Synthesis of 2,6-diaryl-substituted pyridines and their antitumor activities

Article abstract of DOI:10.1016/j.ejmech.2007.05.002

For the development of novel antitumor agents, we designed and synthesized 2,6-diaryl-substituted pyridine derivatives bearing three aryl groups, which are the bioisosteres of terpyridine, and evaluated their biological activities. Most of the 18 prepared compounds showed moderate cytotoxicity against several human cancer cell lines. From the structure-activity relationships we may conclude that the number of aryl groups employed would be critical for their biological activities.

Full text of DOI:10.1016/j.ejmech.2007.05.002

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European Journal of Medicinal Chemistry 43 (2008) 675e682
http://www.elsevier.com/locate/ejmech
Original article
Synthesis of 2,6-diaryl-substituted pyridines and their
antitumor activities
Jong-Keun Son a, Long-Xuan Zhao b, Arjun Basnet a, Pritam Thapa a,
Radha Karki a, Younghwa Na c, Yurngdong Jahng a, Tae Cheon Jeong a,
Byeong-Seon Jeong a, Chong-Soon Lee d, Eung-Seok Lee a,
*
a College of Pharmacy, Yeungnam University, Kyongsan 712-749, South Korea
b Department of Chemistry, Liaoning Normal University, Dalian, Liaoning 116-029, PR China
c College of Pharmacy, Catholic University of Daegu, Kyongsan 712-702, South Korea
d Department of Biochemistry, Yeungnam University, Kyongsan 712-749, South Korea
Received 7 March 2006; received in revised form 26 April 2007; accepted 10 May 2007
Available online 27 May 2007
Abstract
For the development of novel antitumor agents, we designed and synthesized 2,6-diaryl-substituted pyridine derivatives bearing three aryl
groups, which are the bioisosteres of terpyridine, and evaluated their biological activities. Most of the 18 prepared compounds showed moderate
cytotoxicity against several human cancer cell lines. From the structureeactivity relationships we may conclude that the number of aryl groups
employed would be critical for their biological activities.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Terpyridine; Cytotoxicity; Topoisomerase I inhibition; Anticancer agent; Bioisostere
1. Introduction
topoisomerase I or II inhibitory activity [11]. It would be
very interesting to design and prepare terpyridine isosteres
employing three aryl groups and to evaluate cytotoxicity and
topoisomerase I inhibitory activity. In addition, we anticipated
that we may obtain valuable information on the correlation
between the number of aryl groups employed in terpyridine
isosteres and biological activities such as cytotoxicity and
topoisomerase I inhibitory activity. In connection with the
previous studies, in the present study, we designed and pre-
pared 18 terpyridine bioisosteres employing three aryl groups
which have aromatic substituents including phenyl, furyl,
thienyl or pyridyl units at 2,6-position on pyridine, and evalu-
ated them for their cytotoxicity against several human cancer
cell lines and topoisomerase I inhibitory activity (Fig. 1).
Terpyridine has been extensively studied as a ligand in
a wide range of metal complexes [1,2] and DNA binding
agents [3e6]. Metal complexes of terpyridine can efficiently
intercalate into nucleic acid [7]. Recently, we reported that ter-
pyridine derivatives showed a strong cytotoxicity against sev-
eral human cancer cell lines as well as considerable
topoisomerase I inhibitory activity [8e12]. Although the cyto-
toxicity and topoisomerase I inhibitory activity of terpyridine
derivatives have been reported [9e12], a systematic study on
terpyridine isosteres has not been evaluated yet. From the re-
sults of the previous studies, terpyridine isosteres employing
four aryl groups showed strong cytotoxicity against several hu-
man cancer cell lines or strong topoisomerase I or II inhibitory
activity [9,10,12]. However, terpyridine derivatives employing
three aryl groups showed relatively weaker cytotoxicity and
2. Chemistry
Synthetic methods for the preparation via the modified
Krohnke synthesis [13,14] of 2,6-diaryl-substituted pyridine
* Corresponding author. Tel.: þ82 53 810 2827; fax: þ82 53 810 4654.
