Tricyclic pyrazoles: An efficient approach to cannabinoid analogues with a tricyclic framework incorporating the pyrrole and pyrazole moieties

Article abstract of DOI:10.1055/s-0032-1316703

In this paper we report the synthesis of some new cannabinoid analogues that share with rimonabant, a potent and selective CB₁ antagonist, the 2,4-dichlorophenyl and piperidin-1-yl substituents on the pyrazole and amide nitrogens, respectively. The general synthesis involves the preparation of a cyclic ketone condensed with a pyrrole, followed by Claisen condensation with diethyl oxalate; from here, an aza-annulation reaction with a substituted hydrazine followed by an amidation step complete the synthesis. Georg Thieme Verlag Stuttgart.New York.

Full text of DOI:10.1055/s-0032-1316703

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PAPER
paper
Tricyclic Pyrazoles: An Efficient Approach to Cannabinoid Analogues with a
Tricyclic Framework Incorporating the Pyrrole and Pyrazole Moieties
Tricyclic Pyrazoles
Giansalvo Pinna,*a Gérard A. Pinna,a Giorgio Chelucci,b Salvatore Baldinob
a
Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy
Fax +39(79)228720; E-mail: pinlab@uniss.it
b
Dipartimento di Agraria, Università di Sassari, Viale Italia 39, 07100 Sassari, Italy
Received: 11.05.2012; Accepted after revision: 14.06.2012
Continuing our interest in this field, we have undertaken a
Abstract: In this paper we report the synthesis of some new canna-
study to prepare new cannabinoid binders related to both
binoid analogues that share with rimonabant, a potent and selective
rimonabant and its derivatives Aa–c (Figure 1). Thus, we
are developing practical and extendable methods to build
CB1 antagonist, the 2,4-dichlorophenyl and piperidin-1-yl substitu-
ents on the pyrazole and amide nitrogens, respectively. The general
synthesis involves the preparation of a cyclic ketone condensed compounds with a tricyclic framework incorporating the
with a pyrrole, followed by Claisen condensation with diethyl oxa-
late; from here, an aza-annulation reaction with a substituted hydra-
zine followed by an amidation step complete the synthesis.
biologically interesting pyrrole and pyrazole moieties,
and with a central ring that can be modulate in size, name-
ly compounds of general formula B (Figure 1). In this pa-
per we wish to report the results obtained in the synthesis
Key words: cannabinoids, tricyclic pyrazoles, Friedel–Crafts acyl-
ation, Claisen condensation, aza-annulation
of some representatives of this family B′, which share
with rimonabant the 2,4-dichlorophenyl and piperidin-1-
yl substituents on the pyrazole and amide nitrogens, re-
spectively (Figure 1).
The endogenous cannabinoid system (ECS) in mammals
incorporates a variety of cellular elements as potential rec-
ognition sites at which a broad group of compounds,
termed cannabinoids, interact. At present, a number of
cannabinoid binders have been identified, which can be
roughly classified into a variety of chemical families (exo-
cannabinoids), including tricyclic cannabinols,1 bicyclic
cannabinols,2,3 indoles, pyrroles, and indenes,4 anan-
damide analogues,5 and diarylpyrazoles.6 A prototypical
example of a diarylpyrazole with a potent and selective
CB1 antagonist property is rimonabant, which, however,
has been withdrawn from the market due to various psy-
chiatric side effects (Figure 1).7
O
O
N
N
R3
N
H
N
H
( )n
N
N
R1
N
Cl
Cl
R2
Aa–c (a: n = 1, b: n = 2, c: n = 3)
Cl
rimonabant
O
The 4-alkyl-5-arylpyrazole skeleton of rimonabant has
been modified by us, giving rise to 1,4-dihydroben-
zo[4,5]cyclopenta[1,2-c]pyrazole Aa,8 1,4,5-trihydroben-
zo[5,6]cyclohexa[1,2-c]pyrazole Ab,9 and 1,4,5,6-
tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-based li-
gands Ac10 (Figure 1). These compounds displayed inter-
esting cannabinoid-binding affinity and subtype
selectivity. Interestingly, changes to the size and shape of
the tricyclic unit in ligands Aa–c revealed intriguing ef-
fects on the biological activity. Thus, increasing the length
of the carbon bridge between C4 of the pyrazole and the
4-chlorophenyl group from one to three methylene units
led to a marked increase in the CB1 binding affinity and
selectivity. Moreover, the presence of a substituent, such
as F, Cl, Br, or Me, on the phenyl ring of the tricyclic sys-
tem generally gave an increase in the affinity and selectiv-
ity for CB2 receptors.8
N
R
O
N
( )n
R3
H
N
R1
N
( )n
N
H
N
N
N
Cl
N
R2
B
Cl
B': n = 1; R = Me, Cl
n = 2, 3; R = Cl
Figure 1
The planned retrosynthesis of the derivatives of general
formula B is showed in Scheme 1. In this approach, the fi-
nal amidation step is preceded by the aza-annulation of a
2,4-dioxobutanoic acid esters D with a substituted hydra-
zine. The polyoxo compounds D can be made through
Claisen condensation between the appropriate substituted
cyclic ketone E and diethyl oxalate. Finally, substituted
cyclic ketone E can be built from 2-substituted pyrroles F
by an N-alkylation/acylation sequence.
SYNTHESIS 2012, 44, 2798–2804
Advanced online publication: 31.07.2012
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DOI: 10.1055/s-0032-1316703; Art ID: SS-2012-Z0439-OP
© Georg Thieme Verlag Stuttgart · New York

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Tricyclic Pyrazoles
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To begin to fulfill the strategy for the target derivatives B the pyrrolizin-1-ones 3a,b (Scheme 2). However, while
(Scheme 1), we devoted our attention to a reliable synthe- the unsubstituted compound 3a was obtained in 70%
sis of substituted pyrrole-fused cyclopentanones E (n = 1). yield, the methyl counterpart 3b was unexpectedly formed
Thus, pyrrole and 2-methylpyrrole were treated with acry- in only 23% yield. Therefore, an alternative synthesis of
lonitrile in the presence of Triton B to give the N-alkylat- 3b was also investigated (vide infra). To obtain 5-chloro-
ed derivatives 2a,b in 82% and 70% yields, respectively. 2,3-dihydro-1H-pyrrolizin-1-one (3c) the direct halogena-
The intramolecular Friedel–Crafts acylation of 2a,b gave tion of 3a was preferred to the synthesis from 2-chloro-
pyrrole. Thus, treatment of 3a with N-chlorosuccinimide
O
O
in tetrahydrofuran at 60 °C gave 3c in good yield (71%).
