A one-pot domino reaction for the synthesis of 3-arylindolizines from pyridines, benzyl halides, and dihalide-substituted electron-deficient alkenes

Article abstract of DOI:10.1055/s-0030-1258266

3-Arylindolizines were prepared by one-pot domino reactions from benzyl halides with pyridine (or isoquinoline) and cyclic or acyclic dihalide-substituted electron-deficient alkenes in the presence of potassium carbonate via in situ generated N-ylide intermediate. Both electron-donating and electron-withdrawing groups are tolerated in the aryl ring of benzyl halides. The yields range from moderate to high. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258266

PAPER
4007
A One-Pot Domino Reaction for the Synthesis of 3-Arylindolizines from
Pyridines, Benzyl Halides, and Dihalide-Substituted Electron-Deficient
Alkenes
S
ynthesis of 3-Ary
u
lindolizine
s
a
in
a
O
ne-Po
y
t
D
omino R
o
a
Jiangsu Key Laboratory for Chemistry of Low-Dimensional Materials, School of Chemistry and Chemical Engineering,
Huaiyin Normal University, Huaian 223300, P. R. of China
Fax +86(517)83525100-1; E-mail: huayouhu@hytc.edu.cn
Department of Chinese Language and Literature, Huaiyin Normal University, Huaian 223300, P. R. of China
b
Received 3 August 2010; revised 23 August 2010
First, the reaction scope is rather limited. The N-substitu-
ent in the ylide has almost always been an electron-
deficient group such as acyl or cyanomethyl or 4-nitro-
phenyl,12 while ylides with an electron-rich group such as
Abstract: 3-Arylindolizines were prepared by one-pot domino re-
actions from benzyl halides with pyridine (or isoquinoline) and cy-
clic or acyclic dihalide-substituted electron-deficient alkenes in the
presence of potassium carbonate via in situ generated N-ylide inter-
mediate. Both electron-donating and electron-withdrawing groups a benzyl at the nitrogen atom, were rarely applied with
success.13 As a result, the regioselective synthesis of 3-
are tolerated in the aryl ring of benzyl halides. The yields range
from moderate to high.
arylindolizines and their annulated derivatives proved so
Key words: N-ylides, indolizine polycycles, 1,3-dipolar cycloaddi-
tions, one-pot reaction, electron-deficient alkenes
far rather difficult and have to rely on some specific strat-
egy other than 1,3-dipolar cycloadditions.14 Also, only
electron-deficient alkynes and electron-deficient alkenes
(with oxidant) were used as dipolarophile. Moreover, they
Indolizine has been drawing continuous research interest used isolated pyridinium salt instead of more effective
of synthetic chemists because of the presence of this skel- one-pot domino reaction.10–12
eton in many natural products1,2 such as amorine,1 eryth-
We have previously reported that 2,3-annulated indoliz-
raline,1 swainonine,1 slaframine,1 crepidine,1 gephyro-
ines can be obtained as rearrangement products by the re-
toxine,1 cryptowoline,2 and cryptowoline.2 These natural
action of 2,3-dichloro-1,4-naphthoquinone with N-
products and many synthetic indolizine derivatives exhib-
ylides.15 In this paper, the successful use of N-benzyl
it a variety of biological activities, such as antibacterial,3a
ylides in the 1,3-dipolar cycloadditions and the regiose-
phosphatase and aromatase inhibiting,3b,c antioxidant,3d
lective synthesis of a series of 3-arylindolizines by an one-
antidepressant,3g and antitumor activities.4 They are also
pot domino reaction of pyridines, benzyl halides, and cy-
known to be calcium entry blockers3e and 5-hydroxy-
clic or acyclic dihalide-substituted electron-deficient alk-
tryptamine receptor antagonists.3f In particular, 1,2-annu-
enes under oxidant-free conditions are described. A wide
lated indolizine frameworks are found in several naturally
range of substituents, either electron-donating or electron-
occurring alkaloids with important biological activity,
withdrawing, such as 4-nitro, 2-bromo, 3-fluoro, 3-chloro,
such as camptothecin5 and nuevamine.6 A few synthetic
4-methyl, 4-methoxy, etc. are tolerated in the aryl ring of
1,2-annulated indolizines have also displayed interesting
benzyl halides.
biological activity to serve as brain protecting and anti-
At first, the isolated N-benzylpyridinium bromide 2a and
2,3-dichloronaphthoquinone (3a) were treated in DMF
with sodium carbonate under room temperature for eight
days. The reaction mixture was separated by chromatog-
raphy to give 4a in 23% yield as an orange solid. The
structure of 4a was unambiguously established by an X-
ray diffraction measurement. The ORTEP diagram of 4a
is shown in Figure 1.16
cancer agents.7 Polycyclic indolizine compounds have
been found to have long wavelength absorption and fluo-
rescence in the visible region. The synthesis of these poly-
cyclic indolizine derivatives has therefore attracted
increasing research interest with the aim of developing
new pharmaceuticals, novel classes of dyes, and biologi-
cal markers.8
It is well recognized that 1,3-dipolar cycloaddition9 is one
of the most efficient methods for preparing indolizines,10
since Boekelheide and his co-workers first applied this
synthetic strategy in 1961.11 However, the reactions re-
ported before have some drawbacks relating to the reac-
tion scope and the chemo- and regioselectivity control.
