
×
ESI (m/z): calcd for C26H27FN2O2 418.2; found 419.21 [M + 1]; IR cm−1: 1687.
2-(2-Chlorophenoxy)-N-(1-benzylpiperidin-4-yl)-N-phenylacetamide (12c). Following the general procedure,
benzaldehyde derivative 11 (R3 = H) (46.2 mg, 0.435 mmol); compound 6c (150 mg, 0.435 mmol);
sodium triacetoxyborohydride (138.5 mg, 0.6538 mmol) and acetic acid (39.5 mg, 0.6538 mmol)◦in
◦
1.2-dichloroethane (5 mL) was stirred for 24 h at 20 C to afford 12c (0.0946 g, 50%); m.p.: 83 C;

Molecules 2020, 25, 299
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1H-NMR (CDCl3, 400 MHz): 1.47 (m, 2H, CH2); 1.84 (m, 2H, CH2); 2.14 (m, 2H, CH2); 2.94 (m, 2H,
CH2); 3.48 (s, 2H, CH2); 4.35 (s, 2H, CH2); 4.64 (m, H, CH); 6.73–7.47 (m, 14H aromatic). 13C-NMR
(100 MHz, CDCl3)
(2× CHAr); 122.09 (2
(CHAr); 129.71 (2
δ
: 30.23 (2
×
CH2); 43.37 (2
×
CH2); 52.88 (CH); 62.90 (CH2); 67.66 (CH2); 114.01
CHAr); 128,21 (2 CHAr); 129.12
×
CHAr).; 123.26 (C); 127.11 (C); 127.46 (2
×
×
×
CHAr); 130.18 (2 CHAr); 130.41 (CHAr); 136.99 (C); 153.94 (C); 166.67 (C). ESI
(m/z): calcd for C26H27ClN2O2 434.2; found 435.18 [M + 1]; IR cm−1: 1683 (CO).
×
2-(2-Chlorophenoxy)-N-(1-benzylpiperidin-4-yl)-N-(3-fluorophenyl) acetamide (12d). Following the general
procedure, benzaldehyde derivatives 11 (R3 = H(o)) (43.91 mg, 0.4142 mmol); compound 6d (150,
0.4142 mmol); sodium triacetoxyborohydride (131.6 mg, 0.6213 mmol) and acetic acid (37.3 mg,
0.6213 mmol) in 1,2-dichloroethane (5 mL) was stirred for 24 h at 20 ◦C, giving 12d (0.0936 g, 54%);
m.p.: 73 ◦C. 1H-NMR (CDCl3, 600 MHz): 1.25 (m, 2H, CH2); 1.43 (m, 2H, CH2); 1.78 (m, 2H, CH2);
2.14 (m, 2H, CH2); 2.92 (s, 2H, CH2); 3.49 (s, 2H, CH2).; 4.36 (s, 2H, CH2); 4.63 (m, H, CH); 6.73–7.47
(m, 13H aromatic). 13C-NMR (150 MHz, CDCl3)
(CH2); 67.77 (CH2); 114.03 (2 CHAr); 116.50 (CHAr); 116.67 (C); 117.63 (d, J = 21.36 Hz, CHAr); 122.39
(2× CHAr); 123.31 (C); 126.11 (d, J = 2.51 Hz, CHAr); 127.65 (CHAr); 128.43 (CHAr); 129.41 (CHAr);
δ
: 30.12 (2
×
CH2); 43.37 (2
×
CH2); 52.82 (CH); 62.90
×
130.60 (2 CHAr); 130.93 (d, J = 8.79 Hz, CHAr); 138.36 (C); 153.81 (C); 161.95 (d, J = 250.14 Hz, C);
×
166.67 (C). ESI (m/z): calcd for C26H26ClFN2O2 452.2; found 453.18 [M + 1]; IR cm−1: 1689 (CO).
