Metal-Free Catalyzed Synthesis of Fluorescent Indolizine Derivatives

Article abstract of DOI:10.1021/acs.joc.1c01292

A mild and high efficient method to prepare indolizines by two-component reaction with the acid as the catalyst was developed. In this reaction, a new ring efficiently formed in one-step reaction. A wide range of substrates could be applied and the desired products were obtained in 8-95% yields under metal-free conditions. Different indolizine derivatives (compounds 3a-3n) were synthesized by general conditions and microwave irradiation conditions, and compound 3a gave the best results with an isolated yield of 95% and 82%, respectively. The structures of synthesized compounds were characterized by spectral analysis, and compound 3m was confirmed by single crystal X-ray analysis. UV-vis absorption and fluorescence properties of these compounds were correlated with substituent groups on indolizine rings.

Full text of DOI:10.1021/acs.joc.1c01292

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Metal-Free Catalyzed Synthesis of Fluorescent Indolizine Derivatives
Yu-Chang Yuan, Tian-Zhen Liu, and Bao-Xiang Zhao*
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ABSTRACT: A mild and high efficient method to prepare
indolizines by two-component reaction with the acid as the
catalyst was developed. In this reaction, a new ring efficiently
formed in one-step reaction. A wide range of substrates could be
applied and the desired products were obtained in 8−95% yields
under metal-free conditions. Different indolizine derivatives
(compounds 3a−3n) were synthesized by general conditions and
microwave irradiation conditions, and compound 3a gave the best
results with an isolated yield of 95% and 82%, respectively. The
structures of synthesized compounds were characterized by spectral analysis, and compound 3m was confirmed by single crystal X-
ray analysis. UV−vis absorption and fluorescence properties of these compounds were correlated with substituent groups on
indolizine rings.
coumarin,5,6 1,8-naphthalene diimide,7,8 etc. Although indoli-
INTRODUCTION
■
zine skeleton has favorable properties, it can be only found in
Heterocyclic compounds play a prominent part in the field of
organic and medicinal chemistry. Indolizine is one of the major
classes of nitrogen-containing heterocycle. Indolizine skeleton
has been embodied in many natural and therapeutic products
few fluorescent sensors.9,10 Therefore, the development of an
efficient method for the construction of indolizines has been
received a great deal of attention, particularly in the field of
synthetic chemistry and chemical biology. Construction of
which have biological activities. As shown in Figure 1, several
indolizine derivatives have been reported as antimicrobial,1
antitubercular,2 antiproliferative,3 showing anti-inflammatory
activity,2 and inhibitors of Alzheimer’s disease.4
indolizine derivatives through direct functionalization of C−H
bonds with simple and readily available starting substrates is of
considerable interest in organic synthesis. Transition-metal-
catalyzed direct C−H bond activation is one of the most
powerful and useful tools to construct nitrogen-containing
heterocycle in the past few years.11,12 Compared to a
transition-metal-catalyzed approach, few metal-free approaches
for the synthesis of nitrogen-containing heterocycle have been
developed. The reaction accomplished under transition-metal
free conditions was advantageous because it avoided the metal
contamination in the final product.
A number of synthetic methodologies have been reported
for the construction of indolizine derivatives in recent years. As
shown in Figure 2, Li’s group reported the Rh catalyzed
reaction for the synthesis of 3-allylindolizines.13 Xu’s group
reported an efficient synthesis method of indolizine derivatives
by the cyclization of propargylic pyridines with aroyl
chlorides.14 Shanmugam et al. reported the base-promoted
one-pot three-component domino reaction to synthesize
indolizine derivatives.15 Zou et al. developed a one-pot
Figure 1. Biologically active molecules that incorporate indolizine.
The importance of fluorescent molecules has been well
proved in the past few years. Fluorescent probe, as a
fluorescent molecule, has been used extensively in biological
science and clinical diagnosis. As a research tool, fluorescent
probe has a lot of advantages such as excellent sensitivity, low
cost, a large linear range of analysis, and ease of handling.
