Synthesis and biological evaluation of novel pyrrolopyrrolizinones as anticancer agents

Article abstract of DOI:10.1016/j.bmc.2006.09.022

We herein describe the synthesis of novel 3-(het)aryl-pyrrolo[2,3-b]pyrrolizin-8(1H)-ones starting from commercial (het)aryl-acetonitriles. A more convergent route was also described through the first synthesis of ethyl 3-amino-4-bromo-1H-pyrrole-2-carbox

Full text of DOI:10.1016/j.bmc.2006.09.022

Bioorganic & Medicinal Chemistry 14 (2006) 8162–8175
Synthesis and biological evaluation of novel pyrrolopyrrolizinones
as anticancer agents
C. Rochais,a V. Lisowski,b P. Dallemagnea and S. Raulta,*
aCentre d’Etudes et de Recherche sur le Me´dicament de Normandie, Universite´ de Caen Basse-Normandie, 5,
rue Vaube´nard, 14032 CAEN Cedex, France
bFaculte´ de Pharmacie de Montpellier, 15 avenue Charles Flahault BP 14491, 34093 Montpellier Cedex 5, France
Received 11 July 2006; revised 25 August 2006; accepted 13 September 2006
Available online 29 September 2006
Abstract—We herein describe the synthesis of novel 3-(het)aryl-pyrrolo[2,3-b]pyrrolizin-8(1H)-ones starting from commercial
(het)aryl-acetonitriles. A more convergent route was also described through the first synthesis of ethyl 3-amino-4-bromo-1H-pyr-
role-2-carboxylate 17. The antiproliferative activities of these compounds were tested toward various cell lines and one of them
10k shows interesting cytotoxic properties, although it was less potent than our lead compound in thiophene series 1k.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
tions. Aiming to improve the latter, a study has
recently been developed in our laboratory to encapsulate
the lead in lipidic nanocaps,4 with encouraging results.
In the view to identify novel microtubule polymerization
inhibitors, we have recently described an unknown het-
erocyclic family of potent compounds: thienopyrrolizi-
nones (Fig. 1), or ‘tripentones’.1 The first hit in that
series 1a, detected by the National Cancer Institute,
exhibits an in vitro cytotoxic activity in submicromolar
concentrations in all cell lines tested. Further pharmaco-
modulations2 realized on that core have conducted to a
new lead 1k substituted in position 3 by a 4-methoxy-3-
hydroxyphenyl group.
Furthermore in order to specify structural requirements
we decided to extend the study toward synthesis of novel
tripentones based on other heterocyclic rings such as
pyrrole.
2. Chemistry
According to the route elaborated in the thiophene ser-
ies, o-aminoesters appeared as crucial intermediates to-
ward expected tripentones. We have recently
developed novel methyl 3-amino-4-(het)aryl-1H-pyr-
role-2-carboxylates 2a–j in an efficient three step synthe-
sis,5 derived from Elliot’s procedure.6
Indeed pharmacological evaluations of 1k over a panel
of tumoral cell lines revealed nanomolar activities range.
According to results of preliminary flow cytometric
studies, tripentones were first supposed to interact with
the mitotic spindle.
Tubulin polymerization inhibitory tests were then
performed and showed an IC50 of 2.9 lM, similar to
the reference deoxypodophyllotoxin (2.4 lM).
Applying the developed four step sequence to these es-
ters led to the N-unprotected ketones 5a–k (Scheme 1).7
However first in vivo evaluations of 1k by the NCI3 were
disappointing and pointed out its insufficient bioavaili-
bility due to a lack of solubility in physiological condi-
O
S
N
R
Keywords: Cyclization; Pyrroles; Fused-ring systems; L1210 murine
leukemia cells.
1a R=pOMe
1k R=pOMemOH
*
Corresponding author. Tel.: +33 2 31 93 64 58; fax: +33 2 31 93 11
88; e-mail: sylvain.rault@unicaen.fr
Figure 1.
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.09.022

C. Rochais et al. / Bioorg. Med. Chem. 14 (2006) 8162–8175
8163
CO2Me
CO2Me
H
N
H
N
i
NH2
N
a (Het)Ar = pOMeC6H4
b (Het)Ar = m,pdiOMeC6H3
c (Het)Ar = pFC6H4
(Het)Ar
(Het)Ar
3a-j
2a-j
d (Het)Ar = pMeC6H4
ii
e (Het)Ar = 2-thienyl
f (Het)Ar = C6H5
g (Het)Ar = pClC6H4
h (Het)Ar = m,pdiClC6H3
i (Het)Ar = 3-thienyl
O
O
R
H
N
N
iii
N
N
N
j (Het)Ar = mOBnpOMeC6H3
k (Het)Ar = mOHpOMeC6H3
(Het)Ar
(Het)Ar
5a-i
5j
5k
4a-i R=H
4j R=H
6j R=Boc
v
iv
Scheme 1. Reagents and conditions: (i) 2,5-dimethoxyTHF, 4-chloropyridine hydrochloride, dioxane, 100 ꢁC, 57–99%; (ii) pyrrolidine, 87 ꢁC, 47–
69%; (iii) (a) POCl3, 70 ꢁC; (b) 10% NaOH, 50 ꢁC, 2–32%; (iv) (Boc)2O, TEA, DMAP, CH2Cl2, 25 ꢁC, 78%; (v) (a) 33% HBr in AcOH, 25 ꢁC; (b)
NaOH 1 N, MeOH, 25 ꢁC, 55%.
Aminoesters 2a–j were first submitted to a modified8
Clauson-Kaas procedure9 (Scheme 1), with 2,5-dim-
ethoxytetrahydrofuran and 4-chloropyridine hydrochlo-
Table 1. Cytotoxicity results for compounds 5a–x
O
X
ride to afford esters 3a–j. These esters were then
submitted to amidification in refluxing pyrrolidine to
obtain amides 4a–j. The latter afforded expected tripen-
tones 5a–j through ring closure under Vilsmeier–Haack
conditions and alkaline treatment. In a previous study,7
we showed that the ring closure procedure was im-
proved through N-protection of carboxamides 4j as
Boc-substituted compounds 6j. The O-deprotection of
benzylated 5j was realized using a 33% hydrobromic
acid solution in glacial acetic acid, followed by an alka-
line hydrolysis of the acetate intermediate,7 to obtain the
expected compound 4k.
N
(Het)Ar
Compound
X
(Het)Ar
IC50, lM IC50, lM
L1210
HT29
1a
1k
5a
5b
5c
5d
5e
5f
S
S
p-OMe–C6H4
(m-OH,p-OMe)–C6H3
0.19
0.015
64.6
11.8
13.4
10.9
25.3
36.9
34.3
12.7
26.7
8.9
Not tested
Not tested
23.2
NH p-OMe–C6H4
NH (m–p-di-OMe)–C6H3
NH p-F–C6H4
Not tested
26
12.5
NH p-Me–C6H4
NH 2-Thienyl
NH C6H5
26.6
26.7
The antiproliferative properties of this first series of pyr-
rolo[2,3-b]pyrrolizinones 5a–k were then evaluated (see
Pharmacological results, Table 1).
5g
5h
5i
NH p-Cl–C6H4
21.9
19.9
NH m,p-di-Cl–C6H3
NH 3-Thienyl
NH (m-OBn,p-OMe)–C6H3
24
13.4
5j
5k
According to the benefits of N-protection, we decided to
realize novel modulations on that structure through
other N-substitution reactions and particularly with
the m-hydroxy-p-methoxyphenyl derivatives j, our best
series for a biological point of view (Scheme 2). However
these alkylation reactions were first optimized in the eas-
ily obtained p-chlorophenyl series g.
NH (m-OH,p-OMe)–C6H3 12.2
19.3
In order to realize selective modulations of the phenol
moiety, we also managed to obtain a selective N-pro-
tected tricycle. Unfortunately, all our attempts to depro-
tect the N-benzyl group failed in the case of compound
12k. Even if hydrogenation of reduced 12k conducted to
the benzyl compound 13 (Scheme 3).
Carboxamides 4g, j were then alkylated to afford methyl
7g, j, ethyl 8g, j, and benzyl 9g, j compounds in quanti-
tative yields using sodium hydride as a base. The prod-
ucts 7–9g, j were then introduced in the ring closure
procedure to afford in good to excellent yields the corre-
sponding tripentones 10g, j, 11g, j, and 12g, j, respective-
ly. We could here notice the important influence of the
N-substitution toward the yield enhancement of the ring
closure reaction. O-Deprotections of benzylated com-
pounds were then realized as previously described to af-
ford corresponding phenol compounds 10k–12k in good
yields.
According to the previous procedure, we decided to test
novel selective protecting groups. Mesylated amide 14j
(Scheme 2) was isolated, but the ring closure appeared
inefficient in that case. Ketone 15j was then obtained
from the tripentone 5j and was O-deprotected to afford
the attempted compound 15k. A selection of these N-
substituted pyrrolopyrrolizinones was evaluated (see
pharmacological results, Table 2) and showed an inter-
esting improvement of activity.

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C. Rochais et al. / Bioorg. Med. Chem. 14 (2006) 8162–8175
O
O
R
i
N
N
H
N
N
N
N
Ar
Ar
7g,j R=Me
8g,j R=Et
4g,j
9g,j R=Bn
14j R=SO2Me
ii
O
N
R
O
O
N
H
R
N
iii
iv
N
N
N
Ar
Ar
5j
OH
OMe
10k R=Me
11k R=Et
12k R=Bn
10g,j R=Me
11g,j R=Et
12g,j R=Bn
15j R=SO2Me
15k R=SO2Me
Scheme 2. Reagents and conditions: (i) NaH, RX, DMF, 0–25 ꢁC, 82–95%; (ii) (a) POCl3, 70 ꢁC; (b) 10% NaOH, 50 ꢁC, 60–95%; (iii) NaH,
MeSO2Cl, DMF, 0–25 ꢁC, 93%; (iv) (a) 33% HBr in AcOH, 25 ꢁC; (b) NaOH 1 N, MeOH, 25 ꢁC, 40–85%.
O
O
O
CO2Me
NH2
H
R
Bn
N
Bn
N
N
N
i
N
N
N
X
X
16
17
Figure 2.
OBn
OH
MeO
12k
MeO
13
Indeed, this compound could be modulated through
modern cross-coupling reactions. As previously ex-
posed, one of the crucial intermediates toward 16 could
be the corresponding methyl 3-amino-4-halogeno-1H-
pyrrole-2-carboxylate 17 (Fig. 2).
Scheme 3. Reagents: (i) H2, Pd, MeOH, 55%.
Table 2. Growth percentage (%) at 1 · 10ꢀ4 mol for compounds
5k,10k,12k, and 15k
The chemical strategy adopted for the access to 17 was
based on halogenation of ethyl 3-aminopyrrole-2-car-
boxylate, described by Furneaux.10 Astonishingly best
results were obtained without any nitrogen protection
either on the amino or the pyrrole moieties, and using
N-bromosuccinimide as bromination agent (Scheme 4).
The resulting pyrrole 17 was then introduced in the ex-
posed sequence to lead to the amide 18. The latter was
then alkylated or protected to conduct after ring closure
and alkaline hydrolysis to two novel brominated tripen-
tones 22 and 23.
O
R
N
N
OH
OMe
Compound
R
MCF7
NCI-H460
SF-268
5k
H
Me
62
19
66
65
81
6
99
58
98
84
10k
12k
15k
Functionalization of our structure was achieved through
Suzuki cross-coupling reaction with two various arylbo-
ronic acids. Use of p-methoxyphenylboronic acid and 2-
methoxypyridine-5-boronic acid11 afforded tripentones
24 and 25 in excellent yield. According to these good re-
sults this second route appeared to be really effective and
will be developed in the future in order to allow access to
novel tripentones.
Bn
SO2Me
53
84
In order to introduce more diversity on these structures
and to obtain a more convergent route, the synthesis of
an halogenated tripentone 16 was then studied (Fig. 2).

C. Rochais et al. / Bioorg. Med. Chem. 14 (2006) 8162–8175
8165
CO2Et
CO2Et
H
N
H
N
CO2Et
NH2
H
i
ii
N
N
NH2
Br
iii
Br
17
18
O
O
O
N
H
N
R
R
N
iv
v
N
N
N
N
N
Br
Br
Br
22 R=Me
23 R=H
19
20 R=Me
21 R=Boc
vi
O
R
N
24 R=Me, (Het)Ar=pMeOC6H4
25 R=Me, (Het)Ar=pMeO-mpyridine
N
(Het)Ar
Scheme 4. Reagents and conditions: (i) NBS, CHCl3, AcOH, 0 ꢁC to rt, 40%; (ii) 2,5-dimethoxyTHF, 4-chloropyridine hydrochloride, dioxane,
100 ꢁC, 99%; (iii) pyrrolidine, 87 ꢁC, 43%; (iv) (Boc)2O, TEA, DMAP, CH2Cl2, 25 ꢁC, 99% or NaH, MeI, DMF, 0–25 ꢁC, 99%; (v) (a) POCl3, 70 ꢁC;
(b) 10% NaOH, 50 ꢁC, 43–86%; (vi) (Het)ArB(OH)2, Pd(PPh3)4, Na2CO3, DMF, 110 ꢁC, 87–90%.
3. Pharmacological results
were then selected and tested. Results are exposed in
Table 2 in percent of growth of the treated cells when
compared to the untreated control cells.
The antiproliferative properties of the first series of
unprotected compounds 5a–k were evaluated on the
murine leukemia L1210 and on HT29 cell lines and
are reported in Table 1.
Only 10k (NSC 733670), which reduced the growth of
two cell lines to less than 32%, was selected for evalua-
tion in the full panel of 60 cell lines over a 5-log dose
range.12 However, we could point out the strong influ-
ence of a small substituent on the growth percentage
for our product, since compound 10k appears much
more potent than non-substituted tripentone 5k or other
substituted ones 12k and 15k. These first results could
also suggest an important steric hindrance on that
position.
This first series of compounds appeared less active than
the thiophene isomers, with IC50 values ranging from 8.9
to 64 lM. Compared now more precisely, the lead series
substituted by a 4-methoxy-3-hydroxyphenyl group,
compound 1k appeared 1000 times more potent than
its isomer 5k. The presence of the free NH group
instead of the S seems to have a significant harmful effect
on biological activities. In order to explore this influ-
ence, a selection of the N-substituted compounds was
screened by the National Cancer Institute. The protocol
developed by the NCI began with a one dose primary
anticancer assay on 3 cell lines panel consisting of the
MCF7 (breast), NCI-H460 (lung), and SF-268 (central
nervous system). Compounds 5k, 10k, 12k, and 15k
A selection of the results was reported in comparison
with compound 1a in Table 3 in the form of their GI50.
If 10k appeared as the much active derivative in the pyr-
role series, with a strong enhancement through N-substi-
tution of the tripentone core, this compound remains
Table 3. GI50 (lM) of 1 and 10k on various cell lines
Cell lines
Compound
Leukemia
MOLT4
NSCLa
HCC2298
CNSb
SF295
Ovarian
OVCAR-3
Renal
A498
Prostate
DU145
Breast
HS578T
1a
10k
0.04
7.21
0.3
2.48
0.44
5.22
0.04
3.39
0.6
2.82
0.2
12.5
0.05
0.6
a Non-small cell lung.
b Central nervous system.

