A facile approach to indolizines via tandem reaction

Article abstract of DOI:10.3987/COM-08-11570

Indolizines were synthesized by a novel tandem reaction at rt. The operation was simple and convenient. Various indolizine derivatives were obtained in good yields. The reaction mechanism was also proposed.

Full text of DOI:10.3987/COM-08-11570

HETEROCYCLES, Vol. 78, No. 3, 2009
725
HETEROCYCLES, Vol. 78, No. 3, 2009, pp. 725 - 736. © The Japan Institute of Heterocyclic Chemistry
Received, 5th October, 2008, Accepted, 17th November, 2008, Published online, 18th November, 2008
DOI: 10.3987/COM-08-11570
A FACILE APPROACH TO INDOLIZINES VIA TANDEM REACTION
Yan-Qing Ge, Jiong Jia, He Yang, Gui-Long Zhao, Fu-Xu Zhan, and Jianwu
Wang*
School of Chemistry and Chemical Engineering, Shandong University, Jinan,
Shandong 250100, P. R. China. E-mail: jwwang@sdu.edu.cn
Abstract – Indolizines were synthesized by a novel tandem reaction at rt. The
operation was simple and convenient. Various indolizine derivatives were
obtained in good yields. The reaction mechanism was also proposed.
INTRODUCTION
Indolizines have attracted considerable attention from medicinal and organic chemists because of the
interesting similarities and diversions in structure to indole.1 Synthetic indolizines play important roles as
calcium entry blockers,2 potential central nervous system depressants,3 5-HT3 receptor antagonist,4
histamine H3 receptor antagonists,5 cardiovascular agents,6 and PLA2 inhibitors.7 They have also drawn
much attention owing to their possible usage as dyes and chemosensors.8
Several condensation reactions, 1,3-dipolar cycloadditions, and 1,5-dipolar cyclizations are known to
facilitate the formation of indolizines.9 The most general method is the formation of the five-member ring
moiety in the indolizine framework.1b Chichibabin-type cyclocondensation requires elevated temperatures
and/or extended reaction time and, thus, may not be compatible with some functionality.10 Also, it
provides low to moderate yields of the products.11 Dipolar cycloaddition of pyridinium ylides with
alkynes,12 cyclopropenone13 or cyclopropenes14 is limited to the use of symmetric substrates, producing
indolizines with two identical substituents at the pyrrole ring. Therefore new methods for the synthesis of
indolizine that allow functional groups variation on indolizine nucleus are highly desirable.
Currently, transition metal-catalyzed C-N bond-forming reactions have become important methods for the
preparation of indolizines in both academic and pharmaceutical research areas,15 most of which are
realized by the formation of five-membered ring starting from six-membered pyridine derivatives. The
formation of six-membered rings moiety in indolizine framework starting from five-membered ring
system is less known.16 Our previous work17 prompted us to find a novel method to synthesize the
indolizine derivatives. Herein an intramolecular condensation of α-carbon of α, β-unsaturated esters with

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HETEROCYCLES, Vol. 78, No. 3, 2009
aldehydes was discovered and the indolizine derivatives were conveniently synthesized by a novel
tandem reaction under very mild conditions. The reaction mechanism was also proposed.
RESULTS AND DISCUSSION
Pyrrole-2-carboxaldehydes 1a-j were easily prepared as described in the literature.18 Vilsmeier-Haack
reaction of pyrrole resulted in pyrrole-2-carboxaldehyde 1a. The Vilsmeier-Haack intermediate 7 formed
from pyrrole may be acylated under normal Friedel-Crafts reaction conditions or brominated giving the
corresponding substituted pyrrole-2-carboxaldehydes 1b-j in good yields. Pyrrole-2-carboxaldehydes 1a-j
reacted with ethyl γ- bromo-α, β-unsaturated esters in DMF and suitable base at rt and the unexpected
products indolizines were obtained.
The effects of solvent and base on the yields of the reaction were evaluated using 4-acetyl-2-pyrrole
carboxaldehyde 1d and 2a as a model substrate, and the results were summarized in Table 1.
First, aprotic solvents of different polarities such as dichloromethane, tetrahydrofuran, acetone,
acetonitrile, and DMF, and protic solvents such as MeOH and EtOH were examined. It was noted that
protic and strong polar aprotic solvents were significantly preferred over weak aprotic solvents. The
reaction was fastest in MeOH, but it afforded transesterified indolizine byproduct. Second, the choice of
base was found to have a significant impact on the reaction. Strong bases such as sodium ethoxide and
potassium hydroxide gave no products. Neither did weak bases such as magnesium oxide, potassium
bicarbonate, and triethylamine. Carbonate bases, however, were found to be effective. Highest yield was
obtained with potassium carbonate. Third, the yield of 3g increased when 1d was the limiting reagent and
the number of equivalents of 2a was increased from one to two. However, an additional increase of 2a to
three had no beneficial effect on the yield. Eventually, the desired 3g was obtained in good yield under
conditions of 2 equivalents of 2a and 2.2 equivalents of potassium carbonate in DMF at rt (entry 1, Table
1). Under these conditions, a variety of differently substituted pyrrole-2-carboxaldehydes 1 with ester,
acetyl, benzoyl, and bromine functionalities underwent smooth reaction with 2 to afford indolizines 3 in
good yields (Table 2).
The structure of 3g was further confirmed by X-ray crystallographic analysis as shown in Figure 1.
Figure 1. Crystal Structure of 4f

