The first approach to the synthesis of 1-unsubstituted 2- arylindolizines by intramolecular 1,5-dipolar cyclization of 2-(2- arylethenyl)pyridinium ylides in the presence of tetrakis(pyridine)cobalt (II) dichromate

Article abstract of DOI:10.1055/s-1999-3673

The first approach to the preparation of 1-unsubstituted 2- arylindolizines by intramolecular 1,5-dipolar cyclization of 2-(2- arylethenyl)pyridinium ylides 2a-v in the presence of tetrakis(pyridine)cobalt (II) dichromate was developed. Several kinds of n

Full text of DOI:10.1055/s-1999-3673

166
PAPER
The First Approach to the Synthesis of 1-Unsubstituted 2-Arylindolizines by
Intramolecular 1,5-Dipolar Cyclization of 2-(2-Arylethenyl)pyridinium Ylides
in the Presence of Tetrakis(pyridine)cobalt (II) Dichromate
Jian Zhou,a Yuefei Hu,*a,b Hongwen Hua,b
a Department of Chemistry, Nanjing University, Nanjing 210093, PeopleÕs Republic of China
b Coordination Chemistry Institute, Nanjing University, Nanjing 210093, PeopleÕs Republic of China
Fax: +86(25)3317761; E-mail pyorg@nju.edu.cn
Received 13 April 1998; revised 2 June 1998
Abstract: The first approach to the preparation of 1-unsubstituted
2-arylindolizines by intramolecular 1,5-dipolar cyclization of 2-(2-
arylethenyl)pyridinium ylides 2aÐv in the presence of tetrakis(pyri-
dine)cobalt (II) dichromate was developed. Several kinds of novel
1-unsubstituted 2-aryl-3-acetyl-, 3-benzoyl-, 3-ethoxycarbonyl-
and 3-(4-nitrobenzoyl)indolizines 3aÐv were synthesized under the
mild conditions in reasonable to moderate yields.
Key words: 1-unsubstituted 2-arylindolizines, intramolecular 1,5-
dipolar cyclization, pyridinium ylides, tetrakis(pyridine)cobalt (II)
dichromate
Scheme 1
are not commercially available and also not convenient to
prepare in the laboratories. Herein we report a new ap-
proach for the preparation of 1-unsubstituted 2-aryl-
indolizines by intramolecular 1,5-dipolar cyclization of 2-
(2-arylethenyl)pyridinium ylides in the presence of
tetrakis(pyridine)cobalt (II) dichromate (TPCD).
Perhydro derivatives of indolizine occurr in natural prod-
ucts.1,2 However, indolizines with discrete aromatic nu-
cleus could be synthesized only in laboratories. For both
theoretical and practical reasons, synthetic indolizines
have attracted special attention in past years.1,3 Many of
them have been used as photographic sensitisers,1b,4 bio-
logical markers5 and potential candidates for pharma-
ceutical researches.6 A Japanese group recommended 1-
methoxycarbonylindolizine-3,5-dicarbaldehyde as a de-
rivatization reagent for amino compounds in high-perfor-
mance capillary electrophoresis (HPCE).7
TPCD, a bimetallic coordination compound, is a mild and
versatile oxidant,13 and is used widely in organic synthe-
sis.14 In our previous papers,15 alkenes instead of alkynes
were used successfully in a 1,3-dipolar cycloaddition re-
action with pyridinium ylides to prepare indolizines in the
presence of TPCD. These results persuaded us to try to
modify TsuchiyaÕs procedure by using 2-(2-phenylethe-
nyl)pyridinium N-ylide (from pyridinium salt 2a) instead
of 2-(2-phenylethynyl)pyridinium N-ylide. As expected,
no desired product was detected in the absence of TPCD
after a solution of 2a and triethylamine in toluene was re-
fluxed for 5 hours (Scheme 1). However, when equimolar
amounts of TPCD was added to the reaction mixture, 2a
was converted smoothly to the corresponding indolizine
3a (Scheme 2).