8166
C. Rochais et al. / Bioorg. Med. Chem. 14 (2006) 8162–8175
less active than the first hit in the thiophene series 1a
with moderate GI50 values ranging from 0.6 to
12.5 lM in the selected cell lines.
158.51, 127.83, 124.76, 123.48, 122.82, 118.68, 117.05,
114.60, 113.98, 108.74, 55.18, 51.72. MS (EI+) m/z:
296,1. Anal. Calcd for C17H16N2O3: C, 68.91; H, 5.44;
N, 9.45. Found: C, 69.01; H, 5.42; N, 9.13.
These results revealed the crucial role of the thiophene
ring in the tripentone cytotoxic activities. Any modifica-
tion on that position in our novel pyrrole series conducts
to less active compounds, especially with large N-substi-
tuent or loss of this substitution. Moreover the weak
activity of 10k actually did not allow us to realize further
studies in an in vivo model or any solubility evaluation.
However, the novel synthetic route exposed only in pyr-
role series, opens wide opportunities to explore with
more diversity the nature of the aromatic substituants.
4.2.2. Methyl 40-(3,4-dimethoxyphenyl)-10H-1,30-bipyr-
role-20-carboxylate (3b). This compound was obtained
from 2b as described for 3a as beige solid in 72% yield.
Mp 158–161 ꢁC. IR (KBr): m = 3385(NH), 3123, 3088,
2955, 1704(CO), 1588, 1575, 1437, 1249, 1115, 1013,
1
728 cmꢀ1. H NMR (400 MHz, CDCl3): d = 9.3 (br s,
1H, NH), 7.10 (d, J = 3.3 Hz, 1H, H5), 6.78 (d,
0
J = 8.3 Hz, 1H, H5 ), 6.73 (dd, J = 1.8, 8.3 Hz, 1H,
0
H6 ), 6.69 (m, 2H, Hapyrrole), 6.26 (m, 2H, Hbpyrrole),
0
6.21 (d, J = 1.8 Hz, 1H, H2 ), 3.84 (s, 3H, OCH3), 3.76
In conclusion, we have described here the synthesis and
the antiproliferative activities of novel pyrrolo[2,3-
b]pyrrolizinones, which gave crucial information in the
development of novel tripentone compounds. Finally a
novel and convergent synthesis was reported through
Suzuki cross-coupling and will be applied to afford more
diversity on these new structures.
(s, 3H, OCH3), 3.61 (s, 3H, OCH3). 13C NMR
(100 MHz, CDCl3): d = 160.71, 148.73, 147.62, 127.71,
125.12, 123.19, 122.83, 118.97, 118.44, 117.05, 110.92,
109.33, 108.82, 55.61, 55.44, 51.61. MS (EI+) m/z:
326.1. Anal. Calcd for C18H18N2O4: C, 66.25; H, 5.56;
N, 8.58. Found: C, 66.41; H, 5.48; N, 8.74.
4.2.3. Methyl 40-(4-fluorophenyl)-10H-1,30-bipyrrole-20-
carboxylate (3c). This compound was obtained from 2c
as described for 3a as beige solid in 90% yield. Mp
172 ꢁC. IR (KBr): m = 3295, 3139, 3043, 2951,
4. Experimental
4.1. General
1
1671(CO), 1570, 1443, 1383, 1159, 1137, 726 cmꢀ1. H
NMR (400 MHz, CDCl3): d = 9.3 (br s, 1H, NH), 7.07
(d, J = 3.4 Hz, 1H, H5), 6.90 (m, 4H, Harom), 6.66 (m,
2H, Hapyrrole), 6.26 (m, 2H, Hbpyrrole), 3.77 (s, 3H,
OCH3). 13C NMR (100 MHz, CDCl3): d = 161.85 (d,
J = 246 Hz), 160.54, 128.31 (d, J = 7 Hz), 129.29,
128.01, 122.88, 122.76, 118.92, 117.26, 115.45 (d,
J = 21 Hz), 108.97, 51.79. MS (EI+) m/z: 284.0. Anal.
Calcd for C16H17FN2O2: C, 67.60; H, 4.61; N, 9.85.
Found: C, 67.87; H, 4.56; N, 9.53.
Commercial reagents were used as received without
additional purification. Melting points were determined
on a Ko¨fler melting point apparatus and are uncorrect-
ed. IR spectra were taken with a Perkin-Elmer spectrum
1
BX FT-IR spectrometer. H NMR (400 MHz) and 13C
(100 MHz) were recorded on a JEOL Lambda 400 Spec-
trometer. Chemical shifts are expressed in parts per mil-
lion downfield from TMS as an internal standard. Mass
spectrum was recorded on a JEOL JMS GCMate with
ionizing potential of 70 eV. Elemental analyses for new
compounds were performed at the ‘Institut de Recher-
che en Chimie Organique Fine’ (Rouen).
4.2.4. Methyl 40-(4-methylphenyl)-10H-1,30-bipyrrole-20-
carboxylate (3d). This compound was obtained from 2d
as described for 3a as beige solid in 78% yield. Mp
128 ꢁC. IR (KBr): m = 3293, 3133, 2999, 2950,
1672(CO), 1576, 1467, 1413, 1289, 1202, 1079,
4.2. Clauson-Kaas reaction procedure
1
721 cmꢀ1. H NMR (400 MHz, CDCl3): d = 9.3 (br s,
4.2.1. Methyl 40-(4-methoxyphenyl)-10H-1,30-bipyrrole-
1H, NH), 7.06 (m, 3H, Harom + H5), 6.84 (d,
J = 8.7 Hz, 2H, Harom), 6.68 (m, 2H, Hapyrrole), 6.26
(m, 2H, Hbpyrrole), 3.76 (s, 3H, OCH3), 2.29 (s, 3H,
CH3). 13C NMR (100 MHz, CDCl3): d = 160.82,
136.72, 129.55, 129.47, 128.30, 126.76, 123.95, 123.04,
119.21, 117.33, 108.96, 51.95, 21.33. MS (EI+) m/z:
280.0. Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75;
N, 9.99. Found: C, 73.13; H, 6.04; N, 10.34.
20-carboxylate (3a).
A
solution of 2,5-dim-
ethoxytetrahydrofuran (0.46 mL, 3.6 mmol) in dioxane
(20 mL) was stirred for 15 min with 4-chloropyridine
hydrochloride (0.54 g, 3.6 mmol). The aminoester 2a
(0.8 g, 3.25 mmol) was added and the reaction mixture
was refluxed for 1.5 h and filtered through a small pad
of Celite. The solvent was evaporated to give a brown
residue that was dissolved in methylene chloride
(100 mL). The solution was washed with an 1 N aqueous
hydrochloric acid solution (2· 100 mL), dried (MgSO4),
and evaporated to give 3a as a beige solid (550 mg, 57%)
that was crystallized from Et2O. Mp 110 ꢁC. IR (KBr):
m = 3335(NH), 3100, 2949, 2838, 1697(CO), 1584,
4.2.5. Methyl 40-(2-thienyl)-10H-1,30-bipyrrole-20-carbox-
ylate (3e). This compound was obtained from 2e as de-
scribed for 3a as brown solid in 92% yield. Mp
130 ꢁC. IR (KBr): m = 3301, 3116, 3110, 2948,
1734(CO), 1587, 1402, 1441, 1217, 1165, 735,
1
1508, 1438, 1380, 1264, 1081, 721 cmꢀ1
.
1H NMR
702 cmꢀ1. H NMR (400 MHz, CDCl3): d = 9.3 (br s,
(400 MHz, CDCl3): d = 9.3 (br s, 1H, NH), 7.05 (d,
J = 3.2 Hz, 1H, H5), 6.87 (d, J = 8.7 Hz, 2H, Harom),
6.77 (d, J = 8.7 Hz, 2H, Harom), 6.68 (m, 2H, Hapyrrole),
6.26 (m, 2H, Hbpyrrole), 3.76 (s, 3H, OCH3), 3.75 (s, 3H,
OCH3). 13C NMR (100 MHz, CDCl3): d = 160.60,
1H, NH), 7.13 (m, 2H, Hthio + H5), 6.89 (m, 1H, Hthio),
6.71 (m, 2H, Hapyrrole), 6.45 (m, 1H, Hthio), 6.26 (m, 2H,
Hbpyrrole), 3.75 (s, 3H, OCH3). 13C NMR (100 MHz,
CDCl3): d = 160.55, 133.77, 127.69, 127.58, 123.83,
123.62, 122.90, 118.77, 118.54, 118.27, 103.14, 52.04.

