Iodine Mediated Base-Controlled Regio-Selective Annulation of 2-(Pyridin-2-yl)acetate Derivatives with Acrylic Esters for the Synthesis of Indolizines

Article abstract of DOI:10.1002/adsc.202000103

An iodine mediated base-controlled reaction between 2-(pyridin-2-yl)acetate derivatives and acrylic esters has been developed for the selective synthesis of 1,3-disubstituted indolizines and 1,2-disubstituted indolizines. A single-pot reaction of 2-(pyridin-2-yl)acetate derivatives and acrylic esters in the presence of CsOAc delivers 1,3-disubstitued indolizines, while KHCO₃ promotes the formation of C3-iodo indolizines, which could be further de-iodinated in the presence of copper powder, affording 1,2-disubstituted indolizines via a sequential stepwise fashion. A plausible reaction mechanism involving radical process has been proposed for this reaction. Pd-catalzyed reaction of C3-iodo indolizines with aryl boronic acids has been described. (Figure presented.).

Full text of DOI:10.1002/adsc.202000103

Title: Iodine Mediated Base-Controlled Regio-Selective Annulation
of 2-(Pyridin-2-yl)acetate derivatives with Acrylic Esters for the
Synthesis of Indolizines
Authors: Youlai Fang, Fei Li, Yuzhu Yang, Xiaolan Liu, and Weidong
Pan
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000103
Link to VoR: http://dx.doi.org/10.1002/adsc.202000103

10.1002/adsc.202000103
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iodine Mediated Base-Controlled Regio-Selective Annulation of
2-(Pyridin-2-yl)acetate derivatives with Acrylic Esters for the
Synthesis of Indolizines
Youlai Fanga,b, Fei Lia,b, Yuzhu Yanga,b*, Xiaolan Liua,b, Weidong Pana,b*
a
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 3491 Baijin
Road, Guiyang 550014, P. R. China
The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 3491
b
Baijin Road, Guiyang 550014, P. R. China
Email: yangyuzhu15@126.com, wdpan@163.com
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An iodine mediated base-controlled reaction
between 2 ‑ (pyridin-2-yl)acetate derivatives and acrylic
esters has been developed for the selective synthesis of 1,3-
disubstituted indolizines and 1,2-disubstituted indolizines. A
single-pot reaction of 2‑(pyridin-2-yl)acetate derivatives and
acrylic esters in the presence of CsOAc delivers 1,3-
disubstitued indolizines, while KHCO3 promotes the
formation of C3-iodo indolizines, which could be further de-
iodinated in the presence of copper powder, affording 1,2-
disubstituted indolizines via a sequential stepwise fashion. A
plausible reaction mechanism involving radical process has
been proposed for this reaction. Pd-catalzyed reaction of C3-
iodo indolizines with aryl boronic acids has been described.
Keywords: iodine; base-controlled; regio-selective; radical
process; proto-deiodination
Considering the wide range of biological activities,
developing efficient synthetic method of indolizines
has attracted wide attention in the fields of organic
chemistry and chemical biology.[10] The majority for
the preparation of indolizines include Tschitschibabin
reaction,[11] 1,3-dipolar cycloaddition,[12] 1,5-dipolar
cyclizations,[13] I2-mediated oxidative cyclization,[14]
Introduction
As an important class of nitrogen-containing
heterocyclic compounds, indolizine derivatives have a
wide range of biological properties.[1] Several
molecules bearing the indolizine scaffold have been
proved to behave significant biological activities
(Figure 1) such as antioxidant and free radical
transition-metal-catalyzed
intramolecular
cyclization[15] and intermolecular cyclization.[16] To
the best of our knowledge, oxidant and solvent were
proven to switch the regio-selectivity for the
annulation reaction of 2-alkyl pyridines with cinnamic
acids by copper catalysis. The results were reported
independently by Cai’s group [17] and Zhang’s group
scavenging
effects,[2]
antimicrobial,[3]
anti-
inflammatory,[4] Histamine H3 receptor antagonists,[5]
phosphatase
inhibitors,[6]
HIV
inhibitors
inhibitory
of
15-
lipoxygenase,[7]
activities.[8]
Substituted indolizines have also been used in
materials science due to their luminescent
properties.[9]
[18]
(Scheme 1a and 1b). Most of the reactions
between 2-alkyl pyridines with alkenes developed by
groups of Jia, Yan and Pan delivered 1,3-disubstituted
indolizines (Scheme 1a).[19] Methods for the synthesis
of 1,2-disubstituted indolizines include Cu-catalyzed
I2-mediated oxidative condensation protocol by
Adimurthy’s group[14f] and Cu-catalyzed redox-
neutral annulation protocol by Zhang’s group
(Scheme 1b). However, few of the above reports
Figure 1. Biologically active indolizines.
1
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10.1002/adsc.202000103
Advanced Synthesis & Catalysis
Table 1. Optimization of the Reaction Conditionsa.
discussed the issue of regio-selectivity for the
preparation of 1,3-disubstituted indolizines and 1,2-
disubstituted indolizines. Herein we report the
selective synthesis of 1,3-disubsituted indolizines and
1,2-disubstituted indolizines via base-controlled
reactions between commercially available 2-pyridyl
acetates derivatives and acrylic esters. In the presence
of CsOAc, a single-pot reaction delivers 1,3-
disubstitued indolizines, while KHCO3 promotes the
formation of C3-iodo-indolizines, which could
undergo de-iodination to afford 1,2-disubstituted
indolizines in two steps (Scheme 1c).
Yieldb of Yieldb of
entry
base
solvent
3ba
4ba
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16c
17
18
19d
20d
-
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
0
20
3
0
0
50
0
K2CO3
Na2CO3
Cs2CO3
Li2CO3
NaHCO3
KHCO3
KOAc
NaOAc
CsOAc
CsF
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
CsOAc
CsOAc
KHCO3
CsOAc
4
trace
trace
3
31
21
45
36
9
trace
trace
trace
8
32
41
3
0
trace
64
21
0
0
7
50
46
20
trace
28
0
0
68
0
DCE
DCE
DCM
Toluene
DMSO
DMF
DCE
DCM
toluene
DCE
DCE
35
Scheme 1. Protocols for the selective synthesis of 1,3- and
1,2-disubstituted indolizines.
a)
Reaction conditions: 1b (0.3 mmol), 2a (0.6 equiv), 4.0
equiv I2 and 8.0 equiv base in solvent (1.0 mL) at 90 °C of
oil bath for 11 h. b) Isolated yield. c) NIS instead of I2. d) 3.0
equiv I2 was used.
Results and Discussion
We set out the optimization study with 2-pyridyl
acetates (1b) and methyl acrylate (2a) as model
substrates. No product was detected when only iodine
was used as oxidant without external base (Table 1,
entry 1). When K2CO3 is added, product 3ba can be
isolated in 20% yield (Table 1, entry 2). A series of
carbonate bases were then screened in this reaction
system to improve the yield of 3ba (Table 1, entries
3−5). It is surprising that product 4ba was isolated in
50% yield when Na2CO3 is used as base, while only
3% of product 3ba was isolated under these
conditions (Table 1, entry 3). Further optimization of
external basses indicated KHCO3 delivered higher
yield 64% of product 4ba (Table 1, entry 7). Bases
containing acetate anions promoted the formation of
product 3ba (Table 1, entries 8-10). Product 3ba can
be isolated in 45% yield when CsOAc was added as
base (Table 1, entry 10). Further screening of solvents
and oxidants resulted in no better yield for product
3ba, while product 4ba was isolated 68% yield when
3 equiv iodine was used (Table 1, entry 19).
Scheme 2. Scope of 2-pyridyl acetates derivatives for the
synthesis of 1,3-disubstituted indolizines.
Under the optimized reaction conditions, we
extended the substrate scope of 2-pyridyl acetates
derivatives for the synthesis of 1,3-disubstituted
indolizines (Scheme 2). Steric hindrance effect was
observed when different groups were employed in
this reaction. Methyl, ethyl, isopropyl, butyl and tert-
butyl substituted substrates delivered similar yields
(3aa-3ea). Ethyl 2-(6-methylpyridin-2-yl)acetate with
2
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10.1002/adsc.202000103
Advanced Synthesis & Catalysis
ortho-methyl group in the pyridine ring delivered
lower yield 27% of the product 3fa. When 2-(pyridin-
2-yl)acetonitrile was performed in this reaction, no
product can be isolated.
