Synthesis of novel pyrazolopyrrolizinones as prospective anticancer agents

Article abstract of DOI:10.3987/COM-06-10824

Herein we describe the access of novel pyrazolopyrrolizinones from commercial arylacetonitriles. The first step conducts to the corresponding aminoester which was first submitted to Clauson-Kaas procedure. Amidification and cyclisation afford then the fir

Full text of DOI:10.3987/COM-06-10824

HETEROCYCLES, Vol. 68, No. 10, 2006
2063
HETEROCYCLES, Vol. 68, No. 10, 2006, pp. 2063 - 2077. © The Japan Institute of Heterocyclic Chemistry
Received, 22nd June, 2006, Accepted, 23rd August, 2006, Published online, 25th August, 2006. COM-06-10824
SYNTHESIS OF NOVEL PYRAZOLOPYRROLIZINONES AS
PROSPECTIVE ANTICANCER AGENTS
Christophe Rochais, Jana Sopkovà-de Oliveira Santos, Patrick Dallemagne,
and Sylvain Rault*
CERMN, Faculty of Pharmacy, 1, rue Vaubénard, 14032 Caen Cedex, France.
sylvain.rault@unicaen.fr.
Abstract – Herein we describe the access of novel pyrazolopyrrolizinones from
commercial arylacetonitriles. The first step conducts to the corresponding
aminoester which was first submitted to Clauson-Kaas procedure. Amidification
and cyclisation afford then the first examples of the expected heterocycles. In
order to improve the sequence and to obtain N-substituted isomers,
3-aryl-5-(pyrrolidin-1-ylcarbonyl)-4-(1H-pyrrol-1-yl)-1H-pyrazoles (5) were
alkylated and conduct to two different N-substituted pyrazoles. These novel
products were separated by chromatography and clearly identified using different
analytical techniques. Application of the cyclisation procedure conducts then to
the two corresponding final title products.
INTRODUCTION
In previous studies novel thienopyrrolizinones, or “tripentones” were reported by our team to be potent
agents with antiproliferative activity in the nanomolar range in relation to an antitubulin action.1 In fact,
the lead compound MR 22388 (Figure 1) exhibits a nanomolar IC50 toward various cell lines. In order to
define more precisely the SAR in this series, new modulations on this core were planned and dedicated to
increase the structural diversity. Synthesis of the aza-analogs (1) in pyrrole series was then first
described.2 In relation with numerous references of novel biologically active compounds based on a
pyrazole nucleus,3 we then wished to explore a second new family and we describe herein the synthesis of
novel diaza-analogs of MR22388 belonging to the pyrazole series (2).

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HETEROCYCLES, Vol. 68, No. 10, 2006
O
X
X
CO2R
Y
Y
N
NH2
O
O
OBn
OH
X = S, Y = CH MR 22388
X = NR, Y = CH 1
X = NR, Y = N
3
X = NR, Y = N
2
Figure 1
RESULTS AND DISCUSSION
According to the route developed in the previous series,1,2,4 the corresponding pyrazole aminoesters (3)
appeared as the key intermediates in the synthesis of the final “tripentones” so the first step consisted in
the preparation of ethyl 4-amino-5-aryl-1H-pyrazole-3-carboxylates. This synthesis was first described by
Tarzia5 in one step from arylacetonitriles, and more recently by Majid6 through an interesting ring-closure
procedure from a α,β-dicarbonyl compound treated with an excess of hydrazine. Because of the
accessibility of the starting material, we decided to expand the Tarzia’s method in our series from
commercially available arylacetonitriles (Figure 2). The isovannilic acetonitrile was however prepared in
our laboratory according to previous procedure.7 In the presence of ethyl diazoacetate in sodium ethoxide
solution, selected acetonitrile afforded in one step the expected aminoesters (3a-d) in 40 to 77% yield.
H
N
(Hét)Ar
EtONa
EtOH
O
CO2Et
a
b
c
d
m,pdiOMeC6H3
pMeC6H4
pClC6H4
N
N2
+
CN
Ar
EtO
40-77%
Ar
NH2
pOMemOBnC6H3
3a-d
Figure 2
In order to achieve the synthesis of the tripentones, aminoesters (3a-d) were involved in a four step
synthesis beginning by the synthesis of a pyrrole nucleus from the free amine through a Clauson-Kaas
procedure.8 Smoothly conditions were used for this reaction using 4-chloropyridine hydrochloride in
dioxane instead of acetic acid, in the presence of 2,5-dimethoxytetrahydrofurane (2,5-DMTHF) (Figure
3).9 The pyrroles (4a-d) were obtained in good to quantitative yields and afforded in refluxing pyrrolidine
the corresponding carboxamides (5a-d). These amides appeared as crucial intermediates toward the
ring-closure procedure using Vilsmeier conditions. In refluxing phosphorus oxychloride the
corresponding pyrrolidinium salts (6a-d) were intermediary formed, without isolation they were finally
hydrolysed under alkaline conditions to afford the first examples of the ketones (2b-d) in moderate to low
yields. In the dimethoxyphenyl series however, no traces of the tripentones (2a) were found.

HETEROCYCLES, Vol. 68, No. 10, 2006
2065
O
H
H
H
N
N
CO2Et
N
N
CO2Et
N
2,5-DMTHF
4-Clpyridine, HCl
N
N
pyrrolidine
66-98%
60-85%
Ar
N
Ar
N
Ar
NH2
5a-d
3a-d
4a-d
POCl3
Cl
H
N
N+
H
O
N
N
N
NaOH 10%
5-30%
N
N
Ar
Ar
2b-d
6a-d
Figure 3
As already discussed in the pyrrole series, we decided to investigate influence of the N-substitution of the
pyrazole ring on the ring-closure. So, the carboxamide (5d) was N-methylated in dimethylformamide
using sodium hydride and methyl iodide. The pyrazole can exist as a mixture of two tautomers, and
abstraction of the proton under treatment with NaH conduct to the delocalisation of the negative charge
between the two pyrazole nitrogens (Figure 4),10 this substitution with iodomethane takes place on N1
and N2 and resulted in a mixture of the two isomers (7) and (8).
O
O
O
_
N
N
H
N
N
N
NaH
DMF
N
N
N
N
N
N
N
MeO
MeO
OBn
N
OBn
5d
MeO
OBn
DMF
MeI
Me
41%
58%
O
1
O
N
Me
N
N
N
2
N
H6'
H6'
N
N
H5'
H5'
MeO
H2'
H2'
MeO
OBn
7
8
OBn
Figure 4
These two carboxamides were then separated on silica gel chromatography affording regioisomers (7) and
(8) in 41 and 58% yield respectively. The determination of the two different structures was first attempted