C. Rochais et al. / Bioorg. Med. Chem. 14 (2006) 8162–8175
8167
MS (EI+) m/z: 272.0. Anal. Calcd for C14H12N2O2S: C,
61.75; H, 4.44; N, 10.29. Found: C, 61.45; H, 4.67; N,
10.45.
4.2.10. Methyl 40-(3-benzyloxy-4-methoxyphenyl)-10H-
1,30-bipyrrole-20-carboxylate (3j). This compound was
obtained from 2j as described for 3a as beige solid in
70% yield. Mp 180 ꢁC. IR (KBr): m = 3289, 3151,
3036, 2998, 2930, 1671(CO), 1569, 1515, 1474, 1446,
4.2.6. Methyl 40-phenyl-10H-1,30-bipyrrole-20-carboxylate
(3f). This compound was obtained from 2f as described
for 3a as beige solid in 96% yield. Mp 168 ꢁC. IR (KBr):
m = 3312, 3125, 2948, 1708(CO), 1585, 1398, 1264, 1162,
1381, 1247, 1147, 749 cmꢀ1
.
1H NMR (400 MHz,
CDCl3): d = 9.2 (br s, 1H, NH), 7.34 (m, 5H, Harom),
7.02 (d, J = 2.9 Hz, 1H, H5), 6.79 (d, J = 8.2 Hz, 1H,
1084, 738, 673 cmꢀ1
.
1H NMR (400 MHz, CDCl3):
H5 ), 6.70 (m, 3H, H6 þ Hapyrrole), 6.29 (m, 3H,
0
0
0
d = 9.2 (br s, 1H, NH), 7.22 (m, 3H, Harom), 7.10 (d,
J = 3.1 Hz, 1H, H5), 6.96 (m, 2H, Harom), 6.68 (m, 2H,
Hapyrrole), 6.27 (m, 2H, Hbpyrrole), 3.77 (s, 3H, OCH3).
13C NMR (100 MHz, CDCl3): d = 160.66, 132.29,
128.53, 128.16, 126.78, 126.66, 123.68, 122.82, 119.27,
117.19, 108.80, 51.76. MS (EI+) m/z: 266.1. Anal. Calcd
for C16H14N2O2: C, 72.17; H, 5.30; N, 10.52. Found: C,
72.01; H, 5.02; N, 10.43.
Hbpyrrole + H2 ), 4.85 (s, 2H, CH2Ph), 3.85 (s, 3H,
OCH3), 3.75 (s, 3H, OCH3). 13C NMR (100 MHz,
CDCl3): d = 160.57, 148.41, 148.07, 137.15, 128.37,
127.79, 127.66, 127.36, 124.98, 123.38, 122.89, 119.16,
118.50, 117.16, 111.94, 111.70, 108.94, 70.42, 55.92,
51.70. MS (EI+) m/z: 402.2. Anal. Calcd for
C24H22N2O4: C, 71.63; H, 5.51; N, 6.96. Found: C,
72.00; H, 5.48; N, 6.85.
4.2.7. Methyl 40-(4-chlorophenyl)-10H-1,30-bipyrrole-20-
carboxylate (3g). This compound was obtained from
2g as described for 3a as beige solid in 99% yield.
Mp 194ꢁC. IR (KBr): m = 3403, 3155, 3101, 2947,
1710(CO), 1585, 1438, 1377, 1192, 1083, 723,
4.2.11. Ethyl 40-bromo-10H-1,30-bipyrrole-20-carboxylate
(18). This compound was obtained from 17 as described
for 3a as yellow solid in 99% yield. Mp 112 ꢁC. IR
(KBr): m = 3263, 2963, 2928, 1675(CO), 1417, 1290,
1
1127, 721 cmꢀ1. H NMR (400 MHz, CDCl3): d = 9.3
579 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d = 9.3 (br
(br s, 1H, NH), 6.98 (d, J = 3.4 Hz, 1H, H5), 6.80 (m,
2H, Hapyrrole), 6.29 (m, 2H, Hbpyrrole), 4.21 (q,
J = 7.1 Hz, 2H, OCH2), 1.19 (t, J = 7.1 Hz, 3H, CH3).
13C NMR (100 MHz, CDCl3): d = 159.37, 129.68,
122.92, 120.94, 116.88, 108.58, 97.24, 60.98, 14.01. MS
(EI+) m/z: 294.2 (M+), 282.2 (Mꢀ). Anal. Calcd for
C11H11BrN2O2: C, 46.67; H, 3.92; N, 9.89. Found: C,
46.56; H, 4.05; N, 9.87.
s, 1H, NH), 7.19 (d, J = 8.5 Hz, 2H, Harom), 7.05 (d,
J = 3.3 Hz, 1H, H5), 6.84 (d, J = 8.5 Hz, 2H, Harom),
6.66 (m, 2H, Hapyrrole), 6.26 (m, 2H, Hbpyrrole), 3.77
(s, 3H, OCH3). 13C NMR (100 MHz, CDCl3):
d = 160.69, 132.79, 130.94, 128.91, 128.19, 128.06,
122.89, 122.83, 119.25, 117.60, 109.25, 52.02. MS
(EI+) m/z: 300.1. Anal. Calcd for C16H13ClN2O2: C,
63.90; H, 4.36; N, 9.31. Found: C, 64.21; H, 4.56;
N, 9.10.
4.3. Typical amidification reaction procedure
4.2.8. Methyl 40-(3,4-dichlorophenyl)-10H-1,30-bipyrrole-
20-carboxylate (3h). This compound was obtained from
2h as described for 3a as beige solid in 80% yield. Mp
166 ꢁC. IR (KBr): m = 3398, 3125, 2946, 1708(CO),
4.3.1. 40-(4-Methoxyphenyl)-20-(pyrrolidin-1-ylcarbonyl)-
10H-1,30-bipyrrole (4a). A solution of 3a (500 mg,
1.69 mmol) in pyrrolidine (20 mL) was refluxed for
12 h. After the mixture was cooled and evaporated,
the yellow oil was dissolved in chloroform (100 mL)
and the solution was washed with an 1 N aqueous
hydrochloric acid solution (2· 100 mL), dried (CaCl2),
and evaporated to give a brown solid. This residue
was purified by silica gel chromatography, eluting by
cyclohexane/ethyl acetate (1:2) to furnish carboxamide
4a as a beige solid (300 mg, 53%). Mp 166 ꢁC. IR
(KBr): m = 3219, 2971, 2927, 2869, 1590(CO), 1447,
1
1583, 1439, 1274, 1250, 1058, 1014, 732, 572 cmꢀ1. H
NMR (400 MHz, CDCl3): d = 9.4 (br s, 1H, NH), 7.16
0
(d, J = 8.3 Hz, 1H, H5 ), 7.12 (d, J = 3.3 Hz, 1H, H5),
0
7.02 (d, J = 1.8 Hz, 1H, H2 ), 6.65 (m, 3H, Hapyrrole
þ
H6 ), 6.29 (m, 2H, Hbpyrrole), 3.77 (s, 3H, OCH3). 13C
NMR (100 MHz, CDCl3): d = 160.56, 132.63, 132.44,
130.67, 130.60, 130.58, 128.47, 125.84, 122.74, 121.77,
119.28, 117.85, 109.51, 51.94. MS (EI+) m/z: 336.1.
Anal. Calcd for C16H12Cl2N2O2: C, 57.33; H, 3.61; N,
8.36. Found: C, 57.64; H, 3.60; N, 8.34.
0
1
1243, 1175, 1032, 832, 731 cmꢀ1. H NMR (400 MHz,
CDCl3): d = 9.9 (br s, 1H, NH), 6.97 (d, J = 3.2 Hz,
1H, CHN), 6.87 (d, J = 8.7 Hz, 2H, Harom), 6.78 (d,
J = 8.7 Hz, 2H, Harom), 6.61 (m, 2H, Hapyrrole), 6.19
(m, 2H, Hbpyrrole), 3.77 (s, 1H, OCH3), 3.56 (m, 2H,
Hapyrrolidine), 2.52 (m, 2H, Hapyrrolidine), 1.77 (m, 2H,
Hbpyrrolidine), 1.60 (m, 2H, Hbpyrrolidine). 13C NMR
(100 MHz, CDCl3): d = 161.45, 158.18, 128.21, 126.38,
126.08, 125.48, 122.15, 121.23, 117.56, 113.81, 109.48,
55.14, 46.44, 46.14, 24.95, 21.32. MS (EI+) m/z: 335.2.
Anal. Calcd for C20H21N3O2: C, 71.62; H, 6.31; N,
12.53. Found: C, 71.54; H, 6.45; N, 12.57.
4.2.9. Methyl 40-(3-thienyl)-10H-1,30-bipyrrole-20-carbox-
ylate (3i). This compound was obtained from 2i as de-
scribed for 3a as brown solid in 99% yield. Mp 152 ꢁC.
IR (KBr): m = 3293, 3130, 3098, 2946, 1675(CO), 1443,
1399, 1349, 1196, 1133, 786, 729 cmꢀ1
.
1H NMR
(400 MHz, CDCl3): d = 9.4 (br s, 1H, NH), 7.22 (d,
J = 3.3 Hz, 1H, H5), 7.14 (m, 1H, Hthio), 6.80 (m, 1H,
Hthio), 6.71 (m, 2H, Hapyrrole), 6.54 (m, 1H, Hthio), 6.32
(m, 2H, Hbpyrrole), 3.74 (s, 3H, OCH3). 13C NMR
(100 MHz, CDCl3): d = 160.25, 136.97, 133.19, 132.28,
131.48, 125.56, 121.96, 119.73, 118.46, 111.27, 107.24,
51.19. MS (EI+) m/z: 272.0. Anal. Calcd for
C14H12N2O2S: C, 61.75; H, 4.44; N, 10.29. Found: C,
61.74; H, 4.56; N, 10.24.
4.3.2. 40-(3,4-Dimethoxyphenyl)-20-(pyrrolidin-1-ylcar-
bonyl)-10H-1,30-bipyrrole (4b). This compound was ob-
tained from 3b as described for 4a as yellow solid in
69% yield. Mp 150 ꢁC. IR (KBr): m = 3223, 2973, 2950,

8168
C. Rochais et al. / Bioorg. Med. Chem. 14 (2006) 8162–8175
2879, 2839, 1587(CO), 1515, 1484, 1447, 1247, 1221,
1136, 1025, 723 cmꢀ1 1H NMR (400 MHz, CDCl3):
m/z: 311.1. Anal. Calcd for C17H17N3OS: C, 65.57; H,
5.50; N, 13.49. Found: C, 65.43; H, 5.85; N, 13.31.
.
d = 10.6 (br s, 1H, NH), 7.02 (d, J = 3.1 Hz, 1H, H5),
0
6.78 (d, J = 8.2 Hz, 1H, H5 ), 6.71 (dd, J = 1.8, 8.2 Hz,
4.3.6.
40-Phenyl-20-(pyrrolidin-1-ylcarbonyl)-10H-1,30-
0
1H, H6 ), 6.63 (m, 2H, Hapyrrole), 6.24 (d, J = 1.8 Hz,
0
1H, H2 ), 6.20 (m, 2H, Hbpyrrole), 3.84 (s, 3H, OCH3),
bipyrrole (4f). This compound was obtained from 3f as
described for 4a as white solid in 47% yield. Mp
184 ꢁC. IR (KBr): m = 3192, 2970, 2869, 1590(CO),
3.60 (s, 5H, OCH3 + Hapyrrolidine), 2.57 (m, 2H,
Hapyrrolidine), 1.78 (m, 2H, Hbpyrrolidine), 1.61 (m, 2H,
Hbpyrrolidine). 13C NMR (100 MHz, CDCl3): d = 161.71,
148.63, 147.42, 126.11, 123.52, 122.19, 120.83, 120.47,
118.95, 117.92, 110.93, 109.92, 109.51, 55.71, 55.34,
46.61, 46.42, 26.03, 23.81. Anal. Calcd for
C21H23N3O3: C, 69.02; H, 6.34; N, 11.50. Found: C,
69.21; H, 6.39; N, 11.48. HRMS (EI+) m/z: 365.17253
(M+, 71.2, C21H23N3O3 required 365.17392).
1438, 1347, 1081, 1067, 910, 696 cmꢀ1 1H NMR
.
(400 MHz, CDCl3): d = 10.2 (br s, 1H, NH), 7.21 (m,
3H, Harom), 7.03 (d, J = 3.1 Hz, 1H, H5), 6.95 (d,
J = 7.1 Hz, 2H, Harom), 6.61 (m, 2H, Hapyrrole), 6.20
(m, 2H, Hbpyrrole), 3.57 (m, 2H, Hapyrrolidine), 2.53 (m,
2H, Hapyrrolidine), 1.78 (m, 2H, Hbpyrrolidine), 1.61 (m,
2H, Hbpyrrolidine). 13C NMR (100 MHz, CDCl3):
d = 161.72, 133.33, 128.58, 127.26, 126.53, 123.93,
122.32, 121.62, 120.90, 118.31, 109.76, 46.68, 46.67,
26.26, 24.10. MS (EI+) m/z: 305.1. Anal. Calcd for
C19H19N3O: C, 74.73; H, 6.27; N, 13.76. Found: C,
75.10; H, 6.23; N, 14.03.
4.3.3. 40-(4-Fluorophenyl)-20-(pyrrolidin-1-ylcarbonyl)-
10H-1,30-bipyrrole (4c). This compound was obtained
from 3c as described for 4a as beige solid in 47% yield.
Mp 222 ꢁC. IR (KBr): m = 3215, 2970, 2880, 1598(CO),
1474, 1212, 837, 729 cmꢀ1
.
1H NMR (400 MHz,
4.3.7. 40-(4-Chlorophenyl)-20-(pyrrolidin-1-ylcarbonyl)-
10H-1,30-bipyrrole (4g). This compound was obtained
from 3g as described for 4a as white solid in 48% yield.
Mp 210 ꢁC. IR (KBr): m = 3214, 2966, 2877, 1589(CO),
CDCl3): d = 10.03 (br s, 1H, NH), 6.99 (d, J = 3.1 Hz,
1H, H5), 6.90 (m, 4H, Harom), 6.59 (m, 2H, Hapyrrole),
6.20 (m, 2H, Hbpyrrole), 3.56 (m, 2H, Hapyrrolidine), 2.53
(m, 2H, Hapyrrolidine), 1.78 (m, 2H, Hbpyrrolidine), 1.61
(m, 2H, Hbpyrrolidine). 13C NMR (100 MHz, CDCl3):
d = 163.33, 160.31 (d, J = 241 Hz), 129.09, 128.63 (d,
J = 9 Hz), 128.45, 123.58, 122.08, 120.77, 117.73,
115.28 (d, J = 23 Hz), 109.71, 46.45, 46.32, 26.07,
23.89. MS (EI+) m/z: 323.2. Anal. Calcd for
C19H19FN3O: C, 70.57; H, 5.61; N, 12.99. Found: C,
70.62; H, 5.46; N, 13.12.
1
1447, 1387, 1137, 1078, 829, 724, 622 cmꢀ1. H NMR
(400 MHz, CDCl3): d = 10.6 (br s, 1H, NH), 7.18 (d,
J = 8.3 Hz, 2H, Harom), 7.02 (d, J = 3.3 Hz, 1H, H5),
6.85 (d, J = 7.8 Hz, 2H, Harom), 6.59 (m, 2H, Hapyrrole),
6.21 (m, 2H, Hbpyrrole), 3.57 (m, 2H, Hapyrrolidine), 2.53
(m, 2H, Hapyrrolidine), 1.78 (m, 2H, Hbpyrrolidine), 1.61
(m, 2H, Hbpyrrolidine). 13C NMR (100 MHz, CDCl3):
d = 161.36, 132.11, 131.63, 128.56, 128.23, 123.65,
122.01, 120.81, 120.24, 118.18, 109.82, 46.53, 46.35,
26.04, 23.85. MS (EI+) m/z: 339.0. Anal. Calcd for
C19H18ClN3O: C, 67.16; H, 5.34; N, 12.37. Found: C,
67.24; H, 5.53; N, 12.45.
4.3.4. 40-(4-Methylphenyl)-20-(pyrrolidin-1-ylcarbonyl)-
10H-1,30-bipyrrole (4d). This compound was obtained
from 3d as described for 4a as beige solid in 53% yield.
Mp 200 ꢁC. IR (KBr): m = 3237, 2966, 2877, 1589(CO),
1444, 1384, 1137, 823, 728, 623 cmꢀ1
.
1H NMR
4.3.8. 40-(3,4-Dichlorophenyl)-20-(pyrrolidin-1-ylcarbon-
yl)-10H-1,30-bipyrrole (4h). This compound was obtained
from 3h as described for 4a as yellow solid in 51% yield.
Mp 226 ꢁC. IR (KBr): m = 3210, 2971, 2869, 1585(CO),
(400 MHz, CDCl3): d = 10.0 (br s, 1H, NH), 7.04 (d,
J = 7.8 Hz, 2H, Harom), 7.01 (d, J = 3.3 Hz, 1H, H5),
6.84 (d, J = 7.8 Hz, 2H, Harom), 6.62 (m, 2H, Hapyrrole),
6.20 (m, 2H, Hbpyrrole), 3.56 (m, 2H, Hapyrrolidine), 2.53
(m, 2H, Hapyrrolidine), 2.30 (s, 3H, CH3), 1.77 (m, 2H,
Hbpyrrolidine), 1.60 (m, 2H, Hbpyrrolidine). 13C NMR
(100 MHz, CDCl3): d = 161.54, 135.95, 130.11, 129.10,
126.92, 123.66, 122.14, 121.48, 120.65, 117.84, 109.48,
46.44, 46.35, 26.10, 23.92, 21.10. MS (EI+) m/z: 319.1.
Anal. Calcd for C20H21N3O: C, 75.21; H, 6.63; N,
13.16. Found: C, 75.22; H, 6.53; N, 13.15.
1
1451, 1134, 759, 722, 627 cmꢀ1. H NMR (400 MHz,
CDCl3): d = 10.7 (br s, 1H, NH), 7.25 (d, J = 8.0 Hz,
0
1H, H5 ), 7.05 (d, J = 3.3 Hz, 1H, H5), 7.03 (d,
0
J = 1.9 Hz, 1H, H2 ), 6.66 (dd, J = 1.9, 8.0 Hz, 1H,
0
H6 ), 6.58 (m, 2H, Hapyrrole), 6.24 (m, 2H, Hbpyrrole),
3.56 (m, 2H, Hapyrrolidine), 2.54 (m, 2H, Hapyrrolidine),
1.78 (m, 2H, Hbpyrrolidine), 1.62 (m, 2H, Hbpyrrolidine).
13C NMR (100 MHz, CDCl3): d = 161.18, 133.29,
132.47, 130.41, 130.29, 128.78, 126.22, 123.64, 122.13,
121.36, 119.64, 118.23, 110.24, 46.66, 46.65, 26.21,
23.98. MS (EI+) m/z: 375.0. Anal. Calcd for
C19H17Cl2N3O: C, 67.16; H, 5.34; N, 12.37. Found: C,
67.12; H, 5.56; N, 12.42.
4.3.5. 20-(Pyrrolidin-1-ylcarbonyl)-40-thien-2-yl-10H-1,30-
bipyrrole (4e). This compound was obtained from 3e as
described for 4a as beige solid in 65% yield. Mp 174 ꢁC.
IR (KBr): m = 3202, 2973, 2877, 1587(CO), 1479, 1447,
1432, 842, 735 cmꢀ1 1H NMR (400 MHz, CDCl3):
.
d = 10.2 (br s, 1H, NH), 7.09 (m, 2H, Hthio + H5), 6.89
4.3.9. 20-(Pyrrolidin-1-ylcarbonyl)-40-thien-3-yl-10H-1,30-
bipyrrole (4i). This compound was obtained from 3e as
described for 4i as beige solid in 68% yield. Mp
201 ꢁC. IR (KBr): m = 3242, 2971, 2882, 2826,
1588(CO), 1447, 1344, 1188, 1077, 1029, 854,
0
(dd, J = 5.1, 3.4 Hz, 1H, H3 ), 6.64 (m, 2H, Hapyrrole),
6.46 (d, J = 3.4 Hz, 1H, Hthio), 6.23 (m, 2H, Hbpyrrole),
3.51 (m, 2H, Hapyrrolidine), 2.49 (m, 2H, Hapyrrolidine),
1.72 (m, 2H, Hbpyrrolidine), 1.58 (m, 2H, Hbpyrrolidine).
13C NMR (100 MHz, CDCl3): d = 161.04, 134.53,
127.55, 123.69, 123.54, 122.78, 122.61, 117.96, 116.33,
109.77, 108.76, 46.77, 46.62, 24.50, 22.86. MS (EI+)
1
734 cmꢀ1. H NMR (400 MHz, CDCl3): d = 9.6 (br s,
1H, NH), 7.21 (m, 1H, Hthio), 7.05 (d, J = 3.1 Hz,
0
1H, H5), 6.77 (d, J = 5.0 Hz, 1H, H4 ), 6.66 (m, 2H,