Next we examined different electron deficient
alkenes under this optimized reaction conditions
(Scheme 3). Most of the acrylic esters derivatives
were tolerated under this reaction conditions to
deliver the corresponding indolizine products in
moderate yields. The structure of product 3bb was
confirmed by single-crystal X-ray diffraction (CCDC
1922193).[20] When allylic group was substituted in
the esters, decreased yield was observed (3bf in 23%).
It is noteworthy that acrylonitrile also works in this
reaction to give the corresponding product 3bg
containing cyano group in 42% yield.
Scheme 4. Scope of 2-pyridyl acetates derivatives for the
synthesis of C3-iodo indolizines.
Scheme 3. Scope of acrylic ester derivatives for the
synthesis of 1,3-disubstituted indolizines.
Scheme 5. Scope of acrylic ester derivatives for the
synthesis of C3-iodo indolizines.
For the iodine mediated synthesis of C3-iodo
indolizines, we extended the scope of 2-pyridyl
acetates derivatives under the optimal reaction
conditions in Scheme 4. Generally, the reactions
proceeded smoothly to produce the corresponding
products in good yields. Moderate yields were
obtained with less steric hindrance groups in the
products. When phenyl groups were attached in the
substrates, the yield of product 4ea dropped to 23%.
When ethyl 2-(6-methylpyridin-2-yl)acetate with
ortho-methyl group in the pyridine ring was employed
in this reaction, no product was detected. 2-(Pyridin-
2-yl)acetonitrile containing cyano group resulted no
product. In addition, the structure of product 4ba was
confirmed by single-crystal X-ray diffraction (CCDC
1922194). [21]
Next the scope of acrylic esters was examined
under the optimized reaction conditions. A series of
acrylic ester substrates were compatible with this
reaction to give the corresponding products in
moderate yield. However, tert-butyl and allylic
substituted substrates resulted in products 4bd and
4bf in lower yields. It is noteworthy that phenyl and
benzyl substituted substrates delivered the products
4bg in 68% yield and 4bh in 61% yield.
To gain more insight for the elucidation of the
reaction mechanism, further investigation was
performed. Indolizine 5aa was prepared with known
method[22] and was then performed in the reaction
o
with 3 equiv iodine. After 11 hours in DCE at 90 C,
C3-iodo product 4aa was isolated in 66% yield
(Scheme 6a). However, no reaction was observed
3
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10.1002/adsc.202000103
Advanced Synthesis & Catalysis
when 3ba was employed under the exact same
Under the optimized reaction conditions for the
reaction conditions (Scheme 6b). Therefore it is synthesis of product 3ba, 2 equiv BHT (butylated
reasonable that C3-iodo product 4aa was formed by hydroxytoluene) was added. No desired product was
electrophilic iodination of 5aa, which resulted from detected while the coupling product 7a between BHT
the regio-selective annulations. Due to the none- and α-C position of 2-pyridyl acetate. This result
reactive site of C2 position of indolizine 3ba, no indicated the reaction proceeds in radical process and
iodination reaction was occurred.
product 3ba was formed by carbon radical initiated
annulation reaction. Similar control experiment was
performed for the synthesis of 4ba in the hope of
trapping the nitrogen radical which initiated
annulation reaction. Neither desired product nor other
coupling product was detected. Possible explanation
could be that the nitrogen radical is too reactive to be
trapped, and the formed N-O bond is unstable in the
coupling product.
Based on the above experimental results and
previous reports,[23] plausible mechanism is proposed
in Scheme 7. For the synthesis of product 3ba, the
initial oxidation of 2b by iodine would produce
radical intermediate A, which reacts with 2a to form
intermediate B, followed by intramolecular
cyclization to give the intermediate C. Further
oxidation of intermediate C by iodine delivers carbon
cation intermediate D, which undergo deprotonation
and dehydrogenative aromatization to give the final
product 3ba (Scheme 7, path a). For the synthesis of
4ba, the initial imine-enamine tautomerism generates
the enamine intermediate E, which undergo oxidation
by iodine to form nitrogen radical intermediate F.
Cyclization of intermediate F with 2a would produce
intermediate G, which undergo oxidation to form
carbon cation intermediate H. Further deprotonation
and dehydrogenative aromatization delivers the
product 5ba. Due to the excess amount of iodine in
the reaction, electrophilic addition of product 5ba
with iodine would generate the intermediate I, which
undergo deprotonation to produce the final C3-iodo
indolizine product 4ba (Scheme 7, path b). In
summary, the regio-selectivity was tuned under
different basic reaction conditions, which generates
carbon or nitrogen radical intermediates of 2-pyridyl
acetates at the initial stage of the reaction. The
following radical annulation resulted in indolizine
products with two different substitution pattern.
Scheme 6. Control experiments.
Due to the excess amount of iodine, the formed
indolizine product 5 would react with iodine to
deliver the C3-iodo indolizines. It is difficult to
control the reaction to stop at the stage of product 5.
We next conduct the proto-deiodination reaction from
C3-iodo indolizines to prepare the corresponding
deiodination product 4 in Scheme 8. To the best of
our knowledge, there is no report about direct
deiodination of iodo-indolizines. After optimization
Scheme 7. Plausible mechanism.
4
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10.1002/adsc.202000103
Advanced Synthesis & Catalysis
study of the reaction conditions for deiodination (see
Table S1)，excellent yields of desired products were
obtained（Scheme 8). Generally most of the C3-iodo
indolizines could be quantitatively converted into
deiodized products. Only for those compounds with
larger substituents at C2 position, the yield slightly
decreases (5bd in 87% yield).
Scheme 10. Gram scale reaction for 3ba and 4ba.
Demonstration of the prepared C3-iodo indolizines
on Pd-catalyzed arylation reactions with aromatic
boronic acid was shown in Scheme 9. The product 8a
from phenyl boronic acid was isolated in 76% yield.
Electronic effect was observed in this reaction as aryl
boronic acid with methoxy group delivered the
corresponding product 8b in a lower 42% yield while
electron-withdrawing group fluoro resulted in product
8c with a higher 62% yield. Besides the phenyl
boronic acids, thiophen-2-ylboronic acid and furan-2-
ylboronic acid could also be employed in this
reaction system to give the expected heteroarylated
products 8d in 68% yield and 8e in 65% yield.
Gram-Scale reactions were performed to verify the
practicality of our protocol. The reaction of 1b with
methyl acrylate at 10 mmol scale provided 1,3-
disubstituted indolizines product 3ba in 33% yield
while the C3-iodo indolizines product 4ba was
isolated in 42% yield (Scheme 10).
Scheme 8. Proto-deiodination of C3-iodo indolizines.
Conclusion
In conclusion, we have developed an iodine
mediated base-controlled regio-selective annulation
reaction of 2-pyridyl acetate derivatives and acrylic
esters, in which the generation of carbon radical or
nitrogen radical would initiate the radical cyclization,
leading to the selective synthesis of 1,3-disubstituted
indolizines and C3-iodo indolizines. Further
investigation reveals that copper powder with KHCO3
would promote the de-iodization reaction of the
prepared C3-iodo indolizines, which delivers 1,2-
disubstituted indolizines. Moreover, the prepared C3-
iodo indolizines could also be applied in Pd-catalzyed
arylation reaction with aryl boronic acids. Exploration
and detailed mechanism investigation of this iodine
mediated regio-selective annulation reaction are
currently ongoing in our laboratory.
Scheme 9. Pd-catalyzed arylation of C3-iodo indolizines
4ba with aryl boronic acids.
5
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10.1002/adsc.202000103
Advanced Synthesis & Catalysis
Experimental Section
6.96 (td, J = 7.0, 1.1 Hz, 1H), 5.26 (hept, J = 6.2 Hz, 1H),
3.91 (s, 3H), 1.38 (d, J = 6.3 Hz, 6H). 13C NMR (150 MHz,
CDCl3) δ 163.8, 161.6, 139.1, 127.9, 125.6, 124.4, 119.7,
114.4, 114.3, 105.8, 67.3, 51.4, 22.3. HRMS (ESI-TOF)
m/z: [M+H]+ calcd. for C14H16NO4: 262.1074. Found:
262.1075.