E-mail address: eslee@yu.ac.kr (E.-S. Lee).
¨
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.05.002

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J.-K. Son et al. / European Journal of Medicinal Chemistry 43 (2008) 675e682
Me
N
R2
Me
Me
MeO
MeO
R2
toluene
N
N
6
2
Me
N
+
+
N
reflux, 3h
R1
R2
O
O
N
3 (R2= c,d)
20 (R2= c,d)
DMF-DMA
α-Terpyridine
Bioisosteres of terpyridine
R1, R2: phenyl, furyl, thienyl or pyridyl
Me
1) t-BuOK, THF
R2
Fig. 1. Structures of a-terpyridine and 2,6-diaromatic substituted pyridine
derivatives.
R1
N
r.t., 14 h
Me
R1
R2
2) NH4OAc, AcOH
N
O
O
1 (R1= e-g)
20 (R2= c,d)
derivatives are summarized in Scheme 1. Treatment of aryl
methyl ketone 1 with pyridine-I2 by refluxing afforded the
desired pyridinium salts 2 [15]. The reaction of aryl methyl
ketone 3 with Me2NH2Cl in the presence of conc. HCl and
paraformaldehyde in absolute EtOH generated the Mannich
base hydrochlorides 4 [16], which were neutralized by addi-
tion of ammonium hydroxide solution to afford the Mannich
bases 5. Subsequent addition reaction with 2 and 5 in the pres-
ence of NH4OAc in hot EtOH afforded compounds 6e19 in
20.0e43.3% of overall yields.
Since some of the products 21e24 starting from 3- or
4-acetyl pyridine 3 (R2 ¼ c, d) were not prepared by utilizing
pyridinium salt like 2, a different synthetic method [17] was
accomplished as shown in Scheme 2. A toluene solution of
3 (R2 ¼ c, d) in the presence of DMFeDMA was refluxed
for 3 h to yield enaminone intermediates 20. The solution of
potassium tert-butoxide and 1 (R2 ¼ eeg) in anhydrous THF
was stirred at room temperature for 2 h, and each enaminone
intermediate 20 was added to the solution and allowed to
stir at the same temperature for 14 h. To the mixture were
added NH4OAc and acetic acid to afford products 21e24 in
20.5e29.3% of overall yields.
21-24
Scheme 2. Synthetic pathway for the 2,6-diaryl pyridines 21e24.
and the compounds could be obtained in short steps. The 18
prepared compounds are shown in Fig. 2.
The HPLC results of the prepared compounds displayed
that they had high purity in a range of 96.7e100.0%. The
1
data of H NMR, 13C NMR, ESI LC/MS, HPLC including
retention time, melting point and yield for final products are
shown in Table 1.
For the evaluation of antitumor cytotoxicity, four different
human cancer cell lines were utilized: A549 (human lung car-
cinoma), SK-OV-3 (human ovary adenocarcinoma), SK-MEL-2
(human malignant melanoma), and HCT15 (human colon
adenocarcinoma). The IC50 values of 2,6-diaryl-substituted
pyridine derivatives 6e19 and 21e24 against above human
cancer cell lines are shown in Table 2. Most of the prepared
compounds showed moderate cytotoxicity, generally
10e80 mM, against human cancer cell lines, although they
are less potent than a-terpyridine and doxorubicin used as
control references. However, the prepared compounds did not
exhibit significant topoisomerase I inhibitory activity. Some
of the topoisomerase I inhibitory results are shown in Fig. 3.
In comparison with previous study, terpyridine bioisosteres
employing four aryl groups indicated relatively strong cyto-
toxicity and topoisomerase I or II inhibitory activity
[9,10,12]. Some of the prepared compounds showed much
stronger cytotoxicity than doxorubicin and a-terpyridine, or
much stronger topoisomerase I inhibition than camptothecin.
