Synthesis of phenyl- and pyridyl-substituted benzyloxybenzaldehydes by suzuki-miyaura coupling reactions

Article abstract of DOI:10.2174/1570180816666181106123809

Background: Aryl-methoxybenzaldehydes substituted in various positions may serve as valuable starting materials for the synthesis of biologically active compounds. Methods: Biaryl-methoxybenzaldehydes and pyridyl-aryl-methoxybenzaldehydes were synthesized

Full text of DOI:10.2174/1570180816666181106123809

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Letters in Drug Design & Discovery, 2019, 16, 1-10
1
RESEARCH ARTICLE
Synthesis of Phenyl- and Pyridyl-substituted Benzyloxybenzaldehydes by
Suzuki-Miyaura Coupling Reactions
Hedvig Bölcskeia,b,*, Andrea Német-Hanzelika, Zsófia Dubrovaya, Viktor Hádaa and György Keglevichb
b
aGedeon Richter Plc. Budapest X., Gyömrői út 30-32., Budapest 10. Pf.27. H-1475, Hungary; Department of Organic
Chemistry and Technology, Budapest University of Technology and Economics H-1521Budapest, Hungary
Abstract: Background: Aryl-methoxybenzaldehydes substituted in various positions may serve as
valuable starting materials for the synthesis of biologically active compounds.
Methods: Biaryl-methoxybenzaldehydes and pyridyl-aryl-methoxy-benzaldehydes were synthe-
sized by the Suzuki-Miyaura cross-coupling reactions as intermediates of potential drug substances.
Three different catalytic approaches were compared. The classical Suzuki method utilising
tetrakis(triphenylphosphine)palladium and sodium ethoxide, the protocol applying palladium ace-
A R T I C L E H I S T O R Y
tate and tri(o-tolyl)phosphine and the method using tetrakis(triphenylphosphine)palladium and ce-
sium carbonate, were studied.
Received: April 19, 2018
Revised: October 22, 2018
Accepted: November 01, 2018
Results: The selected boronic acids were the classical phenylboronic acid, as well as 4-pyridine-
and 3-pyridineboronic acids. 26 New biaryl-methoxybenzaldehydes or pyridyl-phenyl-
methoxybenzaldehydes have been synthesized, which may be intermediates for pharmaceutically
DOI:
10.2174/1570180816666181106123809
active compounds.
Conclusion: The method of Anderson et al. was preferred, because it provides satisfactory results
in all cases.
Keywords: Suzuki-Miyaura cross-coupling reaction, biaryl-oxyaryl-aldehyde, Phenylboronic acid, Pyridineboronic acids,
tetrakis(triphenylphosphine)palladium, Palladium acetate.
1. INTRODUCTION
compound:
4-[(3’-phenyl)-phenylmethoxy]-benzaldehyde
was prepared by the coupling reaction of 3-bromo-
benzlyalcohol and 4-hydroxy-benzaldehyde followed by a
Suzuki-Miyaura coupling with boronic acid. The thia-
zoidine-2,4-dione derivative of 4-[(3’-phenyl)- phen-
ylmethoxy]-benzaldehyde showed peroxisome proliferator
activated receptor (PPAR)γ/free fatty acid used the above
mentioned 4-[(3’-phenyl)-phenylmethoxy]-benzaldehyde in
synthesis of 5-benzylidenerhodanides with receptor (FFAR1)
dual agonist activity [4]. Panetta et al. used the above men-
tioned 4-[(3’-phenyl)-phenylmethoxy]- benzaldehyde in the
synthesis of 5-benzylidenerhodanides with cathepsin D in-
hibitory activity [5]. 4-[(4-phenylphenyl)methoxy]benzal-
dehyde seemed to be a useful intermediate in the synthesis of
the corresponding thiazolidinedione with 15-hydroxypro-
staglandin dehydrogenase (15-PGDH) inhibitory activity
(Fig. 1) [6, 7].
The benzyloxy-benzyl moiety is a frequent building
block in biologically active compounds. These moieties can
be introduced utilising the corresponding benzyloxy-
benzaldehydes, e.g. the voltage gated sodium channel block-
ers Safinamide and Ralfinamide (Fig. 1). Both compounds
were obtained by the reductive amination of the correspond-
ing fluor-benzyloxybenzaldehyde using alanin-amide [1]. 3-
[(4’-Phenyl)-phenylmethoxy]-benzaldehyde was synthesized
by the alkylation of 3-hydroxy-benzaldehyde with 4-
biphenyl-methylbromide (K2CO3, DMF), and it served as an
intermediate in the synthesis of orally active 5-lipoxygenase
inhibitors [2]. 4-hydroxy-benzaldehyde was alkylated with
2-phenyl-phenylmethylbromide (PTBD, acetonitrile) and the
4-[(2’-phenyl)-phenylmethoxy]-benzaldehyde obtained was
subjected to reductive amination to result in N’-[4-biphenyl-
2-yl-methoxy´benzyl]-N.N-dimethyl-propane-1,3-diamine,
which is a dual-acting diamine antiplasmodial and chloro-
quine resistance modulating agent [3]. The analogous
Our task was to synthesize a compound library of various
aryl- and heteroaryl-substituted benzyloxybenzaldehydes.
The synthesis of these compounds was planned by the Su-
zuki-Miyaura coupling reaction of the halogenated (iodi-
nated) benzyloxybenzaldehyde and aryl- or heteroaryl-
boronic acid (Scheme 1). The bioisosteric replacement of a
phenyl group into a pyridine ring may be advantageous [8].
*Address correspondence to this author at the Department of Organic Chem-
istry and Technology, Budapest University of Technology and Economics,
H-1521, Budapest, Hungary; Tel: +36-1-463-2208 Fax: +36-1-463-3648;
E-mail: h.bolcskei@mail.bme.hu
1570-1808/19 $58.00+.00
©2019 Bentham Science Publishers

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Letters in Drug Design & Discovery, 2019, Vol. 16, No. 0
Bölcskei et al.
NH2
NH2
F
N
N
H
H
O
F
O
O
O
Ralfinamide
Safinamide
N
N
N
H
N
O
O
OH
Antiplasmodial and chloroquine resistance
modulating agent
5-Lipoxygenase inhibitor
O
S
NH
S
O
O
NH
O
O
O
15-PGDH) inhibitor
PPAR /FFAR1 dual agonist
Fig. (1). Biologically active compounds with aryl-benzyloxy-benzyl moiety.
Thus, we used phenylboronic, pyridine-3-boronic and pyri-
dine-4-boronic acids.
(aryl-aryl) bond by the reaction of an organic boronic deriva-
tive (regarding boronic acid or boronate ester) and a halogen
compound (RX) in presence of a Pd catalyst. The reaction
conditions described by Suzuki in his original paper [10]
were throughly studied and modified [11]. Since then, many
applications have been published and reviewed [12, 13
Sometimes a simple Pd/C [14] or Pd(OAc)2 [15] seemed to
be a successful catalyst. Several new difficult and more effi-
cient Pd catalysts were developed [16, 17]. The Suzuki-
Miyaura coupling method may also be performed by the
high throughput parallel synthesis under microwave condi-
tions [18], or by continuous flow accomplishment [19]. This
approach was applied in course of the synthesis of several
drugs on a large industral scale (e.g. the nonpeptide angio-
tensin II antagonist, Losartan [20] and other “sartans” [21] or
the triple reuptake inhibitor, GSK-1360707) [22]).
It was expected, that the iodo-derivatives will be more
active in Suzuki-Miyaura coupling reactions than the bromi-
nated phenyl derivatives. Our starting materials, the iodo-
benzyloxybenzaldehydes were prepared by the alkylation of
hydroxybenzaldehydes with iodo-benzylbromides in acetone
or acetonitrile at a higher temperature in the presence of po-
tassium-carbonate [9] (Scheme 1).
