New route synthesis of indolizines via 1,3-dipolar cycloaddition of pyridiniums and alkynes

Article abstract of DOI:10.1016/j.tetlet.2009.09.143

A convenient synthesis of 2,3-di and 1,2,3-trisubstituted indolizines has been achieved via a 1,3-dipolar cycloaddition of pyridiniums and alkynes. Various alkynes and diynes were used instead of dimethyl acetylenedicarboxylate (DMAD) and its analogues in

Full text of DOI:10.1016/j.tetlet.2009.09.143

Tetrahedron Letters 50 (2009) 6981–6984
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New route synthesis of indolizines via 1,3-dipolar cycloaddition
of pyridiniums and alkynes
*
Yongjia Shang , Min Zhang, Shuyan Yu, Kai Ju, Cuie Wang, Xinwei He
Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Key Laboratory of Molecule-Based Materials, College of Chemistry and Materials Science,
Anhui Normal University, Wuhu 241000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 July 2009
Revised 23 September 2009
Accepted 25 September 2009
Available online 29 September 2009
A convenient synthesis of 2,3-di and 1,2,3-trisubstituted indolizines has been achieved via a 1,3-dipolar
cycloaddition of pyridiniums and alkynes. Various alkynes and diynes were used instead of dimethyl
acetylenedicarboxylate (DMAD) and its analogues in the traditional method. The corresponding 1,2,3-tri-
substituted indolizines are useful building blocks for the construction of complex indolizine derivatives.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indolizine
1,3-Dipolar cycloaddition
Bridgehead N-heterocycles
Alkyne
Diyne
Bridgehead nitrogen heterocycles are important natural products.
Among those, indolizines have received much attention in recent
years1 due to their intriguing molecular structures featured with a
able dipolarophiles to extend the classic synthesis of indolizine
derivatives.
Herein, we report a new synthesis of a series of indolizine deriv-
atives in high yields via the 1,3-dipolar cycloaddition between
pyridinium (1) and alkyne (2) (Scheme 1), and the representative
X-ray structure of one of the indolizine derivatives.
The starting ylide was derived from 1-(2-oxo-2-phenylethyl)
pyridinium bromide (1a) in the presence of K2CO3 in DMF at room
temperature. To this mixture was added phenylacetylene (2a), the
resulting mixture was heated at 120 °C in the sealed flask using the
oil bath. After 10 h, the major product 3a was formed in good yield
which was monitored by TLC. After purification via column chro-
matography, compound 3a was isolated in 85% yield and was char-
acterized by NMR, IR, and MS.
Optimization of this 1,3-dipolar cycloaddition process between
1a and 2a is summarized in Table 1. In DMF, this reaction smoothly
generated the desired product 3a in 85% yield (Table 1, entries 2
and 3) in 2–10 h from 90 °C to reflux. Two equivalents of base
was necessary to achieve high yield (Table 1, entries 2 and 6), while
10 p-delocalized electrons, and their important biological activities.
These molecules have found various pharmaceutical applications as
anti-tuberculosis agents,2 PLA2 inhibitors,3 histamine H3 receptor
antagonists,4 5-HT3 receptor antagonists,5 MPtpA/MPtpB phospha-
tases inhibitors, associated with many infectious diseases,6 and as
15-lipoxygenase inhibitors.7 Thus, there is a growing interest in the
synthesis of indolizine derivatives.
Indolizines can be prepared by the 1,3-dipolar cycloaddition
reaction between pyridiniums and carboxylic acid8,1c in the pres-
ence of a mild base, and many five-membered heterocycles9 can be
generated from this method. Recently, many new synthetic
approaches have been developed to prepare functionalized indoli-
zines.10 However, transition-metal catalyst is often required, and
in some cases the starting materials were not easy to synthesize.
Thus, it is necessary to develop a practical syntheticroute for the effi-
cient synthesis of indolizine derivatives. The classic 1,3-dipolar
cycloaddition between pyridinium-related heteroaromatic ylides
and alkynes is very attractive due to its versatility and efficiency.11,12
Surprisingly, only DMAD and its analogues have been used in this
process.13 From our continuous research interest in the 1,3-dipolar
cycloaddition,14 we anticipated that various alkynes could be suit-
O
R2
R3
R1
base
N
R2
N
2
Br
O
3
1
R3
R1
* Corresponding author. Tel.: +86 553 3937138; fax: +86 553 3869302.
E-mail address: shyj@mail.ahnu.edu.cn (Y. Shang).
Scheme 1. Preparation of indolizines through the classic 1,3-dipolar cycloaddition
reaction.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.143

