One-pot synthesis of iodoindolizine derivatives via a novel multicomponent reaction

Article abstract of DOI:10.3184/174751913X13667371904771

A one-pot reaction was developed to synthesise a variety of 1-iodoindolizines from substituted acetophenone, acetic acid, pyridine, and molecular iodine. The structure of 3-benzoyl-1-iodoindolizine (2a) and 1,3-dibenzoylindolizine (3a) was further confirmed by X-ray single crystal analysis.

Full text of DOI:10.3184/174751913X13667371904771

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 323
JUNE, 323–326
One-pot synthesis of iodoindolizine derivatives via a novel
multicomponent reaction
Peiyun Yan, Juanjuan Liu, Qian Sun, Juan Yao, Zhiheng Xue and Cunde Wang*
School of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou 225002, P. R. China
A one-pot reaction was developed to synthesise a variety of 1-iodoindolizines from substituted acetophenone, acetic
acid, pyridine, and molecular iodine. The structure of 3-benzoyl-1-iodoindolizine (2a) and 1,3-dibenzoylindolizine (3a)
was further confirmed by X-ray single crystal analysis.
Keywords: multicomponent reaction, 1-iodoindolizine, 3-acylindolizine, acetophenone, molecular iodine
The indolizines are important bridgehead nitrogen heterocy-
cles of natural products which have received much attention
due to their interesting molecular structures featuring 10
π-delocalised electrons. Indolizine derivatives have potential
pharmaceutical applications that have encouraged the design
and synthesis of new analogues with increased pharmacologi-
cal activities.1–7 Compounds containing the indolizine moiety
have a wide range of biological activities, such as the central
nervous system depressants,8 calcium entry blockers,9 and
antimycobacterial agents.10 Furthermore substituted indol-
izines and their derivatives have also been used extensively
as versatile building blocks for the synthesis of dyes,11 bio-
logical markers12,13 and electroluminescent materials14,15 with
enhanced electronic and photonic properties. Thus, efficient
new approaches for the preparation of chemically and biologi-
cally relevant indolizines are of great significance in chemical
research, especially those with halo substituents.
Many substituted indolizines have been synthesised by
various conventional named routes such as the Schmidt reac-
tion, the Tschitschibabin reaction, 1,3-dipolar cycloadditions
of pyridinium methylides with electron deficient alkynes
or alkenes16 1,5-dipolar cyclisations17,18 and metal-catalysed
intra-molecular cycloisomerisations of pyridines with specific
C-2 functionalisation.19,20 Although, there are several methods
for the preparation of the substituted indolizine derivatives,
to the best of our knowledge, there have been no reports of
a one-pot reaction that give a 1-haloindolizine derivative.
The 1-haloindolizine structure is unusual and may find
its application in related transformation leading to useful
products.
Results and discussion
Our initial test reaction on the model compound 2a (Scheme 1)
was run at room temperature for 40h, but no reaction occurred
(Table 1, entry 1). It is known that 1,3-dipolar cycloadditions
of pyridinium methylides with electron deficient alkynes or
alkenes can form an indolizine frame, in fact, in this one-pot
reaction a pyridinium methylide might be prepared first, how-
ever, the formation of pyridinium methylide must be carried
out under heating. We observed the reactions using higher
temperature worked well when the reaction was carried out
using acetophenone (1), acetic acid, pyridine, and molecular
iodine, the yield of the desired product 2a was 24%, Table 1,
entry 2, 53% Table 1, entry 3, and 45%, Table 1, entry 4 at 110,
120, 130 °C respectively. At higher temperatures, an unex-
pected product 1,3-dibenzoylindolizine (3a) was also isolated.
In order to optimise other reaction conditions, reaction time,
solvents and the ratio of reactants were measured. As shown
in Table 1, the reaction gave a satisfactory yield in pyridine at
120 °C over 40 h.