Encouraged by this result, the reactivity in DMF with dif-
ferent bases under room temperature was investigated,
and the results are given in Table 1 (entries 1–7). As
shown in Table 1, potassium carbonate was found to be
the best base, yielding 4a in 65% yield at room tempera-
ture. The results on the search for a better solvent
(Table 1, entries 7–18) show that the low polarity solvent
1,4-dioxane was the best with an increased yield of 79%.
However, the reaction was too slow and took six days to
reach completion. Therefore, the reaction temperature
SYNTHESIS 2010, No. 23, pp 4007–4014
x
x.
x
x
.
2
0
1
0
Advanced online publication: 22.09.2010
DOI: 10.1055/s-0030-1258266; Art ID: F13510SS
© Georg Thieme Verlag Stuttgart · New York

4008
H. Hu et al.
PAPER
Table 1 Screening of Reaction Conditions for the Synthesis of In-
dolizine 4a
Entrya Base
Solventb
DMF
Temp (°C) Time (h) Yield (%)c
1
2
Na2CO3
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
7 d
30
7 d
16
26
Et3N
DMF
0
3
Li2CO3
K3PO4
t-BuOK
DBU
DMF
trace
23
4
DMF
5
DMF
3
3
trace
trace
65
6
DMF
7
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
24
36
16
48
29
8
DMA
36
Figure 1 ORTEP diagram of compound 4a
9
DMSO
MeCN
CH2Cl2
acetone
toluene
benzene
40
10
11
12
13
14
15
16
17
18
19
20d
21e
43
was raised and it was found that at 50 °C, the reaction
could be finished within 24 hours with similar yield (entry
19).
61
4 d
12
After that, the one-pot reaction protocol was tried without
preliminary preparation and isolation of the N-ylide. Pyri-
dine and 5% excess of benzyl bromide were mixed first
and kept at room temperature for 4 hours, then 1,4-diox-
ane, 3a, and potassium carbonate were added to the mix-
ture. The mixture was then reacted at 70 °C for 12 hours.
To our delight, this was found to give an even better yield
of the product 4a (85%) (entry 20). By using 2.05 equiva-
lents of benzyl bromide and 2.0 equivalents of pyridine,
the yield of N-benzylpyridinium bromide (4a) was in-
creased to 98% (entry 21).
8 d
7 d
7 d
7 d
4 d
6d
47
56
cyclohexane r.t.
trace
trace
78
hexane
THF
r.t.
r.t.
1,4-dioxane r.t.
1,4-dioxane 50
1,4-dioxane 70
1,4-dioxane 70
79
24
81
The use of benzyl chloride instead of benzyl bromide was
also examined. The result shows that benzyl chloride is
less reactive than benzyl bromide and the formation of
corresponding pyridinium salt needs higher temperature
and longer time, but comparable overall yield as when us-
ing benzyl bromide can be obtained. Then, various substi-
tuted benzyl halides bearing function groups like 4-
12
12
85
98
a Unless otherwise stated, all the reactions were carried out using N-
benzylpyridinium bromide (0.45 mmol), 2, 3-dichloronaphthoqui-
none (0.30 mmol), and base (1.20 mmol).
b All reactions were run at 0.10 M.
methoxy, 4-methyl, 2-bromo, 3-fluoro, 3-chloro, and 4- c Isolated yield.
d Pyridine (0.45 mmol) and benzyl bromide (0.47 mmol) were stirred
nitro were tried. The results shown in Table 2 indicate that
electron-donating groups like 4-methyl and 4-methoxy
and electron-withdrawing groups like halogen and 4-nitro
were tolerated in the phenyl ring of benzyl halides. How-
ever, the N-ylides that are sterically hindered at the ortho-
position of the N atom such as those derived from 2-me-
thylpyridine, 2-bromopyridine, and quinoline, fail to give
corresponding indolizines.
at r.t. for 4 h, then 2,3-dichloronaphthoquinone (0.30 mmol), K2CO3
(1.20 mmol), and 1,4-dioxane (3 mL) were added.
e Pyridine (0.60 mmol) and benzyl bromide (0.63 mmol) were stirred
at r.t. for 4 h, then 2,3-dichloronaphthoquinone (0.30 mmol), K2CO3
(1.20 mmol), and 1,4-dioxane (3 mL) were added.