Melting points were measured in a WRX-4 melting point
apparatus purchased from Shanghai YICE Instrumental
1
Company; H and 13C NMR spectra were recorded at 400
(500, 600) and 100 (125, 150) MHz, respectively using
CDCl3 as the solvent. (INOVA 400 MHz NMR
Spectrometer, WNMR-I 500 MHz NMR Spectrometer,
Bruker Avance NEO 600 MHz NMR Spectrometer)
HRMS data were recorded on an agilent 6540 mass
spectrometer with electro spray ionization and TOF mass
analyzer. All column chromatography was performed using
silica gel (200-300 microns). Unless otherwise noted,
commercially available chemicals were used as received.
1-Butyl 3-methyl indolizine-1,3-dicarboxylate (3da)
(Eluent: ethyl acetate/petroleum ether = 1/20, v/v); 38%
o
yield (Yellow solid. m.p. 51-52 C, 31 mg). 1H NMR (600
MHz, CDCl3) δ 9.51 (d, J = 7.0 Hz, 1H), 8.33 (d, J = 9.0
Hz, 1H), 7.97 (s, 1H), 7.35 – 7.27 (m, 1H), 6.97 (t, J = 6.9
Hz, 1H), 4.32 (t, J = 6.6 Hz, 2H), 3.92 (s, 3H), 1.81 – 1.71
(m, 2H), 1.50 (q, J = 7.5 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H).
13C NMR (150 MHz, CDCl3) δ 164.4, 161.7, 139.2, 128.0,
125.8, 124.5, 119.7, 114.6, 105.5, 64.0, 51.5, 31.1, 19.5,
14.0. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C15H18NO4: 276.1230. Found: 276.1229.
General procedure and analytical data for product 3: A
sealed tube was loaded with I2 (1.2 mmol, 304.8 mg),
CsOAc (2.4 mmol, 460.7 mg), ethyl 2-pyridylacetate (1b,
0.3 mmol, 49.6 mg), methyl acrylate (2a, 0.6 mmol, 51.6
mg), and 1 mL DCE. The reaction mixture was stirred in
oil bath at 90 °C for 11 h. After completion of the reaction,
the reaction mixture was diluted with EtOAc, and washed
with 10% Na2S2O3 solution (50 mL). Then, the mixture
was extracted with EtOAc (20 mL×3), and the combined
organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. The remaining crude product was
then purified through column chromatography using silica
gel (EtOAc/petroleum ether = 1/20) to produce 3ba as a
white solid with a 40% yield.
1-(tert-Butyl) 3-methyl indolizine-1,3-dicarboxylate
(3ea)
(Eluent: ethyl acetate/petroleum ether = 1/20, v/v); 35%
o
yield ( White solid. m.p. 125-127 C, 29 mg). 1H NMR
(600 MHz, CDCl3) δ 9.48 (d, J = 7.1 Hz, 1H), 8.29 (d, J =
9.0 Hz, 1H), 7.91 (s, 1H), 7.27 (ddd, J = 8.8, 7.2, 0.9 Hz,
1H), 6.95 (td, J = 6.9, 1.4 Hz, 1H), 3.91 (s, 3H), 1.62 (s,
9H). 13C NMR (150 MHz, CDCl3) δ 163.7, 161.6, 138.9,
127.8, 125.4, 124.5, 119.7, 114.3, 114.1, 107.0, 80.3, 51.4,
28.6. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C15H18NO4: 276.1230. Found: 276.1240.
Dimethyl indolizine-1,3-dicarboxylate (3aa, CAS:
82884-78-4)[24]
(Eluent: ethyl acetate/petroleum ether = 1/20, v/v); 46%
yield (White solid. m.p. 182-183 oC, 32 mg). 1H NMR (600
MHz, CDCl3) δ 9.49 (d, J = 7.1 Hz, 1H), 8.31 (d, J = 9.0
Hz, 1H), 7.96 (s, 1H), 7.30 (ddd, J = 9.0, 6.8, 1.2 Hz, 1H),
6.97 (td, J = 6.9, 1.4 Hz, 1H), 3.90 (s, 3H), 3.90 (s, 3H).
13C NMR (150 MHz, CDCl3) δ 164.6, 161.6, 139.2, 127.9,
125.8, 124.4, 119.6, 114.6, 105.0, 51.5, 51.3. HRMS (ESI-
TOF) m/z: [M+H]+ calcd. for C12H12NO4: 234.0761.
Found: 234.0757.
1-Ethyl 3-methyl 5-methylindolizine-1,3-dicarboxylate
(3fa)
(Eluent: ethyl acetate/petroleum ether = 1/20, v/v); 27%
o
1
yield (Yellow solid. m.p. 81-83 C, 21 mg). H NMR (600
MHz, CDCl3) δ 8.30 (d, J = 8.9 Hz, 1H), 7.98 (s, 1H), 7.28
(dd, J = 8.9, 6.9 Hz, 1H), 6.79 (d, J = 6.9 Hz, 1H), 4.37 (q,
J = 7.1 Hz, 2H), 3.90 (s, 3H), 2.71 (s, 3H), 1.40 (t, J = 7.1
Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 164.2, 161.2,
141.4, 139.0, 127.1, 126.3, 117.3, 116.8, 116.4, 105.1, 60.0,
52.1, 22.7, 14.6. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C15H16NO4: 262.1074. Found: 262.1078.
1-Ethyl 3-methyl indolizine-1,3-dicarboxylate (3ba,
CAS: 394212-94-3)[25]
(Eluent: ethyl acetate/petroleum ether = 1/20, v/v); 40%
Diethyl indolizine-1,3-dicarboxylate (3bb, CAS: 55814-
13-6)[26]
o
1
yield (White solid. m.p. 96-98 C, 30 mg). H NMR (600
MHz, CDCl3) δ 9.51 (d, J = 7.1 Hz, 1H), 8.33 (d, J = 9.0
Hz, 1H), 7.99 (s, 1H), 7.31 (ddd, J = 8.9, 6.8, 1.0 Hz, 1H),
6.98 (td, J = 6.9, 1.3 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.92
(s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz,
CDCl3) δ 164.3, 161.7, 139.2, 128.0, 125.8, 124.5, 119.7,
114.6, 105.4, 60.1, 51.5, 14.7. HRMS (ESI-TOF) m/z:
[M+H]+ calcd. for C13H14NO4: 248.0917. Found 248.0920.
(Eluent: ethyl acetate/petroleum ether = 1/20, v/v); 42%
o
1
yield (Yellow solid. m.p.130-131 C, 33 mg). H NMR
(600 MHz, CDCl3) δ 9.50 (d, J = 7.1 Hz, 1H), 8.31 (d, J =
9.0 Hz, 1H), 7.97 (s, 1H), 7.29 (ddd, J = 9.0, 6.8, 1.2 Hz,
1H), 6.96 (td, J = 6.9, 1.4 Hz, 1H), 4.37 (q, J = 7.1 Hz, 4H),
1.43 – 1.38 (m, 6H). 13C NMR (150 MHz, CDCl3) δ 164.3,
161.3, 139.1, 128.0, 125.6, 124.3, 119.6, 114.8, 114.4,
105.2, 60.3, 60.0, 14.6, 14.5. HRMS (ESI-TOF) m/z:
[M+H]+ calcd. for C14H16NO4: 262.1074. Found: 262.1073.
1-Isopropyl 3-methyl indolizine-1,3-dicarboxylate (3ca)
(Eluent: ethyl acetate/petroleum ether = 1/20, v/v); 38%
o
yield (White solid. m.p. 120-123 C, 30 mg). 1H NMR
3-Butyl 1-ethyl indolizine-1,3-dicarboxylate (3bc)
(600 MHz, CDCl3) δ 9.52 – 9.45 (m, 1H), 8.32 (d, J = 9.0
Hz, 1H), 7.97 (s, 1H), 7.29 (ddd, J = 8.9, 6.8, 0.9 Hz, 1H),
6
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10.1002/adsc.202000103
Advanced Synthesis & Catalysis
(Eluent: ethyl acetate/petroleum ether = 1/20, v/v); 36% 125.2, 120.5, 115.0, 112.7, 106.0, 96.7, 60.3, 14.5. HRMS
1
yield (White solid. m.p. 44-45oC, 31 mg). H NMR (600 (ESI-TOF) m/z: [M+H]+ calcd. for C12H11N2O2: 215.0815.
MHz, CDCl3) δ 9.52 (d, J = 7.1 Hz, 1H), 8.32 (d, J = 9.0 Found: 215.0815.
