Synthesis of a library of 1,2,3,7-tetrasubstituted indolizines using poly(ethylene glycol) as soluble support

Article abstract of DOI:10.1002/jhet.5570430340

A library of 1,2,3,7-tetrasubstituted indolizines has been synthesized using poly(ethylene glycol) (PEG) as soluble polymer support. The PEG-bound pyridinium salts reacted with alkenes or alkynes in the presence of Et ₃N via 1,3-dipolar cycload

Full text of DOI:10.1002/jhet.5570430340

May-Jun 2006
781
Synthesis of a Library of 1,2,3,7-Tetrasubstituted Indolizines using
Poly(ethylene glycol) as Soluble Support
Guizhou Yue,*a Zuxing Chen,b Guichun Yangb
aSchool of Life Science, Sichuan Agriculture University, Ya’an, Sichuan, 625014, P. R. China
E-mail: ygzyx99@tom.com
bFaculty of Chemistry and Material Science, Hubei University, Wuhan, Hubei, 430062, P. R. China
Received August 28, 2005
O
R1
O
O
alkenes or alkynes
R2
O
N
O
R
1,3-dipolar cycloaddition
N
O
Br
R
A library of 1,2,3,7-tetrasubstituted indolizines has been synthesized using poly(ethylene glycol) (PEG)
as soluble polymer support. The PEG-bound pyridinium salts reacted with alkenes or alkynes in the
presence of Et3N via 1,3-dipolar cycloaddition to give PEG-bound indolizine derivatives, which were
cleaved by 1 % KCN/MeOH to afford 1,2,3,7-tetrasubstituted indolizines in good to excellent yields.
J. Heterocyclic Chem., 43, 781 (2006).
Introduction.
fluorescent ꢀ-cyclodextrines to be chemosensors and to
detect volatile organic molecules and adamatane
derivatives [12].
In recent years, the synthesis of small organic
molecules on soluble polymeric supports has become a
significant field of interest in particular its application in
the field of combinatorial chemistry [1]. It combines the
advantages of the conventional liquid-phase synthesis
and easy separation purification of the products in solid-
phase synthesis. Moreover, the soluble polymer-bound
species allow using routine analytical methods (NMR,
TLC or IR) to monitor the reaction process and to
determine the structures of products attached to polymer
support directly.
The methods for synthesis of indolizine are classified
mainly as Scholtz and Tschitschibabin reaction, 1,3-
dipolar cycloaddition and 1,5-dipolar cyclization [13].
Recently there was reported to synthesize indolizines
bearing [Os3(μ-H)2(CO)10] by the rearrangement of diyne
[14]. Although there are many methods, the second one
has been widely utilized in the synthesis of indolizines.
The synthesis of indolizines on solid support by this
method was also reported [15].
In particular, among the soluble supports, poly(ethyl-
ene glycol) (PEG) are the most interesting polymers
because they can be easily functionalized with different
spacers or reactive groups and are commercially
available, inexpensive, non-toxic, highly resistant to
drastic physical and chemical conditions, and are also
soluble in a wide variety of solvents and easily precip-
itated from ether [2]. Because of their advantages, PEG
and its monomethyl analogs are also known to be a rapid
and recoverable reaction media for Heck reaction [3],
Baylis-Hillman reaction [4], asymmetric dihydroxylation
[5], asymmetric aldol condensation [6], and cross-
coupling reactions [7] etc.
Indolizine derivatives are a well-known class of hetero-
cycles that are very attractive due to their versatility in a
large number of applications and their important
biological and medical properties. For example, recently
they were as potent inhibitors [8] and dyes [9] and
exhibited acute antibacterial and antifungal activities [10]
etc. In addition, they were used to synthesize novel meso-
substituted indolizine porphyrins [11] and a new class of
Results and Discussion.
We have already described PEG-bound pyridinium-type
salts in which PEG was attached to N atom of pyridine
using bromoacetyl bromide as the reagent utilized to
synthesize a linker [16]. In an extension of our work on
PEG-bound pyridinium salt, herein we report that isonico-
tinic acid attached to PEG employing esterification,
followed to react with bromides to afford PEG-bound
pyridinum salts. The salts, respectively, reacted with
alkenes or alkynes via 1,3-dipolar cycloaddition to give
PEG-bound indolizine derivatives, followed by cleavage to
obtain 1,2,3,7-tetrasubstituted indolizines. For comparison
to our synthesis of 1,2,3-trisubstitiuted indolizines [16a],
the synthesis of 1,2,3,7-tetrasubstituted ones had three
variable groups. Commercially available difunctional PEG
3400 was chosen as a soluble polymer support.
As shown in Scheme 1, PEG was coupled with isonico-
tinic acid using 3.0 equiv of dicyclohexyl carbodiimide
(DCC) and 0.3 equiv of 4-dimethylaminopyridine (DMAP)
in dry dimethyl formamide (DMF) at r. t. overnight to get

782
G. Yue, Z. Chen and G. Yang
Vol 43
Scheme 2
Scheme 1
O
O
O
R3
O
O
O
RCOCH2Br 2
isonicotinic acid
R3
Et3N, DMF, 90 oC, r. t.