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727
Table 1. Solvent and Base Effects on the Tandem Reaction
O
K2CO3, DMF
O
CO2Et
O
NH
CHO
N
Br
OEt
1d
2a
3g
Isolated
Entry
Base (equiv)
Solvent
Time (h)
Yield (%)
1
2
K2CO3(2.2)
K2CO3(2.2)
K2CO3(2.2)
K2CO3(2.2)
K2CO3(2.2)
K2CO3(2.2)
K2CO3(2.2)
MgO(2.2)
DMF
MeCN
acetone
THF
8
12
12
72
72
6
79
70
53
65
0
3
4
5
DCM
MeOH
EtOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
EtOH
6
75
73
0
7
7
8
72
72
72
5
9
KHCO3(2.2)
0
10
11
12
13
14
15
triethylamine (2.2)
Na2CO3(2.2)
LiOH(2.2)
NaOH(2.2)
KOH
0
55
63
33
0
5
0.5
5
NaOEt
5
0
On the basis of the above results and the literature,16 we proposed the reaction mechanism as follows:
Firstly, an intermolecular SN2 reaction between pyrrole-2-carboxaldehydes 1 and ethyl γ-
bromo-crotonates 2 occurs, and the intermediate 4 is formed. Subsequently, intermediate 4 is
deprotonated by the existing base to form a γ-carbon anion of the ester, and in turn the electron pair
transfers from the γ position to α position. Then the formed β, γ-unsaturated α-carbanion of ester cyclizes
with the aldehyde group by intramolecular nucleophilic addition to afford intermediate 5 and then 6. The
final products indolizines 3 can be obtained in situ from 6 by eliminating a water. The whole process is
shown in Scheme 1.
In summary, we have developed a novel and general method for the synthesis of N-bridgehead
indolizines with special substituent on them, especially with an ester group on the pyridine ring under
very mild conditions. The operations are simple and convenient. Various indolizine derivatives were
obtained using simple procedures in good yields. The reaction mechanism was also proposed.

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HETEROCYCLES, Vol. 78, No. 3, 2009
Table 2. Synthesis of Indolizines Derivatives from Pyrroles
R1
R2
CO2Et
R3
K2CO3, DMF
R1
R3
O
NH
N
Br
R2
OEt
OHC
2
3
1
Entry
R1
R2
R3
Product
Isolated
Yield(%)
78
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
H
H
H
H
H
H
Br
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
Me
H
Me
H
Me
H
Me
H
Me
H
Me
H
Me
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
76
75
76
65
62
79
76
81
78
85
81
86
84
80
76
82
CO2Me
CO2Me
Br
Br
Ac
Ac
propionyl
propionyl
benzoyl
benzoyl
4-nitrobenzoyl
4-nitrobenzoyl
4-methoxybenzoyl
4-methoxybenzoyl
2-fluorobenzoyl
2-fluorobenzoyl
Me
H
Me
76
79
75
2,4-dichlorobenzoyl
2,4-dichlorobenzoyl
3t
EXPERIMENTAL
All reagents and solvents were purchased from Sinopharm Chemical Reagent Co. Ltd and used without
further purification unless otherwise noted. Starting materials were prepared according to literatures.
1
Thin-layer chromatography (TLC) was conducted on silica gel 60 F254 plates (Merck KGaA). H NMR
spectra were recorded on a Bruker Avance 300 (300 MHz) spectrometer, using CDCl3 or DMSO-d6 as
solvents and tetramethylsilane (TMS) as an internal standard. Melting points were determined on an
XD-4 digital micro-melting point apparatus and are uncorrected. IR spectra were recorded with an IR
spectrophotometer Avtar 370 FT-IR (Termo Nicolet). Elemental analyses were performed on a Vario EL
III (Elementar Analysensysteme GmbH) spectroanalyzer. MS spectra were recorded on a Trace DSQ
mass spectrometer.

HETEROCYCLES, Vol. 78, No. 3, 2009
729
EtO2C
H
B-
H
N
R3
B-
R3
CO2Et
+
CHO
N
R1
Br
H
R1
R3
2
1
O
4
R3
CO2Et
CO2Et
N
N
O-
OH
R1
R1
6
5
R3
-H2O
CO2Et
N
R1
3
Scheme 1. Mechanism of the tandem reaction
General procedure for the synthesis and analytical data of 1a-j
Pyrrole-2-aldehydes 1a-j were easily prepared according to the literature.18
1H-Pyrrole-2-carbaldehyde (1a) 18
1H NMR (300 MHz, CDCl3): δ 10.36 (s, 1H), 7.18 (s, 1H), 7.01 (m, 1H), 6.36 (m, 1H). 13C NMR (75.4
Hz, CDCl3): δ 179.5, 132.9, 126.9, 121.8, 111.4.
Methyl 5-formyl-1H-pyrrole-3-carboxylate (1b) 18
1H NMR (300 MHz, CDCl3): δ 10.13 (s, 1H), 9.57 (d, 1H, J = 1.2 Hz), 7.71 (dd, 1H, J = 1.2 Hz, 3.0 Hz),
7.40 (dd, 1H, 2.4 Hz, 1.5 Hz), 3.86 (s, 3H). 13C NMR (75.4 Hz, CDCl3): δ 180.0, 164.0, 133.1, 129.7,
121.3, 118.8, 51.6.
4,5-Dibromo-1H-pyrrole-2-carbaldehyde (1c) 18
1H NMR (300 MHz, CDCl3): δ 10.28 (s, 1H), 9.35 (s, 1H), 6.97 (d, 1H, J = 2.4 Hz). 13C NMR (75.4 Hz,
CDCl3): δ 177.7, 133.1, 123.0, 113.0, 101.9.
4-Acetyl-1H-pyrrole-2-carbaldehyde (1d) 18
1H NMR (300 MHz, CDCl3): δ 9.98 (s, 1H), 9.61 (s, 1H), 7.70 (s, 1H), 7.39 (t, 1H, J = 1.8 Hz), 2.48 (s,
3H). 13C NMR (75.4 MHz, CDCl3): δ 193.0, 180.2, 133.4, 129.2, 128.0, 120.2, 27.4.
4-Propionyl-1H-pyrrole-2-carbaldehyde (1e) 18
1H NMR (300 MHz, CDCl3): δ 10.02 (s, 1H), 9.60 (s, 1H), 7.72 (s, 1H), 7.39 (s, 1H), 2.84 (q, 2H, J = 7.4
Hz), 1.22 (t, 3H, J = 7.4 Hz). 13C NMR (75.4 MHz, CDCl3): δ 196.4, 180.5, 133.3, 129.6, 127.3, 120.7,
32.9, 8.3.

