Expanding the chemical space: Discovery of new anticancer 3-arylbenzofuran derivatives

Article abstract of DOI:10.1002/jhet.4043

A new chemical space was generated via C₂-functionalization of 3-arylbenzofurans. Mannich reaction of 3-arylbenzofurans with secondary amines and formaldehyde allowed for installation of aminomethyl unit at C₂ position of benzofurans. A formyl group at C₂ site introduced as a result of Vilsmeier-Haack formylation of 3-arylbenzofurans was employed as a reacting partner for three-component Kabachnik-Fields reaction with various amines and triethyl phosphite to give a wide variety of aminomethylphosphonates. Furthermore, several benzo[d]oxazoles and pyrrolo[1,2-a]quinoxalines were prepared by using the formyl group. Biological screening of the synthesized compounds revealed that the benzofuran bearing a pyrrolo[1,2-a]quinoxaline moiety (5b) most potently inhibited the viability of human blood cancer cells, but not solid tumor cells. Caspase activity assay, analysis of Annexin V-positive cells, and Western blot analysis indicated that 5b-induced death of human lymphoma U937 cells could result from its potential to induce the caspase-dependent apoptotic death of blood cancer cells with inhibition of ERK activation.

Full text of DOI:10.1002/jhet.4043

Received: 13 April 2020
DOI: 10.1002/jhet.4043
Revised: 13 May 2020
Accepted: 23 May 2020
A R T I C L E
Expanding the chemical space: Discovery of new anticancer
3-arylbenzofuran derivatives
Jinhwang Kim1 | Hyeon-Min Cha2 | Mikyung Park3 | Dileep K. Singh1
Gi H. Bae1 | Seong H. Kim2,3 | Ikyon Kim1
|
1College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, South Korea
2Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, South Korea
3Innovative Target Research Center, Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, South Korea
Correspondence
Seong H. Kim, Graduate School of New
Abstract
Drug Discovery and Development,
Chungnam National University, Daejeon,
South Korea.
A
new chemical space was generated via C2-functionalization of
3-arylbenzofurans. Mannich reaction of 3-arylbenzofurans with secondary amines
and formaldehyde allowed for installation of aminomethyl unit at C2 position of
benzofurans. A formyl group at C2 site introduced as a result of Vilsmeier-Haack
formylation of 3-arylbenzofurans was employed as a reacting partner for three-
component Kabachnik-Fields reaction with various amines and triethyl phosphite
to give a wide variety of aminomethylphosphonates. Furthermore, several benzo
[d]oxazoles and pyrrolo[1,2-a]quinoxalines were prepared by using the formyl
group. Biological screening of the synthesized compounds revealed that the
benzofuran bearing a pyrrolo[1,2-a]quinoxaline moiety (5b) most potently
inhibited the viability of human blood cancer cells, but not solid tumor cells.
Caspase activity assay, analysis of Annexin V-positive cells, and Western blot anal-
ysis indicated that 5b-induced death of human lymphoma U937 cells could result
from its potential to induce the caspase-dependent apoptotic death of blood cancer
cells with inhibition of ERK activation.
Email: hwan@krict.re.kr
Ikyon Kim, College of Pharmacy and
Yonsei Institute of Pharmaceutical
Sciences, Yonsei University, Incheon,
South Korea.
Email: ikyonkim@yonsei.ac.kr
Present address
Dileep K. Singh, Department of
Chemistry, Bipin Bihari College, Jhansi,
Uttar Pradesh, India
Funding information
National Research Foundation of Korea,
Grant/Award Numbers:
NRF-2017R1A2A2A05069364,
NRF-2018R1A6A1A03023718,
NRF-2020R1A2C2005961; Korea Research
Institute of Chemical Technology, Grant/
Award Numbers: KK1932-20,
KK1803-F00, KK1703-F02
1 | INTRODUCTION
Notably, 3-arylbenzofuran skeleton represents a key
pharmacophore in a number of medicinal research areas
Despite extensive use of the privileged structures in
medicinal chemistry for drug discovery, there are still
many rooms to generate new chemical spaces[1] based
on them as numerous substitution patterns around the
core framework are possible. As shown in Figure 1,
3-arylbenzofuran moiety, a subclass of benzofurans, has
been frequently observed in many natural products as
well as unnatural medicinal agents.
by having a distinctive functional moiety at C2 position,
exhibiting antibacterial, anticancer, or antihyperglycemic
activity.[2] Thus, expansion of this heterocyclic chemical
space via generation of new 3-arylbenzofurans with
unique substitution patterns would offer opportunities
for biological exploration associated with these chemical
entities, which would deliver discovery of useful thera-
peutic agents for the treatment of diseases. These
J Heterocyclic Chem. 2020;1–15.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals LLC.
1

2
KIM ET AL.
FIGURE 1 Some bioactive natural and unnatural compounds bearing a 3-arylbenzofuran unit
observations as well as our continued research interest
on benzofurans[3] led us to design and synthesize novel
3-arylbenzofuran compounds by installing new func-
tional groups at C2 site for biological evaluation. Here,
we wish to report our strategy to extend new chemical
territory based on 3-arylbenzofuran and their biological
activity.
aminomethylation method as some benzofurans with an
aminomethyl moiety at C2 site were reported to
display intriguing biological activities.[4] Thus, several
3-arylbenzofurans 1[5] were treated with formaldehyde and
amine in the presence of acetic acid at 100ꢀC to give the
corresponding aminomethylated benzofurans 2 (Scheme 1).
Next, Vilsmeier-Haack formylation[6] of 1 was carried
out to afford aldehyde 3 as an intermediate for further
diversification at C2 site (Scheme 2).[7] The resulting alde-
hyde of 3 was used to make aminomethylphosphonates[8]
by three-component Kabachnik-Fields reaction[9] with
2 | RESULTS AND DISCUSSION
As a means to introduce novel substituents at C2 position
of 3-arylbenzofurans, we first used the Mannich
amines and triethyl phosphite under FeCl3 catalysis.[10]
new benzofuran chemical library 4 bearing diverse
A

KIM ET AL.
3
SCHEME 1 Synthesis of New 3-Arylbenzofurans 2. aReaction conditions: 1, formaldehyde (3.0 equiv), amine (4.0 equiv), and AcOH
(19.0 equiv) in EtOH/H2O (2:1), 100ꢀC. bIsolated yield (%)
aminomethylphosphonates was constructed under opti-
mized conditions.
attention to evaluate the biological activity of the com-
pounds. Anticancer screening results revealed that the
benzofuran bearing a pyrrolo[1,2-a]quinoxaline moiety
(5b) exhibited the most potent activity among the com-
pounds evaluated; IC50 of 5b on the viability of human
acute myeloid leukemia (AML) U937 cells was 9.34 μM
(Figure 2A). Cytarabine, one of the major regimens in the
treatment of AML, was used as a reference.[15] Benzofu-
rans having a morpholinomethyl (2d) or piperidinomethyl
group (2e) at C2 position displayed weak potency.
Furthermore, as shown in Scheme 3, the formyl
group of 3 was utilized to form pyrrolo[1,2-a]quinoxa
line[11] and benzo[d]oxazole[12] as these two hetero-
aromatic moieties have been known to display interesting
pharmacological functions including antibacterial and
anticancer activities.[13,14]
Having established a novel chemical library (2, 4, 5,
and 6) starting from 3-arylbenzofurans, we turn our

4
KIM ET AL.
Likewise, decreased anticancer activities were observed
with compounds possessing an aminomethylphosphonate
(4). Decreased potency of 5c implied that a big substituent
such as benzyl had a negative impact on anticancer activ-
ity. Interestingly, benzofuran-benzo[d]oxazole hybrid (6b)
showed less anticancer potency than 5b, indicating the
importance of the nitrogen-containing heterocycles on
anticancer activity. In addition, the caspase activity assay
and the analysis of Annexin V-positive cells revealed that
the caspase-dependent apoptosis could result in the 5b-
induced death of U937 cells as done by cytarabine
(Figure 2B,C).[16]
Furthermore, anticancer activity of 5b compared
with those of 5a and 5c was investigated in other
blood cancer cells such as human T-lymphoblastic
leukemia Jurkat cells and human leukemia HL-60
cells, and solid tumor cell lines such as human hepa-
toblastoma HepG2 cells and human gastric cancer
Hs746T cells. As shown in U937 cells, 5b exhibited
the potential anticancer activity in Jurkat and HL-60,
but not in solid tumor cells (Table 1). Both 5a and
5c did not show any cytotoxic activity in cancer cells
used in this study. This result suggested that antican-
cer activity of 5b could be specific in blood cancer
cells. This hypothesis might be evaluated in a further
study using several blood cancer cells and NCI-60
tumor cell lines screen.
Since activation of caspase-3 requires its proteo-
lytic processing, the caspase-dependent cell death by
5b was confirmed by Western blot analysis; the
cleaved form of caspase-3 was increased by 5b
(Figure 3).[17] The nuclear enzyme poly(ADP-ribose)
polymerase (PARP) is one of the main targets of
caspase-3 and its cleavage serves as a marker of apo-
ptotic cells.[18] The 5b-mediated induction of cleaved
PARP was also confirmed by Western blot analysis
using anti-PARP antibody and anti-cleaved PARP
antibody as shown in the second image and the third
image in Figure 3, respectively. Cleavages of both
caspase-3 and PARP by 5a or 5c were not observed
here. In addition, the effect of 5b on the activation
of survival-related ERK and stress-responsive-JNK
was investigated.[19] As shown in Figure 3, 5b, not
5a or 5c, strongly inhibited the phosphorylation of
ERK, but not JNK. This result suggested that ERK
signaling pathway could be associated with 5b-
mediated induction of caspase-dependent apoptosis
in U937 cells.
3 | CONCLUSIONS
SCHEME 2 Synthesis of New 3-Arylbenzofurans 4. aReaction
conditions: From 1 to 3: 1, POCl3 (3.0 equiv), DMF (3.0 equiv),
CH2Cl2, 0ꢀC. From 3 to 4: 3, amine (1.2 equiv), triethyl phosphite
(1.5 equiv), FeCl3 (0.1 equiv), EtOH, 100ꢀC. bIsolated yield (%)
In conclusion, with an aim to expand the chemical space
based on 3-arylbenzofuran core skeleton, C2-

KIM ET AL.
5
5a (69)
5b (85)
5c (44)
6a (41)
6b (68)
6c (70)
SCHEME 3 Synthesis of New 3-Arylbenzofurans 5 and 6. aReaction conditions: From 3 to 5: 3, 2-(1H-pyrrol-1-yl)aniline (1.2 equiv),
and DBSA (0.2 equiv), THF, 60ꢀC. From 3 to 6: 3, 2-aminophenol (2.0 equiv), and DBSA (0.2 equiv), EtOH, 60ꢀC. DDQ (1.5 equiv), THF,
rt. bIsolated yield (%)
functionalization of 3-arylbenzofuran was carried out,
thereby leading to a new 3-arylbenzofuran chemical
library having a number of nitrogen-containing groups at
C2 site. Biological screening of the synthesized com-
these results and evaluation of these compounds under
different biological settings as well as further extension of
chemical space are underway and the results will be
reported soon.
pounds
showed
that
benzofuran-pyrrolo[1,2-a]
quinoxaline hybrid (5b) strongly inhibit the viability of
human blood cancer cells, but not solid tumor cell lines.
Furthermore, the caspase activity assay, the analysis of
Annexin V-positive cells, and Western blot analysis rev-
ealed that 5b-induced death of U937 cells could result
from its potential to induce the caspase-dependent apo-
ptotic death of blood cancer cells with the inhibition of
ERK activation. More structural optimization based on
4 | EXPERIMENTAL SECTION
4.1 | General methods
Unless specified, all reagents and starting materials
were purchased from commercial sources and used as
received without purification. “Concentrated” refers to

