Microwave-assisted synthesis of substituted hexahydropyrrolo[3,2-c] quinolines

Article abstract of DOI:10.3390/12010049

New compounds with the ethyl hexahydro-1H-pyrrolo[3,2-c]quinoline-2- carboxylate skeleton were prepared by microwave-assisted intramolecular 1,3-dipolar cycloaddition reactions. The reactions were carried out under solvent-free conditions and compared with the same reaction in the presence of a solvent and a catalyst. Steric effects on the selectivity of the reaction were noted and evaluated.

Full text of DOI:10.3390/12010049

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Molecules 2007, 12, 49-59
molecules
ISSN 1420-3049
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Full Paper
Microwave-Assisted Synthesis of Substituted Hexahydro-
pyrrolo[3,2-c]quinolines†
Michal Neuschl 1, Darek Bogdal 2 and Milan Potacek 1,*
1
Department of Organic Chemistry, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic
2
Faculty of Chemical Engineering and Technology, Politechnika Krakowska, Warszawska 24, 31-155
Krakow, Poland, E-mail: pcbogdal@cyf-kr.edu.pl
* Author to whom correspondence should be addressed; E-mail:potacek@chemi.muni.cz
† This paper is dedicated to Professor Stefan Toma on the occasion of his birthday.
Received: 22 December 2006; in revised form: 15 January 2007 / Accepted: 23 January 2007 /
Published: 24 January 2007
Abstract: New compounds with the ethyl hexahydro-1H-pyrrolo[3,2-c]quinoline-2-
carboxylate skeleton were prepared by microwave-assisted intramolecular 1,3-dipolar
cycloaddition reactions. The reactions were carried out under solvent-free conditions and
compared with the same reaction in the presence of a solvent and a catalyst. Steric effects
on the selectivity of the reaction were noted and evaluated.
Keywords: Azomethine ylide, intramolecular 1,3-dipolar cycloaddition, microwave -
assisted synthesis, hexahydro-1H-pyrrolo[3,2-c]quinoline.
Introduction
The pyrrolo[3,2-c]quinoline skeleton can be found in Nature in the alkaloids martinelline and
martinellic acid, isolated from South American plant root extracts [1-3]. These alkaloids are also
known for their biological activity as antagonists of the bradykinine B1 and B2 receptors and their
antibiotic activity against both Gram-positive and Gram-negative bacteria [4]. These properties have
led to the investigation of possible synthetic pathways leading to these substances. Intramolecular
cycloaddition of sarcosine (N-methylglycine) to N-(2-formylphenyl)-N-allyl-4-toluenesulfonamide in
refluxing DMF led to cis–fused pyrrolino[3,2-c]quinoline derivatives via an azomethine ylide formed

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Molecules 2007, 12
in situ. The cycloaddition was accompanied with decarboxylation, which was very important for the
subsequent synthetic steps. These attempts were further developed into a total synthesis of the
martinelline skeleton [5,6].
Generally, application of microwaves in synthesis leads to substantial reductions in reaction times,
yield increases, solvent and waste minimization, and sometimes, to chemo-, regio- and
stereoselectivity changes. During microwave irradiation the 2,450 MHz frequency is typically used
and, since the individual oriented polar molecules present cannot match the resulting very fast changes
in the electric field, this results in the transformation of part of the applied energy into heat, thus
producing a temperature increase [7,8]. In the past we have investigated intramolecular microwave -
assisted 1,3-dipolar cycloaddition reactions of in situ generated azomethine ylides leading to
hexahydrochromeno-[4,3-b]pyrroles 3 [9,10]. A simple protocol was developed for these reactions,
whereby the ylides were generated under microwave irradiation by the reaction of ortho-(3-
alkenyl)oxybenzaldehydes 1 with secondary amines 2, prepared in turn by N-alkylation of alkyl
aminoacetates. The subsequent cycloadditions gave the products 3 in very good yields and selectivity
(Scheme 1).
Scheme 1.
R3
EWG
N
O
O
R1
R2
H
R3
N
µW
R1
H
+
EWG
H
200 oC
R2
H
O
3
2
1
In addition, the effect of various electron-withdrawing groups (EWG) on the stability and
reactivity of the dipoles was established. In this paper we would like to report the behaviour of
protected ortho-(3-alkenyl)amino benzaldehyde 4 in a similar microwave assisted reaction with
secondary amines 5. The aim of our study of these reactions under microwave conditions was the
creation of ylides capable of undergoing a subsequent intramolecular 1,3-dipolar cycloaddition
(Scheme 2).
Scheme 2.
R
CO2Et
N1
O
2
H
9
6
9b
3
R
N
H
µW
8
7
3a
+
CO2Et
H
H
4
N
N
5
PG
PG
4
5a-c
6a-c