Table 1 Optimisation of temperature, time and solvents in the
synthesis of 2a
Entry 1a/I2/AcOH/Pyridine/T(°C)/t(h)/Solventa
Yield/%b
1
2
3
4
5
6
7
8
9
1/1/1/Pyridine/rt/40/Pyridine
1/1/1/Pyridine/110/40/Pyridine
1/1/1/Pyridine/120/40/Pyridine
1/1/1/Pyridine/130/40/Pyridine
1/1/1/Pyridine/120/35/Pyridine
1/1/1/Pyridine/120/45/Pyridine
1/1.5/1/Pyridine/120/40/Pyridine
1/1/1.5/Pyridine/120/40/Pyridine
1/1/1/Pyridine(1mL)/120/40/
DMSO(10mL)
0 (2a), 0 (3a)
24 (2a), 0 (3a)
53 (2a), 18 (3a)
45 (2a), 24 (3a)
46 (2a), 18 (3a)
53 (2a), 20 (3a)
52 (2a), 15 (3a)
50 (2a), 22 (3a)
32 (2a), 0 (3a)
In one of our electroluminescent materials and medicinal
chemistry programs, we needed 1-iodoindolizines to prepare
more complex analogues containing an indolizine core. Indoli-
zine can serve as an isosteric replacement for some nitrogen
heterocycles and is found to possess interesting biological
activities. We report a simple synthesis of 1-halo function-
alised indolizine derivatives from one-pot reaction of substi-
tuted acetophenone (1), acetic acid, pyridine, and molecular
iodine.
10
1/1/1/Pyridine(1mL)/120/40/
DMF(10mL)
18 (2a), 0 (3a)
a 1a/I2/AcOH (mol/mol/mol).
b Isolated yield.
Scheme 1 One-pot synthesis of 1-iodoindolizine derivatives from substituted acetophenone, acetic acid, pyridine, and
molecular iodine.
* Correspondent. E-mail: wangcd@yzu.edu.cn

324 JOURNAL OF CHEMICAL RESEARCH 2013
Table 2 One-pot synthesis of 1-iodo indolizine derivatives
Entry
Ar
Yield/%a
1
2
3
4
5
6
C6H5
53 (2a), 18 (3a)
54 (2b), 20 (3b)
56 (2c)
p-MeC6H4
p-MeOC6H4
pyridin-2-yl
p-BrC6H4
45 (2d)
53 (2e), 23 (3c)
51 (2f)
m-MeOC6H4
a Isolated yield.
A number of commercially available substituted acetophe-
nones were condensed with acetic acid, pyridine, and molecu-
lar iodine under optimised reaction condition (Scheme 1), and
the results are summarised in Table 2. As shown in Table 2,
both halo substituted and electron-rich acetophenones are
applicable to the reaction, giving the products in moderate
yields.
Unambiguous evidence for the structure and stereochemis-
try of 2a and 3a was obtained from a single crystal X-ray anal-
ysis. ORTEP diagrams of 2a and 3a are shown in Figs 1 and 2.
The crystallographic data of 2a and 3a are listed in Table 3.
Crystallographic data for 2a and 3a have been deposited
with the Cambridge Crystallographic Data Centre with the
deposition number CCDC 919705 and 919706. These data can
be obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax +44 1223 336033,
E-mail: deposit@ccdc.cam.ac.uk].
In conclusion, we have described a novel four-component
synthesis of 1-iodo functionalised indolizines from one-
pot reaction between substituted acetophenone, acetic acid,
pyridine, and molecular iodine to afford 1-iodo functionalised
1-iodo-3-aroylindolizines in moderate yields. The structure of
3-benzoyl-1-iodoindolizine (2a) and 1,3-dibenzoylindolizine
(3a) was further confirmed by X-ray single crystal analysis.
Fig. 2 Molecular structure of 1,3-dibenzoylindolizine (3a).
Non-hydrogen atoms are shown at the 30% probability level.
70 eV. X-ray crystallographic analysis was performed with a Smart-
1000 CCD diffractometer using monochromatic Mo KR radiation (λ)
0.71073 Å) and integrated with the SAINT-Plus program. All calcula-
tions were performed with programs from the SHELXTL crystallo-
graphic software package. The elemental analyses were performed
in a Perkin-Elmer 240C instrument. Flash chromatography was
performed on silica gel (230–400 mesh) eluting with an ethyl acetate–
hexanes mixture. All reactions were monitored by TLC. All reagents
and solvents were purchased from commercial sources and purified
commonly before used.
Synthesis of 1-iodo-3-aroylindolizines; general procedure
The appropriate substituted acetophenone (1.6 mmol), molecular
iodine (1.6 mmol, 0.42 g) and acetic acid (1.6 mmol, 0.12g, 0.3 mL)
were dissolved in 10 mL of pyridine at room temperature, and the
resultant mixture was stirred at 120 °C for 40 h, and the completion of
reaction was confirmed by TLC (EtOAc/hexanes 1:10). After the mix-
ture was cooled to room temperature, the excess pyridine was removed
under reduced pressure. Subsequently, the residues were treated with
dichloromethane (15 mL), the precipitated solid was filtered off and
washed with dichloromethane (5 mL) twice, the merged filtrate was
washed with water and brine, dried over anhydrous sodium sulfate.
