The synthesis of (iodobenzyl)oxybenzaldehydes, useful intermediates for biologically active targets

Article abstract of DOI:10.2174/1570180813666160804142245

The benzyloxy-benzyl moiety is a valuable building block in medicinal chemistry, e.g. in case of the voltage gated sodium channel blockers Safinamide and Ralfinamide. To prepare further derivatives a series of (iodobenzyl)oxybenzaldehydes (3a-3i) useful intermediates for the synthesis of biologically active compounds were synthesized in high yields by O-benzylation of 2-, 3- and 4- hydroxybenzaldehydes (2a-2c) with a variety of iodobenzylbromides (1a-1c). The title compounds were obtained in 77-100 % yield in 2-5 hours. Longer reaction time or addition of water favoured the formation of aldol-type by-products, mainly 4-hydroxy-4-{[(iodophenyl)methoxy]phenyl}butan-2-one derivatives (5a-5g), which contained the iodine group and the 4-hydroxy-butan-2-one moiety in various positions. In one case (3E-)-4-{3-[(2-iodophenyl)methoxy]phenyl}but-3-en-2-one (6c) with a double bond has been isolated. These side-reactions could be avoided by using acetonitrile as solvent. The structures of the new products were established by high resolution MS and NMR measurements, where 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.

Full text of DOI:10.2174/1570180813666160804142245

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Letters in Drug Design & Discovery, 2017, 14, 233-239
RESEARCH ARTICLE
ISSN: 1570-1808
eISSN: 1875-628X
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The Synthesis of (Iodobenzyl)oxybenzaldehydes, Useful Intermediates for
Biologically Active Targets
BENTHAM
S
CIENCE
Hedvig Bölcskeia,*, Andrea Német-Hanzelika, István Greinera, Zsófia Dubrovaya, Viktor Hádaa
and György Keglevichb
b
aGedeon Richter Plc. H-1475 P.O.B. 27 Budapest, 10. Hungary; Department of Organic Chemistry and Technology,
Budapest University of Technology and Economics H-1521 Budapest, Hungary
Abstract: The benzyloxy-benzyl moiety is a valuable building block in medicinal chemistry, e.g. in
case of the voltage gated sodium channel blockers Safinamide and Ralfinamide. To prepare further
derivatives a series of (iodobenzyl)oxybenzaldehydes (3a-3i) useful intermediates for the synthesis
of biologically active compounds were synthesized in high yields by O-benzylation of 2-, 3- and 4-
A R T I C L E H I S T O R Y
hydroxybenzaldehydes (2a-2c) with a variety of iodobenzylbromides (1a-1c). The title compounds
were obtained in 77-100 % yield in 2-5 hours. Longer reaction time or addition of water favoured the
Received: March 17, 2016
Revised: July 20, 2016
formation of aldol-type by-products, mainly 4-hydroxy-4-{[(iodophenyl)methoxy]phenyl}butan-2-one
Accepted: July 20, 2016
derivatives (5a-5g), which contained the iodine group and the 4-hydroxy-butan-2-one moiety in
DOI:
various positions. In one case (3E-)-4-{3-[(2-iodophenyl)methoxy]phenyl}but-3-en-2-one (6c) with a
10.2174/1570180813666160804142
double bond has been isolated. These side-reactions could be avoided by using acetonitrile as solvent.
245
The structures of the new products were established by high resolution MS and NMR measurements,
1
1
where 1H-1H, direct H-13C, long-range H-13C scalar spin-spin connectivities were established from
1D H, 13C, 2D gHSQCAD, zTOCSY and gHMBCAD NMR experiments.
1
Keywords: Alkylation, hydroxybenzaldehyde, iodobenzylbromide, (iodobenzyloxy)benzaldehydes, aldol reaction, aldol con-
densation.
1. INTRODUCTION
The synthesis of these compounds (4) was planned by the
Suzuki-Miyaura coupling reaction of the corresponding
halogenated benzyloxybenzaldehyde e.g. (3), and aryl- and
heteroaryl boronic acid (Scheme 1) [3].
The benzyloxy-benzyl moiety is a common building
block in medicinal chemistry as shown by e.g. the voltage
gated sodium channel blockers Safinamide and Ralfinamide
(Fig. 1). Both of them were obtained by the reductive amina-
tion of the corresponding fluor-benzyloxy-benzaldehyde
with alanin-amide [1, 2].
It was expected, that the bromo-derivatives were less
active in the Suzuki-Miyaura coupling reaction than the
iodo-compounds. Thus, we focused on the preparation of the
corresponding iodo-derivatives (3). The series of reactions
mentioned above leads to the intermediates of potentially
biologically active compounds.