However, terpyridine derivatives employing three aryl groups
showed relatively weaker cytotoxicity and topopisomerase I
inhibition [11]. Since the prepared compounds in this study
were employed three aryl groups, the biological activity would
be lower than four aryl groups. From the structureeactivity
relationships we may conclude that the number of aryl groups
employed would be critical for their biological activities.
In conclusion, we have designed and prepared the eighteen
2,6-diaryl-substituted pyridine derivatives employing three
aryl groups in connection with previous study, and evaluated
their antitumor cytotoxicity and topoisomerase I inhibitory
activity. Most of the prepared compounds showed moderate
cytotoxicity against several human cancer cell lines although
they are less potent than control references. But the prepared
compounds did not exhibit significant topoisomerase I inhibi-
tory activity. From the structureeactivity relationships we may
conclude that the number of aryl groups employed would be
critical for their biological activities. This study may provide
3. Results and discussion
The synthetic method for the preparation of 2,6-diaromatic
substituted pyridine derivatives was relatively easy and simple,
I
N
R1
R1
I2, pyridine
reflux, 3 h
O
O
1 (R1= a-g)
2 (R1= a-g)
Me
N
Me
c-HCl, HCHO
R2
HCl
R2
R2
Me2NH2Cl
N
NH4OH
Me
Me
EtOH, reflux, 16 h
O
O
O
2
3 (R = e-g)
4 (R2= e-g)
5(R2= e-g)
Me
N
I
N
R1
R2
NH4OAc, EtOH
reflux, 18 h
Me
+
R1
R2
O
N
O
2 (R1= a-g)
5 (R2= e-g)
6-19
S
O
S
N
N
c
N
d
a
b
e
f
g
Scheme 1. Synthetic pathway for the 2,6-diaryl pyridines 6e19.

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J.-K. Son et al. / European Journal of Medicinal Chemistry 43 (2008) 675e682
677
S
S
S
S
S
N
S
N
O
N
N
N
N
9
6
7
8
O
O
O
O
N
N
N
N
N
N
N
S
10
11
12
13
O
N
N
N
S
S
S
N
S
N
S
14
15
16
17
S
S
O
N
S
N
N
N
S
N
N
18
19
21
22
O
N
N
N
23
24
Fig. 2. Structures of the prepared compounds.
valuable information to the researchers working on the devel-
opment of antitumor agents. Structureeactivity relationship
study of the 2,6-diaryl-substituted pyridine derivatives indi-
cates that there is not a significant correlation according to
substituted aromatic compounds, but in general furan-contain-
ing compounds 8, 11e13 and 23 showed relatively weaker
cytotoxicity.
elution of 50% B in A to 100% B at a flow rate of 1.0 mL/min
at 254 nm UV detection, where mobile phase A was doubly
distilled water and mobile phase B was 90% acetonitrile in
water. Retention time was given in minutes, and purity of com-
pounds was described as percent (%). ESI LC/MS analyses
were performed with a Finnigan LCQ AdvantageÒ LC/MS/
MS spectrometry utilizing XcaliburÒ program. For ESI LC/
MS, LC was performed with a 5 mL injection volume on
a GL ScienceÒ 5 mm ODS reverse-phase C18 LC/MS column
(150 ꢀ 1.5 mm, i.d.) with a gradient elution of 10% B in A to
90% B in A for 10 min and retaining 90% B in A for 10 min at
a flow rate of 180 mL/min, where mobile phase A was 0.1%
formic acid in water and mobile phase B was 0.1% formic
acid in acetonitrile. MS ionization conditions were as following:
Sheath gas flow rate: 70 arb, Aux gas flow rate: 20 arb, I spray
voltage: 4.5 kV, capillary temp.: 215 ꢁC, capillary voltage:
21 V, tube lens offset: 10 V.
4. Experimental
4.1. Materials and methods
Compounds used as starting materials and reagents were
purchased from Aldrich Chemical Co., Fluka, Tokyokasei,
Junsei and were used without further purification. Thin-layer
chromatography (TLC) and column chromatography were per-
formed with Kieselgel 60 F254 (Merck) and silica gel Kieselgel
60, (230e400 mesh, Merck), respectively. All compounds
containing aromatic ring were visualized on TLC plates with
UV light. Nuclear magnetic resonance (NMR) spectra were
taken on a Bruker AMX 250 MHz for 1H NMR and
62.5 MHz for 13C NMR, and tetramethylsilane (TMS) was
used as an internal standard. Chemical shifts (d) were recorded
in parts per million, and coupling constants (J ) in hertz. Melt-
ing points were determined in open capillary tubes on electro-
thermal 1A 9100 digital melting point apparatus and were
uncorrected. HPLC analyses were performed in Beckman
HP controller and Beckmann UV detector using Beckmann
ultraspere HPLC column (4.6 mm ꢀ 150 mm, 5 mm Microsorb
C-18 column) with a 20 mL injection volume with a gradient
4.1.1. General procedure for the preparation
of compounds 2
A mixture of 1aeg (20 mmol) and I2 (20 mmol) in pyridine
(25 mL) was refluxed for 3 h. After cooling the mixture to
20 ꢁC, the precipitate was filtered and washed with cold pyri-
dine several times, which was used in the next step without
further purification.
4.1.1.1. 1-(2-Oxo-phenylethyl)pyridinium iodide 2a. Light
brown solid; yield 99.9%; mp 175.0e179.0 ꢁC; 1H NMR
(250 MHz, CDCl3) d 9.00 (d, J ¼ 6.5 Hz, 2H, pyridinium
H-2, H-6), 8.74 (dt, J ¼ 7.8, 1.2 Hz, 1H, pyridinium H-4),

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678
J.-K. Son et al. / European Journal of Medicinal Chemistry 43 (2008) 675e682
Table 1
Spectral data of the prepared compounds
Compd.
no.
Purity by HPLC:
% (retention
time: min)
1H NMR (200 MHz), d (ppm), J (Hz)/13C NMR (62.5 MHz), d (ppm)/ESI LC/MS ([MH]þ)/melting point (ꢁC)/total yield (%)
6
100.0 (13.5 min)
8.68 (ddd, J ¼ 4.8, 1.8, 0.9 Hz, 1H, pyridine H-60), 8.58 (ddd, J ¼ 7.8, 1.2, 0.9 Hz, 1H, pyridine H-30),