With this compound in hand, the substitution of the chlo-
rine atom with a methyl group was explored. Unfortunate-
ly, Suzuki cross-coupling of 3c with methylboronic acid
in the presence of palladium(II) acetate/tricyclohex-
ylphosphine failed to give 3b. In order to obtain the target
compound 3b, 5-bromo-2,3-dihydro-1H-pyrrolizin-1-one
(3d) was synthesized by bromination of 3a with N-bromo-
succinimide in tetrahydrofuran at low temperature (92%
yield). As expected, Suzuki cross-coupling of 3d with
methylboronic acid in the presence of palladium(II) ace-
tate/tricyclohexylphosphine was in this case successful
affording 3b in 80% yield. Next, the yield of this coupling
reaction could be improved to 87% when palladium(II)
acetate/2-(dicyclohexylphosphino)-2′,6′-diisopropoxybi-
phenyl (RuPhos) was used as the catalyst.
R3
R1
R1
amidation
N
OEt
( )
( )
n
n
H
N
N
aza-annulation
N
N
N
R2
N
R2
C
B
O
O
R1
Claisen
condensation
R1
R1
( )
OEt
( )
n
N
NH
n
N
O
O
E
F
D
Scheme 1
R1
R1
R1
N
a
b
NH
N
N
With multigram quantities of 5-substituted 2,3-dihydro-
1H-pyrrolizin-1-ones 3 in hand, their conversion into the
desired derivatives B was pursued according to the
planned retrosynthesis. The treatment of ketones 3a–c
with diethyl oxalate in the presence of sodium ethoxide at
room temperature afforded the expected 1,3-diketo esters,
which were in all cases detected only as the enol form 4a–
c (72–86% yields) (Scheme 3). Compounds 4a–c and 2,4-
dichlorophenylhydrazine hydrochloride were heated in
ethanol to afford the pyrazole derivatives 5a–c in good
yields (70–86%). An alternative access to the chlorine de-
rivative 5c was obtained by treating 5a with N-chlorosuc-
cinimide in tetrahydrofuran at 60 °C (62% yield). The
O
1a, b
2a (82%), 2b (70%)
3a (70%), 3b (23%)
a: R1 = H, b: R1 = Me
R1
N
N
N
c or d
e
O
O
O
3c (R1 = Cl, 71%)
3d (R1 = Br, 92%)
3a
3b (0% from 3c,
87% from 3d)
Scheme 2 Reagents and conditions: (a) CH2=CHCN, Triton B, 8–12
°C to r.t.; (b) (i) AlCl3, KCl, NaCl, 120 °C, (ii) H2O, 40 °C, 1 h then
90 °C, 1 h; (c) NCS, THF, 60 °C, 5 h; (d) NBS, THF, –50 to –10 °C,
2 h; (e) MeB(OH)2, Pd(OAc)2/RuPhos, Cs2CO3, toluene–H2O, 130
°C, 30 min.
O
O
R1
R1
OEt
OH
OEt
R1
b
a
d
N
N
N
N
N
O
3a–c
O
Cl
4a (86%)
4b (72%)
4c (80%)
a: R1 = H
b: R1 = Me
c: R1 = Cl
Cl
5a (86%)
5b (72%)
O
O
N
c
R1
R1
5c (70% from 4c)
(62% from 5a)
OH
NH
N
N
N
N
e
N
N
Cl
Cl
Cl
Cl
6b (85%)
6c (90%)
7b (33%)
7c (61%)
Scheme 3 Reagents and conditions: (a) Na, EtOH, diethyl oxalate, r.t., 1 h; (b) 2,4-Cl2C6H3NHNH2·HCl, EtOH, 80 °C, 48 h; (c) NCS, THF, 60
°C, 5 h; (d) LiOH, THF, 60 °C, 3 h; (e) EDC, BtOH, CH2Cl2, then 1-aminopiperidine, r.t., 12 h.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2798–2804

2800
G. Pinna et al.
PAPER
ethyl ester groups in 5b,c were converted with lithium hy- that obtained with path a, making it the preferred route
droxide in tetrahydrofuran at 60 °C into the related acids when taking into account that it gave cleaner products.
6b,c (85–90% yields), which were reacted in sequence
Following path b compound 8b was converted into the
with N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide
1,3-diketo ester 13b in 67% yield. In the next step the
and 1-hydroxybenzotriazole, and then with piperidin-1-
treatment of 13b with 2,4-dichlorophenylhydrazine hy-
drochloride gave a mixture of products from which the ex-
pected pyrazole derivative 11b was isolated in moderate
amine to give the target compounds 7b and 7c in 33% and
61% yields, respectively.
For the synthesis of the analogue of A, where the central 50% yield. Finally, compounds 11a,b were converted in
ring in the tricyclic unit of A is a six- or seven-membered very similar yields over two steps (~40%) into 15a,b by
ring and the R1 substituent is a chlorine atom, two conver- hydrolysis followed by amidation under the usual reaction
gent paths were pursued (Scheme 4). These routes follow conditions.
the reliable methodologies employed to obtain com-
In conclusion, we report a practical synthesis of com-
pounds 7b,c by using as starting materials the known cy-
pounds of structure B′ (Figure 1), which share with
clic ketones 6,7-dihydroindolizin-8(5H)-one (8a) and
rimonabant the 2,4-dichlorophenyl and piperidin-1-yl
substituents on the pyrazole and amide nitrogens, respec-
tively. The CB binding affinity and selectivity of these
new compounds will be determined, thus indicating which
5,6,7,8-tetrahydro-9H-pyrrolo[1,2-a]azepin-9-one (8b).
Initially, the ketone 8a was converted into the pyrazole
derivative 9a by Claisen condensation with ethyl oxalate,
followed by aza-cyclization with 2,4-dichlorophenylhy-
further structural modifications will be pursued to modu-
drazine (54% yield in two steps) (path a). Chlorination of
late advantageously their biological activity.
