Convenient synthesis of 2-aryl-1-haloindolizines from pyridinium salts and 2-aryl-1,1-dihaloalk-1-enes

Article abstract of DOI:10.1055/s-0030-1260215

2-Aryl-1-haloindolizines were synthesized from pyridinium salts and 2-aryl-1,1-dihaloalk-1-enes using a DBU/THF system. 2-Aryl-1,1-dihaloalk-1-enes containing electron-withdrawing or -donating groups were efficiently converted into the corresponding 2-aryl-1-haloindolizines in moderate to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1260215

PAPER
3447
Convenient Synthesis of 2-Aryl-1-haloindolizines from Pyridinium Salts and
2-Aryl-1,1-dihaloalk-1-enes
S
ynthesis of 2-Ary
i
l-1-hal
w
oindolizine
s
via
a
e1,3-Dipolarn
Cycloaddition Yang,a,b Chunxiang Kuang,*a Hui Jin,a Qing Yang*c
a
Department of Chemistry, Tongji University, Siping Road 1239, Shanghai 200092, P. R. of China
Fax +86(21)65983191; E-mail: kuangcx@tongji.edu.cn
b
c
School of Biology and Chemical Engineering, Jiaxing University, Jiaxing 314001, P. R. of China
Department of Biochemistry, School of Life Sciences, Fudan University, Handan Road 220, Shanghai 200433, P. R. of China
E-mail: yangqing68@fudan.edu.cn
Received 7 July 2011; revised 13 August 2011
cy,18 but, unfortunately, the starting materials are not
commercially available and they are also not easy to syn-
thesize in the laboratory.
Abstract: 2-Aryl-1-haloindolizines were synthesized from pyridin-
ium salts and 2-aryl-1,1-dihaloalk-1-enes using a DBU/THF sys-
tem. 2-Aryl-1,1-dihaloalk-1-enes containing electron-withdrawing
or -donating groups were efficiently converted into the correspond-
ing 2-aryl-1-haloindolizines in moderate to excellent yields.
Herein, we report a convenient and metal-free synthesis of
a series of new 2-aryl-1-haloindolizines 3 with moderate
to excellent yields. The 1,3-dipolar cycloaddition between
pyridinium salts 1 and 1,1-dihaloalk-1-enes 2 in a 1,8-di-
Key words: 2-aryl-1-haloindolizines, pyridinium, 1,1-dihaloalk-1-
enes, haloalkyne, 1,3-dipolar cycloaddition
azabicyclo[5.4.0]undec-7-ene–tetrahydrofuran
system
(Scheme 1) is exploited. To the best of our knowledge, the
synthesis of ethyl 2-aryl-1-haloindolizine-3-carboxylates
and 2-aryl-1-haloindolizine-3-carbonitriles has not yet
been reported.
Indolizine is an isomer of indole;1 its molecular structure,
which features 10p-delocalized electrons, has been of the-
oretical interest for a long time.2 Additionally, hydroge-
nated indolizines are key features in the skeletons of many
important bioactive natural products, such as taberso-
nine,3 strychnine,4 and vinblastine.5
X
X
Y
DBU
THF
X
Ar
EWG
+
N
Indolizine derivatives are important heterocyclic com-
pounds, they are widely used in biology as pesticides and
medicines. For example, they can be used as pigments,6
herbicides,7 potential phospholipase inhibitors,8 calcium
entry blockers,9 antileishmanial medicines,10 antiviral
drugs,11 as well as histamine H3 receptor antagonists;12
they also display antimycobacterial activity.13 In addition,
they are key intermediates in the preparation of various al-
kaloids that have important biological activity.14 There-
fore, the synthesis of indolizine derivatives has received
increased interest.
N
Ar
EWG
1
2
3
Scheme 1 Synthesis of 2-aryl-1-haloindolizines
To determine suitable reaction conditions, 1-[(ethoxycar-
bonyl)methyl]pyridinium bromide (1a) and 1-(2,2-dibro-
movinyl)-4-nitrobenzene (2a) were used as model
substrates. A mixture of 1a, 2a, and DBU in tetrahydrofu-
ran was then heated at 70 °C in a sealed tube using an oil
bath. After 12 hours, the product 3a was isolated in 85%
yield. The reaction of 1a and 2a using different bases, var-
ious mole ratios, different solvents, and various reaction
temperatures was investigated. The optimization of this
1,3-dipolar cycloaddition process between 1a and 2a is
summarized in Table 1.