The second step of our reaction sequence was the cou-
pling reaction of the iodo derivatives. Among the transition
metal-catalyzed cross couplings, the Suzuki-Miyaura reac-
tion is a very useful tool for the construction of a new C-C
3'
O
4'
2'
1'
O
Ar
ArB(OH)2
I
O
O
2. EXPERIMENTAL SECTION
5'
6'
1
Analysis of the reaction products was carried out by
HPLC-UV-MS before the column chromatographic purifica-
tion. The applied method was the following:
2a-i Ar = phenyl-
1a 2-[(2-Iodophenyl)methoxy]benzaldehyde
3a-i Ar = pyridine-3-yl-
1b 2-[(3-Iodophenyl)methoxy]benzaldehyde
4a-i Ar = pyridine-4-yl-
1c 2-[(4-Iodophenyl)methoxy]benzaldehyde
1d 3-[(2-Iodophenyl)methoxy]benzaldehyde
1e 3-[(3-Iodophenyl)methoxy]benzaldehyde
1f 3-[(4-Iodophenyl)methoxy]benzaldehyde
1g 4-[(2-Iodophenyl)methoxy]benzaldehyde
1h 4-[(3-Iodophenyl)methoxy]benzaldehyde
1i 4-[(4-Iodophenyl)methoxy]benzaldehyde
2.1. LC-MS Analysis
LC-MS experiments were carried out on an Agilent 1200
liquid chromatography system coupled with an 6120 MSD
(Agilent Technologies, Palo Alto, CA, USA), equipped with
a vacuum degasser, a binary pump, an autosampler, a col-
umn temperature controller and a diode array detector.
Scheme 1. Suzuki cross-coupling reaction.

Synthesis of Phenyl- and Pyridyl-substituted Benzyloxybenzaldehydes
Letters in Drug Design & Discovery, 2019, Vol. 16, No. 0
3
Analysis was at 40 °C on an Kinetex C18 column (5 cm x 2.1
mm, 2.6 µm) (Phenomenex, Torrance, CA, USA) with a
mobile phase flow rate of 0.9 mL/min. Composition of elu-
ent A was 0.1% (v/v) trifluoroacetic acid in water (pH 1.9),
eluent B was the mixture of acetonitrile and water in 95:5
(v/v) with 0.1% (v/v) trifluoroacetic acid. A fast linear gradi-
ent of 0-100% B was applied at a range of 0-4 min, then
100% B held for 3 min. This was followed by a 2 min
equilibration period prior to the next injection. The injection
volume was set at 1 µL and the sample concentration was
uniformly 1.0 mg/mL (solved in DMSO). The amount of
reaction products (%) were calculated from peak areas
(mAU*s) registered at 240 nm. Confirmation of compound
identity was based on detection of the appropriate protonated
molecular ion [M+H]+ or the [M+Na]+ adduct ion. The MSD
operating parameters were as follows: positive ionization
mode, scan spectra from m/z 100 to 800, drying gas tempera-
ture 350 °C, nitrogen flow rate 12 L/min, nebuliser pressure
60 psi, quadrupole temperature 100 °C, capillary voltage
3000 V and fragmentor voltage 50 V.
corresponding aryl boronic acid (0.33 mmol) and 2.0 M solu-
tion of sodium ethoxide in ethanol (0.3 ml). The reaction was
purged with argon, and then tetrakis(triphenylphosphine)
palladium (0.0035g, 0.003 mmol) was added. The reaction
was carried out at 80°C for 6 h with stirring under argon at-
mosphere. Then, the mixture was cooled to room tempera-
ture, filtered through a 1 cm thick Celite layer, which was
washed with dichloromethane,. The solvent was removed
under reduced pressure. The residue was purified by column
chromatography using Kieselgel 60 (0.040-0.063 mm) to
give the corresponding compound as an oil.
2.3.2. General Procedure for the Suzuki Cross Coupling
Using Method N by Novák et al. [15]
A stirred mixture of aryl iodide (0.500 g, 1.48 mmol) in
dimethoxyethane (13.3 mL/100 mg aryl halide) was treated
with the corresponding aryl boronic acid (1.93 mmol), palla-
dium acetate (0.018 g, 0.08 mmol), tri(o-tolyl)phosphine
(0.045 g, 0.148 mmol) and aqueous tripotassium phosphate
(3.35 mmol, 0.97 mmol/1mL H2O). The mixture was purged
with argon. The reaction was carried out at 110°C for 20-72
h with stirring under argon atmosphere. Then, the mixture
was cooled to room temperature, and filtered through a 1 cm
thick Celite layer, which was washed with dichloromethane.
The solvent was removed under reduced pressure. The resi-
due was purified by column chromatography, using Kiesel-
gel 60 (0.040-0.063 mm) to give the corresponding com-
pound as an oil.
2.2. NMR Spectroscopy
NMR measurements were performed on a Varian 800
MHz NMR spectrometer equipped with a 1H{13C/15N}
Triple Resonance 13C Enhanced Salt Tolerant Cold Probe
operating at 800 MHz for 1H and 201 MHz for 13C, and a
Varian 500 MHz NMR spectrometer equipped with a 1H
{13C/15N} 5 mm PFG Triple Resonance 13C Enhanced
Cold Probe operating at 500 MHz for 1H and 125 MHz for
13C and Varian NMR System 400 Spectrometer equipped
with 5 mm 400 MHz ATB/PFG Probe operating at 400 MHz
for 1H and 101 MHz for 13C, using DMSO-d6 as solvent.
1H chemical shifts were referenced to TMS and 13C chemi-
cal shifts were referenced to solvent. The experiments were
performed at 298 K. 1H-1H, direct 1H-13C, long-range 1H-
13C scalar spin-spin connectivities were established from 1D
1H, 13C, 2D gHSQCAD, zTOCSY and gHMBCAD NMR
experiments. All pulse sequences were applied by using the
standard spectrometer software package.
2.3.3. General Procedure for Suzuki Cross Coupling Using
Method A by Anderson et al. [25]
A stirred mixture of aryl iodide (0.500 g, 1.48 mmol) in
dimethylformamide (2.0 mL/100 mg aryl halide) was treated
with the corresponding aryl boronic acid (2.21 mmol) and
2.0 M aqueous cesium carbonate (4.44 mmol/ 2,2 mL H2O).
The reaction was purged with argon and then tetrakis
(triphenylphosphine)palladium (0.086 g, 0.074 mmol) was
added. The reaction was carried out at 80°C for 21 h with
stirring under argon atmosphere. Then, the mixture was
cooled to room temperature, and was filtered through a 1 cm
thick Celite layer, which was washed with dichloromethane,
and then filtered through Kieselgel 60 (0.040-0.063 mm),
washed with dichloromethane. The solvent was removed
under reduced pressure. The residue was purified by column
chromatography, using Kieselgel 60 (0.040-0.063 mm) to
give the corresonding compound as an oil.
2.3. Mass Spectroscopy
High-resolution MS measurements were carried out on a
Thermo LTQ FT Ultra mass spectrometer using ESI (elec-
trospray) ionization technique (3.0 kV source voltage, 280°C
capillary temperature, solvent: MeOH:H2O 1:1 + 1 V/V% cc.
AcOH). The protonated molecular ion peaks were frag-
mented by CID at a normalized collision energy of 35%. The
relative abundance values of the fragment ions in the MS-
MS spectra are given in brackets.
A part of the high-resolution MS measurements was per-
formed on a Finnigan MAT 95XP mass spectrometer using
EI (electron impact) ionization technique (70 eV, 220°C
source temperature, perfluorokerosene or perfluorotributyl
amine reference compounds). The relative abundance values
of the fragment ions in the MS spectra are given in brackets.
