Synthesis of pyrrolo[2,1-a]isoquinolines by multicomponent 1,3-dipolar cycloaddition

Article abstract of DOI:10.3390/molecules18032635

Pyrrolo[2,1-a]isoquinoline derivatives were synthesized by one-pot threecomponent reactions starting from isoquinoline, 2-bromoacetophenones and different nonsymmetrical acetylenic dipolarophiles using 1,2-epoxypropane as solvent. The structure of the compounds was assigned by IR and NMR spectroscopy.

Full text of DOI:10.3390/molecules18032635

Molecules 2013, 18, 2635-2645; doi:10.3390/molecules18032635
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of Pyrrolo[2,1-a]isoquinolines by Multicomponent
1,3-Dipolar Cycloaddition
Florea Dumitrascu 1, Emilian Georgescu 2, Florentina Georgescu 2, Marcel Mirel Popa 1 and
Denisa Dumitrescu 3,*
1
Center of Organic Chemistry “C. D. Nenitzescu”, Romanian Academy, Spl. Independentei 202B,
Bucharest 060023, Romania; E-Mail: fdumitra@yahoo.com (F.D.)
2
Research Center Oltchim, St. Uzinei 1, Ramnicu Vilcea 240050, Romania;
E-Mail: emilian.georgescu@oltchim.com (E.G.)
3
Faculty of Pharmacy, “Ovidius” University, Aleea Universitatii nr.1, Campus Corp B,
Constantza 900470, Romania
* Author to whom correspondence should be addressed; E-Mail: denisadumitrescu@yahoo.com.
Received: 29 January 2013; in revised form: 18 February 2013 / Accepted: 18 February 2013 /
Published: 27 February 2013
Abstract: Pyrrolo[2,1-a]isoquinoline derivatives were synthesized by one-pot three-
component reactions starting from isoquinoline, 2-bromoacetophenones and different non-
symmetrical acetylenic dipolarophiles using 1,2-epoxypropane as solvent. The structure of
the compounds was assigned by IR and NMR spectroscopy.
Keywords: pyrrolo[2,1-a]isoquinoline; one-pot three component; 1,3-dipolar cycloaddition
1. Introduction
Pyrrolo[2,1-a]isoquinolines are N-bridgehead heterocyclic compounds which are structural
elements of natural products (Figure 1) of great significance for their biological activity, such as
crispine A (Figure 1), with important anticancer activity [1–5]. Recently studied natural products with
pyrrolo[2,1-a]isoquinoline cores are oleracein E [6,7] and trolline [8] (Figure 1), which were isolated
from traditional Chinese medicinal plants.

Molecules 2013, 18
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Figure 1. Natural alkaloids with pyrrolo[1,2-a]isoquinoline core.
MeO
MeO
HO
R1
O
O
N
N
N
O
HO
R2
H
H
Crispine A
Trolline
MeO
MeO
HO
HO
R3
N+
Cl
N
O
R6
R4
R5
H
H
Crispine B
Oleracein E
Lamellarin Class of Alkaloids
Maybe one of the most important classes of natural compounds are the lamellarins (Figure 1),
which are known to posses an array of biological properties such as cell differentiation inhibition and
cytotoxicity [9–13], this leading to numerous studies on lead compounds with analogous structures [14].
In this regard efforts were directed to synthesize aromatic or hydrogenated pyrrolo[2,1-a]-
isoquinoline frameworks in the search for molecules relevant for medicinal purposes. The synthesis
and properties of the pyrrolo[2,1-a]isoquinolines were reviewed in 1997 by Mikhailovskii and
Shklyaev [15], but the synthesis and characterization of these compounds is still of current interest, the
proof being the important number of very recently reported papers [16–19].
One of the important and current methods for the synthesis of pyrrolo[2,1-a]isoquinolines is the
1,3-dipolar cycloaddition reaction of isoquinolinium N-ylides with activated alkynes or olefins [20–28].
Our interest in studying convenient and simple methods for obtaining new pyrroloazine derivatives [29–34]
led us to expand our studies to pyrrolo[2,1-a]isoquinolines [27]. The success in synthesis of such
compounds by two methods involving two step procedures [27] led us to examine the one-pot three
component procedure for the synthesis of pyrrolo[2,1-a]isoquinoline derivatives by 1,3-dipolar
reactions discussed herein. The key components are isoquinoline, substituted bromoacetophenones and
activated acetylenic dipolarophiles which react in 1,2-epoxypropane to yield the desired products with
high efficiency.
2. Results and Discussion
Syntheses involving multicomponent one-pot reactions have provided useful synthetic tools in
obtaining a wide variety of heterocyclic systems [35–37]. Thus a 1,3-dipolar cycloaddition targeting
pyrrolo[2,1-a]isoquinoline derivatives, conducted as a one-pot three component process, seemed to be
a very promising route. The key components of the one-pot three component reaction for the synthesis
of pyrrolo[2,1-a]isoquinolines 4 (Table 1) are isoquinoline (1), the substituted bromoacetophenones 2,
the non-symmetrical electron deficient alkynes 3 and 1,2-epoxypropane which acts both as solvent and
proton scavenger (Scheme 1). Using this methodology the series of compounds listed in Table 1 was
prepared in fair to good yields.