In continuation of our research project to find bioactive
heterocyclic compounds as potential candidates in ag-
ricultural chemistry, a series of 1-unsubstituted 2-aryl-
indolizines 3 was designed as target compounds for
synthesis. The methods for preparation of indolizines
were summarized in several reviews1,8 and some new pro-
cedures were reported very recently.9 Among them,
Tschitschibabin reaction10 and intramolecular 1,5-dipolar
cycloadditionof pyridinium N-allylides11 can introduce an
aryl group to C-2 in indolizine conveniently. But the
methods were limited seriously for our purpose because
the reaction mechanism required a functional group other
than hydrogen on C-1 in indolizine for the most cases.
The best method to prepare the desired 2-arylindolizines
is the TsuchiyaÕs procedure,12 exemplified by the synthe-
sis of 2-phenyl-3-benzoylindolizine (3a) by the thermal
intramolecular 1,5-dipolar cyclization of 2-(2-phenyl-
ethynyl)pyridinium N-ylide in 67% yield (Scheme 1).
However, the fact that 2-arylindolizines are not prepared
any more by this procedure may be due to the fact that
most of the derivatives of 2-(2-phenylethynyl)pyridine
1
Ar
1
Ar
a
b
c
C6H5
2-ClC6H4
4-ClC6
d
e
f
3,4-Cl2C6H3
4-NO2C6H4
4-MeOC6H4
Reagents and conditions: (a) RCH2Br/CHCl3, 50Ð60¡C (79Ð96%);
(b) TPCD/Et3N/toluene, 80Ð90¡C (17Ð54%)
Scheme 2
Synthesis 1999, No. 1,166Ð170 ISSN 0039-7881 © Thieme Stuttgart á New York

PAPER
The First Approach to the Synthesis of 1-Unsubstituted 2-Arylindolizines
167
2-(2-Arylethenyl)pyridines 1aÐf were prepared by known tained in 17Ð54% yields (Tables 1 and 3). The reaction
procedures16 and were converted to their corresponding conditions is very mild and workup procedure is conve-
pyridinium salts 2aÐ2v in high yields simply by the addi- nient. It is worthy to note that the use of excess TPCD has
tion of equimolar amounts of appropriate bromides to a no effect in increasing the yields of the products. Use of
chloroform solution of 1 at 50Ð60¡C. In the case of 2n, DMF as a solvent reduced the yields and made the workup
ethyl acetate was used as a solvent to give a powder salt procedure tedious.
(Tables 1 and Table 2). Unfortunately, all attempts to pre-
The experimental results proved that the aryl group on the
pare 2,6-bis(2-phenylethenyl)pyridinium and 2-(2-
double bond in 2-vinylpyridine and the presence of TPCD
phenylethenyl)quinolinium salts from the corresponding
are necessary for the reaction. For example, the parent 2-
2,6-bis(2-phenylethenyl)pyridine and 2-(2-phenylethenyl)-
vinylpyridinium salt just gave an unidentified product
quinoline, respectively, failed.
mixture and none of components used to prepare TPCD,
such as chromium trioxide or cobalt (II) acetate did show
any activity by themselves.
Table 1 Pyridinium Salts 2a–v and Indolizines 3a–v Prepared
The ylide 4 is formed in the initial step of the reaction with
certainty when the salt 2 is treated with triethylamine. We
assume that one of the resonance structures of the ylide 4
functions as a 1,5-dipole and may be expected to undergo
1,5-dipolar cyclization to afford dihydroindolizines 5,
which could be aromatized in situ by TPCD to yield in-
dolizines 3 (Scheme 3). The fact that dihydroindolizines
can be aromatized easily to give the corresponding in-
dolizines by TPCD15b supports this mechanism. However,
none of the intermediate dihydroindolizines 5 were de-
tected or separated in the above reactions so far.