5"
5"
4"
6"
6"
4"
3"
3'
1"
O
2'
1'
3'
N
O
2'
4'
5'
3"
4'
5'
2"
1"
1
4
2"
O
2
1
6
O
2
6
6'
1'
6'
3
5
3
5
2.3.1. General Procedure for the Suzuki Cross Coupling
Using Method S by Suzuki et al. [10]
4
Fig. (2). Numbering of the compounds 2-4.
A stirred mixture of aryl iodide (0.110 g, 0.30 mmol) in
toluene (2.0 mL/100 mg aryl halide) was treated with the

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Letters in Drug Design & Discovery, 2019, Vol. 16, No. 0
Bölcskei et al.
2.3.3.1. 2-[(2-phenylphenyl)methoxy]benzaldehyde (2a)
2.3.3.6. 3-[(4-phenylphenyl)methoxy]benzaldehyde (2f)
Separated on a chromatographic column with acetoni-
trile: water 8:2 eluent. H NMR (500 MHz, DMSO): δ =
Separated on a chromatographic column with hexane:
ethyl acetate1:1 eluent. H NMR (400 MHz, DMSO): δ =
1
1
5.20 (s, 2H, OCH2), 7.04 (tt, 1H, J=7.5, 0.8 Hz, H-5), 7.09
(dd, 1H, J=8.5, 0.8 Hz, H-3), 7.32-7.38 (m, 1H, H-6’), 7.38-
7.44 (m, 5H, H-2”, H-3”, H-4”, H-5”, H-6”), 7.43-7.49 (m,
2H, H-4’, H-5’), 7.57 (ddd, 1H, J=8.5, 7.5, 1.8 Hz, H-4),
7.67 (dd, 1H, J=7.5, 1.8 Hz, H-6), 7.68-7.71 (m, 1H, H-3’),
10.13 (d, 1H, J= 0.8 Hz, CHO) ppm; MS-EI: m/z (%):
288(M+, 4), 167(100), 152(13). HRMS M: m/z 288.11490,
calculated value for C20H16O2: 288.11448 (delta: 1.5 ppm).
5.25 (s, 2H, OCH2), 7.34-7.42 (m, 2H, H-4, H-4”), 7.47 (m,
3H, H-3”, H-5”), 7.52-7.55 (m, 3H, H-5, H-6, H-2), 7.64 (dt,
1H, J= 7.1, 1.8 Hz, H-4’), 7.68 (m, 2H, H-2”, H-6”), 7.70
(m, 2H, H-3’, H-5’), 9.99 (s, 1H, CHO) ppm; 13C NMR (125
MHz, DMSO): δ = 69.1 (OCH2), 114.0 (C-2), 121.7 (C-4),
122.8 (C-6), 126.7 (C-2”, C-6”), 126.8 (C-3’, C-5’), 127.5
(C-4”), 128.3 (C-2’, C-6’), 129.0 (C-3”, C-5”), 130.5 (C-5),
135.8 (C-1’), 137.7 (C-1), 139.7 (C-1”), 139.9 (C-4’), 158.8
(C-3), 193.0 (CHO) ppm; MS-ESI: MS-MS of m/z 289
(M+H): m/z 167. HRMS M+H: m/z 289.12234, calculated
value for C20H17O2: 289.12231 (delta: 0.1 ppm). 2f is a
known compound, intermediate of a 5-lipoxigenase inhibitor.
Its spectral data have not been published [2].
2.3.3.2. 2-[(3-phenylphenyl)methoxy]benzaldehyde (2b)
Separated on a chromatographic column with n-heptane:
1
ethyl acetate 3:1 eluent. H NMR (400 MHz, DMSO): δ =
5.37 (s, 2H, OCH2), 7.11 (tt, 1H, J= 7.6, 0.8 Hz, H-5), 7.37
(dd, 1H, J= 8.3, 0.8 Hz, H-3), 7.39 (m, 1H, H-4”), 7.46-7.54
(m, 4H, H-5”, H-3”, H-5’, H-6’), 7.63-7.71 (m, 4H, H-4, H-
4’, H-6”, H-2”), 7.73 (dd, 1H, J= 7.6, 1.8 Hz, H-6), 7.82 (br,
1H, H-2’), 10.46 (d, 1H, J= 0.8 Hz, CHO) ppm; MS-EI: m/z
(%): 288(M+, 11), 167(100), 152(11). HRMS M: m/z
288.11447, calculated value for C20H16O2: 288.11448 (delta:
0.0 ppm).
2.3.3.7. 4-[(2-phenylphenyl)methoxy]benzaldehyde (2g)
1
Crystallized from hexane. H NMR (400 MHz, DMSO):
δ = 5.06 (s, 2H, OCH2), 7.07 (m, 2H, H-3, H-5), 7.34 (m,
1H, H-3’), 7.36 (m, 1H, H-4”), 7.40 (m, 3H, H-4’, H-2”, H-
6”), 7.41 (m, 2H, H-3”, H-5”), 7.45 (m, 1H, H-5’), 7.62 (m,
1H, H-6’), 7.83 (m, 2H, H-2, H-6), 9.85 (s, CHO) ppm; 13C
NMR (100 MHz, DMSO): δ = 68.2 (OCH2), 115.1 (C-3, C-
5), 127.4 (C-2”, C-6”), 127.7 (C-4”), 128.3 (C-5’), 128.6 (C-
4’), 128.9 (C-3”, C-5”), 129.8 (C-1), 129.9 (C-6’), 130.0 (C-
3’), 131.8 (C-2, C-6), 133.0 (C-1’), 139.9 (C-1”), 141.9 (C-
2’), 163.0 (C-4), 191.3 (CHO) ppm; m.p. 100-102 °C. MS-
EI: m/z (%): 288(M+, 1), 167(100), 152(11). HRMS M: m/z
288.11463, calculated value for C20H16O2: 288.11448 (delta:
0.5 ppm).
2.3.3.3. 2-[(4-phenylphenyl)methoxy]benzaldehyde (2c)
Separated on a chromatographic column with methyl tert-
1
butyl ether: cyclohexane 1:3 eluent. H NMR (500 MHz,
DMSO): δ = 5.35 (s, 2H, OCH2), 7.11 (tt, 1H, J= 7.5, 0.7 Hz,
H-5), 7.36 (dd, 1H, J= 8.4, 0.7 Hz, H-3), 7.38 (m, 1H, H-4”),
7.48 (m, 2H, H-5”, H-3”), 7.61 (m, 2H, H-6’, H-2’), 7.63-
7.75 (m, 5H, H-4, H-3’, H-5’, H-6”, H-2”), 7.73 (dd, 1H, J=
7.5, 1.8 Hz, H-6), 10.47 (d, 1H, J= 0.7 Hz, CHO) ppm; MS-
EI: m/z (%): 288(M+, 2), 167(100), 152(7). HRMS M: m/z
288.11486, calculated value for C20H16O2: 288.11448 (delta:
1.3 ppm).
2.3.3.8. 4-[(3-phenylphenyl)methoxy]benzaldehyde (2h)
Separated on a chromatographic column with hexane:
1
ethyl acetate 1:1 eluent. H NMR (800 MHz, DMSO): δ =
5.32 (s, 2H, OCH2), 7.25 (m, 2H, H-3, H-5), 7.39 (m, 1H, H-
4”), 7.48 (m, 2H, H-3”, H-5”), 7.48 (m, 2H, H-3”, H-5”),
7.51 (t, 1H, J= 7.6 Hz, H-5’), 7.65 (dt, 1H, J= 7.6, 1.6 Hz, H-
4’), 7.68 (m, H-2”, H-6”), 7.77 (t, 1H, J= 1.6 Hz, H-2’), 7.89
(m, H-2, H-6), 9.87 (s, CHO) ppm; 13C NMR (200 MHz,
DMSO): δ = 69.6 (OCH2), 115.3 (C-3, C-5), 126.2 (C-2’),
126.4 (C-4’), 126.7 (C-2”, C-6”), 126.9 (C-6’), 127.6 (C-4”),
129.0 (C-3”, C-5”), 129.2 (C-5’), 129.8 (C-1), 131.8 (C-2, C-
6), 137.0 (C-1’), 139.8 (C-1”), 140.4 (C-3’), 163.3 (C-4),
191.3 (CHO) ppm; m.p. 63-64 °C. MS- EI: m/z (%): 288(M+,
6), 167(100), 152(10). HRMS M: m/z 288.11444, calculated
value for C20H16O2: 288.11448 (delta: -0.1 ppm).
