A direct method for the synthesis of indolizine derivatives from easily available aromatic ketones, pyridines, and acrylonitrile derivatives

Article abstract of DOI:10.1139/cjc-2012-0534

A concise and efficient strategy has been proposed to synthesize indolizine derivatives from easily available aryl or heteroaryl methyl ketones, pyridines, and acrylonitriles. The mechanistic pathway involved the integration of iodination, pyridinium ylid

Full text of DOI:10.1139/cjc-2012-0534

414
ARTICLE
A direct method for the synthesis of indolizine derivatives from easily
available aromatic ketones, pyridines, and acrylonitrile derivatives
Qun Cai, Yan-Ping Zhu, Yang Gao, Jing-Jing Sun, and An-Xin Wu
Abstract: A concise and efficient strategy has been proposed to synthesize indolizine derivatives from easily available aryl or
heteroaryl methyl ketones, pyridines, and acrylonitriles. The mechanistic pathway involved the integration of iodination,
pyridinium ylide synthesis, and 1,3-dipolar cycloaddition. The protocols were found to be highly efficient in terms of high yields,
operational simplicity, mild reaction conditions, and easy workup. This method has provided an important supplement for the
synthesis of indolizine derivatives via a novel tandem synthesis.
Key words: indolizine derivative, iodination, pyridinium ylide synthesis, 1;3-dipolar cycloaddition, tandem synthesis.
Résumé : On a proposé une stratégie concise et efficace de synthèse des dérivés de l’indolizine en partant d’aryl- ou
d’hétéroarylméthyl-cétones, pyridines et acrylonitriles faciles a` obtenir. Le chemin réactionnel comprenait l’intégration de
l’iodation, de la synthèse de l’ylure de pyridinium et de la cycloaddition 1,3-dipolaire. Les protocoles se sont avérés hautement
efficaces comme l’indiquent les rendements élevés, la simplicité opératoire, les conditions douces de réaction et la facilité du
traitement final. Cette méthode apporte un supplément important a` la synthèse des dérivés de l’indolizine sous la forme d’une
nouvelle synthèse par réaction tandem. [Traduit par la Rédaction]
Mots-clés : dérivés de l’indolizine, iodation, synthèse de l’ylure de pyridinium, cycloaddition 1;3-dipolaire, synthèse par réaction
tandem.
Introduction
Results and discussion
Indolizines represent a significant class of nitrogen-fused het-
erocylces and are highly abundant in many natural products and
biologically active compounds.1–4 They are also known for their
intriguing molecular structures, which are similar to indole with
10 ␲-delocalized electrons.5 Consequently, a variety of methods
have been reported for the synthesis of indolizines.6 The widely
utilized method involves the formation of a five-member ring
moiety in the indolizine framework. This can be classified into
three categories: two typical condensation reactions,7 1,3-dipolar
cycloadditions,8 and 1,5-dipolar cyclizations.9 However, the most
widely-used protocol remains 1,3-dipolar cycloaddition. Accord-
ing to previously published reports, this approach suffers from
limitations such as substrate complexity, high costs, and demand-
ing conditions. Thus, further research into convenient and effi-
cient methods is still of great value for the synthesis of indolizines
from simple and readily available precursors.
In our previous study, we reported a highly efficient method
for the synthesis of ␣-iodination from aromatic ketones in meth-
anol (Scheme 1a).10 According to the previous literature,11
N-alkylpyridinium salt could be converted to indolizine with alk-
ene or alkyne via 1,3-dipolar cycloaddition (Scheme 1b). We there-
fore tried to design a direct one-step synthesis of indolizines from
simple and commercially available aromatic ketones, pyridines,
and acrylonitriles via the tandem integration of iodination, pyri-
dinium ylide synthesis, and 1,3-dipolar cycloaddition (Scheme 1c).
This rational design of tandem reactions12 and multicomponent
reactions13 has recently gained considerable popularity in syn-
thetic chemistry and drug discovery. These processes can improve
atom economy via omitting the need for several workups and
conserving both reagents and solvents.
Initially, we began by treating acetophenyone, pyridine, and
acrylonitrile in the presence of copper(II) oxide and iodine in
methanol at reflux for 22 h (Scheme 1c). Fortunately, the target
product 3-benzoylindolizine-1-carbonitrile 2a was obtained in 23%
yield.
However, in consideration of the low yield obtained after opti-
mizing the reaction conditions, we turn our attention to the
double-solvents system for achieving excellent synthetic effi-
ciency with a sequential process of multiple reactions (Table 1).
According to our previous report in the literature,10 methanol
remained as solvent when synthesizing ␣-iodination of carbonyl
compounds. Then the methanol was evaporated until it was com-
pletely dry. After that, another appropriate solvent was screened
in its respective reflux temperature, which was found to be con-
ducive to the reaction of 1,3-dipolar cycloaddition in the mixture
of ␣-iodide ketone 1c, pyridine, and acrylonitrile to obtain the
corresponding indolizine 2c. As shown in Table 1, DMF and THF
were found to be the suitable solvents for performing the conver-
sion (Table 1, entries 5 and 6). Other solvents, such as MeOH,
CH2Cl2, CH3CN, acetone, and i-PrOH, were also examined but pro-
vided only moderate yields (Table 1, entries 1–4).
