Synthesis and biological evaluation of a series of aminoalkyl-tetralones and tetralols as dual dopamine/serotonin ligands

Article abstract of DOI:10.1016/j.ejmech.2013.10.066

A series of novel α-tetralone and α-tetralol derivatives was synthesized, and their binding affinities for 5-HT_2A and D ₂ receptors, the most important targets implicated in the anti-schizophrenia drug action, were evaluated to eluci

Full text of DOI:10.1016/j.ejmech.2013.10.066

Accepted Manuscript
Synthesis and biological evaluation of a series of aminoalkyl-tetralones and tetralols
as dual dopamine/serotonin ligands
Laura Carro, María Torrado, Enrique Raviña, Christian F. Masaguer, Sonia Lage,
José Brea, María I. Loza
PII:
S0223-5234(13)00717-4
10.1016/j.ejmech.2013.10.066
EJMECH 6529
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 2 July 2013
Revised Date: 25 October 2013
Accepted Date: 26 October 2013
Please cite this article as: L. Carro, M. Torrado, E. Raviña, C.F. Masaguer, S. Lage, J. Brea, M.I. Loza,
Synthesis and biological evaluation of a series of aminoalkyl-tetralones and tetralols as dual dopamine/
serotonin ligands, European Journal of Medicinal Chemistry (2013), doi: 10.1016/j.ejmech.2013.10.066.
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ACCEPTED MANUSCRIPT
O
N
O
F
H2N
N
36:
5-HT2A Ki = 5 nM
D2 Ki = 47 nM

ACCEPTED MANUSCRIPT
Highlights
• A series of α-tetralone and α-tetralol derivatives was synthesized.
• SARs of this class of compounds as 5-HT2A/D2 ligands were studied.
• An amino substituent in position-7 facilitated binding affinities.
• Compounds 25 and 36 were found to be the most promising 5-HT2A/D2 ligands.

ACCEPTED MANUSCRIPT
Synthesis and biological evaluation of a series of aminoalkyl-
tetralones and tetralols as dual dopamine/serotonin ligands
Laura Carroa, María Torradoa, Enrique Raviñaa, Christian F. Masaguera,*, Sonia
Lageb, José Breab, María I. Lozab
a Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela. E-15782, Santiago de
Compostela, Spain
b Departamento de Farmacología, Facultad de Farmacia, Universidad de Santiago de Compostela. E-15782, Santiago de
Compostela, Spain
* Corresponding author. Tel.: +34 881 81 50 99; fax: +34 981 59 49 12.
E-mail addresses: laura.carro@usc.es (L. Carro), maria.torrado@usc.es (M. Torrado),
enrique.ravina@usc.es (E. Raviña), christianf.masaguer@usc.es (C.F. Masaguer), sonia.lage@rai.usc.es
(S. Lage), pepo.brea@usc.es (J. Brea), mabel.loza@usc.es (M.I. Loza)
ABSTRACT
A series of novel α-tetralone and α-tetralol derivatives was synthesized, and their binding affinities for 5-
HT2A and D2 receptors, the most important targets implicated in the anti-schizophrenia drug action, were
evaluated to elucidate how substitutions in the aromatic ring of the pharmacophore affect to the affinity or
selectivity for these receptors. The replacement of the H-7 in the tetrahydronaphthalene system by an
amino group resulted in privileged 5-HT2A affinity of the 6-fluorobenzo[d]isoxazol derivative 36 and the
alcohol 25 both showing a pKi value for 5-HT2A higher than 8.3 and good binding affinities for D2
receptor leading to a Meltzer’s ratio characteristic of an atypical antipsychotic profile. Additionally, a
small collection of 3-aminomethyltetralone derivatives was prepared and examined here for their
affinities and selectivities as 5-HT2A/D2 dual ligands. Compound 11 shows the best profile with good pKi
values for 5-HT2A and D2 receptors leading to a Meltzer’s ratio characteristic of a typical antipsychotic
behavior. These three compounds behaved as competitive antagonists of both 5-HT2A and D2 receptors,
and might be promising pharmacological tools for the investigation of the dual function of the 5HT2A-D2
ligands.
Keywords
Tetralone; Tetralol; Synthesis; Dopamine; Serotonin; Antipsychotic

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1. Introduction
Schizophrenia is a severe mental disorder affecting around 24 million people worldwide, and it
typically begins in late adolescence or early adulthood. It is characterized by a complex symptomatology,
which, in general, involves alterations in cognitive and emotional functioning. Its symptoms can be
grouped as positive, negative and cognitive: positive symptoms including altered behaviour, such as
delusions, hallucinations, extreme emotions, excited motor activity, and incoherent speech. Negative
symptoms are described as a lack of behaviour, such as poverty of speech, social withdrawal, avolition,
anhedonia and affective blunting. At last, cognitive symptoms consist of reduction in working memory,
attention, and verbal fluency [1]. However, there are no specific focal characteristics for the diagnosis of
schizophrenia, and no single symptom is consistently present in all patients. Consequently, its diagnosis
as a single disorder, or as a variety of different disorders, is still debated.
Furthermore, the co-occurrence of depressive symptoms is common in patients with
schizophrenia, with estimates of the prevalence in clinical populations ranging from 25 to 60%.
Depressive symptoms are of great prognostic significance since they are associated with compromised
quality of life and increased risk of psychotic relapse and suicide [2].
For decades, dopamine receptor blockers such as haloperidol have been the treatment of choice
for schizophrenia, but despite the effectiveness of this approach, dopamine antagonism has a number of
drawbacks, causing serious side effects such as motor disorders, tardive dyskinesia, and
hyperprolactinemia [3,4]. Newer antipsychotic drugs, the so-called atypical antipsychotics, show a wider
efficacy against the negative and positive symptoms due to a multireceptorial affinity profile that could be
the reason why, four decades after its introduction into the clinic, clozapine still remains the prototype for
use in cases of treatment-resistant schizophrenia [5].
As a result, the discovery of a more effective, side-effect free therapy for the treatment of
schizophrenia is still needed and remains a challenging research goal.
In the last decades we have been working on the modulation of the butyrophenone system with
the aim of combining the antagonism at the 5-HT2 family and the D2 receptors in a single molecule. So
far, in an attempt to synthesize more efficient compounds for prospective use as antipsychotics, we have
reported the synthesis, pharmacological activity and molecular modelling of the
aminoalkylbenzocycloalkanones, which are conformationally restricted butyrophenone analogues of
haloperidol [6]. Among these compounds, the favorable pharmacological profile of some tetralone
derivatives owing to the general structures I [7] and II [6] (Fig. 1), has prompted us to explore the
structure–activity relationships of this system as a scaffold for the design of new improved analogues of
haloperidol. For example, aminobutyrophenones QF0104B and QF0108B (Fig. 1) showed high affinity
for the 5-HT2A receptor subtype with pKi values of 8.79 and 8.56 nM, respectively, being QF0104B the
most selective compound for the serotonin 5-HT2A receptor subtype, with a 5-HT2A/5-HT2C Ki ratio as