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HETEROCYCLES, Vol. 78, No. 3, 2009
4-Benzoyl-1H-pyrrole-2-carbaldehyde (1f) 18
1H NMR (300 MHz, CDCl3): δ 10.78 (s, 1H), 9.62 (s, 1H), 7.87-7.48 (m, 7H). 13C NMR (75.4 MHz,
CDCl3): δ 190.3, 180.6, 138.7, 133.3, 132.3, 131.6, 129.0, 128.5, 126.4, 122.6.
4-(4-Nitrobenzoyl)-1H-pyrrole-2-carbaldehyde (1g) 18
1H NMR (300 MHz, DMSO-d6): δ 12.99 (s, 1H), 9.65 (s, 1H), 8.37 (d, 2H, J = 8.4 Hz), 8.02 (d, 2H, J =
8.4 Hz), 7.82 (s, 1H), 7.49 (s, 1H). 13C NMR (75.4 MHz, DMSO-d6): δ 188.2, 181.4, 149.6, 144.4, 134.4,
132.7, 130.3, 124.9, 124.2, 121.5.
4-(4-Methoxybenzoyl)-1H-pyrrole-2-carbaldehyde (1h) 18
1H NMR (300 MHz, CDCl3): δ 10.21 (s, 1H), 9.63 (s, 1H), 7.89 (d, 2H, J = 8.7 Hz), 7.71 (d, 1H, J = 1.2
Hz), 7.45 (s, 1H), 6.99 (d, 2H, J = 8.7 Hz), 3.90 (s, 3H). 13C NMR (75.4 MHz, CDCl3): δ 188.6, 180.1,
163.1, 133.1, 131.4, 131.3, 130.4, 126.7, 121.9, 113.8, 55.5.
4-(2-Fluorobenzoyl)-1H-pyrrole-2-carbaldehyde (1i) 18
1H NMR (300 MHz, CDCl3: δ 10.38 (s, 1H), 9.60 (d, 1H, J = 0.6 Hz), 7.67-7.42 (m, 4H), 7.29-7.15 (m,
2H). 13C NMR (75.4 MHz, CDCl3): δ 186.7, 180.3, 161.3, 158.0, 133.4, 133.0, 132.9, 131.2, 130.3, 130.2,
127.8, 127.6, 127.5, 124.4, 124.3, 121.4, 116.6, 116.3.
4-(2,4-Dichlorobenzoyl)-1H-pyrrole-2-carbaldehyde (1j) 18
1H NMR (300 MHz, CDCl3): δ 10.84 (s, 1H), 9.58 (d, 1H, J = 0.6 Hz), 7.56 (t, 1H, J = 1.5 Hz), 7.49 (d,
1H, J = 0.9 Hz), 7.37-7.33 (m, 3H). 13C NMR (75.4 MHz, CDCl3): δ 188.0, 180.4, 137.4, 136.7, 133.7,
132.0, 131.7, 130.3, 129.7, 127.1, 126.8, 121.5.
General procedure for the synthesis and analytical data of 3a-3t
To a 100-mL round-bottomed flask were added 1a-j (6.0 mmol), enoate 2a-b (7.2 mmol), potassium
carbonate (1.60 g, 12.5 mmol) and DMF (30 mL). The mixture was stirred at rt for 6-7 h and then filtered.
The filtrate was concentrated by rotary evaporation. The crude products were purified by column
chromatography.
Ethyl indolizine-7-carboxylate (3a)
1
Yellow oil. H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 7.89 (d, 1H, J = 7.2 Hz), 7.42 (s, 1H), 7.05 (d,
13
1H, J = 7.2 Hz), 6.87 (s, 1H), 6.71 (s, 1H), 4.36 (q, 2H, J = 7.2 Hz), 1.40 (t, 3H, J = 7.2 Hz). C NMR
(75.4 Hz, CDCl3): δ 166.1, 131.5, 124.3, 123.1, 118.6, 115.3, 115.1, 109.4, 104.4, 60.8, 14.4. IR (KBr)
ν = 3103, 3061, 2981, 2936, 1706, 1629, 1520, 1478, 1260, 1199, 1130, 1092, 752 cm−1. HRMS (EI): m/z
Calcd. for: C11H12NO2 [M+H]+: 190.2185; Found: 190.2188. Anal. Calcd for C11H11NO2: C, 69.83; H,
5.86; N, 7.40. Found: C, 69.86; H, 5.84; N, 7.41.
Ethyl 6-methylindolizine-7-carboxylate (3b)
Yellow solid: mp 44-45 °C. 1H NMR (300 MHz, CDCl3): δ 8.18 (s, 1H), 7.69 (s, 1H), 7.32 (s, 1H), 6.81 (t,
1H, J = 3.0 Hz), 6.63 (d, 1H, J = 3.6 Hz), 4.33 (q, 2H, J = 7.2 Hz), 2.46 (s, 3H), 1.40 (t, 3H, J = 7.2 Hz).