Molecules 2013, 18
Scheme 1. The one-pot three component synthesis of the new compounds.
2637
Me
O
N
COAr
E
ArCOCH Br
+
+
2
N
E
1
2
3
4
Table 1. New pyrrolo[2,1-a]isoquinolines 4.
No.
4a
4b
4c
4d
4e
4f
R
E
Ar
M.p. (°C)
171–173
218–220
Yield (%)
71
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
COMe
COMe
COMe
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
4-MeOC6H4
3-NO2C6H4
70
3,4-(MeO)2C6H3 198–200
65
2-ClC6H4
222–225
205–208
209–212
208–211
162–164
150–152
186–187
201–203
209–211
140–142
180–186
190–192
152–154
151–153
60
2,4-Cl2C6H3
3-NO2C6H4
4-NO2C6H4
1-naphthyl
2-napthyl
69
70
4g
4h
4i
64
72
67
4j
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-FC6H4
69
4k
4l
78
63
4m
4n
4o
4p
4q
4r
65
2,4-Cl2C6H3
4-BrC6H4
52
66
2-HOC6H4
4-MeOC6H4
64
61
3,4-(MeO)2C6H3 173–176
69
The reaction mechanism (Scheme 2) for formation of the pyrroloisoquinolines 4 involves in the first
step the generation of isoquinolinium N-ylides 6A by the action the isoquinolinium bromides 5 on the
epoxide which, on nucleophilic ring opening by bromide anion, generates an alkoxide for
deprotonation of the salt to form 6A. Subsequently, the 1,3-dipolar cycloaddition between the
1,3-dipole 6B and the unsymmetrical acetylenic dipolarophiles afford the corresponding primary
cycloadducts 7 which undergoes a spontaneous in situ rearrangement and dehydrogenation leading to
the fully aromatic compounds 4.
It is important to mention that no hydrogenated intermediates were isolated as for the previously
reported two step procedure [27]. By comparison with the two step procedure the yields are
appreciably lower but this minor inconvenience is significantly overcome by the more simple
procedure and economy of both time and materials.
The structures of the new pyrroloisoquinolines were assigned by IR and NMR spectroscopy. The FT-IR
spectra of the compounds present the characteristic bands for carbonyl groups that appear in the
expected ranges, and the characteristic bands for the particular functional groups present in each
example are also observed. On the basis of NMR data it was found that the cycloaddition reaction

Molecules 2013, 18
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between isoquinolinium N-ylides and unsymmetrical dipolarophile is completely regioselective, as
only one regioisomer was obtained. This is proven by the signal of the H-2 hydrogen which appears as
a sharp singlet.
Scheme 2. Reaction mechanism.
Me
O
ArCOCH2Br
Br
+
N
+
N
+
N
CHCOAr
CH2COAr
-
1
2
5
6A
E
N
N
N
COAr
COAr
- 2H
CHCOAr
+
H
E
E
6B
7
4
In the 1H-NMR spectra of compounds 4 the general characteristic features are the chemical shifts of
atoms H-5, H-6 and H-10. The two protons in the pyridine moiety, namely H-5 and H-6, appear as two
doublets with a coupling constant of 7.4 Hz. The H-10 hydrogen appears as a deshielded multiplet due
to the spatial vicinity with the carbonyl group in the acetyl or ester groups. The 13C-NMR spectra show
all the expected signals. The most characteristic feature is the strong shielding observed for C-1 which
appears at around 110 ppm as a consequence of its relative β position with respect to the pyrrole
nitrogen. For the compounds 4a–c the carbon C-1 appears slightly deshielded to 118 ppm due to the
influence of an acetyl group instead of an ester group. The carbon atoms in the carbonyl groups were
observed in the expected ranges.
3. Experimental
3.1. General
Melting points were determined on a Boëtius hot plate microscope and are uncorrected. The
elemental analysis was carried out on a COSTECH Instruments EAS32 apparatus. The IR spectra were
recorded on a FT-IR Bruker Vertex 70. The NMR spectra were recorded on a Varian Gemini 300 BB
1
13
instrument, operating at 300 MHz for H-NMR and 75 MHz for C-NMR. Supplementary evidence
was given by HETCOR and COSY experiments.
3.2. General Procedure for the Synthesis of Pyrrolo[2,1-a]isoquinolines 4
Isoquinoline (1, 3 mmol), phenacyl bromide 2 (3 mmol) and the corresponding acetylenic
dipolarophile (2-butyn-3-one, methyl propiolate, ethyl propiolate) 3 (5 mmol) in 1,2-epoxypropane (15 mL)
were stirred at reflux for 20 h. The solvent was partly removed by evaporation, methanol or ethanol

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(10 mL) was added and the mixture was left overnight in the refrigerator. The solid formed was
filtered, washed with ethanol and crystallized from CHCl3/MeOH.