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HETEROCYCLES, Vol. 68, No. 10, 2006
using their 1H NMR spectrum. We could indeed notice some differences between the chemical shifts of
specific signals concerning the two isomers (Table 1).
Product
H6’
7.01
6.78
H5’
6.86
6.90
H2’
6.80
6.60
Hαpyrrole
6.67
Hβpyrrole
6.29
NMe
4.01
3.68
OMe
3.89
3.88
7
8
6.60
6.14
Table 1: Example of 1H-NMR chemical shifts of compounds (7) and (8).
Because of a good resolution the aromatic protons H2’, H5’ and H6’ which appeared in both products
respectively as a small doublet, a doublet of doublet and a large doublet which attribution was easy. But
the major difference between these two compounds was the chemical shifts of the N-methyl group. The
electronic effect of the carbonyl on the near N-methyl in the case of compound (7) conducts to a signal at
4.01 ppm. In the case of compound (8) the same group appears as a singulet at 3.68 ppm. This difference
was then turned to account through 1H NMR-NOE experiments.10,11 In the case of compound (7) specific
irradiation at the resonance frequency of the N-methyl group only yielded to background noise. The same
experiment performed on 8 (the more polar isomer) yielded significant peaks on the proton H2’ and H5’
signals, both situated on α position of the aromatic substituant. As the NOE effect is only observed over
short distances (2-4 Å), compound (8) was assigned as the expected N2-methyl derivative. Structural
assignment of the other members was then realize by analogy to these compound and more particularly to
the specific downfield of ca 0.2 ppm in the case of H6’ and H2’ chemical shift.
Finally the conclusive evidence of this theoretical explanation was given by X-Ray crystallography
resolution of both isomers, realized in our laboratory, presented below (Figure 5).
Figure 5 : X-Ray crystallography of compounds (7) (left) and (8) (right).
The carboxamides could then be separately introduced into the ring-closure reaction to afford the
expected tripentones (9) and (10) (Figure 6). As already discussed, we could see an impressive
enhancement of the ring-closure yields when the pyrazole moiety was substituted as well in N1 position
than in N2 one with 72 and 75% yield respectively. A O-debenzylation reaction could be easily conducted

HETEROCYCLES, Vol. 68, No. 10, 2006
2067
using an HBr solution in acetic acid media, followed by alkaline hydrolysis to afford in good yields the
N-substituted isomers (11) and (12).
O
1)HBr 33%
AcOH
2)NaOH 1N
MeOH/H2O
N1
N1
Me
N1
O
Me
Me
O
1)POCl3
2)NaOH 10%
H2O
N
N
2
N
2
N
2
N
N
72-75%
53-99%
N
7 N1-Me
8 N2-Me
9 N1-Me
10 N2-Me
11 N1-Me
12 N2-Me
MeO
MeO
MeO
OBn
OH
OBn
Figure 6
In front of the influence of N-protecting groups in the ring-closure reaction, we then decided to look for
cleavable protecting groups in order to realize the synthesis of N-unsubstituted tripentones with good
yields. Benzyl group was the first group to be investigated. Benzylic carboxamides (13) and (14) were
easily obtained and separated from corresponding amide (5d). These two compounds furnished the
desired tripentones (15) and (16) which could be O-deprotected with HBr. However, all the classical
methodologies usually employed to cleave benzyl group on nitrogen heterocycles failed. We have also
noticed that Boc-protection which gave good results in pyrrolic series2, was however inefficient in the
case of pyrazole series. Only unprotected amide (5d) was recovered isolated after 3h in refluxing
phosphorus oxychloride.
O
O
H
N1
PhH2C
N
N
N
2
N
BnBr
NaH
DMF
N
N
N
79%
13 N1-Bn
14 N2-Bn
MeO
MeO
OBn
OBn
5d
1)POCl3
2)NaOH 10%
50-85%
1)HBr 33%
AcOH
2)NaOH 1N
MeOH/H2O
H2O
N1
PhCH2
O
N1
PhCH2
O
N
N
2
2
30-90%
N
N
15 N1-Bn
OBn 16 N2-Bn
17 N1-Bn
18 N2-Bn
MeO
MeO
OH
Figure 7

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HETEROCYCLES, Vol. 68, No. 10, 2006
Numerous protecting groups were then evaluated, including silyl11, trityl12 and paramethoxybenzyl
groups, but none allowed us to improve the yield of the synthesis of the unprotected pyrazole tripentones
(2).
CONCLUSION
In conclusion, we have developed an efficient synthesis of first pyrazolopyrrolizinones whose suitability as
biologically active agents, particularly in the antineoplastic domain, is currently under investigation.
EXPERIMENTAL
General. Commercial reagents were used as received without additional purification. Melting points were
determined on a Köfler melting point apparatus and are uncorrected. IR spectra were taken with a Perkin
1
13
Elmer spectrum BX FT-IR spectrometer. H NMR (400 MHz) and C (100 MHz) were recorded on a
JEOL Lambda 400 Spectrometer. Chemical shifts are expressed in parts per million downfield from TMS
as an internal standard. MS were recorded on a JEOL JMS GCMate with ionising potential of 70eV.
Elemental analyses for new compounds were performed at the “Institut de Recherche en Chimie
Organique Fine” (Rouen).
General synthesis of pyrazolic aminoester
Ethyl 4-amino-5-(3-benzyloxy-4-methoxyphenyl)-2H-pyrazole-3-carboxylate (3d)
To 3-benzyloxy-4-methoxyphenylacetonitrile (7g, 27.6 mmol) solved in 60 mL EtOH was added sodium
ethoxide (2.07g, 30.4 mmol) freshly prepared. Mixture was cooled down to 0°C and ethyl diazoacetate
(3.20mL, 30.4 mmol) were added. The reaction mixture was stirred over-night and diluted with 100 mL
water and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (2 ×
100 mL), dried (MgSO4) and evaporated to give a dark solid. This residue was purified by silica gel
chromatography, eluting by cyclohexane:EtOAc (1:2) to furnish aminoester (3d) as a orange solid (6.94 g,
62%). Mp 148°C. IR (KBr): ν = 3166 (NH), 2920, 2845, 1707(CO), 1606, 1462, 1382, 1257, 1136, 1021
cm-1. 1H NMR (400 MHz, CDCl3): δ = 10.3 (bs, 1H, NH), 7.35 (m, 6H, Haromatic + H6’), 7.21 (d, 4JH2’H6’
=
3
3
1.9 Hz, 1H, H2’), 6.93 (d, JH5’H6’ = 8.3 Hz, 1H, H5’), 5.17 (s, 2H, CH2Ph), 4.36 (q, J = 7.1 Hz, 2H,
3
13
OCH2), 4.0 (bs, 2H, NH2), 3.90 (s, 3H, OCH3), 1,38 (t, J = 7.1 Hz, 3H, CH3). C NMR (100 MHz,
CDCl3): δ = 160.85, 149.41, 148.34, 136.94, 132.16, 128.56, 127.87, 127.40, 124.52, 120.03, 119.47,
112.42, 112.14, 111.77, 70.97, 60.71, 56.08, 14.45. MS (EI+) m/z: 367.2. Anal. Calcd for C20H21N3O4: C
65.38, H 5.76, N 11.44. Found: C 65.45, H 5.36, N 11.45.
General Clauson-Kaas reaction procedure
Ethyl 3-(3,4-dimethoxyphenyl)-4-(1H-pyrrol-1-yl)-1H-pyrazole-5-carboxylate (4a)

