1-(1-Arylethylpiperidin-4-yl)thymine analogs as antimycobacterial TMPK inhibitors

Article abstract of DOI:10.3390/molecules25122805

A series of Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors based on a reported compound 3 were synthesized and evaluated for their capacity to inhibit MtbTMPK catalytic activity and the growth of a virulent M. tuberculosis strain (H37Rv). Modifications of the scaffold of 3 failed to afford substantial improvements in MtbTMPK inhibitory activity and antimycobacterial activity. Optimization of the substitution pattern of the D ring of 3 resulted in compound 21j with improved MtbTMPK inhibitory potency (three-fold) and H37Rv growth inhibitory activity (two-fold). Moving the 3-chloro substituent of 21j to the para-position afforded isomer 21h, which, despite a 10-fold increase in IC50-value, displayed promising whole cell activity (minimum inhibitory concentration (MIC) = 12.5 μM).

Full text of DOI:10.3390/molecules25122805

Article
1-(1-Arylethylpiperidin-4-yl)thymine Analogs
as Antimycobacterial TMPK Inhibitors
1
1
1
2
3
Yanlin Jian , Fabian Hulpia , Martijn D. P. Risseeuw , He Eun Forbes
,
Guy Caljon ,
4
2
1,
Hélène Munier-Lehmann , Helena I. M. Boshoff and Serge Van Calenbergh *
1
Laboratory for Medicinal Chemistry (FFW), Ghent University, Ottergemsesteenweg 460, B-9000 Gent,
Belgium; yanlin.jian@ugent.be (Y.J.); fabian.hulpia@ugent.be (F.H.); martijn.risseeuw@ugent.be (M.D.P.R.)
Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of
2
Allergy and Infectious Disease, National Institutes of Health, 9000 Rockville Pike, Bethesda,
MD 20892, USA; grace.chun@nih.gov (H.E.F.); hboshoff@niaid.nih.gov (H.I.M.B.)
Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, Universiteitsplein 1 (S7),
3
B-2610 Wilrijk, Belgium; Guy.Caljon@uantwerpen.be
Unit of Chemistry and Biocatalysis, Department of Structural Biology and Chemistry, Institut Pasteur,
4
CNRS UMR3523, 28 Rue du Dr. Roux, CEDEX 15 75724 Paris, France; helene.munier-lehmann@pasteur.fr
* Correspondence: serge.vancalenbergh@ugent.be; Tel.: +32 9 264 81 24
Academic Editor: Athina Geronikaki
Received: 6 May 2020; Accepted: 14 June 2020; Published: 17 June 2020
Abstract: A series of Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors based on a reported
compound 3 were synthesized and evaluated for their capacity to inhibit MtbTMPK catalytic activity
and the growth of a virulent M. tuberculosis strain (H37Rv). Modifications of the scaffold of 3 failed
to afford substantial improvements in MtbTMPK inhibitory activity and antimycobacterial activity.
Optimization of the substitution pattern of the D ring of 3 resulted in compound 21j with improved
MtbTMPK inhibitory potency (three-fold) and H37Rv growth inhibitory activity (two-fold). Moving
the 3-chloro substituent of 21j to the para-position afforded isomer 21h, which, despite a 10-fold
increase in IC50-value, displayed promising whole cell activity (minimum inhibitory concentration
(MIC) = 12.5 μM).
Keywords: tuberculosis; Mycobacterium tuberculosis; MtbTMPK; 1-(1-arylethylpiperidin-4-
yl)thymine
1. Introduction
Tuberculosis (TB) is an airborne infectious disease caused by Mycobacterium tuberculosis (M.
tuberculosis). Still belonging to the top ten causes of death worldwide, TB was responsible for claiming
1.5 million lives in 2018, thereby preceding AIDS [1]. The World Health Organization (WHO)
launched the “END TB” strategy in 2014, aiming at reducing the incidence of TB by 90% and the
number of deaths from TB by 95% by 2035 compared with 2015 levels [2]. Nevertheless, the progress
towards this sustainable development goal is disappointing, and the continuing increase in drug-
resistant TB cases makes the situation more challenging [1,3].
Patients with drug-sensitive TB are currently treated with a combination regimen, consisting of
a two-month treatment with first-line agents rifampicin, isoniazid, pyrazinamide and ethambutol,
followed by a four-month treatment with rifampicin and isoniazid. Although this schedule has
decreased TB mortality, these gains are being threatened by the advent of coinfection with HIV/AIDS,
poor patient adherence and a deficient health care system. Additionally, the emergence of multidrug-
resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) further erodes the ambitions of
Molecules 2020, 25, 2805; doi:10.3390/molecules25122805
www.mdpi.com/journal/molecules

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the WHO program [1]. In the case of MDR/XDR TB, a wide palette of second- and third-line anti-TB
drugs are used, e.g., fluoroquinolones, ethionamide, thioacetazone, clarithromycin and clofazimine
[4,5]. However, this regimen not only requires more toxic and costly medications; it also requires a
longer treatment duration (up to 24 months), resulting in a poor outcome. Moreover, soon after their
introduction, resistance has already developed to the newly approved agents bedaquiline [6] and
delamanid [7], with the use of pretomanid restricted to a limited and specific population of patients
[8]. Thus, novel anti-TB agents are needed to effectively shorten the treatment regime and cure MDR-
/XDR-TB.
Thymidylate kinase, a key enzyme for the synthesis of the DNA building block thymidine-5′-
triphosphate, is indispensable for bacterial survival [9–11]. The availability of co-crystal structures of
MtbTMPK [12–16] has aided the discovery of MtbTMPK inhibitors, featuring both nucleoside [14,17–
20] and non-nucleoside [14,15,20,21] structures.
A previous work from our laboratory started from compound 1 (Figure 1), originally reported
by AstraZeneca as an inhibitor of TMPK’s of Gram-positive bacteria [22]. After we found that it also
potently inhibited MtbTMPK, a SAR investigation demonstrated that it could be converted to the
achiral inhibitor 2 [14]. Further modifications led to the identification of 1-(1-arylethylpiperidin-4-
yl)thymine analog 3, which, compared to 1, displayed a nine-fold lower minimum inhibitory
concentration (MIC) value for H37Rv [14].
Figure 1. Structures of reported MtbTMPK inhibitors 1, 2 and 3 and their TMPK inhibitory potency
and antitubercular activity [14,20]. Compound 3 was resynthesized and re-evaluated herein as a
reference. MIC: minimum inhibitory concentration.
In this manuscript, we describe our optimization efforts towards finding potent
antimycobacterial agents based on 3 by introducing modifications on the A/B/C/D ring (Figure 2) and
by altering the linker part. An overview of the synthesized analogs is presented in Figure 2.

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Figure 2. An overview of the synthesized compounds 3, 21a-21q, 26 and 27 in this study.
2. Results and Discussion
2.1. Chemistry
The envisioned analogs were synthesized according to a literature-reported procedure [14].
3
Briefly, the synthesis encompassed the reductive amination of N -benzyloxymethyl (BOM)-protected
piperidinyl thymine with the appropriate aldehyde, followed by trifluoroacetic acid (TFA)-mediated
BOM deprotection to yield the desired analogs [14]. The required aldehyde intermediates (Scheme 1)
were obtained through the reduction of commercially available substituted methyl phenylacetate
esters with LiAlH4 [23] and subsequent re-oxidation by pyridinium chlorochromate (PCC) [24,25].
When the required methyl esters were not commercial available, substituted phenoxy- or
benzyloxyaryl analogs were obtained through either Chan-Lam coupling of hydroxyphenylacetic
methyl ester with a boronic acid [26] or alkylation of the hydroxyphenylacetic methyl ester with
benzyl bromide under basic conditions [27].

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Scheme 1. Synthesis of crude aldehyde intermediates. Reagents and conditions: (a) LiAlH4 and
tetrahydrofuran (THF); (b) pyridinium chlorochromate (PCC) and dichloromethane (DCM); (c)
substituted phenylboronic acid, pyridine, 4Å molecular sieves, Cu(OAc)2 and 1,2-dichloroethane; (d)
substituted benzyl bromide, K2CO3/Cs2CO3, NaI and dimethylformamide (DMF) and (e) substituted
fluorobenzene, K2CO3, DMF and 90 °C.
Due to the low yield of 17a–17c in the Chan-Lam coupling reaction, a different synthetic route
was applied for the synthesis of aldehydes 18a–18c, which was based on nucleophilic aromatic
substitution of the phenol with the appropriate 4-subsituted fluorobenzene [28]. Then, a PCC-
mediated oxidation furnished the desired aldehydes, which were used without further purification
in the reductive amination step (Scheme 2).

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Scheme 2. Synthesis of the final compounds. Reagents and conditions: (a) 28, sodium
triacetoxyborohydride and 1,2-dichloroethane; (b) trifluoroacetic acid (TFA), Et3SiH and 73 °C; (c) (±)-
29, sodium triacetoxyborohydride and 1,2-dichloroethane; (d) (i) aq. NaOH, MeOH and 50 °C; (ii) 1N
aq. HCl and H2O; (e) 28, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride
(EDC.HCl), 4-dimethylaminopyridine (DMAP) and DCM; (f) Pd/C (10%), H2, HCOOH (0.5%) and
isopropanol/H2O (10/1 v/v) and (g) 4-phenylpiperidine, sodium triacetoxyborohydride and 1,2-
dichloroethane.
3
Compounds 21a–21q and 23 were synthesized via reductive amination of N -BOM-protected
piperidinyl thymine with the appropriate aldehyde [14], followed by trifluoroacetic acid (TFA)-
mediated BOM deprotection (Scheme 2) [29]. Potential dimerization during the TFA-mediated
deprotection [14] was precluded by adding Et3SiH as a cation scavenger [29].
Amide 26 was obtained via N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC)-mediated
coupling of 28 with 2-(3-phenoxyphenyl)acetic acid, which was obtained by hydrolysis of the
corresponding methyl ester. The BOM group in the resulting amide intermediate was removed by
catalytic hydrogenation with Pd/C [30].
A one-step reductive amination of 4-phenylpiperidine with aldehyde 12b afforded the phenyl
analog 27.
2.2. Biological Activity
All synthesized compounds were evaluated for their capacity to inhibit MtbTMPK. Our
previously reported analog 3, the starting point, was resynthesized and its reported inhibitory
potency confirmed (Table 1, IC50 values of 11 and 17 μM, respectively) [14]. Replacement of the
thymine ring by a phenyl (27) led to a complete loss of the inhibitory potency. Additionally,
repositioning of the thymine ring from the para to the meta-position of the piperidine ring [20,22]

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(racemic compound 23) resulted in a substantial (> 10-fold) loss in the inhibitory potency. In-line with
earlier observations, with a one-carbon linker [14,21], amide analog 26 displayed a weak enzyme
inhibition.
Table 1. Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitory potency of the compounds.
(3, 23, 26, 27)
(21a-21c, 21e, 21n)
Compound
3
R1
IC50 (μM) a
Compound
21a
R2
IC50 (μM)
17 ± 2
680 ± 90
27
NI b
21b
21n
NI b
(±)-23
192 ± 53
95 ± 14
26
230 ± 63
21c
21e
100 ± 15
160 ± 22
a Values for which standard deviations are given are the calculated mean values of at least two
measurements. b NI: no inhibition at a concentration of 0.2 mM.
Having established that 1-(1-arylethylpiperidin-4-yl)thymine is preferable for inhibitory
potency, our efforts were then directed toward the exploration of the biphenyl ether tail. Deletion of
the terminal phenoxy group (analog 21a) resulted in a 40-fold decrease in inhibitory potency. Docking
studies based on the X-ray co-crystal structure of MtbTMPK with our previously reported 1-
(piperidin-4-yl)thymine inhibitor (PDB 5NR7) [14] were performed to rationalize the observed SAR.
Docking indicated that the loss of a hydrophobic interaction with Tyr39 accounts for the drop in
inhibitory potency (Figure 3A). The addition of a methylene moiety between the terminal phenyl ring
and C-phenoxy group (analog 21n) caused a five-fold decrease in the inhibitory potency. The docking
pose of compound 21n in MtbTMPK (Figure 3B) showed that the elongated benzyloxy phenyl
resulted in a weaker hydrophobic interaction with Tyr39 than the phenoxy moiety of 3. Omitting the
oxygen atom between the two phenyl rings led to a complete loss of enzyme inhibitory potency
(compound 21b). Moreover, moving the terminal phenoxy ring of 3 to the ortho or para-position of
ring C (compounds 21c/21e) had a negative effect on the inhibitory activity.

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Figure 3. (A) Structure overlay of compound 3 (cyan) and 21a (yellow) docked in the MtbTMPK (PDB
5NR7) [14] active site. (B) Structure overlay of compound 3 (cyan) and 21n (green) docked in the
MtbTMPK (PDB 5NR7) [14] active site. All residues interacting with the inhibitors, including the
hydrophobic contact (gray wire) and hydrogen-bonding interaction (residues in orange wire,
hydrogen bonds indicated in magenta), were calculated using LigPlus [31]. Illustration was created
using Chimera [32].
Based on these results, further optimization efforts focused on the substitution pattern of the
terminal phenyl ring of 3 and 21n. As shown in Table 2, most of the substituted analogs exhibited a
small decrease in inhibitory activity compared to 3. Of note, the introduction of sterically demanding
electron withdrawing substituents (21k/21l/21m) resulted in a significant drop in MtbTMPK
inhibitory potency.
Table 2. MtbTMPK inhibitory activity of the compounds.
H
O
N
O
N
O
N
R
Compound
3
R
IC50 (μM) a
Compound
21k
R
IC50 (μM)
17 ± 2
126 ± 10
21f
21g
21h
49 ± 7
45 ± 2
49 ± 8
21l
21m
21o
91 ± 10
135 ± 22
70 ± 9
21i
34 ± 5
21p
ND b
21j
5.0 ± 0.7
21q
44 ± 2
a Values for which standard deviations are given are the calculated mean values of at least two
measurements. b Solubility issue.