R4
OH
O
N
O
N
R
5
O
DCC, DMAP, DMF
r. t., overnight
DCM, r. t.
overnight
O
N
R
Br
R1
1
3
N
Br
R1
O
3
R1CH=CHR2
4
6'
O
R
KCN/CH3OH
r. t., overnight
H3COOC
R2
O
R3
R2
Et3N, TPCD, DMF
90 oC, 3-4h
H3COOC
N
N
KCN/CH3OH
r. t., overnight
R4
O
6
7
O
R
R
N
7'
O
R
PEG-bound pyridine 1. The IR spectroscopy of 1 exhibited
characteristc C=O absorption band at 1729 cm-1 and an O-H
1
In order to extend the scope of the application of
PEG-bound pyridinium salts [16], the similar reaction
of PEG-bound pyridinium salts 3 with alkynes 5 was
also carried out. As shown in Scheme 2, 3 reacted with
5 in the presence of Et3N in DMF at 90° for 3 h to
generate PEG-bound indolizines 6', followed by the
same method of cleavage and purification to afford
indolizines 7' in all overall yields of 62-92% (Table 2).
absorption band was not observed, furthermore, H NMR
spectroscopy of 1 showed that the signals of the pyridine
protons were at ꢀ 8.67 and 7.82 ppm. Treatment of 1 with
bromides 2 overnight, followed by precipitation and
washing with cold anhydrous Et2O to afford the PEG-bound
pyridinium salts 3. TLC showed the absence of excess
reagent and any by-products. The salts 3, respectively, were
treated with 3.0 equiv of alkenes 4, 0.5 equiv of
tetrakis(pyridine) cobalt(II) dichromate (TPCD) and 2.0
equiv of Et3N in dry DMF at 90° for 3-4 h to afford PEG-
bound indolizines 6. In this reaction, 3 were deprotonated by
Et3N to give the resonance-stabilized PEG-bound
pyridinium ylides, 1,3-dipoles, that readily underwent a 1,3-
dipolar cycloaddition with 4 to the dihydroindolizines,
followed by aromatization using oxidant TPCD to get PEG-
bound indolizines as the expected cycloadduct. TPCD, a
bimetallic coordination compound, was a mild and versatile
oxidant [17] and was used widely in organic synthesis [18]
including the synthesis of indolizines [19]. Compounds 6
were cleaved from PEG by 1% KCN in methanol solution at
r.t. overnight to give, after purification by column chromato-
graphy, indolizines 7a1-7 and 7b1-7 in all overall yields of
48-91% (Table 1), which were unambiguously confirmed
by IR, 1H and 13C NMR spectra and elemental analyses.
1
The structures of 7' were confirmed by IR, H and 13C
NMR spectra and elemental analyses. In a step in the
reaction of 6', PEG-bound pyridinium ylides reacted
with 5 by a 1,3-dipolar cycloaddition, followed by
aromatization to give the PEG-bound indolizines but
not adding TPCD.
Table 2
Synthesis of indolizines 7'a1-2 and 7'b1-2 on soluble support.
Entry
R
R3
R4
Yield(%)
7'[b]
6'[a]
a1
a2
b1
b2
Me
Me
Ph
H
COOMe
COOMe
COOMe
COOMe
98
97
99
97
62
75
92
74
COOMe
H
COOMe
Ph
[a] Based on a step of the reaction; [b] Based on the loading capacity of
PEG.
Table 1
Synthesis of indolizines 7a1-7 and 7b1-7 on soluble support.
Conclusion
Entry
R
R1
R2
Yeild(%)
6[a]
7[b]
78
88
85
90
50
65
48
91
80
82
72
70
81
75
We have successfully demonstrated polymer-supported
methodology for the efficient synthesis of 1,2,3,7-
tetrasubstituted indolizines. In each step of the reaction
sequence, the PEG-bound intermediates were purified by
simple precipitation and washing by cold anhydrous Et2O.
The pure products are usually obtained in good to
excellent yields after easy purification. Synthesis and
screening of focused combinatorial libraries may lead to
the discovery of interesting biological activities.
a1
a2
a3
a4
a5
a6
a7
b1
b2
b3
b4
b5
b6
7b7
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
COPh
COMe
CN
4-FPh
Ph
H
97
98
97
99
97
96
96
99
96
98
97
96
97
97
2,3-cyclohexanone
COPh
COPh
COMe
COPh
COMe
CN
(4-F-3-OPh)Ph
4-BrPh
2-furyl
4-FPh
Ph
H
2,3-cyclohexanone
COPh
COPh
COPh
(4-F-3-OPh)Ph
3-O2NPh
Acknowledgements.
Ph
Ph
3-NCPh
This work was supported by Sichuan Agriculture
University and the National Natural Sciences Foundation
of China (NO: 20372019).
[a] Based on a step of the reaction; [b] Based on the
loading capacity of PEG.

