Iodine-Mediated Oxidative Cyclization of 2-(Pyridin-2-yl)acetate Derivatives with Alkynes: Condition-Controlled Selective Synthesis of Multisubstituted Indolizines

Article abstract of DOI:10.1055/s-0039-1690229

An iodine-mediated oxidative cyclization reaction between 2-(pyridin-2-yl)acetate derivatives and different alkynes has been developed, which provides regioselective and chemoselective syntheses of multiply substituted indolizines under modified reaction

Full text of DOI:10.1055/s-0039-1690229

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–L
paper
A
en
L. He et al.
Paper
Synthesis
Iodine-Mediated Oxidative Cyclization of 2-(Pyridin-2-yl)acetate
Derivatives with Alkynes: Condition-Controlled Selective Synthesis
of Multisubstituted Indolizines
Lisheng Hea,b,c
Yuzhu Yang*a,b,c
Xiaolan Liua,b,c
Guangyan Lianga,b,c
Chunyan Lia,b,c
Daoping Wanga,b,c
Weidong Pan*a,b,c
EWG
25 examples
29–94%
R1 = Ar, COOEt
EWG = COOR, COMe
R1
H
0
0
0
0-
0
0
0
2-9
5
0
5-7
9
5
2
N
I2 (2 equiv), dppe (20 mol%), Na2CO3 (2 equiv)
DMF, N2, 160 °C, 4 h
R1
EWG
12 examples
25–52%
R2
R3
R3
N
EWG
I2 (1 equiv), Na2CO3 (2 equiv)
DMA, N2, 160 °C, 4 h
R
2 = Ar, R3 = CHO, COOEt
EWG = COOR
N
R2
a College of Pharmacy, Guizhou Medical University, 9 Beijing
Road, Guiyang, Guizhou 550004, P. R. of China
b State Key Laboratory of Functions and Applications of Medicinal
Plants, Guizhou Medical University, 3491 Baijin Road, Guiyang
550014, P. R. of China
c The Key Laboratory of Chemistry for Natural Products of
Guizhou Province and Chinese Academy of Sciences, 3491 Baijin
Road, Guiyang 550014, P. R. of China
EWG
7 examples
57–76%
R4
CHO
N
R
4 = aryl, alkyl
I2 (3.5 equiv), dppe (20 mol%), CuI (2 equiv)
Na2CO3 (2 equiv), DMF, N2, 160 °C, 4 h
EWG = COOEt
R4
O
yangyuzhu15@126.com
wdpan@163.com
Received: 20.08.20109
Accepted after revision: 07.10.2019
Published online: 29.10.2019
and Adimurthy13 (Scheme 1a). However, only terminal
alkynes were investigated and no issue of regioselectivity or
chemoselectivity was discussed in the above reports. Here-
in we report our results of the condition-controlled selec-
tive syntheses of multiply substituted indolizines from 2-
(pyridin-2-yl)acetates and alkynes. Under iodine-promoted
reaction conditions, terminal alkynes and 3-phenylpropio-
late could react with 2-(pyridin-2-yl)acetates to give substi-
tuted indolizines regioselectively via radical process. Addi-
tionally, 3-phenylpropiolaldehyde could react with 2-(pyri-
din-2-yl)acetates to chemoselectively give C3-acylated
indolizines via a condensation/intramolecular cyclization
pathway, or give C2-carbaldehyde substituted indolizines
via an annulation pathway (Scheme 1b).
DOI: 10.1055/s-0039-1690229; Art ID: ss-2019-f0459_op
Abstract An iodine-mediated oxidative cyclization reaction between
2-(pyridin-2-yl)acetate derivatives and different alkynes has been devel-
oped, which provides regioselective and chemoselective syntheses of
multiply substituted indolizines under modified reaction conditions.
Plausible mechanisms have been proposed to explain the selective syn-
theses of indolizines. This protocol can be also applied to the stepwise
synthesis of 2,2′-biindolizines.
Key words indolizines, iodine, radical process, regioselective, chemo-
selective
As N-fused heterocycles, indolizines are ubiquitous scaf-
folds found in many natural products and bioactive com-
pounds.1 Functionalized indolizines have found wide appli-
cations in pharmaceuticals with several biological activi-
ties, such as antitubercular,2 anti-inflammatory,3
antifungal,4 anticancer,5 antioxidant,6 and usage as molecu-
lar probes.7 Accordingly, the development of efficient meth-
ods for the generation of indolizines continues to receive
considerable attention in organic chemistry over the years.
The majority of the approaches for indolizine synthesis in-
clude 1,3-dipolar cycloaddition,8 intramolecular cyclization
of pyridine derivatives with alkynes,9 and intermolecular
cyclization of 2-alkylpyridine derivatives with alkenes.10 It
is noteworthy that the reaction of terminal alkynes with 2-
(pyridin-2-yl)acetate derivatives for the synthesis of 1,3-
disubstituted indolizines under metal catalysis or in the
presence of iodine have been reported by Agrawal,11 Lei,12
(a) Previous work
COOEt
Metal or Iodine
R
COOEt
+
N
N
R = aryl, alkyl
R
(b) This work
COOEt
COOEt
COOEt
R1
H
Ar
COOEt
COOEt
I2, ligand
base, solvent
N
N
I2, base
solvent
N
N
R1
Ar
regioselective
R1 = aryl, COOEt
COOEt
COOEt
R2
CHO
Ar
CHO
CHO
N
COOEt
CuI, I2, ligand,
base, solvent
I2, base
solvent
N
R2
Ar
O
R2 = aryl, alkyl
chemoselective
Scheme 1 Synthesis of indolizines via cyclization of 2-(pyridin-2-yl)-
acetate derivatives and alkynes
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–L
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
L. He et al.
Paper
Synthesis
We performed the reaction of ethyl 2-(pyridin-2-yl)ace-
tate (1a) and phenylacetylene (2a) as model substrates for
optimization. It was found that the combination of iodine
and dppe in the presence of Na2CO3 afforded the highest
93% yield after stirring in DMF at 160 °C for 4 hours (Table 1,
entry 1). By decreasing or increasing the amount of iodine,
the yield of the desired product dropped. No product was
detected in the absence of iodine (entries 2–4). The results
revealed that iodine was necessary for initiating the reac-
tion. Without the addition of dppe, the yield decreased to
69%, while increasing the amount of dppe to 40 mol% deliv-
ered the product in slightly decreased yield (entries 5, 6).
After screening other phosphine ligands as well as nitrogen
ligands, it was found that dppe was still the best choice (en-
tries 7–14). Only trace amount of product could be detected
without the addition of Na2CO3, while decreasing or in-
creasing the amount of Na2CO3 leads to no better yields (en-
tries 15–17). Furthermore, other bases such as Li2CO3,
K2CO3, or Cs2CO3 led to decreased yields (entries 18–20). In
spite of DMF, other solvents like NMP, DMA, and DMSO
could also be used for this reaction, albeit affording the
product in lower yields (entries 21–23). After the investiga-
tion of concentration of this reaction, 0.1 M concentration
could generate the product 3a with the highest yield (en-
tries 24, 25). Subsequently, the reaction temperature, the
reaction time, and the atmosphere were investigated. It was
found that decreasing the temperature to 140 °C could not
increase the yield (entry 26), shortening the reaction time
to 1 hour or 2 hours, and prolonging the reaction time to 8
hours resulted in reduced yields (entry 27–29). The ratio of
the reactants was also examined and the results indicated
that the best case is the ratio of 1a and 2a equals to 0.5 (en-
tries 30, 31). Finally the yield dropped to 67% when the re-
action was performed under air atmosphere (entry 32).
With the optimal reaction conditions in hand, we next
extended the scope of 2-(pyridin-2-yl)acetate derivatives
(Scheme 2). Different 2-pyridyl esters (COOMe, COOiPr,
COOtBu, and COOnBu groups) reacted well with phenylacet-
ylene (2a) to afford the corresponding indolizines 3b–e in
moderate to good yields. When 1-(pyridin-2-yl)propan-2-
one was used under these reaction conditions, the product
3f was isolated in only 38% yield. Ethyl 2-(6-methylpyridin-
2-yl)acetate could react with phenylacetylene to give the
product 3g in 74% yield. Ethyl 2-(5-methylpyridin-2-yl)-
acetate and ethyl 2-(5-bromopyridin-2-yl)acetate are also
work well under these conditions to afford the correspond-
ing products 3h in 60% yield and 3i in 48% yield.
and NO2) at the para-position in phenylacetylene gave the
products 4c–g in moderate to good yields (69–94%). Fur-
thermore, arylalkynes with electron-donating groups (such
as Me, Bu, OMe, and Ph) at the para-position proceeded
smoothly to deliver the desired products 4h–k in moderate
t
Table 1 Optimization of Reaction Conditionsa
COOEt
standard conditions
I2 (2 equiv)
N
dppe (20 mol%)
Na2CO3 (2 equiv)
COOEt
+
N
DMF (0.1 M), N2
160 °C , 4 h
1a
2a
3a
Entry
Deviation from the standard conditions
Yield (%)b of 3a
1
2
no change
93
0
without I2
3
1 equiv I2
45
64
69
90
69
85
78
83
69
67
61
68
4
4
3 equiv I2
5
without dppe
6
40% dppe
7
PPh3 instead of dppe
dppp instead of dppe
dppb instead of dppe
DPEphos instead of dppe
P(4-MeOC6H4)3 instead of dppe
P(4-FC6H4)3 instead of dppe
1,10-phenanthroline instead of dppe
2,2′-bipyridine instead of dppe
without Na2CO3
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
1 equiv Na2CO3
46
70
51
54
47
72
64
25
64
80
35
72
75
74
47
60
67
3 equiv Na2CO3
Li2CO3 instead of Na2CO3
K2CO3 instead of Na2CO3
Cs2CO3 instead of Na2CO3
DMA instead of DMF
NMP instead of DMF
DMSO instead of DMF
0.2 M instead of 0.1 M
0.07 M instead of 0.1 M
140 °C instead of 160 °C
1 h instead of 4 h
2 h instead of 4 h
Subsequently, we investigated the scope of alkynes un-
der the optimized conditions (Scheme 3). Most of the ter-
minal alkyne substrates could proceed smoothly under the
conditions to give the corresponding products in moderate
yields. The ortho-fluorinated product 4a was isolated in
only 54% yield possibly due to the steric hindrance effect.
Notably, electron-withdrawing groups (such as F, CF3, Cl, Br,
8 h instead of 4 h
ratio of 1a/2a = 1:1
ratio of 1a/2a = 2:1
under air atmosphere
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), I2 (0.4 mmol), dppe
(0.04 mmol), Na2CO3 (0.4 mmol) in DMF (2 mL) at 160 °C for 4 h.
b Isolated yield.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–L

C
L. He et al.
Paper
Synthesis
sired products 5i–k. 3-(Thiophen-2-yl)propiolaldehyde
could also be employed in this reaction to give the corre-
sponding product 5l, but in only 25% yield. However, sub-
strates with substituents on the pyridine ring are not com-
patible with the reaction conditions: only trace amounts of
products were detected. When hept-2-ynal or ethyl hept-2-
ynoate were subjected to this reaction, no product was iso-
lated.
