A concise formation of N-substituted 3,4-diarylpyrroles-synthesis and cytotoxic activity

Article abstract of DOI:10.1039/c3ob42309c

A short synthesis of N-substituted 3,4-diarylpyrroles by condensation of a phenacyl halide with a primary amine and a phenylacetaldehyde is reported. The key step is an intramolecular cyclization of an in situ generated enamine onto a ketone. Using differently substituted aromatic reactants and N-(3-aminopropyl)azatricyclodecane as the amine component, the preparation of analogs of the cytotoxic marine alkaloid halitulin could be achieved. The cytotoxicity of some of the compounds obtained by this method was studied, and one of them proved to be a very potent derivative, acting at a nanomolar concentration, in a caspase-independent cell death mechanism.

Full text of DOI:10.1039/c3ob42309c

Organic &
Biomolecular Chemistry
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A concise formation of N-substituted 3,4-
diarylpyrroles – synthesis and cytotoxic activity†
Cite this: Org. Biomol. Chem., 2014,
12, 1518
Maxim Egorov,a,b Bernard Delpech,*a Geneviève Aubert,a Thierry Cresteil,a
Maria Concepcion Garcia-Alvarez,a Pascal Collina,c and Christian Marazano‡a
A short synthesis of N-substituted 3,4-diarylpyrroles by condensation of a phenacyl halide with a primary
amine and a phenylacetaldehyde is reported. The key step is an intramolecular cyclization of an in situ
generated enamine onto a ketone. Using differently substituted aromatic reactants and N-(3-amino-
propyl)azatricyclodecane as the amine component, the preparation of analogs of the cytotoxic marine
alkaloid halitulin could be achieved. The cytotoxicity of some of the compounds obtained by this method
was studied, and one of them proved to be a very potent derivative, acting at a nanomolar concentration,
in a caspase-independent cell death mechanism.
Received 19th November 2013,
Accepted 13th January 2014
DOI: 10.1039/c3ob42309c
www.rsc.org/obc
Introduction
In the context of a biomimetic approach toward manzamine
alkaloids, we developed a method for the generation of 2,3-
dihydropyridinium salts involving the intramolecular addition
of an enamine onto an aldehyde (Scheme 1).1 This procedure
was based on a biogenetic proposal initially formulated by
Baldwin and Whitehead.2
Following this principle, it was anticipated that the cycliza-
tion of a β-ketoenamine could lead to a 1,3,4-trisubstituted
pyrrole (Scheme 2), and more particularly to the 3,4-diaryl-
pyrrole moiety of compounds such as the marine alkaloid
halitulin (Fig. 1).
Scheme 2 A possible pathway toward 1,3,4-trisubstituted pyrroles.
Scheme 1 Biomimetic formation of a 2,3-dihydropyridinium ion.
Fig. 1 Structure of halitulin.
aCentre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS,
Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.
This framework is also present in lamellarins and related
derivatives obtained from marine organisms.3 Halitulin, iso-
lated from the marine sponge Haliclona tulearensis,4 presents
interesting biological properties, including cytotoxicity against
E-mail: bernard.delpech@cnrs.fr; Fax: (+33)1 6907 7247
bATLANTHERA, 3 rue Aronnax, 44821 Saint-Herblain Cedex, France
cUniversité Paris 7 Denis Diderot, 5 rue Garancière, 75006 Paris, France
†Electronic supplementary information (ESI) available: Experimental procedures
and 1H and 13C NMR spectra for all compounds. See DOI: 10.1039/c3ob42309c
‡Deceased, November 12, 2008.
several tumor cell lines at concentrations of 12–25 ng mL−1
.
