When Indolizine Meets Quinoline: Diversity-Oriented Synthesis of New Polyheterocycles and Their Optical Properties

Article abstract of DOI:10.1021/acscombsci.5b00031

Fluorescence-based technologies play a pivotal role in various biomedical applications. Here we report an efficient route to a new class of fluorophores, indolizino[3,2-c]quinolines, via the oxidative Pictet-Spengler cyclization strategy. The condensation

Full text of DOI:10.1021/acscombsci.5b00031

Research Article
pubs.acs.org/acscombsci
When Indolizine Meets Quinoline: Diversity-Oriented Synthesis
of New Polyheterocycles and Their Optical Properties
Sujin Park,† Dah In Kwon,‡ Jeeyeon Lee,*,‡ and Ikyon Kim*,†
†College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University 85 Songdogwahak-ro, Yeonsu-gu,
Incheon 406-840, Republic of Korea
‡College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul,
151-742, Republic of Korea
S
* Supporting Information
ABSTRACT: Fluorescence-based technologies play a pivotal role in various
biomedical applications. Here we report an efficient route to a new class of
fluorophores, indolizino[3,2-c]quinolines, via the oxidative Pictet−Spengler
cyclization strategy. The condensation of several 2-methylpyridines with
2-bromo-2′-nitroacetophenone allowed for the rapid assembly of indolizines
with a 2-nitrophenyl group at the C2 position. The subsequent reduction of
the nitro group under mild conditions followed by oxidative Pictet−Spengler
cyclization with various aryl aldehydes in the presence of a catalytic amount
of FeCl3 furnished the indolizino[3,2-c]quinolines in good overall yields.
We also examined the photophysical properties of this new series of
polyheterocyclic compounds. Several indolizino[3,2-c]quinolines were found
to have unique and desirable optical properties, suggesting that these com-
pounds may be suitable for use as prospective fluorescent probes in aqueous
systems.
KEYWORDS: Pictet−Spengler cyclization, fluorescence-based technologies, indolizine, quinoline, polyheterocycles
which are dependent on the physicochemical properties of the
environment surrounding the molecule.12
INTRODUCTION
■
Indolizines1 and quinolines2 are two privileged structures
commonly employed in various small molecule drug discovery
programs. Figure 1 shows some examples of compounds con-
taining either indolizine or quinoline as their basic core structure;
these compounds have been reported to exhibit a wide range
of pharmacologically intriguing properties depending on the
substitution patterns on these rings.3
Here, we report a facile route to synthesize highly func-
tionalized indolizino[3,2-c]quinolines using an FeCl3-catalyzed
oxidative Pictet−Spengler reaction as the key step. In addition,
the spectroscopic properties of the indolizino[3,2-c]quinoline-
containing fluorophores were investigated. The synthesis
described herein allows for the efficient preparation of novel
fluorophores using a combinatorial strategy, which provides a
new synthetic platform for the development of indolizino[3,2-c]-
quinolines-based fluorescence sensors.
As part of our ongoing efforts to design and develop efficient
methods for synthesizing new chemical scaffolds with distinctive
substitution patterns,4 we became interested in a hybrid struc-
ture5,6 of indolizines and quinolines (Scheme 1). More specifi-
cally, these hybrid molecules can be viewed as a merger of
3-acylindolizines7 and 2-arylquinolines. Since 3-acylindolizines
and 2-arylquinolines are known to exhibit anticancer activity, we
expected that the new heteroaromatic compounds contain-
ing both entities might exhibit not only anticancer activity but
also other interesting properties to be utilized as fluorescence
sensors.8 Fused heterocyclic systems with strong fluorescence
are intriguing since they can be used as molecular probes in
biochemical research,9 particularly for monitoring interactions
with target molecules.10 Because of the tremendous demands for
new fluorophores with unique photophysical properties, con-
siderable efforts have been devoted to develop novel synthetic
scaffolds containing new heterocyclic ring systems.11 Of
particular importance in monitoring ligand−target interactions
are environment-sensitive fluorophores, the optical properties of
RESULTS AND DISCUSSION
■
Synthesis. As outlined in Scheme 2, we envisioned that
2-(2-aminophenyl)indolizines 2 would react with aryl aldehydes 3
in the presence of a certain catalyst to afford the desired product,
indolizino[3,2-c]quinolines (1), by oxidative Pictet−Spengler-
type cyclization.13 The substrate 2 would, in turn, be easily
prepared by the base-mediated condensation of the 2-picolines
5 and 2-bromo-2′-nitroacetophenone, leading to the formation
of the 2-(2-nitrophenyl)indolizines 4 and the subsequent
reduction of a nitro group to an amino group.