Prod-
ucts
R
Ar
Yields (%)a
2
3
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COMe
COMe
COMe
COMe
COMe
COMe
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
C6H5
92
89
94
85
87
90
85
96
79
89
81
84
80
90
85
88
92
87
83
84
80
86
19
18
44
22
20
25
28
21
37
54
44
21
18
17
19
27
20
17
21
26
23
31
2-ClC6H4
4-ClC6H4
3,4-Cl2C6H3
4-NO2C6H4
4-MeOC6H4
C6H5
2-ClC6H4
4-ClC6H4
3,4-Cl2C6H3
4-NO2C6H4
4-MeOC6H4
C6H5
2-ClC6H4
4-ClC6H4
3,4-Cl2C6H3
4-NO2C6H4
4-MeOC6H4
C6H5
2-ClC6H4
4-ClC6H4
3,4-Cl2C6H3
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
t
u
v
Scheme 3
a Yield based on the isolated product.
In conclusion, the first procedure of intramolecular 1,5-di-
polar cyclization of 2-(2-arylethenyl)pyridinium ylides
2aÐv effected by TPCD was developed. The reaction us-
ing alkenes instead of alkynes as starting materials pro-
vides a convenient and general method for the preparation
of 1-unsubstituted 2-arylindolizines, which are quite diffi-
cult to prepare by any other published method.
Table 2 2-(2-Arylethenyl)pyridinium Salts 2a–v Prepared
Prod- mp (°C) IR (KBr)
uct
Prod- mp (°C)
uct
IR (KBr)
ν (cm–1)
ν (cm–1)
2a
2b
2c
2d
2e
2f
2g
2h
2i
230–236 1687, 1616
237–240 1687, 1616
206–210 1687, 1616
235–237 1687, 1616
2l
194–196
185–186
186–188
198–200
200–202
182–184
180–182
234–236
229–231
232–234
230–232
1729, 1602
1743, 1623
1743, 1616
1750, 1623
1750, 1616
1736, 1616
1743, 1602
1609, 1518
1609, 1518
1623, 1525
1616, 1518
2m
2n
2o
2p
2q
2r
2s
2t
2u
2v
All melting points were determined on a Yanaco melting point ap-
paratus and are uncorrected. IR spectra were recorded on a Nicolet
1
FT-IR 5DX spectrometer with KBr pellets. H NMR spectra were
78
1687, 1595
recorded on a Bruker ACF-300 spectrometer with TMS as internal
reference. J Values are given in Hz. MS spectra were obtained on a
ZAB-HS mass spectrometer with 70 eV. Elemental analyses were
performed on a Perkin-Elmer 240C instrument.
202–206 1687, 1602
206–208 1687, 1623
146–148 1729, 1616
210–212 1722, 1609
193–195 1729, 1616
210–213 1722, 1609
2j
2k
2-(2-Arylethenyl)pyridinium Salts 2aÐv; General Procedure
A mixture of 2-(2-arylethenyl)pyridine 1 (20 mmol) and the appropri-
ate bromide (20 mmol) in CHCl3 (15 mL) was allowed to stand over-
night at r.t. and then was stirred at 50Ð60¡C for several hours. The
precipitated 2-(2-arylethenyl)-pyridinium salts 2 (79Ð96%) were col-
lected by filtration and washed with CHCl3 (3 × 5 mL). They were
used in the next step directly without further purification.
Under the standard conditions, a stirred suspension of py-
ridinium salts 2aÐv, triethylamine, and TPCD in toluene
was heated at 80Ð90¡C for 4Ð6 hours (monitored by
TLC). After the solid was filtered off and toluene was
evaporated, the corresponding indolizines 3aÐv were ob-
Synthesis 1999, No. 1, 166–170 ISSN 0039-7881 © Thieme Stuttgart · New York

