Iodine-promoted synthesis of acylindolizine derivatives from acetylenecarboxylates and pyridinium, isoquinolinium, or quinolinium ylides

Article abstract of DOI:10.1007/s00706-013-1120-6

An iodine-promoted synthesis of acylindolizinecarboxylates via 1,3-dipolar cycloaddition of nitrogen ylides with acetylenecarboxylates and subsequent aromatization for the generation of a wide range of structurally interesting, pharmacologically and photoelectrically significant compounds is reported. Only readily available materials, mild conditions, and operationally trivial reaction protocols were required. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-013-1120-6

Monatsh Chem
DOI 10.1007/s00706-013-1120-6
ORIGINAL PAPER
Iodine-promoted synthesis of acylindolizine derivatives
from acetylenecarboxylates and pyridinium, isoquinolinium,
or quinolinium ylides
•
Juanjuan Liu Peiyun Yan Yan Li Zhengquan Zhou Weijian Ye
•
•
•
•
•
Juan Yao Cunde Wang
Received: 12 July 2013 / Accepted: 9 November 2013
Ó Springer-Verlag Wien 2013
Abstract An iodine-promoted synthesis of acylindolizi-
necarboxylates via 1,3-dipolar cycloaddition of nitrogen
ylides with acetylenecarboxylates and subsequent aroma-
tization for the generation of a wide range of structurally
interesting, pharmacologically and photoelectrically sig-
nificant compounds is reported. Only readily available
materials, mild conditions, and operationally trivial reac-
tion protocols were required.
pharmaceuticals, agrochemicals, and functional materials
(e.g., they exhibit cardiovascular [6], anticancer [7, 8],
HIV-1 integrase inhibiting [9, 10], anti-inflammatory [11–
13], central nervous system depressant [14], calcium entry
blocking [15], antimycobacterial [16], analgesic [17],
antioxidant [18, 19], antitubercular [20–22], and phospha-
tase inhibitory activities [23–25]). The novel indolizine
derivatives have been a rich source of candidates with
potential pharmaceutical applications that have encouraged
the design and synthesis of new analogues with increased
pharmacological activity [23, 26–32]. Furthermore substi-
tuted indolizines and their derivatives were also used
extensively as versatile building blocks for the synthesis of
dyes [33], biological markers [34, 35], and electrolumi-
nescent materials [36, 37] with enhanced electronic and
photonic properties. Thus, efficient new approaches for the
preparation of chemically and biologically relevant ind-
olizines are of great significance. Consequently, many
synthetic methods have been developed for the preparation
of substituted indolizines, pyrrolo[1,2-a]quinolones, and
pyrrolo[2,1-a]isoquinolines [38]. The most frequently used
reactions started from pyridine derivatives and completed
the bicyclic skeleton by construction of the pyrrole ring
[32, 39–41]. Among them, the conventional 1,3-dipolar
cycloadditions of pyridinium (quinolinium, isoquinolini-
um) methylides with electron-deficient alkynes or alkenes
[32, 42–51] are becoming more and more important.
In recent times, the use of molecular iodine has received
considerable attention as an inexpensive, nontoxic, readily
available catalyst or oxidizing reagent for various organic
transformations to afford the corresponding products in
excellent yields with high selectivity [52, 53].
Keywords Indolizine Á Iodine Á Acetylenecarboxylate Á
1,3-Dipolar cycloaddition Á Aromatization
Introduction
The indolizines are important nitrogen-containing hetero-
cyclic compounds, which have received much attention
owing to their interesting molecular structures featured
with ten p-delocalized electrons similar to the indoles.
Indolizines, pyrrolo[1,2-a]quinolones, and pyrrolo[2,1-
a]isoquinolines from 5,6- and 7,8-benzo-fused indolizines,
respectively, are widely found in the alkaloids [1–5].
Numerous investigations indicate that compounds con-
taining the indolizine moiety have a wide range of
biological activities suitable for applications as
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-013-1120-6) contains supplementary
material, which is available to authorized users.