ACCEPTED MANUSCRIPT
high as 150 [6]. Moreover, these compounds display pKi values at D2 receptor slightly lower than those at
5-HT2A receptors which is in accordance to the proposed binding profile for an atypical antipsychotic.
O
O
NRR
NRR
II
I
O
N
O
O
O
F
N
N
F
QF0108B
QF0104B
Fig. 1. Chemical structure of some representative reported tetralone derivatives
In an extension of our work on the development of new conformationally constrained
aminobutyrophenones as potential dual antagonists on dopamine D2 and serotonin 5-HT2A human
receptors, we report herein the synthesis and binding affinities of a novel collection of compounds based
on the 1-tetralone and 1-tetralol scaffolds (Fig. 2): 6-acetyl- and 6-phenyl-3-(aminomethyl)-1-tetralones
(III), 7-amino- and 7-nitro-2-(aminoethyl)-1-tetralones (IV), and 7-amino- and 7-nitro-(2-aminoethyl)-1-
tetraloles (V). The addition of substituents to a lead structure to achieve an in-depth study of the effect of
different groups at the aromatic ring on affinity for serotonin and dopamine receptors is necessary and
often used to find additional binding interactions with the target. This strategy involves, for instance, the
addition of substituents such as nitro or amino groups to probe for extra hydrogen or ionic bonding
interactions.
O
OH
O
R'
NRR
R'
NRR
NRR
R'= -Ac, -Ph
R'
III
IV
V
R'= -NO2, -NH2
Fig. 2. General structures of new compounds based on the 1-tetralone and 1-tetralol scaffolds
2. Results and discussion
2.1. Chemistry
2.1.1. 6-Acetyl- and 6-phenyl-3-(aminomethyl)-1-tetralones.
In a continuation of our study to indentify new structures as dopamine and serotonin ligands, we
have reported the synthesis of some intermediates belonging to the 1-tetralone scaffold using Stille,
Suzuki and Sonogashira palladium-catalyzed cross-coupling reactions from triflate 1 (Scheme 1) [8].
Among these intermediates we selected the 6-acetyl- and 6-phenyl-1,2,3,4-tetrahydro-4-oxonaphthalen-2-

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carboxylates 2 and 3 as starting materials of a new series of compounds bearing the tetralone core
substituted by a polar or a bulky group (10-13).
As it is depicted in Scheme 1, the synthesis started with the simultaneous reduction of both
carbonyl groups in 2 and 3 using LiAlH4 in THF at room temperature giving the corresponding
trihydroxy derivative 4 and diol 5, respectively, in good yield. The selective oxidation of the secondary
hydroxyl group with MnO2 afforded the hydroxyketones 6 and 7 in 70% yield. Next, activation of the
hydroxyl group as a tosyl led to the sulfonates 8 and 9 in satisfactory yields. Finally, nucleophilic
replacement with two different piperidines, 4-(6-fluorobenzisoxazol-3-yl)piperidine (A) and 4-(4-
fluorobenzoyl)piperidine (B), afforded the targeted 6-acetyl- and 6-phenyl-3-aminoketones 10-13 in fair
to good yields.
OH
O
O
O
(d)
(a)
(b)
(c)
OH
OH
R'
TfO
COOCH3
R'
COOCH3
R'
1
2: R' = Ac
3: R' = Ph
4: R' = CHOHCH3
5: R' = Ph
6: R' = Ac
7: R' = Ph
O
O
O
O
(e)
N
OTs
NRR
NRR=
N
R'
R'
F
N
F
10: R' = Ac, NRR = A
11: R' = Ph, NRR = A
8: R' = Ac
9: R' = Ph
A
B
12: R' = Ac, NRR = B
13: R' = Ph, NRR = B
Scheme 1. Reagents and conditions: (a) for 2: Me3Sn[C(OEt)=CH2], PdCl2(PPh3)2, LiCl, DMF, 110 ºC, 12 h (78%);
for 3: PhSnMe3, Pd(PPh3)4, LiCl, dioxane, 100 ºC, 9 h (87%); (b) LiAlH4, THF, rt, 18-24h (85%); (c) MnO2, THF,
rt, 15h (70%); (d) ClTs, Pyr, rt, 24h (66%); (e) HNRR, benzene, 90ºC, 12-70h (12-61%).
2.1.2. 7-Amino- and 7-nitro-2-(aminoethyl)-1-tetralone, and 7-amino- and 7-nitro-2-(aminoethyl)-1-
tetralol series.
The synthetic route for the preparation of the target tetralones and tetralols started from
commercially available α-tetralone. As depicted in Scheme 2, α-tetralone underwent thermal
condensation with glyoxylic acid and p-TsOH to give the unsaturated acid 14, which was reduced with
zinc in acetic acid to afford 1,2,3,4-tetrahydro-l-oxo-naphthalene-2-acetic acid (15) both steps according
to previously reported procedures [9,10]. Despite an effective direct nitration of acid 15 has not been
previously reported, a similar approach to the Hay’s method [11] using a 33% mixture of nitric acid in
concentrated sulphuric acid was applied to give the 7-nitroacid 16 in satisfactory yield.
An alternative route via 7-nitrotetralone was considered for the preparation of the acid 16:
nitration of α-tetralone was accomplished with the mentioned method giving the 7-nitrotetralone 17 in
65% yield. Compound 17 was submitted to thermal condensation with glyoxylic acid in good yield

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followed by reduction with zinc and acetic acid of the resulting alkanylidene acetic acid 18 to give the 7-
nitroketoacid 16 in 49% overall yield. Coupling of acid 16 with secondary amines was carried out within
dichloromethane in the presence of 1-HOBt and DCC to gain the ketoamides 19 and 20 in yields around
80%.
O
O
O
(a)
(b)
COOH
COOH
N
COOH
15
(c)
14
c)
O
O
O
O
O2N
O2N
O2N
O2N
NRR
(a)
(b)
(d)
COOH
O
19: NRR = A
20: NRR = C
17
18
16
O
N
NRR=
N
F
N
OCH3
C
A
Scheme 2. Reagents and conditions: (a) Glyoxylic acid / p-TsOH, 160 ºC, 1 h (90-95%); (b) Zn / AcOH, 75 ºC, 1 h
(84-94%); (c) HNO3 / H2SO4, –20 ºC, 45 min (60-65%); (d) HNRR, 1-HOBt, DCC, DCM, 0 ºC, 1 h, then rt
overnight (82-83%).
As outlined in Scheme 3, the 7-nitrotetralols 21 and 22 and their 7-amino counterparts 23 and 24
were readily obtained from key compounds 19 and 20: aluminium hydride reduction of these ketoamides
gave their corresponding 7-nitroalcohols 21 and 22 in moderate yield. We attribute the low yield achieved
to the chemical instability of starting materials in the presence of reducing agents such as lithium
aluminium or aluminium hydrides since their fragmentation moieties were identified in the reaction crude
by means of NMR.
The best reducing agent for the aromatic nitro group needed to be deeply explored: catalytic
hydrogenation of the piperazine compound 22 using 10% palladium on activated charcoal did not allow to
isolate the desired compound. However, the change of the catalyst from palladium to 10% platinum
dioxide led to the aminoalcohol 23 in good yield.
With regard to the piperidine compound 21, its nitro group was reduced using palladium on
activated charcoal as catalyst leading to the desired amino derivative 24 and the by-product 25 (Scheme
3) in a ratio of about 1.2:1, in 45% overall yield. Both alcohols, 24 and 25, had almost identical Rf values
(silica gel, ethyl acetate) seeming to be the same compound by TLC. Modifying the stationary phase from
silica gel to aluminium oxide and using a mixture of acetone:methanol (1:9) as mobile phase increased
the delta Rf sufficiently to allow the purification and characterization of both compounds. In an attempt to