NH2
F
N
H
NH2
O
N
H
O
The alkylation of phenols is a well-known procedure. It
was named after Williamson, who developed this reaction in
1850 [4]. The Williamson ether synthesis was extended in
many cases i.e. concerning hydroxybenzaldehydes [5].
Katritzky et al. isolated 2-alkoxy-5-methoxy-benzaldehydes
with alkylbromides or iodides in acetone in the presence of
potassium carbonate [6]. Chang et al. alkylated substituted
hydroxybenzaldehydes with benzyl chloride in the presence
of potassium-carbonate and potassium iodide in acetone [7].
Lu et al. used dimethylformamide as the solvent at a higher
F
O
O
Ralfinamide
Safinamide
Fig. (1). Molecular structure of Ralfinamide and Safinamide.
In the synthesis of a diverse set of potentially biologically
active compounds, we needed several aryl- and heteroaryl-
substituted benzyloxybenzaldehydes (4) as intermediates**.
o
temperature (120 C) in course of the alkylation of 4-bromo-
*Address correspondence to this author at the Department of Organic
Chemistry and Technology, Budapest University of Technology and Eco-
nomics, H-1521, Budapest, Hungary; Tel: +36-1-463-2208, Fax: +36-1-463-
3648; E-mail: h.bolcskei@mail.bme.hu
2-hydroxy-benzaldehyde with 4-chloro-benzyl chloride [8].
Heating benzylchloride with 2-hydroxy-benzaldehyde
and potassium carbonate in acetone for 3 hours, Majhi et al.
**Bölcskei, H. et al. unpublished data
1875-628X/17 $58.00+.00
©2017 Bentham Science Publishers

234 Letters in Drug Design & Discovery, 2017, Vol. 14, No. 2
Bölcskei et al.
O
Potassium carbonate was used in most of the cases, but
cesium carbonate or cesium hydroxide can also promote
O-alkylation in the presence of tetrabutylammonium iodide
and molecular sieves [10]. Voelter et al. published that
CsF-celite combinations in acetonitrile provided an efficient
method for the alkylation of phenols with benzyl halogenides
[11]. Keglevich and his coworkers studied the benzylation
of cresols using phase transfer catalysis and microwave irra-
diation. Benzylation of phenols led mostly to O-alkylation,
but modification of the reaction conditions resulted in
C-alkylation [12]. Using acetonitrile as the solvent, the
benzylations were fully selective, but complete conversions
were obtained only in the presence of cesium carbonate [13].
+
Br
I
OH
2a ortho
1a ortho
2b meta
1b meta
2c para
1c para
3'
O
4'
2'
1'
O
Ar
I
5'
O
O
6'
1
4
3a-i
Reagents
Product
2. RESULTS AND DISCUSSIONS
1
2
Starting from the corresponding iodobenzyl bromide, we
applied the Chang’s conditions [7] (acetone, potassium
carbonate) for the iodobenzylation of our o-, m-, p-hydroxy-
benzaldehydes. In this way, a series of iodo-benzyloxy-
benzaldehydes (3a-i) was synthesized in high yields, eight of
which (except 2-[(2-iodobenzyl)oxy]benzaldehyde 3a) are
new compounds according to the databases Reaxys and
SciFinder.
ortho
meta
para
ortho
ortho
ortho
meta
meta
meta
para
3a
3b
3c
3d
3e
3f
ortho
meta
para
Our results were summarized in Table 1.
ortho
meta
para
3g
3h
3i
In a few cases, when we applied longer heating in course
of the reaction to reach the complete consumption of the
starting material, aldol addition and aldol condensation were
observed with the participation of acetone used as solvent as
side reactions. The general scheme of the aldol condensation
is shown in Scheme 2.
para
para
Scheme 1. The planned synthetic protocol: alkylation followed by
Suzuki-Miyaura reaction.
The conditions of the alkylation (acetone, potassium car-
bonate, etc.) are often used, and it is rare that aldol-type reac-
tion occurs simultaneously. The by-products of aldol-type
prepared 2-[(2-iodobenzyl)oxy]benzaldehyde, which is one
of our target compounds [9].
Table 1. Products obtained by alkylation (3a-i).
Reagents
Reaction
Time (h)
Yield
Product
(%)
1
2
1a
1a
1b
1c
1a
1a
1b
1c
1a
1a
1b
1c
2a
2a
2a
2a
2b
2b
2b
2b
2c
2c
2c
2c
2.5
2.0
2.5
2.0
3.3
2.0
2.0
3.0
2.0
2.0
5.0
1.75
99
100
98
3aa
3ab
3ba
3ca
3da
3db
3ea
3fa
99
77
100
98
93
100
100
87
3ga
3gb
3ha
3ia
100
aAcetone was the solvent, see general procedure
bAcetonitrile was the solvent, see general procedure.