J. Liu Á P. Yan Á Y. Li Á Z. Zhou Á W. Ye Á J. Yao Á
C. Wang (&)
School of Chemistry and Chemical Engineering,
Yangzhou University, 180 Siwangting Street,
Yangzhou 225002, People’s Republic of China
e-mail: wangcd@yzu.edu.cn
In one of our electroluminescent materials and medicinal
chemistry programs, we needed acylindolizinecarboxylate to
prepare more complex analogues containing the indolizine
123

J. Liu et al.
core. General and regioselective synthetic methods for
3-acylindolizines from easily available starting materials are
highly desirable. Although there are several methods for the
preparation of the substituted indolizine derivatives, to the
best of our knowledge, there have been no reports that
molecular iodine catalyzed the synthesis of indolizine and
benzoindolizine derivatives from N-heterocyclic ylides and
electron-deficient alkynes. We here report a simple synthesis
of 3-acylindolizines and their benzo-analogues by the more
general 1,3-dipolar cycloaddition reactions of pyridinium
(quinolinium, isoquinolinium) ylides using molecular iodine
as an efficient promoter.
oxidant reagents such as 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) and and tetrakispyridinecobalt(II)
dichromate (TPCD), leading to the fully aromatic indoli-
zine core ring. In keeping with our continuing interest in
the construction of indolizine and benzoindolizine hetero-
cycles directly from readily available materials, we
attempted to synthesize the indolizines and benzoindoli-
zines from pyridinium (quinolinium, isoquinolinium)
ylides and electron-deficient alkynes under mild condi-
tions. Initially, on the basis of our previous results [54–56],
the reaction was carried out firstly by stirring the mixture of
pyridinium salt 1a and dimethyl acetylenedicarboxylate
(DMAD, 2a) in DMSO in the presence of 10 mol%
molecular iodine at room temperature for 2 h, and a yield
of 20 % of the desired product 3a was obtained (Table 1,
entry 1). Encouraged by the result, the reaction conditions
were then screened with the aim of optimizing the yield of
3a. Compound 3a could be obtained in 57 % yield when
molecular iodine (50 mol%) was subjected to the reaction
at room temperature for 2 h (Table 1, entry 4). Further
increase of the amount of molecular iodine had no signif-
icant beneficial effect on the reaction. Extending the
reaction time to 3 h resulted in a very slightly higher yield
(Table 1, entry 6). Elevating the reaction temperature to
50 °C was also examined, but was less effective than room
Results and discussion
It is known that one of the promising methods in the
synthesis of the indolizine core is the 1,3-dipolar cyclo-
addition reaction of their corresponding N-ylides. Usually,
the reaction of the N-ylides with the acetylenic dipolaro-
philes led to the formation of the primary cycloadducts in
the presence of appropriate promotors, following which the
cycloadducts rearranged to the dihydro intermediates.
Finally such intermediates were susceptible to further
aromatization, under the reaction conditions or by using
Table 1 Optimization of temperature, time, and solvents in the synthesis of 3a
CO2CH3
CO2CH3
CO2CH3
Selected conditions
N
N
I
+
O
O
CO2CH3
1a
2a
3a
Entry
I2/mol%
Solvent
Temp.
Time/h
Yield/%
1
10
20
40
50
60
50
50
50
50
50
50
50
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
H2O
rt
2
20
37
41
57
57
58
50
18
55
22
25
34
2
rt
2
3
rt
2
4
rt
2
5
rt
2
6
rt
3
7
50 °C
rt
1.5
2
8
9
DMF
rt
2
10
11
12
PhCH3
CH3CN
CH3OH
rt
2
rt
2
rt
2
123

Iodine-promoted synthesis of acylindolizine derivatives
Table 2 I2-promoted preparation of alkyl indolizinecarboxylates 3a–3n
CO2R1
R2
CO2R1
I2, DMSO, rt, 2 h
N
+
N
X
R2
R
R
3a-3n
1a-1g
2a-2c
Entry
X
R
R1
R2
Product
Yield/%
M.p./°C
Lit. m.p./°C
1
I
C6H5CO
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
CH3
CO2CH3
3a
3b
3c
3d
3e
3f
57
64
68
52
72
70
58
66
61
65
54
63
52
85
168.0–169.0
132.0–133.0
148.0–149.6
168.1–169.2
114.8–116.1
189.2–190.5
96.5–97.8
160–162 [32]
130–132 [32]
147–149 [32]
–
2
I
p-BrC6H4CO
CO2CH3
CO2CH3
CO2CH3
CO2CH3
CO2CH3
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
H
3
I
p-CH3OC6H4CO
o-CH3C6H4CO
p-CH3C6H4CO
p-O2NC6H4CO
C6H5CO
4
I
5
I
105–106 [44]
189–191 [44]
91–93 [32]
152–155 [32]
116–117 [32]
–
6
I
7
I
3g
3h
3i
8
I
p-BrC6H4CO
p-CH3OC6H4CO
o-CH3C6H4CO
p-CH3C6H4CO
p-O2NC6H4CO
p-O2NC6H4CO
CN
152.6–154.2
116.4–117.8
152.6–153.8
126.7–128.0
155.2–157.6
179.6–180.4
129.1–130.5
9
I
10
11
12
13
14
I
3j
I
3k
3l
120–122 [32]
156–159 [32]
–
I
I
3m
3n
Cl
CO2CH3
125–128 [49]
temperature (Table 1, entry 7). The reaction of pyridinium
salt 1a and DMAD (2a) could proceed in other solvents,
such as water, DMF, toluene, acetonitrile, and ethanol
(Table 1, entries 8–12). Among those tested, DMSO
proved to be the best. The use of DMF is similarly effective
as DMSO. A series of experiments revealed that the opti-
mal results were obtained when the reaction of pyridinium
salt 1a (1.0 equiv.) and DMAD (1.0 equiv.) together with
50 mol% iodine in DMSO was mixed and the resultant
mixture was stirred for 2 h at room temperature, whereby
the yield of 3a reached 57 % (Table 1, entry 4).