HETEROCYCLES, Vol. 78, No. 3, 2009
731
13C NMR (75.4 MHz, CDCl3): δ 166.7, 130.7, 124.0, 123.5, 119.5, 119.3, 117.1, 114.9, 114.0, 103.6, 60.5,
18.9, 14.4. IR (KBr) ν = cm−1. HRMS (EI): m/z Calcd. for: C12H14NO2 [M+H]+: 204.2451; Found:
204.2455. Anal. Calcd for C12H13NO2: C, 70.92; H, 6.45; N, 6.89. Found: C, 70.96; H, 6.46; N, 6.91.
7-Ethyl 2-methyl indolizine-2,7-dicarboxylate (3c)
1
Yellow solid: mp 105-107 °C. H NMR (300 MHz, CDCl3): δ 8.18 (s, 1H), 7.86 (t, 2H), 7.13-7.09 (m,
13
2H), 4.36 (q, 2H, J = 7.2 Hz), 3.89 (s, 3H), 1.39 (t, 3H, J = 7.2 Hz). C NMR (75.4 MHz, CDCl3): δ
165.5, 164.9, 131.4, 124.7, 124.2, 121.3, 120.4, 117.9, 111.3, 105.6, 61.1, 51.7, 14.4. IR (KBr) ν= 3137,
2954, 2896, 1711, 1701, 1635, 1495, 1266, 1215, 1165, 1085, 1011, 763, 556 cm−1. HRMS(EI): m/z
Calcd. for: C13H14NO4 [M+H]+: 248.2546; Found: 248.2552. Anal. Calcd for C13H13NO4: C, 63.15; H,
5.30; N, 5.67. Found: C, 63.18; H, 5.33; N, 5.69.
7-Ethyl 2-methyl 6-methylindolizine-2,7-dicarboxylate (3d)
Yellow solid: mp 128-129 °C. 1H NMR (300 MHz, CDCl3):δ8.15 (s, 1H), 7.78 (d, 2H, J = 0.6 Hz), 7.65
(d, 2H, J = 0.9 Hz), 4.34 (q, 2H, J = 7.2 Hz), 3.89 (s, 3H), 2.45 (d, 2H, J = 0.9 Hz),1.40 (t, 3H, J = 7.2 Hz).
13C NMR (75.4 MHz, CDCl3): δ 166.1, 165.1, 130.7, 125.0, 123.6, 121.5, 120.8, 116.8, 105.0, 60.8, 51.6,
18.9, 14.3. IR (KBr) ν= 3143, 3068, 2944, 1718, 1688, 1640, 1536, 1220, 1154, 1061, 1004, 776, 751
cm−1. HRMS(EI): m/z Calcd. for: C14H16NO4 [M+H]+: 262.2811; Found: 262.2813. Anal. Calcd for
C14H15NO4: C, 64.36; H, 5.79; N, 5.36. Found: C, 64.41; H, 5.77; N, 5.37.
Ethyl 2,3-dibromoindolizine-7-carboxylate (3e)
1
Yellow solid: mp 78-80 °C. H NMR (300 MHz, CDCl3):δ8.10 (s, 1H), 7.93 (d, 1H, J = 7.5 Hz), 7.23
13
(dd, 1H, J = 1.5, 7.5 Hz), 6.89 (s, 1H), 4.38 (q, 2H, J = 7.2 Hz), 1.41 (t, 3H, J = 7.2 Hz). C NMR
(75.4 MHz, CDCl3): δ 165.4, 132.4, 122.7, 121.5, 120.1, 110.8, 107.6, 106.8, 97.9, 61.2, 14.3. IR (KBr)
ν= 3120, 2988, 2907, 1711, 1628, 1517, 1463, 1246, 1145, 1018, 752, 744 cm−1. HRMS(EI): m/z Calcd.
for: C11H10 Br2NO2 [M+H]+: 348.0106; Found: 348.0107. Anal. Calcd for C11H9Br2NO2: C, 38.07; H,
2.61; N, 4.04. Found: C, 38.11; H, 2.62; N, 4.06.
Ethyl 2,3-dibromo-6-methylindolizine-7-carboxylate (3f)
1
Yellow solid: mp 99-101 °C. H NMR (300 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.94 (s, 1H), 7.08 (s, 1H),
4.28 (q, 2H, J = 7.2 Hz), 2.46 (s, 3H), 1.33 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, DMSO-d6): δ 165.7,
131.6, 122.5, 121.2, 106.9, 106.7, 97.2, 61.1, 18.6, 14.6. IR (KBr) ν= 3123, 2986, 2933, 2898, 1697, 1627,
1517, 1496, 1472, 1423, 1251, 1175, 1131, 1071, 1017, 964, 916, 776, 605cm−1. HRMS(EI): m/z Calcd.
for: C12H12Br2NO2 [M+H]+: 362.0372; Found: 362.0376. Anal. Calcd for C12H11Br2NO2: C, 39.92; H,
3.07; N, 3.88. Found: C, 39.95; H, 3.08; N,3.88.
Ethyl 2-acetylindolizine-7-carboxylate (3g)