Under optimal conditions, the scope of aromatic ketones was
examined by various substituents (Scheme 2). The phenyl ring
bearing electron-donating groups could all form the desired prod-
ucts in moderate to high yields (Scheme 2, 2a–2e). Meanwhile,
substrates with halogen substituents on the phenyl ring were
transformed into the corresponding 1,3-disubstituted indolizines
in moderate yields (Scheme 2, 2f–2h). It is noteworthy that the
sensitive functional hydroxyl group did not affect the yield under
standard conditions, and the expected product was obtained in
Received 21 December 2012. Accepted 12 March 2013.
Q. Cai, Y.P. Zhu, Y. Gao, J.J. Sun, and A.X. Wu. The Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152
Luoyu Road, Wuhan, Hubei 430079, China.
Corresponding author: An-Xin Wu (e-mail: chwuax@mail.ccnu.edu.cn).
Can. J. Chem. 91: 414–419 (2013) dx.doi.org/10.1139/cjc-2012-0534
Published at www.nrcresearchpress.com/cjc on 19 March 2013.

Cai et al.
415
Scheme 1. Integration of two linear tandem reactions to synthesize indolizine derivatives.
Table 1. Effect of solvent on the reaction of pyridinium ylide synthesis and 1,3-dipolar cycloaddition to
synthesize indolizine derivatives.
Entry
Solvent
Temperature (°C)
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
MeOH
CH2Cl2
CH3CN
Acetone
DMF
65
40
82
56
130
65
22
22
22
22
22
22
22
48
50
65
45
78
75
53
THF
i-PrOH
80
Note: Reagents and conditions: 1-(4-methoxyphenyl)ethanone (1 equiv.), CuO (>98% power, 1 equiv.), I2 (1 equiv.). pyridine
(2 equiv.), and acrylonitrile (5 equiv.).
66% yield (Scheme 2, 2i). Furthermore, biphenyl, naphthyl, and
heteroaryl methyl ketones also led to the corresponding products
in moderate yields (Scheme 2, 2j–2n). In addition, the structure of
2c was further confirmed by X-ray diffraction analysis (Fig. 1).
Subsequently, the scope was also extended to different substi-
tuted pyridines and alkenes. When the pyridines were substituted
with electron-donating groups (e.g., 4-Me, 3-Me, 2,4-Me2) or an
electron-withdrawing group (e.g., 4-COOCH3), the corresponding
products were all obtained in good yields (80%–89%) (Scheme 3,
2o–2r). Notably, two products (2p-1 and 2p-2, ratio 1:2) were ob-
tained when 3-methylpyridine was utilized for the synthesis of
corresponding indolizines. Similar to acrylonitrile, alkenes bear-
ing ester groups such as COOCH3 and COOC2H5 underwent the
reaction smoothly to afford the corresponding compounds in 75%
and 78% yields, respectively (Scheme 3, 2s and 2t).
On the basis of these experimental results, a possible mecha-
nism is proposed in Scheme 4 using acetophenyone (1a), pyridine
(A), and acrylonitrile (B) as examples. It is suggested that ace-
tophenyone 1a initially tautomerized to 3a, which then reacted
with iodine to afford the intermediate ␣-iodo ketone 4a.10 Subse-
quently, 4a was converted to N-alkylpyridinium salt 5a by cou-
pling with pyridine. Next, the N-alkylpyridinium salt could be
deprotoned by base to give the pyridinium ylide 6a. Finally, as a
dipole,14 6a reacted with acrylonitrile to generate 7a via 1,3-
dipolar cycloaddition followed by oxidation aromatization15 to
provide the desired product 2a.
Conclusions
In conclusion, we have successfully developed a convenient and
facile procedure for the synthesis of indolizine derivatives, which
proceeded in good yields by the integration of iodination, pyri-
dinium ylide synthesis, and 1,3-dipolar cycloaddition in the pres-
ence of a MeOH–THF double-solvents system. This tandem
protocol requires only simple and readily available substrates and
mild reaction conditions with further advantages found in the
ease of operation, high yields, and wide functional group toler-
ance. It has provided an important supplement for the synthesis
of indolizine derivatives. Further studies on the synthetic applica-
tions of this reaction will be reported in due course.
Experimental section
General
All aryl methyl ketones, pyridine derivatives, and other re-
agents were obtained from commercial suppliers and used with-
Published by NRC Research Press

416
Can. J. Chem. Vol. 91, 2013
Scheme 2. Scope of aromatic ketones to synthesize indolizine derivatives. The reaction was performed with 1 (1 mmol), CuO (>98% powder,
1 mmol), I2 (1 mmol), 3 (2 mmol), and 4 (5 mmol) in THF (10 mL) at 65 °C for 22 h.
Fig. 1. Single crystal X-ray structure of 2c.
out further purification. TLC analysis was performed using
precoated glass plates. Column chromatography was performed
using silica gel (200–300 mesh). IR spectra were recorded on a
Perkin-Elmer PE-983 infrared spectrometer as KBr pellets with
decoupling spectrophotometers. HRMS were obtained on a
Bruker Apex-Ultra 7.0T FTMS equipped with an electrospray
source (ESI). The X-ray crystal structure determination of 2c was
obtained on a Bruker SMART APEX CCD system. Melting points
were determined using an XT-4 apparatus and not corrected.