HETEROCYCLES, Vol. 68, No. 10, 2006
2069
A solution of 2,5-dimethoxytetrahydrofuran (1.07 mL, 8.20 mmol) in dioxane (50 mL) was stirred for 15
min with 4-chloropyridine hydrochloride (1.24g, 8.20 mmol). The aminoester (2g, 6.90 mmol) was added
and the reaction mixture was refluxed for 4h and filtered through a small pad of Celite. The solvent was
evaporated to give a brown residue that was dissolved in CH2Cl2 (100 mL). The solution was washed
with 1N HCl (2 × 100 mL), dried (MgSO4) and evaporated to give (3a) as a white solid (2.3 g, 98%) that
was crystallized from Et2O. Mp 168°C. IR (KBr): ν = 3256(NH), 2960, 2929, 2857, 1736(CO), 1515,
1
1457, 1260, 1245, 1090, 1021, 719 cm-1. H NMR (400 MHz, CDCl3): δ = 8.5 (bs, 1H, NH), 6.95 (dd,
4JH2’H6’ = 1.95 Hz, 3JH5’H6’ = 8.3 Hz, 1H, H6’), 6.90 (d, 3JH5’H6’ = 8.3 Hz, 1H, H5’), 6.69 (m, 2H, Hαpyrrole),
6.58 (d, 4JH2’H6’ = 1.95 Hz, 1H, H2’), 6.31 (m, 2H, Hβpyrrole), 4.24 (q, 3J = 7.1 Hz, 2H, OCH2), 3.86 (s, 3H,
3
13
OCH3), 3.66 (s, 3H, OCH3), 1.21 (t, J = 7.1 Hz, 3H, CH3). C NMR (100 MHz, CDCl3): δ = 163.02,
149.52, 149.01, 124.34, 122.80, 122.21, 121.65, 118.68, 111.11, 110.99, 109.68, 109.03, 61.42, 55.82,
55.64, 13.91. MS (EI+) m/z: 341.1. Anal. Calcd for C18H19N3O4: C 63.33, H 5.61, N 12.31. Found: C
63.45, H 5.63, N 12.35.
Ethyl 3-(4-methylphenyl)-4-(1H-pyrrol-1-yl)-1H-pyrazole-5-carboxylate (4b)
From Ethyl 4-amino-5-(4-methylphenyl)-2H-pyrazole-3-carboxylate (3b) (0.7g); beige solid (4b) (0.56g,
66%). Mp 142°C. IR (KBr): ν = 3243(NH), 2998, 2956, 2927, 1726(CO), 1457, 1329, 1194, 1180, 1087,
1020, 728 cm-1. 1H NMR (400 MHz, CDCl3): δ = 8.6 (bs, 1H, NH), 7.11 (m, 4H, Haromatic), 6.66 (m, 2H,
Hαpyrrole), 6.29 (m, 2H, Hβpyrrole), 4.23 (q, 3J = 7.1 Hz, 2H, OCH2), 2.31 (s, 3H, CH3), 1.17 (t, 3J = 7.1 Hz,
13
3H, CH3). C NMR (100 MHz, CDCl3): δ = 159.69, 144.89, 139.26, 129.75, 128.36, 126.36, 126.02,
122.94, 122.71, 109.69, 61.58, 21.49, 14.10. MS (EI+) m/z: 295.3. Anal. Calcd for C17H17N3O2: C 69.14,
H 5.80, N 14.23. Found: C 68.82, H 5.36, N 11.05.
Ethyl 3-(4-chlorophenyl)-4-(1H-pyrrol-1-yl)-1H-pyrazole-5-carboxylate (4c)
From Ethyl 4-amino-5-(4-chlorophenyl)-2H-pyrazole-3-carboxylate (3c) (0.8g); beige solid (4c) (0.75g,
79%). Mp 114°C. IR (KBr): ν = 3436(NH), 2985, 2956, 2905, 1727(CO), 1597, 1374, 1214, 1086, 864,
733 cm-1. 1H NMR (400 MHz, CDCl3): δ = 12.5 (bs, 1H, NH), 7.20 (d, 3J = 8.5 Hz, 2H, Haromatic), 7.10 (d,
3J = 8.5 Hz, 2H, Haromatic), 6.60 (m, 2H, Hαpyrrole), 6.25 (m, 2H, Hβpyrrole), 4.22 (q, 3J = 7.1 Hz, 2H, OCH2),
1.16 (t, 3J = 7.1 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ = 159.36, 145.05, 135.08, 129.51, 129.20,
127.89, 127.84, 123.07, 122.77, 110.03, 61.81, 14.05. MS (EI+) m/z: 315.2. Anal. Calcd for
C16H14N3O2Cl: C 60.86, H 4.47, N 13.31. Found: C 61.23, H 4.36, N 13.63.
Ethyl 3-(3-benzyloxy4-methoxyphenyl)-4-(1H-pyrrol-1-yl)-1H-pyrazole-5-carboxylate (4d)
From Ethyl 4-amino-5-(3-benzyloxy-4-methoxyphenyl)-2H-pyrazole-3-carboxylate (3d) (6.8g); beige
solid (4d) (6.38g, 83%). Mp 182°C. IR (KBr): ν = 3245(NH), 2956, 2931, 2833, 1736(CO), 1513, 1257,
1237, 1204, 1086, 1021, 737, 698 cm-1. 1H NMR (400 MHz, CDCl3): δ = 8.5 (bs, 1H, NH), 7.30 (m, 5H,
Hphenyl), 6.94 (dd, 4JH2’H6’ = 1.95 Hz, 3JH5’H6’ = 8.5 Hz, 1H, H6’), 6.80 (d, 3JH5’H6’ = 8.5 Hz, 1H, H5’), 6.67