I2 (2 equiv)
dppe (20 mol%)
Na2CO3 (2 equiv)
COOR
COOR
COOEt
Ph
+
N
N
DMF (0.1 M), 160 °C
N2, 4 h
Ph
2a
COOMe
1
3
COOiPr
COOtBu
N
N
N
N
Based upon the above conditions for the annulation re-
action involving 3-phenylpropiolaldehyde, the addition of
copper iodide and dppe could switch the product to C3-ac-
ylated indolizines 6a in 76% yield (Scheme 5; for detailed
optimization, see Table S2 in SI). Thus, a condition-con-
trolled chemoselective synthesis of C2-carbaldehyde-sub-
stituted indolizines and C3-acylated indolizines has been
established. Substrates bearing both electron-withdrawing
groups (F and Cl) and an electron-donating group (OMe) at
the para-position were compatible with the reaction condi-
tions, delivering the indolizine products 6b–d in 54–71%
yields. Moreover, 3-(thiophen-2-yl)propiolaldehyde and
hept-2-ynal could also react in this reaction, affording the
corresponding product 6e in 57% yield and 6f in 59% yield,
respectively. Ethyl 2-(5-methylpyridin-2-yl)acetate deliv-
3a, 93%
3b, 65%
3c, 69%
3d, 66%
O
COOEt
COOnBu
COOEt
COOEt
N
N
N
N
N
Br
3h, 60%
3g, 74%
3i, 48%
3e, 73%
3f, 38%
Scheme 2 Substrate scope of 2-(pyridin-2-yl)acetates 1. Reagents and
conditions: 1 (0.2 mmol), 2a (0.4 mmol), I2 (0.4 mmol), dppe (0.04
mmol), Na2CO3 (0.4 mmol), in DMF (2 mL) at 160 °C for 4 h. Isolated
yields are shown.
yields (60–78%). The terminal alkynes containing thio-
phene moiety or pyridine moiety could also afford the cor-
responding products 4l–o in 43–60% yields. When ethyl
propiolate was subjected to the reaction conditions, the de-
sired product 4p was isolated in only 29% yield, and the
structure was confirmed by single-crystal X-ray diffraction
(see ORTEP diagram in SI).
I2 (2 equiv)
COOEt
dppe (20 mol%)
Na2CO3 (2 equiv)
COOEt
R
N
N
DMF (0.1 M), 160 °C
N2, 4 h
R
It is noteworthy that in this reaction system, internal
alkynes such as ethyl phenylpropynoate could also work
under modified reaction conditions to give the regiospecific
products in moderate yields (Scheme 4). 3-Phenylpropiolal-
dehyde was chosen as model substrate for optimization (Ta-
ble S1 in SI). The amount of iodine was investigated and one
equivalent of iodine showed better yield (Table S1, entries
1–5). It is gratifying that the yield of product 5h increased
to 52% when the reaction was conducted in DMA solvent
without ligand (entry 7). Other solvents such as NMP and
DMSO do not help to increase the yield (entries 8, 9). After
the optimization process, we began to extend the substrate
scope of this reaction. Various 2-alkylpyridine derivatives
bearing different ester groups (such as COOEt, COOMe,
COOiPr, COOtBu, and COOnBu) were well tolerated under the
optimized reaction conditions and the corresponding indol-
izine derivatives 5a–e were obtained in 31–47% yields. The
structure of 5a was confirmed by single-crystal X-ray dif-
fraction (see ORTEP diagram in SI). In addition, substrates
with both electron-withdrawing group (Cl) and electron-
donating group (OMe) at the para-position reacted under
these conditions to afford the products 5f in 44% yield and
5g in 33% yield. 3-Phenylpropiolaldehyde also worked well
in this reaction to give the annulation product 5h with C2-
carbaldehyde group in 52% yield. Substrates with electron-
withdrawing groups (F and Cl) and electron-donating
groups group (OMe) at the para-position afforded the de-
2
1a
4
COOEt
COOEt
N
COOEt
F
COOEt
N
N
N
F
CF3
F
4c, 69%
4a, 54%
4b, 71%
COOEt
4d, 77%
COOEt
COOEt
COOEt
N
N
N
N
Cl
Br
NO2
4e, 77%
4f, 77%
4g, 94%
4h, 75%
COOEt
COOEt
COOEt
N
COOEt
N
N
N
S
O
Ph
4k, 72%
4l, 59%
4i, 78%
4j, 60%
COOEt
COOEt
COOEt
COOEt
S
N
N
N
N
COOEt
N
N
4p, 29%
4m, 60%
4n, 51%
4o, 43%
Scheme 3 Substrate scope of alkynes 2. Reagents and conditions: 1a
(0.2 mmol), 2 (0.4 mmol), I2 (0.4 mmol), dppe (0.04 mmol), Na2CO3
(0.4 mmol) in DMF (2 mL) at 160 °C for 4 h. Isolated yields are shown.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–L

D
L. He et al.
Paper
Synthesis
the coupling product 9 was isolated in 49% yield. Then 18O-
labeled water was added to the reaction of 1a with 3-phen-
ylpropiolaldehyde for the synthesis of C3-acylated indol-
izines. Product 6a′ with 18O in the carbonyl group was not
detected by using 18O2 as atmosphere in the reaction
(Scheme 7, eq 2). The products 6a and 6a′ were detected by
LC–MS when the reaction was performed with the combi-
nation of DMF and H218O (Scheme 7, eq 3).
COOR1
R3
I
2 (1 equiv)
Na2CO3 (2 equiv)
R2
R3
+
COOR
N
N
N
1
DMA (0.1 M), 160 °C
N2, 4 h
R2
2
1
5
COOnBu
COOtBu
COOEt
COOiPr
COOEt
COOEt
COOEt
COOMe
COOEt
COOEt
N
N
N
N
On the basis of the above results and previous reports,15
a plausible mechanism of the regioselective annulation re-
action is proposed as shown in Scheme 8. In Path A, oxida-
tion of 1a by I2 generates the radical intermediate A, which
5a, 47%
5b, 31%
5e, 35%
5c, 37%
5d, 31%
COOEt
CHO
COOEt
CHO
COOEt
COOEt
COOEt
COOEt
COOEt
CHO
N
N
N
N
N
COOEt
dppe (20 mol%)
Na2CO3 (2 equiv)
Cl
F
Cl
O
I2 (3.5 equiv), CuI (2 equiv)
5j, 38%
5i, 38%
5h, 52%
5f, 44%
5g, 33%
N
R
CHO
+
COOEt
N
DMF (0.1 M), 160 °C
N2, 4 h
R
COOEt
CHO
1a
O
COOEt
6
COOEt
COOEt
2
COOEt
CHO
CHO
Br
CHO
CHO
N
N
N
N
N
COOEt
COOEt
COOEt
S
N
N
N
O
5o, trace
5n, trace
5l, 25%
5m, trace
5k, 36%
O
O
O
F
Cl
COOEt
COOEt
COOEt
CHO
6a, 76%
6b, 60%
6c, 71%
COOEt
N
N
COOEt
COOEt
C4H9
5q, trace
C4H9
5p, trace
N
N
N
n-C4H9
Scheme 4 Substrate scope of 2-(pyridin-2-yl)acetates 1 and internal
alkynes 2. Reagents and conditions: 1 (0.2 mmol), 2 (0.4 mmol), I2 (0.2
mmol), Na2CO3 (0.4 mmol) in DMF (2 mL) at 160 °C for 4 h. Isolated
yields are shown.
O
O
O
O
S
6f, 59%
6d, 54%
6e, 57%
COOEt
COOEt
COOEt
N
N
O
N
Br
n-C4H9
ered the expected product 6g in 54% yield, while ethyl 2-(6-
methylpyridin-2-yl)acetate and ethyl 2-(5-bromopyridin-
2-yl)acetate did not react: only trace amounts of products
were detected.
O
O
6g, 54%
6h, trace
6i, trace
Scheme 5 Substrate scope of ynals 2. Reagents and conditions: 1a (0.2
mmol), 2 (0.4 mmol), I2 (0.7 mmol), CuI (0.4 mmol), dppe (0.04
mmol), Na2CO3 (0.4 mmol), in DMF (2 mL) at 160 °C for 4 h. Isolated
yields are given.
To the best of our knowledge, there is no report describ-
ing the preparation of 2,2′-biindolizines, while only one pa-
per from You’s group reported the synthesis of 3,3′-biindol-
izines via palladium-catalyzed homo-coupling reaction.14
The demonstration of this protocol for the synthesis of 2,2′-
biindolizines is shown in Scheme 6. The reaction of 1a with
1,4-diphenylbuta-1,3-diyne could proceed under the stan-
dard conditions smoothly to generate 7a in 38% yield. The
reaction of 7a with 1a afforded 2,2′-biindolizine 8a in 66%
yield. When the reaction was performed with the aliphatic
diyne, dodeca-5,7-diyne, under the same conditions, the
corresponding product was isolated with 7b in 35% yield
and 8b in 28% yield.
In order to elucidate the mechanism of the reaction,
control experiments were investigated (Scheme 7). First,
radical trapping experiment (Scheme 7, eq 1) was per-
formed in the presence of 2,2,6,6-tetramethylpiperidinyl-
oxyl (TEMPO). The addition of 2 equivalents of TEMPO led
to the oxidative process being remarkably suppressed and
I
2 (2 equiv)
dppe (20 mol%)
Na2CO3 (2 equiv)
COOEt
+
COOEt
R
R
R
N
N
DMF (0.1 M), 160 °C
N2, 4 h
R
1a
7
R = Ph, 7a, 38%
R = n-C4H9, 7b, 35%
I2 (4 equiv)
dppe (40 mol%)
Na2CO3 (4 equiv)
COOEt
R
COOEt
R
N
COOEt
R
+
N
N
DMF (0.05 M), 160 °C
N2, 4 h
N
R
COOEt
7
1a
8
R = Ph, 8a, 66%
R = n-C4H9, 8b, 28%
Scheme 6 Demonstration of this protocol for the stepwise synthesis of
2,2′-biindolizines 8
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–L

E
L. He et al.
Paper
Synthesis
reacts with ethyl propiolate to afford the radical intermedi-
ate B. Subsequently, intramolecular cyclization would gen-
erate the intermediate C, which undergoes oxidation to
form the intermediate D in the presence of I2. Further
deprotonation and dehydrogenative aromatization would
give the final product 4p. In Path B, the imine–enamine tau-
tomerism would generate the intermediate F under basic
conditions. Oxidation of the intermediate F would produce
nitrogen radical in the intermediate G, which reacts with
ethyl 3-phenylpropiolate to give the intermediate H fol-
lowed by intramolecular ring closure to afford the interme-
diate I. Similar transformation involving oxidation, depro-
tonation, and dehydrogenative aromatization would pro-
duce the final product 5a.
For the C3-acylated product from 3-phenylpropiolalde-
hyde via condensation/intramolecular cyclization sequence,
a plausible mechanism is proposed as shown in Scheme 9
based on the results from control experiments and previous
reports.16 The initial condensation of starting materials
would generate the intermediate L, followed by the com-
plexation with iodine to form the iodonium complex M.
The intramolecular cyclization would produce the interme-
diate N. Isomerization of the intermediate N would gener-
ate the intermediate O, which reacts with water to form the
intermediate P. Subsequent deprotonation, deiodination,
and deprotonation would generate the final product.