1
absorption in cm−1. H NMR spectra were recorded on a Varian
Mercury 400 or 600 MHz spectrometer. Chemical shifts are re-
ported in ppm, relative to the internal standard of tetramethylsi-
lane. Data are reported as follows: chemical shift, multiplicity
(singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m)), cou-
pling constants (Hz). 13C NMR spectra were recorded on a Varian
Mercury 400 (100 MHz) or 600 (150 MHz) with complete proton
General procedure for synthesis of indolizine derivatives
(2a as an example)
Finely powered CuO (80 mg, 1.0 mmol) and I2 (254 mg, 1.0 mmol)
were added to a well-stirred solution of the acetophenyone
(1.0 mmol) in anhydrous MeOH (20 mL). The mixture was refluxed
Published by NRC Research Press

Cai et al.
417
Scheme 3. Scope of pyridines and alkenes to synthesize indolizine derivatives. The reaction was performed with 1 (1 mmol), CuO
(>98% powder, 1 mmol), I2 (1 mmol), 3 (2 mmol), and 4 (5 mmol) in THF (10 mL) at 65 °C for 22 h.
Scheme 4. A possible reaction mechanism.
at 65 °C. After disappearance of the reactants (monitored by TLC),
the mixture was filtered and the solvent was evaporated on a
rotary evaporator and washed three times with ethyl acetate. Af-
ter that, it was mixed with pyridine (2.0 mmol) and acrylonitrile
(5.0 mmol) for about 22 h (monitored by TLC). The residue was
poured into 10% Na2S2O3 solution (50 mL), the mixture was ex-
tracted with CH2Cl2, and the organic layer was dried (Na2SO4).
Removal of the solvent and purification of the residue by column
chromatography gave the target products 2a as a white solid.
688 cm−1. HRMS (ESI): m/z [M+H]+ calcd. for C16H11N2O: 247.0866;
found: 247.0864.
3-(4-Methylbenzoyl)indolizine-1-carbonitrile (2b)
White solid. mp 154–155 °C. 1H NMR (CDCl3, 600 MHz): ␦ (ppm)
9.92 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.71 (d, J = 7.8 Hz, 2 H),
7.62 (s, 1H), 7.48 (t, J = 7.2 Hz, 1H), 7.32 (d, J = 7.8 Hz, 2H), 7.14 (t, J =
7.2 Hz, 1H), 2.46 (s, 3H). 13C NMR (CDCl3, 150 MHz): ␦ (ppm) 184.9,
142.7, 141.0, 136.3, 129.3, 129.1, 129.0, 128.9, 127.6, 122.9, 117.4, 115.7,
115.2, 84.5, 21.55. IR (KBr): 2919, 2222, 1633, 1618, 1520, 1481, 1441,
1342, 1231, 1183, 881, 752 cm−1. HRMS (ESI): m/z [M+H]+ calcd. for
C17H13N2O: 261.1022; found: 261.1021.
3-Benzoylindolizine-1-carbonitrile (2a)
White solid. mp 122–123 °C. 1H NMR (CDCl3, 400 MHz): ␦ (ppm)
9.96 (d, J = 7.2 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 6.8 Hz, 2H),
7.62 (t, J = 7.6 Hz, 2H), 7.63–7.49 (m, 3H), 7.17 (t, J = 7.2 Hz, 1H). 13
C
3-(4-Methoxybenzoyl)indolizine-1-carbonitrile (2c)
1
Gray solid. mp 188–189 °C. H NMR (CDCl3, 600 MHz): ␦ (ppm)
NMR (CDCl3, 150 MHz): ␦ (ppm) 184.8, 140.9, 138.9, 131.8, 129.7,
129.0, 128.7, 128.3, 127.7, 122.6, 117.2, 115.7, 115.0, 84.6. IR (KBr):
3127, 2223, 1622, 1518, 1479, 1341, 1227, 1159, 878, 752, 710, 692,
9.88 (d, J = 7.2 Hz, 1H), 7.83 (d, J = 8.4 Hz, 3H), 7.63 (s, 1H), 7.47 (t,
J = 7.8 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.03 (d, J = 8.4 Hz, 2H), 3.92 (s,
Published by NRC Research Press

418
Can. J. Chem. Vol. 91, 2013
3H). 13C NMR (CDCl3, 150 MHz): ␦ (ppm) 184.0, 162.9, 141.0, 131.5,
131.2, 129.8, 128.4, 127.4, 123.0, 117.4, 115.5, 115.3, 113.8, 84.3, 55.5. IR
(KBr): 3115, 2221, 1620, 1599, 1480, 1345, 1261, 1233, 1159, 1030, 883,
754, 607 cm−1. HRMS (ESI): m/z [M+Na]+ calcd. for C17H12N2NaO2:
299.07891; found: 299.0787.
(CDCl3, 150 MHz): ␦ (ppm) 184.5, 144.8, 141.2, 139.8, 137.9, 129.5,
129.0, 128.1, 127.7, 127.2, 127.1, 123.0, 117.5, 115.7, 115.0, 84.9. IR
(KBr): 3029, 2221, 1633, 1613, 1519, 1482, 1342, 1231, 882, 750,
694 cm−1. HRMS (ESI): m/z [M+H]+ calcd. for C22H15N2O: 323.1179;
found: 323.1176.