6
KIM ET AL.
FIGURE 2 The effect of compounds on the viability of U937 cells was evaluated at 10 μM using CCK-8 assay A. Apoptotic activity of
5b was evaluated by measuring capspase-3/7 activity B, and counting Annexin V-positive cells C. *, P < 0.001
TABLE 1 IC50 of 5a, 5b, and 5c in
viability of cancer cells
5a (μM)
>30
5b (μM)
9.34
5c (μM)
>30
Cytarabine (μM)
U937
0.19
0.15
Jurkat
HL-60
HepG2
Hs746T
>30
8.90
>30
>30
7.52
>30
0.16
>30
>30
>30
6.50
>30
>30
>30
19.78
the removal of volatile solvents via distillation using a
rotary evaporator. “Dried” refers to pouring onto, or
passing through, anhydrous magnesium sulfate followed
by filtration. Flash chromatography was performed
using silica gel (230-400 mesh) with hexanes, ethyl ace-
tate, and dichloromethane as the eluents. All reactions
were monitored by thin-layer chromatography on
0.25 mm silica plates (F-254) visualizing with UV light.
Melting points were measured using a capillary melting
point apparatus. 1H and 13C NMR spectra were recorded
on 400 MHz NMR spectrometer and were described as
chemical shifts, multiplicity (s, singlet; d, doublet; t,
triplet; q, quartet; and m, multiplet), coupling constant
in hertz (Hz), and number of protons. HRMS were mea-
sured with electrospray ionization (ESI) and Q-TOF
mass analyzer.
4.1.1 | General procedure for the
synthesis of 2
To a vial charged with 1 (0.089 mmol), amine (4.0 equiv),
and formaldehyde (3.0 equiv) in ethanol (1 mL) and H2O
(0.5 mL) was added acetic acid (19.0 equiv) at room tem-
perature. After being stirred at 100ꢀC for 3 hours, the
reaction mixture was concentrated under reduced pres-
sure. The residue was purified by silica gel column chro-
matography (n-hexane: ethyl acetate:dichloromethane) to
give 2.
4-((6-Methoxy-3-phenylbenzofuran-2-yl)methyl)
morpholine (2a)
White solid, mp: 131ꢀC-132ꢀC; 1H NMR (400 MHz,
CDCl3) δ 7.56 to 7.51 (m, 2H), 7.51 to 7.42 (m, 3H),

KIM ET AL.
7
7.10 (s, 1H), 6.98 (s, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 3.75 to
6.69 (m, 6H), 2.50 (br s, 4H); 13C NMR (100 MHz, CDCl3)
δ 149.1, 148.3, 146.9, 132.5, 129.4, 129.0, 127.6, 20.2,
101.4, 95.6, 67.0, 56.6, 56.4, 54.0, 53.5; HRMS (ESI-
QTOF) m/z [M + Na]+ calcd for C21H23NNaO4 376.1519,
found 376.1515.
4-((5,6-Dimethoxy-3-(4-methoxyphenyl)benzofuran-2-yl)
methyl)morpholine (2d)
Light yellow solid, mp: 114ꢀC to 115ꢀC; 1H NMR
(400 MHz, CDCl3) δ 7.46 (d, J = 8.4 Hz, 2H), 7.09 (s, 1H),
7.04 (d, J = 8.4 Hz, 2H), 6.96 (s, 1H), 3.93 (s, 3H), 3.88 (s,
6H), 3.72 (t, J = 4.4 Hz, 4H), 3.68 (s, 2H), 2.49 (br s, 4H);
13C NMR (100 MHz, CDCl3) δ 159.1, 149.0, 148.2, 146.8,
130.5, 124.7, 120.5, 114.4, 101.4, 95.6, 67.0, 56.6, 56.4,
55.5, 54.0, 53.5; HRMS (ESI-QTOF) m/z [M + H]+ calcd
for C22H26NO5 384.1805, found 384.1801.
1-((5,6-Dimethoxy-3-(4-methoxyphenyl)benzofuran-2-yl)
methyl)piperidine (2e)
1
Orange solid, mp: 101ꢀC to 102ꢀC; H NMR (400 MHz,
CDCl3) δ 7.45 (d, J = 8.8 Hz, 2H), 7.10 (s, 1H), 7.03 (d,
J = 8.4 Hz, 2H), 6.95 (s, 1H), 3.93 (s, 3H), 3.88 (s, 3H),
3.87 (s, 3H), 3.65 (s, 2H), 2.41 (br s, 4H), 1.65 to 1.53 (m,
4H), 1.40 (br s, 2H); 13C NMR (100 MHz, CDCl3) δ 158.9,
149.7, 149.0, 148.0, 146.6, 130.5, 124.9, 120.6, 120.2, 114.3,
101.4, 95.7, 56.6, 56.4, 55.4, 54.5, 54.3, 26.0, 24.3; HRMS
(ESI-QTOF) m/z [M + H]+ calcd for C23H28NO4
382.2013, found 382.2011.
FIGURE 3 The effect of compounds on the levels of proteins
related to apoptosis and signaling cascades. U937 cells were
incubated with 10 μM of each compound for 1 day, and then
protein expression levels were determined by Western blot analysis
7.39 (t, J = 7.2 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.88
(dd, J = 2.4, 8.8 Hz, 1H), 3.86 (s, 3H), 3.75 to 3.70 (m,
6H), 2.51 (br s, 4H); 13C NMR (100 MHz, CDCl3) δ
158.3, 155.5, 132.3, 129.4, 128.9, 127.6, 121.8, 120.3,
111.9, 96.2, 67.0, 55.9, 54.0, 53.5; HRMS (ESI-QTOF)
m/z [M + H]+ calcd for C20H22NO3 324.1594, found
324.1593.
4-((4,6-Dimethoxy-3-(4-methoxyphenyl)benzofuran-2-yl)
methyl)morpholine (2f)
1
White solid, mp: 122ꢀC; H NMR (400 MHz, CDCl3) δ
7.39 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.69 (d,
J = 1.6 Hz, 1H), 6.30 (d, J = 1.6 Hz, 1H), 3.87 (s, 3H), 3.84
(s, 3H), 3.73 to 3.68 (m, 7H), 3.60 (s, 2H), 2.45 (br s, 4H);
13C NMR (100 MHz, CDCl3) δ 159.1, 158.8, 156.4, 154.7,
131.7, 125.0, 113.2, 111.4, 94.5, 88.4, 67.0, 55.9, 55.6, 55.4,
53.5, 53.4; HRMS (ESI-QTOF) m/z [M + H]+ calcd for
C22H26NO5 384.1805, found 384.1805.
4-((6-Methoxy-3-(4-methoxyphenyl)benzofuran-2-yl)
methyl)morpholine (2b)
1
White solid, mp: 106ꢀC to 107ꢀC; H NMR (400 MHz,
CDCl3) δ 7.46 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz,
1H), 7.07 (d, J = 2.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H),
6.87 (dd, J = 2.4, 8.4 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H),
3.72 (t, J = 4.8 Hz, 4H), 3.69 (s, 2H), 2.50 (br s, 4H);
13C NMR (100 MHz, CDCl3) δ 159.1, 158.2, 155.4,
148.6, 130.5, 124.6, 122.0, 120.3, 120.27, 114.3, 111.8,
96.2, 67.0, 55.9, 55.5, 54.0, 53.6; HRMS (ESI-QTOF)
m/z [M + H]+ calcd for C21H24NO4 354.1700, found
354.1704.[20]
4-((4,6-Dimethoxy-3-[3-methoxyphenyl]benzofuran-2-yl)
methyl)morpholine (2g)
White solid, mp: 84ꢀC to 85ꢀC; 1H NMR (400 MHz,
CDCl3) δ 7.31 (t, J = 7.6 Hz, 1H), 7.09 to 7.04 (m, 2H),
6.90 (d, J = 7.2 Hz, 1H), 6.69 (d, J = 1.6 Hz, 1H), 6.32 (d,
J = 1.6 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.74 to 3.68
(m, 7H), 3.62 (s, 2H), 2.47 (br s, 4H); 13C NMR
(100 MHz, CDCl3) δ 159.2, 159.0, 156.4, 154.6, 148.1,
134.1, 128.6, 123.1, 120.6, 116.1, 113.0, 111.1, 95.6, 88.4,
67.0, 55.9, 55.5, 55.4, 53.6, 53.4; HRMS (ESI-QTOF) m/z
[M + H]+ calcd for C22H26NO5 384.1805, found
384.1800.
4-((5,6-Dimethoxy-3-phenylbenzofuran-2-yl)methyl)
morpholine (2c)
1
White solid, mp: 106ꢀC to 108ꢀC; H NMR (400 MHz,
CDCl3) δ 7.56 to 7.47 (m, 4H), 7.40 (t, J = 6.8 Hz, 1H),