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improve this moderate yield we changed the catalyst to 10% platinum dioxide affording only the 7-
aminoalcohol 25 from 21 in 57% yield. Although compound 25 was, at the beginning, beyond the interest
of our study, it was completely characterized to confirm the presumed structure.
To limit the formation of by-products, it was decided to replace the catalytic hydrogenation by
tin(II) chloride reduction, following the method described by Barker [12]. Initially, we reduced the nitro
group in ketoamide 19 using SnCl2 in THF, providing its corresponding 7-amino derivative 26
quantitatively. Subsequently, reduction of its keto and amide groups was carried out using aluminium
hydride giving tetralol 24 in moderate yield.
O
O
O2N
NRR
H2N
NRR
(a)
O
O
19: NRR = A
20: NRR = C
26: NRR = A
(b)
(b)
OH
OH
OH
H2N
NRR
O2N
NRR
H2N
NRR
(c)
(d)
23: NRR = C
25: NRR = D
21: NRR = A
22: NRR = C
24: NRR = A
25: NRR = D
O
OH
O
N
N
NRR=
F
N
N
N
OCH3
F
A
C
D
Scheme 3. Reagents and conditions: (a) SnCl2, THF, rt, 6h (99%); (b) 1M AlH3 / THF, 0ºC, 1h (25-30%); (c) Pd / C
10%, H2, THF, rt, overnight (20-25%); (d) PtO2 10%, H2, THF, rt, overnight (57-70%).
Owing the 7-nitro- and 7-aminoalcohols 21-25 and in an attempt of achieving the target
aminoketones, we examined agents such as MnO2 and PDC to oxidize the hydroxyl group to ketone. To
our disappointment, all the assays met with failure, since we were not able to identify the desired
aminoketones in the reaction crude.
Viewing the unlucky results we designed the classical synthetic approach consisting of protection
of the ketone group as a ketal, reduction of the amide group and hydrolysis to restore the ketone moiety.
Protection of the ketone group in 19 and 20 was carried out in a flask equipped with a Dean-Stark
apparatus by using ethylene glycol, p-TSA in refluxing benzene, isolating the ketals 27 and 28,
respectively, in yields ranging from 65-75%. Next, reduction of their amide group with freshly-prepared
1M aluminium hydride in THF afforded the corresponding aminoketals 29 and 30 in acceptable yields.
Finally, deketalyzation to restore carbonyl groups was made by cautious dropwise addition of 1M HCl to
a solution of the ketal in THF, providing the desired nitroaminoketones 31 and 32 quantitatively.

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O
O
O
O
O
O
O
H2N
NRR
O2N
NRR
O2N
NRR
O2N
NRR
(a)
(b)
(c) or (d)
O
O
19: NRR = A
20: NRR = C
27: NRR = A
28: NRR = C
29: NRR = A
30: NRR = C
33: NRR = A
34: NRR = C
35: NRR = D
(e)
O
(e)
O
O2N
NRR
(f)
H2N
NRR
31: NRR = A
32: NRR = C
36: NRR = A
37: NRR = C
38: NRR = D
Scheme 4. Reagents and conditions.(a) Ethane-1,2-diol, p-TsOH, benzene, reflux, 16h (65-75%); (b) 1M AlH3 /
THF, 0 ºC, 1h (62-66%); (c) Pd/C 10%, THF, rt, overnight (25-35%); (d) PtO2 10%, THF, rt, overnight (35-60%);
(e) 1M HCl, THF, rt, overnight (91-99%); (f) SnCl2·2H2O, THF, 60 ºC, 20h (67%).
Applying the conditions used for our aminoalcohols (Scheme 3), we reduced the nitro group in
aminoketal 29 by catalytic hydrogenation using Pd/C gave the aminoketals 33 and 35 in a ratio of about
1.4:1 in 60% overall yield. Changing the catalyst from Pd to PtO2 afforded only the 7-aminoketal 35 from
29 in 35% yield. The 7-amino derivative 34 was also obtained by means of catalytic hydrogenation of 30
(Scheme 4) in 60% yield.
Finally, hydrolysis of the ketals 33, 34 and 35 using a 10% HCl solution afforded the 7-
aminoketones 36, 37 and 38, respectively, in almost quantitative yields. Again, reduction of 31 with
tin(II) chloride gave the 7-aminoketone 36 straightforwardly in 67% yield.
2.2. Pharmacology
The affinities of the new compounds for cloned human D2 and 5-HT2A receptors were evaluated
in in vitro binding assays using the radioligands [3H]spiperone and [3H]ketanserin, respectively. Ki values
(expressed as pKi) are summarized in Table 1.
Regarding the 3-(aminomethyl)tetralone series, the binding affinities towards 5-HT2A and D2
receptors are displayed on Table 1. All four compounds, excluding 13 (pKi= 6.20), inhibited the binding
of the [3H]ketanserin on 5-HT2A receptors with pKi values higher than reference compound haloperidol
(pKi= 6.78). Despite compounds 10, 11 and 12 displayed the best values (pKi= 7.50, 7.80 and 7.20,
respectively), they were lower than those shown by clozapine and risperidone (pKi= 8.04 and 9.30).
Concerning D2 dopamine receptor, compounds 10, 11 and 12 exhibited values ranging from 7.30
and 7.76 superior in all the cases to that of clozapine (pKi= 6.65). Since compound 13 did not show
affinity on this receptor, it cannot be suited as a potential antipsychotic on the basis of the dopamine
hypothesis.
Meltzer et al proposed the so-called Meltzer index (pKi 5-HT2A/pKi D2) as a predictive value of
the behavior of an antipsychotic in which a relatively high 5-HT2A receptor affinity compared to the D2