However, most of the fluorescent probes were based on the
Received: June 3, 2021
https://doi.org/10.1021/acs.joc.1c01292
J. Org. Chem. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

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Figure 2. Representative examples and synthetic methods for indolizines.
a
chemoselective domino condensation method by which a
fused pyrrolo−pyrazino−indolizine was formed.16 However,
these methods have some disadvantages such as using
expensive and toxic metals as catalysts, reactants being difficult
to prepare, and harsh reaction conditions.
Table 1. Optimization of Reaction Conditions
On the basis of previous research,17 in the interest of green
chemistry and atom economy, we report the direct synthesis of
functionalized indolizines from pyridinone and α, β-unsatu-
rated aldehydes or ketones under transition-metal-free catalytic
conditions. X-ray crystal structures and optical properties of
new indolizine derivatives are reported to investigate their
potential application in small molecule fluorescent probe.
b
entry
solvent
additive
temp (°C)
yield (%)
1
2
3
4
CH3COOH
EtOH
CH3COONH4
EtONa
117
78
117
117
117
26
85%
c
nd
c
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
nd
CH3COONa
CH3COONa
CH3COONa
CH3COONa
CH3COONa
89%
95%
81%
76%
78%
d
5
6
7
8
RESULTS AND DISCUSSION
■
60
100
For the screening of the reaction conditions, we first selected
phenyl(pyridin-2-yl)methanone for the condensation with (E)-
but-2-enal under the influence of an appropriate additive. For
optimization of this condensation strategy, we examined the
same reaction under different additive and temperature (Table
1). As shown in Table 1, no reaction occurred in the absence
of the sodium acetate (Table 1, entry 3). While in the presence
of sodium acetate, 3a was obtained in 89% yield (Table 1,
entry 4). Ammonium acetate also exhibited a promising
reaction ability, and the yield of 3a reached 85% (Table 1,
entry 1). Sodium ethoxide was proved to be unsuitable for this
reaction (Table 1, entry 2). It was found that reflux
temperature (117 °C) was enough to ensure a good yield of
3a (entries 4−8).
a
Conditions: 2 mmol of 1a, 3 mmol of 2a, 2 mmol of additive.
b
c
d
Isolated yield. Not detected. 6 mmol of 2a.
presence of 1 equiv of sodium acetate in 25 mL of acetic acid
at 117 °C (Table 1, entry 5). To extend substrates, we next
selected 2-acetylpyridine (1b) and (E)-but-2-enal as the model
substrates with various solvent to screen the optimal reaction
conditions, and the details are summarized in Table 2. Initially,
by heating the reactants in EtOH at reflux temperature for 4 h
in the presence of 3 equiv of acetic acid and 3 equiv of sodium
acetate, we did not detect the formation of product 3b (Table
2, entry 1). Unfortunately, changing solvent such as N,N-
dimethylformamide, acetonitrile, toluene, and dioxane also did
not give the desired product 3b (Table 2, entries 2−5).
From Table 1 we get a better reaction condition, that is
compound 1 (2 mmol), compound 2 (6 mmol) in the
B
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However, using acetic acid as the solvent, product 3b was
isolated with the yield of 55% (Table 2, entry 7). Further
research found that the amount of sodium acetate has no
obvious impact on the yields of 3b (Table 2, entries 7−9).
Thus, the model reaction was carried out employing
compound 1b (2 mmol), compound 2a (6 mmol) in the
presence of 3 equiv of sodium acetate in 25 mL of acetic acid
at 117 °C (Table 2, entry 8).
With the optimized conditions in hand, the substrate scope
of this reaction was tested (Scheme 1). Products 3a−3n could
be obtained in 8−95% yields under the optimal conditions. As
evidenced in Scheme 1, when R3 was aryl group, both α, β-
unsaturated aldehydes and ketone participated in this reaction
readily, affording the desired indolizine derivatives in good to
excellent yields. When substituent R3 was alkyl, the yields of
desired indolizine derivatives were low.