Several cyclic dichloro-substituted unsaturated carbonyl
compounds like 2,3-dichloro-1H-inden-1-one, 3,4-
dichloro-1-phenyl-1H-pyrrole-2,5-dione, 2,3,5,6-tetra-
chlorocyclohexa-2,5-diene-1,4-dione, 4,5-dichloro-3,6-
For the synthesis of 1,2 and 6,7-bisannulated indolizines,
isoquinoline was used in place of pyridine. These reac-
tions also proceeded smoothly by the one-pot protocol to
give the products (Table 3).
dioxocyclohexa-1,4-diene-1,2-dicarbonitrile,
and
4a,6,7,8a-tetrachloro-1,4-methanonaphthalene-5,8-dione,
have also been tried to react with the benzyl ylides, but
they failed to give the corresponding indolizines
(Figure 2).
For checking the scope of alkenes, several cyclic or acy-
clic dihalide-substituted electron-deficient alkenes 3b–f
and 2,3-dibromonaphthoquinone (3g) were applied to the
standard reaction condition (Table 4).
It is interesting to note that the reactions of the N-ben-
zoylpyridinium ylides with 2,3-dichloro-1,4-naphtho-
Synthesis 2010, No. 23, 4007–4014 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Arylindolizines in a One-Pot Domino Reaction
4009
Table 2 Synthesis of Indolizines from Pyridine
O
X
X
1,4-dioxane
N
+
R
N
K2CO3, heat
N
3a
1a, X = Br, R = H
O
R
1b, X = Cl, R = H
R
1c, X = Br, R = 2-Br
1d, X = Cl, R = 4-Me
1e, X = Cl, R = 3-F
1f, X = Cl, R = 4-OMe
1g, X = Cl, R = 3-Cl
1h, X = Br, R = 4-O2N
2
4
Benzyl halide
Temp (°C), time (h)a
Temp (°C), time (h)b
70, 12
Product, yield (%)c
4a, 98
1a
1b
1c
1d
1e
1f
r.t., 4
70, 6
r.t., 4
70, 6
70, 6
70, 6
70, 6
r.t., 4
70, 12
4a, 98
80, 12
4c, 82
70, 24
4d, 61
70, 24
4e, 81
70, 12
4f, 75
1g
1h
70, 24
4g, 73
80, 12
4h, 91
a Reaction temperature and time for forming the pyridinium salts.
b Reaction temperature and time for forming the indolizines.
c Isolated yield.
Table 3 Synthesis Indolizines from Isoquinoline
O
X
1,4-dioxane
+
R
N
X
K2CO3, heat
N
N
3a
O
1a, X = Br, R = H
1b, X = Cl, R = H
1d, X = Cl, R = 4-Me
1e, X = Cl, R = 3-F
1f, X = Cl, R = 4-MeO
1g, X = Cl, R = 3-Cl
1h, X = Br, R = 4-O2N
R
R
6
5
Benzyl halide
Temp (°C), time (h)a
Temp (°C), temp (h)b
70, 24
Product, yield (%)c
6a, 56
1a
1b
1d
1e
1f
70, 4
70, 4
70, 4;
70, 4
70, 4
70, 4
50, 6
70, 24
6a, 57
70, 20
6d, 63
70, 24
6e, 75
70, 29
6f, 65
1g
1h
70, 20
6g, 89
50, 15
6h, 90
a Time and temperature for forming the pyridinium salts.
b Time and temperature for forming the indolizines.
c Isolated yield.
quinone proceed by a novel reaction sequence not mal 1,3-dipolar cycloadditions to give the regioisomeric
involving 1,3-dipolar cycloaddition to give 2,3-annulated 1,2-annulated indolizines as products. The mechanistic
indolizines; however, similar reactions of the N-benzylpy- origin for this difference warrants further study.
ridinium ylides with the same quinone take place by nor-
Synthesis 2010, No. 23, 4007–4014 © Thieme Stuttgart · New York

4010
H. Hu et al.
PAPER
Table 4 Synthesis Indolizines from Different Alkenes
O
R2
R1
Br
Br
1,4-dioxane
K2CO3, heat
N
+
N
N
X2
X1
O
R1
3b–f
R2
7
2a
X1, X2 = Cl, Br, I
Alkene
Temp (°C), time (h)a
Product, yield (%)b
O
O
O
O
N
70, 15
Cl
Cl
3b
7a, 66
O
OMe
MeO
O
N
70, 2.5
Br
Br
3c
7b, 22
7b, 64
MeO
Cl
O
70, 3
70, 4
I
3d
CO2Me
CO2Me
Br
CO2Me
N
Br
CO2Me
3e
7c, 68
CO2Et
CO2Et
Br
CO2Et
N
Br
70, 3
CO2Et
3f
7d, 53
4a, 40
O
Br
Br
70, 18
O
3g
a Compound 2a was prepared from pyridine (0.60 mmol) and benzyl bromide (0.63 mmol) by stirring at r.t. for 4 h.
b Isolated yield.
