Synthesis of some new indolizines

Article abstract of DOI:10.1002/jhet.5570420102

The reaction between 4-dimethylaminopyridine (DMAP) and 2-bromoacetophenone(s) readily gives 1-[2-(4-substitutedphenyl)-2-oxoethyl]-4- (dimethylamino)pyridinium bromide (1-14). Action of aqueous NaOH on 1-8 generates the corresponding pyridinium ylide (15

Full text of DOI:10.1002/jhet.5570420102

Jan-Feb 2005
5
Synthesis of Some New Indolizines
K. Sarkunam and M. Nallu
Department of Chemistry, Bharathidasan University,
Tiruchirappalli – 620 024. Tamilnadu, INDIA.
E-mail: mnallu46@yahoo.com
Received April 7, 2004
The reaction between 4-dimethylaminopyridine (DMAP) and 2-bromoacetophenone(s) readily gives 1-
[2-(4-substitutedphenyl)-2-oxoethyl]-4-(dimethylamino)pyridinium bromide (1-14). Action of aqueous
NaOH on 1-8 generates the corresponding pyridinium ylide (15-22), which is isolated as a colored stable
crystalline solid. Addition of 15-22 to dimethylacetylene dicarboxylate (DMAD) gives dimethyl 3-(substi-
tutedbenzoyl)-7-(dimethylamino)indolizine-1,2-dicarboxylate (23-30) in 46-62% yield.
J. Heterocyclic Chem., 42, 5 (2005).
Introduction.
corresponding acetophenones using literature proce-
dures [13]. Suitable conditions have been chosen to give
2-bromoacetophenone(s) selectively. These compounds
were purified by repeated recrystalisation and column
chromatography.
Chemists are attracted continuously by indolizines due
to their applications in various fields. In pharmaceutical
industries, indolizine derivatives are employed as CNS
depressant [1] cardiovascular agents [2] and calcium entry
blockers [3]. They are also used in the treatment of angina
pectoris [4]. Some of the indolizine derivatives are found
to be anti-inflammatory agent [5,6]. Indolizines are also
used as spectral sensitizers [7], dyes [8], and intermediates
in the synthesis of electron-enriched cycloazines [9]. To c-
ontinue with these important studies, attempts are made to
improve the methods of synthesis [10] as well as synthesis
of new indolizines. To the best of our knowledge,
indolizines with –NMe substituents at 7- position have
not so far been reported. Early studies revealed that com-
pounds containing aryl-NMe group would affect the
metabolic activation due to the electronic and physico-
chemical influence exerted by the –NMe group [11].
Hence, we made an attempt to construct the indolizine
The reaction between 2-bromoacetophenone(s) and
DMAP has been carried out to give 1-[2-(substituted-
phenyl)-2-oxoethyl]-4-(dimethylamino)pyridinium bro-
mide (1-14) (Scheme 1). Compound 1 was reported in our
previous report [12]. The physical and spectral data of 2-
14 were collected and are presented in the experimental
section. The presence of electron withdrawing group at
the 4'-position of 2-bromoacetophenones facilitates the
cleavage of the C-Br bond through electronic effects.
Methanolic solutions of 2-14 exhibit analogous absorp-
tion spectra with two maxima in the range of 281-293 (π-
π*) and 211-218 (n-π*) nm. The former is characteristic of
the 4-dimethylaminopyridinium moiety and the later is due
to the carbonyl function. In the IR spectra of compounds 2-
14, the carbonyl frequency is affected to some extent by
the substituents present in the phenyl ring. Electron with-
2
2
2
with –NMe at the 7-position. Our continuous work on
2
dimethylaminopyridine (DMAP) quaternary salts and the
isolation of stable pyridinium ylides [12] helped us to
achieve the target indolizines.
drawing groups such as Cl, Br and NO increases the car-
2
bonyl frequencies (shorter wavelength). On the other hand
the electron releasing group CH decreases the wave num-
3
Results and Discussion.
ber. The presence of Cl (2), Br (3), NO (9 and 10) and OH
2
(11 and 12) are reflected from their stretching bands.
2-Bromoacetophenones have been prepared from their

6
K. Sarkunam and M. Nallu
In the H NMR spectra of compounds 2-14, the sharp
Vol. 42
1
observed in the ir spectra. The ylidic proton resonance of
16-18 is observed as a singlet in the down field region of δ
6.30-6.33 ppm. The carbonyl group conjugated to the car-
banion makes the ylide to be more stable by resonance
(Scheme 3). The negative charge on carbon shifts to more
electronegative oxygen atom, which is better capable of
holding this charge than carbon. This leads to formation of
the enolate ylide. Further, the ylide is stabilized by field
effect caused by the positive nitrogen adjacent to the nega-
tively charged carbon. The stability of the 15-22 varies
from days to hours. Interestingly ylides 15 and 16 are sta-
ble for about 10-15 days and 17-20 and 22 are stable for 4-
6 hours at 30 °C. Ylide 21 was not stable enough to char-
acterize. All isolated ylides are stable for extended periods
of time in a vacuum. The variation in the stability of ylides
may be explained in terms of the nature of the substituent
on the phenyl ring. Electron withdrawing group at the 4'-
position may develop a residual positive charge on the car-
bonyl carbon, which may disturb the conjugation between
the ylidic carbon and the carbonyl carbon.
singlet around at δ 5.89 ppm corresponds to the methylene
protons. The chemical shifts of methylene protons are
exaggerated by substituents present in the phenyl ring. The
2-H and 6-H protons of the pyridine ring of compounds 2-
14 appeared in the down field region around at δ 8.20 as a
doublet compared to the 3-H and 5-H protons. This is
because of the electron withdrawing effect of the endo-
cyclic nitrogen atom. A broad singlet at δ 8.73 ppm in
compound 10 corresponds to the 2-H proton of phenyl
ring. This down field shift may be due to the inductive
effect of the NO group at C3. The disappearance of signal
2
through a D O exchange experiment on 11 and 12 estab-
2
lished the presence of OH. However, the down field shift
of the OH proton in compound 12 around 1 ppm more than
that of the OH proton in 11 may be due to hydrogen bond-
13
ing between the OH and carbonyl group. The C NMR
spectra of 2-14 agree with the assigned structures. Mass
spectra of these compounds show the molecular ion peak
+
without the bromide counter ion (M-Br) .
