Microwave-assisted multi-step synthesis of novel pyrrolo-[3,2-c]quinoline derivatives

Article abstract of DOI:10.1016/j.tet.2008.04.034

A new approach for the synthesis of original substituted pyrrolo-[3,2-c]quinoline derivatives using microwave-assisted chemistry is described. The use of microwave activation in this synthesis resulted in high yielding and clean steps. The key step for introducing diversity is the amination or the Pd-catalyzed cross-coupling of an imidoyl chloride derivative, obtained in a straightforward manner and in good yield.

Full text of DOI:10.1016/j.tet.2008.04.034

Tetrahedron 64 (2008) 5949–5955
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Microwave-assisted multi-step synthesis of novel pyrrolo-[3,2-c]quinoline
derivatives
,
b
a
a
b
Hafid Benakki a , Evelina Colacino , Christophe Andre , Farhate Guenoun ,
´
a
a,
*
´ ´
Jean Martinez , Frederic Lamaty
a
´
´
´
`
Institut des Biomolecules Max Mousseron, UMR 5247 CNRS-Universite Montpellier 1 et Universite Montpellier 2, Place Eugene Bataillon, 34095 Montpellier Cedex 05, France
b Universite´ My Isma¨ıl, Faculte´ des Sciences, BP 11201, Zitoune, Mekne`s, Morocco
a r t i c l e i n f o
a b s t r a c t
Article history:
A new approach for the synthesis of original substituted pyrrolo-[3,2-c]quinoline derivatives using mi-
crowave-assisted chemistry is described. The use of microwave activation in this synthesis resulted in
high yielding and clean steps. The key step for introducing diversity is the amination or the Pd-catalyzed
cross-coupling of an imidoyl chloride derivative, obtained in a straightforward manner and in good yield.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 11 February 2008
Received in revised form 31 March 2008
Accepted 8 April 2008
Available online 11 April 2008
Keywords:
Microwave activation
Suzuki coupling
Aza-Baylis–Hillman
Ring-closing metathesis
1. Introduction
researchers to plan new synthetic approaches8,10,15,16 for the
preparation of these molecules.
Microwave-assisted chemistry2 has greatly expanded in recent
years with the arrival of specifically adapted equipment for the
synthesis. The microwave-assisted synthesis found its first appli-
cations in organic chemistry, where some reactions proved to be
100 times faster with the microwave heating than with traditional
ones (oil bath, etc.). The involved reactions are very often cleaner.
Many organic reactions have been explored and adapted under
microwave activation.3,4 Examples of multi-step synthesis in which
each step requiring heating performed under microwave are scarce
in the literature. We report herein a new microwave-enhanced
multi-step synthetic pathway for the preparation of pyrrolo-[3,2-
c]quinoline derivatives.
The pyrrolo-[3,2-c]quinoline and its analogue pyrroloquinoxa-
line skeleton (Fig. 1) have been known for several years as one of
the most widely used motifs in medicinal chemistry. Several
derivatives of such heterocycles possess a wide spectrum of
biological activities, including most notably antitumor5 and hypo-
tensive6 properties, gastric (Hþ/Kþ)-ATPase inhibition,7–9 anti-in-
flammatory activities,10 and 5-HT3 agonism11–13 (Fig. 1). The
discovery of bradykinine receptor agonist in an extract from the
tropical plant Martinella iquitosensis14 has renewed the interest of
The wide potential of such a structure core unit has prompted us
to develop an alternative synthetic route for the synthesis of 4-
amino-1-methyl-4-1H-pyrrolo-[3,2-c]quinoline and 4-aryl-1-meth-
yl-4-1H-pyrrolo-[3,2-c]quinoline derivatives.
As a continuation of our ongoing studies in the development of
novel routes for the synthesis of substituted pyrroles,17,18 an alter-
native and convenient pathway leading to new series of pyrrolo-
[3,2-c]quinoline derivatives is presented. The key intermediate is
an imidoyl chloride and the diversity was introduced efficiently
using microwave-activated amination11–13,19–22 and Suzuki2,19,22–27
cross-coupling reaction. In recent years these methods have found
a widespread application in several areas of organic synthesis
because they lead to the Csp2 —N or Csp2 —Csp2 bond formation,
which cannot be easily formed using classical transformations.
The proposed retrosynthetic approach of imidoyl chloride 8 is
presented in Scheme 1.
Examination of Scheme 1 reveals that, 4-chloro-1-methyl-
1H-pyrrolo-[3,2-c]quinoline can be obtained from the
corresponding amide via a chlorination reaction, and 1-methyl-
1H-pyrrolo-[3,2-c]quinolin-4(5H)-one in turn would arise from
cyclization of 1-methyl-2-(2-aminophenyl)-1H-pyrrole-3-carboxy-
late. The latter precursor would be synthesized according to
the procedure, which has been developed in our group,18 via
an aza-Baylis–Hillman/ring-closing metathesis/aromatization se-
quence.28–30
* Corresponding author.
E-mail address: frederic.lamaty@univ-montp2.fr (F. Lamaty).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.034

5950
H. Benakki et al. / Tetrahedron 64 (2008) 5949–5955
R2
NH
N
H
N
N
RO2C
N
N
H
N
H
N
N
F3C
N
N
R3
H
NH
N
R1
H
N
NH2
NH
Martinelline R =
General structure for
3 CGS 12066B
(H+/K+)-ATPase inhibitors
Martinellinic acid R = H
Figure 1. Examples of active pyrroloquinoline and quinoxaline derivatives.
Ts
O
N
N
HN
N
O
H
OMe
+
Ts-NH2
+
CO2Me
CO2Me
NO2
NO2
N
8
Cl
N
O
NO2
H
Scheme 1. Retrosynthesis of imidoyl chloride 8.