TEMPO (2 equiv)
I2 (2 equiv)
dppe (20 mol%)
COOEt
N
Ph
O
+
9, 49%
COOEt
N
(1)
(2)
N
Na2CO3 (2 equiv)
DMF,160 °C, 4 h
2a
1a
CuI (2 equiv)
dppe (20 mol%)
Na2CO3 (2 equiv)
COOEt
Ph
COOEt
+
N
N
+
COOEt
Ph
CHO
N
I2 (3.5 equiv)
DMF, 18O2, 160 °C, 4 h
Ph
18O
1a
O
6a', 0%
COOEt
6a, 72%
COOEt
CuI (2 equiv)
dppe (20 mol%)
Na2CO3 (2 equiv)
(3)
+
+
N
N
Ph
CHO
COOEt
N
I2 (3.5 equiv)
DMF, H218O, 160 °C, 4 h
Ph
Ph
1a
O
18O
6a', 32%
6a, 34%
Scheme 7 Control experiments
O
H
I2
base
COOEt
COOEt
+
Ph
COOEt
N
N
N
– H2O
EtOOC
1a
H
COOEt
COOEt
Ph
I
N
N
Ph
COOEt
N
M
L
A
EtOOC
C
COOEt
I2
I–
H
B
SET, – e–
I–
COOEt
COOEt
COOEt
COOEt
SET
Path A:
H2O
N
N
N
N
I2
– H+
H
I
I
I
I
COOEt
N
OH2
Ph
OH
Ph
COOEt
N
Ph
Ph
COOEt
N
– H+
N
Q
P
O
EtOOC
1a
EtOOC
[O]
Path B:
– I–
E
D
imine–enamine
tautomerism
proton transfer
COOEt
COOEt
COOEt
N
– H+
N
N
H
COOEt
COOEt
N
N
F
Ph
Ph
O
OH
EtOOC
Ph
COOEt
I2
4p
5a
R
6a
SET, – e–
I–
Scheme 9 Plausible mechanism for product 6
[O]
Ph
COOEt
We also performed the reaction in gram scale to verify
the feasibility of this protocol (Scheme 10). When 4 mmol
2-(pyridin-2-yl)acetate was subjected to this reaction, 0.82
gram of the product 3a was isolated (78% yield).
N
COOEt
N
G
COOEt
Ph
COOEt
K
– H+
I2 (2 equiv)
COOEt
dppe (20 mol%)
Na2CO3 (2 equiv)
I–
I2
COOEt
+
COOEt
Ph
H
H
N
N
N
DMF, 160 °C
N2, 4 h
COOEt
N
COOEt
N
SET, – e–
Ph
Ph
2a
1
3a
Ph
Ph
COOEt
COOEt
COOEt
H
I
J
4 mmol, 0.66 g
8 mmol, 0.82 g
0.82 g, 78 % isolated yield
Scheme 8 Plausible mechanism for product 4 and 5
Scheme 10 Gram-scale synthesis of product 3a
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–L

F
L. He et al.
Paper
Synthesis
In summary, we have developed the iodine-mediated
condition-controlled oxidative cyclization for the selective
synthesis of indolizines. Regioselective annulation reaction
has been accomplished via carbon-radical or nitrogen-
radical initiated reaction pathways. Chemoselective synthe-
sis of C2-carbaldehyde substituted indolizines or C3-acylat-
ed indoliznes has been realized via different reaction path-
ways. More detailed mechanism investigation and applica-
tion of the reaction system to the synthesis of other
molecules are currently ongoing in our laboratory.
Isopropyl 3-Phenylindolizine-1-carboxylate (3c)13
[CAS Reg. No. 1795248-49-5]
Eluent: EtOAc/PE (1/20, v/v); yield: 38.2 mg (69%); yellow oil.
1H NMR (400 MHz, CDCl3):  = 8.27 (t, J = 7.5 Hz, 2 H), 7.54 (d, J = 7.7
Hz, 2 H), 7.49 (t, J = 7.6 Hz, 2 H), 7.39 (t, J = 7.3 Hz, 1 H), 7.32 (s, 1 H),
7.06 (dd, J = 9.1, 6.7 Hz, 1 H), 6.69 (t, J = 6.9 Hz, 1 H), 5.36–5.24 (m, 1
H), 1.41 (s, 3 H), 1.40 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 164.6, 136.2, 131.2, 129.0, 128.6,
127.9, 126.3, 123.3, 122.1, 120.2, 116.1 (d, J = 1.6 Hz), 112.5, 104.7,
66.6, 22.3.
HR-ESI-MS: m/z calcd for C18H17NO2 [M + H]+: 280.1332; found:
280.1342.
All reactions were performed under N2, unless otherwise stated. The
solvents were dried before use by standard procedures. Melting
points were measured with a WRX-4 melting point apparatus pur-
chased from Shanghai YICE Instrumental Company. 1H NMR and 13C
NMR spectra were recorded in CDCl3 on a 400 MHz, 500 MHz or 600
MHz instrument. All 1H NMR spectra were measured relative to the
signals for residual CHCl3 (7.26 ppm) and all 13C NMR spectral data
are reported relative to CDCl3 (77.16 ppm). HRMS data were recorded
on a micrOTOF instrument using ESI technique. All column chroma-
tography were performed using silica gel (200–300 microns). Unless
otherwise noted, commercially available chemicals were used as re-
ceived.
tert-Butyl 3-Phenylindolizine-1-carboxylate (3d)18
[CAS Reg. No. 1428552-42-4]
Eluent: EtOAc/PE (1/10, v/v); yield: 38.6 mg (66%); yellow oil.
1H NMR (400 MHz, CDCl3):  = 8.25 (dd, J = 15.8, 8.1 Hz, 2 H), 7.54 (d,
J = 7.6 Hz, 2 H), 7.49 (t, J = 7.5 Hz, 2 H), 7.40 (d, J = 7.3 Hz, 1 H), 7.28 (s,
1 H), 7.03 (dd, J = 9.1, 6.7 Hz, 1 H), 6.67 (t, J = 6.9 Hz, 1 H), 1.65 (s, 9 H).
13C NMR (100 MHz, CDCl3):  = 164.6, 135.9, 131.3, 129.0, 128.6,
127.9, 126.1, 123.2, 121.8, 120.1, 116.3, 116.3, 112.3, 105.9, 79.6, 28.6.
HR-ESI-MS: m/z calcd for C19H19NO2 [M + H]+: 294.1489; found:
294.1498.
Butyl 3-Phenylindolizine-1-carboxylate (3e)18
[CAS Reg. No. 1394827-53-2]
Products 3a–i, 4a–p; Typical Procedure for Ethyl 3-Phenylindol-
izine-1-carboxylate (3a)17
[CAS Reg. No. 93315-81-2]
Eluent: EtOAc/PE (1/20, v/v); yield: 42.6 mg (73%); yellow oil.
Under N2 atmosphere, ethyl 2-(pyridin-2-yl)acetate (1a; 33.0 mg, 0.2
mmol), phenylacetylene (2a; 40.9 mg, 0.4 mmol), I2 (101.5 mg, 0.4
mmol), dppe (15.9 mg, 0.04 mmol), and Na2CO3 (42.4 mg, 0.4 mmol)
were mixed in DMF (2 mL). The reaction tube was heated in an oil
bath at 160 °C for 4 h. After completion of the reaction, the reaction
mixture was washed with sat. aq Na2S2O3 and extracted with EtOAc (3
40 mL), dried (anhyd Na2SO4), and the solvent was removed under re-
duced pressure. The remaining crude product was then purified
through column chromatography using silica gel (EtOAc/PE 1/5, v/v)
to afford 3a as a dark green solid; yield: 49.3 mg (93%); mp 68–70 °C.
1H NMR (400 MHz, CDCl3):  = 8.27 (t, J = 7.7 Hz, 2 H), 7.54 (d, J = 7.7
Hz, 2 H), 7.49 (t, J = 7.5 Hz, 2 H), 7.39 (t, J = 7.3 Hz, 1 H), 7.31 (s, 1 H),
7.06 (dd, J = 9.1, 6.6 Hz, 1 H), 6.69 (t, J = 6.9 Hz, 1 H), 4.35 (t, J = 6.7 Hz,
2 H), 1.79 (pent, J = 6.9 Hz, 2 H), 1.52 (q, J = 7.5 Hz, 2 H), 1.00 (t, J = 7.4
Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 165.1, 136.2, 131.2, 129.0, 128.6,
128.0, 123.3, 122.2, 120.1, 116.1, 116.1, 112.5, 104.2, 63.4, 31.1, 19.4,
13.8.
HR-ESI-MS: m/z calcd for C19H19NO2 [M + H]+: 294.1489; found:
1H NMR (400 MHz, CDCl3):  = 8.28 (t, J = 7.9 Hz, 2 H), 7.54 (d, J = 7.7
Hz, 2 H), 7.49 (t, J = 7.6 Hz, 2 H), 7.39 (t, J = 7.3 Hz, 1 H), 7.31 (s, 1 H),
7.10–7.03 (m, 1 H), 6.69 (t, J = 6.9 Hz, 1 H), 4.40 (q, J = 7.2 Hz, 2 H),
1.43 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 165.0, 136.3, 131.2, 129.0, 128.6,
127.9, 123.3, 122.2, 120.1, 116.1, 116.0, 112.5, 104.2, 59.5, 14.6.
294.1496.
1-(3-Phenylindolizin-1-yl)ethanone (3f)19
[CAS Reg. No. 1126444-46-9]
Eluent: EtOAc/PE (1/10, v/v); yield: 17.6 mg (38%); pale yellow solid;
mp 132–134 °C.
1H NMR (600 MHz, CDCl3):  = 8.53 (dt, J = 9.0, 1.3 Hz, 1 H), 8.29 (dt,
J = 6.9, 1.1 Hz, 1 H), 7.56–7.53 (m, 2 H), 7.51 (dd, J = 8.6, 6.8 Hz, 2 H),
7.44–7.40 (m, 1 H), 7.19 (s, 1 H), 7.16 (ddd, J = 9.0, 6.6, 1.1 Hz, 1 H),
6.77 (td, J = 6.8, 1.4 Hz, 1 H), 2.56 (s, 3 H).
HR-ESI-MS: m/z calcd for C17H15NO2 [M + H]+: 266.1176; found:
266.1181.
Methyl 3-Phenylindolizine-1-carboxylate (3b)17
13C NMR (150 MHz, CDCl3):  = 193.1, 135.9, 131.1, 129.2, 128.7,
[CAS Reg. No. 947381-33-1]
128.2, 123.89, 123.2, 121.1, 116.5, 113.6, 113.5, 28.0.
HR-ESI-MS: m/z calcd for C16H13NO [M + H]+: 236.1070; found:
Eluent: EtOAc/PE (1/10, v/v); yield: 32.3 mg (65%); yellow solid; mp
111–113 °C.
1H NMR (400 MHz, CDCl3):  = 8.28 (t, J = 8.6 Hz, 2 H), 7.54 (d, J = 7.7
Hz, 2 H), 7.49 (t, J = 7.5 Hz, 2 H), 7.41 (d, J = 7.3 Hz, 1 H), 7.29 (s, 1 H),
7.07 (dd, J = 9.0, 6.7 Hz, 1 H), 6.70 (t, J = 6.9 Hz, 1 H), 3.92 (s, 3 H).
236.1074.
Ethyl 5-Methyl-3-phenylindolizine-1-carboxylate (3g)
13C NMR (100 MHz, CDCl3):  = 165.4, 136.4, 131.2, 129.0, 128.6,
128.0, 126.4, 123.3, 122.3, 120.1, 116.0, 112.6, 103.82, 50.9.
Eluent: EtOAc/PE (1/20, v/v); yield: 41 mg (74%); yellow solid; mp
115–117 °C.
HR-ESI-MS: m/z calcd for C16H13NO2 [M + H]+: 252.1019; found:
252.1028.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–L

G
L. He et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 8.27 (d, J = 9.0 Hz, 1 H), 7.39 (q, J = 6.4,
5.6 Hz, 5 H), 7.20 (s, 1 H), 7.00 (dd, J = 9.0, 6.8 Hz, 1 H), 6.45 (d, J = 6.7
Hz, 1 H), 4.38 (t, J = 7.1 Hz, 2 H), 2.12 (s, 3 H), 1.40 (t, J = 7.1 Hz, 3 H).
HR-ESI-MS: m/z calcd for C17H14FNO2 [M + H]+: 284.1081; found:
284.1093.