C. Rochais et al. / Bioorg. Med. Chem. 14 (2006) 8162–8175
8169
Hapyrrole), 6.62 (m, 1H, Hthio), 6.24 (m, 2H, Hbpyrrole),
3.55 (m, 2H, Hapyrrolidine), 2.56 (m, 2H, Hapyrrolidine),
1.81 (m, 2H, Hbpyrrolidine), 1.65 (m, 2H, Hbpyrrolidine).
13C NMR (100 MHz, CDCl3): d = 161.27, 133.01,
126.67, 125.27, 123.56, 122.59, 121.39, 119.58, 118.03,
117.65, 109.84, 46.79, 46.66, 26.32, 22.89. MS (EI+) m/
z: 311.1. Anal. Calcd for C17H17N3O2S: C, 65.57; H,
5.50; N, 13.49. Found: C, 65.78; H, 5.43; N, 13.56.
d = 9.8 (br s, 1H, NH), 7.39 (d, J = 8.6 Hz, 2H, Harom),
6.97 (d, J = 8.6 Hz, 2H, Haromatic), 6.98 (d, J = 2.9 Hz,
1H, H2), 6.87 (d, 1H, J = 2.3 Hz, 1H, H5), 6.55 (d,
J = 3.5 Hz, 1H, H7), 5.96 (dd, J = 2.3, 3.5 Hz, 1H,
H
ꢀ6), 3.85 (s, 3H, OCH3). 13C NMR (100 MHz,
CDCl3): d = 179.74, 158.93, 158.32, 133.11, 129.12,
127.79, 127.23, 125.27, 116.51, 115.32, 114.73, 113.62,
109.41, 55.24. MS (EI+) m/z: 264.1. Anal. Calcd for
C16H12N2O2: C, 72.72; H, 4.58; N, 10.60. Found: C,
73.05; H, 4.43; N, 10.45.
4.3.10. 40-(3-Benzyloxy-4-methoxyphenyl)-20-(pyrrolidin-
1-ylcarbonyl)-10H-1,30-bipyrrole (4j). This compound
was obtained from 3j as described for 4a as beige solid
in 50% yield. Mp 151 ꢁC. IR (KBr): m = 3190, 2968,
2929, 1587(CO), 1448, 1250, 1111, 1024, 731,
4.4.2. 3-(3,4-Dimethoxyphenyl)pyrrolo[2,3-b]pyrrolizin-
8(1H)-one (5b). This compound was obtained from 4b
as described for 5a as red solid in 30% yield. Mp
190 ꢁC. IR (KBr): m = 3142, 2965, 2924, 2828,
1655(CO), 1637, 1453, 1349, 1249, 1156, 1129, 1080,
1
697 cmꢀ1. H NMR (400 MHz, CDCl3): d = 10.5 (br s,
1H, NH), 7.29 (m; 5H, Harom), 6.95 (d, J = 3.2 Hz,
0
1H, H5), 6.79 (d, J = 8.3 Hz, 1H, H5 ), 6.68 (dd,
0
J = 1.7, 8.3 Hz, 1H, H6 ), 6.62 (m, 2H, Hapyrrole), 6.30
1
728 cmꢀ1. H NMR (400 MHz, CDCl3): d = 9.9 (br s,
0
1H, NH), 7.04 (dd, J = 1.8, 8.2 Hz, 1H, H6 ), 6.97 (d,
0
(d, J = 1.7 Hz, 1H, H2 ), 6.22 (m, 2H, Hbpyrrole),
0
J = 3.0 Hz, 1H, H2), 6.88 (d, J = 1.8 Hz, 1H, H2 ), 6.84
0
(d, 1H, J = 8.4 Hz, 1H, H5 ), 6.81 (d, J = 2.2 Hz, 1H,
4.85 (s, 2H, OCH2), 3.84 (s, 3H, OCH3), 3.57 (m, 2H,
Hapyrrolidine), 2.55 (m, 2H, Hapyrrolidine), 1.77 (m, 2H,
Hbpyrrolidine), 1.61 (m, 2H, Hbpyrrolidine). 13C NMR
(100 MHz, CDCl3): d = 161.37, 148.18, 147.99, 137.04,
128.40, 127.68, 127.38, 125.80, 123.49, 122.38, 121.39,
120.82, 119.56, 117.43, 112.47, 111.74, 109.66, 70.43,
55.97, 46.49, 46.37, 25.30, 21.10. MS (EI+) m/z: 441.0.
Anal. Calcd for C26H26N3O3: C, 73.45; H, 6.16; N,
9.52. Found: C, 73.42; H, 6.04; N, 9.86.
H5), 6.47 (d, J = 3.6 Hz, 1H, H7), 5.88 (dd, J = 2.2,
3.6 Hz, 1H, Hꢀ6), 3.84 (s, 6H, OCH3). 13C NMR
(100 MHz, CDCl3): d = 174.93, 149.33, 148.42, 140.21,
136.22, 126.69, 125.13, 124.87, 121.71, 119.12, 114.63,
113.12, 112.21, 111.71, 110.13, 56.10, 56.04. MS (EI+)
m/z: 294.1. Anal. Calcd for C17H14N2O3: C, 69.37; H,
4.79; N, 9.52. Found: C, 69.41; H, 4.88; N, 9.49.
4.4.3. 3-(4-Fluorophenyl)pyrrolo[2,3-b]pyrrolizin-8(1H)-
one (5c). This compound was obtained from 4c as de-
scribed for 5a as red solid in 30% yield. Mp 252 ꢁC.
IR (KBr): m = 3175, 2990, 2965, 2932, 1663(CO), 1586,
4.3.11. 40-Bromo-20-(pyrrolidin-1-ylcarbonyl)-10H-1,30-
bipyrrole (19). This compound was obtained from 18 as
described for 4a as white solid in 43% yield. Mp 164 ꢁC.
IR (KBr): m = 3421, 2956, 2924, 1855, 1549(CO), 1451,
1
1534, 1522, 1385, 1224, 1150, 826, 720 cmꢀ1. H NMR
1
1383, 1344, 1261, 1088, 801 cmꢀ1. H NMR (400 MHz,
(400 MHz, CDCl3): d = 10.3 (br s, 1H, NH), 7.44 (d,
J = 8.5 Hz, 2H, Harom), 7.13 (d, J = 8.5 Hz, 2H, Harom),
6.93 (d, J = 2.9 Hz, 1H, H2), 6.84 (d, 1H, J = 2.8 Hz,
1H, H5), 6.56 (d, J = 3.7 Hz, 1H, H7), 5.97 (dd,
J = 2.8, 3.7 Hz, 1H, H6). 13C NMR (100 MHz, CDCl3):
d = 170.78, 167.89, 161.75 (d, J = 246 Hz), 136.13,
128.73, 128.25 (d, J = 8 Hz), 125.57, 125.25, 120.78,
115.92 (d, J = 21 Hz), 113.26, 111.83, 111.56. HRMS
(EI+) m/z: 252.0699 (M+, 100, C15H9N2OF required
252.0699).
CDCl3): d = 11.0 (br s, 1H, NH), 6.92 (d, J = 2.9 Hz,
1H, H5), 6.79 (m, 2H, Hapyrrole), 6.26 (m, 2H, Hbpyrrole),
3.53 (m, 2H, Hapyrrolidine), 2.45 (m, 2H, Hapyrrolidine),
1.73 (m, 2H, Hbpyrrolidine), 1.64 (m, 2H, Hbpyrrolidine).
13C NMR (100 MHz, CDCl3): d = 160.81, 125.19,
122.12, 120.16, 119.85, 109.63, 94.12, 46.52, 46.38,
26.01, 23;91. MS (EI+) m/z: 309.2 (M+), 307.2 (Mꢀ).
Anal. Calcd for C13H14BrN3O: C, 50.67; H, 4.58; N,
13.63. Found: C, 51.19; H, 4.69; N, 13.07.
4.4. Typical cyclization reaction procedure
4.4.4. 3-(4-Methylphenyl)pyrrolo[2,3-b]pyrrolizin-8(1H)-
one (5d). This compound was obtained from 4d as de-
scribed for 5a as red solid in 23% yield. Mp 255 ꢁC.
IR (KBr): m = 3136, 2924, 2860, 1669(CO), 1517 1322,
1148, 820, 773, 721 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d = 10.2 (br s, 1H, NH), 7.36 (d, J = 7.9 Hz, 2H, Harom),
7.24 (d, J = 7.9 Hz, 2H, Harom), 6.96 (d, J = 2.9 Hz, 1H,
H2), 6.90 (d, 1H, J = 2.3 Hz, 1H, H5), 6.55 (d,
J = 3.6 Hz, 1H, H7), 5.96 (dd, J = 2.3, 3.6 Hz, 1H, H6),
2.39 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3):
d = 173.71, 157.90, 137.09, 135.99, 129.70, 129.09,
126.59, 125.67, 121.76, 114.43, 114.39, 113.33, 112.06,
21.34. MS (EI+) m/z: 248.1. Anal. Calcd for
C16H12N2O: C, 77.40; H, 4.87; N, 11.28. Found: C,
77.24; H, 4.56; N, 11.12.
4.4.1. 3-(4-Methoxyphenyl)pyrrolo[2,3-b]pyrrolizin-8(1H)-
one (5a). A solution of the carboxamide 4a (250 mg,
0.75 mmol) in phosphorus oxychloride (20 mL) was stir-
red at 70 ꢁC for 3 h. After cooling, the reaction mixture
was concentrated to give the intermediary iminium salt
which was slowly added to a 10% aqueous sodium
hydroxide solution (50 mL) and heated at 80 ꢁC for
3 h. After cooling, the resulting suspension was extract-
ed with ethyl acetate (2· 50 mL) and the combined
organic layers were washed with water (2· 100 mL)
and brine (100 mL), dried (MgSO4), and evaporated to
give a dark red solid. This residue was purified by silica
gel chromatography, eluting by cyclohexane/ethyl ace-
tate (1:1) to furnish thienopyrrolizinone 5a as a red solid
(30 mg, 10%). Mp 243 ꢁC. IR (KBr): m = 3091, 2964,
2932, 2834, 1654(CO), 1643, 1434, 1350, 1249, 1153,
4.4.5.
3-(Thien-2-yl)pyrrolo[2,3-b]pyrrolizin-8(1H)-one
(5e). This compound was obtained from 4e as described
for 5a as red solid in 28% yield. Mp 243 ꢁC. IR (KBr):
1140, 1023, 723 cmꢀ1 1H NMR (400 MHz, CDCl3):
.