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HETEROCYCLES, Vol. 68, No. 10, 2006
(m, 2H, Hαpyrrole), 6.65 (d, 4JH2’H6’ = 1.95 Hz, 1H, H2’), 6.32 (m, 2H, Hβpyrrole), 4.87 (s, 2H, CH2Ph), 4.24 (q,
3
3J = 7.1 Hz, 2H, OCH2), 3.84 (s, 3H, OCH3), 1.19 (t, J = 7.1 Hz, 3H, CH3). 13C NMR (100 MHz,
CDCl3): δ = 159.61, 150.09, 148.24, 136.78, 128.53, 128.42, 127.82, 127.46, 122.85, 122.09, 121.40,
119.20, 111.68, 111.45, 111.26, 109.64, 70.43, 61.33, 55.92, 13.90. MS (EI+) m/z: 417.2. Anal. Calcd for
C24H23N3O4: C 69.05, H 5.55, N 10.07. Found: C 68.68, H 5.32, N 10.33.
General amidification reaction procedure:
3-(3,4-Dimethoxyphenyl)-5-(pyrrolidin-1-ylcarbonyl)-4-(1H-pyrrol-1-yl)-1H-pyrazole (5a)
A solution of (4a) (1g, 2.93 mmol) in pyrrolidine (30 mL) was refluxed for 24 h. After the mixture was
cooled and evaporated, the yellow oil was dissolved in CH2Cl2 (200 mL) and the solution was washed
with 1N HCl (2 × 100 mL), dried (CaCl2) and evaporated to give a brown oil. This residue was purified
by silica gel chromatography, eluting by cyclohexane:AcOEt (1:2) to furnish carboxamide (5a) as a
yellow solid (990 mg, 56%). Mp 210°C. IR (KBr): ν = 3435(NH), 3007, 2954, 1600(CO), 1582, 1498,
1236, 1228, 1133, 1021, 736 cm-1. 1H NMR (400 MHz, CDCl3): δ = 11.7 (bs, 1H, NH), 6.85 (d, 3JH5’H6’
=
8.3 Hz, 1H, H6’), 6.82 (d, 3JH5’H6’ = 8.3 Hz, 1H, H5’), 6.72 (m, 2H, Hαpyrrole), 6.62 (s, 1H, H2’), 6.27 (m, 2H,
Hβpyrrole), 3.87 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.59 (m, 2H, Hαpyrrolidine), 2.98 (m, 2H, Hαpyrrolidine), 1.83
13
(m, 2H, Hβpyrrolidine), 1.75 (m, 2H, Hβpyrrolidine). C NMR (100 MHz, CDCl3): δ = 160.22, 149.55, 149.20,
122.79, 122.39, 119.72, 119.31, 111.37, 110.44, 110.39, 109.78, 109.74, 56.10, 55.92, 47.47, 46.75, 26.33,
24.21. MS (EI+) m/z: 366.2. Anal. Calcd for C20H22N4O3: C 65.56, H 6.05, N 15.29. Found: C 65.45, H
6.24, N 15.47.
3-(4-Methylphenyl)-5-(pyrrolidin-1-ylcarbonyl)-4-(1H-pyrrol-1-yl)-1H-pyrazole (5b)
From (4b) (0.5g); orange solid (5b) (0.46g, 85%). Mp 180°C. IR (KBr): ν = 3190(NH), 2956, 2923, 2875,
1609(CO), 1588, 1465, 1450, 1321, 823, 722 cm-1. 1H NMR (400 MHz, CDCl3): δ = 11.5 (bs, 1H, NH),
7.12 (m, 4H, Haromatic), 6.68 (m, 2H, Hαpyrrole), 6.25 (m, 2H, Hβpyrrole), 3.56 (m, 2H, Hαpyrrolidine), 2.96 (m,
13
2H, Hαpyrrolidine), 2.33 (s, 3H, CH3), 1.78 (m, 4H, Hβpyrrolidine). C NMR (100 MHz, CDCl3): δ = 155.79,
138.85, 138.16, 129.65, 129.33, 126.73, 122.48, 119.76, 110.14, 109.17, 47.28, 46.47, 26.18, 24.14, 21.48.
MS (EI+) m/z: 320.1. Anal. Calcd for C19H20N4O: C 71.23, H 6.29, N 17.49. Found: C 71.45, H 6.65, N
17.45.
3-(4-Chlorophenyl)-5-(pyrrolidin-1-ylcarbonyl)-4-(1H-pyrrol-1-yl)-1H-pyrazole (5c)
From (4c) (0.7g); orange solid (5c) (0.51g, 67%). Mp 230°C. IR (KBr): ν = 3172(NH), 2970, 2923, 2880,
1611(CO), 1587, 1465, 1087, 1018, 831, 723 cm-1. 1H NMR (400 MHz, CDCl3): δ = 11.4 (bs, 1H, NH),
7.19 (d, 3J = 8.2 Hz, 2H, Haromatic), 7.08 (d, 3J = 8.2 Hz, 2H, Haromatic), 6.50 (m, 2H, Hαpyrrole), 6.18 (m, 2H,
Hβpyrrole), 3.47 (m, 2H, Hαpyrrolidine), 2.67 (m, 2H, Hαpyrrolidine), 1.71 (m, 2H, Hβpyrrolidine), 1.59 (m, 2H,
13
Hβpyrrolidine). C NMR (100 MHz, CDCl3): δ = 159.70, 141.59, 134.62, 129.05, 128.62, 128.49, 128.25,