8.29 (dd, J ¼ 7.8, 0.9 Hz, 1H, pyridine H-3), 7.85 (dt, J ¼ 7.8, 1.8 Hz, 1H, pyridine H-40), 7.82 (t, J ¼ 7.8 Hz, 1H,
pyridine H-4), 7.67 (dd, J ¼ 7.8, 0.9 Hz, 1H, pyridine H-5), 7.66 (dd, J ¼ 3.6, 1.1 Hz, 1H, thiophene H-5), 7.42
(dd, J ¼ 5.1, 1.1 Hz, 1H, thiophene H-3), 7.32 (ddd, J ¼ 7.8, 4.8, 1.2 Hz, 1H, pyridine H-50), 7.14 (dd, J ¼ 5.1, 3.7 Hz,
1H, thiophene H-4)/155.81, 155.52, 151.79, 148.99, 145.24, 137.61, 136.91, 127.99, 127.56, 124.50, 123.81, 121.31, 118.99,
118.56/239/76.2 ꢁC/27.5%
7
8
97.3 (14.4 min)
98.8 (14.8 min)
7.63 (dd, J ¼ 8.5, 7.2 Hz, 1H, pyridine H-4), 7.62 (dd, J ¼ 3.7, 1.1 Hz, 2H, thiophene H-5, H-50), 7.47 (d, J ¼ 7.8 Hz,
2H, pyridine H-3, H-5), 7.40 (dd, J ¼ 5.0, 1.1 Hz, 2H, thiophene H-3, H-30), 7.11 (dd, J ¼ 5.0, 3.7 Hz, 2H,
thiophene H-4, H-40)/152.09, 144.83, 137.28, 127.91, 127.73, 124.68, 116.66/244/75.1ꢁ C/24.0%
7.69 (t, J ¼ 7.8 Hz, 1H, pyridine H-4), 7.61 (dd, J ¼ 3.7, 1.1 Hz, 1H, thiophene H-5), 7.53 (dd, J ¼ 7.8, 0.9 Hz, 1H,
pyridine H-3), 7.52 (dd, J ¼ 1.8, 0.8 Hz, 1H, furan H-5), 7.49 (dd, J ¼ 7.8, 0.9 Hz, 1H, pyridine H-5), 7.39 (dd, J ¼ 5.1,
1.1 Hz, 1H, thiophene H-3), 7.17 (dd, J ¼ 3.4, 0.7 Hz, 1H, furan H-3), 7.10 (dd, J ¼ 5.1, 3.7 Hz, 1H, thiophene H-4),
6.53 (dd, J ¼ 3.4, 1.8 Hz, 1H, furan H-4)/153.64, 152.20, 148.98, 144.92, 143.22, 137.22, 127.90, 127.60, 124.65,
116.85, 116.40, 112.02, 108.98/228/84.3 ꢁC/38.7%
9
99.0 (16.6 min)
100.0 (16.5 min)
8.12 (dd, J ¼ 7.8, 1.1 Hz, 2H, pyridine H-3, H-5), 7.74 (t, J ¼ 7.8 Hz, 1H, pyridine H-4), 7.65 (dd, J ¼ 3.6, 1.0 Hz, 1H,
thiophene H-5), 7.62e7.57 (m, 2H, phenyl H-2, H-6), 7.53e7.44 (m, 3H, phenyl H-3, H-4, H-5), 7.25 (dd, J ¼ 5.0,
1.0 Hz, 1H, thiophene H-3), 7.12 (dd, J ¼ 5.0, 3.7 Hz, 1H, thiophene H-4)/157.52, 153.09, 146.33, 139.78, 138.25, 129.96,
129.55, 128.79, 128.46, 127.76, 125.35, 119.14, 117.82/238/74.8 ꢁC/25.0%
10
8.00 (dd, J ¼ 3.0, 1.0 Hz, 1H, thiophene H-5), 7.74 (dd, J ¼ 5.0, 1.0 Hz, 1H, thiophene H-3), 7.70 (t, J ¼ 7.8 Hz, 1H,
pyridine H-4), 7.62 (d, J ¼ 3.7 Hz, 1H, thiophene H-20), 7.50 (dd, J ¼ 13.7, 7.8 Hz, 2H, pyridine H-3, H-5), 7.40
(dd, J ¼ 5.0, 0.7 Hz, 1H, thiophene H-50), 7.40 (dd, J ¼ 5.0, 2.1 Hz, 1H, thiophene H-40), 7.08 (dd, J ¼ 5.0, 3.7 Hz, 1H,