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Interestingly, the introduction of a 3-chloro (21j) but not a 4-chloro substituent (21h) afforded a
significant improvement in the inhibitory potency due to an edge-to-face π-stacking interaction
between the 3-chlorobenzene ring and Tyr39, as found for compound 3 (Figure 4). Introduction of a
3-chloro substituent in the benzyl analog 21n also had a beneficial impact on the inhibitory activity.
Figure 4. (A) Structure overlay of compound 3 (cyan), 21j (yellow) and 21h (purple) in the MtbTMPK
(PDB 5NR7) [14] active site. (B) Detailed representation of the interactions of the D rings of 3, 21h and
21j, with the side chain of Tyr39. All residues interacting with the inhibitors, including the
hydrophobic contact (gray wire) and hydrogen-bonding interaction (residues in orange wire,
hydrogen bonds indicated in magenta), were calculated using LigPlus [31]. Illustration was created
using Chimera [32].
Finally, all compounds were evaluated for their in vitro antimycobacterial activity (Table 3).
Consistent with the observations on the enzyme inhibitory activities, modifications of the scaffold of
3 did not yield analogs with superior antimycobacterial activity (21a-21c, 21e, 21n, 23 and 26). Remarkably,
analog 27, in which the thymine moiety is replaced by a phenyl ring, showed potent antimycobacterial
activity but lacked selectivity, as evidenced by its equipotent cytotoxicity. The introduction of substituents
on the distal phenyl ring of 3 afforded several analogs with improved antimycobacterial activity (21f–21j).
Substitution of the D-ring of the benzyloxy analog 21n also contributed to the growth inhibitory activity.
However, the selectivity vs. MRC-5 fibroblasts was modest.
Table 3. Antimycobacterial activity against H37Rv and cytotoxicity against MRC-5 fibroblasts of the
compounds in this study.
MIC a
(H37Rv, μM) (MRC-5, μM)
IC50
MIC
IC50
Compound
SI b
Compound
SI
(H37Rv, μM) (MRC-5, μM)
3
37
>50
>50
50
>50
19
19
12.5
25
>64
>64
22.22
26.81
>64
8.42
5.66
5.81
>64
>1.73
-
-
0.54
-
0.44
0.30
0.46
>2.56
1.33
21k
21l
21m
21n
21o
21p
21q
23
≥50
37
37
37
19
12.5
25
>50
>50
6.25
>64
>64
>64
27.57
7.08
4.22
19.84
21.77
>64
-
21a
21b
21c
21e
21f
21g
21h
21i
21j
>1.73
>1.73
0.74
0.37
0.34
0.79
-
26
27
-
19
25.24
8.06
1.29
a Minimum inhibitory concentration (MIC) is the minimum concentration required to inhibit >99% growth of
Mycobacterium tuberculosis H37Rv in the liquid culture. b Selectivity index (SI): IC50 (MRC-5)/MIC (H37Rv).

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3. Materials and Methods
3.1. Enzymatic Assay
The enzymatic assay was performed as previously reported on the recombinant purified
MtbTMPK [14,33]. As described by Blondin et al. [34], compounds were evaluated by a serial dilution
method using the spectrophotometric assay at fixed concentrations of adenosine triphosphate (ATP)
(0.5 mM) and thymidine monophosphate (dTMP; 0.05 mM). The reaction medium includes 50-mM
Tris-HCl; pH 7.4; 50-mM KCl; 2-mM MgCl2; 0.2-mM nicotinamide adenine dinucleotide (NADH); 1-
mM phosphoenol pyruvate and 2 units each of coupling enzymes (lactate dehydrogenase, pyruvate
kinase and nucleoside diphosphate kinase). From the experimental data, the IC50 value was calculated
using KaleidaGraph 4.5.3.
3.2. Computational Studies
For the molecular modeling, X-ray structure of the MtbTMPK (PDB entry 5NR7 [14]) was
analyzed using AutoDock vina and AutodockTools-1.5.6. [35]. In ChemDraw 3D 16.0, the PDB files
of all ligands were generated after the energy was minimized (minimum RMS gradient: 0.001). The
PDBQT file of the ligands and receptors were prepared by AutodockTools-1.5.6, including atom
types, atomic partial charges and the information on the ligand torsional degrees. Using a grid
spacing of 0.375 and 60 x 60 x 60 numbers of grid points, the prepared PDBQT files of ligands and
receptors were docked (centered on the MtbTMPK active site PHE70 CE2, the coordinates x, y and z
were -0.997, 26.240 and -4.528, correspondingly) through the Lamarckian 4.2 method. Each ligand
was docked in Autodock vina 3 times, with each time generating 20 possible conformations. Chimera
in combination with LigPlus were used to analyze the results.
3.3. In Vitro Antituberculosis Assay
The MIC values of all compounds were determined as previously described [36]. In brief, M.
tuberculosis H37Rv (ATCC 27294) was grown to optical density at 650 nm wavelength (OD650nm) 0.2 in
Middlebrook 7H9 medium supplemented with 0.4% glucose, 0.03% Bacto casitone and 0.05%
Tyloxapol (7H9/glucose/casitone/Tyloxapol) prior to further 1000-fold dilution in fresh medium.
Drugs were 2-fold serially diluted in duplicate in 7H9/glucose/casitone/Tyloxapol (50 μL/well) in a
concentration range spanning 100-0.049 μM in sterile 96-well U-bottom clear polystyrene microtiter
plates. Isoniazid and DMSO as positive and negative controls, respectively. An equal volume (50 μL)
of diluted cells was added to the plates with the serial drug dilution. Plates were sealed in Ziplock
bags and incubated at 37 °C. After 7–14 days, plates were read with an enlarging inverted mirror
plate reader. The MIC was recorded as the concentration that fully inhibited all visible growth.
3.4. In Vitro Cytotoxicity Assay
The cytotoxicity of compounds on MRC-5 fibroblasts was performed exactly as previously
reported [14].
3.5. Chemistry
All reagents and solvents were purchased from standard commercial sources and were of
analytical grade. All synthetic compounds described in this study were checked with analytical TLC
(Macherey−Nagel precoated F254 aluminum plates, Düren, Germany), visualized under UV light at
254 nm and purified by column chromatography (CC) on a Reveleris X2 (Grace, BÜCHI, Flawil,
Switzerland) automated flash unit. All final compounds and some intermediates were measured with
Varian Mercury 300/75 MHz (Palo Alto, CA, USA) or a Bruker AVANCE (Fällanden, Zürich,
®
Switzerland) Neo 400/100 MHz spectrometer at 298.15 K using tetramethylsilane (TMS) as an
1
internal standard. The analysis and confirmation of the final compounds were conducted with H,
13
C, HSQC and HMBC NMR spectral data (Supplementary Material). High-resolution mass
TM
spectrometry was performed on a Waters LCT Premier XE (Waters, Zellik, Belgium) time-of-flight

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(TOF) mass spectrometer equipped with a standard electrospray ionization (ESI) and modular
TM
LockSpray interface (Waters, Zellik, Belgium). The purity of the tested compounds was determined
by LC-MS analysis using a Waters AutoPurification system equipped with a Waters Cortecs C18
column (2.7 μm, 100 × 4.6 mm), as was a gradient system of formic acid in H2O (0.2%, v/v)/MeCN
with a gradient of 95:5 to 0:100 in 6.5 min at a flow rate of 1.44 mL/min.
General procedure A: Synthesis of biphenyl ether aldehyde building blocks. According to a
literature report [26], hydroxyphenylacetic ester derivatives (1.0 eq), phenylboronic acid derivatives
(3.0 eq.), Cu(OAc)2 (2.0 eq.), 4Å molecular sieves (0.18 g/mmol ester) and pyridine (3.0 eq.) in 1,2-
dichloroethane (6.0 mL/mmol ester) afforded the biphenyletheracetic ester intermediates. To a
solution of the biphenyletheracetic ester intermediates (1.0 eq.) in dry tetrahydrofuran (THF) (6.0
mL/mmol ester intermediate) was added LiAlH4 (2.0 eq.) at 0 °C under N2 atmosphere, and the
resulting mixture was then stirred at room temperature for 1 h [23]. After complete consumption of
+
+
the starting material, the reaction mixture was quenched with aq. Na /K tartrate solution (5.0
mL/mmol LiAlH4), and the mixture was stirred at room temperature overnight and then filtered. The
collected filtrate was dried and concentrated to afford a crude alcohol intermediate, which was
oxidized by PCC (2.0 eq.) for 2 h in dichloromethane (DCM) (5.0 mL/mmol PCC) [24,25]. The reaction
mixture was filtered through a short silica column. The collected filtrate was concentrated in vacuo
and used in the next step without any additional purification.
General procedure B: Synthesis of final compounds. To a solution of aldehyde intermediates
(1.0 eq.) and 28 (1.0 eq.) in 1,2-dichloroethane (33 mL/mmol aldehyde) was added sodium
triacetoxyborohydride (2.0 eq.). The resulting mixture was stirred at room temperature for overnight
to afford the BOM-protected intermediate [14], which was deprotected with TFA (17 mL/mmol
aldehyde) in the presence of triethylsilane [29] (17 mL/mmol aldehyde) at 73 °C for 4 h. After cooling
down to room temperature, the reaction mixture was evaporated in vacuo to remove TFA, and the
residue was adjusted to pH 6 with 1N aq. HCl. Purification of the resulting mixture by column
chromatography gave the desired compounds.
2-([1,1’-Biphenyl]-4-yl)acetaldehyde (6). To a solution of methyl 2-([1,1’-biphenyl]-4-yl)acetate (0.3
g, 1.3 mmol) in dry THF (7.8 mL) was added LiAlH4 (0.10 g, 2.7 mmol) to give alcohol intermediate,
which was oxidized with PCC (0.56 g, 2.6 mmol) in DCM (13.0 mL) to yield aldehyde 6 (C14H12O, 0.22
g, 1.1 mmol).
2-(2-Phenoxyphenyl)acetaldehyde (12a). Following the general procedure A, methyl 2-(2-
hydroxyphenyl)acetate (1.1 g, 8.1 mmol), phenylboronic acid (2.9 g, 24 mmol), Cu(OAc)2 (2.9 g, 16
mmol), 4Å molecular sieves (1.5 g) and pyridine (1.9 mL, 24 mmol) in 1,2-dichloroethane (49 mL)
afforded the ester intermediate methyl 2-(2-phenoxyphenyl)acetate 10a (eluent system: 10%
1
ethylacetate in petroleum ether, C15H14O3, 0.40 g, 1.6 mmol, 21% yield). H NMR (300 MHz, CDCl3) δ
ppm 3.63 (s, 3 H, OCH3), 3.72 (s, 2 H, CH2), 6.90 (dd, J = 8.1, 1.0 Hz, 1 H, Ph), 6.95–7.01 (m, 2 H, Ph),
13
7.06–7.15 (m, 2 H, Ph), 7.21–7.37 (m, 4 H, Ph). C NMR (75 MHz, CDCl3) δ ppm 35.6 (1 C, CH2), 51.8
(1 C, OCH3), 118.3 (2 C, Ph), 118.8 (1 C, Ph), 123.0 (1 C, Ph), 123.6 (1 C, Ph), 125.8 (1 C, Ph), 128.6 (1 C,
Ph), 129.6 (2 C, Ph), 131.4 (1 C, Ph), 155.0 (1 C, Ph), 157.2 (1 C, Ph), 171.7 (1 C, CO). Then, 10a (0.20 g,
0.83 mmol) was treated with LiAlH4 (63 mg, 1.7 mmol) in dry THF (5.0 mL) to give alcohol
intermediate, which was oxidized with PCC (0.34 g, 1.6 mmol) in DCM (8.0 mL) to yield aldehyde
12a (C14H12O2, 0.15 g, 0.70 mmol).
2-(3-Phenoxyphenyl)acetaldehyde (12b). Following the general procedure A, methyl 2-(3-
hydroxyphenyl)acetate (1.1 g, 8.1 mmol), phenylboronic acid (2.9 g, 24 mmol), Cu(OAc)2 (2.9 g, 16
mmol), 4Å molecular sieves (1.5 g) and pyridine (1.9 mL, 24 mmol) in 1,2-dichloroethane (49 mL)
afforded the ester intermediate methyl 2-(3-phenoxyphenyl)acetate 10b (eluent system: 10%
1
ethylacetate in petroleum ether, C15H14O3, 0.80 g, 3.3 mmol, 41% yield). H NMR (300 MHz, CDCl3) δ
ppm 3.62 (s, 2 H, CH2), 3.71 (s, 3 H, OCH3), 6.90 - 6.95 (m, 1 H, Ph), 6.98 (t, J = 2.1 Hz, 1 H, Ph), 7.01–
13
7.07 (m, 3 H, Ph), 7.13 (tt, J = 7.4, 1.1 Hz, 1 H, Ph), 7.26–7.40 (m, 3 H, Ph). C NMR (75 MHz, CDCl3) δ
ppm 40.9 (1 C, CH2), 52.0 (1 C, OCH3), 117.3 (1 C, Ph), 119.0 (2 C, Ph), 119.7 (1 C, Ph), 123.3 (1 C, Ph),