The filtrate was purified by flash chromatography (silica gel, EtOAc/
hexanes, 1/20) to give product 2a–f and 3a–c (Scheme 1, Table 2).
3-Benzoyl-1-iodoindolizine (2a): Yellow solid; m.p. 140–141 °C
Experimental
All melting points were determined in aYanaco melting point appara-
tus and are uncorrected. IR spectra were recorded in a Nicolet FT-IR
5DX spectrometer. The 1H NMR (600 MHz) and 13C NMR (150 MHz)
spectra were recorded in a Bruker AV-600 spectrometer with TMS as
internal reference in CDCl3 solutions. The J values are given in hertz.
1
Only discrete or characteristic signals for the H NMR are reported.
The MS spectra were obtained on a ZAB-HS mass spectrometer with
1
(CH2Cl2/PE); H NMR (CDCl3, 600 MHz) δ (ppm): 9.88 (d, J =
6.0 Hz, 1H), 7.71 (d, J = 6.6 Hz, 2H), 7.50 (t, J = 8.4 Hz, 2H), 7.44–
7.40 (m, 3H), 7.24 (t, J = 6.6 Hz, 1H), 6.92 (s, 1H); 13C NMR (CDCl3,
150 MHz) δ (ppm): 182.93, 139.21, 138.54, 131.74, 130.14, 128.10,
127.90, 127.85(2C), 127.28(2C), 124.62, 123.42, 117.90, 113.52; IR
(KBr, cm−1): 2939, 2839, 1612, 1560, 1514, 1460, 1258, 1131, 1031,
839, 679; MS(EI)(m/z): 348 [(M+1)+] (100%). Anal. Calcd for
C15H10INO: C, 51.90; H, 2.90; N, 4.03. Found: C, 51.78; H, 2.69; N,
4.12%.
1,3-Dibenzoylindolizine (3a): Yellow solid; m.p. 205–206 °C
1
(CH2Cl2/PE); H NMR (CDCl3, 600 MHz) δ (ppm): 9.96 (d, J =
7.2 Hz, 1H), 8.60 (d, J = 9.0 Hz, 1H), 7.74–7.72 (m, 4H), 7.55 (s, 1H),
7.51 (t, J = 7.8 Hz, 1H), 7.48 (t, J = 7.2 Hz, 2H), 7.42–7.32 (m, 4H),
7.14 (t, J = 7.2 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ (ppm): 190.43,
185.64, 140.86, 139.94, 139.76, 131.63, 131.57, 130.52, 129.16,
129.02, 128.96(2C), 128.93(2C), 128.43(2C), 128.39(2C), 122.46,
120.43, 116.38, 113.68; IR (KBr, cm−1): 1686, 1605, 1503, 1452,
1423, 1326, 1181, 1068, 930, 805, 707, 549; MS(EI)(m/z): 326
[(M+1)+] (100%). Anal. Calcd for C22H15NO2: C, 81.21; H, 4.65; N,
4.30. Found: C, 81.10; H, 4.52; N, 4.39%.
1-Iodo-3-(4-methylbenzoyl)indolizine (2b):Yellow solid; m.p. 160–
1
161 °C (CH2Cl2/PE); H NMR (CDCl3, 600 MHz) δ (ppm): 9.92 (d,
Fig. 1 Molecular structure of 3-benzoyl-1-iodoindolizine (2a).
Non-hydrogen atoms are shown at the 30% probability level.
J = 7.2 Hz, 1H), 7.70 (d, J = 7.8 Hz, 2H), 7.56 (d, J = 9.0 Hz, 1H),

JOURNAL OF CHEMICAL RESEARCH 2013 325
Table 3 Crystallographic data of 2a and 3a
Entry
Compound 2a
Compound 3a
Empirical formula
Formula weight
Wavelength/Å
Temperature/K
Crystal system
space group
C16H10INO
C22H15NO2
359.15
325.35
0.71073
296(2)
0.71073
296(2)
Tetragonal,
P4(3)2(1)2
Orthorhombic,
P2(1)2(1)2(1)
a = 8.5765(9) Å
b = 9.6914(10) Å
c = 15.4438(16) Å
α = 90°
a = 10.2367(4) Å
b = 10.2367(4) Å
c = 32.000(3) Å
α = 90°
Unit cell dimensions
β = 90°
β = 90°
γ = 90°
γ = 90°
Volume/Å3
Z,
1283.7(2)
3353.3(4)
4,
8,
Calculated density/g cm−3
Absorption coefficient/mm−1
F(000)
1.858
1.289
2.484
0.083
696
1360
Crystal size/mm
θ range for data collection
h,k,l ranges
0.21 ×0.19 ×0.17
1.48 to 27.32°
–11<=h<=10, –12<=k<=11,
–19<=l<=19
11090/2896
[R(int) = 0.0290]
99.9%
0.21 × 0.19 × 0.17
1.34 to 27.62°.