2. Results and discussion
bycrystallization in a mixture of dichloromethane, diethylether, and
pentane was reacted with allyl bromide42 in the presence of K2CO3
in DMF to yield quantitatively the corresponding diene 2. The
reaction was performed either at room temperature within 12 h or
heating under microwave irradiation at 100 ꢀC within 10 min
without affecting the yield. Diene 2 was used in the next step
without further purification. Pyrroline 3 was formed using ring-
closing metathesis43 known to be an efficient method for the
synthesis of heterocyclic structures from linear precursors. While
cyclization of the diene 2 was complete within 12 h at room
Scheme 2 describes the synthesis of the imidoyl chloride unit.8
The first step in this strategy was the synthesis of the
unsaturated
b-aminoester 1 through the 3-component one-pot
aza-version of the Baylis–Hillman reaction.18,31–41 The reaction was
performed using a nitrobenzaldehyde excess and methylacrylate, in
the presence of DABCO, molecular sieves, titanium isopropoxide as
a Lewis acid, and i-PrOH as solvent to yield 64% of 1 along with 30%
of the corresponding
b
-hydroxyester. The
b-aminoester 1 recovered
H
Ts
Ts
O
H
N
N
DABCO
o
CO2Me
CO2Me
Br
TAMIS 4A
+
Ts-NH2
+
CO2Me
Ti(OiPr)4
isopropanol
64 %
K2CO3
DMF
98%
NO2
NO2
1
NO2
2
GRUBBS II
CH2Cl2
MW / 100 °C
87%
Ts
N
N
N
HN
CH3I
Cs2CO3
t
H2 / Pd / C
BuOK
MeOH
98%
CO2Me
NO2
CO2Me
CO2Me
NO2
DMF
98%
DMF
89%
CO2Me
NO2
NH2
3
5
4
6
CH3COOH
sec-Butanol
MW / 100 °C
98%
N
N
POCl3
MW / 100 °C
98%
N
Cl
N
O
H
7
8
Scheme 2. Procedure for the preparation of imidoyl chloride.8

H. Benakki et al. / Tetrahedron 64 (2008) 5949–5955
5951
OH
R1
N
N
N
HN
Ar
B
R2
OH
R1
CH3CN / MW
140 °C/5h
Pdcat / Cs2CO3
water / dioxane
4h / MW / 100 °C
N
9 a-f
N
R2
N
8
Cl
N
10 a-k
Ar
Scheme 3. Amination and arylation of imidoyl chloride skeleton.
Table 1
temperature using 10% second generation Grubbs’ catalyst with 87%
yield, it could be conveniently accelerated by microwave using only
4% of the catalyst. Under these conditions (microwaves, 100 ꢀC,
CH2Cl2) completion of the cyclization was reached within 2 h
yielding 84% of 3. An interesting point is that the cyclization of 2 was
slower than in the case of other similar dienes without a nitro
group.18 This result might be due to the coordinating effect44–46
between the nitro substituent and the ruthenium catalyst. The next
step was cleavage of the tosyl group.17,47,48 Using t-BuOK in DMF at
room temperature, 89% of substituted pyrrole 4 was obtained
within 2 h via elimination–aromatization. The pyrrole 4 was reacted
with methyl iodide42 in the presence of Cs2CO3 in DMF to yield the
protected pyrrole 5 in quantitative yield. It should be noted that
conversionwas incomplete when K2CO3 was used instead of Cs2CO3.
Reduction10 with Pd/C under H2 atmosphere yielded the stable
amine derivative 6 in excellent yield after simple filtration over
Celite and evaporation of the solvent. Cyclization of the latter amine
was first carried out using sodium hydride in THF. The conversion
was complete but the cyclic product was difficult to recover since it
was soluble only in DMSO. Finally a solution of 6 in sec-butanol in
the presence of 1% acetic acid49 was irradiated with microwaves for
4 h at 100 ꢀC to afford the cyclic unit 7 in quantitative yield without
further purifications. The key step in this strategy was the in-
troduction of chlorine in the 4-position. This was achieved by
transformation of the amide function into an imidoyl chloride using
phosphorus oxychloride.11 The reaction was carried out using clas-
sical conditions (refluxing 7 in phosphorus oxychloride for 7 h) or
activation by microwave irradiation for only 15 min.
Aminationa products of imidoyl chloride 8
Entry
Amine
Product
Yield (%)
1
2
3
4
5
6
Pyrrolidine
Piperidine
4-Methylpiperazine
Morpholine
Benzylamine
Pyrrole
9a
9b
9c
9d
9e
9f
95
85
80
63
73
87
a
CH3CN, MW, 140 ꢀC, 5 h.
a catalytic system.2,23 The reaction was heated from 80 to 180 ꢀC and
monitored by HPLC. After 2 h at 180 ꢀC the boronic acid disappeared
completely, although some of the imidoyl chloride remained. The
reaction was complete by addition of one more equivalent of
boronic acid. A column chromatography was necessary to obtain the
pure final product. By using the PEPPSI51 precatalyst (Pyridine-En-
hanced Precatalyst Preparation Stabilization and Initiation) instead
of Pd(OAc)2, and in the presence of Cs2CO3, the desired compounds
were obtained by heating at 100 ꢀC under microwaves. These
products were obtained in pure form after usual work-up without
further purification. PEPPSI is a Pd complex stabilized by NHC
(N-Heterocyclic Carbene) and pyridine ligands. They are known to
allow rapid and quantitative C–C bond formation in Suzuki cross-
coupling reactions.51 These results suggest that bulky NHC ligands
lead to fast reductive elimination, with no side reactions or catalyst
decomposition similarly with bulky phosphines.52,53 This catalyst
seemed well adapted to Pd-catalyzed microwave-enhanced re-
actions. Results are summarized in Table 2.
Various substituents can be borne by the boronic acid. The
position of the substituent on the aromatic ring did not seem to
influence the outcome of the reaction since the more hindered
o-tolyl boronic acid (entry 2) or o-anisyl boronic acid (entry 5) gave
essentially the same yield of product as in the case of m- or p-tolyl
boronic acid (entries 3 and 4). Fluorinated quinolines could also be
synthesized (entries 6 and 7). Finally this method provided access
to a variety of polyaromatic compounds (entries 8–11).
In contrast to what has been emphasized in the literature,9,50
the introduction of chlorine atom together with microwave-acti-
vated transformations allowed us to introduce successfully differ-
ent substituent in the 4-position of the skeleton. These reactions
are highlighted in Scheme 3.
