Michael-Aldol Double Elimination Cascade to Make Pyridines: Use of Chromone for the Synthesis of Indolizines

Article abstract of DOI:10.1021/acs.joc.1c00981

A domino Michael-aldol double elimination route to indolizines having two different acyl groups at the C5 and C7 positions is described where chromone is employed as a two-carbon unit for the synthesis of a pyridine moiety for the first time. Various analogues were readily accessed in good yields under metal-free and eco-friendly conditions. Further manipulation of the resulting products allowed entry to novel indolizine-heterocycle adducts, which are difficult to access by other methods.

Full text of DOI:10.1021/acs.joc.1c00981

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Michael-Aldol Double Elimination Cascade to Make Pyridines: Use of
Chromone for the Synthesis of Indolizines
Dirgha Raj Joshi and Ikyon Kim*
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ABSTRACT: A domino Michael-aldol double elimination route
to indolizines having two different acyl groups at the C5 and C7
positions is described where chromone is employed as a two-
carbon unit for the synthesis of a pyridine moiety for the first time.
Various analogues were readily accessed in good yields under
metal-free and eco-friendly conditions. Further manipulation of the
resulting products allowed entry to novel indolizine-heterocycle
adducts, which are difficult to access by other methods.
indolizines having two acyl motifs at the C1 and C3 positions.
Here, we wish to describe our results on the synthesis of new
indolizines12 and further functionalization.
INTRODUCTION
■
Chromone, also known as 4H-chromen-4-one, is a basic
skeleton in a number of naturally occurring flavonoids and
isoflavonoids. Not surprisingly, because of a variety of
biological activities associated with this privileged core, it
has been frequently employed as a key substructure of many
small-molecule drug discovery programs, displaying intriguing
pharmacological properties including antiasthmatic, anti-
cancer, and antimicrobial activities (Figure 1).1
RESULTS AND DISCUSSION
■
The reaction conditions were optimized with 1a and 11a
(Table 1). Dimerization of 11a in the presence of base has
been reported.13 To increase the yield of the desired product
12a by avoiding dimerization of 11a, 3 equiv of chromone 1a
was used.14 To our delight, reaction with Cs2CO3 (1.2 equiv)
in CH3CN at 80 °C gave indolizine 12a in 95% yield, whereas
no reaction was observed at room temperature (entries 1 and
2). Other bases such as Et3N or K2CO3 were far less efficient
(entries 3 and 4). Screening of other solvents revealed that
CH3CN is the best (entries 5−9). Use of piperidinium acetate
as a catalyst only produced (E)-1-(2-hydroxyphenyl)-3-
(piperidin-1-yl)prop-2-en-1-one (B) which resulted from
ring opening of chromone 1a by piperidine. This implies
the reaction mechanism of this protocol is that the reaction
occurs via a Michael-aldol double dehydration sequence, not
via Knoevenagel-aldol condensation.
From the synthetic chemistry point of view, as it contains
an α,β-unsaturated carbonyl group, it has been utilized as a C2
or C3 unit in some annulation reactions, thereby leading to
useful heterocyclic systems (Scheme 1a). For example, Shen
and co-workers established the synthesis of 3,4-diacylquino-
lines (2) from isatin and chromone (1) where chromone (1)
was employed as a two-carbon partial structure of quinolines.2
In addition, access to 3-acylpyrazolo[1,5-a]pyridine (3),3
xanthone (4),4 and pyrazoles (5)5 was enabled by use of
chromone (1) as an annulation partner. Participation of
chromone (1) as a C3 unit was demonstrated in syntheses of
pyrazoles (6),6 isoxazoles (7),7 and pyrimidines (8).8 More
recently, Huang and Dong reported the synthesis of
indolizines (10) from chromones (1) and pyridinium salts
(9) through the synthesis of the pyrrole moiety by the
sequence involving 1,3-dipolar cycloaddition, ring-opening,
and aromatization.9 Encouraged by our successful [4+2]
annulation approach to quinone-indolizine hybrid structures
via formation of a pyridine ring,10 we wondered if adoption of
the similar [4+2] cyclization protocol would afford novel
indolizines (12) from chromone (1) and pyrrole derivatives
(11) through the intermediate A (Scheme 1b). Notably, it
would allow installation of two different acyl groups at the C5
and C7 sites,11 whereas Huang’s method produced the
Having found the optimal conditions, the reaction scope
was examined with various 11 (Scheme 2). In general,
electron-poor or electron-rich aromatic rings (G) in 11 were
well tolerated under these conditions to afford the
corresponding indolizines 12b−j in good yields, although
Received: April 27, 2021
Published: July 22, 2021
https://doi.org/10.1021/acs.joc.1c00981
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© 2021 American Chemical Society
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Figure 1. Bioactive chromones.
a
Scheme 1. Synthetic Plan
Table 1. Reaction Optimization
temperature
b
entry
base (equiv)
solvent
(°C)
time (h) yield (%)
1
2
3
4
5
6
7
8
9
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Et3N (2.0)
K2CO3 (2.0)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
CH3CN
CH3CN
CH3CN
CH3CN
DMF
toluene
DMSO
THF
80
RT
80
80
80
80
80
80
130
1
12
5
6
24
4
1
2
12
95
NR
NR
10
70
64
65
90
c
piperidinium
acetate (1.0)
Cs2CO3 (1.2)
EtOH
d
10
CH3CN
80
1
93
a
A mixture of 11a (50 mg, 0.23 mmol) and 1a (3 equiv) in solvent (3
mL) was stirred at the indicated temperature for the indicated time.
Isolated yields (%). Only B was observed. 11a (730 mg, 3.4 mmol)
b
c
d
was used.
pyrrole derivatives 11 containing additional bromo or ethyl
ester to these conditions led to 12ae and 12af, respectively.
Application of this annulation method to other pyrrole
derivatives was attempted (Scheme 4a). When N-substituted
2-acetylpyrrole and 2-benzoylpyrrole 13a,b were used instead
of 11, the corresponding indolizines 14a,b bearing a methyl
and phenyl substituent at the C8 position were obtained,
respectively. The chemical structure of 14a was unequivocally
confirmed by X-ray crystallographic analysis (Figure S1).15
Reaction of 13c with 1a under the similar conditions
produced 14c in 26% yield.16 Post-functionalization of 12a
was carried out to demonstrate the expandability of the
synthesized indolizine chemical space (Scheme 4b). Using the
2-hydroxybenzoyl moiety in 12a for introduction of an
additional ring permitted facile access to indolizines 15−17
possessing benzofuran, chromene, and coumarin frameworks.
The chemical structure of 15 was firmly established by X-ray
crystallographic analysis (Figure S2).17 Oxidation18 of 12w
went smoothly to afford quinone 18 in 74% yield (Scheme
4c).
better chemical yields were obtained in cases of 11 having an
electron-donating aryl moiety. Modest yields of products
12k−l were observed when G was furan or methyl.
More diverse 1 and 11 were allowed to react under the
optimized conditions (Scheme 3). Reactions of several
chromones 1 possessing additional functional groups such as
alkoxy, alkyl, or halogen with 11 delivered the corresponding
indolizines 12m−12ad in good to excellent yields, displaying a
good functional group tolerance. Similarly, exposure of 1a and
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a b
,
Scheme 2. Synthesis of 12
a
A mixture of 11 (0.23 mmol), 1a (3 equiv), and Cs2CO3 (1.2 equiv) in CH3CN (3 mL) was stirred at 80 °C for 1 h unless otherwise noted.
b
c
d
e
Isolated yield (%). Cs2CO3 (1.5 equiv) was used. Reaction time: 5 h. Cs2CO3 (1.5 equiv) was used. Reaction time: 10 h. Cs2CO3 (1.5 equiv)
was used. Reaction time: 2 h.
Double annulation with 19 and 11a (2.2 equiv) was
performed (Scheme 5). However, only a mono annulation
event took place to furnish 20 as a major product.19 We
suspected this may be due to the decreased reactivity of the
chromone carbonyl group by the hydroxyl at the C7 site so
the hydroxy moiety was protected as a methyl ether to give
21. To our delight, the second annulation of 21 with 11e went
smoothly to afford 22 in 85% yield.
As the reaction begins with Michael addition of 11 to 1 as
suggested in the mechanism, we expected the reaction would
proceed faster by increasing the electrophilicity of 1. To this
end, we employed 3-formylchromone 2320 as a reaction
partner (Scheme 6). Indeed, the reaction went faster under
similar conditions to give 12a. The reaction could be
explained as a consequence of formyl transfer (C to O) and
subsequent elimination which are shown in C and D.