Ethyl 3-(4-Fluorophenyl)indolizine-1-carboxylate (4c)13
13C NMR (100 MHz, CDCl3):  = 165.0, 137.9, 136.1, 134.8, 131.1,
128.0, 127.2, 122.3, 118.8 (d, J = 2.0 Hz), 118.0, 114.2, 103.2, 59.4,
29.7, 22.9, 14.6.
[CAS Reg. No. 1621928-41-3]
Eluent: EtOAc/PE (1/20, v/v); yield: 34.6 mg (69%); yellow solid; mp
98–100 °C.
HR-ESI-MS: m/z calcd for C18H17NO2 [M + H]+: 280.1332; found:
280.1344.
1H NMR (400 MHz, CDCl3):  = 8.25 (d, J = 9.1 Hz, 1 H), 8.17 (d, J = 7.1
Hz, 1 H), 7.49 (d, J = 5.4 Hz, 1 H), 7.47 (d, J = 5.3 Hz, 1 H), 7.26 (s, 1 H),
7.18 (t, J = 8.5 Hz, 2 H), 7.06 (dd, J = 9.0, 6.7 Hz, 1 H), 6.69 (t, J = 6.9 Hz,
1 H), 4.38 (q, J = 7.1 Hz, 2 H), 1.41 (t, J = 7.1 Hz, 3 H).
Ethyl 6-Methyl-3-phenylindolizine-1-carboxylate (3h)
Eluent: EtOAc/PE (1/20, v/v); yield: 33.2 mg (60%); yellow solid; mp
108–110 °C.
13C NMR (100 MHz, CDCl3):  = 164.9, 163.6, 136.2, 130.5, 130.4,
1H NMR (500 MHz, CDCl3):  = 8.22 (d, J = 8.9 Hz, 1 H), 8.12 (s, 1 H),
7.59 (d, J = 6.6 Hz, 2 H), 7.54 (t, J = 6.7 Hz, 2 H), 7.44 (s, 1 H), 7.30 (s, 1
H), 6.98 (d, J = 8.9 Hz, 1 H), 4.43 (q, J = 5.8, 4.6 Hz, 2 H), 2.30 (s, 3 H),
1.47 (t, J = 7.0 Hz, 3 H).
123.0, 122.2, 120.1, 116.2, 116.0, 112.7, 104.2, 59.5, 14.6.
HR-ESI-MS: m/z calcd for C17H14FNO2 [M + H]+: 284.1081; found:
284.1088.
13C NMR (125 MHz, CDCl3):  = 165.1, 135.3, 131.5, 129.1, 128.7,
127.9, 126.1, 125.5, 122.2, 121.1, 120.9, 119.6, 119.5, 115.9, 103.9,
59.5, 18.5, 14.7.
HR-ESI-MS: m/z calcd for C18H17NO2 [M + H]+: 280.1332; found:
280.1339.
Ethyl 3-[4-(Trifluoromethyl)phenyl]indolizine-1-carboxylate
(4d)20
[CAS Reg. No. 1714114-01-8]
Eluent: EtOAc/PE (1/20, v/v); yield: 50.9 mg (77%); yellow solid; mp
91–93 °C.
1H NMR (400 MHz, CDCl3):  = 8.33–8.24 (m, 2 H), 7.74 (d, J = 8.1 Hz, 2
H), 7.67 (d, J = 8.1 Hz, 2 H), 7.37 (s, 1 H), 7.10 (dd, J = 9.2, 6.6 Hz, 1 H),
6.75 (t, J = 7.0 Hz, 1 H), 4.39 (q, J = 7.1 Hz, 2 H), 1.42 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 164.7, 136.8, 134.8, 128.3, 126.1,
126.0, 124.7, 123.0, 122.7, 120.3, 117.0, 113.1, 104.8, 59.7, 29.7, 14.6.
Ethyl 6-Bromo-3-phenylindolizine-1-carboxylate (3i)
Eluent: EtOAc/PE (1/20, v/v); yield: 33.2 mg (48%); yellow solid; mp
105–107 °C.
1H NMR (600 MHz, CDCl3):  = 8.38 (s, 1 H), 8.16 (d, J = 10.1 Hz, 1 H),
7.52 (d, J = 4.5 Hz, 4 H), 7.44 (d, J = 4.1 Hz, 1 H), 7.28 (s, 1 H), 7.11 (d,
J = 1.6 Hz, 1 H), 4.39 (q, J = 7.1 Hz, 2 H), 1.42 (t, J = 7.1 Hz, 3 H).
HR-ESI-MS: m/z calcd for C18H14F3NO2 [M + H]+: 334.1049; found:
334.1056.
13C NMR (150 MHz, CDCl3):  = 164.7, 134.3, 130.6, 129.3, 128.7,
128.5, 126.8, 125.2, 123.3, 120.9, 116.5, 107.8, 105.6, 59.8, 14.6.
HR-ESI-MS: m/z calcd for C17H14BrNO2 [M + H]+: 345.0208; found:
345.0210.
Ethyl 3-(4-Chlorophenyl)indolizine-1-carboxylate (4e)17
[CAS Reg. No. 1621928-42-4]
Eluent: EtOAc/PE (1/20, v/v); yield: 46 mg (77%); yellow solid; mp
107–109 °C.
1H NMR (400 MHz, CDCl3):  = 8.26 (d, J = 9.1 Hz, 1 H), 8.21 (d, J = 7.1
Hz, 1 H), 7.45 (s, 4 H), 7.28 (s, 1 H), 7.10–7.03 (m, 1 H), 6.70 (t, J = 6.8
Hz, 1 H), 4.38 (q, J = 7.1 Hz, 2 H), 1.41 (t, J = 7.1 Hz, 3 H).
Ethyl 3-(2-Fluorophenyl)indolizine-1-carboxylate (4a)13
[CAS Reg. No. 1631741-05-3]
Eluent: EtOAc/PE (1/20, v/v); yield: 30.7 mg (54%); pale yellow oil.
1H NMR (400 MHz, CDCl3):  = 8.29 (d, J = 9.1 Hz, 1 H), 7.89 (dd, J = 7.1,
3.4 Hz, 1 H), 7.50 (dd, J = 7.5, 1.6 Hz, 1 H), 7.44 (d, J = 7.2 Hz, 1 H), 7.37
(s, 1 H), 7.29 (d, J = 7.6 Hz, 1 H), 7.22 (d, J = 9.1 Hz, 1 H), 7.12 (dd, J =
9.0, 6.7 Hz, 1 H), 6.74 (t, J = 6.9 Hz, 1 H), 4.41 (q, J = 7.1 Hz, 2 H), 1.43
(t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 164.8, 136.4, 133.7, 129.7, 129.6,
129.3, 125.0, 123.1, 122.4, 120.2, 116.3, 116.3, 112.8, 104.4, 59.58,
14.6.
HR-ESI-MS: m/z calcd for C17H14ClNO2 [M + H]+: 300.0786; found:
300.0795.
13C NMR (100 MHz, CDCl3):  = 164.8, 136.4, 133.7, 129.7, 129.6,
129.3, 125.0, 123.1, 122.4, 120.2, 116.3, 116.3, 112.8, 104.4, 59.6, 14.6.
HR-ESI-MS: m/z calcd for C17H14FNO2 [M + H]+: 284.1081; found:
284.1092.
Ethyl 3-(4-Bromophenyl)indolizine-1-carboxylate (4f)17
[CAS Reg. No. 1714114-00-7]
Eluent: EtOAc/PE (1/20, v/v); yield: 52.6 mg (77%); yellow solid; mp
99–101 °C.
1H NMR (400 MHz, CDCl3):  = 8.25 (d, J = 9.1 Hz, 1 H), 8.21 (d, J = 7.2
Hz, 1 H), 7.60 (d, J = 8.2 Hz, 2 H), 7.39 (d, J = 8.2 Hz, 2 H), 7.28 (s, 1 H),
7.06 (dd, J = 9.0, 6.7 Hz, 1 H), 6.70 (t, J = 6.9 Hz, 1 H), 4.38 (q, J = 7.1 Hz,
2 H), 1.41 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 164.8, 136.4, 132.2, 130.1, 129.9,
125.0, 123.0, 122.4, 121.8, 120.2, 116.3, 112.8, 104.5, 59.6, 14.6.
HR-ESI-MS: m/z calcd for C17H14BrNO2 [M + H]+: 344.0281; found:
344.0284.
Ethyl 3-(3-Fluorophenyl)indolizine-1-carboxylate (4b)13
[CAS Reg. No. 2027550-24-7]
Eluent: EtOAc/PE (1/20, v/v); yield: 40 mg (71%); yellow oil.
1H NMR (400 MHz, CDCl3):  = 8.28 (t, J = 8.0 Hz, 2 H), 7.51–7.37 (m, 1
H), 7.33 (d, J = 3.9 Hz, 2 H), 7.24 (dt, J = 9.8, 2.0 Hz, 1 H), 7.08 (dd, J =
9.1, 6.8 Hz, 2 H), 6.72 (t, J = 6.9 Hz, 1 H), 4.39 (q, J = 7.1 Hz, 2 H), 1.42
(t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 164.8, 136.5, 133.3, 133.2, 130.7,
130.6, 124.0, 123.9, 123.2, 122.5, 120.2, 116.6, 116.5, 112.8, 104.5,
59.6, 14.6.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–L

H
L. He et al.
Paper
Synthesis
Ethyl 3-(4-Nitrophenyl)indolizine-1-carboxylate (4g)19
Eluent: EtOAc/PE (1/20, v/v); yield: 48.9 mg (72%); yellow solid; mp
143–145 °C.
[CAS Reg. No. 158670-22-5]
1H NMR (400 MHz, CDCl3):  = 8.36 (d, J = 7.1 Hz, 1 H), 8.31 (d, J = 9.1
Hz, 1 H), 7.73 (d, J = 8.0 Hz, 2 H), 7.66 (d, J = 7.7 Hz, 2 H), 7.62 (d, J = 8.0
Hz, 2 H), 7.49 (t, J = 7.6 Hz, 2 H), 7.43–7.36 (m, 2 H), 7.12–7.05 (m, 1
H), 6.72 (t, J = 6.9 Hz, 1 H), 4.43 (q, J = 7.1 Hz, 2 H), 1.45 (t, J = 7.1 Hz, 3
H).
13C NMR (100 MHz, CDCl3):  = 165.0, 140.7, 140.3, 136.4, 130.1,
128.9, 128.8, 127.7, 127.6, 127.0, 126.0, 123.4, 122.3, 120.2, 116.2,
112.7, 104.4, 59.6, 14.7.
Eluent: EtOAc/PE (1/10, v/v); yield: 51.1 mg (94%); orange-red solid;
mp 140–142 °C.
1H NMR (600 MHz, CDCl3):  = 8.37 (d, J = 7.1 Hz, 1 H), 8.30 (dd, J =
15.8, 8.7 Hz, 3 H), 7.71 (d, J = 8.3 Hz, 2 H), 7.43 (s, 1 H), 7.17–7.11 (m, 1
H), 6.81 (t, J = 6.9 Hz, 1 H), 4.38 (q, J = 7.1 Hz, 2 H), 1.41 (t, J = 7.2 Hz, 3
H).
13C NMR (150 MHz, CDCl3):  = 164.5, 146.5, 137.8, 137.5, 130.6,
128.0, 124.6, 124.0, 123.4, 123.2, 120.5, 118.20, 113.7, 105.6, 59.9,
14.6.
HR-ESI-MS: m/z calcd for C23H19NO2 [M + H]+: 342.1489; found:
342.1495.
HR-ESI-MS: m/z calcd for C17H14N2O4 [M + H]+: 311.1026; found:
311.1035.
Ethyl 3-(Thiophen-3-yl)indolizine-1-carboxylate (4l)22
[CAS Reg. No. 1638213-47-4]
Ethyl 3-(p-Tolyl)indolizine-1-carboxylate (4h)17
Eluent: EtOAc/PE (1/10, v/v); yield: 31.9 mg (59%); pale yellow solid;
mp 111–113 °C.