The Synthesis of (Iodobenzyl)oxybenzaldehydes
Letters in Drug Design & Discovery, 2017, Vol. 14, No. 2 235
Table 2. Formation of Aldol-products 5a-e and 5g.
Reagents
Reaction time (h)
Yield (%)a
Aldol Product
1a
1b
1a
1b
1c
1c
2a
2a
2b
2b
2b
2c
25
25
25
16
16
25
20
72
99
15
30
99
5ab
5bb
6cc
5db
5eb
5gb
aArea percentage of the aldol-type products in the crude mixtures as determined by LC-MS.
baldol adduct
cdehydrated aldol product
O
O
occurred in water, or in the presence of water [17,18]. In our
model reactions, the addition of water shifted the reaction to
the direction of formation of the aldol adduct (see Table 3).
I
3'
HO
HO
I
2'
1'
4'
5'
1
O
O
2
Table 3. Product composition of the reaction starting from 1b
and 2c.
6
5
6'
3"
5b
5a
3
2"
I
4
Solvents
Composition [%]*
4"
O
2'
1"
3
1'
3f
5f
3'
O
1
5"
4
2
6"
acetone
acetone
1ekv H2O
5ekv H2O
82
62
18
27
I
6c
OH
O
*Determined on the basis of the area percentage in the LC-MS spectrum.
O
5d
I
OH
O
3. CONCLUSION
O
A complete set of iodobenzyloxybenzaldehydes (3a-i)
was prepared, eight of which are new compounds. They can
be valuable building blocks in the synthesis of biologically
active compounds. In course of the O-benzylation allowing
longer reaction times, aldol type by-products were formed
and isolated. All of the new products were identified by
NMR spectroscopy and mass spectrometry.
5e
I
I
O
O
4. EXPERIMENTAL SECTION
4.1. LC-MS Analysis
5f
5g
OH
O
OH
O
LC-MS experiments were carried out on an Agilent 1200
liquid chromatography system coupled with 6120 MSD
(Agilent Technologies, Palo Alto, CA, USA), equipped with
vacuum degasser, binary pump, autosampler, column
temperature controller and diode array detector. Analysis
was done at 40°C on 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 eluent 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 gradient of
0-100% B was applied at a range of 0-4 min, then 100% B
held for 3 min. This was followed by 2 min equilibration
period prior to the next injection. The injection volume was
Fig. (2). Aldol-type by-products.
shown in Figure 2 were formed in reaction times of 16-25
hours. Applying a reaction time of 16 hours, starting from 1b
and 2b or 1c and 2b, the relative amount of aldol-type
products beside the desired product was only 15% and 30%
respectively. The relative amount of the side products in
most cases was increased by the reaction time (Table 2).
Using acetonitrile as the solvent, these side reactions could
be avoided.
Several examples are known in the literature, when aldol
reaction took place between acetone and benzaldehyde using
various types of catalysts improving the selectivity of the
reaction, e.g. [14,15,16]. Sometimes, the aldol reaction

236 Letters in Drug Design & Discovery, 2017, Vol. 14, No. 2
Bölcskei et al.
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 temperature 350°C,
nitrogen flow rate 12 L/min, nebuliser pressure 60 psi,
quadrupole temperature 100°C, capillary voltage 3000 V,
fragmentor voltage 50 V.
Alkylation in Acetonitrile. The hydroxy-benzaldehyde
(2.1 g, 16.8 mmol) was treated with the corresponding
iodobenzylbromide (5.0 g, 16.8 mmol) in acetonitrile (60
ml), in the presence of potassium carbonate (4.0 g, 29 mmol)
and potassium iodide (0.6 g, 3.6 mmol). The mixture was
agitated at 70 °C for 2 h, and cooled to room temperature.
The reaction mixture was then diluted with 100 ml of dis-
tilled water, and 5 ml of brine was added, then the product
was filtered off as a white solid.