Indolizine derivatives can be prepared by various meth-
ods. One approach is based on the 1,3-dipolar cycloaddi-
tion reaction between pyridinium salts and electron-
deficient alkynes or alkenes,15 but in most cases, only a
few terminal alkynes or alkenes, dimethyl acetylenedicar-
boxylate or dimethyl maleate as well as their analogues
could be used in this process.16 Recently, new synthetic
methods have been developed for their preparation,17
however, these approaches often require a transition metal
catalyst. Therefore, it is necessary to develop a convenient
synthetic route for the preparation of indolizine deriva-
tives. The classic synthesis of 2-arylindolizines mediated
by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in the
Tsuchiya’s procedure is very attractive due to its efficien-
When 1a reacted with 2a in the presence of DBU (3 equiv)
as a base in tetrahydrofuran solvent (70 °C, 12 h), the de-
sired product 3a was smoothly generated in 85% yield
(entry 3). Changing the base to cesium carbonate, potassi-
um carbonate, or DBU with potassium carbonate de-
creased the yields to 65%, 60%, and 80%, respectively
(entries 1, 2, and 4). Using the conditions of entry 3 but at
a temperature of 25 °C did not yield 3a (entry 5). Chang-
ing the solvent to N,N-dimethylformamide and dimethyl
sulfoxide decreased the yields to 30% and 5%, respective-
ly (entries 6 and 7). Using a molar ratio of 1a to 2a 1:2
SYNTHESIS 2011, No. 21, pp 3447–3452
x
x.
x
x
.
2
0
1
1
Advanced online publication: 07.09.2011
DOI: 10.1055/s-0030-1260215; Art ID: H67911SS
© Georg Thieme Verlag Stuttgart · New York

3448
Y. Yang et al.
PAPER
Table 2 Synthesis of 2-Aryl-1-haloindolizines 3
Table 1 Optimization of the Synthesis of 3a
X
Br
Br
Br–
Br
X
Y
DBU
X
N
+
Ar
+
NO2
NO2
N
N
THF
Ar
N
90 °C, 12 h
CO2Et
EWG
EWG
CO2Et
1a Y = Br, EWG = CO2Et
1b Y = Cl, EWG = CN
2
3
1a
2a
3a
Entry 1a
2a
Base
Solvent Temp TimeYielda
(°C) (h) (%)
Entry Pyridinium 1,1-Dihaloalk-1-ene 2
Product Yield
(%)
(mmol) (mmol) (3 equiv)
salt 1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
X
Ar
1
2
3
4
5
6
7
8
9
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.30
0.30
Cs2CO3
K2CO3
DBU
THF
THF
THF
70
70
70
70
25
70
12 65
12 60
12 85
12 80
1
2
2a
2b
2c
2d
2e
2f
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Br
Cl
4-O2NC6H4
4-FC6H4
4-ClC6H4
2-ClC6H4
4-BrC6H4
3-BrC6H4
4-F3CC6H4
4-NCC6H4
3a
3b
3c
3d
3e
3f
95
63
85
44
76
72
62
54
46
40
36
31
45
35
72
80
67
3
b
DBU + K2CO3 THF
4
DBU
DBU
DBU
DBUc
DBUc
THF
6
0
5
DMF
12 30
12
6
DMSO 70
5
7
2g
2h
2i
3g
3h
THF
THF
90
70
12 95
12 90
8
9
4-MeO2CC6H4 3i
a Isolated yield.
b DBU (1.5 equiv) + K2CO3 (1.5 equiv).
c DBU (4.5 equiv).
10
11
12
13
14
15
16
17
2j
Ph
3j
2k
2l
4-MeC6H4
4-MeOC6H4
3-pyridyl
2-naphthyl
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
3k
3l
with DBU in tetrahydrofuran at 90 °C gave the major
product 3a in 95% yield (entry 8).