Table 2. Screening of Conditions for Model Reaction with
1b and 2a
a
b
Brønsted acid
(6.0 mmol)
additive
(6.0 mmol)
temp yield
entry
solvent
(°C)
(%)
c
1
2
3
4
5
6
7
8
9
CH3CH2OH
DMF
CH3CN
toluene
dioxane
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CF3COOH
CH3COONa
CH3COONa
CH3COONa
CH3COONa
CH3COONa
CH3COONa
CH3COONa
CH3COONa
CH3COONa
78
153
81
111
101
101
117
117
117
nd
nd
nd
nd
nd
nd
c
c
c
c
c
dioxane
d
e
CH3COOH
CH3COOH
CH3COOH
55%
56%
52%
As shown in Figure 3, substrates with both electron-
withdrawing groups and electron-donating groups on the
pyridine ring (e.g., −COCH3, −OCH3, −CH3) have also been
examined under the current conditions; however, the reactions
a
b
c
d
2 mmol of 1b, 6 mmol of 2a, Isolated yield. Not detected.
2
e
mmol. 10 mmol.
a b
,
Scheme 1. Substrate Scope
a
b
General heat method reaction conditions: 1 (2 mmol), 2 (6 mmol), and sodium acetate (6 mmol) in acetic acid (25 mL) at 117 °C. Microwave-
assisted synthesis reaction conditions: a mixture of 1 (2 mmol), 2 (6 mmol), and sodium acetate (6 mmol) in acetic acid (25 mL) was placed into
c
d
the microwave reactor and irradiated at 110 °C for 30 min. Isolated yields of general heat method. Isolated yields of microwave-assisted synthesis
method.
C
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compounds 3a−3n display similar maximum absorption
ranging from 390 to 409 nm. It can be found that compounds
with aldehyde in C-2 position of indolizine moiety have red
shift than that with the ketone group.
The maximum molar extinction coefficients of 3a−3n in
acetonitrile, dimethyl sulfoxide, and dichloromethane are
different. Although the difference is less, it can be observed
that the enhancement order is generally ε (acetonitrile) < ε
(dimethyl sulfoxide) < ε (dichloromethane).
Fluorescence spectral characteristics of compounds 3a−3n
in acetonitrile, dimethyl sulfoxide, and dichloromethane
solution with the concentration of 5 × 10−6 M were
investigated. Most of the products showed an emission band
centered between 470 and 510 nm (Table 4).
Figure 3. Unreacted compounds.
are messy and no desired products can be isolated, which
might be attributed to the steric effects.
The microwave-assisted reactions have many advantages, so
we attempted to synthesize the indolizine derivatives under
microwave irradiation conditions. On the basis of the
previously investigated reaction, different indolizine derivatives
(compounds 3a−3n) were synthesized under microwave
condition, and some examples got good yields. Compounds
3a gave the best results with an isolated yield of 82%.
A plausible mechanism was described for the reaction of
phenyl(pyridin-2-yl)methanone (1a) and (E)-but-2-enal (2a)
as a model case in Scheme 2. The initial Michael addition of
Table 4. Maximum Wavelength (nm) of Excitation and
a
Fluorescence Emission of Compounds 3a−3n
acetonitrile
dimethyl sulfoxide
dichloromethane
λex
(nm)
λem
(nm)
λex
(nm)
λem
(nm)
λex
(nm)
λem
(nm)
Scheme 2. Plausible Mechanism
compound
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
398
405
395
399
397
393
394
390
391
389
393
392
392
382
500
495
497
505
498
498
507
475.5
478
475
482.5
470
482
454
401
404
397
397
400
397
398
391
394
390
395
394
394
383
503.5
499.5
502.5
504.5
502.5
502
509.5
479.5
478.5
479
401
405
396
399
399
395
405
391
394
390
394
394
394
382
500.5
498
497
503.5
499.5
497
508
478.5
479.5
477.5
485.5
473.5
486
486
472.5
486
the pyridyl nitrogen onto protonated (E)-but-2-enal led to the
formation of enolate (A). The intramolecular aldol reaction of
enolate (A) followed by the proton transfer gave intermediate
B. Subsequent removal of the H2O produced intermediate C
that should be highly acidic. Finally, the desired product 3a
was obtained by the deprotonation of intermediate C.
The UV−vis spectrum characteristics of compounds 3a−3n
measured in acetonitrile, dimethyl sulfoxide, and dichloro-
methane solutions with the concentration of 1.2 × 10−4 M,
respectively, are summarized in Table 3. As shown in Table 3,
457
456.5
a
Slits: 15 nm/5 nm.