8
KIM ET AL.
4-((5-(Benzyloxy)-6-methoxy-3-(4-methoxyphenyl)
benzofuran-2-yl)methyl)morpholine (2h)
114.8, 105.4, 95.4, 71.9, 56.5, 55.6; HRMS (ESI-QTOF) m/z
[M+Na]+ calcd for C24H20NaO5 411.1203, found 411.1207.
1
White solid, mp: 103ꢀC to 104ꢀC; H NMR (400 MHz,
CDCl3) δ 7.45 (d, J = 7.2 Hz, 2H), 7.41 to 7.28 (m, 5H),
7.10 (s, 1H), 7.05 to 6.96 (m, 3H), 5.11 (s, 2H), 3.93 (s,
3H), 3.88 (s, 3H), 3.76 to 3.62 (m, 6H), 3.50 (s, 4H); 13C
NMR (100 MHz, CDCl3) δ 159.0, 149.5, 145.7, 137.4,
130.4, 128.6, 128.0, 127.7, 120.5, 114.4, 105.2, 96.0, 72.2,
67.0, 56.5, 55.5, 54.0, 53.5; HRMS (ESI-QTOF) m/z [M
+ H]+ calcd for C28H30NO5 460.2118, found 460.2114.
4.1.3 | General procedure for the
synthesis of 4
To a solution of 3 (0.12 mmol) in ethanol (1 mL) were
added amine (1.2 equiv), triethyl phosphite (1.5 equiv),
and FeCl3 (0.1 equiv) at room temperature. After being
stirred at 100ꢀC for 16 hours, the reaction mixture was
concentrated in vacuo. The residue was purified by silica
gel column chromatography (n-hexane: ethyl acetate: dic-
hloromethane) to give 4.
4.1.2 | General procedure for the
synthesis of 3
In a vial charged with anhydrous N,N-dimethylformamide
(3.0 equiv) was dropwise added phosphoryl chloride (3.0
equiv) at 0ꢀC and the reaction mixture was stirred for
20 minutes. To this mixture was dropwise added a solution
of 1 (2.23 mmol) in CH2Cl2 (7.5 mL) at 0ꢀC. After being
stirred at room temperature for 15 hours, the reaction mix-
ture was quenched with H2O. After evaporation of organic
solvent, the resulting suspended solid was filtered and
dried to give 3, which was used for the next step without
further purification.
Diethyl ((6-methoxy-3-phenylbenzofuran-2-yl)
(phenylamino)methyl)phosphonate (4a)
White solid, mp: 96ꢀC; 1H NMR (400 MHz, CDCl3) δ 7.60
to 7.42 (m, 5H), 7.37 (d, J = 8.4 Hz, 1H), 7.04 (s, 1H), 6.98
(t, J = 7.6 Hz, 2H), 6.85 (d, J = 8.4 Hz, 1H), 6.65 (t,
J = 6.8 Hz, 1H), 6.36 (d, J = 8.0 Hz, 2H), 5.07 (dd, J = 9.6,
24.0 Hz, 1H), 4.67 (br s, 1H), 4.32 to 4.20 (m, 2H), 4.19 to
4.10 (m, 1H), 4.02 to 3.91 (m, 1H), 3.84 (s, 3H), 1.34 (t,
J = 7.0 Hz, 3H), 1.19 (t, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 158.5, 155.5, 146.1, 146.0, 145.8, 145.6,
131.8, 131.76, 129.33, 129.3, 129.13, 129.1, 128.0, 120.4,
119.1, 114.2, 112.2, 96.2, 63.9, 63.8, 63.5, 63.4, 55.9, 49.6,
48.0, 16.7, 16.6, 16.5, 16.4; HRMS (ESI-QTOF) m/z [M
+ H]+ calcd for C26H29NO5P 466.1778, found 466.1773.
6-Methoxy-3-phenylbenzofuran-2-carbaldehyde (3a)
Light yellow solid, mp: 108ꢀC to 110ꢀC; 1H NMR
(400 MHz, CDCl3) δ 9.77 (s, 1H), 7.65 to 7.60 (m, 3H), 7.59
to 7.51 (m, 3H), 7.09 (d, J = 2.0 Hz, 1H), 6.99 (dd, J = 2.0,
8.8 Hz, 1H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
179.1, 162.4, 157.3, 147.6, 135.2, 130.0, 129.53, 129.5, 129.3,
123.2, 120.5, 115.1, 95.7, 56.0; HRMS (ESI-QTOF) m/z [M
+ H]+ calcd for C16H13O3 253.0859, found 253.0860.
Diethyl ((6-methoxy-3-phenylbenzofuran-2-yl)(m-
tolylamino)methyl)phosphonate (4b)
1
White solid, mp: 102ꢀC to 105ꢀC; H NMR (400 MHz,
CDCl3) δ 7.60 to 7.51 (m, 4H), 7.46 (t, J = 6.8 Hz, 1H),
7.38 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 6.90 to
6.82 (m, 2H), 6.46 (d, J = 7.6 Hz, 1H), 6.22 (d, J = 8.0 Hz,
1H), 6.08 (s, 1H), 5.06 (dd, J = 10.4, 24.8 Hz, 1H), 4.64
(dd, J = 5.2, 10.0 Hz, 1H), 4.33 to 4.22 (m, 2H), 4.19 to
4.09 (m, 1H), 4.04 to 3.91 (m, 1H), 3.83 (s, 3H), 2.04 (s,
3H), 1.35 (t, J = 7.0 Hz, 3H), 1.19 (t, J = 7.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 158.5, 155.5, 146.3, 146.2,
145.7, 145.6, 138.9, 129.4, 129.36, 129.1, 128.9, 128.0,
120.3, 119.9, 114.6, 112.2, 111.7, 96.2, 63.9, 63.85, 63.5,
63.4, 55.8, 49.3, 47.7, 21.5, 16.7, 16.65, 16.5, 16.4; HRMS
(ESI-QTOF) m/z [M + H]+ calcd for C27H31NO5P
480.1934, found 480.1931.
5,6-Dimethoxy-3-(4-methoxyphenyl)benzofuran-
2-carbaldehyde (3b)
Light yellow solid, mp: 183ꢀC to 186ꢀC; 1H NMR
(400 MHz, CDCl3) δ 9.71 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H),
7.12 to 7.07 (m, 3H), 7.05 (s, 1H), 3.99 (s, 3H), 3.91 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 178.6, 160.7, 152.9,
151.6, 148.2, 147.6, 135.1, 131.2, 121.9, 119.3, 114.9, 101.9,
95.3, 56.5, 56.5, 55.6; HRMS (ESI-QTOF) m/z [M + H]+
calcd for C18H17O5 313.1071, found 313.1070.
5-(Benzyloxy)-6-methoxy-3-(4-methoxyphenyl)
benzofuran-2-carbaldehyde (3c)
Light yellow solid, mp: 139ꢀC to 140ꢀC; 1H NMR
(400 MHz, CDCl3) δ 9.70 (s, 1H), 7.49 to 7.43 (m, 4H), 7.42
to 7.30 (m, 3H), 7.10 (d, J = 6.8 Hz, 2H), 7.06 (d,
J = 8.4 Hz, 2H), 5.14 (s, 2H), 3.98 (s, 3H), 3.91 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 178.7, 160.6, 153.7, 151.9,
147.5, 147.1, 136.7, 131.2, 128.7, 128.2, 127.7, 121.8, 119.2,
Diethyl ((6-methoxy-3-phenylbenzofuran-2-yl)
((2-methoxyphenyl)amino)methyl)phosphonate (4c)
Light yellow solid, mp: 143ꢀC to 144ꢀC; 1H NMR
(400 MHz, CDCl3) δ 7.58 to 7.48 (m, 4H), 7.44 (t,
J = 7.2 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.06 (d,
J = 2.0 Hz, 1H), 6.84 (dd, J = 2.4, 8.8 Hz, 1H), 6.67 (d,

KIM ET AL.
9
J = 7.2 Hz, 1H), 6.60 (t, J = 7.6 Hz, 1H), 6.54 (t,
J = 7.6 Hz, 1H), 6.10 (d, J = 7.2 Hz, 1H), 5.22 (dd,
J = 5.2, 10.0 Hz, 1H), 5.10 (dd, J = 10.4, 23.6 Hz, 1H),
4.32 to 4.20 (m, 2H), 4.19 to 4.10 (m, 1H), 4.04 to 3.95
(m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 1.33 (t, J = 7.0 Hz,
3H), 1.20 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 158.5, 155.6, 147.7, 146.3, 146.2, 131.84, 131.8,
129.4, 129.37, 129.1, 127.9, 120.8, 120.3, 118.3, 112.1,
111.4, 109.8, 96.3, 63.8, 63.78, 63.45, 63.4, 55.9, 55.5,
49.2, 47.6, 16.7, 16.6, 16.5, 16.45; HRMS (ESI-QTOF) m/
z [M + H]+ calcd for C27H31NO6P 496.1884, found
496.1887.
1.36 (t, J = 7.0 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 158.6, 155.6, 151.1, 146.9,
145.5, 134.9, 130.1, 129.42, 129.4, 129.3, 128.2, 122.0,
121.5, 120.5, 119.0, 113.8, 112.6, 112.3, 96.2, 63.9, 63.86,
63.7, 63.6, 55.9, 49.3, 47.7, 16.7, 16.7, 16.5, 16.4; HRMS
(ESI-QTOF) m/z [M + H]+ calcd for C26H28ClNO5P
500.1388, found 500.1384.
Ethyl 3-(((diethoxyphosphoryl)(6-methoxy-
3-phenylbenzofuran-2-yl)methyl)amino)benzoate (4g)
1
Yellow solid, mp: 139ꢀC to 140ꢀC; H NMR (400 MHz,
CDCl3) δ 7.60 to 7.50 (m, 4H), 7.45 (t, J = 7.0 Hz, 1H),
7.37 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.15
(br s, 1H), 7.06 to 7.00 (m, 2H), 6.85 (dd, J = 2.0, 8.4 Hz,
1H), 6.49 (dd, J = 1.6, 8.0 Hz, 1H), 5.12 (dd, J = 10.0,
24.0 Hz, 1H), 4.82 (dd, J = 5.2, 10.0 Hz, 1H), 4.32 to 4.20
(m, 3H), 4.17 to 4.08 (m, 2H), 4.02 to 3.92 (m, 1H), 3.83
(s, 3H), 1.37 to 1.29 (m, 6H), 1.20 (t, J = 7.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 166.6, 158.6, 155.5, 145.9,
145.7, 145.6, 145.5, 131.4, 129.32, 129.3, 129.1, 129.06,
128.1, 120.4, 120.2, 118.1, 115.2, 112.3, 96.1, 63.9, 63.8,
63.77, 63.7, 63.6, 63.5, 60.9, 55.8, 49.7, 48.1, 16.7, 16.6,
16.5, 16.4, 16.3, 16.2; HRMS (ESI-QTOF) m/z [M + H]+
calcd for C29H33NO7P 538.1989, found 538.1985.
Diethyl (((3,5-dimethoxyphenyl)amino)(6-methoxy-
3-phenylbenzofuran-2-yl)methyl)phosphonate (4d)
Light yellow solid, mp: 140ꢀC to 142ꢀC; 1H NMR
(400 MHz, CDCl3) δ 7.65 to 7.58 (m, 2H), 7.52 (t,
J = 7.6 Hz, 2H), 7.45 to 7.39 (m, 2H), 7.05 (d, J = 2.0 Hz,
1H), 6.86 (dd, J = 2.0, 8.4 Hz, 1H), 5.80 (s, 1H), 5.57 (d,
J = 2.0 Hz, 2H), 5.08 (dd, J = 10.0, 24.4 Hz, 1H), 4.73 (dd,
J = 5.6, 10.0 Hz, 1H), 4.33 to 4.21 (m, 2H), 4.19 to 4.09 (m,
1H), 4.01 to 3.89 (m, 1H), 3.84 (s, 3H), 3.49 (m, 6H), 1.36
(t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 161.5, 158.5, 155.5, 147.8, 147.7, 146.1,
146.1, 131.7, 129.3, 129.27, 129.1, 128.0, 120.4, 112.2, 96.2,
92.4, 92.1, 64.0, 63.9, 63.6, 63.5, 55.8, 55.1, 49.5, 47.9, 16.7,
16.6, 16.5, 16.4; HRMS (ESI-QTOF) m/z [M + Na]+ calcd
for C28H32NNaO7P 548.1809, found 548.1809.
Diethyl (((3-cyanophenyl)amino)(6-methoxy-
3-phenylbenzofuran-2-yl)methyl)phosphonate (4h)
Yellow solid, mp: 59ꢀC to 61ꢀC; 1H NMR (400 MHz,
CDCl3) δ 7.63 to 7.47 (m, 5H), 7.39 (d, J = 8.8 Hz, 1H),
7.05 (t, J = 7.8 Hz, 1H), 7.00 (d, J = 1.6 Hz, 1H), 6.90 (d,
J = 7.6 Hz, 1H), 6.87 (dd, J = 2.4, 8.8 Hz, 1H), 6.60 (dd,
J = 1.6, 8.4 Hz, 1H), 6.42 (s, 1H), 5.05 to 4.92 (m, 2H),
4.35 to 4.23 (m, 2H), 4.30 to 4.09 (m, 1H), 4.03 to 3.88 (m,
1H), 3.82 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H), 1.21 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.8,
155.6, 146.2, 146.0, 144.9, 144.8, 131.3, 129.8, 129.5, 129.3,
129.26, 128.5, 122.5, 122.4, 122.3, 121.3, 120.5, 118.9,
118.8, 116.2, 113.0, 112.5, 96.2, 63.9, 63.85, 63.8, 55.9,
49.1, 47.5, 16.7, 16.6, 16.5, 16.4; HRMS (ESI-QTOF) m/z
[M + Na]+ calcd for C27H27N2NaO5P 513.1550, found
513.1558.
Diethyl (((4-fluorophenyl)amino)(6-methoxy-
3-phenylbenzofuran-2-yl)methyl)phosphonate (4e)
1
White solid, mp: 96ꢀC; H NMR (400 MHz, CDCl3) δ
7.57 to 7.49 (m, 4H), 7.48 to 7.42 (m, 1H), 7.37 (d,
J = 8.8 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 6.87 (dd, J = 2.0,
8.8 Hz, 1H), 6.67 (t, J = 8.6 Hz, 2H), 6.28 (dd, J = 4.4,
8.8 Hz, 2H), 4.98 (dd, J = 10.4, 24.4 Hz, 1H), 4.59 to 4.51
(m, 1H), 4.33 to 4.20 (m, 2H), 4.20 to 4.10 (m, 1H), 4.02 to
3.91 (m, 1H), 3.84 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H), 1.20 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.6,
157.9, 155.5, 145.8, 141.9, 131.7, 129.3, 129.27, 129.1,
128.1, 121.5, 120.4, 115.7, 115.5, 115.45, 115.4, 112.3, 96.2,
63.9, 63.8, 63.6, 63.5, 55.9, 50.5, 48.8, 16.7, 16.6, 16.5, 16.4;
HRMS (ESI-QTOF) m/z [M + H]+ calcd for
C26H28FNO5P 484.1684, found 484.1685.
Diethyl ((6-methoxy-3-phenylbenzofuran-2-yl)
(morpholino)methyl)phosphonate (4i)
White solid, mp: 84ꢀC to 86ꢀC; 1H NMR (400 MHz,
CDCl3) δ 7.54 to 7.44 (m, 4H), 7.40 (d, J = 8.8 Hz, 2H),
7.14 (s, 1H), 6.90 (d, J = 7.2 Hz, 1H), 4.34 to 4.18 (m, 3H),
4.18 to 4.06 (m, 1H), 4.05 to 3.91 (m, 1H), 3.88 (s, 3H),
3.71 to 3.57 (m, 4H), 2.91 (br s, 2H), 2.48 (br s, 2H), 1.35
(t, J = 7.0 Hz, 3H), 1.18 (t, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 158.7, 155.6, 145.5, 132.0, 129.4,
129.1, 127.9, 121.4, 120.4, 112.5, 96.2, 67.5, 63.5, 63.4,
62.8, 62.7, 60.6, 59.0, 55.9, 52.2, 16.8, 16.7, 16.6, 16.5;
Diethyl (((3-chlorophenyl)amino)(6-methoxy-
3-phenylbenzofuran-2-yl)methyl)phosphonate (4f)
1
White solid, mp: 138ꢀC to 139ꢀC; H NMR (400 MHz,
CDCl3) δ 7.59 to 7.51 (m, 4H), 7.47 (br s, 1H), 7.38 (d,
J = 8.8 Hz, 1H), 7.03 (s, 1H), 6.93 to 6.82 (m, 2H), 6.60 (d,
J = 7.6 Hz, 1H), 6.30 to 6.22 (m, 2H), 4.99 (dd, J = 10.4,
24.8 Hz, 1H), 4.79 to 4.73 (m, 1H), 4.32 to 4.21 (m, 2H),
4.21 to 4.10 (m, 1H), 4.03 to 3.91 (m, 1H), 3.84 (s, 3H),