(Table 2), which appear as two doublets with the coupling
constant J = ca. 7.1 Hz. The hydrogen H-5 is the most
deshielded proton in the range 9.92–9.57 ppm. Similarly,
1
the main characteristics of the H NMR spectra of com-
pounds 5a–5m (Table 3) are the signals of the hydrogen
atoms H-5 and H-6, which appear as two doublets with the
coupling constant J = 7.5 Hz. The hydrogens H-5 and
H-10 are the most deshielded protons and appear at
8.81–8.29 ppm. The hydrogen H-6 appears shielded in the
range 7.28–7.09 ppm. In the 1H NMR spectra of com-
pounds 7a–7m, the general characteristic feature is the
chemical shifts of atoms H-4 and H-9, which appear
strongly deshielded because of the spatial vicinity of the
carbonyl groups attached to positions 1 and 3 of the pyrrole
ring. The H-4 and H-9 protons appear as two doublets with
d = 7.80–7.68 and 8.26–8.20 ppm, respectively. The 13C
NMR spectra contain all the expected signals. Addition-
ally, the stereochemistry of cycloadducts 3a–3n, 5a–5m,
and 7a–7m was determined by X-ray analysis of com-
pounds 3j, 5j, 5d, and 7k as representative examples
(Figs. 1, 2, 3, 4).
To determine the scope of the protocol, a number of
available pyridinium, isoquinolinium, or quinolinium salts
generated from pyridine or isoquinoline or quinoline with
substituted 2-haloacetophenone or 2-chloroacetonitrile
were cyclo-condensed with acetylenecarboxylates under
the optimized reaction conditions established for the syn-
thesis of 3a. The results are summarized in Tables 2, 3, and
4. Both electron-deficient and electron-rich aromatic
acylmethyl pyridinium, isoquinolinium, or quinolinium
salts were similarly viable affording the products in mod-
erate to good yields.
The reaction mechanism shown in Scheme 1 is pro-
posed. First, the weak Lewis acid molecular iodine induced
the keto–enol tautomerism of the arylaceto group to form a
resonance-stabilized enolate ion, which is followed by
nucleophilic addition to the alkyne to form an alkene with a
negative charge. Next, the intermediate alkene ion
The structures of the prepared compounds were assigned
1
with the aid of H and 13C NMR. The spectra are in good
accordance with the proposed structures. The main char-
1
acteristic of the H NMR spectra are the signals of the
hydrogen atoms H-5 and H-8 of compounds 3a–3n
123