2-[(2-Iodophenyl)methoxy]benzaldehyde (3a). Sepa-
rated by column chromatography with cyclohexane: ethyl
acetate 9:1 eluent. M.p. 81 °C. 1H NMR (400 MHz, DMSO):
δ = 5.23 (s, 2H, OCH2), 7.13 (t, 1H, J 5,6= 7.6 Hz, J5,4=7.6
Hz, H-5,), 7.15 (td, 1H, J3’,4’=7.7 Hz, J;4’,5’=7.7 Hz, J4’,6’=1.6
Hz, H-4’), 7.35 (d, 1H, J3,4= 8.3 Hz, H-3), 7.47 (td, 1H, J 5’,4’
=7.7 Hz, J;5’,6’ =7.7 Hz, J5’,3’=1.2 Hz, H-5’), 7.64 (dd, 1H,
4.2. NMR Spectroscopy
NMR measurements were performed on a Varian 800
1
MHz NMR spectrometer equipped with H{13C/15N} Triple
Resonance 13C Enhanced Salt Tolerant Cold Probe operating
1
at 800 MHz for H and 201 MHz for 13C, and a Varian 500
J5’,6’=7.7 Hz, J4’,6’=1.6 Hz, H-6’), 7.70 (ddd, 1H, J4,5=7.6 Hz,
1
J4,3=8.3 Hz, J4,6=1.8 Hz, H-4), 7.74 (dd, 1H, J6,5=7.6 Hz,
J6,4=1.8 Hz, H-6), 7.95 (dd, 1H, J3’,4’=7.7 Hz, J3’,5’=1.2 Hz,
H-3’), 10.43 (d, 1H, JCHO,5= 0.7 Hz, CHO) ppm; 13C NMR
(400 MHz, DMSO): δ = 73.8 (OCH2), 99.1 (C-2’), 114.1 (C-
3), 121.2 (C-5), 124.5 (C-1), 127.9 (C-6), 128.5 (C-5’),
130.2 (C-6’), 130.4 (C-4’), 136.4 (C-4), 138.3 (C-1’), 139.3
(C-3’), 160.4 (C-2), 189.1 (CHO) ppm; MS-EI: m/z (%):
338(M+, 10), 309(14), 217(100), 211(3). M: m/z 337.97998,
calculated value for C14H11O2I: 337.97982 (delta: 0.5 ppm).
MHz NMR spectrometer equipped with H {13C/15N} 5 mm
PFG Triple Resonance 13C Enhanced Cold Probe operating
1
at 500 MHz for H 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
1
1
for 13C, using DMSO-d6 as solvent. H-1H, direct H-13C,
long-range 1H-13C scalar spin-spin connectivities were
established from D H, 13C, 2D gHSQCAD, zTOCSY and
1
1
gHMBCAD NMR experiments.
2-[(3-Iodophenyl)methoxy]benzaldehyde (3b). Crystal-
1
lized from cold ethyl acetate. M.p. 74-77 °C. H NMR (800
4.3. MS Spectrometry
MHz, DMSO): δ = 5.27 (s, 2H, OCH2), 7.10 (tt, 1H, J6,5=7.5
Hz, J5,4=7.5 Hz, J5,3=0.8 Hz, J5,CHO=0.8 Hz, H-5), 7.23 (t,
1H, J4’,5’=7.7 Hz, J5’,6’=7.7 Hz, H-5’), 7.29 (dd, 1H, J3,4=8.4
Hz, J3,5=0.8 Hz, H-3), 7.55 (d, 1H, J5’,6’=7.7 Hz, H-6’), 7.66
(ddd, 1H, J4,5=7.5 Hz, J4,3=8.4 Hz, J4,6=1.8 Hz, H-4), 7.72 (d,
1H, J4’,5’=7.7, H-4’), 7.73 (dd, 1H, J6,5=7.5 Hz, J6,4=1.8 Hz,
H-6), 7.90 (m, 1H, H-2’), 10.42 (d, 1H, JCHO,5=0.8 Hz, CHO)
ppm; 13C NMR (500 MHz, DMSO) δ 68.8 (OCH2), 94.9 (C-
3’), 114.0 (C-3), 121.1 (C-5), 124.6 (C-1), 126.9 (C-6’),
128.1 (C-6), 130.8 (C-5’), 136.0 (C-2’), 136.3 (C-4), 136.7
(C-4’), 139.2 (C-1’), 160.3 (C-2), 189.2 (CHO) ppm; MS-EI:
m/z (%): 338(M+, 14), 309(12), 217(100), 211(1). M: m/z
337.97994, calculated value for C14H11O2I: 337.97982 (delta:
0.3 ppm).
High-resolution MS measurements were carried out on a
Thermo LTQ FT Ultra mass spectrometer using ESI
(electrospray) 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
fragmented by CID at normalized collision energy of 35%.
The relative abundance values of the fragment ions in the
MS-MS spectra are given in brackets. Part of the
high-resolution MS measurements was performed 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). Melting points given were measured
on a hot-stage microscope.