A total synthesis of halitulin has been reported by Steglich.5
1518 | Org. Biomol. Chem., 2014, 12, 1518–1524
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Methods for the synthesis of pyrroles have been reviewed,6
including those concerning compounds with two aryl groups
at adjacent positions7 and chiral molecules or natural products
containing the pyrrole framework.8 The process depicted in
Scheme 2 is reminiscent of the Knorr and Hantzsch pyrrole
syntheses,6 but these reactions have been conducted mostly
with active methylene compounds (β-diketones or β-keto-
esters), leading to pyrroles substituted at position 3 by an acyl
or an alkoxycarbonyl group. To the best of our knowledge,
aralkyl ketones were used only for the formation of tri- or tetra-
substituted 1H-pyrroles.9
Scheme 4 Formation of a 1-benzyl-3,4-diarylpyrrole (5) from an iso-
lated enaminoketone (4).
It should be noted that the pathway shown in Scheme 2
might allow the formation of heterocycles with different R2
and R3 substituents, unlike the synthesis of symmetric 1,3,4-
trisubstituted pyrroles by condensation of phenethylamines in
10
the presence of Pd(OAc)2 and Cu(OAc)2 or via the one-pot
Scheme 5 Sequential synthesis of a 1,2,3,4-tetrasubstituted pyrrole.
AgOAc-mediated reaction of primary amines with aldehydes.11
As a part of a programme aimed at the synthesis of halitu-
lin and analogs, we examined the formation of N-substituted
3,4-diarylpyrroles according to Scheme 2.
Results and discussion
Chemistry
The formation of the precursor, for the desired cyclization,
should result from the condensation of an α-haloketone, first
with a primary amine, and then with an aldehyde. To test the
feasibility of the reaction, even if α-alkylaminoketones are not
very stable derivatives,12 we first prepared separately com-
pound 1 by reacting phenacyl bromide with benzylamine. By
treatment of 1 with phenylacetaldehyde in methanol at room
temperature, 1-benzyl-3,4-diphenylpyrrole 213 was obtained in
high yield (96%), showing the efficiency of the process
(Scheme 3).
Scheme 6 Formation of 1,3-dialkyl,4-arylpyrroles.
(compound 9) can be obtained, starting from chloroacetone
and phenylacetaldehyde. In this case, the product is best
obtained using a one-pot procedure, due to the higher instabil-
ity of the intermediate aminoketone.
The unstable intermediate enamine 4 with a p-methoxy-
benzoyl group, which could be isolated as a crystalline solid,
starting from 3 (p-An = 4-methoxyphenyl), readily led to the
corresponding pyrrole 5 when heated in methanol at 50 °C,
strengthening the mechanistic proposal depicted in Scheme 2
(Scheme 4).
This strategy allows the preparation of 1,2,3,4-tetrasubsti-
tuted pyrroles, as exemplified by the formation of 7 via amino-
ketone 6 derived from 2,4′-dibromopropiophenone (Scheme 5).
When aliphatic aldehydes are used, the procedure is not
efficient, as indicated by the low yield of 814 (Scheme 6), due to
the decreased stability of the non-conjugated enamine.
However, the same type of substitution for the pyrrole
As halitulin presents catechol-type substituents, the for-
mation of a pyrrole with a 3,4-dihydroxyphenyl group was envi-
saged, following the same methodology.
Condensation of benzylamine with the commercially avail-
able 2-chloro-3′,4′-dihydroxyacetophenone 10, in the presence
of sodium iodide, led to the unstable aminoketone 11, which
was rapidly treated with 3,4-dimethoxyphenylacetaldehyde,15
affording pyrrole 12 (Scheme 7).
The method has been extended to other derivatives and the
results for the synthesis of substituted N-benzylpyrroles,
according to the general Scheme 8, are summarized in Table 1.
Bromo- or chloroketones were used as starting materials and,
in the latter case, halogen exchange was achieved in situ with
sodium iodide.
After the development of this new pyrrole synthesis, it was
envisioned to apply it to the formation of halitulin analogs
and to investigate some of their biological activities. We modi-
fied the hydrophobic moiety bound to the pyrrole nitrogen,
which is present in the natural product, keeping the three-
carbon linker between the two nitrogen atoms but not the aza-
cyclodecane ring. For this, N-(3-aminopropyl)azatricyclodecane
Scheme 3 Sequential formation of 1-benzyl-3,4-diphenylpyrrole 2.