HETEROCYCLES, Vol. 68, No. 10, 2006
2071
122.26, 111.04, 110.64, 46.99, 46.69, 26.16, 24.04. MS (EI+) m/z: 340.1. Anal. Calcd for C18H17N4OCl: C
63.44, H 5.03, N 16.44. Found: C 63.45, H 5.36, N 16.40.
3-(3-Benzyloxy-4-methoxyphenyl)-5-(pyrrolidin-1-ylcarbonyl)-4-(1H-pyrrol-1-yl)-1H-pyrazole (5d)
From (4d) (5g); orange solid (5d) (3.34g, 63%). Mp 182°C. IR (KBr): ν = 3173(NH), 2956, 2931, 2833,
1613(CO), 1455, 1254, 1014, 731 cm-1. 1H NMR (400 MHz, CDCl3): δ = 8.5 (bs, 1H, NH), 7.30 (m, 5H,
4
3
3
Hphenyl), 6.92 (dd, JH2’H6’ = 1.7 Hz, JH5’H6’ = 8.3 Hz, 1H, H6’), 6.80 (d, JH5’H6’ = 8.3 Hz, 1H, H5’), 6.68
(m, 3H, Hαpyrrole + H2’), 6.27 (m, 2H, Hβpyrrole), 4.90 (s, 2H, CH2Ph), 3.84 (s, 3H, OCH3), 3.57 (m, 2H,
13
Hαpyrrolidine), 3.01 (m, 2H, Hαpyrrolidine), 1.80 (m, 2H, Hβpyrrolidine), 1.72 (m, 2H, Hβpyrrolidine). C NMR (100
MHz, CDCl3): δ = 160.08, 149.86, 148.18, 128.45, 128.24, 127.82, 127.76, 127.46, 122.53, 121.91,
119.51, 119.41, 111.74, 111.69, 110.13, 110.10, 70.49, 55.93, 47.20, 46.41, 26.02, 23.93. MS (EI+) m/z:
442.4. Anal. Calcd for C26H26N4O3: C 70.57, H 5.92, N 12.66. Found: C 70.34, H 5.46, N 12.49.
Ring-closure reaction procedure:
3-(4-Methylphenyl)pyrazolo[3,4-b]pyrrolizin-8(1H)-one (2b)
A solution of the carboxamide (5b) (400 mg, 1.25 mmol) in phosphorous oxychloride (20 mL) was stirred
at 70°C for 3 h. After cooling, the reaction mixture was concentrated to give the intermediary iminium
salt which was slowly added to an 10% aqueous NaOH (100 mL) and heated at 80°C for 3 h. After
cooling, the resulting suspension was extracted with AcOEt (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:AcOEt (1:1) to
furnish pyrazolopyrrolizinone (2b) as a red solid (10 mg, 2%). Mp 212°C. IR (KBr): ν = 3206, 2958,
1
2924, 2855, 1682(CO), 1626, 1600, 1469, 1366, 1262, 1161, 1062, 1012 cm-1. H NMR (400 MHz,
CDCl3): δ = 10.3 (bs, 1H, NH), 7.48 (d, 3J = 8.1 Hz, 2H, Haromatic), 7.35 (d, 3J = 8.1 Hz, 2H, Haromatic), 7.00
4
3
4
3
(dd, JH5H7 = 0.7 Hz, JH5H6 = 2.4 Hz, 1H, H5), 6.81 (dd, JH5H7 = 0.7 Hz, JH6H7 = 3.9 Hz, 1H, H7), 6.22
3
3
(dd, JH5H6 = 2.4 Hz, JH6H7 = 3.9 Hz, 1H, H6), 2.44 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ =
178.43, 139.43, 132.22, 129.48, 127.32, 126.69, 123.33, 123.23, 116.71, 114.22, 114.13, 111.38, 21.35.
MS (EI+) m/z: 249.1. Anal. Calcd for C15H11N3O: C 72.28, H 4.45, N 16.86. Found: C 72.43, H 4.36, N
16.85.
3-(4-Chlorophenyl)pyrazolo[3,4-b]pyrrolizin-8(1H)-one (2c)
From (5c) (300mg); red solid (2c) (100mg, 42%). Mp 252°C. IR (KBr): ν = 3185(NH), 3106, 2927,
1686(CO), 1463, 1401, 1366, 1162, 1060, 825, 735 cm-1. 1H NMR (400 MHz, CDCl3): δ = 13.7 (bs, 1H,
NH), 7.51 (m, 4H, Haromatic), 6.96 (d, 3JH5H6 = 2.0 Hz, 1H, H5), 6.79 (d, 3JH6H7 = 3.8 Hz, 1H, H7), 6.21 (dd,
3
13
3JH5H6 = 2.0 Hz, JH6H7 = 3.8 Hz, 1H, H6). C NMR (100 MHz, CDCl3): δ = 165.98, 143.41, 136.99,
129.25, 127.13, 126.28, 126.10, 123.70, 120.23, 114.19, 114.13, 113.57. MS (EI+) m/z: 269.1. Anal.
Calcd for C14H8N3OCl: C 62.35, H 2.99, N 15.58. Found: C 62.48, H 3.18, N 15.70.

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HETEROCYCLES, Vol. 68, No. 10, 2006
3-(3-Benzyloxy-4-methoxyphenyl)pyrazolo[3,4-b]pyrrolizin-8(1H)-one (2d)
From (5d) (400mg); red solid (2c) (20mg, 6%). Mp 214°C. IR (KBr): ν = 3108(NH), 2923, 2852,
1
1704(CO), 1602, 1467, 1454, 1260, 1225, 1070, 1018 cm-1. H NMR (400 MHz, CDCl3): δ = 10.5 (bs,
1H, NH), 7.40, (m, 5H, Haromatic), 7.15 (dd, 4JH2’H6’ = 2.0 Hz, 3JH5’H6’ = 8.3 Hz, 1H, H6’), 7.03 (d, 3JH5’H6’
8.3 Hz, 1H, H5’), 6.99 (d, 4JH2’H6’ = 2.0 Hz, 1H, H2’), 6.73 (d, 3JH6H7 = 3.7 Hz, 1H, H7), 6.27 (d, 3JH5H6
=
=
3
3
2.2 Hz, 1H, H5), 6.04 (dd, JH5H6 = 2.2 Hz, JH6H7 = 3.7 Hz, 1H, H6), 5.28 (s, 2H, CH2Ph), 3.98 (s, 3H,
OCH3). 13C NMR (100 MHz, CDCl3): δ = 173.26, 150.85, 148.72, 137.13, 136.61, 129.06, 128.23,
127.93, 127.56, 116.84, 120.71, 119.90, 119.64, 114.98, 114.22, 112.46, 112.09, 112.20, 71.01, 56.29.
MS (EI+) m/z: 371.1. Anal. Calcd for C22H17N3O3: C 71.15, H 4.61, N 11.31. Found: C 70.78, H 4.81, N
11.52.
3-(3-Benzyloxy-4-methoxyphenyl)-1-methylpyrazolo[3,4-b]pyrrolizin-8(1H)-one (9)
From (7) (250mg); red solid (9) (150mg, 72%). Mp 180°C. IR (KBr): ν = 2959, 2927, 2837, 1690(CO),
1
1501, 1445, 1255, 1017, 694 cm-1. H NMR (400 MHz, CDCl3): δ = 7.42 (m, 5H, Harom), 7.26 (dd,
4JH2’H6’ = 1.9 Hz, 3JH5’H6’ = 8.3 Hz, 1H, H6’), 7.17 (d, 4JH2’H6’ = 1.9 Hz, 1H, H2’), 6.99 (d, 3JH5’H6’ = 8.3 Hz,
4
3
4
1H, H5’), 6.68 (dd, JH5H7 = 0.7 Hz, JH6H7 = 3.9 Hz, 1H, H7), 6.44 (dd, JH5H7 = 0.7 Hz, 3JH5H6 = 2.4 Hz,
1H, H5), 5.95 (dd, 3JH5H6 = 2.4 Hz, 3JH6H7 = 3.9 Hz, 1H, H6), 5.25 (s, 2H, OCH2), 3.96 (s, 3H, CH3), 3.94
(s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ = 168.37, 150.10, 148.45, 138.77, 136.86, 136.24, 134.77,
133.26, 128.77, 127.96, 127.02, 123.56, 122.16, 119.83, 115.99, 113.07, 112.14, 112.07, 70.89, 56.13,
37.94. MS (EI+) m/z: 385.2. Anal. Calcd for C23H19N3O3: C 71.68, H 4.97, N 10.90. Found: C 72.05, H
4.68, N 11.15.
3-(3-Benzyloxy-4-methoxyphenyl)-2-methylpyrazolo[3,4-b]pyrrolizin-8(1H)-one (10)
From (8) (230mg); red solid (10) (160mg, 75%). Mp 205°C. IR (KBr): ν = 2959, 2928, 2835, 1693(CO),
1
1514, 1464, 1255, 1019, 821 cm-1. H NMR (400 MHz, CDCl3): δ = 7.32 (m, 6H, Harom + H6’), 7.04 (d,
3JH5’H6’ = 8.3 Hz, 1H, H5’), 6.87 (d, 4JH2’H6’ = 1.5 Hz, 1H, H2’), 6.68 (d, 3JH6H7 = 3.9 Hz, 1H, H7), 6.23 (d,
3JH5H6 = 2.7 Hz, 1H, H5), 6.01 (dd, 3JH5H6 = 2.7 Hz, 3JH6H7 = 3.9 Hz, 1H, H6), 5.27 (s, 2H, OCH2Ph), 4.00
13
(s, 3H, OCH3), 3.66 (s, 3H, NCH3). C NMR (100 MHz, CDCl3): δ = 173.71, 150.77, 148.13, 138.28,
136.52, 131.40, 128.90, 126.97, 126.82, 124.44, 122.08, 119.53, 119.26, 114.46, 114.07, 113.99, 113.66,
112.13, 70.84, 56.14, 38.19. MS (EI+) m/z: 385.2. Anal. Calcd for C23H19N3O3: C 71.68, H 4.97, N 10.90.
Found: C 71.87, H 4.99, N 10.92.
3-(3-Benzyloxy-4-methoxyphenyl)-1-benzylpyrazolo[3,4-b]pyrrolizin-8(1H)-one (15)
From (14) (140mg); red solid (15) (110mg, 85%). Mp 146°C. IR (KBr): ν = 2925, 2847, 1696(CO), 1442,
1
1361, 1271, 1248, 1217, 1018, 704 cm-1. H NMR (400 MHz, CDCl3): δ = 7.35 (m, 11H, Harom + H6’),
7.16 (d, 4JH2’H6’ = 2.0 Hz, 1H, H2’), 6.98 (d, 3JH5’H6’ = 8.3 Hz, 1H, H5’), 6.65 (dd, 4JH5H7 = 0.7 Hz, 3JH6H7
=
=
4
3
3
3.9 Hz, 1H, H7), 6.41 (dd, JH5H7 = 0.7 Hz, 3JH5H6 = 2.4 Hz, 1H, H5), 5.93 (dd, JH5H6 = 2.4 Hz, JH6H7