From Figure 4 and Table 4 it can be found that the
maximum emission spectra of compounds in three different
solvents are also mainly depended on the groups in C-2
position of indolizine moiety. Thus, compounds with an
aldehyde group at C-2 position of indolizine have red shift than
Table 3. Maximum Absorption Wavelength (λmax) and Maximum Molar Extinction Coefficients (εmax) of 3a−3n in
Acetonitrile, Dimethyl Sulfoxide, and Dichloromethane
acetonitrile
εmax (M−1 cm−1
dimethyl sulfoxide
εmax (M−1 cm−1
dichloromethane
εmax (M−1 cm−1
)
compound
λmax (nm)
)
λmax (nm)
)
λmax (nm)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
404.5
404.5
398.5
399.5
403
397.5
406
389
3625
2208
4458
1892
3917
4975
1783
3767
2258
4258
4350
2633
4842
3792
408
407.5
402
3725
2267
4558
2008
4200
5100
1900
3783
2342
4450
4525
2850
4450
3958
408
3783
2467
4708
2033
4158
5317
1942
4242
2383
4600
4783
2975
5492
4150
407.5
401.5
403
406.5
400.5
409.5
391.5
399.5
391
399.5
400
398.5
377.5
401.5
406.5
400.5
409.5
392
400.5
390.5
398.5
399.5
390.5
377
396
388.5
396.5
396.5
395.5
375
D
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Figure 4. (a, b) Fluorescence spectra of compounds 3a−n in dimethyl sulfoxide (5 × 10−6 M). (c) Normalized fluorescence spectra of compounds
3a−n in dimethyl sulfoxide (5 × 10−6 M). (d) Fluorescence spectra of compounds 3a in different solutions (5 × 10−6 M).
that without aldehyde group. For example, it can be seen from
Figure 5 that compound 3a with the aldehyde group at C-2
respectively. No significant differences were observed in the
maximum emission wavelength in these solvents. Interestingly,
the effects of solvents on the fluorescence intensities of 3a−3n
are obvious. It can be observed that the fluorescence intensities
order is generally: Facetonitrile < Fdichloromethane < Fdimethyl sulfoxide
.
However, when the compound is dissolved in ethanol,
fluorescence quenching occurs.
CONCLUSION
■
In summary, a simple, one-pot, metal-free reaction for the
preparation of indolizines has been established. By using this
approach, a series of indolizines were synthesized in good
yields (up to 95%). These examples demonstrate that the
Brønsted acid-catalyzed synthesis of indolizine derivatives has a
wide applicability. All obtained the indolizine derivatives
exhibited interesting optical properties in solution, with a
wide variety of fluorescent emissions (467−510 nm). On the
basis of these promising emission properties, further studies are
in progress to test these indolizine derivatives as fluorescent
probe.
Figure 5. Visual fluorescence color photograph of compounds (from
left to right: 3a, 3c, 3e, 3f, 3h, 3j, 3k, 3l, 3m, 3n) in three different
solvents. (a) Dimethyl sulfoxide. (b) Dichloromethane. (c)
Acetonitrile. (UV lamp, 365 nm).
position of indolizine moiety has a red shift compared with 3h.
The intensity of fluorescence was also correlated with
substituents on indolizine moiety. Generally, fluorescence
intensity of compounds with the aldehyde group at C-2
position of indolizine was weaker than others in three different
solvents, respectively.