May-Jun 2006
Synthesis of Indolizines using Poly(ethylene glycol) as Soluble Support
783
EXPERIMENTAL
Methyl 3-acetyl-1-benzoyl-2-(4-fluorophenyl)-7-indolizinecarb-
oxylate (7a1).
All organic solvents and bases were dried by standard
methods. PEG3400 (Aldrich, 3015-3685) and PEG-bound
compounds were melted in vacuum at 80° for about 30 min
before use, to remove any trace of moisture. Melting points were
measured on a X-6 digital melting point apparatus and
uncorrected. IR spectra were recorded on an IR-Spectrum One
This compound was obtained as yellow green crystals, mp
1
197°; IR: C=O 1723 (strong), C=O 1625 (strong) cm-1;ꢀ H
NMR: ꢀ 9.98 (d, 1H, 5-H, J = 7.2 Hz), 8.59 (d, 1H, 8-H, J = 1.8
Hz,), 7.59 (dd, 1H, 6-H, J = 1.8, 7.2 Hz), 7.49 (d, 2H, phenyl
protons, J = 7.8 Hz), 7.37 (t, 1H, phenyl proton, J = 7.2 Hz),
7.21-7.19 (m, 4H, phenyl protons), 6.91 (dd, 2H, phenyl protons,
I
J = 7.2, 7.8 Hz), 3.94 (s, 3H, COOMe), 2.00 (s, 3H, COMe); 13
C
spectrometer (Perin Elmer), using KBr pellets. H NMR (600
MHz) and 13C NMR (150 MHz) spectra were recorded on a
Varian Unity INOVA 600 spectrometer in CDCl3 using TMS
(0.03 %) as internal standard. Elemental analyses were done on
a PE 2400 CHN analyzer.
NMR: ꢀ C=O 192.8, C=O 190.9, C=O 165.6, 139.4, 138.9,
137.1, 132.8, 132.7, 132.6, 130.3, 129.7, 128.6, 128.4, 128.2,
123.5, 121.7, 118.6, 115.7, 114.8, OCH3 53.3, CH3 31.3.
Anal. Calcd. for C25H18NO4F: C, 72.28, H, 4.37, N, 3.37.
Found: C, 72.30, H, 4.34, N, 3.40.
Preparation of PEG-bound Pyridine (1).
Methyl 1,3-diacetyl-2-phenyl-7-indolizinecarboxylate (7a2).
To a solution of PEG3400 (10.00 g, 5.88 mmoles-OH) in dry
DMF (50 mL) were added isonicotinic acid (2.17 g, 17.64
mmoles), DCC (3.63 g, 17.64 mmoles) and DMAP (0.22 g, 1.76
mmoles) and stirred at r.t. overnight. The solvent was
evaporated under vacuum, followed by precipitation with cold
anhydrous Et2O (500 mL), washing with cold anhydrous Et2O
(100 mL ꢀ 3) and drying under vacuum, to give a white solid 1,
10.26 g (98%); IR: CH2 2882 (strong), C=O 1729 (strong) cm-1;
1H NMR: ꢀ 8.67 (d, 2H, pyridinyl protons, J = 4.2 Hz), 7.82 (d,
2H, pyridinyl protons, J = 4.2 Hz), 4.40-3.06 (m, 4nH,
-O(CH2CH2O)n-).
This compound was obtained as yellow spiculate crystals, mp
212°; IR: C=O 1718 (strong), C=O 1624 (strong) cm-1; 1H NMR:
ꢀ 10.03 (d, 1H, 5-H, J = 7.2 Hz), 9.29 (d, 1H, 8-H, J = 1.8 Hz),
7.62 (dd, 1H, 6-H, J= 1.8, 7.2 Hz), 7.54-7.43 (m, 5H, phenyl
protons), 3.99 (s, 3H, COOMe), 1.90 (s, 3H, COMe), 1.86 (s,
3H, COMe); 13C NMR: ꢀ C=O 195.5, C=O 190.8, C=O 165.8,
140.3, 137.4, 136.1, 130.2, 129.5, 129.4, 129.4, 128.7, 123.8,
123.0, 118.2, 115.4, OCH3 53.1, CH3 31.4, CH3 31.2.ꢀ
Anal. Calcd. for C20H17NO4: C, 71.63, H, 5.11, N, 4.18.
Found: C, 71.66, H, 5.10, N, 4.20.ꢀ
General Procedure for Preparation of PEG-bound Pyridinium
Salts (3).
Methyl 3-acetyl-1-cyano-7-indolizinecarboxylate (7a3).