Compound 8 was used for the preparation of substituted pyr-
roloquinolines. Reactions with amines and boronic acids were
studied. The first tested reaction was the nucleophilic substitution
of the chlorine atom by amines. Preliminary tests were carried out
using different amines as nucleophiles and NaH as a base in THF but
no product could be obtained under these conditions. Then the
procedure described by Campiani11 and co-workers was tried;
a mixture of imidoyl chloride 8 and amine in ethylene glycol was
heated using classical heating or activation by microwave irradia-
tions. In both cases the reaction was incomplete. In sharp contrast,
by using CH3CN instead of ethylene glycol, completion of all the
reactions was reached, even with less nucleophilic pyrrole. The
reaction gave good to excellent yields with various amines. Results
are summarized in Table 1. A lower yield was obtained in the case of
morpholine (entry 4) due to the difficulty in separating the
expected product 9d from the starting amine.
Often, the introduction of specific substituents other than sim-
ple alkyl ones in the 4-position on the performed skeleton required
laborious steps coupled with drastic experimental conditions.10,16
To our knowledge, this is the first time that introduction of various
substituents was carried out without any problems.
Table 2
Arylationa of imidoyl chloride
Entry Aryl
Product Yield (%)
1
2
3
4
5
6
7
8
Phenyl
o-Tolyl
m-Tolyl
p-Tolyl
2-Methoxyphenyl
4-Fluorophenyl
4-Trifluromethoxyphenyl
Naphthalen-1-yl
Biphenyl
10a
10b
10c
10d
10e
10f
10g
10h
10i
84
70
74
73
75
90
76
84
80
91
73
The chlorine atom could be substituted by cyclic secondary
amines such as pyrrolidine, morpholine or piperazine. Benzylamine
gave also good yield of the expected product. As a last example,
pyrrole reacted with
pyrroloquinoline.
8
to give
a
pyrrole-substituted
9
10
11
Benzofuran-2-yl
1,2,3,4-Tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl 10k
10j
The second investigated reaction was the Suzuki coupling of the
imidoyl chloride with a boronic acid. First, Pd(OAc)2, PPh3 in the
presence of K2CO3 in a mixture of water/dioxane (1:1) was used as
a
Water/dioxane (1:1), PEPPSI (0.02 equiv), Cs2CO3 (1.5 equiv), MW, 100 ꢀC, 4 h.

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H. Benakki et al. / Tetrahedron 64 (2008) 5949–5955
3. Conclusion
232 ml of CH2Cl2, and the mixture was stirred overnight at room
temperature. Then 0.48 ml of DMSO (50 equiv/Ru) was added and
the mixture was stirred for 24 h at room temperature. The solvent
was evaporated under vacuum. Column chromatography over silica
gel and Et2O/cyclohexane (1:9 to 3:7) as developing solvent affords
0.81 g (87%) of the desired 2,5-dihydropyrrole 3.
A new approach to the synthesis of a series of 4-amino-1-
methyl-4-1H-pyrrolo-[3,2-c]quinoline and 4-aryl-1-methyl-4-1H-
pyrrolo-[3,2-c]quinoline derivatives is described. This approach is
based on high yielding steps, which do not need cumbersome
purifications. In contrast to previously described methods, this new
pathway allowed convenient introduction onto the 4-position the
title ring system of a variety of amines and aryl compounds. This is
largely due the use of microwave activation during several steps of
the synthesis.
Conditions B. A solution of Cl2(PCy3)-(IMes)Ru]CHPh (6.4
in CH2Cl2 (3 ml) was added to a solution of N-allyl- -aminoester
(500 mg, 1.16 mmol) in CH2Cl2 (9 ml), and the mixture was irradi-
ated by microwaves for 2 h at 150 ꢀC. Then 165
l of DMSO
mmol)
b
m
(50 equiv/Ru) was added and the mixture was stirred for an addi-
tional time of 24 h. The solvent was dried under vacuum. Column
chromatography over silica gel and Et2O/cyclohexane (1:9 to 3:7) as
developing solvent affords 380 mg (82%) of the desired 2,5-dihy-
dropyrrole 3.
4. Experimental section
4.1. Methyl 2-((2-nitrophenyl)(p-toluenesulfonylamino)-
methyl)acrylate (1)
Mp 125–127 ꢀC; 1H NMR (CDCl3, Me4Si)
d 2.36 (s, 3H), 3.45 (s,
3H), 4.29 (td, 1H, J¼2.68 Hz), 4.54 (ddd, 1H, J¼6 Hz), 6.61–6.64 (m,
1H), 6.68 (t, 1H, J¼2 Hz), 7.27 (d, 2H, J¼8.27 Hz), 7.31–7.36 (m, 1H),
7.48–7.50 (t, 2H, J¼4.23 Hz, J0¼3.8 Hz), 7.74 (d, 2H, J¼8.27 Hz), 7.83
To a mixture of p-toluenesulfonamide (9 g, 52.6 mmol), DABCO
(885 mg, 7.9 mmol), and molecular sieves (4 Å, 10.5 g, 200 mg/
mmol of substrate) in 27 ml of 2-propanol were added 2-nitro-
benzaldehyde (11.9 g, 78.8 mmol), methyl acrylate (7.44 g,
86.7 mmol), and titanium isopropoxide (0.3 g, 1.05 mmol). The re-
action mixture was stirred at room temperature overnight and
filtered over Celite. The Celite was rinsed three times with CH2Cl2.
The solvent was evaporated and the residue was dissolved in AcOEt,
neutralized with aqueous KHSO4 (10%), and washed with saturated
NaHCO3 and brine. The organic layer was dried over MgSO4, fil-
tered, and evaporated. Hot crystallization in a 5:5:1 mixture of
pentane, diethylether, and dichloromethane afforded 13 g (63%) of
(d, 1H, J¼8.22 Hz); 13C NMR (CDCl3, Me4Si)
d 21.6, 52.1, 55.7, 62.3,
124.6,127.8,128.6,129.7,130.0,133.1,133.4,135.1,135.7,136.6,144.2,
148.7, 161.6; ESIMS m/z 827 (2MþNa)þ, 425 (MþNa)þ, 403.2
(MþH)þ; HRMS calcd for C19H19N2O6S, 403.0964; found, 403.0970.