1-Acetyl-3-(4-methylbenzoyl)-pyrrolo[2,1-a]isoquinoline (4a). Light yellow crystals, m.p. 171–173 °C;
Yield 71%. Anal. Calcd. C22H17NO2: C 80.71, H 5.23, N 4.28; Found: C 80.51, H 5.02, N 4.57. FT-IR
1
(cm−1): 1172, 1332, 1359, 1444, 1517, 1619, 1655, 2920. H-NMR (CDCl3) δ: 2.47, 2.64 (2s, 6H,
2Me); 7.29 (d, 1H, J = 7.4 Hz, H-6); 7.35 (d, 2H, J = 8.0 Hz, H-3', H-5'); 7.64–7.68 (m, 2H, H-7, H-8);
7.71 (s, 1H, H-2); 7.73–7.75 (m, 1H, H-9); 7.78 (d, 2H, J = 8.0 Hz, H-2', H-6'); 9.60 (d, 1H, J = 7.4 Hz,
H-5); 9.80–9.82 (m, 1H, H-10). 13C-NMR (CDCl3) δ: 21.7, 30.1 (2Me); 116.2 (C-6); 119.2 (C-1);
123.7, 124.9, 130.9, 137.2 (C-3, C-6a, C-10a, C-10b); 125.0 (C-5); 126.7, 127.8, 129.7, 129.9 (C-2, C-7,
C-8, C-9); 128.4 (C-10); 129.3, 129.5 (C-2', C-3', C-5', C-6'); 136.5 (C-1'); 142.7 (C-4'); 185.9
(COAr); 193.7 (COO).
1-Acetyl-3-(3-nitrobenzoyl)-pyrrolo[2,1-a]isoquinoline (4b). Light yellow crystals, m.p. 218–220 °C;
Yield 70%. Anal. Calcd. C21H14N2O4: C 70.39, H 3.94, N 7.82; Found: C 70.65, H 3.72, N 8.08. FT-IR
(cm−1): 1180, 1339, 1446, 1514, 1615, 1666, 3004. 1H-NMR (CDCl3) δ: 2.64 (s, 3H, Me); 7.33 (d, 1H,
J = 7.4 Hz, H-6); 7.66–7.77 (m, 4H, H-7, H-8, H-9, H-5'); 7.65 (s, 1H, H-2); 8.15–8.19 (m, 1H, H-6');
8.43–8.47 (m, 1H, H-4'); 8.68 (t, 1H, J = 1.9 Hz, H-2'); 9.60 (d, 1H, J = 7.4 Hz, H-5); 9.73–9.76 (m, H,
13
H-10). C-NMR (CDCl3) δ: 30.0 (Me); 116.8 (C-6); 119.9 (C-1); 123.9 (C-2'); 122.5, 124.6, 130.9,
137.1 (C-3, C-6a, C-10a, C-10b); 124.6 (C-5); 126.7, 128.0, 129.7, 130.1 (C-2, C-7, C-8, C-9); 128.4
(C-10); 129.7, 130.2, 134.6 (C-4', C-5', C-6'); 141.3 (C-1'); 148.2 (C-3'); 182.7 (COAr); 193.4 (COO).
1-Acetyl-3-(3,4-dimethoxylbenzoyl)-pyrrolo[2,1-a]isoquinoline (4c). Light yellow crystals, m.p.
198–200 °C; Yield 65%. Anal. Calcd. C23H19NO4: C 73.98, H 5.13, N 3.75; Found: C 74.31, H 5.37, N
4.06. FT-IR (cm−1): 1175, 1269, 1360, 1451, 1512, 1623, 1665, 2966. 1H-NMR (CDCl3) δ: 2.65 (s, 3H,
Me); 3.97, 3.98 (2s, 6H, 2MeO); 6.97 (d, 1H, J = 8.2 Hz, H-5'); 7.22 (d, 1H, J = 7.4 Hz, H-6); 7.48–7.51
(m, 2H, H-2', H-6'); 7.60–7.71 (m, 3H, H-7, H-8, H-9); 7.72 (s, 1H, H-2); 9.46 (d, 1H, J = 7.4 Hz,
H-5); 9.77–9.80 (m, 1H, H-10). 13C-NMR (CDCl3) δ: 30.0 (2Me); 29.9 (Me); 56.1 (2MeO); 110.1,
111.9 (C-2', C-5'); 115.9 (C-6); 118.9 (C-1); 123.5, 124.9, 130.5, 136.1 (C-3, C-6a, C-10a, C-10b);
123.7 (C-6'); 124.6 (C-5); 126.6, 127.6, 129.4, 129.5 (C-2, C-7, C-8, C-9); 128.2 (C-10); 132.3 (C-1');
149.1, 152.6 (C-3', C-4'); 184.5 (COAr); 193.4 (COO).
Methyl 3-(2-chlorobenzoyl)-pyrrolo[2,1-a]isoquinoline-1-carboxylate (4d). Light yellow crystals, m.p.