J. Liu et al.
Table 3 I2-promoted preparation of 3-aroylpyrrolo[2,1-a]isoquinolinecarboxylates 5a–5m
CO2R1
R2
CO2R1
I2, DMSO, rt, 2 h
+
N
R
N
R2
I
O
4a-4f
2a-2c
5a-5m
O
R
Entry
R
R1
R2
Product
Yield/%
M.p./°C
Lit. m.p./°C
1
H
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
CO2CH3
CO2CH3
CO2CH3
CO2CH3
CO2CH3
CO2CH3
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
H
5a
5b
5c
5d
5e
5f
65
71
66
63
68
86
90
51
63
76
63
93
63
162.2–163.8
194.8–195.8
150.8–152.1
186.2–197.6
152.5–153.2
199.8–200.5
123.0–125.3
166.8–168.7
128.7-129.2
128.1–130.2
147.5–150.0
155.6–157.8
169.3–170.4
161–163 [32]
194–197 [49]
145–147 [47]
–
2
p-Br
3
p-OCH3
o-CH3
p-CH3
p-NO2
H
4
5
151–153 [48]
198–200 [48]
122–123 [47]
160–162 [47]
127-129 [47]
–
6
7
5g
5h
5i
8
p-Br
9
p-OCH3
o-CH3
p-CH3
p-NO2
p-CH3
10
11
12
13
5j
5k
5l
140–142 [48]
143–145 [48]
–
5m
Table 4 I2-promoted preparation of 3-aroylpyrrolo[1,2-a]quinolinecarboxylates 7a–7m
R1
CO2
R1
CO2
R
r
R2
I2 DM
SO
t 2 h
,
,
,
+
N
N
I
R2
O
O
6a-6f
2a-2c
7a-7m
R
Entry
R
R1
R2
Product
Yield/%
M.p./°C
Lit. m.p./°C
1
H
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
CO2CH3
CO2CH3
H
7a
7b
7c
7d
7e
7f
67
59
67
64
59
68
77
66
63
67
56
70
68
205.3–206.3
202.9–204.1
198.7–199.6
201.5–202.9
193.4–194.8
245.7–247.1
162.5–164.0
155.2–157.7
167.7–169.1
166.4–167.9
101.2–102.9
196.3–196.8
[200
200–203 [47]
2
p-Br
215–217 [50]
3
p-OCH3
o-CH3
p-CH3
p-NO2
H
–
4
CO2CH3
CO2CH3
CO2CH3
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
H
–
5
190–194 [48]
6
–
7
7g
7h
7i
160–162 [47]
8
p-Br
151–153 [48]
9
p-OCH3
o-CH3
p-CH3
p-NO2
p-Br
165–167 [47]
10
11
12
13
7j
–
7k
7l
–
194–195 [47]
–
7m
123

Iodine-promoted synthesis of acylindolizine derivatives
Fig. 3 ORTEP diagram of compound 5d. Displacement ellipsoids
are drawn at 30 % probability level
Fig. 1 ORTEP diagram of compound 3j. Displacement ellipsoids are
drawn at 30 % probability level
Fig. 4 ORTEP diagram of compound 7k. Displacement ellipsoids
are drawn at 30 % probability level
Fig. 2 ORTEP diagram of compound 5j. Displacement ellipsoids are
drawn at 30 % probability level
photoelectrically significant compounds. As this acylindoli-
undergoes nucleophilic addition to the pyridinium ring to
give an intermediate dihydropyrrole ring, which is fol-
lowed by iodine-prompted aromatization to yield the
acylindolizinecarboxylate.
zinecarboxylate-forming
protocol
requires
only
commercially available materials, mild conditions, and
operationally trivial reaction protocols, we anticipate that this
method will be widely used in the synthesis of natural alka-
loids andmany biologically relevant molecules. Further work
on the utilization and extension of the scope of the method-
ology is currently under investigation in our laboratory.
Conclusions
We have demonstrated a facile and efficient synthesis of
acylindolizinecarboxylate derivatives via 1,3-dipolar cyclo-
addition of pyridinium, isoquinolinium, or quinolinium with
acetylenecarboxylates and subsequent aromatization in the
presence of molecular iodine for the generation of a wide
range of structurally interesting, pharmacologically and
Experimental
All melting points were determined on a Yanaco melting
point apparatus. IR spectra were recorded on a Nicolet FT-
IR 5DX spectrometer. The 1H NMR (600 MHz) and
123

J. Liu et al.
Scheme 1
R
R
R
R
N
N
N
I2
N
I
I
I
I
H
I2
O
I2
O
O
I2
O
R1
R
CO2
R
R
N
-
HI
N
N
R1
CO2
R1
CO2
R2
R2
R2
O
I2
O
O
I2
N
N
R1
CO2
R
R1
CO2
R
O
R2
O
R2
13C NMR (150 MHz) spectra were recorded on a Bruker
AV-600 spectrometer with TMS as the internal reference in
CDCl3 solutions. The J values are given in Hertz. Only
discrete or characteristic signals for the 1H NMR are
reported. The MS spectra were obtained on a ZAB-HS
mass spectrometer at 70 eV. X-ray crystallographic ana-
thiosulfate, 2 9 15 cm3 water, and 15 cm3 brine, and dried
over Na2SO4. The solvent was removed to give a solid,
which was purified by chromatography (silica gel, 20 %
EtOAc in petroleum ether (PE) (60–90 °C)) to yield the
desired products 3a–3n.