8170
C. Rochais et al. / Bioorg. Med. Chem. 14 (2006) 8162–8175
0
7.29 (s, 1H, H2 ), 7.21 (d, J = 4.7 Hz, 1H, H3 ), 6.95 (d,
0
m = 3125, 3079, 2963, 2928, 1662(CO), 1588, 1535, 1416,
1387, 779, 727, 708 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d = 9.9 (br s, 1H, NH), 7.09 (m, 4H, Hthio + H5), 6.99 (d,
J = 2.2 Hz, 1H, H2), 6.55 (d, J = 3.5 Hz, 1H, H7), 5.96
(dd, J = 2.7, 3.5 Hz, 1H, Hꢀ6). 13C NMR (100 MHz,
CDCl3): d = 162.55, 154.82, 138.27, 133.68, 131.83,
127.74, 125.67, 123.99, 122.08, 120.50, 119.67, 114.65,
112.25. MS (EI+) m/z: 240.0. Anal. Calcd for
C13H8N2OS: C, 64.98; H, 3.36; N, 11.66. Found: C,
65.23; H, 3.32; N, 11.66.
J = 2.2 Hz, 1H, H2), 6.90 (d, J = 2.6 Hz, 1H, H5), 6.55
(d, J = 3.3 Hz, 1H, H7), 5.96 (dd, J = 2.6, 3.3 Hz, 1H,
H
ꢀ6). 13C NMR (100 MHz, CDCl3): d = 170.43,
141.24, 137.63, 129.60, 126.88, 126.75, 125.78, 125.21,
121.72, 120.65, 114.59, 112.48, 108.47. MS (EI+) m/z:
239.9. Anal. Calcd for C13H8N2OS: C, 64.98; H, 3.36;
N, 11.66. Found: C, 65.34; H, 3.32; N, 11.56.
4.4.10.
3-(3-Benzyloxy-4-methoxyphenyl)pyrrolo[2,3-
b]pyrrolizin-8(1H)-one (5j). This compound was ob-
tained from 4j as described for 5a in 2% yield, or from
6j as described for 5a as red solid in 32% yield. Mp
244 ꢁC. IR (KBr): m = 3133, 2968, 2931, 2902, 2840,
1670(CO), 1520, 1381, 1257, 1145, 1016, 762,
4.4.6. 3-Phenylpyrrolo[2,3-b]pyrrolizin-8(1H)-one (5f).
This compound was obtained from 4f as described for
5a as red solid in 5% yield. Mp 243 ꢁC. IR (KBr):
m = 3111, 2978, 2891, 1647(CO), 1533, 1398, 1289,
1
1100, 762, 732 cmꢀ1
.
1H NMR (400 MHz, CDCl3):
706 cmꢀ1. H NMR (400 MHz, CDCl3): d = 12.0 (br s,
d = 9.7 (br s, 1H, NH), 7.46 (m, 5H, Harom), 6.98 (d,
J = 2.8 Hz, 1H, H2), 6.91 (d, J = 2.2 Hz, 1H, H5), 6.55
(d, J = 3.5 Hz, 1H, H7), 5.97 (dd, J = 2.2, 3.5 Hz, 1H,
1H, NH), 7.40 (m, 5H, Harom), 7.02 (m, 3H, Harom),
6.81 (d, J = 2.7 Hz, 1H, H2), 6.75 (d, J = 2.1 Hz, 1H,
H5), 6.46 (d, J = 3.4 Hz, 1H, H7), 5.93 (dd, J = 2.1,
3.4 Hz, 1H, Hꢀ6), 5.17 (s, 2H, OCH2), 3.79 (s, 3H,
OCH3). 13C NMR (100 MHz, CDCl3): d = 169.42,
148.26, 148.01, 138.41, 137.13, 135.44, 128.48, 127.82,
127.48, 126.36, 124.68, 124.59, 121.22, 119.20, 112.85,
112.79, 112.05, 111.97, 111.87, 69.73, 55.69. MS (EI+)
m/z: 370.1. Anal. Calcd for C23H18N2O3: C, 74.58; H,
4.90; N, 7.56. Found: C, 74.56; H, 4.87; N, 7.49.
H
ꢀ6). 13C NMR (100 MHz, CDCl3): d = 174.93,
156.33, 135.42, 131.21, 129.22, 128.69, 126.33, 125.71,
125.67, 116.52, 115.33, 114.72, 109.41. MS (EI+) m/z:
264.0. Anal. Calcd for C15H10N2O: C, 76.91; H, 4.30;
N, 11.96. Found: C, 77.23; H, 4.23; N, 11.75.
4.4.7. 3-(4-Chlorophenyl)pyrrolo[2,3-b]pyrrolizin-8(1H)-
one (5g). This compound was obtained from 4g as de-
scribed for 5a as red solid in 16% yield. Mp 255 ꢁC.
IR (KBr): m = 3138, 2963, 2920, 1688(CO), 1573, 1515,
4.4.11. 3-(4-Chlorophenyl)-1-methylpyrrolo[2,3-b] pyrr-
olizin-8(1H)-one (10g). This compound was obtained
from 7g as described for 5a as red solid in 72% yield.
Mp 180 ꢁC. IR (KBr): m = 3109, 2934, 2920, 1660(CO),
1
1379, 1092, 820, 713, 580 cmꢀ1. H NMR (400 MHz,
CDCl3): d = 9.7 (br s, 1H, NH), 7.41 (m, 4H, Harom),
6.93 (d, J = 3.2 Hz, 1H, H2), 6.84 (dd, J = 0.7, 2.7 Hz,
1H, H5), 6.55 (dd, J = 0.7, 3.7 Hz, 1H, H7), 5.97 (dd,
J = 2.7, 3.7 Hz, 1H, Hꢀ6). 13C NMR (100 MHz,
CDCl3): d = 181.73, 139.65, 136.20, 134.41, 132.72,
131.16, 129.19, 127.93, 125.79, 125.21, 120.96, 113.55,
111.99. MS (EI+) m/z: 269.9. Anal. Calcd for
C15H9N2OCl: C, 67.05; H, 3.38; N, 10.43. Found: C,
67.03; H, 3.34; N, 10.24.
1
1564, 1398, 1359, 1154, 1092, 799, 706 cmꢀ1. H NMR
(400 MHz, CDCl3): d = 7.32 (d, J = 8.7 Hz, 2H, Harom),
7.29 (d, J = 8.7 Hz, 2H, Harom), 6.75 (d, J = 2.6 Hz, 1H,
H5), 6.57 (s, 1H, H2), 6.48 (d, J = 3.7 Hz, 1H, H7), 5.91
(dd, J = 2.6, 3.7 Hz, 1H, Hꢀ6), 3.67 (s, 3H, NCH3). 13C
NMR (100 MHz, CDCl3): d = 180.28, 148.14, 137.85,
132.81, 132.62, 131.45, 130.77, 129.23, 127.77, 120.71,
116.12, 113.69, 112.05, 34.87. MS (EI+) m/z: 282.3.
Anal. Calcd for C16H11ClN2O: C, 67.97; H, 3.92; N,
9.91. Found: C, 67.89; H, 3.57; N, 9.74.
4.4.8.
3-(3,4-Dichlorophenyl)pyrrolo[2,3-b]pyrrolizin-
8(1H)-one (5h). This compound was obtained from 4h
as described for 5a as red solid in 14% yield. Mp
260 ꢁC. IR (KBr): m = 3142, 2978, 2905, 2847,
1674(CO), 1571, 1555, 1371, 1353, 1136, 821,
4.4.12. 3-(3-Benzyloxy-4-methoxyphenyl)-1-methylpyr-
rolo[2,3-b]pyrrolizin-8(1H)-one (10j). This compound
was obtained from 7j as described for 5a in 95% yield.
Mp 144 ꢁC. IR (KBr): m = 2963, 2925, 2854, 1682(CO),
1
718 cmꢀ1. H NMR (400 MHz, CDCl3): d = 10.1 (br s,
1
1525, 1392, 1257, 1136, 1029, 820, 732 cmꢀ1. H NMR
0
1H, NH), 7.56 (d, J = 1.8 Hz, 1H, H2 ), 7.50 (d, 1H,
0
J = 8.3 Hz, 1H, H5 ), 7.30 (dd, J = 1.8, 8.3 Hz, 1H,
0
H6 ), 6.96 (d, J = 2.7 Hz, 1H, H2), 6.84 (d, J = 2.4 Hz,
(400 MHz, CDCl3): d = 7.42 (m, 5H, Harom), 6.98 (dd,
0 0
J = 1.7, 8.2 Hz, 1H, H6 ), 6.94 (d, J = 8.2 Hz, 1H, H5 ),
0
6.90 (d, J = 1.7 Hz, 1H, H2 ), 6.53 (s, 1H, H2), 6.49 (d,
1H, H5), 6.58 (d, J = 3.6 Hz, 1H, H7), 6.01 (dd,
J = 2.4, 3.6 Hz, 1H, Hꢀ6). 13C NMR (100 MHz,
CDCl3): d = 179.79, 156.27, 133.78, 131.84, 130.70,
130.63, 129.84, 129.14, 127.78, 125.26, 119.29, 116.56,
115.33, 114.78, 109.44. MS (EI+) m/z: 304.0. Anal. Calcd
for C15H8N2OCl2: C, 59.43; H, 2.66; N, 9.24. Found: C,
59.34; H, 2.54; N, 9.34.
J = 3.7 Hz, 1H, H7), 6.32 (d, J = 2.4 Hz, 1H, H5), 5.82
(dd, J = 2.4, 3.7 Hz, 1H, Hꢀ6), 5.23 (s, 2H, OCH2),
3.94 (s, 3H, OCH3), 3.71 (s, 3H, NCH3). 13C NMR
(100 MHz, CDCl3): d = 165.46, 156.42, 148.98, 147.79,
135.90, 128.76, 128.57, 127.93, 127.85, 127.32, 126.88,
126.85, 120.72, 119.97, 119.67, 115.52, 113.31, 112.25,
111.86, 70.82, 56.12, 34.72. MS (EI+) m/z: 384.2. Anal.
Calcd for C24H20N2O3: C, 61.75; H, 4.44; N, 10.29.
Found: C, 61.64; H, 4.35; N, 10.14.
4.4.9.
3-(Thien-3-yl)pyrrolo[2,3-b]pyrrolizin-8(1H)-one
(5i). This compound was obtained from 4i as described
for 5a as red solid in 4% yield. Mp 250 ꢁC. IR (KBr):
m = 3124, 3084, 2967, 2926, 1662(CO), 1536, 1384,
4.4.13. 3-(4-Chlorophenyl)-1-ethylpyrrolo[2,3-b]pyrroli-
zin-8(1H)-one (11g). This compound was obtained from
8g as described for 5a as red solid in 66% yield. Mp
1143, 826, 767, 715, 577 cmꢀ1
.
1H NMR (400 MHz,
0
CDCl3): d = 9.8 (br s, 1H, NH), 7.09 (m, 1H, H4 ),