4.4. Methyl 2-(2-nitrophenyl)-1H-pyrrole-3-carboxylate (4)
To a stirred solution of 2,5-dihydropyrrole (2 g, 4.97 mmol) in
50 ml of DMF was added t-BuOK (2.78 g, 24.8 mmol). The mixture
was stirred at room temperature for 2 h, then 350 ml of AcOEt was
added and the mixture was neutralized with a 1% aqueous solution
of KHSO4 and washed with NaHCO3 saturated water, and brine. The
organic layer was dried over MgSO4, filtered, and evaporated. Col-
umn chromatography over silica gel and Et2O/cyclohexane (1:9 to
1:1) as developing solvent yields 1.09 g (89%) of 4.
b
-aminoester 1.
Mp 109–111 ꢀC; 1H NMR (CDCl3, Me4Si)
d 2.41 (s, 3H), 3.58 (s,
3H), 5.69 (s,1H), 5.98 (d,1H, J¼8.62 Hz), 6.11 (d,1H, J¼8.62 Hz), 6.23
(s, 1H), 7.23–7.29 (m, 2H), 7.38–7.41 (m, 1H), 7.52–7.57 (m, 1H), 7.70
(d, 3H, J¼8.12 Hz), 7.84 (d, 1H, J¼8.06 Hz); 13C NMR (CDCl3, Me4Si)
d
21.1, 52.1, 54.4, 124.5, 127.2, 128.8, 129.1, 129.6, 130.1, 133.1, 133.4,
1H NMR (CDCl3, Me4Si)
d
3.55 (s, 3H), 6.64 (t, 1H, J¼2.8 Hz), 6.76
137.1, 137.4, 143.6, 148.0, 165.4; ESIMS m/z 781.25 (2MþH)þ, 391.1
(MþH)þ, 220.00 (MꢁTsNH)þ; HRMS calcd for C18H19O6N2S,
391.0964; found, 391.0978.
(t, 1H, J¼2.8 Hz), 7.37 (d, 1H, J¼1.5 Hz), 7.44–7.49 (m, 1H), 7.52–7.58
(m, 1H), 7.94 (d, 1H, J¼1.5 Hz), 8.6 (s, 1H); 13C NMR (CDCl3, Me4Si)
d
51.0, 111.4, 113.4, 118.7, 124.4,127.3, 129.5, 131.4, 132.4, 132.5, 149.5,
164.8; ESIMS m/z 215.1 (MꢁOCH3)þ, 247.2 (MþH)þ, 264.2
(MþH2O)þ, 269.2 (MþNa)þ; HRMS calcd for C12H11N2O4, 247.0719;
found, 247.0738.
4.2. Methyl 2-((N-allyl-N-tosylamino)(2-nitrophenyl)-
methyl)acrylate (2)
To a mixture of
b
-aminoester 1 (4 g, 10.2 mmol) and K2CO3 (14 g,
4.5. Methyl 1-methyl-2-(2-nitrophenyl)-1H-pyrrole-3-
102 mmol) in 140 ml of DMF was added allylbromide (2.99 g,
108 mmol). The reaction mixture was stirred overnight at room
temperature, then filtered and diluted with AcOEt. The organic
layer was successively washed with water and brine, dried over
carboxylate (5)
To
a mixture of 4 (1 g, 4.06 mmol) and Cs2CO3 (5.29 g,
16.25 mmol) in 250 ml of DMF was added methyliodide (2.3 g,
16.25 mmol). The reaction mixture was stirred overnight at room
temperature, the solvent was evaporated, and the residue was di-
luted with AcOEt. The organic layer was washed with water and
brine, dried over MgSO4, filtered, and evaporated, to yield 1 g (98%)
of 5.
MgSO4, filtered, and evaporated, to yield 4.29 g (98%) of N-allyl-
aminoester 2.
b-
Mp 83–85 ꢀC; 1H NMR (CDCl3, Me4Si)
d 2.33 (s, 3H), 3.46 (s, 3H),
4.01 (dd, 1H, J¼6.57 Hz, J0¼6.43 Hz), 8.03 (dd, 1H, J¼6.57 Hz,
J0¼6.43 Hz), 4.88–4.89 (m, 1H), 4.90 (d, 1H, J¼1.23 Hz), 5.40–5.49
(m, 2H), 6.36 (s, 1H), 6.37 (s, 1H), 7.15–7.18 (m, 2H), 7.36–7.41 (m,
1H), 7.54–7.59 (m, 3H), 7.69 (d, 1H, J¼7.71 Hz), 7.85 (d, 1H,
Mp 125–127 ꢀC; 1H NMR (CDCl3, Me4Si)
d 3.35 (s, 3H), 3.49 (s, 3H),
6.56 (d,1H, J¼2.97 Hz), 6.63 (d,1H, J¼2.97 Hz), 7.31 (dd,1H, J¼1.6 Hz,
J¼8.08 Hz); 13C NMR (CDCl3, Me4Si)
d 43.1, 50.8, 52.1, 58.5, 118.7,
J’¼1.6 Hz), 7.50–7.64 (m, 1H), 7.74 (d, 1H, J¼8.27 Hz), 8.03 (dd, 1H,
125.3, 127.7, 128.7, 129.3, 129.6, 130.5, 131.5, 132.9, 133.2, 133.7,
134.4, 137.8, 138.3, 143.3, 148.0, 165.4; ESIMS m/z 883.4 (2MþNa)þ,
453.2 (MþNa)þ, 431.2 (MþH)þ, 220.4 (MꢁTsNC3H5)þ, 188.4
(MꢁTsNC3H5ꢁOMe)þ; HRMS calcd for C21H23N2O6S, 431.1277;
found, 431.1272.
J¼1.3 Hz, J’¼1.3 Hz); 13C NMR (CDCl3, Me4Si)
d 31.9, 50.8,110.2,113.5,
122.9, 124.3,127.8, 129.8,132.8, 133.0, 133.2, 149.9, 164.6; ESIMS m/z
283.2 (MþNa)þ, 261.2 (MþH)þ, 229.2 (MꢁOCH3)þ; HRMS calcd for
C13H13N2O4, 261.0875; found, 261.0870.