6982
Y. Shang et al. / Tetrahedron Letters 50 (2009) 6981–6984
Table 1
more K2CO3 did not increase the reaction yield. Changing solvent
to CH3CN, THF, and H2O reduced the yields to 75%, 78%, and 40%,
respectively. (Table 1, entries 4, 5, and 8). When DCM was used
as a solvent, the desired product was obtained in very low yield
(Table 1, entry 7). Low yield was obtained when Et3N was used
as a base (Table 1, entry 9). Thus, the optimized reaction condition
was in DMF at 90 °C with 2 equiv of K2CO3.15
Optimization of the reaction condition for the 1,3-dipolar cycloaddition of pyridinium
1a and alkyne 2a to generate 3a
O
base, solvent
2a
N
N
3a
Br
O
1a
We then investigated the scope of this reaction with various
pyridiniums 1b, 1c, 1d, 1e, and 1f, as shown in Table 2. In most
cases, the desired indolizines were smoothly generated in high
yields (Table 2, entries 2, 3, and 6). The presence of strong elec-
tron-withdrawing group on pyridinium (1e) greatly reduced the
reaction yield and only trace amount of 3j was obtained (Table 2,
entry 5). Surprisingly, the presence of electron-donating substitu-
ent on pyridinium (1d) also provided 3d in relatively low yield (Ta-
ble 2, entry 4). We attributed this substituent effect to the
formation of a potassium salt (phenolate) during the process of
ylide formation.
Entry
Basea
Solvent
Temp (°C)
Time (h)
Yieldd (%)
1
2
3
4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Et3N
DMF
DMF
DMF
CH3CN
THF
DMF
DCM
H2O
120
90
Reflux
Reflux
Reflux
90
rt
90
90
10
2
2
2
2
10
10
2
85
85
85
75
78
30
5
5
6b
7
8c
9
40
66
DMF
2
a
b
c
2 equiv base was used.
1 equiv base was used.
1 equiv PTC was used.
Yields refer to pyridinium.
Similar to 2a, 2b also gave a good result under this reaction con-
dition and afforded corresponding 2,3-disubstituted indolizines
d
Table 2
1,3-Dipolar cycloaddition between pyridiniums 1 and alkynes 2 to synthesize 2,3-disubstituted indolizines 3
Entry
Pyridinium
Alkyne
Product
Yielda (%)
O
O
Ph
Ph
Ph
Ar
1
85
N
N
N
2a
Br
1a
3a
O
O
Ar
Ph
N
Br
2
3
4
5
1b
1c
1d
1e
2a
2a
2a
2a
Ar = p-MeC6H4 3b
Ar = p-MeOC6H4 3c
Ar = o-OHC6H4 3d
Ar = p-NO2C6H4 3e
80
84
30
Trace
O
O
6
7
2a
79
81
N
Br
N
Ph
1f
3f
O
Ph
1a
N
2b
p-MeC6H4
3g
O
O
Ar
p-MeC6H4
Ar
N
N
Br
8
9
1b
1c
2b
2b
Ar = p-MeC6H4 3h
Ar = p-MeOC6H4 3i
80
85
O
N
10
1f
2b
78
40
p-MeC6H4
3j
O
Ph
n-C5H11
11
1a
2c
N
3k
a
Yields refer to pyridinium.