In the meantime, we serendipitously discovered that
exposure of 12a to Cs2CO3 (2 equiv) in CH3CN at 80 °C
for 2 h gave rise to 24 in 90% yield (Scheme 7). The chemical
structure of 24 was again verified by X-ray crystallographic
analysis (Figure S3).21 Oddly, this chromone-indolizine hybrid
structure was not observed when a large excess of Cs2CO3
(∼3.5 equiv) was used in the reaction of 1a and 11a. A one-
pot sequential experiment was also carried out. Thus, more
Cs2CO3 (3 equiv) was added in the reaction mixture after
formation of 12a from 1a and 11a under the optimized
conditions was confirmed by TLC. Only 25% yield of 24 was
isolated from the reaction mixture even after heating at 80 °C
for 17 h. Unfortunately, the desired hybrid products were
obtained in low yields upon subjection of other 12
compounds to these conditions.22
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a b
,
Scheme 3. Synthesis of 12
a
A mixture of 11 (0.23 mmol), 1 (3 equiv), and Cs2CO3 (1.2 equiv) in CH3CN (3 mL) was stirred at 80 °C for 1 h unless otherwise noted.
b
Isolated yield (%).
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Scheme 4. Application and Derivatization
Scheme 5. Double Annulation Attempt
cascade procedure enabled facile access to new indolizines
with unique substitution patterns in good yields. Simple
elaboration of the products permitted indolizine-heterocycle
hybrids, further extending the indolizine chemical space.
CONCLUSIONS
■
In summary, chromone was utilized as a two-carbon unit of
the [4+2] annulation process to make a pyridine part of
indolizine. A base-promoted Michael-aldol double elimination
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(5-Benzoylindolizin-7-yl)(2-hydroxyphenyl)methanone (12a).
Scheme 6. Use of 23
Yellow solid (74 mg, 95%); mp: 161−163 °C; Rf = 0.3 in 10%
1
EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 11.61 (s, 1H),
8.92 (s, 1H), 8.16 (s, 1H), 7.85 (d, J = 6.0 Hz, 2H), 7.72 (d, J = 7.5
Hz, 1H), 7.68−7.58 (m, 2H), 7.59−7.45 (m, 3H), 7.18−7.00 (m,
3H), 6.98−6.87 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ
197.3, 190.9, 162.7, 138.0, 136.1, 133.0, 132.8, 132.3, 130.0, 129.8,
128.7, 128.2, 123.4, 122.4, 120.2, 119.2, 118.8, 118.7, 117.6, 109.0;
HRMS (ESI-QTOF) m/z [M + H]+ calcd for C22H16NO3 342.1125,
found 342.1128.
(5-(4-Fluorobenzoyl)indolizin-7-yl)(2-hydroxyphenyl)methanone
(12b).
Scheme 7. Synthesis of Chromone-Indolizine Hybrid 24
Yellow solid (57 mg, 69%); mp: 185−187 °C; Rf = 0.3 in 10%
1
EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 11.59 (s, 1H),
8.84 (s, 1H), 8.15 (s, 1H), 7.99−7.81 (m, 2H), 7.71 (d, J = 7.7 Hz,
1H), 7.59 (s, 1H), 7.56−7.48 (m, 1H), 7.26−7.17 (m, 2H), 7.15−
7.02 (m, 3H), 6.98−6.90 (m, 1H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 193.3, 189.0, 164.6 (d, JCF = 251.3 Hz), 155.7, 134.1(d,
JCF = 2.6 Hz), 133.1, 132.5, 132.4 (d, JCF = 9.3 Hz), 129.8, 128.9,
128.3, 125.2, 123.6, 121.6, 119.8, 119.2, 117.3, 116.5, 115.7, 115.5,
109.6; 19F NMR (376 MHz, CDCl3) δ −105.1; HRMS (ESI-QTOF)
m/z [M + H]+ calcd for C22H15FNO3 360.1030, found 360.1036.
(5-(4-Chlorobenzoyl)indolizin-7-yl)(2-hydroxyphenyl)meth-
anone (12c).
Efforts to find new chemical scaffolds for biological study are
being continued in our laboratory.
EXPERIMENTAL SECTION
■
General Methods. Unless specified, all reagents and starting
materials were purchased from commercial sources and used as
received without purification. “Concentrated” refers to 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 acetate, and
dichloromethane as the eluents. All reactions were monitored by
thin-layer chromatography on 0.25 mm silica plates (F-254)
visualized with UV light. Melting points were measured using a
capillary melting point apparatus. 1H and 13C NMR spectra were
recorded on a 400 MHz NMR spectrometer and were described as
chemical shifts, multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet), coupling constant in hertz (Hz), and number
of protons. HRMS was measured with an electrospray ionization
(ESI) and Q-TOF mass analyzer. X-ray crystal structures of 14a, 15,
and 24 were determined with a SuperNova, Dual, Cu at home/near,
AtlasS2 diffractometer.
1
Yellow gum (60 mg, 70%); Rf = 0.3 in 10% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ 11.57 (s, 1H), 8.89 (s, 1H), 8.15 (s,
1H), 7.80 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 7.9 Hz, 1H), 7.60 (s, 1H),
7.51 (d, J = 8.0 Hz, 3H), 7.12 (s, 1H), 7.08 (d, J = 8.8 Hz, 1H), 7.06
(d, J = 3.6 Hz, 1H), 6.94 (t, J = 7.3 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 197.3, 189.7, 162.8, 139.4, 136.3, 136.2, 133.0,
132.3, 131.2, 129.8, 129.1, 128.4, 123.4, 122.4, 120.3, 119.2, 118.9,
118.8, 117.8, 109.2; HRMS (ESI-QTOF) m/z [M + H]+ calcd for
C22H15ClNO3 376.0735, found 376.0738.
(5-(4-Bromobenzoyl)indolizin-7-yl)(2-hydroxyphenyl)meth-
anone (12d).
General Procedure for the Synthesis of 12. A mixture of 11a
(50 mg, 0.23 mmol, 1 equiv), 1a (100 mg, 0.69 mmol, 3 equiv), and
Cs2CO3 (90 mg, 0.28 mmol, 1.2 equiv) in CH3CN (3 mL) was
stirred at 80 °C (heating mantle was used) for 1 h. The reaction
mixture was concentrated under reduced pressure to give the crude
residue, which was purified by silica gel column chromatography
(Hexane/EtOAc = 20:1 to 10:1) to afford 12a (74 mg, 95%) as a
yellow solid.
1
Yellow gum (91 mg, 94%); Rf = 0.3 in 10% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ 11.57 (s, 1H), 8.89 (s, 1H), 8.15 (s,
1H), 7.77−7.63 (m, 5H), 7.60 (s, 1H), 7.52 (t, J = 7.4 Hz, 1H),
7.15−7.01 (m, 3H), 6.93 (t, J = 7.4 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 197.2, 189.8, 162.8, 136.8, 136.2, 133.0, 132.3,
132.1, 131.3, 129.7, 128.4, 127.9, 123.4, 122.5, 120.3, 119.2, 118.9,
Scale-Up Experiment. 12a (1.08 g, 93%) was obtained when the
reaction was carried out with 11a (0.73 g, 3.4 mmol).
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118.8, 117.8, 109.3; HRMS (ESI-QTOF) m/z [M + H]+ calcd for
C22H15BrNO3 420.0230, found 420.0230.
(7-(2-Hydroxybenzoyl)indolizin-5-yl)(4-methoxyphenyl)meth-
anone (12e).
1H), 7.95 (d, J = 8.0 Hz, 2H), 7.80−7.71 (m, 3H), 7.71−7.62 (m,
3H), 7.56−7.39 (m, 4H), 7.17−7.01 (m, 3H), 6.94 (t, J = 7.3 Hz,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.4, 190.5, 162.8,
145.7, 139.9, 136.6, 136.1, 133.0, 132.3, 130.5, 130.2, 129.1, 128.4,
128.1, 127.4, 127.4, 123.5, 122.0, 120.1, 119.2, 118.9, 118.7, 117.6,
109.0; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C28H20NO3
418.1438, found 418.1430.
(5-(2-Naphthoyl)indolizin-7-yl)(2-hydroxyphenyl)methanone
(12i).
1
Yellow gum (82 mg, 96%); Rf = 0.3 in 10% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ 11.63 (s, 1H), 8.68 (s, 1H), 8.11 (s,
1H), 7.89 (d, J = 7.4, 2H), 7.73 (d, J = 7.9 Hz, 1H), 7.54 (s, 1H),
7.51 (d, J = 7.3 Hz, 1H), 7.08 (d, J = 6.7 Hz, 2H), 7.05−6.98 (m,
3H), 6.94 (t, J = 7.6 Hz, 1H), 3.91 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 197.5, 189.5, 163.8, 162.7, 136.0, 132.7, 132.3,
130.5, 130.1, 127.7, 123.6, 120.4, 119.5, 119.3, 118.8, 118.6, 117.2,
114.1, 108.5, 55.7; HRMS (ESI-QTOF) m/z [M + H]+ calcd for
C23H18NO4 372.1230, found 372.1213.