Received: February 17, 2015
Revised: June 16, 2015
© XXXX American Chemical Society
A
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Figure 1. Representative biological modulators containing an indolizine or quinoline nucleus.
Scheme 1. Design of New Hybrid Compounds from
Indolizines and Quinolines
was obtained in higher yield with PTSA. The structure of 1{1}
was unambiguously established by an X-ray crystallographic
analysis as shown in Figure 2. Elevating the temperature slightly
led to an increased yield of 1{1} with the use of PTSA, while no
improvement was observed with PPTS (entries 1−4). Using
either InCl3 or BiCl3 led to the formation of 1{1}′ as a major
product even at 60 °C in modest yield (entries 5−7). Although
AlCl3 furnished 1{1} in 64% yield at room temperature, no
significant change was observed at 60 °C (entries 8 and 9,
respectively). In contrast, 1{1} was obtained as the only iso-
lable compound in the presence of a catalytic amount of FeCl3
(entry 10).18 The isolated yield was improved in this case by
increasing the reaction temperature (entries 11 and 12). With
respect to the amount of catalyst, the use of 0.2 equiv of FeCl3
was found to exhibit the best chemical yield (entries 13−15).
Having optimized the conditions for the oxidative Pictet−
Spengler cyclization, we reacted 2 with various aryl aldehydes 3
(Figure 3) in the presence of FeCl3. The results are shown in
Table 2. In general, both electron-rich and electron-poor aryl
aldehydes furnished the corresponding indolizino[3,2-c]-
quinolines 1 in good to excellent yields. In the case of pyridine-2-
carboxaldehyde, the yield was low even in the presence of
0.5 equiv of FeCl3 (entry 14). However, reactions with other
heterocyclic aldehydes, such as 3{16}−3{19}, provided the corre-
sponding products in good yields (entries 15, 23, 28, 29, and 33).
Indolizines with electron-withdrawing groups at the C1 position,
2{4} and 2{5}, underwent oxidative cyclization more easily than
the other compounds, 2{1}−2{3}, resulting in better isolated
yields.
Scheme 2. Synthetic Strategy for the Synthesis of
Indolizino[3,2-c]quinolines
We began this study by preparing several indolizines contain-
ing a 2-nitrophenyl group at the C2 position. As shown in
Scheme 3, two different methods were employed for the
synthesis of 4. A two-step sequence involving salt formation
and base-mediated cyclization was used in case of 4{1}−4{3},14
whereas the direct one-pot assembly of indolizines was utilized
for 4{4} and 4{5}.15
Finally, additional functional groups were added onto these
polycyclic compounds for further diversification (Scheme 5).
The Suzuki−Miyaura cross−coupling of 1{24} and 1{27} with
several boronic acids afforded the corresponding products 6−9
in good yields.19 Moreover, a bromo group was introduced
onto this tetracyclic compound by exposing 1{7} to N-bromo-
succinimide at room temperature to afford 10, providing a func-
tional handle for subsequent cross-coupling reactions.20
Optical Properties of Indolizino[3,2-c]quinolines. With
a series of indolizino[3,2-c]quinoline analogs in hand, their
photophysical properties were examined by spectroscopic
To reduce nitroarenes to the corresponding amines,16 sodium
dithionite17 was used as a reducing agent (Scheme 4). Thus,
indolizines 4{1}−4{5} were converted to their corresponding
amine congeners 2{1}−2{5}, respectively, in good yields under
very mild reaction conditions. An optimization study for oxida-
tive Pictet−Spengler cyclization was conducted with 2{1} and
4-bromobenzaldehyde (3{1}) in the presence of various cata-
lysts, as shown in Table 1. When either PTSA or PPTS (entries 1
and 3, respectively) was used as catalyst, the desired product
1{1} was isolated along with byproduct 1{1}′, although 1{1}
B
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a,b
Scheme 3. Synthesis of 2-(2-Nitrophenyl)indolizines
a
For 4{1}−4{3}: A mixture of 2-bromo-2′-nitroacetophenone (4.1 mmol) and picoline (1.3 equiv) in acetone (12 mL) was heated at 90 °C for 3 h.