2n
2m
2o
2a
2o
3m
3n
3o
3p
3q
Hence, the optimum reaction conditions are 1:2 mol ratio
of 1a to 2a, DBU (4.5 equiv) the base in tetrahydrofuran
solvent, 90 °C reaction temperature, and 12 hours of reac-
tion time (entry 8). Under these optimized conditions, the
substrate scope was investigated. Apparently, these newly
developed conditions are applicable to a series of 2-aryl-
1-haloindolizines (Table 2).
Table 2 shows that 1,1-dihaloalk-1-enes 2 carrying either
an electron-withdrawing group (such as nitro 2a, halogens
2b–f, trifluoromethyl 2g, cyano 2h, and methoxycarbonyl
2i) or an electron-donating substituent (such as methyl 2k,
and methoxy 2l) all proceeded smoothly with moderate to
excellent yields.
um salt 1b decreased the yield of the indolizines 3 (cf. 3a
and 3o with and 3p and 3q).
We also used compound 1a and 1,1-dibromo-4,8-dimeth-
ylnona-1,7-diene in a attempt to synthesize ethyl 1-bro-
mo-2-(2,6-dimethylhept-5-enyl)indolizine-3-carboxylate,
but unfortunately it was unsuccessful. The result indicated
that it was hard for alkyl-substituted 1,1-dihaloalk-1-enes
to react with compound 1a to prepare 2-alkyl-1-haloin-
dolizines.
Higher yields were obtained when 1,1-dihaloalk-1-enes 2
carried an electron-withdrawing group. Generally speak-
ing, a higher yield was obtained using substrates 2 that
have an electron-withdrawing group (hence a stronger
electron-withdrawing inductive effect). Higher yields
were also obtained when the substrates had a substituent
in the para-position than in the ortho-position, cf. 2c and
2d, because of steric hindrance. 1,1-Dihaloalk-1-enes 2
bearing a meta group also produced good yields, but these
were still lower than those bearing a para group, cf. 2e and
2f. An electron-withdrawing group at the para-position
has a stronger electron-withdrawing inductive effect than
a group at the meta-position. Compared with 1a, the pres-
ence of a strong electron-withdrawing group on pyridini-
To elucidate the probable reaction mechanism, the reac-
tion of 1-(2,2-dibromovinyl)-4-nitrobenzene (2a) was
performed in the presence of DBU, and the expected 1-(2-
bromoethynyl)benzene (4) was obtained. Then pyridini-
um salt 1a reacted with compound 4 using DBU as a base
to generate indolizine 3a in 97% yield in tetrahydrofuran
solvent at 90 °C (Scheme 2). Based on the experimental
data, a probable mechanism for the synthesis of 2-aryl-1-
haloindolizines 3 is proposed.
Synthesis 2011, No. 21, 3447–3452 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Aryl-1-haloindolizines via a 1,3-Dipolar Cycloaddition
3449
Br
Br
DBU
N
NO2
+
Br
NO2
N
THF
CO2Et
90 °C
CO2Et
97%
1a
4
3a
Scheme 2 1,3-Dipolar cycloaddition between 1a and 4
IR (KBr): 2979, 1678, 1606, 1536, 1508, 1455, 1369, 1351, 1307,
1222, 1185, 1121, 753, 567 cm–1.
A haloalkyne was obtained by the elimination of hydro-
gen bromide from 1,1-dihaloalk-1-enes 2 using DBU as a
base. Pyridinium salt 1 was deprotonated by DBU to give 1H NMR (400 MHz, CDCl3): d = 9.45 (d, J = 7.2 Hz, 1 H), 7.40–
7.35 (m, 3 H), 7.10 (t, J = 8.4 Hz, 2 H), 6.97 (t, J = 7.8 Hz, 1 H),
the corresponding ylide, which acted in a dipolar manner
to react with the haloalkyne. Hence, 2-aryl-1-haloindoliz-
ines 3 were generated via 1,3-dipolar cycloaddition.
6.76 (t, J = 7.0 Hz, 1 H), 4.39 (q, J = 7.2, 6.8 Hz, 2 H), 1.39 (t,
J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 162.2 (d, J = 245.4 Hz, 1 C),
161.2, 134.9, 132.2 (d, J = 8.0 Hz, 2 C), 128.8 (d, J = 3.1 Hz, 1 C),
In conclusion, we have synthesized a series of novel 2-
aryl-1-haloindolizines with moderate to excellent yields
by the reaction of pyridinium salts and 1,1-dihaloalk-1-
enes in the presence of the mild base DBU. The synthesis
of a series of new 1,2,3-trisubstituted indolizines was con-
venient and metal-free. These indolizines are important
heterocyclic compounds used in medicinal and biological
research.