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Synthesis of 3-Arylindolizines in a One-Pot Domino Reaction
4011
7.88 (d, J = 7.2 Hz, 1 H), 7.74 (t, J = 7.2 Hz, 1 H), 7.55–7.70 (m, 5
H), 7.32 (dd, J = 8.4, 7.6 Hz, 1 H), 6.87 (t, J = 7.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 181.8, 179.2, 136.4, 135.5, 133.4,
132.5, 130.6, 129.8, 129.0, 128.5, 128.4, 126.8, 126.4, 126.3, 124.5,
121.7, 121.5, 115.6, 110.8.
O
O
O
O
O
Cl
Cl
CN
CN
Cl
Cl
Cl
Cl
Cl
O
Cl
MS (MALDI-TOF): m/z = 324 (M + H+).
O
Cl
Cl
Anal. Calcd for C22H13NO2: C, 81.72; H, 4.05; N, 4.33. Found: C,
81.68; H, 4.01; N, 4.23.
Cl
Cl
N
Cl
6-(2-Bromophenyl)benzo[f]pyrido[2,1-a]isoindole-7,12-dione
(4c)
Cl
O
O
Orange solid; mp 258–259 °C.
Figure 2 Dichloro-substituted unsaturated carbonyl compounds
IR (KBr): 2922, 1658, 1537, 1500, 1238 cm–1.
that fail to give indolizine products
1H NMR (400 MHz, CDCl3): d = 8.56 (d, J = 9.0 Hz, 1 H), 8.33 (d,
J = 8.4 Hz, 1 H), 8.16 (d, J = 8.4 Hz, 1 H), 7.83 (d, J = 8.1 Hz, 1 H),
7.75 (t, J = 7.2 Hz, 1 H), 7.68 (d, J = 7.5 Hz, 2 H), 7.44–7.58 (m, 3
H), 7.36 (dd, J = 8.7, 7.2 Hz, 1 H), 6.92 (t, J = 6.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 181.7, 179.1, 136.5, 135.2, 134.9,
133.54, 133.53, 133.4, 132.5, 131.5, 130.2, 128.0, 126.8, 126.54,
126.46, 126.39, 125.2, 124.8, 122.6, 121.4, 115.7, 110.5.
In conclusion, we have developed a convenient one-pot
procedure for the regioselective synthesis of 3-arylin-
dolizine derivatives from easily available starting materi-
als by the more general 1,3-dipolar cycloaddition strategy.
This strategy takes advantage of the successful use of N-
benzyl ylides as the dipoles in the reactions. Further re-
search will focus on the mechanistic issue of the reactions
and the fluorescent properties of these new polycyclic in-
dolizine compounds.
MS (MALDI-TOF): m/z = 402 (M + H+).
Anal. Calcd for C22H12BrNO2: C, 65.69; H, 3.01; N, 3.48. Found: C,
65.46; H, 3.21; N, 3.37.
6-p-Tolylbenzo[f]pyrido[2,1-a]isoindole-7,12-dione (4d)
Orange solid; mp 304–305 °C.
IR (KBr): 3120, 1664, 1628, 1593, 1538, 1506, 1436, 1236 cm–1.
All organic solutions were concentrated by rotary evaporation un-
der reduced pressure. Flash column chromatography was performed
employing 300–400 mesh silica gel. TLC was performed using
plates precoated to a depth of 0.25mm with 300–400 mesh silica gel
impregnated with a fluorescent indicator. All chemicals and sol-
vents were obtained from commercial vendors and used without
further purification. Melting points are uncorrected. IR spectra were
obtained using a Nicolet Avator 360 spectrometer. Data were pre-
sented as frequency of absorption (cm–1). Element analyses were
1H NMR (400 MHz, CDCl3): d = 8.53 (d, J = 9.2 Hz, 1 H), 8.32 (d,
J = 7.6 Hz, 1 H), 8.18 (d, J = 7.6 Hz, 1 H), 8.09 (d, J = 7.2 Hz, 1 H),
7.74 (t, J = 6.8 Hz, 1 H), 7.66 (t, J = 7.2 Hz, 1 H), 7.53 (d, J = 8.0
Hz, 2 H), 7.42 (d, J = 8.0 Hz, 2 H), 7.30 (dd, J = 8.4, 7.6 Hz, 1 H),
6.85 (t, J = 6.8 Hz, 1 H), 2.50 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 181.8, 179.1, 139.9, 136.4, 135.6,
135.1, 133.3, 132.4, 130.5, 129.7, 128.7, 126.8, 126.4, 126.3, 125.4,
124.5, 121.6, 121.5, 115.5, 110.8, 21.6.