1
Yellow gum (54 mg, 60%); Rf = 0.3 in 10% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ 11.63 (s, 1H), 8.90 (s, 1H), 8.35 (s,
1H), 8.17 (s, 1H), 8.05−7.85 (m, 4H), 7.74 (d, J = 7.3 Hz, 1H),
7.68 (s, 1H), 7.66−7.54 (m, 2H), 7.48 (t, J = 7.2 Hz, 1H), 7.12 (s,
1H), 7.05 (d, J = 8.1 Hz, 2H), 6.91 (t, J = 7.0 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 197.4, 190.8, 162.8, 136.1, 135.5, 135.2,
133.0, 132.4, 132.3, 131.4, 130.2, 129.5, 128.8, 128.7, 128.1, 128.0,
127.2, 125.5, 123.6, 122.2, 120.1, 119.2, 118.9, 118.7, 117.6, 108.9;
HRMS (ESI-QTOF) m/z [M + H]+ calcd for C26H18NO3 392.1281,
found 392.1266.
(7-(2-Hydroxybenzoyl)indolizin-5-yl)(3-methoxyphenyl)-
methanone (12f).
(7-(2-Hydroxybenzoyl)indolizin-5-yl)(p-tolyl)methanone (12j).
1
Yellow gum (81 mg, 95%); Rf = 0.3 in 10% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ11.62 (s, 1H), 8.89 (s, 1H), 8.14 (s, 1H),
7.71 (d, J = 7.8 Hz, 1H), 7.65 (s, 1H), 7.50 (t, J = 7.6 Hz, 1H),
7.45−7.35 (m, 3H), 7.16 (d, J = 7.0 Hz, 1H), 7.13−7.00 (m, 3H),
6.92 (t, J = 7.3 Hz, 1H), 3.88 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ197.3, 190.7, 162.7, 159.8, 139.2, 136.1, 133.0, 132.3,
129.9, 129.6, 128.2, 123.4, 122.5, 122.3, 120.2, 119.2, 119.0, 118.8,
118.7, 117.6, 114.5, 109.0, 55.6; HRMS (ESI-QTOF) m/z [M + H]+
calcd for C23H18NO4 372.1230, found 372.1200.
Yellow solid (70 mg, 86%); mp: 150−153.5 °C; Rf = 0.3 in 10%
EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 11.63 (s, 1H),
1
(5-(2,5-Dimethoxybenzoyl)indolizin-7-yl)(2-hydroxyphenyl)-
methanone (12g).
8.83 (s, 1H), 8.13 (s, 1H), 7.77 (d, J = 7.6 Hz, 2H), 7.72 (d, J = 7.5
Hz, 1H), 7.60 (s, 1H), 7.52 (t, J = 7.1 Hz, 1H), 7.33 (d, J = 7.3 Hz,
2H), 7.14−7.05 (m, 2H), 7.03 (d, J = 3.1 Hz, 1H), 6.94 (t, J = 7.4
Hz), 2.46 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.5,
190.7, 162.7, 143.9, 136.1, 135.2, 132.9, 132.4, 130.3, 130.0, 129.4,
128.0, 123.5, 121.7, 119.9, 119.2, 118.9, 118.7, 117.4, 108.8, 21.8;
HRMS (ESI-QTOF) m/z [M + H]+ calcd for C23H18NO3 356.1281,
found 356.1277.
1
(5-(Furan-2-carbonyl)indolizin-7-yl)(2-hydroxyphenyl)meth-
anone (12k).
Yellow gum (88 mg, 95%); Rf = 0.2 in 10% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ 11.66 (s, 1H), 9.26 (s, 1H), 8.18 (s,
1H), 7.67 (d, J = 7.4 Hz, 1H), 7.61 (s, 1H), 7.49 (s, 1H), 7.15 (s,
1H), 7.10−6.98 (m, 3H), 6.99−6.92 (m, 2H), 6.89 (s, 1H), 3.80 (s,
3H), 3.75 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.3,
190.5, 162.8, 153.6, 151.3, 136.0, 133.4, 132.3, 130.2, 128.8, 128.3,
124.0, 123.4, 120.9, 119.2, 118.7, 118.6, 117.9, 117.6, 114.7, 113.2,
109.1, 56.5, 55.9; HRMS (ESI-QTOF) m/z [M + H]+ calcd for
C24H20NO5 402.1336, found 402.1339.
(5-([1,1′-Biphenyl]-4-carbonyl)indolizin-7-yl)(2-hydroxyphenyl)-
methanone (12h).
Yellow solid (37 mg, 48%); mp: 117−119 °C; Rf = 0.3 in 30%
EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 11.64 (s, 1H),
1
8.78 (s, 1H), 8.12 (s, 1H), 8.06 (s, 1H), 7.74 (s, 2H), 7.52 (t, J = 7.0
Hz, 1H), 7.37 (s, 1H), 7.08 (d, J = 8.7 Hz, 1H), 7.06 (s, 1H), 7.01
(s, 1H), 6.94 (t, J = 7.0 Hz, 1H), 6.63 (s, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 197.4, 176.4, 162.7, 151.8, 147.7, 136.1, 132.8,
132.4, 129.5, 128.2, 123.5, 121.0, 120.2, 119.8, 119.3, 118.9, 118.7,
117.5, 112.7, 109.0; HRMS (ESI-QTOF) m/z [M + H]+ calcd for
C20H14NO4 332.0917, found 332.0908.
1
Yellow gum (93 mg, 97%); Rf = 0.3 in 10% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ 11.63 (s, 1H), 8.90 (s, 1H), 8.16 (s,
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1-(7-(2-Hydroxybenzoyl)indolizin-5-yl)ethan-1-one (12l).
(5-Benzoylindolizin-7-yl)(2-hydroxy-3,5-dimethylphenyl)meth-
anone (12p).
Yellow solid (33 mg, 52%); mp: 116−117 °C; Rf = 0.3 in 20%
1
EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 11.61 (s, 1H),
Yellow solid (76 mg, 89%); mp: 142−143 °C; Rf = 0.3 in 10%
1
9.18 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H),
7.51 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 3.7
Hz, 1H), 6.99 (d, J = 3.1 Hz, 1H), 6.93 (t, J = 7.2 Hz, 1H), 2.75 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.2, 192.8, 162.7,
136.0, 133.2, 132.2, 129.8, 128.6, 122.9, 121.2, 120.4, 119.2, 118.9,
118.7, 117.9, 109.1, 27.3; HRMS (ESI-QTOF) m/z [M + H]+ calcd
for C17H14NO3 280.0968, found 280.0974.
EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 11.70 (s, 1H),
8.92 (s, 1H), 8.15 (s, 1H), 7.84 (d, J = 6.7 Hz, 2H), 7.68−7.57 (m,
2H), 7.54 (d, J = 6.8 Hz, 2H), 7.32 (s, 1H), 7.21 (s, 1H), 7.12 (s,
1H), 7.05 (s, 1H), 2.28 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3)
δ 197.7, 190.9, 159.1, 138.2, 138.1, 133.1, 132.7, 129.7, 129.6, 128.6,
128.0, 127.5, 127.1, 123.9, 122.7, 120.0, 118.2, 117.5, 108.7, 20.7,
15.7; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C24H20NO3
370.1438, found 370.1438.
(5-Benzoylindolizin-7-yl)(2-hydroxy-4-methoxyphenyl)meth-
anone (12m).
(5-Benzoylindolizin-7-yl)(5-chloro-2-hydroxy-4-methylphenyl)-
methanone (12q).