127.6, 123.1, 116.8, 116.7, 115.5 (d, J = 21.5 Hz, 2 C), 113.3,
111.8, 111.4, 60.4, 14.5.
MS (ESI): m/z (%) = 363 [(M + 2)+, 27], 361 (M+, 28).
HRMS: m/z [M]+ calcd for C17H1379BrFNO2: 361.0113; found:
361.0115.
Ethyl 1-Bromo-2-(4-chlorophenyl)indolizine-3-carboxylate (3c)
Light yellow solid; mp 105.6–106.3 °C.
IR (KBr): 2925, 1678, 1591, 1532, 1503, 1455, 1369, 1347, 1307,
1224, 1185, 1122, 820, 733, 657 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.46 (d, J = 7.2 Hz, 1 H), 7.40–
7.35 (m, 5 H), 6.98 (t, J = 7.8 Hz, 1 H), 6.77 (t, J = 6.8 Hz, 1 H),
4.39 (q, J = 7.0, 7.2 Hz, 2 H), 1.40 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.1, 134.8, 133.3, 131.8 (2 C),
131.4, 128.7 (2 C), 127.7, 123.3, 116.7, 116.4, 113.4, 112.0, 111.3,
60.5, 14.5.
Melting points were recorded using a WRS-2A melting point appa-
ratus and are uncorrected. IR spectra were obtained on a Nexus FT-
IR spectrophotometer.1H and 13C NMR spectra were recorded using
a Bruker Avance 400 MHz spectrometer. Chemical shifts were re-
ported relative to internal TMS [d = 0.00 (1H) and CDCl3 [d = 77.0
(13C)]. MS data were measured with a Varian-310 mass spectrome-
ter. HRMS were determined using a Finnigan-NAT GC/MS/DS
8430 spectrometer. Flash column chromatography was performed
on 300–400 mesh silica gel. Pyridinium salts and 1,1-dihaloalk-1-
enes were prepared according to literature procedures.19–22
MS (ESI): m/z (%) = 381 [(M + 4)+, 12], 379 [(M + 2)+, 48], 377
(M+, 37).
2-Aryl-1-haloindolizines 3; General Procedure
HRMS: m/z [M]+ calcd for C17H1379Br35ClNO2: 376.9819; found:
376.9818.
A mixture of the pyridinium salt (0.15 mmol), the 1,1-dihaloalk-1-
ene (0.30 mmol), and DBU (0.675 mmol) in THF was placed in a
sealed tube. The tube was heated at 90 °C for 12 h using an oil bath.
After the reaction was completed (TLC monitoring), the mixture
was cooled to r.t. The solvent was then evaporated in vacuo. The re-
sulting residue was purified by flash column chromatography (pe-
troleum ether–EtOAc, 10:1) to yield 2-aryl-1-haloindolizines 3.
Ethyl 1-Bromo-2-(2-chlorophenyl)indolizine-3-carboxylate
(3d)
Tan oil.
IR (KBr): 2927, 1678, 1600, 1536, 1459, 1369, 1354, 1342, 1308,
1223, 1188, 1122, 754, 683 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.57 (d, J = 7.2 Hz, 1 H), 7.57 (d,
J = 4.0 Hz, 1 H), 7.40 (s, 3 H), 7.19 (d, J = 8.8 Hz, 1 H), 7.06 (t,
J = 7.2 Hz, 1 H), 6.87 (t, J = 6.4 Hz, 1 H), 4.48 (q, J = 6.4, 6.8 Hz,
2 H), 1.49 (t, J = 7.0 Hz, 3 H).
Ethyl 1-Bromo-2-(4-nitrophenyl)indolizine-3-carboxylate (3a)
Yellow solid; mp 171.2–171.5 °C.
IR (KBr): 2962, 1679, 1593, 1531, 1505, 1464, 1349, 1226, 855,
740, 677 cm–1.
