CuBr2-Promoted Multicomponent Aerobic Reaction for the Synthesis of 1,2,3-Triaroylindolizines

Article abstract of DOI:10.1002/jhet.3618

An efficient synthesis of 1,2,3-triaroylindolizines has been developed via CuBr₂-promoted reaction of three molecules of aromatic methyl ketones and one molecule of pyridine derivative. A wide range of methyl aryl ketones and methyl heteroaryl

Full text of DOI:10.1002/jhet.3618

Month 2019
CuBr2-Promoted Multicomponent Aerobic Reaction for the Synthesis of
1,2,3-Triaroylindolizines
Jinwei Sun,a Junwen Han,b Yuxuan Zhang,b and Yun Liua,b
*
aJiangsu Collaborative Innovation Center of Atmospheric Environment and Equipment Technology, School of Chemistry
and Materials Science, Nanjing University of Information Science and Technology, Nanjing, Jiangsu 210044, P.R. China
bSchool of Chemistry and Material Science, Jiangsu Normal University, Xuzhou, Jiangsu 221116, P.R. China
*E-mail: liu__yun3@sina.com
Received March 25, 2019
DOI 10.1002/jhet.3618
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
An efficient synthesis of 1,2,3-triaroylindolizines has been developed via CuBr2-promoted reaction of
three molecules of aromatic methyl ketones and one molecule of pyridine derivative. A wide range of methyl
aryl ketones and methyl heteroaryl ketones took part in the reaction and generate 1,2,3-triaroylindolizines in
good yields. This protocol also features such advantages as mild reaction conditions and high atom economy
and step economy.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
halogenation of C–H bond is an important synthetic
transformation for the construction of halogenated
compound [26–31]. Recently, we have developed an
efficient synthesis of indolizines by copper-catalyzed
reaction of pyridines, methyl ketones, and alkenoic acid
[32]. In this reaction, α-bromoketones are generated
from methyl ketones in the presence of copper
bromide. We speculated that this protocol can also be
applied to the synthesis of 1,2,3-triaroylindolizines.
Herein, we reported a convenient CuBr2-promoted four-
components reaction of aromatic methyl ketones and
pyridines for the synthesis of 1,2,3-triaroylindolizines
under oxygen atmosphere (Scheme 1d). Various
pyridines and methyl ketones are suitable substrates
under the reaction conditions and provided the desired
products 1,2,3-triaroylindolizines in moderate to high
yields.
As an important class of nitrogen-containing
heterocycles, indolizines exhibit diverse biological
activities and have wide application in medicinal [1–8]
and material field [9–11]. As the result, great efforts have
been made on their synthesis in the past decades [12–16].
Nevertheless, only few routes were disclosed for the
synthesis of 1,2,3-triaroylindolizines so far. The existing
protocols mainly include (a) cyclization of three
molecules of pyridinium bromides in the presence of
oxidant TPCD (Scheme 1a) [17]; (b) piperdine-promoted
reaction of bromoketones with pyridines (Scheme 1b)
[18]; and (c) reaction of pyridines and aromatic methyl
ketones in the presence of iodine and dimethyl sulfoxide
(Scheme 1c) [19]. The former two protocols (a and b)
employ bromoketones as the reactants that are
commercially expensive and need preparation from
methyl ketones before use. Besides, low reaction yields
and limited substrate scope are also shortcomings of
them. Compared with these two protocols, route c has
higher step economy that utilizes methyl ketones directly
as the reactants to form the indolizine products via α-
ketoaldehyde intermediate. However, three equimolar
amount of iodine is required in this reaction that hampers
its synthetic value. Therefore, more convenient synthetic
methods to 1,2,3-triaroylindolizines from methyl ketones
are highly demanded.
RESULTS AND DISCUSSION
At the outset of our work, we chose methyl isonicotinate
1a and acetophenone 2a as the model reactants. Initially,
by heating 1a (2.0 mmol), 2a (1.5 mmol), and CuBr2
(0.5 mmol) in acetonitrile at 90°C for 12 h, we did not
obtain any indolizine product (Table 1, entry 1). Other
solvents such as dioxane, benzene, dichloroethane, and
ethanol were also examined, but no improved result was
given (Table 1, entries 2–5). Pleasingly, changing the
solvent to dimethylformamide (DMF) led to 1,2,3-
triaroylindolizin 3a in 72% yield (Table 1, entry 6). With
Copper-promoted reaction starting from pyridines is an
important protocol for the synthesis of indolizine
derivatives [20–25]. Also, copper-mediated oxidative
© 2019 Wiley Periodicals, Inc.

J. Sun, J. Han, Y. Zhang, and Y. Liu
Vol 000
Scheme 1. Synthesis of 1,2,3-triaroylindolizines.