C. Rochais et al. / Bioorg. Med. Chem. 14 (2006) 8162–8175
8171
158 ꢁC. IR (KBr): m = 3094, 2973, 2920, 1677(CO), 1659,
1565, 1365, 1089, 829, 795, 723 cmꢀ1 1H NMR
C30H24N2O3: C, 78.24; H, 5.25; N, 6.08. Found: C,
78.13; H, 5.34; N, 5.94.
.
(400 MHz, CDCl3): d = 7.30 (m, 4H, Harom), 6.75 (d,
J = 2.4 Hz, 1H, H5), 6.63 (s, 1H, H2), 6.47 (d,
J = 3.3 Hz, 1H, H7), 5.91 (dd, J = 2.4, 3.3 Hz, 1H,
4.4.17. 3-Bromo-1-methylpyrrolo[2,3-b]pyrrolizin-8(1H)-
one (23). This compound was obtained from 20 as de-
scribed for 5a in 86% yield. Mp 130 ꢁC. IR (KBr):
m = 3117, 2924, 2853, 1683(CO), 1573, 1243, 964,
H
ꢀ6), 3.95 (q, J = 7.3 Hz, 2H, NCH2), 1.44 (t,
J = 7.3 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3):
d = 170.38, 138.98, 136.04, 132.74, 130.87, 129.20,
127.77, 126.41, 120.77, 120.62, 113.59, 112.03, 110.81,
43.77, 15.95. MS (EI+) m/z: 296.2. Anal. Calcd for
C17H13ClN2O: C, 68.81; H, 4.42; N, 9.44. Found: C,
68.80; H, 4.38; N, 9.27.
1
720 cmꢀ1. H NMR (400 MHz, CDCl3): d = 6.88 (dd,
J = 0.7, 2.4 Hz, 1H, H5), 6.54 (dd, J = 0.7, 3.7 Hz, 1H,
H7), 6.51 (s, 1H, H2), 6.02 (dd, J = 2.4, 3.7 Hz, 1H,
H
ꢀ6), 3.69 (s, 3H, NCH3). 13C NMR (100 MHz, CDCl3):
d = 170.09, 140.31, 129.49, 120.25, 117.98, 113.99,
112.47, 107.26, 92.14, 34.99. MS (EI+) m/z: 252.1 (M+),
250.1 (Mꢀ). Anal. Calcd for C10H7BrN2O: C, 47.84; H,
2.81; N, 11.16. Found: C, 47.76; H, 2.66; N, 11.10.
4.4.14. 3-(3-Benzyloxy-4-methoxyphenyl)-1-ethylpyrrol-
o[2,3-b]pyrrolizin-8(1H)-one (11j). This compound was
obtained from 8j as described for 5a in 66% yield. Mp
136 ꢁC. IR (KBr): m = 3122, 2931, 2919, 1668(CO),
4.4.18. 3-Bromopyrrolo[2,3-b]pyrrolizin-8(1H)-one (23).
This compound was obtained from 21 as described for
5a in 43% yield. Mp 234 ꢁC. IR (KBr): m = 3121, 2966,
2916, 2855, 1668(CO), 1570, 1525, 1385, 1248, 818,
1506, 1354, 1251, 1220, 1172, 1137, 1023, 726 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d = 7.42 (m, 5H, Harom),
0
6.98 (dd, J = 1.8, 8.3 Hz, 1H, H6 ), 6.94 (d, J = 8.3 Hz,
1
1H, H5 ), 6.91 (d, J = 1.8 Hz, 1H, H2 ), 6.60 (s, 1H,
H2), 6.48 (d, J = 3.6 Hz, 1H, H7), 6.33 (d, J = 2.5 Hz,
1H, H5), 5.82 (dd, J = 2.5, 3.6 Hz, 1H, Hꢀ6), 5.23 (s,
2H, OCH2), 3.99 (q, J = 7.3 Hz, 2H, NCH2), 3.94 (s,
3H, OCH3), 1.49 (s, J = 7.3 Hz, 3H, CH3). 13C NMR
(100 MHz, CDCl3): d = 161.93, 149.09, 148.41, 137.03,
136.11, 131.93, 129.77, 128.91, 128.08, 127.05, 126.55,
125.20, 123.61, 120.77, 119.81, 113.36, 112.87, 112.41,
112.00, 70.98, 56.27, 43.77, 16.11. MS (EI+) m/z: 398.2.
Anal. Calcd for C25H22N2O3: C, 75.36; H, 5.57; N,
7.03. Found: C, 75.24; H, 5.43; N, 7.32.
720 cmꢀ1. H NMR (400 MHz, CDCl3): d = 9.7 (br s,
0
0
1H, NH), 6.92 (dd, J = 0.9, 2.7 Hz, 1H, H5), 6.80 (d,
J = 2.4 Hz, 1H, H2), 6.55 (dd, J = 0.9, 3.9 Hz, 1H, H7),
6.03 (dd, J = 2.7, 3.9 Hz, 1H,
H
ꢀ6). 13C NMR
(100 MHz, CDCl3): d = 177.91, 141.52, 128.45, 121.12,
114.99, 112.82, 112.47, 109.85, 95.44. MS (EI+) m/z:
238.0 (M+), 236.0 (Mꢀ). Anal. Calcd for C9H5BrN2O:
C, 45.60; H, 2.13; N, 11.82. Found: C, 45.59; H, 2.08;
N, 11.76.
4.5. O-Debenzylation procedure
4.4.15. 1-Benzyl-3-(4-chlorophenyl)pyrrolo[2,3-b]pyrroli-
zin-8(1H)-one (12g). This compound was obtained from
9g as described for 5a as red solid in 82% yield. Mp
160 ꢁC. IR (KBr): m = 3061, 3030, 2961, 1666(CO),
4.5.1.
3-(3-Hydroxy-4-methoxyphenyl)pyrrolo[2,3-b]-
pyrrolizin-8(1H)-one (5j). A solution of 5k (0.25 g,
0.68 mmol) in a 33% solution of hydrobromic acid in
glacial acetic acid (15 mL) was stirred at room tempera-
ture for 1 h. After cooling, the reaction mixture was
diluted with water (50 mL) and the resulting precipitate
was extracted with ethyl acetate (3· 20 mL). Then, the
organic layers were combined, washed with water (2·
100 mL), dried (MgSO4), and evaporated to give a dark
red solid. The residue was diluted in methanol (10 mL)
and a molar aqueous solution of NaOH was added
(5 mL) before being stirred for 1 h. The reaction mixture
was concentrated under vacuum, diluted with water,
acidified with 1 M HCl, and extracted with ethyl acetate
(2· 100 mL). The organic layers were combined, washed
with water (2· 100 mL), dried (MgSO4), and evaporated
to give a dark red solid which was purified by silica gel
chromatography, eluting by cyclohexane/ethyl acetate
(3:2) to furnish thienopyrrolizinone 5j as a red solid
(100 mg, 55%). Mp >260 ꢁC. IR (KBr): m = 3368, 3172,
2965, 2927, 1658(CO), 1580, 1282, 1261, 1141, 1006,
1
1565, 1400, 1361, 1260, 1098, 827, 727 cmꢀ1. H NMR
(400 MHz, CDCl3): d = 7.28 (m, 9H, Harom), 6.75 (d,
J = 2.2 Hz, 1H, H5), 6.61 (s, 1H, H2), 6.48 (d,
J = 3.6 Hz, 1H, H7), 5.91 (dd, J = 2.2, 3.6 Hz, 1H,
H
ꢀ6), 5.07 (s, 2H, NCH2). 13C NMR (100 MHz,
CDCl3): d = 170.63, 136.03, 135.98, 132.89, 130.73,
129.19, 128.98, 128.66, 128.48, 128.07, 128.11, 127.84,
126.62, 120.79, 113.77, 112.15, 111.83, 51.93. MS (EI+)
m/z: 358.3. Anal. Calcd for C22H15ClN2O: C, 73.45;
H, 4.21; N, 7.81. Found: C, 73.41; H, 4.19; N, 7.74.
4.4.16. 1-Benzyl-3-(3-benzyloxy-4-methoxyphenyl) pyr-
rolo[2,3-b]pyrrolizin-8(1H)-one (12j). This compound
was obtained from 9j as described for 5a in 60% yield.
Mp 124 ꢁC. IR (KBr): m = 3104, 3061, 2929, 1671(CO),
1
1525, 1405, 1249, 729, 697 cmꢀ1. H NMR (400 MHz,
CDCl3): d = 7.35 (m, 10H, Harom), 6.95 (dd, J = 1.7,
725 cmꢀ1. H NMR (400 MHz, CDCl3): d = 10.9 (br s,
0
1H, NH), 7.04 (d, J = 2.1 Hz, 1H, H2 ), 6.94 (dd,
1
0
8.3 Hz, 1H, H6 ), 6.91 (d, J = 8.3 Hz, 1H, H5 ), 6.88 (d,
0
0
J = 1.7 Hz, 1H, H2 ), 6.58 (s, 1H, H2), 6.49 (d,
0
0
J = 3.7 Hz, 1H, H7), 6.32 (d, J = 2.4 Hz, 1H, H5), 5.82
(dd, J = 2.4, 3.7 Hz, 1H, Hꢀ6), 5.20 (s, 2H, OCH2),
5.11 (s, 2H, NCH2), 3.93 (s, 3H, OCH3). 13C NMR
(100 MHz, CDCl3): d = 170.68, 149.,07, 148.31, 138.77,
136.90, 136.18, 135.97, 128.93, 128.77, 128.38, 128.09,
127.96, 126.94, 126.67, 124.93, 120.82, 119.77, 119.70,
113.42, 112.87, 112.64, 112.31, 111.97, 70.92, 56.16,
51.83. MS (EI+) m/z: 460.0. Anal. Calcd for
J = 2.1, 8.3 Hz, 1H, H6 ), 6.88 (d, J = 8.3 Hz, 1H, H5 ),
6.87 (s, 1H, H2), 6.82 (d, J = 3.2 Hz, 1H, H5), 6.49 (d,
J = 3.7 Hz, 1H, H7), 5.95 (dd, J = 3.2, 3.7 Hz, 1H,
H
ꢀ6), 3.92 (s, 3H, OCH3). 13C NMR (100 MHz,
DMSO-d6): d = 169.73, 159.13, 147.18, 147.09, 126.36,
124.97, 124.95, 121.77, 117.54, 113.81, 113.27, 113.22,
112.24, 110.27, 109.82, 55.97. HRMS (EI+) m/z:
280.08457 (M+, 78, C16H12N2O3 required 280.08477).

8172
C. Rochais et al. / Bioorg. Med. Chem. 14 (2006) 8162–8175
4.5.2. 3-(3-Hydroxy-4-methoxyphenyl)-1-methylpyrrolo-
[2,3-b]pyrrolizin-8(1H)-one (10k). This compound was
obtained from 10j as described for 5k in 41% yield.
Mp 160 ꢁC. IR (KBr): m = 3435, 3123, 2963, 2826,
1635(CO), 1607, 1436, 1401, 1255, 1219, 1027,
NMR (100 MHz, CDCl3): d = 180.75, 169.39, 146.90,
146.76, 135.49, 126.03, 124.71, 124.65, 121.44, 117.19,
113.54, 112.97, 112.84, 111.94, 111.87, 55.67, 39.01. MS
(EI+) m/z: 358.3. Anal. Calcd for C17H14N2O5: C,
56.98; H, 3.94; N, 7.82. Found: C, 56.95; H, 3.85; N, 7.74.
709 cmꢀ1 1H NMR (400 MHz, CDCl3): d = 7.00 (d,
.
0
J = 1.8 Hz, 1H, H2 ), 6.93 (dd, J = 1.8, 8.3 Hz, 1H,
4.5.6. 1-Benzyl-3-(3-hydroxy-4-methoxyphenyl)-5,6,7,7a-
tetrahydropyrrolo[2,3-b]pyrrolizin-8(1H)-one (13).
0
0
H6 ), 6.88 (m, 2H, H5 þ H5), 6.59 (s, 1H, H2), 6.53
(dd, J = 0.7, 3.5 Hz, 1H, H7), 5.96 (dd, J = 2.7, 3.5 Hz,
1H, Hꢀ6), 5.7 (br s, 1H, OH), 3.92 (s, 3H, OCH3),
3.73 (s, 3H, NCH3). 13C NMR (100 MHz, CDCl3):
d = 174.66, 148.34, 146.07, 129.63, 127.93, 127.44,
125.66, 120.25, 118.33, 114.76, 113.41, 112.91, 112.08,
111.74, 111.08, 56.07, 34.76. MS (EI+) m/z: 294.0. Anal.
Calcd for C17H14N2O3: C, 69.38; H, 4.79; N, 9.52.
Found: C, 69.34; H, 4.54; N, 9.67.
A
solution of 12k (0.15 g, 0.33 mmol) and Pd/C (0.15
equiv) in methanol was degassed and stirred at rt under
hydrogen flow for 3 h. The reaction mixture was filtered
on Celite and evaporated to give a dark red solid which
was purified by silica gel chromatography, eluting by
cyclohexane/ethyl acetate (1:2) to furnish tetrahydro-
pyrrolizine 13 as a yellow solid (67 mg, 55%). Mp
98 ꢁC. IR (KBr): m = 3272, 2936, 2901, 2835,
1651(CO), 1563, 1418, 1257, 700 cmꢀ1
.
1H NMR
4.5.3.
3-(3-Hydroxy-4-methoxyphenyl)-1-ethylpyrrolo-
(400 MHz, CDCl3): d = 7.35 (m, 5H, Harom), 7.06 (s,
0
1H, H2), 7.05 (d, J = 1.9 Hz, 1H, H2 ), 6.99 (dd,
[2,3-b]pyrrolizin-8(1H)-one (11k). This compound was
obtained from 11j as described for 5k in 85% yield. Mp
154 ꢁC. IR (KBr): m = 3411, 3115, 2956, 2932,
0
0
J = 1.9, 8.3 Hz, 1H, H6 ), 6.83 (d, J = 8.3 Hz, 1H, H5 ),
5.6 (br s, 1H, OH), 5.20 (d, J = 14.5 Hz, 1H, NCHPh),
5.07 (d, J = 14.5 Hz, 1H, NCHPh), 4.34 (m, 1H, H7),
3.89 (s, 3H, OCH3), 3.32 (m, 1H, H5), 2.92 (m, 1H,
H5), 1.90 (m, 3H, H6 + H7). 13C NMR (100 MHz,
DMSO-d6): d = 159.47, 146.08, 136.75, 133.04, 129.09,
129.07, 129.00, 128.37, 128.32, 128.27, 128.08, 118.00,
112.48, 111.21, 111.09, 79.05, 56.22, 51.79, 51.26,
29.88, 27.95. MS (EI+) m/z: 374.1. Anal. Calcd for
C23H22N2O3: C, 73.78; H, 5.92; N, 7.48. Found: C,
73.64; H, 5.84; N, 7.32.
1579(CO), 1505, 1253, 1024, 804, 723 cmꢀ1. H NMR
1
0
(400 MHz, CDCl3): d = 7.01 (d, J = 1.8 Hz, 1H, H2 ),
0
6.94 (dd, J = 1.8, 8.2 Hz, 1H, H6 ), 6.89 (m, 2H,
0
H5 þ H5), 6.67 (s, 1H, H2), 6.52 (d, J = 3.7 Hz, 1H,
H7), 5.95 (dd, J = 2.8, 3.7 Hz, 1H, Hꢀ6), 5.7 (br s, 1H,
OH), 4.02 (q, J = 7.3 Hz, 2H, NCH2), 3.93 (s, 3H,
OCH3), 1.51 (t, J = 7.3 Hz, 3H, CH3). 13C NMR
(100 MHz, CDCl3): d = 167.75, 146.07, 145.75, 138.94,
130.87, 128.80, 126.43, 125.76, 124.93, 120.84, 118.32,
113.30, 112.91, 111.72, 111.08, 56.06, 43.65, 15.96. MS
(EI+) m/z: 308.1. Anal. Calcd for C18H16N2O3: C,
70.12; H, 5.23; N, 9.09. Found: C, 70.23; H, 5.34; N, 9.05.
4.6. N-Substitution procedure
4.6.1. tert-Butyl 40-(3-benzyloxy-4-methoxyphenyl)-20-
(pyrrolidin-1-ylcarbonyl)-10H-1,30-bipyrrole carboxylate
(6j). To a solution of carboxamide 3j (4.5 g, 10.2 mmol)
in dichloromethane (10 mL) were added 4-dimethylami-
nopyridine (2.22 g, 18.1 mmol) and triethylamine
(2.52 mL, 18.1 mmol). The solution was cooled at 0 ꢁC
using an iced-bath and ditertbutyl dicarbonate (2.37 g,
10.9 mmol) was then added. The reaction mixture was
stirred at rt for 2 h and poured into dichloromethane
(100 mL) and water (100 mL). The organic layer was
washed with water (2· 100 mL), dried (CaCl2), and evap-
orated to give a beige solid which was purified by silica
gel chromatography, eluting by cyclohexane:ethyl ace-
tate (1:1) to furnish amide 6j as a yellow solid (4.33 g,
78%). Mp 90 ꢁC. IR (KBr): m = 2975, 2927, 2875, 1748,
1641(CO), 1487, 1454, 1368, 1249, 1155, 1126, 1079,
4.5.4.
1-Benzyl-3-(3-hydroxy-4-methoxyphenyl)pyr-
rolo[2,3-b]pyrrolizin-8(1H)-one (12k). This compound
was obtained from 12j as described for 5k in 40% yield.
Mp 110 ꢁC. IR (KBr): m = 3402, 2940, 2927, 2840,
1672(CO), 1651, 1506, 1406, 1255, 1175, 701 cmꢀ1. H
1
NMR (400 MHz, CDCl3): d = 7.35 (m, 5H, Harom),
0
6.98 (s, 1H, H2), 6.90 (m, 2H, H5 þ H5), 6.86 (dd,
0
0
J = 1.5, 8.3 Hz, 1H, H6 ), 6.64 (d, J = 1.5 Hz, 1H, H2 ),
6.52 (d, J = 3.9 Hz, 1H, H7), 5.95 (dd, J = 2.7, 3.9 Hz,
1H, Hꢀ6), 5.7 (br s, 1H, OH), 5.13 (s, 2H, NCH2),
3.91 (s, 3H, OCH3). 13C NMR (100 MHz, CDCl3):
d = 164.20, 148.68, 147.53, 142.12, 137.46, 136.16,
128.94, 128.38, 128.12, 127.33, 126.67, 121.02, 120.92,
118.37, 113.47, 112.94, 111.82, 111.06, 111.04, 56.08,
51.86. MS (EI+) m/z: 370.2. Anal. Calcd for
C23H18N2O3: C, 74.58; H, 4.90; N, 7.56. Found: C,
74.53; H, 4.86; N, 7.43.
729 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d = 7.30 (m,
0
6H, Harom + H5), 6.80 (d, J = 8.3 Hz, 1H, H5 ), 6.70
0
(dd, J = 1.9, 8.3 Hz, 1H, H6 ), 6.65 (m, 2H, Hapyrrole),
0
6.35 (d, J = 1.9 Hz, 1H, H2 ), 6.21 (m, 2H, Hbpyrrole),
4.5.5. 3-(3-Hydroxy-4-methoxyphenyl)-1-(methylsulfo-
nyl)pyrrolo[2,3-b]pyrrolizin-8(1H)-one (15k). This com-
pound was obtained from 15j as described for 5k in
42% yield. Mp >260 ꢁC. IR (KBr): m = 3169, 2924,
2852, 1656(CO), 1579, 1388, 1261, 1140, 1006,
4.87 (s, 2H, OCH2), 3.85 (s, 3H, OCH3), 3.47 (m, 2H,
Hapyrrolidine), 3.09 (m, 2H, Hapyrrolidine), 1.81 (m, 2H,
Hbpyrrolidine), 1.68 (m, 2H, Hbpyrrolidine), 1.57 (s, 9H,
(CH3)3). 13C NMR (100 MHz, CDCl3): d = 160.32,
148.88, 148.03, 147.88, 137.04, 128.45, 127.76, 127.33,
125.47, 124.22, 123.46, 122.65, 122.03, 119.79, 116.88,
112.64, 111.76, 109.50, 85.17, 70.56, 55.97, 47.54, 45.29,
27.84 (3CH3), 25.48, 24.42. MS (EI+) m/z: 540.8. Anal.
Calcd for C32H35N3O5: C, 70.96; H, 6.51; N, 7.76.
Found: C, 70.87; H, 6.45; N, 7.64.
1
724 cmꢀ1. H NMR (400 MHz, CDCl3): d = 9.31 (br s,
1H, OH), 7.27 (s, 1H, H2), 7.16 (d, J = 2.4 Hz, 1H, H5),
0
7.03 (d, J = 8.0 Hz, 1H, H5 ), 7.01 (d, J = 2.0 Hz, 1H,
0
0
H2 ), 6.97 (dd, J = 2.0, 8.0 Hz, 1H, H6 ), 6.55 (d,
J = 3.7 Hz, 1H, H7), 6.09 (dd, J = 2.4, 3.7 Hz, 1H,
H
ꢀ6), 3.84 (s, 3H, OCH3), 3.38 (s, 3H, SCH3). 13C