1H NMR (400 MHz, CDCl3):  = 8.29–8.22 (m, 2 H), 7.46 (dd, J = 4.8, 3.1
Hz, 1 H), 7.43 (d, J = 2.8 Hz, 1 H), 7.32 (s, 1 H), 7.30 (d, J = 5.0 Hz, 1 H),
7.05 (dd, J = 9.2, 6.7 Hz, 1 H), 6.71 (t, J = 6.9 Hz, 1 H), 4.39 (q, J = 7.1 Hz,
2 H), 1.42 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 164.9, 136.1, 131.5, 127.5, 126.5,
123.6, 122.6, 122.1, 121.7, 120.0, 116.0, 112.7, 104.0, 59.6, 14.6.
HR-ESI-MS: m/z calcd for C15H13NO2S [M + H]+: 271.0740; found:
271.0748.
[CAS Reg. No. 247075-84-9]
Eluent: EtOAc/PE (1/10, v/v); yield: 41.8 mg (75%); yellow solid; mp
96–98 °C.
1H NMR (400 MHz, CDCl3):  = 8.29–8.21 (m, 2 H), 7.42 (d, J = 7.8 Hz, 2
H), 7.29 (d, J = 7.7 Hz, 3 H), 7.05 (dd, J = 9.1, 6.7 Hz, 1 H), 6.67 (t, J = 6.9
Hz, 1 H), 4.40 (q, J = 7.1 Hz, 2 H), 2.42 (s, 3 H), 1.43 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 165.0, 137.9, 136.2, 129.7, 128.5,
128.2, 126.5, 123.3, 122.0, 120.1, 115.8, 112.4, 104.04, 59.5, 21.3, 14.7.
HR-ESI-MS: m/z calcd for C18H17NO2 [M + H]+: 280.1332: found
280.1344.
Ethyl 3-(Thiophen-2-yl)indolizine-1-carboxylate (4m)19
Ethyl 3-[4-(tert-Butyl)phenyl]indolizine-1-carboxylate (4i)21
[CAS Reg. No. 1621928-45-7]
[CAS Reg. No. 1776070-38-2]
Eluent: EtOAc/PE (1/10, v/v); yield: 32.4 mg (60%); orange-yellow sol-
id; mp 78–80 °C.
1H NMR (600 MHz, CDCl3):  = 8.37 (dd, J = 7.1, 1.1 Hz, 1 H), 8.26 (dt,
J = 9.1, 1.3 Hz, 1 H), 7.41–7.37 (m, 2 H), 7.25 (dd, J = 3.6, 1.2 Hz, 1 H),
7.16 (dd, J = 5.2, 3.6 Hz, 1 H), 7.10–7.07 (m, 1 H), 6.78–6.74 (m, 1 H),
4.39 (q, J = 7.1 Hz, 2 H), 1.42 (t, J = 7.1 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 164.8, 136.6, 132.3, 127.7, 126.2,
125.8, 123.8, 122.5, 120.1, 119.2, 117.5, 113.0, 104.4, 59.7, 14.7.
HR-ESI-MS: m/z calcd for C15H13NO2S [M + H]+: 272.0740; found:
272.0749.
Eluent: EtOAc/PE (1/20, v/v); yield: 49.8 mg (78%); yellow solid; mp
95–97 °C.
1H NMR (400 MHz, CDCl3):  = 8.28 (dd, J = 17.0, 8.1 Hz, 2 H), 7.50 (q,
J = 8.3 Hz, 4 H), 7.29 (s, 1 H), 7.10–7.02 (m, 1 H), 6.68 (t, J = 6.8 Hz, 1
H), 4.40 (q, J = 7.1 Hz, 2 H), 1.43 (t, J = 7.1 Hz, 3 H), 1.39 (s, 9 H).
13C NMR (100 MHz, CDCl3):  = 165.1, 151.0, 136.2, 128.3, 128.3,
126.4, 126.0, 123.5, 122.0, 120.1, 115.8, 115.8, 112.4, 104.1, 59.5, 34.7,
31.3, 14.6.
HR-ESI-MS: m/z calcd for C21H23NO2 [M + H]+: 322.1802; found:
322.1814.
Ethyl 3-(Pyridin-2-yl)indolizine-1-carboxylate (4n)19
Ethyl 3-(4-Methoxyphenyl)indolizine-1-carboxylate (4j)17
[CAS Reg. No. 1776070-49-5]
[CAS Reg. No. 1621928-40-2]
Eluent: EtOAc/PE (1/10, v/v); yield: 26.9 mg (51%); yellow solid; mp
144–146 °C.
1H NMR (400 MHz, CDCl3):  = 10.04 (d, J = 7.2 Hz, 1 H), 8.59 (d, J = 4.8
Hz, 1 H), 8.27 (d, J = 9.0 Hz, 1 H), 7.74 (s, 1 H), 7.67 (d, J = 4.2 Hz, 2 H),
7.15 (dd, J = 9.0, 6.8 Hz, 1 H), 7.09 (d, J = 4.3 Hz, 1 H), 6.82 (t, J = 7.0 Hz,
1 H), 4.39 (d, J = 7.1 Hz, 2 H), 1.43 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 164.7, 151.7, 148.2, 137.8, 136.4, 127.8
(d, J = 1.5 Hz), 123.5 (d, J = 6.5 Hz), 121.0, 120.5, 119.3, 117.8 (d, J = 1.7
Hz), 113.0, 104.5, 59.6, 14.6.
Eluent: EtOAc/PE (1/10, v/v); yield: 35.2 mg (60%); yellow solid; mp
124–126 °C.
1H NMR (400 MHz, CDCl3):  = 8.25 (d, J = 9.1 Hz, 1 H), 8.19 (d, J = 7.1
Hz, 1 H), 7.44 (d, J = 8.3 Hz, 2 H), 7.24 (s, 1 H), 7.03 (dd, J = 8.5, 6.2 Hz,
3 H), 6.67 (t, J = 6.8 Hz, 1 H), 4.39 (q, J = 7.1 Hz, 2 H), 3.86 (s, 3 H), 1.42
(t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 165.1, 159.4, 136.0, 130.1, 123.5,
123.3, 122.0, 120.0, 115.6, 115.5, 114.5, 112.4, 103.9, 59.5, 55.3, 55.3,
14.6.
HR-ESI-MS: m/z calcd for C16H14N2O2 [M + H]+: 267.1128; found:
267.1136.
HR-ESI-MS: m/z calcd for C18H17NO2 [M + H]+: 296.1281; found:
296.1294.
Ethyl 3-(Pyridin-3-yl)indolizine-1-carboxylate (4o)
Ethyl 3-([1,1′-Biphenyl]-4-yl)indolizine-1-carboxylate (4k)13
Eluent: EtOAc/PE (1/3, v/v); yield: 23 mg (43%); yellow solid; mp 80–
82 °C.
[CAS Reg. No. 1776070-42-8]
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–L

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L. He et al.
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Synthesis
1H NMR (400 MHz, CDCl3):  = 8.78 (d, J = 2.3 Hz, 1 H), 8.62–8.57 (m, 1
H), 8.24 (d, J = 9.0 Hz, 1 H), 8.19 (d, J = 7.1 Hz, 1 H), 7.82 (dt, J = 8.1, 2.0
Hz, 1 H), 7.39 (dd, J = 7.9, 4.8 Hz, 1 H), 7.32 (s, 1 H), 7.10–7.03 (m, 1 H),
6.71 (t, J = 6.9 Hz, 1 H), 4.36 (q, J = 7.1 Hz, 2 H), 1.39 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 164.7, 149.3, 148.9, 136.7, 135.6,
127.4, 123.7, 122.8, 122.7, 122.6, 120.3, 116.9, 113.1, 104.7, 59.6, 14.6.
1-Ethyl 1-Isopropyl 3-Phenylindolizine-1,2-dicarboxylate (5c)
Eluent: EtOAc/PE (1/10, v/v); yield: 26 mg (37%); yellow oil.
1H NMR (600 MHz, CDCl3):  = 8.24 (dt, J = 9.0, 1.3 Hz, 1 H), 8.02 (dd,
J = 7.1, 1.2 Hz, 1 H), 7.52–7.46 (m, 4 H), 7.46–7.41 (m, 1 H), 7.09 (ddd,
J = 9.1, 6.6, 1.1 Hz, 1 H), 6.70 (dd, J = 6.9, 1.4 Hz, 1 H), 5.30–5.25 (m, 1
H), 4.26 (q, J = 7.2 Hz, 2 H), 1.36 (d, J = 6.2 Hz, 6 H), 1.21 (t, J = 7.1 Hz, 3
H).
HR-ESI-MS: m/z calcd for C16H14N2O2 [M + H]+: 267.1128; found:
13C NMR (150 MHz, CDCl3):  = 166.4, 163.4, 135.2, 130.0, 129.1,
129.0, 124.7, 123.5, 123.3, 122.4, 120.4, 113.4, 102.4, 67.21, 61.3, 22.2,
14.0.
267.1136.
Diethyl Indolizine-1,3-dicarboxylate (4p)23
HR-ESI-MS: m/z calcd for C21H21NO4 [M + H]+: 352.1543; found:
[CAS Reg. No. 55814-13-6]
352.1549.
Eluent: EtOAc/PE (1/20, v/v); yield: 15 mg (29%); pale yellow solid;
mp 112–114 °C.
1-tert-Butyl 2-Ethyl 3-Phenylindolizine-1,2-dicarboxylate (5d)
1H NMR (600 MHz, CDCl3):  = 9.50 (dt, J = 7.1, 1.1 Hz, 1 H), 8.34–8.29
(m, 1 H), 7.97 (s, 1 H), 7.31–7.27 (m, 1 H), 6.96 (dd, J = 7.0, 1.4 Hz, 1 H),
4.40–4.34 (m, 4 H), 1.41 (td, J = 7.2, 5.2 Hz, 6 H).
13C NMR (150 MHz, CDCl3):  = 164.2, 161.2, 139.1, 127.9, 125.6,
124.2, 119.6, 114.3, 105.2, 60.3, 59.9, 14.6, 14.5.
Eluent: EtOAc/PE (1/10, v/v); yield: 22.6 mg (31%); yellow oil.
1H NMR (600 MHz, CDCl3):  = 8.22 (dt, J = 9.2, 1.3 Hz, 1 H), 8.00 (dd,
J = 7.1, 1.2 Hz, 1 H), 7.49 (d, J = 6.4 Hz, 4 H), 7.45–7.41 (m, 1 H), 7.06
(ddd, J = 9.1, 6.6, 1.1 Hz, 1 H), 6.67 (td, J = 6.8, 1.4 Hz, 1 H), 4.24 (q, J =
7.2 Hz, 2 H), 1.60 (s, 9 H), 1.17 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 166.4, 163.2, 135.1, 130.0, 129.2,
129.0, 128.9, 124.5, 123.4, 123.0, 122.3, 120.4, 113.3, 103.5, 80.3, 61.2,
28.5, 14.0.
HR-ESI-MS: m/z calcd for C14H15NO4 [M + H]+: 262.1074; found:
262.1073.
Products 5a–l; Typical Procedure for Diethyl 3-Phenylindolizine-
1,2-dicarboxylate (5a)24
HR-ESI-MS: m/z calcd for C22H23NO4 [M + H]+: 366.1700; found:
366.1704.
[CAS Reg. No. 1268825-51-9]
Under N2 atmosphere, ethyl 2-(pyridin-2-yl)acetate (1a; 33.0 mg, 0.2
mmol), ethyl phenyl propynoate (69.7 mg, 0.4 mmol), I2 (50.8 mg, 0.2
mmol,), and Na2CO3 (42.4 mg, 0.4 mmol) were mixed in DMA (2 mL).