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receptor is the basis for the difference between ‘atypical’ (pKi 5-HT2A/pKi D2 > 1.12) and ‘typical’ (pKi 5-
HT2A/pKi D2 < 1.10) antipsychotic agents [13]. This hypothesis contributed to the development of the
newer antipsychotic agents, all of which are consistent with the hypothesis of high affinity for 5-HT2A and
low affinity for D2 receptors [4]. Therefore, considering the pKi ratio 5-HT2A/D2, aminoketones 10, 11 and
12 may be classified as potential typical antipsychotics as they displayed a ratio value lower than 1.10.
By comparison with the non-substituted and the 6-methoxy-tetralone derivatives [7], we can
conclude that the addition of substituents is detrimental for the affinity towards 5-HT2A serotonin receptor
subtype, suggesting a potential steric effect of the substituents in the binding site. Observing the behavior
on D2 dopamine receptor, the 6-acetyl-3-(aminomethyl)tetralones 10 and 12 and the 6-phenyl-3-
(aminomethyl)tetralone 37 displayed binding affinity values similar or slightly superior to the non-
substituted and to the 6-methoxy-tetralone counterparts. These results do not allow us to elucidate the
influence of either the presence or the absence of substituents on the binding affinities.
The in vitro receptor binding data corresponding to the 2-aminoethyltetralone and 2-
aminoethyltetralol series are also summarized in Table 1. All ten compounds exhibited binding affinities
for both 5-HT2A and D2 receptors in the nanomolar range [pKi for 5-HT2A receptor: 6.10 (32) – 8.35 (25);
pKi for D2 receptor: 6.19 (25) – 7.72 (22)]. Some of the compounds demonstrate selectivity for one of the
receptors (e.g., compound 25 shows higher binding affinity for the 5-HT2A receptor, while 22 displayed
higher binding affinity for the D2 receptor).
Regarding behavior at 5-HT2A receptor, the binding affinities of all the derivatives that bear the 6-
fluorobenzisoxazolylpiperidine (amine A) are consistently higher than those of the compounds with 2-
methoxyphenyl piperidine (amine C) fragment (the difference in the affinities of the two series is higher
than 1.5 order of magnitude in all compounds, besides in 36 and 37 where the difference is of just 1
order). Also, for the D2 receptor, all compounds (excluding alcohol 21) bearing the 6-
fluorobenzisoxazolylpiperidine moiety (amine A) display higher affinities than those with a 2-
methoxyphenyl piperidine (amine C) moiety included in their structure. All the compounds tested
expressed modest affinity compared to haloperidol or risperidone but similar or higher to that of
clozapine. In general, reduction of ketone group to hydroxyl is detrimental for the affinity on this
receptor. These results are in accordance with the ability to establish key polar interactions with the
residues at positions 3.36 and 5.46 in both 5-HT2A and D2 receptors shown by other related
benzisoxazolylpiperidine derivatives previously reported by our groups [14].
Considering the important role which has been proposed for serotonin receptors, mainly 5-HT2A
subtype, in the action of antipsychotics: improvement of the negative symptoms of schizophrenia and
reduction of the occurrence of extrapyramidal side effects [15], we highlight the potential for
antipsychotic activity shown by compounds 25 and 36 with high affinity at the 5-HT2A receptors (pKi=
8.35 and pKi= 8.30), greater than the one displayed for reference molecules haloperidol and clozapine,

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and moderate affinity for D2 receptor (pKis’ values of 6.19 and 7.33, respectively) leading to an
appropriate affinity ratio at these two receptors for atypicality. This promising behavior could be
attributed not only to the amine moiety but also to the presence of the -NH2 group, which might establish
an additional interaction with an acceptor group in the receptors binding site.
In looking at the influence of the substituents at the seven position of the tetralone or tetralol core,
in the main, reduction of nitro group to amino moiety led to more favorable binding affinities for
serotonin receptor than for dopamine one.
On the basis of the 5-HT2A/D2 antagonism hypothesis, it is also worth mentioning the
aminoketone 36 as a potential atypical antipsychotic, with a Meltzer’s ratio of 1.13, as good as 1.12, the
value from which Meltzer predicts an atypical profile for antipsychotics. Again, a favorable interaction
between -NH2 (in the tetralone ring) and the receptors could be the cause of its hopeful binding profile.
Table 1
Results for binding assays (pKi) on D2 and 5-HT2A receptors in CHO cells of the new synthesized compounds.a
Compound
Code
pKi 5-HT2A
7.50
7.80
7.20
6.20
7.96
6.29
6.80
8.18
8.35
7.72
6.10
8.30
7.37
7.63
6.78
8.04
9.30
pKi D2
7.30
7.76
7.49
<5
pKi ratio 5-HT2A/D2
10
QF0198B
QF0168B
QF0194B
QF0164B
QF0328A
QF0321A
QF0331A
QF0338A
QF0339A
QF0328B
QF0321B
QF0338B
QF0331B
QF0339B
1.03
1.01
0.96
–
11
12
13
21
6.92
7.72
6.75
7.06
6.19
7.43
7.38
7.33
7.30
6.95
9.22
6.65
8.21
1.15
0.81
1.01
1.16
1.35
1.04
0.83
1.13
1.01
1.10
0.73
1.21
1.13
22
23
24
25
31
32
36
37
38
Haloperidol
Clozapine
Risperidone
a Values are means of two separate experiments.

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In order to know the functional behavior of these compounds, we evaluated compounds 11, 25,
and 36 in in vitro functional assays at human 5-HT2A and D2 receptors. These three compounds right-
shifted the concentration-response curve of the agonist showing potency values similar to the binding
ones (Table 2), evidencing a competitive neutral antagonism behavior at both human 5-HT2A and D2
receptors.
Table 2
Results for functional assays (pKB) on human D2 and 5-HT2A receptors in CHO cells of the three selected compounds.
Compound
pKB 5-HT2A
7.84
pKB D2
7.55
11
25
36
7.82
6.32
8.76
7.53
3. Conclusions
A series of α-tetralone and α-tetralol derivatives was synthesized, and their binding affinities for
receptors implicated in schizophrenia were assessed to elucidate how substitutions in the aromatic ring of
the pharmacophore affect the affinity or selectivity for these receptors. In the series of 2-
(aminoethyl)tetralones and 2-(aminoethyl)tetralols, the best results were found to be when H-7 was
substituted by an amino group. In this regard, privileged 5-HT2A affinity could be assigned to 6-
fluorobenzo[d]isoxazol derivative 36 and the alcohol 25 both showing a pKi value for 5-HT2A higher than
8.3 and good binding affinities for D2 receptor leading to a Meltzer’s ratio characteristic of an atypical
antipsychotic profile. Regarding the 3-(aminomethyl)tetralone series, compound 11 shows the best
potential for antipsychotic activity with good pKi values for 5-HT2A and D2 receptors leading to a
Meltzer’s ratio characteristic of a typical antipsychotic behavior. These three compounds behaved as
competitive antagonists of both 5-HT2A and D2 receptors. As some of these compounds show very
promising properties to be used as pharmacological tools for the investigation of the dual function of the
5HT2A-D2 ligands, further studies on these series, including in vivo assays to determine antipsychotic
activity, have to be done considering drug development.
4. Experimental
4.1. Chemicals and instruments
All chemicals were purchased from commercial sources (e.g., Sigma–Aldrich Chemical Co.) and
used without further purification unless otherwise stated. When necessary, solvents were purified by
distillation over an appropriate drying agent under argon atmosphere and used immediately. Melting
points were determined with a Kofler hot stage instrument and are uncorrected. Infrared (IR) spectra were