3-(4-Ethoxybenzoyl)indolizine-1-carbonitrile (2d)
3-(2-Naphthoyl)indolizine-1-carbonitrile (2k)
White solid. mp 170–171 °C. 1H NMR (CDCl3, 400 MHz): ␦ (ppm)
9.86 (d, J = 7.2 Hz, 1H), 7.81 (d, J = 8.8 Hz, 3H), 7.62 (s, 1H), 7.46 (t,
J = 7.8 Hz, 1H), 7.11 (t, J = 7.2 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 4.14 (q,
J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz): ␦
(ppm) 184.0, 162.3, 141.0, 131.3, 131.2, 129.3, 128.4, 127.4, 123.0, 117.4,
115.5, 115.3, 114.2, 84.3, 63.8, 14.7. IR (KBr): 3116, 2221, 1622, 1602,
1517, 1481, 1344, 1259, 1234, 1176, 1161, 1052, 884, 756, 641 cm−1.
HRMS (ESI): m/z [M+H]+ calcd. for C18H15N2O2: 291.1128; found:
291.1134.
Yellow solid. mp 156–157 °C. 1H NMR (CDCl3, 600 MHz): ␦ (ppm)
9.89 (d, J = 6.6 Hz, 1H), 8.30 (s, 1H), 8.00–7.95 (m, 5H), 7.70 (s, 1H),
7.65–7.60 (m, 2H), 7.52 (t, J = 7.8 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H). 13
C
NMR (CDCl3, 150 MHz): ␦ (ppm) 184.6, 141.0, 136.1, 134.7, 132.1,
129.8, 129.2, 129.0, 128.3, 128.0, 127.7, 126.8, 125.0, 122.8, 117.2, 115.7,
115.0, 84.6. IR (KBr):3053, 2217, 1614, 1517, 1482, 1356, 1340, 1217,
1192, 803, 757 cm−1. HRMS (ESI): m/z [M+H]+ calcd. for C20H13N2O:
297.1022; found: 297.1021.
3-(4-Morpholinobenzoyl)indolizine-1-carbonitrile (2l)
3-(Benzo[d][1,3]dioxole-5-carbonyl)indolizine-1-carbonitrile (2e)
Yellow solid. mp 181–182 °C. 1H NMR (CDCl3, 600 MHz): ␦ (ppm)
9.85 (d, J = 7.2 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.64 (s, 1H), 7.47 (d,
J = 7.8 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.32 (s, 1H), 7.13 (t, J = 7.2 Hz,
1H), 6.93 (d, J = 7.8 Hz, 1H), 6.10 (s, 2H). 13C NMR (CDCl3, 150 MHz):
␦ (ppm) 183.5, 151.1, 148.0, 141.1, 133.3, 128.5, 127.6, 125.0, 122.8,
117.5, 115.6, 115.2, 109.1, 108.0, 101.9, 84.5. IR (KBr): 3127, 2224, 1617,
1598, 1479, 1442, 1340, 1249, 1215, 1035, 933, 751 cm−1. HRMS (ESI):
m/z [M+H]+ calcd. for C17H11N2O3: 291.0764; found: 291.0765.
Yellow solid. mp 137–138 °C. 1H NMR (CDCl3, 600 MHz): ␦ (ppm)
9.82 (d, J = 7.2 Hz, 1H), 7.81–7.78 (m, 3H), 7.62 (s, 1H), 7.43 (t, J =
7.2 Hz, 1H), 7.09 (t, J = 6.6 Hz, 1H), 6.95 (d, J = 8.4 Hz, 2H), 3.88 (s, 4H),
3.33 (s, 4H). 13C NMR (CDCl3, 150 MHz): ␦ (ppm) 183.5, 153.7, 140.7,
131.0, 129.1, 129.0, 127.8, 127.0, 123.0, 117.2, 115.4, 115.2, 113.4, 83.9,
66.4, 47.5. IR (KBr): 2218, 1618, 1600, 1518, 1484, 1351, 1234, 1192,
925, 749 cm−1. HRMS (ESI): m/z [M+H]+ calcd. for C20H18N3O2:
332.1394; found: 332.1392.
3-(Furan-3-carbonyl)indolizine-1-carbonitrile (2m)
3-(4-Fluorobenzoyl)indolizine-1-carbonitrile (2f)
Brown solid. mp 140–142 °C. 1H NMR (CDCl3, 600 MHz): ␦ (ppm)
9.95 (d, J = 7.2 Hz, 1H), 8.30 (s, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.69 (s, 1H),
7.46 (t, J = 7.8 Hz, 1H), 7.35 (s, 1H), 7.09 (t, J = 6.6 Hz, 1H), 6.62 (s, 1H).
13C NMR (CDCl3, 150 MHz): ␦ (ppm) 170.0, 152.7, 145.9, 140.7, 129.3,
127.8, 127.6, 121.4, 118.0, 117.2, 115.6, 115.0, 112.2, 85.1. IR (KBr): 3108,
2224, 1603, 1566, 1518, 1473, 1443, 1360, 1341, 1243, 1170, 1012, 835,
753 cm−1. HRMS (ESI): m/z [M+H]+ calcd. for C14H9N2O2: 237.0659;
found: 237.0658.