225–258 °C; Yield 60%. Anal. Calcd. C21H14ClNO3: C 69.33, H 3.88, Cl 9.75, N 3.85; Found: C
1
69.59, H 3.61, Cl 9.47, N 4.14. FT-IR (cm−1): 1181, 1339, 1453, 1524, 1629, 1704, 2951. H-NMR
(CDCl3) δ: 3.87 (s, 3H, Me); 7.30 (d, 1H, J = 7.4 Hz, H-6); 7.39–7.51 (m, 4H, H-7, H-8, H-3', H-5');
7.54 (s, 1H, H-2); 7.64–7.67 (m, 2H, H-9, H-4'); 7.74–7.77 (m, 1H, H-6'); 9.77–9.81 (m, 2H, H-5, H-10).
13C-NMR (CDCl3) δ: 51.8 (Me); 110.6 (C-1); 116.1 (C-6); 123.4, 124.5, 130.8, 137.5 (C-3, C-6a,
C-10a, C-10b); 125.2 (C-5); 126.6, 129.2, 130.3, 131.1 (C-3', C-4', C-5', C-6'); 126.8, 127.9, 129.6,
130.9 (C-2, C-7, C-8, C-9); 128.3 (C-10); 131.5, 139.6 (C-1', C-2'); 164.8 (COO); 184.1 (COAr).
Methyl 3-(3-nitrobenzoyl)-pyrrolo[2,1-a]isoquinoline-1-carboxylate (4e). Light yellow crystals, m.p.
190–192 °C; Yield 69%. Anal. Calcd. C21H14N2O5: C 67.38, H 3.77, N 7.48. Found: C 67.57, H 3.51,

Molecules 2013, 18
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1
N 7.69. FT-IR (cm−1): 1183, 1339, 1459, 1527, 1631, 1712, 2956. H-NMR (CDCl3) δ: 3.90 (s, 3H,
Me); 7.30 (d, 1H, J = 7.4 Hz, H-6); 7.66–7.78 (m, 4H, H-7, H-8, H-9, H-5'); 7.74 (s, 1H, H-2); 8.13–8.16
(m, 1H, H-6'); 8.41–8.45 (m, 1H, H-4'); 8.66 (t, 1H, J = 1.9 Hz, H-2'); 9.61 (d, 1H, J = 7.4 Hz, H-5);
9.81–9.84 (m, H, H-10). 13C-NMR (CDCl3) δ: 52.0 (Me); 110.7 (C-1); 116.3 (C-6); 122.6, 124.6,
130.8, 137.8 (C-3, C-6a, C-10a, C-10b); 124.1 (C-2'); 125.0 (C-5); 126.9, 129.8, 134.8 (C-4', C-5', C-6');
126.1, 128.3, 129.9, 130.5 (C-2, C-7, C-8, C-9); 128.4 (C-10); 141.5 (C-1'); 148.3 (C-3'); 164.7
(COO); 183.0 (COAr).
Methyl 3-(4-nitrobenzoyl)-pyrrolo[2,1-a]isoquinoline-1-carboxylate (4f). Light yellow crystals, m.p.
209–212 °C; Yield 70%. Anal. Calcd. C21H14N2O5: C 67.38, H 3.77, N 7.48. Found: C 67.21, H 4.02,
1
N 7.71. FT-IR (cm−1): 1183, 1339, 1453, 1521, 1617, 1711, 2957. H-NMR (CDCl3) δ: 3.92 (s, 3H,
Me); 7.33 (d, 1H, J = 7.4 Hz, H-6); 7.67–7.80 (m, 3H, H-7, H-8, H-9); 7.74 (s, 1H, H-2); 7.95 (d, 2H,
J = 8.8 Hz, H-2', H-6'); 7.95 (d, 2H, J = 8.8 Hz, H-3', H-5'); 9.66 (d, 1H, J = 7.4 Hz, H-5); 9.83–9.85
13
(m, 1H, H-10). C-NMR (CDCl3) δ: 52.0 (Me); 110.7 (C-1); 116.4 (C-6); 122.7, 124.5, 130.9, 137.8
(C-3, C-6a, C-10a, C-10b); 123.7 (C-2', C-6'); 125.0 (C-5); 126.9, 128.3, 129.9, 130.7 (C-2, C-7, C-8,
C-9); 128.4 (C-10); 130.0 (C-3', C-5'); 145.4 (C-1'); 149.6 (C-3'); 164.7 (COO); 183.5 (COAr).
Methyl 3-(2,4-dichlorobenzoyl)-pyrrolo[2,1-a]isoquinoline-1-carboxylate (4g). Light yellow crystals,
m.p. 205–208 °C; Yield 64%. Anal. Calcd. C21H13Cl2NO3: C 63.34, H 3.29, Cl 17.80, N 3.52. Found:
C 63.59, H 3.51, Cl 18.07, N 3.81. FT-IR (cm−1): 1181, 1366, 1454, 1526, 1626, 1708, 2952. 1H-NMR
(300 MHz, CDCl3) δ: 3.90 (s, 3H, Me); 7.34 (d, 1H, J = 7.4 Hz, H-6); 7.37–7.45 (m, 2H, H-5', H-6');
7.53 (s, 1H, H-2); 7.54 (d, 1H, J = 1.7 Hz, H-3'); 7.66–7.71 (m, 2H, H-8, H-9); 7.76–7.80 (m, 1H, H-7);
13
9.75 (d, 1H, J = 7.4 Hz, H-5); 9.81–9.84 (m, 1H, H-10). C-NMR (75 MHz, CDCl3) δ: 52.0 (Me);
110.8 (C-1); 116.4 (C-6); 123.2, 124.6, 130.9, 132.7, 136.5, 137.8 (C-3, C-6a, C-10a, C-10b, C-1', C-2',
C-4'); 125.2 (C-5); 126.9, 127.1, 128.2, 129.9, 130.2, 130.9, 131.0 (C-2, C-7, C-8, C-9, C-3', C-5', C-6');
128.4 (C-10); 164.7 (COO); 182.9 (COAr).