This compound was obtained as yellow solid, mp 215°;ꢀ IR:
CN 2223 (strong), C=O 1711 (strong), C=O 1650 (strong) cm-1;
1H NMR: ꢀ 9.86 (d, 1H, 5-H, J = 7.2 Hz,), 8.47 (d, 1H, 8-H, J =
1.2 Hz), 7.81 (s, 1H, H-2), 7.59 (dd, 6-H, J = 1.2, 7.2 Hz), 3.98
(s, 3H, COOMe), 2.60 (s, 3H, COMe); 13C NMR: ꢀ C=O 188.3,
C=O 165.0, 139.8, 129.4, 128.6, 127.3, 124.8, 120.1, 115.3,
114.8, 88.2, OCH3 53.4, CH3 28.0.ꢀ
A solution of 1 (10.26 g, 2.84 mmoles), bromoacetone 2a
(1.39 g, 10.15 mmoles) or phenacyl bromide 2b (2.02 g, 10.15
mmoles) in dry CH2Cl2 (40 mL) was stirred at r.t. overnight.
After precipitation from cold anhydrous Et2O (500 mL), the
suspension was filtered, washed with cold anhydrous Et2O (100
mL ꢀ 3) and dried to give yellow solid 3a, 10.70 g (97%) or
orange solid 3b, 10. 92 g (96%); 3a: IR: CH2 2868 (strong), C=O
1731 (strong), C=O 1651 (strong) cm-1; 1H NMR: ꢀ 8.80 (d, 2H,
pyridinyl protons, J = 4.5 Hz), 7.89 (d, 2H, pyridinyl protons, J
= 4.5 Hz), 5.88 (s, 2H, CH2COCH3), 4.60-3.16 (m, 4nH, -
O(CH2CH2O)n-), 2.05 (s, 3H, CH2COCH3); 3b: IR: CH2 2883
(strong), C=O 1731 (strong), C=O 1652 (strong) cm-1; 1H NMR:
ꢀ 8.84 (d, 2H, pyridinyl protons, J = 4.5 Hz), 7.98 (d, 2 H,
pyridinyl protons, J = 4.5 Hz), 7.52 (d, 2H, phenyl protons, J =
7.2 Hz), 7.65 (t, 1H, phenyl proton, J = 7.8 Hz), 7.53 (dd, 2H,
phenyl protons, J = 7.2, 7.8 Hz), 6.47 (s, 2H, CH2COPh), 4.63-
3.27 (m, 4nH, -O(CH2CH2O)n-).
Anal. Calcd. for C13H10N2O3: C, 64.46, H, 4.16, N, 11.56.
Found: C, 64.61, H, 4.20, N, 11.58.
Methyl 2,3-cyclohexanone-7-indolizinecarboxylate (7a4).
This compound was obtained as yellow crystals, mp 188°;ꢀ
IR: CH2 2923 (medium), C=O 1715 (strong), C=O 1626 (strong)
cm-1; 1H NMR: ꢀ 10.02 (d, 1 H, 5-H, J = 7.2 Hz), 9.09 (s, 1H, 8-
H), 7.59 (d, 1H, 6-H, J = 7.2 Hz), 3.98 (s, 3H, COOMe), 3.25 (t,
2H, CH2, J = 6.0Hz), 2.66-2.63 (m, 5H, CH2 and COCH3), 2.29
(t, 2H, CH2, J = 6.0 Hz); 13C NMR: ꢀ C=O 194.4, C=O 189.0,
C=O 165.7, 142.8, 136.5, 129.5, 129.1, 122.3, 121.6, 115.4,
114.8, OCH3 53.2, CH2 38.9, CH3 31.4, CH2 25.6, CH2 24.7.ꢀ
Anal. Calcd. for C16H15NO4: C, 67.36, H, 5.30, N, 4.91.
Found: C, 67.42, H, 5.35, N, 4.93.
Typical Procedure for Preparation of Indolizines (7).
A solution of 3 (0.50 mmoles), 4 (4.00 mmoles), TPCD (0.30
g, 0.50 mmoles) and Et3N (0.20 g, 2.00 mmoles) in dry DMF
(30 mL) was stirred at 90° for 3-4 h. After the solvent was
evaporated under vacuum, the residue was added CH2Cl2 (50
mL) and washed with a 0.02% solution of Na2CO3 in H2O (15
mL). The solution was dried over MgSO4, filtered, concentrated
and precipitated with cold anhydrous Et2O (300 mL) to afford
PEG-bound indolizines 6. The products 6 were treated with a
1% solution of KCN in MeOH (30 mL) and stirred at r.t.
overnight, evaporated MeOH and precipitated with cold
anhydrous Et2O to get the crude products, which were purified
by column chromatography on silica gel (EtOAc-petroleum
ether, 1: 4-1: 2) to give the pure indolizines 7.
Methyl 3-acetyl-4-benzoyl-2-(3-phenoxyl-4-fluorophenyl)-7-in-
dolizinecarboxylate (7a5).