N-(1-(2-Bromobenzyl)piperidin-4-yl)-2-phenoxy-N-phenylacetamide (13a). Following the general procedure
for reductive amination using benzaldehyde derivative 11 (R3 = Br (o)) (75.3 mg, 0.410 mmol);
compound 6a (127 mg, 0.410 mmol); sodium triacetoxyborohydride (130.15 mg, 0.615 mmol) and acetic
acid (36.9 mg, 0.615 mmol)) in 1,2-dichloroethane (5 mL) to give compound 13a (0.119 g, 60%); m.p.
66◦C. 1H-NMR (CDCl3, 600 MHz): 1.44 (m, 2H, CH2); 1.64 (m, 2H, CH2); 2.25 (m, 2H, CH2); 2.90 (m,
2H, CH2); 3.53 (s, 2H, CH2,); 4.23 (s, 2H, CH2); 4.70 (m, H, CH); 6.73–7.47 (m, 14H aromatic). 13C-NMR
(150 MHz, CDCl3)
δ
: 30.50 (2
×
CH2); 53.07 (CH); 53.13 (2
×
CH2); 61.77 (CH2); 66.77 (CH2); 114.80
CHAr);
(2× CHAr); 121.42 (CHAr); 124.69 (C); 127.27 (CHAr); 128.44 (CHAr); 129.20 (CHAr); 129.46 (2
×
129.82 (2
×
CHAr); 130.24 (2 CHAr); 130.64 (CHAr); 132.82 (CHAr); 137.12 (C); 137.21 (C); 158.19 (C);
×
167.33 (C). ESI (m/z): calcd for C26H27BrN2O2 478.1; found 479.13 [M + 1]; IR cm−1: 1678 (CO).
N-(1-(2-Bromobenzyl)piperidin-4-yl)-N-(3-fluorophenyl)-2-phenoxyacetamide (13b). Following the general
procedure, benzaldehyde derivatives 11 (R3 = Br (o)) (84.5 mg; 0.457 mmol); compound 6b (150 mg,
0.457 mmol); sodium triacetoxyborohydride (142.29 mg, 0.685 mmol) and acetic acid (41.16 mg,
0.685 mmol) in 1,2-dichloroethane (5 mL) was stirred for 24 h at 20 ◦C. Yield of 13b: 0.176 g (58%);
◦
IR cm−1: 1687; MS: 469.14 [M + 1]; m.p.: 55 C; H1-NMR (CDCl3, 500 MHz): 1.36 (m, 2H, CH2);
1.83 (m, 2H, CH2); 2.15 (m, 2H, CH2); 2.94 (m, 2H, CH2); 3.50 (s, 2H, CH2,); 4.30 (s, 2H, CH2); 4.67
(m, H, CH); 6.78–7.47 (m, 13H aromatic). 13C-NMR (125 MHz, CDCl3)
δ
: 30.26 (2
CHAr); 116.42 (d, J = 20 Hz, CHAr); 117.52 (d,
CHAr); 126.06 (CHAr); 128.56 (C); 129.53 (4 CHAr); 130.22 (d, J = 11,25
×
CH2); 42.89 (2
×
CH2); 52.98 (CH); 61.65 (CH2); 66.88 (CH2); 114.81 (4
J = 20 Hz, CHAr); 121.47 (2
Hz, C); 132.90 (CHAr); 138.73 (C); 158.05 (C); 161.59 (d, J = 247,5 Hz, C); 167.23 (C). ESI (m/z): calcd for
×
×
×
C26H26BrFN2O2 496.1; found 497.14 [M + 1]. IR cm−1: 1687 (CO).
N-(1-(2-Bromobenzyl)piperidin-4-yl)-2-(2-chlorophenoxy)-N-phenylacetamide (13c). Following the general
procedure, benzaldehyde derivatives 11 (R3 = Br (o)) (80.5 mg; 0.435 mmol); compound 6c (150 mg,
0.435 mmol); sodium triacetoxyborohydride (138 mg, 0.653◦mmol) and acetic acid (39.2 mg, 0.653 mmol)
◦
in 1,2-dichloroethane (5 mL) was stirred for 24 h at 20 C to give 13c (0.122 g, 55%); m.p.: 64 C.