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Molecules 2007, 12
Results and Discussion
The secondary amines 5 needed for the proposed reactions were synthesized from ethyl
bromoacetate in acetonitrile at low temperature according to the literature [11]. Their yields are
presented in Table 1.
Table 1. Yields of the amino components 5 prepared for the azomethine ylide synthesis.
Amine
5a
R
Yield [%]
n-Bu
CH3
Bn
84
85
78
5b
5c
The preparation of the second component − aldehyde 4 − started with 2-nitrobenzaldehyde. Our
initial intention was to reduce the nitro group after protection of the aldehyde moiety by transformation
into an acetal, but although several reported nitro group reduction methods were applied [12-15], we
did not succeed in preparing the target in good yields. As an alternative, the preparation of aldehyde 4
was then carried out via a multi-step synthesis starting from ethyl 2-aminobenzoate. First, the amino
group was protected as the corresponding (toluene)sulfonamide, which afterwards was alkylated with
allyl bromide under mild conditions. This led to ethyl 2-(N-tosyl-N-allylamino)benzoate. In the
following step the ester group was reduced with LiAlH4 and the alcohol thus prepared was finally
oxidized with MnO2 to give the required aldehyde 4 (Scheme 3) [6].
Scheme 3.
O
O
O
OEt
NH2
p-TsCl, pyridine
Br
OEt
OEt
CH2Cl2, r.t.
80%
K2CO3, acetone, r.t.
97%
NH
Ts
N
Ts
O
OH
MnO2
LiAlH4
N
Et2O, 0°C
80%
CH2Cl2, r.t.
70%
N
Ts
Ts
4
The microwave - assisted reaction of aldehyde 4 with amines 5 was optimized using amine 5a as a
model substrate. The reactions were carried out in a Prolabo 402 microwave reactor (300 W, 2,450
MHz) and the reaction temperature was controlled by a thermocouple immersed into the reaction
mixtures. The proposed mechanism of the reaction is shown in Scheme 4. Although the mixture of
components 4 and 5a was homogenized before its introduction to the reaction vessel, full

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Molecules 2007, 12
homogenization did not take place until the melting point of the aldehyde 4 (110 °C) was reached. The
reaction temperature was then slowly increased until decomposition of the reaction mixture occurred at
a temperature of 235 °C. A temperature of 215 °C was finally found to be optimal. The conversion of
aldehyde 4, as well as the product formation, were followed by HPLC. The reaction was complete (no
further increase in the concentrations of the reaction products was observed) within 12 min. The yields
ranged between 94 – 97% (Figure 1).
Scheme 4. The proposed mechanism of the investigated reaction.
O
O
OH
N
H
N
R
CO Et
2
H
N
R
CO Et
2
R
+
HN
CO Et
2
N Ts
N
Ts
Ts
R
n-Bu
CH3
Bn
a
b
c
4
5
-H O
2
CO Et
2
R
N
CO Et
2
H
N
R
N Ts
CO Et
N
2
1,3-DC
R
N Ts
H
N
Ts
6 (a mixture of diastereomers)
Figure 1. Conversion of aldehyde 4 in the presence of amine 5a to the diastereomeric
mixture 6 under microwave irradiation at 215 °C.
100
90
80
70
60
Product 6
50
Aldehyde 4
40
30
20
10
0
0
2
4
6
8
10
Time [min]
12
14
16
18