168
J. Zhou et al.
PAPER
Table 3 1-Unsubstituted 2-Arylindolizines 3a–v Prepared
Prod-
ucta
Color
mp (°C)
137–138b
140–142
89–90
IR (KBr)
1H NMR (CDCl3/TMS)
δ, J (Hz)
MS (70 eV)
m/z (%)
ν (cm–1)
3a
3b
3c
yellow
yellow
yellow
1588, 1497, 744,
695
9.81 (d, 1 H, J = 7.4), 7.54 (d, 1 H, J = 8.8), 7.41 (d, 297 (M+, 100), 220 (45), 192
2 H, J = 6.9), 7.16–6.88 (10 H, m), 6.58 (1 H, s) (23)
1595, 1497, 787,
737, 695
9.83 (d, 1 H, J = 6.7), 7.69 (d, 1 H, J = 6.5), 7.58 (d, 333 (6), 331 (M+, 17), 296
2 H, J = 8.6), 7.44–6.91 (m, 9 H), 6.59 (s, 1 H)
(100), 191 (91)
1595, 1497, 801,
723, 702
9.80 (d, 1 H, J = 7.2), 7.55 (d, 1 H, J = 8.8), 7.39 (d,
2 H, J = 7.1), 7.21–7.16 (m, 2 H), 7.07–6.88 (m, 7 H), (65), 77 (52)
333 (37), 331 (M+, 100), 191
6.93–6.88 (m, 1 H), 6.55 (s, 1 H)
3d
3e
3f
yellow
yellow
yellow
169–171
236–237
154–155
1595, 1479, 865,
821, 744, 695
9.81 (d, 1 H, J = 6.7), 7.57 (d, 1 H, J = 8.6), 7.40 (d, 369 (12), 367 (68), 365 (M+,
2 H, J = 7.0), 7.24–6.88 (m, 8 H), 6.97–6.88 (m, 2 H), 100), 77 (41)
6.57 (s, 1 H)
1595, 1511,
1340, 746, 697
9.81 (d, 1 H, J = 6.4), 7.87 (d, 2 H, J = 8.5), 7.59 (d, 342 (M+, 100), 77 (31)
1 H, J = 7.0), 7.38 (d, 2 H, J = 8.6), 7.26–6.98 (m, 7
H), 6.63 (s, 1 H)
1581, 1497,
1335, 1244, 808,
752, 695
9.80 (d, 1 H, J = 6.5), 7.54 (d, 1 H, J = 8.5), 7.42 (d, 327 (M+, 100), 77 (18)
2 H, J = 7.1), 7.20–6.98 (m, 6 H), 6.90 (d, 1 H, J =
6.6), 6.55 (d, 3 H, J = 7.6), 3.70 (s, 3 H)
3g
3h
yellow
yellow
oil
94
1623, 1504,
1406, 744, 702
10.02 (d, 1 H, J = 6.8), 7.51–7.41 (m, 6 H), 7.15 (m, 235 (M+, 45), 220 (54), 108
1 H), 6.88 (m, 1 H), 6.48 (s, 1 H), 2.07 (s, 3 H)
(100)
3142, 3058,
10.01 (d, 1 H, J = 7.1), 7.55–6.90 (m, 7 H), 6.46 (s, 1 271 (8), 269 (M+, 22), 234
1616, 1497,
H), 2.02 (s, 3 H) (100)
1406, 1328, 752
3i
yellow
yellow
yellow
yellow
78–80
1602, 1497,
1420, 1391,
1328
9.98 (d, 1 H, J = 7.1), 7.51 (d, 1 H, J = 8.8), 7.44–6.87 271 (33), 269 (M+, 98), 254
(m, 6 H), 6.45 (s, 1 H), 2.07 (s, 3 H) (100), 219 (59), 191 (51)
3j
3k
3l
119–121
190–192
105–107
1609, 1497,
1413, 1370,
1328, 794
9.97 (d, 1 H, J = 7.1), 7.61 (s, 1 H), 7.52 (d, 2 H, J = 307 (11), 305 (66), 303 (M+,
8.6), 7.28–6.92 (m, 3 H), 6.46 (s, 1 H), 2.10 (s, 3 H)
100), 288 (96), 253 (61), 225
(55), 190 (36)
1616, 1511,
1349, 887