Y. Shang et al. / Tetrahedron Letters 50 (2009) 6981–6984
6983
Table 3
1,3-Dipolar cycloaddition of pyridiniums and diynes to synthesize 1,2,3-trisubstituted indolizines
Entry
Pyridinium
Diyne
Product
Yielda (%)
Ph
Ar
O
O
Ph
Ar
N
N
2d
Br
1
2
3
1a
1b
1c
2d
2d
2d
Ar = C6H5 3l
Ar = p-MeC6H4 3m
Ar = p-MeOC6H4 3n
88
87
91
Ph
Ph
4
1f
2d
86
O
N
3o
p-MeC H
6
4
Ar
O
p-MeC H
6
4
Ar
O
N
N
2e
Br
5
6
7
1a
1b
1c
2e
2e
2e
Ar = C6H5 3p
Ar = p-MeC6H4 3q
Ar = p-MeOC6H4 3r
89
90
93
p-MeC H
6
4
p-MeC H
6
4
8
1f
2e
O
87
N
3s
a
Yields refer to pyridiniums.
3g–3j in 78–85% yield (Table 2, entries 7–10). Unfortunately, when
2c was used, only 40% 3k was obtained (Table 2, entry 11), associ-
ated with the inert nature of 1-heptyne.
Surprisingly, when 2d, a byproduct of our multicomponent
reaction of sulfonyl azide, terminal alkyne, and 2-(benzylideneami-
no)phenol, was used to react with 1a, the corresponding 1,2,3-tri-
substituted indolizine 3l was obtained as the major product in high
yield (Table 3, entry 1). Each reaction of 1b, 1c, and 1f with 2d pro-
vided the corresponding 1,2,3-trisubstituted indolizines 3m, 3n,
and 3o in 87%, 91%, and 86% yields, respectively (Table 3, entries
2–4). The X-ray structure of 3m is illustrated in Figure 1.16 This
high regioselectivity might be attributed to the relatively strong
electronic negativity on the C2 and C3 of 2d and 2e than those on
the C1 and C4 of 2d and 2e.
As a development of phenylacetylenic coupling,17 this process
can be used for the efficient construction of a series of 1-alkynyl
indolizines by reacting pyridiniums with various diynes.
We propose a plausible mechanism for the synthesis of indoli-
zines as shown in Scheme 2. Pyridinium could be deprotoned by
K2CO3 to give the corresponding ylide, which would act as a dipolar
to react with alkyne and generate indolizine via 1,3-dipolar
cycloaddition.
O
O
O
R1
K2CO3
R1
R1
N
N
N
Br
H
R2
R3
K2CO3
N
H
R2
R2
R3
N
O
O
R3
R1
R1
Scheme 2. Proposed mechanism for the 1,3-dipolar cycloaddition between pyrid-
Figure 1. The single-crystal X-ray structure of 3m.
iniums and alkynes.

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Y. Shang et al. / Tetrahedron Letters 50 (2009) 6981–6984
7. Teklu, S.; Gundersen, L.-L.; Larsen, T.; Malterud, K. E.; Rise, F. Bioorg. Med. Chem.
In summary, we have synthesized a series of novel indolizine
2005, 13, 3127.
8. (a) Uchida, T.; Matsumoto, K. Synthesis 1976, 209.
derivatives in good to excellent yields by reacting pyridiniums
and alkynes in the presence of a mild base. This synthetic approach
was also suitable for the reaction between pyridiniums and diynes,
from which a series of novel indolizines were obtained in high
yields. Further investigation of this reaction and the electronic
properties of the resulting compounds are carried out in our
laboratory.
9. (a) Broggini, G.; Garanti, L.; Molteni, G.; Zecchi, G. Tetrahedron 1998, 54, 2843–
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Acknowledgments
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14. Shang, Y.; Feng, Z.; Yuan, L.; Wang, S. Tetrahedron 2008, 64, 5779.
15. General procedure for the synthesis of indolizines by 1,3-dipolar cycloaddition: To
pyridinium(1 equiv) in DMF was added K2CO3 (2 equiv) at room temperature.
After 15 min, alkyne (1.2 equiv) was added, and the resulting mixture was
The authors thank National Natural Science Foundation of Chi-
na (Grant 20872001) and the Education Commission of Anhui
Province (Grant TD200707).
References and notes
heated in oil base at 90 °C for 2 h in
a sealed reaction flask. Upon the
completion of this reaction, the mixture was cooled to room temperature,
diluted with ethyl acetate, and washed with brine. The combined organic
layers were dried over Na2SO4, filtered, and evaporated in vacuo. The resulting
residue was purified by flash column chromatography (petroleum ether/ethyl
acetate = 10:1, v/v) to afford indolizine 3. Compound 3a: mp = 145–146 °C; 1H
NMR (300 MHz, CDCl3): d 6.99 (t, J = 6.6 Hz, 1H, ArH), 7.26–7.34 (m, 2H, ArH),
7.42–7.57 (m, 8H, ArH), 7.84–7.90 (m, 3H, ArH), 10.04 (d, J = 6.9 Hz, 1H, ArH);
13C NMR (75 MHz, CDCl3): d 114.3, 117.6, 122.2, 125.1, 125.4, 126.6, 127.5,
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127.9, 128.2, 128.9, 129.0, 130.9, 134.6, 136.4, 140.8, 184.6 ppm. IR (KBr) m:
3055, 3028, 2360, 1600, 1570, 1543, 1469, 1419, 1354, 1230 cmÀ1; HRMS (ESI)
calcd for C21H16NO [M+H]+: 298.1187, found: 298.1220; Anal. Calcd for
C21H15NO: C, 84.82; H, 5.08; N, 4.71; O, 5.38. Found: C, 84.66; H, 5.24; N,
4.55; O, 5.24.
16. Crystallographic data (excluding structure factors) for the structure in this
Letter have been deposited with the Cambridge Crystallographic Data Centre as
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free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
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