This compound was obtained as light yellow solid; IR: C=O
1722 (strong), C=O 1623 (strong), C=O 1589 (strong) cm-1; H
1
NMR: ꢀ 9.98 (d, 1H, 5-H, J = 7.2 Hz), 8.63 (s, 1H, 8-H), 7.61 (d,
1H, 6-H, J = 7.2 Hz), 7.55 (d, 2H, phenyl protons, J = 7.8 Hz),
7.48 (t, 1H, phenyl proton, J = 7.2 Hz), 7.35-7.29 (m, 4H, phenyl
protons), 7.14 (t, 1H, phenyl proton, J = 7.2 Hz), 7.05 (d, 2H,
phenyl protons, J = 9.6 Hz), 6.94 (d, 1H, phenyl proton, J = 6.6
Hz), 6.82 (d, 2H, phenyl protons, J= 7.8 Hz), 3.96 (s, 3H,
COOMe), 2.08 (s, 3H, COMe); 13C NMR: ꢀ C=O 192.6, C=O

784
G. Yue, Z. Chen and G. Yang
Vol 43
190.7, C=O 165.5, 157.1, 154.5, 152.9, 144.3, 141.3, 139.3,
138.5, 137.8, 137.1, 132.8, 131.3, 130.3, 129.8, 128.6, 128.3,
127.4, 124.1, 124.0, 123.3, 121.7, 118.1, 114.9, OCH3 53.1, CH3
31.3.
128.6, 128.3, 128.1, 127.6, 123.6, 123.0, 118.1, 114.9, OCH3
53.2, CH3 31.3.
Anal. Calcd. for C25H19NO4: C, 75.55, H, 4.82, N, 3.52.
Found: C, 75.57, H, 4.88, N, 3.59.
Anal. Calcd. for C31H22NO5F: C, 73.36, H, 4.37, N, 2.76.
Found: C, 73.42, H, 4.33, N, 2.70.
Methyl 3-benzoyl-1-cyano-7-indolizinecarboxylate (7b3).
This compound was obtained as light yellow spiculate
crystals, mp 211°;ꢀ IR: CN 2220 (strong), C=O 1731 (strong),
Methyl 3-acetyl-1-benzoyl-2-(4-bromo)phenyl-7-indolizinecarb-
oxylate (7a6).
1
C=O 1627 (strong) cm-1; H NMR: ꢀ 9.93 (d, 1H, 5-H, J = 7.2
This compound was obtained as yellow crystals, mp 186°; IR:
CH3 2952 (medium), C=O 1723 (strong), C=O 1635 (strong),
Hz), 8.55 (d, 1H, 8-H, J = 1.2 Hz), 7.81 (d, 2H, phenyl protons, J
= 7.2 Hz), 7.70 (s, 1H, H-2), 7.69, (dd, 1H, 6-H, J = 1.2, 7.2 Hz),
7.64 (t, 1H, phenyl proton, J = 7.8 Hz), 7.54 (dd, 2H, phenyl
protons, J = 7.2, 7.8 Hz), 4.03 (s, 3H, COOMe); 13C NMR: ꢀ
C=O 185.9, C=O 165.0, 140.2, 139.1, 132.9, 129.9, 129.4,
129.4, 129.1, 128.9, 124.5, 120.1, 115.2, 114.8, 88.4, OCH3
53.4.
1
1598 (strong) cm-1; H NMR: ꢀ 9.97 (d, 1H, 5-H, J = 7.2 Hz),
8.55 (d, 1H, 8-H, J = 0.6 Hz), 7.58 (d, 1H, 6-H, J = 0.6, 7.2 Hz),
7.48 (d, 2H, phenyl protons, J = 7.8 Hz), 7.40 (t, 1H, phenyl
proton, J = 7.2 Hz), 7.35 (d, 2H, phenyl protons, J = 8.4 Hz),
7.22 (dd, 2H, phenyl protons, J = 7.2, 7.8 Hz), 7.12 (d, 2H,
phenyl protons, J = 8.4 Hz), 3.93 (s, 3H, COOMe), 2.02 (s, 3H,
COMe), 13C NMR: ꢀ C=O 192.6, C=O 190.8, C=O 165.5, 139.4,
138.7, 137.1, 133.4, 132.6, 131.7, 129.6, 129.1, 128.6, 128.5,
128.2, 123.4, 123.2, 121.7, 118.4, 114.8, OCH3 53.1, CH3 31.5.
Anal. Calcd. for C25H18NBrO4: C, 63.04, H, 3.81, N, 2.94.
Found: C, 63.10, H, 3.85, N, 3.83.
Anal. Calcd.. for C18H12N2O3: C, 71.50, H, 3.97, N, 9.21.
Found: C, 71.50, H, 3.95, N, 9.25.
Methyl 2,3-cyclohexanone-7-indolizinecarboxylate (7b4).
This compound was obtained as yellow solid, mp 194°; IR:
CH2 2919 (medium), C=O 1715 (strong), C=O 1649 (strong),
1
C=O 1614 (strong) cm-1; H NMR: ꢀ 9.68 (d, 1H, 5-H, J = 7.2
Methyl 1,3-diacetyl-2-furyl-7-indolizinecarboxylate (7a7).