10
KIM ET AL.
HRMS (ESI-QTOF) m/z [M+Na]+ calcd for
C24H30NNaO6P 482.1703, found 482.1707.
6.65 (t, J = 7.2 Hz, 1H), 6.38 (d, J = 7.6 Hz, 2H), 5.02 (d,
J = 24.4 Hz, 1H), 4.66 (br s, 1H), 4.31 to 4.20 (m, 2H),
4.18 to 4.08 (m, 1H), 4.00 to 3.89 (m, 7H), 3.84 (s, 3H),
1.34 (t, J = 6.8 Hz, 3H), 1.18 (t, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 159.5, 149.2, 148.4, 146.9,
145.8, 145.7, 130.5, 130.48, 129.1, 124.1, 121.4, 120.3,
119.0, 114.6, 114.2, 101.3, 95.7, 63.9, 63.8, 63.5, 63.4, 56.6,
56.4, 55.5, 49.6, 48.0, 16.7, 16.6, 16.5, 16.4; HRMS (ESI-
QTOF) m/z [M + H]+ calcd for C28H33NO7P 526.1989,
found 526.1991.
Diethyl ((6-methoxy-3-phenylbenzofuran-2-yl)(piperidin-
1-yl)methyl)phosphonate (4j)
1
White solid, mp: 115ꢀC to 117ꢀC; H NMR (400 MHz,
CDCl3) δ 7.53 to 7.44 (m, 4H), 7.42 to 7.36 (m, 2H), 7.16
(d, J = 2.0 Hz, 1H), 6.89 (dd, J = 2.0, 8.4 Hz, 1H), 4.36 to
4.18 (m, 3H), 4.15 to 4.05 (m, 1H), 4.03 to 3.93 (m, 1H),
3.87 (s, 3H), 2.89 (br s, 2H), 2.36 (br s, 2H), 1.59 to 1.42
(m, 4H), 1.37 to 1.25 (m, 5H), 1.16 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 158.4, 155.5, 146.54, 146.5,
132.3, 129.4, 129.0, 127.7, 122.6, 122.5, 121.5, 120.3, 112.3,
96.3, 63.5, 63.45, 62.5, 62.4, 61.1, 59.5, 55.9, 53.1, 53.06,
26.7, 24.1, 16.74, 16.7, 16.5, 16.48; HRMS (ESI-QTOF) m/
z [M + Na]+ calcd for C25H32NNaO5P 480.1910, found
480.1914.
Diethyl ((5,6-dimethoxy-3-(4-methoxyphenyl)
benzofuran-2-yl)(m-tolylamino)methyl)
phosphonate (4n)
1
White solid, mp: 128ꢀC to 130ꢀC; H NMR (400 MHz,
CDCl3) δ 7.50 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.8 Hz,
2H), 7.06 (s, 1H), 6.92 to 6.85 (m, 2H), 6.47 (d, J = 7.6 Hz,
1H), 6.23 (d, J = 7.6 Hz, 1H), 6.12 (s, 1H), 5.01 (dd,
J = 10.0, 24.4 Hz, 1H), 4.68 to 4.59 (m, 1H), 4.31 to 4.21
(m, 2H), 4.19 to 4.09 (m, 1H), 4.01 to 3.87 (m, 7H), 3.84
(s, 3H), 2.07 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H), 1.19 (t,
J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.5,
149.2, 148.4, 146.8, 145.8, 145.6, 138.9, 130.5, 128.9, 124.1,
121.3, 120.2, 119.8, 114.6, 111.6, 101.2, 95.7, 63.9, 63.8,
63.4, 63.36, 56.5, 56.4, 55.5, 49.3, 47.7, 21.5, 16.7, 16.6,
16.5, 16.4; HRMS (ESI-QTOF) m/z [M + H]+ calcd for
C29H35NO7P 540.2146, found 540.2142.
Diethyl ((6-methoxy-3-phenylbenzofuran-2-yl)
((4-methoxybenzyl)amino)methyl)phosphonate (4k)
1
White solid, mp: 91ꢀC; H NMR (400 MHz, CDCl3) δ
7.53 to 7.46 (m, 3H), 7.43 (t, J = 7.4 Hz, 2H), 7.37 (t,
J = 7.2 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.94 to 6.86 (m,
3H), 6.62 (d, J = 8.4 Hz, 2H), 4.30 to 4.15 (m, 3H), 4.13 to
4.05 (m, 1H), 4.04 to 3.93 (m, 1H), 3.88 (s, 3H), 3.75 to
3.67 (m, 4H), 3.34 (d, J = 12.8 Hz, 1H), 1.32 (t, J = 7.0 Hz,
3H), 1.18 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 158.7, 158.5, 155.7, 146.7, 146.6, 131.8, 130.7, 129.8,
129.2, 129.1, 129.0, 127.6, 122.0, 121.5, 120.4, 113.6, 112.1,
96.3, 63.6, 63.5, 63.0, 62.9, 55.9, 55.3, 52.1, 50.8, 50.6, 50.4,
16.7, 16.6, 16.5, 16.4; HRMS (ESI-QTOF) m/z [M + H]+
calcd for C28H33NO6P 510.2040, found 510.2045.
Diethyl ((5,6-dimethoxy-3-(4-methoxyphenyl)
benzofuran-2-yl)((2-methoxyphenyl)amino)methyl)
phosphonate (4o)
1
Orange solid, mp: 106ꢀC to 108ꢀC; H NMR (400 MHz,
CDCl3) δ 7.48 (d, J = 8.4 Hz, 2H), 7.10 to 7.04 (m, 3H),
6.87 (s, 1H), 6.70 to 6.54 (m, 3H), 6.12 (d, J = 7.6 Hz, 1H),
5.21 (dd, J = 5.6, 10.0 Hz, 1H), 5.04 (dd, J = 10.4, 24.0 Hz,
1H), 4.30 to 4.20 (m, 2H), 4.19 to 4.09 (m, 1H), 4.02 to
3.94 (m, 1H), 3.91 (s, 6H), 3.84 (s, 3H), 3.78 (s, 3H), 1.33
(t, J = 7.0 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 159.4, 149.2, 148.4, 147.7, 146.8,
135.7, 135.5, 130.54, 130.5, 124.1, 120.8, 118.2, 114.6,
111.4, 109.8, 101.3, 95.7, 63.8, 63.7, 63.4, 63.3, 56.6, 56.4,
55.5, 55.49, 49.2, 47.6, 16.7, 16.6, 16.5, 16.45; HRMS (ESI-
QTOF) m/z [M + H]+ calcd for C29H35NO8P 556.2095,
found 556.2096.
Diethyl (((4-chlorobenzyl)amino)(6-methoxy-
3-phenylbenzofuran-2-yl)methyl)phosphonate (4l)
White solid, mp: 89ꢀC to 90ꢀC; 1H NMR (400 MHz,
CDCl3) δ 7.50 to 7.35 (m, 6H), 7.11 (d, J = 1.2 Hz, 1H),
7.05 (d, J = 8.4 Hz, 2H), 6.95 to 6.88 (m, 3H), 4.28 to 4.16
(m, 3H), 4.14 to 4.04 (m, 1H), 4.02 to 3.93 (m, 1H), 3.88
(s, 3H), 3.72 (d, J = 13.2 Hz, 1H), 3.37 (d, J = 13.2 Hz,
1H), 1.33 (t, J = 7.0 Hz, 3H), 1.19 (t, J = 7.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 158.6, 155.7, 146.3, 137.1,
132.8, 131.6, 129.9, 129.1, 128.3, 127.8, 120.5, 112.3, 96.3,
63.6, 63.5, 63.1, 63.0, 55.9, 52.1, 50.6, 50.5, 16.7, 16.6, 16.5,
16.4; HRMS (ESI-QTOF) m/z [M + H]+ calcd for
C27H30ClNO5P 514.1545, found 514.1542.
Diethyl ((5,6-dimethoxy-3-(4-methoxyphenyl)
benzofuran-2-yl)((4-methoxyphenyl)amino)methyl)
phosphonate (4p)
Diethyl ((5,6-dimethoxy-3-(4-methoxyphenyl)
benzofuran-2-yl)(phenylamino)methyl)
phosphonate (4m)
1
Brown solid, mp: 115ꢀC to 116ꢀC; H NMR (400 MHz,
CDCl3) δ 7.45 (d, J = 8.4 Hz, 2H), 7.10 to 7.05 (m, 3H),
6.87 (s, 1H), 6.58 (d, J = 8.8 Hz, 2H), 6.35 (d, J = 8.8 Hz,
2H), 4.92 (dd, J = 10.4, 24.4 Hz, 1H), 4.44 to 4.36 (m, 1H),
4.31 to 4.20 (m, 2H), 4.18 to 4.06 (m, 1H), 4.01 to 3.88 (m,
1
Yellow solid, mp: 130ꢀC to 131ꢀC; H NMR (400 MHz,
CDCl3) δ 7.48 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz,
2H), 7.06 (s, 1H), 7.00 (t, J = 8.4 Hz, 2H), 6.88 (s, 1H),