Yellow solid. mp 166–167 °C. 1H NMR (CDCl3, 600 MHz): ␦ (ppm)
9.90 (d, J = 6.6 Hz, 1H), 7.84–7.82 (m, 3H), 7.61 (s, 1H), 7.51 (t, J =
7.2 Hz, 1H), 7.22 (t, J = 7.8 Hz, 2H), 7.17 (t, J = 6.6 Hz, 1H). 13C NMR
(CDCl3, 150 MHz): ␦ (ppm) 183.4, 165.7, 164.0, 141.1, 135.2, 131.3,
131.2, 129.7, 129.3, 128.9, 127.9, 122.5, 117.4, 115.9, 115.7, 115.5, 115.0,
84.7. IR (KBr): 3123, 2221, 1621, 1602, 1515, 1483, 1359, 1342, 1231,
1151, 883, 841, 760, 608 cm−1. HRMS (ESI): m/z [M + H]+ calcd. for
C16H10FN2O: 265.0772; found: 265.0772.
3-(Thiophene-3-carbonyl)indolizine-1-carbonitrile (2n)
3-(4-Chlorobenzoyl)indolizine-1-carbonitrile (2g)
White solid. mp 148–149 °C. 1H NMR (CDCl3, 600 MHz): ␦ (ppm)
9.87 (d, J = 7.2 Hz, 1H), 7.98 (s, 1H), 7.83–7.79 (m, 2H), 7.57 (d, J =
4.8 Hz, 1H), 7.49–7.44 (m, 2H), 7.13 (t, J = 7.2 Hz, 1H). 13C NMR
(CDCl3, 150 MHz): ␦ (ppm) 178.2, 141.6, 141.0, 131.0, 129.3, 129.0,
127.8, 127.6, 126.5=123.0=117.3=115.6, 115.0, 84.5. IR (KBr): 3090, 2223,
1623, 1518, 1481, 1422, 1336, 1240, 1157, 873, 753, 714 cm−1. HRMS
(ESI): m/z [M+H]+ calcd. for C14H9N2OS: 253.0430; found: 253.0429.
White solid. mp 214–215 °C. 1H NMR (CDCl3, 600 MHz): ␦ (ppm)
9.92 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.61 (s, 1H),
7.53–7.51 (m, 3H), 7.18 (t, J = 7.2 Hz, 1H). 13C NMR (CDCl3, 150 MHz):
␦ (ppm) 183.6, 141.3, 138.3, 137.4, 130.3, 129.4, 129.0, 128.8, 128.0,
122.5, 117.5, 116.0, 114.9, 85.0. IR (KBr): 3124, 2222, 1633, 1619, 1517,
1343, 1227, 1163, 1084, 879, 837, 758 cm−1. HRMS (ESI): m/z [M+H]+
calcd. for C16H10ClN2O: 281.0476; found: 281.0475.
3-Benzoyl-7-methylindolizine-1-carbonitrile (2o)
3-(4-Bromobenzoyl)indolizine-1-carbonitrile (2h)
Brown solid. mp 171–172 °C. 1H NMR (CDCl3, 400 MHz): ␦ (ppm)
9.83 (d, J = 5.4 Hz, 1H), 7.78 (d, J = 5.4 Hz, 2H), 7.60–7.52 (m, 5H), 6.99
(s, 1H), 2.52 (s, 3H). 13C NMR (CDCl3, 100 MHz): ␦ (ppm) 184.7, 141.6,
139.7, 139.2, 131.7, 129.4, 129.0, 128.8, 128.4, 122.4, 118.3, 116.1, 115.3,
83.4, 21.4. IR (KBr): 3102, 2361, 2221, 1614, 1575, 1525, 1478, 1339,
1231, 1158, 803, 719, 702 cm−1. HRMS (ESI): m/z [M+H]+ calcd. for
C17H13N2O: 261.1022; found: 261.1016.
White solid. mp 209–210 °C. 1H NMR (CDCl3, 600 MHz): ␦ (ppm)
9.92 (d, J = 6.0 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.67 (s, 4H), 7.60 (s, 1H),
7.52 (t, J = 7.2 Hz, 1H), 7.17 (t, J = 10.2 Hz, 1H); 13C NMR (CDCl3, 150
MHz): ␦ (ppm) 183.7, 141.3, 137.9, 131.8, 130.4, 130.0, 129.0, 128.1,
126.9, 122.5, 117.5, 116.0, 114.9, 85.1. IR (KBr): 3120, 2222, 1620, 1518,
1481, 1357, 1342, 1228, 1163, 879, 804, 758 cm−1. HRMS (ESI): m/z
[M+H]+ calcd. for C16H10BrN2O: 324.9971; found: 324.9969.
3-Benzoyl-6-methylindolizine-1-carbonitrile (2p-1) and 3-benzoyl-8-
methylindolizine-1-carbonitrile (2p-2) were mixed, ratio 1:2
3-(4-Hydroxybenzoyl)indolizine-1-carbonitrile (2i)
Yellow solid. mp 220–221 °C. 1H NMR (DMSO, 600 MHz): ␦ (ppm)
10.34 (s, 1H), 9.72 (d, J = 6.6 Hz, 1H), 7.92–7.90 (m, 2H), 7.76 (d, J =
7.8 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.31 (t, J = 6.0 Hz, 1H), 6.93 (d, J =
7.8 Hz, 2H); 13C NMR (DMSO, 100 MHz): ␦ (ppm) 183.0, 161.5, 140.3,
131.6, 129.4, 128.9, 128.2, 128.0, 122.5, 117.1, 116.0, 115.4, 115.3, 83.1.