DMF as the solvent, the kind of copper salts was then
screened. CuBr2 has been found to work the best
(Table 1, entries 7–10). Further optimization showed that
0.5 equimolar amount of CuBr2 was enough to assure the
high yield of 3a in oxygen atmosphere, while no 3a was
found in the absence of CuBr2 (Table 1, entry 11–13).
Next, we examined the effect of oxidants other than
oxygen, including K2S2O8, DTBP, and TBHP, but no
better results were obtained (Table 1, entries 14–16). In
addition, the loading of 1a could be decreased to
0.75 mmol, but adding extra base could not reduce the
amount of 1a further (Table 1, entries 17–20). Finally,
we lowered the reaction temperature to 70°C and found
3a was formed only in 61% yield (Table 1, entry 21).
Therefore, the optimal conditions were heating 1a
(0.75 mmol), 2a (1.5 mmol), and CuBr2 (0.25 mmol) in
DMF at 90°C for 12 h in a sealed tube under oxygen
atmosphere.
Table 1
Optimization of reaction conditionsa.
Entry
Solvent
Copper (mmol)
Oxidant (mmol)
Yield (%)b
1
2
3
4
5
6
7
8
CH3CN
Dioxane
Benzene
DCE
CuBr2 (0.5)
CuBr2 (0.5)
CuBr2 (0.5)
CuBr2 (0.5)
CuBr2 (0.5)
CuBr2 (0.5)
CuBr (0.5)
CuI (0.5)
CuCl2 (0.5)
CuCl (0.5)
CuBr2 (0.25)
CuBr2 (0.15)
None
CuBr2 (0.25)
CuBr2 (0.25)
CuBr2 (0.25)
CuBr2 (0.25)
CuBr2 (0.25)
CuBr2 (0.25)
CuBr2 (0.25)
CuBr2 (0.25)
Air
Air
Air
Air
Air
Air
Air
Air
0
0
0
0
0
72
0
0
26
0
Ethanol
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
9
Air
Air
10
11
12
13
14
15
16
17c
18d
19e
20f
21g
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
K2S2O8 (1)
DTBP (1)
TBHP (1)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
72
58
0
20
42
15
72
60
Trace
Trace
61
DMF, dimethylformamide.
aConditions: heating 1a (2.0 mmol), 2a (1.5 mmol), copper salt, and oxidant at 90°C for 12 h.
bIsolated yields based on 2a.
c1a (0.75 mmol).
d1a (0.5 mmol).
e1a (0.5 mmol), K2CO3 (1.0 mmol).
f1a (0.5 mmol), Et3N (1.0 mmol).
gHeating at 70°C.
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Aerobic Synthesis of 1,2,3-Triaroylindolizines
With the optimized conditions in hand, we firstly
explore the scope of methyl ketones by using various
kinds of methyl ketones 2 to react with methyl
isonicotinate 1a under the optimal conditions (Table 2). It
showed that a variety of acetophenones 2b–2l containing
electron-withdrawing (F, Cl, and CO2Me) or electron-
Table 2
,
Scope of methyl ketonesa b
.
aConditions: 1a (0.75 mmol), 2 (1.5 mmol), CuBr2 (0.25 mmol), and DMF (5 mL).
bIsolated yields based on 2.
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J. Sun, J. Han, Y. Zhang, and Y. Liu
Vol 000
donating groups (Me, Et, and OMe) on the para-position,
meta-position, or ortho-position of the Ar ring participate
this reaction smoothly, providing the corresponding
1,2,3-traroylindolizines 3b–3l in moderate to good yields.
Besides, employing 1-(furan-2-yl)ethanone 2m or
1-(thiophen-2-yl)ethanone 2n as reactant, we also isolated
the desired product 3m or 3n in 70% or 46% yields,
respectively. However, when aliphatic methyl ketone 2o
was used to this reaction, the desired product 3o was not
detected.
Next, the scope of pyridines was examined (Table 3). It
showed that pyridines with electron-withdrawing groups
and annulated pyridines are all good substrates. For
example, 4-benzoylpyridine 1b reacted with methyl
Table 3
Scope of pyridinesa b
,
.
Entry
1
1
Product
2
3
4
5c
aConditions: 1 (0.75 mmol), 2a (1.5 mmol), CuBr2 (0.25 mmol), and DMF (5 mL).
bIsolated yields based on 2.
cHeating in the air for 18 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Aerobic Synthesis of 1,2,3-Triaroylindolizines
Scheme 2. Control experiment.
ketones 2 well, forming 1,2,3-triaroylindolizines 4a in 62%
yield. When methyl nicotinate 1c was employed as
reactant, two isomers 4b and 4c were isolated in similar
yields simultaneously. Also, both isoquinoline 1d and
quinoline 1e formed the corresponding indolizine
products 4d and 4e in good yields. For pyridines 1f and
1g without substituent or with electron-donating group,
higher yields of 4f and 4g were obtained in the air than
under O2 atmosphere.