KIM ET AL.
11
7H), 3.84 (s, 3H), 2.07 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H),
1.19 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
159.3, 153.0, 149.0, 148.2, 146.7, 145.8, 139.6, 139.5, 130.3,
123.9, 123.89, 121.3, 120.2, 120.1, 115.7, 114.45, 114.4,
101.1, 95.5, 63.7, 63.6, 63.2, 63.15, 56.4, 56.2, 55.6, 55.3,
50.6, 49.0, 16.5, 16.48, 16.3, 16.28; HRMS (ESI-QTOF) m/
z [M + H]+ calcd for C29H35NO8P 556.2095, found
556.2095.
49.3, 47.7, 16.7, 16.65, 16.5, 16.45; HRMS (ESI-QTOF)
m/z [M + H]+ calcd for C28H32ClNO7P 560.1599, found
560.1597.
Ethyl 3-(((diethoxyphosphoryl)(5,6-dimethoxy-
3-(4-methoxyphenyl)benzofuran-2-yl)methyl)amino)
benzoate (4t)
White solid, mp: 74ꢀC to 77ꢀC; 1H NMR (400 MHz,
CDCl3) δ 7.49 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 7.6 Hz,
1H), 7.16 (s, 1H), 7.12 to 7.00 (m, 4H), 6.88 (s, 1H), 6.50
(d, J = 7.2 Hz, 1H), 5.07 (dd, J = 10.4, 24.4 Hz, 1H), 4.83
to 4.74 (m, 1H), 4.35 to 4.20 (m, 4H), 4.19 to 4.08 (m, 1H),
4.01 to 3.87 (m, 7H), 3.84 (s, 3H), 1.40 to 1.28 (m, 6H),
1.20 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
166.6, 159.5, 149.2, 148.5, 146.9, 145.9, 145.8, 131.4, 130.5,
130.48, 129.1, 123.8, 120.2, 118.1, 115.3, 114.7, 101.3, 95.6,
63.8, 63.77, 63.54, 63.5, 60.9, 56.5, 56.4, 55.5, 49.7,
48.1, 16.7, 16.6, 16.5, 16.4, 14.4; HRMS (ESI-QTOF) m/z
[M + Na]+ calcd for C31H36NNaO9P 620.2020, found
620.2028.
Diethyl ((5,6-dimethoxy-3-(4-methoxyphenyl)
benzofuran-2-yl)((3,5-dimethoxyphenyl)amino)methyl)
phosphonate (4q)
Yellow solid, mp: 75ꢀC to 77ꢀC; 1H NMR (400 MHz,
CDCl3) δ 7.53 (d, J = 8.8 Hz, 2H), 7.10 to 7.04 (m, 3H),
6.91 (s, 1H), 5.81 (s, 1H), 5.61 to 5.57 (m, 2H), 5.02 (dd,
J = 10.0, 24.4 Hz, 1H), 4.74 to 4.65 (m, 1H), 4.30 to 4.21
(m, 2H), 4.17 to 4.09 (m, 1H), 3.97 to 3.87 (m, 7H), 3.85
(s, 3H), 3.54 (s, 6H), 1.35 (t, J = 7.0 Hz, 3H), 1.18 (t,
J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.5,
159.5, 149.2, 148.5, 147.9, 147.8, 146.9, 130.5, 124.0,
123.98, 121.0, 120.9, 120.2, 120.18, 114.6, 101.4, 95.7, 92.6,
92.0, 63.9, 63.8, 63.5, 63.4, 56.6, 56.4, 55.5, 55.1, 49.6, 48.0,
16.7, 16.65, 16.5, 16.4; HRMS (ESI-QTOF) m/z [M + H]+
calcd for C30H37NO9P 586.2200, found 586.2205.
Diethyl (((3-cyanophenyl)amino)(5,6-dimethoxy-
3-(4-methoxyphenyl)benzofuran-2-yl)methyl)
phosphonate (4u)
1
Yellow solid, mp: 144ꢀC to 146ꢀC; H NMR (400 MHz,
Diethyl ((5,6-dimethoxy-3-(4-methoxyphenyl)
benzofuran-2-yl)((4-fluorophenyl)amino)methyl)
phosphonate (4r)
CDCl3) δ 7.49 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz,
2H), 7.06 (t, J = 8.0 Hz, 1H), 7.00 (s, 1H), 6.91 (d,
J = 7.6 Hz, 1H), 6.89 (s, 1H), 6.63 (d, J = 8.4 Hz, 1H), 6.43
(s, 1H), 5.00 to 4.88 (m, 2H), 4.32 to 4.21 (m, 2H), 4.21 to
4.11 (m, 1H), 4.01 to 3.90 (m, 4H), 3.89 (s, 3H), 3.85 (s,
3H), 1.37 (t, J = 6.8 Hz, 3H), 1.20 (t, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 159.8, 149.2, 148.7, 147.0,
146.3, 146.1, 130.5, 130.46, 129.8, 123.5, 122.5, 119.0,
118.9, 116.1, 115.0, 112.9, 101.3, 95.6, 63.9, 63.8, 63.7,
56.5, 56.4, 55.6, 49.1, 47.5, 16.7, 16.6, 16.5, 16.4; HRMS
(ESI-QTOF) m/z [M + Na]+ calcd for C29H31NNaO7P
573.1767, found 573.1763.
1
White solid, mp: 116ꢀC to 118ꢀC; H NMR (400 MHz,
CDCl3) δ 7.46 (d, J = 6.8 Hz, 2H), 7.13 to 7.03 (m, 3H),
6.88 (s, 1H), 6.69 (t, J = 8.4 Hz, 2H), 6.31 (br s, 2H), 4.93
(dd, J = 10.4, 24.4 Hz, 1H), 4.54 (br s, 1H), 4.32 to 4.08
(m, 3H), 4.02 to 3.87 (m, 7H), 3.85 (s, 3H), 1.35 (t,
J = 6.8 Hz, 3H), 1.19 (t, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 159.5, 157.9, 155.5, 149.2, 148.5,
146.9, 145.4, 130.4, 123.9, 120.2, 115.7, 115.5, 115.4, 114.7,
101.3, 95.6, 63.8, 63.76, 63.5, 63.45, 56.6, 56.4, 55.5, 50.4,
48.8, 16.7, 16.6, 16.5, 16.45; HRMS (ESI-QTOF) m/z [M
+ H]+ calcd for C28H32FNO7P 544.1898, found 5444.1893.
Diethyl ((5,6-dimethoxy-3-(4-methoxyphenyl)
benzofuran-2-yl)(morpholino)methyl)
phosphonate (4v)
Diethyl (((3-chlorophenyl)amino)(5,6-dimethoxy-
3-(4-methoxyphenyl)benzofuran-2-yl)methyl)
phosphonate (4s)
1
White solid, mp: 143ꢀC to 145ꢀC; H NMR (400 MHz,
CDCl3) δ 7.41 (d, J = 8.4 Hz, 2H), 7.17 (s, 1H), 7.04 (d,
J = 8.4 Hz, 2H), 6.90 (s, 1H), 4.28 to 4.20 (m, 3H), 4.15 to
4.07 (m, 1H), 4.01 to 3.92 (m, 4H), 3.91 to 3.85 (m, 6H),
3.71 to 3.58 (m, 4H), 2.90 (br s, 2H), 2.47 (br s, 2H), 1.35
(t, J = 7.0 Hz, 3H), 1.17 (t, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 159.3, 149.3, 148.6, 146.9, 145.3,
145.2, 130.52, 130.5, 124.3, 123.1, 123.0, 120.1, 114.6,
101.2, 95.8, 67.5, 63.4, 63.35, 62.7, 62.67, 60.6, 58.9, 56.6,
56.4, 55.5, 52.2, 52.1, 16.8, 16.7, 16.6, 16.5; HRMS (ESI-
QTOF) m/z [M + Na]+ calcd for C26H34NNaO8P
542.1914, found 542.1911.
1
White solid, mp: 142ꢀC to 143ꢀC; H NMR (400 MHz,
CDCl3) δ 7.49 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz,
2H), 7.05 (s, 1H), 6.94 to 6.86 (m, 2H), 6,61 (d, J = 8.0 Hz,
1H), 6.31 to 6.25 (m, 2H), 4.94 (dd, J = 10.4, 24.4 Hz, 1H),
4.75 (dd, J = 6.0, 9.6 Hz, 1H), 4.30 to 4.20 (m, 2H), 4.19 to
4.09 (m, 1H), 4.00 to 3.89 (m, 7H), 3.85 (s, 3H), 1.36 (t,
J = 7.2 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 159.6, 148.6, 147.0, 146.95, 146.9,
145.2, 134.9, 130.61, 130.6, 130.1, 118.9, 114.8, 113.8,
112.7, 101.3, 95.6, 63.9, 63.8, 63.6, 63.56, 56.6, 56.4, 55.5,