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124.0 (1 C, Ph), 129.7 (3 C, Ph), 135.7 (1 C, Ph), 156.9 (1 C, Ph), 157.4 (1 C, Ph), 171.6 (1 C, CO). Then,
10b (0.20 g, 0.83 mmol) was treated with LiAlH4 (63 mg, 1.7 mmol) in dry THF (5.0 mL) to give alcohol
intermediate, which was oxidized with PCC (0.35 g, 1.6 mmol) in DCM (8.0 mL) to yield aldehyde
12b (C14H12O2, 0.15 g, 0.71 mmol).
2-(4-Phenoxyphenyl)acetaldehyde (12c). Following the general procedure A, methyl 2-(4-
hydroxyphenyl)acetate (0.60 g, 4.4 mmol), phenylboronic acid (1.6 g, 13 mmol), Cu(OAc)2 (1.6 g, 8.8
mmol), 4Å molecular sieves (0.70 g) and pyridine (1.1 mL, 13 mmol) in 1,2-dichloroethane (26 mL)
afforded the ester intermediate methyl 2-(4-phenoxyphenyl)acetate 10c (eluent system: 10%
1
ethylacetate in petroleum ether, C15H14O3, 0.66 g, 2.7 mmol, 62% yield). H NMR (300 MHz, CDCl3) δ
ppm 3.63 (s, 2 H, CH2), 3.72 (s, 3 H, OCH3), 6.95–7.06 (m, 4 H, Ph), 7.08–7.15 (m, 1 H, Ph), 7.23–7.29
13
(m, 2 H, Ph), 7.31–7.39 (m, 2 H, Ph). C NMR (75 MHz, CDCl3) δ ppm 40.3 (1 C, CH2), 52.0 (1 C,
OCH3), 118.8 (4 C, Ph), 123.2 (1 C, Ph), 128.7 (1 C, Ph), 129.6 (2 C, Ph), 130.5 (2 C, Ph), 156.3 (1 C, Ph),
157.0 (1 C, Ph), 172.0 (1 C, CO). Then, 10c (0.20 g, 0.83 mmol) was treated with LiAlH4 (63 mg, 1.6
mmol) in dry THF (5.0 mL) to give alcohol intermediate, which was oxidized with PCC (0.3 g, 1.4
mmol) in DCM (7.0 mL) to yield aldehyde 12c (C14H12O2, 0.13 g, 0.62 mmol).
2-(3-(p-Tolyloxy)phenyl)acetaldehyde (12d). Following the general procedure A, methyl 2-(3-
hydroxyphenyl)acetate (0.60g, 4.4 mmol), p-tolylboronic acid (1.8 g, 13 mmol), Cu(OAc)2 (1.6 g, 8.8
mmol), 4Å molecular sieves (0.79 g) and pyridine (1.1 mL, 13 mmol) in 1,2-dichloroethane (26 mL)
afforded the ester intermediate methyl 2-(3-(p-tolyloxy)phenyl)acetate 10d (eluent system: 10%
1
ethylacetate in petroleum ether, C16H16O3, 0.34 g, 1.3 mmol, 30% yield). H NMR (300 MHz, CDCl3) δ
ppm 2.37 (s, 3 H, CH3), 3.62 (s, 2 H, CH2), 3.72 (s, 3 H, OCH3), 6.89–6.99 (m, 4 H, Ph), 7.00–7.05 (m, 1
13
H, Ph), 7.14–7.21 (m, 2 H, Ph), 7.25–7.32 (m, 1 H, Ph). C NMR (75 MHz, CDCl3) δ ppm 20.6 (1 C,
CH3), 40.9 (1 C, CH2), 51.9 (1 C, OCH3), 116.7 (1 C, Ph), 119.1 (3 C, Ph), 123.5 (1 C, Ph), 129.6 (1 C, Ph),
130.1 (2 C, Ph), 132.9 (1 C, Ph), 135.6 (1 C, Ph), 154.4 (1 C, Ph), 157.9 (1 C, Ph), 171.6 (1 C, CO). Then,
10d (0.20 g, 0.78 mmol) was treated with LiAlH4 (59 mg, 1.6 mmol) in dry THF (4.7 mL) to give alcohol
intermediate, which was oxidized with PCC (0.28 g, 1.3 mmol) in DCM (6.5 mL) to yield aldehyde
12d (C15H14O2, 0.13 g, 0.58 mmol).
2-(3-(3,4-Dichlorophenoxy)phenyl)acetaldehyde (12e). Following the general procedure A, methyl 2-
(3-hydroxyphenyl)acetate (0.60 g, 4.4 mmol), (3,4-dichlorophenyl)boronic acid (2.5 g, 13 mmol),
Cu(OAc)2 (1.6 g, 8.8 mmol), 4Å molecular sieves (0.79 g) and pyridine (1.1 mL, 13 mmol) in 1,2-
dichloroethane
(26
mL)
afforded
the
ester
intermediate
methyl
2-(3-(3,4-
dichlorophenoxy)phenyl)acetate 10e (eluent system: 10% ethylacetate in petroleum ether,
1
C15H12Cl2O3, 0.73 g, 2.3 mmol, 53% yield). H NMR (300 MHz, CDCl3) δ ppm 3.63 (s, 2 H, CH2), 3.71
(s, 3 H, OCH3), 6.86 (dd, J = 8.9, 2.8 Hz, 1 H, Ph), 6.90–6.99 (m, 2 H, Ph), 7.06–7.12 (m, 2 H, Ph), 7.31 (d,
13
J = 7.9 Hz, 1 H, Ph), 7.37 (d, J = 8.8 Hz, 1 H, Ph). C NMR (75 MHz, CDCl3) δ ppm 40.8 (1 C, CH2), 52.1
(1 C, OCH3), 117.8 (1 C, Ph), 118.0 (1 C, Ph), 120.2 (1 C, Ph), 120.3 (1 C, Ph), 125.1 (2 C, Ph), 130.0 (1 C,
Ph), 130.9 (1 C, Ph), 133.1 (1 C, Ph), 136.1 (1 C, Ph), 156.1 (1 C, Ph), 156.3 (1 C, Ph), 171.5 (1 C, CO).
Then, 10e (0.20 g, 0.64 mmol) was treated with LiAlH4 (49 mg, 1.3 mmol) in dry THF (3.8 mL) to give
alcohol intermediate, which was oxidized with PCC (0.23 g, 1.1 mmol) in DCM (5.5 mL) to yield
aldehyde 12e (C14H10Cl2O2, 0.10 g, 0.36 mmol).
2-(3-(4-Chlorophenoxy)phenyl)acetaldehyde (12f). Following the general procedure A, methyl 2-(3-
hydroxyphenyl)acetate (0.60 g, 4.4 mmol), (4-chlorophenyl)boronic acid (2.1 g, 13 mmol), Cu(OAc)2
(1.6 g, 8.8 mmol), 4Å molecular sieves (0.79 g) and pyridine (1.1 mL, 13 mmol) in 1,2-dichloroethane
(26 mL) afforded the ester intermediate methyl 2-(3-(4-chlorophenoxy)phenyl)acetate 10f (eluent
1
system: 10% ethylacetate in petroleum ether, C15H13ClO3, 0.40 g, 1.4 mmol, 33% yield). H NMR (300
MHz, CDCl3) δ ppm 3.62 (s, 2 H, CH2), 3.71 (s, 3 H, OCH3), 6.87–6.99 (m, 4 H, Ph), 7.05 (d, J = 7.3 Hz,
13
1 H, Ph), 7.25–7.34 (m, 3 H, Ph). C NMR (75 MHz, CDCl3) δ ppm 40.9 (1 C, CH2), 52.1 (1 C, OCH3),
117.4 (1 C, Ph), 119.8 (1 C, Ph), 120.2 (2 C, Ph), 124.5 (1 C, Ph), 128.4 (1 C, Ph), 129.8 (2 C, Ph), 129.9 (1
C, Ph), 136.0 (1 C, Ph), 155.7 (1 C, Ph), 157.1 (1 C, Ph), 171.6 (1 C, CO). Then, 10f (0.20 g, 0.72 mmol)
was treated with LiAlH4 (55 mg, 1.5 mmol) in dry THF (4.3 mL) to give alcohol intermediate, which

Molecules 2020, 25, 2805
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was oxidized with PCC (0.31 g, 1.5 mmol) in DCM (7.5 mL) to yield aldehyde 12f (C14H11ClO2, 0.13 g,
0.53 mmol).
2-(3-(4-Methoxyphenoxy)phenyl)acetaldehyde (12g). Following the general procedure A, methyl 2-
(3-hydroxyphenyl)acetate (0.60 g, 4.4 mmol), (4-methoxyphenyl)boronic acid (2.0 g, 13 mmol),
Cu(OAc)2 (1.6 g, 8.8 mmol), 4Å molecular sieves (0.79 g) and pyridine (1.1 mL, 13 mmol) in 1,2-
dichloroethane
(26
mL)
afforded
the
ester
intermediate
methyl
2-(3-(4-
methoxyphenoxy)phenyl)acetate 10g (eluent system: 10% ethylacetate in petroleum ether, C16H16O4,
1
0.33 g, 1.2 mmol, 28% yield). H NMR (300 MHz, CDCl3) δ ppm 3.60 (s, 2 H, CH2), 3.70 (s, 3 H, OCH3),
3.82 (s, 3 H, (Ph)OCH3), 6.82–6.87 (m, 1 H, Ph), 6.88–6.94 (m, 3 H, Ph), 6.95–7.03 (m, 3 H, Ph), 7.22–
13
7.29 (m, 1 H, Ph). C NMR (75 MHz, CDCl3) δ ppm 41.0 (1 C, CH2), 52.0 (1 C, OCH3), 55.6 (1 C,
(Ph)OCH3), 114.8 (2 C, Ph), 116.0 (1 C, Ph), 118.4 (1 C, Ph), 120.9 (2 C, Ph), 123.2 (1 C, Ph), 129.6 (1 C,
Ph), 135.6 (1 C, Ph), 149.8 (1 C, Ph), 155.9 (1 C, Ph), 158.6 (1 C, Ph), 171.7 (1 C, CO). Then, 10g (0.20 g,
0.74 mmol) was treated with LiAlH4 (56 mg, 1.5 mmol) in dry THF (4.4 mL) to give alcohol
intermediate, which was oxidized with PCC (0.32 g, 1.5 mmol) in DCM (7.5 mL) to yield aldehyde
12g (C15H14O3, 0.14 g, 0.58 mmol).
2-(3-(3-Chlorophenoxy)phenyl)acetaldehyde (12h). Following the general procedure A, methyl 2-(3-
hydroxyphenyl)acetate (0.40 g, 2.9 mmol), 3-chlorophenylboronic acid (1.4 g, 8.8 mmol), Cu(OAc)2
(1.1 g, 5.9 mmol), 4Å molecular sieves (0.50 g) and pyridine (0.71 mL, 8.8 mmol) in 1,2-dichloroethane
(17 mL) afforded the ester intermediate methyl 2-(3-(3-chlorophenoxy)phenyl)acetate 10h (eluent
1
system: 10% ethylacetate in petroleum ether, C15H13ClO3, 0.28 g, 1.0 mmol, 34% yield). H NMR (300
MHz, CDCl3) δ ppm 3.63 (s, 2 H, CH2), 3.71 (s, 3 H, OCH3), 6.88–6.96 (m, 2 H, Ph), 6.98 (t, J = 1.9 Hz, 1
13
H, Ph), 7.00 (t, J = 2.2 Hz, 1 H, Ph), 7.04–7.14 (m, 2 H, Ph), 7.17–7.36 (m, 2 H, Ph). C NMR (75 MHz,
CDCl3) δ ppm 40.9 (1 C, CH2), 52.1 (1 C, OCH3), 116.8 (1 C, Ph), 117.9 (1 C, Ph), 118.9 (1 C, Ph), 120.2
(1 C, Ph), 123.3 (1 C, Ph), 124.8 (1 C, Ph), 130.0 (1 C, Ph), 130.5 (1 C, Ph), 135.0 (1 C, Ph), 136.0 (1 C,
Ph), 156.5 (1 C, Ph), 158.1 (1 C, Ph), 171.5 (1 C, CO). Then, 10h (0.20 g, 0.72 mmol) was treated with
LiAlH4 (55 mg, 1.4 mmol) in dry THF (4.3 mL) to give alcohol intermediate, which was oxidized with
PCC (0.19 g, 0.87 mmol) in DCM (4.3 mL) to yield aldehyde 12h (C14H11ClO2, 0.10 g, 0.41 mmol).
2-(3-(Benzyloxy)phenyl)acetaldehyde (15a). According to a literature procedure [27] with minor
changes, methyl 2-(3-hydroxyphenyl)acetate (0.30 g, 2.2 mmol), benzyl bromide (0.26 mL, 2.2 mmol),
K2CO3 (0.61 g, 4.4 mmol), sodium iodide (33 mg, 0.22 mmol) in dimethylformamide (DMF) (10 mL)
at room temperature for overnight afforded the ester intermediate methyl 2-(3-
(benzyloxy)phenyl)acetate 13a (eluent system: 10% ethylacetate in petroleum ether, C16H16O3, 0.33 g,
1
1.3 mmol, 58% yield). H NMR (300 MHz, CDCl3) δ ppm 3.65 (s, 2 H, CH2), 3.73 (s, 3 H, OCH3), 5.10
13
(s, 2 H, (Ph)CH2O), 6.83–7.05 (m, 3 H, Ph), 7.21–7.52 (m, 6 H, Ph). C NMR (75 MHz, CDCl3) δ ppm
41.1 (1 C, CH2), 52.0 (1 C, OCH3), 69.8 (1 C, (Ph)CH2O), 113.4 (1 C, Ph), 115.8 (1 C, Ph), 121.8 (1 C, Ph),
127.5 (2 C, Ph), 127.9 (1 C, Ph), 128.5 (2 C, Ph), 129.5 (1 C, Ph), 135.4 (1 C, Ph), 136.9 (1 C, Ph), 158.9 (1
C, Ph), 171.8 (1 C, CO). Then, 13a (0.20 g, 0.78 mmol) was treated with LiAlH4 (59 mg, 1.6 mmol) in
dry THF (4.7 mL) to give alcohol intermediate, which was oxidized with PCC (0.34 g, 1.6 mmol) in
DCM (8.0 mL) to yield aldehyde 15a (C15H14O2, 0.14 g, 0.62 mmol).
2-(3-((2-Chlorobenzyl)oxy)phenyl)acetaldehyde (15b). Following the procedure as described for 15a,
methyl 2-(3-hydroxyphenyl)acetate (0.40 g, 2.9 mmol), 1-(bromomethyl)-2-chlorobenzene (0.60 g, 2.9
mmol), K2CO3 (0.81 g, 5.9 mmol), sodium iodide (44 mg, 0.29 mmol) in DMF (13 mL) afforded the
ester intermediate methyl 2-(3-((2-chlorobenzyl)oxy)phenyl)acetate 13b (eluent system: 10%
1
ethylacetate in petroleum ether, C16H15ClO3, 0.26 g, 0.89 mmol, 30% yield). H NMR (300 MHz, CDCl3)
δ ppm 3.63 (s, 2 H, CH2), 3.71 (s, 3 H, OCH3), 5.17 (s, 2 H, (Ph)CH2O), 6.86–7.01 (m, 3 H, Ph), 7.23–7.36
13
(m, 3 H, Ph), 7.41 (dd, J = 7.0, 2.1 Hz, 1 H, Ph), 7.53–7.63 (m, 1 H, Ph). C NMR (75 MHz, CDCl3) δ
ppm 41.2 (1 C, CH2), 52.1 (1 C, OCH3), 67.1 (1 C, (Ph)CH2O), 113.4 (1 C, Ph), 116.0 (1 C, Ph), 122.1 (1
C, Ph), 126.9 (1 C, Ph), 128.8 (1 C, Ph), 129.0 (1 C, Ph), 129.3 (1 C, Ph), 129.6 (1 C, Ph), 132.6 (1 C, Ph),
134.7 (1 C, Ph), 135.5 (1 C, Ph), 158.7 (1 C, Ph), 171.8 (1 C, CO). Then, 13b (0.20 g, 0.69 mmol) was
treated with LiAlH4 (52 mg, 1.4 mmol) in dry THF (4.1 mL) to give alcohol intermediate, which was