4.6. Methyl 1-methyl-2-(2-aminophenyl)-1H-pyrrole-3-
4.3. Methyl 2,5-dihydro-2-(2-nitrophenyl)-1-tosyl-1H-
carboxylate (6)
pyrrole-3-carboxylate (3)
To a solution of 5 (1 g, 3.84 mmol) in methanol (200 ml) was
added 10% (0.35 g) of Pd(OH)2/C. The mixture was stirred for 2 h at
room temperature under H2 atmosphere. The crude product was
Conditions A. Cl2(PCy3)-(IMes)Ru]CHPh (0.1 g, 0.32 mmol) was
added to a solution of N-allyl-b-aminoester (1 g, 2.32 mmol) in

H. Benakki et al. / Tetrahedron 64 (2008) 5949–5955
5953
filtered over Celite, washed with warmed methanol, and evapo-
rated to afford 0.86 g (98%) of the title compound as a white solid.
d 3.33 (s, 3H), 3.53 (s,
2H), 3.59 (s, 3H), 6.59–6.62 (m, 2H), 6.69–6.77 (m, 2H), 6.97 (dd, 1H,
1H NMR (CD3OD, Me4Si)
d
2.01–2.06 (m, 4H), 3.79 (t, 4H,
J¼6.4 Hz), 4.06 (s, 3H), 6.84 (d, 1H, J¼3.2 Hz), 7.12 (d, 1H, J¼3.2 Hz),
Mp 113–115 ꢀC; 1H NMR (CDCl3, Me4Si)
7.27 (t, 1H, J¼7.3 Hz), 7.41 (t, 1H, J¼7.3 Hz), 7.60 (d, 1H, J¼8.3 Hz),
8.15 (d, 1H, J¼8.3 Hz); 13C NMR (CD3OD, Me4Si)
d 26.4, 38.8, 51.2,
J¼J’¼1.4 Hz), 7.12–7.19 (m, 1H); 13C NMR (CDCl3, Me4Si)
d
34.3, 50.9,
106.4, 111.7, 115.9, 121.8, 122.4, 124.5, 128.9, 131.1, 136.1, 150.6, 158.0;
ESIMS m/z 252.0 (MþH)þ; HRMS calcd for C16H18N3, 252.1501;
found, 252.1500.
110.0, 113.6, 115.5, 117.4, 118.2,122.5,129.9,131.4, 135.5, 145.8,165.0;
ESIMS m/z 461.1 (2MþH)þ, 253.1 (MþNa)þ, 231.1 (MþH)þ, 199.1
(MꢁOCH3)þ; HRMS calcd for C13H15N2O2, 231.1045; found,
231.1040.
4.9.2. 1-Methyl-4-(piperidin-10-yl)-1H-pyrrolo-[3,2-c]-
quinoline (9b)
4.7. 1-Methyl-1H-pyrrolo-[3,2-c]quinolin-4(5H)-one (7)
To a solution of 6 (0.25 g, 1.08 mmol) in sec-butanol (10 ml), was
The crude product was purified by silica gel chromatography
(CH2Cl2/MeOH¼100:1) to yield 20.9 mg (85%) of the title
compound.
added 100
m
l of acetic acid. The mixture was irradiated with mi-
1H NMR (CD3OD, Me4Si)
d 1.65–1.72 (m, 6H), 3.66 (t, 4H,
crowaves for 4 h at 100 ꢀC. The solvent was evaporated under re-
duced pressure to yield 0.21 g (98%) of the product as a white solid.
J¼4.86 Hz), 4.08 (s, 3H), 6.54 (d, 1H, J¼3.0 Hz), 6.90 (d, 1H,
J¼3.0 Hz), 7.19–7.25 (m, 1H), 7.37–7.42 (m, 1H), 7.78–7.92 (m, 1H),
Mp 285–289 ꢀC; 1H NMR (CD3OD, Me4Si)
d
4.95 (s, 3H), 7.42 (d,
8.14 (d, 1H, J¼8.2 Hz); 13C NMR (CD3OD, Me4Si)
d 25.1, 26.2, 38.2,
1H, J¼2.9 Hz), 7.99–8.04 (m, 2H), 7.50–8.25 (m, 2H), 8.96 (d, 1H,
49.7, 102.5, 113.9, 116.8, 119.9, 122.2, 126.2, 127.8, 131.1, 135.6, 150.6,
158.0; ESIMS m/z 266.3 (MþH)þ; HRMS calcd for C17H20N3,
266.1657; found, 266.1642.
J¼8.08 Hz), 12.08 (s, 1H); 13C NMR (CD3OD, Me4Si)
d 40.2, 106.5,
116.2, 118.7, 119.0, 123.8, 124.1, 129.5,131.7, 135.6, 139.1, 161.9; ESIMS
m/z 419.1 (2 MþNa)þ, 397.1 (2 MþH)þ, 221.1 (MþNa)þ, 199.1
(MþH)þ; HRMS calcd for C12H11N2O, 199.0871; found, 199.0874.
4.9.3. 1-Methyl-4-(4-methylpiperazin-1-yl)-1H-pyrrolo-
[3,2-c]quinoline (9c)
4.8. 4-Chloro-1-methyl-1H-pyrrolo-[3,2-c]quinoline (8)
The crude product was purified by silica gel chromatography
(CH2Cl2/MeOH¼100:1) to yield 20.73 mg (80%) of the title
compound.
Thermal conditions.
A mixture of quinolinone 7 (500 mg,
2.52 mmol) and freshly distilled POCl3 (30 ml) was refluxed for 7 h.
The cooled crude product was poured into ice-water and the
precipitate was extracted with CH2Cl2 (3ꢂ40 ml). The combined
extracts were dried over MgSO4 and concentrated under reduced
pressure. The product was recovered as a white solid. The pre-
cipitate in the aqueous phase was filtered and washed with water.
The solid fractions were combined yielding 530 mg (98%) of
imidoyl chloride 8.
1H NMR (CD3OD, Me4Si)
d
2.31 (s, 3H), 2.58 (t, 4H, J¼4.9 Hz), 3.76
(t, 4H, J¼4.9 Hz), 4.12 (s, 3H), 6.54 (d, 1H, J¼3.1 Hz), 6.89 (d, 1H,
J¼3.1 Hz), 7.18–7.26 (m, 1H), 7.37–7.43 (m, 1H), 7.83 (d, 1H,
J¼8.2 Hz), 8.14 (d, 1H, J¼8.2 Hz); 13C NMR (CD3OD, Me4Si)
d 38.2,
46.2, 48.2, 55.2, 102.2, 113.5, 116.9, 120.0, 122.4, 126.3, 127.9, 128.1,
135.7, 144.4, 154.9; ESIMS m/z 281.2 (MþH)þ; HRMS calcd for
C17H21N4, 281.1766; found, 281.1777.