Hz, 1H), 7.97 (s, 1H), 7.30 (ddd, J = 8.8, 6.8, 1.0 Hz, 1H),
6.97 (td, J = 6.9, 1.2 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.33
(t, J = 6.6 Hz, 2H), 1.76 (dt, J = 14.5, 6.7 Hz, 2H), 1.49 (dq,
J = 14.8, 7.4 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H), 0.99 (d, J =
7.4 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 165.7, 162.8,
138.1, 130.0, 127.0, 123.8, 120.7, 114.3, 104.6, 65.7, 63.9,
60.1, 30.6, 19.3, 14.4, 13.8. HRMS (ESI-TOF) m/z:
[M+H]+ calcd. for C16H20NO4: 290.1387. Found: 290.1388.
General procedure and analytical data for product 4: A
sealed tube was loaded with I2 (0.9 mmol, 228.6 mg),
KHCO3 (2.4 mmol, 331.7 mg), ethyl 2-pyridylacetate (1b,
0.3 mmol, 49.6 mg), methyl acrylate (2a, 0.6 mmol, 51.6
mg), and 1 mL DCE. The reaction mixture was stirred in
oil bath at 90 °C for 11 h. After completion of the reaction,
the reaction mixture was diluted with EtOAc, and washed
with 10% Na2S2O3 solution (50 mL). Then, the mixture
was extracted with EtOAc (20 mL×3), and the combined
organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. The remaining crude product was
then purified through column chromatography using silica
gel (EtOAc/petroleum ether = 1/20) to produce 4ba as a
yellow solid with a 68% yield.
3-(tert-Butyl) 1-ethyl indolizine-1,3-dicarboxylate (3bd)
(Eluent: ethyl acetate/petroleum ether = 1/20, v/v); 32%
o
1
yield (Yellow solid. m.p. 79-80 C, 28 mg). H NMR (600
MHz, CDCl3) δ 9.51 (d, J = 7.1 Hz, 1H), 8.31 (d, J = 9.0
Hz, 1H), 7.90 (s, 1H), 7.29 – 7.26 (m, 1H), 6.93 (t, J = 6.9
Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.61 (s, 9H), 1.42 (t, J =
7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 164.5, 160.9,
138.9, 128.0, 125.4, 124.1, 119.6, 116.0, 114.2, 104.8, 81.3,
60.0, 28.6, 14.7. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C16H20NO4: 290.1387. Found: 290.1388.
Dimethyl 3-iodoindolizine-1,2-dicarboxylate (4aa)
(Eluent: ethyl acetate/petroleum ether = 1/20, v/v); 64%
o
1
yield (Yellow solid. m.p. 94-96 C, 68 mg). H NMR (600
MHz, CDCl3) δ 8.12 (d, J = 4.8 Hz, 1H), 8.11 (d, J = 3.3
Hz, 1H), 7.14 (t, J = 8.3 Hz, 1H), 6.89 (t, J = 7.5 Hz, 1H),
3.98 (s, 3H), 3.88 (s, 3H). 13C NMR (150 MHz, CDCl3) δ
166.0, 163.3, 138.2, 137.3, 129.6, 127.2, 124.0, 120.2,
114.5, 104.6, 52.8, 51.5. HRMS (ESI-TOF) m/z: [M+H]+
calcd. for C12H11INO4: 359.9727. Found 359.9730.
1-Ethyl 3-hexyl indolizine-1,3-dicarboxylate (3be)
(Eluent: ethyl acetate/petroleum ether = 1/30, v/v); 35%
o
1
yield (White solid. m.p. 58-60 C, 33 mg). H NMR (600
MHz, CDCl3) δ 9.53 (d, J = 7.1 Hz, 1H), 8.38 – 8.31 (m,
1H), 7.98 (s, 1H), 7.31 (ddd, J = 8.9, 6.8, 1.1 Hz, 1H), 6.98
(td, J = 6.9, 1.3 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.32 (t, J
= 6.7 Hz, 2H), 1.77 (dq, J = 7.8, 6.7 Hz, 2H), 1.45 (d, J =
7.9 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H), 1.37 – 1.33 (m, 4H),
0.91 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
164.3, 161.3, 139.1, 128.0, 125.6, 124.2, 119.7, 114.8,
114.4, 105.2, 64.5, 60.0, 31.6, 28.9, 25.8, 22.8, 14.6, 14.1.
HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C18H24NO4:
318.1700. Found: 318.1710.
1-Ethyl 2-methyl 3-iodoindolizine-1,2-dicarboxylate
(4ba)
(Eluent: ethyl acetate/petroleum ether = 1/20, v/v); 68%
o
1
yield (Yellow solid. m.p. 110-112 C, 76 mg). H NMR
(600 MHz, CDCl3) δ 8.14 (d, J = 9.1 Hz, 1H), 8.10 (d, J =
7.1 Hz, 1H), 7.13 (ddd, J = 9.1, 6.7, 1.1 Hz, 1H), 6.89 (td, J
= 6.9, 1.1 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H),
1.36 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
166.1, 162.9, 138.2, 129.6, 127.2, 123.9, 120.3, 114.5,
104.8, 64.3, 60.3, 52.8, 14.5. HRMS (ESI-TOF) m/z:
[M+H]+ calcd. for C13H13INO4: 373.9884. Found: 373.9884.
3-Allyl 1-ethyl indolizine-1,3-dicarboxylate (3bf)
(Eluent: ethyl acetate/petroleum ether = 1/20, v/v); 23%
1
yield (Yellow solid. m.p. 72-76oC, 19 mg). H NMR (600
MHz, CDCl3) δ 9.50 (d, J = 6.9 Hz, 1H), 8.33 (d, J = 9.0
Hz, 1H), 8.02 (s, 1H), 7.33 – 7.29 (m, 1H), 6.97 (t, J = 6.8
Hz, 1H), 6.08 –6.00 (m, 1H), 5.43 (d, J = 17.2 Hz, 1H),
5.29 (d, J = 10.4 Hz, 1H), 4.83 (d, J = 5.6 Hz, 2H), 4.37 (q,
J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). 13C NMR (150
MHz, CDCl3) δ 164.2, 160.8, 139.3, 132.5, 128.0, 125.8,
124.5, 119.7, 118.3, 114.5, 114.4, 105.4, 64.9, 60.0, 14.6.
HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C15H16NO4:
274.1074. Found: 274.1072.
1-Isopropyl 2-methyl 3-iodoindolizine-1,2-dicarboxylate
(4ca)
(Eluent: ethyl acetate/petroleum ether = 1/20, v/v); 50%
o
1
yield (Yellow solid. m.p. 108-109 C, 58 mg). H NMR
(600 MHz, CDCl3) δ 8.14 (d, J = 9.1 Hz, 1H), 8.10 (d, J =
7.1 Hz, 1H), 7.15 – 7.09 (m, 1H), 6.88 (t, J = 6.9 Hz, 1H),
5.23 (hept, J = 6.2 Hz, 1H), 3.97 (s, 3H), 1.34 (d, J = 6.3
Hz, 6H). 13C NMR (150 MHz, CDCl3) δ 166.2, 162.5,
138.3, 129.6, 127.2, 123.8, 120.3, 114.4, 105.2, 67.6, 64.2,
52.8, 22.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C14H15INO4: 388.0040. Found: 388.0044.
Ethyl 3-cyanoindolizine-1-carboxylate (3bg, CAS:
1408337-51-8)[25]
(Eluent: ethyl acetate/petroleum ether = 1/10, v/v); 42%
yield (White solid. m.p. 101-103 oC, 27 mg). 1H NMR (600
MHz, CDCl3) δ 8.33 – 8.28 (m, 2H), 7.76 (s, 1H), 7.31
(ddd, J = 9.0, 6.8, 1.2 Hz, 1H), 7.02 (td, J = 6.8, 1.3 Hz,
1H), 4.36 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H). 13C
NMR (150 MHz, CDCl3) δ 163.3, 137.8, 126.0, 125.7,
1-Butyl 2-methyl 3-iodoindolizine-1,2-dicarboxylate
(4da)
(Eluent: ethyl acetate/petroleum ether = 1/30, v/v); 56%
o
1
yield (Yellow solid. m.p. 43-44 C, 67 mg). H NMR (600
MHz, CDCl3) δ 8.12 (d, J = 9.1 Hz, 1H), 8.08 (d, J = 7.0
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000103
Advanced Synthesis & Catalysis
Hz, 1H), 7.14 – 7.08 (m, 1H), 6.87 (t, J = 6.9 Hz, 1H), 4.28
(t, J = 6.7 Hz, 2H), 3.96 (s, 3H), 1.71 (p, J = 6.8 Hz, 2H),
1.44 (h, J = 7.4 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR
(150 MHz, CDCl3) δ 166.1, 163.0, 138.2, 129.6, 127.1,
123.9, 120.2, 114.4, 104.7, 64.2, 64.1, 52.8, 30.9, 19.3,
13.8. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C15H17INO4: 402.0197. Found 402.0203.