C. Rochais et al. / Bioorg. Med. Chem. 14 (2006) 8162–8175
8173
4.6.2. tert-Butyl 40-bromo-20-(pyrrolidin-1-ylcarbonyl)-
10H-1,30-bipyrrole carboxylate (21). This compound
was obtained from 19 as described for 13 as a white solid
in 99% yield. Mp 140 ꢁC. IR (KBr): m = 3139, 2977, 2974,
Mp 175 ꢁC. IR (KBr): m = 2954, 2925, 1621(CO), 1448,
1370, 1069, 994, 725 cmꢀ1 1H NMR (400 MHz,
.
CDCl3): d = 6.78 (m, 2H, Hapyrrole), 6.71 (s, 1H, H5),
6.24 (m, 2H, Hbpyrrole), 3.72 (s, 3H, NCH3), 3.49 (m,
2H, Hapyrrolidine), 2.54 (m, 2H, Hapyrrolidine), 1.75 (m,
2H, Hbpyrrolidine), 1.61 (m, 2H, Hbpyrrolidine). 13C NMR
(100 MHz, CDCl3): d = 159.73, 125.44, 123.70, 121.52,
121.47, 109.38, 91.05, 46.64, 45.66, 36.15, 25.70, 24.02.
MS (EI+) m/z: 323.8 (M+), 321.4 (Mꢀ). Anal. Calcd
for C14H16BrN3O: C, 52.19; H, 5.01; N, 13.04. Found:
C, 52.45; H, 5.06; N, 13.34.
1
1755, 1631(CO), 1359, 1271, 1154, 719 cmꢀ1. H NMR
(400 MHz, CDCl3): d = 7.33 (s, 1H, H5), 6.85 (m,
2H, Hapyrrole), 6.26 (m, 2H, Hbpyrrole), 3.47 (m, 2H,
Hapyrrolidine), 2.95 (m, 2H, Hapyrrolidine), 1.80 (m, 2H,
Hbpyrrolidine), 1.69 (m, 2H, Hbpyrrolidine), 1.56 (s, 9H,
(CH3)3). 13C NMR (100 MHz, CDCl3): d = 181.93,
159.50, 125.90, 121.59, 120.54, 120.39, 109.62, 97.16,
85.85, 47.27, 45.39, 27.77, 25.43, 24.37. MS (EI+) m/z:
409.1 (M+), 407.1 (Mꢀ). Anal. Calcd for C18H22BrN3O3:
C, 52.95; H, 5.43; N, 10.29. Found: C, 53.04; H, 5.34; N,
10.23.
4.6.6. 40-(4-Chlorophenyl)-10-ethyl-20-(pyrrolidin-1-ylcar-
bonyl)-10H-1,30-bipyrrole (8g). To a cooled solution of
4g (200 mg, 0.59 mmol) in dimethylformamide (5 mL)
were successively added sodium hydride at 55% in a
mineral oil (31 mg, 0.71 mmol) and ethyl iodide
(57 lL, 0.71 mmol). The reaction mixture was stirred
at rt for 1 h, diluted with water (100 mL), and extracted
with diethyl ether (2· 100 mL). The combined organic
layers were washed with brine (2· 100 mL), dried
(MgSO4), and evaporated to furnish amide 8g as a pale
yellow solid (180 mg, 82%). Mp 119 ꢁC. IR (KBr):
m = 2990, 2923, 2860, 1620(CO), 1556, 1447, 1384,
1084, 991, 835, 729 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d = 7.17 (d, J = 8.5 Hz, 2H, Harom), 6.88 (d, J = 8.5 Hz,
2H, Harom), 6.82 (s, 1H, H5), 6.54 (m, 2H, Hapyrrole), 6.15
(m, 2H, Hbpyrrole), 4.11 (q, J = 7.1 Hz, 2H, NCH2), 3.49
(m, 2H, Hapyrrolidine), 2.65 (m, 2H, Hapyrrolidine), 1.75 (m,
2H, Hbpyrrolidine), 1.55 (m, 2H, Hbpyrrolidine), 1,39 (t,
J = 7.1 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3):
d = 160.93, 132.01, 131.78, 128.67, 128.34, 123.39,
121.85, 121.66, 120.12, 117.65, 109.47, 47.09, 45.61,
43.66, 25.77, 24.17, 16.99. MS (EI+) m/z: 367.2. Anal.
Calcd for C21H22ClN3O: C, 68.56; H, 6.03; N, 11.42.
Found: C, 68.47; H, 5.94; N, 11.32.
4.6.3.
40-(4-Chlorophenyl)-10-methyl-20-(pyrrolidin-1-
ylcarbonyl)-10H-1,30-bipyrrole (7g). To a cooled solution
of 4g (350 mg, 1.03 mmol) in dimethylformamide
(10 mL) were successively added sodium hydride at
55% in a mineral oil (54 mg, 1.23 mmol) and methyl io-
dide (77 lL, 1.23 mmol). The reaction mixture was stir-
red at rt for 1 h, diluted with water (100 mL), and
extracted with diethyl ether (2· 100 mL). The combined
organic layers were washed with brine (2· 100 mL), dried
(MgSO4), and evaporated to furnish amide 7g as a white
solid (310 mg, 85%). Mp 132 ꢁC. IR (KBr): m = 2949,
2913, 2847, 1608(CO), 1451, 1375, 1261, 1090, 804,
721 cmꢀ1 1H NMR (400 MHz, CDCl3): d = 7.17 (d,
.
J = 8.3 Hz, 2H, Harom), 6.87 (d, J = 8.3 Hz, 2H, Harom),
6.76 (s, 1H, H5), 6.54 (m, 2H, Hapyrrole), 6.16 (m, 2H,
Hbpyrrole), 3.75 (s, 3H, NCH3), 3.49 (m, 2H, Hapyrrolidine),
2.65 (m, 2H, Hapyrrolidine), 1.75 (m, 2H, Hbpyrrolidine), 1.55
(m, 2H, Hbpyrrolidine). 13C NMR (100 MHz, CDCl3):
d = 160.56, 131.94, 131.50, 128.54, 128.23, 123.52,
122.32, 121.99, 121.51, 117.62, 109.43, 46.88, 45.53,
35.91, 25.67, 23.97. MS (EI+) m/z: 353.1. Anal. Calcd
for C20H20ClN3O: C, 67.89; H, 5.70; N, 11.87. Found:
C, 67.85; H, 5.60; N, 11.84.
4.6.7.
40-(3-Benzyloxy-4-methoxyphenyl)-1-ethyl-20-
(pyrrolidin-1-ylcarbonyl)-10H-1,30-bipyrrole (8j). This
compound was obtained from 4j as described for 8g as
pale yellow solid in 94% yield. Mp 130 ꢁC. IR (KBr):
m = 2976, 2949, 2929, 1620(CO), 1478, 1453, 1413,
4.6.4. 40-(3-Benzyloxy-4-methoxyphenyl)-10-methyl-20-
(pyrrolidin-1-ylcarbonyl)-10H-1,30-bipyrrole (7j). This
compound was obtained from 4j as described for 7g as
pale yellow solid in 95% yield. Mp 170 ꢁC. IR (KBr):
m = 2956, 2926, 2872, 1629(CO), 1584, 1545, 1480,
1
1253, 1221, 1138, 1024, 733 cmꢀ1. H NMR (400 MHz,
CDCl3): d = 7.29 (m; 5H, Harom), 6.79 (d, J = 8.3 Hz,
0
1H, H5 ), 6.66 (s, 1H, H5), 6.70 (dd, J = 1.8, 8.3 Hz,
1387, 1257, 1142, 1024, 739 cmꢀ1
.
1H NMR
1H, H5 ), 6.59 (m, 2H, Hapyrrole), 6.37 (d, J = 1.8 Hz,
0
1H, H2 ), 6.19 (m, 2H, Hbpyrrole), 4.86 (s, 2H, OCH2),
0
(400 MHz, CDCl3): d = 7.29 (m, 5H, Harom) , 6.79 (d,
0
0
J = 8.3 Hz, 1H, H5 ), 6.69 (m, 2H, H6 þ H5), 6.58 (m,
4.11 (q, J = 7.2 Hz, 2H, NCH2), 3.85 (s, 3H, OCH3),
3.51 (m, 2H, Hapyrrolidine), 2.74 (m, 2H, Hapyrrolidine),
1.76 (m, 2H, Hbpyrrolidine), 1.60 (m, 2H, Hbpyrrolidine),
1,40 (t, J = 7.1 Hz, 3H, CH3). 13C NMR (100 MHz,
CDCl3): d = 160.87, 147.89, 147.86, 137.09, 128.27,
127.53, 127.24, 125.77, 123.15, 121.72, 121.34, 119.44,
119.25, 118.34, 112.53, 111.63, 109.10, 70.34, 55.84,
46.95, 45.36, 43.32, 25.58, 23.94, 16.77. MS (EI+) m/z:
469.4. Anal. Calcd for C29H31N3O3: C, 74.18; H, 6.65;
N, 8.95. Found: C, 73.95; H, 6.54; N, 8.67.
0
2H, Hapyrrole), 6.35 (d, J = 1.7 Hz, 1H, H2 ), 6.19 (m,
2H, Hbpyrrole), 4.86 (s, 2H, OCH2), 3.85 (s, 3H,
OCH3), 3.75 (s, 3H, NCH3), 3.51 (m, 2H, Hapyrrolidine),
2.69 (m, 2H, Hapyrrolidine), 1.76 (m, 2H, Hbpyrrolidine),
1.61 (m, 2H, Hbpyrrolidine). 13C NMR (100 MHz,
CDCl3): d = 160.61, 147.83, 145.37, 137.05, 128.26,
127.52, 127.20, 125.58, 123.43, 121.69, 121.47, 119.28,
118.43, 117.44, 112.54, 111.60, 109.17, 70.32, 55.82,
46.85, 45.38, 35.72, 25.59, 23.87. MS (EI+) m/z: 455.1.
Anal. Calcd for C28H29N3O3: C, 76.81; H, 6.26; N,
7.90. Found: C, 76.74; H, 6.11; N, 7.99.
4.6.8.
40-(4-Chlorophenyl)-10-benzyl-20-(pyrrolidin-1-
ylcarbonyl)-10H-1,30-bipyrrole (9g). To a cooled solution
of 4g (500 mg, 1.47 mmol) in dimethylformamide
(10 mL) were successively added sodium hydride at
55% in a mineral oil (77 mg, 1.77 mmol) and benzyl bro-
4.6.5. 40-Bromo-10-methyl-20-(pyrrolidin-1-ylcarbonyl)-
10H-1,30-bipyrrole (20). This compound was obtained
from 19 as described for 7g as a white solid in 99% yield.

