First synthesis of arylpyrrolo- and pyrazolopyrrolizinones as useful agents with potential biological interest

Article abstract of DOI:10.1016/j.tetlet.2004.06.047

Novel arylpyrrolo- and pyrazolopyrrolizinones were prepared in three or four steps starting from aminoarylpyrrole and pyrazole carboxylates through the cyclisation of a Vilsmeier-Haack intermediate. This synthesis was enhanced by diverse N-protections of

Full text of DOI:10.1016/j.tetlet.2004.06.047

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6353–6355
First synthesis of arylpyrrolo- and pyrazolopyrrolizinones as
useful agents with potential biological interest
Christophe Rochais,a,b Vincent Lisowski,a,b Patrick Dallemagneb,* and Sylvain Raulta,b
aCentre d’Etudes et de Recherche sur le Mꢀedicament de Normandie, 1 rue Vaubꢀenard 14032 Caen Cedex, France
bUFR des Sciences Pharmaceutiques, Boulevard Becquerel 14032 Caen Cedex, France
Received 2 June 2004; accepted 11 June 2004
Abstract—Novel arylpyrrolo- and pyrazolopyrrolizinones were prepared in three or four steps starting from aminoarylpyrrole and
pyrazole carboxylates through the cyclisation of a Vilsmeier–Haack intermediate. This synthesis was enhanced by diverse N-pro-
tections of the aza-heterocycle and furnish new series with potential biological interest.
ꢀ 2004 Elsevier Ltd. All rights reserved.
We recently reported the synthesis and the biological
evaluation of novel thienopyrrolizinones among which
derivative MR 22388 exhibited a potent antiproliferative
activity in relation with an antitubulin action.1 With the
aim to increase the structural diversity of these com-
pounds, we wish to describe herein the first synthesis of
their aza-analogs belonging to the pyrrolo 1 and pyr-
azolo 2 series (Fig. 1).
CN
Ar
i
H
N
H
N
CO2Me
CO2Et
NH2
N
Ar
NH2
Ar
3
4
Using the route elaborated in the thiophene series, the
starting materials we needed to reach this goal were
aminoarylpyrrole and pyrazole carboxylates. We very
recently described the synthesis of methyl 3-amino-4-
aryl-1H-pyrrole-2-carboxylates 3 in three steps starting
from commercial arylacetonitriles (Scheme 1).2 We used
Scheme 1. Reagents and conditions: (i) N2CHCO2Et, EtONa, EtOH,
25 ꢁC.
the same starting materials and ethyl diazoacetate to
prepare ethyl 4-amino-5-aryl-1H-pyrazole-3-carboxy-
lates 4 according to Tarzia’s method.3
O
O
H
S
N
The methyl aminopyrrolecarboxylates 3 were first in-
volved in a four steps sequence beginning with a Clau-
son-Kaas and Zdenek4 reaction leading to 5 (Scheme
2).5 The latter was then treated with refluxing pyrrol-
idine to form the carboxamide 66 before cyclisation
under Vilsmeier conditions (refluxing POCl3) to an
iminium salt, which was finally hydrolysed under alka-
line conditions to give the pyrrolopyrrolizinones 1 in
moderate to low yields (Table 1).7;8
N
X
N
Ar
1 X = CH
2 X = N
OH
MeO
MR 22388
Figure 1.
N-Substitution of the pyrrole ring of 6 improved the
cyclisation yield since methyl 8, ethyl 9 and benzyl 10
derivatives led to the corresponding pyrrolizinones 12,
13 and 14, respectively in excellent yields (Table 1).
Keywords: Cyclisation; Pyrroles; Pyrazoles; Fused-ring systems.
* Corresponding author. Tel.: +33-2-31-56-59-10; fax: +33-2-31-93-11-
88; e-mail: dallemagne@pharmacie.unicaen.fr
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.047