The reaction tube was heated in an oil bath at 160 °C for 4 h. After
completion of the reaction, the reaction mixture was washed with
sat. aq Na2S2O3 and extracted with EtOAc (3 × 40 mL), dried (anhyd
Na2SO4), and the solvent was removed under reduced pressure. The
remaining crude product was then purified through column chroma-
tography using silica gel (EtOAc/PE 1/10) to afford 5a as a pale yellow
solid; yield: 31.6 mg (47%); mp 40–42 °C.
1H NMR (600 MHz, CDCl3):  = 8.24 (dd, J = 9.2, 1.3 Hz, 1 H), 8.04–8.01
(m, 1 H), 7.52–7.48 (m, 4 H), 7.46–7.43 (m, 1 H), 7.11 (ddd, J = 9.2, 6.6,
1.1 Hz, 1 H), 6.71 (td, J = 6.9, 1.4 Hz, 1 H), 4.37 (q, J = 7.1 Hz, 2 H), 4.26
(q, J = 7.2 Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3 H), 1.20 (t, J = 7.1 Hz, 3 H).
1-Butyl 2-Ethyl 3-Phenylindolizine-1,2-dicarboxylate (5e)
Eluent: EtOAc/PE (1/10, v/v); yield: 25.6 mg (35%); yellow solid; mp
83–85 °C.
1H NMR (600 MHz, CDCl3):  = 8.24 (dt, J = 9.1, 1.3 Hz, 1 H), 8.02 (dt,
J = 7.2, 1.1 Hz, 1 H), 7.52–7.47 (m, 4 H), 7.46–7.41 (m, 1 H), 7.10 (ddd,
J = 9.2, 6.6, 1.1 Hz, 1 H), 6.70 (td, J = 6.8, 1.4 Hz, 1 H), 4.32 (t, J = 6.7 Hz,
2 H), 4.25 (q, J = 7.1 Hz, 2 H), 1.76–1.71 (m, 2 H), 1.52–1.43 (m, 2 H),
1.19 (t, J = 7.1 Hz, 3 H), 0.97 (t, J = 7.4 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 166.4, 164.0, 135.3, 130.0, 129.0,
129.0, 124.8, 123.5, 123.5, 122.4, 120.4, 113.4, 102.1, 63.9, 61.3, 31.0,
19.3, 14.0, 13.8.
HR-ESI-MS: m/z calcd for C22H23NO4 [M + H]+: 366.1700; found:
366.1705.
13C NMR (150 MHz, CDCl3):  = 166.3, 163.8, 149.5, 135.3, 130.0,
129.0, 129.0, 124.9, 123.9, 123.5, 123.4, 122.4, 122.1, 120.4, 113.4,
102.1, 61.3, 59.9, 14.5, 14.0.
HR-ESI-MS: m/z calcd for C20H19NO4 [M + H]+: 338.1387; found:
338.1390.
Diethyl 3-(4-Chlorophenyl)indolizine-1,2-dicarboxylate (5f)
Eluent: EtOAc/PE (1/20, v/v); yield: 32.6 mg (44%); brown oil.
1H NMR (600 MHz, CDCl3):  = 8.25 (dt, J = 9.2, 1.2 Hz, 1 H), 7.97 (dd,
J = 7.1, 1.1 Hz, 1 H), 7.52–7.43 (m, 4 H), 7.12 (ddd, J = 9.1, 6.6, 1.1 Hz, 1
H), 6.73 (td, J = 6.9, 1.3 Hz, 1 H), 4.37 (q, J = 7.1 Hz, 2 H), 4.27 (q, J = 7.1
Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3 H), 1.24 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 166.1, 163.7, 135.4, 135.1, 131.4,
129.4, 127.5, 123.6, 123.2, 120.5, 113.7, 61.5, 60.0, 14.5, 14.1.
1-Ethyl 1-Methyl 3-Phenylindolizine-1,2-dicarboxylate (5b)
Eluent: EtOAc/PE (1/10, v/v); yield: 20 mg (31%); yellow solid; mp 80–
82 °C.
1H NMR (600 MHz, CDCl3):  = 8.23 (dt, J = 9.1, 1.3 Hz, 1 H), 8.02 (d, J =
7.2 Hz, 1 H), 7.53–7.47 (m, 4 H), 7.45 (d, J = 6.8 Hz, 1 H), 7.11 (ddd, J =
9.1, 6.6, 1.1 Hz, 1 H), 6.71 (td, J = 6.9, 1.4 Hz, 1 H), 4.27 (q, J = 7.1 Hz, 2
H), 3.89 (s, 3 H), 1.20 (t, J = 7.1 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 166.3, 164.3, 135.3, 130.1, 129.1,
129.0, 125.1, 123.6, 122.3, 120.4, 113.5, 101.8, 61.4, 51.2, 14.1.
HR-ESI-MS: m/z calcd for C19H17NO4 [M + H]+: 324.1230; found:
324.1233.
HR-ESI-MS: m/z calcd for C20H18ClNO4 [M + H]+: 372.0997; found:
372.1000.
Diethyl 3-(4-Methoxyphenyl)indolizine-1,2-dicarboxylate (5g)
Eluent: EtOAc/PE (1/5, v/v); yield: 24.2 mg (33%); brown oil.
1H NMR (600 MHz, CDCl3):  = 8.23 (dd, J = 9.2, 1.5 Hz, 1 H), 7.97 (d, J =
7.1 Hz, 1 H), 7.45–7.40 (m, 2 H), 7.11–7.06 (m, 1 H), 7.02 (d, J = 8.6 Hz,
2 H), 6.69 (td, J = 6.9, 1.4 Hz, 1 H), 4.36 (q, J = 7.1 Hz, 2 H), 4.26 (q, J =
7.2 Hz, 2 H), 3.86 (s, 3 H), 1.38 (t, J = 7.1 Hz, 3 H), 1.23 (t, J = 7.1 Hz, 3
H).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–L

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L. He et al.
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Synthesis
13C NMR (150 MHz, CDCl3):  = 166.5, 163.9, 160.1, 135.11, 131.5,
124.8, 123.5, 123.3, 122.1, 121.0, 120.3, 114.5, 113.3, 101.8, 61.28,
59.9, 55.4, 14.5, 14.1.
HR-ESI-MS: m/z calcd for C21H21NO5 [M + H]+: 368.1492; found:
368.1498.
Ethyl 2-Formyl-3-(thiophen-2-yl)indolizine-1-carboxylate (5l)
Eluent: EtOAc/PE (1/10, v/v); yield: 15.1 mg (25%); brown solid; mp
72–74 °C.
1H NMR (600 MHz, CDCl3):  = 10.76 (s, 1 H), 8.32 (d, J = 8.4 Hz, 1 H),
8.02 (d, J = 7.1 Hz, 1 H), 7.59 (d, J = 6.2 Hz, 1 H), 7.27 (dd, J = 3.5, 1.1 Hz,
1 H), 7.22 (dd, J = 5.1, 3.6 Hz, 1 H), 7.16 (dd, J = 9.2, 6.6 Hz, 1 H), 6.79 (t,
J = 6.9 Hz, 1 H), 4.45 (q, J = 7.1 Hz, 2 H), 1.45 (t, J = 7.2 Hz, 3 H).
Ethyl 2-Formyl-3-phenylindolizine-1-carboxylate (5h)
13C NMR (150 MHz, CDCl3):  = 189.9, 164.4, 136.5, 131.0, 128.9,
128.8, 127.6, 126.6, 124.4, 124.3, 120.9, 114.6, 104.1, 60.4, 14.6.
Eluent: EtOAc/PE (1/10, v/v); yield: 30.4 mg (52%); yellow solid; mp
77–79 °C.
1H NMR (600 MHz, CDCl3):  = 10.77 (s, 1 H), 8.32 (d, J = 9.2 Hz, 1 H),
7.86 (d, J = 7.2 Hz, 1 H), 7.55–7.50 (m, 3 H), 7.44 (dd, J = 8.1, 1.6 Hz, 2
H), 7.13 (dd, J = 10.2, 6.6 Hz, 1 H), 6.72 (t, J = 7.5 Hz, 1 H), 4.46 (q, J =
7.1 Hz, 2 H), 1.46 (t, J = 7.2 Hz, 3 H).
HR-ESI-MS: m/z calcd for C16H13NO3S [M + H]+: 300.0689; found:
300.0688.
Products 6a–g: Typical Procedure for Ethyl 3-Benzoylindolizine-1-
carboxylate (6a)25
13C NMR (150 MHz, CDCl3):  = 190.1, 164.6, 136.1, 130.9, 129.4,
129.1, 129.0, 128.7, 124.8, 123.9, 123.9, 121.1, 114.3, 103.8, 60.3, 14.6.
HR-ESI-MS: m/z calcd for C18H15NO3 [M + H]+: 294.1125; found:
[CAS Reg. No. 40624-43-9]
Under N2 atmosphere, ethyl 2-(pyridin-2-yl)acetate (1a; 33.0 mg, 0.2
mmol), phenylpropynyl aldehyde (52.0 mg, 0.4 mmol), I2 (177.7 mg,
0.7 mmol), dppe (15.9 mg, 0.04 mmol), CuI (77.8 mg, 0.4 mmol), and
Na2CO3 (42.4 mg, 0.4 mmol) were mixed in DMF (2 mL). The reaction
tube was heated in an oil bath at 160 °C for 4 h. After completion of
the reaction, the reaction mixture was washed with sat. aq Na2S2O3
and extracted with EtOAc (3 × 40 mL), dried (anhyd Na2SO4), and the
solvent was removed under reduced pressure. The remaining crude
product was then purified through column chromatography using sil-
ica gel (EtOAc/PE 1/10) to afford 6a as a yellow solid; yield; 44.3 mg
(76%); mp 148–150 °C.
294.1124.
Ethyl 3-(4-Fluorophenyl)-2-formylindolizine-1-carboxylate (5i)
Eluent: EtOAc/PE (1/10, v/v); yield: 23.6 mg (38%); yellow solid; mp
78–80 °C.
1H NMR (600 MHz, CDCl3):  = 10.77 (s, 1 H), 8.32 (d, J = 9.2 Hz, 1 H),
7.82 (d, J = 7.2 Hz, 1 H), 7.43 (dd, J = 8.7, 5.3 Hz, 2 H), 7.22 (t, J = 8.6 Hz,
2 H), 7.13 (dd, J = 8.8, 6.1 Hz, 1 H), 6.74 (t, J = 6.3 Hz, 1 H), 4.46 (q, J =
7.1 Hz, 2 H), 1.45 (t, J = 7.1 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 190.2, 164.5, 162.4, 136.1, 133.0,
132.9, 127.3, 125.1, 124.9, 124.0, 123.6, 121.2, 116.3, 116.1, 114.5,
103.9, 60.3, 14.6.
1H NMR (600 MHz, CDCl3):  = 9.97 (d, J = 7.0 Hz, 1 H), 8.39 (d, J = 8.9
Hz, 1 H), 7.83–7.80 (m, 3 H), 7.58 (t, J = 7.4 Hz, 1 H), 7.51 (t, J = 7.5 Hz,
2 H), 7.46–7.43 (m, 1 H), 7.09 (t, J = 7.5 Hz, 1 H), 4.37 (q, J = 7.1 Hz, 2
H), 1.39 (t, J = 7.1 Hz, 3 H).
HR-ESI-MS: m/z calcd for C18H14FNO3 [M + H]+: 312.1030; found:
312.1029.
13C NMR (150 MHz, CDCl3):  = 185.6, 164.1, 140.0, 131.5, 129.2,
129.1, 129.0, 128.4, 127.7, 122.5, 119.5, 115.3, 106.3, 60.1, 14.6.