Dimethyl 3-(o-methylbenzoyl)indolizine-1,2-dicarboxylate
lysis was performed with
a
Smart-1000 CCD
(3d, C20H17NO5)
diffractometer using monochromatic Mo KR radiation
˚
1
M.p.: 168.1–169.2 °C (PE/EtOAc); H NMR (600 MHz,
(k = 0.71073 A) and integrated with the SAINT-Plus
CDCl3): d = 9.92 (d, J = 7.1 Hz, 1H), 8.34 (d,
J = 8.9 Hz, 1H), 7.47–7.43 (m, 1H), 7.29 (t, J = 7.5 Hz,
1H), 7.22 (d, J = 7.4 Hz, 1H), 7.18–7.10 (m, 3H), 3.78 (s,
3H), 3.20 (s, 3H), 2.28 (s, 3H) ppm; 13C NMR (150 MHz,
CDCl3): d = 187.9, 165.0, 163.2, 139.2, 138.4, 136.6,
132.9, 130.3, 130.1, 129.1, 128.6, 128.1, 124.9, 120.6,
119.9, 116.4, 104.2, 52.3, 51.6, 19.2 ppm; IR (KBr):
program. All calculations were performed with programs
from the SHELXTL crystallographic software package.
The elemental analyses were performed in a Perkin-Elmer
240C instrument. Flash chromatography was performed on
silica gel (230–400 mesh) eluting with ethyl acetate–hex-
ane mixtures. All reactions were monitored by thin-layer
chromatography (TLC). All reagents and solvents were
purchased from commercial sources and purified by stan-
dard methods before used.
ꢀ
m = 2,953, 1,732, 1,705, 1,608, 1,505, 1,456, 1,378, 1,316,
1,253, 1,210, 1,092, 907, 759, 625 cm-1; MS (EI): m/z
(%) = 350.03 ([M-1]?, 100).
I2-promoted preparation of 3-
Diethyl 3-(o-methylbenzoyl)indolizine-1,2-dicarboxylate
aroylindolizinecarboxylates 3a–3n
(3j, C22H21NO5)
1
M.p.: 152.6–153.8 °C (PE/EtOAc); H NMR (600 MHz,
Typical procedure: a solution of N-(aroylmethyl)pyridini-
um iodide or N-(cyanomethyl)pyridinium chloride (1a–1g,
5 mmol), acetylenecarboxylate (2a–2c, 5 mmol), and
0.63 g molecular iodine (2.5 mmol) in 10 cm3 DMSO was
stirred at room temperature for 2 h (monitored by TLC). It
was then poured into 30 cm3 ice–water. The mixture was
extracted with dichloromethane (2 9 20 cm3) and the
combined extracts were washed with 15 cm3 20 % sodium
CDCl3): d = 9.99 (d, J = 7.1 Hz, 1H), 8.45 (d,
J = 8.9 Hz, 1H), 7.55–7.48 (m, 1H), 7.36 (t, J = 7.5 Hz,
1H), 7.32 (d, J = 7.5 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H),
7.22 (t, J = 7.5 Hz, 1H), 7.16 (t, J = 6.9 Hz, 1H), 4.32 (q,
J = 7.1 Hz, 2H), 3.58 (q, J = 7.1 Hz, 2H), 2.37 (s, 3H),
1.32 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.2 Hz, 3H) ppm;
13C NMR (150 MHz, CDCl3): d = 187.9, 164.7, 162.8,
139.3, 138.7, 136.6, 133.0, 130.3, 130.1, 129.1, 128.5,
123

Iodine-promoted synthesis of acylindolizine derivatives
128.1, 124.8, 120.4, 119.9, 116.3, 104.4, 61.7, 60.4, 19.3,
ꢀ
J = 7.4 Hz, 1H), 7.76 (s, 1H), 7.71 (t, J = 7.4 Hz, 3H),
7.60 (d, J = 7.1 Hz, 2H), 7.27 (d, J = 7.6 Hz, 2H), 7.20
(d, J = 7.5 Hz, 1H), 3.85 (s, 3H), 2.40 (s, 3H) ppm; 13C
NMR (150 MHz, CDCl3): d = 184.8, 164.0, 141.4, 136.0,
135.9, 129.5, 128.7, 128.4, 128.2, 128.0, 127.0, 126.7,
125.7, 124.1, 123.6, 122.5, 114.4, 108.6, 50.7, 20.6 ppm;
IR (KBr): mꢀ = 3,146, 2,942, 1,697, 1,614, 1,454, 1,360,
1,334, 1,186, 1,082, 924, 749 cm-1; MS (EI): m/
z (%) = 344.43 ([M?1]?, 100).