This compound was obtained as yellow solid;ꢀIR: C=O 1727
Hz), 9.12 (d, 1H, 8-H, J = 1.2 Hz), 7.68 (d, 2H, phenyl protons, J
= 7.2 Hz), 7.64-7.60 (m, 2H, 6-H and phenyl proton), 7.52 (dd,
2H, phenyl protons, J = 7.2, 7.8 Hz), 4.00 (s, 3H, COOMe), 2.57
(dd, 2H, CH2, J = 5.4, 6.0 Hz), 2.40 (t, 2H, CH2, J = 6.0 Hz),
1.97 (t, 2H, CH2, J = 6.0 Hz); 13C NMR: ꢀ C=O 194.5, C=O
187.7, C=O 165.6, 143.6, 140.9, 136.9, 132.5, 129.5, 129.2,
128.8, 128.6, 121.9, 115.3, OCH3 53.1, CH3 39.2, CH3 25.7, CH3
25.1.
1
(strong), C=O 1635 (strong) cm-1; H NMR: ꢀ 9.97 (d, 1H, 5-H,
J = 7.2 Hz), 9.27 (s, 1H, 8-H), 7.70 (d, 1H, 6-H, J = 7.2 Hz),
7.62 (dd, 1H, furyl proton, J = 1.8, 7.2 Hz), 6.64-6.61 (m, 2H,
furyl protons), 3.99 (s, 3H, COOMe), 2.09 (s, 3H, COMe), 2.05
(s, 3H, COMe); 13C NMR: ꢀ C=O 195.0, C=O 190.4, C=O
165.6, 145.1, 143.7, 137.0, 129.3, 128.5, 128.1, 124.5, 123.2,
118.9, 115.7, 113.7, 112.4, OCH3 53.2, CH3 29.8, CH3 29.7.
Anal. Calcd. for C18H15NO5: C, 66.46, H, 4.65, N, 4.31.
Found: C, 66.56, H, 4.73, N, 4.44.ꢀ
Anal. Calcd. for C21H17NO4: C, 72.61, H, 4.93, N, 4.03.
Found: C, 72.69, H, 4.95, N, 4.10.
Methyl 1,3-dibenzoyl-2-(3-phenoxyl-4-fluorophenyl)-7-indolizi-
necarboxylate (7b5).ꢀ
Methyl 1,3-dibenzoyl-3-(4-fluorophenyl)-7-indolizinecarboxyla-
te (7b1).
This compound was obtained as yellow crystals, mp 95°; IR:
C=O 1723 (strong), C=O 1615 (strong), C=O 1597 (strong)
This compound was obtained as yellow crystals, mp 146°; IR:
1
C=O 1721 (strong), C=O 1614 (strong) cm-1; H NMR: ꢀ 9.55
cm-1; H NMR: ꢀ 9.48 (dd, 1H, 6-H, J = 0.6, 7.2 Hz), 8.78 (d,
1
(d, 1H, 5-H, J = 7.2 Hz), 8.79 (d, 1H, 8-H, J = 1.2 Hz), 7.60 (dd,
1H, 6-H, J = 1.2, 7.2 Hz), 7.45 (d, 2H, phenyl protons, J = 7.2
Hz), 7.38 (d, 2H, phenyl protons, J = 7.2 Hz), 7.27-7.21 (m, 2H,
phenyl protons), 7.10-7.02 (m, 4H, phenyl protons), 6.83 (dd,
2H, phenyl protons, J = 7.2, 7.8 Hz), 6.43 (dd, 2H, phenyl
protons, J = 7.2, 8.4 Hz), 3.97 (s, 3H, COOMe); 13C NMR: ꢀ
C=O 192.9, C=O 188.9, C=O 165.7, 138.9, 138.8, 138.1, 137.6,
133.5, 133.4, 132.6, 132.4, 129.9, 129.5, 128.3, 128.2, 128.0,
127.5, 122.7, 122.1, 117.2, 114.9, 114.7, 114.6, OCH3 53.2.
Anal. Calcd. for C30H20NO4F: C, 75.46, H, 4.22, N, 3.98.
Found: C, 75.44, H, 4.25, N, 3.90.
1H, 8-H, J = 0.6 Hz), 7.59 (d, 1H, 5-H, J = 7.2 Hz), 7.47 (d, 2H,
phenyl protons, J = 7.2 Hz), 7.42 (d, 2H, phenyl protons, J = 7.2
Hz), 7.37-7.13 (m, 8H, phenyl protons), 7.08 (t, 1H, phenyl
proton, J = 7.2 Hz), 6.68-6.51 (m, 5H, phenyl protons), 3.97 (s,
3H, COOMe); 13C NMR: ꢀ C=O 192.6, C=O 188.7, C=O 165.7,
157.0, 154.5, 152.9, 143.2, 141.5, 139.9, 138.9, 138.7, 137.5,
137.0, 132.8, 132.7, 130.6, 130.1, 130.0, 129.4, 128.3, 128.1,
127.3, 124.8, 123.9, 122.5, 122.1, 117.7, 117.2, 114.7, OCH3
53.2.
Anal. Calcd. for C36H24FNO5: C, 75.91, H, 4.25, N, 2.46.
Found: C, 75.80, H, 4.33, N, 2.50.
Methyl 1-acetyl-3-benzoyl-2-phenyl-7-indolizinecarboxylate
(7b2).