1H-NMR (CDCl3, 400 MHz): 1.36 (m, 2H, CH2); 1.86 (m, 2H, CH2); 2.27 (m, 2H, CH2); 2.94 (m, 2H,
CH2); 3.57 (s, 2H, CH2); 4.35 (s, 2H, CH2); 4.742 (m, H, CH); 6.73–747 (m, 13H aromatic). 13C-NMR
(100 MHz, CDCl3)
(2 CHAr); 122.10 (CHAr); 123.35 (C); 124.62 (C); 127.21 (C); 127.47 (2
129.74 (2 CHAr); 130.14 (CHAr); 130.42 (CHAr); 132.72 (2 CHAr); 136.91 (C); 153.93 (C); 166.70 (C).
ESI (m/z): calcd for C26H6BrClN2O2 512.1; found 513.09 [M + 1]; IR cm−1: 1651 (CO).
δ: 30.34 (2
×
CH2); 42.98 (2
×
CH2); 52.97 (CH); 61.63 (CH2); 67.66 (2H, CH2); 113.99
×
×
CHAr); 128.82 (2 CHAr);
×
×
×

Molecules 2020, 25, 299
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N-(1-(2-Bromobenzyl)piperidin-yl)-2-(2-chlorophenoxy)-N-(3-fluorophenyl) acetamide (13d). Following the
general procedure, benzaldehyde derivative 11 (R3 = Br (o)) (76.63 mg, 0.4142 mmol); compound 6d
(150 mg, 0.4142 mmol); sodium triacetoxyborohydride (131.6 mg, 0.6213 mmol) and acetic acid (37.3 mg,
0.6213 mmol) in 1,2-dichloroethane (5 mL) was stirred for 24 h at 20 ◦C to furnish 13d (0.1295 g, 59%);
m.p.: 100 ◦C; 1H-NMR (CDCl3, 600 MHz): 1.33 (m, 2H, CH2); 1.80 (m, 2H, CH2); 2.23 (m, 2H, CH2);
2.92 (m, 2H, CH2); 3.54 (s, 2H, CH2,); 4.37 (s, 2H, CH2); 4.74 (m, H, CH); 6.73–7.47 (m, 12H aromatic).
13C-NMR (150 MHz, CDCl3)
113.95 (2 CHAr); 116.50 (d, J = 21 Hz, CHAr); 117.78 (d, J = 21 Hz, CHAr); 122.38 (CHAr); 123.25 (C);
δ: 30.45 (2
×
CH2); 43.41 (2
×
CH2); 53.04 (CH); 61.72 (CH2); 67.74 (CH2);
×
124.70 (C); 126.17 (CHAr); 127.32 (CHAr); 127.66 (CHAr); 128.51 (CHAr); 130.60 (CHAr); 130.92 (d,
J = 9 Hz, CHAr); 132.86 (CHAr);138.60 (C); 138.51 (C); 153.78 (C); 162.10 (d, J = 249 Hz, C); 166.68 (C).
ESI (m/z): calcd for C26H25BrClFN2O2 530.1; found 531.08 [M + 1]; IR cm−1: 1689 (CO).
N-(1-(2-Chlorobenzyl)piperidin-4-yl)-2-phenoxy-N-phenylacetamide (14a). Following the general procedure
for reductive amination using benzaldehyde derivative 11 (R3 = Cl (o)) (43.5 mg, 0.4838 mmol);
compound 6a (150 mg, 0.4838 mmol); sodium triacetoxyborohydride (153.8 mg, 0.7253 mmol) and
acetic acid (43.5 mg, 0.7253 mmol) in 1,2-dichloroethane (5 mL) gave title compound 14a (0.109 g, 52%);
m.p.: 69 ◦C. 1H-NMR (CDCl3, 500 MHz): 1.47 (m, 2H, CH2); 1.81 (m, 2H, CH2); 2.28 (m, 2H, CH2);
2.94 (m, 2H, CH2); 3.59 (s, 2H, CH2); 4.23 (s, 2H, CH2); 4.67 (m, H, CH); 6.73–7.47 (m, 14H aromatic).