1-Ethyl 2-hexyl 3-iodoindolizine-1,2-dicarboxylate (4be)
(Eluent: ethyl acetate/petroleum ether = 1/20, v/v); 35%
1
yield (Yellow oil, 46 mg). H NMR (600 MHz, CDCl3) δ
8.12 (d, J = 9.1 Hz, 1H), 8.08 (d, J = 7.1 Hz, 1H), 7.13 –
7.08 (m, 1H), 6.86 (t, J = 6.9 Hz, 1H), 4.37 (t, J = 6.8 Hz,
2H), 4.33 (q, J = 7.1 Hz, 2H), 1.77 (dt, J = 14.7, 6.9 Hz,
2H), 1.44 (p, J = 7.2 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H),
1.33-1.28 (m, 4H), 0.90 – 0.86 ((t, J = 6.7 Hz, 3H). 13C
NMR (150 MHz, CDCl3) δ 165.7, 162.9, 138.2, 130.0,
127.1, 123.8, 120.2, 114.3, 104.7, 66.0, 63.9, 60.2, 31.5,
28.6, 25.7, 22.6, 14.4, 14.1. HRMS (ESI-TOF) m/z:
[M+H]+ calcd. for C18H23INO4: 444.0666. Found: 444.0663.
2-Methyl 1-phenyl 3-iodoindolizine-1,2-dicarboxylate
(4ea)
(Eluent: ethyl acetate/petroleum ether = 1/20, v/v); 23%
o
1
yield (Yellow solid. m.p. 141-144 C, 29 mg). H NMR
(600 MHz, CDCl3) δ 8.25 (d, J = 9.1 Hz, 1H), 8.22 (d, J =
7.1 Hz, 1H), 7.46 – 7.42 (m, 2H), 7.28 (d, J = 5.2 Hz, 1H),
7.24 (t, J = 8.3 Hz, 3H), 6.99 (t, J = 6.8 Hz, 1H), 3.98 (s,
3H). 13C NMR (150 MHz, CDCl3) δ 165.9, 161.2, 150.8,
139.0, 129.9, 129.5, 127.5, 125.8, 124.8, 121.9, 120.3,
114.9, 103.7, 65.3, 53.0. HRMS (ESI-TOF) m/z: [M+H]+
calcd. for C17H13INO4: 421.9884. Found: 421.9889.
2-Allyl 1-ethyl 3-iodoindolizine-1,2-dicarboxylate (4bf)
(Eluent: ethyl acetate/petroleum ether = 1/10, v/v); 20%
o
1
yield (Yellow solid. m.p. 85-86 C, 24 mg). H NMR (600
MHz, CDCl3) δ 8.16 (d, J = 9.1 Hz, 1H), 8.12 (d, J = 7.1
Hz, 1H), 7.14 (ddd, J = 9.1, 6.7, 1.1 Hz, 1H), 6.90 (td, J =
6.9, 1.3 Hz, 1H), 6.07 (ddt, J = 17.2, 10.4, 5.8 Hz, 1H),
5.45 (dq, J = 17.2, 1.5 Hz, 1H), 5.31 (dq, J = 10.4, 1.3 Hz,
1H), 4.89 (dt, J = 5.8, 1.4 Hz, 2H), 4.34 (q, J = 7.1 Hz, 2H),
1.36 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
165.3, 162.9, 138.3, 131.9, 129.5, 127.2, 123.9, 120.3,
118.8, 114.5, 104.9, 66.5, 64.4, 60.3, 14.5. HRMS (ESI-
TOF) m/z: [M+H]+ calcd. for C15H15INO4: 400.0040.
Found: 400.0042
Diethyl 3-iodoindolizine-1,2-dicarboxylate (4bb)
(Eluent: ethyl acetate/petroleum ether = 1/20, v/v); 62%
o
1
yield (Yellow solid. m.p. 72-75 C, 72 mg); H NMR (600
MHz, CDCl3) δ 8.15 (d, J = 9.1 Hz, 1H), 8.12 – 8.09 (m,
1H), 7.15 – 7.10 (m, 1H), 6.89 (t, J = 6.9 Hz, 1H), 4.45 (q,
J = 7.2 Hz, 2H), 4.34 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1
Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz,
CDCl3) δ 165.7, 163.0, 138.3, 130.0, 127.2, 123.9, 120.3,
114.4, 104.8, 64.1, 62.0, 60.3, 14.5, 14.3. HRMS (ESI-
TOF) m/z: [M+H]+ calcd. for C14H15INO4: 388.0040.
Found: 388.0052.
1-Ethyl 2-phenyl 3-iodoindolizine-1,2-dicarboxylate
(4bg)
(Eluent: ethyl acetate/petroleum ether = 1/40, v/v); 68%
o
1
yield (Yellow solid. m.p. 108-110 C, 88 mg). H NMR
(600 MHz, CDCl3) δ 8.14 (d, J = 9.1 Hz, 1H), 8.10 (d, J =
7.0 Hz, 1H), 7.45 (t, J = 7.9 Hz, 2H), 7.38 (d, J = 7.5 Hz,
2H), 7.28 (t, J = 7.4 Hz, 1H), 7.13 (ddd, J = 9.1, 6.7, 1.1 Hz,
1H), 6.88 (td, J = 6.9, 1.3 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H),
1.38 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
163.9, 162.8, 150.9, 138.1, 129.5, 128.6, 127.1, 126.0,
124.0, 121.5, 120.1, 114.5, 105.0, 65.02, 60.4, 14.5. HRMS
(ESI-TOF) m/z: [M+H]+ calcd. for C18H15INO4: 436.0040.
Found: 436.0043.
2-Butyl 1-ethyl 3-iodoindolizine-1,2-dicarboxylate (4bc)
(Eluent: ethyl acetate/petroleum ether = 1/20, v/v); 44%
o
1
yield (Yellow solid. m.p. 37-39 C, 55 mg). H NMR (600
MHz, CDCl3) δ 8.11 (d, J = 9.1 Hz, 1H), 8.07 (d, J = 7.0
Hz, 1H), 7.10 (ddd, J = 9.1, 6.7, 0.9 Hz, 1H), 6.85 (td, J =
6.9, 1.2 Hz, 1H), 4.38 (t, J = 6.7 Hz, 2H), 4.33 (q, J = 7.1
Hz, 2H), 1.76 (dt, J = 14.5, 6.8 Hz, 2H), 1.47 (h, J = 7.4 Hz,
2H), 1.35 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H). 13C
NMR (150 MHz, CDCl3) δ 165.7, 162.8, 138.1, 130.0,
127.0, 123.8, 120.1, 114.3, 104.6, 65.7, 63.9, 60.1, 30.6,
19.3, 14.4, 13.8. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C16H19INO4: 416.0353. Found: 416.0356.
2-Benzyl 1-ethyl 3-iodoindolizine-1,2-dicarboxylate
(4bh)
(Eluent: ethyl acetate/petroleum ether = 1/40, v/v); 61%
o
1
yield (Yellow solid. m.p. 98-99 C, 82 mg). H NMR (600
MHz, CDCl3) δ 8.11 (d, J = 9.1 Hz, 1H), 8.04 (d, J = 7.1
Hz, 1H), 7.48 (d, J = 7.3 Hz, 2H), 7.37 (t, J = 7.4 Hz, 2H),
7.32 (t, J = 7.3 Hz, 1H), 7.08 (ddd, J = 9.2, 6.7, 1.1 Hz, 1H),
6.83 (td, J = 6.9, 1.3 Hz, 1H), 5.43 (s, 2H), 4.28 (q, J = 7.1
Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz,
CDCl3) δ 165.4, 162.8, 138.1, 135.5, 129.3, 128.5, 128.5,
128.3, 127.0, 123.8, 120.0, 114.3, 104.7, 67.5, 64.3, 60.1,
14.4. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C19H17INO4: 450.0197. Found: 450.0206.