Molecules 2020, 25, 2805
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oxidized with PCC (0.25 g, 1.2 mmol) in DCM (6.0 mL) to yield aldehyde 15b (C15H13ClO2, 0.14 g, 0.53
mmol).
2-(3-((3,4-Dichlorobenzyl)oxy)phenyl)acetaldehyde (15c). Following the procedure as described for
15a, methyl 2-(3-hydroxyphenyl)acetate (0.40 g, 2.9 mmol), 3,4-dichlorobenzyl bromide (0.70 g, 2.9
mmol), K2CO3 (0.81 g, 5.9 mmol), sodium iodide (44 mg, 0.29 mmol) in DMF (13 mL) afforded the
ester intermediate methyl 2-(3-((3,4-dichlorobenzyl)oxy)phenyl)acetate 13c (eluent system: 10%
1
ethylacetate in petroleum ether, C16H14Cl2O3, 0.75 g, 2.3 mmol, 84% yield). H NMR (300 MHz, CDCl3)
δ ppm 3.62 (s, 2 H, CH2), 3.70 (s, 3 H, OCH3), 5.01 (s, 2 H, (Ph)CH2O), 6.87 (d, J = 8.2 Hz, 1 H, Ph), 6.93
13
(br. s., 2 H, Ph), 7.21–7.30 (m, 2 H, Ph), 7.41–7.48 (m, 1 H, Ph), 7.54 (s, 1 H, Ph). C NMR (75 MHz,
CDCl3) δ ppm 41.1 (1 C, CH2), 52.1 (1 C, OCH3), 68.4 (1 C, (Ph)CH2O), 113.4 (1 C, Ph), 115.8 (1 C, Ph),
122.3 (1 C, Ph), 126.5 (1 C, Ph), 129.2 (1 C, Ph), 129.7 (1 C, Ph), 130.5 (1 C, Ph), 131.8 (1 C, Ph), 132.6 (1
C, Ph), 135.6 (1 C, Ph), 137.3 (1 C, Ph), 158.4 (1 C, Ph), 171.7 (1 C, CO). Then, 13c (0.20 g, 0.62 mmol)
was treated with LiAlH4 (47 mg, 1.2 mmol) in dry THF (3.7 mL) to give alcohol intermediate, which
was oxidized with PCC (0.26 g, 1.2 mmol) in DCM (6.0 mL) to yield aldehyde 15c (C15H12Cl2O2, 0.18
g, 0.60 mmol).
2-(3-((3-Chlorobenzyl)oxy)phenyl)acetaldehyde (15d). Following the procedure as described for 15a,
methyl 2-(3-hydroxyphenyl)acetate (0.40 g, 2.9 mmol), m-chlorobenzyl bromide (0.60 g, 2.9 mmol),
K2CO3 (0.81 g, 5.9 mmol), sodium iodide (44 mg, 0.29 mmol) in DMF (13 mL) afforded the ester
intermediate methyl 2-(3-((3-chlorobenzyl)oxy)phenyl)acetate 13d (eluent system: 10% ethylacetate
1
in petroleum ether, C16H15ClO3, 0.62 g, 2.1 mmol, 73% yield). H NMR (400 MHz, CDCl3) δ ppm 3.61
(s, 2 H, CH2), 3.70 (s, 3 H, OCH3), 5.03 (s, 2 H, (Ph)CH2O), 6.84–6.94 (m, 3 H, Ph), 7.23–7.28 (m, 1 H,
13
Ph), 7.29–7.32 (m, 3 H, Ph), 7.35–7.48 (m, 1 H, Ph). C NMR (101 MHz, CDCl3) δ ppm 41.2 (1 C, CH2),
52.1 (1 C, OCH3), 69.1 (1 C, (Ph)CH2O), 113.4 (1 C, Ph), 115.8 (1 C, Ph), 122.1 (1 C, Ph), 125.3 (1 C, Ph),
127.4 (1 C, Ph), 128.0 (1 C, Ph), 129.6 (1 C, Ph), 129.8 (1 C, Ph), 134.5 (1 C, Ph), 135.5 (1 C, Ph), 139.0 (1
C, Ph), 158.6 (1 C, Ph), 171.9 (1 C, CO). Then, 13d (0.20 g, 0.69 mmol) was treated with LiAlH4 (52 mg,
1.4 mmol) in dry THF (4.1 mL) to give alcohol intermediate, which was oxidized with PCC (0.26 g,
1.2 mmol) in DCM (6.0 mL) to yield aldehyde 15d (C15H13ClO2, 0.14 g, 0.52 mmol).
2-(3-(4-Cyanophenoxy)phenyl)acetaldehyde
(18a).
To
a
solution
of
methyl
2-(3-
hydroxyphenyl)acetate (0.35 g, 2.1 mmol) in THF (13 mL) was added LiAlH4 (0.16 g, 4.2 mmol)
afforded 3-(2-hydroxyethyl)phenol (0.24 g, 1.4 mmol), which was reacted with 4-fluorobenzonitrile
(0.21 g, 1.7 mmol), K2CO3 (0.40 g, 2.9 mmol) in DMF (10 mL) at 90 °C gave 4-(3-(2-
hydroxyethyl)phenoxy)benzonitrile [28] 17a (eluent system: 25% ethylacetate in petroleum ether,
1
C15H13NO2, 0.14 g, 0.59 mmol, 40% yield). H NMR (300 MHz, CDCl3) δ ppm 2.89 (t, J = 6.6 Hz, 2 H,
CH2), 3.89 (t, J = 6.4 Hz, 2 H, CH2(OH)), 6.89–7.06 (m, 4 H, Ph), 7.11 (dd, J = 7.6, 0.59 Hz, 1 H, Ph), 7.36
13
(t, J = 7.4 Hz, 1 H, Ph), 7.49–7.69 (m, 2 H, Ph). C NMR (75 MHz, CDCl3) δ ppm 38.9 (1 C, CH2), 63.3
(1 C, CH2(OH)), 105.8 (1 C, Ph), 110.0 (1 C, Ph), 118.0 (2 C, Ph), 118.3 (1 C, CN), 120.9 (1 C, Ph), 125.7
(1 C, Ph), 130.2 (1 C, Ph), 134.1 (2 C, Ph), 141.4 (1 C, Ph), 154.9 (1 C, Ph), 161.5 (1 C, Ph). Then, 17a was
oxidized by PCC (0.25 g, 1.2 mmol) in DCM (6.0 mL) to give aldehyde 18a (C15H11NO2, 0.11 g, 0.44
mmol).
2-(3-(4-Nitrophenoxy)phenyl)acetaldehyde (18b). Following the procedure described for 18a, 3-(2-
hydroxyethyl)phenol (0.30 g, 2.2 mmol), 1-fluoro-4-nitrobenzene (0.37 g, 2.6 mmol) and K2CO3 (0.60
g, 4.3 mmol) in DMF (16 mL) afforded 2-(3-(4-nitrophenoxy)phenyl)ethan-1-ol 17b (eluent system:
1
25% ethylacetate in petroleum ether, C14H13NO4, 0.52 g, 2.0 mmol, 92% yield). H NMR (300 MHz,
CDCl3) δ ppm 2.90 (t, J = 6.4 Hz, 2 H, CH2), 3.89 (t, J = 6.4 Hz, 2 H, CH2(OH)), 6.93–7.07 (m, 4 H, Ph),
13
7.13 (d, J = 7.6 Hz, 1 H, Ph), 7.37 (t, J = 7.7 Hz, 1 H, Ph), 8.13–8.24 (m, 2 H, Ph). C NMR (75 MHz,
CDCl3) δ ppm 38.8 (1 C, CH2), 63.2 (1 C, CH2(OH)), 117.1 (2 C, Ph), 118.4 (1 C, Ph), 121.0 (1 C, Ph),
125.9 (2 C, Ph), 126.0 (1 C, Ph), 130.3 (1 C, Ph), 136.5 (1 C, Ph), 141.5 (1 C, Ph), 154.9 (1 C, Ph), 163.2 (1
C, Ph). Then, 17b was oxidized by PCC (0.86 g, 4.0 mmol) in DCM (20 mL) to give aldehyde 18b
(C14H11NO4, 0.36 g, 1.4 mmol).