2.3.3.4. 3-[(2-phenylphenyl)methoxy]benzaldehyde (2d)
Separated on a chromatographic column with hexane:
acetone 3:1 eluent. 1H NMR (500 MHz, DMSO): δ = 4.98 (s,
2H, OCH2), 7.18 (ddd, 1H, J= 7.5, 2.7, 1.8 Hz, H-4), 7.28-
7.35 (m, 1H, H-2), 7.30 (m, 1H, H-6’), 7.33 (m, 1H, H-4”),
7.34-7.39 (m, 4H, H-2”, H-3”, H-5”, H-6”), 7.39-7.49 (m,
4H, H-4’, H-5’, H-5, H-6), 7.58 (m, 1H, H-3’), 9.88 (s, 1H,
CHO) ppm; MS-ESI: MS-MS of m/z 289 (M+H): m/z
167(100), 135(16). HRMS M+H: m/z 289.12252, calculated
value for C20H17O2: 289.12231 (delta: 0.7 ppm).
2.3.3.5. 3-[(3-phenylphenyl)methoxy]benzaldehyde (2e)
2.3.3.9. 4-[(4-phenylphenyl)methoxy]benzaldehyde (2i)
Separated on a chromatographic column with hexane:
1
Separated on a chromatographic column with hexane:
ethyl acetate 1:1 eluent and crystallized from dichloro-
ethyl acetate1:1 eluent. H NMR (500 MHz, DMSO): δ =
5.28 (s, 2H, OCH2), 7.36-7.43 (m, 2H, H-4, H-4”), 7.46-7.53
(m, 3H, H-6’, H-3”, H-5”), 7.54-7.58 (m, 3H, H-5, H-6, H-
2), 7.64 (dt, 1H, J= 7.1, 1.8 Hz H-4’), 7.68 (m, 2H, H-2”, H-
6”), 7.78 (s br, 1H, H-2’), 9.99 (s, 1H, CHO) ppm; 13C NMR
(125 MHz, DMSO): δ = 69.5 (OCH2), 114.0 (C-2), 121.7 (C-
4), 122.8 (C-6), 126.1 (C-2’), 126.3 (C-6’), 126.8 (C-4’, C-
2”, C-6”), 127.6 (C-4”), 129.0 (C-3”, C-5”), 129.2 (C-5’),
130.5 (C-5), 137.4 (C-1’), 137.7 (C-1), 139.9 (C-1”), 140.4
(C-3’), 158.9 (C-3), 193.0 (CHO) ppm; MS-ESI: MS-MS of
m/z 289 (M+H): m/z 167. HRMS M+H: m/z 289.12254, cal-
culated value for C20H17O2: 289.12231 (delta: 0.8 ppm).
1
methane: hexane. H NMR (400 MHz, DMSO): δ = 5.29 (s,
2H, OCH2), 7.24 (m, 2H, H-3, H-5), 7.37 (m, 1H, H-4”),
7.48 (m, 2H, H-3”, H-5”), 7.57 (m, 2H, H-2’, H-6’), 7.68 (m,
2H, H-2”, H-6”), 7.71 (m, 2H, H-3’, H-5’), 7.89 (m, 2H, H-
2, H-6), 9.88 (s, CHO) ppm; 13C NMR (125 MHz, DMSO): δ
= 69.4 (OCH2), 115.3 (C-3, C-5), 126.7 (C-2”, C-6”), 126.8
(C-3’, C-5’), 127.6 (C-4”), 128.5 (C-2’, C-6’), 129.0 (C-3”,
C-5”), 129.8 (C-1), 131.8 (C-2, C-6), 135.5 (C-1’), 139.7 (C-
1”), 139.9 (C-4’), 163.3 (C-4), 191.3 (CHO) ppm; m.p. 151-
156 °C. MS-EI: m/z (%): 288(M+, 1), 167(100), 152(7).

Synthesis of Phenyl- and Pyridyl-substituted Benzyloxybenzaldehydes
Letters in Drug Design & Discovery, 2019, Vol. 16, No. 0
5
HRMS M: m/z 288.11418, calculated value for C20H16O2:
288.11448 (delta: -1.0 ppm).
2.3.3.13. 3-{[2-(pyridin-3-yl)phenyl]methoxy}benzaldehyde
(3d)
2.3.3.10. 2-{[2-(pyridin-3-yl)phenyl]methoxy}benzaldehyde
(3a)
Separated on a chromatographic column with dichloro-
methane: methanol 20:1 eluent. 1H NMR (500 MHz,
DMSO): δ = 5.05 (s, 2H, OCH2), 7.23 (m, 1H, H-4), 7.36
(m, 1H, H-2), 7.40 (m, 1H, H-3’), 7.43 (ddd, J= 7.8, 4.8, 0.8
Hz, H-5”), 7.47-7.53 (m, 4H, H-5, H-6, H-4’, H-5’), 7.67 (m,
1H, H-6’), 7.87 (ddd, 1H, J=7.8, 2.3, 1.7 Hz, H-4), 8.56 (dd,
1H, J= 4.8 Hz, 1.7 Hz, H-6), 8.64 (dd, 1H, J=2.3, 0.8 Hz, H-
4”), 9.94 (s, 1H, CHO) ppm; MS-ESI: MS-MS of m/z 290:
m/z 168. HRMS M+H: m/z 290.11764, calculated value for
C19H16O2N: 290.11756 (delta: 0.3 ppm).
1H NMR (500 MHz, DMSO): δ = 5.23 (s, 2H, OCH2),
7.05 (tt, 1H, J=7.5, 0.8 Hz, H-5), 7.13 (dd, 1H, J=8.5, 0.8
Hz, H-3), 7.37-7.40 (m, 1H, H-3’), 7.43 (ddd, 1H, J=7.8, 4.8,
0.9 Hz, H-5”), 7.48-7.54 (m, 2H, H-4’, H-5’), 7.58 (ddd, 1H,
J=8.5, 7.5, 1.8 Hz, H-4), 7.66 (dd, 1H, J=7.5, 1.8 Hz, H-6),
7.71-7.75 (m, 1H, H-6’), 7.87 (ddd, 1H, , J=7.8, 2.4, 1.7 Hz,
H-4”), 8.55 (dd, 1H, , J=4.8, 1.7 Hz, H-6”), 8.64 (dd, 1H, ,
J=2.4, 0.9 Hz, H-2”), 10.08 (d, 1H, J= 0.8 Hz, CHO) ppm;
13C NMR (125 MHz, DMSO): δ = 68.4 (OCH2), 113.7 (C-3),
120.9 (C-5), 123.3 (C-5”), 124.3 (C-1), 127.8 (C-6), 128.4
(C-4’, C-5’), 130.0 (C-6’), 130.4 (C-3’), 133.7 (C-1’), 135.8
(C-3”), 136.1 (C-4”), 136.3 (C-4), 138.2 (C-2’), 148.5 (C-
6”), 148.9 (C-2”), 160.2 (C-2), 188.8 (CHO) ppm; M+H
(ESI): m/z 290.11773, calculated value for C19H16O2N:
290.11756 (delta: 0.6 ppm); MS-MS of m/z 290: m/z 168.