Microwave irradiation. A mixture of quinolinone 7 (500 mg,
2.52 mmol) and freshly distilled POCl3 (10 ml) was irradiated by
microwave for 15 min at 140 ꢀC. Then the crude product was
poured into ice-water and the precipitate was extracted with
CH2Cl2 (3ꢂ40 ml). The combined extracts were dried over MgSO4
and concentrated under reduced pressure. The product was
recovered as a white solid. The precipitate in aqueous phase was
filtered and washed with water. The solid fractions were combined
to yield 530 mg (98%) of imidoyl chloride 8.
4.9.4. 1-Methyl-4-morpholino-1H-pyrrolo-[3,2-c]quinoline (9d)
The crude product was purified by silica gel chromatography
(CH2Cl2/MeOH¼100:1) to yield 15.56 mg (63%) of the title
compound.
1H NMR (CD3OD, Me4Si)
d
3.70 (t, 4H, J¼4.3 Hz, J’¼4.9 Hz), 3.86
(t, 4H, J¼4.3 Hz, J0¼4.9 Hz), 4.14 (s, 3H), 6.51 (d, 1H, J¼3.1 Hz), 6.92
(d, 1H, J¼3.1 Hz), 7.26 (t, 1H, J¼7.0 Hz), 7.42 (t, 1H, J¼7 Hz), 7.85 (d,
1H, J¼8.25 Hz), 8.17 (d, 1H, J¼8.25 Hz); 13C NMR (CD3OD, Me4Si)
d
29.7, 38.2, 49.0, 67.1, 102.0, 113.5, 117.0, 120.0, 122.7, 126.4, 128.1,
Mp 83–85 ꢀC; 1H NMR (CDCl3, Me4Si)
d
4.23 (s, 3H), 6.73 (d, 1H,
135.3, 144.3, 154.9; ESIMS m/z 268.1 (MþH)þ; HRMS calcd for
J¼3.1 Hz), 7.08 (d, 1H, J¼3.1 Hz), 7.51–7.61 (m, 2H), 8.22 (d, 1H,
C16H18N3O, 268.1450; found, 268.1450.
J¼7.6 Hz), 8.30 (dd, 1H, J¼1.74 Hz, J’¼1.06 Hz); 13C NMR (DMSO,
Me4Si)
d
37.6, 101.2, 118.1, 119.7, 121.3, 126.3, 127.0, 128.5, 131.8,
4.9.5. N-Benzyl-1-methyl-1H-pyrrolo-[3,2-c]quinolin-4-amine (9e)
The crude product was purified by silica gel chromatography
(CH2Cl2/MeOH¼100:1) to yield 19.38 mg (73%) of the title
compound.
134.6, 142.7, 144.0; ESIMS m/z 217.1 (MþH)þ; HRMS calcd for
C
12H10N2Cl, 217.0533; found, 217.0548.
4.9. General procedure for the synthesis of 4-amino-1-
methyl-1H-pyrrolo-[3,2-c]quinolines 9a–f
1H NMR (CD3OD, Me4Si)
d
4.14 (s, 3H), 4.89 (d, 2H, J¼4.81 Hz),
6.38 (d, 1H, J¼2.5 Hz), 6.88 (d, 1H, J¼2.9 Hz), 7.19–7.3 (m, 5H), 7.39–
7.43 (m, 2H), 7.84 (d, 1H, J¼8.2 Hz), 8.12 (d, 1H, J¼8.2 Hz); 13C NMR
To a solution of imidoyl chloride 8 (20 mg, 9.25ꢂ10ꢁ2 mmol) in
acetonitrile (2 ml) was added 5 equiv of amine, then the mixture
was irradiated under microwaves for 5 h at 140 ꢀC. The mixture was
diluted with diethylether (20 ml), washed with water (2ꢂ10 ml),
dried over MgSO4, and concentrated under reduced pressure to
obtain the title compounds 9a–e, which were purified by silica gel
chromatography.
(CD3OD, Me4Si) d 38.1, 42.7, 102.4, 118.3, 120.2, 124.2, 125.4, 126.3,
126.5, 128.2, 128.4, 128.9, 129.3, 129.7, 134.5, 139.0, 151.7; ESIMS m/z
288.0 (MþH)þ; HRMS calcd for C19H18N3, 288.1501; found,
288.1496.
4.9.6. 1-Methyl-4-(1H-pyrrol-10-yl)-1H-pyrrolo-[3,2-c]-
quinoline (9f)
The crude product was purified by silica gel chromatography
(CH2Cl2/MeOH¼100:1) to yield 19.88 mg (87%) of the title
compound.
4.9.1. 1-Methyl-4-(pyrrolidin-10-yl)-1H-pyrrolo-[3,2-c]-
quinoline (9a)
The crude product was purified by silica gel chromatography
(CH2Cl2/MeOH¼100:1) to yield 22.09 mg (95%) of the title
compound.
1H NMR (CD3OD, Me4Si)
d 4.22 (s, 3H), 6.34–6.38 (m, 2H), 6.85
(d, 1H, J¼5.45 Hz), 7.06 (d, 1H, J¼5.45 Hz), 7.46 (t, 1H, J¼6.94 Hz),
7.57 (t, 1H, J¼6.94 Hz), 7.64 (d, 2H, J¼6.3 Hz), 8.07 (d, 1H, J¼8.3 Hz),

5954
H. Benakki et al. / Tetrahedron 64 (2008) 5949–5955
8.29 (d, 1H, J¼8.3 Hz); 13C NMR (CD3OD, Me4Si)
d
38.8, 102.1, 110.5,
125.1, 126.3, 128.2, 129.6, 130.4, 130.5, 133.0, 135.0, 144.7, 154.3,
114.1, 118.1, 120.7, 124.9, 126.8, 128.8, 129.7, 129.9, 130.9, 136.8,
143.6; ESIMS m/z 248.1 (MþH)þ; HRMS calcd for C16H14N3,
248.1188; found, 248.1182.
160.2; ESIMS m/z 289.1 (MþH)þ; HRMS calcd for C19H17N2O,
289.1341; found, 289.1342.