2-(tert-Butyl) 1-ethyl 3-iodoindolizine-1,2-dicarboxylate
(4bd)
(Eluent: ethyl acetate/petroleum ether = 1/20, v/v); 17%
yield (Yellow solid, . m.p. 70-71 oC, 22 mg). 1H NMR (600
MHz, CDCl3) δ 8.15 (d, J = 9.1 Hz, 1H), 8.09 (d, J = 7.1
Hz, 1H), 7.11 (ddd, J = 9.1, 6.7, 1.1 Hz, 1H), 6.87 (td, J =
6.9, 1.3 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.65 (s, 9H),
1.38 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
164.5, 163.1, 138.3, 131.0, 127.1, 123.7, 120.3, 114.3,
104.4, 82.6, 63.9, 60.2, 28.3, 14.7. HRMS (ESI-TOF)
m/z:[M+Na]+ calcd. for C16H18INaNO4: 438.0178. Found: General procedure and analytical data for product 5: A
438.0183.
sealed tube was loaded with 4ba (0.1 mmol, 37.3 mg),
KHCO3 (0.6 mmol, 60.1 mg), copper powder (0.4 mmol,
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000103
Advanced Synthesis & Catalysis
25.4 mg) and 1 mL DCE. The reaction mixture was stirred (Eluent: ethyl acetate/petroleum ether = 1/4, v/v); 92%
1
in oil bath at 120 °C for 14 h. After the reaction was yield (Yellow oil, 27 mg). H NMR (600 MHz, CDCl3) δ
completed, the reaction solution was transferred to the 8.24 (d, J = 9.2 Hz, 1H), 8.03 (d, J = 6.9 Hz, 1H), 7.72 (s,
eggplant bottle, silica gel powder was added, and then 1H), 7.48 – 7.42 (m, 2H), 7.28 (t, J = 8.0 Hz, 3H), 7.19 –
concentrated in vacuum. The remaining crude product was 7.12 (m, 1H), 6.84 (t, J = 6.8 Hz, 1H), 3.93 (s, 3H). 13C
then purified through column chromatography using silica NMR (150 MHz, CDCl3) δ 165.3, 162.3, 151.2, 137.1,
gel (EtOAc/petroleum ether = 1/3) to produce 5ba as a 129.5, 126.2, 125.6, 124.2, 122.3, 122.1, 120.7, 117.4,
yellow solid with a 100% yield.
114.2, 101.9, 52.5. HRMS (ESI-TOF) m/z: [M+H]+ calcd.
for C17H14NO4: 296.0917. Found: 296.0917.
Dimethyl indolizine-1,2-dicarboxylate (5aa, CAS:
16959-60-7) [27]
Diethyl indolizine-1,2-dicarboxylate (5bb, CAS: 14174-
98-2) [27]
(Eluent: ethyl acetate/petroleum ether = 1/3, v/v); 100%
o
1
yield (Yellow solid. m.p. 88-90 C, 24 mg). H NMR (600 (Eluent: ethyl acetate/petroleum ether = 1/3, v/v); 100%
o
1
MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 7.8 yield (Yellow solid. m.p. 83-84 C, 27 mg); H NMR (600
Hz, 1H), 7.57 (s, 1H), 7.02 – 6.95 (m, 1H), 6.67 (t, J = 6.6 MHz, CDCl3) δ 8.13 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 6.9
Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H). 13C NMR (150 MHz, Hz, 1H), 7.60 (s, 1H), 7.05 (ddd, J = 9.2, 6.7, 1.0 Hz, 1H),
CDCl3) δ 165.0, 164.2, 136.0, 125.9, 123.2, 121.4, 120.3, 6.74 (td, J = 6.8, 1.1 Hz, 1H), 4.38 (qd, J = 7.1, 4.0 Hz, 4H),
117.0, 113.6, 102.57, 52.1, 51.2. HRMS (ESI-TOF) m/z: 1.39 (td, J = 7.1, 4.6 Hz, 6H). 13C NMR (150 MHz, CDCl3)
[M+H]+ calcd. for C12H12NO4: 234.0761. Found 234.0761.
1-ethyl 2-methyl indolizine-1,2-dicarboxylate (5ba)
(Eluent: ethyl acetate/petroleum ether = 1/3, v/v); 100%
δ 165.1, 164.0, 136.1, 126.0, 123.2, 122.3, 120.7, 116.5,
113.7, 103.1, 61.2, 60.1, 14.6, 14.4. HRMS (ESI-TOF)
m/z: [M+H]+ calcd. for C14H16NO4: 262.1074. Found:
262.1073.
o
1
2-Butyl 1-ethyl indolizine-1,2-dicarboxylate (5bc)
yield (Yellow solid. m.p. 70-72 C, 25 mg). H NMR (600
MHz, CDCl3) δ 8.11 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 6.9
Hz, 1H), 7.61 (s, 1H), 7.05 (ddd, J = 9.1, 6.7, 0.8 Hz, 1H), (Eluent: ethyl acetate/petroleum ether = 1/3, v/v); 95%
1
6.73 (td, J = 6.8, 1.0 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.90 yield (Yellow oil, 27 mg). H NMR (600 MHz, CDCl3) δ
(s, 3H), 1.39 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, 8.11 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 7.1 Hz, 1H), 7.59 (s,
CDCl3) δ 165.4, 163.9, 136.1, 125.9, 123.2, 121.8, 120.6, 1H), 7.04 (dd, J = 8.6, 6.8 Hz, 1H), 6.72 (t, J = 6.3 Hz, 1H),
116.7, 113.7, 103.0, 60.1, 52.2, 14.5. HRMS (ESI-TOF) 4.36 (q, J = 7.1 Hz, 2H), 4.33 – 4.29 (m, 2H), 1.73 (dt, J =
m/z: [M+H]+ calcd. for C13H14NO4: 248.0917. Found: 14.6, 6.9 Hz, 2H), 1.45 (h, J = 7.4 Hz, 2H), 1.38 (t, J = 7.1
248.0917.
Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (150 MHz,
CDCl3) 13C NMR (150 MHz, CDCl3) δ 165.0, 163.9, 136.0,
125.9, 123.1, 122.2, 120.6, 116.5, 113.6, 103.0, 65.1, 60.1,
30.8, 19.3, 14.5, 13.8. HRMS (ESI-TOF) m/z: [M+H]+
calcd. for C16H20NO4: 290.1387. Found: 290.1386.
1-Isopropyl 2-methyl indolizine-1,2-dicarboxylate (5ca)
(Eluent: ethyl acetate/petroleum ether = 1/3, v/v); 92%
1
yield (Yellow oil, 24 mg). H NMR (600 MHz, CDCl3) δ
2-(tert-Butyl) 1-ethyl indolizine-1,2-dicarboxylate (5bd)
8.11 (d, J = 9.2 Hz, 1H), 7.92 (d, J = 6.9 Hz, 1H), 7.59 (s,
1H), 7.04 (ddd, J = 9.2, 6.6, 0.9 Hz, 1H), 6.72 (td, J = 6.8,
1.1 Hz, 1H), 5.26 (p, J = 6.3 Hz, 1H), 3.90 (s, 3H), 1.36 (d, (Eluent: ethyl acetate/petroleum ether = 1/3, v/v); 87%
1
J = 6.3 Hz, 6H). 13C NMR (150 MHz, CDCl3) δ 165.6, yield (Yellow oil, 25 mg). H NMR (600 MHz, CDCl3) δ
163.5, 136.0, 126.0, 123.1, 121.9, 120.6, 116.5, 113.6, 8.09 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 6.9 Hz, 1H), 7.53 (s,
103.4, 67.4, 52.2, 22.3. HRMS (ESI-TOF) m/z: [M+H]+ 1H), 7.02 (dd, J = 9.1, 6.7 Hz, 1H), 6.70 (t, J = 6.8 Hz, 1H),
calcd. for C14H16NO4: 262.1074. Found: 262.1073.
1-Butyl 2-methyl indolizine-1,2-dicarboxylate (5da)
(Eluent: ethyl acetate/petroleum ether = 1/3, v/v); 100%
4.38 (q, J = 7.1 Hz, 2H), 1.60 (s, 9H), 1.39 (t, J = 7.1 Hz,
3H). 13C NMR (150 MHz, CDCl3) δ 164.2, 164.0, 135.9,
125.9, 124.0, 122.9, 120.5, 116.1, 113.4, 102.8, 81.4, 60.0,
28.3, 14.6. HRMS (ESI-TOF) m/z:[M+H]+ calcd. for
C16H20NO4: 290.1387. Found: 290.1386.