14.2, 13.5 ppm; IR (KBr): m = 3,150, 2,988, 1,729, 1,706,
1,616, 1,504, 1,452, 1,316, 1,199, 1,152, 1,117, 1,086, 865,
752, 628 cm-1; MS (EI): m/z (%) = 380.37 ([M?1]?, 60).
Methyl 3-(p-nitrobenzoyl)indolizine-1-dicarboxylate
(3m, C17H12N2O5)
1
M.p.: 179.6–180.4 °C (PE/EtOAc); H NMR (600 MHz,
CDCl3): d = 9.91 (d, J = 6.9 Hz, 1H), 8.36 (d,
J = 8.9 Hz, 1H), 8.30 (d, J = 8.3 Hz, 2H), 7.88 (d,
J = 8.3 Hz, 2H), 7.67 (s, 1H), 7.47 (t, J = 7.9 Hz, 1H),
7.10 (t, J = 6.9 Hz, 1H), 3.83 (s, 3H) ppm; 13C NMR
(150 MHz, CDCl3): d = 181.9, 163.0, 148.3, 144.2, 139.3,
128.7, 128.3, 128.2, 127.6, 122.6, 120.9, 118.6, 115.0,
Methyl 3-(p-methoxybenzoyl)pyrrolo[1,2-a]isoquinoline-1-
carboxylate (7c, C22H17NO4)
1
M.p.: 198.7–199.6 °C (PE/EtOAc); H NMR (600 MHz,
CDCl3): d = 8.25 (d, J = 9.3 Hz, 1H), 8.03 (d, J = 8.3 Hz,
2H), 7.95 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.59
(d, J = 9.3 Hz, 1H), 7.54 (s, 1H), 7.48 (t, J = 7.8 Hz, 1H),
7.40 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 8.3 Hz, 2H), 3.86 (s,
3H), 3.83 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3):
d = 183.3, 163.6, 162.7, 138.8, 132.2, 131.5, 129.9, 127.9,
127.7, 127.5, 127.2, 127.1, 124.3, 124.1, 119.1, 116.7, 112.8,
ꢀ
105.8, 50.4 ppm; IR (KBr): m = 3,107, 1,708, 1,622, 1,512,
1,347, 1,208, 845, 682 cm-1; MS (EI): m/z (%) = 325.30
([M?1]?, 100).
Dimethyl 3-(o-methylbenzoyl)pyrrolo[2,1-a]isoquinoline-
1,2-dicarboxylate (5d, C24H19NO5)
1
M.p.: 186.2–197.6 °C (PE/EtOAc); H NMR (600 MHz,
ꢀ
106.1, 54.6, 50.3 ppm; IR (KBr): m = 2,948, 2,834, 1,703,
CDCl3): d = 9.32 (d, J = 7.4 Hz, 1H), 9.05 (d,
J = 7.8 Hz, 1H), 7.68 (d, J = 6.5 Hz, 1H), 7.60–7.49
(m, 2H), 7.30 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 7.5 Hz,
1H), 7.20 (dd, J = 11.1, 5.2 Hz, 2H), 7.12 (t, J = 7.5 Hz,
1H), 3.81 (s, 3H), 3.16 (s, 3H), 2.37 (s, 3H) ppm; 13C NMR
(150 MHz, CDCl3): d = 187.4, 164.0, 163.9, 138.4, 136.5,
132.8, 129.7, 129.6, 129.4, 129.1, 128.3, 127.7, 127.2,
126.0, 125.5, 124.0, 123.2, 123.1, 121.5, 115.3, 108.2,
1,630, 1,605, 1,548, 1,230, 1,084, 815, 748 cm-1; MS (EI):
m/z (%) = 360.05 ([M?1]?, 100).