Single crystal X-ray analyses of 3 and 4 as typical exam-
ples were solved [14]. Crystal data confirmed the assigned
structure as well as the quinoidal character. The pyri-
dinium systems in 2 and 3 have a substantial degree of
quinoidal character, since the bond lengths C2—C3 and
C5—C6 in 2 and 3 [1.334 (4) Å, 1.339 (5) and 1.339 (5) Å,
1.342 (5) Å] are significantly shorter than those observed
for C3—C4 and C4—C5 [1.406 (4) Å, 1.413 (4) and 1.407
(5) Å, 1.412 (5) Å]. The bond lengths C4—N2 in 2 and 3
are the same within experimental error [1.326 (4) Å, 1.327
(4) Å] and lie between the carbon-nitrogen single and dou-
ble bond distances [1.326 (4) Å, 1.458 (4) in 2 and 1.327
(4) Å, 1.462 (5) in 3, indicating a significant conjugation.
The pyridinium ylides 16-22 were generated by the
action of 1 N NaOH on 1-8 (Scheme 2). The physical and
Dimethyl 3-(substitutedbenzoyl)-7-(dimethylamino)-
indolizine-1,2-dicorboxylate (23-30) have been prepared by
the reaction of 15-22 with dimethyl acetylenedicarboxylate
in DMF in the presence of K CO in 44-62% (Scheme 4).
2
3
Attempts were made to improve the yield by conducting the
reaction in different bases such as Et N, pyridine, NaOH,
3
NaHCO however improved yields were not observed.
3
Further, the reaction was also conducted in a mixture of
DMSO/CH CN and results were less favorable than in
3
DMF. The reaction under this experimental condition did
not yield the dihydroindolizine as reported elsewhere [15].
The structures assigned to indolizines 23-30 are supported
1
13
by their spectral data (IR, H and C NMR and MS).
In the IR spectra of 23-30, the CO at C-3 appeared at
-1
1685-1699 cm , whereas, the ester CO appeared at 1736-
1
-1
1
spectral (IR and H NMR) data were collected and are pre-
1738 cm . The H NMR spectra of 23-30 showed a sharp
sented in Table's 1 and 2 respectively. Compound 15 was
reported in our previous work [12]. Conjugation of the
ylidic carbon with the carbonyl group lowers the ν C=O
singlet at δ 3.06-3.15 ppm, which confirmed the presence
of the –N(CH ) group. The 5-H proton appeared in the
3 2
down field region at δ 9.33-9.77 ppm as a doublet (br, J~7.9
Hz). This is due to the presence of the adjacent ring nitrogen

Jan-Feb 2005
Synthesis of Some New Indolizines
7
Table 1
at C2, which resonates at δ 3.70-3.81 ppm. The down field
Physical and IR (KBr) Data of 15-22
shift of the latter may be due to the electronic influence
exerted by CO at C3. In the C NMR spectra of 23-30, the
13
Compd.
Yield %
mp °C
UV-VIS λ
nm
max
carbonyl group appeared at δ 178-185 ppm. The ester car-
bonyl group attached to the C1 position was observed at δ
163-164 ppm, whereas, the carbonyl group at the C2 posi-
tion was observed at δ 165-166 ppm. Mass spectra of 23-30
showed the molecular ion peak at their exact mass (M ).
Furthermore, the single crystal and molecular structures
16
17
18
19
20
21
22
86
88
83
80
85
-
137-39
139-40(d)
135-36(d)
158-59(d)
180-81(d)
-
388, 282
381, 270
448, 286
464, 286
468, 313, 273
-
+
of some of the compounds (23 and 26) were solved by
82
54-55
365, 282
Table 2
1
IR and H NMR Spectral Data of 16-22
-1
1
Compd
IR (KBr), cm
H NMR (CDCl ), δ ppm
3
Ylidic H
Aliphatic H
3.14 (s, 6H),
3.12 (s, 6H),
Aromatic H
16
17
18
3429,2920, 1654, 1515, 1433 and 734.
3437, 3072, 1657,1545 and 572.
3434, 2917, 1654, 1573 and 820.
6.30 (s, 1H),
6.29 (s, 1H),
6.33 (s, 1H),
9.15 (d, J=7.4, 2H), 7.74 (d, J=8.3, 2H), 7.27
(d, J=8.3, 2H), 6.60 (d, J=7.4, 2H).
9.11 (d, J=7.1, 2H), 7.66 (d, J=8.1, 2H), 7.41
(d, J=8.1, 2H), 6.60 (d, J=7.1, 2H).
3.11 (s, 6H),
9.17 (d, J=7.1, 2H), 7.67 (d, J=7.8, 2H), 7.13
2.35 (s, 3H)
(d, J=7.8, 2H), 6.57 (d, J=7.1, 2H).
19
20
22
3445, 3065, 1652, 1571 and 1174.
3435, 3057, 2920,1651, and 1544.
3417, 2992, 1651, 1582 and 576.