The solvent effect on the fluorescence behavior of all
compounds was studied. Taking 3a as an example, its
maximum emission wavelength is 500, 503.5, and 500.5 nm
in acetonitrile, dimethyl sulfoxide and dichloromethane,
EXPERIMENTAL SECTION
General Experimental Methods. All solvents and raw materials
■
were used as received from commercial suppliers without further
1
purification. H NMR (400 MHz) and 13C{1H} NMR (101 MHz)
spectra were recorded on a Bruker Avance 400 MHz spectrometer,
with DMSO-d6 or CDCl3 as solvent. Thin-layer chromatography
(TLC) was conducted on silica gel 60 F254 plates (Merck KGaA) and
column chromatography was conducted over silica gel (mesh 200−
E
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300). IR spectra were measured by using the IR spectrophotometer
Tensor II FT-IR (Bruker Optics). Melting points were determined on
a XD-4 digital micro melting point apparatus. High-resolution mass
spectrometry (HRMS) was obtained on an Impact II spectrograph
(Bruker). Fluorescence measurements were carried out on a
PerkinElmer LS-55 luminescence spectrophotometer. Quartz cuvettes
with a 1 cm path length and 3 mL volume were used for all
measurements. UV−vis spectra were recorded with the U-4100
spectrophotometer (Hitachi). Microwave reactions were conducted in
a Milestone Start Synth Microwave Reactor. For single-crystal X-ray
diffraction, intensity data and cell parameters were recorded at 293 K
on a Bruker Apex II single crystal diffractometer employing Cu Kα (λ
= 1.54184 Å) and a CCD area detector. Starting materials 1 and 2
were purchased from common chemical suppliers and used without
further purification.
Photophysical Characterization of the Compounds. The
stock solutions of compound 3a−3n (10−3 M) in dimethyl sulfoxide
were prepared. Test solutions (1.2 × 10−4 M) were made in dimethyl
sulfoxide, dichloromethane, and acetonitrile, respectively, for UV−vis
spectra. The diluted solutions (5 × 10−6 M) in dimethyl sulfoxide,
dichloromethane, acetonitrile, and ethanol, respectively, were used for
fluorescence measurements.
Synthesis of Compounds 3a−3n by General Heat Method.
A mixture of phenyl(pyridin-2-yl)methanone (2 mmol), conjugated
unsaturated aldehyde or ketone (6 mmol), and sodium acetate (6
mmol) in acetic acid (25 mL) was stirred at 117 °C in the oil bath.
After 10−20 h, the reaction mixture was cooled to room temperature
and the acetic acid was removed by evaporation under reduced
pressure. The obtained crude product was purified via column
chromatography on silica gel (CH2Cl2) to give desired compounds
3a−3n in 8−95% yield.
Microwave-Assisted Synthesis of Compounds 3a−3n. A
mixture of phenyl(pyridin-2-yl)methanone (2 mmol), conjugated
unsaturated aldehyde or ketone (6 mmol), and sodium acetate (6
mmol) in acetic acid (25 mL) was placed into the microwave reactor
and irradiated at 110 °C for 30 min. Sealed reaction vessels were used,
and the reaction temperature was monitored by external surface
sensor. Power of the START SYNTH MW synthesizer was 750−1000
W. After cooling to room temperature, the acetic acid was removed by
evaporation under reduced pressure. The desired compounds 3a−3n
were obtained in 5−82% yield by purification via column
chromatography on silica gel (CH2Cl2).
NMR (101 MHz, DMSO-d6) δ 187.4, 132.8, 131.1, 130.4, 130.3,
130.1, 129.2, 129.0, 128.3, 128.2, 126.6, 122.9, 121.3, 120.6, 118.8,
114.8, 114.1; IR (KBr) = ν 1678, 1601, 1521, 1482, 752, 698 cm−1;
HRMS (ESI-TOF) m/z calcd. for C21H16NO (M+H)+: 298.1226;
found: 298.1236 C21H15NOK (M+K)+: 336.0785; found: 336.0735.
2-Methyl-8,9-dihydro-7H-pyrrolo[3,2,1-ij]quinoline-1-carbalde-
hyde (3d). Purified by flash chromatography (silica gel, dichloro-
methane) to give the desired product: 40 mg, 10% yield, yellow solid;
1
Mp 87−89 °C; H NMR (400 MHz, CDCl3) δ 10.25 (s, 1H), 7.43
(d, J = 7.2 Hz, 1H), 6.50 (t, J = 6.8 Hz, 1H), 6.23 (d, J = 6.3 Hz, 1H),
3.09 (t, J = 6.0 Hz, 2H), 2.80 (t, J = 6.1 Hz, 2H), 2.67 (s, 3H), 2.02
(p, J = 6.1 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 187.8,
132.7, 130.3, 125.0, 121.1, 118.7, 114.2, 112.8, 110.7, 27.8, 23.4, 22.2,
9.8; IR (KBr) = ν 2937, 1652, 1538, 1501, 1453, 767 cm−1; HRMS
(ESI-TOF) m/z calcd. for C13H14NO (M+H)+: 200.1070; found:
200.1076.