9.98 (d, 1 H, J = 7.2), 8.32 (d, 2 H, J = 8.6), 7.62 (d, 280 (M+, 100), 265 (89), 219
2 H, J = 8.6), 7.55 (d, 1 H, J = 8.8), 7.22–6.93 (m, 2 (69), 190 (31)
H), 6.50 (s, 1 H), 2.05 (s, 3 H)
1609, 1497,
1251, 1033, 836
9.98 (d, 1 H, J = 7.2), 7.50 (d, 1 H, J = 8.8), 7.33 (d, 265 (M+, 12), 250 (97), 207
2 H, J = 8.5), 7.18 (t, 1 H, J = 7.7), 6.98 (d, 2 H, J = (31), 191 (28), 178 (100)
6.9), 6.89 (m, 1 H), 6.47 (s, 1 H), 3.88 (s, 3 H), 2.10
(s, 3 H)
3m
3n
yellow
yellow
oil
oil
1680, 1602,
1504, 1230, 759
9.54 (d, 1 H, J = 6.9), 7.50–7.27 (m, 6 H), 7.05 (m, 1 265 (M+, 58), 193 (100), 192
H), 6.82 (m, 1 H), 6.51 (s, 1 H), 4.21 (q, 2 H, J = 6.9), (23)
1.08 (t, 3 H, J = 6.9)
1680, 1504,
1230, 751, 681
9.52 (d, 1 H, J = 6.9), 7.58–7.42 (m, 2 H), 7.33–7.28 301 (5), 299 (M+, 15), 131
(m, 3 H), 7.05 (t, 1 H, J = 6.9), 6.83 (t, 1 H, J = 6.9), (100)
6.47 (s, 1 H), 4.10 (q, 2 H, J = 7.0), 0.94 (t, 3 H, J =
7.0)
3o
3p
yellow
yellow
52–54
78–80
1673, 1504,
1420, 1228, 836
9.52 (d, 1 H, J = 7.1), 7.48 (d, 1 H, J = 8.9), 7.42–7.34 301 (4), 299 (M+, 11), 139
(m, 4 H), 7.05 (m, 1 H), 6.82 (m, 1 H), 6.47 (s, 1 H), (100), 111 (37)
4.20 (q, 2 H, J = 7.1), 1.11 (t, 3 H, J = 7.1)
1666, 1497,
1420, 829, 781
9.54 (d, 1 H, J = 7.0), 7.60 (d, 1 H, J = 2.0), 7.45 (d, 337 (8), 335 (47), 333 (M+,
2 H, J = 8.4), 7.32 (m, 1 H), 7.07 (m, 1 H), 6.84 (t, 1 73), 263 (63), 261 (100), 225
H, J = 6.9), 6.48 (s, 1 H), 4.22 (q, 2 H, J = 7.1), 1.15 (37)
(t, 3 H, J = 7.1)
Synthesis 1999, No. 1, 166–170 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
The First Approach to the Synthesis of 1-Unsubstituted 2-Arylindolizines
169
Table 3 (continued)
Prod-
ucta
Color
mp (°C)
155–156
IR (KBr)
1H NMR (CDCl3/TMS)
δ, J (Hz)
MS (70 eV)
m/z (%)
ν (cm–1)
3q
yellow
1680, 1595,
1511, 1342,
1229, 857
9.54 (d, 1 H, J = 7.2), 8.25 (d, 2 H, J = 8.8), 7.64 (d, 310 (M+, 58), 282 (22), 238
2 H, J = 8.8), 7.64 (d, 1 H, J = 8.8), 7.10 (m, 1 H), (100)
6.89 (m, 1 H), 6.53 (s, 1 H), 4.21 (q, 2 H, J = 7.1),
1.09 (t, 3 H, J = 7.1)
3r
yellow
99–101
1666, 1503,
1461, 830
9.52 (d, 1 H, J = 6.4), 7.44 (d, 3 H, J = 8.7), 7.02 (m, 295 (M+, 91), 267 (23), 223
1 H), 6.93 (d, 2 H, J = 8.7), 6.79 (m, 1 H), 6.47 (s, 1 (100)
H), 4.21 (q, 2 H, J = 7.1), 1.63 (s, 3 H), 1.13 (t, 3 H,
J = 7.1)
3s
3t
orange