10a with N-chlorosuccinimide in tetrahydrofuran at 60 °C
gave 11a in 65% isolated yield; the the overall yield for
All reagents and solvents were purchased from Aldrich and used as
received. Low boiling petroleum ether (PE) was the fraction bp 40–
60 °C. THF was distilled from Na/benzophenone ketyl and de-
gassed thoroughly with dry N2 directly before use. Melting points
were determined on a Büchi 510 capillary apparatus and are uncor-
rected. NMR spectra were obtained with a Varian VXR-300 spec-
the three steps was 35%. In the alternative route (path b),
the ketone 8a was reacted with N-chlorosuccinimide in
tetrahydrofuran at 60 °C to give 12a (73% yield), which
was converted into 11a in the usual way. This three-step
protocol gave an overall yield of 40%, slightly higher than
O
OEt
Cl
( )
( )
n
a
c
n
N
N
( )
n
N
OH
path b
path a
O
O
O
12a (73%)
12b (81%)
8a, b
a: n = 2
b: n = 3
9a (78%)
O
b
a
Cl
OEt
( )
n
O
N
N
OEt
( )
N
b
n
O
N
OEt
OH
c
Cl
N
Cl
( )
N
n
N
Cl
d
O
Cl
13a (70%)
13b (83%)
11a (65% from 10a)
11a (79% from 13a)
11b (50% from 13b)
Cl
10a (69%)
O
O
N
N
Cl
OH
( )
Cl
N
n
( )
N
n
H
N
N
e
N
N
Cl
Cl
Cl
Cl
14a (64%)
15a (60%)
15b (44%)
14b (92%)
Scheme 4 Reagents and conditions: (a) Na, EtOH, diethyl oxalate, r.t., 1 h; (b) 2,4-Cl2C6H3NHNH2·HCl, EtOH, 80 °C, 8 h; (c) NCS, THF, 60
°C, 5 h; (d) LiOH, THF, 60 °C, 3 h; (e) EDC, BtOH, CH2Cl2, then 1-aminopiperidine, r t, 12 h.
Synthesis 2012, 44, 2798–2804
© Georg Thieme Verlag Stuttgart · New York

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Tricyclic Pyrazoles
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1
trometer at 300 for H and 75.4 MHz for 13C; reference: internal
TMS in CDCl3. IR spectra were recorded on a Jasco FT/IR-460 plus
spectrophotometer. Microwave experiments were carried out by a
Biotage Iniziator-8-microwave system (max pressure 20 bar, IR
temperature sensor). Elemental analyses were performed on a
Perkin-Elmer 240 B analyzer. TLC was performed on Merck silica
gel 60 TLC plates F254 and visualized using UV or phosphomolyb-
dic acid. Flash chromatography was carried out on 230–400 mesh
silica gel.
13C NMR: δ = 187.7, 133.4, 118.2, 108.9, 105.2, 41.7, 39.1.
Anal. Calcd for C7H6BrNO: C, 42.03; H, 3.02; N, 7.00. Found: C,
43.01; H, 3.08; N, 6.92.
5-Methyl-2,3-dihydro-1H-pyrrolizin-1-one (3b) from 3d
In a glass tube fitted with a Teflon screw seal, Pd(OAc)2 (0.03 g,
0.13 mmol), RuPhos (0.12 g, 0.25 mmol), Cs2CO3 (2.43 g, 7.47
mmol), and methylboronic acid (0.43 g, 4.99 mmol) were added to
a soln of 3d (0.50 g, 2.50 mmol), in a degassed mixture of toluene–
H2O (19:1, 2.5 mL). The reactor was flushed with argon and the
mixture was heated in microwave apparatus at 130 °C for 30 min.
The reaction was diluted with H2O (10 mL) and extracted with EtO-
Ac, (3 × 10 mL) The combined organic layers were dried (anhyd
Na2SO4) and filtered, and the solvent was removed under reduced
pressure. The residue was purified by plug chromatography (PE–
EtOAc, 7:3) giving 3b (0.294 g, 87%).
3-(1H-Pyrrol-1-yl)propanenitrile (2a),11 2,3-dihydro-1H-pyrroli-
zin-1-one (3a),11 ethyl 2-hydroxy-2-(1-oxo-2,3-dihydro-1H-pyrro-
lizin-2-ylidene)acetate (4a),12 6,7-dihydroindolizin-8(5H)-one
(8a),13 5,6,7,8-tetrahydro-9H-pyrrolo[1,2-a]azepin-9-one (8b)14
were obtained according to reported procedures.
3-(2-Methyl-1H-pyrrol-1-yl)propanenitrile (2b)
Acrylonitrile (7.75 g, 0.147 mol) was slowly added, keeping the
temperature at 8–12 °C, to a soln of 2-methylpyrrole (7.50 g, 92.5
mmol) in 40% aq Triton B soln (0.77 mL). When the addition was
complete, the mixture was stirred at 12 °C for 30 min and then at r.t.
for an additional 1 h. The obtained red/brown oil was bulb-to-bulb
distilled (oven temperature 90 °C/67 mbar) to give 2b (8.69 g, 70%)
as a colorless oil.
Chlorination with N-Chlorosuccinimide of 3a, 5a, 8a,b, 10a;
General Procedure 1
NCS (0.15 g, 1.09 mmol) was added to a soln of the substrate (0.91
mmol) in THF (4 mL). After stirring at r.t. for few min, the mixture
was heated at 60 °C for 5 h. After cooling, the organic soln was re-
moved under reduced pressure. The crude product was dissolved in
CH2Cl2 (20 mL) and the organic soln was washed with 5% aq
NaHCO3 (3 × 10 mL). The organic phase was dried (anhyd Na2SO4)
and filtered, and the solvent was removed under reduced pressure.
The residue was purified by flash chromatography (PE–EtOAc,
7:3).
IR (Nujol): 2248 cm–1.
1H NMR: δ = 6.62 (t, J = 2.8 Hz, 1.8 Hz, 1 H), 6.09 (t, J = 2.8 Hz, 1
H), 6.00–5.95 (m, 1 H), 4.12 (t, J = 7.0 Hz, 2 H), 2.69 (t, J = 7.0 Hz,
2 H), 2.26 (s, 3 H).
13C NMR: δ = 127.8, 119.5, 117.1, 107.9, 107.5, 41.7, 20.0, 11.5.
5-Chloro-2,3-dihydro-1H-pyrrolizin-1-one (3c)
Following general procedure 1 using 3a gave 3c (0.101 g, 0.65
mmol, 71%) as a yellow solid; mp 76–77 °C; Rf = 0.64 (PE–EtOAc,
1:1).
Anal. Calcd for C8H10N: C, 71.61; H, 7.51; N, 20.88. Found: C,
71.54; H, 7.59; N, 20.95.
IR (Nujol): 1691 cm–1.
5-Methyl-2,3-dihydro-1H-pyrrolizin-1-one (3b) from 2b
A mixture of AlCl3 (18.35 g, 0.138 mol), KCl (3.77 g, 64.45 mmol),
and NaCl (3.83 g, 51.45 mmol) was heated at 130 °C until complete
formation of a brown oily soln. The propanenitrile 2b (5.38 g, 40.84
mmol) was rapidly added and the mixture was vigorous stirred at
this temperature for 10 min. After this time, the hot soln was poured
into ice-H2O (~250 mL) and then the resulting mixture was heated
at 40 °C for 1 h and then at 90 °C for an additional 1 h. The soln was
cooled and extracted with CH2Cl2 (3 × 70 mL). The organic phase
was dried (anhyd Na2SO4) and filtered, and the solvent was re-
moved under reduced pressure. The residue was purified by flash
chromatography (PE–EtOAc, 7:3) to give 3b (1.27 g, 23%) as a
brown solid; mp 55–57 °C; Rf = 0.20 (PE–EtOAc, 85:15).