Yellow solid (82 mg, 96%); mp: 113−114 °C; Rf = 0.3 in 10%
1
EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 12.39 (s, 1H),
Red solid (86 mg, 96%); mp: 120−122 °C; Rf = 0.3 in 10% EtOAc
1
8.90 (s, 1H), 8.08 (s, 1H), 7.83 (d, J = 5.7 Hz, 2H), 7.70−7.40 (m,
5H), 7.09 (s, 1H), 7.01 (s, 1H), 6.51 (s, 1H), 6.45 (d, J = 6.6 Hz,
1H), 3.85 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 196.0,
191.0, 166.1, 166.0, 138.0, 134.0, 133.0, 132.7, 130.0, 129.8, 128.6,
127.5, 123.8, 122.6, 119.7, 117.4, 112.9, 108.3, 107.5, 101.4, 55.7;
HRMS (ESI-QTOF) m/z [M + H]+ calcd for C23H18NO4 372.1230,
found 372.1227.
in hexane; H NMR (400 MHz, CDCl3) δ 11.54 (s, 1H), 8.94 (s,
1H), 8.17 (s, 1H), 7.86 (d, J = 6.9 Hz, 2H), 7.69 (s, 1H), 7.63 (d, J
= 6.0 Hz, 1H), 7.60−7.51 (m, 3H), 7.14 (d, J = 2.5 Hz, 1H), 7.10
(d, J = 3.2 Hz, 1H), 6.96 (s, 1H), 2.41 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 196.0, 190.8, 161.2, 145.3, 137.9, 133.2, 132.8,
131.7, 129.7, 129.6, 128.8, 127.9, 124.2, 123.0, 122.4, 120.7, 120.4,
118.1, 117.8, 109.3, 20.9; HRMS (ESI-QTOF) m/z [M + H]+ calcd
for C23H17ClNO3 390.0891, found 390.0891.
(5-Benzoylindolizin-7-yl)(2-hydroxy-5-methoxyphenyl)meth-
anone (12n).
(5-Benzoylindolizin-7-yl)(5-(tert-butyl)-2-hydroxy-3-iodo-4-
methoxyphenyl)methanone (12r).
Yellow solid (67 mg, 79%); mp: 134−136 °C; Rf = 0.3 in 10%
1
1
Yellow gum (95 mg, 75%); Rf = 0.3 in 10% EtOAc in hexane; H
EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 11.09 (s, 1H),
NMR (400 MHz, CDCl3) δ 12.81 (s, 1H), 8.95 (s, 1H), 8.16 (s,
1H), 7.82 (d, J = 4.8 Hz, 2H), 7.70 (s, 1H), 7.63 (s, 2H), 7.52 (s,
2H), 7.13 (s, 1H), 7.07 (s, 1H), 4.01 (s, 3H), 1.31 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3) δ 196.0, 190.9, 166.7, 162.3, 137.9, 135.7,
133.1, 132.7, 131.5, 129.9, 129.6, 128.7, 128.2, 123.0, 122.5, 120.4,
117.8, 114.7, 109.1, 85.1, 62.3, 34.9, 31.0; HRMS (ESI-QTOF) m/z
[M + H]+ calcd for C27H25INO4 554.0823, found 554.0824.
(5-Benzoylindolizin-7-yl)(1-hydroxynaphthalen-2-yl)methanone
(12s).
8.93 (s, 1H), 8.19 (s, 1H), 7.85 (d, J = 7.1 Hz, 2H), 7.72−7.58 (m,
2H), 7.60−7.46 (m, 2H), 7.20−7.09 (m, 3H), 7.06 (d, J = 3.3 Hz,
1H), 7.02 (d, J = 8.6 Hz, 1H), 3.74 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 196.9, 190.9, 156.8, 151.6, 137.9, 133.0, 132.8,
129.9, 129.7, 128.7, 128.1, 123.4, 123.3, 122.5, 120.2, 119.4, 118.9,
117.6, 115.6, 109.1, 56.1; HRMS (ESI-QTOF) m/z [M + H]+ calcd
for C23H18NO4 372.1230, found 372.1224.
(5-Benzoylindolizin-7-yl)(2-hydroxy-5-methylphenyl)methanone
(12o).
Yellow solid (67 mg, 75%); mp: 169−170.5 °C; Rf = 0.3 in 10%
1
Yellow solid (70 mg, 86%); mp: 164−166 °C; Rf = 0.3 in 10%
EtOAc in hexane; 1H NMR (400 MHz, CDCl3) δ 11.4 (s, 1H), 8.92
(s, 1H), 8.15 (s, 1H), 7.85 (d, J = 6.5 Hz, 2H), 7.61 (s, 2H), 7.57−
7.43 (m, 3H), 7.31 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H),
7.06 (d, J = 2.8 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 2.31 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 197.4, 190.9, 160.6, 138.1,
137.1, 133.1, 132.7, 132.0, 129.8, 129.7, 128.7, 128.0, 127.9, 123.6,
122.6, 120.1, 118.9, 118.5, 117.6, 108.9, 20.7; HRMS (ESI-QTOF)
m/z [M + H]+ calcd for C23H18NO3 356.1281, found 356.1293.
EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 13.64 (s, 1H),
8.95 (s, 1H), 8.49 (d, J = 6.2 Hz, 1H), 8.17 (s, 1H), 7.91−7.81 (m,
2H), 7.77 (d, J = 6.0 Hz, 1H), 7.71−7.58 (m, 4H), 7.58−7.46 (m,
3H), 7.27 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 7.05 (s,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.2, 190.9, 163.4,
138.0, 137.2, 133.1, 132.7, 130.3, 129.9, 129.8, 128.6, 128.0, 127.5,
126.4, 126.1, 125.4, 124.5, 123.7, 122.7, 120.0, 118.1, 117.5, 112.4,
108.7; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C26H18NO3
392.1281, found 392.1277.
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(5-Benzoylindolizin-7-yl)(4-chloro-2-hydroxyphenyl)methanone
(12t).
MHz, CDCl3) δ −105.8; HRMS (ESI-QTOF) m/z [M + H]+ calcd
for C25H21FNO6 450.1347, found 450.1343.
(5-(3-Fluorobenzoyl)indolizin-7-yl)(6-hydroxy-2,3,4-trimethoxy-
phenyl)methanone (12x).
Yellow solid (78 mg, 90%); mp: 104−106 °C; Rf = 0.3 in 10%
1
EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 11.80 (s, 1H),
8.90 (s, 1H), 8.09 (s, 1H), 7.83 (d, J = 5.6 Hz, 2H), 7.63 (d, J = 6.4
Hz, 2H), 7.58 (s, 1H), 7.53 (d, J = 5.6 Hz, 2H), 7.10 (s, 1H), 7.05
(s, 2H), 6.89 (d, J = 6.6 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 196.4, 190.8, 163.3, 141.8, 137.8, 133.1, 132.9, 132.8,
130.0, 129.7, 128.6, 128.0, 123.0, 122.1, 120.3, 119.4, 118.7, 117.7,
117.6, 109.3; HRMS (ESI-QTOF) m/z [M + H]+ calcd for
C22H15ClNO3 376.0735, found 376.0740.
1
Yellow gum (80 mg, 78%); Rf = 0.3 in 30% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ 11.05 (s, 1H), 8.93 (s, 1H), 8.15 (s,
1H), 7.65−7.55 (m, 2H), 7.56−7.44 (m, 2H), 7.29 (d, J = 6.6 Hz,
1H), 7.08 (s, 1H), 7.02 (s, 1H), 6.33 (s, 1H), 3.90 (s, 3H), 3.75 (s,
3H), 3.58 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.6,
189.6, 162.6 (d, JCF = 248.9 Hz), 159.8, 159.6, 153.3, 140.4 (d, JCF
=
(5-Benzoylindolizin-7-yl)(3,5-dichloro-2-hydroxyphenyl)meth-
anone (12u).
6.4 Hz), 135.2, 133.5, 130.3 (d, JCF = 7.7 Hz), 128.5, 128.1, 125.9,
125.5 (d, JCF = 2.8 Hz), 123.7, 120.4, 119.5 (d, JCF = 21.3 Hz), 117.5,
116.6 (d, JCF = 22.7 Hz), 109.2, 108.2, 96.6, 62.1, 61.5, 56.3; 19F
NMR (376 MHz, CDCl3) δ −109.9; HRMS (ESI-QTOF) m/z [M +
H]+ calcd for C25H21FNO6 450.1347, found 450.1345.
(5-(4-Chlorobenzoyl)indolizin-7-yl)(2-hydroxy-4,5-dimethoxy-
phenyl)methanone (12y).
Yellow solid (92 mg, 98%); mp: 132−134 °C; Rf = 0.3 in 10%
1
EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 11.90 (s, 1H),
8.95 (s, 1H), 8.18 (s, 1H), 7.85 (d, J = 7.0 Hz, 2H), 7.69−7.51 (m,
6H), 7.14 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.8,
190.8, 156.9, 137.8, 135.4, 133.2, 133.0, 129.8, 129.8, 129.7, 128.9,
128.4, 124.3, 123.5, 122.3, 122.1, 121.0, 120.6, 118.2, 110.2; HRMS
(ESI-QTOF) m/z [M + H]+ calcd for C22H14Cl2NO3 410.0345,
found 410.0350.