1
obtained using an Elementar Vario MICRO analyzer. H and 13C
NMR spectra were recorded on a Bruker 400 NMR spectrometer,
chemical shifts are expressed in parts per million (d scale) down-
field from TMS and are referenced to residual hydrogen in the NMR
solvent (CHCl3: d = 7.26). Data are presented as follows: chemical
shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet and/or multiple resonances), coupling constant in
hertz (Hz), integration.
MS (MALDI-TOF): m/z = 338 (M + H+).
Anal. Calcd for C23H15NO2: C, 81.88; H, 4.48; N, 4.15. Found: C,
81.78; H, 4.41; N, 4.07.
6-(3-Fluorophenyl)benzo[f]pyrido[2,1-a]isoindole-7,12-dione
(4e)
Compounds 4, 6, and 7; General Procedure
Orange solid; mp 287–288 °C.
A mixture of benzyl bromide (or chloride) (0.63 mmol) and pyri-
dine (or isoquinoline) (0.60 mmol) was taken in a test tube with a
stopper and stirred at the temperature and time shown in Table 2 (or
Tables 3, 4). Then 2,3-dichloro-1,4-naphthoquinone (3a; 68.1 mg,
0.30 mmol) (or alkene 3b–g, 0.3 mmol), K2CO3 (166 mg, 1.20
mmol), and 1,4-dioxane (3.0 mL) were added. The resulting mix-
ture was heated at the temperature and time indicated in Table 2 (or
Tables 3, 4), then allowed to cool to r.t. Brine (10 mL) was added
and the mixture was extracted with CHCl3 (3 × 15 mL). The com-
bined organic layers were dried (Na2SO4). The solvent was evapo-
rated, and the residue obtained was purified by column
chromatography [silica gel, 30% CHCl3 in petroleum ether (bp 60–
90 °C)] to furnish the pure compound 4 (or 6 and 7).
IR (KBr): 3062, 1659, 1632, 1589, 1534, 1502, 1433, 1271, 1236
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.56 (d, J = 8.8 Hz, 1 H), 8.33 (d,
J = 8.0 Hz, 1 H), 8.19 (d, J = 7.6 Hz, 1 H), 8.08 (d, J = 7.2 Hz, 1 H),
7.76 (t, J = 7.2 Hz, 1 H), 7.68 (t, J = 7.2 Hz, 1 H), 7.60 (dd, J = 14.0,
7.6 Hz, 1 H), 7.43 (d, J = 7.6 Hz, 1 H), 7.36 (d, J = 7.2 Hz, 1 H),
7.27–7.31 (m, 1 H), 6.91 (t, J = 6.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 181.7, 179.1, 160.3 (d, J = 246.2
Hz), 136.3, 135.4, 135.2, 133.5, 132.6, 130.6 (d, J = 8.4 Hz), 130.5
(d, J = 8.4 Hz), 126.8, 126.48, 126.47, 126.44, 126.40, 124.2, 122.0,
121.6, 117.8 (d, J = 22.1 Hz), 117.7 (d, J = 20.9 Hz), 115.9, 110.9.
MS (MALDI-TOF): m/z = 342 (M + H+).
6-Phenylbenzo[f]pyrido[2,1-a]isoindole-7,12-dione (4a)
Orange solid; mp 284–285 °C.
IR (KBr): 3069, 1658, 1632, 1593, 1539, 1501, 1432, 1236 cm–1.
Anal. Calcd for C22H12FNO2: C, 77.41; H, 3.54; N, 4.10. Found: C,
77.27; H, 3.60; N, 4.01.
6-(4-Methoxyphenyl)benzo[f]pyrido[2,1-a]isoindole-7,12-dione
(4f)
Orange solid; mp 250–251 °C.
1H NMR (400 MHz, CDCl3): d = 8.55 (d, J = 8.8 Hz, 1 H), 8.33 (d,
J = 7.6 Hz, 1 H), 8.19 (d, J = 6.8 Hz, 1 H), 8.09 (d, J = 6.8 Hz, 1 H),
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H. Hu et al.
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IR (KBr): 3108, 2960, 1658, 1635, 1593, 1551, 1505, 1432, 1237
cm–1.
8-p-Tolylbenz[5,6]isoindolo[1,2-a]isoquinoline-9,14-dione (6d)
Orange solid; mp 257–258 °C.