12
KIM ET AL.
Diethyl ((5,6-dimethoxy-3-(4-methoxyphenyl)
benzofuran-2-yl)(piperidin-1-yl)methyl)
phosphonate (4w)
J = 8.4 Hz, 2H), 7.02 to 6.90 (m, 5H), 4.27 to 4.17 (m, 3H),
4.14 to 4.06 (m, 1H), 4.01 to 3.92 (m, 4H), 3.89 (s, 3H),
3.88 (s, 3H), 3.73 (d, J = 13.6 Hz, 1H), 3.38 (d,
J = 13.6 Hz, 1H), 1.34 (t, J = 7.2 Hz, 3H), 1.19 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.3,
149.3, 148.5, 146.9, 145.9, 137.2, 132.7, 130.1, 129.9, 128.3,
123.94, 123.9, 122.0, 120.0, 114.6, 101.4, 95.7, 63.5, 63.4,
63.0, 62.9, 56.6, 56.4, 55.5, 52.1, 50.6, 50.5, 50.4, 16.7, 16.6,
16.5, 16.4; HRMS (ESI-QTOF) m/z [M + H]+ calcd for
C29H34ClNO7P 574.1756, found 574.1754.
1
Orange solid, mp: 162ꢀC to 163ꢀC; H NMR (400 MHz,
CDCl3) δ 7.42 (d, J = 8.4 Hz, 2H), 7.18 (s, 1H), 7.03 (d,
J = 8.4 Hz, 2H), 6.91 (s, 1H), 4.31 to 4.20 (m, 3H), 4.14 to
4.04 (m, 1H), 4.00 to 3.92 (m, 4H), 3.88 (s, 3H), 3.87 (s,
3H), 2.89 (br s, 2H), 2.35 (br s, 2H), 1.60 to 1.44 (m, 4H),
1.38 to 1.27 (m, 5H) 1.16 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 159.2, 149.2, 148.4, 146.8, 146.3, 146.3,
130.5, 124.6, 122.5, 122.4, 120.2, 114.5, 101.2, 95.9, 63.5,
63.4, 62.5, 62.4, 61.1, 59.5, 56.6, 56.4, 55.4, 53.2, 53.1, 26.7,
24.1, 16.7, 16.69, 16.5, 16.48; HRMS (ESI-QTOF) m/z [M
+ H]+ calcd for C27H37NO7P 518.2302, found 518.2305.
Diethyl ((5-(benzyloxy)-6-methoxy-3-(4-methoxyphenyl)
benzofuran-2-yl)(m-tolylamino)methyl)
phosphonate (4aa)
White solid, mp: 71ꢀC to 72ꢀC; 1H NMR (400 MHz,
CDCl3) δ 7.46 to 7.27 (m, 7H), 7.10 to 7.02 (m, 3H), 6.95
(s, 1H), 6.88 (t, J = 7.6 Hz, 1H), 6.46 (d, J = 7.2 Hz, 1H),
6.21 (d, J = 7.6 Hz, 1H), 6.10 (s 1H), 5.12 to 4.95 (m, 3H),
4.63 (br s, 1H), 4.30 to 4.20 (m, 2H), 4.18 to 4.07 (m, 1H),
4.01 to 3.87 (m, 7H), 2.06 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H),
1.18 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
159.4, 149.7, 149.3, 145.8, 145.6, 138.9, 137.3, 130.4, 128.9,
128.6, 128.0, 127.7, 124.1, 119.8, 114.6, 111.5, 105.0, 96.1,
72.1, 63.9, 63.8, 63.4, 63.38, 56.5, 55.5, 49.3, 47.7, 21.5,
16.7, 16.65, 16.5, 16.4; HRMS (ESI-QTOF) m/z [M + H]+
calcd for C35H39NO7P 616.2459, found 616.2459.
Diethyl ((benzylamino)(5,6-dimethoxy-
3-(4-methoxyphenyl)benzofuran-2-yl)methyl)
phosphonate (4x)
1
White solid, mp: 141ꢀC to 142ꢀC; H NMR (400 MHz,
CDCl3) δ 7.41 (d, J = 8.8 Hz, 2H), 7.16 to 7.09 (m, 4H),
7.06 to 7.01 (m, 2H), 7.01 to 6.95 (m, 3H), 4.28 to 4.14 (m,
3H), 4.12 to 4.04 (m, 1H), 3.99 to 3.91 (m, 4H), 3.89 (s,
3H), 3.87 (s, 3H), 3.76 (d, J = 13.0 Hz, 1H), 3.42 (d,
J = 13.0 Hz, 1H), 2.43 (br s, 1H), 1.33 (t, J = 7.2 Hz, 3H),
1.18 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
159.3, 149.3, 149.32, 148.4, 146.9, 138.8, 130.3, 130.2,
128.6, 128.2, 127.1, 124.1, 124.07, 120.2, 114.5, 101.4, 95.7,
63.5, 63.46, 63.0, 62.9, 56.6, 56.4, 55.5, 52.4, 51.4, 51.3,
50.8, 16.7, 16.6, 16.5, 16.4; HRMS (ESI-QTOF) m/z [M
+ H]+ calcd for C29H35NO7P 520.2095, found 520.2096.
Diethyl ((5-(benzyloxy)-6-methoxy-3-(4-methoxyphenyl)
benzofuran-2-yl)((3,5-dimethoxyphenyl)amino)methyl)
phosphonate (4ab)
1
Yellow solid, mp: 150ꢀC to 151ꢀC; H NMR (400 MHz,
Diethyl ((5,6-dimethoxy-3-(4-methoxyphenyl)
benzofuran-2-yl)((4-methoxybenzyl)amino)methyl)
phosphonate (4y)
CDCl3) δ 7.48 to 7.39 (m, 4H), 7.39 to 7.27 (m, 3H), 7.07
(s, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.98 (s, 1H), 5.80 (s, 1H)
5.57 (s, 2H), 5.12 to 4.95 (m, 3H), 4.70 (dd, J = 5.6, 9.6 Hz,
1H), 4.30 to 4.20 (m, 2H), 4.17 to 4.07 (m, 1H), 3.97 to
3.86 (m, 7H), 3.51 (s, 6H), 1.35 (t, J = 7.2 Hz, 3H), 1.18 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.5,
159.4, 149.7, 147.9, 147.7, 145.8, 137.3, 130.4, 128.6, 128.0,
127.7, 123.9, 120.9, 120.2, 114.6, 105.2, 96.1, 92.5, 92.0,
72.2, 63.9, 63.8, 63.5, 63.46, 56.5, 55.5, 55.1, 49.6, 48.0,
16.7, 16.66, 16.5, 16.4; HRMS (ESI-QTOF) m/z [M + H]+
calcd for C36H41NO9P 662.2513, found 662.2512.
Yellow solid, mp: 92ꢀC to 94ꢀC; 1H NMR (400 MHz,
CDCl3) δ 7.43 (d, J = 8.4 Hz, 2H), 7.13 (s, 1H), 7.02 to
6.96 (m, 3H), 6.92 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 8.4 Hz,
2H), 4.27 to 4.15 (m, 3H), 4.13 to 4.05 (m, 1H), 4.00 to
3.91 (m, 4H), 3.90 (s, 3H), 3.87 (s, 3H), 3.81 (d, J = 9.6 Hz,
1H), 3.75 to 3.67 (m, 4H), 3.34 (d, J = 12.8 Hz, 1H), 1.33
(t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 159.1, 158.5, 149.2, 148.3, 146.7,
146.1, 130.6, 130.1, 130.09, 129.7, 124.0, 123.99, 120.0,
114.4, 113.7, 113.4, 101.2, 95.6, 63.4, 63.3, 62.8, 62.7, 56.4,
56.3, 55.3, 55.1, 51.9, 50.6, 50.4, 50.3, 16.5, 16.46, 16.3,
16.27; HRMS (ESI-QTOF) m/z [M + H]+ calcd for
C30H37NO8P 570.2251, found 570.2251.
Ethyl 3-(((5-(benzyloxy)-6-methoxy-3-(4-methoxyphenyl)
benzofuran-2-yl)(diethoxyphosphoryl)methyl)amino)
benzoate (4ac)
1
Yellow solid, mp: 144ꢀC to 146ꢀC; H NMR (400 MHz,
CDCl3) δ 7.45 to 7.27 (m, 8H), 7.15 (s, 1H), 7.08 to 7.00
(m, 4H), 6.95 (s, 1H), 6.48 (dd, J = 1.6, 8.0 Hz, 1H), 5.13
to 5.00 (m, 3H), 4.79 (dd, J = 5.2, 10.0 Hz, 1H), 4.33 to
4.19 (m, 4H), 4.17 to 4.07 (m, 1H), 4.01 to 3.87 (m, 7H),
1.35 (t, J = 6.0 Hz, 3H), 1.31 (t, J = 6.0 Hz, 3H), 1.19 (t,
J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6,
Diethyl (((4-chlorobenzyl)amino)(5,6-dimethoxy-
3-(4-methoxyphenyl)benzofuran-2-yl)methyl)
phosphonate (4z)
1
Yellow solid, mp: 153ꢀC to 154ꢀC; H NMR (400 MHz,
CDCl3) δ 7.38 (d, J = 8.0 Hz, 2H), 7.13 (s, 1H), 7.07 (d,