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recorded on a JASCO FT/IR-4100 spectrophotometer using Attenuated Total Reflectance (ATR)
technique and values are expressed as νmax cm–1. NMR spectra were recorded on a Bruker WM AMX
(300 MHz for 1H NMR and 75.5 MHz for 13C NMR); chemical shifts (δ) were recorded in ppm downfield
from (CH3)4Si as an internal reference; approximate coupling constants (J) are given in Hz. All observed
signals were consistent with the proposed structures. Mass spectra were collected using a Kratos MS-50
or a Varian Mat-711 mass spectrometer by chemical ionization (CI) or electron impact (EI) methods.
Flash column chromatography was performed using Kieselgel 60 (60–200 mesh, E. Merck AG,
Darmstadt, Germany). Reactions were monitored by thin-layer chromatography (TLC) on Merck 60
GF254 chromatogram sheets using iodine vapor and/or UV light for detection. Unless otherwise noted,
each of the purified compounds was isolated as a single spot. Elemental combustion analyses were
performed using a Perkin-Elmer 240B apparatus. Analyses indicated by the symbols of the elements or
functions were within ± 0.4% of the theoretical values. Hydrochlorides were prepared by dropwise
addition, with cooling, of a saturated solution of HCl gas in anhydrous Et2O to a solution of the amine in
anhydrous Et2O.
4.2. Chemical methods
4.2.1. Methyl 7-acetyl-1,2,3,4-tetrahydro-4-oxonaphthalen-2-carboxylate (2)
To a mixture of triflate 1 (600 mg, 1.68 mmol) and PdCl2(PPh3)2 (118 mg, 0.168 mmol) in DMF
(10 mL) was added tributyl(1-ethoxyvinyl)tin (607 mg, 1.68 mmol) and LiCl (216 mg, 5.10 mmol). The
suspension was stirred at 110 ºC under argon for 12 h. After cooling, and the mixture was filtered though
a celite pad and the filtrate was concentrated under vacuum. The brown solid obtained was purified by
flash column chromatography using 1:3 EtOAc:hexane as eluent to give the title ester 2 (326 mg, 78%) as
a yellowish solid. Mp 97–98 ºC (hexane). IR: 2958, 1726, 1683, 1485, 1418. 1H NMR (CDCl3): δ 2.63 (s,
3H, CH3-); 2.83–3.01 (m, 2H, 2H1); 3.20–3.31 (m, 3H, 1H2, 2H3); 3.72 (s, 3H, -COOCH3); 7.86 (m, 2H,
H6, H8); 8.10 (d, J = 8.7 Hz, 1H, H5). 13C NMR (CDCl3): δ 27.2 (-COCH3); 32.2 (C1); 40.0 (C2); 40.9
(C3); 52.6 (-COOCH3); 127.0 (C6); 127.7 (C8); 129.1 (C5); 135.0 (C4a); 140.9 (C8a); 142.0 (C7); 173.6 (-
COOCH3); 195.5 (C4); 197.8 (-COCH3). MS (CI): m/z = 247 (MH+, 85%); 215 (22). Anal.
C20H14O4·1/7H2O (C, H).
4.2.2. Methyl 1,2,3,4-tetrahydro-4-oxo-7-phenylnaphthalen-2-carboxylate (3)
To a mixture of triflate 1 (800 mg, 2.27 mmol) and Pd(PPh3)4 (262 mg, 0.23 mmol) in dioxane
(15 mL) was added tributylphenyltin (547 mg, 2.27 mmol) and LiCl (288 mg, 6.81 mmol). The
suspension was stirred at 100 ºC under argon for 9 h. After cooling, the solvent was distilled under
reduced pressure and the residue was dissolved in ether, washed with water, 10% HCl and brine. The
organic phase was dried (Na2SO4), and the solvent was evaporated to give a brown solid which was
purified by flash column chromatography using 1:3 EtOAc:hexane as eluent to give the title carboxylate 3
1
(545 mg, 87%) as a white solid. Mp 107–110 ºC (hexane). IR: 1734, 1684, 1605. H NMR (CDCl3): δ