1H NMR (400 MHz, CDCl3): d = 8.52 (d, J = 9.2 Hz, 1 H), 8.32 (d,
J = 7.6 Hz, 1 H), 8.18 (d, J = 7.6 Hz, 1 H), 8.10 (d, J = 6.8 Hz, 1 H),
7.73 (t, J = 7.6 Hz, 1 H), 7.66 (t, J = 7.6 Hz, 1 H), 7.58 (d, J = 8.4
Hz, 2 H), 7.27–7.31 (m, 1 H), 7.13 (d, J = 8.4 Hz, 2 H), 6.65 (t,
J = 6.8 Hz, 1 H), 3.94 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 181.8, 179.1, 160.7, 136.4, 135.6,
135.0, 133.3, 132.4, 132.0, 128.6, 126.8, 126.4, 126.2, 124.5,
121.53, 121.48, 120.4, 115.5, 114.5, 110.7, 55.4.
IR (KBr): 3112, 3066, 3022, 1662, 1639, 1592, 1563, 1499, 1473,
1400, 1266, 1242 cm–1.
1H NMR (400 MHz, CDCl3): d = 10.50 (d, J = 8.4 Hz, 1 H), 8.45 (d,
J = 8.0 Hz, 1 H), 8.16 (d, J = 7.6 Hz, 1 H), 7.72–7.81 (m, 3 H),
7.63–7.70 (m, 3 H), 7.50 (d, J = 8.0 Hz, 2 H), 7.45 (d, J = 8.0 Hz, 2
H), 7.06 (d, J = 7.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 181.4, 179.0, 139.9, 137.0, 134.8,
133.7, 133.4, 132.5, 132.1, 130.7, 129.9, 129.8, 129.6, 128.5, 128.4,
127.5, 126.8, 126.2, 126.1, 126.0, 121.73, 121.69, 118.2, 116.4,
114.7, 21.6.
MS (MALDI-TOF): m/z = 354 (M + H+).
Anal. Calcd for C23H15NO3: C, 78.17; H, 4.28; N, 3.96. Found: C,
78.09; H, 4.37; N, 3.99.
MS (MALDI-TOF): m/z = 388 (M + H+).
Anal. Calcd for C27H17NO2: C, 83.70; H, 4.42; N, 3.62. Found: C,
83.57; H, 4.29; N, 3.52.
6-(3-Chlorophenyl)benzo[f]pyrido[2,1-a]isoindole-7,12-dione
(4g)
Orange solid; mp 236–237 °C.
8-(3-Fluorophenyl)benz[5,6]isoindolo[1,2-a]isoquinoline-9,14-
dione (6e)
Orange solid; mp 311–312 °C.
IR (KBr): 3054, 1659, 1632, 1592, 1536, 1500, 1429, 1269, 1235
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.51 (d, J = 8.4 Hz, 1 H), 8.30 (d,
J = 7.6 Hz, 1 H), 8.16 (d, J = 7.6 Hz, 1 H), 8.04 (d, J = 7.2 Hz, 1 H),
7.73 (t, J = 7.6 Hz, 1 H), 7.68 (t, J = 7.2 Hz, 1 H), 7.62–7.70 (m, 2
H), 7.55 (s, 3 H), 7.30 (t, J = 6.4 Hz, 1 H), 6.88 (t, J = 6.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 181.66, 181.64, 179.0, 136.2,
135.3, 135.1, 134.9, 133.5, 132.6, 130.6, 130.31, 130.28, 129.9,
129.0, 126.8, 126.5, 126.4, 124.2, 122.0, 121.5, 115.9, 110.9.
IR (KBr): 3112, 3065, 1664, 1640, 1588, 1500, 1474, 1428, 1400,
1270, 1224 cm–1.
1H NMR (400 MHz, CDCl3): d = 10.47 (d, J = 7.6 Hz, 1 H), 8.44 (d,
J = 7.6 Hz, 1 H), 8.14 (d, J = 7.6 Hz, 1 H), 7.29–7.82 (m, 8 H), 7.40
(d, J = 7.2 Hz, 1 H), 7.33 (t, J = 8.8 Hz, 2 H), 7.08 (d, J = 7.6 Hz, 1
H).
13C NMR (100 MHz, CDCl3): d = 181.3, 178.9, 163.0 (d, J = 246.3
Hz), 136.9, 134.6, 133.8, 133.6, 132.6, 131.2 (d, J = 8.4 Hz), 130.7
(d, J = 8.5 Hz), 129.8, 129.7, 128.6, 128.5, 127.6, 126.9, 126.76,
126.73, 126.2, 126.0, 122.0, 121.3, 118.2 (d, J = 22.1 Hz), 116.9 (d,
J = 20.5 Hz), 116.8, 114.7.
MS (MALDI-TOF): m/z = 358 (M + H+).