13C-NMR (125 MHz, CDCl3)
CHAr); 126.73 (C); 129.25 (CHAr); 129.47 (4
(CHAr); 130.20 (CHAr); 134.50 (C); 137.02 (C); 158.22 (C); 167.40 (C). ESI (m/z): calcd for C26H27ClN2O2
434.2; found 435.18 [M + 1]; IR cm−1: 1673 (CO).
δ: 30.32 (2
×
CH2); 42.30 (2
×
CH2); 53.03 (CH2); 66.82 (CH2); 114.84
CHAr); 129.58 (CHAr): 129.85
(4× CHAr); 121.45 (2
×
×
N-(1-(2-Chlorobenzylpiperidin-4-yl)-2-(2-chlorophenoxy)-N-phenylacetamide (14c). Following the general
procedure, benzaldehyde derivative 11 (R3 = Cl (o)) (61.02 mg; 0.4359 mmol); compound 6c (150 mg,
0.4359 mmol); sodium triacetoxyborohydride (138.58 mg, 0.6538 mmol) and acetic acid (39.26 mg,
0.6538 mmol) in 1,2-dichloroethane (5 mL) was stirred for 24 h at 20 ◦C to produce 14c (0.1326 g, 65%);
m.p.: 55 ◦C; 1H-NMR (CDCl3, 400 MHz): 1.36 (m, 2H, CH2); 1.75 (m, 2H, CH2); 2.16 (m, 2H, CH2);
2.84 (m, 2H, CH2); 3.49 (s, 2H, CH2); 4.25 (s, 2H, CH2); 4.62 (m, H, CH); 6.64–7.37 (m, 13H aromatic).
13C-NMR (100 MHz, CDCl3)
113.97 (2 CHAr); 122.10 (2
(C); 129.75 (2 CHAr); 130.15 (2
δ
: 30.38 (2
×
CH2); 52.99 (CH); 53.03 (2
CHAr); 129.15 (C); 129.35 (CHAr); 129.44
CHAr); 140.41 (C); 153.92 (C); 166.69 (C). ESI (m/z):
×
CH2); 59.09 (CH2); 67.64 (CH2);
×
×
CHAr); 123.24 (C); 127.47 (2
×
×
×
CHAr); 130.42 (2
×
calcd for C26H26Cl2N2O2 468.1; found 469.14 [M + 1]. IR cm−1: 1687 (CO).
N-(1-(2-Chlorobenzyl)piperidin-4-yl)-2-(2-chlorophenoxy)-N-(3-fluorophenyl) acetamide (14d). Following
the general procedure, benzaldehyde derivative 11 (R3 = Cl(o)) (57.9 mg, 0.4142 mmol); compound
6d (150 mg, 0.4142 mmol); sodium triacetoxyborohydride (131.6 mg, 0.6213 mmol) and acetic acid
(37.3 mg, 0.6213 mmol) in 1,2-dichloroethane (5 mL) was stirred for 24 h at 20 ◦C to give 14d (0.11 g,
55%); m.p.: 85 ◦C; 1H-NMR (CDCl3, 600 MHz): 1.44 (m, 2H, CH2); 1.78 (m, 2H, CH2); 2.22 (m, 2H, CH2);
2.92 (m, 2H, CH2); 3.56 (s, 2H, CH2); 4.36 (s, 2H, CH2); 4.64 (m, H, CH); 6.73–7.37 (m, 12H aromatic).
