Synthesis of a novel pyrrolo-[3,2-c]quinoline N-oxide by aza-Baylis-Hillman adduct of o-nitrobenzaldehyde

Article abstract of DOI:10.1016/j.tetlet.2008.05.121

A new and high yielding approach for the synthesis of a novel pyrrolo-[3,2-c]quinoline N-oxide is described. The key step consisted in the palladium-catalyzed reductive cyclization of an uncommon 3-ketopyrrole derivative of o-nitrobenzaldehyde, obtained in a straightforward manner through an aza-Baylis-Hillman/ring closing metathesis/aromatization reaction. A deoxygenation reaction of this novel pyrrolo-[3,2-c]quinoline N-oxide afforded a new substituted pyrrolo-[3,2-c]quinoline analogue.

Full text of DOI:10.1016/j.tetlet.2008.05.121

Tetrahedron Letters 49 (2008) 4953–4955
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Tetrahedron Letters
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Synthesis of a novel pyrrolo-[3,2-c]quinoline N-oxide by aza-Baylis–Hillman
adduct of o-nitrobenzaldehyde
*
Evelina Colacino, Christophe André, Jean Martinez, Frédéric Lamaty
Institut des Biomolécules Max Mousseron, UMR 5247 CNRS-Université Montpellier 1 et Université Montpellier 2, Place Eugène Bataillon, 34095 Montpellier cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and high yielding approach for the synthesis of a novel pyrrolo-[3,2-c]quinoline N-oxide is
described. The key step consisted in the palladium-catalyzed reductive cyclization of an uncommon
3-ketopyrrole derivative of o-nitrobenzaldehyde, obtained in a straightforward manner through an
aza-Baylis–Hillman/ring closing metathesis/aromatization reaction. A deoxygenation reaction of this
novel pyrrolo-[3,2-c]quinoline N-oxide afforded a new substituted pyrrolo-[3,2-c]quinoline analogue.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 2 May 2008
Revised 23 May 2008
Accepted 27 May 2008
Available online 19 June 2008
Keywords:
Aza-Baylis–Hillman (aza-BH)
Ring closing metathesis (RCM)
3-Keto-pyrrole
Hexacyclic keto-nitrone
Reductive cyclization
Nitrone deoxygenation
Organic N-oxides are useful intermediates for the synthesis of
biologically active compounds.1,2 In particular, the quinoline N-
oxide core unit has been found in drugs exerting microsomal
Na,K-ATPase activity,3 protein kinase inhibition and anticancer,4
antiviral5 or antimalarian activities.6,7 They have also relevant
applications as spin traps in biological studies,8 and are efficient
in age-related diseases,9 due to both in vitro and in vivo10 stability
of resulting nitroxide radicals. The nitrone compound reacts with a
free radical to form a derivative called spin adduct. Once the ad-
duct is formed, it is relatively stable and the radical thus becomes
inactivated and unable to interfere in biochemical processes and
damage cellular tissues.
Considering the wide potential of the quinoline N-oxide core
unit, and as a part of our ongoing projects on the synthesis of het-
erocyclic structures by ring closing metathesis (RCM),11–14 we
decided to explore the unprecedented preparation of pyrrolo-
[3,2-c]quinoline N-oxide in only one step from a biarylic system
constituted by an aryl-pyrrole in which a nitro group is in d-posi-
tion with respect to the keto function. For this purpose, we ex-
tended our aza-Baylis–Hillman (aza-BH) reaction/ring closing
metathesis/aromatization sequence to the preparation of an origi-
nal 2-aryl-3-keto-substituted pyrrole. Aza-BH is a powerful reac-
tion extensively exploited for the synthesis of multifunctional
synthons in organic synthesis.15 It allows the formation of car-
bon–carbon bonds under mild reaction conditions and it consists
in the reaction between protected ammonia [usually with a sulfo-
nyl group such as tosyl (Ts)11,16,17], an aldehyde, and a
,b-unsatu-
rated carbonyl compound, catalyzed by nucleophilic Lewis bases
such as 1,4-diazabicyclo[2,2,2]octane (DABCO).
The synthesis of 4-ethyl-1-methyl-1H-pyrrolo-[3,2-c]quinoline
N-oxide 9 is described in Scheme 1.
a
In the first step, the unsaturated b-aminoketone 4a was synthe-
sized in a combined Lewis acid-[Ti(OiPr)4] and base-catalyzed
(DABCO) three component reaction involving commercial p-tolu-
enesulfonamide 2 in the presence of an excess of o-nitrobenzalde-
hyde 1, and penten-2-one 3 as Michael acceptor.17 The reaction
was performed at room temperature, with a moderate selectivity
between the formation of b-aminoketone 4a (51% yield) and b-
hydroxyketone 4b (38% yield). A worse selectivity was obtained
in the absence of Lewis acid. Extensive degradation of the crude
was observed by running the reaction at a temperature of 100 °C
using microwave irradiation (MW) for only 10 min. This maybe
due to the instability of the Michael acceptor under these condi-
tions. We also performed the reaction under different conditions
(DABCO in i-PrOH) to drive the reaction to completion, but con-
comitant formation of the corresponding hydroxyester 4b was
not avoided. All the attempts to separate 4a from 4b by crystalliza-
tion at different temperatures and using different solvent combina-
tions were unsuccessful, leading always to the degradation of the
crude. b-Aminoketone 4a was eventually recovered after purifica-
tion by column chromatography and allylated with allyl bromide
in a ‘spot to spot’ reaction in the presence of K2CO3 in DMF14
to yield 83% of the corresponding diene 5. The reaction was
* Corresponding author. Tel.: +33 467143847; fax: +33 467144866.
E-mail address: frederic.lamaty@univ-montp2.fr (F. Lamaty).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.121