-
-
-
-
-
-
-
-
-
X-ray studies [16,17]. The dihedral angle between the
planes of the indolizine ring and the benzoyl ring is 58.13
(5)°. The planes of the 1- and 2-carboxylate groups are ori-
ented at angles of 5.97 (9) and 72.05 (7)°, respectively,
with respect to the plane of the indolizine moiety. The car-
boxylate groups are approximately perpendicular to each
other. In addition, the phenyl ring (Cg1) and the six-
membered ring of the indolizine moiety are involved in
weak intermolecular C–H…π interactions. The mecha-
atom, which may deshield the 5-H proton. The 6-H proton
appeared as a doublet of doublet at δ 6.67-6.57 (J~7.9 and
2.8 Hz). This is because of the coupling of 5-H and 8-H
protons. A sharp doublet was observed for 8-H proton at δ
7.26-7.35 ppm with coupling constant ~2.8 Hz. From the
coupling constant, it is inferred that the 8-H proton cou-
pled with 6-H. The methyl protons of the ester attached to
C1 appeared in the slightly up field region at δ 3.35-3.20
ppm compared with that of the methyl protons of the ester

8
K. Sarkunam and M. Nallu
Vol. 42
recorded on a Bruker, AMX 400 MHz and DRX 500 MHz instru-
ment in DMSO-d or CDCl using TMS as internal reference.
6
3
Chemical shifts (δ) are expressed in ppm and coupling constants
are expressed in Hz. Mass spectral measurements were recorded
on ESI-MS (Electrospray Ionization Mass Spectroscopy) in ace-
tonitrile and Double Focusing Mass Spectrometer VG 70-250S
(VG Analytical Ltd., Manchester, UK).
General Procedure for Preparation of 1-[2-(4-Substitutedphenyl)-
2-oxoethyl]-4-(dimethylamino)pyridinium Bromides 2-14.
To a solution of substituted phenacyl bromide(s) (4 mmoles)
and DMAP (4.1 mmoles) in dry acetone or ethyl acetate was
stirred or refluxed for 30 min. After cooling to room temperature
the solid that separated was collected by filtration and washed
with dry acetone to give stable crude salt(s) 2-14, which were
dried in vacuum and recrystallised from ethanol.
1-[2-(4-Methylphenyl)-2-oxoethyl]-4-(dimethylamino)-
pyridinium Bromide (2).
nism for formation of the indolizine derivatives is readily
explained by 1,3-dipolar cycloaddition reactions between
pyridinium ylides 15-22 and dimethyl acetylenedicarboxy-
late (Scheme 5).
This compound was obtained as colorless crystalline solid
(ethanol), yield 90%, mp 185-188 °C; uv λ
(ε): 289 (20783),
max
-1
1
263 (10765); ir: 3038, 2917, 1690, 1215 and 1572 cm ; H nmr:
δ 8.22 (d, 2H, J=7.3 Hz), 7.94 (d, 2H, J=7.9 Hz), 7.45 (d, 2H,
J=7.9 Hz), 7.13 (d, 2H, J=7.3 Hz), 5.9 (s, 2H), 3.24 (s, 6H), 2.4 (s,
Conclusion.
13
3H); C nmr: δ 191.80, 156.08, 145.04, 143.31, 131.44, 129.55,
128.18, 107.37, 62.25, 39.85 and 21.29 ppm; ms: m/z= 255
[M-Br] .
Stable 4-dimethylaminopyridinium ylides are generated
by the action of aqueous NaOH on the salts obtained from
the reaction between DMAP and 2-bromoacetophenones.
Dipolar cycloaddition of 4-dimethylaminopyridinium
ylides with DMAD readily gives indolizines in 44-62%
yield. Attempts were made to improve the yield but
improved yields were not achieved. Dihydroindolizines
are not found under the present experimental conditions.
+
Anal. Calcd. for C
H N OBr: C, 57.15%; H, 6.00%; N,
16 20 2
8.33%. Found: C, 57.12%; H, 6.02%; N, 8.31%.
1-[2-(4-Chlorophenyl)-2-oxoethyl]-4-(dimethylamino)-
pyridinium Bromide (3).
This compound was obtained as a colorless crystalline solid
(ethanol), yield 95%, mp 198-201 °C; uv λ
(ε): 288 (58238)
max
and 217 (16926) nm; ir: 3079, 2927, 1697, 1580, 1212 and 824
-1
1
cm ; H nmr: δ 8.20 (d, 2H, J=7.5 Hz), 8.06 (d, 2H, J=8.5 Hz),
EXPERIMENTAL.
7.74 (d, 2H J=8.5 Hz), 7.14 (d, 2H, J=7.5 Hz), 5.99 (s, 2H), 3.24
13
(s, 6H); C nmr: δ 191.56, 156.06, 143.24, 139.23, 132.65,
130.01, 129.20, 107.41, 62.35 and 39.79 ppm; ms: m/z= 275
[M-Br] .
All melting points were measured on a Boetius micro hot-stage
apparatus and are uncorrected. The infrared spectra of solids
(Potassium bromide) were recorded on a Perkin-Elmer FT-IR
+
Anal. Calcd. for C
H N OCl: C, 50.51%; H, 4.80%; N,
15 17 2
1
13
paragon 1000 spectrometer. The H and C NMR spectra were
7.85%. Found: C, 50.47%; H, 4.82%; N, 7.83%.

Jan-Feb 2005
Synthesis of Some New Indolizines
9
+
1-[2-(4-Bromophenyl)-2-oxoethyl]-4-(dimethylamino)-
pyridinium Bromide (4).
63.91 and 39.20 ppm. ms: m/z= 309 [M-Br] .
Anal. Calcd. for C N OCl Br: C, 46.06%; H, 4.12%; N,
H
15 16
2
2
7.16%. Found: C, 46.02%; H, 4.15%; N, 7.14%. 130.80, 127.78,
107.47, 64.06 and 39.88 ppm. ms: m/z= 309 [M-Br] .
This compound was obtained as colorless crystalline solid
+
(ethanol), yield 94%, mp 228-31 °C; uv λ
267 (18293) nm; ir: 3072, 2727, 1695, 1581, 1212 and 565 cm ;
(ε): 289 (30016),
max
-1
1-[2-(4-Nitrophenyl)-2-oxoethyl]-4-(dimethylamino)pyridinium
Bromide (9).