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2073
13
3.9 Hz, 1H, H6), 5.31 (s, 2H, CH2Ph), 5.25 (s, 2H, CH2Ph), 3.94 (s, 3H, OCH3). C NMR (100 MHz,
CDCl3): δ = 168.90, 150.00, 148.29, 138.07, 137.02, 136.82, 135.48, 135.01, 131.09, 130.14, 128.76,
128.40, 127.94, 126.95, 123.52, 122.13, 119.89, 115.99, 113.06, 112.18, 111.92, 109.92, 70.83, 56.09,
55.19. MS (EI+) m/z: 461.2. Anal. Calcd for C29H23N3O3: C 75.47, H 5.02, N 9.10. Found: C 75.65, H
5.32, N 8.75.
3-(3-Benzyloxy-4-methoxyphenyl)-2-benzylpyrazolo[3,4-b]pyrrolizin-8(1H)-one (16)
From (14) (100mg); red solid (16) (40mg, 50%). Mp 194°C. IR (KBr): ν = 3036, 2935, 2847, 1697(CO),
1522, 1458, 1256, 1203, 1021, 742, 697 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.30 (m, 8H, Harom), 7.05
(m, 2H, Harom), 6.97 (d, 3JH5’H6’ = 8.2 Hz, 1H, H5’), 6.92 (dd, 4JH2’H6’ = 1.9 Hz , 3JH5’H6’ = 8.2 Hz, 1H, H6’),
4
3
3
6.76 (d, JH2’H6’ = 1.9 Hz, 1H, H2’), 6.70 (d, JH6H7 = 3.5 Hz, 1H, H7), 6.27 (d, JH5H6 = 2.5 Hz, 1H, H5),
6.02 (dd, 3JH5H6 = 2.5 Hz, 3JH6H7 = 3.4 Hz, 1H, H6), 5.16 (s, 2H, CH2Ph), 5.03 (s, 2H, CH2Ph), 3.97 (s, 3H,
OCH3). 13C NMR (100 MHz, CDCl3): δ = 173.66, 150.60, 148.09, 147.99, 136.65, 136.38, 136.22,
131.50, 128.69, 128.64, 127.98, 127.83, 127.23, 126.99, 126.95, 126.80, 121.99, 119.43, 119.07, 113.99,
113.66, 111.87, 70.34, 55.96, 54.14. MS (EI+) m/z: 461.2. Anal. Calcd for C29H23N3O3: C 75.47, H 5.02,
N 9.10. Found: C 75.35, H 4.98, N 9.25.
Alkylation procedure :
3-(3-Benzyloxy-4-methoxyphenyl)-1-methyl-5-(pyrrolidin-1-ylcarbonyl)-4-(1H-pyrrol-1-yl)-1H-pyr
azole (7) and 5-(3-Benzyloxy-4-methoxyphenyl)-1-methyl-3-(pyrrolidin-1-ylcarbonyl)-4-(1H-pyrrol
-1-yl)-1H-pyrazole (8)
To a cooled solution of (5d) (750mg, 1.69 mmol) in DMF (7mL) was successively added NaH (88mg,
2.03 mmol) and MeI (97µL, 2.03 mmol). The reaction mixture was stirred at rt for 12h and diluted with
water (100mL) and extracted with Et2O (2 × 100 mL). The combined organic layers were washed with
brine (2 × 100 mL), dried (MgSO4) and evaporated to give an off-white solid. This residue was purified
by silica gel chromatography, eluting by cyclohexane:AcOEt (2:1) to furnish amide (7) as a white solid
1
(320mg, 41%). Mp 118°C. IR (KBr): ν = 3120, 2927, 1631(CO), 1454, 1260, 1015, 741 cm-1. H NMR
(400 MHz, CDCl3): δ = 7.35 (m, 5H, Hphenyl), 7.01 (dd, 4JH2’H6’ = 1.9 Hz, 3JH5’H6’ = 8.3 Hz, 1H, H6’), 6.86
3
4
(d, JH5’H6’ = 8.3 Hz, 1H, H5’), 6.80 (d, JH2’H6’ = 1.9 Hz, 1H, H2’), 6,67 (m, 2H, Hαpyrrole), 6.29 (m, 2H,
Hβpyrrole), 4.97 (s, 2H, OCH2Ph), 4.01 (s, 3H, NCH3), 3.89 (s, 3H, OCH3), 3.57 (m, 2H, Hαpyrrolidine), 2.84
(m, 2H, Hαpyrrolidine), 1.84 (m, 2H, Hβpyrrolidine), 1.72 (m, 2H, Hβpyrrolidine). 13C NMR (100 MHz, CDCl3): δ =
159.05, 149.72, 148.22, 144.13, 137.19, 133.77, 128.60, 127.93, 127.65, 123.77, 122.11, 119.93, 119.76,
112.27, 111.85, 110.28, 70.69, 56.12, 47.20, 45.96, 38.69, 25.87, 24.16. MS (EI+) m/z: 456.2. Anal. Calcd
for C27H28N4O3: C 71.03, H 6.18, N 12.27. Found: C 70.85, H 6.38, N 12.35; and amide (8) as a white
solid (450mg, 58%). Mp 146°C. IR (KBr): ν = 3189, 2925, 2869, 1623(CO), 1455, 1251, 1105, 748 cm-1.
3
1H NMR (400 MHz, CDCl3): δ = 7.35 (m, 5H, Hphenyl), 6.90 (d, JH5’H6’ = 8.3 Hz, 1H, H5’), 6.78 (dd,

