A simple and effective approach to the synthesis of isoquinoline derivatives under solvent-free conditions

Article abstract of DOI:10.2174/138620712800563909

An efficient synthesis of dialkyl pyrrolo[2,1-a]isoquinoline-2,3- dicarboxylates, pyrrolo[1,2-a]quinoline-1,2- dicarboxylates and indolizines is described via one-pot reactions of isoquinoline, quinoline or pyridine and phenacyl bromids with dialkyl acetylenedicarboxylates or diaryloylacetylene under solvent-free conditions at 50°C. The mild reaction conditions and high yields of the products exhibit the good synthetic advantage of these methods.

Full text of DOI:10.2174/138620712800563909

Combinatorial Chemistry & High Throughput Screening, 2012, 15, 503-508
503
A Simple and Effective Approach to the Synthesis of Isoquinoline
Derivatives Under Solvent-Free Conditions
Zinatossadat Hossaini*,1, Faramarz Rostami-Charati2, Somayeh Firoziyan1, Maryam Sabbaghan3 and
Mohammad A. Khalilzadeh1
1Department of Chemistry, Qaemshahr Branch, Islamic Azad University, P.O. Box 163, Qaemshahr, Iran
2Department of Chemistry, Facualty of Science, Gonbad Kavous University, P.O. Box 163, Gonbad, Iran
3Faculty of science, Chemistry Department, Shahid Rajaee Teacher training University, P.O. Box 16785-163, Tehran,
Iran
Abstract: An efficient synthesis of dialkyl pyrrolo[2,1-a]isoquinoline-2,3-dicarboxylates, pyrrolo[1,2-a]quinoline-1,2-
dicarboxylates and indolizines is described via one-pot reactions of isoquinoline, quinoline or pyridine and phenacyl
bromids with dialkyl acetylenedicarboxylates or diaryloylacetylene under solvent-free conditions at 50oC. The mild
reaction conditions and high yields of the products exhibit the good synthetic advantage of these methods.
COR
O
N
Br
COR
Solvent-free
50 oC, 12 h
+
+
R'
N
R'
COR
O
COR
Keywords: Indolizine, isoquinoline, one-pot reactions, phenacyl bromides, solvent-free.
1. INTRODUCTION
solvent-free conditions at 50oC. The products were separated
by column chromatography and characterized on the basis of
their elemental analyses and their IR, 1H NMR and 13C NMR
spectra. The mass spectrum of 4a displayed the molecular
ion peak (M+) at m/z = 417, which confirmed the 1:1:1
adduct of isoquinoline, dimethyl acetylenedicarboxylate
Multicomponent reactions (MCRs), with three or more
reactants merge in a one-pot method to provide a single product,
have gradually become more popular during the last decade [1-
7]. They are efficiently and environmentally valuable because
multi-step syntheses generate large amounts of waste mainly
due to complex isolation procedures often including costly,
toxic, and unsafe solvents after each step. Bridgehead nitrogen
heterocycles are of fascination because they compose a main
class of natural and non-natural products, many of which
display valuable biological activity [8-10]. The isoquinoline
frame is set up in a large number of naturally occurring and
synthetic biologically active heterocyclic compounds [9]. Thus,
as part of a related study on multicomponent reactions, we wish
to report a simple synthesis of functionalized pyrrolo[2,1-
a]isoquinolines, pyrrolo[1,2-a]quinoline and indolizine [11].
The reaction of isoquinoline 1 and dialkyl acetylenedicarboxy-
late 2 in the presence of phenacyl bromides 3 proceeds
smoothly under solvent-free conditions at 50oC to produce
pyrrolo[2,1-a]isoquinoline 4 in excellent yields (Scheme 1).
1
(DMAD) and 4-methoxy phenacyl bromid. The H NMR
spectrum of 4a showed three methoxy groups (ꢀ = 3.62, 3.93
and 3.98), along with multiplets at ꢀ = 6.52-8.22 for the
aromatic moiety. The 13C NMR spectrum of 4a showed 24
different resonances in agreement with the proposed
structure. Although we have not established the mechanism
of the reaction between isoquinoline and activated acetylenes
in the presence of phenacyl bromids in an experimental
manner, a possible explanation is proposed in Scheme 2. The
first step may involve addition of isoquinoline to the
activated acetylenic ester and formation of the 1:1 adducts 5.
Subsequent nucleophilic attack of 5 to phenacyl bromides
yields the 1:1:1 adducts 6, which is converted to 4 by
elimination of hydrogen.
Under similar conditions, reaction of quinoline 9 and
pyridin 11 with dialkyl acetylenedicarboxylates in the
presence of phenacyl bromids proceeds smoothly at 50oC to
produce quinoline derivatives 10a-b and pyridine derivatives
12a-b in 87-93% yields (Scheme 3).