1
yield (Yellow oil, 27 mg). H NMR (600 MHz, CDCl3) δ
1-Ethyl 2-hexyl indolizine-1,2-dicarboxylate (5be)
8.12 (d, J = 9.3 Hz, 1H), 7.93 (d, J = 6.9 Hz, 1H), 7.60 (s,
1H), 7.05 (ddd, J = 9.2, 6.7, 1.0 Hz, 1H), 6.74 (td, J = 6.8,
1.1 Hz, 1H), 4.32 (t, J = 6.7 Hz, 2H), 3.90 (s, 3H), 1.82 – (Eluent: ethyl acetate/petroleum ether = 1/3, v/v); 94%
1
1.69 (m, 2H), 1.51 – 1.43 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). yield (Yellow oil, 30 mg). H NMR (600 MHz, CDCl3) δ
13C NMR (150 MHz, CDCl3) δ 165.5, 164.1, 136.1, 126.0, 8.11 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 6.9 Hz, 1H), 7.59 (s,
123.3, 121.9, 120.7, 116.7, 113.7, 103.1, 64.1, 52.3, 31.1, 1H), 7.06 – 7.01 (m, 1H), 6.72 (t, J = 6.8 Hz, 1H), 4.36 (q,
19.5, 13.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for J = 7.1 Hz, 2H), 4.30 (t, J = 6.8 Hz, 2H), 1.74 (dt, J = 14.7,
C15H18NO4: 276.1230. Found 276.1230.
6.9 Hz, 2H), 1.44 – 1.40 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H),
1.32 (dq, J = 6.9, 3.4 Hz, 4H), 0.89 (t, J = 6.9 Hz, 3H). 13
C
NMR (150 MHz, CDCl3)δ 165.0, 163.9, 136.0, 125.9,
2-Methyl 1-phenyl indolizine-1,2-dicarboxylate (5ea)
123.1, 122.2, 120.6, 116.5, 113.6, 103.0, 65.4, 60.1, 31.6,
9
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10.1002/adsc.202000103
Advanced Synthesis & Catalysis
28.7, 25.8, 22.6, 14.5, 14.1. HRMS (ESI-TOF) m/z: 1H NMR (600 MHz, CDCl3) δ 8.42 (d, J = 4.2 Hz, 1H),
[M+H]+ calcd. for C18H24NO4: 318.1700. Found: 318.1699.
7.49 (td, J = 7.8, 1.8 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.11
(dd, J = 7.0, 5.3 Hz, 1H), 7.05 (d, J = 2.9 Hz, 1H), 6.46 (d,
J = 2.9 Hz, 1H), 4.21 (s, 1H), 4.15 – 4.09 (m, 2H), 1.36 (s,
3H), 1.25 (t, J = 7.1 Hz, 3H), 1.20 (s, 9H), 1.02 (s, 9H). 13C
NMR (150 MHz, CDCl3) δ 185.9, 170.9, 155.0, 148.7,
147.5, 146.4, 144.5, 142.7, 135.6, 123.3, 122.7, 63.0, 61.2,
42.5, 35.0, 34.9, 29.4, 29.1, 24.9, 14.3. HRMS (ESI-TOF)
m/z: [M+H]+ calcd. for C24H34NO3: 384.2533. Found:
384.2532.
2-Allyl 1-ethyl indolizine-1,2-dicarboxylate (5bf)
(Eluent: ethyl acetate/petroleum ether = 1/3, v/v); 100%
1
yield (Yellow oil, 27 mg). H NMR (600 MHz, CDCl3) δ
8.12 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 6.9 Hz, 1H), 7.63 (s,
1H), 7.04 (dd, J = 9.3, 6.9 Hz, 1H), 6.73 (t, J = 6.8 Hz, 1H),
6.08 – 6.00 (m, 1H), 5.41 (dd, J = 17.2, 1.5 Hz, 1H), 5.27
(dd, J = 10.4, 1.3 Hz, 1H), 4.82 (dt, J = 5.7, 1.3 Hz, 2H),
4.37 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). 13C NMR
(150 MHz, CDCl3) δ 164.5, 163.9, 136.1, 132.3, 125.9,
123.2, 121.7, 120.6, 118.4, 116.9, 113.7, 103.1, 65.8, 60.1,
14.5. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C15H16NO4: 274.1074. Found: 274.1073.
Pd-catalyzed arylation of C3-iodo indolizines 4ba with
aryl boronic acid for the product 8: A Sealed tube was
loaded with Pd(OAc)2 (0.01 mmol, 2.3 mg), KOAc (0.4
mmol, 39.2 mg), 1-ethyl 2-methyl 3-iodoindolizine-1,2-
dicarboxylate (4ba, 0.2 mmol, 74.6 mg), aryl boronic acid
(0.3 mmol), and 1 mL NMP. The reaction mixture was
stirred in oil bath at 100 °C for 4 h. After completion of the
reaction, the reaction mixture was diluted with EtOAc, and
washed with brine (20 mL). Then, the mixture was
extracted with EtOAc (15 mL×3), and the combined
organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. The remaining crude product was
then purified through column chromatography using silica
gel (EtOAc/petroleum ether = 1/5) to produce 8a as a
yellow solid with a 76% yield (49 mg).
1-Ethyl 2-phenyl indolizine-1,2-dicarboxylate (5bg)
(Eluent: ethyl acetate/petroleum ether = 1/4, v/v); 100%
yield (Yellow solid. m.p. 77-78 oC, 31 mg). 1H NMR (600
MHz, CDCl3) δ 8.17 (d, J = 9.2 Hz, 1H), 7.99 (d, J = 5.9
Hz, 1H), 7.83 (s, 1H), 7.44 (t, J = 7.8 Hz, 2H), 7.29 (d, J =
8.4 Hz, 2H), 7.28 – 7.25 (m, 1H), 7.12 – 7.07 (m, 1H), 6.78
(t, J = 6.8 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1
Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 163.9, 163.1,
151.0, 136.3, 129.5, 126.0, 125.8, 123.4, 121.7, 120.8,
120.7, 117.8, 113.9, 103.5, 60.3, 14.5. HRMS (ESI-TOF)
m/z: [M+H]+ calcd. for C18H16NO4: 310.1074. Found:
310.1073.
1-Ethyl 2-methyl 3-phenylindolizine-1,2-dicarboxylate
(8a)
(Eluent: ethyl acetate/petroleum ether = 1/5, v/v); 76%
o
1
yield (Yellow solid. m.p. 95-96 C, 49 mg). H NMR (600
MHz, CDCl3) δ 8.24 (dd, J = 9.1, 1.2 Hz, 1H), 8.04 (dd, J =
7.1, 1.2 Hz, 1H), 7.51 – 7.48 (m, 4H), 7.45 (dd, J = 5.8, 2.8
Hz, 1H), 7.10 (ddd, J = 9.3, 6.5, 1.2 Hz, 1H), 6.72 – 6.68
(m, 1H), 4.37 (d, J = 7.2 Hz, 2H), 3.80 (s, 3H), 1.38 (t, J =
7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 167.0, 163.9,
135.4, 130.0, 129.2, 129.1, 129.0, 125.0, 123.6, 122.1,
120.5, 113.6, 102.2, 60.0, 52.5, 14.6. HRMS (ESI-TOF)
m/z: [M+H]+ calcd. for C19H18NO4: 324.1236. Found:
324.1244.
2-Benzyl 1-ethyl indolizine-1,2-dicarboxylate (5bh)
(Eluent: ethyl acetate/petroleum ether = 1/4, v/v); 90%
o
1
yield (Yellow solid. m.p. 82-83 C, 29 mg). H NMR (600
MHz, CDCl3) δ 8.10 (d, J = 9.2 Hz, 1H), 7.89 (d, J = 7.5
Hz, 1H), 7.61 (s, 1H), 7.45 (d, J = 7.4 Hz, 2H), 7.37 (t, J =
7.4 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H), 7.06 – 7.00 (m, 1H),
6.70 (t, J = 6.8 Hz, 1H), 5.36 (s, 2H), 4.32 (q, J = 7.1 Hz,
2H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3)
13C NMR (150 MHz, CDCl3) δ 164.5, 163.8, 136.0, 128.5,
128.3, 128.2, 125.8, 123.1, 121.5, 120.5, 117.0, 113.6,
103.1, 66.8, 60.0, 14.4. HRMS (ESI-TOF) m/z: [M+H]+
calcd. for C19H18NO4: 324.1230. Found: 324.1230.