Ethyl 3-(1-Naphthoyl)-pyrrolo[2,1-a]isoquinoline-1-carboxylate (4h). Light yellow crystals, m.p.
162–164 °C; Yield 72%. Anal. Calcd. C26H19NO3: C 79.37, H 4.87, N 3.56. Found: C 79.62, H 4.61, N
1
3.78. FT-IR (cm−1): 1186, 1357, 1460, 1527, 1615, 1714, 3039. H-NMR (CDCl3) δ: 1.31 (t, 3H,
J = 7.1 Hz, Me); 4.32 (q, 2H, J = 7.1 Hz, CH2); 7.35 (d, 1H, J = 7.4 Hz, H-6); 7.49–7.59, 7.91–7.96,
8.14–8.20 (3m, 5H, H-3', H-5', H-6', H-7', H-8'); 7.62 (s, 1H, H-2); 7.66–7.69 (m, 2H, H-8, H-9); 7.72
(dd, 1H, J = 7.1, 1.3 Hz, H-4'); 7.77–7.82 (m, 1H, H-7); 8.02 (bd, 1H, H-2'); 9.79–9.84 (m, 1H, H-10);
13
9.92 (d, 1H, J = 7.4 Hz, H-5). C-NMR (CDCl3) δ: 14.3 (Me); 60.6 (CH2); 110.5 (C-1); 115.8 (C-6);
124.5, 124.6, 130.6, 130.9, 133.7, 137.2, 137.5 (C-3, C-6a, C-10a, C-10b, C-1', C-4a, C-8a); 125.3
(C-5); 124.4, 125.4, 126.4, 126.7, 126.9, 127.1, 127.8, 128.2, 130.7, 130.8 (C-7, C-8, C-9, C-2', C-3', C-4',
C-5', C-6', C-7', C-8'); 128.3 (C-10); 129.4 (C-2); 164.5 (COO); 187.1 (COAr).
Ethyl 3-(2-Naphthoyl)-pyrrolo[2,1-a]isoquinoline-1-carboxylate (4i). Beige crystals, m.p. 150–152 °C;
Yield 67%. Anal. Calcd. C26H19NO3: C 79.37, H 4.87, N 3.56. Found: C 79.71, H 5.11, N 3.89. FT-IR
(cm−1): 1184, 1361, 1452, 1524, 1611, 1704, 3057. 1H-NMR (CDCl3) δ: 1.37 (t, 3H, J = 7.1 Hz, Me);
4.38 (q, 2H, J = 7.1 Hz, CH2); 7.29 (d, 1H, J = 7.4 Hz, H-6); 7.58–7.70, 7.93–8.02 (2m, 8H, H-8, H-9,
H-3', H-4', H-5', H-6', H-7', H-8'); 7.74–780 (m, 1H, H-7); 7.87 (s, 1H, H-2); 8.37 (bs, 1H, H-1'); 9.67

Molecules 2013, 18
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(d, 1H, J = 7.4 Hz, H-5); 9.82–9.87 (m, 1H, H-10). 13C-NMR (CDCl3) δ: 14.3 (Me); 60.5 (CH2); 110.2
(C-1); 115.4 (C-6); 123.4, 124.5, 130.4, 132.3, 134.8, 136.8, 137.0 (C-3a, C-6a, C-10a, C-10b, C-2', C-4a',
C-8a'); 125.0 (C-5); 125.5, 126.6, 126.7, 127.6, 127.7, 127.8, 128.0, 129.1, 129.2, 129.9, 130.1 (C-2,
C-7, C-8, C-9, C-1', C-3', C-4', C-5', C-6', C-7', C-8'); 128.2 (C-10); 164.5 (COO); 185.7 (COAr).