13C NMR (100 MHz, CDCl3): d = 161.2, 135.3, 134.9, 133.5, 131.9,
129.8, 129.4, 127.7, 126.7, 123.0, 117.3, 115.5, 113.2, 112.5, 111.8,
60.4, 14.5.
1H NMR (400 MHz, CDCl3): d = 9.60 (d, J = 7.2 Hz, 1 H), 8.37 (d,
J = 8.4 Hz, 2 H), 7.73 (d, J = 8.0 Hz, 2 H), 7.53 (d, J = 9.6 Hz, 1 H),
7.16 (t, J = 7.8 Hz, 1 H), 6.93 (t, J = 7.0 Hz, 1 H), 4.50 (q, J = 7.0,
7.2 Hz, 2 H), 1.50 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.0, 146.7, 140.1, 134.8, 131.0
(2 C), 130.6, 127.9, 124.2, 123.8 (2 C), 116.4, 115.2, 113.8, 111.2,
60.7, 14.4.
MS (ESI): m/z (%) = 381 [(M + 4)+, 10], 379 [(M + 2)+, 45], 377
(M+, 33).
HRMS: m/z [M]+ calcd for C17H1379Br35ClNO2: 376.9819; found:
376.9820.
MS (ESI): m/z (%) = 390 [(M + 2)+, 38], 388 (M+, 40).
HRMS: m/z [M]+ calcd for C17H1379BrN2O4: 388.0058; found:
Ethyl 1-Bromo-2-(4-bromophenyl)indolizine-3-carboxylate
(3e)
Yellow solid; mp 102.2–103.1 °C.
388.0060.
IR (KBr): 2978, 1678, 1591, 1457, 1368, 1343, 1307, 1223, 1185,
1122, 819, 753, 655, 502 cm–1.
Ethyl 1-Bromo-2-(4-fluorophenyl)indolizine-3-carboxylate (3b)
Yellow green solid; mp 124.1–125.0 °C.
Synthesis 2011, No. 21, 3447–3452 © Thieme Stuttgart · New York

3450
Y. Yang et al.
PAPER
Ethyl 1-Bromo-2-[4-(methoxycarbonyl)phenyl]indolizine-3-
carboxylate (3i)
Yellow solid; mp 131.4–132.3 °C.
1H NMR (400 MHz, CDCl3): d = 9.55 (d, J = 7.2 Hz, 1 H), 7.63 (d,
J = 8.4 Hz, 2 H), 7.46 (d, J = 9.2 Hz, 1 H), 7.40 (d, J = 8.4 Hz, 2 H),
7.08 (t, J = 7.8 Hz, 1 H), 6.87 (t, J = 6.4 Hz, 1 H), 4.48 (q, J = 7.0,
7.2 Hz, 2 H), 1.49 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.1, 134.7, 132.1 (2 C), 131.9,
131.7 (2 C), 127.7, 123.3, 121.5, 116.7, 116.4, 113.4, 112.1, 111.2,
60.5, 14.5.
IR (KBr): 2925, 1722, 1678, 1608, 1498, 1459, 1369, 1349, 1308,
1277, 1224, 1179, 1123, 750, 708, 658 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.57 (d, J = 7.2 Hz, 1 H), 8.17 (d,
J = 7.6 Hz, 2 H), 7.62 (d, J = 8.0 Hz, 2 H), 7.51 (d, J = 8.8 Hz, 1 H),
7.10 (t, J = 7.6 Hz, 1 H), 6.88 (t, J = 7.0 Hz, 1 H), 4.49 (q, J = 7.2,
6.8 Hz, 2 H), 3.98 (s, 3 H), 1.49 (t, J = 7.0 Hz, 3 H).
MS (ESI): m/z (%) = 425 [(M + 4)+, 48], 423 [(M + 2)+, 80], 421
(M+, 50).
HRMS: m/z [M]+ calcd for C17H1379Br2NO2: 420.9313; found:
420.9315.
13C NMR (100 MHz, CDCl3): d = 167.0, 161.1, 137.8, 134.9, 130.4
(2 C), 129.7 (2 C), 128.8, 127.8, 123.6, 116.7, 116.5, 113.6, 112.3,
111.2, 60.5, 52.2, 14.5.