Scheme 3. Plausible reaction mechanism.
To shed light on the reaction mechanism, several control
experiments were carried out (Scheme 2). First, we
employed (E)-1,2-dibenzoylethylene 5 (0.5 mmol) to
react with 1a (0.75 mmol) and acetophenone
2
(0.5 mmol) in the presence of 30 mol% CuBr2 under
oxygen atmosphere and obtained products 6a and 6b in
71% and 76% yields, respectively (Scheme 2a). Second,
using bromoketone 7 to react with 1a under the standard
conditions, we also got 3a in good yield (Scheme 2b).
These results illustrated that compounds 5 and 7 were the
possible reaction intermediates. Third, adding 0.5 mmol
of TEMPO into the model reaction did not inhibit the
formation of 3a, which has ruled out the radical
mechanism (Scheme 2c).
CONCLUSION
In summary, we have demonstrated an efficient copper-
promoted reaction to access 1,2,3-triaroylindolizines from
aromatic methyl ketones and pyridines. This protocol
needs only 0.5 equimolar amount of copper salt to
combine three molecules of acetophenone and one
molecule of pyridine derivative together, giving 1,2,3-
triaroylindolizines in satisfied yields.
Based on our experimental results,
a plausible
mechanism is proposed in Scheme 3. First, the reaction
of acetophenone 2a and CuBr2 generated α-brmoketone 7
that reacted with 1a, forming pyridinium salt I [32].
Then, I was transformed to yield II with the aid of
pyridine. Subsequently, nucleophilic substitution between
EXPERIMENTAL
1
Melting points are uncorrected. H NMR spectra were
measured on 400 MHz with CDCl3 as solvent. The
chemical shifts (δ) are reported in parts per million
relative to the residual deuterated solvent signal, and
coupling constants (J) are given in Hertz. 13C NMR
spectra were measured on 100 MHz with CDCl3 as
II and
7
followed by β-elimination gave 1,2-
dibenzoylethylene 5. At last, intermediate 5 underwent
1,3-dipolar cycloaddition with II and subsequent
oxidative aromatization by the aid of copper salt and
oxygen, giving the final product 3a.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. Sun, J. Han, Y. Zhang, and Y. Liu
Vol 000
solvent. HRMS (ESI) data were obtained in the electron
impact mode.
132.0, 129.5, 129.4, 128.8, 128.4, 127.9, 127.3, 126.7,
126.6, 122.7, 122.0, 117.0, 115.4, 52.7.HRMS (ESI) m/
z calcd for C31H19Cl3NO5 [M + H]+ 590.0329, found
General procedure for the preparation of 3.
Methyl
isonicotinate 1a (0.75 mmol), methyl ketone
(1.5 mmol), and copper bromide (0.25 mmol) were
mixed in 5 mL of DMF in a sealed tube and heated at
2
590.0317.
Methyl 1,2,3-tris(2-chlorobenzoyl)indolizine-7-carboxylate
(3e). Yellow solid; yield: 166.1 mg (56%); mp: 170–
172°C. 1H NMR (400 MHz, CDCl3) δ 3.97 (s, 3H),
6.92 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H),
7.07–7.23 (m, 8H), 7.32 (td, J = 8.0, 1.2 Hz, 1H), 7.44
(dd, J = 7.6, 0.8 Hz, 1H), 7.75 (dd, J = 7.6, 1.6 Hz,
1H), 8.57 (s, 1H), 10.02 (d, J = 7.2 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 188.2, 188.1, 185.1, 164.6, 140.8,
138.9, 137.9, 137.6, 134.4, 133.6, 133.2, 131.9, 131.5,
131.3, 131.2, 130.2, 129.8, 129.5, 129.0, 128.9, 126.6,
126.2, 126.1, 122.4, 121.8, 116.9, 115.9, 52.9. HRMS
(ESI) m/z calcd for C31H19Cl3NO5 [M + H]+ 590.0329,
90°C for 12
h under oxygen atmosphere. After
completion of the reaction, the mixture was cooled to
room temperature and separated by flash column
chromatography (ethyl acetate/hexane) on silica gel to
afford product 3.
Methyl 1,2,3-tribenzoylindolizine-7-carboxylate (3a).
Yellow solid; yield: 176.1 mg (72%); mp: 172–174°C.