MS-ESI: MS-MS of m/z 290: m/z 168. HRMS M+H: m/z
290.11773, calculated value for C19H16O2N: 290.11756
(delta: 0.6 ppm).
2.3.3.14. 3-{[3-(pyridin-3-yl)phenyl]methoxy}benzaldehyde
(3e)
Separated on a chromatographic column with hexane:
1
dichloromethane : isopropyl alcohol 6:3:1 eluent. H NMR
(500 MHz, DMSO): δ = 5.29 (s, 2H, OCH2), 7.41 (dt, 1H, J=
6.9, 2.5 Hz, H-4), 7.50 (ddd, J= 7.9, 4.8, 0.8 Hz, H-5”), 7.53-
7.59 (m, 5H, H-2, H-5, H-6, H-5’, H-6’), 7.72 (m, 1H, H-4’),
7.86 (s br, 1H, H-2’), 8.10 (ddd, 1H, J=7.9, 2.4, 1.6 Hz, H-
4), 8.60 (dd, 1H, J= 4.8 Hz, 1.6 Hz, H-6), 8.91 (dd, 1H,
J=2.4, 0.8 Hz, H-4”), 9.99 (s, 1H, CHO) ppm; 13C NMR
(125 MHz, DMSO): δ = 69.3 (OCH2), 114.0 (C-2), 121.7 (C-
4), 122.8 (C-6), 123.9 (C-5”), 126.3 (C-2’), 126.5 (C-4’),
127.5 (C-6’), 129.4 (C-5’), 130.5 (C-5), 134.2 (C-4”), 135.3
(C-3”), 137.3 (C-3’), 137.7 (C-1, C-1’), 147.7 (C-2”), 148.6
(C-6”), 158.8 (C-3), 193.0 (CHO) ppm; MS-ESI: MS-MS
of m/z 290: m/z 169(100), 262(4). HRMS M+H: m/z 290.
11768, calculated value for C19H16O2N: 290.11756 (delta:
0.4 ppm).
2.3.3.11. 2-{[3-(pyridin-3-yl)phenyl]methoxy}benzaldehyde
(3b)
1H NMR (400 MHz, DMSO): δ = 5.38 (s, 2H, OCH2),
7.11 (tt, 1H, J= 7.6 Hz, 0.8 Hz, H-5), 7.36 (dd, 1H, J= 8.7
Hz, 0.8 Hz, H-3), 7.51 (ddd, 1H, J= 7.9 Hz, 4.8 Hz, 0.8 Hz,
H-5”), 7.55 (m, 1H, H-5’), 7.59 (dt, 1H, J= 7.7 Hz, 1.6 Hz,
H-6’), 7.67 (ddd, 1H, J= 8.7 Hz, 7.6 Hz, 1.8 Hz, H-4), 7.72
(m, 1H, H-4’), 7.74 (dd, 1H, J= 7.6 Hz, 1.8 Hz, H-6), 7.90 (t,
1H, J= 1.6 Hz, H-2’), 8.10 (ddd, 1H, J= 7.9 Hz, 2.5 Hz, 1.6
Hz, H-4”), 8.59 (dd, 1H, J= 4.8 Hz, 1.6 Hz, H-6”), 8.92 (dd,
1H, J= 2.5 Hz, 0.8 Hz, H-2”), 10.46 (d, 1H, J= 0.8 Hz, CHO)
ppm; 13C NMR (100 MHz, DMSO): δ = 69.7 (OCH2), 114.1
(C-3), 121.0 (C-5), 123.9 (C-5”), 124.6 (C-1), 126.1 (C-2’),
126.5 (C-4’), 127.9 (C-6), 127.3 (C-6’), 129.4 (C-5’), 134.2
(C-4”), 135.3 (C-3”), 136.3 (C-4), 137.3 (C-3’), 137.4 (C-
1’), 147.7 (C-2”), 148.6 (C-6”), 160.5 (C-2), 189.3 (CHO)
ppm; M+H (ESI): m/z 290.11773, calculated value for
C19H16O2N: 290.11756 (delta: 0.6 ppm); MS-MS m/z (%) =
290 (%): m/z 168. MS-EI: m/z (%): 289(M+, 7), 260(8),
168(100). HRMS M: m/z 289.11012, calculated value for
C19H15O2N: 289.10973 (delta: 1.3 ppm).
2.3.3.15. 3-{[4-(pyridin-3-yl)phenyl]methoxy}benzaldehyde
(3f)
Separated on a chromatographic column with hexane:
1
dichloromethane : isopropyl alcohol 6:3:1 eluent. H NMR
(500 MHz, DMSO): δ = 5.28 (s, 2H, OCH2), 7.40 (m, 1H, H-
4), 7.50 (ddd, 1H, J= 7.9, 4.8, 0.8 Hz, H-5”), 7.53-7.58 (m,
3H, H-2, H-5, H-6), 7.61 (m, 2H, H-2’, H-6’), 7.78 (m, 2H,
H-3’, H-5’), 8.10 (ddd, 1H, J=7.9, 2.4, 1.6 Hz, H-4”), 8.58
(dd, 1H, J= 4.8, 1.6 Hz, H-6”), 8.92 (dd, 1H, J=2.4, 0.8 Hz,
H-2”), 9.99 (s, 1H, CHO) ppm; 13C NMR (125 MHz,
DMSO): δ = 69.0 (OCH2), 113.9 (C-2), 121.7 (C-4), 122.8
(C-6), 123.9 (C-5”), 127.0 (C-3’, C-5’), 128.5 (C-2’, C-6’),
130.5 (C-5), 134.1 (C-4”), 135.2 (C-3”), 136.7 (C-1’, C-4’),
137.7 (C-1), 147.6 (C-2”), 148.6 (C-6”), 158.8 (C-3), 192.9
(CHO) ppm; MS-ESI: MS-MS of m/z 290: m/z 169(100),
262(1). HRMS M+H: m/z 290.11765, calculated value for
C19H16O2N: 290.11756 (delta: 0.3 ppm).
2.3.3.12. 2-{[4-(pyridin-3-yl)phenyl]methoxy}benzaldehyde
(3c)
1H NMR (500 MHz, DMSO): δ = 5.37 (s, 2H, OCH2),
7.12 (ddt, 1H, J= 7.7, 7.4, 0.8 Hz, H-5), 7.36 (dd, 1H, J= 8.5,
0.8 Hz, H-3), 7.51 (ddd, J= 8.0, 4.8, 0.8 Hz, H-5”), 7.62-7.71
(m, 2H, H-2’, H-6’), 7.68 (ddd, 1H, J=8.5, 7.4, 1.7 Hz, H-4),
7.75 (dd, 1H, J= 7.7, 1.7 Hz, H-6), 7.77-7.81 (m, 2H, H-3’,
H-5’), 8.10 (ddd, 1H, J=8.0, 2.4, 1.6 Hz, H-4”), 8.60 (dd,
1H, J= 4.8, 1.6 Hz, H-6”), 8.92 (dd, 1H, J= 2.4, 0.8 Hz, H-
2”), 10.48 (d, 1H, J5= 0.8 Hz, CHO) ppm; M (EI): m/z
289.10972, calculated value for C19H15O2N: 289.10973 (del-
ta: -0.04 ppm); MS-EI: m/z (%) = 289 (%): 289(4) [M+],
260(1), 168(100). MS-EI: m/z (%): 289(M+, 4), 260(1),
168(100). HRMS M: m/z 289.10972, calculated value for
C19H15O2N: 289.10973 (delta: -0.04 ppm).