1-(4-Chlorophenyl)-3-methylindolizine-2-carbaldehyde (3e). Pu-
rified by flash chromatography (silica gel, dichloromethane) to give
the desired product: 507 mg, 94% yield, yellow solid; Mp 102−105
1
°C; H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.14 (dt, J =
6.7, 1.3 Hz, 1H), 7.54−7.49 (m, 2H), 7.48−7.42 (m, 3H), 6.89−6.77
(m, 2H), 2.76 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ
188.3, 132.5, 132.0, 131.7, 131.2, 129.0, 128.4, 126.1, 123.3, 120.4,
119.4, 118.3, 113.5, 9.7; IR (KBr) = ν 1668, 1528, 1489 cm−1; HRMS
(ESI-TOF) m/z calcd. for C16H13ClNO (M+H)+: 270.0680; found:
270.0699.
1-(4-Chlorophenyl)-3-phenylindolizine-2-carbaldehyde (3f). Pu-
rified by flash chromatography (silica gel, dichloromethane) to give
the desired product: 292 mg, 44% yield, yellow solid; Mp 177−179
°C; 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.01 (dt, J = 7.2,
1.1 Hz, 1H), 7.73−7.57 (m, 5H), 7.55−7.36 (m, 5H), 6.92 (m, 1H),
6.75 (m, 1H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 187.4, 132.1,
131.8, 131.3, 131.2, 131.1, 130.3, 129.3, 129.1, 128.1, 128.0, 123.0,
121.3, 121.1, 118.6, 114.1, 112.8; IR (KBr) = ν 1679, 1594, 1524,
1483 cm−1; HRMS (ESI-TOF) m/z calcd. for C21H15ClNO (M+H)+:
332.0837; found: 332.0821.
1,3,7-Trimethylindolizine-2-carbaldehyde (3g). Purified by flash
chromatography (silica gel, dichloromethane) to give the desired
1
product: 88 mg, 24% yield, yellow solid; Mp 40−41 °C; H NMR
(400 MHz, CDCl3) δ 10.29 (s, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.05 (d,
J = 1.4 Hz, 1H), 6.38 (dd, J = 7.3, 1.7 Hz, 1H), 2.65 (s, 3H), 2.49 (s,
3H), 2.25 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 188.3, 129.9,
126.1, 124.9, 122.4, 121.1, 116.7, 115.8, 107.9, 21.2, 9.7, 9.0.; IR
(KBr) = ν 2914, 1671, 1542, 1503, 1433 1382, 773 cm−1; HRMS
(ESI-TOF) m/z calcd. for C12H14NO (M+H)+: 188.1070; found:
188.1060.
Crystal Structure. Suitable single crystals of 3m for X-ray
structural analysis were obtained by slow solvent evaporation from
mixed solution of dichloromethane and n-hexane at room temperature
for 7 days.
3-Methyl-1-phenylindolizine-2-carbaldehyde (3a). Purified by
flash chromatography (silica gel, dichloromethane) to give the
desired product: 447 mg, 95% yield, yellow solid; Mp 86−88 °C;
1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.13 (dt, J = 5.4, 1.4
Hz, 1H), 7.52−7.41 (m, 5H), 7.41−7.31 (m, 1H), 6.86−6.76 (m,
2H), 2.76 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 190.2, 133.1,
130.9, 129.5, 128.7, 126.9, 124.3, 121.9, 121.4, 119.7, 118.0, 117.6,
113.8, 10.4; IR (KBr) = ν 1668, 1532, 1495 cm−1; HRMS (ESI-TOF)
m/z calcd. for C16H14NO (M+H)+: 236.1070; found: 236.1078.