A mixture of indolizinium salt (4.1 mmol) and Et3N (5 equiv) in CH3CN (20 mL) was heated at 60 °C for 16 h. For 4{4} and 4{5}: A mixture of 2-
bromo-2′-nitroacetophenone (2.2 mmol), methyl (or ethyl) 2-pyridylacetate (1.5 equiv), and NaHCO3 (2 equiv) in acetone (10 mL) was heated at
b
90 °C for 16 h. Isolated yields (%)
a,b
maxima of indolizino[3,2-c]quinolines were observed at around
380−430 nm, allowing for excitation with visible light. Emission
maxima were observed at around 480−540 nm in aqueous
solution. The most notable feature was the large Stokes shifts
(90−110 nm) observed in most indolizino[3,2-c]quinoline
analogs, demonstrating clear separation between the excita-
tion and emission wavelengths. The emission spectra were
found to be in a range similar to those of Alexa Fluor 488 or
Fluorescein;21 however, their excitation wavelengths were
significantly distant from the emission wavelengths. These
characteristics suggest that the compounds may be suitable for
biological applications such as cell imaging with multi-
fluorescence technology.
Scheme 4. Synthesis of 2-(2-Aminophenyl)indolizines
Among these series, 1{7} containing the p-methoxyphenyl
group attached to the C ring exhibited high fluorescence with a
maximum emission at 514 nm (Figure 4). The methoxy group
at the para position was found to be critical for enhanced fluo-
rescence intensity, which can be rationalized by the opposite
location of the electron-donating methoxy group with the
electron-deficient quinoline nitrogen. Significant dipole mo-
ment changes are expected upon excitation in this molecule.
Overall, electronic effects appeared to be well correlated with
the spectral properties of indolizino[3,2-c]quinolines: the
bromo or nitro group attached at the para position of the
aromatic ring did not induce fluorescence (1{5}, 1{18}, and
1{36}), while the electron-rich methoxy group at the para
position induced strong fluorescence (1{7}). The naphthalene
substituent at the C6 position of 1{12} also resulted in high
fluorescence, but the 2-naphthalene moiety shown in 1{13} led
to a decrease in emission intensity. The carboxylic ester group
at the C12 position of the B ring led to increased fluorescence,
except for the substituent with the nitro group at the para
a
A mixture of 4 (1 mmol), sodium dithionite (5 equiv), and K2CO3
(5 equiv) in CH3CN/H2O (1:1, 10 mL) was stirred at rt for 2 h.
b
Isolated yields (%)
methods. To characterize a new class of fluorophores for
biological applications, the desired properties are high emission
intensity in water, and large Stokes shift to prevent self-
quenching (to minimize homotransfer of energy). In addition,
good solubility to minimize aggregations with proteins is
necessary for both medicinal chemistry and fluorophore
development. In particular, compounds with these properties
are highly demanded for protein labeling dyes. Table 3
summarizes the absorption and emission maxima along with
the relative fluorescence intensities. In general, the absorption
C
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a
Table 1. Reaction Optimization
b
yield (%)
entry
catalyst (equiv)
temperature (°C)
1{1}
1{1}′
1
PTSA (0.1)
PTSA (0.1)
PPTS (0.1)
PPTS (0.1)
InCl3 (0.1)
InCl3 (0.1)
BiCl3 (0.1)
AlCl3 (0.1)
AlCl3 (0.1)
FeCl3 (0.1)
FeCl3 (0.1)
FeCl3 (0.1)
FeCl3 (0.2)
FeCl3 (0.3)
FeCl3 (0.5)
rt
60
rt
36
46
18
16
5
33
25
62
56
55
34
41
23
28
2
3
4
60
rt
5
6
60
60
rt
27
10
64
56
41
71
72
83
77
41
7
8
9
60
rt
10
11
12
13
14
15
40
60
60
60
60
a
A mixture of 2{1} (0.1 mmol), 4-bromobenzaldehyde (1.2 equiv), and catalyst in CH2Cl2 (2 mL) was stirred at the indicated temperature for 16 h
b
unless otherwise noted. Isolated yield (%).
and 516 nm, respectively) compared to those measured in
ethanol (λmax= 465 nm for both molecules). The quantum
yields of 1{7} and 1{12} increased significantly when measured
in ethanol using Coumarin 153 as the standard (0.816 and
0.402, respectively). These molecules are thought to have large
dipole moment changes upon excitation. In contrast, 1{33}
exhibited an opposite trend, with a blue-shifted emission maxi-
mum in water (λmax= 433 nm). It is noteworthy that solvent-
dependent spectroscopic features can be tuned by the addition
of different substituents onto indolizino[3,2-c]quinolines.