Molecules 2020, 25, 2805
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2-(3-(4-(Trifluoromethyl)phenoxy)phenyl)acetaldehyde (18c). Following the procedure described for
18a, 3-(2-hydroxyethyl)phenol (0.30 g, 2.2 mmol), 1-fluoro-4-(trifluoromethyl)benzene (0.43 g, 2.6
mmol) and CsCO3 (0.85 g, 2.6 mmol) in DMF (16 mL) at 90 °C gave 2-(3-(4-
(trifluoromethyl)phenoxy)phenyl)ethan-1-ol 17c (eluent system: 25% ethylacetate in petroleum ether,
1
C15H13F3O2, 0.13 g, 0.46 mmol, 21% yield). H NMR (300 MHz, CDCl3) δ ppm 2.87 (t, J = 6.6 Hz, 2 H,
CH2), 3.86 (t, J = 6.6 Hz, 2 H, CH2(OH)), 6.89–6.98 (m, 2 H, Ph), 7.01–7.12 (m, 3 H, Ph), 7.33 (t, J = 6.6
13
Hz, 1 H, Ph), 7.58 (d, J = 8.8 Hz, 2 H, Ph). C NMR (75 MHz, CDCl3) δ ppm 38.9 (1 C, CH2), 63.3 (1 C,
CH2(OH)), 117.7 (1 C, Ph), 117.8 (2 C, Ph), 120.4 (2 C, Ph), 124.2 (q, J = 271.5 Hz, 1 C, CF3), 125.1 (1 C,
Ph), 127.0 (2 C, Ph), 130.0 (1 C, Ph), 141.1 (1 C, Ph), 155.9 (1 C, Ph), 160.3 (1 C, Ph). Then, 17c was
oxidized by PCC (0.20 g, 0.92 mmol) in DCM (4.6 mL) to give aldehyde 18c (C15H11F3O2, 0.12 g, 0.43
mmol).
5-Methyl-1-(1-phenethylpiperidin-4-yl)pyrimidine-2,4(1H,3H)-dione (21a). Following the general
procedure B, phenylacetaldehyde (36 mg, 0.30 mmol), 28 (0.10 g, 0.30 mmol) and sodium
triacetoxyborohydride (0.13 g, 0.61 mmol) in dichloroethane (10 mL) afforded the BOM-protected
intermediate, which was deprotected with TFA (5.0 mL) in the presence of triethylsilane (5.0 mL) at
1
73 °C for 4 h to give the 21a (eluent system: 5% MeOH in DCM, 53 mg, 0.17 mmol, 56% yield). H
NMR (300 MHz, DMSO-d6) δ ppm 1.53–1.93 (m, 7 H, 5-CH3, piperdyl-3-yl, piperidyl-5-yl), 2.00–2.16
(m, 2 H, piperidyl-2a-yl, piperidyl-6a-yl), 2.57 (d, J = 8.2 Hz, 2 H, CH2N), 2.66–2.82 (m, 2 H, PhCH2),
3.06 (d, J = 10.8 Hz, 2 H, piperidyl-2b-yl, piperidyl-6b-yl), 4.16–4.36 (m, 1 H, piperidyl-4-yl), 7.10–7.37
13
(m, 5 H, Ph), 7.63 (s, 1 H, H-6), 11.19 (s, 1 H, NH). C NMR (75 MHz, DMSO-d6) δ ppm 12.0 (1 C, 5-
CH3), 29.9 (2 C, piperdyl-3-yl, piperidyl-5-yl), 33.0 (1 C, PhCH2), 52.4 (2 C, piperidyl-2-yl, piperidyl-
6-yl), 52.6 (1 C, piperidyl-4-yl), 59.3 (1 C, CH2N), 108.9 (1 C, C-5), 125.8 (1 C, Ph), 128.2 (2 C, Ph), 128.6
+
(2 C, Ph), 137.7 (1 C, C-6), 140.4 (1 C, Ph), 150.8 (1 C, C-2), 163.7 (1 C, C-4). HRMS (ESI): m/z [M + H]
Calcd. for [C18H23N3O2 + H] 314.1863, found 314.1855.
+
1-(1-(2-([1,1’-Biphenyl]-4-yl)ethyl)piperidin-4-yl)-5-methylpyrimidine-2,4(1H,3H)-dione
(21b).
Following the general procedure B, 6 (60 mg, 0.30 mmol), 28 (0.10 g, 0.30 mmol) and sodium
triacetoxyborohydride (0.13 g, 0.61 mmol) in dichloroethane (10 mL) afforded the BOM-protected
intermediate, which was deprotected with TFA (5.0 mL) in the presence of triethylsilane (5.0 mL) at
1
73 °C for 4 h to give the 21b (eluent system: 5% MeOH in DCM, 39 mg, 0.10 mmol, 33% yield). H
NMR (400 MHz, DMSO-d6) δ ppm 1.72–1.93 (m, 5 H, piperdyl-3a-yl, piperidyl-5a-yl, 5-CH3), 1.98–
2.20 (m, 2 H, piperdyl-3b-yl, piperidyl-5b-yl), 2.89–3.04 (m, 2 H, PhCH2), 3.26–3.61 (m, 4 H, piperidyl-
2-yl, piperidyl-6-yl), 4.39–4.53 (m, 1 H, piperidyl-4-yl), 7.33–7.40 (m, 3 H, Ph), 7.46 (t, J = 7.6 Hz, 2 H,
13
Ph), 7.59–7.71 (m, 5 H, H-6, Ph), 11.30 (s, 1 H, NH), 2 H (CH2N) could not be observed. C NMR (101
MHz, DMSO-d6) δ ppm 12.1 (1 C, 5-CH3), 27.7 (2 C, piperdyl-3-yl, piperidyl-5-yl), 29.9 (1 C, PhCH2),
51.4 (3 C, piperidyl-2-yl, piperidyl-6-yl, piperidyl-4-yl), 109.1 (1 C, C-5), 126.6 (2 C, Ph), 126.8 (2 C,
Ph), 127.4 (1 C, Ph), 128.9 (2 C, Ph), 129.3 (2 C, Ph), 137.5 (3 C, C-6, Ph), 139.9 (1 C, Ph), 150.8 (1 C, C-
+
2), 163.7 (1 C, C-4), C (CH2N) could not be observed. HRMS (ESI): m/z [M + H] Calcd. for [C24H27N3O2
+
+ H] 390.2176, found 390.2186.
5-Methyl-1-(1-(2-phenoxyphenethyl)piperidin-4-yl)pyrimidine-2,4(1H,3H)-dione (21c). Following the
general procedure B, 12a (64 mg, 0.30 mmol), 28 (0.10 g, 0.30 mmol) and sodium
triacetoxyborohydride (0.13 g, 0.61 mmol) in dichloroethane (10 mL) afforded the BOM-protected
intermediate, which was deprotected with TFA (5.0 mL) in the presence of triethylsilane (5.0 mL) at
1
73 °C for 4 h to give the 21c (eluent system: 5% MeOH in DCM, 40 mg, 0.098 mmol, 32% yield). H
NMR (300 MHz, DMSO-d6) δ ppm 1.52–1.62 (m, 2 H, piperdyl-3a-yl, piperidyl-5a-yl), 1.68–1.84 (m, 5
H, 5-CH3, piperdyl-3b-yl, piperidyl-5b-yl), 1.92–2.04 (m, 2 H, piperidyl-2a-yl, piperidyl-6a-yl), 2.50–
2.55 (m, 2 H, CH2N), 2.64–2.75 (m, 2 H, PhCH2), 2.92 (d, J = 11.1 Hz, 2 H, piperidyl-2b-yl, piperidyl-
6b-yl), 4.12–4.26 (m, 1 H, piperidyl-4-yl), 6.85–6.92 (m, 3 H, Ph), 7.02–7.15 (m, 2 H, Ph), 7.17–7.26 (m,
13
1 H, Ph), 7.29–7.38 (m, 3 H, Ph), 7.57 (d, J = 1.2 Hz, 1 H, H-6), 11.16 (s, 1 H, NH). C NMR (75 MHz,
DMSO-d6) δ ppm 12.0 (1 C, 5-CH3), 27.3 (1 C, PhCH2), 29.9 (2 C, piperdyl-3-yl, piperidyl-5-yl), 52.3 (2
C, piperidyl-2-yl, piperidyl-6-yl), 52.3 (1 C, piperidyl-4-yl), 57.9 (1 C, CH2N), 108.9 (1 C, C-5), 117.1 (2
C, Ph), 119.8 (1 C, Ph), 122.6 (1 C, Ph), 124.2 (1 C, Ph), 127.7 (1 C, Ph), 129.9 (2 C, Ph), 131.1 (1 C, Ph),

Molecules 2020, 25, 2805
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131.8 (1 C, Ph), 137.6 (1 C, C-6), 150.8 (1 C, C-2), 153.8 (1 C, Ph), 157.6 (1 C, Ph), 163.6 (1 C, C-4). HRMS
+
+
(ESI): m/z [M + H] Calcd. for [C24H27N3O3 + H] 406.2125, found 406.2133.
5-Methyl-1-(1-(4-phenoxyphenethyl)piperidin-4-yl)pyrimidine-2,4(1H,3H)-dione (21e). Following the
general procedure B, 12c (64 mg, 0.30 mmol), 28 (0.10 g, 0.30 mmol) and sodium triacetoxyborohydride
(0.13 g, 0.61 mmol) in dichloroethane (10 mL) afforded the BOM-protected intermediate, which was
deprotected with TFA (5.0 mL) in the presence of triethylsilane (5.0 mL) at 73 °C for 4 h to give the
1
21e (eluent system: 5% MeOH in DCM, 65 mg, 0.16 mmol, 53% yield). H NMR (300 MHz, DMSO-d6)
δ ppm 1.57–1.93 (m, 7 H, 5-CH3, piperdyl-3-yl, piperidyl-5-yl), 1.97–2.16 (m, 2 H, piperidyl-2a-yl,
piperidyl-6a-yl), 2.54 (d, J = 7.3 Hz, 2 H, CH2N), 2.64–2.77 (m, 2 H, PhCH2), 3.04 (d, J = 11.1 Hz, 2 H,
piperidyl-2b-yl, piperidyl-6b-yl), 4.19–4.29 (m, 1 H, piperidyl-4-yl), 6.87–6.98 (m, 4 H, Ph), 7.04–7.13
(m, 1 H, Ph), 7.18–7.26 (m, 2 H, Ph), 7.29–7.41 (m, 2 H, Ph), 7.60 (d, J = 0.9 Hz, 1 H, H-6), 11.17 (s, 1 H,
13
NH). C NMR (75 MHz, DMSO-d6) δ ppm 12.0 (1 C, 5-CH3), 29.9 (2 C, piperdyl-3-yl, piperidyl-5-yl),
32.2 (1 C, PhCH2), 52.4 (2 C, piperidyl-2-yl, piperidyl-6-yl), 52.6 (1 C, piperidyl-4-yl), 59.3 (1 C, CH2N),
108.9 (1 C, C-5), 118.2 (2 C, Ph), 118.7 (2 C, Ph), 123.1 (1 C, Ph), 130.0 (2 C, Ph), 130.1 (2 C, Ph), 135.6 (1
C, Ph), 137.7 (1 C, C-6), 150.8 (1 C, C-2), 154.6 (1 C, Ph), 157.0 (1 C, Ph), 163.7 (1 C, C-4). HRMS (ESI):
+
+
m/z [M + H] Calcd. for [C24H27N3O3 + H] 406.2125, found 406.2124.
5-Methyl-1-(1-(3-(p-tolyloxy)phenethyl)piperidin-4-yl)pyrimidine-2,4(1H,3H)-dione (21f). Following
the general procedure B, 12d (69 mg, 0.30 mmol), 28 (0.10 g, 0.30 mmol) and sodium
triacetoxyborohydride (0.13 g, 0.61 mmol) in dichloroethane (10 mL) afforded the BOM-protected
intermediate, which was deprotected with TFA (5.0 mL) in the presence of triethylsilane (5.0 mL) at
1
73 °C for 4 h to give the 21f (eluent system: 5% MeOH in DCM, 40 mg, 0.095 mmol, 31% yield). H
NMR (400 MHz, DMSO-d6) δ ppm 1.64 (d, J = 10.6 Hz, 2 H, piperdyl-3a-yl, piperidyl-5a-yl), 1.73 - 1.87
(m, 5 H, 5-CH3, piperdyl-3b-yl, piperidyl-5b-yl), 2.05 (t, J = 11.1 Hz, 2 H, piperidyl-2a-yl, piperidyl-
6a-yl), 2.28 (s, 3 H, PhCH3), 2.54 (d, J = 8.4 Hz, 2 H, CH2N), 2.72 (t, J = 7.5 Hz, 2 H, PhCH2), 3.02 (d, J =
11.5 Hz, 2 H, piperidyl-2b-yl, piperidyl-6b-yl), 4.19–4.29 (m, 1 H, piperidyl-4-yl), 6.77 (d, J = 8.1 Hz, 1
H, Ph), 6.87 (s, 1 H, Ph), 6.90 (d, J = 8.3 Hz, 2 H, Ph), 6.98 (d, J = 7.6 Hz, 1 H, Ph), 7.19 (d, J = 8.4 Hz, 2
13
H, Ph), 7.26 (t, J = 7.8 Hz, 1 H, Ph), 7.61 (s, 1 H, H-6), 11.20 (s, 1 H, NH). C NMR (101 MHz, DMSO-
d6) δ ppm 12.0 (1 C, 5-CH3), 20.2 (1 C, PhCH3), 30.0 (2 C, piperdyl-3-yl, piperidyl-5-yl), 32.8 (1 C,
PhCH2), 52.4 (2 C, piperidyl-2-yl, piperidyl-6-yl), 52.5 (1 C, piperidyl-4-yl), 59.0 (1 C, CH2N), 108.9 (1
C, C-5), 115.5 (1 C, Ph), 118.4 (1 C, Ph), 118.8 (2 C, Ph), 123.4 (1 C, Ph), 129.7 (1 C, Ph), 130.3 (2 C, Ph),
132.5 (1 C, Ph), 137.7 (1 C, C-6), 142.7 (1 C, Ph), 150.8 (1 C, C-2), 154.2 (1 C, Ph), 157.1 (1 C, Ph), 163.7
+
+
(1 C, C-4). HRMS (ESI): m/z [M + H] Calcd. for [C25H29N3O3 + H] 420.2282, found 420.2286.
1-(1-(3-(3,4-Dichlorophenoxy)phenethyl)piperidin-4-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (21g).
Following the general procedure B, 12e (85 mg, 0.30 mmol), 28 (0.10 g, 0.30 mmol) and sodium
triacetoxyborohydride (0.13 g, 0.61 mmol) in dichloroethane (10 mL) afforded the BOM-protected
intermediate, which was deprotected with TFA (5.0 mL) in the presence of triethylsilane (5.0 mL) at
1
73 °C for 4 h to give the 21g (eluent system: 5% MeOH in DCM, 56 mg, 0.12 mmol, 39% yield). H
NMR (400 MHz, DMSO-d6) δ ppm 1.79 (s, 3 H, 5-CH3), 1.91–2.06 (m, 2 H, piperdyl-3a-yl, piperidyl-
5a-yl), 2.10–2.19 (m, 2 H, piperdyl-3b-yl, piperidyl-5b-yl), 2.96–3.08 (m, 2 H, PhCH2), 3.09–3.22 (m, 2
H, piperidyl-2a-yl, piperidyl-6a-yl), 3.25–3.37 (m, 2 H, CH2N), 3.56–3.73 (m, 2 H, piperidyl-2b-yl,
piperidyl-6b-yl), 4.46–4.59 (m, 1 H, piperidyl-4-yl), 7.02 (dd, J = 8.9, 2.9 Hz, 2 H, Ph), 7.06 (br. s., 1 H,
Ph), 7.15 (d, J = 7.3 Hz, 1 H, Ph), 7.30 (d, J = 2.8 Hz, 1 H, Ph), 7.34–7.46 (m, 2 H, H-6, Ph), 7.65 (d, J = 8.9
13
Hz, 1 H, Ph), 11.34 (s, 1 H, NH). C NMR (101 MHz, DMSO-d6) δ ppm 12.2 (1 C, 5-CH3), 27.1 (2 C,
piperdyl-3-yl, piperidyl-5-yl), 29.4 (1 C, PhCH2), 50.5 (1 C, piperidyl-4-yl), 51.2 (2 C, piperidyl-2-yl,
piperidyl-6-yl), 56.3 (1 C, CH2N), 109.3 (1 C, C-5), 117.8 (1 C, Ph), 118.7 (1 C, Ph), 119.5 (1 C, Ph), 120.2
(1 C, Ph), 125.16 (d, J = 43.5 Hz, 1 C, Ph), 130.6 (1 C, Ph), 131.6 (2 C, Ph), 132.0 (1 C, Ph), 137.4 (1 C, C-
6), 139.6 (1 C, Ph), 150.7 (1 C, C-2), 155.8 (1 C, Ph), 156.4 (1 C, Ph), 163.7 (1 C, C-4). HRMS (ESI): m/z
+
+
[M + H] Calcd. for [C24H25Cl2N3O3 + H] 474.1346, found 474.1333.
1-(1-(3-(4-Chlorophenoxy)phenethyl)piperidin-4-yl)-5-methylpyrimidine-2,4(1H,3H)-dione
(21h).
Following the general procedure B, 12f (75 mg, 0.30 mmol), 28 (0.10 g, 0.30 mmol) and sodium
triacetoxyborohydride (0.13 g, 0.61 mmol) in dichloroethane (10 mL) afforded the BOM-protected