1,3-Dimethylindolizine-2-carbaldehyde (3b). Purified by flash
chromatography (silica gel, dichloromethane) to give the desired
1-(3-Methyl-1-phenylindolizin-2-yl)ethan-1-one (3h). Purified by
flash chromatography (silica gel, dichloromethane) to give the desired
product: 428 mg, 86% yield, yellow solid; Mp 117−119 °C; 1H NMR
(400 MHz, DMSO-d6) δ 8.12−8.04 (m, 1H), 7.51−7.43 (m, 2H),
7.35 (tt, J = 7.9, 1.3 Hz, 3H), 7.32−7.24 (m, 1H), 6.82−6.70 (m,
2H), 2.61 (s, 3H), 2.05 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-
d6) δ 198.1, 134.9, 130.1, 128.6, 126.6, 124.8, 123.1, 122.6, 118.5,
118.1, 113.3, 112.6, 31.3, 10.2; IR (KBr) = ν 1657, 1596, 1527, 1494
cm−1; HRMS (ESI-TOF) m/z calcd. for C17H16NO (M+H)+:
250.1226; found: 250.1234.
1-(1,3-Dimethylindolizin-2-yl)ethan-1-one (3i). Purified by flash
1
chromatography (silica gel, dichloromethane) to give the desired
product: 193 mg, 56% yield, yellow solid; Mp 56−57 °C; H NMR
1
product: 74 mg, 20% yield, yellow solid; Mp 88−91 °C; H NMR
(400 MHz, CDCl3) δ 10.33 (s, 1H), 7.59 (dd, J = 7.1, 1.1 Hz, 1H),
7.33 (dt, J = 9.1, 1.3 Hz, 1H), 6.63−6.50 (m, 2H), 2.68 (s, 3H), 2.53
(s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 188.3, 129.8, 125.3,
122.3, 121.6, 119.1, 116.1, 112.9, 110.0, 9.7, 9.0; IR (KBr) = ν 3112,
2921, 1662, 1532, 1511, 1431, 738 cm−1; HRMS (ESI-TOF) m/z
calcd. for C11H12NO (M+H)+: 174.0913; found: 174.0908.
(400 MHz, DMSO-d6) δ 8.00−7.91 (m, 1H), 7.51−7.44 (m, 1H),
6.68−6.57 (m, 2H), 2.62 (s, 3H), 2.52 (s, 3H), 2.44 (s, 3H); 13C{1H}
NMR (101 MHz, DMSO-d6) δ 196.9, 128.7, 124.3, 122.6, 122.4,
118.4, 115.8, 112.0, 107.5, 31.8, 10.8; IR (KBr) = ν 3096, 2916, 1728,
1646, 1425, 738 cm−1; HRMS (ESI-TOF) m/z calcd. for C12H14NO
(M+H)+: 188.1070; found: 188.1066.
1,3-Diphenylindolizine-2-carbaldehyde (3c). Purified by flash
chromatography (silica gel, dichloromethane) to give the desired
product: 452 mg, 76% yield, yellow solid; Mp 169−170 °C; 1H NMR
(400 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.99 (dt, J = 7.3, 1.0 Hz, 1H),
7.71−7.53 (m, 5H), 7.54−7.43 (m, 5H), 7.41−7.32 (m, 1H), 6.89
(dd, J = 9.2, 6.3 Hz, 1H), 6.74 (td, J = 7.0, 1.3 Hz, 1H); 13C{1H}
1-(1-(4-Chlorophenyl)-3-methylindolizin-2-yl)ethan-1-one (3j).
Purified by flash chromatography (silica gel, dichloromethane) to
give the desired product: 486 mg, 86% yield, yellow solid; Mp 175−
1
177 °C; H NMR (400 MHz, CDCl3) δ 7.69 (dd, J = 6.8, 1.4 Hz,
1H), 7.42−7.34 (m, 2H), 7.33−7.22 (m, 3H), 6.65 (m, 1H), 6.62−
F
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The Journal of Organic Chemistry
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Article
6.57 (m, 1H), 2.63 (s, 3H), 2.12 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 199.3, 133.9, 132.6, 131.6, 129.4, 128.7, 125.3, 123.0, 121.9,
118.6, 118.1, 112.9, 112.7, 31.6, 10.4; IR (KBr) = ν 1662, 1586, 1567,
1489 cm−1; HRMS (ESI-TOF) m/z calcd. for C17H15ClNO (M+H)+:
284.0837; found: 284.0840.