Table 5 and Figure 6 present the emission maxima obtained
in various solvents. The strong correlation between solvent
polarity and fluorescence emissions was not clearly observed.
However, because of the environment-sensitive features of
indolizino[3,2-c]quinolines demonstrated herein, these are
expected to be suitable for use as fluorescence probes to
monitor biological processes such as drug-target binding or
protein dynamics.10b,12a
In this study, we report the design, synthesis, and optical
characterization of indolizino[3,2-c]quinolines as a new class of
hybrid heterocycles. By using a diversity-oriented approach, we
developed a facile synthetic method for a series of indolizino-
[3,2-c]quinolines with unique optical properties that are well
suited to fluorescence probe applications. The rapid construc-
tion of 2-aminophenyl-substituted indolizines and facile
oxidative Pictet−Spengler-type cyclization with aryl aldehydes
in the presence of FeCl3 allow for diverse indolizino[3,2-c]-
quinolines in good overall yields. The additional introduction of
several functional groups to this scaffold was also demonstrated
with a bromo group of several indolizino[3,2-c]quinolines by
using Pd-catalyzed Suzuki−Miyaura cross-coupling reactions.
We are currently investigating an extension of this method for
the synthesis of other heterocycles as well as biological appli-
cations of the synthesized compounds under various conditions.
Figure 2. Crystal structure of 1{1}.
position of the aromatic ring (1{36}). The electron-with-
drawing nitro group consistently quenched fluorescence even in
the presence of a carboxylic ester (1{36}). Meanwhile, the
methyl substituent at the C11 position of 1{22} led to dimin-
ished fluorescence compared with that of 1{11}. Substitutions
at the R3 position on the phenyl group exhibited strong corre-
lations of fluorescence with their electronic effects (Figure 5),
while no direct relationship was observed with respect to the
substituent at R1 with the optical properties.
Having screened several indolizino[3,2-c]quinoline com-
pounds as potential fluorescent probes (Figure 4), we further
determined their spectroscopic properties in various solvents.
As shown in Table 5, the emission spectra of these indolizino-
[3,2-c]quinoline compounds were dependent on solvent
polarity. Among the compounds with strong fluorescence,
1{7}, 1{12}, 1{34}, and 1{38} exhibited positive solvatochro-
mic effects,22 inducing a bathochromic shift of the peak
emission in aqueous solution (Table 5). The emission maxima
of 1{7} and 1{12} were notably red-shifted in H2O (λmax= 511
D
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Figure 3. Various aldehydes used in oxidative Pictet−Spengler cyclization.
Table 2. Oxidative Pictet−Spengler Cyclization of 2 with
Although practical issues regarding excitation near UV range and
autofluorescence originated from endogenous fluorophores
(such as aromatic amino acids and flavin coenzymes in cells)
need to be addressed, the knowledge obtained in the present
work provides solid foundations for the development of novel
environment-sensitive fluorophores.
a
Various Aldehydes 3
EXPERIMENTAL PROCEDURES
■
b
entry
2
3
1
yield (%)
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 chro-
matography was performed using silica gel (230−400 mesh)
with hexanes, ethyl acetate, and dichloromethane as eluent. All
reactions were monitored by thin-layer chromatography on
0.25 mm silica plates (F-254) visualizing with UV light. 1H and
13C NMR spectra were recorded on 400 MHz NMR spec-
trometer and were described as chemical shifts, multiplicity
(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), cou-
pling constant in hertz (Hz), and number of protons. HRMS
were measured with electrospray ionization (ESI) and Q-TOF
mass analyzer.
1
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{2}
2{3}
2{3}
2{3}
2{3}
2{3}
2{3}
2{4}
3{1}
1{1}
83
56
55
45
55
62
65
52
53
71
68
83
47
2
3{2}
1{2}
3
3{4}
1{3}
4
3{5}
1{4}
5
3{6}
1{5}
6
3{7}
1{6}
7
3{8}
1{7}
8
3{9}
1{8}
9
3{10}
3{11}
3{12}
3{13}
3{14}
3{15}
3{16}
3{1}
1{9}
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
1{10}
1{11}
1{12}
1{13}
1{14}
1{15}
1{16}
1{17}
1{18}
1{19}
1{20}
1{21}
1{22}
1{23}
1{24}
1{25}
1{26}
1{27}
1{28}
1{29}
1{30}
c
28
78
83
80
71
91
79
77
68
79
89
44
75
83
58
93
77
Representative Procedure for the Synthesis of 4.