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(Kirckpatrick).18 In addition, it seemed interesting to see the
role of this hydrophobic part of the molecule in the biological
activity.
The aromatic moieties, characteristic of halitulin, were also
simplified to examine the influence of the oxygens and of the
quinoline part on the natural product activity.
Different conditions were tested for the formation of the
pyrrole nucleus substituted by aryl groups, using 14 as the
amine component, and the following one-pot procedure was
found to be optimal for the preparation of compounds 15a–g
(Scheme 10 and Table 2).
It was found, on one occasion, that a change of solvent
(replacement of THF by DMF) and a shorter time of contact of
phenacyl chloride 10 with sodium iodide, for the procedure
shown in Scheme 10, led to the formation of N-substituted
2,4-diarylpyrrole 16, albeit in a poor yield (Scheme 11). It is
Scheme 7 Synthesis of a pyrrole bearing catechol groups.
Scheme 8 General scheme for the synthesis of N-benzylpyrroles.
Table 1 Yields of the compounds prepared according to Scheme 8
Scheme 10 One-pot synthesis of N-substituted 3,4-diarylpyrroles
15a–g.
R1
R2
R3
X
Pyrrole
Yield
H
H
CH3
H
H
H
CH3
Ph
Ph
Ph
Ph
CH3
Br
Br
Br
Br
Cl
Cl
Br
2
5
7
8
9
12
13
93%
92%
95%
5%
60%
69%
82%
Table 2 Yields of compounds 15a–g prepared according to Scheme 10
4-CH3OC6H4
4-BrC6H4
4-CH3OC6H4
CH3
3,4-(HO)2C6H3
4-BrC6H4
Ar1
Ar2
X
Pyrrole
Yield
Ph
3,4-(HO)2C6H3
3,4-(HO)2C6H3
3,4-(HO)2C6H3
Ph
Ph
Cl
Cl
Cl
Br
Br
Br
Br
15a
15b
15c
15d
15e
15f
24%
20%
19%
61%
52%
29%
37%
3,4-(CH3O)2C6H3
3,4-(CH3O)2C6H3
3,4-OCH2OC6H3
3,4-(CH3O)2C6H3
Ph
4-CH3OC6H4
Ph
14 was chosen as the primary amine component (see 4-CH3OC6H4
Scheme 2), instead of the isohaliclorensin moiety of halitu-
3,4-OCH2OC6H3
3,4-(CH3O)2C6H3
4-CH3OC6H4
15g
lin.16 The thirteen-membered macrocyclic amine was selected
due to its rapid access starting from the commercially available
laurolactam (Scheme 9),17 and also because this achiral
moiety is present in motuporamine A, another cytotoxic
alkaloid isolated from the marine sponge Xestospongia exigua
Scheme 9 Preparation of primary amine 14.
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Scheme 11 Formation of N-substituted 2,4-diarylpyrrole 16.
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position 3 on the pyrrole ring is described as a more favoured
process.20
The formation of pyrroles substituted with two nitro-
catechol groups at positions 3 and 4 was envisaged following
Scheme 10, with the aim that these functionalities could be
used as potential precursors for the dihydroxyquinoline
moieties present in halitulin.21 The aldehyde and the bromo-
ketone, chosen as partners in the three-component reaction,
were easily accessible, especially as the catechol monomethyl
ethers 19 and 21. These compounds were prepared, each in
two steps, from the commercially available and cheap
eugenol and 4′-hydroxy-3′-methoxyacetophenone, respectively
(Scheme 14). Both syntheses began with a regioselective
nitration, leading to 18 and 20, respectively. Oxidative cleavage
of olefin 18 afforded aldehyde 19 and bromination of ketone
20 provided phenacyl bromide 21.