KIM ET AL.
13
159.5, 149.7, 149.4, 145.9, 145.88, 145.8, 130.4, 130.39,
129.1, 128.6, 128.0, 127.7, 120.2, 115.3, 114.6, 105.0, 96.0,
72.1, 63.9, 63.8, 63.6, 63.5, 60.9, 56.5, 55.5, 49.7, 48.1, 16.7,
16.6, 16.5, 16.4, 14.4; HRMS (ESI-QTOF) m/z [M + H]+
calcd for C37H41NO9P 674.2513, found 674.2515.
16.5, 16.45, 16.3, 16.26; HRMS (ESI-QTOF) m/z [M
+ H]+ calcd for C35H39NO7P 616.2459, found 616.2458.
4.1.4 | General procedure for the
synthesis of 5
Diethyl ((5-(benzyloxy)-6-methoxy-3-(4-methoxyphenyl)
benzofuran-2-yl)((3-cyanophenyl)amino)methyl)
phosphonate (4ad)
To a solution of 3 (0.12 mmol) in tetrahydrofuran (1 mL)
were added 2-(1H-pyrrol-1-yl)aniline (1.2 equiv) and
DBSA (0.2 equiv) at room temperature. After being
stirred at 60ꢀC for 48 hours, the reaction mixture was
concentrated under reduced pressure. The reaction mix-
ture was basified with aq. NaHCO3 solution and
extracted with ethyl acetate (1 mL × 3). The organic layer
was dried over MgSO4 and concentrated in vacuo. The
residue was purified by silica gel column chromatogra-
phy (n-hexane:ethyl acetate:dichloromethane) to give 5.
Yellow solid, mp: 68ꢀC to 70ꢀC; 1H NMR (400 MHz,
CDCl3) δ 7.45 to 7.29 (m, 7H), 7.11 (d, J = 8.4 Hz, 2H),
7.08 to 7.01 (m, 2H), 6.96 (s, 1H), 6.90 (d, J = 7.6 Hz, 1H),
6.60 (d, J = 8.0 Hz, 1H), 6.41 (s, 1H), 5.13 to 5.03 (m, 2H),
5.00 to 4.88 (m, 2H), 4.31 to 4.20 (m, 2H), 4.20 to 4.11 (m,
1H), 4.01 to 3.91 (m, 4H), 3.89 (s, 3H), 1.37 (t, J = 7.0 Hz,
3H), 1.20 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 159.7, 149.7, 149.6, 146.1, 146.0, 130.4, 130.37, 129.8,
128.6, 128.0, 127.7, 122.5, 116.2, 115.0, 104.9, 96.0, 72.1,
63.9, 63.81, 63.8, 56.5, 55.6, 49.1, 47.5, 16.7, 16.6, 16.5,
16.4; HRMS (ESI-QTOF) m/z [M + H]+ calcd for
C35H36NO7P 627.2255, found 627.2254.
4-(6-Methoxy-3-phenylbenzofuran-2-yl)pyrrolo[1,2-a]
quinoxaline (5a)
Orange solid, mp: 228ꢀC to 229ꢀC; H NMR (400 MHz,
1
CDCl3) δ 7.93 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.81 (d,
J = 8.0 Hz, 1H), 7.66 to 7.58 (m, 3H), 7.49 (t, J = 7.8 Hz,
1H), 7.43 to 7.31 (m, 4H), 7.20 (s, 1H), 7.03 (d, J = 3.2 Hz,
1H), 6.97 (d, J = 8.4 Hz, 1H), 6.81 (s, 1H), 3.92 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 159.5, 155.9, 147.2, 144.9,
130.5, 130.1, 128.3, 127.7, 125.3, 121.5, 114.4, 114.2, 113.7,
113.1, 109.3, 96.0, 55.9; HRMS (ESI-QTOF) m/z [M
+ H]+ calcd for C26H19N2O2 391.1441, found 391.1445.
Diethyl ((5-(benzyloxy)-6-methoxy-3-(4-methoxyphenyl)
benzofuran-2-yl)(morpholino)methyl)phosphonate (4ae)
1
White solid, mp: 101ꢀC to 103ꢀC; H NMR (400 MHz,
CDCl3) δ 7.47 to 7.43 (m, 2H), 7.40 to 7.28 (m, 5H), 7.17
(s, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.98 (s, 1H), 5.14 to 5.06
(m, 2H), 4.29 to 4.19 (m, 3H), 4.16 to 4.06 (m, 1H), 4.01
to 3.92 (m, 4H), 3.88 (s, 3H), 3.71 to 3.57 (m, 4H), 2.88
(br s, 2H), 2.46 (br s, 2H), 1.35 (t, J = 7.0 Hz, 3H), 1.17
(t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.3,
149.7, 149.5, 145.9, 145.2, 137.3, 130.4, 128.6, 128.0,
127.7, 124.2, 123.0, 120.1, 114.6, 105.0, 96.2, 72.1, 67.5,
63.4, 63.35, 62.8, 62.7, 60.6, 58.9, 56.5, 55.5, 52.1,
52.06, 16.8, 16.7, 16.6, 16.5; HRMS (ESI-QTOF) m/z
[M + Na]+ calcd for C32H38NNaO8P 618.2227, found
618.2231.
4-(5,6-Dimethoxy-3-(4-methoxyphenyl)benzofuran-2-yl)
pyrrolo[1,2-a]quinoxaline (5b)
1
Brown solid, mp: 140ꢀC to 141ꢀC; H NMR (400 MHz,
CDCl3) δ 7.92 (br s, 1H), 7.82 (t, J = 7.2 Hz, 2H), 7.59 (d,
J = 8.8 Hz, 2H), 7.47 (t, J = 7.0 Hz, 1H), 7.39 (t,
J = 7.0 Hz, 1H), 7.21 (s, 1H), 7.11 to 7.05 (m, 2H), 6.97 (d,
J = 8.8 Hz, 2H), 6.82 (dd, J = 2.8, 4.0 Hz, 1H), 4.00 (s,
3H), 3.93 (s, 3H), 3.86 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 159.3, 149.8, 149.79, 147.4, 145.0, 131.4, 130.5,
127.8, 125.4, 125.0, 114.4, 114.2, 113.9, 113.7, 109.5, 101.8,
95.5, 56.6, 56.5, 55.5; HRMS (ESI-QTOF) m/z [M + H]+
calcd for C28H23N2O4 451.1652, found 451.1656.
Diethyl ((benzylamino)(5-(benzyloxy)-6-methoxy-
3-(4-methoxyphenyl)benzofuran-2-yl)methyl)
phosphonate (4af)
White solid, mp: 82ꢀC to 83ꢀC; 1H NMR (400 MHz,
CDCl3) δ 7.47 (d, J = 7.2 Hz, 2H), 7.38 (t, J = 7.4 Hz, 2H),
7.35 to 7.29 (m, 3H), 7.16 to 7.08 (m, 4H), 7.05 (s, 1H),
7.03 to 6.98 (m, 2H), 6.94 (d, J = 8.4 Hz, 2H), 5.17 to 5.07
(m, 2H), 4.27 to 4.14 (m, 3H), 4.12 to 4.03 (m, 1H), 3.99 to
3.09 (m, 4H), 3.87 (s, 3H), 3.74 (d, J = 13.2 Hz, 1H), 3.39
(d, J = 13.2 Hz, 1H), 1.32 (t, J = 7.2 Hz, 3H), 1.17 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.1,
149.7, 149.1, 146.0, 145.96, 145.6, 138.6, 137.2, 130.02,
130.0, 128.5, 128.4, 128.0, 127.6, 114.3, 105.0, 96.0, 72.0,
63.4, 63.3, 62.8, 62.76, 56.4, 55.3, 52.3, 51.3, 51.1, 50.6,
4-(5-(Benzyloxy)-6-methoxy-3-(4-methoxyphenyl)
benzofuran-2-yl)pyrrolo[1,2-a]quinoxaline (5c)
1
Yellow solid, mp: 128ꢀC to 129ꢀC; H NMR (400 MHz,
CDCl3) δ 7.92 (s, 1H), 7.83 (t, J = 7.2 Hz, 2H), 7.52 to 7.45
(m, 5H), 7.39 (t, J = 7.4 Hz, 3H), 7.33 (t, J = 7.0 Hz, 1H),
7.22 (s, 1H), 7.16 (s, 1H), 7.05 (d, J = 4.0 Hz, 1H), 6.93 (d,
J = 8.8 Hz, 2H), 6.81 (dd, J = 2.8, 4.0 Hz, 1H), 5.16 (s,
2H), 4.00 (s, 3H), 3.86 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 159.2, 150.5, 150.2, 146.2, 145.0, 131.3, 130.4,

14
KIM ET AL.
128.7, 128.1, 127.8, 127.7, 125.3, 114.3, 114.1, 113.8, 113.6,
109.4, 105.5, 95.7, 72.1, 56.5, 55.4; HRMS (ESI-QTOF) m/
z [M + H]+ calcd for C34H27N2O4 527.1965, found
527.1967.
2-(5-(Benzyloxy)-6-methoxy-3-(4-methoxyphenyl)
benzofuran-2-yl)benzo[d]oxazole (6c)
1
Yellow solid, mp: 166ꢀC to 167ꢀC; H NMR (400 MHz,
CDCl3) δ 7.75 (d, J = 6.8 Hz, 1H), 7.58 (d, J = 8.8 Hz,
2H), 7.49 to 7.44 (m, 3H), 7.39 (t, J = 7.2 Hz, 2H), 7.36 to
7.28 (m, 3H), 7.18 (s, 1H), 7.10 to 7.04 (m, 3H), 5.14 (s,
2H), 3.98 (s, 3H), 3.93 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 159.9, 151.6, 150.9, 150.3, 146.6, 141.8, 137.0,
131.3, 128.7, 128.1, 127.8, 126.2, 125.3, 124.9, 122.8, 120.8,
120.3, 114.1, 110.7, 105.3, 95.5, 72.0, 56.5, 55.5; HRMS
(ESI-QTOF) m/z [M + H]+ calcd for C30H24NO5
478.1649, found 478.1640.
4.1.5 | General procedure for the
synthesis of 6
To a solution of 3 (0.12 mmol) in ethanol (1 mL) were
added 2-aminophenol (2.0 equiv) and DBSA (0.2 equiv)
at room temperature. After being stirred at 60ꢀC for
12 hours, the reaction mixture was concentrated in
vacuo. The reaction mixture was basified with
aq. NaHCO3 solution and extracted with ethyl acetate
(1 mL × 3). The organic layer was dried over MgSO4 and
concentrated in vacuo. The resulting residue was
suspended in ethanol and filtered to give the intermedi-
ate as a yellow solid. To a solution of this intermediate
(0.042 mmol) in tetrahydrofuran (1 mL) was added
DDQ (1.5 equiv) at room temperature. After being
stirred at room temperature for 1 hour, the reaction
mixture was concentrated under reduced pressure. The
reaction mixture was basified with aq. NaHCO3 solution
and extracted with ethyl acetate (1 mL × 3). The organic
layer was dried over MgSO4 and concentrated in vacuo.
The residue was purified by silica gel column chroma-
tography (n-hexane:ethyl acetate:dichloromethane) to
give 6.
ACKNOWLEDGMENTS
We thank the National Research Foundation of Korea
(NRF-2017R1A2A2A05069364, NRF-2018R1A6A1A0302
3718, and NRF-2020R1A2C2005961) for generous finan-
cial support. MP and SHK were supported by project
grants from Korea Research Institute of Chemical Tech-
nology (KK1703-F02, KK1803-F00, and KK1932-20).
ORCID
Ikyon Kim https://orcid.org/0000-0002-0849-5517
REFERENCES
[1] (a) R. S. Bohacek, C. McMartin, W. C. Guida, Med. Res. Rev.
1996, 16, 3. (b) C. M. Dobson, Nature 2004, 432, 824. (c) J.-
L. Reymond, M. Awale, ACS Chem. Neurosci. 2012, 3, 649.
(d) K. Passador, S. Thorimbert, C. Botuha, Syntheis 2019,
51, 384.
[2] (a) M. S. Malamas, J. Sredy, C. Moxham, A. Katz, W. Xu,
R. McDevitt, F. O. Adebayo, D. R. Sawicki, L. Seestaller,
D. Sullivan, J. R. Taylor, J. Med. Chem. 2000, 43, 1293.
(b) M. Kuramoto, Y. Sakata, K. Terai, I. Kawasaki, J.-
i. Kunitomo, T. Ohishi, T. Yokomizo, S. Takeda, S. Tanaka,
Y. Ohishi, Org. Biomol. Chem. 2008, 6, 2772. (c) M. Mielczarek,
R. V. Thomas, C. Ma, H. Kandemir, X. Yang, M. Bhadbhade,
D. S. C. Black, R. Griffith, P. J. Lewis, N. Kumar, Bioorg. Med.
Chem. 2015, 23, 1763.
[3] (a) I. Kim, J. Choi, Org. Biomol. Chem. 2009, 7, 2788.
(b) I. Kim, K. Kim, J. Choi, J. Org. Chem. 2009, 74, 8492.
(c) K. Kim, I. Kim, Org. Lett. 2010, 12, 5314. (d) M. Nayak,
Y. Jung, I. Kim, Org. Biomol. Chem. 2016, 14, 8074. (e) Y. Jung,
I. Kim, Org. Biomol. Chem. 2016, 14, 10454. (f) Y. Jung,
D. K. Singh, I. Kim, Beilstein J. Org. Chem. 2016, 12, 2689.
(g) M. Nayak, D. K. Singh, I. Kim, Tetrahedron 2017, 73, 1831.
(h) M. Nayak, D. K. Singh, I. Kim, Synthesis 2017, 49, 2063.
(i) D. K. Singh, I. Kim, J. Org. Chem. 2018, 83, 1667.
(j) D. K. Singh, S. S. Prasad, I. Kim, Org. Chem. Front. 2019,
6, 669.
2-(6-Methoxy-3-phenylbenzofuran-2-yl)benzo[d]
oxazole (6a)
1
White solid, mp: 171ꢀC; H NMR (400 MHz, CDCl3) δ
7.77 (d, J = 6.8 Hz, 1H), 7.72 (d, J = 7.2 Hz, 2H), 7.59 to
7.48 (m, 4H), 7.44 (d, J = 8.0 Hz, 1H), 7.36 to 7.29 (m, 2H),
7.17 (s, 1H), 6.96 (d, J = 8.8 Hz, 1H), 3.91 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 160.5, 156.6, 156.1, 150.3, 141.7,
130.6, 130.1, 128.7, 128.6, 126.3, 125.5, 125.0, 122.1, 122.0,
120.4, 113.8, 110.8, 95.9, 55.9; HRMS (ESI-QTOF) m/z
[M + H]+ calcd for C22H16NO3 342.1125, found 342.1130.
2-(5,6-Dimethoxy-3-(4-methoxyphenyl)benzofuran-2-yl)
benzo[d]oxazole (6b)
1
Yellow solid, mp: 164ꢀC to 165ꢀC; H NMR (400 MHz,
CDCl3) δ 7.75 (d, J = 6.8 Hz, 1H), 7.66 (d, J = 8.4 Hz,
2H), 7.46 (d, J = 8.4 Hz, 1H), 7.36 to 7.28 (m, 2H), 7.18
(s, 1H), 7.11 (d, J = 8.4 Hz, 2H), 7.00 (s, 1H), 4.00 (s,
3H), 3.94 (s, 3H), 3.91 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 159.9, 156.3, 150.9, 150.6, 150.3, 147.8, 141.7,
137.6, 131.3, 126.3, 125.3, 124.9, 122.9, 120.9, 120.3,
114.2, 110.7, 101.7, 95.3, 56.6, 56.5, 55.5; HRMS (ESI-
QTOF) m/z [M + Na]+ calcd for C24H19NNaO4
424.1155, found 424.1156.
[4] (a) B.-L. Zhang, C.-Q. Fan, L. Dong, F.-D. Wang, J.-M. Yue,
Eur. J. Med. Chem. 2010, 45, 5258. (b) W.-C. Wan, W. Chen,
L.-X. Liu, Y. Li, L.-J. Yang, X.-Y. Deng, X.-Y. Zhang, H.-
B. Zhang, X.-D. Yang, Med. Chem. Res. 2014, 23, 1599.
(c) M. Giroud, J. Ivkovic, M. Martignoni, M. Fleuti, N. Trapp,
W. Haap, A. Kuglstatter, J. Benz, B. Kuhn, T. Schirmeister,