HR-ESI-MS: m/z calcd for C18H16NO3 [M + H]+: 294.1125; found:
294.1131.
Ethyl 3-(4-Chlorophenyl)-2-formylindolizine-1-carboxylate (5j)
Eluent: EtOAc/PE (1/10, v/v); yield: 25 mg (38%); yellow solid; mp 84–
86 °C.
1H NMR (600 MHz, CDCl3):  = 10.77 (s, 1 H), 8.33 (d, J = 9.2 Hz, 1 H),
7.83 (d, J = 7.1 Hz, 1 H), 7.51 (d, J = 8.3 Hz, 2 H), 7.39 (d, J = 8.3 Hz, 2 H),
7.16–7.12 (m, 1 H), 6.74 (td, J = 6.9, 1.3 Hz, 1 H), 4.46 (q, J = 7.2 Hz, 2
H), 1.45 (t, J = 7.1 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 190.2, 164.5, 136.2, 135.6, 132.3,
129.3, 127.6, 127.0, 124.9, 124.0, 123.6, 121.2, 114.6, 104.1, 60.4, 14.6.
Ethyl 3-(4-Fluorobenzoyl)indolizine-1-carboxylate (6b)26
[CAS Reg. No. 1003050-05-2]
Eluent: EtOAc/PE (1/10, v/v); yield: 37.3 mg (60%); pale yellow solid;
mp 102–104 °C.
1H NMR (600 MHz, CDCl3):  = 9.91 (d, J = 7.0 Hz, 1 H), 8.38 (d, J = 8.9
Hz, 1 H), 7.84 (dd, J = 8.7, 5.4 Hz, 2 H), 7.78 (s, 1 H), 7.46–7.43 (m, 1 H),
7.19 (t, J = 8.6 Hz, 2 H), 7.08 (t, J = 6.3 Hz, 1 H), 4.37 (q, J = 7.1 Hz, 2 H),
1.40 (t, J = 7.1 Hz, 3 H).
HR-ESI-MS: m/z calcd for C18H14ClNO3 [M + H]+: 328.0735; found:
328.0734.
13C NMR (150 MHz, CDCl3):  = 184.1, 165.6, 164.0, 139.9, 136.1,
131.4, 131.3, 129.2, 128.8, 127.8, 122.3, 119.6, 115.6, 115.5, 115.4,
106.4, 60.2, 14.6.
HR-ESI-MS: m/z calcd for C18H14FNO3 [M + H]+: 312.1030; found:
312.1029.
Ethyl 2-Formyl-3-(4-methoxyphenyl)indolizine-1-carboxylate
(5k)
Eluent: EtOAc/PE (1/10, v/v); yield: 23 mg (36%); yellow solid; mp 83–
85 °C.
1H NMR (600 MHz, CDCl3):  = 10.76 (s, 1 H), 8.30 (d, J = 9.2 Hz, 1 H),
7.87 (d, J = 7.1 Hz, 1 H), 7.38–7.36 (m, 2 H), 7.11 (ddd, J = 9.2, 6.5, 1.1
Hz, 1 H), 7.06–7.03 (m, 2 H), 6.71 (td, J = 6.9, 1.3 Hz, 1 H), 4.45 (q, J =
7.1 Hz, 2 H), 3.88 (s, 3 H), 1.45 (t, J = 7.1 Hz, 3 H).
Ethyl 3-(4-Chlorobenzoyl)indolizine-1-carboxylate (6c)26
[CAS Reg. No. 1003050-06-3]
13C NMR (150 MHz, CDCl3):  = 190.3, 164.6, 160.3, 136.0, 132.3,
128.7, 124.6, 123.9, 123.9, 121.0, 120.9, 114.4, 114.2, 103.6, 60.3, 55.4,
14.6.
HR-ESI-MS: m/z calcd for C19H17NO4 [M + H]+: 324.1230; found:
324.1229.
Eluent: EtOAc/PE (1/10, v/v); yield: 46.4 mg (71%); yellow solid; mp
81–83 °C.
1H NMR (600 MHz, CDCl3):  = 9.92 (d, J = 7.0 Hz, 1 H), 8.39 (d, J = 8.9
Hz, 1 H), 7.77 (d, J = 3.0 Hz, 2 H), 7.75 (s, 1 H), 7.50–7.44 (m, 3 H), 7.09
(t, J = 6.9 Hz, 1 H), 4.37 (q, J = 7.2 Hz, 2 H), 1.40 (t, J = 7.1 Hz, 3 H).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–L

K
L. He et al.
Paper
Synthesis
13C NMR (150 MHz, CDCl3):  = 184.1, 164.0, 140.0, 138.2, 137.8,
130.4, 129.2, 128.8, 128.7, 127.9, 122.2, 119.6, 115.5, 106.5, 60.2, 14.6.
Products 7a,b; Typical Procedure for Ethyl 3-Phenyl-2-(phenyl-
ethynyl)indolizine-1-carboxylate (7a)
HR-ESI-MS: m/z calcd for C18H14ClNO3 [M + H]+: 328.0735; found:
328.0734.
Under N2 atmosphere, ethyl 2-(pyridin-2-yl)acetate (1a; 132.2 mg, 0.8
mmol), 1,4-diphenylbutadiyne (40.4 mg, 0.2 mmol), I2 (101.5 mg, 0.4
mmol), dppe (15.9 mg, 0.04 mmol), and Na2CO3 (42.4 mg, 0.4 mmol)
were mixed in DMF (2 mL). The reaction tube was heated in an oil
bath at 160 °C for 4 h. After completion of the reaction, the reaction
mixture was washed with sat. aq Na2S2O3 and extracted with EtOAc
(3 × 40 mL), dried (anhyd Na2SO4), and the solvent was removed un-
der reduced pressure. The remaining crude product was then purified
through column chromatography using silica gel (EtOAc/PE 1/20, v/v)
to afford 7a as a yellow solid; yield: 28 mg (38%); mp 111–113 °C.
1H NMR (600 MHz, CDCl3):  = 8.43 (dt, J = 6.8, 1.2 Hz, 1 H), 8.33 (dt,
J = 9.1, 1.2 Hz, 1 H), 7.65 (dt, J = 6.4, 1.4 Hz, 2 H), 7.47–7.41 (m, 4 H),
7.41–7.37 (m, 1 H), 7.35–7.30 (m, 3 H), 7.21 (ddd, J = 9.0, 6.7, 1.2 Hz, 1
H), 6.91 (td, J = 6.8, 1.3 Hz, 1 H), 4.26 (q, J = 7.1 Hz, 2 H), 1.22 (t, J = 7.1
Hz, 3 H).
Ethyl 3-(4-Methoxybenzoyl)indolizine-1-carboxylate (6d)25
[CAS Reg. No. 1003050-04-1]
Eluent: EtOAc/PE (1/20, v/v); yield: 35 mg (54%); yellow solid; mp 88–
90 °C.
1H NMR (600 MHz, CDCl3):  = 9.89 (d, J = 7.0 Hz, 1 H), 8.36 (s, 1 H),
7.84 (s, 1 H), 7.82 (d, J = 5.8 Hz, 2 H), 7.43–7.38 (m, 1 H), 7.05 (t, J = 6.5
Hz, 1 H), 7.01 (d, J = 8.8 Hz, 2 H), 4.37 (q, J = 7.1 Hz, 2 H), 3.89 (s, 3 H),
1.40 (t, J = 7.1 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 184.6, 164.2, 162.5, 139.7, 132.4,
131.2, 129.1, 128.4, 127.4, 122.6, 119.5, 115.1, 113.7, 105.9, 60.1, 55.5,
14.6.
13C NMR (150 MHz, CDCl3):  = 164.5, 137.0, 136.3, 133.9, 131.0,
130.7, 128.4, 128.3, 127.5, 127.4, 125.2, 124.2, 122.9, 120.2, 113.4,
108.3, 102.4, 98.5, 79.3, 59.6, 14.2.
HR-ESI-MS: m/z calcd for C19H17NO4 [M + H]+: 324.1230; found:
324.1229.
Ethyl 3-(Thiophene-2-carbonyl)indolizine-1-carboxylate (6e)25
HR-ESI-MS: m/z calcd for C25H19NO2 [M + H]+: 366.1489; found:
366.1497.
[CAS Reg. No. 1003050-07-4]
Eluent: EtOAc/PE (1/10, v/v); yield: 34 mg (57%); yellow solid; mp 81–
83 °C.
1H NMR (600 MHz, CDCl3):  = 9.83 (d, J = 7.1 Hz, 1 H), 8.37 (d, J = 8.9
Hz, 1 H), 8.13 (d, J = 1.6 Hz, 1 H), 7.81 (d, J = 4.7 Hz, 1 H), 7.66 (d, J = 5.0
Hz, 1 H), 7.44–7.39 (m, 1 H), 7.21–7.18 (m, 1 H), 7.05 (t, J = 6.9 Hz, 1
H), 4.40 (q, J = 6.9 Hz, 2 H), 1.42 (t, J = 7.1 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 176.4, 164.1, 144.3, 139.9, 132.1,
132.1, 129.1, 127.8, 127.6, 127.3, 122.2, 119.6, 115.2, 106.4, 60.2, 14.6.
HR-ESI-MS: m/z calcd for C16H13NO3S [M + H]+: 300.0689; found:
300.0688.
Ethyl 3-Butyl-2-(hex-1-yn-1-yl)indolizine-1-carboxylate (7b)
Eluent: EtOAc/PE (1/20, v/v); yield: 22.7 mg (35%); brown oil.
1H NMR (600 MHz, CDCl3):  = 8.21 (d, J = 5.9 Hz, 1 H), 8.18 (d, J = 8.0
Hz, 1 H), 7.08 (s, 1 H), 6.77 (d, J = 14.7 Hz, 1 H), 4.37 (q, J = 7.1 Hz, 2 H),
3.03–2.99 (m, 2 H), 2.59 (t, J = 7.0 Hz, 2 H), 1.69–1.62 (m, 4 H), 1.58 (s,
2 H), 1.41 (t, J = 7.1 Hz, 5 H), 0.98 (t, J = 7.3 Hz, 3 H), 0.95 (t, J = 7.4 Hz,
3 H).
13C NMR (150 MHz, CDCl3):  = 165.1, 137.2, 136.3, 124.7, 123.0,
119.6, 112.5, 108.8, 101.6, 69.9, 59.3, 33.0, 31.0, 26.4, 22.8, 19.6, 14.6,
14.0, 13.6.
HR-ESI-MS: m/z calcd for C21H27NO2 [M + H]+: 326.4522; found:
326.4524.
Ethyl 3-Pentanoylindolizine-1-carboxylate (6f)
Eluent: EtOAc/PE (1/10, v/v); yield: 32 mg (59%); yellow solid; mp 42–
44 °C.
1H NMR (600 MHz, CDCl3):  = 9.93 (d, J = 7.1 Hz, 1 H), 8.33 (d, J = 8.9
Hz, 1 H), 8.01 (s, 1 H), 7.38 (ddd, J = 8.8, 6.8, 1.0 Hz, 1 H), 7.01 (td, J =
7.0, 1.4 Hz, 1 H), 4.40 (q, J = 7.1 Hz, 2 H), 2.93–2.89 (m, 2 H), 1.76 (p, J =
7.7 Hz, 2 H), 1.43 (td, J = 7.4, 3.4 Hz, 5 H), 0.96 (t, J = 7.4 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 191.1, 164.2, 139.3, 129.2, 127.1,
125.6, 122.7, 119.4, 115.1, 105.6, 60.1, 39.2, 27.7, 22.6, 14.6, 14.0.
HR-ESI-MS: m/z calcd for C16H19NO3 [M + H]+: 274.1438; found:
274.1437.