4.10.6. 4-(40-Fluorophenyl)-1-methyl-1H-pyrrolo-[3,2-c]-
quinoline (10f)
4.10. General procedure for the synthesis of 4-aryl-1-methyl-
1H-pyrrolo-[3,2-c]quinolines 10a–k
Following the general procedure, the title compound was
obtained in 90% yield as a white solid (23 mg).
To a mixture of imidoylchloride (20 mg, 9.25ꢂ10ꢁ2 mmol),
1H NMR (CDCl3, Me4Si)
d
4.26 (s, 3H), 6.73 (d, 1H, J¼3.1 Hz), 7.05
PEPPSI (1.25 mg, 1.85
m
mol), Cs2CO3 (45 mg, 1.38ꢂ10ꢁ1 mmol), and
(d, 1H, J¼3.1 Hz), 7.12–7.19 (m, 2H), 7.47–7.60 (m, 2H), 7.93–7.99 (m,
boronic acid (9.25 10ꢁ2 mmol) were added water (1.5 ml) and di-
oxane (1.5 ml), then the mixture was irradiated under microwaves
for 2 h at 100 ꢀC. The mixture was diluted with CH2Cl2 (10 ml),
washed with water (2ꢂ5 ml), dried over MgSO4, and concentrated
under reduced pressure to obtain the title compounds.
2H), 8.2 (d, 1H, J¼7.7 Hz), 8.39 (d, 1H, J¼7.7 Hz); 13C NMR (acetone,
Me4Si)
d 38.3, 102.3, 115.8, 116.1, 120.7, 121.7, 126.2, 127.0, 131.2,
131.5, 131.87, 131.97, 135.7, 137.8, 145.4, 153.3, 162.45, 165.7; ESIMS
m/z 277.1 (MþH)þ; HRMS calcd for C18H14N2F, 277.1141; found,
277.1136.
4.10.1. 1-Methyl-4-phenyl-1H-pyrrolo-[3,2-c]quinoline (10a)
Following the general procedure, the title compound was
obtained in 84% yield as a white solid (20 mg).
4.10.7. 1-Methyl-4-(40-(trifluoromethoxy)phenyl)-1H-pyrrolo-
[3,2-c]quinoline (10g)
Following the general procedure, the title compound was
obtained in 76% yield as a white solid (24.05 mg).
1H NMR (CDCl3, Me4Si)
d
4.25 (s, 3H), 6.78 (d, 1H, J¼3.1 Hz), 7.23
(d, 1H, J¼3.1 Hz), 7.40–7.61 (m, 5H), 7.97 (d, 2H, J¼2.89 Hz), 8.24 (d,
1H NMR (CDCl3, Me4Si)
d
4.24 (s, 3H), 6.73 (d, 1H, J¼3.1 Hz), 7.06
1H, J¼2.89 Hz), 8.34 (d, 1H, J¼2.89 Hz); 13C NMR (CDCl3, Me4Si)
(d, 1H, J¼3.1 Hz), 7.28–7.33 (m, 2H), 7.48–7.60 (m, 2H), 7.98–8.03
d
38.2, 102.4, 118.3, 120.2, 120.4, 125.3, 126.3, 128.5, 128.6, 129.1,
(m, 2H), 8.22 (d, 1H, J¼7.8 Hz), 8.36 (d, 1H, J¼7.8 Hz); 13C NMR
129.7, 130.7, 134.8, 140.3, 144.7, 154.7; ESIMS m/z 259.19 (MþH)þ;
(CDCl3, Me4Si) d 38.2, 102.7, 118.3, 120.17, 120.2, 121.0, 122.2, 125.6,
HRMS calcd for C18H15N2, 259.1235; found, 259.12138.
126.5,129.93,130.6,130.7,135.0,139.0,144.6, 149.7, 153.2; ESIMS m/
z 342.9 (MþH)þ; HRMS calcd for C19H14N2OF3, 343.1058; found,
343.1082.
4.10.2. 1-Methyl-4-o-tolyl-1H-pyrrolo-[3,2-c]quinoline (10b)
Following the general procedure, the title compound was
obtained in 70% yield as a white solid (17.6 mg).
4.10.8. 1-Methyl-4-(naphthalen-10-yl)-1H-pyrrolo-[3,2-c]-
quinoline (10h)
1H NMR (CDCl3, Me4Si)
d 2.21 (s, 3H), 4.26 (s, 3H), 6.34 (d, 1H,
J¼3.0 Hz), 7.00 (d, 1H, J¼3.0 Hz), 7.48–7.60 (m, 6H), 8.22 (d, 1H,
Following the general procedure, the title compound was
obtained in 84% yield as a white solid (23.9 mg).
J¼8.3 Hz), 8.38 (d, 1H, J¼8.3 Hz); 13C NMR (300 MHz, CDCl3)
d 20.0,
38.0, 103.1, 118.4, 120.2, 121.7, 124.7, 125.5, 126.2, 128.2, 129.4, 129.6,
130.6, 130.6, 134.2, 136.4, 139.5, 144.5, 156.3; ESIMS m/z 273.1
(MþH)þ; HRMS calcd for C19H17N2, 273.1392; found, 273.1387.
1H NMR (CDCl3, Me4Si)
d
4.27 (s, 3H), 6.27 (d, 1H, J¼3 Hz), 6.97
(d, 1H, J¼3 Hz), 7.33–7.68 (m, 5H), 7.69 (d, 1H, J¼6.8 Hz), 7.81 (m,
3H), 8.27 (d, 1H, J¼8.2 Hz), 8.43 (d, 1H, J¼8.2 Hz); 13C NMR (CDCl3,
Me4Si)
d 38.1, 103.3, 118.5, 120.3, 122.5, 125.3, 125.6, 126.0, 126.4,
4.10.3. 1-Methyl-4-m-tolyl-1H-pyrrolo-[3,2-c]quinoline (10c)
Following the general procedure, the title compound was
obtained in 74% yield as a white solid (18.7 mg).
127.9, 128.1, 129.6, 130.8, 131.8, 132.8, 133.5, 134.0, 134.4, 137.5,
138.4, 144.6, 155.2; ESIMS m/z 309.1 (MþH)þ; HRMS calcd for
C22H17N2, 309.1392; found, 309.1387.