1H NMR (400 MHz, CDCl3) δ 3.97 (s, 3H), 7.06 (t,
J = 7.6 Hz, 2H), 7.13–7.17 (m, 4H), 7.25–7.39 (m, 7H),
7.45 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 7.2 Hz, 1H), 8.73
(s, 1H), 9.50 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 191.2, 191.1, 187.7, 164.9, 139.5, 139.4,
138.3, 136.6, 136.3, 132.9, 132.4, 132.3, 128.9, 128.8,
128.7, 128.1, 128.0, 127.3, 123.3, 122.3, 117.8, 114.9,
52.8. HRMS (ESI) m/z calcd for C31H22NO5 [M + H]+
found 590.0346.
Methyl 1,2,3-tri(4-(methoxycarbonyl)benzoyl)indolizine-7-
carbo-xylate (3f). Yellow solid; yield: 129.9 mg (39%);
1
mp: 169–171°C. H NMR (400 MHz, CDCl3) δ 3.97 (s,
9H), 4.03 (s, 3H), 7.56 (s, 1H), 7.79 (dd, J = 7.2, 1.6 Hz,
1H), 7.84 (dd, J = 8.0, 1.2 Hz, 4H), 8.13–8.19 (m, 7H),
9.31 (s, 1H), 10.02 (d, J = 7.6 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 189.3, 184.9, 166.2, 166.1, 164.8,
142.9, 142.7, 139.5, 134.3, 133.0, 132.9, 130.3, 130.0,
129.9, 129.7, 129.5, 128.7, 128.6, 128.5, 123.2, 122.4,
115.8, 52.8, 52.4, 52.3. HRMS (ESI) m/z calcd for
488.1498, found 488.1482.
Methyl 1,2,3-tris(4-fluorobenzoyl)indolizine-7-carboxylate
(3b). Yellow solid; yield: 179.2 mg (66%); mp: 178–
1
180°C. H NMR (400 MHz, CDCl3) δ 3.98 (s, 3H), 6.80
(t, J = 8.4 Hz, 2H), 6.87–6.92 (m, 4H), 7.34–7.44 (m,
4H), 7.51–7.54 (m, 2H), 7.66 (d, J = 7.2 Hz, 1H), 8.68
(s, 1H), 9.46 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 189.8, 189.3, 186.0, 165.6 (d, J = 256 Hz),
164.3 (d, J = 253 Hz), 165.3 (d, J = 252 Hz), 164.7,
136.3, 135.9, 135.7 (d, J = 3 Hz), 135.5 (d, J = 3 Hz),
135.4 (d, J = 3 Hz), 134.7 (d, J = 3 Hz), 131.5, 131.4,
131.3, 131.2, 131.1, 128.3, 127.3, 123.0, 122.1, 117.5,
115.6, 115.5, 115.4, 115.3, 115.2, 115.1.
C37H28NO11 [M + H]+ 662.1662, found 662.1646.
Methyl 1,2,3-tris(4-methylbenzoyl)indolizine-7-carboxylate
(3g). Yellow solid; yield: 215.9 mg (82%); mp: 210–
1
212°C. H NMR (400 MHz, CDCl3) δ 2.25 (s, 3H), 2.29
(s, 3H), 2.33 (s, 3H), 3.96 (s, 3H), 6.87 (d, J = 8.0 Hz,
2H), 6.94–6.98 (m, 4H), 7.17 (d, J = 8.0 Hz, 2H), 7.30
(d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.59 (d,
J = 7.2 Hz, 1H), 8.69 (s, 1H), 9.40 (d, J = 7.2 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 191.0, 190.9, 187.5,
165.0, 143.7, 143.2, 136.9, 136.7, 136.3, 136.2, 135.9,
129.1, 129.0, 128.9, 128.8, 128.7, 128.6, 128.5, 127.4,
127.1, 123.5, 122.3, 118.0, 114.5, 52.7, 21.7, 21.6, 21.5.
HRMS (ESI) m/z calcd for C34H28NO5 [M + H]+
530.1967, found 530.1982.
HRMS (ESI) m/z calcd for C31H19F3NO5 [M + H]+
542.1215, found 542.1201.