Products 8a,b; Typical Procedure for Diethyl 3,3′-Diphenyl-[2,2′-
biindolizine]-1,1′-dicarboxylate (8a)
Under N2 atmosphere, ethyl 2-(pyridin-2-yl)acetate (1a; 66.0 mg 0.4
mmol), ethyl 3-phenyl-2-(phenylethynyl)indolizine-1-carboxylate
(7a; 36.5 mg, 0.1 mmol), I2 (101.5 mg, 0.4 mmol), dppe (15.9 mg, 0.04
mmol), and Na2CO3 (42.4 mg, 0.4 mmol) were mixed in DMF (2 mL).
The reaction tube was heated in an oil bath at 160 °C for 4 h. After
completion of the reaction, the reaction mixture was washed with
sat. aq Na2S2O3 and extracted with EtOAc (3 × 40 mL), dried (anhyd
Na2SO4), and the solvent was removed under reduced pressure. The
remaining crude product was then purified through column chroma-
tography using silica gel (EtOAc/PE 1/20, v/v) to afford 8a as a yellow
solid; yield: 34.7 mg (66%); yellow solid; mp 134–136 °C.
1H NMR (600 MHz, CDCl3):  = 8.35–8.30 (m, 2 H), 7.42 (d, J = 6.9 Hz, 2
H), 7.16–7.13 (m, 4 H), 7.10 (dd, J = 8.2, 6.5 Hz, 4 H), 6.93 (dt, J = 7.0,
1.4 Hz, 4 H), 6.65 (td, J = 6.8, 1.3 Hz, 2 H), 4.20 (qt, J = 7.1, 3.7 Hz, 4 H),
1.14 (t, J = 7.1 Hz, 6 H).
13C NMR (150 MHz, CDCl3):  = 164.9, 137.2, 135.2, 134.0, 129.6,
127.2, 127.0, 123.5, 123.4, 120.3, 113.2, 112.9, 102.6, 59.5, 14.1.
Ethyl 3-Benzoyl-6-methylindolizine-1-carboxylate (6g)
Eluent: EtOAc/PE (1/10, v/v); yield: 33.1 mg (54%); brown solid; mp
123–125 °C.
1H NMR (600 MHz, CDCl3):  = 9.80 (s, 1 H), 8.27 (d, J = 9.0 Hz, 1 H),
7.82–7.78 (m, 2 H), 7.75 (s, 1 H), 7.59–7.54 (m, 1 H), 7.50 (t, J = 7.4 Hz,
2 H), 7.30 (d, J = 9.1 Hz, 1 H), 4.36 (q, J = 7.1 Hz, 2 H), 2.43 (d, J = 1.2 Hz,
3 H), 1.38 (t, J = 7.1 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 185.4, 164.1, 140.0, 138.6, 131.3,
130.6, 128.9, 128.8, 128.3, 127.3, 125.3, 122.2, 118.7, 106.0, 59.9, 18.5,
14.5.
HR-ESI-MS: m/z calcd for C34H28N2O4 [M + H]+: 529.2122; found:
529.2121.
HR-ESI-MS: m/z calcd for C19H17NO3 [M + H]+: 308.3490; found:
308.3493.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–L

L
L. He et al.
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Synthesis
Ethyl 3,3′-Dibutyl-1′-ethyl-[2,2′-biindolizine]-1-carboxylate (8b)
(3) Das, A. K.; Som, S. Orient. J. Chem. 2006, 2, 415.
(4) Sharma, P.; Kumar, A.; Sharma, S.; Rane, N. Bioorg. Med. Chem.
Lett. 2005, 15, 937.
(5) James, D. A.; Koya, K.; Li, H.; Liang, G. Q.; Xia, Z. Q.; Ying, W. W.;
Wu, Y. M.; Sun, L. J. Bioorg. Med. Chem. Lett. 2008, 18, 1784.
(6) Teklu, S.; Gundersen, L.-L.; Riseand, F.; Tilset, M. Tetrahedron
2005, 61, 4643.
(7) Kim, E.; Koh, M.; Ryu, J.; Park, S. B. J. Am. Chem. Soc. 2008, 130,
12206.
(8) For selected examples, see: (a) Wang, W.; Han, J.; Sun, J.; Liu, Y.
J. Org. Chem. 2017, 82, 2835. (b) Shen, B.; Li, B.; Wang, B. Org.
Lett. 2016, 18, 2816. (c) Brioche, J.; Meyer, C.; Cossy, J. Org. Lett.
2015, 17, 2800.
(9) For selected examples, see: (a) Schwier, T.; Sromek, A. W.; Yap,
D. M. L.; Chernyak, D.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129,
9868. (b) Yan, B.; Liu, Y. Org. Lett. 2007, 9, 4323. (c) Smith, C. R.;
Bunnelle, E. M.; Rhodes, A. J.; Sarpong, R. Org. Lett. 2007, 9,
1169.
(10) For selected examples, see: (a) Liu, R.-R.; Hong, J.-J.; Lu, C.-J.; Xu,
M.; Gao, J.-R.; Jia, Y.-X. Org. Lett. 2015, 17, 3050. (b) Gao, M.;
Tian, J.; Lei, A. Chem. Asian J. 2014, 9, 2068. (c) Liu, J.-L.; Liang,
Y.; Wang, H.-S.; Pan, Y.-M. Synlett 2015, 26, 2024.
(11) Pandya, A. N.; Fletcher, J. T.; Villa, E. M.; Agrawal, D. K. Tetrahe-
dron Lett. 2014, 55, 6922.
(12) Tang, S.; Liu, K.; Long, Y.; Qi, X.; Lan, Y.; Lei, A. Chem. Commun.
2015, 51, 8769.
(13) Reddy, N. N. K.; Mohan, D. C.; Adimurthy, S. Tetrahedron Lett.
2016, 57, 1074.
(14) Xia, J.-B.; Wang, X.-Q.; You, S.-L. J. Org. Chem. 2009, 74, 456.
(15) (a) Liu, Q.; Liu, T.; Ma, N.; Tu, C.; Wang, R.; Zhang, G. J. Org.
Chem. 2019, 84, 7255. (b) Jiang, S.; Liu, Z.; Lu, W.; Wang, G. Org.
Chem. Front. 2018, 5, 1188. (c) Yang, H.; Tan, Y.; Yang, Y.; Sun, X.;
Miao, C. J. Org. Chem. 2016, 81, 1157. (d) Liu, T.; Zhang, Z.; Liu,
Q.; Zhang, P.; Jia, P.; Zhang, Z.; Zhang, G. Org. Lett. 2014, 16,
1020. (e) Tang, D.; Wu, P.; Liu, X.; Chen, Y.; Guo, S.; Chen, W.;
Chen, B. J. Org. Chem. 2013, 78, 2746. (f) Liwosz, T. W.; Chemler,
S. R. Chem. Eur. J. 2013, 19, 12771.
Eluent: EtOAc/PE (1/20, v/v); yield: 27.2 mg (28%); yellow oil.
1H NMR (400 MHz, CDCl3):  = 8.30 (d, J = 9.0 Hz, 2 H), 7.24 (s, 2 H),
7.12–7.06 (m, 2 H), 6.62–6.56 (m, 2 H), 4.40 (q, J = 7.1 Hz, 4 H), 2.73–
2.63 (m, 4 H), 1.43 (t, J = 7.1 Hz, 10 H), 1.22–1.11 (m, 4 H), 0.70 (t, J =
7.3 Hz, 6 H).
13C NMR (100 MHz, CDCl3):  = 165.3, 137.6, 136.4, 123.3, 123.1,
119.9, 112.6, 112.3, 102.3, 59.4, 33.2, 26.3, 22.9, 14.6, 13.8.
HR-ESI-MS: m/z calcd for C30H36N2O4 [M + H]+: 489.2676; found:
489.2680.
Ethyl 2-(Pyridin-2-yl)-2-[(2,2,6,6-tetramethylpiperidin-1-
yl)oxy]acetate (9)
Under N2 atmosphere, ethyl 2-(pyridin-2-yl)acetate (1a; 33.0 mg, 0.2
mmol), phenylacetylene (2a; 40.9 mg, 0.4 mmol), TEMPO (63.8 mg,
0.4 mmol), I2 (101.5 mg, 0.4 mmol), dppe (15.9 mg, 0.04 mmol), and
Na2CO3 (42.4 mg, 0.4 mmol) were mixed in DMF (2 mL). The reaction
tube was heated in an oil bath at 160 °C for 4 h. After completion of
the reaction, the reaction mixture was washed with sat. aq Na2S2O3
and extracted with EtOAc (3 × 40 mL), dried (anhyd Na2SO4), and the
solvent was removed under reduced pressure. The remaining crude
product was then purified through column chromatography using sil-
ica gel (EtOAc/PE 1/5, v/v) to afford the product 9 as a brown oil; yield:
31.4 mg (49%).
1H NMR (600 MHz, CDCl3):  = 8.56 (d, J = 4.4 Hz, 1 H), 7.73 (td, J = 7.7,
1.7 Hz, 1 H), 7.62 (d, J = 7.8 Hz, 1 H), 7.23–7.20 (m, 1 H), 5.42 (s, 1 H),
4.23–4.13 (m, 2 H), 1.50 (d, J = 6.8 Hz, 2 H), 1.42 (s, 2 H), 1.32 (d, J =
11.7 Hz, 1 H), 1.28–1.21 (m, 7 H), 1.19 (s, 3 H), 1.13 (s, 3 H), 0.71 (s, 3
H).
13C NMR (150 MHz, CDCl3):  = 171.2, 158.1, 149.1, 136.8, 122.9,
121.8, 89.7, 61.0, 60.1, 40.2, 33.3, 32.9, 20.3, 17.1, 14.2.
HR-ESI-MS: m/z calcd for C18H28N2O3K [M + K]+: 359.1732; found:
359.1731.
(16) (a) Ficher, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Huo, Z.;
Yamamoto, Y. J. Am. Chem. Soc. 2008, 130, 15720. (b) Aggarwal,
T.; Kumar, S.; Verma, A. K. Org. Biomol. Chem. 2016, 14, 7639.
(17) Roy, S. Eur. J. Org. Chem. 2019, 765.
(18) Liu, Y.; Hu, H.; Zhou, J.; Wang, W.; He, Y.; Wang, C. Org. Biomol.
Chem. 2017, 15, 5016.
Funding Information
Financial supports from the Natural Science Foundation of Guizhou
Province
of
China
(QKHJC[2017]1117,
QKHJC[2018]1109,
QKHPTRC[2017]5718), and West Light Foundation of The Chinese
Academy of Sciences are acknowledged.
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(19) Wang, C.; Jia, H.; Li, Z.; Zhang, H.; Zhao, B. RSC Adv. 2016, 6,
21814.
(20) Cai, C.; Gu, J. Org. Biomol. Chem. 2016, 14, 9966.
(21) Yan, R.; Xiang, L.; Zhang, F.; Chen, B.; Pang, X.; Yang, X.; Huang,
G. RSC Adv. 2015, 5, 29424.
Supporting Information
Supporting information for this article is available online at
(22) Helan, V.; Gulevich, A.; Gevorgyan, V. Chem. Sci. 2015, 6, 1928.
(23) Douglas, T.; Pordea, A.; Dowden, J. Org. Lett. 2017, 19, 6396.
(24) Li, G.; Hu, H.; Kan, Y.; Ma, K. J. Org. Chem. 2014, 34, 903.
(25) He, Y.; Yin, W.; Wang, J.; Huang, J.; Pang, X.; Gan, C.; Yang, F.;
Huang, C. Org. Chem. Front. 2018, 5, 1772.
https://doi.org/10.1055/s-0039-1690229.
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References
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© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–L