Anal. Calcd for C22H12ClNO2: C, 73.85; H, 3.38; N, 3.91. Found: C,
73.87; H, 3.27; N, 3.78.
6-(4-Nitrophenyl)benzo[f]pyrido[2,1-a]isoindole-7,12-dione
MS (MALDI-TOF): m/z = 392 (M + H+).
(4h)
Anal. Calcd for C26H14FNO2: C, 79.79; H, 3.61; N, 3.58. Found: C,
79.97; H, 3.77; N, 3.61.
Orange solid; mp 236–237 °C.
IR (KBr): 3108, 2925, 1666, 1635, 1593, 1510, 1436, 1347, 1236
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.51 (d, J = 8.4 Hz, 1 H), 8.30 (d,
J = 7.6 Hz, 1 H), 8.16 (d, J = 7.6 Hz, 1 H), 8.04 (d, J = 7.2 Hz, 1 H),
7.73 (t, J = 7.6 Hz, 1 H), 7.68 (t, J = 7.2 Hz, 1 H), 7.62–7.70 (m, 2
H), 7.55 (s, 3 H), 7.30 (t, J = 6.4 Hz, 1 H), 6.88 (t, J = 6.4 Hz, 1 H).
8-(4-Methoxyphenyl)benz[5,6]isoindolo[1,2-a]isoquinoline-
9,14-dione (6f)
Orange solid; mp 277–278 °C.
IR (KBr): 3112, 2924, 1658, 1610, 1557, 1499, 1473, 1422, 1399,
1264, 1248 cm–1.
13C NMR (100 MHz, CDCl3): d = 181.66, 181.64, 179.0, 136.2,
135.3, 135.1, 134.9, 133.5, 132.6, 130.6, 130.31, 130.28, 129.9,
129.0, 126.8, 126.5, 126.4, 124.2, 122.0, 121.5, 115.9, 110.9.
1H NMR (400 MHz, CDCl3): d = 10.52 (d, J = 8.2 Hz, 1 H), 8.46 (d,
J = 7.5 Hz, 1 H), 8.19 (d, J = 7.4 Hz, 1 H), 7.74–7.86 (m, 3 H),
7.64–7.73 (m, 3 H), 7.55 (d, J = 8.1 Hz, 2 H), 7.17 (d, J = 8.2 Hz, 2
H), 7.09 (d, J = 7.3 Hz, 1 H), 3.96 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 181.5, 179.0, 160.7, 137.1, 134.9,
133.7, 133.4, 132.5, 132.3, 132.0, 130.0, 129.6, 128.50, 128.47,
127.5, 126.9, 126.3, 126.1, 121.74, 121.73, 121.6, 120.9, 116.5,
114.7, 114.6, 55.4.
MS (MALDI-TOF): m/z = 370 (M + H+).
Anal. Calcd for C22H12N2O4: C, 71.74; H, 3.28; N, 7.61. Found: C,
71.74; H, 3.24; N, 7.48.
8-Phenylbenz[5,6]isoindolo[1,2-a]isoquinoline-9,14-dione (6a)
Orange solid; mp 285–286 °C.
MS (MALDI-TOF): m/z = 404 (M + H+).
IR (KBr): 3110, 3064, 1662, 1639, 1592, 1563, 1499, 1474, 1400,
1267, 1245 cm–1.
Anal. Calcd for C27H17NO3: C, 80.38; H, 4.25; N, 3.47. Found: C,
80.18; H, 4.37; N, 3.30.
1H NMR (400 MHz, CDCl3): d = 10.50 (d, J = 8.4 Hz, 1 H), 8.45 (d,
J = 8.0 Hz, 1 H), 8.16 (d, J = 7.6 Hz, 1 H), 7.73–7.81 (m, 3 H),
7.59–7.71 (m, 8 H), 7.07 (d, J = 7.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 181.4, 179.0, 137.0, 134.8, 133.7,
133.4, 132.5, 131.8, 130.9, 129.9, 129.8, 129.6, 129.2, 129.0,
128.51, 128.48, 127.5, 126.9, 126.2, 126.1, 121.8, 121.6, 116.5,
114.7.
8-(3-Chloropheny)benz[5,6]isoindolo[1,2-a]isoquinoline-9,14-
dione (6g)
Orange solid; mp 253–254 °C.
IR (KBr): 3065, 2923, 2853, 1714, 1665, 1593, 1498, 1471, 1424,
1397, 1266, 1243 cm–1.
1H NMR (400 MHz, CDCl3): d = 10.47 (d, J = 8.4 Hz, 1 H), 8.44 (d,
J = 7.6 Hz, 1 H), 8.14 (d, J = 7.6 Hz, 1 H), 7.50–7.81 (m, 10 H),
7.09 (d, J = 7.2 Hz, 1 H).
MS (MALDI-TOF): m/z = 374 (M + H+).
