Synthesis of tricyclic condensed rings incorporating the pyrazole or isoxazole moieties bonded to a 4-piperidinyl substituent

Article abstract of DOI:10.3390/molecules18078147

In this paper we report the synthesis of new compounds based on the pyrazole and isoxazole framework fused to a cycloalkene unit, and bearing as a substituent the 1-piperidinyl group as new examples of potential antipsychotic molecules. The general synthesis involves the acylation of a chloro-substituted cyclic ketone with a 1-substituted piperidine-4-carboxylate derivative, followed by heterocyclization of the formed 1,3-dioxo compound with a hydrazine or hydroxylamine.

Full text of DOI:10.3390/molecules18078147

Molecules 2013, 18, 8147-8159; doi:10.3390/molecules18078147
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of Tricyclic Condensed Rings Incorporating
the Pyrazole or Isoxazole Moieties Bonded to a
4-Piperidinyl Substituent
Giansalvo Pinna 1,*, Giovanni Loriga 2, Gérard A. Pinna 1 and Giorgio Chelucci 3
1
Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari,
Italy; E-Mail: pinger@uniss.it
2
C.N.R. Istituto di Farmacologia Traslazionale, UOS Cagliari, Edificio 5, Loc Piscinamanna,
09010 Pula (CA), Italy; E-Mail: giovanni.loriga@ift.cnr.it
3
Dipartimento di Agraria, Università di Sassari, Viale Italia 39, 07100 Sassari, Italy;
E-Mail: chelucci@uniss.it
* Author to whom correspondence should be addressed; E-Mail: pinlab@uniss.it;
Tel.: +39-079-228721; Fax: +39-079-22872.
Received: 3 June 2013; in revised form: 1 July 2013 / Accepted: 2 July 2013 /
Published: 10 July 2013
Abstract: In this paper we report the synthesis of new compounds based on the pyrazole
and isoxazole framework fused to a cycloalkene unit, and bearing as a substituent the
1-piperidinyl group as new examples of potential antipsychotic molecules. The general
synthesis involves the acylation of a chloro-substituted cyclic ketone with a 1-substituted
piperidine-4-carboxylate derivative, followed by heterocyclization of the formed 1,3-dioxo
compound with a hydrazine or hydroxylamine.
Keywords: heterocyclization; hydrazine; hydroxylamine; tricyclic isoxazoles;
tricyclic pyrazoles
1. Introduction
Among the compounds with antipsychotic properties [1] there are the heteropentalenes A–C [2],
characterized by a pyrazole and isoxazole framework bonded to p-chlorophenyl and 4-piperidinyl
substituents (Figure 1). In continuation of our interest in the field of the synthesis of biologically active

Molecules 2013, 18
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compounds [3], we have now devoted our attention to obtain tricyclic compounds E related to the
heteropentalenes A–C as new potential antipsychotic compounds.
A well known strategy to affect the biological activity of organic compounds is to decrease their
conformational flexibility. In fact, it has been proposed that appropriate structural constraints could
restrict a pharmacophoric structural element to a sufficiently small region of conformational space
thereby permitting the ligand to bind to its designated receptor with high affinity and selectivity [4,5].
A way to achieve this goal with heteropentalenes A–C could be to connect the unsubstituted
central carbon of the heteropentalene and the α-carbon of the phenyl group with an alkylidene bridge
(formula D, Figure 1).
In this line, we have developed a practical and extensible method to build compounds with a
tricyclic framework incorporating the pyrazole and isoxazole framework and with the central ring that
can be modulated in size, namely compounds with the general formula E shown in Figure 1. These
new compounds share with A–C the chlorine on the aryl ring and the 4-(1-benzyl)- or
4-(1-phenylethyl)-piperidinyl substituents on the isoxazole and pyrazole moieties (Figure 1).
Figure 1. Leads and target molecules.
Cl
Cl
Cl
Et
Me
Me
HN
O
N
N
N
O
N
N
N
Bn
CH2Bn
CH2Bn
A
B
C
Cl
Cl
bridge
( )
n
n = 1, 2, 3
X
X
Y
X = NH, N, O; Y = N, O
R = Bn, BnCH2
Y
N
R
N
R
D
E
The planned retrosynthesis of the derivatives E is shown in Scheme 1. In this approach, the final
heterocyclization of the 1,3-dioxo compounds F with hydrazine or hydroxylamine is preceded by
acylation of the chloro-substituted cyclic ketones G with the 1-substituted piperidine-4-carboxylate
derivatives H.
Scheme 1. Retrosynthesis approach.
Cl
Cl
heterocyclization
( )
n
( )
n
X
O
N R
Y
N
R
O
E
F
n
( )
R1O
O
acylation
+
R
N
Cl
O
H
G

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2. Results and Discussion
To begin the synthesis of the target derivatives E (Scheme 1), the known cyclic ketones 1a–c [6,7]
were acylated by reaction of the corresponding sodium enolate, obtained by reaction with sodium
hydride, with the reagent formed by reaction of the N-Boc protected isonipecotic acid 9 with
1,1′-carbonyldiimidazole [8] (Scheme 2). In this way, 1,3-dicarbonyl derivatives 2a–c were obtained in
62–63% yields. Next, these compounds were submitted to N-deprotection by treatment with
trifluoroacetic acid in CH2Cl2. However, while 2b and 2c were easily deprotected giving compounds
3b and 3c in high yields (92–95%), the removal of the N-Boc group from 2a failed. Further attempts to
deprotect 2a with HCOOH, 3N HCl in AcOEt, CF3COOH and Et3SiH, and SnCl4 in AcOEt all failed
unexpectedly, therefore, alternative approaches to the target compounds 6a, 7a and 8a were
investigated next (see below).
Compounds 3b,c were converted in 59–72% yields into the related N-benzyl and N-phenylethyl
derivatives 4b,c and 5b,c by reaction with benzyl chloride and 2-phenyl-1-iodoethane, respectively.
With the key 1,3-dicarbonyl derivatives 4b,c and 5b,c in hand, their conversion into the desired
derivatives E was pursued according to the planned retrosynthetic scheme. Compounds 4b,c and
hydrazine in methanol were stirred at room temperature to afford the pyrazole derivatives 6b and 6c in
good yields (78% and 50%, respectively). Treatment of 5b,c with hydroxylamine hydrochloride in
EtOH/AcOH at 80 °C gave isoxazoles 7b,c and 8b,c as mixtures of regioisomers in moderate to good
yields. With 5b isoxazoles 7b and 8b were obtained in a 4/1 ratio, while 5c gave isoxazoles 7c and 8c
in a 3.2/1 ratio [9].
Scheme 2. Synthesis of compounds 6b, 6c, 7b, 7c, 8b and 8c.
Cl
Cl
n
( )
a
b
( )
( )
n
Cl
n
O
O
O
N
Boc
NH
1a-c
O
O
n
1 2 3
2a (66%), 2b (63%), 2c (62%)
3a (0%), 3b (>95%), 3c (92%)
a b c
Cl
Cl
Cl
c
R = BnCH2
+
( )
( )
( )
n
n
n
e
O
N
R
N
O
O
N
O
N
N
CH2Bn
8b (5%), 8c (12%)
7b/8b = 4/1
7c/8c = 3/1
CH2Bn
R = Bn
4b: R = Bn (59%)
7b (20%), 7c (35%)
d
5b: R = BnCH2 (70%)
4c: R = Bn (72%)
Cl
5c: R = BnCH2 (62%)
( )
n
HO
O
Boc
N
HN
N
N
9
Bn
6b (78%), 6c (50%)
Reagents and conditions: (a) (i) NaH, DMF, rt; (ii) 9, 1,1'-carbonyldiimidazole, DMF, rt,
45 min; (iii) 120 °C, 6 h; (b) CF3COOH, CH2Cl2, rt, 2 h; (c) BnCl or BnCH2I. DMF,
i-Pr2NEt, 25–60 °C, 12h; (d) H2N-NH2, MeOH, rt, 12 h; (e) NH2OH, EtOH, AcOH, 80 °C,
12 h.

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To obtain compound 6a the synthetic routes outlined in Scheme 3 were followed. Firstly, the
sodium enolate of the ketone 1a was reacted with phenyl 1-benzylpiperidine-4-carboxylate 12, but the
1,3-dicarbonyl intermediate 4a failed to give the expected pyrazole 6a by treatment with hydrazine in
AcOH/MeOH at 80 °C. However, when the same enolate was treated with phenyl 1-(phenylcarbonyl)-
piperidine-4-carboxylate 13 [10], obtained by esterification with phenol of the parent acid (Scheme 5),
the formed 1,3-dicarbonyl 10b afforded by treatment with hydrazine in AcOH/MeOH at 80 °C the
substituted pyrazole 11 in 82% yield. Finally, LiAlH4 reduction of the carbonyl group to the methylene
unit afforded the target pyrazole 6a in 80% yield (66% overall yield from 1a).
This satisfactory result appeared to open a way to isoxazoles 7a and 8a by simple replacing of
the piperidine derivative 13 with the analogue 16 (Scheme 4). However, the treatment of the
1,3-dicarbonyl intermediate 14, obtained in turn by reaction of 1a with 16, with hydroxylamine
hydrochloride in EtOH/AcOH at 80 °C failed to afford the expected isoxazoles 15. This unexpected
result prompted us to verify another route based on the on the use of the N-benzylpyperidine 17 that
was obtained by esterification with phenol of the parent acid (Scheme 5). We were pleased to find that
the1,3-dicarbonyl intermediate 5a, formed by reaction of the enolate of the ketone 1a with 17, could be
directly converted in the usual way into a mixture of isoxazoles 7a and 8a in 41% and 12% yield,
respectively (Scheme 4).
Scheme 3. Synthesis of compound 6a.
Cl
a
R = Bn
d
Cl
b or c
O
O
N R
1a
O
4a,10b
Cl
Cl
R = COPh
d
e
HN
HN
N
N
Ph
N
N
Bn
O
6a (80%)
PhO
11 (82%)
Ph
O
PhO
a: R = Bn; b: R = COPh
N Bn
N
O
O
12
13
Reagents and conditions: (a) (i) NaH, benzene, rt, (b) 12, reflux, 3.5 h; (c) 13, reflux, 3.5 h;
(d) H2N-NH2, AcOH, EtOH, 80 °C, 4 h; (e) LiAlH4, THF, rt, 12 h.

Molecules 2013, 18
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Scheme 4. Synthesis of compounds 7a and 8a.
Cl
Cl
a
b
Cl
O
Bn
O
X
O
Y
Bn
N
1a
N
O
O
15 (X = N, O
c
14
Y = N, O)
Cl
Cl
Cl
d
+
N
O
O
N
CH2Bn
O
N
N
N
CH2Bn
CH2Bn
O
5a
7a (12%)
8a (41%)
Bn
O
PhO
O
PhO
O
N
N CH2Bn
16
17
Reagents and conditions: (a) (i) NaH, benzene, rt, (ii) 16, reflux; (b) NH2OH, AcOH,
EtOH, 80 °C; (c) (i) NaH, benzene, rt, (ii) 17, reflux, 4 h; (b) NH2OH, AcOH, EtOH,
80 °C, 7 h.
Scheme 5. Synthesis of compounds 13 and 17.
HO
O
PhO
O
a
N R
N R
18: R = COPh
19: R = CH2CH2Ph
13: R = COPh (62%)
17: R = CH2CH2Ph (64%)
Reagents and conditions: (a) PhOH, EDC, DMAP, CH2Cl2, 40 °C, 14 h.
3. Experimental
3.1. General
All reagents and solvents were purchased from commercial suppliers and used as received. Low
boiling petroleum ether corresponds to the fraction collected between 40 and 60 °C. THF was distilled
from sodium-benzophenone ketyl and degassed thoroughly with dry nitrogen directly before use.
Melting points were determined on a Büchi 510 capillary apparatus and are uncorrected. IR spectra
were recorded on a J ASCO FT/IR-460 plus equipment.The NMR spectra were obtained with a Varian
1
13
VXR-300 spectrometer at 200 MHz for H and 50 MHz for C. Chemical shifts are reported in ppm
downfield from internal Me4Si in CDCl3. The following abbreviations were used to describe peak
patterns where appropriate: singlet (s), doublet (d), triplet (t), multiplet (m) and broad resonances (br).
Elemental analyses were performed on a Perkin-Elmer 240 B analyser. TLC was performed on Merck
silica gel 60 TLC plates F254 and visualized using UV or phosphomolibdic acid. Flash
chromatography was carried out on silica gel (40–60 mesh). The chloroketone 1a was a commercial
compound. 6-Chloro-3,4-dihydronaphthalen-1-one (1b) [6], 7-chloro-2,3,4,5-tetrahydrobenzocyclo-

Molecules 2013, 18
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heptan-1-one (1c) [7], N-Boc-nipecotic acid [8] and the piperidines 18 [10] and 19 [11] were obtained
following the corresponding literature procedures.
3.2. General Procedure for the Synthesis of the Compounds 2a–2c
A solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (9, 2.85 g, 12.45 mmol) and
1,1′-carbonyldiimidazole (2.29 g, 14.11 mmol) in DMF (3 mL) was stirred at room temperature for 45
min. This solution was added dropwise to a solution prepared by stirring for 20 min the suitable ketone
1a, 1b or 1c (7.64 mmol) with NaH (60% in oil, 0.93 g, 23.20 mmol) in DMF (20 mL). The resulting
mixture was heated for the appropriate time. After cooling, H2O was added and the mixture was
extracted with Et2O (3 × 30 mL). The organic phase was dried over Na2SO4, filtered and the solvent
was removed under reduced pressure. The residue was purified by flash chromatography.
tert-Butyl
4-(5-chloro-1-oxo-2,3-dihydro-1H-indene-2-carbonyl)piperidine-1-carboxylate
(2a).
According to the general procedure, the reaction between 1a and 9 was carried out at 30 °C for 7 h.
The residue was purified by flash chromatography (petroleum ether/EtOAc = 9:1) affording 2a: yield
1
66%; red solid; Mp 102–103 °C. Rf = 0.10 (petroleum ether/AcOEt = 9:1). H-NMR: δ 1.48 (s, 9H),
1.60–1.95 (m, 4H), 2.40–2.64 (m, 1H), 2.64–2.98 (m, 2H), 3.62 (s, 2H), 4.13–4.33 (m, 2H), 7.40 (d,
1H, J = 8.0 Hz), 7.48 (s, 1H), 7.74 (d, 1H, J = 8.0 Hz), 13.80 (brs, 1H). 13C-NMR: δ 27.9 (CH2), 28.4
(3 × CH3), 29.8 (2 × CH2), 41.8 (CH), 43.4 (2 × CH2), 79.7 (C), 108.8 (C), 124.2 (CH), 126.0 (CH),
128.1 (CH), 136.7 (C), 139.1 (C), 148.6 (C), 154.7(CO), 182.7 (CO), 191.3 (COH). IR: (nujol) ν 1703
(CO), 1655 (CO), 1605 (CO) cm−1. Anal. Calcd for C20H24ClNO4: C, 63.57; H, 6.40; N, 3.71. Found:
C, 63.65; H, 6.49; N, 3.81.
tert-Butyl 4-(6-chloro-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carbonyl)piperidine-1-carboxylate (2b).
According to the general procedure, the reaction between 1b and 9 was carried out at 110 °C for 7 h.
The residue was purified by flash chromatography (petroleum ether/EtOAc = 8:2) affording 2b: yield
1
63%; red solid; Mp 120–121 °C. Rf = 0.43 (petroleum ether/AcOEt = 8:2). H-NMR: δ 1.47 (s, 9H),
1.59–1.87 (m, 5H), 2,67 (d, 2H, J = 7.4 Hz), 2.80–2.88 (m, 4H), 4.18 (d, 2H, J = 7.4 Hz), 7.24 (d, 1H,
J = 10.2 Hz), 7.31 (s, 1H), 7.87 (d, 1H, J = 8.2 Hz), 16.65 (s, 1H). 13C-NMR: δ 21.9 (CH2), 27.8
(CH2), 28.4 (3 × CH3), 29.3 (2 × CH2), 41.4 (CH), 43.3 (2 × CH2), 79.6 (C), 104.6 (C), 126.2 (CH),
127.2 (CH), 127.3 (CH), 127.5 (C), 136.7 (C), 142.2 (C), 157.3 (CO), 179.0 (CO), 197.8 (COH). IR:
(nujol) ν 1707 (CO), 1650 (CO), 1611 (CO) cm−1. Anal. Calcd for C21H26ClNO4: C, 64.36; H, 6.69;
N, 3.57. Found: C, 64.88; H, 6.65; N, 3.59.
tert-Butyl
4-(2-chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-carbonyl)piperidine-1-
carboxylate (2c). According to the general procedure the reaction between 1c and 9 was carried out at
70 °C for 7 h. The residue was purified by flash chromatography (petroleum ether/EtOAc = 9:1)
affording 2c: yield 63%; yellow solid; Mp 134–136 °C. Rf = 0.31 (petroleum ether/AcOEt = 9:1).
1H-NMR: δ 1.48 (s, 9H), 1.53–1.92 (m, 7H), 1.92–2.13 (m, 1H), 2.18 (t, 2H, J = 6.8 Hz), 2.55–2.90
(m, 3H), 4.10–4.31 (m, 2H), 7.21 (s, 1H), 7.27–7.42 (m, 1H), 7.57 (d, 1H, J = 8.2 Hz), 16.78 (s, 1H).
13C-NMR: δ 22.7 (CH2), 28.3 (3 × CH2), 28.5 (CH3), 31.1 (CH2), 31.3 (2 × CH2), 40.9 (CH), 43.2
(2 × CH2), 79.5 (C), 108.2 (C), 126.8 (CH), 128.7 (CH), 129.0 (CH), 131.0 (C), 136.4 (C), 141.4 (C),

Molecules 2013, 18
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154.5 (CO), 186.2 (CO), 194.4 (COH). IR: (nujol) ν 1706 (CO), 1652 (CO), 1613 (CO) cm−1. Anal.
Calcd for C22H28ClNO4: C, 65.10; H, 6.95; N, 3.45. Found: C, 66.08; H, 6.98; N, 3.42.
3.3. General Procedure for the Synthesis of Compounds 3b, 3c
A solution of CF3COOH (1.46 g, 12.8 mmol) in CH2Cl2 (4.6 mL) was added dropwise to a solution
of the 1,3-dicarbonyl compound 2b or 2c (1.28 mmol) in CH2Cl2 (9.2 mL). After stirring 2 h at room
temperature, CH2Cl2 was added. The resulting mixture was washed two times with a 10% solution of
K2CO3 and then with H2O. The organic phase was dried over Na2SO4, filtered and the solvent was
removed under reduced pressure. The residue was purified by flash chromatography.
6-Chloro-2-(piperidine-4-carbonyl)-3,4-dihydronaphthalen-1(2H)-one (3b). Compound 2b was
converted into the title product 3b according to the general procedure. The residue was purified by
flash chromatography (CHCl3/MeOH = 8:2) affording 3b: yield 63%; yellow solid; Mp 150–154 °C.
1
Rf = 0,10 (CHCl3/MeOH 8:2); H-NMR: δ 2.62–2.85 (m, 4H), 2.58–2.77 (m, 4H), 2.80–2.95 (m, 4H),
3.10-3.34 (m, 2H), 7.21 (s, 1H), 7.32 (d, 1H, J = 8.2 Hz), 7.86 (d, 1H, J = 8.2 Hz), 8.52–9.20 (brs, 1H).
13C-NMR: δ 21.9 (CH2), 27.5 (CH2), 31.3 (2 × CH2), 42.0 (CH), 45.1 (2 × CH2), 109.2 (C), 126.3
(CH), 127.4 (CH), 129.1 (CH), 137.0 (C), 137.2 (C), 144.5(C), 189.0 (CO), 192.4 (COH) IR: (nujol) ν
3453 (NH), 1701 (CO), 1680 (CO) cm−1. Anal. Calcd for C16H18ClNO2: C, 65.86; H, 6.22; N, 4.80.
Found: C, 65.56; H, 6.26; N, 4.83.
2-Chloro-6-(piperidine-4-carbonyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (3c). Compound 2c
was converted into the title product 3c according to the general procedure. The residue was purified by
flash chromatography (CHCl3/MeOH = 8:2) affording 3c: yield 63%; white solid; Mp 138–142 °C.
1
Rf = 0,11 (CHCl3/MeOH = 8:2); H-NMR: δ 1.60–1.92 (m, 4H), 1.92–2.10 (m, 2H), 2.18 (t, 2H,
J = 6.2 Hz), 2.58–2.85 (m, 5H), 2.90–2.98 (m, 1H), 3.12–3.28 (m, 2H), 7.21 (s, 1H), 7.33 (d, 1H,
13
J = 8.0 Hz), 7.56 (d, 1H, J = 8.0 Hz), 8.00–9.00 (brs, 1H). C-NMR: δ 22.8 (CH2), 28.7 (CH2), 31.1
(2 × CH2), 31.5 (CH), 40.6 (CH2), 45.1 (2 × CH2), 108.2 (C), 126.8 (CH), 128.7 (CH), 129.0 (CH),
136.0 (C), 136.8 (C), 141.5 (C), 188.0 (CO), 194.4 (COH). IR: (nujol) ν 3,430 (NH), 1,703 (CO),
1,680 (CO) cm−1. Anal. Calcd for C17H20ClNO2: C, 66.77; H, 6.59; N, 4.58. Found: C, 67.37; H, 6.64;
N, 4.53.
3.4. General Procedure for the Synthesis of the Compounds 4b, 4c and 5b, 5c
To a solution of the 1,3-dicarbonyl compound 3b or 3c (3.27 mmol) in DMF (18.25 mL) was added
i-Pr2NEt (0.59 g, 4.58 mmol) and then the appropriate halide (1.1 eq). The mixture was then stirred at
room temperature or heated under reflux for the necessary time. Water was added and the mixture was
extracted with AcOEt. The organic phase was washed with brine, dried over Na2SO4, filtered and the
solvent was removed under reduced pressure. The residue was purified by flash chromatography.
2-(1-Benzylpiperidine-4-carbonyl)-6-chloro-3,4-dihydronaphthalen-1(2H)-one (4b). A solution of the
ketone 3b and benzyl chloride in DMF was stirred at room temperature for 12 h. After workup the
residue was purified by flash chromatography (petroleum ether/EtOAc = 1:1) affording 4b: yield 59%;
1
brown oil; Rf = 0.46 (petroleum ether/EtOAc = 1:1); H-NMR: δ 1.51–1.80 (m, 4H), 1.90 (d, 2H,

Molecules 2013, 18
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J = 11 Hz), 2.03 (d, 2H, J = 13.2 Hz), 2.58–2.76 (m, 1H), 2.84 (t, 2H, J = 7.4 Hz), 3.00 (d, 2H, J = 9.6 Hz),
3.55 (s, 2H), 7.20 (s, 1H), 7.29–7.40 (m, 6H), 7.86 (d, 1H, J = 8.6 Hz), 16.68 (s, 1H). 13C-NMR: δ 22.8
(CH2) , 28.6 (CH2), 32.1 (2 × CH2), 33.5 (CH), 45.1 (2 × CH2), 64.5 (CH2), 118.4 (C), 126.7 (CH),
126.9 (CH), 127.5 (CH), 128.3 (2 × CH), 128.6 (CH), 128.9 (CH), 129.1 (C), 129.3 (CH), 131.2 (C),
139.6 (C), 142.3 (C), 184.9 (CO), 195.3 (COH) IR: (nujol) ν 1,710 (CO), 1,682 (CO) cm−1. Anal.
Calcd for C23H24ClNO2: C, 72.34; H, 6.33; N, 3.67. Found: C, 72.41; H, 6.38; N, 3.75.
6-(1-Benzylpiperidine-4-carbonyl)-2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (4c).
A
solution of the ketone 3c and benzyl chloride in DMF was stirred at room temperature for 12 h. After
workup, the residue was purified by flash chromatography (petroleum ether/EtOAc = 1:1) affording
1
4c: yield 72%; brown oil; Rf = 0.37 (petroleum ether/EtOAc = 1:1); H-NMR: δ 1.61–2.24 (m, 8H),
2.53–2.76 (m, 2H), 2.76–3.11 (m, 5H), 3.54 (s, 2H), 7.00–7.48 (m, 6H), 7.55 (d, 1H, J = 8.2 Hz), 8.00
(s, 1H), 16.8 (s, 1H). 13C-NMR: δ 22.9 (CH2), 28.5 (CH2), 31.0 (2 × CH2), 31.4 (CH2), 31,6 (CH), 52.8
(2 × CH2), 62.9 (CH2), 108.4 (C), 126.6 (CH), 126.8 (CH), 127.2 (CH), 127.5 (CH), 128.0 (CH), 128.3
(2 × CH), 128.7 (CH), 129.3 (C), 131.0 (C), 139.6 (C), 145.1 (C), 194.9 (CO), 195.3 (COH). Anal. IR:
(nujol) ν 1,705 (CO), 1,682 (CO) cm−1. Calcd for C24H26ClNO2: C, 72.81; H, 6.62; N, 3.54. Found: C,
72.21; H, 6.65; N, 3.57.
6-Chloro-2-(1-phenethylpiperidine-4-carbonyl)-3,4-dihydronaphthalen-1(2H)-one (5b). A solution of
the ketone 3b and phenylethyl iodide in DMF was heated at 60 °C for 12 h. After workup, the residue
was purified by flash chromatography (petroleum ether/EtOAc = 2:8) affording 5b: yield 70%; brown
1
oil; Rf = 0.42 (petroleum ether/EtOAc = 1:1); H-NMR: δ 1.26–2.53 (m, 11H), 2.54–2.75 (m, 2H),
2.75–2.99 (m, 2H), 3.04–3.23 (m, 2H), 7.08–7.45 (m, 6H), 7.49 (m, 1H), 7.71 (d, 1H, J = 9.0 Hz),
14,27 (s, 1H). 13C-NMR: δ 22.8 (CH2), 28.7 (CH2), 32.1 (CH2), 32.6 (2 × CH2), 33.5 (CH), 45.3 (2 × CH2),
64.5 (CH2) , 117.9 (C), 126.6 (CH), 128.3 (CH), 128.8 (CH), 128.9 (2 × CH), 129.1 (2 × CH), 129.2
(CH), 131.2 (C), 139.6 (C), 141.5 (C), 142.3 (C), 194.9 (CO), 195.3 (COH) Anal. IR: (nujol) ν 1,700
(CO), 1,681 (CO) cm−1. Calcd for C24H26ClNO2: C, 72.81; H, 6.62; N, 3.54. Found: C, 72.11; H, 6.66;
N, 3.58.
2-Chloro-6-(1-phenethylpiperidine-4-carbonyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (5c). A
solution of the ketone 3c and phenylethyl iodide in DMF was heated at 60 °C for 12 h. After workup,
the residue was purified by flash chromatography (CHCl3/acetone = 9:1) affording 5c: yield 62%;
1
brown oil; Rf = 0.33 (CHCl3/acetone = 9:1); H-NMR: δ 1.72–1.89 (m, 3H), 1.95–2.28 (m, 7H),
2.53–2.92 (m, 7H), 3.12 (d, 2H, J = 9.6), 7.20 (s, 1H), 7.23–7.25 (m, 6H), 7.56 (d, 1H, J = 8.4 Hz),
16.7 (s, 1H). 13C-NMR: δ 22.8 (CH2), 28.8 (CH2), 31.2 (CH2), 31.7 (2 × CH2), 33.5 (CH2), 41.0 (CH),
53.2 (2 × CH2), 60.7 (CH2), 108.3 (CH), 126.0 (CH), 126.6 (CH), 126.8 (CH), 127.5 (2 × CH), 128.3
(CH), 128.6 (2 × CH), 128.7 (C), 129.1 (C), 131.0 (C), 141.5 (C), 187.9 (CO), 195.3 (COH). IR:
(nujol) ν 1,699 (CO), 1,676 (CO) cm−1. Anal. Calcd for C25H28ClNO2: C, 73.25; H, 6.88; N, 3.42.
Found: C, 73.76; H, 6.84; N, 3.46.

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3.5. General Procedure for the Synthesis of Compounds 6b, 6c
A solution of the 1,3-dicarbonyl compound 4b or 4c (0,68 mmol) and hydrazine hydrate (0.32 g,
6,39 mmol) in MeOH (9 mL) was stirred overnight at room temperature. Water was added and the
mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na2SO4, filtered and
the solvent was removed under reduced pressure. The residue was purified by flash chromatography.
3-(1-Benzylpiperidin-4-yl)-7-chloro-4,5-dihydro-1H-benzo[g]indazole (6b). Compound 4b was
converted into the title product 6b according to the general procedure. After workup, the residue was
purified by flash chromatography (CHCl3/acetone = 9:1) affording 6b: yield 78%; yellow solid; Mp
1
173–174 °C; Rf = 0.51 (CH2Cl2/MeOH = 95:5); H-NMR: δ 1.80–2.27 (m, 6H), 2.71–2.82 (m, 3H),
2.91 (t, 2H, J = 7.2 Hz), 3.01 (t, 2H, J = 7.2 Hz), 3.56 (s, 2H), 7.20–7.40 (m, 7H), 7.64–7.71 (m, 1H).
13C-NMR: δ 18.9 (CH2), 29.6 (CH2), 31.3 (2 × CH2), 33.7 (CH), 53.6 (2 × CH2), 63.3 (CH2), 111.2 (C)
123.2 (CH), 126.9 (CH), 127.1 (CH), 127.4 (CH), 127.5 (C), 128.2 (2 × CH), 129.2 (2 × CH), 132.7
(C), 137.8 (C), 138.3 (C). 142.3 (CN), 142.8 (CN). Anal. Calcd for C23H24ClN3: C, 73.10; H, 6.40; N,
11.12. Found: C, 73.91; H, 6.43; N, 11.07.
3-(1-Benzylpiperidin-4-yl)-8-chloro-1,4,5,6-tetrahydrobenzo[3,4]cycloepta[2,1-c]pyrazole
(6c).
Compound 4c was converted into the title product 6c according to the general procedure. After
elaboration, the residue was purified by flash chromatography (CHCl3/acetone = 9:1) affording 6c:
1
yield 50%; yellow solid; Mp 165–166 °C; Rf = 0.51 (CH2Cl2/MeOH = 95:5); H-NMR: δ 1.68–2.32
(m, 8H), 2.51–2.90 (m, 5H), 3.04 (d, 2H, J = 9.8 Hz), 3.59 (s, 2H), 7.10–7.42 (m, 7H), 7.60–7.72
(m, 1H), 9.10–10,01 (brs, 1H). 13C-NMR: δ 24.1 (CH2), 26.9 (CH2), 29.7 (CH2), 31.0 (2 × CH2), 34.8
(CH), 53.8 (2 × CH2), 63.2 (CH2), 112.5 (C), 125.7 (CH), 126.4 (CH), 127.1 (CH), 127.4 (CH), 127.5
(2 × CH), 128.2 (2 × CH), 129.3 (2 × C), 129.6 (C), 134.5 (C) 141.3 (CN, 142.8 (CN). Anal. Calcd for
C24H26ClN3: C, 73.55; H, 6.69; N, 10.72 Found: C, 73.25; H, 6.88; N, 10.42.
3.6. 1H-1-Oxa-2-aza-7-chloro-3-(1-phenethylpiperidin-4-yl)-4,5-dihydronaphto[2,1-d]isoxazole (7b)
and 1H-1-oxa-2-aza-8-chloro-3-(1-phenethylpiperidin-4-yl)-5,6-dihydro-4H-benzo[3,4]cycloepta[1,2-
d]isoxazole (7c)
A solution of the 1,3-dicarbonyl compound 5b or 5c (2.44 mmol) and hydroxylamine hydrochloride
(1.02 g, 14.64 mmol) in EtOH (12.2 mL) containing 4 drops of AcOH was heated under reflux
for 24 h. Water was added and the mixture was extracted with CHCl3. The organic phase was dried
over Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified
by flash chromatography (CHCl3/MeOH = 97:3) to give 7b or 7c.
Compound 7b. Yield 20%; brown solid; Mp 170–172 °C; Rf = 0.11 (CHCl3/MeOH = 97:3); 1H-NMR
(DMSO-d6): δ 1.50–1.80 (m, 9H), 1.42–2.10 (m, 4H), 2.48 (t, 2H, J = 7.0 Hz), 2.69 (t, 2H, J = 7.0 Hz),
7.12–7.42 (m, 8H). 13C-NMR: δ 28.4 (CH2), 29.5 (CH2), 32.7 (CH2), 38.2 (2 × CH2), 40.7 (CH), 52.7
(2 × CH2), 59.7 (CH2), 117.8 (C), 125.0 (CH), 125.4 (CH), 125.8 (CH), 126.5 (CH), 127.9 (2 × CH),
128.2 (2 × CH), 128.6 (C), 130.9 (C), 136.4 (C), 144.1 (C), 157.3 (CN), 166.1 (CO). Anal. Calcd for
C24H25ClN2O: C, 73.36; H, 6.41; N, 7.13. Found: C, 73.96; H, 6.44; N, 7.10.

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1
Compound 7c. yield 35%; brown solid; Mp 114–117 °C; Rf = 0.24 (CHCl3/MeOH = 8:2); H-NMR
(DMSO-d6): δ 1.82–2.10 (m, 4H), 2.11–2.33 (m, 4H), 2.60–2.76 (m, 5H), 2.70–2.98 (m, 4H),
3.10–3.21 (m, 2H), 7.12–7.20 (m, 7H), 7.88 (d, 1H, J = 8.2 Hz). 13C-NMR: δ 23.9 (CH2), 24.5 (CH2),
29.8 (2 x CH2), 33.6 (CH2), 35.2 (CH), 53.5 (2 x CH2), 60.7 (CH2), 113.8 (C), 126.1 (CH), 126.7 (CH),
128.1 (CH), 128.2 (CH), 128.3 (2 x CH), 128.6 (2 x CH), 129.6 (C), 134.7 (C), 141.5 (C), 142.1 (C),
161.2 (CN), 166.6 (CO) Anal. Calcd for C25H27ClN2O: C, 73.79; H, 6.69; N, 6.88. Found: C, 73.25; H,
6.71; N, 6.91.
3.7. 2H-1-Aza-2-oxa-7-chloro-3-(1-phenethylpiperidin-4-yl)-4,5-dihydronaphto[1,2-c]isoxazole (8b)
and 2H-1-aza-2-oxa-8-chloro-3-(1-phenethylpiperidin-4-yl)-5,6-dihydro-4H-benzo[3,4]cycloepta[2,1-
c]isoxazole (8c)
A solution of the 1,3-dicarbonyl compound 5b or 5c (2.44 mmol) and hydroxylamine hydrochloride
(1.02 g, 14.64 mmol) in EtOH (12.2 mL) containing 15 drops of AcOH was heated under reflux
for 24 h. After cooling, H2O was added and the mixture was extracted with CHCl3. The organic phase
was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was
purified by flash chromatography (CHCl3/acetone = 8:2) to give 8b or 8c.
1
Compound 8b. Yield 5%; brown solid; Mp 165–166 °C; Rf = 0.24 (CHCl3/acetone = 97:3); H-NMR
(CDCl3/DMSO-d6): δ 1.43–1.70 (m, 4H), 1.71–1.93 (m, 4H), 1.95–2.10 (m, 1H), 2.42–2.65 (m, 4H),
2.52 (t, 2H, J = 7.2 Hz), 2.65 (t, 2H, J = 7.2 Hz), 7.05–7.38 (m, 5H), 7.42–7.84 (m, 2H), 8.32 (d, 1H,
J = 9.2 Hz). 13C-NMR (CDCl3/DMSO-d6): δ 28.3 (CH2), 29.5 (CH2), 32.6 (CH2), 38.2 (2 × CH2), 40.7
(CH), 53.1 (2 × CH2), 59.8 (CH2), 118.0 (C), 120.2 (CH), 124.1 (CH), 125.4 (CH), 125.0 (CH), 125.8
(2 × CH), 127.9 (2 × CH), 128.6 (C), 131.2 (C), 134.8 (C), 140.3 (C), 161.2 (CN), 167.9 (CO).
Anal. Calcd for C24H25ClN2O: C, 73.36; H, 6.41; N. 7.13. Found: C, 72.86; H, 6.44; N. 7.01.
Compound 8c. Yield 12%; light brown solid; Mp 125–126 °C; Rf = 0.47 (CHCl3/acetone = 8:2);
1H-NMR: δ 1.95–2.38 (m, 8H), 2.52–2.78 (m, 5H) 2.78–3.01 (m, 4H), 3.15 (d, 2H, J = 9.6 Hz),
13
7.08–7.40 (m, 7H), 7.89 (d, 1H, J = 8.4 Hz). C-NMR: δ 20.7 (CH2), 27.0 (CH2), 29.2 (CH2), 33.0
(2 × CH2), 33.2, (CH2), 39.3 (CH), 53.1 (2 × CH2), 60.4 (CH2), 111.2 (C), 126.3 (CH), 126.7 (CH),
126.8 (CH), 127.8 (CH), 128.5 (2 × CH), 128.7 (2 × CH2), 129.2 (C), 129.7 (C), 135.2 (C), 142.7 (C),
161.8 (CN), 170.4 (CO). Anal. Calcd for C25H27ClN2O: C, 73.79; H, 6.69; N, 6.88. Found: C, 73.19; H,
6.62; N, 6.83.
(4-(6-Chloro-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)piperidin-1-yl)(phenyl)metanone (11). 5-Chloro-
2,3-dihydro-1H-inden-1-one 1a (0.2 g, 1.23 mmol) and NaH (60% in oil, 0.12 g, 3.08 mmol) were
added in sequence to a solution of phenyl 1-(phenylcarbonyl)piperidine-4-carboxylate 13 (0.33 g,
1.23 mmol) and the resulting mixture was heated under reflux for 3.5 h. After cooling a 50% aqueous
solution of acetic acid was added and the resulting mixture was concentrated under reduced pressure.
The residue was taken up in EtOH (4 mL) and AcOH (0.21 mL, 3.69 mmol). Hydrazine hydrate
(0.09 mL, 1.85 mmol) was added and the resulting mixture was heated under reflux for 4 h. After
cooling, the solvent was evaporated under reduced pressure and the residue was taken up in CH2Cl2.
The organic phase was dried over Na2SO4, filtered and the solvent removed under reduced pressure.

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The residue was purified by flash chromatography (CHCl3/acetone = 95:5) affording 11: yield 82%;
1
yellow solid; Mp 167–170 °C; Rf = 0,24 (CHCl3/MeOH = 95:5); H-NMR: δ 1.58–2.21 (m, 6H),
2.90–3.21 (m, 3H), 3.63 (s, 2H), 7.33 (d, 1H, J = 8.0 Hz), 7.37–7.50 (m, 6H), 7.6 (d, 1H, J = 8.0 Hz).
13C-NMR: δ 27.3 (CH2), 29.1 (2 × CH2), 29.4 (CH), 34.2 (2 × CH2), 120.7 (C), 126.2 (CH), 126.9
(CH), 127.3 (CH), 128.5 (2 × CH), 129.8 (2 × CH2), 129.9 (CH), 132.1(C), 132.7 (C), 133.8 (C), 141.6
(C), 150.1 (CN) 157.3 (CN), 170.5 (CO). Anal. Calcd for C22H20ClN3O: C, 69.93; H, 5.33; N, 11.12.
Found: C, 70.34; H, 5.31; N, 11.17.
3-(1-Benzylpiperidin-4-yl)-6-chloro-1,4-dihydroindeno[1,2-c]pyrazole (6a). A solution of the amide
11 (0.14 g, 0.37 mmol) in THF (2 mL) was added dropwise to a suspension of LiAlH4 (56.0 mg,
1.48 mmol) in THF (2 mL) at 0 °C. After stirring at room temperature for 12 h the mixture was diluted
with Et2O (2,5 mL) and then NaOH (1 M, 0.1 mL) e H2O (0.3 mL) were added. The formed solid was
filtered and diluted with CH2Cl2. The organic phase was dried over anhydrous Na2SO4, filtered and the
solvent was removed under reduced pressure. The residue was purified by flash chromatography
(CHCl3/acetone = 95:5) affording 6a: yield 80%; yellow solid; Mp 146–148 °C; Rf = 0.25
1
(CHCl3/MeOH 95:5); H-NMR: 1.75–2.16 (m, 6H), 2.60–2.80 (m, 1H), 2.95 (m, 2H), 3.50 (m, 1H),
3.53 (s, 2H), 3.59 (s, 2H), 7.17–7.37 (m, 6H), 7.42 (s, 1H), 7.61 (d, 1H, J = 8.0 Hz), 9.25–10.35 (brs,
1H). 13C-NMR: δ 28.7 (CH2), 30.3 (2 × CH2), 31.0 (CH), 52.5 (2 × CH2), 62.3 (CH2), 119.7(C), 125.3
(CH), 126.2 (CH), 126.6 (CH), 127.6 (2 × CH), 128.8 (2 × CH), 130.8 (CH), 133.0 (C), 136.5 (C),
141.1 (C), 141.4 (C) 143.6 (CN) 149.7 (CN). Anal. Calcd for C22H22ClN3: C, 72.62; H, 6.09; N, 11.55.
Found: C, 72.70; H, 6.15; N, 11.59.
3.8. 1H-1-Oxa-2-aza-6-chloro-3-(1-phenethylpiperidin-4-yl)-1,4dihydroindeno[2,1-d]isoxazole (7a)
and 2H-1-aza-2-oxa-6-chloro-3-(1-phenethylpiperidin-4-yl)-1,4dihydroindeno[1,2-c]isoxazole (8a)
To a solution of phenyl 1-(phenylethyl)piperidine-4-carboxylate 17 (0.50 g, 1.23 mmol) were added
in sequence 5-chloro-2,3-dihydro-1H-inden-1-one 1a (0.2 g, 1.23 mmol) and NaH (60% in oil, 0.12 g,
3.08 mmol). The resulting mixture was heated under reflux for 4 h. After cooling a 50% aqueous
solution of acetic acid was added and the resulting mixture was concentrated under reduced pressure.
To the residue was taken up in EtOH (5 mL), AcOH (0.21 mL, 3.69 mmol) and hydroxylamine
hydrochloride (0.128 mg, 1.85 mmol) was added. The resulting mixture was heated under reflux for 8
h. The solvent was evaporated under reduced pressure and the residue was taken up in CH2Cl2. The
organic phase was dried over Na2SO4,, filtered and the solvent removed under reduced pressure. The
residue was purified by flash chromatography (CHCl3/acetone = 8:2) to give 7a and 8a.
Compound 7a. Yield 12%; brown solid; Mp 149–151 °C; Rf = 0,20 (CHCl3/acetone = 8:2); 1H-NMR:
δ 1.60–2.04 (m, 9H), 2.49 (t, 2H, J = 7.2 Hz), 2.62 (t, 2H, J = 7.2 Hz), 3.55 (s, 2H) 7.23–7.42 (m, 8H).
13C-NMR: δ 28.8 (CH2), 30.6 (CH2), 31.1 (2 × CH2), 31.7 (CH), 52.5 (2 × CH2), 62.4 (CH2), 119.7
(C), 125.4 (CH), 126.2 (CH), 126.7 (CH), 127.8 (2 × CH), 128.8 (2 × CH), 130.9 (CH), 134.0 (C),
136.0 (C), 142.5 (C), 153.7 (C), 161.0 (CN), 166.4 (CO). Anal. Calcd for C23H23ClN2O: C, 72.91; H,
6.12; N, 7.39. Found: C, 73.12; H, 6.10; N, 7.43.

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1
Compound 8a. Yield 41%; brown solid; Mp 157–160 °C; Rf = 0.41 (CHCl3/MeOH 8:2); H-NMR
(DMSO-d6): δ 1.82–2.10 (m, 5H), 2.11–2.33 (m, 4H), 2.60–2.70 (m, 2H), 2.73–2.88 (m, 2H), 3.57
(s, 2H), 7.12–7.28 (m, 8H). 13C-NMR: δ 28.8 (CH2), 30.5 (CH2), 31.2 (2 x CH2), 31.4 (CH), 53.2
(2 × CH2), 62.3 (CH2), 119.6 (C), 125.3 (CH), 126.5 (CH), 126.6 (CH), 127.8 (2 × CH2), 128.8
(2 × CH2), 130.9 (CH) 134.1 (C), 136.5 (C), 142.4 (C), 151.9 (C), 162.3 (CN) 169.2 (CO). Anal. Calcd
for C23H23ClN2O: C, 72.91; H, 6.12; N, 7.39. Found: C, 73.10; H, 6.14; N, 7.46.
3.9. Phenyl 1-benzoylpiperidine-4-carboxylate (13) and phenyl 1-phenethylpiperidine-4-carboxylate (17)
A mixture of the acid 18 or 19 (2.19 mmol) in CH2Cl2 (40 ml), 1-3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (0.84 g, 4.38 mmol), dimethylaminopiridine (0.54 g, 4.38 mmol) and
phenol (0.62 g, 6.57 mmol) was heated under reflux for 14 h. After cooling, the reaction mixture was
diluted with CH2Cl2 and washed with a saturated NH4Cl solution (3 × 20 mL). The separated organic
phase was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the
residue was purified by flash chromatography affording the product 13 or 17.
Compound 13. purified by flash chromatography by using as the eluent petroleum ether/EtOAc = 1:1);
1
yield 62%; yellow oil; Rf = 0.46 (petroleum ether/EtOAc = 1:1); H-NMR: δ 1.65–2.10 (m, 6H),
13
2.70–2.90 (m, 1H), 3.10–3.25 (m, 2H), 7.00–7.45 (m, 10H). C-NMR: δ 28.2 (2 × CH2), 41.1 (CH),
46.8 (2 × CH2), 121.3 (2 × CH), 125.9 (CH), 126.8 (2 × CH), 128.4 (2 × CH), 129.4 (2 × CH), 129.6
(CH), 135.8 (C), 150.4 (C), 170.4 (CO), 172.6 (CO). IR: (nujol) ν 1,752 (CO), 1,628 (CO) cm−1.
Anal. Calcd for C19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found: C, 73.85; H, 6.25; N, 4.46.
Compound 17. purified by flash chromatography by using as the eluent CHCl3/MeOH = 9:1; yield
64%; yellow oil; Rf = 0,27 (CHCl3/MeOH = 9:1); 1H-NMR: δ 1.80–2.20 (m, 4H), 2.56–2.65 (m, 2H),
2.80–2.90 (m, 3H), 3.00–3.15 (m, 2H), 3.43 (t, 2H, J = 5.4 Hz), 7.06 (d, 2H, J = 8.4 Hz), 7.20-7.42
(m, 8H). 13C-NMR: δ 28.2, (2 x CH2) 33.8 (CH2), 41.1 (CH), 46.8 (2 x CH2), 57.4 (CH2), 122.5
(2 × CH), 126.9 (2 × CH), 127.3 (CH), 128.4 (2 × CH), 129.0 (2 × CH), 129.5 (CH), 135.9 (C), 151.4
(C), 170.4 (CO). IR: (nujol) ν 1,750 (CO) cm−1. Anal. Calcd for C20H23NO2: C, 77.64; H, 7.49; N,
4.53. Found: C, 77.75; H, 7.42; N, 4.58.
4. Conclusion
In conclusion, we have reported a practical synthesis of the tricyclic heterocycles E incorporating
the pyrazole or isoxazole framework (Figure 1). These new products share with the antipsychotic
compounds A–C two substituents, namely the chlorine on the aryl ring and the 4-(1-benzyl)- or
4-(1-phenylethyl)piperidinyl group on the isoxazole and pyrazole moieties. The antipsychotic activity
of these new compounds will be determined, thus indicating which further structural modifications
should be pursued to advantageously modify their biological activity.
Acknowledgements
The authors pay their thanks to Regione Autonoma della Sardegna (RAS) for the financial support
(RAS: project: CRP-26417).

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Conflict of Interest
The authors declare no conflict of interest.
References and Notes
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13
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Sample Availability: Not available.
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