IR (KBr): 3361, 2224, 1612, 1573, 1516, 1482, 1422, 1342, 1231, 1169,
883, 756 cm−1. HRMS (ESI): m/z [M+H]+ calcd. for C16H11N2O2:
263.2628; found: 263.0814.
White solid. mp 127–128 °C. 1H NMR (CDCl3, 400 MHz): ␦ (ppm)
9.85 (d, J = 6.8 Hz, 1H), 9.80 (s, 1H), 7.80–7.73 (m, 4H), 7.63–7.51 (m,
8H), 7.37 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 6.0 Hz, 1H), 7.06 (t, J = 7.2 Hz,
2H), 2.84 (s, 3H), 2.47 (s, 3H). 13C NMR (CDCl3, 100 MHz): ␦ (ppm)
185.0, 140.1, 139.2, 131.9, 131.8, 130.6, 128.9, 128.4, 128.0, 127.3, 117.0,
116.7, 115.8, 84.1, 18.5. IR (KBr): 3122, 3058, 2223, 1619, 1576, 1520,
1481, 1428, 1349, 1245, 1158, 860, 776, 748, 712, 691 cm−1. HRMS
(ESI): m/z [M+H]+ calcd. for C17H13N2O: 261.1022; found: 261.1022.
3-([1,1=-Biphenyl]-4-carbonyl)indolizine-1-carbonitrile (2j)
3-Benzoyl-6,8-dimethylindolizine-1-carbonitrile (2q)
White solid. mp 159–160 °C. 1H NMR (CDCl3, 600 MHz): ␦ (ppm)
9.94 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 9.0 Hz, 1H),
7.73–7.64 (m, 5H), 7.49–7.38 (m, 4H), 7.13 (t, J = 7.2 Hz, 1H). 13C NMR
Brown solid. mp 214–215 °C. 1H NMR (CDCl3, 400 MHz): ␦ (ppm)
9.68 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.62–7.50 (m, 4H), 7.09 (s, 1H),
2.79 (s, 3H), 2.41 (s, 3H). 13C NMR (CDCl3, 100 MHz): ␦ (ppm) 184.8,
Published by NRC Research Press

Cai et al.
419
Pharm. Sci. 2007, 30, 26. doi:10.1016/j.ejps.2006.09.006; (c) Nash, R. J.;
Fellows, L. E.; Dring, J. V.; Striton, C. H.; Carter, D.; Hegarty, M. P.;
Bell, E. A. Phytochemistry 1988, 27, 1403. doi:10.1016/0031-9422(88)80203-6.
(4) Danac, R.; Leontie, L.; Carlescu, A.; Rusu, G. I. Mater. Chem. Phys. 2012, 134,
1042. doi:10.1016/j.matchemphys.2012.03.110.
139.4, 138.8, 131.7, 131.1, 130.4, 128.8, 128.4, 127.8, 125.9, 125.3, 122.4,
117.1, 83.4, 18.4. IR (KBr): 3115, 2213, 1621, 1517, 1481, 1409, 1347,
1286, 1147, 842, 787, 728, 673 cm−1. HRMS (ESI): m/z [M+H]+ calcd.
for C18H15N2O: 275.1179; found: 261.1022.
(5) (a) Borrows, E. T.; Holland, D. O. Chem. Rev. 1948, 42, 611. doi:10.1021/
cr60133a005; (b) Michael, J. P. Nat. Prod. Rep. 2002, 19, 719. doi:10.1039/
b104969k.
Methyl 3-benzoyl-1-cyanoindolizine-7-carboxylate (2r)
Red solid. mp 212–213 °C. 1H NMR (CDCl3, 400 MHz): ␦ (ppm) 9.93
(d, J = 7.2 Hz, 1H), 8.54 (s, 1H), 7.81 (d, J = 7.6 Hz, 2H), 7.70–7.62 (m,
3H), 7.55 (t, J = 7.2 Hz, 2H), 4.03 (s, 3H). 13C NMR (CDCl3, 100 MHz):
␦ (ppm) 185.3, 164.4, 139.6, 138.5, 132.4, 129.4, 128.9, 128.8, 128.6,
128.3, 123.9, 119.5, 114.7, 114.3, 87.9, 52.9. IR (KBr): 3118, 2960, 2221,
1730, 1627, 1529, 1471, 1344, 1233, 1132, 971, 838, 761 712, 673 cm−1.
HRMS (ESI): m/z [M+Na]+ calcd. for C18H12N2NaO3: 327.0744; found:
327.0740.
(6) (a) For general review, see Uchida, T.; Matsumoto, K. Synthesis 1976, 209.
doi:10.1055/s-1976-23994; for selected examples, see (b) Kim, M.; Vedejs, E.
J. Org. Chem. 2004, 69, 6945. doi:10.1021/jo040191e; (c) Virieux, D.;
Guillouzic, A. F.; Cristau, H. J. Tetrahedron 2006, 62, 3710. doi:10.1016/j.tet.