4954
E. Colacino et al. / Tetrahedron Letters 49 (2008) 4953–4955
O
Ts
Br
K2CO3
O
X
O
N
DABCO
H
Ti(O-i-Pr)4
+
+
Ts NH2
i-PrOH
MS 4 A
9 h, r.t.
Grubbs II
CH2Cl2
NO2
O
DMF
NO2
NO2
20 h, r.t.
12 h, r.t.
1
2
3
4a X = TsNH 51%
5 83%
+
Ts
NO2
4b X = OH
38%
N
O
6 86%
N
N
N
O
HN
NO2
NO2
t
-BuOK
DMF
0ºC
2.5 h
CH3I
H2 / Pd-C
H2 / Pd-C
Cs2CO3
N
N
O
DMF
MeOH
MeOH
12 h, r.t.
O
12 h, r.t.
12 h, r.t.
10 38%
9 82%
8 98%
7 47%
Scheme 1. Synthesis of 4-ethyl-1-methyl-1H-pyrrolo-[3,2-c]quinoline N-oxide 9.
performed either at room temperature within 12 h or under micro-
wave irradiation at 100 °C for only 10 min without affecting the
yield. After purification by chromatography, diene 5 was subse-
quently submitted to the ring closing metathesis (RCM) reaction
known to be an efficient method for the synthesis of heterocyclic
structures from linear precursors.18–21 Cyclization of diene 5 bring-
ing to the novel conjugated cyclic enone 6 was complete within
12 h at room temperature using 5% 2nd generation air stable Grub-
bs’ catalyst in good yield. Attempts to accelerate the reaction by
microwave (100 °C, CH2Cl2)16 were unsuccessful, due to degrada-
tion of the starting material.
10 (Scheme 1). The last compound was recovered by column chro-
matography in a moderate yield, along with traces of the corre-
sponding amine.
In conclusion, an efficient synthesis of 2-substituted-3-keto-
pyrrole has been developed, through a sequential aza-BH/ring clos-
ing metathesis/aromatization as a novel route to access to a novel
hexacyclic nitrone, after palladium-catalyzed reductive cyclization.
A deoxygenation reaction provides also an easy conversion into the
imine. Biological tests are in progress to evaluate the full potential
of the novel structure presented here.
Few examples for the formation of 3-carboxy-substituted five
membered heterocyclic alkenes through RCM reaction22–26 are
reported, as well as their synthesis starting from aza-BH
adducts,11,16,17,27,28 but none of them focus on the synthesis of
2-aryl-3-keto-substituted pyrrole according to this procedure.
The next step was cleavage of the tosyl group.29–31 Using t-
BuOK in DMF at room temperature, 47% of the substituted pyrrole
7 was obtained within 2.5 h via elimination/aromatization steps.
We supposed that the moderate yield resulted from the isomeriza-
tion of pyrroline, or to secondary reactions involving the enol form
of ketone. Then, pyrrole 7 was reacted with methyl iodide32 in the
presence of Cs2CO3 in DMF to yield the corresponding methylated
pyrrole 8 in high yield. Similar structures, in which a methyl group
is used to protect pyrrole ring, have been synthesized to afford very
potent antiviral, antibacterial and anticancer agents.33,34 Directly
used without any purification, methyl-protected pyrrole 8 was
hydrogenated at room temperature in methanol using Pd/C under
H2 atmosphere,35 yielding a very polar compound, which was iden-
tified as the stable hitherto unknown 4-ethyl-1-methyl-1H-pyrrol-
o-[3,2-c]quinoline N-oxide 936 with the nitrone function confined
to a ring structure in good yield, after purification by column chro-
matography. The conversion was not quantitative and 16% of the
starting material was still present in the mixture, as determined
by 1H NMR of the crude. The synthesis of differently substituted
quinoline N-oxides has been described starting from the Baylis–
Hillman adduct of o-nitrobenzaldehyde: in acidic medium, to
access penta-37 or hexa-cyclic38,39 nitrones, or through an hydroge-
nation/cyclization cascade reaction,40 but no examples are
reported for pyrrolo-quinoline N-oxide structures.
Acknowledgements
We thank the CNRS and la Ligue contre le Cancer for financial
support.
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