1
Yellow gum (83 mg, 83%); Rf = 0.2 in 30% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ 12.25 (s, 1H), 8.88 (s, 1H), 8.12 (s,
1H), 7.78 (d, J = 7.9 Hz, 2H), 7.56 (s, 1H), 7.50 (d, J = 7.9 Hz, 2H),
7.11 (s, 1H), 7.08 (s, 1H), 7.02 (d, J = 3.0 Hz, 1H), 6.55 (s, 1H),
3.94 (s, 3H), 3.74 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
195.6, 189.7, 161.0, 157.0, 141.9, 139.3, 136.3, 133.0, 131.1, 129.9,
129.1, 127.4, 123.9, 122.5, 119.9, 117.6, 113.6, 110.8, 108.4, 101.1,
56.8, 56.4; HRMS (ESI-QTOF) m/z [M + H]+ calcd for
C24H19ClNO5 436.0946, found 436.0942.
(5-Benzoylindolizin-7-yl)(5-bromo-2-hydroxyphenyl)methanone
(12v).
(5-(4-Chlorobenzoyl)indolizin-7-yl)(2-hydroxy-4,6-dimethoxy-
phenyl)methanone (12z).
Red solid (74 mg, 77%); mp: 162−163 °C; Rf = 0.3 in 10% EtOAc
1
in hexane; H NMR (400 MHz, CDCl3) δ 11.49 (s, 1H), 8.95 (s,
1H), 8.19 (s, 1H), 7.89−7.79 (m, 3H), 7.63 (d, J = 6.4 Hz, 1H),
7.61−7.49 (m, 4H), 7.14 (d, J = 7.5 Hz, 2H), 6.98 (d, J = 8.7 Hz,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ 196.2, 190.8, 161.6,
138.6, 137.9, 134.2, 133.2, 132.8, 129.7, 128.8, 128.1, 122.7, 122.3,
120.7, 120.6, 120.5, 117.9, 110.4, 109.6; HRMS (ESI-QTOF) m/z
[M + H]+ calcd for C22H15BrNO3 420.0230, found 420.0222.
(5-(4-Fluorobenzoyl)indolizin-7-yl)(6-hydroxy-2,3,4-trimethoxy-
phenyl)methanone (12w).
1
Yellow gum (77 mg, 77%); Rf = 0.2 in 10% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ 11.60 (s, 1H), 8.88 (s, 1H), 8.02 (s,
1H), 7.76 (d, J = 8.2 Hz, 2H), 7.58−7.48 (m, 2H), 7.48 (s, 1H),
7.06 (d, J = 2.5 Hz, 1H), 6.97 (d, J = 3.0 Hz, 1H), 6.17 (s, 1H), 5.97
(s, 1H), 3.85 (s, 3H), 3.58 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 194.7, 189.8, 166.2, 165.3, 161.1, 139.0, 136.6, 133.5,
131.1, 129.0, 128.9, 127.8, 126.7, 123.2, 120.0, 117.2, 108.5, 105.5,
94.1, 91.7, 55.8, 55.7; HRMS (ESI-QTOF) m/z [M + H]+ calcd for
C24H19ClNO5 436.0946, found 436.0950.
(5-(4-Chlorobenzoyl)indolizin-7-yl)(6-hydroxy-2,3,4-trimethoxy-
phenyl)methanone (12aa).
1
Yellow gum (76 mg, 74%); Rf = 0.3 in 30% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ 11.01 (s, 1H), 8.86 (s, 1H), 8.14 (s,
1H), 7.95−7.80 (m, 2H), 7.53 (s, 1H), 7.23−7.12 (m, 2H), 7.07 (s,
1H), 7.0 (s, 1H), 6.34 (s, 1H), 3.91 (s, 3H), 3.76 (s, 3H), 3.57 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.7, 189.6, 165.5 (d,
JCF = 254.6 Hz), 159.8, 159.5, 153.3, 135.2, 134.4 (d, JCF = 2.8 Hz),
132.4 (d, JCF = 9.1 Hz), 128.8, 127.8, 125.9, 123.0, 120.2, 117.3,
116.0, 115.8, 109.0, 108.3, 96.6, 62.2, 61.5, 56.3; 19F NMR (376
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1
Yellow gum (64 mg, 60%); Rf = 0.2 in 40% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ 11.01 (s, 1H), 8.90 (s, 1H), 8.15 (s,
1H), 7.79 (d, J = 6.5 Hz, 2H), 7.55 (s, 1H), 7.48 (d, J = 7.8 Hz, 2H),
7.07 (s, 1H), 7.01 (s, 1H), 6.34 (s, 1H), 3.91 (s, 3H), 3.76 (s, 3H),
3.57 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.6, 189.8,
159.8, 159.5, 153.3, 139.0, 136.6, 135.2, 133.5, 131.2, 129.0, 128.7,
127.9, 125.9, 123.3, 120.3, 117.4, 109.1, 108.3, 96.6, 62.2, 61.5, 56.3;
HRMS (ESI-QTOF) m/z [M + H]+ calcd for C25H21ClNO6
466.1052, found 466.1049.
(2-Bromo-5-(4-methoxybenzoyl)indolizin-7-yl)(2-hydroxyphen-
yl)methanone (12ae).
Yellow solid (81 mg, 78%); mp: 177−179.5 °C; Rf = 0.3 in 30%
1
(5-(3-Chlorobenzoyl)indolizin-7-yl)(6-hydroxy-2,3,4-trimethoxy-
phenyl)methanone (12ab).
EtOAc in hexane; H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H),
8.60 (s, 1H), 8.14 (s, 1H), 7.85 (d, J = 6.7 Hz, 2H), 7.45 (s, 1H),
7.43−7.31 (m, 2H), 7.27 (s, 1H), 7.13 (d, J = 6.8 Hz, 2H), 7.0 (d, J
= 7.0 Hz, 1H), 6.95 (d, J = 6.1 Hz, 1H), 3.88 (s, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 193.4, 188.5, 163.3, 155.8, 133.0,
132.8, 132.2, 129.9, 129.2, 129.1, 126.3, 125.2, 125.0, 119.6, 119.3,
118.3, 116.5, 114.0, 109.9, 105.4, 55.7; HRMS (ESI-QTOF) m/z [M
+ H]+ calcd for C23H17BrNO4 450.0335, found 450.0313.
Ethyl 7-(2-Hydroxybenzoyl)-5-(4-methoxybenzoyl)indolizine-2-
carboxylate (12af).
1
Yellow gum (78 mg, 73%); Rf = 0.3 in 30% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ 11.01 (s, 1H), 8.93 (s, 1H), 8.15 (s,
1H), 7.79 (s, 1H), 7.68 (d, J = 6.3 Hz, 1H), 7.63−7.50 (m, 2H),
7.44 (d, J = 6.3 Hz, 1H), 7.08 (s, 1H), 7.02 (s, 1H), 6.33 (s, 1H),
3.90 (s, 3H), 3.74 (s, 3H), 3.58 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 194.5, 189.6, 159.7, 159.5, 153.3, 140.0, 135.2, 135.0,
133.5, 132.4, 129.8, 129.6, 128.5, 128.1, 127.8, 125.8, 123.8, 120.4,
117.5, 109.3, 108.2, 96.6, 62.2, 61.5, 56.3; HRMS (ESI-QTOF) m/z
[M + H]+ calcd for C25H21ClNO6 466.1052, found 466.1052.
(5-(3,4-Dichlorobenzoyl)indolizin-7-yl)(6-hydroxy-2,3,4-trimeth-
oxyphenyl)methanone (12ac).
Yellow solid (92 mg, 90%); mp: 109−110.5 °C; Rf = 0.2 in 30%
1
EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 11.55 (s, 1H),
9.02 (s, 1H), 8.06 (s, 1H), 7.89 (d, J = 7.2 Hz, 2H), 7.70 (d, J = 6.3
Hz, 1H), 7.53 (s, 2H), 7.37 (s, 1H), 7.07 (d, J = 7.4 Hz, 1H), 7.01
(d, J = 7.5 Hz, 2H), 6.94 (s, 1H), 4.38−4.31 (m, 2H), 3.9 (s, 3H),
1.46−1.34 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.3,
188.9, 164.2, 164.1, 162.8, 136.5, 132.5, 132.3, 131.2, 129.6, 128.5,
125.3, 123.2, 121.6, 121.1, 119.0, 118.9, 118.8, 114.2, 109.1, 60.8,
55.7, 14.5; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C26H22NO6
444.1442, found 444.1419.