1
H nmr: δ 8.19 (d, 2H, J=7.3 Hz), 7.79 (d, 2H, J=8.4 Hz), 7.88 (d,
2H, J=8.4 Hz), 7.23 (d, 2H, J= 7.3 Hz), 5.97 (s, 2H), 3.24 (s, 6H);
This compound was obtained as yellow crystalline solid
13
C nmr: δ 191.74, 156.06, 143.23, 132.95, 132.17, 130.03,
(ethanol), yield 90%, mp 184-87 °C; uv λ
(865) nm; ir: 3046, 2898, 1704, 1572, 1531, 1216 cm ; H nmr:
(ε): 290 (2161), 217
+
max
128.50, 107.41, 62.30 and 39.78 ppm; ms: m/z= 320 [M-Br] .
-1
1
Anal. Calcd. for C
H N OBr : C, 44.92%; H, 4.27%; N,
15 17 2 2
δ 8.46 (d, 2H, J=8.8 Hz), 8.27 (d, 2H, J=8.8 Hz), 8.22 (d, 2H,
6.98%. Found: C, 44.89%; H, 4.28%; N, 6.97%.
13
J=7.6 Hz), 7.16 (d, 2H, J= 7.6 Hz), 6.07 (s, 2H), 3.25 (s, 6H);
C
1-[2-(4-Methoxyphenyl)-2-oxoethyl]-4-(dimethylamino)pyri-
dinium Bromide (5).
nmr: δ 191.84, 156.10, 150.49, 143.19, 139.09, 138.62, 129.62,
124.07, 107.46, 62.71 and 39.87 ppm; ms: m/z= 286 [M-Br] .
+
Anal. Calcd. for C
11.44%. Found: C, 49.05%; H, 4.68%; N, 11.43%.
H N O Br: C, 49.06%; H, 4.67%; N,
15 17 3 3
This compound was obtained as colorless crystalline solid
(ethanol), yield 91%, mp 117-119 °C; uv λ
(ε): 293 (43995), 218
max
-1 1
(15091); ir: 3072, 2833, 1689, 1574, 1213 and 1110 cm ; H nmr: δ
8.22 (d, 2H, J=7.3 Hz), 7.94 (d, 2H, J=7.9 Hz), 7.45 (d, 2H, J=7.9
Hz), 7.13 (d, 2H, J=7.3 Hz), 5.96 (s, 2H), 3.23 (s, 6H), 3.36 (s, 3H);
1-[2-(3-Nitrophenyl)-2-oxoethyl]-4-(dimethylamino)pyridinium
Bromide (10).
This compound was obtained as yellow crystalline solid
(ethanol), yield 90%, mp 241-243 °C; uv λ
280 (3704) nm; ir: 3050, 1650, 1573, 1220, 836 cm ; H nmr: δ
8.73 (s, 1H), 8.58-8.61 (dd, 1H, J= 7.9 and 1.7 Hz), 8.46 (d, 1H,
J=7.7 Hz), 8.22 (d, 2H, J=7.5 Hz), 7.96 (t, 1H, J=7.7 Hz), 7.16 (d,
2H, J=7.5 Hz), 6.11 (s, 2H), 3.25 (s, 6H); C nmr: δ 191.33,
156.05, 148.02, 143.135, 135.142, 130.96, 128.333, 122.40,
107.376, 62.51and 39.83 ppm; ms: m/z= 286 [M-Br] .
Anal. Calcd. for C
13
C nmr: δ 190.60, 164.05, 156.01, 143.31, 130.52, 126.71, 114.31,
(ε): 291 (4998),
+
max
107.34, 62.03, 55.77 and 39.98 ppm; ms: m/z= 271 [M-Br] .
-1
1
Anal. Calcd. for C
H N O Br: C, 54.56%; H, 5.72%; N,
16 20 2 2
7.95%. Found: C, 54.53%; H, 5.73%; N, 7.93%.
13
1-[2-(Biphenyl)-2-oxoethyl]-4-(dimethylamino)pyridinium
Bromide (6).
+
This compound was obtained as colorless crystalline solid
H N O Br: C, 49.06%; H, 4.67%; N,
15 17 3 3
(ethanol), yield 89%, mp 246-48 °C; uv λ : 295 (57312) and
max
11.44%. Found: C, 49.01%; H, 4.69%; N, 11.41%.
-1
1
215 (18336) nm; ir: 3057, 2923, 1686, 1570 and 1201 cm ; H
nmr: δ 8.24 (d, 2H, J=7.6 Hz), 8.13 (d, 2H, J=8.4 Hz), 7.97 (d,
2H, J=8.4 Hz), 7.82 (d, 2H, J=7.3 Hz), 7.55 (t, 2H, J=7.3 Hz),
7.48 (t, 1H, J=7.3 Hz), 7.15 (d, 2H, J=7.6 Hz), 6.05 (s, 2H), 3.25
1-[2-(4-Hydroxyphenyl)-2-oxoethyl]-4-(dimethylamino)pyri-
dinium Bromide (11).
This compound was obtained as colorless crystalline solid
(ethanol), yield 85%, mp 221-24°C; uv λ
13
(s, 6H); C nmr: δ 191.98, 156.06, 145.57, 143.31, 138.56,
(ε): 295 (38063),
max
132.73, 129.17, 128.89, 128.68, 127.07, 107.41, 62.40 and 39.85
-1
1
218 (12839) nm; ir: 3459, 3082, 1657, 1577 and 1215 cm ; H
nmr: δ 10.69 (br s, 1H), 8.19 (d, 2H, J=6.8 Hz), 7.92 (d, 2H, J=8.5
Hz), 7.11 (d, 2H, J=6.8 Hz), 6.96 (d, 2H, J= 8.5 Hz), 5.89 (s, 2H),
+
ppm; ms: m/z= 317 [M-Br] .
Anal. Calcd. for C
H N OBr: C, 63.32%; H, 5.57%; N,
21 22 2
7.03%. Found: C, 63.29%; H, 5.60%; N, 7.0%.