Scheme 12 Bis O-demethylation of 15c to give 15h.
For the key pyrrole synthesis, condensation of 21 with 14
and 19 was conducted under slightly modified conditions,
compared to those of Scheme 10, the procedure being simpli-
fied and improved by using DMSO as the solvent (Scheme 15).
This led to compound 22, the nitro groups of which were
reduced by catalytic hydrogenation, affording 23.
For the demethylation of 22, BBr3 was used and, depending
on the conditions, the monomethyl ether 24 and/or the bis
nitrocatechol derivative 25 could be isolated. Reduction of the
nitro functions of 25, using catalytic hydrogenation, led to
pyrrole 26 bearing two aminocatechol moieties (Scheme 16).
Since halitulin is a toxic compound against different cell
lines, the cytotoxicity of several pyrrolic products obtained by
the presently reported methodology was examined.
assumed that, in the latter case, the imine/enamine resulting
from the condensation of phenylacetaldehyde and amine 14
reacted as the nucleophilic partner in the substitution reaction
involving the iodoketone generated in situ.
Hydrochlorides of derivatives 15a–g and 16 were generally
obtained by adding 2 M HCl in methanol to a chloroform solu-
tion of the pyrrolic tertiary amine.
BBr3-induced O-demethylation of 15c led to the bis(cate-
chol) analog 15h (Scheme 12).
When harsher conditions were used for the demethylation
of 15c (48% HBr, 150 °C),19 a rearrangement was observed,
leading to the 2,4-diarylpyrrole 17, and a mechanistic proposal
is given in Scheme 13. The electron-donating substituents on
the phenyl group, and especially the para-hydroxyl, should
make easier the migration of the aryl group via an intermedi-
ate such as i, and the formation of 17 could result from a
Cytotoxic studies
steric decompression (release of the strain due to the two adja- IC50 were measured for selected compounds using the resoru-
cent aryl substituents on the pyrrole nucleus). To the best of fin fluorescence test (72 h) and the values are reported in
our knowledge, this type of rearrangement has not been Table 3 (the structure of the pyrroles which have been tested is
reported but the migration of a substituent from position 2 to shown in Fig. 2).
Scheme 13 Demethylation of 15c with rearrangement of a 3,4-diarylpyrrole into 2,4-diarylpyrrole 17.
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Scheme 14 Preparation of phenylacetaldehyde 19 and phenacyl bromide 21.
Scheme 15 Formation of pyrrole 22 by condensation of bromoketone 21 with amine 14 and aldehyde 19, and reduction of the nitro functionalities.
Scheme 16 Demethylation of compound 22 with BBr3 and reduction of the bis nitrocatechol derivative 25 by catalytic hydrogenation.
From Table 3, it can be seen that the most potent com- reference (Table 4), and with another cell proliferation assay
pound is 25 with the 3-(azatricyclodecan-1-yl)propyl group as a (MTS reagent).
substituent for the pyrrole nitrogen and bearing two nitro-
As shown in Table 4, IC50 for compound 25 remains in the
catechol moieties. The cytotoxicity of 25 is in the nanomolar nanomolar range, whatever the cell line (0.6 to 77 nM), with a
range, in the same order as for halitulin, and this questions 5-fold more sensitive absolute value with the MTS reagent
the role of the quinoline part in the biological activity of the used for this cell proliferation test than that obtained with
natural product. A loss of activity is observed when replacing resorufin (compare the K562 cell line in Tables 3 and 4). With
one or two nitrocatechol groups by their monomethyl counter- the HL60R line, overexpressing the efflux pump P-gp in com-
part (compare compound 25 with 22 and 24), as well as by sub- parison with their counterpart HL60, a similar IC50 value is
stituting the nitro by an amino group (compare 25 with 26).
In vitro IC50 were therefore measured for 25 with another
observed.