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HETEROCYCLES, Vol. 78, No. 3, 2009
Yellow solid: mp 105-106 °C. 1H NMR (300 MHz, CDCl3): δ 8.21 (s, 1H), 7.88 (t, 2H, J = 3.6 Hz), 7.15
(dd, 1H, J = 1.5 Hz, 7.5 Hz), 7.07 (s, 1H), 4.37 (q, 2H, J = 7.2 Hz), 2.58 (s, 3H), 1.40 (t, 3H, J = 7.2 Hz).
13C NMR (75.4 MHz, CDCl3): δ 194.5, 165.4, 131.7, 129.8, 124.9, 124.4, 120.6, 117.1, 111.6, 104.6, 61.2,
27.7, 14.3. IR (KBr) ν = 3129, 3110, 2996, 2977, 1711, 1666, 1629, 1488, 1454, 1219, 1175, 1093, 818,
750, 653 cm−1. HRMS(EI): m/z Calcd. for: C13H14NO3 [M+H]+: 232.2552; Found: 232.2550. Anal. Calcd
for C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.52; H, 5.66; N, 6.07.
Ethyl 2-acetyl-6-methylindolizine-7-carboxylate (3h)
Yellow solid: mp 126 °C. 1H NMR (300 MHz, CDCl3): δ 8.17 (s, 1H), 7.77 (s, 1H), 7.66 (s, 1H), 7.00 (s,
13
1H), 4.35 (q, 2H, J = 7.2 Hz), 2.56 (s, 3H), 2.46 (s, 3H), 1.40 (t, 3H, J = 7.2 Hz). C NMR (75.4 MHz,
CDCl3): δ 194.6, 166.0, 131.0, 129.5, 125.3, 123.8, 121.8, 121.7, 116.0, 104.1, 60.9, 27.7, 18.9, 14.3. IR
(KBr) ν = 3115, 2980, 2923, 1704, 1667, 1636, 1467, 1282, 1229, 1183, 1069, 853, 769, 661 cm−1.
HRMS(EI): m/z Calcd. for: C14H16NO3 [M+H]+: 246.2817; Found: 246.2815. Anal. Calcd for C14H15NO3:
C, 68.56; H, 6.16; N, 5.71. Found: C, 68.59; H, 6.17; N, 5.71.
Ethyl 2-propionylindolizine-7-carboxylate (3i)
Yellow solid: mp 103-104 °C. 1H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 7.87 (d, 2H, J = 6.9 Hz), 7.13
(dd, 1H, J = 1.5 Hz, 7.5 Hz), 7.08 (s, 1H), 4.38 (q, 2H, J = 7.2 Hz), 2.95 (q, 2H, J = 7.2 Hz), 1.40 (t, 3H, J
13
= 7.2 Hz), 1.24 (t, 3H, J = 7.2 Hz). C NMR (75.4 MHz, CDCl3): δ 197.6, 165.5, 131.7, 129.4, 124.9,
124.5, 120.5, 116.7, 111.6, 104.4, 61.2, 33.3, 14.4, 8.3. IR (KBr) ν= 3140, 2985, 2970, 1715, 1673, 1630,
1488, 1259, 1160, 1093, 777, 758, 629 cm−1. HRMS(EI): m/z Calcd. for: C14H16NO3 [M+H]+: 246.2817;
Found: 246.2817. Anal. Calcd for C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.59; H, 6.17; N,
5.72.
Ethyl 6-methyl-2-propionylindolizine-7-carboxylate (3j)
Yellow solid: mp 111-112 °C. 1H NMR (300 MHz, CDCl3:δ8.17 (s, 1H), 7.78 (d, 2H, J = 0.6 Hz), 7.66
(s, 1H), 7.01 (s, 1H), 4.35 (q, 2H, J = 7.2 Hz), 2.94 (q, 2H, J = 7.2 Hz), 2.46 (d, 2H, J = 0.9 Hz), 1.40 (t,
13
3H, J = 7.2 Hz), 1.23 (t, 3H, J = 7.2 Hz). C NMR (75.4 MHz, CDCl3): δ 197.7, 166.1, 131.0, 129.1,
124.9, 125.3, 123.8, 121.7, 121.6, 115.7, 103.8, 60.9, 33.2, 30.9, 18.9, 14.3, 8.4. IR (KBr) ν= 3114, 2971,
2937, 1701, 1664, 1479, 1264, 1163, 1082, 791 cm−1. HRMS(EI): m/z Calcd. for: C15H18NO3 [M+H]+:
260.3083; Found: 260.3088. Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.47; H,
6.63; N, 5.42.
Ethyl 2-benzoylindolizine-7-carboxylate (3k)
Yellow solid: mp 108-109 °C. 1H NMR (300 MHz, CDCl3): δ 8.23 (s, 1H), 7.94-7.88 (m, 4H), 7.62-7.48
(m, 3H), 7.17-7.13 (m, 2H),4.38 (q, 2H, J = 7.2 Hz), 1.40 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz,
CDCl3): δ 191.4, 165.4, 139.0, 132.2, 131.6, 129.4, 128.5, 128.4, 124.8, 124.5, 120.7, 118.8, 111.7, 106.5,
61.2, 14.4. IR (KBr) ν= 3056, 2984, 1714, 1633, 1485, 1400, 1274, 1233, 1119, 883, 748, 690 cm−1.