Methyl 1-acetyl-3-benzoyl-2-(3-nitrophenyl)-7-indolizinecarbo-
xylate (7b6).
This compound was obtained as yellow crystals, mp 155°; IR:
C=O 1723 (strong), C=O 1645 (strong), C=O 1611 (strong)
cm-1; 1H NMR: ꢀ 9.47 (d, 1H, 5-H, J = 7.2 Hz), 9.21 (d, 1H, 8-H,
J = 1.2 Hz), 7.61 (dd, 1H, 6-H, J = 1.2, 7.2 Hz), 7.36 (d, 2H,
phenyl protons, J = 7.2 Hz), 7.20 (t, 1H, phenyl protons, J = 7.2
Hz), 7.13-7.04 (m, 7H phenyl protons), 4.01 (s, 3H, COOMe),
1.91 (s, 3H, COMe); 13C NMR: ꢀ C=O 196.4, C=O 189.1, C=O
165.8, 139.6, 139.2, 137.3, 134.1, 132.0, 131.4, 129.6, 128.8,
This compound was obtained as yellow solid, mp 185°; IR:
1
C=O 1723 (strong), C=O 1621(strong), 1534 (NO2) cm-1; H
NMR: ꢀ 9.62 (d, 1H, 5-H, J = 7.2 Hz), 8.80 (d, 1H, 8-H, J = 1.2
Hz), 7.69 (s, 1H, phenyl proton), 7.66-7.63 (m, 2H, 6-H and
phenyl proton), 7.44 (d, 2H, phenyl protons, J = 7.2 Hz), 7.36 (d,
2H, phenyl protons, J = 7.2 Hz), 7.23 (t, 2H, phenyl protons, J =
7.8 Hz), 7.15 (dd, 1H, phenyl proton, J = 7.2, 7.8 Hz), 7.08 (dd,
2H, phenyl protons, J = 7.2, 7.8 Hz), 6.99 (dd, 2H, phenyl

May-Jun 2006
Synthesis of Indolizines using Poly(ethylene glycol) as Soluble Support
785
1
protons, J = 7.2, 7.8 Hz,), 6.94 (t, 1H, phenyl proton, J = 7.8
Hz), 3.98 (s, 3 H, COOMe); 13C NMR: ꢀ C=O 192.3, C=O
188.4, C=O 165.5, 147.2, 138.9, 138.9, 137.7, 137.2, 136.6,
135.2, 132.7, 132.4, 129.7, 128.6, 128.4, 128.6, 128.3, 127.7,
126.7, 126.8, 122.9, 122.2, 117.2, 115.1, 115.1, OCH3 53.2.
Anal. Calcd. for C30H19N2O6: C, 71.57, H, 3.80, N, 5.56.
Found: C, 71.63, H, 3.86, N, 5.60.ꢀ
(strong), C=O 1628 (strong) cm-1; H NMR: ꢀ 9.95 (d, 1H, 5-H,
J = 7.2 Hz), 9.06 (s, 1H, 8-H), 7.89 (s, 1H, 2-H), 7.83 (d, 2H,
phenyl protons, J = 7.2 Hz), 7.65-7.60 (m, 2H, 6-H and phenyl
proton), 7.53 (t, 2H, phenyl protons, J = 7.8 Hz), 4.01 (s, 3H,
COOMe), 3.95 (s, 3H, COOMe); 13C NMR: ꢀ C=O 186.5, C=O
165.7, C=O 164.5, 139.8, 138.7, 132.4, 129.7, 129.5, 129.1,
129.0, 128.6, 124.1, 122.2, 114.7, 109.2, OCH3 53.2, CH3 52.1.
Anal. Calcd. for C19H15NO5: C, 67.65, H, 4.48, N, 4.15.
Found: C, 67.66, H, 4.39, N, 4.11.
Methyl 1,3-dibenzoyl-3-(4-cynaophenyl)-7-indolizinecarboxyl-
ate (7b7).
Trimethyl 3-benzoyl-1,2,7-indolizinetricarboxylate (7'b2).
This compound was obtained as yellow solid, mp 187°; IR:
CN 2228 (strong), C=O 1723 (strong), C=O 1621 (strong), 1599
(strong) cm-1; 1H NMR: ꢀ 9.55 (d, 1 H, 5-H, J = 7.2 Hz), 8.76 (s,
1H, 8-H), 7.63 (d, 1H, 6-H, J = 7.2 Hz), 7.44 (d, 2H, phenyl
protons, J= 7.8 Hz), 7.36 (d, 1H, phenyl proton, J = 7.8 Hz),
7.31-7.23 (m, 2H, phenyl protons), 7.11-6.99 (m, 8H, phenyl
protons), 3.97 (s 3H, COOMe); 13C NMR: ꢀ C=O 192.3, C=O
188.4, C=O 165.5, 138.8, 138.6, 138.1, 137.6, 136.9, 133.0,
132.8, 132.3, 131.3, 129.9, 129.9, 128.4, 128.4, 127.6, 122.6,
122.2, 118.8, 117.2, 115.3, 115.0, 111.2, OCH3 53.2.