Ethyl 3-(2-nitrobenzoyl)-pyrrolo[2,1-a]isoquinoline-1-carboxylate (4j). Yellow crystals, m.p. 186–187 °C;
Yield 69%. Anal. Calcd. C22H16N2O5: C 68.04, H 4.15, N 7.21. Found: C 68.41, H 4.47, N 7.47. FT-IR
1
(cm−1): 1184, 1349, 1454, 1524, 1621, 1712, 2984. H-NMR (CDCl3) 1.35 (t, 3H, J = 7.1 Hz, Me);
4.35 (q, 2H, J = 7.1 Hz, CH2); 7.34 (d, 1H, J = 7.4 Hz, H-6); 7.41 (s, 1H, H-2); 7.62–7.73, 7.77–7.83
(2m, 6H, H-7, H-8, H-9, H-3', H-4', H-5'); 8.22–8.26 (m, 1H, H-6'); 9.74 (d, 1H, J = 7.4 Hz, H-5);
9.77–9.82 (m, 1H, H-10). 13C-NMR (CDCl3) δ: 14.5 (Me); 60.7 (CH2); 111.1 (C-1); 116.2 (C-6);
123.0, 124.7, 130.9, 136.2, 137.5 (C-3, C-6a, C-10a, C-10b, C-1'); 124.8 (C-5); 125.1 (C-3'); 126.9,
127.9, 129.0, 129.4, 129.6, 130.6, 133.2 (C-2, C-7, C-8, C-9, C-4', C-5', C-6'); 128.3 (C-10); 147.1 (C-2');
164.5 (COO); 188.0 (COAr).
Ethyl 3-(3-Nitrobenzoyl)-pyrrolo[2,1-a]isoquinoline-1-carboxylate (4k). Yellow crystals, m.p.
203–205 °C; Yield 78%. Anal. Calcd. C22H16N2O5: C 68.04, H 4.15, N 7.21. Found: C 68.31, H 3.98,
N 7.11. FT-IR (cm−1): 1189, 1349, 1455, 1531, 1625, 1720. 1H-NMR (CDCl3) δ: 1.40 (t, 3H, J = 7.1 Hz,
Me); 4.41 (q, 2H, J = 7.1 Hz, CH2); 7.34 (d, 1H, J = 7.4 Hz, H-6); 7.67–7.83 (m, 4H, H-7, H-8, H-9,
H-5'); 7.77 (s, 1H, H-2); 8.16–8.20, 8.44–8.48 (2m, 2H, H-4', H-6'); 8.70 (t, 1H, J = 1.8 Hz, H-2'); 9.66
(d, 1H, J = 7.4 Hz, H-5); 9.80–9.86 (m, 1H, H-10). 13C-NMR (CDCl3) δ: 14.6 (Me); 61.0 (CH2); 111.2
(C-1); 116.3 (C-6); 122.6, 124.6, 130.9, 137.8 (C-3a, C-6a, C-10a, C-10b); 124.1 (C-4'); 125.1 (C-5);
127.0, 128.4, 129.9 (C-7, C-8, C-9); 126.2, 130.3 (C-2', C-5'); 128.2 (C-10); 129.8 (C-2); 134.8 (C-6')
141.5 (C-1'); 148.3 (C-3'); 164.4 (COO); 183.3 (COAr).
Ethyl 3-(4-nitrobenzoyl)-pyrrolo[2,1-a]isoquinoline-1-carboxylate (4l). Yellow crystals, m.p. 209–211 °C;
Yield 63%. Anal. Calcd. C22H16N2O5: C 68.04; H 4.15; N 7.21. Found: C 68.37; H 4.51; N 7.61.
FT-IR (cm−1): 1185, 1348, 1452, 1529, 1624, 1718. 1H-NMR (CDCl3) δ: 1.41 (t, 3H, J = 7.1 Hz, Me);
4.41 (q, 2H, J = 7.1 Hz, CH2); 7.34 (d, 1H, J = 7.4 Hz, H-6); 7.68–7.72 (m, 2H, H-8, H-9); 7.74 (s, 1H,
H-2); 7.76–7.82 (m, 1H, H-7); 7.99 (d, 2H, J = 8.8 Hz, H-2', H-6'); 8.40 (d, 2H, J = 8.8 Hz, H-3', H-5');
9.67 (d, 1H, J = 7.4 Hz, H-5); 9.80–9.86 (m, 1H, H-10). 13C-NMR (CDCl3) δ: 14.5 (Me); 61.0 (CH2);
111.0 (C-1); 116.3 (C-6); 123.8 (C-3', C-5'); 123.7, 124.5, 130.7, 137.6 (C-3a, C-6a, C-10a, C-10b);
125.1 (C-5); 126.9, 128.9, 129.8 (C-7, C-8, C-9); 128.4 (C-10); 129.7 (C-2); 130.1 (C-2', C-6'); 145.4
(C-1'); 149.6 (C-4'); 164.4 (COO); 183.5 (COAr).
Ethyl 3-(4-fluorobenzoyl)-pyrrolo[2,1-a]isoquinoline-1-carboxylate (4m). Yellow crystals, m.p.