2006.01.055; (d) Peng, W. M.; Zhu, S. Z. J. Chem. Soc., Perkin Trans. 1 2001, 3204.
doi:10.1039/B103586J; (e) Ong, C. W.; Lai, M. C.; Jan, J. J.; Chang,
Y. A. Heterocycles 2002, 57, 1303. doi:10.3987/COM-02-9494; (f) Kaloko, J.;
Hayford, A. Org. Lett. 2005, 7, 4305. doi:10.1021/ol051860t; (g) Chernyak, N.;
Tilly, D.; Li, Z.; Gevorgyan, V. ARKIVOC 2011, 5, 76. doi:10.3998/ark.5550190.
0012.509.
(7) For selected examples, see (a) Scholtz, M. Ber. Dtsch. Chem. Ges. 1912, 45, 734.
doi:10.1002/cber.191204501108; (b) Boekelheide, V.; Windgassen, R. J. J. Am.
Chem. Soc. 1959, 81, 56; (c) Jørgensen, A. S.; Jacobsen, P.; Christiansen, L. B.;
Bury, P. S.; Kanstrup, A.; Thorpe, S. M.; Naerum, L.; Wassermann, K. Bioorg.
Med. Chem. Lett. 2000, 10, 2383. doi:10.1016/S0960-894X(00)00474-1;
(d) Basavaiah, D. Tetrahedron Lett. 2003, 44, 4365. doi:10.1016/S0040-4039(03)
00934-1; (e) Li, L. H.; Chua, W. K. S. Tetrahedron Lett. 2011, 52, 1392. doi:10.
1016/j.tetlet.2011.01.087.
(8) For selected examples, see (a) Bora, U.; Saikia, A.; Boruah, R. C. Org. Lett.
2003, 5, 435. doi:10.1021/ol020238n; (b) Shang, Y. J.; Zhang, M.; Yu, S. Y.;
Ju, K.; Wang, C.; He, X. W. Tetrahedron Lett. 2009, 50, 6981. doi:10.1016/j.tetlet.
2009.09.143; (c) Shen, Y. M.; Lv, P. C.; Chen, W.; Liu, P. G.; Zhang, M. Z.;
Zhu, H. L. Eur. J. Med. Chem. 2010, 45, 3184. doi:10.1016/j.ejmech.2010.02.056;
(d) Zhu, H. J.; Stöckigt, J.; Yu, Y. P.; Zou, H. B. Org. Lett. 2011, 13, 2792.
doi:10.1021/ol200883w; (e) Cui, P. P.; Xu, L.; Shi, Z. J.; Gan, L. B. J. Org. Chem.
2011, 76, 4210. doi:10.1021/jo200601y; (f) Yang, Y. Z.; Xie, C. S.; Xie, Y. J.;
Zhang, Y. H. Org. Lett., 2012, 14 (4), 957. doi:10.1021/ol300067h.
(9) For selected examples, see (a) Tan, Y.; Ahmed, S. A.; Dürr, H.; Huch, V.;
Abdel-Wahab, A. Chem. Commun. 2001, 1246. doi:10.1039/B101044L; (b)
Kakehi, A.; Ito, S.; Hirata, K.; Zuo, P. Chem. Pharm. Bull. 2000, 48, 865. doi:10.
1248/cpb.48.865; (c) Kakeshi, A.; Suga, H.; Kaneko, Y.; Fujii, T.;
Tanaka, N. Chem. Pharm. Bull. 2005, 53, 1430. doi:10.1248/cpb.53.1430; (d)
Basavaiah, D.; Devendar, B.; Lenin, D. V.; Satyanarayana, T. Synlett 2009, 411.
doi:10.1055/s-0028-1087533; (e) Zhu, H. J.; Stöckigt, J.; Yu, Y. P.; Zou, H. B. Org.
Lett. 2011, 13, 2792. doi:10.1021/ol200883w.
Methyl 3-benzoylindolizine-1-carboxylate (2s)
Brown solid. mp 159–160 °C. 1H NMR (CDCl3, 600 MHz): ␦ (ppm)
9.95 (d, J = 6.6 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 7.81–7.80 (m, 3H), 7.56
(t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.2 Hz, 2H), 7.43 (t, J = 7.2 Hz, 1H), 7.07
(t, J = 7.2 Hz, 1H), 3.89 (s, 3H). 13C NMR (CDCl3, 150 MHz): ␦ (ppm)
185.3, 164.2, 139.7, 131.3, 129.6, 128.9, 128.7, 128.5, 128.2, 127.7,
122.4, 119.2, 115.2, 105.7, 51.2. IR (KBr): 3123, 2956, 2361, 2340, 1702,
1622, 1520, 1479, 1452, 1343, 1205, 1081, 1022, 892, 746, 723,
656 cm−1. HRMS (ESI): m/z [M+H]+ calcd. for C17H14NO3: 280.0968;
found: 280.0965.