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HRMS(EI): m/z Calcd. for: C18H16NO3 [M+H]+: 294.3245; Found: 294.3249. Anal. Calcd for C18H15NO3:
C, 73.71; H, 5.15; N, 4.78. Found: C, 73.75; H, 5.16; N, 4.77.
Ethyl 2-benzoyl-6-methylindolizine-7-carboxylate (3l)
Yellow solid: mp 142-143 °C. 1H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 7.93-7.90 (t, 2H), 7.78 (s, 1H),
7.69 (s, 1H),7.62-7.48 (m, 3H), 7.06 (s, 1H),4.35 (q, 2H, J = 7.2 Hz), 2.47 (s, 3H),1.40 (t, 3H, J = 7.2 Hz).
13C NMR (75.4 MHz, CDCl3): δ 191.5, 166.0, 139.2, 132.1, 130.8, 129.4, 128.3, 128.2, 125.3, 123.8,
121.9, 121.8, 117.8, 105.9, 60.9, 18.9, 14.3. IR (KBr) ν= 3118, 2978, 1707, 1629, 1478, 1395, 1230, 1194,
1119, 1062, 884, 724 cm−1. HRMS(EI): m/z Calcd. for: C19H18NO3 [M+H]+: 308.3511; Found: 308.3514.
Anal. Calcd for C19H17NO3: C, 74.25; H, 5.58; N, 4.56. Found: C, 74.29; H, 5.60; N, 4.55.
Ethyl 2-(4-nitrobenzoyl)indolizine-7-carboxylate (3m)
Yellow solid: mp 163-164 °C. 1H NMR (300 MHz, CDCl3): δ 8.38-8.35 (m, 2H), 8.24 (s, 1H), 8.07-8.04
(m, 2H), 7.93-7.88 (m, 2H), 7.22-7.19 (dd, 1H, J = 1.8, 7.2 Hz), 7.09 (s, 1H), 4.39 (q, 2H, J = 7.2 Hz),
1.41 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 189.5, 165.2, 149.8, 144.1, 132.0, 130.1, 127.6,
125.0, 124.5, 123.6, 121.4, 118.8, 112.2, 106.2, 61.3, 14.3. IR (KBr) ν= 3139, 3113, 2985, 1724, 1642,
1600, 1526, 1480, 1348, 1296, 1241, 1178, 1122, 848, 746cm−1. HRMS(EI): m/z Calcd. for:
C18H15N2O5 [M+H]+: 339.3221; Found: 339.3226. Anal. Calcd for C18H14N2O5: C, 63.90; H, 4.17; N,
8.28. Found: C, 63.96; H, 4.18; N, 8.26.
Ethyl 6-methyl-2-(4-nitrobenzoyl)indolizine-7-carboxylate (3n)
Yellow solid: mp 164-165 °C. 1H NMR (300 MHz, CDCl3): δ 8.37-8.35 (d, 2H, J = 8.1 Hz), 8.20 (s, 1H),
8.06-8.03 (d, 2H, J = 8.1 Hz), 7.78 (s, 1H), 7.71 (s, 1H), 7.01 (s, 1H),4.36 (q, 2H, J = 7.2 Hz), 2.48 (s,
13
1H),1.41 (t, 3H, J = 7.2 Hz). C NMR (75.4 MHz, CDCl3): δ 189.5, 165.8, 149.7, 144.3, 131.2, 130.1,
127.2, 125.2, 123.8, 123.6, 122.6, 122.5, 117.7, 105.6, 61.0, 18.9, 14.3. IR (KBr) ν= 3141, 3109, 2981,
2939, 2849, 1709, 1639, 1599, 1524, 1476, 1384, 1349, 1277, 1252, 1128, 1069, 846, 710cm−1.
HRMS(EI): m/z Calcd. for: C19H17N2O5 [M+H]+: 353.3487; Found: 353.3488. Anal. Calcd for
C19H16N2O5: C, 64.77; H, 4.58; N, 7.95. Found: C, 64.79; H, 4.57; N, 7.96.
Ethyl 2-(4-methoxybenzoyl)indolizine-7-carboxylate (3o)
Yellow solid: mp 158-159 °C. 1H NMR (300 MHz, CDCl3): δ 8.23 (s, 1H), 7.99-7.94 (m, 2H), 7.91-7.87
(m, 2H), 7.17-7.14 (dd, 1H, J = 1.5, 7.2 Hz), 7.11 (s, 1H), 7.02-6.97 (m, 2H), 4.38 (q, 2H, J = 7.2 Hz),
3.90 (s, 3H), 1.40 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 190.0, 165.5, 163.0, 131.8, 131.6,
131.4, 128.9, 124.8, 124.4, 120.5, 118.4, 113.6, 111.5, 106.4, 61.2, 55.5, 14.4. IR (KBr) ν= 3135, 2984,
2937, 2839, 1712, 1627, 1602, 1575, 1490, 1278, 1248, 1233, 1175, 1120, 1028, 848, 759cm−1.
HRMS(EI): m/z Calcd. for: C19H18NO4 [M+H]+: 324.3505; Found: 324.3510. Anal. Calcd for C19H17NO4:
C, 70.58; H, 5.30; N, 4.33. Found: C, 70.63; H, 5.31; N, 4.32.
Ethyl 2-(4-methoxybenzoyl)-6-methylindolizine-7-carboxylate (3p)