2. RESULTS AND DISCUSSION
Isoquinoline reacts with the electron deficient acetylenic
compound 2 in the presence of phenacyl bromids under
3. CONCLUSION
*Address correspondence to this author at the Department of Chemistry,
Qaemshahr Branch, Islamic Azad University, P.O. Box 163, Qaemshahr,
Iran; Tel: +981232145140; Fax: +981232211647;
In conclusion, we have developed a convenient and one-
pot method for preparing stabilized pyrrolo[2,1-
a]isoquinolines, pyrrolo[1,2-a]quinolines and indolizines.
E-mail: zshossaini@yahoo.com
1875-5402/12 $58.00+.00
© 2012 Bentham Science Publishers

504 Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 6
Hossaini et al.
COR
O
N
Br
COR
Solvent-free
50 oC, 12 h
+
+
R'
N
R'
COR
COR
O
1
2
3
4
Yield (%) of 4
2, 3, 4
R
R'
a
b
c
OMe
OEt
MeO
MeO
90
92
87
O-i-pro
OtBt
MeO
MeO
MeO
MeO
d
e
85
90
93
C6H5
f
4-CH3-C6H4
OMe
g
89
Br
Br
Br
Br
OEt
h
i
85
87
90
O-i-pro
OtBt
j
C6H5
Br
83
83
k
l
4-CH3-C6H4 Br
Scheme 1. Reactions of isoquinoline and dialkyl acetylenedicarboxylate in the presence of phenacyl bromides.
_
Br
+
3
N
1 + 2
COR
COR
+
N
O
COR
COR
Ar
_
5
6
+
-HBr
-H2
N
N
4
COR
_
O
COR
Ar
COR
Ar
COR
O
8
7
Scheme 2. Possible mechanism for the formation of compound 4.
1
The present method carries the advantage that these reactions
are performed under solvent-free conditions and the
substrates can be reacted without any prior activation or
modification. The simplicity of the present procedure makes
it an interesting alternative to complex multistep approaches.
The procedure described here provides an acceptable one-pot
method for the preparation of functionalized pyrrolo [2,1-
a]isoquinolines, pyrrolo[1,2-a]quinoline and indolizine.
ted. H NMR and 13C NMR spectra were obtained with a
Bruker FT-500 spectrometer in chloroform-d1, and
tetramethylsilane (TMS) was used as an internal standard.
Mass spectra were recorded with a Finnigan Mat TSQ-70
spectrometer. Infrared (IR) spectra were acquired on a
Nicollet Magna 550-FT spectrometer. Elemental analyses
were carried out with
apparatus. The results of elemental analyses (C, H, N) were
within 0.4% of the calculated values.
a Perkin-Elmer model 240-C
MATERIALS AND METHODS
General Procedure for Preparation of Compounds 4a-l,
10 and 12
Dibenzoylacetylene and 4,4'-dimethylphenoylacetylen
were prepared by a known procedure [12, 13]. Other
chemicals used in this work were purchased from Fluka and
used without further purification. Melting points were
measured on a Kofler hot stage apparatus and are uncorrec-
A mixture of phenacyl bromides 3 (2 mmol) and
activated acetylenes 2 (2 mmol) was warmed about 50°C.
Then, isoquinoline 1, quinoline 9 or pyridine 11 (2 mmol)

Synthesis of Isoquinoline Derivatives
Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 6 505
O
CO2Me
Br
Solvent-free
50 oC, 12 h
O
+
+
N
N
R
CO2Me
MeO2C
R
CO2Me
10
9
2
3
Yield (%) of 10
R
3, 10
MeO
Br
a
90
92
b
O
CO2R
O
Br
N
Solvent-free
50 oC, 12 h
+
+
N
MeO
CO2R
RO2C
OMe
CO2R
11
12
2
3
Yield (%) of 12
2, 12
R
a
Me
Et
93
87
b
Scheme 3. Reactions of quinoline or pyridine and dialkyl acetylenedicarboxylate in the presence of phenacyl bromides.
was added slowly. The reaction mixture was stirred for 12 h
at 50°C, and then poured into 15 mL of water. The resulting
precipitate was separated by filtration and using EtOH to
afford the pure title compounds.
5.86 (1 H, d, 3JHH = 7.6 Hz, CH), 6.52 (1 H, d, 3JHH = 7.4 Hz,
CH), 6.76 (1 H, d, JHH = 7.4 Hz, CH), 7.02-7.06 (4 H, m, 4
3
3
3
CH), 7.19 (2 H, t, JHH = 7.5 Hz, 2 CH), 8.23 (1 H, d, JHH
=
7.6 Hz, CH) ppm. 13C NMR (125.7 MHz, CDCl3): ꢀ = 13.8
(Me), 14.0 (Me), 55.6 (MeO), 62.7 (CH2O), 66.4 (CH2O),
105.7 (C), 108.6 (CH), 113.8 (C), 113.9 (2 CH), 123.6 (CH),
124.2 (CH), 124.7 (CH), 126.8 (CH), 128.0 (CH), 130.2 (C),
130.5 (C), 131.4 (2 CH), 131.5 (2 C), 132.5 (C), 161.2
(C=O), 163.7 (C=O), 164.0 (C), 199.0 (C=O) ppm. Anal.