4{1}−4{3}. A mixture of 2-bromo-2′-nitroacetophenone
(4.1 mmol) and picoline (1.3 equiv) in acetone (12 mL) was
heated at 90 °C for 3 h. After it was cooled down to room
temperature, the reaction mixture was suction-filtered and washed
with CH2Cl2 (5 mL). The solid was used directly for the next step
without further purification. A mixture of indolizinium salt
(4.1 mmol) and Et3N (5 equiv) in CH3CN (20 mL) was heated
at 60 °C for 16 h. After concentration of the reaction mixture under
reduced pressure, the resulting residue was purified by silica gel
column chromatography (hexanes/ethyl acetate/dichloromethane =
30:1:2) to give 4{1}−4{3}.
3{3}
3{6}
3{9}
3{10}
3{11}
3{12}
3{18}
3{8}
3{10}
3{12}
3{13}
3{17}
3{18}
3{1}
2-(2-Nitrophenyl)indolizine (4{1}): orange solid, mp 104.6−
105.3 °C (891.0 mg, 85%); IR (ATR) ν = 3065, 2922, 1604,
1
1517, 1454, 1357 cm−1; H NMR (400 MHz, CDCl3) δ 7.86
E
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Table 2. continued
Table 3. Fluorescence Intensities and Emission Wavelengths
of Indolizino[3,2-c]quinolines
b
entry
2
3
1
yield (%)
31
32
33
34
35
36
37
38
39
2{4}
2{4}
2{4}
2{5}
2{5}
2{5}
2{5}
2{5}
2{5}
3{11}
3{13}
3{19}
3{3}
1{31}
1{32}
1{33}
1{34}
1{35}
1{36}
1{37}
1{38}
1{39}
93
99
λmax em
a
emission
emission
b
c
λabs (nm)
400
(nm)
intensity
intensitynorm
88
1{1}
1{5}
1{6}
1{7}
1{9}
522
32.7
−
0.14
0.00
0.24
0.99
0.26
0.26
0.74
1.00
0.17
0.02
0.03
0.05
0.04
0.00
0.11
0.05
0.14
0.06
0.38
100
95
371, 402
380, 400
430
−
519
3{5}
55.0
231.3
59.7
60.8
171.3
232.9
39.6
4.7
3{6}
75
514.5
519
3{9}
93
380, 400
3{12}
3{14}
98
1{10} 399, 421
1{11} 399, 421
1{12} 399, 421
1{13} 399, 421
1{14} 400
527.5
513
100
a
514
A mixture of 2 (0.14 mmol), ArCHO (1.2 equiv), and FeCl3
(0.2 equiv) in CH2Cl2 (3 mL) was heated at 60 °C for 16 h unless
otherwise noted. Isolated yields (%). FeCl3 (0.5 equiv) was used.
532
b
c
532
1{15} 407
536
7.5
1{16} 395
531.5
535.5
−
11.8
9.4
Scheme 5. Further Functionalization of 1 for Additional
Diversity
1{17} 375, 395
1{18} 375, 395
1{20} 375, 395
1{21} 373, 391
1{22} 391
a
−
527.5
25.5
11.7
31.7
15.0
89.5
535
524.5
523.5
512
1{23} 400
1{24} 386, 406,
430
1{25} 386, 406,
518
513
82.4
75.1
0.35
0.32
430
1{26} 386, 406,
430
1{29} 391, 411
1{31} 362, 383
1{32} 362, 380
1{33} 362, 383
1{34} 362, 383
1{35} 362, 383
1{36} 384
505.5
478
493
432.5
476
474
−
482
480.5
515
13.4
80.5
0.06
0.35
0.62
0.97
0.91
0.42
0.00
0.80
0.90
0.46
143.5
226.5
211.7
98.9
a
−
A mixture of 1{24} or 1{27} (0.07 mmol), Pd(PPh3)4 (0.05 equiv),
arylboronic acid (1.1 equiv), and K2CO3 (3 equiv) in toluene/MeOH/
H2O (1:1:1, 1.5 mL) was heated at 120 °C for 4 h. A mixture of 1{7}
(0.1 mmol) and N-bromosuccinimide (1 equiv) in CH2Cl2 (2 mL)
was stirred at rt for 1 h.