Molecules 2020, 25, 2805
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intermediate, which was deprotected with TFA (5.0 mL) in the presence of triethylsilane (5.0 mL) at
1
73 °C for 4 h to give the 21h (eluent system: 5% MeOH in DCM, 40 mg, 0.091 mmol, 30% yield). H
NMR (300 MHz, DMSO-d6) δ ppm 1.57–1.67 (m, 2 H, piperdyl-3a-yl, piperidyl-5a-yl), 1.68–1.87 (m, 5
H, 5-CH3, piperdyl-3b-yl, piperidyl-5b-yl), 2.03 (t, J = 12.3 Hz, 2 H, piperidyl-2a-yl, piperidyl-6a-yl),
2.54 (d, J = 8.5 Hz, 2 H, CH2N), 2.72 (t, J = 7.4 Hz, 2 H, PhCH2), 3.00 (d, J = 12.0 Hz, 2 H, piperidyl-2b-
yl, piperidyl-6b-yl), 4.22 (tt, J = 12.1, 4.5 Hz, 1 H, piperidyl-4-yl), 6.83 (dd, J = 7.8, 1.9 Hz, 1 H, Ph), 6.92
(s, 1 H, Ph), 6.96–7.06 (m, 3 H, Ph), 7.24–7.33 (m, 1 H, Ph), 7.38–7.43 (m, 2 H, Ph), 7.59 (s, 1 H, H-6),
13
11.17 (s, 1 H, NH). C NMR (75 MHz, DMSO-d6) δ ppm 12.0 (1 C, 5-CH3), 30.0 (2 C, piperdyl-3-yl,
piperidyl-5-yl), 32.7 (1 C, PhCH2), 52.4 (2 C, piperidyl-2-yl, piperidyl-6-yl), 52.5 (1 C, piperidyl-4-yl),
59.0 (1 C, CH2N), 108.9 (1 C, C-5), 116.3 (1 C, Ph), 119.2 (1 C, Ph), 120.0 (2 C, Ph), 124.3 (1 C, Ph), 126.9
(1 C, Ph), 129.8 (2 C, Ph), 129.9 (1 C, Ph), 137.6 (1 C, C-6), 143.0 (1 C, Ph), 150.8 (1 C, C-2), 155.8 (1 C,
+
+
Ph), 156.1 (1 C, Ph), 163.7 (1 C, C-4). HRMS (ESI): m/z [M + H] Calcd. for [C24H26ClN3O3 + H] 440.1736,
found 440.1750.
1-(1-(3-(4-Methoxyphenoxy)phenethyl)piperidin-4-yl)-5-methylpyrimidine-2,4(1H,3H)-dione
(21i).
Following the general procedure B, 12g (74 mg, 0.30 mmol), 28 (0.10 g, 0.30 mmol) and sodium
triacetoxyborohydride (0.13 g, 0.61 mmol) in dichloroethane (10 mL) afforded the BOM-protected
intermediate, which was deprotected with TFA (5.0 mL) in the presence of triethylsilane (5.0 mL) at
1
73 °C for 4 h to give the 21i (eluent system: 5% MeOH in DCM, 40 mg, 0.092 mmol, 30% yield). H
NMR (400 MHz, DMSO-d6) δ ppm 1.65 (d, J = 10.6 Hz, 2 H, piperdyl-3a-yl, piperidyl-5a-yl), 1.74–1.87
(m, 5 H, piperdyl-3b-yl, piperidyl-5b-yl, 5-CH3), 2.05 (t, J = 11.3 Hz, 2 H, piperidyl-2a-yl, piperidyl-
6a-yl), 2.52–2.56 (m, 2 H, CH2N), 2.70 (t, J = 8.3 Hz, 2 H, PhCH2), 3.02 (d, J = 11.4 Hz, 2 H, piperidyl-
2b-yl, piperidyl-6b-yl), 3.74 (s, 3 H, OCH3), 4.19–4.29 (m, 1 H, piperidyl-4-yl), 6.72 (d, J = 8.1 Hz, 1 H,
Ph), 6.83 (s, 1 H, Ph), 6.92–7.01 (m, 5 H, Ph), 7.24 (t, J = 7.9 Hz, 1 H, Ph), 7.61 (s, 1 H, H-6), 11.20 (s, 1
13
H, NH). C NMR (101 MHz, DMSO-d6) δ ppm 12.0 (1 C, 5-CH3), 30.0 (2 C, piperdyl-3-yl, piperidyl-
5-yl), 32.8 (1 C, PhCH2), 52.4 (2 C, piperidyl-2-yl, piperidyl-6-yl), 52.5 (1 C, piperidyl-4-yl), 55.4 (1 C,
OCH3), 59.0 (1 C, CH2N), 108.9 (1 C, C-5), 114.7 (1 C, Ph), 115.0 (2 C, Ph), 117.6 (1 C, Ph), 120.6 (2 C,
Ph), 123.0 (1 C, Ph), 129.6 (1 C, Ph), 137.7 (1 C, C-6), 142.6 (1 C, Ph), 149.4 (1 C, Ph), 150.8 (1 C, C-2),
+
+
155.5 (1 C, Ph), 157.9 (1 C, Ph), 163.7 (1 C, C-4). HRMS (ESI): m/z [M + H] Calcd. for [C25H29N3O4 + H]
436.2231, found 436.2234.
1-(1-(3-(3-Chlorophenoxy)phenethyl)piperidin-4-yl)-5-methylpyrimidine-2,4(1H,3H)-dione
(21j).
Following the general procedure B, 12h (75 mg, 0.30 mmol), 28 (0.10 g, 0.30 mmol) and sodium
triacetoxyborohydride (0.13 g, 0.61 mmol) in dichloroethane (10 mL) afforded the BOM-protected
intermediate, which was deprotected with TFA (5.0 mL) in the presence of triethylsilane (5.0 mL) at
1
73 °C for 4 h to give the 21j (eluent system: 5% MeOH in DCM, 63 mg, 0.14 mmol, 47% yield). H
NMR (400 MHz, DMSO-d6) δ ppm 1.65 (d, J = 9.8 Hz, 2 H, piperdyl-3a-yl, piperidyl-5a-yl), 1.71–1.89
(m, 5 H, piperdyl-3b-yl, piperidyl-5b-yl, 5-CH3), 2.06 (t, J = 11.0 Hz, 2 H, piperidyl-2a-yl, piperidyl-
6a-yl), 2.53–2.62 (m, 2 H, CH2N), 2.69–2.79 (m, 2 H, PhCH2), 3.03 (d, J = 11.6 Hz, 2 H, piperidyl-2b-yl,
piperidyl-6b-yl), 4.17–4.31 (m, 1 H, piperidyl-4-yl), 6.88 (dd, J = 8.1, 1.8 Hz, 1 H, Ph), 6.92–7.00 (m, 2
H, Ph), 7.02 (t, J = 2.2 Hz, 1 H, Ph), 7.08 (d, J = 7.8 Hz, 1 H, Ph), 7.15–7.21 (m, 1 H, Ph), 7.33 (t, J = 7.8
13
Hz, 1 H, Ph), 7.37–7.43 (m, 1 H, Ph), 7.60 (d, J = 0.9 Hz, 1 H, H-6), 11.20 (s, 1 H, NH). C NMR (101
MHz, DMSO-d6) δ ppm 12.0 (1 C, 5-CH3), 30.0 (2 C, piperdyl-3-yl, piperidyl-5-yl), 32.7 (1 C, PhCH2),
52.4 (3 C, piperidyl-2-yl, piperidyl-6-yl, piperidyl-4-yl), 58.9 (1 C, CH2N), 108.9 (1 C, C-5), 116.7 (1 C,
Ph), 116.8 (1 C, Ph), 118.0 (1 C, Ph), 119.6 (1 C, Ph), 123.0 (1 C, Ph), 124.7 (1 C, Ph), 130.0 (1 C, Ph),
131.4 (1 C, Ph), 133.9 (1 C, Ph), 137.6 (1 C, C-6), 143.1 (1 C, Ph), 150.8 (1 C, C-2), 155.5 (1 C, Ph), 158.1
+
+
(1 C, Ph), 163.7 (1 C, C-4). HRMS (ESI): m/z [M + H] Calcd. for [C24H26ClN3O3 + H] 440.1736, found
440.1740.
4-(3-(2-(4-(5-Methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-
yl)ethyl)phenoxy)benzonitrile (21k). Following the general procedure B, 18a (72 mg, 0.30 mmol), 28 (0.10
g, 0.30 mmol) and sodium triacetoxyborohydride (0.13 g, 0.61 mmol) in dichloroethane (10 mL)
afforded the BOM-protected intermediate, which was deprotected with TFA (5.0 mL) in the presence
of triethylsilane (5.0 mL) at 73 °C for 4 h to give the 21k (eluent system: 5% MeOH in DCM, 50 mg,