10-Phenyl-3,4-dihydropyrido[1,2-a]indol-1(2H)-one (3k). Purified
by flash chromatography (silica gel, dichloromethane) to give the
desired product: 376 mg, 72% yield, yellow solid; Mp 143−144 °C;
(113−115 °C17). The NMR data match those of the reported
molecule.17 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.1 Hz, 1H),
7.55 (d, J = 7.0 Hz, 2H), 7.49 (d, J = 9.2 Hz, 1H), 7.41 (t, J = 7.6 Hz,
2H), 7.30 (t, J = 7.4 Hz, 1H), 6.67 (m, 1H), 6.61 (td, J = 6.7, 1.4 Hz,
1H), 3.01 (t, J = 6.3 Hz, 2H), 2.68−2.59 (m, 2H), 2.33 (p, J = 6.4 Hz,
2H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 194.8, 133.8, 133.3,
130.1, 129.6, 127.7, 126.0, 123.6, 119.4, 119.0, 118.5, 112.6, 111.4,
54.9, 22.8, 20.7.
10-Methyl-3,4-dihydropyrido[1,2-a]indol-1(2H)-one (3l). Purified
by flash chromatography (silica gel, dichloromethane) to give the
desired product: 31 mg, 8% yield, yellow solid; Mp 113−114 °C;
(123−125 °C17). The NMR data match those of the reported
molecule.17 1H NMR (400 MHz, CDCl3) δ 7.55 (dd, J = 7.1, 1.2 Hz,
1H), 7.32 (dt, J = 9.2, 1.3 Hz, 1H), 6.61−6.46 (m, 2H), 2.92 (t, J =
6.2 Hz, 2H), 2.64−2.57 (m, 2H), 2.54 (s, 3H), 2.26 (p, J = 6.4 Hz,
2H); 13C{1H} NMR (101 MHz, CDCl3) δ 197.4, 131.0, 130.1, 122.0,
121.1, 119.3, 116.1, 112.2, 107.9, 39.5, 23.6, 21.3, 9.7.
AUTHOR INFORMATION
Corresponding Author
■
Bao-Xiang Zhao − Institute of Organic Chemistry, School of
Chemistry and Chemical Engineering, Shandong University,
Jinan 250100, PR China; orcid.org/0000-0001-9620-
6959; Email: bxzhao@sdu.edu.cn
Authors
Yu-Chang Yuan − Institute of Organic Chemistry, School of
Chemistry and Chemical Engineering, Shandong University,
Jinan 250100, PR China
Tian-Zhen Liu − Institute of Organic Chemistry, School of
Chemistry and Chemical Engineering, Shandong University,
Jinan 250100, PR China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01292
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (No.
31871407, 31741083), the Natural Science Foundation of
Shandong Province (ZR2018MB042). The authors acknowl-
edge the assistance of Shandong University Structural
Constituent and Physical Property Research Facilities.
10-(4-Chlorophenyl)-3,4-dihydropyrido[1,2-a]indol-1(2H)-one
(3m). Purified by flash chromatography (silica gel, dichloromethane)
to give the desired product: 515 mg, 87% yield, yellow solid; Mp
1
179−181 °C; H NMR (400 MHz, CDCl3) δ 7.67 (dt, J = 7.1, 1.2
Hz, 1H), 7.52−7.46 (m, 2H), 7.43 (dt, J = 9.2, 1.2 Hz, 1H), 7.39−
7.33 (m, 2H), 6.75−6.66 (m, 1H), 6.62 (td, J = 6.7, 1.3 Hz, 1H), 3.01
(t, J = 6.3 Hz, 2H), 2.68−2.60 (m, 2H), 2.32 (p, J = 6.4 Hz, 2H);
13C{1H} NMR (101 MHz, CDCl3) δ 195.7, 132.6, 132.4, 132.3,
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ASSOCIATED CONTENT
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sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01292.
1H and 13C{1H} NMR, IR spectra, and HRMS spectra of
compounds, UV−vis absorption and fluorescence
emission spectra of the compounds (PDF)
Accession Codes
CCDC 2085860 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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