13C-NMR (150 MHz, CDCl3)
113.95 (2 CHAr); 116.62 (d, J = 21 Hz, CHAr); 117.78 (d, J = 21 Hz, CHAr); 122.36 (CHAr); 123.25 (C);
δ: 30.42 (2
×
CH2); 53.04 (CH); 53.37 (2
×
CH2); 59.17 (CH2); 67.74 (CH2);
×
126.16 (CHAr); 126.68 (CHAr); 127.66 (CHAr); 128.24 (CHAr); 129.55 (CHAr); 130.59 (CHAr); 130.91 (d,
J = 10.5 Hz, CHAr); 134.34 (C); 136 (C); 138.44 (d, J = 7.5 Hz, C); 153.78 (C); 162.09 (d, J = 249 Hz, C);
166.62 (C). ESI (m/z): calcd for C26H25Cl2FN2O2 486.1; found 487.13 [M + 1]; IR cm−1: 1688 (CO).
N-(1-(2.4-Dihydroxybenzyl) piperidin-4-yl)-2-phenoxy-N-phenylacetamide (15a). Following the general
procedure for reductive amination using benzaldehyde derivative 11 (R3 = OH (o), OH (p)) (66.86 mg,
0.4838 mmol); compound 6a (150 mg, 0.4838 mmol); sodium triacetoxyborohydride (153.8 mg,
0.725 mmol) and acetic acid (43 mg, 0.725 mmol) in 1,2-dichloroethane (5 mL) give compound 15a
(0.1233 g, 59%); m.p. 68 ◦C. 1H-NMR (CDCl3, 600 MHz): 1.42 (m, 2H, CH2); 2.23 (m, 2H, CH2); 3.03 (m,
2H, CH2); 3.16 (m, 2H, CH2); 3.60 (s, 2H, CH2); 4.23 (s, 2H, CH2); 4.86 (m, H, CH); 5.30 (s, 2 OH);
×

Molecules 2020, 25, 299
12 of 16
6.73–7.42 (m, 13HAr). 13C-NMR (150 MHz, CDCl3)
δ
: 30.27 (2
×
CH2); 43.66 (2
×
CH2); 51.96 (CH2);
×
52.80 (CH); 67.24 (CH2); 114.57 (CHAr); 114.79 (4
(CHAr); 129.98 (CHAr); 130.09 (CHAr); 136.57 (C); 156.45 (C); 156.66 (C); 157.51 (C); 158.10 (C); 166.78
×
CHAr); 121.57 (CHAr); 129.52 (4 CHAr); 129.73
(C). ESI (m/z): calcd for C26H28O4 432.2; found 433.22 [M + 1]; IR cm−1: 1661 (CO).
N-(-1(2-Hydroxy-6-methoxybenzyl)piperidin-4-yl)-2-phenoxy-N-phenylacetamide (16a). Following the
general procedure reductive amination using benzaldehyde derivative 11 (R3= OMe (o), OH (o))
(73.55 mg, 0.4838 mmol); compound 6a (150 mg, 0.4838 mmol); sodium triacetoxyborohydride (153.8
mg, 0.7253 mmol) and acetic acid (43.5 mg, 0.7253 mmol) in 1.2-dichloroethane (5 mL) give the title
compound 16a (0.114 g, 53%); mp 68 ◦C. 1H-NMR (CDCl3, 600 MHz): 1.44 (m, 2H, CH2); 1.87 (m, 2H,
CH2); 2.25 (m, 2H, CH2); 3.02 (m, 2H, CH2); 3.75 (s, 5H, CH2, CH3); 4.22 (s, 2H, CH2); 4.62 (m, H, CH);
6.68–7.38 (m, 13HAr). 13C-NMR (150 MHz, CDCl3)
52.62 (CH); 55.61 (CH3); 66.68 (CH2); 101.61 (CHAr); 109.32 (C); 114.91 (2
128.71 (CHAr); 129.49 (2 CHAr); 129.51 (2 CHAr); 130.03 (2 CHAr); 130.06 (2
(C); 157.71 (C); 158.14 (C); 159.11 (C); 167.54 (C). ESI (m/z): calcd for C27H30N2O4 446.2; found 447.29
[M + 1]; IR cm−1: 1678 (CO).