Synthesis of 14a. A mixture of 13a (50 mg, 0.19 mmol, 1
equiv), 1a (83 mg, 0.57 mmol, 3 equiv), and Cs2CO3 (74 mg, 0.23
mmol, 1.2 equiv) in CH3CN (3 mL) was stirred at 80 °C (heating
mantle was used) for 5 h. The reaction mixture was concentrated
under reduced pressure to give the crude residue, which was purified
by silica gel column chromatography (Hexane/EtOAc = 10:1 to 5:1)
to afford 14a (52 mg, 70%) as a yellow solid. The crystal 14a for X-
ray crystallographic analysis was obtained via dissolution of the
compound in a mixed solvent (toluene/dichloromethane/hexane,
2:2:1) and slow evaporation of the solvent at room temperature.
(5-(4-Chlorobenzoyl)-8-methylindolizin-7-yl)(2-hydroxyphenyl)-
methanone (14a). Yellow solid (52 mg, 70%); mp: 182−184 °C; Rf
1
Yellow gum (81 mg, 71%); Rf = 0.3 in 30% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ 11.03 (bs, 1H), 8.90 (s, 1H), 8.16 (s,
1H), 7.92 (s, 1H), 7.64 (s, 1H), 7.62−7.46 (m, 2H), 7.08 (s, 1H),
7.02 (s, 1H), 6.34 (s, 1H), 3.91 (s, 3H), 3.75 (s, 3H), 3.58 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 194.4, 188.5, 159.9, 159.6,
153.2, 138.0, 137.0, 135.2, 133.5, 131.6, 130.6, 128.8, 128.3, 125.8,
123.7, 120.5, 117.6, 109.5, 108.2, 96.7, 62.2, 61.5, 56.3; HRMS (ESI-
QTOF) m/z [M + H]+ calcd for C25H20Cl2NO6 500.0662, found
500.0661.
(7-(6-Hydroxy-2,3,4-trimethoxybenzoyl)indolizin-5-yl)(4-meth-
oxyphenyl)methanone (12ad).
= 0.3 in 20% EtOAc in hexane; 1H NMR (400 MHz, CDCl3) δ
12.04 (s, 1H), 8.86 (s, 1H), 7.73 (d, J = 7.7 Hz, 2H), 7.54−7.47 (m,
1H), 7.47−7.39 (m, 3H), 7.14 (s, 1H), 7.11−7.02 (m, 2H), 7.0 (s,
1H), 6.88−6.8 (m, 1H), 2.57 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 201.2, 189.4, 163.3, 139.1, 137.1, 136.5, 135.2, 134.5,
133.1, 131.1, 129.0, 127.6, 123.3, 122.9, 120.1, 119.0, 118.8, 116.6,
105.3, 16.54; HRMS (ESI-QTOF) m/z [M + H]+ calcd for
C23H17ClNO3 390.0891, found 390.0891.
1
Yellow gum (101 mg, 95%); Rf = 0.2 in 30% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ 10.99 (s, 1H), 8.70 (s, 1H), 8.09 (s,
1H), 7.88 (d, J = 7.9 Hz, 2H), 7.50 (s, 1H), 7.13−6.82 (m, 4H),
6.33 (s, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.77 (s, 3H), 3.59 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 194.9, 189.8, 163.5, 159.6,
159.4, 153.4, 135.1, 133.2, 132.3, 130.4, 129.5, 127.2, 126.1, 121.3,
119.6, 116.9, 114.0, 108.4, 108.4, 96.5, 62.1, 61.5, 56.2, 55.6; HRMS
(ESI-QTOF) m/z [M + H]+ calcd for C26H24NO7 462.1547, found
462.1540.
Synthesis of 14b. A mixture of 13b (50 mg, 0.16 mmol, 1
equiv), 1a (68 mg, 0.47 mmol, 3 equiv), and Cs2CO3 (61 mg, 0.19
mmol, 1.2 equiv) in CH3CN (3 mL) was stirred at 80 °C (heating
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mantle was used) for 4.5 h. The reaction mixture was concentrated
under reduced pressure to give the crude residue, which was purified
by silica gel column chromatography (Hexane/EtOAc = 30:1 to
10:1) to afford 14b (64 mg, 91%) as a yellow gum.
(7-(2-Hydroxybenzoyl)-8-phenylindolizin-5-yl)(4-methoxyphen-
yl)methanone (14b).
1H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.1, 185.1, 154.6,
147.5, 138.3, 137.4, 134.3, 133.0, 132.4, 130.0, 128.6, 128.4, 127.8,
125.9, 125.6, 124.3, 122.1, 117.8, 117.3, 116.1, 112.7, 104.6; HRMS
(ESI-QTOF) m/z [M + H]+ calcd for C30H20NO3 442.1438, found
442.1454.
Synthesis of 16. A mixture of 12a (50 mg, 0.15 mmol, 1equiv),
ethyl propiolate (22 mg, 0.22 mmol, 1.5 equiv), and K2CO3 (41 mg,
0.3 mmol, 2 equiv) in CH3CN (3 mL) was stirred at 80 °C (heating
mantle was used) for 0.5 h. The reaction mixture was concentrated
under reduced pressure to give the crude residue, which was purified
by silica gel column chromatography (Hexane/EtOAc = 10:1 to 5:1)
to afford 16 (58 mg, 90%) as a yellow solid.
1
Yellow gum (64 mg, 91%); Rf = 0.3 in 10% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ 11.78 (s, 1H), 8.73 (s, 1H), 7.90 (d, J =
8.4 Hz, 2H), 7.46 (d, J = 5.4 Hz, 2H), 7.42 (d, J = 7.2 Hz, 1H),
7.39−7.28 (m, 4H), 7.23 (s,1H), 7.04 (s, 1H), 6.99 (d, J = 8.5 Hz,
2H), 6.87 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 2.6 Hz, 1H), 6.72−6.64
(m, 1H), 3.89 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 201.6,
189.4, 163.7, 162.6, 137.3, 136.5, 135.8, 133.7, 133.3, 132.3, 130.3,
129.4, 129.3, 129.0, 128.6, 123.5, 121.1, 120.0, 118.7, 118.4, 118.1,
116.8, 114.1, 106.7, 55.7; HRMS (ESI-QTOF) m/z [M + H]+ calcd
for C29H22NO4 448.1543, found 448.1539.
Ethyl 4-(5-Benzoylindolizin-7-yl)-4-hydroxy-4H-chromene-3-car-
boxylate (16).
Synthesis of 14c. A mixture of 13c (20 mg, 0.15 mmol, 1 equiv),
1a (65 mg, 0.45 mmol, 3 equiv), and Cs2CO3 (58 mg, 0.18 mmol,
1.2 equiv) in CH3CN (2 mL) was stirred at 80 °C (heating mantle
was used) for 1.5 h. The reaction mixture was concentrated under
reduced pressure to give the crude residue, which was purified by
silica gel column chromatography (Hexane/EtOAc = 20:1 to 5:1) to
afford 14c (10 mg, 26%) as a yellow solid.
Yellow solid (58 mg, 90%); mp: 113−114 °C, Rf = 0.2 in 20%
1
EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.88
(s, 1H), 7.80 (s, 1H), 7.64 (d, J = 7.0 Hz, 2H), 7.62−7.54 (m, 1H),
7.49−7.38 (m, 3H), 7.30−7.21 (m, 1H), 7.21−7.10 (m, 2H), 7.07
(d, J = 8.1 Hz, 1H), 6.96 (s, 1H), 6.71 (s, 1H), 5.03 (s, 1H), 4.26−
4.11 (m, 2H), 1.27 (t, J = 6.5 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 191.0, 167.0, 150.2, 147.8, 138.4, 135.3, 134.1, 132.5,
130.0, 129.8, 129.1, 128.6, 128.4, 125.7, 125.3, 121.7, 120.3, 116.7,
116.3, 115.9, 110.4, 103.2, 68.5, 61.1, 14.3; HRMS (ESI-QTOF) m/z
[M + H]+ calcd for C27H22NO5 440.1492, found 440.1502.
7-(2-Hydroxybenzoyl)indolizine-5-carbonitrile (14c).
Synthesis of 17. A mixture of 12a (50 mg, 0.15 mmol, 1 equiv),
ethyl acetoacetate (29 mg, 0.22 mmol, 1.5 equiv), and Cs2CO3 (95
mg, 0.29 mmol, 2 equiv) in toluene (3 mL) was stirred at 120 °C
(heating mantle was used) for 24 h. The reaction mixture was
concentrated under reduced pressure to give the crude residue, which
was purified by silica gel column chromatography (Hexane/EtOAc =
10:1 to 3:1) to afford 17 (40 mg, 67%) as a yellow gum.