Calcd for C26H23NO6 (445.47): C, 70.10; H, 5.20; N, 3.14.
Found: C, 69.98; H, 5.10; N, 3.04 %.
Dimethyl 1-(4-methoxybenzoyl)pyrrolo[2,1-a]isoquinoline-
2,3-dicarboxylate (4a)
Pale yellow crystals, yield: 0.75 g (90%), m.p. 112-
114°C. IR (KBr): ꢀ = 1729, 1713, 1697 and 1534 cm-1.1H
NMR (500 MHz, CDCl3): 3.62 (MeO), 3.93 (3 H, s, MeO),
3.98 (3 H, s, MeO), 6.52 (1 H, d, 3JHH = 7.5 Hz, CH), 6.75 (1
3
3
H, d, JHH = 7.4 Hz, CH), 6.93 (1 H, d, JHH = 7.5 Hz, CH),
7.00-7.07 (4 H, m, 4 CH), 7.13-7.20 (2 H, m, 2 CH), 8.22 (1
Di(iso-propyl) 1-(4-methoxybenzoyl)pyrrolo[2,1-a]isoquin-
oline-2,3-dicarboxylate (4c)
3
H, d, JHH = 7.8 Hz, CH) ppm. 13C NMR (125.7 MHz,
CDCl3): ꢀ = 52.3 (MeO), 53.3 (MeO), 53.8 (MeO), 105.7
(C), 108.9 (CH), 113.8 (CH), 113.9 (2 CH), 115.4 (C), 123.6
(CH), 124.7 (CH), 126.6 (C), 126.9 (CH), 128.0 (CH), 130.1
(C), 130.5 (C), 131.3 (2 CH), 131.5 (2 C), 160.6 (C=O),
163.9 (C), 164.2 (C=O), 192.3 (C=O) ppm. MS (EI, 70 eV):
m/z (%) = 417 (M+, 20), 386 (68), 310 (100), 107 (100), 31
(84). Anal. Calcd for C24H19NO6 (417.42): C, 69.06; H, 4.59;
N, 3.36. Found: C, 68.97; H, 4.48; N, 3.27 %.
Yellow powder, yield: 0.82 g (87%), m.p. 137-139°C. IR
1
(KBr): ꢀ = 1739, 1714, 1705 and 1574 cm-1. H NMR (500
MHz, CDCl3): ꢁ = 1.35 (6 H, d, 3JHH = 6.7 Hz, 2 CH3), 1.42
(6 H, d, 3JHH = 6.7 Hz, 2 CH3), 3.90 (3 H, s, MeO), 5.18 (1 H,
m, CH), 5.42 (1 H, m, CH), 6.86 (1 H, d, 3JHH = 7.5 Hz, CH),
7.19 (1 H, d, 3JHH = 7.7 Hz, CH), 7.32 (2 H, d, 3JHH = 7.4 Hz,
3
3
2 CH), 7.53 (1 H, t, JHH = 7.4 Hz, CH), 7.62 (1 H, t, JHH
7.4 Hz, CH), 7.72 (1 H, d, JHH = 7.5 Hz, CH), 8.45 (2 H, d,
=
3
3JHH = 7.5 Hz, 2 CH), 9.25 (1 H, d, JHH = 7.7 Hz, CH)
3
ppm.13C NMR (125.7 MHz, CDCl3): ꢀ = 21.6 (2 CH3), 22.4
(2 CH3), 53.4 (MeO), 68.8 (CHMe2), 70.5 (CHMe2), 108.6
(C), 113.2 (C), 117.0 (2 CH), 119.6 (C), 124.2 (2 C), 124.5
(CH), 125.3 (CH), 126.4 (CH), 127.5 (2 CH), 128.4 (CH),
129.0 (C), 129.6 (2 CH), 130.1 (C), 132.6 (C), 163.2 (C=O),
163.7 (C=O), 189.8 (C=O) ppm. Anal. Calcd for C28H27NO6
Diethyl 1-(4-methoxybenzoyl)pyrrolo[2,1-a]isoquinoline-2,
3-dicarboxylate (4b)
Yellow powder, yield: 0.82 g (92%), m.p. 142-144°C. IR
1
(KBr): ꢀ = 1722, 1715, 1700 and 1579 cm-1. H NMR (500
MHz, CDCl3): ꢁ = 0.95 (3 H, t, 3JHH = 7.2 Hz, CH3), 1.40 (3
H, t, JHH = 7.2 Hz, CH3), 3.92 (3 H, s, MeO), 4.02 (2 H, q,
3
3
3JHH = 7.2 Hz, OCH2), 4.43 (2 H, q, JHH = 7.2 Hz, OCH2),

506 Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 6
Hossaini et al.
(473.52): C, 71.02; H, 5.75; N, 2.96. Found: C, 70.92; H,
5.67; N, 2.88 %.