Anal. Calcd for C26H15NO2: C, 83.63; H, 4.05; N, 3.75. Found: C,
83.53; H, 3.81; N, 3.64.
Synthesis 2010, No. 23, 4007–4014 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Arylindolizines in a One-Pot Domino Reaction
MS (ESI): m/z = 309 (M+).
4013
13C NMR (100 MHz, CDCl3): d = 181.3, 178.8, 136.9, 135.0, 134.6,
133.8, 133.6, 132.6, 130.96, 130.93, 129.81, 129.76, 129.75, 129.3,
128.6, 128.5, 127.6, 126.9, 126.2, 126.0, 123.4, 122.1, 121.3, 116.9,
114.7.
Anal. Calcd for C18H15NO4: C, 69.89; H, 4.89; N, 4.53. Found: C,
69.84; H, 4.90; N, 4.46.
MS (MALDI-TOF): m/z = 408 (M + H+).
Diethyl 3-Phenylindolizine-1,2-dicarboxylate (7d)
Orange oil.
Anal. Calcd for C26H14ClNO2: C, 76.57; H, 3.46; N, 3.43. Found: C,
76.37; H, 3.54; N, 3.37.
IR (KBr): 2978, 1729, 1695, 1512, 1443, 1396 cm–1.
1H NMR (400 MHz CDCl3): d = 8.27 (d, J = 9.1 Hz, 1 H), 8.04 (d,
J = 7.0 Hz, 1 H), 7.59–7.43 (m, 5 H), 7.12 (dd, J = 8.8, 6.9 Hz, 1 H),
6.72 (t, J = 6.9 Hz, 1 H), 4.39 (q, J = 7.1 Hz, 2 H), 4.28 (q, J = 7.1
Hz, 2 H), 1.41 (t, J = 7.1 Hz, 3 H), 1.23 (t, J = 7.1 Hz, 3 H).
8-(4-Nitrophenyl)benz[5,6]isoindolo[1,2-a]isoquinoline-9,14-di-
one (6h)
Orange solid; mp >330 °C.
IR (KBr): 3107, 1661, 1593, 1507, 1473, 1399, 1345, 1268, 1244
cm–1.
1H NMR (400 MHz, CDCl3): d = 10.52 (d, J = 8.4 Hz, 1 H), 8.51 (d,
J = 8.4 Hz, 2 H), 8.48 (d, J = 8.4 Hz, 1 H), 8.17 (d, J = 7.6 Hz, 1 H),
7.85 (d, J = 8.4 Hz, 2 H), 7.82 (t, J = 7.0 Hz, 2 H), 7.77–7.71 (m, 4
H), 7.18 (d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 181.5, 178.9, 148.5, 137.3, 136.9,
135.9, 134.40, 134.36, 133.3, 132.8, 132.3, 130.1, 129.8, 128.9,
128.6, 128.4, 127.7, 127.1, 126.3, 126.0, 124.2, 120.5, 117.4, 115.1.
13C NMR (100 MHz, CDCl3): d = 166.2, 163.8, 135.3, 130.1, 129.1,
129.01, 128.99, 124.9, 123.5, 123.3, 122.4, 120.4, 113.4, 102.2,
61.2, 59.9, 14.5, 14.0.
MS (ESI): m/z =337 (M+).
Anal. Calcd for C20H19NO4: C, 71.20; H, 5.68; N, 4.15. Found: C,
71.21; H, 5.64; N, 4.08.
Acknowledgment
MS (MALDI-TOF): m/z = 419 (M + H+).
This work was supported by the Jiangsu Key Laboratory for Chemi-
stry of Low-Dimensional Materials (JSKC09067) and Huaiyin
Normal University.
Anal. Calcd for C26H14N2O4: C, 74.64; H, 3.37; N, 6.70. Found: C,
74.57; H, 3.46; N, 6.53.
12-Phenyl-6H-chromeno[3,4-a]indolizin-6-one (7a)
Orange solid; mp 193–194 °C.
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IR (KBr): 3059, 1706, 1638, 1606, 1504, 1408 cm–1.
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Methyl 3-Phenylindolizine-1-carboxylate (7b)
Orange solid; mp 86–87 °C.
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J = 11.2 Hz, 1 H), 7.57 (d, J = 7.1 Hz, 2 H), 7.52 (t, J = 7.3 Hz, 2
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Synthesis 2010, No. 23, 4007–4014 © Thieme Stuttgart · New York

4014
H. Hu et al.
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(16) Detailed X-ray crystallographic data for compound 4a
(CCDC 760516) are available free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 (1223)336033, E-mail:
deposit@ccdc.cam.ac.uk].
Synthesis 2010, No. 23, 4007–4014 © Thieme Stuttgart · New York