Ethyl 3-benzoylindolizine-1-carboxylate (2t)
Brown solid. mp 145–146 °C. 1H NMR (CDCl3, 400 MHz): ␦ (ppm)
9.99 (d, J = 7.2 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 5.6 Hz, 3H),
7.59–7.45 (m, 4H), 7.11 (t, J = 7.2 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.40
(t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz): ␦ (ppm) 185.3, 163.9,
139.7, 139.6, 131.3, 130.0, 129.0, 128.8, 128.2, 127.5, 122.3, 119.3, 115.1,
106.1, 60.0, 14.4. IR (KBr): 3032, 2943, 2358, 2330, 1718, 1604, 1520,
1462, 1422, 1383, 1217, 1073, 989, 887, 762, 721 cm−1. HRMS (ESI): m/z
[M+Na]+ calcd. for C18H15NNaO3: 316.0939; found: 316.0944.
(10) Yin, G. D.; Gao, M.; She, N. F.; Hu, S. L.; Wu, A. X.; Pan, Y. J. Synthesis 2007,
3113. doi:10.1055/s-2007-983880.
Supplementary material
(11) (a) Zhou, J.; Zhang, L. D.; Hu, Y. F.; Hu, H. W. J. Chem. Res. 1999, 552. doi:10.
1039/A902053E; (b) Boultadakis, E.; Chung, B.; Elsegood, M. R. J.;
Weaver, G. W. Synlett 2002, 1547. doi:10.1055/s-2002-33507; (c) Wu, K.;
Chen, Q. Y. Synthesis 2003, 35; (d) Matsuda, Y.; Kohra, S.; Katou, K.;
Uemura, T.; Yamashita, K. Heterocycles 2003, 60, 405. doi:10.3987/COM-02-
9655.
Supplementary data are available with the article through the
journal Web site at http://nrcresearchpress.com/doi/suppl/10.1139/
cjc-2012-0534. CCDC-915168 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained, free of
charge, via www.ccdc.cam.ac.uk/products/csd/request/ (or from
the Cambridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK (fax: 44-1223-336033 or e-mail: deposit@ccdc.
cam.ac.uk)).
(12) For selected examples, see (a) Climent, M. J.; Corma, A.; Iborra, S. RSC Adv.,
2012, 2, 16. doi:10.1039/C1RA00807B; (b) Zhu, J. P.; Bienaymé, H. Multicompo-
nent Reactions; Wiley-VCH: Weinheim, Germany, 2005; (c) Weber, L.;
Illegen, K.; Almstter, M. Synlett 1999, 366. doi:10.1055/s-1999-2612; (d)
Armsaterong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.;
Keating, T. A. Acc. Chem. Res. 1996, 29, 123. doi:10.1021/ar9502083.
(13) For selected examples, see (a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino
Reactions in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006;
(b) Zhou, J. Chem. Asian J. 2010, 5, 422. doi:10.1002/asia.200900458; (c)
Yang, Y.; Gao, M.; Wu, L. M.; Deng, C.; Zhang, D. X.; Gao, Y.; Zhu, Y. P.;
Wu, A. X. Tetrahedron 2011, 67, 5142. doi:10.1016/j.tet.2011.05.058; (d) Gao, M.;
Yang, Y.; Wu, Y. D.; Deng, C.; Cao, L. P.; Meng, X. G.; Wu, A. X. Org. Lett. 2010,
12, 1856. doi:10.1021/ol100473f; (e) Gao, M.; Yang, Y.; Wu, Y. D.; Deng, C.;
Shu, W. M.; Zhang, D. X.; Cao, L. P.; She, N. F.; Wu, A. X. Org. Lett. 2010, 12,
4026. doi:10.1021/ol1015948; (f) Paulvannan, K. J. Org. Chem. 2004, 69, 1207.
doi:10.1021/jo030231z; (g) Kim, S. The Chemical Record 2001, 415. doi:10.1002/
tcr.10000; (h) Yin, G. D.; Wang, Z. H.; Chen, A. H.; Gao, M.; Wu, A. X.;
Pan, Y. J. J. Org. Chem. 2008, 73, 3377. doi:10.1021/jo702585s.
Acknowledgements
We are grateful to Central China Normal University and the
National Science Foundation of China (grants 21032001 and
21272085) for support of this work.
References
(1) For recent reviews, see (a) Micheal, J. P. Alkaloids 2001, 55, 91. doi:10.1016/
S0099-9598(01)55004-X; (b) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139. doi:10.
1039/B612166G; (c) Michael, J. P. Nat. Prod. Rep. 2007, 24, 191. doi:10.1039/
b509525p.
(2) Chai, W.; Breitenbucher, J. G.; Kwok, A.; Li, X.; Wong, V.; Carruthers, N. I.;
Lovenberg, T. W.; Mazur, C.; Wilson, S. J.; Axe, F. U.; Jones, T. K. Bioorg. Med.
Chem. Lett. 2003, 13, 1767. doi:10.1016/S0960-894X(03)00299-3.
(14) Mao, Z. J.; Li, X. J.; Lin, X. F.; Lu, P.; Wang, Y. G. Tetrahedron 2012, 68, 85.
doi:10.1016/j.tet.2011.10.083.
(3) (a) Darwash, E. S. Molecules 2008, 13, 1066. doi:10.3390/molecules13051066;
(b) Gundersen, L. L.; Charnock, C.; Negussie, A. H.; Rise, F.; Teklu, S. Eur. J.
(15) Kucukdisli, M.; Opatz, T. Eur. J. Org. Chem. 2012, 4555. doi:10.1002/ejoc.
201200424.
Published by NRC Research Press