Methyl 1,2,3-tris(4-chlorobenzoyl)indolizine-7-carboxylate
(3c). Yellow solid; yield: 204.9 mg (70%); mp: 168–
1
170°C. H NMR (400 MHz, CDCl3) δ 3.98 (s, 3H), 7.09
(d, J = 8.0 Hz, 2H), 7.18–7.27 (m, 6H), 7.32 (d,
J = 7.6 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.67 (d,
J = 7.2 Hz, 1H), 8.68 (s, 1H), 9.48 (d, J = 7.2 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 190.1, 189.4, 186.1,
164.7, 140.0, 139.1, 129.0, 137.6, 137.4, 136.5, 136.0,
130.2, 130.1, 129.9, 128.6, 128.5, 128.4, 127.4, 122.9,
122.0, 117.4. 115.3. 52.9. HRMS (ESI) m/z calcd for
Methyl
1,2,3-tris(4-ethylbenzoyl)indolizine-7-carboxylate
(3h). Yellow solid; yield: 231.8 mg (81%); mp: 135–
137°C. 1H NMR (400 MHz, CDCl3) δ 1.09–1.23 (m,
9H), 2.51–2.62 (m, 6H), 3.95 (s, 3H), 6.86 (d,
J = 8.0 Hz, 2H), 6.95 (t, J = 8.0 Hz, 4H), 7.16 (d,
J = 8.0 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.38 (d,
J = 7.6 Hz, 2H), 7.60 (dd, J = 7.2, 0.8 Hz, 1H), 8.71 (s,
1H), 9.43 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 191.0, 190.9, 187.6, 165.0, 149.8, 149.3,
137.2, 137.1, 136.5, 136.3, 136.0, 129.1, 129.0, 128.9,
127.6, 127.5, 127.4, 127.1, 123.5, 122.3, 118.1, 114.6,
52.7, 29.0, 29.0, 28.9, 28.8, 15.5, 15.3, 15.2. HRMS
(ESI) m/z calcd for C37H34NO5 [M + H]+ 572.2437,
found 572.2420.
C31H19Cl3NO5 [M + H]+ 590.0329, found 590.0313.
Methyl 1,2,3-tris(3-chlorobenzoyl)indolizine-7-carboxylate
(3d). Yellow solid; yield: 183.6 mg (62%); mp: 156–
158°C. 1H NMR (400 MHz, CDCl3) δ 4.00 (s, 3H),
7.10–7.27 (m, 6H), 7.28–7.36 (m, 5H), 7.42 (d,
J = 7.6 Hz, 1H), 7.72 (dd, J = 7.2, 1.6 Hz, 1H), 8.80
(s, 1H), 9.56 (d, J = 7.6 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 189.7, 189.1, 185.6, 164.4, 140.8,
140.7, 139.2, 136.6, 136.1, 134.8, 134.4, 132.9, 132.1,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Aerobic Synthesis of 1,2,3-Triaroylindolizines
Methyl 1,2,3-tris(4-methoxybenzoyl)indolizine-7-carboxylate
Methyl 1,2,3-tri(furan-2-carbonyl)indolizine-7-carboxylate
(3i).
Yellow solid; yield: 245.7 mg (85%); mp: 159–
(3m). Yellow solid; yield: 159.6 mg (70%); mp: 164–
1
161°C. H NMR (400 MHz, CDCl3) δ 3.74 (s, 3H), 3.77
166°C. 1H NMR (400 MHz, CDCl3) δ 3.98 (s, 3H),
6.42–6.43 (m, 3H), 6.98 (d, J = 3.6 Hz, 1H), 7.10 (dd,
J = 10.0, 3.6 Hz, 2H), 7.26–7.29 (m, 2H), 7.48 (d,
J = 0.8 Hz, 1H), 7.59 (dd, J = 7.2, 1.6 Hz, 1H), 8.82 (s,
1H), 9.28 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 178.1, 177.1, 173.4, 164.9, 153.4, 153.0,
152.6, 146.9, 146.5, 146.1, 135.9, 133.4, 127.6, 126.7,
122.4, 122.3, 119.2, 118.4, 116.4, 114.8, 112.8, 112.6,
112.5, 52.7. HRMS (ESI) m/z [M + H]+ calcd for
C25H16NO8: 458.0876, found 458.0890.
(s, 3H), 3.82 (s, 3H), 3.96 (s, 3H), 6.59 (d, J = 8.8 Hz,
2H), 6.65–6.68 (m, 4H), 7.32 (d, J = 8.8 Hz, 2H), 7.43
(d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.56 (dd,
J = 7.2, 1.6 Hz, 1H), 8.68 (s, 1H), 9.32 (d, J = 7.6 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ 190.0, 189.8, 186.4,
185.1, 163.3, 163.2, 163.1, 135.7, 135.6, 132.3, 132.2,
132.0, 131.3, 131.2, 131.0, 127.0, 126.9, 123.4, 122.3,
117.9, 114.3, 113.4, 113.3, 112.9, 55.5, 55.4, 55.3.
HRMS (ESI) m/z [M + H]+ calcd for C34H28NO8:
Methyl
1,2,3-tri(thiophene-2-carbonyl)indolizine-7-
578.1815, found 578.1795.