Yellow solid; mp: 116−117 °C (10 mg, 26%); Rf = 0.2 in 10%
1
EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 11.51 (s, 1H),
8.12 (s, 1H), 7.87 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.61 (s, 1H),
7.55 (t, J = 7.6 Hz, 1H), 7.15−7.06 (m, 2H), 7.03 (s, 1H), 6.96 (t, J
= 7.3 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 196.4, 162.9,
136.5, 132.2, 131.0, 128.0, 124.4, 120.8, 119.1, 118.9, 118.89, 117.7,
117.1, 113.6, 109.5, 108.6; HRMS (ESI-QTOF) m/z [M + H]+ calcd
for C16H11N2O2 263.0815, found 263.0820.
3-Acetyl-4-(5-benzoylindolizin-7-yl)-2H-chromen-2-one (17).
Synthesis of 15. A mixture of 12a (50 mg, 0.15 mmol, 1 equiv),
2-bromoacetophenone (35 mg, 0.18 mmol, 1.2 equiv), and K2CO3
(51 mg, 0.37 mmol, 2.5 equiv) in CH3CN (3 mL) was stirred at 100
°C (heating mantle was used) for 4 h. The reaction mixture was
concentrated under reduced pressure to give the crude residue, which
was purified by silica gel column chromatography (Hexane/EtOAc =
20:1 to 10:1) to afford 15 (49 mg, 76%) as a red solid. The crystal
15 for X-ray crystallographic analysis was obtained via dissolution of
the compound in a mixed solvent (toluene/dichloromethane/hexane,
2:2:1) and slow evaporation of the solvent at room temperature.
(7-(2-Benzoylbenzofuran-3-yl)indolizin-5-yl)(phenyl)methanone
(15).
1
Yellow gum (40 mg, 67%); Rf = 0.2 in 20% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 7.84 (d, J = 7.4 Hz, 2H),
7.67 (s, 1H), 7.63−7.55 (m, 2H), 7.55−7.47 (m, 2H), 7.44−7.35
(m, 2H), 7.26 (s, 1H), 7.13−7.08 (m, 1H), 7.07 (s, 1H), 6.89 (s,
1H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.2,
190.9, 158.6, 153.6, 150.6, 137.9, 133.5, 133.2, 132.9, 130.1, 129.9,
128.7, 127.9, 124.9, 123.0, 119.3, 118.4, 118.2, 117.4, 116.9, 105.5,
31.5; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C26H18NO4
408.1230, found 408.1246.
Synthesis of 18. To a solution of 12aa (30 mg, 0.06 mmol) in
CH3CN/H2O (2:1, 1.5 mL) was dropwise added a solution of
PhI(OCOCF3)2 (28 mg, 1 equiv) in CH3CN/H2O (2:1, 1.5 mL) at
rt. After 10 min, the reaction mixture was quenched with saturated
aq. sodium bicarbonate (0.5 mL) and extracted with dichloro-
methane (3 mL × 3). The organic layer was dried over MgSO4,
concentrated under reduced pressure, and purified by column
chromatography (Hexane/EtOAc = 2:1 to 1:1) to afford 18 (21
mg, 74%) as a yellow gum.
Red solid (49 mg, 76%); mp: 197−198 °C, Rf = 0.3 in 10% EtOAc in
1
hexane; H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.01 (s, 1H),
7.98 (d, J = 7.8 Hz, 2H), 7.85 (d, J = 6.7 Hz, 2H), 7.75 (d, J = 7.4
Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.59−7.48 (m, 3H), 7.49−7.40
(m, 4H), 7.40−7.34 (m, 1H), 7.32 (s, 1H), 7.04 (s, 1H), 6.85 (s,
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2-(5-(4-Chlorobenzoyl)indolizine-7-carbonyl)-3,5-dimethoxycy-
clohexa-2,5-diene-1,4-dione (18).
Synthesis of 22. A mixture of 11e (15 mg, 0.06 mmol, 1 equiv),
21 (30 mg, 0.07 mmol, 1.2 equiv), and Cs2CO3 (23 mg, 0.07 mmol,
1.2 equiv) in CH3CN (4 mL) was stirred at 80 °C (heating mantle
was used) for 1 h. The reaction mixture was concentrated under
reduced pressure to give the crude residue, which was purified by
silica gel column chromatography (Hexane/EtOAc = 10:1 to 2:1) to
afford 22 (33 mg, 85%) as a yellow solid.
(5-Benzoylindolizin-7-yl)(5-(6-hydroxy-5-(4-methoxybenzoyl)-
indolizine-7-carbonyl)-2-methoxyphenyl)methanone (22).
1
Yellow gum (21 mg, 74%); Rf = 0.2 in 50% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.10 (s, 1H), 7.79 (d, J =
8.3 Hz, 2H), 7.73 (d, J = 1.2 Hz, 1H), 7.52 (d, J = 8.3 Hz, 2H),
7.15−7.01 (m, 2H), 5.92 (s, 1H), 3.88 (s, 3H), 3.87 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 189.8, 188.6, 186.0, 177.4,
157.5, 153.4, 139.5, 136.2, 133.3, 131.3, 129.7, 129.1, 129.1, 124.2,
122.3, 121.6, 120.0, 118.3, 111.0, 107.1, 60.8, 56.9; HRMS (ESI-
QTOF) m/z [M + H]+ calcd for C24H17ClNO6 450.0739, found
450.0741.
Synthesis of 20. A mixture of 19 (70 mg, 0.33 mmol, 1 equiv),
11a (155 mg, 0.73 mmol, 2.2 equiv), and Cs2CO3 (279 mg, 0.86
mmol, 2.6 equiv) in CH3CN (4 mL) was stirred at 80 °C (heating
mantle was used) for 1 h. The reaction mixture was concentrated
under reduced pressure to give the crude residue, which was purified
by silica gel column chromatography (Hexane/EtOAc/MeOH =
10:2:1 to 5:1:1) to afford 20 (129 mg, 96%) as a yellow solid.
6-(5-Benzoylindolizine-7-carbonyl)-7-hydroxy-4H-chromen-4-
one (20).
Yellow solid (33 mg, 85%); mp: 158−160 °C, Rf = 0.3 in 30%
1
EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 12.72 (s, 1H),
8.91 (s, 1H), 8.63 (s, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.90 (s, 1H),
7.87−7.7 (m, 5H), 7.61 (d, J = 7.0 Hz, 1H), 7.56−7.47 (m, 2H),
7.45 (s, 1H), 7.08 (s, 1H), 7.05−6.96 (m, 2H), 6.97−6.83 (m, 3H),
6.62 (s, 1H), 3.84 (s, 3H), 3.72 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 196.1, 191.3, 191.1, 189.5, 167.8, 163.7, 163.5, 138.1,
135.1, 133.4, 133.0, 132.8, 132.2, 130.3, 130.1, 129.8, 129.8, 128.9,
128.7, 127.1, 124.5, 123.3, 121.7, 120.7, 120.5, 120.4, 119.6, 117.5,
117.4, 114.1, 112.7, 109.6, 108.7, 100.6, 56.3, 55.5; HRMS (ESI-
QTOF) m/z [M + H]+ calcd for C40H29N2O7 649.1969, found
649.1973.
Synthesis of 12a from 23 and 11a. A mixture of 11a (50 mg,
0.23 mmol, 1 equiv), 23 (40 mg, 0.23 mmol, 1 equiv), and Cs2CO3
(90 mg, 0.28 mmol, 1.2 equiv) in CH3CN (3 mL) was stirred at 70
°C (heating mantle was used) for 10 min. The reaction mixture was
concentrated under reduced pressure to give the crude residue, which
was purified by silica gel column chromatography (Hexane/EtOAc =
20:1 to 10:1) to afford 12a (63 mg, 80%) as a yellow solid.
Synthesis of 24. After a mixture of 12a (20 mg, 0.06 mmol, 1
equiv) and Cs2CO3 (39 mg, 0.12 mmol, 2 equiv) in CH3CN (2 mL)
was stirred at 80 °C for 2 h, the reaction mixture was concentrated
under reduced pressure and the residue was purified by silica gel
column chromatography (Hexane/EtOAc = 20:1 to 10:1) to give 24
(18 mg, 90%) as a yellow solid. The crystal 24 for X-ray
crystallographic analysis was obtained via dissolution of the
compound in a mixed solvent (toluene/dichloromethane, 5:1) and
slow evaporation of the solvent at room temperature.
Yellow solid (129 mg, 96%); mp: 202−204.5 °C, Rf = 0.3 in 50%
1
EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 12.02 (s, 1H),
8.96 (s, 1H), 8.67 (s, 1H), 8.23 (s, 1H), 7.89 (d, J = 5.3 Hz, 2H),
7.80 (d, J = 3.2 Hz, 1H), 7.64−7.54 (m, 2H), 7.54−7.44 (m, 2H),
7.13 (d, J = 9.8 Hz, 2H), 7.0 (s, 1H), 6.32 (d, J = 3.7 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 196.8, 190.9, 176.5, 166.2,
160.7, 155.5, 137.9, 133.4, 132.8, 132.4, 129.9, 129.6, 128.8, 128.3,
122.7, 122.5, 120.9, 118.3, 118.1, 117.6, 113.1, 110.2, 105.8; HRMS
(ESI-QTOF) m/z [M + H]+ calcd for C25H16NO5 410.1023, found
410.1020.