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HETEROCYCLES, Vol. 68, No. 10, 2006
3
4
4JH2’H6’ = 1.9 Hz, JH5’H6’ = 8.3 Hz, 1H, H6’), 6.60 (m, 2H, Hαpyrrole), 6.53 (d, JH2’H6’ = 1.9 Hz, 1H, H2’),
6.14 (m, 2H, Hβpyrrole), 5.00 (s, 2H, OCH2Ph), 3.88 (s, 3H, OCH3), 3.68 (s, 3H, NCH3), 3.58 (m, 2H,
H
αpyrrolidine), 3.24 (m, 2H, Hαpyrrolidine), 1.80 (m, 4H, Hβpyrrolidine). 13C NMR (100 MHz, CDCl3): δ = 161.76,
150.37, 148.02, 141.13, 137.65, 136.69, 128.63, 127.96, 127.20, 122.42, 122.37, 120.97, 119.66, 114.90,
111.64, 109.18, 70.93, 55.94, 47.73, 45.88, 38.08, 25.96, 24.14. MS (EI+) m/z: 456.2. Anal. Calcd for
C27H28N4O3: C 71.03, H 6.18, N 12.27. Found: C 71.04, H 6.25, N 12.35.
3-(3-Benzyloxy-4-methoxyphenyl)-1-benzyl-5-(pyrrolidin-1-ylcarbonyl)-4-(1H-pyrrol-1-yl)-1H-pyra
zole (13) and 5-(3-Benzyloxy-4-methoxyphenyl)-1-benzyl-3-(pyrrolidin-1-ylcarbonyl)-4-(1H-pyrrol
-1-yl)-1H-pyrazole (14)
To a cooled solution of 5d (250mg, 0.57 mmol) in DMF (7mL) was successively added NaH (30mg, 0.68
mmol) and benzyl bromide (81µL, 0.68 mmol). The reaction mixture was stirred at rt for 12h and diluted
with water (100mL) and extracted with Et2O (2 × 100 mL). The combined organic layers were washed
with brine (2 × 100 mL), dried (MgSO4) and evaporated to give an off-white solid. This residue was
purified by silica gel chromatography, eluting by cyclohexane:EtOAc (3:2) to furnish amide (13) as a
yellow solid (140mg, 46%). Mp 152°C. IR (KBr): ν = 2964, 2929, 2876, 1633(CO), 1455, 1436, 1259,
1
4
1220, 1133, 1025, 723 cm-1. H NMR (400 MHz, CDCl3): δ = 7.35 (m, 10H, Harom), 7.04 (dd, JH2’H6’
=
2.0 Hz, 3JH5’H6’ = 8.3 Hz, 1H, H6’), 6.84 (d, 3JH5’H6’ = 8.3 Hz, 1H, H5’), 6,82 (d, 4JH2’H6’ = 2.0 Hz, 1H, H2’),
6.63 (m, 2H, Hαpyrrole), 6.23 (m, 2H, Hβpyrrole), 5.47 (s, 2H, NCH2Ph), 4.96 (s, 2H, OCH2Ph), 3.87 (s, 3H,
OCH3), 3.31 (m, 2H, Hαpyrrolidine), 2.38 (m, 2H, Hαpyrrolidine), 1.63 (m, 2H, Hβpyrrolidine), 1.29 (m, 2H,
13
Hβpyrrolidine). C NMR (100 MHz, CDCl3): δ = 159.00, 149.53, 148.02, 143.55, 137.03, 136.61, 133.39,
128.56, 128.42, 128.22, 128.07, 127.75, 127.49, 123.65, 121.90, 120.14, 119.81, 112.15, 111. 63, 109.96,
70.56, 55.94, 55.19, 46.72, 45.33, 25.14, 23.87. MS (EI+) m/z: 532.2. Anal. Calcd for C33H32N4O3: C
74.41, H 6.06, N 10.52. Found: C 74.35, H 5.97, N 10.76.; and amide (14) as a yellow solid (100mg,
34%). Mp 142°C. IR (KBr): ν = 2961, 2920, 2869, 1631(CO), 1526, 1449, 1251, 1136, 1016, 759, 699
cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.30 (m, 8H, Harom), 7.04 (m, 2H, Harom), 6.90 (d, 3JH5’H6’ = 8.3 Hz,
1H, H5’), 6.65 (dd, 4JH2’H6’ = 2.0 Hz, 3JH5’H6’ = 8.3 Hz, 1H, H6’), 6.64 (m, 2H, Hαpyrrole), 6.46 (d, 4JH2’H6’
=
2.0 Hz, 1H, H2’), 6.12 (m, 2H, Hβpyrrole), 5.20 (s, 2H, NCH2Ph), 4.81 (s, 2H, OCH2Ph), 3.87 (s, 3H, OCH3),
3.59 (m, 2H, Hαpyrrolidine), 3.35 (m, 2H, Hαpyrrolidine), 1.84 (m, 2H, Hβpyrrolidine), 1.61 (m, 2H, Hβpyrrolidine). 13C
NMR (100 MHz, CDCl3): δ = 158.99, 150.63, 148.11, 141.60, 137.00, 135.17, 128.91, 128.73, 128.09,
127.39, 127.38, 127.09, 124.49, 122.74, 114.89, 113.15, 111.76, 109.25, 109.21, 109.19, 70.78, 56.05,
53.77, 48.14, 46.16, 27.28, 26.21. MS (EI+) m/z: 532.2. Anal. Calcd for C33H32N4O3: C 74.41, H 6.06, N
10.52. Found: C 74.33, H 6.24, N 10.52.
O-Deprotection procedure :
3-(3-Hydroxy-4-methoxyphenyl)-1-methylpyrazolo[3,4-b]pyrrolizin-8(1H)-one (11)