2.3.3.16. 4-{[2-(pyridin-3-yl)phenyl]methoxy}benzaldehyde
(3g)
HAN-157-jav Separated on a chromatographic column
with hexane:acetone 3:2 eluent. 1H NMR (400 MHz,
DMSO): δ = 5.10 (s, 2H, OCH2), 7.06-7.11 (m, 2H, H-3, H-
5), 7.39-7.42 (m, 1H, H-5’), 7.44 (ddd, 1H, J= 7.9, 4.8, 0.8
Hz, H-5”), 7.50-7.54 (m, 2H, H-4’, H-5’), 7.66-7.70 (m, 1H,
H-6’), 7.82-7.88 (m, 3H, H-2, H-6, H-4”), 8.57 (dd, 1H, J=
4.8, 1.6 Hz, H-6”), 8.64 (dd, 1H, J= 2.4 Hz, 0.8 Hz, H-2”),
9.87 (s, 1H, CHO) ppm; MS-ESI: MS-MS of m/z 290: m/z

6
Letters in Drug Design & Discovery, 2019, Vol. 16, No. 0
Bölcskei et al.
168(100), 262(29). HRMS M+H: m/z 290.11772, calculated
value for C19H16O2N: 290.11756 (delta: 0.6 ppm).
2.3.3.21. 2-{[4-(pyridin-4-yl)phenyl]methoxy}benzaldehyde
(4c)
2.3.3.17. 4-{[3-(pyridin-3-yl)phenyl]methoxy}benzaldehyde
(3h)
Separated on a chromatographic column with hexane:
dichloromethane : isopropyl alcohol 7:2:1 eluent. H NMR
1
(500 MHz, DMSO): δ = 5.38 (s, 2H, OCH2), 7.11 (tt, 1H, J=
7.5, 0.7 Hz, H-5), 7.35 (d, 1H, J= 8.3 Hz, H-3), 7.66-7.70
(m, 3H, H-4, H-2’, H-6’), 7.73 (m, 3H, H-6, H-3”, H-5”),
7.86 (m, 2H, H-3’, H-5’), 8.65 (m, 2H, H-2”, H-6”), 10.47
(d, 1H, J= 0.7 Hz, CHO) ppm; 13C NMR (125 MHz,
DMSO): δ = 69.4 (OCH2), 114.1 (C-3), 121.0 (C-5), 121.3
(C-3”), 121.3 (C-3”), 124.6 (C-1), 127.1 (C-3’, C-5’), 128.0
(C-6), 128.5 (C-2’, C-6’), 136.4 (C-4), 136.7 (C-4’), 137.7
(C-1’), 146.6 (C-4”), 150.3 (C-2”, C-6”), 160.5 (C-2), 189.2
(CHO) ppm; HRMS M (EI): m/z 289.11059, calculated va-
lue for C19H15O2N: 289.10973 (delta: 3.0 ppm); MS-EI: m/z
(%) = 289 (%): 289(4) [M+], 260(2), 168(100). MS-EI: m/z
(%): 289(M+, 4), 260(2), 168(100). M: m/z 289.11059, calcu-
lated value for C19H15O2N: 289.10973 (delta: 3.0 ppm).
HAN-166-jav Separated on a chromatographic column
with hexane:acetone 3:2 eluent. 1H NMR (500 MHz,
DMSO): δ = 5.32 (s, 2H, OCH2), 7.25 (m, 2H, H-3, H-5),
7.51 (ddd, 1H, J= 8.0, 4.7, 0.7 Hz, H-5”), 7.54 (m, 1H, H-
6’), 7.58 (m, 1H, H-5’), 7.72 (m, 1H, H-4’), 7.86 (s br, 1H,
H-2’), 7.89 (m, 2H, H-2, H-6), 8.10 (ddd, 1H, J=8.0, 2.4, 1.6
Hz, H-4”), 8.60 (dd, 1H, J= 4.7 Hz, 1.6 Hz, H-6”), 8.92 (dd,
1H, J=2.4, 0.7 Hz, H-2”), 9.88 (s, 1H, CHO) ppm; 13C NMR
(125 MHz, DMSO): δ = 69.5 (OCH2), 115.3 (C-3, C-5),
123.9 (C-5”), 126.4 (C-2’), 126.6 (C-4’), 127.6 (C-6’), 129.4
(C-5’), 129.8 (C-1), 131.8 (C-2, C-6), 134.2 (C-4”), 135.3
(C-3”), 137.3 (C-1’, C-3’), 147.7 (C-2”), 148.6 (C-6”), 163.2
(C-4), 191.3 (CHO) ppm; MS-ESI: MS-MS of m/z 290: m/z
169(100), 262(18). HRMS M+H: m/z 290.11767, calculated
value for C19H16O2N: 290.11756 (delta: 0.4 ppm).
2.3.3.22. 3-{[2-(pyridin-4-yl)phenyl]methoxy}benzaldehyde
(4d)
2.3.3.18. 4-{[4-(pyridin-3-yl)phenyl]methoxy}benzaldehyde
(3i)
Separated on a chromatographic column with dichloro-
methane: methanol 20:1 eluent. 1H NMR (400 MHz,
DMSO): δ = 5.09 (s, 2H, OCH2), 7.21-7.25 m (m, 1H, H-4),
7.36-7.42 (m, 2H, H-2, H-3’), 7.44-7.48 (m, 2H, H-3”, H-
5”), 7.49-7.55 (m, 4H, H-5, H-6, H-4’, H-5’), 7.66-7.70 (m,
1H, H-6’), 8.59-8.62 (m, 2H, H-2”, H-6”), 9.95 (s, 1H,
CHO) ppm; M+H (ESI): m/z 290.11773, calculated value for
C19H16O2N: 290.11756 (delta: 0.6 ppm); MS-EI: m/z (%) =
290 (%):262(4), 168(100). MS-ESI: MS-MS of m/z 290: m/z
262(4), 168(100). HRMS M+H: m/z 290.11773, calculated
value for C19H16O2N: 290.11756 (delta: 0.6 ppm).
Separated on a chromatographic column with hexa-
ne:acetone 3:2 eluent. 1H NMR (400 MHz, DMSO): δ = 5.32
(s, 2H, OCH2), 7.23-7.26 (m, 2H, H-3, H-5), 7.50 (ddd, 1H,
J= 7.9, 4.8, 0.9 Hz, H-5”), 7.60-7.62 (m, 1H, H-2’, H-6’),
7.77-7.79 (m, 2H, H-3’, H-5’), 7.88-7.90 (m, 2H, H-2, H-6),
8.10 (ddd, 1H, J=7.9, 2.5, 1.6 Hz, H-4”), 8.58 (dd, 1H, J=
4.8, 1.6 Hz, H-6”), 8.91 (dd, 1H, J= 2.5 Hz, 0.9 Hz, H-2”),
9.88 (s, 1H, CHO) ppm; . MS-ESI: MS-MS of m/z 290: m/z
168(100), 262(2). HRMS M+H: m/z 290.11775, calculated
value for C19H16O2N: 290.11756 (delta: 0.7 ppm).
2.3.3.23. 3-{[3-(pyridin-4-yl)phenyl]methoxy}benzaldehyde
(4e)
2.3.3.19. 2-{[2-(pyridin-4-yl)phenyl]methoxy}benzaldehyde
(4a)
Separated on a chromatographic column with hexane:
dichloromethane : isopropyl alcohol 6:3:1 eluent. H NMR
Separated on a chromatographic column with hexane:
dichloromethane : isopropyl alcohol 6:3:1 eluent. . H NMR
1
1
(400 MHz, DMSO): δ = 5.30 (s, 2H, OCH2), 7.39-7.44 m
(m, 1H, H-4), 7.54-7.61 (m, 4H, H-2, H-5, H-6, H-5’), 7.61-
7.68 (m, 1H, H-6’), 7.71-7.74 (m, 2H, H-3”, H-5”), 7.79 (dt,
1H, J= 7.2, 1.8 Hz, H-4’), 7.94 (t, 1H, J=1.8 Hz, H-2’), 8.59-
8.62 (m, 2H, H-2”, H-6”), 10.01 (s, 1H, CHO) ppm; MS-
ESI: MS-MS of m/z 290: m/z 262(4), 169(100). HRMS
M+H: m/z 290.11762, calculated value for C19H16O2N:
290.11756 (delta: 0.2 ppm).