6354
C. Rochais et al. / Tetrahedron Letters 45 (2004) 6353–6355
CO2Y
NH2
CO2Y
N
O
H
H
R
N
i
N
N
X
X
i
N
1i, 12i, 13i
Ar
Ar
5
X = CH, Y = Me
3
X = CH, Y = Me
15 X = N, Y = Et
4
X = N, Y = Et
R1 = Ac 1k, 12k, 13k
R1 1j, 12j, 13j
OR1
ii
MeO
=
H
ii
-
+
PO2Cl2
O
N
Scheme 3. Reagents and conditions: (i) 33% HBr in AcOH, 25 ꢁC;
(ii) NaOH 1 N, MeOH, 25 ꢁC.
R
N
H
iii
N
N
X
X
N
iv
N
followed by alkaline hydrolysis of the resulting acet-
oxyderivatives 1k, 12k, 13k (Scheme 3).
Ar
Ar
6
X = CH, R = H
The same chemical pathway was used to achieve the
synthesis of the pyrazolopyrrolizinones 2 (Scheme 2).
The aminoesters 4 led successively to 15 and 16, which
were cyclised under treatment with boiling POCl3 fol-
lowed by hydrolysis to give ketones 2.
O
8
9
X = CH, R = Me
X = CH, R = Et
v
R
10 X = CH, R = Bn
11 X = CH, R = Boc
N
X
N
16 X = N, R = H
Ar
1
X = CH, R = H
12 X = CH, R = Me
13 X = CH, R = Et
14 X = CH, R = Bn
As for the pyrrole series, the yield of the cyclisation was
improved by N-protection of the pyrazole ring. How-
ever, benzylation of 16i (NaH in DMF) took place
equally on N1 and N2, due to the delocalisation of the
negative charge between the two pyrazole nitrogens
under treatment with NaH (Scheme 4).
2
X = N, R = H
Scheme 2. Reagents and conditions: (i) 2,5-dimethoxyTHF, 4-chlo-
ropyridine hydrochloride, dioxane, 100 ꢁC; (ii) pyrrolidine, 87 ꢁC; (iii)
POCl3, 70 ꢁC; (iv) 10% NaOH; (v) NaH, RX, DMF, 0–25 ꢁC or
(Boc)2O, TEA, DMAP, CH2Cl2, 25 ꢁC.
The regioisomers 17 and 18 were separated, cyclised and
hydrolysed as previously into 19 and 20 in 85% and 50%
yield, respectively. O-Debenzylation was achieved as
above with respect of the N-benzyl group of 21 and 22.
Table 1. Preparation of 1a–i, 12d,i, 13d,i, 14d,i and 2d,i from corre-
sponding carboxamides
Compd Ar
R
X
Yield (%)
(from)a
16i
1a
1b
1c
2-Thienyl
3-Thienyl
H
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
28 (6a)
4 (6b)
5 (6c)
i
H
Phenyl
4-Cl-phenyl
H
O
1d
1e
H
16 (6d)
32 (6e)
23 (6f)
O
N
4-F-phenyl
4-Me-phenyl
H
N
N
N
N
1f
H
N
N
1g
1h
1i
4-MeO-phenyl
3,4-DiCl-pheyl
3-BnO,4-MeO-phenyl
4-Cl-phenyl
H
10 (6g)
14 (6h)
2 (6i); 32 (11i)
72 (8d)
95 (8i)
N
H
H
12d
12i
13d
13i
14d
14i
2d
2i
Me
Me
Et
Et
Bn
Bn
H
OBn
OBn
3-BnO,4-MeO-phenyl
4-Cl-phenyl
17 MeO
18 MeO
66 (9d)
66 (9i)
ii
iii
ii
iii
3-BnO,4-MeO-phenyl
4-Cl-phenyl
85%
50%
82 (10d)
61 (10i)
42 (16d)
6 (16i)
3-BnO,4-MeO-phenyl
4-Cl-phenyl
3-BnO,4-MeO-phenyl
O
O
N
N
N
N
H
N
N
N
a Isolated yields after column chromatography.
OR
OR
MeO
MeO
In the case of the N-Boc derivative 11i, N-deprotection
occurred under the cyclisation conditions leading di-
rectly to 1i in 32% yield.
19 R = Bn
21 R = H
20 R = Bn
22 R = H
iv
v
iv
v
The analogs of MR 22388, 1j, 12j and 13j, bearing a
m-hydroxy, p-methoxyphenyl ring in 3-position were
finally obtained by O-debenzylation of 1i, 12i and 13i,
respectively, under treatment with HBr in acetic acid
Scheme 4. Reagents and conditions: (i) BnBr, NaH, DMF, 0–25 ꢁC;
(ii) POCl3, 70 ꢁC; (iii) 10% NaOH, 80 ꢁC; (i) 33% HBr in AcOH, 25 ꢁC;
(ii) NaOH 1 N, MeOH, 25 ꢁC; (iv) 33% HBr in AcOH, 25 ꢁC; (v)
NaOH 1 N, MeOH, 25 ꢁC.