1{37} 362, 383
1{38} 362, 383
1{39} 362, 383
186.2
210.7
106.5
a
b
Excited at the longest absorption maxima. Fluorescence spectra
recorded in H2O at 2 μM. Normalized fluorescence intensity.
c
(d, J = 6.8 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.61−7.49 (m,
2H), 7.43−7.35 (m, 2H), 7.33 (d, J = 8.8 Hz, 1H), 6.67 (t, J =
6.8 Hz, 1H), 6.53−6.41 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 133.3, 131.9, 131.7, 129.7, 127.4, 125.2, 123.8, 123.5,
119.4, 117.9, 111.2, 110.9, 98.7; HRMS (ESI) calcd for
C14H11N2O2 239.0815 ([M + H]+), found 239.0813.
4{4} and 4{5}. A mixture of 2-bromo-2′-nitroacetophenone
(2.2 mmol), methyl (or ethyl) 2-pyridylacetate (1.5 equiv), and
NaHCO3 (2 equiv) in acetone (10 mL) was heated at 90 °C
for 16 h. After concentration of the reaction mixture under
reduced pressure, the resulting residue was diluted with CH2Cl2
(10 mL) and washed with H2O (10 mL). The aqueous layer
was extracted with CH2Cl2 (10 mL) one more time. The
organic layer was dried over MgSO4 and concentrated in vacuo.
The residue was purified by silica gel column chromatography
(hexanes/ethyl acetate/dichloromethane = 10:1:2) to give 4{4}
and 4{5}.
J = 7.6 Hz, 1H), 6.72 (t, J = 6.8 Hz, 1H), 3.67 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 164.9, 149.8, 136.6, 133.0,
132.3, 130.6, 128.4, 125.9, 124.2, 123.2, 120.5, 113.4, 113.0,
101.4, 50.8; HRMS (ESI) calcd for C16H13N2O4 297.0870 ([M
+ H]+), found 297.0872.
Representative Procedure for the Synthesis of 2. A
mixture of 4 (1 mmol), sodium dithionite (5 equiv), and
K2CO3 (5 equiv) in CH3CN/H2O (1:1, 10 mL) was stirred at
room temperature for 2 h. After concentration of the reaction
mixture under reduced pressure, the resulting residue was
diluted with CH2Cl2 (10 mL) and washed with H2O (10 mL).
The aqueous layer was extracted with CH2Cl2 (10 mL) one
more time. The organic layer was dried over MgSO4 and con-
centrated in vacuo to give 2.
2-(Indolizin-2-yl)aniline (2{1}): pale yellow solid, mp 141.8−
142.6 °C (188.1 mg, 90%); IR (ATR) ν = 3446, 3360, 3064,
1
Methyl 2-(2-Nitrophenyl)indolizine-1-carboxylate (4{4}):
2921, 1610, 1452, 1290 cm−1; H NMR (400 MHz, CDCl3) δ
yellow solid, mp 147.2−148.2 °C (495.4 mg, 76%); IR
7.91 (d, J = 6.8 Hz, 1H), 7.47 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H),
7.31 (d, J = 7.6 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.82 (t, J =
7.6 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.68 (dd, J = 6.8, 8.8 Hz,
1
(ATR) ν = 3081, 2982, 1685, 1504, 1346, 1220 cm−1; H
NMR (400 MHz, CDCl3) δ 8.19 (d, J = 9.2 Hz, 1H), 8.05 (d,
J = 8.4 Hz, 1H), 7.98 (d, J = 6.8 Hz, 1H), 7.59 (t, J = 7.2 Hz,
1H), 7.49 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.07 (t,
1H), 6.60 (s, 1H), 6.47 (t, J = 6.8 Hz, 1H), 4.04 (br s, 2H); 13
C
NMR (100 MHz, CDCl3) δ 144.1, 133.2, 130.6, 128.0, 127.1,
F
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Figure 4. Absorption and emission spectra of 1{7}, 1{12}, 1{33}, 1{34}, and 1{38} measured in water.
Table 4. Optical Properties of Screened Fluorophores with
Strong Fluorescence
extinction coefficient
λabs
λem
Stokes shift
(cm−1
a
(cm−1 M−1
)
(nm) (nm)
)
Φ
1{7}
6547
11656
9012
430
405
383
369
369
515
515
433
476
481
38383
52739
30150
60919
63103
0.121
0.053
0.033
0.061
0.084
1{12}
1{33}
1{34}
1{38}
10780
10580
a
Quantum yields were determined using rhodamine 6G as the
standard (Φ = 0.86 in water). The excitation/emission wavelengths for
rhodamine 6G are 425−575/505−750 nm.