orange
orange
orange
138–140
149–150
194–196
226–228
1595, 1511,
1342, 857, 730,
702
8.26 (d, 2 H, J = 8.7), 8.13 (d, 1 H, J = 7.0), 7.55 (d, 314 (M+, 100), 268 (23)
2 H, J = 8.7), 7.47 (d, 1 H, J = 8.9), 7.32–7.27 (m, 6
H), 6.83 (m, 1 H), 6.57 (t, 1 H, J = 6.6)
1588, 1511,
1342, 857, 773
8.23 (d, 1 H, J = 7.1), 8.19 (d, 2 H, J = 5.4), 7.49–7.39 350 (37), 348 (100)
(m, 4 H), 7.23–7.20 (m, 4 H), 6.84 (m, 1 H), 6.60 (m,
1 H)
3u
3v
1595, 1511,
1342, 864, 857
8.28 (d, 2 H, J = 8.6), 8.09 (d, 1 H, J = 7.1), 7.53 (d,
350 (34), 348 (M+, 100), 302
2 H, J = 8.6), 7.45 (d, 1 H, J = 8.7), 7.24–7.16 (m, 5 (39)
H), 6.82 (m, 1 H), 6.56 (m, 1 H)
1595, 1511,
1342, 829
8.31 (d, 2 H, J = 8.8), 8.07 (d, 1 H, J = 7.1), 7.56–7.30 386 (12), 384 (66), 382 (M+,
(m, 6 H), 7.01 (m, 1 H), 6.70 (m, 1 H), 6.59 (m, 1 H) 100), 336 (31)
a Satisfactory elemental analyses obtained: C ± 0.28, H ± 0.30, N ± 0.29.
b Lit. mp 136–138°C;12 137–137.5°C.17
1-Unsubstituted 2-Arylindolizines 3aÐv; General Procedure
(b) Okada, S.; Sawada, K.; Kozo, A.; Watarabe, S.; Tanaka,
H. Brit. UK Pat. Appl., GB 2 287 706, 1995; Chem. Abstr.
1995, 124, 175847.
(c) Hagishita, S.; Yamada, M.; Shirahase, K.; Okada, T.; Mu-
rakami, Y.; Ito, Y.; Matsuura, T.; Wada, M.; Kato, T.; Ueno,
M.; Chikazawa, Y.; Yamada, K.; Ono, T.; Teshirogi, I.; Ohta-
ni, M. J. Med. Chem. 1996, 39, 3636.
A
stirred suspension of 2-(2-arylethenyl)pyridinium salt 2
(10 mmol) and TPCD (6.08 g, 10 mmol) in toluene (100 mL) was
treated dropwise with Et3N (0.92 g, 10 mmol) at 80Ð90¡C. After 4
to 6 h (monitored by TLC), the solid was filtered off and washed
with acetone (3 × 10 mL). The solvent was removed from the com-
bined filtrates under vacuum to give the crude product 3, which was
purified by column chromatography [silica gel, 10% EtOAc in pe-
troleum ether (bp 60Ð90¡C)].
(7) Oguri, S.; Uchida, C.; Miyake, Y.; Miki, Y.; Kakehi, K. The
Analyst 1995, 120, 63.
(8) (a) Prostakov, N. S.; Batibaev, O. B. Russ. Chem. Rev. 1975,
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(b) Uchida, T.; Matsumoto, K. Synthesis 1976, 209.
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Acknowledgement
We are grateful to Natural Science Foundation of China for finan-
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