2-[(4-Iodophenyl)methoxy]benzaldehyde (3c). Sepa-
rated by column chromatography with hexane: ethyl acetate
1
4.4. General Procedure
10:1 eluent. M.p. 84-86 °C. H NMR (500 MHz, DMSO): δ
= 5.26 (s, 2H, OCH2), 7.10 (tt, 1H, J5,4=7.6 Hz, J5,6=7.6 Hz,
Alkylation in Acetone. A stirred mixture of the
appropriate hydroxy benzaldehyde (2.1 g, 16.8 mmol) was
treated with the corresponding iodobenzylbromide (5.0 g,
16.8 mmol) in acetone (60 ml), in the presence of potassium
carbonate (4.0g, 29 mmol) and potassium iodide (0.6 g, 3.6
J5,CHO=0.7 Hz, J5,3=0.7 Hz, H-5), 7.29 (dd, 1H, J3,4=8.4 Hz,
J3,5=0.7 Hz, H-3), 7.34 (m, 2H, H-2’,H-6’), 7.65 (ddd, 1H,
J4,6=1.8 Hz, J4,3=8.4 Hz, J4,5=7.6 Hz, H-4), 7.72 (dd, 1H,
J6,5=7.6 Hz, J4,6=1.8 Hz, H-6), 7.78 (m, 2H, H-3’, H-5’),
10.42 (d, 1H, JCHO,5=0.7 Hz, CHO) ppm; 13C NMR (500
MHz, DMSO): δ = 69.2 (OCH2), 94.1 (C-4’), 114.1 (C-3),
121.1 (C-5), 124.5 (C-1), 127.9 (C-6), 129.8 (C-2’, C-6’),
136.3 (C-1’), 136.4 (C-4), 137.3 (C-3’, C-5’), 160.4 (C-2),
189.2 (CHO) ppm; MS-EI: m/z (%): 338(M+, 9), 309(8),
217(100), 211(1). M: m/z 337.97973, calculated value for
C14H11O2I: 337.97982 (delta: -0.3 ppm).
#
mmol) . The reaction was stirred at the boiling point for 2-5
h, and then cooled to room temperature. The acetone
was evaporated, the residue was taken up in ethyl acetate
- distilled water (50:50 mL). After drying the organic layer
(Na2SO4), the solvent was removed, and the residue was
purified by column chromatography, with Kieselgel
60 (0.040-0.063 mm) or crystallized to give the compound as
#
a white solid. Studying the formation of side product 5f,
3-[(2-Iodophenyl)methoxy]benzaldehyde (3d). Sepa-
1 or 5 equivalent of distilled water was also added to the
rated by column chromatography with hexane: ethyl acetate
1
reaction mixture (see Table 3).
10:1 eluent. M.p. 74-76 °C. H NMR (500 MHz, DMSO): δ

The Synthesis of (Iodobenzyl)oxybenzaldehydes
Letters in Drug Design & Discovery, 2017, Vol. 14, No. 2 237
= 5.13 (s, 2H, OCH2), 7.14 (td, 1H, J4’,3’=7.6 Hz, J4’,5’=7.6
Hz, J4’,6’=1.7 Hz, H-4’), 7.38 (m, 1H, H-4), 7.45 (td, 1H,
J5’,4’=7.6 Hz, J5’,6’=7.6 Hz, J5’,3’=1.1 Hz, H-5’), 7.53 (m, 1H,
H-2), 7.55-7.59 (m, 3H, H-5, H-6, H-6’), 7.94 (dd, 1H,
(OCH2), 94.9 (C-3’), 115.3 (C-3, C-5), 127.1 (C-6’), 129.9
(C-1), 130.7 (C-5’), 131.8 (C-2,C-6), 136.2 (C-2’), 136.8 (C-
4’), 139.0 (C-1’), 163.1 (C-4), 191.4 (CHO) ppm; MS-ESI:
MS-MS of m/z 339 (M+H): m/z 311(5), 217(100). M+H: m/z
338.98793, calculated value for C14H12O2I: 338.98766 (delta:
0.8 ppm).
J3’,4’=7.6 Hz, J3’,5’=1.1 Hz, H-3’), 9.99 (s, 1H, CHO) ppm;
13C NMR (500 MHz, DMSO): δ = 73.5 (OCH2), 99.4 (C-2’),
113.8 (C-2), 121.6 (C-4), 123.0 (C-6), 128.5 (C-5’), 130.0
(C-6’), 130.3 (C-4’), 130.5 (C-5), 137.7 (C-1), 138.5 (C-1’),
139.2 (C-3’), 158.7 (C-3), 192.9 (CHO) ppm; MS-ESI: MS-
MS of m/z 339 (M+H): m/z 217. M+H: m/z 338.98798, cal-
culated value for C14H12O2I: 338.98766 (delta: 0.9 ppm).