1H NMR: δ = 6.72 (d, J = 4.2 Hz, 1 H), 6.38 (d, J = 4.2 Hz, 1 H),
4.22 (t, J = 6.2 Hz, 2 H), 3.10 (t, J = 6.2 Hz, 2 H).
13C NMR: δ = 188.2, 131.4, 119.5, 114.6, 108.3, 40.6, 39.0.
Anal. Calcd for C7H6ClNO: C, 54.04; H, 3.89; N, 9.00. Found: C,
53.96; H, 3.95; N, 9.04.
3-Chloro-6,7-dihydroindolizin-8(5H)-one (12a)
Following general procedure 1 using 8a gave 12a (0.111 g, 0.66
mmol, 73%) as a yellow oil; Rf = 0.52 (PE–EtOAc, 7:3).
IR (film): 1653 cm–1.
1H NMR: δ = 7.01 (d, J = 4.2 Hz, 1 H), 6.21 (d, J = 4.2 Hz, 1 H),
4.06 (t, J = 6.2 Hz, 2 H), 2.60 (t, J = 6.2 Hz, 2 H), 2.36–2.22 (m, 2
H).
13C NMR: δ = 187.5, 133.5, 119.0, 115.2, 109.0, 105.2, 42.8, 37.9.
IR (Nujol): 1680 cm–1.
1H NMR: δ = 6.69 (d, J = 4.0 Hz, 1 H), 6.26 (d, J = 4.0 Hz, 1 H),
4.14 (t, J = 6.0 Hz, 2 H), 3.07 (t, J = 6.0 Hz, 2 H), 2.30 (s, 3 H).
13C NMR: δ = 182.9, 149.5, 134.7, 116.7, 110.7, 45.1, 14.1, 11.7.
Anal. Calcd for C8H8ClNO: C, 56.65; H, 4.75; N, 8.26. Found: C,
56.74; H, 4.83; N, 8.20.
Anal. Calcd for C8H9NO: C, 71.09; H, 6.71; N, 10.36. Found: C,
71.16; H, 6.78; N, 10.41.
3-Chloro-5,6,7,8-tetrahydro-9H-pyrrole[1,2-a]azepin-9-one
(12b)
Following general procedure 1 using 8b gave 12b (0.136 g, 0.74
mmol, 81%) as a yellow oil; Rf = 0.54 (PE–EtOAc, 7:3).
IR (film): 1690 cm–1.
1H NMR: δ = 6.98 (d, J = 4.2 Hz, 1 H), 6.16 (d, J = 4.2 Hz, 1 H),
4.27 (t, J = 6.4 Hz, 2 H), 2.75 (t, J = 6.4 Hz, 2 H), 2.20–1.80 (m, 4
H).
13C NMR: δ = 190.7, 134.1, 119.2, 116.0, 109.5, 44.2, 40.1, 39.3,
25.7.
5-Bromo-2,3-dihydro-1H-pyrrolizin-1-one (3d)
NBS (4.57 g, 25.67 mmol) was added portionwise to a soln of 3a
(2.39 g, 19.74 mmol) in THF (79 mL) at –50 °C. After 5 min at –50
°C, the temperature was raised to –10 °C and then the mixture was
stirred at this temperature for 2 h. The solvent was removed under
reduced pressure, the residue was dissolved in CH2Cl2 (100 mL)
and the organic phase was washed with H2O (3 × 50 mL) The or-
ganic phase was dried (anhyd Na2SO4) and filtered, and the solvent
was evaporated under reduced pressure. The residue was purified
by flash chromatography (PE–EtOAc, 7:3) giving 3d (3.95 g, 92%)
as a brownish solid; mp 52–53 °C; Rf = 0.25 (PE–EtOAc, 7:3).
Anal. Calcd for C9H10ClNO: C, 58.86; H, 5.49; N, 7.63. Found: C,
58.93; H, 5.40; N, 7.68.
IR (Nujol): 1687 cm–1.
1H NMR: δ = 6.77 (d, J = 4.2 Hz, 1 H), 6.48 (d, J = 4.2 Hz, 1 H),
4.19 (t, J = 6.2 Hz, 2 H), 3.11 (t, J = 6.2 Hz, 2 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2798–2804

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G. Pinna et al.
PAPER
Claisen Condensation of 3a–c, 8a, 12a,b with Ethyl Oxalate;
General Procedure 2
Anal. Calcd for C12H13NO4: C, 61.27; H, 5.57; N, 5.95. Found: C,
61.34; H, 5.50; N, 5.91.
Na metal (0.09 g, 3.70 mmol) was cautiously added portionwise to
dry EtOH (4.4 mL) under stirring until all the Na had reacted. Ethyl
oxalate (0.60 g, 4.07 mmol) and then the ketone (3.70 mmol) were
added sequentially. The soln was stirred at r.t. for 1 h and then slow-
ly poured into ice. To this cold mixture 2 M HCl soln was added and
the resulting suspension was filtered, and the collected solid was
dried in air.
Ethyl 2-[3-Chloro-8-oxo-5,6-dihydroindolizin-7(8H)-ylidene]-
2-hydroxyacetate (13a)
Following general procedure 2 using 12a gave 13a (0.698 g, 2.59
mmol, 70%) as a yellow solid; mp 77–78 °C; Rf = 0.60 (PE–EtOAc,
7:3).
IR (Nujol): 1728, 1608 cm–1.
1H NMR: δ = 15.81 (s, 1 H), 7.09 (d, J = 4.2 Hz, 1 H), 6.28 (d, J =
4.2 Hz, 1 H), 4.37 (q, J = 7.0 Hz, 2 H), 4.04 (t, J = 6.6 Hz, 2 H), 3.28
(t, J = 6.6 Hz, 2 H), 1.41 (t, J = 7.0 Hz, 3 H).
13C NMR: δ = 179.8, 162.5, 162.4, 127.8, 123.8, 115.7, 110.5,
106.0, 61.9, 41.1, 23.1, 13.8.
Ethyl 2-Hydroxy-2-[1-oxo-1H-pyrrolizin-2(3H)-ylidene]ace-
tate (4a)
Following general procedure 2 using 3a gave 4a (0.703 g, 3.18
mmol, 86%) as a yellow solid; mp 70–71 °C; Rf = 0.56 (PE–EtOAc,
7:3).
IR (Nujol): 1718, 1668, 1631 cm–1.
1H NMR: 12.98 (br s, 1 H), 7.16 (m, 1 H), 6.86 (d, J = 4.2 Hz, 1 H),
6.60–6.55 (m, 1 H), 5.09 (s, 2 H), 4.40 (q, J = 7.0 Hz, 2 H), 1.42 (t,
J = 7.0 Hz, 3 H).
Anal. Calcd for C12H12ClNO4: C, 53.44; H, 4.49; N, 5.19. Found: C,
53.40; H, 4.52; N, 5.16.
Ethyl 2-[3-Chloro-9-oxo-6,7-dihydro-5H-pyrrole[1,2-a]azepin-
8(9H)-ylidene]-2-hydroxyacetate (13b)
Following general procedure 2 using 12b gave 13b (0.807 g, 3.07
mmol, 83%) as a yellow solid; mp 80–82 °C; Rf = 0.64 (PE–EtOAc,
7:3).
13C NMR: δ = 184.0, 162.5, 149.8, 133.4, 123.8, 118.1, 117.5,
109.7, 62.4, 47.0, 14.1.
Anal. Calcd for C11H11NO4: C, 59.73; H, 5.01; N, 6.33. Found: C,
59.79; H, 5.09; N, 6.29.
IR (Nujol): 1812, 1707, 1599 cm–1.
1H NMR: δ = 15.08 (br s, 1 H), 6.96 (d, J = 4.2 Hz, 1 H), 6.22 (d,
J = 4.2 Hz, 1 H), 4.35 (q, J = 7.0 Hz, 2 H), 4.30–4.10 (m, 2 H), 2.80–
2.40 (m, 2 H), 2.20–1.95 (m, 2 H), 1.41 (t, J = 7.0 Hz, 3 H).
13C NMR: δ = 178.7, 160.9, 158.2, 128.8, 118.0, 115.9, 100.6, 57.1,
45.4, 29.7, 25.3, 14.1.
Ethyl 2-Hydroxy-2-[5-methyl-1-oxo-1H-pyrrolizin-2(3H)-yli-
dene]acetate (4b)
Following general procedure 2 using 3b gave 4b (0.625 g, 2.66
mmol, 72%) as a yellow solid; mp 66–68 °C; Rf = 0.14 (PE–EtOAc,
8:2).
IR (Nujol): 1718, 1664, 1631 cm–1.
Anal. Calcd for C13H14ClNO4: C, 55.04; H, 4.97; N, 4.94. Found: C,
55.09; H, 4.91; N, 4.97.
1H NMR (200 MHz, CDCl3): δ = 13.03 (br s, 1 H), 6.82 (d, J = 4.0
Hz, 1 H), 6.31 (d, J = 4.0 Hz, 1 H), 4.91 (s, 2 H), 4.41 (q, J = 7.0 Hz,
2 H), 2.34 (s, 3 H), 1.42 (t, J = 7.0 Hz, 3 H).
13C NMR: δ = 182.9, 162.7, 149.5, 134.7, 132.2, 117.8, 116.7,
110.6, 62.3, 45.1, 14.1, 11.7.
Aza-annulation of 4a–c, 9a, 13a,b with 2,4-Dichlorophenylhy-
drazine; General Procedure 3
A mixture of keto-enol ester (2.26 mmol) and 2,4-dichlorophenyl-
hydrazine hydrochloride (0.57 g, 2.71 mmol) in abs EtOH (14.90
mL) was heated under reflux for 8–48 h. The mixture was allowed
to cool to r.t. and poured into ice-water (100 mL). The precipitate
was filtered and the collected solid was dried. Plug chromatography
of this crude solid (PE–EtOAc, 9:1) gave the pure product as a yel-
low/white solid.
Anal. Calcd for C12H13NO4: C, 61.27; H, 5.57; N, 5.95. Found: C,
61.20; H, 5.61; N, 6.00.
Ethyl 2-[5-Chloro-1-oxo-1H-pyrrolizin-2(3H)-ylidene]-2-hy-
droxyacetate (4c)
Following general procedure 2 using 3c gave 4c (0.756 g, 2.96
mmol, 80%) as a yellow solid; mp 76–77 °C; Rf = 0.28 (PE–EtOAc,
7:3).
Ethyl 1-(2,4-Dichlorophenyl)-1,4-dihydropyrazolo[3,4-a]pyrro-
lizine-3-carboxylate (5a)
Following general procedure 3 using 4a gave 5a (0.703 g, 1.94
mmol, 86%) as a yellow solid; mp 130–131 °C; Rf = 0.41 (PE–EtO-
Ac, 8:2).
IR (Nujol): 1718 1672, 1644 cm–1.
1H NMR: δ = 12.00–13.00 (br s, 1 H), 6.84 (d, J = 3.8 Hz, 1 H), 6.42
(d, J = 3.8 Hz, 1 H), 4.99 (s, 2 H), 4.41 (q, J = 7.0 Hz, 2 H), 1.42 (t,
J = 6.8 Hz, 3 H).
13C NMR: δ = 183.2, 162.3, 150.6, 132.2, 121.1, 118.0, 116.5,
115.4, 110.6, 62.7, 45.8.
IR (Nujol): 1720 cm–1.
1H NMR: δ = 7.60 (d, J = 2.2 Hz, 1 H), 7.55 (s, 1 H), 7.41 (dd, J =
8.4, 2.2 Hz, 1 H), 7.02 (s, 1 H), 6.24 (dd, J = 3.4, 2.8 Hz, 1 H), 5.93
(d, J = 3.4 Hz, 1 H), 4.98 (s, 2 H), 4.45 (q, J = 7.2 Hz, 2 H), 1.43 (t,
J = 6.9 Hz, 3 H).
Anal. Calcd for C11H10ClNO4: C, 51.68; H, 3.94; N, 5.48. Found: C,
51.61; H, 3.87; N, 5.53.
13C NMR: δ = 161.7, 144.8, 135.7, 135.6, 130.8, 130.7, 130.3,
129.2, 127.9, 126.8, 126.5, 119.4, 112.1, 99.6, 61.4, 46.3, 14.3.
Ethyl 2-Hydroxy-2-[8-oxo-5,6-dihydroindolizin-7(8H)-yli-
dene]acetate (9a)
Following general procedure 2 using 8a gave 9a (0.680 g, 2.89
mmol, 78%) as a yellow solid; mp 72–73 °C; Rf = 0.52 (PE–EtOAc,
7:3).
Anal. Calcd for C17H13Cl2N3O2: C, 56.37; H, 3.62; N, 11.60. Found:
C, 56.46; H, 3.64; N, 11.58.
Ethyl 1-(2,4-Dichlorophenyl)-6-methyl-1,4-dihydropyrazo-
lo[3,4-a]pyrrolizine-3-carboxylate (5b)
Following general procedure 3 using 4b gave 5b (0.613 g, 1.63
mmol, 72%) as a yellow solid; mp 160–162 °C; Rf = 0.17 (PE–EtO-
Ac, 9:1).
IR (Nujol): 1713 cm–1.
1H NMR: δ = 7.59 (s, 1 H), 7.56 (d, J = 8.6 Hz, 1 H), 7.40 (d, J =
8.6 Hz, 1 H), 5.94 (d, J = 3.6 Hz, 1 H), 5.89 (d, J = 3.6 Hz, 1 H),
IR (Nujol): 1718, 1606 cm–1.
1H NMR: δ = 15.97 (s, 1 H), 7.11 (d, J = 3.9 Hz, 1 H), 6.95 (d, J =
3.9 Hz, 1 H), 6.34 (dd, J = 1.8, 3.9 Hz, 1 H), 4.37 (q, J = 6.9 Hz, 2
H), 4.09 (t, J = 6.9 Hz, 2 H), 3.27 (t, J = 6.9 Hz, 2 H), 1.41 (t, J =
6.9 Hz, 3 H).
13C NMR: δ = 181.0, 162.9, 162.1, 128.7, 118.0, 116.0, 111.7,
106.8, 62.0, 44.1, 23.9, 14.1.
Synthesis 2012, 44, 2798–2804
© Georg Thieme Verlag Stuttgart · New York

PAPER
Tricyclic Pyrazoles
2803
4.80 (s, 2 H), 4.46 (q, J = 7.0 Hz, 2 H), 2.29 (s, 3 H), 1.44 (t, J = 7.0
IR (Nujol): 1718 cm–1.
Hz, 3 H).
1H NMR: δ = 7.60–7.30 (m, 3 H), 5.90 (d, J = 4.2 Hz, 1 H), 5.36 (d,
J = 4.2 Hz, 1 H), 4.44 (q, J = 7.0 Hz, 2 H), 4.20–4.00 (m, 2 H), 3.40–
3.20 (m, 2 H), 2.27–2.00 (m, 2 H), 1.42 (t, J = 7.0 Hz, 3 H).
13C NMR: δ = 162.9, 142.8, 137.2, 136.5, 136.1, 133.9, 131.0,
130.6, 128.3, 121.6, 119.7, 118.3, 108.9, 107.2, 61.3, 44.9, 27.3,
24.5, 14.7.
13C NMR: δ = 161.7, 145.1, 138.6, 135.7, 135.6, 130.6, 130.2,
129.2, 129.0, 127.9, 126.0, 124.9, 109.6, 99.8, 61.3, 44.3, 14.3,
11.8.
Anal. Calcd for C18H15Cl2N3O2: C, 57.46; H, 4.02; N, 11.17. Found:
C, 57.50; H, 4.00; N, 11.15.
Anal. Calcd for C19H16Cl3N3O2: C, 53.73; H, 3.80; N, 9.89. Found:
C, 53.85; H, 3.83; N, 9.84.
Ethyl 6-Chloro-1-(2,4-dichlorophenyl)-1,4-dihydropyrazo-
lo[3,4-a]pyrrolizine-3-carboxylate (5c)
From 5a using general procedure 1 5c (0.222 g, 0.56 mmol, 62%);
from 4c using general procedure 3 gave 5c (0.626 g, 1.58 mmol,
70%) as a yellow solid; mp 170–171 °C; Rf = 0.26 (PE–EtOAc,
85:15).
Hydrolysis of 5b,c, 11a,b; General Procedure 4
A soln of 0.8 M LiOH (0.58 g, 13.82 mmol) was added dropwise to
a soln of the tricyclic ester (6.91 mmol) in THF (32 mL). The result-
ing mixture was heated under reflux for 3 h and then the solvent was
evaporated under reduce pressure. The residue was dissolved in
H2O (50 mL) and 2 M aq HCl was added until pH 1. The precipitate
was filtered and the collected solid was dried in air.
IR (Nujol): 1718 cm–1.
1H NMR: δ = 7.60 (d, J = 2.2 Hz, 1 H), 7.57 (d, J = 8.6 Hz, 1 H),
7.40 (dd, J = 8.6, 2.2 Hz, 1 H), 6.10 (d, J = 4.0 Hz, 3 H), 5.94 (d, J =
4.0 Hz, 1 H), 4.89 (s, 2 H), 4.46 (q, J = 7.0 Hz, 2 H), 1.44 (t, J = 7.0
Hz, 1 H).
13C NMR: δ = 161.7, 144.9, 138.7, 135.8, 135.6, 130.8, 130.4,
129.2, 128.0, 126.8, 126.5, 119.3, 112.1, 99.6, 61.4, 46.3, 14.4.
1-(2,4-Dichlorophenyl)-6-methyl-1,4-dihydropyrazolo[3,4-
a]pyrrolizine-3-carboxylic Acid (6b)
Following general procedure 4 using 5b gave 6b (2.042 g, 5.87
mmol, 85%) as a yellow solid; mp 253–255 °C; Rf = 0.42 (CHCl3–
MeOH, 9:1).
Anal. Calcd for C17H12Cl3N3O2: C, 51.48; H, 3.05; N, 10.59. Found:
C, 51.55; H, 2.99; N, 10.54.
IR (Nujol): 1701 cm–1.
1H NMR: δ = 13.00–12.50 (br s, 1 H), 7.62 (s, 1 H), 7.56 (d, J = 8.4
Hz, 1 H), 7.42 (d, J = 8.4 Hz, 1 H), 6.00–5.95 (m, 1 H), 5.93–5.90
(m, 1 H), 4.83 (s, 2 H), 2.29 (s, 3 H).
13C NMR: δ = 162.8, 144.4, 138.7, 135.2, 134.8, 129.6, 128.6,
128.4, 127.4, 125.5, 124.3, 108.9, 99.2, 43.8, 11.3.
Ethyl 1-(2,4-Dichlorophenyl)-4,5-dihydro-1H-pyrazolo[4,3-
g]indolizine-3-carboxylate (10a)
Following general procedure 3 using 9a gave 10a (0.587 g, 1.56
mmol, 69%) as a yellow solid; mp 186–187 °C; Rf = 0.44 (PE–EtO-
Ac, 85:15).
IR (Nujol): 1708 cm–1.
Anal. Calcd for C16H11Cl2N3O2: C, 55.19; H, 3.18; N, 12.07. Found:
C, 55.11; H, 3.28; N, 12.08.
1H NMR: δ = 7.60 (s, 1 H), 7.48–7.34 (m, 2 H), 6.76 (m, 1 H), 6.05
(d, J = 4.0 Hz, 1 H), 5.48 (d, J = 4.0 Hz, 1 H), 4.44 (q, J = 6.9 Hz, 2
H), 4.16 (t, J = 6.9 Hz, 2 H), 3.31 (t, J = 6.9 Hz, 2 H), 1.43 (t, J =
6.9 Hz, 3 H).
13C NMR: δ = 162.5, 140.8, 137.1, 136.5, 135.8, 133.6, 130.4,
130.2, 127.9, 122.5, 120.4, 113.8, 108.5, 104.6, 61.0, 44.8, 21.4,
14.4.
6-Chloro-1-(2,4-dichlorophenyl)-1,4-dihydropyrazolo[3,4-
a]pyrrolizine-3-carboxylic Acid (6c)
Following general procedure 4 using 5c gave 6c (2.292 g, 6.22
mmol, 90%) as a yellow solid; mp 262–264 °C; Rf = 0.24 (CHCl3–
MeOH, 9:1).
IR (Nujol): 1708 cm–1.
1H NMR (CDCl3, DMSO-d6): δ = 12.40–11.80 (br s, 1 H), 7.70–
7.50 (m, 3 H), 6.08 (d, J = 3.2 Hz, 1 H), 5.95 (d, J = 3.2 Hz, 1 H),
4.89 (s, 2 H).
13C NMR (CDCl3, DMSO-d6): δ = 162.4, 143.9, 139.0, 135.2,
134.9, 130.2, 129.6, 128.7, 126.6, 126.2, 120.1, 112.8, 111.6, 98.8,
46.2.
Anal. Calcd for C18H15Cl2N3O2: C, 57.46; H, 4.02; N, 11.17. Found:
C, 57.55; H, 4.06; N, 11.14.
Ethyl 7-Chloro-1-(2,4-dichlorophenyl)-4,5-dihydropyrazo-
lo[4,3-g]indolizine-3-carboxylate (11a)
Using 10a and general procedure 1 gave 11a (0.378 g, 0.59 mmol,
65%); using 13a and general procedure 3 gave 11a (0.735 g, 1.79
mmol, 79%) as a yellow solid; mp 186–187 °C; Rf = 0.44 (PE–EtO-
Ac, 85:15).
Anal. Calcd for C15H8Cl3N3O2: C, 48.88; H, 2.19; N, 11.40. Found:
C, 48.99; H, 2.15; N, 11.47.
IR (Nujol): 1704 cm–1.
7-Chloro-1-(2,4-dichlorophenyl)-4,5-dihydropyrazolo[4,3-g]in-
dolizine-3-carboxylic Acid (14a)
Following general procedure 4 using 11a gave 14a (1.691 g, 4.42
mmol, 64%) as a brown solid; mp 239–240 °C; Rf = 0.44 (CHCl3–
MeOH, 9:1).
1H NMR: δ = 7.60 (s, 1 H), 7.44–7.33 (m, 2 H), 5.96 (d, J = 3.9 Hz,
1 H), 5.30 (d, J = 3.9 Hz, 1 H), 4.45 (q, J = 6.9 Hz, 2 H), 4.13 (t, J =
6.9 Hz, 2 H), 3.34 (t, J = 6.9 Hz, 2 H), 1.43 (t, J = 6.9 Hz, 3 H).
13C NMR (50 MHz, CDCl3): δ = 163.5, 140.3, 136.1, 136.0, 135.9,
133.6, 131.4, 130.2, 128.2, 122.6, 121.4, 114.8, 108.7, 104.6, 61.3,
44.3, 22.4, 14.4.
IR (Nujol): 1703 cm–1.
1H NMR (CDCl3, DMSO-d6): δ = 11.20–10.80 (br s, 1 H), 7.72 (s,
1 H). 7.55–7.50 (m, 2 H), 5.96 (d, J = 3.9 Hz, 1 H), 5.41 (d, J = 3.9
Hz, 1 H), 4.13 (t, J = 6.9 Hz, 2 H), 3.32 (t, J = 6.9 Hz, 2 H).
Anal. Calcd for C18H14Cl3N3O2: C, 52.64; H, 3.44; N, 10.23. Found:
C, 52.77; H, 3.46; N, 10.29.
13C NMR (CDCl3, DMSO-d6): δ = 162.6, 143.2, 139.7, 135.7,
134.9, 130.2, 129.8, 127.5, 122.7, 121.4, 120.8, 110.8, 110.4, 107.3,
46.3, 16.9.
Ethyl 8-Chloro-1-(2,4-dichlorophenyl)-1,4,5,6-tetrahydropyr-
azolo[3,4-c]pyrrolo[1,2-a]azepine-3-carboxylate (11b)
Following general procedure 3 using 13b gave 11b (0.479 g, 1.13
mmol, 50%) as a pink solid; mp 108–110 °C. Rf = 0.55 (PE–EtOAc,
8:2).
Anal. Calcd for C16H10Cl3N3O2: C, 50.22; H, 2.63; N, 10.98. Found:
C, 50.34; H, 2.67; N, 11.07.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2798–2804

2804
G. Pinna et al.
PAPER
8-Chloro-1-(2,4-dichlorophenyl)-1,4,5,6-tetrahydropyrazo-
lo[3,4-c]pyrrolo[1,2-a]azepine-3-carboxylic Acid (14b)
Following general procedure 4 using 11b gave 14b (2.520 g, 6.36
mmol, 92%) as a orange solid; mp 112–113 °C; Rf = 0.50 (CHCl3–
MeOH, 9:1).
1H NMR: δ = 7.60–7.30 (m, 4 H), 5.95 (d, J = 3.9 Hz, 1 H), 5.40 (d,
J = 3.9 Hz, 1 H), 4.10 (t, J = 6.9 Hz, 2 H), 3.39 (t, J = 6.9 Hz, 2 H),
2.90–2.70 (m, 4 H), 1.80–1.60 (m, 4 H), 1.60–1.38 (m, 2 H).
13C NMR: δ = 159.5, 142.3, 136.7, 135.7, 133.6, 130.6, 130.4,
128.2, 120.4, 118.9, 113.0, 107.4, 104.3, 57.1, 42.1, 25.4, 23.3,
20.6.
IR (Nujol): 1701 cm–1.
1H NMR (CDCl3, DMSO-d6): δ = 11.80–11.40 (br s, 1 H), 7.81 (s,
1 H), 7.70–7.60 (m, 2 H), 5.97 (d, J = 4.0 Hz, 1 H), 5.29 (d, J = 4.0
Hz, 1 H), 3.80–3.20 (m, 4 H), 2.55–2.45 (m, 2 H).
Anal. Calcd for C21H20Cl3N5O: C, 54.27; H, 4.34; N, 15.07. Found:
C, 54.41; H, 4.31; N, 15.14.
8-Chloro-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1,4,5,6-tet-
rahydropyrazolo[3,4-c]pyrrolo[1,2-a]azepine-3-carboxamide
(15b)
Following general procedure 5 using 14b gave 15b (0.211 g, 0.44
mmol, 44%) as an orange solid; mp 72–73 °C; Rf = 0.18 (PE–EtO-
Ac, 7:3).
13C NMR (CDCl3, DMSO-d6): δ = 166.5, 141.3, 136.3, 135.7,
134.2, 130.5, 130.1, 128.1, 123.2, 118.2, 110.8, 110.2, 107.4, 43.4,
29.6, 19.3.
Anal. Calcd for C17H12Cl3N3O2: C, 51.48; H, 3.05; N, 10.59. Found:
C, 51.59; H, 3.01; N, 10.71.
IR (Nujol): 1651 cm–1.
Amidation of 6b,c, 14a,b; General Procedure 5
EDC (1.2 mmol) and BtOH (1.2 mmol) were added sequentially to
a suspension of the tricyclic acid (1 mmol) in CH2Cl2 (15 mL). After
1 h the suspension became a soln and then 1-aminopiperidine (2
mmol) was added and stirring was continued at r.t. for 12 h. The or-
ganic phase was washed with H2O (3 × 10 mL) and dried (anhyd
Na2SO4), and concentrated under reduced pressure. The residue was
purified by flash chromatography (PE–EtOAc, 7:3).
1H NMR: δ = 7.60–7.30 (m, 4 H), 5.89 (d, J = 4.2 Hz, 1 H), 5.34 (d,
J = 4.2 Hz, 1 H), 4.30–4.05 (m, 2 H), 3.90–3.57 (m, 4 H), 3.02 (t,
J = 7.2 Hz, 2 H), 2.20–2.00 (m, 2 H), 1.90–1.42 (m, 6 H).
13C NMR: δ = 163.2, 146.5, 136.2, 135.9, 133.5, 133.6, 130.7,
130.4, 128.2, 121.8, 117.9, 116.4, 108.4, 106.9, 57.0, 48.4, 44.7,
43.0, 26.8, 22.9.
Anal. Calcd for C22H22Cl3N5O: C, 55.19; H, 4.63; N, 14.63. Found:
C, 55.31; H, 4.61; N, 14.62.
1-(2,4-Dichlorophenyl)-6-methyl-N-(piperidin-1-yl)-1,4-dihy-
dropyrazolo[3,4-a]pyrrolizine-3-carboxamide (7b)
Following general procedure 5 using 6b gave 7b (0.141 g, 0.33
mmol, 33%) as an orange solid; mp 157–158 °C; Rf = 0.21 (PE–
EtOAc, 8:2).
Acknowledgement
Financial support from the University of Sassari is gratefully
acknowledged.
IR (Nujol): 1645 cm–1.
1H NMR: δ = 7.65–7.60 (m, 2 H), 7.55 (d, J = 8.6 Hz, 1 H), 7.42 (d,
J = 8.6 Hz, 1 H), 5.94 (d, J = 3.0 Hz, 1 H), 5.87 (d, J = 3.0 Hz, 1 H),
4.83 (s, 2 H), 2.88 (t, J = 5.0 Hz, 4 H), 2.27 (s, 3 H), 1.80–1.60 (m,
4 H), 1.50–1.35 (m, 2 H).
References
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(2) Devane, W. A.; Dyzarz, F. A. III; Johnson, M. R.; Melvin,
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(7) (a) Rinaldi-Carmona, M.; Barth, F.; Héaulme, M.; Shire, D.;
Calandra, B.; Congy, C.; Martinez, S.; Maruani, J.; Néliat,
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13C NMR: δ = 158.5, 145.2, 135.7, 135.5, 130.6, 129.2, 128.8,
128.0, 125.2, 124.8, 118.1, 109.5, 99.7, 57.1, 44.4, 25.3, 23.2, 11.9.
Anal. Calcd for C21H21Cl2N5O: C, 58.61; H, 4.92; N, 16.27. Found:
C, 58.78; H, 4.95; N, 16.38.
6-Chloro-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1,4-dihy-
dropyrazolo[3,4-a]pyrrolizine-3-carboxamide (7c)
Following general procedure 5 using 6c gave 7c (0.275 g, 0.61
mmol, 61%) as an orange solid; mp 170–172 °C; Rf = 0.21 (PE–
EtOAc, 8:2).
IR (Nujol): 1648 cm–1.
1H NMR: δ = 7.65–7.60 (m, 2 H), 7.53 (d, J = 8.6 Hz, 1 H), 7.42 (d,
J = 8.6 Hz, 1 H), 7.40–7.30 (m, 1 H), 6.08 (d, J = 3.8 Hz, 1 H), 5.92
(d, J = 3.8 Hz, 1 H), 4.91 (s, 2 H), 3.00–2.80 (m, 2 H), 1.80.1.60 (m,
4 H), 1.50–1.30 (m, 2 H).
13C NMR: δ = 160.7, 142.9, 142.7, 135.4, 130.6, 130.3, 130.1,
129.8, 128.4, 128.3, 127.7, 125.8, 115.6, 109.2, 100.5, 47.7, 45.7,
43.8, 26.7, 24.6.
(9) Murineddu, G.; Rulu, S.; Mussinu, J. M.; Loriga, G.; Grella,
G. E.; Caral, M. A. M.; Lazzarl, P.; Pani, L.; Pinna, G. A.
Bioorg. Med. Chem. 2005, 13, 3309.
Anal. Calcd for C20H18Cl3N5O: C, 53.29; H, 4.03; N, 15.54. Found:
C, 53.40; H, 4.00; N, 15.42.
(10) Mussinu, J. M.; Ruiu, S.; Mule, A. C.; Pau, A.; Carai, M. A.
M.; Loriga, G.; Murineddu, G.; Pinna, G. A. Bioorg. Med.
Chem. 2003, 11, 251.
(11) Yang, Z.; Zhang, S. J. Indian Chem. Soc. 2002, 79, 698.
(12) Adams, R.; Miyano, S.; Fleš, D. J. Am. Chem. Soc. 1960, 82,
1466.
7-Chloro-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4,5-dihy-
dropyrazolo[4,3-g]indolizine-3-carboxamide (15a)
Following general procedure 5 using 14a gave 15a (0.278 g, 0.60
mmol, 60%) as an orange solid; mp 165–166 °C; Rf = 0.23 (PE–
EtOAc, 7:3).
IR (Nujol): 1639 cm–1.
(13) Dismore, A.; Mandy, K.; Michael, J. P. Org. Biomol. Chem.
2006, 4, 1032.
(14) Callington, E. W.; Jones, G. J. Chem. Soc. 1969, 1028.
Synthesis 2012, 44, 2798–2804
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