Methyl 1,2,3-tris(3-methoxybenzoyl)indolizine-7-carboxylate
(3j). Yellow solid; yield: 220.3 mg (76%); mp: 137–
carboxylate (3n). Yellow solid; yield: 117.2 mg (46%);
1
mp: 208–210°C. H NMR (400 MHz, CDCl3) δ 3.97 (s,
139°C. 1H NMR (400 MHz, CDCl3) δ 3.61 (s, 3H),
3.66 (s, 6H), 3.98 (s, 3H), 6.63 (s, 1H), 6.86–7.04 (m,
10H), 7.13 (t, J = 8.0 Hz, 1H), 7.65 (dd, J = 7.6,
1.6 Hz, 1H), 8.80 (s, 1H), 9.48 (d, J = 7.6 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 190.8, 190.7, 187.3,
164.7, 159.2, 159.1, 140.7, 140.6, 139.7, 136.3, 136.2,
129.0, 128.9, 128.8, 127.8, 127.0, 123.2, 122.3, 122.2,
121.7, 121.6, 119.9, 119.4, 119.3, 117.6, 114.8, 112.2,
112.1, 111.3, 55.1, 55.0, 52.6. HRMS (ESI) m/z
[M + H]+ calcd for C34H28NO8: 578.1815, found
3H), 6.85–7.01 (m, 3H), 7.36 (d, J = 2.0 Hz, 2H), 7.43
(d, J = 2.8 Hz, 1H), 7.56–7.59 (m, 4H), 8.72 (s, 1H),
9.18 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 183.0,
182.4, 178.9, 164.9, 146.2, 145.1, 144.7, 135.4, 135.3,
134.8, 134.4, 134.3, 134.2, 134.0, 133.9, 128.1, 127.7,
127.6, 127.4, 126.7, 123.2, 122.3, 117.5, 114.7, 52.8.
HRMS (ESI) m/z [M + H]+ calcd for C25H16NO5S3:
506.0191, found 506.0177.
General procedure for the preparation of 4. Pyridines 1
(0.75 mmol), acetophenone 2a (1.5 mmol), and copper
bromide (0.25 mmol) were mixed in 5 mL of DMF in a
sealed tube and heated at 90°C for 12 h under oxygen
atmosphere. After completion of the reaction, the mixture
was cooled to room temperature and separated by flash
column chromatography (ethyl acetate/hexane) on silica
578.1810.
Methyl 1,2,3-tris(2-methoxybenzoyl)indolizine-7-carboxylate
(3k). Yellow solid; yield: 215.8 mg (75%); mp: 162–
1
164°C. H NMR (400 MHz, CDCl3) δ 3.52 (s, 3H), 3.55
(s, 3H), 3.56 (s, 3H), 3.98 (s, 3H), 6.46 (d, J = 8.4 Hz,
1H), 6.52 (t, J = 7.6 Hz, 1H), 6.60–6.68 (m, 4H), 7.02–
7.09 (m, 4H), 7.16 (td, J = 7.6, 1.6 Hz, 1H), 7.27–7.34
(m, 1H), 7.66 (dd, J = 7.2, 2.0 Hz, 1H), 8.89–8.90 (m,
1H), 9.97 (dd, J = 7.6, 1.2 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 190.0, 188.3, 186.6, 165.3, 159.1,
157.0, 156.9, 143.2, 137.2, 134.3, 131.8, 131.7, 131.0,
129.6, 129.4, 128.8, 128.5, 126.0, 122.5, 119.9, 119.7,
119.6, 117.1, 114.9, 111.1, 110.7, 55.5, 55.4, 55.3, 52.8.
HRMS (ESI) m/z calcd for C34H28NO8: 578.1815, found
578.1796.
gel to afford product 4.
Indolizine-1,2,3,7-tetrayltetrakis(phenylmethanone) (4a).
Yellow solid; yield: 165.9 mg (62%); mp: 210–212°C.
1H NMR (400 MHz, CDCl3) δ 7.08 (t, J = 7.6 Hz, 2H),
7.12–7.17 (m, 4H), 7.26–7.44 (m, 9H), 7.52 (d,
J = 7.6 Hz, 2H), 7.62 (d, J = 7.2 Hz, 2H), 7.83 (d,
J = 7.6 Hz, 2H), 8.40 (s, 1H), 9.55 (d, J = 7.6 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 193.6, 191.2, 191.1,
187.7, 139.4, 139.3, 138.2, 136.7, 136.3, 136.0, 134.7,
133.1, 132.9, 132.4, 132.3, 130.1, 129.8, 128.8, 128.7,
128.1, 128.0, 127.6, 123.4, 123.0, 118.0, 115.3. HRMS
(ESI) m/z [M + H]+ calcd for C36H24NO4: 534.1705,
Methyl
1,2,3-tris(2,4-dimethylbenzoyl)indolizine-7-
carboxylate (3l). Yellow solid; yield: 229.2 mg (80%);
1
mp: 130–132°C. H NMR (400 MHz, CDCl3) δ 1.85 (s,
found 534.1688.