8174
C. Rochais et al. / Bioorg. Med. Chem. 14 (2006) 8162–8175
mide (210 lL, 1.77 mmol). The reaction mixture was
stirred at rt for 1 h, diluted with water (100 mL), and
extracted with diethyl ether (2· 100 mL). The combined
organic layers were washed with brine (2· 100 mL),
dried (MgSO4), and evaporated to furnish amide 9g as
a pale yellow solid (550 mg, 86%). Mp 196 ꢁC. IR
(KBr): m = 3046, 2973, 2927, 1619(CO), 1571, 1472,
70.93, 56.15, 42.14. MS (EI+) m/z: 447.9. Anal. Calcd
for C24H20N2O5S: C, 64.27; H, 4.49; N, 6.25. Found:
C, 63.34; H, 4.35; N, 6.14.
4.7. Ethyl 3-amino-4-bromo-1H-pyrrole-2-carboxylate
(17)
1455, 1433, 1362, 1091, 1079, 730 cmꢀ1
.
1H NMR
To a cooled solution of ethyl 3-amino-1H-pyrrole-2-car-
boxylate (4 g, 26.6 mmol) in a mixture of chloroform
(15 mL) and acetic acid (15 mL), was slowly added N-
bromosuccinimide (4.7 g, 26.6 mmol). The reaction mix-
ture was stirred at rt for 1 h 30, diluted with water
(100 mL), and extracted with ethyl acetate (2· 100 mL).
The combined organic layers were washed with brine
(2· 100 mL), dried (MgSO4), and evaporated to give a yel-
low oil which was purified by silica gel chromatography,
eluting bycyclohexane/ethyl acetate (2:1)tofurnishamide
17 as a yellow solid (2.2 g, 40%). Mp 92 ꢁC. IR (KBr):
m = 3402, 3301, 3202, 3131, 2991, 2869, 1674(CO), 1614,
1431, 1133, 769, 589 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d = 8.4 (br s, 1H, NH), 6.76 (s, 1H, H5), 4.3 (m, 4H, NH2
+OCH2), 1.35 (t, J = 7.1 Hz, 3H, CH3). 13C NMR
(100 MHz, CDCl3): d = 160.32, 133.82, 129.61, 122.05,
87.78, 60.02, 14.65. MS (EI+) m/z: 234.2 (M+), 232.2
(Mꢀ). Anal. Calcd for C7H9BrN2O2: C, 36.07; H, 3.89;
N, 12.02. Found: C, 36.32; H, 3.70; N, 12.31.
(400 MHz, CDCl3): d = 7.20 (m, 7H, Harom), 6.91 (d,
J = 8.5 Hz, 2H, Harom), 6.90 (s, 1H, H5), 6.53 (m, 2H,
Hapyrrole), 6.13 (m, 2H, Hbpyrrole), 5.24 (s, 2H, CH2Ph),
3.28 (m, 2H, Hapyrrolidine), 2.33 (m, 2H, Hapyrrolidine),
1.56 (m, 2H, Hbpyrrolidine), 1.27 (m, 2H, Hbpyrrolidine).
13C NMR (100 MHz, CDCl3): d = 160.81, 137.54,
132.11, 131.63, 128.68, 128.62, 128.42, 127.99, 127.76,
123.99, 122.42, 121.59, 121.15, 117.64, 109.47, 52.46,
46.85, 45.29, 25.34, 24.03. MS (EI+) m/z: 429.4. Anal.
Calcd for C26H24ClN3O: C, 72.63; H, 5.63; N, 9.77.
Found: C, 72.52; H, 5.49; N, 9.78.
4.6.9.
40-(3-Benzyloxy-4-methoxyphenyl)-10-benzyl-20-
(pyrrolidin-1-ylcarbonyl)-10H-1,30-bipyrrole (9j). This
compound was obtained from 4j as described for 9g as
pale yellow solid in 99% yield. Mp 136 ꢁC. IR (KBr):
m = 3057, 2965, 2930, 1623(CO), 1513, 1465, 1450,
1411, 1250, 1218, 1027, 732 cmꢀ1
.
1H NMR
(400 MHz, CDCl3): d = 7.30 (m, 10H, Harom), 6.85 (s,
0
1H, H5), 6.79 (d, J = 8.3 Hz, 1H, H5 ), 6.73 (dd,
4.8. Typical Suzuki cross-coupling reaction
0
J = 1.9, 8.3 Hz, 1H, H6 ), 6.59 (m, 2H, Hapyrrole), 6.38
0
(d, J = 1.9 Hz, 1H, H2 ), 6.18 (m, 2H, Hbpyrrole),
4.8.1. 3-(4-Methoxyphenyl)-1-methylpyrrolo[2,3-b] pyrr-
olizin-8(1H)-one (24). To a solution of tripentone 22
(30 mg, 0.19 mmol) in DMF (2 mL) under argon were
successively added Pd(PPh3)4 (6 · 10ꢀ3 mmol, 5%), 4-
methoxyphenylboronic acid (0.3 mmol) and the mixture
was heated at 70 ꢁC. Sodium carbonate (1.07 mmol) dis-
solved in water was then added and the reaction mixture
was stirred at 110 ꢁC under argon for 14 h and extracted
with ethyl acetate (2· 100 mL). The combined organic
layers were washed with brine (2· 100 mL), dried
(MgSO4), and evaporated to give a yellow oil which
was purified by silica gel chromatography, eluting by
cyclohexane/ethyl acetate (3:2) to furnish tripentone 24
as an orange solid (30 mg, 90%). Mp 180 ꢁC. IR (KBr):
m = 3115, 2920, 1714(CO), 1682, 1506, 1395, 1249,
5.23 (s, 2H, NCH2), 4.86 (s, 2H, OCH2), 3.82 (s,
3H, OCH3), 3.29 (m, 2H, Hapyrrolidine), 2.39 (m, 2H,
Hapyrrolidine), 1.60 (m, 2H, Hbpyrrolidine), 1.27 (m, 2H,
Hbpyrrolidine). 13C NMR (100 MHz, CDCl3): d = 160.88,
148.14, 148.03, 137.68, 137.22, 128.99, 128.77, 128.53,
128.38, 127.77, 127.63, 127.37, 125.75, 123.88, 121.79,
120.58, 119.51, 118.48, 112.82, 111.83, 109.21, 70.55,
55.99, 52.24, 46.83, 45.17, 25.27, 23.93. MS (EI+) m/z:
530.8. Anal. Calcd for C34H33N3O3: C, 76.81; H, 6.26;
N, 7.90. Found: C, 76.90; H, 6.45; N, 7.56.
4.6.10. 3-(3-Benzyloxy-4-methoxyphenyl)-10-(methyl sul-
fonyl)pyrrolo[2,3-b]pyrrolizin-8(1H)-one (15j). To
a
cooled solution of 5j (150 mg, 0.41 mmol) in dimethyl-
formamide (5 mL) were successively added sodium hy-
dride at 55% in a mineral oil (12 mg, 0.49 mmol) and
methylsulfonyl chloride (48 lL, 0.49 mmol). The reac-
tion mixture was stirred at rt for 12 h, diluted with water
(100 mL), and extracted with diethyl ether (2· 100 mL).
The combined organic layers were washed with brine
(2· 100 mL), dried (MgSO4) and evaporated to furnish
amide 15j as a yellow solid (170 mg, 93%). Mp 132 ꢁC.
IR (KBr): m = 2924, 2854, 1681(CO), 1521, 1365, 1250,
833 cmꢀ1 1H NMR (400 MHz, CDCl3): d = 7.36 (d,
.
J = 8.5 Hz, 2H, Harom), 6.95 (d, J = 8.5 Hz, 2H, Harom),
6.85 (d, J = 2.7 Hz, 1H, H5), 6.60 (s, 1H, H2), 6.53 (d,
J = 3.9 Hz, 1H, H7), 5.96 (dd, J = 2.7, 3.4 Hz, 1H,
H
ꢀ6), 3.84 (s, 3H, OCH3), 3.73 (s, 3H, NCH3). 13C
NMR (100 MHz, CDCl3): d = 170.84, 158.83, 145.34,
131.65, 130.35, 127.85, 124.71, 120.98, 120.72, 114.51,
113.21, 113.77, 111.85, 55.37, 34.74. MS (EI+) m/z:
278.1. Anal. Calcd for C17H14N2O2: C, 73.37; H, 5.07;
N, 10.07. Found: C, 73.34; H, 5.12; N, 10.14.
1171, 1082, 771, 552 cmꢀ1
.
1H NMR (400 MHz,
CDCl3): d = 7.34 (m, 5H, Harom), 7.21 (s, 1H, H2),
0
7.03 (dd, J = 1.9, 8.3 Hz, 1H, H6 ), 6.97 (d, J = 8.3 Hz,
4.8.2. 3-(4-Methoxyphenyl)-1-methylpyrrolo[2,3-b]pyrr-
olizin-8(1H)-one (25). This compound was obtained
from 22 as described for 24 and using 6-methoxypyri-
din-3-boronic acid as an orange solid in 87% yield.
Mp 184 ꢁC. IR (KBr): m = 3108, 2924, 2852, 1659(CO),
0
0
1H, H5 ), 6.91 (d, J = 1.9 Hz, 1H, H2 ), 6.61 (d,
J = 3.7 Hz, 1H, H7), 6.35 (d, J = 2.7 Hz, 1H, H5), 5.88
(dd, J = 2.7, 3.7 Hz, 1H, Hꢀ6), 5.23 (s, 2H, OCH2),
3.95 (s, 3H, OCH3), 3.59 (s, 3H, SCH3). 13C NMR
(100 MHz, CDCl3): d = 168.44, 150.08, 148.44, 143.55,
136.68, 134.94, 128.83, 128.08, 126.95, 125.99, 123.23,
122.56, 121.94, 120.46, 115.76, 113.36, 113.06, 112.35,
1494, 1392, 1279, 1030, 706 cmꢀ1
.
1H NMR
0
(400 MHz, CDCl3): d = 8.27 (d, J = 2.4 Hz, 1H, H2 ),
0
7.63 (dd, J = 2.4, 8.5 Hz, 1H, H6 ), 6.55 (dd, J = 0.8,

C. Rochais et al. / Bioorg. Med. Chem. 14 (2006) 8162–8175
8175
0
2.7 Hz, 1H, H5), 6.81 (d, J = 8.5 Hz, 1H, H5 ), 6.62 (s,
References and notes
1. Lisowski, V.; Enguehard, C.; Lancelot, J. C.; Caignard,
1H, H2), 6.54 (dd, J = 0.8, 3.6 Hz, 1H, H7), 5.98 (dd,
J = 2.7, 3.6 Hz, 1H, Hꢀ6), 3.97 (s, 3H, OCH3), 3.75 (s,
3H, NCH3). 13C NMR (100 MHz, CDCl3): d = 168.70,
152.64, 144.59, 137.01, 134.75, 127.69, 121.48, 120.85,
120.62, 119.96, 119.15, 113.66, 112.10, 111.28, 53.61,
34.84. MS (EI+) m/z: 279.2. Anal. Calcd for
C16H13N3O2: C, 68.81; H, 4.69; N, 15.04. Found: C,
68.75; H, 4.43; N, 15.21.
´
D.-H.; Lambel, S.; Leonce, S.; Pierre, A.; Atassi, G.;
Renard, P.; Rault, S. Bioorg. Med. Chem. Lett. 2001, 11,
2205.
2. Lisowski, V.; Leonce, S.; Kraus-Berthier, L.; Sopkova-de
´
Oliveira Santos, J.; Pierre, A.; Atassi, G.; Caignard, D.-H.;
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4.9. Pharmacology. Standard proliferation assay
The principle of this assay and its application to antican-
cer drug screening have been the subject of publica-
tions.13 Adherent cells were trypsinized and seeded in
96-well microplates at the indicated densities, previously
determined to maintain control cells in the exponential
phase of growth for the duration of the experiment
and to obtain a linear relationship between the optical
density and the number of viable cells.14 The plates were
incubated with the tested compounds for four doubling
times, the maximum duration being 7 days. At the end
of this period, an amount of 15 lL of 5 mg/mL 3-(4,5-di-
´
4. Malzert-Freon, A.; Vrignaud, S.; Saulnier, P.; Lisowski,
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9. Clauson-Kaas, N.; Zdenek, T. Acta Chem. Scand. 1952, 6,
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methylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide
10. Furneaux, R. H.; Tyler, P. C. J. Org. Chem. 1999, 64,
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11. Parry, P. R.; Wang, C.; Batsanov, A. S.; Bryce, M. R.;
Tarbit, B. J. Org. Chem. 2002, 67, 7541.
(MTT, Sigma Chemical Co., St. Louis, MO) was added
to each well and the plates were incubated for 4 h at
37 ꢁC. The medium was aspirated, and the formazan
was solubilized by 100 lL DMSO. The optical density
(OD) was read at 540 nm with a plate reader (Multiskan
MCC, Labsystem) connected to a computer. The per-
centage of growth was calculated for each well: %
growth [(OD treated cells)/(OD control cells)] · 100.
The percentages of growth of the tri- or hexaplicate were
then averaged and plotted as a function of the log of the
concentration. The IC50 (concentration reducing by 50%
of the OD) was calculated by a linear regression
performed on the linear zone of the curve.
12. Monks, A.; Scudiero, D.; Skekan, P.; Shoemaker, R.;
Paull, K.; Viscita, D.; Hose, C.; Langley, J.; Cronise, P.;
Vaigro-Wolff, A. J. Natl. Cancer Inst. 1991, 83, 757.
13. Alley, M. C.; Scudiero, D. A.; Monks, A.; Hursey, M. L.;
Czerwinski, M. J.; Fine, D. L.; Abott, B. J.; Mayo, J. G.;
Shoemaker, R. H.; Boyd, M. R. Cancer Res. 1988, 48,
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14. Pierre, A.; Krauss-Berthier, L.; Atassi, G.; Cros, S.;
Poupon, M. F.; Lavielle, G.; Berlion, M.; Bizzari, J. P.
Cancer Res. 1991, 51, 2312.