–10<=h<=13, –13<=k<=13
–41<=l<=41
29610/3873
[R(int) = 0.0372]
99.9%
Reflections collected/unique
Completeness
Data/restraints/parameters
2896/0/163
1.061
3873/0/226
0.820
Goodness-of-fit on F2
Final R indices [I>2sigma(I)]
R indices (all data)
R1 = 0.0195, wR2 = 0.0417
R1 = 0.0214, wR2 = 0.0430
0.262 and –0.542
R1 = 0.0418, wR2 = 0.1277
R1 = 0.0586, wR2 = 0.1508
0.144 and –0.24
Largest diff. peak and hole(e Å−3)
7.47 (s, 1H), 7.30 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 8.4 Hz, 1H),
6.98 (t, J = 7.2 Hz, 1H), 2.45 (s, 3H); 13C NMR (CDCl3, 150 MHz)
δ (ppm): 183.90, 141.71, 139.40, 137.50, 132.55, 129.05(2C), 128.98,
128.75(2C), 128.08, 125.41, 124.57, 118.92, 114.39, 21.55; IR (KBr,
cm−1): 3031, 2916, 1610, 1561, 1503, 1464, 1343, 1298, 1181, 1071,
877, 744, 607; MS(EI)(m/z): 362 [(M+1)+] (100%). Anal. Calcd for
C16H12INO: C, 53.21; H, 3.35; N, 3.88. Found: C, 53.02; H, 3.60; N,
4.04%.
J = 6.6 Hz, 1H), 8.67 (d, J = 4.2 Hz, 1H), 8.28 (s, 1H), 8.00 (d, J =
7.8 Hz, 1H), 7.83 (t, J = 7.2 Hz, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.39–
7.37 (m, 1H), 7.26 (t, J = 7.8 Hz, 1H), 6.94 (t, J = 7.2 Hz, 1H); 13C
NMR (CDCl3, 150 MHz) δ (ppm): 181.46, 138.79, 137.98, 131.58,
130.55, 129.40, 128.02, 124.93, 124.86, 123.12, 118.00, 113.74,
54.51; IR (KBr, cm−1): 2920, 1730, 1664, 1554, 1461, 1393, 1228,
1143, 1083, 873, 834, 746, 463; MS(EI)(m/z): 425 [(M+1)+] (82%),
426 [(M+2)+] (100%). Anal. Calcd for C15H9BrINO: C, 42.29; H,
2.13; N, 3.29. Found: C, 42.14; H, 2.22; N, 3.44%.
1,3-Di(4-methylbenzoyl)indolizine (3b): Yellow solid; m.p. 161–
1
1,3-Di(4-bromobenzoyl)indolizine (3c): Yellow solid; m.p. 184–
162 °C (CH2Cl2/PE); H NMR (CDCl3, 600 MHz) δ (ppm): 9.92 (d,
1
185 °C (CH2Cl2/PE); H NMR (CDCl3, 600 MH) δ (ppm): 9.93 (d,
J = 6.6 Hz, 1H), 8.57 (d, J = 9.0 Hz, 1H), 7.93 (d, J = 9.6 Hz, 3H),
7.66 (t, J = 7.8 Hz, 2H), 7.57 (s, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.21–
7.17 (m, 3H), 7.10 (t, J = 7.2 Hz, 1H), 2.34 (s, 6H); 13C NMR (CDCl3,
150 MHz) δ (ppm): 189.31, 187.53, 171.06, 143.56, 141.24, 141.15,
139.76, 136.21, 136.02, 129.22, 128.17, 128.14, 128.08, 128.04,
127.71, 125.60, 121.48, 119.38, 115.16, 112.71, 20.73, 20.54; IR
(KBr, cm−1): 2917, 1674, 1610, 1565, 1500, 1416, 1281, 1177, 1150,
1015, 962, 873, 759, 602; MS(EI)(m/z): 354 [(M+1)+] (86%). Anal.
Calcd for C24H19NO2: C, 81.56; H, 5.42; N, 3.96. Found: C, 81.72; H,
5.30; N, 4.22%.