(C=O), 193.6 (C=O) ppm. Anal. Calcd for C36H27NO4 (537.61):
C, 80.43; H, 5.06; N, 2.61. Found: C, 80.37; H, 4.89; N, 2.57%.
Di(tert-butyl) 1-(4-methoxybenzoyl)pyrrolo[2,1-a]isoquino-
line-2,3-dicarboxylate (4d)
Dimethyl 1-(4-bromobenzoyl)pyrrolo[2,1-a]isoquinoline-
2,3-dicarboxylate (4g)
Pale yellow crystal, yield: 0.85 g (85%), m.p. 190-192
°C. IR (KBr): ꢀ = 1736, 1715, 1710 and 1586 cm-1. 1H NMR
(500 MHz, CDCl3): ꢁ = 1.62 (9 H, s, 3 CH3), 1.73 (9 H, s, 3
CH3), 3.87 (3 H, s, MeO), 7.18 (2 H, d, 3JHH = 7.5 Hz, 2 CH),
7.32 (1 H, d, 3JHH = 7.6 Hz, CH), 7.52 (2 H, d, 3JHH = 7.7 Hz,
Pale yellow crystals, yield: 0.83 g (89%), m.p. 104-
106°C. IR (KBr): ꢀ = 1729, 1716, 1705 and 1657 cm-1.1H
NMR (500.13 MHz, CDCl3): ꢁ = 3.53 (3 H, s, CH3O), 3.98
(3 H, s, CH3O), 5.89 (1 H, d, 3JHH = 7.6 Hz, CH), 6.51 (1 H,
d, 3JHH = 7.2 Hz, CH), 6.68 (1 H, d, 3JHH = 7.2 Hz, CH), 7.02-
7.21 (3 H, m, 3 CH), 7.72 (2 H, d, 3JHH = 7.2 Hz, 2 CH), 8.10
2 CH), 7.74 (1 H, d, 3JHH = 7.2 Hz, CH), 7.75 (1 H, t, 3JHH
=
3
3
7.2 Hz, CH), 7.94 (1 H, t, JHH = 7.5 Hz, CH), 8.57 (1 H, d,
3JHH = 7.5 Hz, 1 CH), 9.22 (1 H, d, 3JHH = 7.7 Hz, CH) ppm.
13C NMR (125.7 MHz, CDCl3): ꢀ = 28.5 (3 CH3), 28.7 (3
CH3), 53.0 (MeO), 83.5 (CMe3), 84.2 (CMe3), 106.7 (C),
115.0 (C), 117.4 (2 CH), 120.18 (C), 124.5 (C), 125.0 (CH),
125.7 (CH), 127.5 (CH), 128.5 (CH), 129.5 (2 CH), 130.2
(C), 130.3 (2 CH), 131.8 (2 C), 132.4 (C), 164.0 (C=O),
164.7 (C=O), 190.2 (C=O) ppm. Anal. Calcd for C30H31NO6
(501.58): C, 71.84; H, 6.23; N, 2.79. Found: C, 71.75; H,
6.17; N, 2.68 %.
(2 H, d, JHH = 7.6 Hz, 2 CH) ppm. 13C NMR (125.7 MHz,
CDCl3): ꢀ = 53.4 (MeO), 53.9 (MeO), 105.3 (C), 109.1 (CH),
123.4 (CH), 124.0 (CH), 124.9 (CH), 127.1 (CH), 128.3
(CH), 129.0 (C), 130.2 (C), 130.4 (2 CH), 131.2 (C), 131.4
(C), 131.9 (C), 132.2 (2 CH), 135.8 (C), 145.7 (C), 161.5
(C=O), 164.0 (C=O), 193.4 (C=O) ppm. MS (EI, 70 eV): m/z
(%) = 466 (M+, 15), 435 (68), 312 (48), 129 (84), 154 (100),
31 (84). Anal. Calcd for C23H16BrNO5 (466.29): C, 59.25; H,
3.46; N, 3.00. Found: C, 59.18; H, 3.38; N, 2.94%.
Diethyl 1-(4-bromobenzoyl)pyrrolo[2,1-a]isoquinoline-2,3-
dicarboxylate (4h)
Dibenzoyl 1-(4-methoxybenzoyl)pyrrolo[2,1-a]isoquinoline-
2,3-dicarboxylate (4e)
Yellow powder, yield: 0.84 g (85%), m.p. 145-147°C. IR
(KBr): ꢀ = 1727, 1710, 1708 and 1630 cm-1. 1H NMR (500.13
MHz, CDCl3): ꢁ = 1.37 (3 H, t, 3JHH = 7.2 Hz, CH3), 1.45 (3 H,
t, 3JHH = 7.2 Hz, CH3), 4.42 (2 H, q, 3JHH = 7.2 Hz, OCH2), 4.46
(2 H, q, 3JHH = 7.2 Hz, OCH2), 6.31 (1 H, d, 3JHH = 7.6 Hz, CH),
7.03-7.05 (2 H, m, 2 CH), 7.19 (1 H, d, 3JHH = 7.2 Hz, CH), 7.41
(2 H, d, JHH = 7.2 Hz, 2 CH), 7.58 (2 H, d, JHH = 7.2 Hz, 2
CH), 7.61-7.65 (2 H, m, 2 CH) ppm. 13C NMR (125.7 MHz,
CDCl3): ꢀ = 14.1 (CH3), 14.2 (CH3), 62.5 (OCH2), 62.7 (OCH2),
105.3 (C), 109.1 (CH), 123.4 (CH), 124.0 (CH), 124.9 (CH),
127.1 (CH), 128.3 (CH), 129.0 (C), 130.2 (C), 130.4 (2 CH),
131.2 (C), 131.4 (C), 131.9 (C), 132.2 (2 CH), 135.8 (C), 145.7
(C), 161.5 (C=O), 164.0 (C=O), 191.5 (C=O) ppm. Anal. Calcd
for C25H20BrNO5 (494.29): C, 60.74; H, 4.08; N, 2.83. Found:
C, 60.67; H, 3.92; N, 2.76%.
Yellow powder, yield: 0.92 g (90%), m.p. 188-190°C. IR
1
(KBr): ꢀ = 1715, 1710, 1690 and 1548 cm-1. H NMR (500
3
MHz, CDCl3): ꢁ = 3.85 (3 H, s, MeO), 7.15 (2 H, d, JHH
=
3
7.6 Hz, CH ), 7.30 (2 H, d, JHH = 7.6 Hz, 2 CH), 7.38 (5 H,
m, 5 CH), 7.50 (1 H, d, 3JHH = 7.4 Hz, CH), 7.53 (1 H, t, 3JHH
= 7.4 Hz, CH), 7.62 (1 H, t, JHH = 7.2 Hz, CH), 7.64 (4 H,
3
3
3
m, 4 CH), 7.74 (1 H, d, 3JHH = 7.2 Hz, CH), 8.05 (1 H, t, 3JHH
3
= 7.9 Hz, CH), 8.12 (1 H, d, JHH = 7.9 Hz, CH), 9.24 (1 H,
d, 3JHH = 7.6 Hz, CH) ppm. 13C NMR (125.7 MHz, CDCl3): ꢀ
= 53.4 (MeO), 118.0 (2 CH), 120.5 (2 C), 121.2 (C), 122.5
(CH), 123.4 (CH), 124.5 (C), 125.6 (CH), 126.5 (CH), 128.4
(CH), 129.3 (2 CH), 129.5 (CH), 129.7 (2 CH), 130.6 (2
CH), 130.8 (C), 131.2 (2 CH), 131.5 (2 CH), 134.5 (CH),
134.8 (C ), 135.0 (CH), 137.5 (C), 139.0 (C), 139.5 (C),
142.4 (C), 189.8 (C=O), 192.2 (C=O), 193.8 (C=O) ppm.
MS (EI, 70 eV): m/z (%) = 509 (M+, 25), 380 (84), 129 (48),
107 (100), 77 (100). Anal. Calcd for C34H23NO4 (509.56): C,
80.14; H, 4.55; N, 2.75. Found: C, 80.04; H, 4.46; N, 2.68
%.
Di(iso-propyl)1-(4-bromobenzoyl)pyrrolo[2,1-a]isoquinoli-
ne-2,3-dicarboxylate (4i)
Yellow powder, yield: 0.91 g (87%), m.p. 136-138°C. IR
1
(KBr): ꢀ = 1717, 1712, 1710 and 1620 cm-1. H NMR (500
MHz, CDCl3): ꢁ = 1.36 (6 H, d, 3JHH = 7.0 Hz, 2 CH3), 1.45 (6
H, d, 3JHH = 7.0 Hz, 2 CH3), 5.23 (1 H, m, CH), 5.42 (1 H, m,
CH), 6.24 (1 H, d, 3JHH = 7.7 Hz, CH), 6.64 (1 H, d, 3JHH = 7.6
Hz, CH), 6.75 (1 H, d, 3JHH = 7.8 Hz, CH), 7.02-7.21 (3 H, m, 3
CH), 7.75 (2 H, d, 3JHH = 7.5 Hz, 2 CH), 8.12 (2 H, d, 3JHH = 7.6
Hz, 2 CH) ppm. 13C NMR (125.7 MHz, CDCl3): ꢀ = 21.5 (2
CH3), 22.6 (2 CH3), 69.2 (CHMe2), 71.4 (CHMe2), 108.7 (C),
111.4 (CH), 123.5 (CH), 124.4 (CH), 125.2 (CH), 127.5 (CH),
128.6 (CH), 129.2 (C), 130.4 (C), 130.8 (2 CH), 131.5 (C),
131.7 (C), 132.4 (C), 132.5 (2 CH), 136.0 (C), 145.6 (C), 162.5
(C=O), 164.3 (C=O), 193.7 (C=O) ppm. Anal. Calcd for
C27H24BrNO5 (522.39): C, 62.08; H, 4.63; N, 2.68. Found: C,
61.97; H, 4.58; N, 2.56%.
Di(4-methylbenzoyl)-1-(4-methoxybenzoyl)pyrrolo[2,1-a]is-
oquinoline-2,3-dicarboxylate (4f)
Yellow crystals, yield: 0.99 g (93%), m.p. 182-184°C. IR
(KBr): ꢀ = 1720, 1715, 1669 and 1587 cm-1. 1H NMR (500.13
MHz, CDCl3): ꢁ = 2.35 (3 H, s, Me), 2.37 (3 H, s, Me), 3.98 (3
3
H, s, MeO), 7.07(2 H, d, JHH = 7.5 Hz, 2 CH), 7.15 (1 H, d,
3JHH = 7.5 Hz, CH), 7.25 (1 H, t, 3JHH = 7.4 Hz, CH), 7.38 (2 H,
t, 3JHH = 7.3 Hz, 2 CH), 7.45 (2 H, d, 3JHH = 7.6 Hz, 2 CH ), 7.47
3
3
(2 H, d, JHH = 7.6 Hz, 2 CH), 7.62 (2 H, d, JHH = 7.6 Hz, 2
CH), 7.85 (2 H, d, 3JHH = 7.5 Hz, 2 CH), 8.15 (2 H, t, 3JHH = 7.9
Hz, 2 CH), 8.27 (1 H, d, 3JHH = 7.9 Hz, CH), 9.42 (1 H, d, 3JHH
=
7.5 Hz, CH) ppm.13C NMR (125.7 MHz, CDCl3): ꢀ = 21.5
(CH3), 22.0 (CH3), 52.8 (MeO), 117.2 (2 C), 120.0 (CH), 122.5
(CH), 124.2 (C), 125.0 (C), 125.7 (CH), 127.3 (2 CH), 128.6 (2
CH), 129.0 (CH), 130.4 (2 CH), 130.6 (C), 130.8 (2 CH), 131.0
(2 CH), 131.4 (C), 133.8 (2 CH), 135.6 (2 CH), 136.2 (C), 137.4
(C), 144.5 (C), 144.8 (2 C), 145.6 (C), 190.4 (C=O), 192.0
Di(tert-butyl) 1-(4-bromobenzoyl)pyrrolo[2,1-a]isoquinoli-
ne-2,3-dicarboxylate (4j)
Pale yellow crystals, yield: 0.99 g (90%), m.p. 191-
1
193°C. IR (KBr): ꢀ = 1710, 1700, 1697 and 1657 cm-1. H

Synthesis of Isoquinoline Derivatives
Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 6 507
NMR (500 MHz, CDCl3): ꢁ = 1.52 (9 H, s, 3 CH3), 1.68 (9
H, s, 3 CH3), 6.30 (1 H, d, JHH = 7.5 Hz, CH), 6.65 (1 H, d,
(1 H, d, 3JHH = 7.6 Hz, CH), 8.16 (1 H, d, 3JHH = 7.8 Hz, CH),
3
3
8.25 (1 H, d, JHH = 7.5 Hz, CH) ppm.13C NMR (125.7 MHz,
3JHH = 7.6 Hz, CH), 6.78 (1 H, d, JHH = 7.5 Hz, CH), 7.12-
CDCl3): ꢀ = 51.9 (MeO), 52.8 (MeO), 53.4 (MeO), 117.0 (2 C),
117.6 (2 CH), 119.7 (2 CH), 124.2 (C), 125.2 (2 CH), 126.5 (C),
129.0 (2 CH), 129.5 (CH), 129.8 (C), 130.2 (CH), 132.4 (C),
132.8 (C), 133.5 (C), 163.5 (C=O), 165.2 (C=O), 189.8 (C=O)
ppm. Anal. Calcd for C24H19NO6 (417.42): C, 69.06; H, 4.59; N,
3.36. Found: C, 68.95; H, 4.50; N, 3.25%.
3
7.25 (3 H, m, 3 CH), 7.82 (2 H, d, 3JHH = 7.6 Hz, 2 CH), 8.15
3
(2 H, d, JHH = 7.5 Hz, 2 CH) ppm.13C NMR (125.7 MHz,
CDCl3): ꢀ = 28.5 (3 CH3), 29.2 (3 CH3), 83.6 (CMe3), 84.4
(CMe3), 107.5 (C), 112.4 (CH), 122.8 (CH), 124.5 (CH),
125.6 (CH), 127.4 (CH), 128.5 (CH), 129.6 (C), 130.4 (C),
130.8 (2 CH), 131.7 (2 C), 132.2 (C), 132.6 (2 CH), 136.3
(C), 146.2 (C), 162.4 (C=O), 164.2 (C=O), 192.7 (C=O)
ppm. Anal. Calcd for C29H28BrNO5 (550.45): C, 63.28; H,
5.13; N, 2.54. Found: C, 63.17; H, 5.04; N, 2.48%.
Dimethyl 1-(4-bromobenzoyl)pyrrolo[2,1-a]quinoline-2,3-
dicarboxylate (10b)
1
Yellow powder, yield: 92%, m.p. 124-126°C. H NMR
(500.13 MHz, CDCl3): ꢁ = 3.82 (3 H, s, MeO), 3.87 (3 H, s,
MeO), 7.14 (2 H, d, 3JHH = 7.5 Hz, 2 CH), 7.36 (2 H, d, 3JHH
= 7.5 Hz, 2 CH), 7.47 (1 H, d, 3JHH = 7.5 Hz, CH), 7.52 (1 H,
Dibenzoyl 1-(4-bromobenzoyl)pyrrolo[2,1-a]isoquinoline-
2,3-dicarboxylate (4k)
3
3
Yellow powder, yield: 0.93 g (83%), m.p. 188-190°C. IR
(KBr): ꢀ = 1715, 1700, 1690 and 1659 cm-1. 1H NMR
(500.13 MHz, CDCl3): ꢁ = 7.18 (2 H, d, JHH = 7.5 Hz, 2
t, JHH = 7.6 Hz, CH), 7.58 (1 H, t, JHH = 7.6 Hz, CH), 7.65
(1 H, d, 3JHH = 7.6 Hz, CH), 8.07 (1 H, d, 3JHH = 7.8 Hz, CH),
8.17 (1 H, d, 3JHH = 7.8 Hz, CH) ppm.13C NMR (125.7 MHz,
CDCl3): ꢀ = 52.0 (MeO), 52.6 (MeO), 116.7 (2 C), 118.4 (2
CH), 120.2 (2 CH), 123.8 (C), 125.4 (2 CH), 125.8 (C),
128.3 (2 CH), 129.0 (CH), 130.1 (C), 130.5 (CH), 131.9 (C),
132.6 (C), 132.8 (C), 163.7 (C=O), 166.0 (C=O), 190.2
(C=O) ppm.
3
3
CH), 7.35 (2 H, d, JHH = 7.4 Hz, 2 CH), 7.42 (4 H, m, 4
3
CH), 7.53 (1 H, d, JHH = 7.5 Hz, CH), 7.60 (1 H, t, JHH
3
=
7.2 Hz, CH), 7.68 (1 H, t, 3JHH = 7.2 Hz, CH), 7.72 (4 H, m, 4
3
3
CH), 7.78 (1 H, d, JHH = 7.5 Hz, CH), 8.24 (2 H, t, JHH
=
7.8 Hz, 2 CH), 8.32 (1 H, d, 3JHH = 7.8 Hz, CH), 9.30 (1 H, d,
3JHH = 7.6 Hz, CH) ppm. 13C NMR (125.7 MHz, CDCl3): ꢀ =
117.8 (CH), 118.6 (CH), 120.3 (C), 120.8 (C), 123.4 (CH),
124.5 (C), 125.5 (CH), 126.7 (2 CH), 128.4 (CH), 129.3 (2
CH), 129.6 (2 CH), 130.3 (2 CH), 130.6 (2 CH), 131.0 (C),
131.5 (2 CH), 132.2 (CH), 134.2 (CH), 134.3 (2 C ), 134.7
(CH), 137.6 (2 C), 138.9 (C), 139.3 (C), 190.4 (C=O), 192.5
(C=O), 194.3 (C=O) ppm. Anal. Calcd for C33H20BrNO3
(558.43): C, 70.98; H, 3.61; N, 2.51. Found: C, 70.86; H,
3.54; N, 2.45%.
Dimethyl 1-(4-methoxybenzoyl)-2,3-indolizinedicarboxylate
(12a)
Yellow crystal, yield: 0.68 g (93%), m.p. 112-114°C.IR
(KBr): ꢀ = 1725, 1716, 1711 and 1642 cm-1.1H NMR (500
MHz, CDCl3): ꢁ = 3.87 (3 H, s, MeO), 3.90 (3 H, s, MeO),
3
3.93 (3 H, s, MeO), 7.14 (2 H, t, JHH = 7.5 Hz, 2 CH), 7.35
3
(2 H, d, JHH = 7.4 Hz, 2 CH), 7.46 (2 H, d, 3JHH = 7.8 Hz, 2
3
3
CH), 8.40 (1 H, d, JHH = 7.3 Hz, CH), 9.34 (1 H, d, JHH
=
7.5 Hz, CH) ppm.13C NMR (125.7 MHz, CDCl3): ꢀ = 52.3
(MeO), 52.8 (MeO), 53.0 (MeO), 113.8 (2 C), 117.4 (2 CH),
120.5 (C), 121.4 (CH), 126.4 (CH), 128.3 (2 CH), 129.4 (C),
130.2 (2 CH), 139.2 (2 C), 163.4 (C=O), 164.2 (C=O), 190.4
(C=O) ppm. Anal. Calcd for C20H17NO6 (367.36): C, 65.39;
H, 4.66; N, 3.81. Found: C, 65.28; H, 4.58; N, 3.75%.
Di(4-methylbenzoyl)-1-(4-bromobenzoyl)pyrrolo[2,1-a]iso-
quinoline-2,3-dicarboxylate (4l)
Yellow crystals, yield: 0.97 g (83%), m.p. 182-184°C. IR
1
(KBr): ꢀ = 1714, 1710, 1658 and 1624 cm-1. H NMR (500
MHz, CDCl3): ꢁ = 2.37 (3 H, s, Me), 2.42 (3 H, s, Me), 7.10
3
3
(2 H, d, JHH = 7.5 Hz, 2 CH), 7.27 (1 H, t, JHH = 7.6 Hz,
CH), 7.34 (1 H, t, 3JHH = 7.5 Hz, CH), 7.42 (1 H, t, 3JHH = 7.6
Hz, CH), 7.48 (2 H, d, JHH = 7.6 Hz, 2 CH ), 7.52 (2 H, d,
Diethyl 1-(4-methoxybenzoyl)-2,3-indolizinedicarboxylate
(12b)
3
3JHH = 7.8 Hz, 2 CH), 7.63 (2 H, d, JHH = 7.6 Hz, 2 CH),
3
1
Yellow powder, yield: 87%, m.p. 118-120°C. H NMR
3
3
3
(500 MHz, CDCl3): ꢁ = 1.35 (3 H, t, JHH = 7.3 Hz, CH3),
7.82 (2 H, d, JHH = 7.5 Hz, 2 CH), 8.12 (2 H, t, JHH = 7.9
Hz, 2 CH ), 8.21 (2 H, d, 3JHH = 7.9 Hz, 2 CH), 9.45 (1 H, d,
3JHH = 7.5 Hz, CH) ppm.13C NMR (125.7 MHz, CDCl3): ꢀ =
21.5 (CH3), 22.4 (CH3), 116.9 (2 C), 119.2 (CH), 122.4
(CH), 124.0 (C), 124.5 (C), 125.7 (2 CH), 126.4 (CH), 127.5
(CH), 128.6 (2 CH), 129.0 (2 CH), 129.2 (CH), 129.6 (C),
130.0 (CH), 130.5 (2 CH), 130.9 (C), 134.2 (2 CH), 135.6 (2
CH), 136.3 (C), 137.5 (C), 144.6 (C), 144.9 (2 C), 145.6 (C),
193.7 (C=O), 194.2 (C=O), 194.8 (C=O) ppm. Anal. Calcd
for C35H24BrNO3 (586.48): C, 71.68; H, 4.12; N, 2.39.
Found: C, 71.56; H, 4.00; N, 2.26%.
1.42 (3 H, t, 3JHH = 7.3 Hz, CH3), 3.87 (3 H, s, MeO), 4.38 (2
3
3
H, q, JHH = 7.2 Hz, OCH2), 4.45 (2 H, q, JHH = 7.3 Hz,
OCH2), 7.15 (2 H, t, 3JHH = 7.4 Hz, 2 CH), 7.38 (2 H, d, 3JHH
= 7.4 Hz, 2 CH), 7.52 (2 H, d, 3JHH = 7.6 Hz, 2 CH), 8.34 (1
3
3
H, d, JHH = 7.5 Hz, CH), 8.94 (1 H, d, JHH = 7.5 Hz, CH)
ppm.13C NMR (125.7 MHz, CDCl3): ꢀ = 13.7 (CH3), 14.2
(CH3), 52.8 (MeO), 62.6 (OCH2), 63.0 (OCH2), 114.0 (2 C),
116.8 (2 CH), 121.2 (C), 121.8 (CH), 125.7 (CH), 128.0 (2
CH), 129.6 (C), 130.4 (2 CH), 140.2 (2 C), 163.5 (C=O),
164.4 (C=O), 190.4 (C=O) ppm.
Dimethyl 1-(4-methoxybenzoyl)pyrrolo[2,1-a]quinoline-
2,3-dicarboxylate (10a)
ACKNOWLEDGEMENT
It would be acknowledged that this work was financially
supported by the Nation Elite Foundation.
Yellow powder, yield: 0.75 g (90%), m.p. 108-110°C. IR
(KBr): ꢀ = 1719, 1712, 1710 and 1635 cm-1.1H NMR (500.13
MHz, CDCl3): ꢁ = 3.85 (3 H, s, MeO), 3.90 (3 H, s, MeO), 3.95
(3 H, s, MeO), 7.19 (2 H, d, 3JHH = 7.6 Hz, 2 CH), 7.45 (2 H, d,
3JHH = 7.5 Hz, 2 CH), 7.52 (1 H, d, 3JHH = 7.5 Hz, CH), 7.60 (1
H, t, 3JHH = 7.8 Hz, CH), 7.65 (1 H, t, 3JHH = 7.6 Hz, CH), 7.82
CONFLICT OF INTEREST
Declared none.

508 Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 6
Hossaini et al.
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Received: October 7, 2011
Revised: December 14, 2011
Accepted: December 20, 2011