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2.81–2.88 (m, 1H, 1H1); 2.90–3.01 (m, 1H, 1H1); 3.23–3.31 (m, 3H, H2, H3); 3.74 (s, 3H, -CH3); 7.40–
7.58 (m, 4H, H6, H3 Ph, H4 Ph, H5 Ph); 7.60–7.63 (m, 3H, H8, H2 and H6 Ph,); 8.01 (d, J = 8.2 Hz, 1H, H5).
13C NMR (CDCl3): δ 32.6 (C1); 40.6 (C2); 41.2 (C3); 52.7 (CH3); 126.5 (C6); 127.7 (C4 Ph); 127.8 (C2 and
C6 Ph); 128.3 (C3 and C5 Ph); 128.8 (C5); 129.4 (C8); 131.1 (C4a); 140.1 (C8a); 142.4 (C1 Ph); 147.0 (C7);
1
174.0 (COO); 195.9 (C4). MS (CI): m/z = 281 (MH+, 100 %); 279 (45). Anal. C18H16O3· /5H2O (C, H).
4.2.3. 1,2,3,4-Tetrahydro-6-(1-hydroxyethyl)-3-(hydroxymethyl)naphthalen-1-ol (4)
To a suspensión of LiAlH4 (670 mg, 17.78 mmol) in anhydrous THF (5 mL), a solution of the
ester 2 (440 mg, 1.78 mmol) in anhydrous THF (30 mL) was added dropwise at 0 ºC under argon. The
mixture was stirred at room temperature for 24 h, and then quenched by careful addition of H2O (1 mL),
10% aqueous NaOH (1.5 mL) and H2O (6 mL) at 0 ºC. The reaction mixture was filtered in vacuo and the
filtrate evaporated. The crude obtained was dissolved in CH2Cl2, dried over Na2SO4, concentrated under
reduced pressure and finally purified by column chromatography using EtOAc:hexane (2:1) as eluent to
afford the titled alcohol 4 as a white solid (335 mg, 85%). Mp 132–134 ºC (hexane). IR: 3263, 2926,
1
2439, 1665, 1609, 1569, 1440, 1369, 1325. H NMR (CD3OD): δ 1.44 (d, J = 5.2 Hz, 3H,-CH3); 1.88–
2.01 (m, 1H, 1H4); 2.25–2.33 (m, 1H, H3); 2.51–2.61 (m, 1H, 1H4); 2.83–2.89 (m, 1H, 1H2); 3.36 (d, J =
11.4 Hz, 1H, 1H2); 3.61–3.78 (m, 2H, -CH2OH); 4.76–4.81 (m, 2H, H1, CH3CHOH); 7.12–7.22 (m, 2H,
H5, H7); 7.52 (d, J = 7.9 Hz, 1H, H8). 13C NMR (CD3OD): δ 24.9 (CH3CHOH-); 32.8 (C4); 36.3 (C3); 36.4
(C2); 66.6 (-CH2OH); 68.8 (C1); 69.5 (CH3CHOH-); 123.1 (C7); 125.5 (C5); 126.6 (C8); 136.1 (C4a); 139.0
(C8a); 143.1 (C6). MS (CI): m/z =223 (MH+, 6%); 205 ([MH-18]+, 54); 187 ([MH-36]+, 100). Anal.
C13H18O3·⅛H2O (C, H).
4.2.4. 1,2,3,4-Tetrahydro-3-(hydroxymethyl)-6-phenylnaphthalen-1-ol (5)
Following the same procedure, diol 5 was synthesized from ketoester 3 as a white solid in 85%
1
yield. Mp 204–205 ºC (EtOAc). IR: 3298, 2947, 2459, 1598, 1563. H NMR (DMSO): δ 1.88–2.13 (m,
1H, 1H4); 2.43–2.49 (m, 1H, 1H3); 2.52–2.78 (m, 1H, H4); 2.80–2.86 (m, 1H, 1H2); 3.14–3.28 (m, 1H,
1H2); 3.36–3.40 (m, 2H, -CH2OH); 4.56-4.63 (m, 1H, 1H1); 7.29–7.34 (m, 2H, H5, H7); 7.40–7.57 (m, 3H,
H8, H3´, H5´); 7.60–7.62 (m, 3H, H2 Ph, H6 Ph, H4 Ph). 13C NMR (DMSO): δ 32.6 (C4); 35.9 (C3); 36.5
(C2); 65.8 (-CH2OH); 67.5 (C1); 126.3 (C4 Ph); 126.4 (C2 and C6 Ph); 127.0 (C8); 127.1 (C3 and C5 Ph);
127.9 (C7); 128.7 (C5); 136.2 (C6); 138.1 (C4a); 140.1 (C8a); 140.5 (C1 Ph). MS (CI): m/z =255 (MH+, 22
%); 219 (100). Anal. C17H18O2 (C, H).
4.2.5. 6-Acetyl-3,4-dihydro-3-(hydroxymethyl)naphthalen-1(2H)-one (6)
MnO2 (3.90 g, 45.61 mmol) was added to a stirred solution of triol 4 (290 mg, 1.31 mmol) in
THF (40 mL) under argon. After stirring for 15 h at room temperature, the mixture was filtered and the
filtrate was concentrated in vacuo. The residue obtained was purified by column chromatography using
EtOAc:hexane (2:1) as eluent to afford the required hydroxyketone 6 as a light yellow solid (200 mg,

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70%). Mp 86–88 ºC. IR: 3322, 3023, 1787, 1679, 1584, 1566, 1508. 1H NMR (CDCl3): δ 2.43–2.56 (m,
2H, 2H4); 2.62 (s, 3H, -CH3CO); 2.83 (dd, J = 1.5 Hz, J = 13.0 Hz, 1H, H3); 2.90 (dd, J = 10.0 Hz, J =
16.3 Hz, 1H, 1H2); 3.11–3.17 (m, 1H, 1H2); 3.70–3.77 (m, 2H, -CH2OH); 7.84 (d, J = 6.9 Hz, 2H, H5,
H7); 8.10 (d, J = 6.8 Hz, 1H, H8). 13C NMR (CDCl3): δ 27.4 (CH3CO-); 32.8 (C4); 38.0 (C3); 42.1 (C2);
66.4 (-CH2OH); 126.8 (C7); 127.9 (C8); 129.4 (C5); 136.9 (C8a); 141.5 (C4a); 143.7 (C6); 197.7 (C1); 198.8
(COCH3). MS (CI): m/z = 219 (MH+, 100%); 200 (27). Anal. C13H14O3·2/5H2O (C, H).
4.2.6. 3,4-Dihydro-3-(hydroxymethyl)-6-phenylnaphthalen-1(2H)-one (7)
Following the same procedure, compound 7 was synthesized from 5 as a yellow solid in 73%
1
yield. Mp 108–109 ºC (hexane). IR: 3457, 3019, 2886, 2814, 1660, 1604, 1560. H NMR (CDCl3): δ
2.44–2.54 (m, 2H, 2H4); 2.75–2.97 (m, 2H, 1H2, H3); 3.12–3.18 (m, 1H, 1H2); 3.07–3.74 (m, 2H, -
CH2OH); 7.34–7.49 (m, 4H, H7, H3 Ph, H4 Ph, H5 Ph); 7.53–7.63 (m, 3H, H5, H2 and H6 Ph); 8.10 (d, J =
8.13 Hz, 1H, H8). 13C NMR (CDCl3): δ 33.1 (C4); 38.3 (C3); 42.1 (C2); 66.6 (-CH2OH); 126.1 (C7); 127.7
(C4 Ph); 128.0 (C2 and C6 Ph); 128.1 (C8); 128.7 (C3 and C5 Ph); 129.3 (C5); 131.6 (C8a); 140.3 (C1 Ph);
144.0 (C6); 146.8 (C4a); 198.1 (C1). MS (CI): m/z = 253 (MH+, 100%); 252 (92). Anal. C17H16O2 (C, H).
4.2.7. (6-Acetyl-1,2,3,4-tetrahydro-1-oxonaphthalen-3-yl)methyl 4-methylbenzenesulfonate (8)
To a solution of hydroxyketone 6 (170 mg, 0.78 mmol) in anhydrous pyridine (3 mL), tosyl
chloride (223 mg, 1.17 mmol) was added at 0 ºC, and the mixture was stirred for 24 h. Then the mixture
was added to ice and the precipitate formed was collected by filtration, dried under high vacuum and
purified by column chromatography using EtOAc:hexane (2:1) as eluent to give the titled tosylate as a
1
white solid (190 mg, 66%). Mp 112–114 ºC (2-propanol). IR: 1686, 1600, 1569, 1416, 1359, 1179. H
NMR (CDCl3): δ 2.44 (dd, J = 11.8 Hz, J = 16.3 Hz, 1H, 1H4); 2.46 (s, 3H, CH3Ph-); 2.62 (s, 3H,
CH3CO-); 2.57–2.66 (m, 1H, H3); 2.74 (ddd, J = 1.7 Hz, J = 3.4 Hz, J = 16.3 Hz, 1H, 1H4); 2.90 (dd, J =
10.5 Hz, J = 16.3 Hz, 1H, 1H2); 3.09 (dd, J = 2.5 Hz, J = 16.3 Hz, 1H, 1H2); 4.00–4.12 (m, 2H, -CH2O-);
7.36 (d, J = 6.9 Hz, 2H, H3 and H5 Ph); 7.79 (d, J = 8.4 Hz, 2H, H2 and H6 Ph); 7.81 (s, 1H, H5); 7.84 (d, J
= 8.2 Hz, 1H, H7); 8.07 (d, J = 8.0 Hz, 1H, H8). 13C NMR (CDCl3): δ 22.1 (CH3Ph); 27.3 (COCH3); 32.4
(C4); 35.1 (C3); 41.4 (C2); 72.5 (CH2O); 127.0 (C7); 128.0 (C8); 128.3 (C5); 129.4 (C2 and C6 Ph); 130.4
(C3 and C5 Ph); 132.9 (C1 Ph); 135.2 (C8a); 141.0 (C4a); 142.6 (C6); 145.6 (C4 Ph); 196.0 (C1); 198.0 (CO).
MS (CI): m/z = 373 (MH+, 18); 201 (100%). Anal. C20H20O5S (C, H, S).
4.2.8. (1,2,3,4-Tetrahydro-1-oxo-6-phenylnaphthalen-3-yl)methyl 4-methylbenzenesulfonate (9)
Following the same procedure, the titled compound was obtained from 7 as a white solid in 60%
1
yield. Mp 110–111 ºC (cyclohexane). IR: 2923, 1671, 1602, 1598. H NMR (CDCl3): δ 2.36–2.45 (m,
3H, -CH3, 1H4); 2.62–2.69 (m, 2H, H3, 1H4); 2.74 (dd, J = 1.7 Hz, J = 3.6 Hz, 1H, 1H2); 2.85–3.13 (m,
1H, 1H2); 4.00–4.12 (m, 2H, -CH2O-); 7.34–7.61 (m, 9H); 7.80 (dd, J = 1.6 Hz, J = 6.6 Hz, 2H, H2 and
H6 Ph-SO2); 8.06 (d, J = 8.1 Hz, 1H, H8). 13C NMR (CDCl3): δ 21.6 (CH3); 32.3 (C3); 34.9 (C4); 41.0