141–143 °C; Yield 65%. Anal. Calcd. C22H16FNO3: N 3.88. Found: N 4.11. FT-IR (cm−1): 1182, 1360,
1457, 1619, 1709. 1H-NMR (CDCl3) 1.41 (t, 3H, J = 7.1 Hz, Me); 4.41 (q, 2H, J = 7.1 Hz, CH2); 7.18
(t, 2H, J = 8.8 Hz, H-2', H-6'); 7.21 (d, 1H, J = 7.4 Hz, H-6); 7.64–7.71 (m, 2H, H-8, H-9); 7.74 (s, 1H,
H-2); 7.75–7.80 (m, 1H, H-7); 7.91 (dd, 2H, J = 8.8, 5.4 Hz, H-3', H-5'); 9.60 (d, 1H, J = 7.4 Hz, H-5);
9.80–9.85 (m, 1H, H-10). 13C-NMR (CDCl3) δ: 14.6 (Me); 60.8 (CH2); 110.5 (C-1); 115.7 (C-6); 115.8
(d, J = 21.8 Hz, C-3', C-5'); 123.3, 124.7, 130.7, 137.1 (C-3, C-6a, C-10a, C-10b); 125.1 (C-5); 126.8,

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127.9, 129.8 (C-7, C-8, C-9); 128.3 (C-10); 129.5 (C-2); 131.8 (d, J = 9.2 Hz, C-2', C-6'); 136.2 (d,
J = 2.9 Hz, C-1'); 164.7 (COO); 165.1 (d, J = 252.2 Hz, C-4'); 184.5 (COAr).
Ethyl 3-(2,4-dichlorobenzoyl)-pyrrolo[2,1-a]isoquinoline-1-carboxylate (4n). Cream crystals, m.p.
184–186 °C; Yield 52%. Anal. Calcd. C22H15Cl2NO3: C 64.09; H 3.67; Cl 17.20, N 3.40. Found: C
1
64.44; H 4.02; Cl 17.51, N 3.21. FT-IR (cm−1): 1184, 1366. 1453, 1525, 1626, 1703, 2974. H-NMR
(CDCl3) 1.39 (t, 3H, J = 7.1 Hz, Me); 4.39 (q, 2H, J = 7.1 Hz, CH2); 7.33 (d, 1H, J = 7.4 Hz, H-6); 7.39
(dd, 1H, J = 8.3, 1.8 Hz, H-5'); 7.44 (d, 1H, J = 8.3 Hz, H-6'); 7.52 (s, 1H, H-2); 7.54 (d, 1H, J = 1.8 Hz,
H-3'); 7.65–7.70 (m, 2H, H-8, H-9); 7.75–7.80 (m, 1H, H-7); 9.77 (d, 1H, J = 7.4 Hz, H-5); 9.78–9.83
13
(m, 1H, H-10). C-NMR (CDCl3) δ: 14.5 (Me); 60.6 (CH2); 111.2 (C-1); 116.2 (C-6); 123.0, 124.5,
130.8, 132.6, 136.3, 137.6, 137.7 (C-3, C-6a, C-10a, C-10b, C-1', C-2', C-4'); 125.2 (C-5); 126.8,
127.0, 128.0, 130.1, 130.2, 130.7 (C-7, C-8, C-9, C-3', C-5', C-6'); 128.3 (C-10); 129.7 (C-2); 164.3
(COO); 184.9 (COAr).
Ethyl 3-(4-bromobenzoyl)-pyrrolo[2,1-a]isoquinoline-1-carboxylate (4o). Beige crystals, m.p. 190–192 °C;
Yield 66%. Anal. Calcd. C22H16BrNO3: C 62.58; H 3.82; Br 18.92, N 3.32. Found: C 62.87; H 3.59; Br
1
19.31, N 3.63. FT-IR (cm−1): 1183, 1359, 1453, 1525, 1627, 1705, 2983. H-NMR (CDCl3) δ: 1.43 (t,
3H, J = 7.1 Hz, Me); 4.34 (q, 2H, J = 7.1 Hz, CH2); 7.23 (d, 1H, J = 7.4 Hz, H-6); 7.61–7.76 (m, 8H, H-2,
H-7, H-8, H-9, H-2', H-3', H-5', H-6'); 9.55 (d, 1H, J = 7.4 Hz, H-5); 9.79–9.85 (m, 1H, H-10). 13C-NMR
(CDCl3) δ: 14.6 (Me); 60.8 (CH2); 110.5 (C-1); 115.7 (C-6); 123.0, 124.5, 130.6, 137.1 (C-3, C-6a,
C-10a, C-10b); 125.0 (C-5); 126.6 (C-4'); 126.8, 127.8, 129.7, 129.9 (C-2, C-7, C-8, C-9); 128.4
(C-10); 130.8, 131.7 (C-2', C-3', C-5', C-6'); 138.6 (C-4'); 164.4 (COO); 184.5 (COAr).
Ethyl 3-(2-hydroxybenzoyl)-pyrrolo[2,1-a]isoquinoline-1-carboxylate (4p). Yellow crystals, m.p.