J = 6.6 Hz, 1H), 8.59 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 4H),
7.57 (d, J = 7.8 Hz, 3H), 7.54–7.52 (t, 2H), 7.45 (s, 1H), 7.17 (t,
J = 7.2 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ (ppm): 188.11,
183.32, 139.95, 137.55, 137.38, 130.79, 130.74, 129.42, 128.87,
128.46, 128.20, 125.58, 125.50, 121.23, 119.43, 115.70, 112.46; IR
(KBr, cm−1): 1616, 1584, 1556, 1505, 1482, 1438, 1339, 1224, 1176,
1062, 877, 613; MS(EI)(m/z): 480 [M+] (53%), 450 [(M+2)+] (73%).
Anal. Calcd for C22H13Br2NO2: C, 54.69; H, 2.71; N, 2.90. Found: C,
54.82; H, 2.66; N, 3.08%.
1-Iodo-3-(3-methoxybenzoyl)indolizine (2f): Yellow solid; m.p.
116–117 °C (CH2Cl2/PE); 1H NMR (CDCl3, 600 MHz) δ (ppm): 9.67
(d, J = 6.6 Hz, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.43 (s, 1H), 7.34 (t,
J = 7.8 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 10.8 Hz, 2H),
7.03 (d, J = 7.8 Hz, 1H), 6.93 (t, J = 7.2 Hz, 1H), 3.80 (s, 3H); 13C
NMR (CDCl3, 150 MHz) δ (ppm): 182.61, 158.52, 140.52, 138.63,
131.79, 128.26, 128.03, 124.67, 123.37, 120.42, 117.95, 116.26,
113.55, 112.67, 54.44; IR (KBr, cm−1): 3075, 2924, 2844, 1624, 1584,
1466, 1347, 1241, 1176, 1030, 869, 789, 748, 690; MS(EI)(m/z): 378
[(M+1)+] (100%). Anal. Calcd for C16H12INO2: C, 50.95; H, 3.21; N,
3.71. Found: C, 51.20; H, 3.30; N, 3.98%.
1-Iodo-3-(4-methoxybenzoyl)indolizine (2c): Yellow solid; m.p.
146–147 °C (CH2Cl2/PE); 1H NMR (CDCl3, 600 MHz) δ (ppm): 9.81
(d, J = 6.6 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 9.0 Hz, 1H),
7.41 (s, 1H), 7.20 (t, J = 10.2 Hz, 1H), 6.94 (d, J = 9.6 Hz, 2H), 6.89
(t, J = 6.6 Hz, 1H), 3.82 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm):
183.08, 162.28, 139.24, 132.73, 132.15, 131.06, 128.89, 125.20,
124.53, 118.90, 114.24, 113.62, 55.46, 54.28; IR (KBr, cm−1): 3061,
2968, 1608, 1565, 1504, 1467, 1337, 1258, 1172, 1024, 879, 741, 607;
MS(EI)(m/z): 378 [(M+1)+] (100%). Anal. Calcd for C16H12INO2: C,
50.95; H, 3.21; N, 3.71. Found: C, 51.06; H, 3.34; N, 3.90%.
(1-Iodoindolizin-3-yl)(pyridin-2-yl)methanone (2d): Yellow solid;
m.p. 166–167 °C (CH2Cl2/PE); 1H NMR (CDCl3, 600 MHz) δ (ppm):
9.84 (d, J = 7.2 Hz, 1H), 7.59–7.56 (m, 4H), 7.50 (d, J = 9.0 Hz, 1H),
7.36 (s, 1H), 7.26–7.23 (m, 1H), 6.94 (t, J = 7.2 Hz, 1H); 13C NMR
(CDCl3, 150 MHz) δ (ppm): 178.51, 155.82, 147.36, 138.77, 135.97,
133.54, 128.42, 124.98, 124.47, 122.97, 122.82, 117.94, 113.70,
55.63; IR (KBr, cm−1): 2919, 2850, 1595, 1499, 1463, 1341, 1291,
1231, 1134, 1049, 942, 806, 700, 485; MS(EI)(m/z): 349 [(M+1)+]
(100%). Anal. Calcd for C14H9IN2O: C, 48.30; H, 2.61; N, 8.05.
Found: C, 48.22; H, 2.80; N, 8.26%.
Financial support of this research by the National Natural
Science Foundation of China (NNSFC 21173181) is gratefully
acknowledged by authors. A Project Funded by the Priority
Academic Program Development of Jiangsu Higher Education
Institutions.
Received 11 January 2013; accepted 4 March 2013
Paper 1301718 doi: 10.3184/174751913X13667371904771
Published online: 12 June 2013
1-Iodo-3-(4-bromobenzoyl)indolizine (2e): Yellow solid; m.p. 179–
180 °C (CH2Cl2/PE); 1H NMR (CDCl3, 600 MHz) δ (ppm): 10.01 (d,

326 JOURNAL OF CHEMICAL RESEARCH 2013
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