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(C2); 72.3 (-CH2O-); 125.9 (C7); 127.2 (C4 Ph); 127.5 (C2 and C6 Ph); 127.8 (C8); 127.9 (C3 and C5 Ph);
128.4 (C2 and C6 Ph-SO2); 129.0 (C5); 130.0 (C3 and C5 Ph-SO2); 130.8 (C8a); 132.7 (C1 Ph); 139.7 (C1
Ph-SO2); 142.4 (C6); 145.1 (C4a), 146.6 (C4 Ph-SO2), 195.2 (CO). MS (CI): m/z = 407 (MH+, 86%), 237
(100), 235 (62). Anal. C24H22O4S (C, H, S).
4.2.9.
6-Acetyl-3-[(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)methyl]-3,4-dihydronaphthalen-
1(2H)-one (10)
Tosylate 8 (70 mg, 0.19 mmol) and 4-(6-fluorobenzo[d]isoxazol-3-yl)piperidine (124 mg, 0.56
mmol) were dissolved in benzene (20 mL), and the solution was refluxed for 24 h under argon. After
cooling to room temperature, solvent was distilled under reduced pressure and the residue obtained
dissolved in CH2Cl2 and washed with H2O. The organic phase was dried (Na2SO4) and concentrated to
give an oily residue which was purified by column chromatography using EtOAc:hexane (3:1) as eluent
to afford the required amine 10 (48 mg, 61%) as a white solid. Mp 168–170 ºC. IR: 3345, 2955, 2924,
1
1684, 1607, 1491. H NMR (CDCl3): δ 2.04–2.14 (m, 6H, CH2-N(HCH-CH2)2-CH-); 2.25–2.35 (m, 4H,
CH2-N(HCH-CH2)2-CH-); 2.40–2.53 (m, 6H, 2H2, H3, 2H4, -N(CH2-CH2)2-CH); 2.63 (s, 3H, -CH3); 7.06
(dt, J = 2.2 Hz, J = 8.8 Hz, 1H, H5 bzx); 7.22–7.23 (m, 1H, H7 bzx); 7.70 (dd, J = 5.0 Hz, J = 8.7 Hz, 1H,
H4 bzx); 7.85 (m, 2H, H5 , H7); 8.01 (d, J = 8.0 Hz, 1H, H8). 13C NMR (CDCl3): δ 27.4 (CH3CO); 31.0
(N(CH2CH2)2C); 31.0 (N(CH2CH2)2C); 33.5 (C3); 34.9 (N(CH2CH2)2CH); 34.9 (C4); 44.1 (C2); 54.3
(N(CH2CH2)2C); 54.6 (N(CH2CH2)2C); 63.8 (CH2N<); 97.9 (d, J = 26.4 Hz, C7 bzx); 112.8 (d, J = 25.6
Hz, C5 bzx); 117.9 (C3a bzx); 123.0 (d, J = 11.3 Hz, C4 bzx); 126.7 (C7); 128.0 (C8); 128.3 (C5); 153.2
(C8a); 141.3 (C4a); 144.0 (C6); 162.4 (C3 bzx); 164.1 (C6 bzx); 166.3 (d, J = 16.6 Hz, C7a bzx); 197.7 (C1);
198.2 (CO). MS (CI): m/z= 420 (M+, 12%). Anal. C25H25FN2O3·H2O (C, H, N).
4.2.10.
3-[(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)methyl]-3,4-dihydro-6-phenylnaphthalen-
1(2H)-one (11).
Following the same procedure, amine 11 was synthesized from tosylate 9 as a white solid in 38%
yield. Mp 162–164 ºC (2-propanol). IR: 3299, 2953, 2924, 1680, 1606, 1493. 1H NMR (CDCl3): δ 2.06–
2.19 (m, 6H, CH2-N(HCH-CH2)2-CH-); 2.21–2.38 (m, 4H, CH2-N(HCH-CH2)2-CH-); 2.41–2.51 (m, 6H,
2H2, H3, 2H4, -N(CH2-CH2)2CH); 7.07 (dt, J = 2.2 Hz, J = 8.8 Hz, 1H, H5 bzx); 7.23 (d, J = 8.3 Hz, 1H,
H7 bzx); 7.39–7.49 (m, 4H, H7, H3 Ph, H4 Ph, H5 Ph); 7.50–7.69 (m, 3H, H5, H2 and H6 Ph); 7.71–7.72 (m,
1H, H4 bzx); 8.10 (d, J = 8.1 Hz, 1H, H8). 13C NMR (CDCl3): δ 31.0 (N(CH2CH2)2C); 33.6 (C3); 35.0
(N(CH2CH2)2CH); 35.1 (C4); 44.1 (C2); 54.3 and 54.7 (N(CH2CH2)2C); 64.0 (CH2N<); 97.4 (d, J =26.5
Hz, C7 bzx); 112.2 (d, J = 25.5 Hz, C5 bzx); 117.9 (C3a bzx); 122.5 (d, J = 11.2 Hz, C4 bzx); 125.5 (C7);
127.7 (C2 and C6 Ph); 128.0 (C4 Ph); 128.1 (C8); 128.7 (C5); 129.3 (C3 and C5 Ph); 131.3 (C8a); 140.2 (C1
Ph); 146.1 (C4a); 161.8 (C3 bzx); 164.8 (C6 bzx); 166.5 (d, J = 16.4 Hz, C7a bzx); 197.8 (C1). MS (CI):
m/z= 455 (MH+, 52%). Anal. C29H27FN2O2·¼H2O (C, H, N).