Dimethyl 3-(o-methylbenzoyl)pyrrolo[1,2-a]quinoline-1,2-
dicarboxylate (7d, C24H19NO5)
1
M.p.: 201.5–202.9 °C (PE/EtOAc); H NMR (600 MHz,
CDCl3): d = 8.26 (d, J = 9.4 Hz, 1H), 7.83 (d,
J = 8.5 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.70 (d,
J = 7.6 Hz, 1H), 7.66 (d, J = 9.4 Hz, 1H), 7.48 (d,
J = 7.5 Hz, 3H), 7.33 (d, J = 7.6 Hz, 1H), 7.25 (t,
J = 7.9 Hz, 1H), 3.87 (s, 3H), 3.35 (s, 3H), 2.57 (s, 3H)
ppm; 13C NMR (150 MHz, CDCl3): d = 187.9, 165.3,
163.4, 139.9, 137.9, 137.4, 132.6, 132.3, 131.5, 131.0,
130.3, 129.1, 128.9, 128.8, 127.4, 125.8, 125.3, 119.4,
ꢀ
51.3, 51.0, 18.5 ppm; IR (KBr): m = 2,952, 1,730, 1,710,
1,602, 1,571, 1,504, 1,361, 1,259, 1,219, 1,171, 1,103,
1,026, 900, 785, 567 cm-1; MS (EI): m/z (%) = 402.23
([M?1]?, 100).
Diethyl
3-(o-methylbenzoyl)pyrrolo[2,1-a]isoquinoline-
1,2-dicarboxylate (5j, C26H23NO5)
ꢀ
117.7, 105.3, 52.2, 51.7, 20.4 ppm; IR (KBr): m = 2,949,
1
M.p.: 128.1–130.2 °C (PE/EtOAc); H NMR (600 MHz,
CDCl3): d = 9.32 (d, J = 7.5 Hz, 1H), 9.07 (d,
J = 7.6 Hz, 1H), 7.67 (d, J = 7.0 Hz, 1H), 7.61–7.50
(m, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.19 (dd, J = 12.9,
7.3 Hz, 2H), 7.13 (t, J = 7.5 Hz, 1H), 4.30 (q, J = 7.1 Hz,
2H), 3.48 (q, J = 7.0 Hz, 2H), 2.39 (s, 3H), 1.25 (t,
J = 7.1 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H) ppm; 13C NMR
(150 MHz, CDCl3): d = 187.3, 163.6, 138.4, 136.6, 132.8,
129.8, 129.7, 129.6, 129.1, 128.3, 127.9, 127.0, 126.0,
125.6, 124.0, 123.3, 123.2, 121.3, 115.1, 108.5, 60.5, 60.3,
1,751, 1,702, 1,639, 1,482, 1,443, 1,199, 1,091, 815, 743,
642, 619 cm-1; MS (EI): m/z (%) = 402.11 ([M?1]?,
100).
Dimethyl 3-(p-nitrobenzoyl)pyrrolo[1,2-a]quinoline-1,2-
dicarboxylate (7f, C23H16N2O7)
1
M.p.: 245.7–247.1 °C (PE/EtOAc); H NMR (600 MHz,
CDCl3): d = 8.25 (d, J = 8.5 Hz, 2H), 8.21 (d,
J = 9.4 Hz, 1H), 8.04 (d, J = 8.5 Hz, 2H), 7.76 (d,
J = 7.9 Hz, 1H), 7.62 (d, J = 9.4 Hz, 1H), 7.51 (d,
J = 8.0 Hz, 1H), 7.40 (p, J = 6.9 Hz, 2H), 3.84 (s, 3H),
3.41 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3):
d = 184.0, 164.0, 162.2, 149.5, 141.4, 136.8, 131.3,
129.7, 128.7, 128.4, 128.2, 127.9, 125.0, 124.3, 124.2,
122.7, 118.0, 116.8, 105.0, 51.5, 50.9 ppm; IR (KBr):
ꢀ
18.7, 12.9, 12.5 ppm; IR (KBr): m = 3,138, 3,069, 2,980,
1,719, 1,623, 1,507, 1,472, 1,397, 1,350, 1,223, 1,190,
1,105, 921, 790, 739, 651 cm-1
z (%) = 430.55 ([M?1]?, 72).