(400 MHz, DMSO): δ = 5.26 (s, 2H, OCH2), 7.06 (tt, 1H, J=
7.5, 0.8 Hz, H-5), 7.14 (d, 1H, J= 8.7 Hz, H-3), 7.39 (m, 1H,
H-3’), 7.46 (m, 2H, H-3”, H-5”), 7.49-7.67 (m, 4H, H-4, H-
6, H-4’, H-5’), 7.73 (m, 1H, H-6’), 8.58 (m, 2H, H-2”, H-
6”), 10.03 (d, 1H, J = 0.8 Hz, CHO) ppm; M (EI): m/z
289.11035, calculated value for C19H15O2N: 289.10973 (del-
ta: 2.1 ppm); m/z (%) = 289 (%): 289 (4) [M+], 260 (3), 168
(100). MS-EI: m/z (%): 289(M+, 4), 260(3), 168(100).
HRMS M: m/z 289.11035, calculated value for C19H15O2N:
289.10973 (delta: 2.1 ppm).
2.3.3.24. 3-{[4-(pyridin-4-yl)phenyl]methoxy}benzaldehyde
(4f)
2.3.3.20. 2-{[3-(pyridin-4-yl)phenyl]methoxy}benzaldehyde
(4b)
Separated on a chromatographic column with dichloro-
methane: methanol 20:1 eluent. 1H NMR (400 MHz,
DMSO): δ = 5.29 (s, 2H, OCH2), 7.39 (m, 1H, H-4), 7.53-
7.61 (m, 3H, H-2, H-5, H-6), 7.63 (m, 2H, H-2’, H-6’), 7.73
(m, 2H, H-3”, H-5”), 7.85 (m, 2H, H-3’, H-5’), 8.65 (m, 2H,
H-2”, H-6”), 10.00 (s, 1H, CHO) ppm; 13C NMR (400 MHz,
DMSO): δ = 68.9 (OCH2), 114.0 (C-2), 121.2 (C-3”, C-5”),
121.7 (C-4), 122.9 (C-6), 127.0 (C-3’, C-5’), 128.5 (C-2’, C-
6’), 130.4 (C-5), 136.6 (C-4’), 137.7 (C-1), 137.9 (C-1’),
146.6 (C-4”), 150.3 (C-2”, C-6”), 158.8 (C-3), 193.0 (CHO)
ppm; MS-ESI: MS-MS of m/z 290: m/z 169. HRMS M+H:
m/z 290.11767, calculated value for C19H16O2N: 290.11756
(delta: 0.4 ppm).
Separated on a chromatographic column with hex-
1
ane:acetone 3:1 eluent. H NMR (400 MHz, DMSO): δ =
5.39 (s, 2H, OCH2), 7.13 (tt, 1H, J= 7.5, 0.6 Hz, H-5), 7.37
(dd, 1H, J= 8.4, 0.6 Hz, H-3), 7.55-7.71 (m, 1H, H-4), 7.55-
7.71 (m, 1H, H-5’), 7.55-7.71 (m, 1H, H-6’), 7.72-7.77 (m,
3H, H-6, H-3”, H-5”), 7.80 (dt, 1H, J= 7.7, 1.7 Hz, H-4’),
7.97 (t, 1H, J= 1.7 Hz, H-2’), 8.64-8.69 (m, 2H, H-2”, H-6”),
10.46 (d, 1H, J = 0.6 Hz, CHO) ppm; MS-EI: m/z (%):
289(M+, 10), 260(6), 168(100). HRMS M: m/z 289.10983,
calculated value for C19H15O2N: 289.10973 (delta: 0.3 ppm).

Synthesis of Phenyl- and Pyridyl-substituted Benzyloxybenzaldehydes
Letters in Drug Design & Discovery, 2019, Vol. 16, No. 0
7
2.3.3.25. 4-{[2-(pyridin-4-yl)phenyl]methoxy}benzaldehyde
(4g)
As the catalyst used is especially sensitive to oxygen, the
solid components were dissolved under an argon atmosphere
to obtain a pale yellow reaction mixture. During the reaction,
the solution undergoes a sequence of color changes from
yellow to dark red, and then to dark brown or black, simi-
larly to the observations of others [17]. This color change is
generally indicative of the completion of the reaction in such
coupling transformations; however, we found that the reac-
tion proceeded further also in the dark brown or black mix-
ture in several cases. The dark colour of the reaction mixture
comes from the palladium metal formed in the reaction,
which has to be filtered off not to disturb the following ex-
traction or chromatographic purification. The UV-active
triphenylphosphine and triphenylphosphine oxide formed in
the reaction were removed by chromatographic purification.
Separated on a chromatographic column with hexa-
ne:acetone 3:2 eluent. 1H NMR (400 MHz, DMSO): δ = 5.12
(s, 2H, OCH2), 7.08 (m, 2H, H-3, H-5), 7.40 (m, 1H, H-3’),
7.45 (m, 2H, H-3”, H-5”), 7.50-7.59 (m, 2H, H-4’, H-5’),
7.67 (m, 1H, H-6’), 7.84 (m, 2H, H-2, H-6), 8.60 (m, 2H, H-
2”, H-6”), 9.86 (s, 1H, CHO) ppm; MS-ESI: MS-MS of m/z
290: m/z 262(22), 168(100). HRMS M+H: m/z 290.11776,
calculated value for C19H16O2N: 290.11756 (delta: 0.7 ppm).
2.3.3.26. 4-{[3-(pyridin-4-yl)phenyl]methoxy}benzaldehyde
(4h)
Separated on a chromatographic column with dichloro-
methane: methanol 20:1 eluent. 1H NMR (500 MHz,
DMSO): δ = 5.33 (s, 2H, OCH2), 7.26 (m, 2H, H-3, H-5),
7.59 (m, 1H, H-5’), 7.60 (m, 1H, H-6’), 7.73 (m, 2H, H-3”,
H-5”), 7.80 (dt, 1H, J= 6.5, 2.2 Hz, H-4”), 7.90 (m, 2H, H-2,
H-6), 7.93 (s br, 1H, H-2’), 8.66 (m, H-2”, H-6”), 9.88 (s,
CHO) ppm; 13C NMR (125 MHz, DMSO): δ = 69.4 (OCH2),
115.3 (C-3, C-5), 121.3 (C-3”, C-5”), 126.3 (C-2’), 126.6 (C-
4’), 128.7 (C-6’), 129.5 (C-5’), 131.8 (C-2, C-6), 132.0 (C-
3’), 137.4 (C-1’), 146.7 (C-4”), 150.3 (C-2”, C-6”), 163.2
(C-4), 191.3 (CHO) ppm; MS-ESI: MS-MS of m/z 290: m/z
262(18), 169(100). HRMS M+H: m/z 290.11769, calculated
value for C19H16O2N: 290.11756 (delta: 0.5 ppm).
As the polarity of iodine and phenyl or hetaryl groups is
rather similar, separations proved to be difficult by thin layer
chromatography. However, an HPLC-UV-MS analytical
method was successful in determining the percentage of the
reactants and reaction products in the crude reaction mix-
tures. Thus, we used this analytical method to follow the
course of reactions and, allowed enough time for the comple-
tion. Based on the results of HPLC-UV-MS analysis, it was
possible to separate the target products from the by-products
by column chromatography (Table 1).