Synthesis of 21. A mixture of 20 (100 mg, 0.24 mmol, 1 equiv),
iodomethane (45 μL, 0.72 mmol, 3 equiv), and K2CO3 (68 mg, 0.48
mmol, 2 equiv) in acetone (5 mL) was stirred at 60 °C (heating
mantle was used) for 0.5 h. The reaction mixture was concentrated
under reduced pressure to give the crude residue, which was purified
by silica gel column chromatography (Hexane/EtOAc/MeOH =
10:2:1 to 5:2:1) to afford 21 (105 mg, 100%) as a yellow solid.
6-(5-Benzoylindolizine-7-carbonyl)-7-methoxy-4H-chromen-4-
one (21).
5-Benzoyl-7H-chromeno[3,2-g]indolizin-7-one (24).
Yellow solid (18 mg, 90%); mp: 246−248 °C, Rf = 0.2 in 10%
1
EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.31
(d, J = 7.4 Hz, 1H), 7.93 (s, 1H), 7.9−7.82 (m, 2H), 7.80−7.71 (m,
1H), 7.70−7.60 (m, 2H), 7.59−7.50 (m, 2H), 7.46 (d, J = 7.4 Hz,
1H), 7.42 (s, 1H), 7.04 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3)
δ 190.6, 174.5, 155.7, 153.1, 138.2, 134.5, 132.9, 129.9, 128.8, 128.3,
126.6, 125.4, 124.9, 123.0, 121.9, 119.1, 118.2, 115.7, 109.2, 106.4;
HRMS (ESI-QTOF) m/z [M + H]+ calcd for C22H14NO3 340.0968,
found 340.0972.
Yellow solid (105 mg, 100%); mp: 206−208 °C, Rf = 0.2 in 50%
EtOAc in hexane; 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.20
(s, 1H), 7.97 (s, 1H), 7.89−7.76 (m, 4H), 7.68−7.58 (m, 1H),
7.57−7.41 (m, 2H), 7.07 (s, 1H), 7.02−6.91 (m, 2H), 6.34 (d, J =
4.9 Hz, 1H), 3.88 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
191.0, 176.4, 161.6, 158.98, 155.2, 137.9, 133.2, 132.7, 129.8, 129.2,
128.6, 127.1, 127.0, 123.7, 121.1, 120.8, 118.2, 117.6, 113.3, 110.0,
99.9, 56.5; HRMS (ESI-QTOF) m/z [M + Na]+ calcd for
C26H17NNaO5 446.0999, found 446.0998.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00981.
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1H and 13C NMR spectra of synthesized compounds
and crystal structure data for 14a, 15, and 24 (PDF)
H.-X. Diversity-oriented synthesis of pyrazoles derivatives from
flavones and isoflavones leads to the discovery of promising reversal
agents of fluconazole resistance in Candida albicans. Bioorg. Med.
Chem. Lett. 2018, 28, 1545−1549.
Accession Codes
CCDC 2059332, 2059333, and 2080248 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
(7) Szabó, V.; Borbély, J.; Theisz, E.; Janzsó, G. A new pathway in
the reactions of chromones and hydroxylamine in anhydrous
solutions. Tetrahedron Lett. 1982, 23, 5347−5350.
(8) (a) Oluwadiya, J. O. The reaction of amines with isoflavones. I.
Formation of phenolic pyrimidines. J. Heterocycl. Chem. 1983, 20,
1111−1112. (b) Xie, F.; Zhao, H.; Li, D.; Chen, H.; Quan, H.; Shi,
X.; Lou, L.; Hu, Y. Synthesis and Biological Evaluation of 2,4,5-
Substituted Pyrimidines as a New Class of Tubulin Polymerization
Inhibitors. J. Med. Chem. 2011, 54, 3200−3205.
(9) Dong, K.-K.; Huang, Q. Metal-free synthesis of novel
indolizines from chromones and pyridinium salts via 1,3-dipolar
cycloaddition, ring-opening and aromatization. Tetrahedron Lett.
2019, 60, 1871−1874.
(10) Joshi, D. R.; Seo, Y.; Heo, Y.; Park, S.-h.; Lee, Y.; Namkung,
W.; Kim, I. Domino [4 + 2] Annulation Access to Quinone-
Indolizine Hybrids: Anticancer N-Fused Polycycles. J. Org. Chem.
2020, 85, 10994−11005.
AUTHOR INFORMATION
Corresponding Author
Ikyon Kim − College of Pharmacy and Yonsei Institute of
Pharmaceutical Sciences, Yonsei University, Incheon 21983,
Republic of Korea; orcid.org/0000-0002-0849-5517;
Phone: +82 32 749 4515; Email: ikyonkim@yonsei.ac.kr;
Fax: +82 32 749 4105
■
(11) Although some papers including ours described the syntheses
of indolizines with two acyl groups at the C5 and C7 sites, 7-(2-
hydroxybenzoyl)indolizines reported here have not been published
yet, to the best of our knowledge. See: (a) Abe, N.; Fukumoto, Y.;
Fujii, H.; Kakehi, A. Synthesis and Some Reactions of Ethyl (2-
Alkylimino-1,2-dihydro-1-azaazulen-1-yl)acetates. Heterocycles 2002,
56, 171−180. (b) Zhu, H.; Stöckigt, J.; Yu, Y.; Zou, H. One-Pot”
Multicomponent Approach to Indolizines and Pyrido[1,2-a]indoles.
Org. Lett. 2011, 13, 2792−2794. (c) Kim, M.; Jung, Y.; Kim, I.
Domino Knoevenagel Condensation/Intramolecular Aldol Cycliza-
tion Route to Diverse Indolizines with Densely Functionalized
Pyridine Units. J. Org. Chem. 2013, 78, 10395−10404. (d) Gong, M.;
Guo, J.; Jiang, P.; Zhang, Y.; Fu, Z.; Huang, W. Facile Synthesis of
Polysubstituted Indolizines via One-Pot Reaction of 1-Acetylaryl 2-
Formylpyrroles and Enals. Chem. - Asian J. 2020, 15, 352−355.
(12) (a) Sadowski, B.; Klajn, J.; Gryko, D. T. Recent advances in
the synthesis of indolizines and their π-expanded analogues. Org.
Biomol. Chem. 2016, 14, 7804−7828. (b) de Souza, C. R.; Goncalves,
A. C.; Amaral, M. F. Z. J.; Dos Santos, A. A.; Clososki, G. C. Recent
Synthetic Developments and Reactivity of Aromatic Indolizines.
Targets Heterocycl. Syst. 2016, 20, 365−392.
(13) Shao, N.; Li, J.; Zhu, H.; Zhang, S.; Zou, H. Functionalized N-
containing heterocyclic scaffolds derived from N-substituted pyrroles
via inter- and intramolecular annulations. Tetrahedron 2018, 74,
6088−6094.
(14) The unreacted chromone 1a was recovered during column
chromatography (Hexane/EtOAc = 10:1 to 3:1).
(15) CCDC 2059332 contains the supplementary crystallographic
data for 14a. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(16) In addition, as suggested by one of the reviewers, reactions of
methyl 1-(2-(4-methoxyphenyl)-2-oxoethyl)-1H-pyrrole-2-carboxy-
late and ethyl 2-(2-formyl-1H-pyrrol-1-yl)acetate with chromone
were conducted under the optimized conditions, respectively.
However, these resulted in a complex mixture.
Author
Dirgha Raj Joshi − College of Pharmacy and Yonsei Institute
of Pharmaceutical Sciences, Yonsei University, Incheon
21983, Republic of Korea; orcid.org/0000-0002-0303-
5677
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00981
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Research Foundation of Korea (NRF-
2018R1A6A1A03023718 and NRF-2020R1A2C2005961) for
generous financial support.
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data for 15. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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equiv) to effect a double annulation event (see the Experimental
Section). Later, we found that the use of 19 (1.2 equiv), 11a (1.0
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The Journal of Organic Chemistry
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Article
equiv), and Cs2CO3 (1.2 equiv) is enough to make 20 in a similar
yield.
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(21) CCDC 2080248 contains the supplementary crystallographic
data for 24. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(22) More general reaction conditions for this transformation need
to be optimized.
10248
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J. Org. Chem. 2021, 86, 10235−10248