Ethyl 1-Bromo-2-(3-bromophenyl)indolizine-3-carboxylate (3f)
Tan solid; mp 89.4–90.2 °C.
MS (ESI): m/z (%) = 403 [(M + 2)+, 46], 401 (M+, 47).
HRMS: m/z [M]+ calcd for C19H1679BrNO4: 401.0263; found:
IR (KBr): 2925, 1678, 1595, 1454, 1368, 1348, 1307, 1223, 1186,
1123, 750, 700, 651 cm–1.
401.0265.
1H NMR (400 MHz, CDCl3): d = 9.46 (d, J = 7.2 Hz, 1 H), 7.58 (s,
1 H), 7.45 (d, J = 8.0 Hz, 1 H), 7.38 (t, J = 9.8 Hz, 2 H), 7.28 (t,
J = 7.8 Hz, 1 H), 7.00 (t, J = 7.8 Hz, 1 H), 6.78 (t, J = 6.8 Hz, 1 H),
4.39 (q, J = 7.2, 6.8 Hz, 2 H), 1.40 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.2, 135.1, 134.8, 133.3, 130.3,
130.0, 129.2, 127.7, 123.5, 122.4, 116.7, 116.1, 113.5, 112.1, 111.3,
60.5, 14.5.
Ethyl 1-Bromo-2-phenylindolizine-3-carboxylate (3j)
Yellow-green oil.
IR (KBr): 2960, 2928, 1678, 1603, 1453, 1369, 1354, 1343, 1308,
1224, 1186, 1122, 734, 701, 659 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.55 (d, J = 7.2 Hz, 1 H), 7.54–
7.49 (m, 5 H), 7.42 (d, J = 6.8 Hz, 1 H), 7.06 (t, J = 7.8 Hz, 1 H),
6.85 (t, J = 6.8 Hz, 1 H), 4.49 (q, J = 7.0, 7.2 Hz, 2 H), 1.49 (t,
J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.3, 134.9, 132.9, 130.5 (2 C),
128.4 (2 C), 127.6, 127.4, 123.0, 117.8, 117.0, 113.3, 111.8, 111.3,
60.4, 14.5.
MS (ESI): m/z (%) = 425 [(M + 4)+, 50], 423 [(M + 2)+, 85], 421
(M+, 53).
HRMS: m/z [M]+ calcd for C17H1379Br2NO2: 420.9313; found:
420.9312.
MS (ESI): m/z (%) = 345 [(M + 2)+, 28], 343 (M+, 30).
HRMS: m/z [M]+ calcd for C17H1479BrNO2: 343.0208; found:
Ethyl 1-Bromo-2-[4-(trifluoromethyl)phenyl]indolizine-3-car-
boxylate (3g)
Yellow-green solid; mp 97.1–98.0 °C.
343.0210.
IR (KBr): 2961, 1679, 1617, 1500, 1459, 1369, 1351, 1324, 1225,
1166, 1123, 756, 743, 654 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.48 (d, J = 7.2 Hz, 1 H), 7.67 (d,
J = 8.0 Hz, 2 H), 7.56 (d, J = 8.0 Hz, 2 H), 7.40 (d, J = 8.8 Hz, 1 H),
7.01 (t, J = 7.8 Hz, 1 H), 6.79 (t, J = 6.8 Hz, 1 H), 4.40 (q, J = 7.0,
7.2 Hz, 2 H), 1.40 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.1, 136.8, 134.9, 130.7 (2 C),
129.3 (q, J = 32.3 Hz, 1 C), 127.8, 126.9 (q, J = 269.8 Hz, 1 C),
125.4 (q, J = 3.7 Hz, 2 C), 123.6, 116.6, 116.1, 113.6, 112.3, 111.2,
60.6, 14.5.
Ethyl 1-Bromo-2-p-tolylindolizine-3-carboxylate (3k)
Yellow-green oil.