thiophene H-4)/152.91, 152.18, 145.32, 141.99, 137.34, 127.91, 127.60, 126.28, 126.15, 124.46, 123.81, 118.12,
116.62/244/104.1 ꢁC/39.0%
11
12
95.9 (11.5 min)
97.4 (8.6 min)
8.68 (ddd, J ¼ 4.8, 1.7, 0.9 Hz, 1H, pyridine H-60), 8.54 (ddd, J ¼ 7.7, 1.2, 0.9 Hz, 1H, pyridine H-30), 8.29 (dd, J ¼ 7.8,
1.0 Hz, 1H, pyridine H-3), 7.85 (t, J ¼ 7.8 Hz, 1H, pyridine H-4), 7.84 (dt, J ¼ 7.7, 1.7 Hz, 1H, pyridine H-40),
7.71 (dd, J ¼ 7.8, 1.0 Hz, 1H, pyridine H-5), 7.56 (dd, J ¼ 1.8 Hz, 0.7 Hz, 1H, furan H-5), 7.32 (ddd, J ¼ 7.7, 4.8, 1.2 Hz, 1H,
pyridine H-50), 7.19 (dd, J ¼ 3.4, 0.7 Hz, 1H, furan H-3), 6.56 (dd, J ¼ 3.4, 1.8 Hz, 1H, furan H-4)/156.00, 155.70,
153.93, 149.04, 148.76, 143.22, 137.55, 136.84, 123.77, 121.24, 119.15, 118.39, 112.00, 108.62/223/52.5 ꢁC/21.3%
9.27 (dd, J ¼ 2.2, 0.7 Hz, 1H, pyridine H-20), 8.66 (dd, J ¼ 4.8, 1.6 Hz, 1H, pyridine H-40), 8.40 (ddd, J ¼ 8.0, 2.1, 1.8 Hz,
1H, pyridine H-50), 7.82 (t, J ¼ 7.8 Hz, 1H, pyridine H-4), 7.69 (dd, J ¼ 7.8, 0.9 Hz, 1H, pyridine H-3), 7.62 (dd, J ¼ 7.7,
0.9 Hz, 1H, pyridine H-5), 7.56 (dd, J ¼ 1.7, 0.7 Hz, 1H, furan H-5), 7.43 (ddd, J ¼ 8.0, 4.8, 0.8 Hz, 1H, pyridine H-60),
7.20 (dd, J ¼ 3.4, 0.7 Hz, 1H, furan H-3), 6.54 (dd, J ¼ 3.4, 1.8 Hz, 1H, furan H-4)/154.34, 153.69, 149.93, 149.59,
148.33, 143.43, 137.61, 134.68, 134.39. 123.53, 118.51, 117.45, 112.11, 109.09/223/82.8 ꢁC/20.0%
7.73 (dd, J ¼ 8.5, 7.2 Hz, 1H, pyridine H-4), 7.55 (d, J ¼ 7.8 Hz, 2H, pyridine H-3, H-5), 7.54 (d, J ¼ 0.8 Hz, 2H, furan
H-5, H-50), 7.14 (dd, J ¼ 3.4, 0.7 Hz, 2H, furan H-3, H-30), 6.53 (dd, J ¼ 3.4, 1.8 Hz, 2H, furan H-4, H-40)/153.67, 149.13,
143.27, 137.19, 116.68, 111.98, 108.87/212/92.3 ꢁC/36.6%
13
14
100.0 (10.8 min)
100.0 (15.6 min)
8.08 (dd, J ¼ 8.1, 1.5 Hz, 2H, pyridine H-3, H-5), 7.76 (t, J ¼ 7.8 Hz, 1H, pyridine H-4), 7.64e7.58 (m, 2H, phenyl H-2,
H-6), 7.54 (dd, J ¼ 1.8, 0.8 Hz, 1H, furan H-5), 7.52e7.41 (m, 3H, phenyl H-3, H-4, H-5), 7.19 (dd, J ¼ 3.4, 0.8 Hz, 1H,
furan H-3), 6.54 (dd, J ¼ 3.4, 1.8 Hz, 1H, furan H-4)/156.93, 154.07, 149.19, 143.16, 139.20, 137.31, 129.50, 129.00,
128.65, 128.28, 126.95, 118.54, 116.74, 112.00, 108.72/222/oil/26.2%
15
16
17
18
96.7 (11.1 min)