13
3.23 (s, 3H); C nmr: δ 190.34, 162.90, 155.93, 143.05, 130.84,
+
1-[2-(2-Methoxyphenyl)-2-oxoethyl]-4-(dimethylamino)pyri-
dinium Bromide (7).
125.21, 115.61, 107.11 and 39.65. ms: m/z= 257 [M-Br] .
Anal. Calcd. for C
H N O Br: C, 53.27%; H, 5.36%; N,
15 18 2 2
8.28%. Found: C, 53.24%; H, 5.37%; N, 8.25%.
This compound was obtained as colorless crystalline solid
(ethanol), yield 86%, mp 220-222 °C; uv λ
(ε): 290 (29259),
max
1-[2-(2-Hydroxyphenyl)-2-oxoethyl]-4-(dimethylamino)pyri-
dinium Bromide (12).
-1
219 (14377) nm; ir: 3017, 2898, 1673, 1571, 1207 and 1110 cm ;
1
H nmr: δ 8.00 (d, 2H, J=8.9 Hz), 7.61 (dd, 1H, J=7.8 and 1.7
This compound was obtained as colorless crystalline solid
Hz), 7.46 (td, 1H, J=7.0 and 1.7 Hz), 7.08 (d, 1H, J=8.4 Hz), 6.89
(t, 1H, J=7.9 Hz), 6.86 (d, 2H, J=7.7 Hz), 5.54 (s, 2H), 3.78 (s,
(ethanol), yield 84%, mp 157-60 °C; uv λ
(ε): 290 (25977),
max
-1
1
13
211 (26092) nm; ir: 3449, 2997, 1664, 1574 and 1221 cm ; H
nmr: δ 11.25 (br s, 1H), 8.24 (d, 2H, J=7.5 Hz), 7.84 (br d, 1H,
J=7.1 Hz), 7.56 (t, 1H, J= 8.2 Hz), 7.14 (d, 1H, J=8.2 Hz), 7.10
(d, 2H, J=7.6 Hz), 6.99 (t, 1H, J= 7.1 Hz), 5.83 (s, 2H), 3.23 (s,
3H), 2.98 (s, 6H); C nmr: δ 192.09, 159.90, 156.04, 143.38,
135.94, 130.30, 123.45, 120.85, 113.08, 107.20, 66.12, 56.28,
+
39.83 ppm; ms: m/z= 271 [M-Br] .
Anal. Calcd. for C
H N O Br: C, 54.56%; H, 5.72%; N,
16 20 2 2
13
6H); C nmr: δ 193.20, 159.58, 156.05, 143.43, 136.04, 130.0,
7.95%. Found: C, 54.54%; H, 5.74%; N, 7.94%.
120.61, 119.43, 117.68, 107.19, 65.30 and 39.84. ms: m/z= 257
[M-Br] .
1-[2-(2,4-Dichlorophenyl)-2-oxoethyl]-4-(dimethylamino)pyri-
dinium Bromide (8).
+
Anal. Calcd. for C
H N O Br: C, 53.27%; H, 5.36%; N,
15 18 2 2
This compound was obtained as colorless crystalline solid
8.28%. Found: C, 53.24%; H, 5.37%; N, 8.26%.
(ethanol), Yield 88%, mp 260-62 °C; uv λ
(ε): 290 (77334)
max
1-[2-(4-Benzyloxyphenyl)-2-oxoethyl]-4-(dimethylamino)pyri-
dinium Bromide (13).
-1
and 222 (28693) nm; ir: 3072, 2996, 1709, 1569, 1214, 780 cm ;
1
H nmr: δ 8.26 (d, 2H, J=7.7 Hz), 8.13 (d, 1H, J=8.4 Hz), 7.86 (d,
1H, J=1.9 Hz), 7.72 (dd, 1H, J=8.4 and 1.9 Hz), 7.16 (d, 2H,
J=7.7 Hz), 5.98 (s, 2H), 3.25 (s, 6H); C nmr: δ 192.13, 155.97,
This compound was obtained as colorless crystalline solid
13
(ethanol), yield 89%, mp 236-39 °C; uv λ
(ε): 293 (84680)
max
143.01, 137.85, 132.85, 132.53, 132.29, 130.64, 127.62, 107.32,
and 221 (31427) nm; ir: 3040, 1674, 1572, 2911, 1212 and 1113

10
K. Sarkunam and M. Nallu
Vol. 42
-1
1
cm ; H nmr: δ 8.21 (d, 2H, J=7.2 Hz), 7.89 (d, 1H, J=6.4 Hz),
Dimethyl 3-(4-methylbenzoyl)-7-(dimethylamino)indolizine-
7.69-7.62 (m, 3H), 7.45-7.35 (m, 4H), 7.15 (d, 2H, J=7.5 Hz),
1,2-dicarboxylate (24).
13
7.10 (d, 2H, J=7.3 Hz), 5.7 (s, 2H), 5.4 (s, 2H), 3.23 (s, 6H).
C
This compound was obtained as yellow crystalline solid (ethyl
acetate), yield 49%, mp 170-172 °C; uv λ : 419, 325 and 265
nm; ir: 3097, 2942, 1736, 1691, 1589, 1231 and 1200 cm ; H
nmr: 9.42 (d, 1H, J=7.9 Hz), 7.47 (d, 2H, J=8.0 Hz), 7.27 (d, 1H,
J=2.7 Hz), 7.14 (d, 2H, J=9.8 Hz), 6.59-6.57 (dd, 1H, J= 7.9 and
nmr: δ 190.59, 163.10, 156.06, 143.34, 136.34, 130.50, 128.04,
max
127.75, 126.93, 115.17, 107.34, 69.69, 62.03 and 39.85 ppm; ms:
-1
1
+
m/z= 347 [M-Br] .
Anal. Calcd. for C
H N O Br: C, 61.69%; H, 5.65%; N,
22 24 2 2
6.54%. Found: C, 61.66%; H, 5.66%; N, 6.53%.