Molecules 2020, 25, 2805
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1
0.12 mmol, 43% yield). H NMR (400 MHz, DMSO-d6) δ ppm 1.79 (s, 3 H, 5-CH3), 2.00 (d, J = 10.8 Hz,
2 H, piperdyl-3a-yl, piperidyl-5a-yl), 2.21 (d, J = 11.6 Hz, 2 H, piperdyl-3b-yl, piperidyl-5b-yl), 3.05
(br. s., 2 H, PhCH2), 3.15 (br. s., 2 H, piperidyl-2a-yl, piperidyl-6a-yl), 3.32 (s, 2 H, CH2N), 3.66 (br. s.,
2 H, piperidyl-2b-yl, piperidyl-6b-yl), 4.44–4.63 (m, 1 H, piperidyl-4-yl), 7.03–7.16 (m, 4 H, Ph), 7.21
(d, J = 6.6 Hz, 1 H, Ph), 7.35–7.53 (m, 2 H, Ph, H-6), 7.86 (d, J = 8.4 Hz, 2 H, Ph), 11.32 (br. s., 1 H, NH).
13
C NMR (101 MHz, DMSO-d6) δ ppm 12.2 (1 C, 5-CH3), 27.1 (2 C, piperdyl-3-yl, piperidyl-5-yl), 29.3
(1 C, PhCH2), 50.3 (1 C, piperidyl-4-yl), 51.2 (2 C, piperidyl-2-yl, piperidyl-6-yl), 56.2 (1 C, CH2N),
105.2 (1 C, Ph), 109.3 (1 C, C-5), 118.1 (2 C, Ph), 118.7 (2 C, Ph, CN), 120.5 (1 C, Ph), 125.6 (1 C, Ph),
130.7 (1 C, Ph), 134.7 (2 C, Ph), 137.3 (1 C, C-6), 139.7 (1 C, Ph), 150.7 (1 C, C-2), 154.7 (1 C, Ph), 161.0
+
+
(1 C, Ph), 163.6 (1 C. C-4). HRMS (ESI): m/z [M + H] Calcd. for [C25H26N4O3 + H] 431.2078, found
431.2085.
5-Methyl-1-(1-(3-(4-nitrophenoxy)phenethyl)piperidin-4-yl)pyrimidine-2,4(1H,3H)-dione
(21l).
Following the general procedure B, 18b (78 mg, 0.30 mmol), 28 (0.10 g, 0.30 mmol) and sodium
triacetoxyborohydride (0.13 g, 0.61 mmol) in dichloroethane (10 mL) afforded the BOM-protected
intermediate, which was deprotected with TFA (5.0 mL) in the presence of triethylsilane (5.0 mL) at
1
73 °C for 4 h to give the 21l (eluent system: 5% MeOH in DCM, 67 mg, 0.15 mmol, 40% yield). H
NMR (400 MHz, DMSO-d6) δ ppm 1.79 (s, 3 H, 5-CH3), 1.93–2.06 (m, 2 H, piperdyl-3a-yl, piperidyl-
5a-yl), 2.20 (d, J = 11.6 Hz, 2 H, piperdyl-3b-yl, piperidyl-5b-yl), 2.98–3.08 (m, 2 H, PhCH2), 3.09–3.24
(m, 2 H, piperidyl-2a-yl, piperidyl-6a-yl), 3.41–3.55 (m, 2 H, CH2N), 3.67 (d, J = 10.6 Hz, 2 H, piperidyl-
2b-yl, piperidyl-6b-yl), 4.44–4.62 (m, 1 H, piperidyl-4-yl), 7.09–7.17 (m, 4 H, Ph), 7.24 (d, J = 7.5 Hz, 1
H, Ph), 7.38 (s, 1 H, H-6), 7.49 (t, J = 7.8 Hz, 1 H, Ph), 8.27 (d, J = 9.1 Hz, 2 H, Ph), 11.32 (s, 1 H, NH).
13
C NMR (101 MHz, DMSO-d6) δ ppm 12.2 (1 C, 5-CH3), 27.0 (2 C, piperdyl-3-yl, piperidyl-5-yl), 29.3
(1 C, PhCH2), 50.5 (1 C, piperidyl-4-yl), 51.2 (2 C, piperidyl-2-yl, piperidyl-6-yl), 56.2 (1 C, CH2N),
109.3 (1 C, C-5), 117.5 (2 C, Ph), 118.9 (1 C, Ph), 120.7 (1 C, Ph), 125.9 (1 C, Ph), 126.2 (2 C, Ph), 130.8 (1
C, Ph), 137.3 (1 C, C-6), 139.4 (1 C, Ph), 142.3 (1 C, Ph), 150.7 (1 C, C-2), 154.5 (1 C, Ph), 162.7 (1 C, Ph),
+
+
163.6 (1 C, C-4). HRMS (ESI): m/z [M + H] Calcd. for [C24H26N4O5 + H] 451.1976, found 451.1971.
5-Methyl-1-(1-(3-(4-(trifluoromethyl)phenoxy)phenethyl)piperidin-4-yl)pyrimidine-2,4(1H,3H)-dione
(21m). Following the general procedure B, 18c (85 mg, 0.30 mmol), 28 (0.10 g, 0.30 mmol) and sodium
triacetoxyborohydride (0.13 g, 0.61 mmol) in dichloroethane (10 mL) afforded the BOM-protected
intermediate, which was deprotected with TFA (5.0 mL) in the presence of triethylsilane (5.0 mL) at
1
73 °C for 4 h to give the 21m (eluent system: 5% MeOH in DCM, 64 mg, 0.14 mmol, 44% yield). H
NMR (400 MHz, DMSO-d6) δ ppm 1.79 (s, 3 H, 5-CH3), 2.00 (d, J = 12.0 Hz, 2 H, piperdyl-3a-yl,
piperidyl-5a-yl), 2.20 (d, J = 11.4 Hz, 2 H, piperdyl-3b-yl, piperidyl-5b-yl), 2.99 - 3.08 (m, 2 H, PhCH2),
3.16 (d, J = 9.5 Hz, 2 H, piperidyl-2a-yl, piperidyl-6a-yl), 3.39–3.55 (m, 2 H, CH2N), 3.67 (d, J = 10.6 Hz,
2 H, piperidyl-2b-yl, piperidyl-6b-yl), 4.47–4.59 (m, 1 H, piperidyl-4-yl), 7.05 (d, J = 7.9 Hz, 1 H, Ph),
7.10–7.20 (m, 4 H, Ph), 7.39 (br. s., 1 H, H-6), 7.44 (t, J = 7.8 Hz, 1 H, Ph), 7.75 (d, J = 8.5 Hz, 2 H, Ph),
19
13
11.32 (s, 1 H, NH). F NMR (377 MHz, DMSO-d6) δ ppm -60.16 (s, 3 F). C NMR (101 MHz, DMSO-
d6) δ ppm 12.2 (1 C, 5-CH3), 27.1 (2 C, piperdyl-3-yl, piperidyl-5-yl), 29.3 (1 C, PhCH2), 50.4 (1 C,
piperidyl-4-yl), 51.1 (2 C, piperidyl-2-yl, piperidyl-6-yl), 56.3 (1 C, CH2N), 109.3 (1 C, C-5), 118.0 (2 C,
Ph), 118.4 (1 C, Ph), 120.2 (1 C, Ph), 123.20 (q, J = 32.6 Hz, 1 C, Ph), 124.27 (q, J = 271.3 Hz, 1 C, CF3),
125.2 (1 C, Ph), 127.5 (2 C, Ph), 130.6 (1 C, Ph), 137.3 (1 C, C-6), 139.6 (1 C, Ph), 150.7 (1 C, C-2), 155.2
+
+
(1 C, Ph), 160.3 (1 C, Ph), 163.6 (1 C, C-4). HRMS (ESI): m/z [M + H] Calcd. for [C25H26F3N3O3 + H]
474.1999, found 474.1989.
1-(1-(3-(Benzyloxy)phenethyl)piperidin-4-yl)-5-methylpyridine-2,4(1H,3H)-dione (21n). Following
the general procedure B, 15a (69 mg, 0.30 mmol), 28 (0.10 g, 0.30 mmol) and sodium
triacetoxyborohydride (0.13 g, 0.61 mmol) in dichloroethane (10 mL) afforded the BOM-protected
intermediate, which was deprotected with TFA (5.0 mL) in the presence of triethylsilane (5.0 mL) at
1
73 °C for 4 h to give the 21n (eluent system: 5% MeOH in DCM, 58 mg, 0.14 mmol, 46% yield). H
NMR (400 MHz, DMSO-d6) δ ppm 1.66 (d, J = 10.8 Hz, 2 H, piperdyl-3a-yl, piperidyl-5a-yl), 1.74–1.90
(m, 5 H, 5-CH3, piperdyl-3b-yl, piperidyl-5b-yl), 2.07 (t, J = 11.3 Hz, 2 H, piperidyl-2a-yl, piperidyl-
6a-yl), 2.55 (t, J = 9.0 Hz, 2 H, CH2N), 2.70 (t, J = 7.4 Hz, 2 H, PhCH2), 3.04 (d, J = 11.3 Hz, 2 H, piperidyl-

Molecules 2020, 25, 2805
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2b-yl, piperidyl-6b-yl), 4.20–4.31 (m, 1 H, piperidyl-4-yl), 5.08 (s, 2 H, (Ph)CH2O), 6.82 (t, J = 7.8 Hz, 2
H, Ph), 6.90 (s, 1 H, Ph), 7.19 (t, J = 7.9 Hz, 1 H, Ph), 7.30–7.35 (m, 1 H, Ph), 7.39 (t, J = 7.4 Hz, 2 H, Ph),
13
7.43–7.48 (m, 2 H, Ph), 7.63 (s, 1 H, H-6), 11.20 (s, 1 H, NH). C NMR (101 MHz, DMSO-d6) δ ppm 12.0
(1 C, 5-CH3), 30.0 (2 C, piperdyl-3-yl, piperidyl-5-yl), 33.0 (1 C, PhCH2), 52.4 (2 C, piperidyl-2-yl,
piperidyl-6-yl), 52.4 (1 C, piperidyl-4-yl), 59.2 (1 C, CH2N), 69.0 (1 C, (Ph)CH2O), 108.9 (1 C, C-5), 112.1
(1 C, Ph), 115.2 (1 C, Ph), 121.1 (1 C, Ph), 127.7 (2 C, Ph), 127.8 (1 C, Ph), 128.4 (2 C, Ph), 129.2 (1 C,
Ph), 137.2 (1 C, Ph), 137.7 (1 C, C-6), 142.0 (1 C, Ph), 150.8 (1 C, C-2), 158.4 (1 C, Ph), 163.7 (1 C, C-4).
+
+
HRMS (ESI): m/z [M + H] Calcd. for [C25H29N3O3 + H] 420.2282, found 420.2277.
1-(1-(3-((2-Chlorobenzyl)oxy)phenethyl)piperidin-4-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (21o).
Following the general procedure B, 15b (79 mg, 0.30 mmol), 28 (0.10 g, 0.30 mmol) and sodium
triacetoxyborohydride (0.13 g, 0.61 mmol) in dichloroethane (10 mL) afforded the BOM-protected
intermediate, which was deprotected with TFA (5.0 mL) in the presence of triethylsilane (5.0 mL) at
1
73 °C for 4 h to give the 21o (eluent system: 5% MeOH in DCM, 90 mg, 0.20 mmol, 65% yield). H
NMR (400 MHz, DMSO-d6) δ ppm 1.73–2.23 (m, 7 H, piperdyl-3-yl, piperidyl-5-yl, 5-CH3), 2.92 (br.
s., 2 H, PhCH2), 3.21–3.67(m, 4 H, piperidyl-2-yl, piperidyl-6-yl), 4.35–4.68 (m, 1 H, piperidyl-4-yl),
5.12 (s, 2 H, (Ph)CH2O), 6.85–6.93 (m, 2 H, Ph), 6.97 (br. s., 1 H, Ph), 7.26 (t, J = 7.8 Hz, 1 H, Ph), 7.36–
13
7.49 (m, 4 H, Ph), 7.52 (s, 1 H, H-6), 11.31 (br. s., 1 H, NH), 2 H (CH2N) could not be observed. C
NMR (101 MHz, DMSO-d6) δ ppm 12.2 (1 C, 5-CH3), 27.0 (2 C, piperdyl-3-yl, piperidyl-5-yl), 30.2 (1
C, PhCH2), 50.4 (1 C, piperidyl-4-yl), 51.5 (2 C, piperidyl-2-yl, piperidyl-6-yl), 68.2 (1 C, (Ph)CH2O),
109.2 (1 C, C-5), 112.7 (1 C, Ph), 115.6 (1 C, Ph), 121.4 (1 C, Ph), 126.2 (2 C, Ph), 127.3 (1 C, Ph), 127.8 (1
C, Ph), 129.7 (1 C, Ph), 130.4 (1 C, Ph), 133.1 (1 C, Ph), 137.5 (1 C, C-6), 139.7 (1 C, Ph), 150,8 (1 C, C-2),
+
158.3 (1 C, Ph), 163.7 (1 C, C-4), C (CH2N) could not be observed. HRMS (ESI): m/z [M + H] Calcd.
+
for [C25H28ClN3O3 + H] 454.1892, found 454.1902.
1-(1-(3-((3,4-Dichlorobenzyl)oxy)phenethyl)piperidin-4-yl)-5-methylpyrimidine-2,4(1H,3H)-dione
(21p). Following the general procedure B, 15c (90 mg, 0.30 mmol), 28 (0.10 g, 0.30 mmol) and sodium
triacetoxyborohydride (0.13 g, 0.61 mmol) in dichloroethane (10 mL) afforded the BOM-protected
intermediate, which was deprotected with TFA (5.0 mL) in the presence of triethylsilane (5.0 mL) at
1
73 °C for 4 h to give the 21p (eluent system: 5% MeOH in DCM, 55 mg, 0.11 mmol, 37% yield). H
NMR (400 MHz, DMSO-d6) δ ppm 1.79 (s, 3 H, 5-CH3), 1.92–2.06 (m, 2 H, piperdyl-3a-yl, piperidyl-
5a-yl), 2.08–2.24 (m, 2 H, piperdyl-3b-yl, piperidyl-5b-yl), 2.85–3.02 (m, 2 H, PhCH2), 3.06–3.22 (m, 2
H, piperidyl-2a-yl, piperidyl-6a-yl), 3.24–3.34 (m, 2 H, CH2N), 3.65 (br. s., 2 H, piperidyl-2b-yl,
piperidyl-6b-yl), 4.45–4.59 (m, 1 H, piperidyl-4-yl), 5.13 (s, 2 H, (Ph)CH2O), 6.85–6.95 (m, 2 H, Ph),
6.98 (br. s., 1 H, Ph), 7.28 (t, J = 7.9 Hz, 1 H, Ph), 7.38–7.48 (m, 2 H, H-6, Ph), 7.68 (d, J = 8.3 Hz, 1 H,
13
Ph), 7.73 (d, J = 1.5 Hz, 1 H, Ph), 11.33 (s, 1 H, NH). C NMR (101 MHz, DMSO-d6) δ ppm 12.2 (1 C,
5-CH3), 27.2 (2 C, piperdyl-3-yl, piperidyl-5-yl), 29.7 (1 C, PhCH2), 50.6 (1 C, piperidyl-4-yl), 51.2 (2 C,
piperidyl-2-yl, piperidyl-6-yl), 56.5 (1 C, CH2N), 67.5 (1 C, (Ph)CH2O), 109.3 (1 C, C-5), 112.8 (1 C, Ph),
115.5 (1 C, Ph), 121.5 (1 C, Ph), 127.8 (1 C, Ph), 129.4 (1 C, Ph), 129.8 (1 C, Ph), 130.4 (1 C, Ph), 130.7 (1
C, Ph), 131.1 (1 C, Ph), 137.4 (1 C, C-6), 138.3 (2 C, Ph), 150.7 (1 C, C-2), 158.2 (1 C, Ph), 163.7 (1 C, C-
+
+
4). HRMS (ESI): m/z [M + H] Calcd. for [C25H27Cl2N3O3 + H] 488.1502, found 488.1518.
1-(1-(3-((3-Chlorobenzyl)oxy)phenethyl)piperidin-4-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (21q).
Following the general procedure B, 15d (79 mg, 0.30 mmol), 28 (0.10 g, 0.30 mmol) and sodium
triacetoxyborohydride (0.13 g, 0.61 mmol) in dichloroethane (10 mL) afforded the BOM-protected
intermediate, which was deprotected with TFA (5.0 mL) in the presence of triethylsilane (5.0 mL) at
1
73 °C for 4 h to give the 21q (eluent system: 5% MeOH in DCM, 38 mg, 0.084 mmol, 28% yield). H
NMR (400 MHz, DMSO-d6) δ ppm 1.78 (s, 5 H, 5-CH3, piperdyl-3a-yl, piperidyl-5a-yl), 2.00 (br. s., 2
H, piperdyl-3b-yl, piperidyl-5b-yl), 2.84 (br. s., 2 H, PhCH2), 4.31–4.46 (m, 1 H, piperidyl-4-yl), 5.12 (s,
2 H, (Ph)CH2O), 6.87 (t, J = 8.3 Hz, 2 H, Ph), 6.94 (br.s., 1 H, Ph), 7.23 (t, J = 7.8 Hz, 1 H, Ph), 7.37–7.47
(m, 3 H, Ph), 7.50–7.59 (m, 2 H, Ph, H-6), 11.26 (s, 1 H, NH), 2 H (CH2N) and 4 H (piperidyl-2-yl,
13
piperidyl-6-yl) could not be observed. C NMR (101 MHz, DMSO-d6) δ ppm 12.1 (1 C, 5-CH3), 28.6
(2 C, piperdyl-3-yl, piperidyl-5-yl), 31.3 (1 C, PhCH2), 51.5 (1 C, piperidyl-4-yl), 51.7 (2 C, piperidyl-
2-yl, piperidyl-6-yl), 68.1 (1 C, (Ph)CH2O), 109.0 (1 C, C-5), 112.5 (1 C, Ph), 115.4 (1 C, Ph), 121.3 (1 C,