98.0 (8.5 min)
99.6 (15.3 min)
100.0 (15.8 min)
8.69 (ddd, J ¼ 4.8, 1.5, 0.8 Hz, 1H, pyridine H-60), 8.59 (d, J ¼ 8.0 Hz, 1H, pyridine H-30), 8.31 (dd, J ¼ 7.8, 0.7 Hz, 1H,
pyridine H-3), 8.02 (dd, J ¼ 3.0, 1.2 Hz, 1H, thiophene H-2), 7.85 (t, J ¼ 7.8 Hz, 1H, pyridine H-4), 7.81 (dd, J ¼ 5.1,
1.2 Hz, 1H, pyridine H-40), 7.80 (td, J ¼ 7.8, 1.3 Hz, 1H, thiophene H-4), 7.65 (dd, J ¼ 7.8, 0.8 Hz, 1H, pyridine H-5),
7.43 (dd, J ¼ 5.0, 3.0 Hz, 1H, thiophene H-5), 7.32 (ddd, J ¼ 7.5, 4.8, 1.1 Hz, 1H, pyridine H-50)/156.21, 155.65, 152.67,
149.04, 142.34, 137.67, 136.84, 126.33, 126.22, 123.74, 123.55, 121.22, 120.12, 118.99/239/81.4 ꢁC/24.8%
9.30 (d, J ¼ 2.0 Hz, 1H, pyridine H-20), 8.66 (dd, J ¼ 4.8, 1.6 Hz, 1H, pyridine H-60), 8.43 (dt, J ¼ 8.0, 1.9 Hz, 1H,
pyridine H-40), 8.03 (dd, J ¼ 3.0, 2.0 Hz, 1H, thiophene H-2), 7.82 (t, J ¼ 7.8 Hz, 1H, pyridine H-4), 7.78 (dd, J ¼ 5.0,
1.8 Hz, 1H, thiophene H-4), 7.65 (t, J ¼ 7.7 Hz, 2H, pyridine H-3, H-5), 7.43 (dd, J ¼ 7.8, 4.8 Hz, 1H, pyridine H-50),
7.42 (dd, J ¼ 5.0, 3.0 Hz, 1H, thiophene H-5)/154.21, 153.47, 149.88, 148.34, 142.05, 137.69, 134.78, 134.31, 126.33,
126.24, 123.90, 123.51, 119.15, 118.32/239/80.6 ꢁC/27.0%
7.97 (dd, J ¼ 3.0, 1.2 Hz, 1H, thiophene H-2), 7.73 (t, J ¼ 7.8 Hz, 1H, pyridine H-4), 7.71 (dd, J ¼ 5.1, 3.8 Hz, 1H,
thiophene H-4), 7.57 (dd, J ¼ 7.8, 0.9 Hz, 1H, pyridine H-3), 7.53 (dd, J ¼ 1.7, 0.8 Hz, 1H, furan H-5), 7.47 (dd, J ¼ 7.8,
0.9 Hz, 1H, pyridine H-5), 7.39 (dd, J ¼ 5.1, 3.0 Hz, 1H, thiophene H-5), 7.16 (dd, J ¼ 3.4, 0.7 Hz, 1H, furan H-3), 6.54
(dd, J ¼ 3.4, 1.8 Hz, 1H, furan H-4)/156.80, 153.08, 142.50, 139.37, 137.42, 128.96, 128.65, 126.93, 126.38, 126.10,
123.61, 118.45, 118.33/238/73.4 ꢁC/43.3%
8.14e8.10 (m, 2H, phenyl H-2, H-6), 8.02 (dd, J ¼ 3.0, 1.2 Hz, 1H, thiophene H-2), 7.79 (dd, J ¼ 5.1, 1.3 Hz, 1H,
thiophene H-4), 7.77 (t, J ¼ 7.8 Hz, 1H, pyridine H-4), 7.63 (dd, J ¼ 7.8, 0.9 Hz, 1H, pyridine H-5), 7.56 (dd, J ¼ 7.7,
0.9 Hz, 1H, pyridine H-3), 7.53e7.45 (m, 3H, phenyl H-3, H-4, H-5), 7.41 (dd, J ¼ 5.0, 3.0 Hz, 1H, thiophene H-5)/153.96,
153.11, 149.13, 143.17, 142.17, 137.31, 126.31, 126.16, 123.74, 118.38, 116.46, 112.00, 108.68/228/105.7 ꢁC/28.8%