HETEROCYCLES, Vol. 68, No. 10, 2006
2075
A solution of the tripentone (9) (50mg, 0.13 mmol) in a 33% solution of HBr in AcOH (10 mL) was
stirred at rt for 1 h. 50mL of ice-water mixture were then added and the mixture stirred for 1h. The
resulting suspension was extracted with AcOEt (2 × 50 mL) and the combined organic layers were
washed with water (2 × 100 mL) and brine (100 mL), dried (MgSO4) and evaporated. The resulting
product was solved in a mixture of MeOH (10mL) and 1N NaOH (10mL) and stirred at rt for 1h. The
reaction mixture was then concentrated under vacuum, acidified using 1N HCl and extracted with AcOEt
(2 × 50 mL). 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:AcOEt (1:1) to furnish pyrazolopyrrolizinone (11) as a red solid
(40 mg, 99%). Mp 130°C. IR (KBr): ν = 3392(OH), 3118, 2935, 1683(CO), 1487, 1436, 1261, 1133, 762
1
4
3
cm-1. H NMR (400 MHz, CDCl3): δ = 7.20 (dd, JH5H7 = 1.6 Hz, JH6H7 = 3.9 Hz, 1H, H7), 6.85 (d,
4JH2’H6’ = 2.1 Hz, 1H, H2’), 6.84 (dd, 4JH5H7 = 1.6 Hz, 3JH5H6 = 2.7 Hz, 1H, H5), 6.69 (d, 3JH5’H6’ = 8.5 Hz,
1H, H5’), 6.60 (dd, 4JH2’H6’ = 2.1 Hz, 3JH5’H6’ = 8.5 Hz, 1H, H6’), 6.30 (dd, 3JH5H6 = 2.7 Hz, 3JH6H7 = 3.9 Hz,
1H, H6), 5.0 (bl, 1Hdeutérable, OH), 3.96 (s, 3H, CH3), 3,83 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ =
161.64, 146.95, 146.12, 145.88, 130.40, 128.91, 125.18, 124.75, 120.12, 118.79, 117.71, 113.26, 110.97,
109.29, 55.81, 39.47. MS (EI+) m/z: 295.3. Anal. Calcd for C16H13N3O3: C 65.08, H 4.44, N 14.23.
Found: C 65.24, H 4.65, N 14.01.
3-(3-Hydroxy-4-methoxyphenyl)-2-methylpyrazolo[3,4-b]pyrrolizin-8(1H)-one (12)
From (10) (70mg); red solid (12) (30mg, 53%). Mp 126°C. IR (KBr): ν = 3240(OH), 3115, 2943, 2840,
1698(CO), 1489, 1457, 1276, 1224, 762 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.08 (dd, 4JH5H7 = 1.6 Hz,
3JH6H7 = 3.9 Hz, 1H, H7), 6.79 (d, 3JH5’H6’ = 8.3 Hz, 1H, H5’), 6.75 (m, 2H, H5 + H2’), 6.62 (dd, 4JH2’H6’
=
2.1 Hz, 3JH5’H6’ = 8.3 Hz, 1H, H6’), 6.17 (dd, 3JH5H6 = 2.7 Hz, 3JH6H7 = 3.9 Hz, 1H, H6), 3.87 (s, 3H, CH3),
13
3.85 (s, 3H, CH3). C NMR (100 MHz, CDCl3): δ = 189.26, 147.19, 145.66, 138.94, 135.90, 131.79,
124.53, 123.33, 121.36, 120.99, 120.15, 115.2, 110.75, 109.39, 55.88, 37.91. MS (EI+) m/z: 295.2. Anal.
Calcd for C16H13N3O3: C 65.08, H 4.44, N 14.23. Found: C 65.09, H 4.46, N 14.42.
3-(3-Hydroxy-4-methoxyphenyl)-1-benzylpyrazolo[3,4-b]pyrrolizin-8(1H)-one (17)
From (15) (100mg); red solid (17) (30mg, 30%). Mp 178°C. IR (KBr): ν = 3448(OH), 2963, 2926, 2855,
1686(CO), 1457, 1435, 1269, 1123, 1021, 802 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.46 (m, 2H, Harom),
7.30 (m, 4H, Harom + H2’), 7.17 (dd, 4JH2’H6’ = 1.9 Hz, 3JH5’H6’ = 8.3 Hz, 1H, H6’), 7.00 (d, 3JH5H6 = 2.4 Hz,
1H, H5), 6.90 (d, 3JH5’H6’ = 8.3 Hz, 1H, H5’), 6.68 (d, 3JH6H7 = 3.9 Hz, 1H, H5), 6.04 (dd, 3JH5H6 = 2.4 Hz,
13
3JH6H7 = 3.9 Hz, 1H, H6), 5.7 (bs, 1H, OH), 5.30 (s, 2H, NCH2Ph), 3.92 (s, 3H, OCH3). C NMR (100
MHz, CDCl3): δ = 168.35, 147.03, 146.16, 138.20, 136.44, 135.61, 135.11, 131.01, 128.89, 128.56,
128.53, 124.38, 122.40, 118.68, 116.16, 113.08, 112.96, 111.01, 56.15, 55.35. MS (EI+) m/z: 371.2. Anal.
Calcd for C22H17N3O3: C 71.15, H 4.61, N 11.31. Found: C 71.05, H 4.72, N 11.46.

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HETEROCYCLES, Vol. 68, No. 10, 2006
3-(3-Hydroxy-4-methoxyphenyl)-2-benzylpyrazolo[3,4-b]pyrrolizin-8(1H)-one (18)
From (16) (40mg); red solid (18) (30mg, 30%). Mp 178°C. IR (KBr): ν = 3448(OH), 2963, 2926, 2855,
1686(CO), 1457, 1435, 1269, 1123, 1021, 802 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.36 (m, 3H, Harom),
4
3
7.11 (m, 2H, Harom), 6.95 (d, JH2’H6’ = 2.2 Hz, 1H, H2’), 6.93 (d, JH5’H6’ = 8.3 Hz, 1H, H5’), 6.85 (dd,
4JH2’H6’ = 2.2 Hz, 3JH5’H6’ = 8.3 Hz, 1H, H6’), 6.73 (dd, 4JH5H7 = 0.7 Hz, 3JH5H7 = 3.6 Hz, 1H, H7), 6.67 (dd,
4JH5H7 = 0.7 Hz, 3JH6H5 = 2.4 Hz, 1H, H5), 6.10 (dd, 3JH5H6 = 2.4 Hz, 3JH6H7 = 3.9 Hz, 1H, H6), 5.8 (bs, 1H,
OH), 5.28 (s, 2H, NCH2Ph), 3.96 (s, 3H, OCH3). 13C NMR (100 MHz, CDCl3): δ = 174.38, 148.18,
146.81, 137.35, 136.83, 129.24, 129.09, 128.49, 127.75, 127.65, 127.52, 121.62, 120.58, 120.16, 115.45,
114.69, 114.24, 111.62, 56.59, 54.79. MS (EI+) m/z: 371.2. Anal. Calcd for C22H17N3O3: C 71.15, H 4.61,
N 11.31. Found: C 71.35, H 4.83, N 11.52.
X-Ray Crystallography. Suitable crystals of the title compounds were obtained by slow evaporation
from methylene chloride/methanol (v/v) at room temperature, and they were mounted on a glass fiber.
Diffraction data were collected on an Enraf-Nonius CAD4 diffractometer with Mo Kα radiation (λ) 0.710
73 Å) at room temperature. Data were measured using θ-2θ scan. The data treatment, polarization and
14
decay corrections, was carried out with JANA98 program. The crystal structure was solved by direct
methods using the SHELX97 package.15 All nonhydrogen atoms were refined anisotropically.
ACKNOWLEDGEMENTS
We thank the Société de Chimie Thérapeutique and Les Laboratoires Servier for a doctoral grant to Ch. R.
and Mr. Dat for the NMR experiment.
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