4-[(4-Iodophenyl)methoxy]benzaldehyde (3i). Sepa-
rated by column chromatography with hexane: ethyl acetate
1
5:2 eluent. M.p. about 130 °C (subl.). H NMR (500 MHz,
DMSO): δ = 5.20 (s, 2H, OCH2), 7.20 (m, 2H, H-3, H-5),
7.29 (m, 2H, H-2’,H-6’), 7.78 (m, 2H, H-3’, H-5’), 7.87 (m,
2H, H-2, H-6), 9.87 (s, 1H, CHO) ppm; 13C NMR (500
MHz, DMSO): δ = 69.0 (OCH2), 94.2 (C-4’), 115.3 (C-3,C-
5), 129.9 (C-1), 130.0 (C-2’, C-6’), 131.8 (C-2, C-6), 136.2
(C-1’), 137.3 (C-3’, C-5’), 163.1 (C-4), 191.3 (CHO) ppm;
MS-ESI: MS-MS of m/z 339 (M+H): m/z 311(1), 217(100).
M+H: m/z 338.98790, calculated value for C14H12O2I:
338.98766 (delta: 0.7 ppm).
3-[(3-Iodophenyl)methoxy]benzaldehyde (3e). Sepa-
rated by column chromatography with hexane: ethyl acetate
1
10:1 eluent. H NMR (500 MHz, DMSO): δ = 5.18 (s, 2H,
OCH2), 7.22 (t, 1H, J5’,6’=7.8 Hz, J5’,4’=7.8 Hz, H-5’), 7.37
(m, 1H, H-4), 7.50 (d, 1H, J5’,6’=7.8 Hz, H-6’), 7.52 (m, 1H,
H-2), 7.53-7.57 (m, 2H, H-5, H-6), 7.72 (d, 1H, J4’,5’=7.8
Hz, H-4’), 7.86 (s br, 1H, H-2’), 9.98 (s, 1H, CHO) ppm; 13C
NMR (500 MHz, DMSO): δ = 68.4 (OCH2), 94.8 (C-3’),
113.9 (C-2), 121.6 (C-4), 122.9 (C-6), 127.0 (C-6’), 130.4
(C-5), 130.7 (C-5’), 136.1 (C-2’), 136.6 (C-4’), 137.6 (C-1),
139.3 (C-1’), 158.6 (C-3), 192.9 (CHO) ppm; MS-ESI: MS-
MS of m/z 339 (M+H): m/z 311(2), 217(100), 135(2). M+H:
m/z 338.98786, calculated value for C14H12O2I: 338.98766
(delta: 0.6 ppm).
By-products Formed by Aldol Reactions
4-Hydroxy-4-{2-[(2-iodophenyl)methoxy]phenyl}bu-
tan-2-one (5a). Separated by column chromatography with
1
hexane: acetone 3:1 eluent. H NMR (500 MHz, DMSO) δ
2.04 (s, 3H, CH3), 2.51-2.58 (m, 1H, butan-2-one CH2),
2.70-2.75 (m, 1H, butan-2-one CH2), 5.05 (s, 2H, OCH2),
5.30 (d, 1H, J=4.9 Hz, OH), 5.36-5.41 (m, 1H, butan-2-one
CH), 7.00 (td, 1H, J5,4=7.5 Hz, J5,6=7.5 Hz, J5,3=0.9 Hz, H-
5), 7.04 (dd, 1H, J3,4=8.2 Hz, J3,5=0.9 Hz, H-3), 7.14 (ddd,
1H, J4’,3’=7.8 Hz, J4’,5’=7.5 Hz, J4’,6’=1.6 Hz, H-4’), 7.25
(ddd, 1H, J4,3=8.2 Hz, J4,5=7.5 Hz, J4,6=1.8 Hz, H-4), 7.45
(td, 1H, J5’,4’= 7.5Hz, J5’,6’= 7.5Hz, J5’,3’=1.1 Hz, H-5’), 7.47
(dd, 1H, J6,5=7.5 Hz, J6,4=1.8 Hz, H-6), 7.58 (dd, 1H,
J6’,5’=7.5 Hz, J6’,4’=1.6 Hz, H-6’), 7.94 (dd, 1H, J3’,4’=7.8 Hz,
3-[(4-Iodophenyl)methoxy]benzaldehyde (3f). Sepa-
rated by column chromatography with hexane: ethyl acetate
1
30:1 eluent. H NMR (400 MHz, DMSO): δ = 5.17 (s, 2H,
OCH2), 7.28 (m, 2H, H-2’, H-6’), 7.49 (m, 1H, H-2), 7.53
(m, 2H, H-5, H-6), 7.55 (m, 1H, H-4), 7.77 (m, 2H, H-3’, H-
5’), 9.97 (s, 1H, CHO) ppm; 13C NMR (500 MHz, DMSO): δ
= 68.7 (OCH2), 94.0 (C-4’), 113.9 (C-2), 121.7 (C-4), 122.9
(C-6), 129.9 (C-2’, C-6’), 130.5 (C-5), 136.5 (C-1’), 137.3
(C-3’, C-5’), 137.6 (C-1), 158.6 (C-3), 192.9 (CHO) ppm;
MS-ESI: MS-MS of m/z 339 (M+H): m/z 311(1), 217(100),
135(2). M+H: m/z 338.98786, calculated value for
C14H12O2I: 338.98766 (delta: 0.6 ppm).