152–154 °C; Yield 64%. Anal. Calcd. C22H17NO4: C 73.53; H 4.77; N 3.90. Found: C 73.88; H 4.46; N
4.21. FT-IR (cm−1): 1188, 1339, 1451, 1584, 1618, 1708, 2984. 1H-NMR (CDCl3) 1.42 (t, 3H, J = 7.1 Hz,
Me); 4.43 (q, 2H, J = 7.1 Hz, CH2); 6.98–7.04 (m, 1H, H-5'); 7.07 (dd, 1H, J = 8.4, 1.1 Hz, H-3'); 7.26 (d,
1H, J = 7.4 Hz, H-6); 7.49–7.54 (m, 1H, H-4'); 7.61–7.67 (m, 2H, H-8, H-9); 7.71–7.77 (m, 1H, H-7);
7.87 (s, 1H, H-2); 7.90 (dd, 1H, J = 7.9, 1.6 Hz, H-6'); 9.21 (d, 1H, J = 7.4 Hz, H-5); 9.78–9.83 (m,
13
1H, H-10); 11.4 (s, 1H, OH). C-NMR (CDCl3) δ: 14.5 (Me); 60.6 (CH2); 110.7 (C-1); 115.4 (C-6);
118.3, 118.9 (C-2', C-5'); 120.9, 122.8 124.7, 130.5, 137.2 (C-3, C-6a, C-10a, C-10b, C-1'); 124.8 (C-5);
126.7, 127.9, 129.4, 129.6, 132.0, 135.2 (C-2, C-6, C-7, C-8, C-9, C-4', C-6'); 128.2 (C-10); 162.3 (C-2');
164.5 (COO); 188.0 (COAr).
Ethyl 3-(4-methoxybenzoyl)-pyrrolo[2,1-a]isoquinoline-1-carboxylate (4q). Beige crystals, m.p.
147–149 °C; Yield 61%. Anal. Calcd. C23H19NO4: C 73.98; H 5.13; N 3.75. Found: C 74.29; H 4.89;
1
N 4.11. FT-IR (cm−1): 1192, 1262, 1369, 1456, 1530, 1624, 1713, 2975. H-NMR (CDCl3) δ: 1.41 (t,
3H, J = 7.1 Hz, Me); 3.92 (s, 3H, MeO); 4.41 (q, 2H, J = 7.1 Hz, CH2); 7.04 (d, 2H, J = 8.8 Hz, H-3', H-5');
7.35 (d, 1H, J = 7.4 Hz, H-6); 7.62–7.68 (m, 2H, H-8, H-9); 7.73–7.78 (m, 1H, H-7); 7.81 (s, 1H, H-2);
7.90 (d, 2H, J = 8.8 Hz, H-2', H-6'); 9.55 (d, 1H, J = 7.4 Hz, H-5); 9.79–9.85 (m, 1H, H-10). 13C-NMR
(CDCl3) δ: 14.5 (Me); 55.6 (MeO); 60.6 (CH2); 111.0 (C-1); 113.7 (C-3', C-5'); 115.3 (C-6); 123.7,
124.5, 130.5, 136.7 (C-3, C-6a, C-10a, C-10b); 125.1 (C-5); 126.8, 127.8, 129.1 (C-7, C-8, C-9); 128.1
(C-10); 129.2 (C-2); 131.6 (C-2', C-6'); 132.4 (C-1'); 162.8 (C-4'); 164.8 (COO); 184.3 (COAr).

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Ethyl 3-(3,4-dimethoxybenzoyl)-pyrrolo[2,1-a]isoquinoline-1-carboxylate (4r). Light brown crystals,
m.p. 174–176 °C; Yield 69%. Anal. Calcd. C24H21NO5: C 71.45; H 5.25; N 3.47. Found: C 71.78; H
5.57; N 3.79. FT-IR (cm−1): 1184, 1266, 1458, 1515, 1625, 1709, 2957. 1H-NMR (CDCl3) 1.40 (t, 3H,
J = 7.1 Hz, Me); 3.97, 3.99 (2s, 6H, 2MeO); 4.37 (q, 2H, J = 7.1 Hz, CH2); 6.98 (d, 1H, J = 8.3, H-6');
7.26 (d, 1H, J = 7.4 Hz, H-6); 7.48 (d, 1H, J = 2.1, H-3'); 7.54 (dd, 1H, J = 8.3, 2.1 Hz, H-5'); 7.84 (s,
1H, H-2); 7.61–7.67 (m, 2H, H-8, H-9); 7.72–7.78 (m, 1H, H-7); 9.52 (d, 1H, J = 7.4 Hz, H-5);
9.80–9.85 (m, 1H, H-10). 13C-NMR (CDCl3) δ: 14.5 (Me); 56.1 (2MeO); 60.5 (CH2); 110.1 (C-1);
110.3, 112.3 (C-2', C-5'); 115.2 (C-6); 123.6, 124.8, 130.5, 132.5, 136.7 (C-3, C-6a, C-10a, C-10b,
C-1'); 123.8 (C-6'); 125.1 (C-5); 126.7 (C-7); 127.7, 129.1 (C-8, C-9); 128.1 (C-10); 129.2 (C-2);
149.1, 152.7 (C-3', C-4'); 164.7 (COO); 184.7 (COAr).
4. Conclusions
In conclusion, new pyrrolo[2,1-a]isoquinolines were obtained by a simple one-pot three component
cycloaddition reaction starting from readily available materials. The structures of the new compounds
were assigned by IR and NMR spectroscopy. The regioselectivity of the cycloaddition was deduced on
1
the basis of H-NMR data. The reaction is of potential interest due to importance of obtaining
combinatorial libraries of compounds and due to the interest shown in the biological activity of
compounds containing pyrrolo[2,1-a]isoquinoline skeletons.
Conflict of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 4a–r are available from the authors.
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