This compound was obtained as yellow green solid, mp 195°;
IR: CH3 2952 (strong), C=O 1725 (strong), C=O 1629 (strong),
1
C=O 1599 (strong) cm-1; H NMR: ꢀ 9.54 (d, 1H, 5-H, J = 7.2
Hz), 9.03 (d, 1H, 8-H, J = 1.2 Hz), 7.80 (d, 2H, phenyl protons, J
= 7.8 Hz), 7.63 (dd, 1H, 6-H, J = 1.2, 7.2 Hz), 7.58 (t, 1H,
phenyl proton, J = 7.2 Hz), 7.47 (dd, 2H, phenyl protons, J = 7.2,
7.8 Hz), 4.01 (s, 3H, COOMe), 3.93 (s, 3H, COOMe), 3.32 (s,
3H, COOMe); 13C NMR: ꢀ C=O 187.4, C=O 165.5, C=O 165.2,
C=O 163.5, 139.6, 137.1, 132.9, 132.2, 129.2, 128.9, 128.7,
128.4, 122.9, 122.6, 115.2, 107.3, OCH3 53.3, OCH3 52.8, OCH3
52.5.
Anal. Calcd. for C31H20N2O4: C, 76.85, H, 4.16, N, 5.78.
Found: C, 76.89, H, 4.21, N, 5.79.
Anal. Calcd. for C21H17NO7: C, 63.80, H, 4.33, N, 3.54.
Found: C, 63.81, H, 4.39, N, 3.53.
Typical procedure for Preparation of Indolizines (7').
A solution of 3 (0.50 mmole), 5 (4.00 mmoles), and Et3N
(0.20 g, 2.00 mmoles) in DMF (30 mL) was stirred at 90° for 2
h. After the solvent was evaporated under vacuum, the residue
was added to CH2Cl2 (50 mL), washed, dried, filtered,
concentrated, precipitated and cleaved by using the procedure
described above for 7 to give crude materials. They were
purified by column chromatography on silica gel (EtOAc-
petroleum ether, 1: 3-1: 2) to give the pure indolizines 7'.
REFERENCES AND NOTES
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Dimethyl 3-acetyl-1,7-indolizinedicarboxylate (7'a1).
This compound was obtained as yellow crystals, mp 198°;ꢀ
IR: CH3 2924 (medium), C=O 1723 (strong), C=O 1699 (strong)
1
cm-1; H NMR: ꢀ 9.88 (d, 1H, 5-H, J = 7.2 Hz), 9.00 (s, 1H, 8-
H), 8.054 (s, 1H, 2-H), 7.56 (d, 6-H, J = 7.2 Hz), 3.99 (s, 3H,
COOMe), 3.98 (s, 3H, COOMe), 2.63 (s, 3H, COMe); 13C
NMR: ꢀ C=O 188.8, C=O 164.7, C=O 164.5, 138.1, 129.0,
128.3, 127.0, 124.4, 122.2, 114.7, 108.9, OCH3 53.3, OCH3 52.2,
CH3 30.2.ꢀ
[7a] V. V. Namboodiri and R. S. Varma, Green Chem., 3, 146 (2001);
[b] J.-H. Li, X.-C. Hu, Y. Liang and Y.-X. Xie, Tetrahedron, 62, 31
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Anal. Calcd. for C14H13NO5: C, 61.09, H, 4.76, N, 5.09.
Found: C, 61.11, H, 4.68, N, 5.10.
Trimethyl 3-acetyl-1,2,7-indolizinetricarboxylate (7'a2).
This compound was obtained as light yellow crystals, mp
179°; IR: CH3 2957 (medium), C=O 1722 (strong), C=O 1705
1
(strong), C=O 1652 (strong) cm-1; H NMR: ꢀ 9.95 (d, 1H, 5-H,
J = 7.8 Hz), 8.96 (d, 1H, 8-H, J = 1.2 Hz), 7.60 (dd, 1H, 6-H, J =
1.2, 7.8 Hz), 4.06 (s, 3H, COOMe), 4.00 (s, 3H, COOMe), 3.97
(s, 3H, COOMe), 2.55 (s, 3H, COMe); 13C NMR: ꢀ C=O 188.5,
C=O 167.2, C=O 165.4, C=O 163.4, 136.6, 132.3, 129.2, 129.2,
122.3, 121.5, 115.5, 107.0, OCH3 53.9, OCH3 53.3, OCH3 52.5,
CH3 29.0.
Anal. Calcd. for C16H15NO7: C, 57.66, H, 4.54, N, 4.20.
Found: C, 57.70, H, 4.58, N, 4.22.
[11] S. Zhao, M. G. P. S. Neves, A. C. Tomé, A. M. S. Silva and J. A.
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Dimethyl 3-benzoyl-1,7-indolizinedicarboxylate (7'b1).
This compound was obtained as light yellow crystals, mp
186°; IR: CH3 2953 (medium), C=O 1729 (strong), C=O 1712

786
G. Yue, Z. Chen and G. Yang
Vol 43
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