Figure 5. Substituent effect at the R3 position on the fluorescence
quantum yield.
The residue was purified by silica gel column chromatography
(hexanes/ethyl acetate/dichloromethane) to give 1.
125.1, 121.7, 119.0, 118.7, 117.5, 115.7, 111.1, 110.6, 99.0;
HRMS (ESI) calcd for C14H13N2 209.1073 ([M + H]+), found
209.1066.
Representative Procedure for the Synthesis of 1. A
mixture of 2 (0.14 mmol), ArCHO (1.2 equiv), and FeCl3 (0.2
equiv) in CH2Cl2 (3 mL) was heated at 60 °C for 16 h. The
reaction mixture was washed with H2O (3 mL). The aqueous
layer was extracted with CH2Cl2 (3 mL) one more time. The
organic layer was dried over MgSO4 and concentrated in vacuo.
6-(4-Bromophenyl)indolizino[3,2-c]quinoline (1{1}): yellow
solid, mp 205.5−205.8 °C (43.4 mg, 83%); IR (ATR) ν = 2921,
1
2852, 1630, 1480, 1354 cm−1; H NMR (400 MHz, CDCl3) δ
8.39 (d, J = 7.6 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.89 (d, J =
6.8 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.73−7.68 (m, 1H),
7.69−7.62 (m, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.31 (s, 1H),
7.07 (t, J = 7.6 Hz, 1H), 6.48 (d, J = 6.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 147.4, 143.1, 139.1, 138.9, 132.6, 131.9,
G
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arylboronic acid (1.1 equiv), and K2CO3 (3 equiv) in toluene/
MeOH/H2O (1:1:1, 1.5 mL) was heated at 120 °C for 4 h. After
concentration of the reaction mixture under reduced pressure, the
resulting residue was diluted with CH2Cl2 (3 mL) and washed
with H2O (3 mL). The aqueous layer was extracted with CH2Cl2
(3 mL) one more time. The organic layer was dried over MgSO4
and concentrated in vacuo to give the crude mixture, which was
purified by silica gel column chromatography (hexanes/ethyl
acetate/dichloromethane = 5:1:2) to give 6−9.
Table 5. Emission Maxima of Screened Fluorophores
Measured in Various Solvents at Room Temperature
H2O
λem
(nm)
DMSO
λem
(nm)
DMF
λem
(nm)
EtOH
λem
(nm)
MC
EtOH/CHCl3
= 1:5 λem (nm) (nm)
λem
entry
1{7}
511
516
431
476
478.5
512
469
478
453
470
450
465
466
467.5
453.5
450
467
469
1{12}
1{33}
1{34}
1{38}
514
465.5
447.5
449.5
444
453
453.5
451.5
448
472.5
452.5
447.5
9-(3,5-Dimethoxyphenyl)-6-(4-methoxyphenyl)indolizino-
[3,2-c]quinoline (6): yellow solid, mp 177.5−177.8 °C (28.0 mg,
87%); IR (ATR) ν = 2996, 2920, 1582, 1404, 1438, 1377, 1150,
1024 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 8.0 Hz,
1H), 8.25 (d, J = 8.0 Hz, 1H), 8.19 (s, 1H), 7.74−7.52 (m, 5H),
7.33 (d, J = 9.6 Hz, 1H), 7.25 (s, 1H), 7.14 (d, J = 8.4 Hz, 2H),
6.43 (s, 1H), 6.40 (s, 1H), 3.90 (s, 3H), 3.79 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 161.4, 160.5, 148.5, 143.2, 139.4, 138.1,
132.1, 130.3, 129.5, 127.7, 125.8, 124.6, 123.7, 123.6, 123.1,
122.5, 121.7, 119.2, 114.9, 104.1, 99.8, 92.4, 55.6, 55.5; HRMS
(ESI) calcd for C30H25N2O3 461.1860 ([M + H]+), found
461.1859.
Synthesis of 10. A mixture of 1{7} (0.1 mmol) and N-
bromosuccinimide (1 equiv) in CH2Cl2 (2 mL) was stirred at
room temperature for 1 h. After concentration of the reaction
mixture under reduced pressure, the resulting residue was
purified by silica gel column chromatography (hexanes/ethyl
acetate/dichloromethane = 10:1:2) to give 10.