J
3’,5’=1.1 Hz, H-3’) ppm; MS-ESI: MS-MS of m/z 419
(M+Na): m/z 361(100), 333(1), 202(2). M+Na: m/z
419.01168, calculated value for C17H17O3INa: 419.01146
(delta: 0.5 ppm).
4-Hydroxy-4-{2-[(3-iodophenyl)methoxy]phenyl}bu-
4-[(2-Iodophenyl)methoxy]benzaldehyde (3g). Sepa-
rated by column chromatography with hexane: ethyl acetate
5:2 eluent. M.p. 71.4-74.8 °C . 1H NMR (500 MHz, DMSO):
δ = 5.18 (s, 2H, OCH2), 7.15 (td, 1H, J4’,3’=7.7 Hz, J4’,5’=7.7
Hz, J4’,6’=1.6 Hz, H-4’), 7.23 (m, 2H, H-3, H-5), 7.46 (td,
1H, J5’,4’=7.7 Hz, J5’,6’=7.7 Hz, J5’,3’=1.1 Hz, H-5’), 7.57
(dd, 1H, J6’,5’=7.7 Hz, J6’,4’=1.6 Hz, H-6’), 7.90 (m, 2H, H-2,
H-6), 7.95 (dd, 1H, J3’,4’=7.7 Hz, J3’,5’=1.1 Hz, H-3’), 9.89
(s, 1H, CHO) ppm; 13C NMR (500 MHz, DMSO): δ = 73.7
(OCH2), 99.5 (C-2’), 115.2 (C-3, C-5), 128.6 (C-5’), 130.0
(C-1), 130.2 (C-6’), 130.5 (C-4’), 131.9 (C-2, C-6), 138.2
(C-1’), 139.3 (C-3’), 163.2 (C-4), 191.4 (CHO) ppm; MS-
ESI: MS-MS of m/z 339 (M+H): m/z 311(3), 217(100).
M+H: m/z 338.98786, calculated value for C14H12O2I:
338.98766 (delta: 0.6 ppm).
tan-2-one (5b). Separated by column chromatography with
1
hexane: acetone 5:1 eluent. H NMR (500 MHz, DMSO) δ
2.12 (s, 3H, CH3, 2.53-2.60 (m, 1H, butan-2-one CH2), 2.65-
2.71 (m, 1H, butan-2-one CH2), 5.07-5.14 (m, 2H, OCH2),
5.33 (d, 1H, J=4.9 Hz, OH), 5.36-5.41 (m, 1H, butan-2-one
CH), 6.98 (td, 1H, J5,4=7.4 Hz, J5,6=7.4 Hz, J5,3=0.8 Hz, H-
5), 7.02 (dd, 1H, J3,4=8.2 Hz, J3,5=0.8 Hz, H-3), 7.21 (t, 1H,
J5’,4’=7.8 Hz, J5’,6’=7.8 Hz, H-5’), 7.22 (ddd, 1H, J4,3=8.2
Hz, J4,5=7.4 Hz, J4,6=1.7 Hz, H-4), 7.46 (dd, 1H, J6,5=7.4 Hz,
J6,4=1.7 Hz, H-6), 7.49 (ddd, 1H, J6’,5’=7.8 Hz, J6’,2’=1.6 Hz,
J
6’,4’=1.0 Hz, H-6’), 7.70 (ddd, 1H, J4’,5’=7.8 Hz, J4’,2’=1.6
Hz, J4’,6’=1.0 Hz, H-4’), 7.89 (t, 1H, J2’,4’=1.6 Hz, J2’,6’=1.6
Hz, H-2’) ppm; MS-ESI: MS-MS of m/z 419 (M+Na): m/z
361(100), 333(1>), 202(1). M+Na: m/z 419.01109, calcula-
ted value for C17H17O3INa: 419.01146 (delta: -0.9 ppm).