3H), 2.10 (s, 6H), 2.14 (s, 3H), 2.19 (s, 3H), 2.29 (s,
3H), 3.97 (s, 3H), 6.49 (d, J = 7.2 Hz, 1H), 6.65 (d,
J = 7.6 Hz, 1H), 6.72 (s, 2H), 6.79 (s, 1H), 6.87 (t,
J = 8.4 Hz, 2H), 6.96 (d, J = 7.6 Hz, 1H), 7.22 (d,
J = 8.0 Hz, 1H), 7.65 (dd, J = 7.2, 2.0 Hz, 1H), 8.73 (s,
1H), 9.76 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 192.8, 191.2, 189.2, 165.0, 142.8, 141.1,
140.7, 140.6, 140.0, 137.3, 137.0, 136.9, 136.8, 136.1,
134.0, 133.3, 132.2, 131.3, 131.2, 129.2, 128.6, 128.0,
125.6, 125.5, 125.2, 123.5, 122.2, 118.2, 114.9, 21.5,
21.4, 21.2, 21.1, 19.5, 19.4. HRMS (ESI) m/z calcd for
C37H34NO5: 572.2437, found 572.2460.
Methyl 1,2,3-tribenzoylindolizine-6-carboxylate (4b).
Yellow solid; yield: 100.8 mg (41%); mp 206–
208°C.1H NMR (400 MHz, CDCl3) δ 4.00 (s, 3H),
7.06 (t, J = 7.6 Hz, 2H), 7.15–7.20 (m, 4H), 7.27–7.30
(m, 3H), 7.36–7.40 (m, 4H), 7.47 (d, J = 7.5 Hz,
2H), 7.91 (d, J = 9.2 Hz, 1H), 7.99 (d, J = 9.6 Hz,
1H), 10.23 (s, 1H). 13C NMR (100 MHz, CDCl3) δ
191.3, 190.9, 187.5, 164.8, 139.4, 138.2, 138.1, 138.9,
132.9, 132.3, 131.7, 128.8, 128.7, 128.2, 128.1, 128.0,
126.5, 123.0, 119.7, 119.2, 52.7. HRMS (ESI) m/z
[M + H]+ calcd for C31H22NO5: 488.1498, found
488.1507.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. Sun, J. Han, Y. Zhang, and Y. Liu
Vol 000
Methyl 1,2,3-tribenzoylindolizine-8-carboxylate (4c).
Yellow solid; yield: 93.1 mg (38%); mp 215–216°C. H
General procedure for the preparation of 6.
Methyl
isonicotinate 1a (2.0 mmol), methyl ketone 2 (0.5 mmol),
alkene 5 (0.5 mmol), and copper bromide (0.15 mmol)
were mixed in 5 mL of DMF in a sealed tube and heated
at 90°C for 12 h under oxygen atmosphere. After
completion of the reaction, the mixture was cooled to
room temperature and separated by flash column
chromatography (ethyl acetate/hexane) on silica gel to
afford product 6.
1
NMR (400 MHz, CDCl3) δ 3.45 (s, 3H), 7.05 (t,
J = 7.6 Hz, 2H), 7.11–7.14 (m, 3H), 7.23 (t, J = 7.2 Hz,
3H), 7.26–7.42 (m, 6H), 7.66 (d, J = 7.6 Hz, 2H), 7.83
(d, J = 7.2 Hz, 1H), 9.76 (d, J = 6.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 191.7, 187.1, 165.3, 139.9, 138.4,
138.3, 136.4, 132.7, 132.6, 132.4, 131.9, 130.5, 129.3,
128.9, 128.8, 128.7, 128.1, 127.9, 127.8, 123,7, 121.4,
117.2, 114.3, 51.8. HRMS (ESI) m/z [M + H]+ calcd for
Methyl
1,2-dibenzoyl-3-(4-chlorobenzoyl)indolizine-7-
carboxylate (6a). Yellow solid; yield: 185.8 mg (71%);
C31H22NO5: 488.1498, found 488.1483.
Pyrrolo[2,1-a]isoquinoline-1,2,3-triyltris(phenylmethanone)
1
mp 185–187°C. H NMR (400 MHz, CDCl3) δ 3.96 (s,
(4d).