δ
: 30.30 (2
×
CH2); 43.72 (2
CHAr); 121.49 (CHAr);
CHAr); 136.81
×
CH2); 52.45 (CH2);
×
×
×
×
×
N-(1-(Perfluorobenzyl)piperidin-4-yl)-2-phenoxy-N-phenylacetamide (17a). Following the general procedure,
benzaldehyde derivative 11 (R3 = 5xF (o,m,p)) (94.87 mg; 0.483 mmol); compound 6a (150 mg,
0.483 mmol); sodium triacetoxyborohydride (153 mg, 0.7258 mmol) and acetic acid (43 mg, 0.7258 mmol)
in 1,2-dichloroethane (5 mL) was stirred for 24 h at 20 ◦C to afford 17a (0.118 g, 50%); m.p.: 104 ◦C.
1H-NMR (CDCl3, 600 MHz): 1.42 (m, 2H, CH2); 1.79 (m, 2H, CH2); 2.24 (m, 2H, CH2); 2.88 (m, 2H,
CH2); 3.65 (s, 2H, CH2); 4.21 (s, 2H, CH2); 4.60 (m, H, CH); 6.73–7.42 (m, 10H aromatic). 13C-NMR
(150 MHz, CDCl3)
δ
: 30.27 (2
×
CH2); 48.64 (CH2); 52.18 (2
CHAr); 129.84 (2
C); 146.42 (C); 158.15 (C); 167.36 (C). ESI (m/z):
×
CH2); 52.40 (CH); 66.77 (CH2); 114.81
(2× CHAr); 121.46 (CHAr); 129.27 (CHAr); 129.47 (2
×
×
CHAr); 110.16 (C); 130.22
(2× CHAr); 136.56 (C); 136.88 (C); 138.16 (C); 144.42 (2
×
calcd for C26H23F5 N2O2 490.2; found 491.17 [M +1]; IR cm−1: 1683 (CO).
N-(3-Fluorophenyl)-N-(1-(perfluorobenzyl)piperidin-4-yl)-2-phenoxyacetamide (17b). Following the general
procedure, benzaldehyde derivative 11 (R3 = 5xF (o,m,p)) (89.6 mg, 0.457 mmol); compound 6b (150 mg,
0.457 mmol); sodium triacetoxyborohydride (142.29 mg, 0.685 mmol) and acetic acid (41.16 mg,
0.685 mmol) in 1,2-dichloroethane (5 mL) was stirred for 24 h at 20 ◦C, to furnish 17b (0.125 g, 54%);
m.p.: 95 ◦C. 1H-NMR (CDCl3, 600 MHz): 1.42 (m, 2H, CH2); 1.9 (m, 2H, CH2); 2.24 (m, 2H, CH2);
2.93 (m, 2H, CH2); 3.69 (s, 2H, CH2); 4.28 (s, 2H, CH2); 4.58 (m, H, CH); 6.73–7.42 (m, 9H aromatic).
13C-NMR (150 MHz, CDCl3)
113.98 (2 CHAr); 116.90 (d, J = 19.5 Hz, CHAr); 117.60 (d, J = 21 Hz, CHAr); 122.52 (CHAr); 122.66
(CHAr); 123.18 (C); 125.95 (CHAr); 127.69 (2 CHAr); 130.66 (CHAr); 131.15 (C); 131.29 (d, J = 10.5 Hz,
δ: 30.27 (2
×
CH2); 43.66 (2 CH2); 51.79 (CH2); 52.40 (CH); 67.24 (CH2);
×
×
×
CHAr); 137.81 (2
×
C); 138.26 (2 C); 146.67 (C); 153.70 (C); 162 (d, J = 249 Hz, C); 167.77 (C). ESI (m/z):
×
calcd for C26H25Cl2FN2O2 508.2; found 509.11 [M + 1]; IR cm−1: 1676 (CO).
2-(2-Chlorophenoxy)-N-(1-(perfluorobenzyl)piperidin-4-yl)-N-phenylacetamide (17c). Following the general
procedure, benzaldehyde derivatives 11 (R3 = 5xF (o,m,p)) (85.57 mg; 0.435mmol); compound 6c
(150 mg, 0.435 mmol); sodium triacetoxyborohydride (138 mg, 0.653 mmol) and acetic acid (39.2 mg,
0.653 mmol) in 1,2-dichloroethane (5 mL) was stirred for 24 h at 20 ◦C. Yield of 17c: 0.139 g (61%);
m.p.: 78 ◦C; 1H-NMR (CDCl3, 600 MHz): 1.42 (m, 2H, CH2); 1.79 (m, 2H, CH2); 2.24 (m, 2H, CH2);
2.93 (m, 2H, CH2); 3.69 (s, 2H, CH2,); 4.28 (s, 2H, CH2); 4.58 (m, H, CH); 6.73–7.42 (m, 9H aromatic).
13C-NMR (150 MHz, CDCl3)
113.85 (2× CHAr); 122.51 (CHAr); 123.18 (C); 127.61 (2
(2× CHAr); 136.27 (C); 136.50 (2 C); 138.47 (2 C); 146.49 (C); 146.31 (C); 153.88 (C); 167.77 (C). ESI
(m/z): calcd for C26H22ClF5 N2O2 524.1; found 525.13 [M + 1]; IR cm−1: 1683 (CO).
δ
: 30.27 (2
×
CH2); 48.64 (CH2); 52.18 (2
×
CH2); 52.40 (CH); 67.24 (CH2);
×
CHAr); 129.61 (CHAr); 130.11 (CHAr); 130.56
×
×

Molecules 2020, 25, 299
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2-(2-Chlorophenoxy)-N-(3-fluorophenyl)-N-(1-(perfluorobenzyl) piperidin-4-yl) acetamide (17d). Following
the general procedure, benzaldehyde derivative 11 (R3 = 5xF (o, m,p)) (81.19 mg, 0.4142 mmol);
compound 6d (150 mg, 0.4142 mmol); sodium triacetoxyborohydride (131.6 mg, 0.6213 mmol) and
acetic acid (37.3 mg, 0.6213 mmol) in 1,2-dichloroethane (5 mL) was stirred for 24 h at 20 ◦C to provide
17d (0.1324 g, 59%); m.p.: 125 ◦C; 1H-NMR (CDCl3, 600 MHz): 1.42 (m, 2H, CH2); 1.9 (m, 2H, CH2);
2.24 (m, 2H, CH2); 2.93 (m, 2H, CH2); 3.69 (s, 2H, CH2); 4.28 (s, 2H, CH2); 4.58 (m, H, CH); 6.73–7.42
(m, 8H aromatic). 13C-NMR (150 MHz, CDCl3)
(CH); 67.24 (CH2); 113.98 (CHAr); 116.90 (d, J = 19.5 Hz, CHAr); 117.60 (d, J = 21 Hz, CHAr); 122.52
δ: 30.27 (2
×
CH2); 43.66 (2 CH2); 51.79 (CH2); 52.40
×
(CHAr); 122.66 (C); 123.18 (C); 125.95 (CHAr); 127.69 (CHAr); 130.66 (CHAr); 131.15 (C); 131.29 (d,
J = 10.5 Hz, CHAr); 137.81 (2
×
C); 138.26 (2 C); 146.67 (C); 153.70 (C); 162 (d, J = 249 Hz, C); 167.77
×
(C). ESI (m/z): calcd for C26H22ClF5 N2O2 542.1; found 543.13 [M + 1]; IR cm−1: 1695 (CO).
3.3. Biological Assays
3.3.1. Antiplasmodial Assay
The antimalarial activity of extracts/compounds was evaluated against P. falciparum 3D7 and
P. falciparum W2 strains, using the fluorescence-based SYBR Green I assay approach in 96-well
microplates as described by Smilkstein et al. [34] with some modifications. Positive control wells
for each assay contained no inhibitor while negative controls contained Chloroquine (CQ). The
CQ molecule was provided from World Wide Antimalarial Resistance Network (wwarn Network).
Experiments were run in duplicate with both test and control drugs employed at varying concentrations.
Stock solutions (extracts) were prepared in dimethyl-sulfoxide (DMSO) and diluted with culture
medium to give a maximum DMSO concentration of 0.5% in a final well volume of 200
1% parasitemia and 2.5% haematocrit. Extracts and negative control (chloroquine (CQ)) were prepared
by two-fold dilution, in a dose-titration range of 0.098–100 g/mL, to obtain 11 concentrations each,
µL containing
µ
in duplicate. The concentrations used for CQ were between 0.5 and 1000 nM. After 48 h incubation,
the plates were subjected to 3 freeze thaw cycles to achieve complete hemolysis. The parasite lysis
suspension was diluted 1:5 in SYBR Green I lysis buffer (10 mM NaCl, 1 mM Tris HCl pH 8, 2.5 mM
EDTA pH 8, 0.05% SDS, 0,01 mg/mL proteinase K and 10X SYBR Green I). Incorporation of SYBR
Green I in parasite DNA amplification was measured using the Master epRealplex cycler® (Eppendorf,
Montesson, France) according the following program to increase the SYBR green incorporation: 90 ◦C
for 1 min, decrease in temperature from 90 ◦C to 10 ◦C for 5 min with reading the fluorescence 10 ◦C
for 1 min and a new reading at 10 ◦C for 2 min. The IC50 was calculated by nonlinear regression using
icestimator website 1.2 version: http://www.antimalarial-icestimator.net/MethodIntro.htm.
3.3.2. Cytotoxicity on HUVEC
HUVEC cells were cultured in Gibco™ RPMI 1640 medium (Life Technologies, Saint-Aubin,
France) complemented with 10% Fetal Bovine Serum and 1 mM l-glutamine (Sigma-Aldrich, Lesquin,
France) and incubated in 5% CO2 at 37 ◦C. The cytotoxicity of extracts was evaluated using the SYBR
Green I assay as previously described. HUVEC were seeded in a 96-well plate at 100,000 cells/well
and incubated for 24 h to adhere. After discarding the old medium, the cells were incubated in the
medium containing eight concentrations (0.78–100 µg/mL) of each extract in duplicate. After 48 h
incubation, cells were visualized using an inverted microscope to check their morphology or the cell
viability. The medium was subsequently removed and replaced by lysis buffer without SYBR Green
I and the plates were subjected to 3 freeze-thaw cycles. The cell lysis suspension was diluted 1:2 in
SYBR Green I lysis buffer. The incorporation of SYBR Green I in cell DNA and the IC50 analysis were
obtained as previously.

Molecules 2020, 25, 299
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4. Conclusions
In this study, we have prepared a small library of new nitrogen heterocycles displaying piperidine
scaffolds using a flexible synthetic approach. Eighteen new derivatives were prepared in good yield.
The antimalarial activity of these compounds has been described. The compounds were tested against
P. falciparum 3D7 strains and W2. The best result is observed with the compounds 13b against the 3D7
strain and 12a against the W2 one with a selectivity index greater than chloroquine. We observed that
modification with different R groups, for example compound 12a (R1 = R2 = R3 = H) in 13b (R1 = F,
R2 = H, R3 = Br) significantly modulated the activity of the tested molecules. These molecules could
be further optimized to provide good malaria drug candidates.
Author Contributions: R.S. performed the synthetic, drew the molecules and searched the literatures, A.G. and
C.C. designed the target compounds, provided guidance to optimization the synthesis process and wrote paper,
S.C. conceived and performed the biological assay. All authors have read and agreed to the published version of
the manuscript.
Funding: This work was supported by the French cooperation.
Acknowledgments: We thank Universit
é
de REIMS, Institut de chimie mol
éculaire de Reims (ICMR), France,
for recording NMR, Universit
é Paris XI, France, for bioactive tests and the French cooperation for the attribution
of the bourse for Rokhyatou Seck.
Conflicts of Interest: The authors declare no conflicts of interest.
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−
Sample Availability: Samples of the compounds are not available from the authors.
©
2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).