(3E-)-4-{3-[(2-Iodophenyl)methoxy]phenyl}but-3-en-
4-[(3-Iodophenyl)methoxy]benzaldehyde (3h). Sepa-
1
2-one (6c). Crystallized from hexane:ethyl acetate 1:1. H
rated by column chromatography with hexane: ethyl acetate
1
NMR (400 MHz, DMSO) δ 2.34 (s, 3H, CH3); 5.10 (s, 2H,
OCH2), 6.85 (d, 1H, J3,4=16.4 Hz, but-3-en-2-one C(3)H),
7.08 (ddd, 1H, J4’,5’=7.8 Hz, J4’,2’=2.7 Hz, J4’,6’=1.0 Hz, H-
4’), 7.14 (td, 1H, J4”,3”= 7.6 Hz, J4”,5”= 7.6 Hz, J4”,6”= 1.7
5:2 eluent. M.p. 51 °C. H NMR (500 MHz, DMSO): δ =
5.21 (s, 2H, OCH2), 7.21 (m, 2H, H-3, H-5), 7.22 (m, 1H, H-
5’), 7.49 (d, 1H, J6’,5’=7.8 Hz, H-6’), 7.72 (d, 1H, J4’,5’=8.0
Hz, H-4’), 7.86 (s, 1H, H-2’), 7.88 (m, 2H, H-2, H-6), 9.88
(s, 1H, CHO) ppm; 13C NMR (500 MHz, DMSO): δ = 68.6
Hz, H-4”), 7.32 (dt, 1H, J6’,5’= 7.8 Hz, J6’,2’= 1.1 Hz, J6’,4’
=

238 Letters in Drug Design & Discovery, 2017, Vol. 14, No. 2
Bölcskei et al.
1.1 Hz, H-6’), 7.38 (t, 1H, J5’,4’= 7.8 Hz, J5,’6’= 7.8 Hz, H-
5’), 7.39-7.42 (m, 1H, H-2’), 7.45 (td, 1H, J5”,4”= 7.6 Hz,
J5”,6”= 7.6 Hz, J5”,3”= 1.2 Hz, H-5”), 7.57 (dd, 1H, J6”,5”= 7.6
Hz, J6”,4”= 1.7 Hz, H-6”), 7.61 (d, 1H, J4,3=16.4 Hz, but-3-
en-2-one C(4)H), 7.93 (dd, 1H, J3”,4”= 7.6 Hz, J3”,5”= 1.2 Hz,
H-3”) ppm; MS-ESI: MS-MS of m/z 379 (M+H): m/z
361(15), 321(11), 252(12), 234(33), 217(100), 194(25),
145(4). M+H: m/z 379.01933, calculated value for
C17H16O2I: 379.01895 (delta: 1.0 ppm).
J=4.6 Hz, OH), 6.92-6.95 (m, 2H, H-3, H-5), 7.24-7.27 (m,
4H, H-2, H-6, H-2’, H-6’), 7.74-7.76 (m, 2H, H-3’, H-5’)
ppm; MS-ESI: MS-MS of m/z 419 (M+Na): m/z 361. M+Na:
m/z 419.01176, calculated value for C17H17O3INa: 419.01146
(delta: 0.7 ppm).
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
4-Hydroxy-4-{3-[(3-iodophenyl)methoxy]phenyl}bu-
tan-2-one (5d). Separated by column chromatography with
hexane: ethyl acetate 1:1 eluent. 1H NMR (400 MHz,
DMSO) δ 2.11 (s, 3H, CH3), 2.61-2.75 (m, 2H, butan-2-one
CH2), 4.94-5.00 (m, 1H, butan-2-one CH), 5.07 (s, 2H,
OCH2), 5.38 (d, 1H, J=4.8 Hz, OH), 6.86 (ddd, 1H, J4,5=8.0
Hz, J4,2=2.7 Hz, J4,6=1.0 Hz, H-4), 6.94 (m, 1H, H-6), 7.00-
7.02 (m, 1H, H-2), 7.20 (t, 1H, J5’,4’=7.8 Hz, J5’,6’=7.8 Hz,
H-5’), 7.23 (t, 1H, J5,4=8.0 Hz, J5,6=8.0 Hz, H-5), 7.47 (ddd,
1H, J6’,5’=7.8 Hz, J6’,2’=1.7 Hz, J6’,4’=1.0 Hz, H-6’), 7.71
(ddd, 1H, J4’,5’=7.8 Hz, J4’,2’=1.7 Hz, J4’,6’=1.0 Hz, H-4’),
7.83 (t, 1H, J2’,4’=1.7 Hz, J2’,6’=1.7 Hz, H-2’) ppm; MS-EI:
m/z (%): 396(M+, 4), 378(4), 338(12), 217(100), 90(26). M:
m/z 396.01953, calculated value for C17H17O3I: 396.02170
(delta: -2.2 ppm).
ACKNOWLEDGEMENTS
The authors are grateful to Árpád Könczöl for
LC-MS measurements and to Irini Bozonász and István
Abrudbányay for their valuable technical help in the prepara-
tive organic chemistry V. Háda is grateful to Ibolya Kreutz-
Kun and Erika Pallag for technical assistance in the MS
measurements. Zs. Dubrovay is grateful to Magdolna Nagy
for technical assistance in the NMR measurements.
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