At first, we tried the classical Suzuki (method S) condi-
tions [10] to get the corresponding products. Toluene was
used as the solvent instead of benzene because of the car-
cinogen hazard of the latter one. In a few cases, after a reac-
tion time of 6 hours, the reactant was consumed, but the
conversion was only around 50%, or even lower (19% with
2i). Thus, we tried to find another suitable method.
2.3.3.27. 4-{[4-(pyridin-4-yl)phenyl]methoxy}benzaldehyde
(4i)
Separated on a chromatographic column with dichloro-
methane: methanol 10:1 eluent. 1H NMR (500 MHz,
DMSO): δ = 5.32 (s, 2H, OCH2), 7.26 (m, 2H, H-3, H-5),
7.61-7.64 (m, 2H, H-2’, H-6’), 7.71-7.74 (m, 2H, H-3”, H-
5”), 7.84-7.87 (m, 2H, H-3’, H-5’), 7.88-7.91 (m, 2H, H-2,
H-6), 8.63-8.67 (m, H-2”, H-6”), 9.88 (s, CHO) ppm; MS-
ESI: MS-MS of m/z 290: m/z 262(2), 169(100). HRMS
M+H: m/z 290.11773, calculated value for C19H16O2N:
290.11756 (delta: 0.6 ppm).
Bedford et al. chose a more cost-effective protocol, using
Pd(OAc)2 catalyst. They preferred K3PO4 over Cs2CO3, as
the latter is known to lead to the formation of a by-product
from the homocoupling reaction of phenylboronic acid. The
water present in 2.5–3.5% did not appear to have a signifi-
cant impact on the process. It was found that the conversion
to product is limited by the aggregation of the catalyst and
the precipitated bulk metal, which can be suppressed by de-
creasing the catalyst loading [23].
3. RESULTS AND DISCUSSION
The Suzuki cross-coupling reactions discussed in this
paper involve the substitution of a iodo group to a phenyl or
hetaryl group as it is shown in Scheme 2.
In doing so, we carried out the Suzuki cross-coupling
reaction based on the process used by Novák et al. (method
S
ArB(OH)2
NaOEt/EtOH, Pd[(C6H5)3P]4, toluol
Ar
I
O
O
N
ArB(OH)2
O
O
K3PO4/H2O, Pd(OAc)2, (o-tolyl)3P, DME
Ar: Ph-, pyridin-3-yl,
pyridin-4-yl
ArB(OH)2
A
Cs2CO3/H2O, Pd[(C6H5)3P]4, DMF
Scheme 2. Description of the three different protocols, leading to 2a-i, 3a-i, 4a-i.

8
Letters in Drug Design & Discovery, 2019, Vol. 16, No. 0
Bölcskei et al.
Table 1. Results of the reactions of iodo-derivatives with phenylboronic acid.
LC-UV-MS* (%)
Starting Material
1
Ar
2a
Method
Reaction Time (h)
Product
S
N
A
S
6
20.5
21
6
51
85
87
49
81
91
42
64
47
85
52
79
43
32
52
93
49
98
19
89
47
n.d.
n.d.
34
1a
1b
2b
N
A
S
20.5
21
6
6
n.d.
47
1c
1d
1e
1f
2c
2d
2e
2f
N
S
14
5
22
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
36
N
S
35
6
N
S
20
6
N
S
48
6
1g
1h
1i
2g
2h
2i
N
S
10
6
N
S
10
6
n.d.
73
N
10
n.d.
* Area percentage of the desired compound in the crude product as determined by LC-UV-MS. n.d. not detected.
N) [15]. They studied the Suzuki reactions of halogenated
vindoline derivatives and optimized the conditions. Their
results with large space-filling molecules inspired us to use
the same conditions in our special cases. Using phenylboronic
acid, we got the products in good yields after 10-48 hours.
There was no starting material in the mixture (Table 1).
into consideration, the change of a phenyl ring into a
bioisoster pyridine moiety seemed to be advantageous in our
case [8, 24-26]. Thus, we attempted the synthesis of the cor-
responding pyridine derivatives. The reaction of 3- and 4-
pyridine boronic acids with our iodine derivatives gave the
coupled products in poor yields, or the reactions did not start
at all in a few cases. After this, we had to modify the condi-
tions (Tables 2 and 3.).
From the point of view of medicinal chemistry, the
change of a phenyl ring into a bioisoster pyridine moiety
may be advantageous, the physicochemical parameters, e.g.
the lipophilicity, the log P value becomes lower, or the bio-
logical activity is better. [8]. The substitution of –CH= with
–N= is often used in drug development [8] Ritchie and co-
workers studied thoroughly the effect of aromatic ring count
on the drug candidates [24-26]. According to their results,
the increasing aromatic ring count is disadvantageous from
the point of view of physico-chemical parameters of com-
pounds under development (aqueous solubility, lipophilicity
(logP), protein binding, P450 inhibition, hERG activity). The
order of developability is the following: carboaromatics >>
heteroaromatics > carboaliphatics > heteroaliphatics. In
compliance with it, the heteroaromatic ring count increased
recently among the oral drugs on the market. Taking all this
The conditions of the special type of Suzuki-Miyaura
coupling reactions were further optimized by Anderson at al.
(method A) [27]. Adapting their method, we observed yield
of 56-94 % even in the cases, where the Novák’s method did
not work (Table 3).
CONCLUSION
Comparing all the three sets of reaction conditions, (see
the Tables 1-3.), it was found that in a few cases, Anderson’s
method gave the highest yields [27].
Comparing the results obtained for products 2g, 2h and
2i (Table 1) with those obtained for 3g, 3h and 3i (Table 2),
and for 4g, 4h and 4i (Table 3), the method of Novák et al.

Synthesis of Phenyl- and Pyridyl-substituted Benzyloxybenzaldehydes
Letters in Drug Design & Discovery, 2019, Vol. 16, No. 0
9
Table 2. Results of the reactions of iodo-derivatives with pyridine-3-boronic acid
LC-UV-MS* (%)
1
Ar
Method
Reaction Time (h)
Product
Starting Material
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
A
A
A
A
A
A
N
A
N
A
N
A
21
21
21
21
21
21
8
92
86
88
87
92
94
11
93
16
87
16
56
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
1g
1h
1i
3g
3h
3i
21
8
21
8
21
Table 3. Results of the reactions of iodo derivatives with pyridine-4-boronic acid.
LC-UV-MS* (%)
1
Ar
Method
Reaction Time (h)
Product
Starting Material
1a
1b
1c
1d
1e
1f
4a
4b
4c
4d
4e
4f
A
A
A
A
A
A
N
A
N
A
N
A
7
81
86
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
98
21
21
21
21
21
8
60
84
84
79
n.d.
74
1g
1h
1i
4g
4h
4i
21
8
n.d.
99
n.d.
76
21
8
n.d.
99
n.d.
68
21
n.d.
[15] is superior for the reaction of phenylboronic acid over
pyridylboronic acids. This finding is in line with those of
Morris et al., who compared the reaction efficiency of
pyridyl-salicylaldehydes in Ni- or Pd-mediated cross-
coupling [28], and concluded that pyridylboronic acid rea-
gents undergo more facile protodeboronation than phenylbo-
ronic acids. Moreno-Manas et al. commented on the self-
coupling of aryl groups of the arylboronic acids when the
cross-coupling reaction itself is very slow [29]. However,
according to our findings, it must depend on the actual
mechanism. The method of Suzuki et al. using phenylbo-
ronic acid may result in the formation of the by-products in a
quantity of up to 50% within 6 hours; while side reactions
are usually absent even after 21 hours by using the method
of Anderson et al.
CONSENT FOR PUBLICATION
Not applicable.

10 Letters in Drug Design & Discovery, 2019, Vol. 16, No. 0
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CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
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Rossi, R.; Carpita,A.; Messeri, T. Synthetic Applications of
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