In an effort to elucidate the mechanism by which com-
panel of human cancer cell lines, using colchicine as a pound 25 can induce cell death, proapoptotic caspase 3–7
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Table 3 Cytotoxicity of selected compounds against different cell lines
with IC50 (μM) (see Fig. 2 for the structures)
Table 4 IC50 (μM) for compound 25 with different cell lines
Cell line
25a
Colchicine
Pyrrolea HCT-116
U87
MDA-231
K562
KB
0.005/0.006
0.001/0.002
0.002/0.002
0.048/0.077
0.013/0.010
0.022/0.034
0.028/0.034
0.015/0.012
0.0006/0.001
0.013/0.018
0.016/0.020
ndb
12
ndb
ndb
ndb
9
ndb
6
HepG2*
HepG2* (2nd)
PC3
0.007/0.017
0.001/0.0009
∼10/∼10
0.0005/0.0012
<0.001/0.0007
0.485/0.514
0.0005/0.001
0.001/0.001
0.003/0.003
2.87/3.20
12
20
14
15
8
20
20
18
35
3
15a
15b
15c
15d
15e
15f
15g
15h
17c
22
23
24
25
26
ndb
ndb
20
ndb
10
HL60
nad
ndb
ndb
ndb
9
20
HL60 (2nd)
HL60R
K562
PaCa
OVCAR8
MCF7
ndb
ndb
ndb
3
ndb
ndb
ndb
2
30
20
ndb
nad
ndb
nad
ndb
nad
a As the hydrochloride salt.
nad (>30 μM) nad (>30 μM) nad (>30 μM) nad (>30 μM)
5
7
ndb
0.1
30
0.03
0.045
0.075
nad
nad
nad
nad
a As the hydrochloride salt, except for 12 and 17 (hydrobromide salt).
b Not determined. c 2,4-Diarylpyrrole. d No activity.
Fig. 3 Apoptotic effects of compound 25 and TNFα in HCT-116 cells.
Results are the accumulation of rhodamine in cells expressed as the per-
centage of control cells following 24 h of treatment with 25 at different
concentrations and TNFα at 20 ng mL−1
.
Fig. 4 Western blot analysis of LC3 in compound 25-treated HCT-116
cells. HCT-116 cells were treated without (column 1) or with 25 at con-
centrations of 5, 10, 25, 50 and 100 nM, respectively (columns 2 to 6).
After drug treatment, HCT-116 cells were lysed and proteins were sub-
jected to SDS-PAGE. An immunoblot was performed using anti-LC3 and
anti-tubulin antibodies.
Fig. 2 General structure of compounds which have been tested.
activity was determined. From the data presented in Fig. 3, it
can be concluded that 25 displayed no caspase-dependent
apoptotic activity, compared to TNFα or doxorubicin on HL60
cells (not shown) used as positive controls.
suggest that the autophagic response is, at least in part,
involved in the mechanism of cytotoxicity induced by 25.
Therefore, in order to determine whether compound 25
induced other cell death mechanisms, we investigated the
autophagic response using the expression of LC3-II protein. As
shown in Fig. 4, the expression of LC3-II proteins in HCT-116
Conclusions
cells was found to increase in a dose dependent manner after A concise one-pot synthesis of unsymmetrically substituted
24 h of treatment with 25, starting at 25 nM. These results 3,4-diarylpyrroles, involving an intramolecular cyclization of
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in situ generated β-ketoenamines, is reported. The methodo-
logy is an alternative to the Hantzsch or Knorr pyrrole syn-
thesis which is not limited to compounds bearing an electron-
withdrawing substituent. If at least one aryl group could con-
veniently be introduced, since the formation of sufficiently
stable enamines derived from phenylacetaldehyde or its substi-
tuted derivatives proved to be necessary, it was possible to
obtain compounds with one alkyl group at position 3. The
method could be extended to the synthesis of 2,4-diaryl-
pyrroles either by reversing the order of introduction of the reac-
tants or using an unprecedented rearrangement. Simplified
analogs of halitulin were prepared using the present methodo-
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