IR (KBr): 2924, 2854, 1678, 1509, 1454, 1369, 1351, 1309, 1224,
1188, 1121, 816, 753, 663, 505 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.45 (d, J = 7.2 Hz, 1 H), 7.40 (d,
J = 9.2 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H),
6.94 (t, J = 7.4 Hz, 1 H), 6.74 (t, J = 7.0 Hz, 1 H), 4.38 (q, J = 7.0,
7.2 Hz, 2 H), 2.36 (s, 3 H), 1.39 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.3, 137.1, 134.9, 130.3 (2 C),
129.9, 129.2 (2 C), 127.6, 122.8, 117.7, 117.1, 113.2, 111.7, 111.4,
60.4, 21.3, 14.5.
MS (ESI): m/z (%) = 413 [(M + 2)+, 77], 411 (M+, 79).
HRMS: m/z [M]+ calcd for C18H1379BrF3NO2: 411.0082; found:
MS (ESI): m/z (%) = 359 [(M + 2)+, 92], 357 (M+, 95).
HRMS: m/z [M]+ calcd for C18H1679BrNO2: 357.0365; found:
411.0083.
357.0368.
Ethyl 1-Bromo-2-(4-cyanophenyl)indolizine-3-carboxylate (3h)
Yellow solid; mp 145.1–146.1 °C.
Ethyl 1-Bromo-2-(4-methoxyphenyl)indolizine-3-carboxylate
(3l)
Yellow-green oil.
IR (KBr): 2918, 2849, 2223, 1679, 1606, 1459, 1367, 1349, 1229,
1125, 754, 549 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.58 (d, J = 7.2 Hz, 1 H), 7.79 (d,
J = 8.4 Hz, 2 H), 7.66 (d, J = 8.0 Hz, 2 H), 7.49 (d, J = 8.8 Hz, 1 H),
7.13 (t, J = 7.8 Hz, 1 H), 6.91 (t, J = 7.0 Hz, 1 H), 4.49 (q, J = 7.2,
6.8 Hz, 2 H), 1.49 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.0, 138.0, 134.7, 132.3 (2 C),
131.0 (2 C), 127.9, 124.0, 119.0, 116.4, 115.5, 113.7, 112.6, 111.1,
110.8, 60.6, 14.4.
IR (KBr): 2927, 2852, 1678, 1612, 1454, 1369, 1351, 1307, 1288,
1248, 1223, 1188, 1121, 835, 755, 639, 579 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.44 (d, J = 7.2 Hz, 1 H), 7.38 (d,
J = 9.2 Hz, 1 H), 7.34 (d, J = 8.8 Hz, 2 H), 6.94 (t, J = 7.8 Hz, 3 H),
6.74 (t, J = 6.8 Hz, 1 H), 4.38 (q, J = 7.0, 7.2 Hz, 2 H), 3.80 (s, 3 H),
1.39 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.2, 158.9, 135.0, 131.6 (2 C),
127.6, 125.1, 122.8, 117.5, 117.1, 114.0 (2 C), 113.2, 111.6, 111.5,
60.3, 55.3, 14.5.
MS (ESI): m/z (%) = 370 [(M + 2)+, 35], 368 (M+, 37).
HRMS: m/z [M]+ calcd for C18H1379BrN2O2: 368.0161; found:
368.0163.
MS (ESI): m/z (%) = 375 [(M + 2)+, 78], 373 (M+, 80).
Synthesis 2011, No. 21, 3447–3452 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Aryl-1-haloindolizines via a 1,3-Dipolar Cycloaddition
3451
HRMS: m/z [M]+ calcd for C18H1679BrNO3: 373.0314; found:
1-Chloro-2-(4-nitrophenyl)indolizine-3-carbonitrile (3q)
373.0315.
Yellow solid; mp 250.0–251.0 °C.
IR (KBr): 3078, 2252, 2126, 1590, 1503, 1343, 824, 762, 617 cm–1.
Ethyl 1-Bromo-2-(3-pyridyl)indolizine-3-carboxylate (3m)
Yellow-green solid; mp 120.3–121.2 °C.
1H NMR (400 MHz, CDCl3): d = 8.38 (d, J = 8.4 Hz, 2 H), 8.30 (d,
J = 6.8 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 2 H), 7.65 (d, J = 8.8 Hz, 1 H),
7.23 (t, J = 7.8 Hz, 1 H), 7.02 (t, J = 6.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 146.8, 137.9, 133.7, 130.0 (2 C),
125.5, 124.9, 124.2 (2 C), 122.2, 117.5, 114.7, 111.9, 111.4, 104.5.