13
2.8 Hz), 3.74 (s, 3H), 3.23 (s, 3H), 3.07 (s, 6H), 2.33 (s, 3H);
C
nmr: δ 184.40, 165.76, 163.09, 149.40, 141.76, 133.02, 132.33,
1-[2-(2-Benzyloxyphenyl)-2-oxoethyl]-4-(dimethylamino)pyri-
dinium Bromide (14).
130.14, 129.47, 113.83, 105.26, 95.55, 52.88, 51.26, 39.90 and
+
21.07 ppm; ms: m/z= 394 [M] .
This compound was obtained as colorless crystalline solid
Anal. Calcd. for C
H N O : C, 66.99%; H, 5.62%; N,
22 19 2 5
(ethanol), yield 85%, mp 203-206 °C; uv λ
(ε): 290 (32382)
max
7.10%. Found: C, 66.96%; H, 5.64%; N, 7.08%.
-1
and 213 (20391) nm; ir: 3036, 2920, 1665, 1569, and 1225 cm ;
Dimethyl 3-(4-Chlorobenzoyl)-7-(dimethylamino)indolizine-
1,2-dicarboxylate (25).
1
H nmr: δ 8.21 (d, 2H, J=7.2 Hz), 7.90-7.85 (m, 1H), 7.69-7.62
(m, 3H), 7.44 (t, 2H), 7.377 (m, 2H), 7.14 (t, 2H, J=7.5 Hz), 7.10
13
(d, 2H, J=7.3 Hz), 5.77 (s, 2H), 5.43 (s, 2H), 3.23 (s, 6H).
C
This compound was obtained as yellow crystalline solid (ethyl
nmr: δ 191.87, 158.81, 156.06, 143.29, 135.78, 130.50, 128.59,
acetate), yield 41%, mp 110-112 °C; uv λ : 419, 325 and 265 nm;
ir: 3090, 2942, 1736, 16851599, 1231, 1200 and 824 cm ; H nmr:
max
-1 1
128.23, 128.13, 127.87, 123.75, 121.05, 114.23, 107.24, 70.43,
+
65.79 and 39.85 ppm; ms: m/z= 347 [M-Br] .
9.53 (d, 1H, J=7.9 Hz), 7.56 (d, 2H, J=8.4 Hz), 7.38 (d, 2H, J=8.4
Hz), 7.35 (d, 1H, J=2.8 Hz), 6.68-6.66 (dd, 1H, J= 7.9 and 2.8 Hz),
Anal. Calcd. for C
H N O Br: C, 61.69%; H, 5.65%; N,
22 24 2 2
13
3.81 (s, 3H), 3.35 (s, 3H), 3.15 (s, 6H); C nmr: δ 183.86, 165.74,
6.54%. Found: C, 61.67%; H, 5.67%; N, 6.52%.
163.83, 149.81, 142.05, 138.73, 137.14, 129.91, 128.12, 118.50,
105.32, 95.63, 52.13, 51.27 and 39.88 ppm; ms: m/z= 414 [M] .
General Procedure for the Preparation of 2-(4-Substituted-
phenyl)-1-[4-(dimethylamino)pyridinium-1-yl]-2-oxoethanides
15-22.
+
Anal. Calcd. for C
H N O Cl: C, 60.80%; H, 4.62%; N,
21 19 2 5
6.75%. Found: C, 60.79%; H, 4.64%; N, 6.74%.
Pyridinium salt (1-8) (4 mmoles) was added to a solution of 1
N NaOH. The reaction mixture was just placed on a water-bath
for 10 min to produce the yellow crystalline solid, which was col-
lected by filtration, washed with a minimum amount of water and
dried in vacuum to give 15-22.
Dimethyl 3-(4-Bromobenzoyl)-7-(dimethylamino)indolizine-
1,2-dicarboxylate (26).
This compound was obtained as yellow crystalline solid (ethyl
acetate), yield 39%, mp 120-122 °C; uv λ : 423, 315 and 266
max
-1
nm; ir: 3094, 2949, 1737, 1685, 1599, 1225, 1205 and 540 cm ;
H nmr: 9.53 (d, 1H, J=7.9 Hz), 7.5-7.56 (m, 2H), 7.47-7.5 (m,
1
General Procedure for the Preparation of Dimethyl 3-
(Substitutedbenzoyl)-7-(dimethylamino)indolizine-1,2-dicar-
boxylate 23-30.
2H), 7.35 (d, 1H, J=2.7, Hz), 6.68-6.65 (dd, 1H, J= 7.8 and 2.9
13
Hz), 3.81 (s, 3H), 3.35 (s, 3H), 3.15 (s, 6H); C nmr: δ 178.65,
160.43, 158.56, 144.56, 136.78, 133.91, 128.65, 125.82, 124.79,
124.65, 120.24, 113.18, 100.06, 90.38, 46.87, 46.0 and 34.61
ppm; ms: m/z= 459 [M] .
To the dark yellow solution of 2-(4-substitutedphenyl)-1-[4-
(dimethylamino)pyridinium-1-yl]-2-oxoethanides (4 mmoles)
(15-22) and potassium carbonate in DMF (6 mmoles, 40 mL)
were added drop wise dimethyl acetylenedicarboxylate (4.5
mmoles). The medium soon turned black and the mixture was
stirred at room temperature for 1 h. After completion of the reac-
tion (TLC), the medium was extracted with the binary system
aqueous hydrogen chloride/ethyl acetate. The organic phase was
+
Anal. Calcd. for C
H N O Br: C, 54.92%; H, 4.17%; N,
21 19 2 5
6.10%. Found: C, 54.93%; H, 4.18%; N, 6.08%.
Dimethyl 3-(4-Methoxybenzoyl)-7-(dimethylamino)indolizine-
1,2-dicarboxylate (27).