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Yellow solid: mp 132-133 °C. 1H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 7.97-7.94 (d, 2H, J = 7.8 Hz),
7.77 (s, 1H), 7.69 (s, 1H), 7.04 (s, 1H), 7.00-6.97 (d, 2H, J = 7.8 Hz), 4.35 (q, 2H, J = 7.2 Hz), 3.90 (s,
13
3H), 2.47 (s, 3H), 1.40 (t, 3H, J = 7.2 Hz). C NMR (75.4 MHz, CDCl3): δ 190.1, 166.1, 163.0, 131.8,
130.7, 128.5, 125.2, 123.7, 121.7, 121.6, 117.4, 113.6, 105.8, 60.8, 55.5, 18.9, 14.4. IR (KBr) ν= 3124,
2978, 2936, 2837, 1710, 1629, 1602, 1574, 1474, 1394, 1277, 1228, 1172, 1118, 1072, 1028, 888, 847,
777, 751, 705cm−1. HRMS(EI): m/z Calcd. for: C20H20NO4 [M+H]+: 338.3771; Found: 338.3775. Anal.
Calcd for C20H19NO4: C, 71.20; H, 5.68; N, 4.15. Found: C, 71.24; H, 5.66; N, 4.15.
Ethyl 2-(2-fluorobenzoyl)indolizine-7-carboxylate (3q)
1
Yellow solid: mp 102-103 °C. H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 7.86-7.82(m, 2H), 7.64-7.49
13
(m, 2H), 7.29-7.13 (m, 3H), 7.08 (s, 1H), 4.37 (q, 2H, J = 7.2 Hz), 1.40 (t, 3H, J = 7.2 Hz). C NMR
(75.4 MHz, CDCl3): δ 188.3, 165.3, 161.5, 158.1, 132.8, 132.7, 131.8, 130.3, 129.3, 128.3, 128.1, 124.9,
124.6, 124.2, 124.1, 120.8, 118.9, 116.5, 116.3, 111.9, 106.0, 61.2, 14.3. IR (KBr) ν= 3069, 2999, 2984,
2937, 1702, 1647, 1612, 1575, 1493, 1400, 1329, 1270, 1213, 1141, 1127, 1019, 886, 825, 754cm−1.
HRMS(EI): m/z Calcd. for: C18H15FNO3 [M+H]+: 312.315; Found: 312.315. Anal. Calcd for C18H14FNO3:
C, 69.45; H, 4.53; N, 4.50. Found: C, 69.46; H, 4.53; N, 4.51.
Ethyl 2-(2-fluorobenzoyl)-6-methylindolizine-7-carboxylate (3r)
Yellow solid: mp 115-117 °C. 1H NMR (300 MHz, CDCl3):δ8.16 (s, 1H), 7.71-7.47 (m, 4H), 7.28-7.15
(m, 2H), 7.00 (s, 1H), 4.34 (q, 2H, J = 7.2 Hz), 2.45 (s, 3H), 1.40 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz,
CDCl3): δ 188.3, 165.9, 161.5, 158.1, 132.6, 132.5, 131.0, 130.3, 130.2, 128.9, 128.5, 128.2, 125.4, 124.1,
124.0, 123.7, 122.1, 122.0, 117.8, 116.5, 116.2, 105.4, 60.8, 18.8, 14.3. IR (KBr) ν= 3141, 3065, 2975,
2929, 1704, 1697, 1656, 1637, 1614, 1521, 1475, 1449, 1232, 1124, 1064, 891, 745cm−1. HRMS(EI): m/z
Calcd. for: C19H17FNO3 [M+H]+: 326.3416; Found: 326.3222. Anal. Calcd for C19H16FNO3: C, 70.14; H,
4.96; N, 4.31. Found: C, 70.18; H, 4.98; N, 4.32.
Ethyl 2-(2,4-dichlorobenzoyl)indolizine-7-carboxylate (3s)
Yellow solid: mp 137-138 °C. 1H NMR (300 MHz, CDCl3): δ 8.19 (s, 1H), 7.84 (d, 1H, J = 7.2 Hz), 7.72
(s, 1H), 7.50 (s, 1H), 7.42 (d, 2H, J = 8.1 Hz), 7.35 (d, 2H, J = 8.1 Hz), 7.15 (d, 1H, J = 7.2 Hz), 7.00 (s,
13
1H), 4.37 (q, 2H, J = 7.2 Hz), 1.40 (t, 3H, J = 7.2 Hz). C NMR (75.4 MHz, CDCl3): δ 189.3, 165.2,
137.7, 136.5, 132.2, 132.1, 130.2, 129.9, 128.6, 127.6, 125.0, 124.6, 121.1, 119.0, 112.1, 105.9, 61.3, 14.3.
IR (KBr) ν= 3123, 3085, 2989, 2902, 1705, 1648, 1630, 1586, 1550, 1479, 1390, 1293, 1232, 1127, 1102,
1021, 887, 834, 766, 751cm−1. HRMS(EI): m/z Calcd. for: C18H14Cl2NO3 [M+H]+: 363.2147; Found:
363.2149. Anal. Calcd for C18H13Cl2NO3: C, 59.69; H, 3.62; N, 3.87. Found: C, 59.72; H, 3.63; N, 3.88.
Ethyl 2-(2,4-dichlorobenzoyl)-6-methylindolizine-7-carboxylate (3t)
Yellow solid: mp 153-154 °C. 1H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H), 7.64-7.62 (m, 2H), 7.50 (d, 1H,
J = 1.8 Hz), 7.43-7.33 (m, 2H), 6.92 (s, 1H), 4.35 (q, 2H, J = 7.2 Hz), 2.45 (s, 3H), 1.40 (t, 3H, J = 7.2