KIM ET AL.
15
F. Diederich, ChemMedChem 2017, 12, 257. (d) Lu, B.;
Shen, X.; He, M.; Liu, D.; Zhang, M. WO 2017084494 A1
20170526.
450 nm using HIDEX sense microplate reader (Turku, Finland).
Cytarabine (Sigma-Aldrich, St. Louis, MO, USA) was used as
the reference compound. Compounds used in this study were
dissolved with DMSO and prepared to 30 mM stock solutions
that were further diluted with cell culture medium. Therefore,
0.1% DMSO was used for the control in all experiments. All
quantitative values are presented as mean SD.
[5] (a) I. Kim, S.-H. Lee, S. Lee, Tetrahedron Lett. 2008, 49, 6579.
(b) J. H. Lee, M. Kim, I. Kim, J. Org. Chem. 2014, 79, 6153.
[6] G. Jones, S. P. Stanforth, Org. React. 1997, 49, 1.
[7] For the synthesis of 3, see the Experimental Section for details.
[8] (a) J. G. Allen, F. R. Atherton, M. J. Hall, C. H. Hassall,
S. W. Holmes, R. W. Lambert, L. J. Nisbet, P. S. Ringrose,
Nature 1978, 272, 56. (b) A. P. Kaplan, P. A. Bartlett, Biochem-
istry 1991, 30, 8165. (c) R. Hirschmann, A. B. Smith III.,
C. M. Taylor, P. A. Benkovic, S. D. Taylor, K. M. Yager,
P. A. Sprengeler, S. Benkovic, Science 1994, 265, 234.
(d) S. A. Beers, C. F. Schwender, D. A. Loughney, E. Malloy,
K. Demarest, J. Jordan, Bioorg. Med. Chem. 1996, 4, 1693.
(e) F. Allerberger, I. Klare, J. Antimicrob. Chemother. 1999, 43,
211. (f) E. Alonso, A. Solis, C. del Pozo, Synlett 2000, 5, 698.
[9] M. B. Haji, J. Org. Chem. 2016, 12, 1269.
[16] Caspase-3/7 activity assay & Apoptosis assay—Cells were
seeded in a 96-well plate at 4 × 103 cells/well and incubated
with 5b or cytarabine for 6 h. Then, caspase-3/7 activity was
evaluated in triplicate using Apo-ONE Homogeneous Caspase-
3/7 Assay (Promega, WI) according to the manufacturer's pro-
tocol. All quantitative values are presented as mean
SD. Statistical differences were analyzed using Student's t-test.
A value of P < 0.05 was considered significant. Apoptosis was
evaluated by counting Annexin V-positive cells. Briefly, cells
were seeded in a 96-well plate at 2 × 103 cells/well and incu-
bated with compounds for three days. Then, cells were incu-
bated with Muse Annexin V & Dead Cell Reagent (Millipore)
according to the manufacturer's protocol and analyzed in
Muse Cell Analyzer (Millipore).
[10] (a) J. Wu, W. Sun, W.-Z. Wang, H.-G. Xia, Chin. J. Chem. 2006,
24, 1054. (b) J. Kim, Y. Heo, Y. Jung, J. Lee, I. Kim, Tetrahe-
dron 2017, 73, 5759.
[11] D. K. Singh, M. Nath, Org. Biomol. Chem. 2015, 13, 1836.
[12] J. Chang, K. Zhao, S. Pan, Tetrahedron Lett. 2002, 43, 951.
[13] (a) A. Huang, C. Ma, Mini-Rev. Med. Chem. 2013, 13, 607.
(b) L. Ronga, M. Del Favero, A. Cohen, C. Soum, P. Le Pape,
S. Savrimtou, N. Pinaud, C. Mullié, S. Daulouede,
P. Vincendeau, N. Farvacques, P. Agnamey, F. Pagniez,
S. Hutter, N. Azas, P. Sonnet, J. Guillon, Eur. J. Med. Chem.
2014, 81, 378. (c) V. Desplat, M. Vincenzi, R. Lucas,
S. Moreau, S. Savrimoutou, S. Rubio, N. Pinaud, D. Bigat,
E. Enriquez, M. Marchivie, S. Routier, P. Sonnet, F. Rossi,
L. Ronga, J. Guillon, ChemMedChem 2017, 12, 940.
(d) T. Wang, Y. Tang, Y. Yang, Q. An, Z. Sang, T. Yang, P. Liu,
T. Zhang, Y. Deng, Y. Luo, Bioorg. Med. Chem. Lett. 2018, 28,
2084.
[14] (a) N. Bramhananda Reddy, V. R. Burra, L. K. Ravindranath,
R. Sreenivasulu, V. N. Kumar, Monatsh. Chem. 2016, 147, 593.
(b) V. Singh, A. Singh, G. Singh, R. K. Verma, R. Mall, Med.
Chem. Res. 2018, 27, 735. (c) A. Kaur, D. P. Pathak, V. Sharma,
S. Wakode, Bioorg. Med. Chem. 2018, 26, 891. (d) V. Šlachtová,
L. Brulíková, ChemistrySelect 2018, 3, 4653.
[15] Cell viability assay – All cell culture materials were purchased
from HyClone (South Logan, UT, USA). Human lymphoma
U937, human T-lymphoblastic leukemia Jurkat (American
Type Culture Collection, Manassas, VA, USA) and human leu-
kemia HL-60 (Korean Cell Line Bank, Seoul, Korea) were
maintained in RPMI-1640 containing 10% fetal bovine serum,
100 U/ml of penicillin, and 100 μg/ml streptomycin. Human
hepatoblastoma HepG2 and human gastric cancer cells
Hs746T (Korean Cell Line Bank) were maintained in MEM
and RPMI-1640 containing 10% fetal bovine serum, 100 U/ml
of penicillin, and 100 μg/ml streptomycin, respectively. Cells
were seeded in a 96-well plate at 2 × 103 cells/well and incu-
bated with compounds for 3 days. Then, cell viability was eval-
uated in triplicate using Cell Counting Kit-8 (Dojindo
Molecular Technologies, Rockville, MD, USA) according to
the manufacturer's protocol. Absorbance was measured at
[17] S. H. Moon, Y. Jung, S. H. Kim, I. Kim, Bioorg. Med. Chem.
Lett. 2016, 26, 110. Briefly, U937 cells (4 × 104 cells/ml) were
seeded in a 100-mm2 dish, incubated for 1 day, and treated
with the compound for 1 day. Then, proteins obtained from
the cell lysates were separated by SDS-polyamide gel and
transferred onto PVDF membranes. The membranes were pro-
bed with the indicated antibodies. All antibodies were pur-
chased form Cell Signaling Technology (MA), and GAPDH
was used as the internal control. Western blot analysis—
Western blot analysis was performed as described in a previ-
ous study with modifications.
[18] (a) D. W. Nicholson, A. Ali, N. A. Thornberry,
J. P. Vaillancourt, C. K. Ding, M. Gallant, Y. Gareau,
P. R. Griffin, M. Labelle, Y. A. Lazebnik, N. A. Munday,
S. M. Raju, M. E. Smulson, T.-T. Yamin, V. L. Yu, D. K. Miller,
Nature 1995, 376, 37. (b) F. J. Oliver, G. de la Rubia, V. Rolli,
M. C. Ruiz-Ruiz, G. de Murcia, J. M. Murcia, J. Biol. Chem.
1998, 273, 33533.
[19] T. Wada, J. M. Penninger, Oncogene 2004, 23, 2838.
[20] A. N. Grinev, S. A. Zotova, I. N. Mikhailova, A. A. Stolyarchuk,
G. I. Stepanyuk, V. V. Matsak, Khim.-Farm. Zh. 1980, 14, 43.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Kim J, Cha H-M,
Park M, et al. Expanding the chemical space:
Discovery of new anticancer 3-arylbenzofuran
derivatives. J Heterocyclic Chem. 2020;1–15. https://
doi.org/10.1002/jhet.4043