This compound was obtained as yellow crystalline solid (ethyl
separated and dried over Na SO . After removal of solvent in vac-
2
4
acetate), yield 66%, mp 135-37 °C; uv λ : 419, 322 and 273 nm;
max
uum, the residue was separated by column (silica gel) with ben-
zene-ethyl acetate (9:1v/v) as eluent to give indolizines 23-30.
-1
1
ir: 3099, 2942, 1736, 1699, 1590, 1230, 1199 and 1143 cm ; H
nmr: 9.33 (d, 1H, J=7.9 Hz), 7.58 (d, 2H, J=8.6 Hz), 7.26 (d, 1H,
J=2.5 Hz), 6.84 (d, 2H, J=8.6 Hz), 6.55-6.58 (dd, 1H, J=7.9 and 2.7
Dimethyl 3-Benzoyl-7-(dimethylamino)indolizine-1,2-dicar-
boxylate (23).
13
Hz), 3.79 (s, 3H), 3.74 (s, 3H), 3.30 (s, 3H), 3.06 (s, 6H); C nmr:
δ 184.68, 165.97, 162.29, 149.45, 141.83, 132.99, 132.46, 130.73,
This compound was obtained as yellow crystalline solid (ethyl
129.59, 113.27, 105.16, 95.45, 55.45, 52.12, 51.19 and 39.89 ppm;
acetate), yield 43%, mp 285-287 °C; uv λ : 298, 343, 323 and
+
max
ms: m/z= 410 [M] .
-1
253 nm; ir: 3094, 2949, 1738, 1688, 1589, 1232 and 1203 cm ;
H nmr: 9.49 (d, 1H, J=7.9 Hz), 7.55 (d, 2H, J=7.18 Hz), 7.42 (d,
Anal. Calcd. for C
H N O : C, 64.38%; H, 5.40%; N,
22 19 2 6
1
6.83%. Found: C, 64.40%; H, 5.42%; N, 6.82%.
2H, J=7.3 Hz), 7.34 (t, 2H, J=7.3 Hz), 7.28 (d, 1H, J=2.6 Hz),
6.61-6.58 (dd, 1H, J=7.9 and 2.8 Hz), 3.73 (s, 3H), 3.20 (s, 3H),
Dimethyl 3-(4-Phenylbenzoyl)-7-(dimethylamino)indolizine-
1,2-dicarboxylate (28).
13
3.07 (s, 6H): C nmr: δ 185.43, 165.78, 163.97, 149.68, 141.97,
140.37, 130.95, 129.89, 128.46, 127.89, 118.81, 105.25, 95.55,
52.01, 51.23 and 39.89 ppm; ms: m/z= 380 [M] .
This compound was obtained as yellow crystalline solid (ethyl
+
acetate), yield 51%, mp 159-61 °C; uv λ : 402, 343, 310 and 261
max
-1 1
Anal. Calcd. for C
H N O : C, 66.31%; H, 5.30%; N,
nm; ir: 3092, 2934, 1737, 1697, 1584, 1221 and 1205 cm ; H nmr:
21 20 2 5
7.36%. Found: C, 66.29%; H, 5.29%; N, 7.34%.
9.49 (d, 1H, J=7.9 Hz), 7.64 (d, 2H, J=8.1 Hz), 7.58-7.56 (m, 4H),

Jan-Feb 2005
Synthesis of Some New Indolizines
11
Appl., EP 235 111 (1987); Chem. Abs., 109, 6405 (1987).
7.40 (t, 2H, J=7.3 Hz), 7.29 (t, 1H, J=7.3 Hz), 6.62-6.59 (dd, 1H,
J=2.7 Hz), 3.74 (s, 3H), 3.23 (s, 3H), 3.08 (s, 6H); C nmr: δ 185.02,
13
[3] J. Gubin, H. Vogelear, H. Inion, C. Houben, J. Lucchetti, J.
Mahaux, G. Rosseels, M. Peiren, M. Clinet, P. Polster and P. Chatelain, J.
Med. Chem., 36, 1425 (1993).
[4] G. Rosseels, M. Peiren, H. Inion, E. Deray, M. Prost, M.
descamps, J. Bauthier, Richard. J, Tornay. C, Colot. M and Claviere. M,
Eur. J. Med. Chem., 17, 581 (1982).
[5] Brown, A. Guilford, Nayler, H. C. John, Bundes Republik
Deutschland P 2046904 (1971); 2046904 (1971); Chem. Abs., 75, 48 933
(1971).
[6] C. Casagrande, A. Invernizzi. R. Ferrini and G. Miragoli.
Farmaco, Edizione Scientifica (Ital.), 26, 1059 (1971).
[7] J. W. Weeler, Eur. Pat. Appl., EP 161 789 (1985); Chem.
Abstr., 104, 170108, (1985).
[8] C. H. Weidner, D. H. Wadsworth, S. L. Bender and D.
Beltman, J. Org.Chem., 54, 3660 (1989).
[9] J. W. Dick, W. K. Gibson, D. Leaver and J. E. Roff, J. Chem.
Soc., Perkin Tran 1., 3150 (1981).
[10] A .R. Katritzky. Guofang Qiu, Baozhen Yang and Hai-Ying
He, J. Org. Chem., 64, 7618 (1999).
[11] J. Ashby and B. M. Elliott, Comprehensive Heterocyclic
Chemistry, Vol 1, A. R. Katritzky. and C. W. Rees, Eds. Pergamon,
Oxford, 1984, 122-23; W. B. Harrell and R. F. Doerge. J. Pharm. Sci., 56,
225 (1967).
[12] M. Nallu, V. Sathiskumar, M. K. Sangeetha and K. Sarkunam,
Indian J Chem., 40B, 295 (2001).
[13] J. Goswami and A. Goswami. J. Indian Chem. Soc., 79, 469
(2002).
[14] T. V. Sundar, V. Parthasarathi, K. Sarkunam, M. Nallu,
Bernhar Walfortd and Heinrich
Lange, Acta Cryst. C60, o464-o466 (2004).