C. Rochais et al. / Tetrahedron Letters 45 (2004) 6353–6355
6355
Other alkylation conditions9 are under investigation in
order to achieve a more selective N-benzylation.
NMR (100 MHz, CDCl3): d 161.85 (d, J ¼ 246 Hz), 160.54,
128.31 (d, J ¼ 7 Hz), 129.29, 128.01, 122.88, 122.76, 118.92,
117.26, 115.45 (d, J ¼ 21 Hz), 108.97, 51.79. MS (EIþ) m=z:
284.0.
In conclusion, we have developed an efficient synthesis
of the first arylpyrrolo- and pyrazolopyrrolizinones
whose suitability as biologically active agents, particu-
larly in the antineoplastic domain, is currently under
investigation.
6. Typical amidification reaction procedure. A solution of 5e
(850 mg, 2.99 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 6e as a beige solid (490 mg, 47%).
Mp 222 ꢁC. IR (KBr): m 3215, 2970, 2880, 1598 (CO), 1474,
Acknowledgements
1
1212, 837, 729 cmꢀ1. H NMR (400 MHz, CDCl3): d 10.03
ꢀ ꢀ
ꢀ
We are grateful to the Societe de Chimie Therapeutique
and Les Laboratoires Servier for a doctoral grant to
Ch.R.
(br s, 1H, NH), 6.99 (d, J ¼ 3:1 Hz, 1H, CHN), 6.90 (m,
4H, Haromatic), 6.59 (m, 2H, Hpyrrole), 6.20 (m, 2H, Hpyrrole),
3.56 (m, 2H, Hpyrrolidine), 2.53 (m, 2H, Hpyrrolidine), 1.78 (m,
2H,
H
pyrrolidine), 1.61 (m, 2H, Hpyrrolidine). 13C NMR
(100 MHz, CDCl3): d 163.33, 160.31 (d, J ¼ 241 Hz),
129.09, 128.63 (d, J ¼ 9 Hz), 128.45, 123.58, 122.08,
120.77, 117.73, 115.28 (d, J ¼ 23 Hz), 109.71, 46.45,
46.32, 26.07, 23.89. MS (EIþ) m=z: 323.2.
References and notes
1. (a) Lisowski, V.; Enguehard, C.; Lancelot, J.-C.; Caignard,
7. Tembo, O. N.; Dallemagne, P.; Rault, S.; Robba, M.
ꢀ
D.-H.; Lambel, S.; Leonce, S.; Pierre, A.; Atassi, G.;
Renard, P.; Rault, S. Bioorg. Med. Chem. Lett. 2001, 11,
2205–2208; (b) Lisowski, V.; Leonce, S.; Kraus-Berthier, L.;
Heterocycles 1993, 36, 2129–2137.
8. Typical cyclisation reaction procedure. A solution of the
carboxamide 6e (400 mg, 1.24 mmol) in phosphorous oxy-
chloride (20 mL) was stirred at 70 ꢁC for 3 h. After cooling,
the reaction mixture was concentrated to give the interme-
diary iminium salt, which was slowly added to an 10%
aqueous sodium hydroxide solution (100 mL) and heated at
80 ꢁC for 3 h. After cooling, the resulting suspension was
extracted 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 acetate (1:1)
to furnish thienopyrrolizinone 1e as a red solid (260 mg,
32%). Mp 252 ꢁC. IR (KBr): m 3175, 2990, 2965, 2932, 1663
(CO), 1586, 1534, 1522, 1385, 1224, 1150, 826, 720 cmꢀ1. 1H
NMR (400 MHz, CDCl3): d 10.32 (br s, 1H, NH), 7.44 (d,
ꢀ
ꢀ
Sopkova de Oliveira Santos, J.; Pierre, A.; Atassi, G.;
Caignard, D.-H.; Renard, P.; Rault, S. J. Med. Chem. 2004,
47, 1448–1464.
2. Rochais, C.; Lisowski, V.; Dallemagne, P.; Rault, S.
Tetrahedron 2004, 60, 2267–2270.
3. Tarzia, G.; Panzone, G.; De Paoli, A.; Schiatti, P.; Selva, D.
Farmaco Edizione Scientifica 1984, 39, 618–636.
4. Clauson-Kaas, N.; Zdenek, T. Acta Chem. Scand. 1952, 6,
667–670.
5. Typical Clauson-Kaas reaction procedure. A solution of 2,5-
dimethoxytetrahydrofuran (0.61 mL, 4.7 mmol) in dioxane
(25 mL) was stirred for 15 min with 4-chloropyridine
hydrochloride (0.705 g, 4.7 mmol). The aminoester 3e
(0.9 g, 3.84 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 5e as a beige solid (980 mg, 90%) that was crystallised
from Et2O. Mp 172 ꢁC. IR (KBr): m 3295, 3139, 3043, 2951,
J ¼ 8:5 Hz, 2H,
H
aromatic), 7.13 (d, J ¼ 8:5 Hz, 2H,
H
aromatic), 6.93 (d, J ¼ 2:9 Hz, 1H, CHN), 6.84 (d,
J ¼ 2:8 Hz, 1H, H-7), 6.56 (d, J ¼ 3:7 Hz, 1H, H-5), 5.97
(dd, J ¼ 2:8, 3.7 Hz, 1H, H-6). 13C NMR (100 MHz,
CDCl3): d 170.78, 167.89, 161.75 (d, J ¼ 246 Hz), 136.13,
128.73, 128.25 (d, J ¼ 8 Hz), 125.57, 125.25, 120.78, 115.92
(d, J ¼ 21 Hz), 113.26, 111.83, 111.56. HRMS (EIþ) m=z:
252.0699 (Mþ, 100, C15H9N2OF required 252.0699).
9. Wang, X.-J.; Tan, J.; Grozinger, K.; Betageri, R.; Kirrane,
T.; Proudfoot, J. R. Tetrahedron Lett. 2000, 41, 5321–
5324.
1671 (CO), 1570, 1443, 1383, 1159, 1137, 726 cmꢀ1 1H
.
NMR (400 MHz, CDCl3): d 9.38 (br s, 1H, NH), 7.07 (d,
J ¼ 3:4 Hz, 1H, CHN), 6.90 (m, 4H, Haromatic), 6.66 (m, 2H,
H
pyrrole), 6.26 (m, 2H, Hpyrrole), 3.77 (s, 3H, OCH3). 13C