Molecules 2020, 25, 2805
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Ph), 126.1 (1 C, Ph), 127.3 (1 C, Ph), 127.7 (1 C, Ph), 129.5 (1 C, Ph), 130.4 (1 C, Ph), 133.1 (1 C, Ph),
137.5 (1 C, C-6), 139.7 (1 C, Ph), 150.8 (1 C, C-2), 158.2 (1 C, Ph), 163.7 (1 C, C-4), C (CH2N) and C (Ph)
+
+
could not be observed. HRMS (ESI): m/z [M + H] Calcd. for [C25H28ClN3O3 + H] 454.1892, found
454.1899.
5-Methyl-1-(1-(3-phenoxyphenethyl)piperidin-3-yl)pyrimidine-2,4(1H,3H)-dione (23). Following the
general procedure B, 12b (65 mg, 0.30 mmol), 29 (0.10 g, 0.30 mmol) and sodium triacetoxyborohydride
(0.13 g, 0.61 mmol) in dichloroethane (10 mL) afforded the BOM-protected intermediate, which was
deprotected with TFA (5.0 mL) in the presence of triethylsilane (5.0 mL) at 73 °C for 4 h to give the 23
1
(eluent system: 5% MeOH in DCM, 57 mg, 0.14 mmol, 46% yield). H NMR (400 MHz, DMSO-d6) δ
ppm 1.43–1.56 (m, 1 H, piperdyl-5a-yl), 1.59–1.80 (m, 6 H, 5-CH3, piperdyl-4-yl, piperdyl-5b-yl), 2.07
(t, J = 12.9 Hz, 1 H, piperdyl-6a-yl), 2.22 (t, J = 10.3 Hz, 1 H, piperdyl-2a-yl), 2.56 (t, J = 4.6 Hz, 2 H,
CH2N), 2.68–2.81 (m, 3 H, piperdyl-6b-yl, PhCH2), 2.82–2.90 (m, 1 H, piperdyl-2b-yl), 4.31–4.43 (m, 1
H, piperdyl-3-yl), 6.81 (dd, J = 8.1, 1.8 Hz, 1 H, Ph), 6.90 (s, 1 H, Ph), 6.95–7.04 (m, 3 H, Ph), 7.12 (t, J =
7.6 Hz, 1 H, Ph), 7.28 (t, J = 7.8 Hz, 1 H, Ph), 7.38 (t, J = 7.9 Hz, 2 H, Ph), 7.68 (s, 1 H, H-6), 11.23 (s, 1
13
H, NH). C NMR (101 MHz, DMSO-d6) δ ppm 12.0 (1 C, 5-CH3), 23.9 (1 C, piperdyl-5-yl), 28.1 (1 C,
piperdyl-4-yl), 32.3 (1 C, PhCH2), 51.0 (1 C, piperdyl-3-yl), 52.2 (1 C, piperdyl-6-yl), 56.5 (1 C, piperdyl-
2-yl), 59.2 (1 C, CH2N), 108.6 (1 C, C-5), 116.1 (1 C, Ph), 118.5 (2 C, Ph), 119.0 (1 C, Ph), 123.3 (1 C, Ph),
123.9 (1 C, Ph), 129.7 (1 C, Ph), 130.0 (2 C, Ph), 138.0 (1 C, C-6), 142.7 (1 C, Ph), 150.8 (1 C, C-2), 156.5
+
+
(1 C, Ph), 156.7 (1 C, Ph), 163.7 (1 C, C-4). HRMS (ESI): m/z [M + H] Calcd. for [C24H27N3O3 + H]
406.2125, found 406.2125.
5-Methyl-1-(1-(2-(3-phenoxyphenyl)acetyl)piperidin-4-yl)pyrimidine-2,4(1H,3H)-dione (26). To
a
solution of 10b (0.2 g, 0.82 mmol) in MeOH (5.0 mL) was added 1M NaOH (5.0 mL), the resulting
reaction mixture was stirred at 50 °C for 2 h. After cooling to room temperature, the reaction mixture
was treated with 1N aq. HCl to pH 2–3. The generated white precipitate was collected through
filtration and dried in vacuo. The intermediate (0.17 g, 0.74 mmol), 28 (0.26 g, 0.79 mmol), EDC HCl
(0.29 g, 1.5 mmol) and 4-dimethylaminopyridine (DMAP) (9.1 mg, 7.4 μmol) were dissolved in DCM
(30 mL), and the reaction mixture was stirred at room temperature for overnight to afford BOM
protected intermediate, which was deprotected with Pd/C (10%), H2 and HCOOH (0.5%) in i-
propanol/H2O (10/1 mL) [30] to give 26 (eluent system: 5% MeOH in DCM, 45 mg, 0.11 mmol, 13%
1
yield). H NMR (300 MHz, DMSO-d6) δ ppm 1.54–1.83 (m, 7 H, 5-CH3, piperdyl-3-yl, piperidyl-5-yl),
2.53–2.67 (m, 1 H, piperidyl-2/6-yl), 3.07 (t, J = 10.8 Hz, 1 H, piperidyl-2/6-yl), 3.59–3.85 (m, 2 H,
COCH2), 4.05 (d, J = 13.5 Hz, 1 H, piperidyl-2/6-yl), 4.43–4.56 (m, 2 H, piperidyl-4-yl, piperidyl-2/6-
yl), 6.82–6.91 (m, 2 H, Ph), 6.95–7.03 (m, 3 H, Ph), 7.08–7.15 (m, 1 H, Ph), 7.31 (t, J = 7.8 Hz, 1 H, Ph),
13
7.34–7.41 (m, 2 H, Ph), 7.53 (d, J = 0.9 Hz, 1 H, H-6), 11.20 (s, 1 H, NH). C NMR (101 MHz, DMSO-
d6) δ ppm 12.1 (1 C, 5-CH3), 29.7 (1 C, piperidyl-3/5-yl), 30.5 (1 C, piperidyl-3/5-yl), 38.9 (1 C,
(CO)CH2), 40.8 (1 C, piperidyl-2/6-yl), 44.7 (1 C, piperidyl-2/6-yl), 52.1 (1 C, piperidyl-4-yl), 109.1 (1
C, C-5), 116.7 (1 C, Ph), 118.7 (2 C, Ph), 119.5 (1 C, Ph), 123.5 (1 C, Ph), 124.4 (1 C, Ph), 129.9 (1 C, Ph),
130.1 (2 C, Ph), 137.7 (1 C, Ph), 138.2 (1 C, C-6), 150.8 (1 C, C-2), 156.6 (1 C, Ph), 156.7 (1 C, Ph), 163.8
+
+
(1 C, C-4), 168.5 (1 C, CO(CH2)). HRMS (ESI): m/z [M + H] Calcd. for [C24H25N3O4 + H] 420.1918,
found 420.1925.
1-(3-Phenoxyphenethyl)-4-phenylpiperidine (27). To a solution of 12b (0.12 g, 0.56 mmol) and 4-
phenylpiperidine (0.14 g, 0.87 mmol) in dichloroethane (10 mL) was added sodium
triacetoxyborohydride (0.24 g, 1.1 mmol), the resulting mixture was stirred at room temperature for
overnight. The reaction mixture was diluted with DCM, and extracted with sat. NaHCO3 and brine.
The collected organic layer was dried, concentrated and purified to give 27 (58 mg, 0.16 mmol, 29%
1
yield). H NMR (300 MHz, CDCl3) δ ppm 1.91 (br. s., 4 H, piperdyl-3-yl, piperidyl-5-yl), 2.12 - 2.31
(m, 2 H, piperidyl-2a-yl, piperidyl-6a-yl), 2.46–2.62 (m, 1 H, piperidyl-4-yl), 2.65–2.77 (m, 2 H, CH2N),
2.83–2.97 (m, 2 H, PhCH2), 3.20 (d, J = 10.8 Hz, 2 H, piperidyl-2b-yl, piperidyl-6b-yl), 6.82 - 6.95 (m, 2
13
H, Ph), 6.96–7.07 (m, 3 H, Ph), 7.12 (t, J = 7.3 Hz, 1 H, Ph), 7.17–7.46 (m, 8 H, Ph). C NMR (75 MHz,
CDCl3) δ ppm 33.0 (2 C, piperdyl-3-yl, piperidyl-5-l), 33.2 (1 C, PhCH2), 42.4 (1 C, piperidyl-4-yl), 54.1
(2 C, piperidyl-2-yl, piperidyl-6-yl), 60.3 (1 C, CH2N), 116.5 (1 C, Ph), 118.8 (1 C, Ph), 119.1 (1 C, Ph),

Molecules 2020, 25, 2805
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123.2 (1 C, Ph), 123.6 (1 C, Ph), 126.2 (1 C, Ph), 126.8 (3 C, Ph), 128.4 (2 C, Ph), 129.6 (1 C, Ph), 129.7 (2
+
C, Ph), 142.1 (1 C, Ph), 145.9 (1 C, Ph), 157.1 (1 C, Ph), 157.8 (1 C, Ph). HRMS (ESI): m/z [M + H] Calcd.
+
for [C25H27NO + H] 358.2166, found 358.2164.
4. Conclusions
Starting from the earlier reported compound 3, 19 analogs were synthesized and evaluated for the inhibitory
potencies of both MtbTMPK and M. tuberculosis (H37Rv) in vitro growths. Selected substituents on the terminal
phenyl ring slightly improved the inhibitory potency. Surprisingly, the 3-Cl analog (21j) was three-fold more
potent than compound 3 as the MtbTMPK inhibitor. Substitution of the distal phenyl ring of 3 and 21n afforded
analogs with superior whole cell antimycobacterial activity compared to 3. These results provide possible
directions for further investigations of MtbTMPK inhibitors as antituberculosis agents.
Supplementary Materials: The following are available online at www.mdpi.com/1420-3049/25/12/2805/s1,
Figure S1–S43: NMR spectra of final compounds.
Author Contributions: Chemistry and writing—original draft preparation, Y.J.; conceptualization, S.V.C.;
methodology, H.E.F., G.C., H.M.-L. and H.I.M.B.; writing—review and editing, F.H., H.M.-L., H.I.M.B. and
S.V.C. and supervision, S.V.C. and M.D.P.R. All authors discussed the results and contributed to the final
manuscript. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by the China Scholarship Council (grant number 201607060021) and, in part,
by the Intramural Research Program of the NIAID, NIH. S.V.C. thanks the Hercules Foundation (project
AUGE/17/22 “Pharm-NMR”).
Conflicts of Interest: The authors declare no conflicts of interest.
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Sample Availability: Samples of the compounds 21a–21q, 23, 26 and 27 are available from the authors.
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