1-Ethyl 2-methyl 3-(4-methoxyphenyl)indolizine-1,2-
dicarboxylate (8b)
(Eluent: ethyl acetate/petroleum ether = 1/5, v/v); 42%
yield (Yellow oil, 30 mg). H NMR (600 MHz, CDCl3) δ
Free radical trapping products 7a: A sealed tube was
loaded with I2 (1.2 mmol, 304.8 mg), CsOAc (2.4 mmol,
460.7 mg), BHT (0.6 mmol ， 132.2mg), ethyl 2-
pyridylacetate (1b, 0.3 mmol, 49.6 mg), methyl acrylate
(2a, 0.6 mmol, 51.6 mg), and 1 mL DCE. The reaction
mixture was stirred in oil bath at 90 °C for 11 h. After
completion of the reaction, the reaction mixture was diluted
with EtOAc, and washed with 10% Na2S2O3 solution (50
mL). Then, the mixture was extracted with EtOAc (20
mL×3), and the combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. The remaining
crude product was then purified through column
chromatography using silica gel (EtOAc/petroleum ether =
1/10) to produce 7a as a yellow oil with a 45% yield (38
mg).
1
8.22 (d, J = 9.1 Hz, 1H), 8.00 – 7.95 (m, 1H), 7.42 (d, J =
8.7 Hz, 2H), 7.08 (ddd, J = 9.0, 6.5, 1.1 Hz, 1H), 7.03 –
6.98 (m, 2H), 6.68 (td, J = 6.8, 1.3 Hz, 1H), 4.36 (q, J = 7.2
Hz, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H).
13C NMR (150 MHz, CDCl3) δ 167.1, 164.0, 160.2, 135.2,
131.5, 125.0, 123.6, 123.4, 121.8, 121.0, 120.4, 114.6,
113.4, 102.0, 60.0, 55.4, 52.5, 14.6. HRMS (ESI-TOF) m/z:
[M+H]+ calcd. for C20H20NO5: 354.1341. Found: 354.1344.
1-ethyl
2-methyl
3-(4-fluorophenyl)indolizine-1,2-
dicarboxylate (8c)
(Eluent: ethyl acetate/petroleum ether = 1/5, v/v); 62%
o
1
yield (Yellow solid. m.p. 115-116 C, 42 mg). H NMR
(600 MHz, CDCl3) δ 8.23 (d, J = 9.1 Hz, 1H), 7.95 (d, J =
10
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000103
Advanced Synthesis & Catalysis
7.1 Hz, 1H), 7.48 (dd, J = 8.6, 5.3 Hz, 2H), 7.19 (t, J = 8.6 [4] K. M. Dawood, H. Abdel-Gawad, M. Ellithey, H.A.
Hz, 2H), 7.11 (ddd, J = 9.1, 6.6, 1.1 Hz, 1H), 6.72 (td, J =
6.9, 1.4 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H),
1.38 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
166.9, 164.0, 163.9, 162.3, 135.3, 132.2, 132.1, 125.0,
123.9, 123.7, 123.4, 122.3, 120.5, 116.5, 116.4, 113.7,
102.3, 60.1, 52.5, 14.6. HRMS (ESI-TOF) m/z: [M+H]+
calcd. for C19H17FNO4: 342.1142. Found: 342.1136.
Mohamed, B. Hegazi, Arch. Pharm. Chem. Life Sci.
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J. Wilson, F. U. Axe, T. K. Jones, Bioorg. Med. Chem.
Lett. 2003, 13, 1767-1770.
[6] T. Weide, L. Arve, H. Prinz, H. Waldmann, H. Kessler,
1-ethyl
2-methyl
3-(thiophen-2-yl)indolizine-1,2-
Bioorg. Med. Chem. Lett. 2006, 16, 59-63.
dicarboxylatec (8d)
[7] S. Teklu, L.-L. Gundersen, T. Larsen, K. E. Malterudb,
F. Risea, Bioorg. Med. Chem. 2005, 13, 3127-3139.
(Eluent: ethyl acetate/petroleum ether = 1/5, v/v); 68%
o
1
yield (Yellow solid. m.p. 109-110 C, 45 mg). H NMR [8] W. Huang, T. Zuo, H. Jin, Z. Liu, Z. Yang, X. Yu, L.
(600 MHz, CDCl3) δ 8.23 (dd, J = 9.1, 1.3 Hz, 1H), 8.19 –
8.15 (m, 1H), 7.50 (dd, J = 5.2, 1.2 Hz, 1H), 7.27 (dt, J =
4.2, 2.1 Hz, 1H), 7.17 (dd, J = 5.2, 3.6 Hz, 1H), 7.13 (ddd,
J = 9.1, 6.6, 1.1 Hz, 1H), 6.76 (td, J = 6.8, 1.4 Hz, 1H),
4.35 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.37 (t, J = 7.1 Hz,
3H). 13C NMR (150 MHz, CDCl3) δ 166.6, 163.7, 135.7,
129.8, 128.8, 128.1, 127.8, 124.0, 123.9, 123.8, 120.3,
117.5, 113.9, 102.3, 60.1, 52.6, 14.5. HRMS (ESI-TOF)
m/z: [M+Na]+ calcd. for C17H15NNaO4S: 352.0619. Found:
352.0616.
Zhang, L. Zhang, Mol. Divers. 2013, 17, 221-243.
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Cazier, P. Blach, Tetrahedron 2005, 61, 3939-3945; c)
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adowski, J. Klajn, D. T. Gryko, Org. Biomol. Chem.
2016, 14, 7804-7828.
1-ethyl
dicarboxylate (8e)
2-methyl
3-(furan-2-yl)indolizine-1,2-
[11] a) A. E. Tschitschibabin, Ber. Dtsch. Chem. Ges. 1927,
60, 1607- 1617. b) J. Hurst, T. Melton, D. G. Wibberley,
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(Eluent: ethyl acetate/petroleum ether = 1/5, v/v); 65%
yield (Yellow oil, 41 mg). H NMR (600 MHz, CDCl3) δ
8.43 (d, J = 7.1 Hz, 1H), 8.23 (d, J = 9.1 Hz, 1H), 7.56 (d, J
1
= 1.8 Hz, 1H), 7.16 – 7.11 (m, 1H), 6.83 – 6.77 (m, 1H), [12] a) F. Li, J. Chen, Y. Hou, Y. Li, X.-Y. Wu, X. Tong,
6.66 (d, J = 3.4 Hz, 1H), 6.53 (dd, J = 3.5, 1.9 Hz, 1H),
4.35 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 1.37 (t, J = 7.1 Hz,
3H). 13C NMR (150 MHz, CDCl3) δ 166.8, 163.6, 143.6,
142.9, 135.7, 125.2, 124.1, 122.6, 120.3, 115.4, 114.0,
111.6, 110.5, 102.5, 60.1, 52.7, 14.5. HRMS (ESI-TOF)
m/z: [M+Na]+ calcd. for C17H15NNaO5: 336.0848. Found:
336.0844.
Org. Lett. 2015, 17, 5376-5379; b) J. Brioche, C. Meyer,
J. Cossy, Org. Lett. 2015, 17, 2800-2803; c) C. Wang,
H. Hu, J. Xu, W. Kan, RSC Adv. 2015, 5, 41255-41258;
d) X. Zhang, G.-P. Lu, Z.-B. Xu, C. Cai, ACS Sustain.
Chem. Eng. 2017, 5, 9279-9285.
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Financial support from the Natural Science Foundation of
Guizhou
Province
of
China
(QKHJC[2017]1117,
QKHJC[2018]1109, QKHPTRC[2017]5718), Chinese Guizhou
Provincial Engineering Research Center for Natural Drugs and
the West Light Foundation of The Chinese Academy of Sciences is
acknowledged.
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10.1002/adsc.202000103
Advanced Synthesis & Catalysis
FULL PAPER
Iodine Mediated Base-Controlled Regio-Selective
Annulation of 2-(Pyridin-2-yl)acetate derivatives
with Acrylic Esters for the Synthesis of Indolizines
Adv. Synth. Catal. Year, Volume, Page – Page
Youlai Fang, Fei Li, Yuzhu Yang*, Xiaolan Liu,
Weidong Pan*
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