130.6, 129.7, 127.8, 126.8, 126.0, 123.7, 123.6, 122.5, 121.0,
119.5, 110.1, 92.4; HRMS (ESI) calcd for C21H14BrN2
373.0335 ([M + H]+), found 373.0336.
6-(4-Bromophenyl)-5,6-dihydroindolizino[3,2-c]quinoline
(1{1}′): pale yellow solid, mp 179.3−180.0 °C; IR (ATR) ν =
1
3356, 2921, 2851, 1608, 1481 cm−1; H NMR (400 MHz,
CDCl3) δ 7.54 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H),
7.37 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.11 (d, J =
8.2 Hz, 2H), 6.99 (t, J = 7.2 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H),
6.74 (s, 1H), 6.62 (dd, J = 6.8, 8.8 Hz, 1H), 6.50 (d, J = 7.6 Hz,
1H), 6.34 (t, J = 6.8 Hz, 1H), 6.04 (s, 1H), 4.29 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 141.3, 140.6, 132.4, 128.6, 127.7,
123.7, 122.4, 121.3, 119.1, 118.4, 117.4, 117.1, 113.6, 110.6,
108.1, 107.8, 92.3, 55.8; HRMS (ESI) calcd for C21H16BrN2
375.0491 ([M + H]+), found 375.0494.
Representative Procedure for the Synthesis of 6−9. A
mixture of 1{24} or 1{27} (0.07 mmol), Pd(PPh3)4 (0.05 equiv),
Figure 6. Emission spectra of screened fluorophores in various solvents.
H
DOI: 10.1021/acscombsci.5b00031
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ACS Combinatorial Science
Research Article
and analogues. Chem. Commun. 2010, 46, 4622−4624. (d) Barluenga,
12-Bromo-6-(4-methoxyphenyl)indolizino[3,2-c]quinoline
(10): yellow solid, mp 221.6−221.9 °C (27.8 mg, 69%); IR
(ATR) ν = 2921, 1609, 1493, 1438, 1356, 1248, 1024 cm−1; 1H
NMR (400 MHz, CDCl3) δ 9.36 (d, J = 7.6 Hz, 1H), 8.26 (d, J
= 8.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.72 (d, J = 8.4 Hz,
2H), 7.67 (t, J = 8.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.22−
7.06 (m, 3H), 6.50 (t, J = 6.8 Hz, 1H), 3.94 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 160.6, 148.2, 143.7, 136.1, 132.0, 130.1,
129.6, 128.0, 127.2, 126.9, 125.6, 124.5, 123.4, 122.1, 120.8,
117.7, 115.0, 110.7, 55.7; HRMS (ESI) calcd for C22H16BrN2O
403.0441 ([M + H]+), found 403.0435.
Optical Characterization. Fluorescence emission spectra
were obtained at 20 °C using JASCO FP-6500 Spectrofluo-
rometer. Ten millimolar stock solutions of indolizino[3,2-c]-
quinolines compounds dissolved in DMSO were diluted with
corresponding solvents. Fluorescence quantum yield was
determined as previously describe using rhodamine 6G as a
standard (Φ = 0.86 in water).21 The slit widths used for
fluorescence measurement were 3 nm for excitation and 5 nm
for emission. Absorption spectra were recorded on PerkinElmer
Lamda 20 UV/vis spectrometer at room temperature.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Compound characterization data and copies of H and 13C
1
NMR spectra of compounds (1, 2, 4, 6−10), a CIF file of 1{1}
(CCDC 1060165), copies of fluorescence spectra of 1, and
copies of fluorescence spectra of screened fluorophores in
organic solvents. The Supporting Information is available free
of charge on the ACS Publications website at DOI: 10.1021/
acscombsci.5b00031.
AUTHOR INFORMATION
Corresponding Authors
*Tel.: +82 2 880 2471. Fax: + 82 2 884 8334. E-mail: jyleeut@
snu.ac.kr.
■
*Tel.: +82 32 749 4515. Fax: +82 32 749 4105. E-mail:
ikyonkim@yonsei.ac.kr;
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by Nano·Material Technology
Development Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of
Education, Science and Technology and the National Research
Foundation of Korea (NRF) grant funded by the Korea
government (MSIP) (2014R1A2A1A11050491) (to I.K.); the
Global Frontier Program for the Intelligent Synthetic Biology
(NRF-2011-0032201), National Research Foundation of Korea
(NRF) grant funded by the Korean government (MSIP)
(2009-0083533), and the Seoul National University Research
Grant (to J.L.).
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