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Hz). 13C NMR (75.4 MHz, CDCl3): δ 189.4, 165.9, 137.9, 136.4, 132.2, 131.3, 130.1, 129.8, 128.2, 126.8,
125.4, 123.8, 122.4, 122.3, 117.8, 105.4, 60.9, 18.8, 14.3. IR (KBr) ν= 3143, 3065, 2983, 2902, 1708,
1656, 1637, 1588, 1521, 1475, 1383, 1340, 1284, 1231, 1125, 1103, 1064, 891, 857, 754cm−1.
HRMS(EI): m/z Calcd. for: C19H16Cl2NO3 [M+H]+: 377.2412; Found: 377.2408. Anal. Calcd for
C19H15Cl2NO3: C, 60.65; H, 4.02; N, 3.72. Found: C, 60.67; H, 4.03; N, 3.72.
ACKNOWLEDGEMENTS
The authors thank the Shandong Natural Science Foundation (No. Y2008B40) and Shandong Excellent
Young and Mid-aged Scientist Promotive Foundation (No. 2008BS04024) for financial support of this
work.We also thank State Key Laboratory of Crystal Materials of Shandong University for crystal data.
REFERENCES
1. For general reviews, see: E. T. Borrow and D. O. Holland, Chem. Rev., 1948, 42, 638; T. Uchida and
K. Matsumoto, Synthesis, 1976, 209; M. Shipman, Sci. Synth., 2001, 10, 745; J. P. Michael,
Alkaloids., 2001, 55, 91; J. P. Michael, Nat. Prod. Rep., 2002, 19, 742.
2. J. Gubin, H. Vogelaer, H. Inion, C. Houben, J. Lucchetti, J. Mahaux, G. Rosseels, M. Peiren, M.
Clinet, P. Polster, and P. Chatelain, J. Med. Chem., 1993, 36, 1425; S. P. Gupta, A. N. Mathur, A. N.
Nagappa, D. Kumar, and S. Kumaran, Eur. J. Med. Chem., 2003, 38, 867.
3. W. B. Harrell and R. F. Doerge, J. Pharm. Sci., 1967, 56, 225.
4. J. Bermudez, C. S. Fake, G. F. Joiner, K. A. Joiner, F. D. King, W. D. Miner, and G. J. Sanger, J.
Med. Chem., 1990, 33, 1924.
5. W. Chai, J. G. Breitenbucher, A. Kwok, X. Li, V. Wong, N. I. Carruthers, T. W. Lovenberg, C.
Mazur, S. J. Wilson, F. U. Axe, and T. K. Jones, Bioorg. Med. Chem. Lett., 2003, 13, 1767.
6. J. Gubin, M. Descamps, P. Chatelain, and D. Nisato, Eur. Pat. Appl. EP 235 111, 1987; L. L.
Gundersen, C. Charnock, A. H. Negussie, F. Rise, and S. Teklu, Eur. J. Pharm. Sci., 2007, 30, 26.
7. S. Hagishita, M. Yamada, K. Shirahase, T. Okada, Y. Murakami, Y. Ito, T. Matsuura, M. Wada, T.
Kato, M. Ueno, Y. Chikazawa, K. Yamada, T. Ono, I. Teshirogi, and M. Ohtani, J. Med. Chem.,
1996, 39, 3636.
8. G. G. Surpateanu, M. Becuwe, N. C. Lungu, P. I. Dron, S. Fourmentin, D. Landy, and G. Surpateanu,
J. Photochem. Photobiol. A., 2007, 185, 312; F. Delattre, P. Oisel, G. Surpateanu, F. Cazier, and P.
Blach, Tetrahedron., 2005, 61, 3939; A. V. Retaru, L. D. Druta, T. Deser, and T. Mueller, Helv.
Chim. Acta, 2005, 88, 1798; H. Sonnenschein, G. Henrich, V. Resch-Genger, and B. Schulz, Dyes
Pigments., 2000, 46, 23; F. D. Saeva and H. R. Luss, J. Org. Chem., 1988, 53, 1804; C. H. Weidner,
D. H. Wadsworth, S. L. Bender, and D. J. Beltman, J. Org. Chem., 1989, 54, 3660.

736
HETEROCYCLES, Vol. 78, No. 3, 2009
9. A. R. Hardin and R. Sarpong, Org. Lett., 2007, 9, 4547; S. Chuprakov and V. Gevorgyan, Org. Lett.,
2007, 9, 4463; I. V. Seregin, A. W. Schammel, and V. Gevorgyan, Org. Lett., 2007, 9, 3433; I. Kim,
J. Choi, H. K.Won, and G. H. Lee, Tetrahedron Lett., 2007, 48, 6863; T. Przewloka, S. Chen, Z. Xia,
H. Li, S. Zhang, D. Chimmanamada, E. Kostik, D. James, K. Koya, and L. Sun, Tetrahedron Lett.,
2007, 48, 5739; I. V. Seregin and V. Gevorgyan, J. Am. Chem. Soc., 2006, 128, 12050; R. S. Tewarl
and A. J. Bajpal, Chem. Eng. Data., 1985, 30, 505.
10. A. R. Katritzky, K. C. Caster, O. Rubio, and O. Schwarz, J. Heterocycl. Chem., 1986, 23, 1315.
11. J. Zhou, Y. Hu, and H. Hu, Synthesis, 1999, 166.
12. A. R. Katritzky, G. Qui, B. Yang, and H. Y. He, J. Org. Chem., 1999, 64, 7618.
13. D. H. Wadsworth, S. L. Bender, D. L. Smith, H. R. Luss and C. H. Weidner, J. Org. Chem., 1986,
51, 4639.
14. K. Matsumot and K. Uchida, J. Chem. Soc., Perkin Trans. 1, 1981, 73.
15. For reviews, see: J. Tsuji, Palladium Reagents and Catalysis, John Wiley & Sons: Chichester, 2004;
I. Nakamura and Y. Yamamoto, Chem. Rev., 2004, 104, 2127.
16. R. Lazzaroni, R. Settambolo, A. Caiazzo, and L. J. Pontorno, J. Organomet. Chem., 2000, 601, 320;
R. Settambolo, A. Caiazzo, and R. Lazzaroni, Tetrahedron Lett., 2001, 42, 4045; R. Settambolo, S.
Miniati, and R. Lazzaroni, Synth. Commun., 2003, 33, 2953; M. Kim and E. Vedejs, J. Org. Chem.,
2004, 69, 6945; D. Virieux, A. F. Guillouzic, and H. J. Cristau, Tetrahedron, 2006, 62, 3710.
17. J. W. Wang, J. Jia, D. J. Hou, H. M. Li, and J. Yin, Chin. J. Org. Chem., 2003, 23, 173.
18. R. M. Silverstein, E. E. Ryskiewicz, and C. Willard, Org. Synth., 1956, 36, 74; P. E. Sonnet, J. Org.
Chem., 1972, 37, 925; H. J. Anderson, C. E. Loader, and A. Foster, Can. J. Chem., 1980, 58, 2527.