1H NMR (CDCl3, Me4Si)
d 2.65 (s, 3H), 4.52 (s, 3H), 7.05 (d, 1H,
J¼3.1 Hz), 7.31 (d, 1H, J¼3.1 Hz), 7.55 (d, 2H, J¼7.9 Hz), 7.72–7.85 (m,
4.10.9. 4-Biphenyl-1-methyl-1H-pyrrolo-[3,2-c]quinoline (10i)
Following the general procedure, the title compound was
obtained in 80% yield as a white solid (20 mg).
2H), 8.14 (d, 2H, J¼7.9 Hz), 8.49 (d, 1H, J¼8.3 Hz), 8.61 (d, 1H,
J¼8.3 Hz); 13C NMR (CDCl3, Me4Si)
d 21.4, 38.1, 103.2, 118.1, 120.2,
121.8, 125.0, 125.7, 126.2, 128.4, 129.2, 129.5, 130.6, 130.7, 134.3,
1H NMR (CDCl3, Me4Si)
d
4.25 (s, 3H), 6.83 (d, 1H, J¼3.1 Hz), 7.23
136.4, 139.5, 144.5, 156.3; ESIMS m/z 273.1 (MþH)þ; HRMS calcd for
(d, 1H, J¼3.1 Hz), 7.28–7.66 (m, 7H), 7.71 (d, 2H, J¼8.4 Hz), 8.07 (d,
C
19H17N2, 273.1392; found, 273.1387.
2H, J¼8.4 Hz), 8.24 (d, 1H, J¼8.3 Hz), 8.37 (d,1H, J¼8.3 Hz); 13C NMR
(CDCl3, Me4Si)
d 38.2, 103.1, 118.3, 120.2, 120.4, 125.4, 126.4, 127.1,
4.10.4. 1-Methyl-4-p-tolyl-1H-pyrrolo-[3,2-c]quinoline (10d)
Following the general procedure, the title compound was
obtained in 73% yield as a white solid (18.4 mg).
127.2, 127.3, 127.4, 127.6, 127.8, 128.82, 128.89, 129.6, 129.7, 130.7,
134.9, 139.3, 140.9, 141.6, 144.8, 154.3; ESIMS m/z 335.1 (MþH)þ;
HRMS calcd for C24H19N2, 335.54; found, 335.1548.
1H NMR (CDCl3, Me4Si)
d 2.48 (s, 3H), 4.31 (s, 3H), 6.87 (s, 1H),
7.12 (s, 1H), 7.38 (d, 2H, J¼9 Hz), 7.57–7.65 (m, 2H), 7.98 (d, 2H,
4.10.10. 4-(Benzofuran-20-yl)-1-methyl-1H-pyrrolo-[3,2-c]-
quinoline (10j)
Following the general procedure, the title compound was
obtained in 91% yield as a white solid (25 mg).
J¼6 Hz), 8.33 (d, 1H, J¼6 Hz), 8.43 (d, 1H, J¼6 Hz); 13C NMR (CDCl3,
Me4Si)
d
21.4, 38.1, 103.1, 118.3, 120.4, 125.2, 126.9, 127.7, 129.0,
129.2, 129.6, 130.6, 134.8, 137.5, 138.7, 144.7, 154.8; ESIMS m/z
273.0 (MþH)þ; HRMS calcd for C19H17N2, 273.1392; found,
273.1391.
1H NMR (CDCl3, Me4Si)
d
4.22 (s, 3H), 7.09 (t, 1H, J¼3.0 Hz), 7.18–
7.33 (m, 3H), 7.45–7.66 (m, 5H), 8.24 (d, 1H, J¼8.1 Hz), 8.32 (d, 1H,
J¼8.1 Hz); 13C NMR (CDCl3, Me4Si)
d 38.2, 103.2, 107.3, 111.8, 118.6,
4.10.5. 4-(20-Methoxyphenyl)-1-methyl-1H-pyrrolo-[3,2-c]-
quinoline (10e)
119.1, 120.2, 121.7, 123.1, 125.2,125.7, 126.5, 128.6, 130.2, 130.7, 135.3,
144.09, 144.5, 155.5, 156.1; ESIMS m/z 299.0 (MþH)þ; HRMS calcd
for C20H15N2O, 299.1184; found, 299.1197.
Following the general procedure, the title compound was
obtained in 75% yield as a white solid (20 mg).
1H NMR (300 MHz, CDCl3)
d
3.83 (s, 3H), 4.25 (s, 3H), 6.67 (d, 1H,
4.10.11. 1-Methyl-4-(10,20,30,40-tetrahydro-10,10,40,40-tetramethyl-
naphthalen-6-yl)-1H-pyrrolo-[3,2-c]quinoline (10k)
Following the general procedure, the title compound was
obtained in 73% yield as a white solid (24.7 mg).
J¼3.1 Hz), 6.96–7.05 (m, 3H), 7.44–7.58 (m, 2H), 7.95 (d, 2H,
J¼8.8 Hz), 8.22 (d, 1H, J¼8.0 Hz), 8.34 (d, 1H, J¼8.0 Hz); 13C NMR
(CDCl3, Me4Si)
d 38.1, 55.4, 103.1, 113.9, 114.5, 118.2, 120.1, 120.3,

H. Benakki et al. / Tetrahedron 64 (2008) 5949–5955
5955
1H NMR (CDCl3, Me4Si)
d 1.21–1.31 (m, 12H), 1.54–1.68 (m, 4H),
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4.26 (s, 3H), 6.77 (d, 1H, J¼3 Hz), 7.04 (d, 1H, J¼3 Hz), 7.40–7.56 (m,
3H), 7.73 (d, 1H, J¼9.0 Hz), 7.88 (s, 1H), 8.23 (d, 1H, J¼3.0 Hz), 8.34
(d, 1H, J¼3.0 Hz); 13C NMR (CDCl3, Me4Si)
d 31.8, 31.9, 34.3, 34.4,
35.1, 35.2, 38.1, 103.3, 112.7, 118.3, 120.1, 124.5, 125.1, 126.2, 127.0,
127.51, 129.5, 130.7, 134.8, 137.4, 138.9, 144.6, 144.8, 145.0, 145.6,
155.2; ESIMS m/z 369.0 (MþH)þ; HRMS calcd for C26H29N2,
369.2331; found, 369.2333.
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Acknowledgements
We thank the MENRT, the CNRS, and la Ligue contre le Cancer for
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