[15a] G. De Bue and J. Nasielski, Bull.Soc.Chim. Belg, 106, 97
(1997); [b] T. Sasaki, K. Kanematsu, Y. Yukimoto and S. Ochiai, J. Org.
Chem., 36, 813 (1971).
165.86, 163.99, 149.68, 143.78, 141.97, 140.34, 139.17, 133.32,
129.87, 129.09, 128.96, 127.95, 127.23, 126.56, 118.94, 105.26,
+
95.55, 52.08, 51.26, and 39.90 ppm; ms: m/z= m/z= 456 [M] .
Anal. Calcd. for C
H N O : C, 71.04%; H, 5.30%; N,
27 24 2 5
6.14%. Found: C, 71.01%; H, 5.31%; N, 6.12%.
Dimethyl 3-(2-Methoxybenzoyl)-7-(dimethylamino)indolizine-
1,2-dicarboxylate (29).
This compound was obtained as yellow crystalline solid (ethyl
acetate), yield 48%, mp 145-146 °C; uv λ : 390, 341, 305 and
max
215 nm; ir: 3094, 2949, 1737, 1685, 1599, 1225, 1205 and 540
-1
1
cm ; H nmr: 9.77 (d, 1H, J=7.9 Hz), 7.33-7.27 (m, 2H), 7.21 (d,
1H, J=1.5 Hz), 6.89 (t, 1H, J=7.5 Hz), 6.85 (d, 1H, J=8.3 Hz),
6.61-6.58 (dd, 1H, J= 7.9 and 2.8 Hz), 3.72 (s, 3H), 3.70 (s, 3H),
13
3.20 (s, 3H), 3.07 (s, 6H); C nmr: δ 183.55, 165.77, 163.86,
157.31, 149.88, 141.91, 134.11, 130.98, 130.44, 129.41, 129.22,
119.77, 110.97, 105.12, 95.62, 55.69, 52.11, 51.19 and 39.86
+
ppm; ms: m/z= 410 [M] .
Anal. Calcd. for C
H N O : C, 64.38%; H, 5.40%; N,
22 19 2 6
6.83%. Found: C, 64.42%; H, 5.42%; N, 6.81%.
Dimethyl 3-(2,4-Dichlorobenzoyl)-7-(dimethylamino)indolizine-
1,2-dicarboxylate (30).
This compound was obtained as yellow crystalline solid (ethyl
acetate), yield 52%, mp 174-75 °C; uv λ : 390, 341, 305 and
max
215 nm; ir: 3086, 2949, 1735, 1689, 1596, 1220, 1208 and 826
-1
1
cm ; H nmr: 9.85 (d, 1H, J= 7.9 Hz), 7.45 (d, 1H, J= 1.6 Hz),
7.36 (d, 1H, J= 2.7 Hz), 7.31-7.28 (m, 3H), 6.69 (dd, 1H, J= 7.9
13
and 2.8 Hz), 3.79 (s, 3H), 3.36 (s, 3H), 3.16 (s, 6H); C nmr: δ
196.29, 166.92, 163.55, 150.30, 146.82, 142.32, 135.90, 133.48,
130.49, 129.35, 126.31, 117.81, 105.41, 95.90, 55.69, 52.28,
51.33 and 39.90 ppm; ms: m/z= 449 [M] .
[16] R. Hema, V. Parthasarathi, K. Ravikumar, K. Sarkunam and
M. Nallu, Acta Cryst. E60, o479-o480 (2004).
[17] R. Hema, V. Parthasarathi, K. Ravikumar, K. Sarkunam and
M. Nallu, Acta Cryst. E60, o537-o538 (2004).
[18a] A. R. Katritzky, C Rees and W, Flitsch. Comprehensive
Heterocyclic Chemistry, Vol 4, W., Eds., pergamon: Oxford, (1984), 443;
[b] W. B. Harrell and R. F. Doerge, J. Pharm. Sci., 56, 225 (1967); [c] R.
A. Nugent and M. Murphy. J. Org. Chem., 52, 2206 (1987); [d] J. Gubin,
J. Lucchetti, J. Mahaux, D. Nisato, G, Rosseels. M. Chinet, P. Polster and
P. Chatelain. J. Med. Chem., 35, 981 (1992).
[19] J. Gubin, H. Vogelear, H. Inion, C. Houben. J. Lucchetti J.
Mahaux D. Nisato, G. Rosseels, M. Chinet, P. Polster and P. Chatelain, J.
Med. Chem., 36, 1425 (1993).
+
Anal. Calcd. for C
H N O Cl : C, 56.14%; H, 4.04%; N,
21 18 2 5 2
6.23%. Found: C, 56.11%; H, 4.03%; N, 6.21%.
Acknowledgment.
The authors express gratitude to Council of Scientific and
Industrial Research (CSIR), New Delhi, INDIA for the financial
assistance (SRF) to KS and thankful to Reilly Industries, Inc.,
USA for providing DMAP as a gift sample. SIF, IISc., Bangalore
are gratefully acknowledged for providing NMR facility.
[20a] E. B. Skibo. Curr. Med. Chem., 3, 47 (1996); [b] V. A.
Anisimova, A. A. Spasov, I. A. Bocharova, O. V. Ostrovskii, T. I.
Panchenko, G. P, Khimiko-Farmatsevticheskii Zhurnal, 30, 22, (1996);
Chem. Abstr., 124, 219939 (1976); [c] X. Wei, Y. Hu. T. Li and H. Hu, J.
Chem. Soc., Perkin Trans 1, 2487 (1993); [d] J. Zhou, Y Hu. and H. Hu,
Synthesis, 166 (1999); [e] J. Zhou, Y. Hu and H. Hu, J. Chem. Res. (S),
136, (1999).
REFERENCES AND NOTES
[1] W. B. Harrell and R. F Doerge, J. Pharm. Sci., 56, 225
(1967).
[2] J. Gubin, M. Descamps, P. Chatelain and D. Nisato, Eur. Pat.