Yellow solid; yield: 127.5 mg (53%); mp 210–
3H), 7.02 (d, J = 8.4 Hz, 2H), 7.14–7.20 (m, 4H), 7.27–
7.31 (m, 4H), 7.36–7.40 (m, 2H), 7.45 (d, J = 7.2 Hz,
2H), 7.65 (dd, J = 7.2, 1.6 Hz, 1H), 8.71 (s, 1H), 9.50 (d,
J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 191.3,
191.0, 186.3, 164.8, 139.2, 138.7, 138.2, 137.8, 136.7,
136.5, 133.1, 132.5, 130.1, 128.9, 128.7, 128.4, 128.2,
128.1, 127.3, 122.9, 122.2, 118.0, 115.1, 52.8. HRMS
(ESI) m/z [M + H]+ calcd for C31H21ClNO5: 522.1108,
found 522.1120.
212°C. 1H NMR (400 MHz, CDCl3) δ 7.07–7.12 (m,
4H), 7.22–7.45 (m, 11H), 7.55 (t, J = 7.6 Hz, 1H), 7.74
(d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 2H), 8.08 (d,
J = 8.4 Hz, 1H), 9.10 (d, J = 7.6 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 194.5, 191.7, 187.5, 140.3, 139.0,
138.4, 133.7, 133.5, 132.5, 132.3, 131.9, 129.6, 129.5,
129.1, 128.8, 128.7, 128.5, 128.3, 128.1, 127.9, 127.4,
125.2, 124.2, 123.9, 123.6, 118.7, 115.9. HRMS (ESI) m/
z [M + H]+ calcd for C33H22NO3: 480.1600, found
Methyl
1,2-dibenzoyl-3-(4-methylbenzoyl)indolizine-7-
carboxylate (6b). Yellow solid; yield: 191.3 mg (76%);
480.1648.
1
mp 169–171°C. H NMR (400 MHz, CDCl3) δ 2.23 (s,
Pyrrolo[1,2-a]quinoline-1,2,3-triyltris(phenylmethanone)
(4e).
Yellow solid; yield: 184.2 mg (77%); mp 172–
3H), 3.96 (s, 3H), 6.86 (d, J = 8.0 Hz, 2H), 7.15 (t,
J = 7.6 Hz, 4H), 7.25–7.31 (m, 4H), 7.33–7.39 (m,
2H), 7.45 (dd, J = 7.2, 1.2 Hz, 2H), 7.62 (dd, J = 7.6,
2.0 Hz, 1H), 8.72 (s, 1H), 9.41 (d, J = 7.6 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 191.3, 191.1, 187.4,
165.0, 143.4, 139.4, 138.4, 136.8, 136.2, 136.1, 132.8,
132.4, 129.0, 128.9, 128.8, 128.7, 128.1, 128.0, 127.8,
127.1, 122.3, 117.7, 114.7, 52.7, 21.5. HRMS (ESI) m/
z [M + H]+ calcd for C32H24NO5: 502.1654, found
502.1637.
174°C. 1H NMR (400 MHz, CDCl3) δ 7.11–7.19 (m,
4H), 7.29–7.36 (m, 6H), 7.41–7.48 (m, 5H), 7.55 (d,
J = 9.6 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.80 (d,
J = 7.2 Hz, 1H), 7.84–7.91 (m, 3H). 13C NMR
(100 MHz, CDCl3) δ 191.9, 191.5, 189.6, 140.2, 138.7,
137.7, 136.1, 134.0, 132.5, 132.4, 132.3, 132.0, 129.7,
129.3, 129.1, 128.9, 128.7, 128.1, 128.0, 127.4, 125.8,
125.5, 118.7, 117.9, 116.0. HRMS (ESI) m/z [M + H]+
calcd for C33H22NO3: 480.1600, found 480.1652.
Indolizine-1,2,3-triyltris(phenylmethanone) (4f).
Yellow
1
solid; yield: 87.6 mg (41%); mp: 202–204°C. H NMR
(400 MHz, CDCl3) δ 7.04 (t, J = 7.2 Hz, 2H), 7.13–7.16
(m, 5H), 7.25–7.29 (m, 3H), 7.34–7.46 (m, 7H), 8.04 (d,
J = 8.8 Hz, 1H), 9.64 (dd, J = 7.2, 0.8 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ 191.9, 191.4, 187.7, 140.0,
139.9, 138.4, 138.1, 137.0, 132.7, 132.0, 131.9, 128.9,
128.8, 128.7, 128.6, 128.1, 128.0, 127.9, 127.7, 122.2,
119.8, 116.2, 115.2. HRMS (ESI) m/z [M + H]+ calcd for
Acknowledgments. This work was supported by the Natural
Science Foundation of the Jiangsu Higher Education
Institutions of China (grant number 17KJB150016) and the
Natural Science Foundation of Jiangsu Province (grant number
BK20170939).
REFERENCES AND NOTES
C29H20NO3: 430.1443, found 430.1458.
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1
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet