An efficient synthesis of pyrrolo[2,1-a]isoquinoline derivatives containing coumarin skeletons via a one-pot, three-component reaction

Article abstract of DOI:10.1007/s11164-015-1928-2

New dialkyl 3-(2-oxo-2H-3-chromenylcarbonyl)pyrrolo[2,1-a]isoquinoline-1,2-dicarboxylate derivatives were prepared by the reaction of 3-(2-bromoacetyl)coumarins, isoquinoline, and dialkyl acetylenedicarboxylates in the presence of triethylamine. This protocol has some advantages such as easy purification, easy performance, and good yields. The structures were confirmed spectroscopically (IR, ¹H- and ¹³C-NMR, and EI-MS) and by elemental analyses. A plausible mechanism for this reaction is proposed (Scheme 2).

Full text of DOI:10.1007/s11164-015-1928-2

Res Chem Intermed
DOI 10.1007/s11164-015-1928-2
An efficient synthesis of pyrrolo[2,1-a]isoquinoline
derivatives containing coumarin skeletons via a one-pot,
three-component reaction
•
Abdolali Alizadeh Rashid Ghanbaripour
Received: 21 November 2014 / Accepted: 12 January 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract New dialkyl 3-(2-oxo-2H-3-chromenylcarbonyl)pyrrolo[2,1-a]isoquino-
line-1,2-dicarboxylate derivatives were prepared by the reaction of 3-(2-bro-
moacetyl)coumarins, isoquinoline, and dialkyl acetylenedicarboxylates in the
presence of triethylamine. This protocol has some advantages such as easy purifica-
tion, easy performance, and good yields. The structures were confirmed spectro-
scopically (IR, 1H- and 13C-NMR, and EI-MS) and by elemental analyses. A plausible
mechanism for this reaction is proposed (Scheme 2).
Keywords 3-(2-Bromoacetyl)coumarin Á Dialkyl acetylenedicarboxylate Á
Pyrrolo[2,1-a]isoquinoline Á Salicylaldehyde
Introduction
Coumarin cores are one of the most important families of oxygen-containing
heterocyclic compounds. They are attractive and versatile molecules that are widely
present in microorganisms, animals, and especially in higher plants such as
Leguminosae, Thymelaeaceae, Apiaceae, Asteraceae, and Rutaceae [1]. Coumarins
have attracted attention due to their antiviral [2, 3], antitumor [4], inhibitor of HIV-1
protease [5], anticholinergic [6], and antipsychotic [7] properties. They have also
been used as optical brightening agents, tunable dye lasers, food additives, and in
fragrances [8, 9].
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-1928-
2) contains supplementary material, which is available to authorized users.
A. Alizadeh (&) Á R. Ghanbaripour
Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
e-mail: aalizadeh@modares.ac.ir
123

A. Alizadeh, R. Ghanbaripour
Among them, 3-substituted coumarins are an important class of compounds that
are found in some drugs and drug candidates, such as warfarin [10], novobiocin
[11], and carbochromen (Fig. 1) [12]. Moreover, electron-accepting substituents at
3-position can improve the fluorescence properties of the coumarins. Due to these
important properties, syntheses of new coumarin derivatives have been considered
by chemists and a range of methods have been reported for their synthesis [13–22].
The nitrogen-containing heterocycles are important organic scaffolds and they are
widely used as key elements in the synthesis of numerous drugs and medicinal agents
[23, 24], and they can act as biomimetic and active pharmacophores [25–27]. Among
them, pyrrolo[2,1-a]isoquinoline skeletons are important heterocyclic systems found
in natural products such as lamellarin and crispine alkaloids [28–32], which exhibit
antiviral and anticancer activities [33, 34] and are widely used in material science and
the drug industry [35, 36]. Due to these properties, they are widely considered in
synthetic organic chemistry and various methods have been devised for their synthesis
[37–43]. In the course of our research program into the design of new routes for the
synthesis of new heterocyclic compounds, we have been interested in the synthesis of
heterocyclic compounds with both coumarin and pyrrolo[2,1-a]isoquinoline skeleton
by a one-pot, three-component reaction.
Experimental
All starting materials were obtained from Merck (Germany) and Fluka (Switzer-
land) and were used without further purification. 3-acetylcoumarin and 3-(2-
bromoacetyl)coumarin were prepared according to published procedures [50, 51].
M.p.: Electrothermal 9100 apparatus. Elemental analyses for C, H, and N: Heraeus
CHN–O–Rapid analyzer. Mass spectra: FINNIGAN-MATT 8430 mass spec-
trometer operating at an ionization potential of 70 eV. 1H- and 13C-NMR spectra: at
500 and 125 MHz, resp., on a BRUKER DRX 500-AVANCE FT-NMR instrument,
in CDCl3 if not otherwise stated. IR Spectra: in KBr on a Shimadzu IR-460
spectrometer.
General procedure (exemplified for 3-acetylcoumarin)
A solution of salicylaldehyde (10 mmol, 1,220 mg), methyl acetoacetate (10 mmol,
1,160 mg), and piperidine (0.5 mmol, 42 mg) in EtOH were magnetically stirred for
O
O
OH
O
O
NH2
OH
OH
O
OH
O
MeO
N
Me
Me
O
Me
O
O
O
O
O
O
O
Me
Me
O
Warfarin
Carbochromen
Novobiocin
Fig. 1 Some biologically active 3-substituent coumarins
123

An efficient synthesis of pyrrolo[2,1-a]isoquinoline
1 h. Then the precipitate was filtered and washed with cold EtOH (10 ml) to afford
the pure 3-acetylcoumarin (Scheme 1).
General procedure (exemplified for 1a)
A solution of 3-acetylcoumarin derivatives (10 mmol, 1,880 mg), NBS (11 mmol,
1,958 mg), and p-toluenesulfonic acid (1 mmol, 172 mg) in chloroform-acetonitrile
(25:5) were magnetically stirred at reflux. After completion of the reaction [about
4 h; TLC (AcOEt/hexane 1:3)], the mixture was cooled and the precipitate was
filtered and washed with EtOH (10 ml) to afford the pure product 3-(2-
bromoacetyl)coumarin derivatives (Scheme 2).
General procedure (exemplified for 3a)
A solution of isoquinoline (1 mmol, 129 mg) and 3-(2-bromoacetyl)coumarin (1a)
(1 mmol, 266 mg) in acetonitrile (5 ml) were magnetically stirred for 1 h at r.t.
Then, triethylamine (1 mmol, 101 mg) was added to the mixture and orange
participate was formed. Then, dialkyl acetylenedicarboxylate (1 mmol, 142 mg)
was added dropwise to the mixture during 5 min and the solution stirred for 4 h.
After completion of the reaction [about 5 h; TLC (AcOEt/hexane 1:3)], the mixture
was filtered and the precipitate was washed with EtOH (4 ml) to afford the pure
product 3a–i (Table 1).
Dimethyl 3-[(2-oxo-2H-chromen-3-yl)carbonyl]pyrrolo[2,1-a]isoquinoline-1,2-
dicarboxylate (Table 2, entry a)
Yield: 319 mg (70 %). White powder, M.p. 224 °C (decomp). (KBr, cm-1): 1,203
(C–O), 1,455, 1,508, and 1,625 (Ar), 1,735 (br., 4 C=O). H NMR (400 MHz,
1
DMSO-d6): d (ppm) = 3.32 (s, 3 H, OMe); 3.87 (s, 3 H, OMe); 7.45 (t, J = 7.4, 1
Scheme 1 Synthesis of 3-acetyl coumarin
O
O
O
Br
PTSA
+
NBS
O
O
O
Scheme 2 Synthesis of 3-(2-bromoacetyl)coumarin
123

A. Alizadeh, R. Ghanbaripour
Table 1 Optimization of the
reaction conditions for the
formation of 3a
Entry
Catalyst (eq)
Solvent
Time (h)
Yield [%]
1
Et3N (1)
MeCN
MeCN
MeCN
MeCN
DMF
4
4
4
4
4
4
4
4
4
3
5
70
20
30
25
60
45
35
45
70
55
70
2
NaOH (1)
K2CO3 (1)
Piperidine (1)
Et3N (1)
3
4
5
6
Et3N (1)
EtOH
7
Et3N (1)
CHCl3
MeCN
MeCN
MeCN
MeCN
8
Et3N (0.7)
Et3N (1.2)
Et3N (1)
9
10
11
Et3N (1)
H, CH of Ar); 7.53 (d, J = 8.4, 1 H, CH of Ar); 7.63 (d, J = 7.6, 1 H, CH6 of
3
pyrroloisoquinoline); 7.72–7.80 (m, 3H, CH of Ar); 7.82 (dd, J = 8.0, 4J = 1.2, 1
H, CH of Ar); 8.00 (d, J = 7.2, 1 H, CH of Ar); 8.46 (s, 1 H, CH4 of coumarin); 8.87
(d, J = 8.0, 1 H, CH of Ar); 9.24 (d, J = 7.2, 1 H, CH5 of pyrroloisoquinoline). 13
C
NMR (100 MHz, DMSO-d6): d (ppm) = 52.5; 52.6; 109.3; 116.4; 116.7, 117.7;
121.8; 123.0; 124.0; 125.2; 125.5; 126.3; 127.6; 128.6; 128.7; 129.8; 129.8; 129.9;
132.5; 134.0; 144.4; 153.9; 157.3; 164.5; 164.6; 180.3. MS (EI, 70 eV): 455 (M?,1),
360 (10), 356 (7), 303 (6), 180 (14), 165 (99), 150 (26), 137 (98), 120 (100), 104
(28), 92 (68), 65 (46). Anal. calc. for C26H17NO7 (455.42): C 68.57, H 3.76, N 3.08;
Found: C 68.45, H 3.97, N 3.21.
Diethyl 3-[(2-oxo-2H-chromen-3-yl)carbonyl]pyrrolo[2,1-a]isoquinoline-1,2-
dicarboxylate (Table 2, entry b)
Yield: 363 mg (75 %). Pale yellow powder. M.p. 200–202 °C. (KBr, cm-1): 1,202
(C–O), 1,485, 1,507, and 1,611, (Ar), 1,722 (br., 4 C=O). H NMR (400 MHz,
1
DMSO-d6): d (ppm) = 1.00 (t, J = 7.0, 3 H, OCH2CH3);1.27 (t, J = 7.2, 3 H,
OCH2CH3); 3.70 (q, J = 7.2, 2 H, OCH2CH3); 4.35 (q, J = 7.0, 2 H, OCH2CH3);
7.45 (td, 3J = 7.0, 4J = 0.8, 1 H, CH of Ar); 7.52 (d, 3J = 8.4, 1 H, CH of Ar); 7.64
(d, 3J = 7.2, 1 H, CH6 of pyrroloisoquinoline); 7.73–7.81 (m, 3 H, CH of Ar); 7.84
3
4
3
4
(dd, J = 7.8, J = 1.8, 1 H, CH of Ar); 8.01 (dd, J = 7.2, J = 1.6, 1 H, CH of
Ar); 8.47 (s, 1 H, CH4 of coumarin); 8.87 (d, J = 7.6, 1 H, CH of Ar); 9.23 (d,
J = 7.6, 1 H, CH5 of pyrroloisoquinoline). 13C NMR (100 MHz, DMSO-d6): d
(ppm) = 13.2; 13.7; 61.4; 61.8; 109.6; 116.38; 116.6; 117.8; 121.8; 123.1; 124.0;
125.2; 125.5; 126.4; 127.6; 128.5; 128.7; 129.8; 129.8; 129.8; 132.4; 134.0; 144.5;
153.9; 157.2; 164.2 (2 CO2); 180.3. MS (EI, 70 eV): 483 (M?, 32), 438 (6), 411
(15), 366 (9), 338 (13), 311 (11), 238 (34), 220 (27), 194 (19), 173 (100), 139 (27),
101 (24). Anal. calc. for C28H21NO7 (483.47): C 69.56, H 4.38, N 2.90; Found: C
69.63, H 4.29, N 2.94.
123

An efficient synthesis of pyrrolo[2,1-a]isoquinoline
Table 2 Prepared dialkyl 3-[(8-
Entry
Compound 1
R’
Yield
[%]
methoxy-2-oxo-2H-chromen-3-
yl)carbonyl]pyrrolo[2,1-
a]isoquinoline-1,2-
O
O
a
Me
70
dicarboxylates
Br
O
O
b
c
Et
75
Br
O
O
O
t-Bu
78
83
Br
O
O
O
d
e
f
Me
Br
Br
O
O
O
O
OMe
OMe
Et
86
91
O
O
t-Bu
Br
O
O
OMe
g
h
i
Me
Et
68
72
77
O
Br
O
O
O
O
Br
O
t-Bu
Di(tert-butyl) 3-[(2-oxo-2H-chromen-3-yl)carbonyl]pyrrolo[2,1-a]isoquinoline-
1,2-dicarboxylate (Table 2, entry c)
Yield: 421 mg (78 %).Yellow powder. M.p. 210–213 °C. (KBr, cm-1): 1,250,
1,210, and 1,156 (C–O), 1,454, 1,508, and 1,611 (Ar), 1723 (br., 4 C=O), H NMR
1
123

A. Alizadeh, R. Ghanbaripour
(400 MHz, DMSO-d6): d (ppm) = 1.16 (s, 9 H, OCMe3); 1.62 (s, 9 H, OCMe3);
7.44 (t, J = 7.6, 1 H, CH of Ar); 7.51 (d, J = 7.2, 2 H, CH of Ar); 7.73–7.78 (m, 3
3
4
3
H, CH of Ar); 7.87 (dd, J = 7.8, J = 1.4, 1 H, CH of Ar); 8.97 (dd, J = 7.2,
4J = 2.0, 1 H, CH of Ar); 8.46 (dd, 3J = 7.2, 4J = 2.0, 1 H, CH of Ar); 8.53 (s, 1 H,
CH4 of coumarin); 8.97 (d, J = 7.2, 1 H, CH5 of pyrroloisoquinoline). 13C NMR
(100 MHz, DMSO-d6): d (ppm) = 27.0; 27.7; 82.4; 82.6; 112.2; 115.8; 116.3;
118.1; 121.8; 123.2; 123.9; 124.2; 125.2; 126.7; 127.3; 127.7; 128.3; 128.8; 129.2;
130.0; 131.9; 134.3; 145.7; 154.0; 157.0; 162.6; 164.1; 180.6. MS (EI, 70 eV): 539
(M?, 13), 483 (6), 427 (57), 383 (13), 338 (10), 238 (24), 211 (100), 194 (43), 166
(39), 148 (53), 120 (52), 91 (58), 56 (74). Anal. calc. for C32H29NO7 (539.58): C
71.23, H 5.42, N 2.60; Found: C 71.11, H 5.49, N 2.57.
Dimethyl 3-[(8-methoxy-2-oxo-2H-chromen-3yl)-carbonyl]pyrrolo
[2,1-a]isoquinoline-1,2-dicarboxylate (Table 2, entry d)
Yield: 403 mg (83 %). Beige powder. M.p. 250–252 °C. (KBr, cm-1): 1,202 and
1,272 (C–O), 1,472, and 1,619 (Ar), 1,728 (br., 4 C=O). H NMR (400 MHz,
1
DMSO-d6): d (ppm) = 3.33 (s, 3 H, OMe); 3.87 (s, 3 H, OMe); 3.97 (s, 3 H, OMe);
7.34–7.40 (m, 2 H, CH of Ar); 7.45 (dd, 3J = 7.8, 4J = 2.2, 1 H, CH of Ar); 7.65 (d,
J = 7.6, 1 H, CH6 of pyrroloisoquinoline); 7.74 (td, 3J = 7.0, 4J = 1.6, 1 H, CH of
Ar); 7.79 (td, 3J = 7.0, 4J = 1.6, 1 H, CH of Ar); 8.01 (dd, 3J = 8.0, 4J = 1.6, 1 H,
CH of Ar); 8.44 (s, 1 H, CH4 of coumarin); 8.88 (d, 3J = 8.0, 1 H, CH of Ar); 9.24
(d, 3J = 7.6, 1 H, CH5 of pyrroloisoquinoline). 13C NMR (100 MHz, DMSO-d6): d
(ppm) = 52.5; 52.6; 56.2; 109.3; 116.0; 116.7; 118.3; 120.7; 121.8; 123.1; 124.0;
125.1; 125.5; 126.4; 127.6; 128.6; 129.8; 129.9; 130.6; 132.5; 143.2; 144.6; 146.4;
157.0; 164.5; 164.6; 180.3. MS (EI, 70 eV): 485 (M?, 74), 454 (14), 426 (19), 310
(26), 252 (30), 193 (100), 164 (80), 129 (69), 115 (39), 89 (62), 76 (61). Anal. calc.
for C27H19NO8 (485.45): C 66.80, H 3.94, N 2.89; Found: C 66.93, H 4.04, N 2.96.
Diethyl 3-[(8-methoxy-2-oxo-2H-chromen-3-yl)carbonyl]pyrrolo
[2,1-a]isoquinoline-1,2-dicarboxylate (Table 2, entry e)
Yield: 442 mg (86 %). Pale yellow powder. M.p. 200 °C (decomp). (KBr, cm-1):
1,203 and 1,274 (C–O), 1,467, and 1,616 (Ar), 1,725 (br., 4 C=O). 1H NMR
(400 MHz, DMSO-d6): d (ppm) = 1.00 (t, 3J = 7.2, 3 H, OCH2CH3); 1.27 (t,
J = 7.2, 3 H, OCH2CH3); 3.70 (q, J = 7.2, 2 H, OCH2CH3); 3.96 (s, 3 H, OMe);
4.35 (q, J = 7.2, 2 H, OCH2CH3); 7.36–7.38 (m, 2 H, CH of Ar); 7.45 (dd,
4
3
3J = 6.4, J = 3.2, 1 H, CH of Ar); 7.63 (d, J = 7.6, 1 H, CH6 of pyrroloiso-
quinoline); 7.74 (td, 3J = 8.0, 4J = 1.2, 1 H, CH of Ar); 7.78 (td, 3J = 7.2,
4J = 1.2, 1 H, CH of Ar); 8.01 (dd, 3J = 7.2 Hz, 4J = 1.6, 1 H, CH of Ar); 8.44 (s,
1 H, CH4 of coumarin), 8.87 (d, J = 7.6, 1 H, CH of Ar), 9.22 (d, J = 7.6, 1 H,
CH5 of pyrroloisoquinoline). 13C NMR (100 MHz, DMSO-d6): d (ppm) = 13.2;
13.7; 56.2; 61.4; 61.8; 109.5; 116.1; 116.6; 118.3; 120.7; 121.7; 123.1; 124.0; 125.1;
125.5; 126.5; 127.6; 128.5; 128.7; 129.8; 130.6; 132.4; 143.1; 144.7; 146.4; 157.0;
164.1 (2 CO2); 180.3. MS (EI, 70 eV): 513 (M?, 39), 485 (25), 441 (18), 396 (8),
311 (14), 238 (31), 220 (23), 203 (74), 164 (32), 129 (100), 102 (36), 76 (19). Anal.
3
3
123

An efficient synthesis of pyrrolo[2,1-a]isoquinoline
calc. for C29H23NO8 (513.50): C 67.83, H 4.51, N 2.73; Found: C 67.91, H 4.45, N
2.68.
Di(tert-butyl) 3-[(8-methoxy-2-oxo-2H-chromen-3-yl)carbonyl]pyrrolo
[2,1-a]isoquinoline-1,2-dicarboxylate (Table 2, entry f)
Yield: 518 mg (91 %). Pale yellow powder. M.p. 219–223 °C. (KBr, cm-1): 1,155
and 1,209 1271 (C–O), 1,470 and 1,622 (Ar), 1,713 (br., 4 C=O). 1H NMR
(400 MHz, DMSO-d6): d (ppm) = 1.17 (s, 9 H, OCMe3); 1.61 (s, 9 H, OCMe3);
3.95 (s, 1 H, OCH3); 7.34–7.39 (m, 2 H, CH of Ar); 7.44 (dd, 3J = 7.6, 4J = 2.0, 1
H, CH of Ar); 7.50 (d, J = 7.6, 1 H, CH6 of pyrroloisoquinoline); 7.72–7.75 (m, 2
H, CH of Ar); 7.95–7.97 (m, 1 H, CH of Ar); 8.46 (dd, J = 6.2, 4J = 3.4, 1 H, CH
of Ar); 8.50 (s, 1 H, CH4 of coumarin); 8.96 (d, J = 7.6, 1 H, CH5 of isoquinolone).
13C NMR (100 MHz, DMSO-d6): d (ppm) = 27.0; 27.7; 56.2; 82.4; 82.6;
112.2;115.8; 116.3; 118.7; 121.0; 121.8; 123.2; 123.9; 124.2; 125.1; 126.8; 127.3;
127.7; 128.3; 129.24 (C6a of pyrroloisoquinoline and CH of Ar), 130.1; 143.3;
146.0; 146.4; 156.7; 162.6; 164.1; 180.6. MS (EI, 70 eV): 569 (M?, 10), 513 (5),
485 (21), 457 (45), 413 (8), 368 (9), 238 (14), 211 (64), 194 (19), 178 (19), 139 (17),
56 (100). Anal. calc. for C33H31NO8 (569.61): C 69.59, H 5.49, N 2.46; Found: C
69.63, H 5.60, N 2.39.
Dimethyl 3-(3-oxo-3H-benzo[f]chromen-2-ylcarbonyl)pyrrolo
[2,1-a]isoquinoline-1,2-dicarboxylate (Table 2, entry g)
Yield: 344 mg (68 %). Dirty yellow powder. M.p. 199–205 °C. (KBr, cm-1): 1,210
(C–O), 1,465, 1,524, and 1,642 (Ar), 1,734 (br., 4 C=O). H NMR (400 MHz,
1
DMSO-d6): d (ppm) = 3.12 (s, 3 H, OMe); 3.83 (s, 3 H, OMe); 7.65–7.70 (m, 3 H,
CH of Ar); 7.74–7.82 (m, 3 H, CH of Ar); 8.03 (dd, 3J = 8.2, 4J = 0.9, 1 H, CH of
3
3
Ar); 8.12 (d, J = 8.0, 1 H, CH of Ar); 8.36 (d, J = 8.8, 1 H, CH of Ar); 8.49 (d,
J = 8.4, 1 H, CH of Ar); 8.96 (d, J = 8.0, 1 H, CH of Ar); 9.30 (s, 1 H, CH1 of
coumarin); 9.32 (d, J = 7.2, 1 H, CH5 of pyrroloisoquinoline). 13C NMR
(100 MHz, DMSO-d6): d (ppm) = 52.2; 52.5; 112.0; 116.6; 116.7; 117.5; 122.0;
122.2; 123.1; 124.1; 125.0; 125.7; 126.5; 127.6; 128.5; 128.9; 129.0; 129.1; 129.9;
129.9; 130.0; 130.2; 132.8; 135.5; 140.8; 154.3; 157.2; 164.4; 164.8; 180.4. MS (EI,
70 eV): 505 (M?, 30), 474 (8), 310 (9), 283 (79), 252 (100), 238 (13), 223 (34), 193
(28), 165 (26), 139 (76), 115 (15), 102 (13), 63 (14). Anal. calc. for C30H19NO7
(505.48): C 71.28, H 3.79, N 2.77; Found: C 71.03, H 3.95, N 2.91.
Diethyl 3-(3-oxo-3H-benzo[f]chromen-2-ylcarbonyl)pyrrolo
[2,1-a]isoquinoline-1,2-dicarboxylate (Table 2, entry h)
Yield: 384 mg (72 %). Beige powder. M.p. 208 °C (decomp). (KBr, cm-1): 1,204
(C–O), 1,466, 1,565, and 1,627 (Ar), 1,726 (br., 4 C=O). H NMR (400 MHz,
1
DMSO-d6): d (ppm) = 0.74 (t, J = 7.2, 3 H, OCH2CH3); 1.23 (t, J = 7.2, 3 H,
OCH2CH3); 3.51 (q, J = 7.2, 2 H, OCH2CH3); 4.31 (q, J = 7.0, 2 H, OCH2CH3);
3
7.65–7.70 (m, 3 H, CH of Ar); 7.73–7.81 (m, 3 H, CH of Ar); 8.02 (dd, J = 8.2,
123

A. Alizadeh, R. Ghanbaripour
4J = 0.9, 1 H, CH of Ar); 8.12 (d, J = 8.0, 1 H, CH of Ar); 8.35 (d, J = 9.2, 1 H,
CH6 of pyrroloisoquinoline); 8.50 (d, J = 8.4, 1 H, CH of Ar); 8.96 (d, J = 8.0, 1
H, CH of Ar); 9.30 (s, 1 H, CH1 of coumarin); 9.31 (d, J = 8.8, 1H, CH of Ar). 13
C
NMR (100 MHz, DMSO-d6): d (ppm) = 12.9; 13.7; 61.4; 61.8; 109.3; 112.0; 116.6
(2 CH of Ar); 122.0; 122.4; 123.2; 124.1; 125.1; 125.7; 126.5; 127.6; 128.4; 128.8;
129.0; 129.2; 129.4; 129.8; 129.88; 129.94; 132.7; 135.5; 140.9; 154.3; 157.1;
164.1; 164.4; 180.5. MS (EI, 70 eV): 533 (M?, 14), 505 (10), 311 (53), 283 (7), 266
(26), 238 (72), 223 (30), 194 (45), 167 (69), 139 (100), 115 (24). Anal. calc. for
C32H23NO7 (533.53): C 72.04, H 4.34, N 2.63; Found: C 71.93, H 4.49, N 2.69.
Di(tert-butyl) 3-(3-oxo-3H-benzo[f]chromen-2-ylcarbonyl)pyrrolo
[2,1-a]isoquinoline-1,2-dicarboxylate (Table 2, entry i)
Yield: 454 mg (77 %). Yellow powder. M.p. 225 °C (decomp). (KBr, cm-1): 1,154
and 1,211 (C–O), 1,554, and 1,624 (Ar), 1,723 (br., 4 C=O). H NMR (400 MHz,
1
DMSO-d6): d (ppm) = 1.05 (s, 9 H, OCMe3); 1.61 (s, 9 H, OCMe3); 7.54 (d,
J = 7.6, 1 H, CH of Ar); 7.67 (t, J = 7.0, 1 H, CH of Ar); 7.68 (d, J = 8.0, 1 H, CH
of Ar); 7.74–7.78 (m, 3 H, CH of Ar); 7.97–7.99 (s, 1 H, CH of Ar); 8.11 (d,
J = 7.6, 1 H, CH of Ar); 8.35 (d, J = 9.2, 1 H, CH of Ar); 8.50–8.54 (m, 2 H, CH
of Ar); 9.05 (d, 3J = 7.6, 4J = 2.0, 1 H, CH5 of isoquinolone); 9.31 (s, 1 H, CH1 of
coumarin). 13C NMR (100 MHz, DMSO-d6): d (ppm) = 26.9; 27.7; 82.4; 82.5;
112.1; 112.5; 115.7; 116.5; 122.1; 122.4; 123.2; 124.0; 124.4; 125.7; 126.5; 127.7;
127.9; 128.2; 128.9; 129.1; 129.2; 129.3; 129.4; 129.9; 130.3; 135.8; 141.6; 154.5;
157.1; 162.8; 164.1; 180.8. MS (EI, 70 eV): 589 (M?, 8), 533 (28), 505 (23), 477
(31), 388 (12), 255 (40), 238 (40), 211 (100), 194 (36), 166 (32), 139 (64), 115 (17),
56 (74). Anal. calc. for C36H31NO7 (589.64): C 73.33, H 5.30, N 2.38; Found: C
73.39, H 5.39, N 2.48.
Results and discussion
Accordingly, and in continuation of our studies on the synthesis of new polycyclic
heterocyclic compounds [43–49], and coumarin moiety, we were encouraged to
synthesize functionalized coumarin bearing pyrrolo[2,1-a]isoquinoline derivatives by
the reaction of 3-(2-bromoacetyl)coumarins 1, isoquinoline and dialkyl acetylenedi-
carboxylates 2 in the presence of one equivalent triethylamine (Scheme 3).
O
O
O
O
CO2R'
N
Br
Et3N (1 eq)
MeCN, 4 h
+
+
N
CO2R
O
O
CO2R
CO2R'
R
R
1
3
2
Scheme 3 Synthesis
a]isoquinoline-1,2-dicarboxylates
of
dialkyl
3-[(8-methoxy-2-oxo-2H-chromen-3-yl)carbonyl]pyrrolo[2,1-
123

An efficient synthesis of pyrrolo[2,1-a]isoquinoline
Initially, we synthesized 3-acetylcoumarin derivatives by the reaction of
salicylaldehydes and b-keto esters in the presence of piperidine as a catalyst [44–
49]. Then 3-(2-bromoacetyl)coumarins 1 were prepared by reaction of 3-acetyl-
coumarin with NBS in the presence of p-toluenesulfonic acid and the products have
been compared to literature [50, 51]. Then, the 3-bromoacetylcoumarin (1a),
isoquinoline and dimethyl acetylenedicarboxylate (2a) were selected as the model
substrates and the effect of solvents and bases has been studied to optimize the
reaction conditions. The best results were obtained by performing the model
reaction in MeCN in the presence of one equivalent triethylamine (see Table 1).
When we used DMF as a solvent, the same results were obtained (TLC) but the
yield of isolated product decreased due to its higher solubility in DMF in
comparison with MeCN and thus we used acetonitrile in this reaction to gain higher
isolated yields. When we used inorganic bases such as K2CO3 and NaOH, complex
mixture has been obtained (Table 1, entry 2, 3). After establishing optimal
conditions, we explored the scope of the reaction leading to product 3.
For this purpose, we extended this promising reaction by using various 3-(2-
bromoacetyl)coumarin 1 and dialkyl acetylenedicarboxylates 2. The reactions are
generally clean and the desired products 3a–i were obtained in good yields.
To extend our knowledge of this transformation, we performed the same
reactions with various alkyl propiolates, but these reactions failed and a complex
mixture was obtained. The alkyl propiolates are unsymmetrical acetylene deriva-
tives, and there are two regioisomeric cycloaddition possible on the triple bond.
They are also highly active molecules in comparison with dialkyl acetylenedicar-
boxylate leading to complex mixtures in this transformation. The structures of
compounds 3a–i were deduced from their elemental analysis, IR, and high-field 1H-
and 13C-NMR spectra. The mass spectrum of 3a displayed the molecular ion peak at
m/z 455, which is in agreement with the proposed structure. The IR spectrum of this
compound showed a broad absorption band due to the four C=O stretching
frequency at 1,735 cm-1, and absorption bands at 1,625, 1,508, 1,455, and
1,203 cm-1 are assigned to the C=C and C–O groups.
1
The H NMR spectrum of 3a showed five doublet signals [d 7.53, (J = 8.4),
7.63, (J = 7.6), 8.00, (J = 7.2), 8.87, (J = 8.0), and 9.24, (J = 7.2)], one triplet
signal (d 7.45, (J = 7.4)), one doublet of doublet signals [d 7.82, (J = 8.0 and
J = 1.2)] and one multiplet signal (d 7.72–7.80) for aromatic H-atoms and also
three sharp singlet signals (d 3.32, 3.87 and 8.46) for two OMe groups and CH of
the chromene ring, respectively. The 13C NMR spectrum of 3a exhibits 26 distinct
signals in agreement with the suggested structure.
According to these results, a plausible mechanism for the three-component
reaction is proposed (Scheme 4). At first, nucleophilic attack of isoquinoline to
3-(2-bromoacetyl)coumarin (1a) leads to isoquinolinium salt 4a. Next, the N-ylide
5a was obtained by deprotonation of 4a with triethylamine. Then, 1,3-cycloaddition
on to the triple bond leads to intermediate 6a, and finally air oxidation of 6a yields
the desired product 3a.
123

A. Alizadeh, R. Ghanbaripour
O
O
O
Br
N
+
Br
O
N
O
O
1a
4a
O
O
N
N
Et3N
CO2Me
O
O
CO2Me
O
O
CO2Me
5a
MeO2C
6a
O
O
N
air oxidation
CO2Me
O
CO2Me
3a
Scheme 4 A plausible mechanism for the formation of products 3a–i
Conclusions
In summary, we have presented the synthesis of new coumarin derivatives 3 by a
three-component reaction. Easy performance, good yields, and easy purification are
the main aspects of the present method. The products described in this article have
two important biological active moieties, coumarin and pyrrolo[2,1-a]isoquinoline.
To our knowledge, this is the first report on this class of coumarins and there are no
other efficient methods for their synthesis. Due to the importance of these two
scaffolds, synthetic and biological applications of compounds 3 can be considered in
the near future.
Acknowledgments We gratefully acknowledge the financial support from the Research Council of
Tarbiat Modares University.
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