;
MS (EI): m/
Methyl 3-(p-methylbenzoyl)pyrrolo[2,1-a]isoquinoline-1-
ꢀ
m = 2,950, 1,719, 1,699, 1,647, 1,534, 1,484, 1,445, 1,346,
carboxylate (5m, C22H17NO3)
1,235, 1,096, 764, 651 cm-1; MS (EI): m/z (%) = 433.24
([M?1]?, 100).
1
M.p.: 169.3–170.4 °C (PE/EtOAc); H NMR (600 MHz,
CDCl3): d = 9.79 (d, J = 7.8 Hz, 1H), 9.56 (d,
123

J. Liu et al.
Diethyl 3-(o-methylbenzoyl)pyrrolo[1,2-a]quinoline-1,2-
dicarboxylate (7j, C26H23NO5)
deposition numbers CCDC 922016–922019. These data
can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax (?44)-1223-
336033, e-mail: deposit@ccdc.cam.ac.uk).
Yellow solid; m.p.: 166.4–167.9 °C (PE/EtOAc); 1H NMR
(600 MHz, CDCl3): d = 8.23 (d, J = 9.4 Hz, 1H), 7.75 (d,
J = 8.4 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.66 (d,
J = 7.4 Hz, 1H), 7.58 (d, J = 9.4 Hz, 1H), 7.45–7.34
(m, 3H), 7.25 (d, J = 7.6 Hz, 1H), 7.19–7.14 (m, 1H), 4.26
(q, J = 7.2 Hz, 2H), 3.65 (q, J = 7.2 Hz, 2H), 2.50 (s,
3H), 1.26 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H)
ppm; 13C NMR (150 MHz, CDCl3): d = 186.9, 164.0,
162.0, 138.9, 137.1, 136.4, 131.6, 131.2, 130.4, 130.1,
129.4, 128.0, 127.8, 127.7, 126.1, 124.6, 124.3, 124.2,
118.4, 116.7, 104.5, 60.5, 59.4, 19.4, 13.2, 12.6 ppm; IR
Acknowledgments Financial support of this research by the
National Natural Science Foundation of China (NNSFC 21173181) is
gratefully acknowledged by the authors. A Project Funded by the
Priority Academic Program Development of Jiangsu Higher Educa-
tion Institutions.
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dicarboxylate (7k, C26H23NO5)
1
M.p.: 101.2–102.9 °C (PE/EtOAc); H NMR (600 MHz,
CDCl3): d = 8.18 (d, J = 9.4, 1H), 7.82 (d, J = 8.1 Hz,
2H), 7.71–7.66 (m, 1H), 7.56 (dd, J = 7.6, 6.6 Hz, 1H),
7.49 (d, J = 9.5 Hz, 1H), 7.36–7.29 (m, 2H), 7.21 (d,
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J = 7.2 Hz, 2H), 2.42 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H),
1.01 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (150 MHz,
CDCl3): d = 186.6, 163.7, 162.3, 144.0, 135.8, 134.1,
131.5, 129.2, 128.3, 128.1, 127.8, 126.5, 126.3, 125.3,
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ꢀ
20.7, 13.2, 12.8, 12.6 ppm; IR (KBr): m = 2,976, 2,924,
1,739, 1,699, 1,635, 1,602, 1,440, 1,258, 1,207, 1,166,
1,091, 747, 495 cm-1; MS (EI): m/z (%) = 430.38
([M?1]?, 100).
Methyl 3-(p-bromobenzoyl)pyrrolo[1,2-a]quinoline-1-car-
boxylate (7m, C21H14BrNO3)
1
M.p.:[200 °C (PE/EtOAc); H NMR (600 MHz, CDCl3):
d = 8.26 (d, J = 9.3 Hz, 1H), 7.98 (d, J = 8.7 Hz, 1H),
7.88 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 7.8 Hz, 1H), 7.67–
7.59 (m, 3H), 7.54 (s, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.43
(t, J = 7.4 Hz, 1H), 3.83 (s, 3H) ppm; 13C NMR
(150 MHz, CDCl3): d = 182.6, 163.3, 139.5, 136.2,
132.1, 130.8, 130.6, 128.7, 128.3, 127.9, 127.8, 126.9,
126.7, 124.6, 124.1, 119.2, 116.6, 106.5, 50.4 ppm; IR
ꢀ
(KBr): m = 2,944, 1,708, 1,638, 1,546, 1,235, 1,085, 815,
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