MS (ESI): m/z (%) = 299 [(M + 2)+, 17], 297 (M+, 50).
HRMS: m/z [M]+ calcd for C15H835ClN3O2: 297.0306; found:
IR (KBr): 3078, 2933, 2851, 1678, 1630, 1460, 1367, 1342, 1324,
1223, 1200, 1125, 809, 752, 711, 690, 566 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.50 (d, J = 7.2 Hz, 1 H), 8.72 (s,
1 H), 8.58 (d, J = 2.8 Hz, 1 H), 7.92 (d, J = 7.6 Hz, 1 H), 7.47 (q,
J = 5.2, 2.4 Hz, 1 H), 7.40 (d, J = 9.2 Hz, 1 H), 7.05 (t, J = 7.6 Hz,
1 H), 6.83 (t, J = 6.8 Hz, 1 H), 4.40 (q, J = 7.2, 6.8 Hz, 2 H), 1.41 (t,
J = 7.2 Hz, 3 H).
297.0308.
13C NMR (100 MHz, CDCl3): d = 160.9, 148.4, 145.6, 141.8, 140.1,
134.9, 130.5, 128.0, 124.3, 116.1, 113.9, 112.8, 112.5, 111.5, 60.7,
14.4.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
MS (ESI): m/z (%) = 346 [(M + 2)+, 59], 344 (M+, 62).
HRMS: m/z [M]+ calcd for C16H1379BrN2O2: 344.0161; found:
344.0164.
Acknowledgment
We gratefully acknowledge the Natural Science Foundation of Chi-
na (No. 30873153), the Key Projects of Shanghai in Biomedicine
(No. 08431902700), and the Scientific Research Foundation of the
State Education Ministry for Returned Overseas Chinese Scholars.
We also would like to thank the Center for Instrumental Analysis,
Tongji University, China.
Ethyl 1-Bromo-2-(2-naphthyl)indolizine-3-carboxylate (3n)
Yellow-green oil.
IR (KBr): 3055, 2926, 1678, 1601, 1453, 1370, 1342, 1330, 1305,
1222, 1118, 817, 745, 651, 559 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.48 (d, J = 7.2 Hz, 1 H), 7.87 (d,
J = 7.2 Hz, 2 H), 7.82 (q, J = 5.8, 3.2 Hz, 2 H), 7.56 (d, J = 8.8 Hz,
1 H), 7.47–7.43 (m, 3 H), 6.97 (t, J = 7.8 Hz, 1 H), 6.77 (t, J = 7.0
Hz, 1 H), 4.40 (q, J = 7.0, 7.2 Hz, 2 H), 1.41 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.3, 135.1, 133.5, 132.6, 130.4,
129.4, 128.5, 128.0 (2 C), 127.8, 127.7, 126.2, 126.1, 123.2, 117.7,
117.0, 113.4, 111.9, 111.5, 60.4, 14.5.
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Yellow solid; mp 171.2–172.1 °C.
IR (KBr ): 2924, 1679, 1593, 1509, 1475, 1349, 1257, 1228, 1190,
1105, 855, 800, 755 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.59 (d, J = 6.8 Hz, 1 H), 8.37 (d,
J = 8.0 Hz, 2 H), 7.75 (d, J = 8.0 Hz, 2 H), 7.57 (d, J = 8.8 Hz, 1 H),
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MS (ESI): m/z (%) = 346 [(M + 2)+, 20], 344 (M+, 58).
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344.0566.
1-Bromo-2-(4-nitrophenyl)indolizine-3-carbonitrile (3p)
Reddish-brown solid; mp 229.2–230.1 °C.
IR (KBr): 3100, 2203, 1595, 1518, 1338, 854, 744, 678 cm–1.
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126.0, 124.5 (2 C), 124.3, 121.8, 118.2, 114.3, 113.1, 110.2, 93.7.
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HRMS: m/z [M]+ calcd for C15H879BrN3O2: 340.9782; found:
340.9785.
Synthesis 2011, No. 21, 3447–3452 © Thieme Stuttgart · New York

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Y. Yang et al.
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Synthesis 2011, No. 21, 3447–3452 © Thieme Stuttgart · New York