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4.2.11. 6-Acetyl-3-[(4-(4-fluorobenzoyl)piperidin-1-yl)methyl]-3,4-dihydronaphthalen-1(2H)-one (12)
Tosylate 8 (220 mg, 0.59 mmol), triethylamine (60 mg, 0.59 mmol)
and 4-(4-
fluorobenzoyl)piperidine hydrochloride (245 mg, 1.18 mmol) were dissolved in benzene (20 mL), and the
solution was refluxed for 12 h under argon. After cooling to room temperature, solvent was eliminated
under reduced pressure and the residue obtained dissolved in CH2Cl2 and washed with H2O. The organic
phase was dried (Na2SO4) and concentrated to give an oily residue which was purified by column
chromatography using EtOAc:hexane (2:1) as eluent to afford the required amine 12 (28 mg, 12%) as a
1
white solid. Mp 154–156 ºC. IR: 3430, 2925, 1685, 1598. H NMR (CDCl3): δ 1.80–1.99 (m, 4H, -
N(CH2-CH2)2CH-); 2.00–2.61 (m, 6H, -CH2-N(CH2-CH2)2C); 2.66–2.96 (m, 5H, 2H2, H3, 2H4); 3.17–
3.24 (m, 1H, -N(CH2-CH2)2CH-); 3.48 (s, 3H, CH3); 7.12 (t, J = 8.3 Hz, 2H, H3 and H5 Ph); 7.82–7.85
(m, 2H, H5, H7); 7.94–7.98 (m, 2H, H2 and H6 Ph); 8.00 (d, J = 8.3 Hz, 1H, H8). 13C NMR (CDCl3): δ
26.9 (COCH3); 28.7 and 28.8 (N(CH2CH2)2C); 33.0 (C3); 34.4 (C4); 43.6 (C2); 53.4 and 54.0
(N(CH2CH2)2C); 63.3 (CH2N<); 115.8 (d, J = 21.9 Hz; C3 and C5 Ph); 126.3 (C7); 127.4 (C8); 129.1 (C5);
130.8 (d, J = 9.6 Hz, C2 and C6 Ph); 132.4 (d, J = 3.0 Hz, C1 Ph); 135.5 (C8a), 140.4 (C6); 143.6 (C4a);
165.6 (d, J = 254.8 Hz, C4 Ph); 197.5 (C1); 197.8 (COCH3); 201.0 (C1). MS (CI): m/z= 408 (MH+, 57%).
Anal. C25H26FNO3·0.35H2O (C, H, N).
4.2.12. 3-[(4-(4-Fluorobenzoyl)piperidin-1-yl)methyl]-3,4-dihydro-6-phenylnaphthalen-1(2H)-one (13).
Following the same procedure, amine 13 was obtained from tosylate 9 as a white solid in 41%
yield. Mp 139–140 ºC (EtOAc/hexane). IR: 2942, 1678, 1598, 1506. 1H NMR (CDCl3): δ 1.72–1.80 (m,
4H, -N(CH2-CH2)2CH-); 2.31–2.47 (m, 6H, -CH2-N(CH2-CH2)2C); 2.74–3.00 (m, 4H, H2, H4); 3.17–3.22
(m, 2H, H3, -N(CH2-CH2)2CH-); 7.10–7.16 (m, 2H, H3 and H5 Ph-F); 7.39–7.55 (m, 5H, H5, H7, H3 Ph, H4
Ph, H5 Ph); 7.96 (dd, J = 5.5 Hz, J = 8.6 Hz, 2H, H2 and H6 Ph-F); 8.08 (d, J = 8.05 Hz, 1H, H8). 13C
NMR (CDCl3): δ 28.9 (N(CH2CH2)2C); 34.3 (C3); 35.1 (C4); 43.7 (C2), 44.0 (N(CH2CH2)2CH); 54.0
(N(CH2CH2)2C); 64.2 (CH2N<); 115.7 (d, J = 21.5 Hz, C3 and C5 Ph-F); 124.6 (C7); 126.9 (C4 Ph); 127.9
(C2 and C6 Ph); 127.9 (C8); 128.6 (C3 and C5 Ph); 129.3 (C5); 131.2 (d, J = 9.4 Hz, C2 and C6 Ph-F); 132.4
(d; J = 3.2 Hz, C1 Ph-F); 133.3 (C8a); 136.5 (C1 Ph); 140.0 (C6); 142.1 (C4a); 165.6 (d, J = 245.9 Hz, C4
Ph-F); 196.9 (C1); 202.1 (CO). MS (CI): m/z= 441 (MH+, 54%), 220 (31). Anal. C29H28FNO2·¾H2O (C,
H, N).
4.2.13. 2-(1,2,3,4-Tetrahydro-1-oxo-2-naphthylidene)acetic acid (14).
A stirred mixture of α-tetralone (2.2 g, 15.0 mmol), glyoxylic acid monohydrate (1.48 g, 16.0
mmol) and a catalytic amount of p-TSA was heated in a Dean-Stark apparatus at 160 ºC for 1 h. After
cooling, the solid formed was thoroughly triturated with ethyl acetate (2 × 50 mL). After filtration to
separate undissolved materials, the filtrate was washed several times with water and dried (Na2SO4), and
the solvent was evaporated to give 2.90 g (95%) of 14. Mp 188–189 ºC (EtOH) (Lit.: 188–189 ºC [10]).

ACCEPTED MANUSCRIPT
IR: 1593, 1631, 1666, 1691, 2599, 2903. 1H NMR (CDCl3-TFA): δ 3.08 (t, J = 6.3 Hz, 2H, H3); 3.45 (m,
2H, H4); 6.92 (s, 1H, -C=CH-COOH); 7.33 (d, J = 7.7 Hz, 1H, H5); 7.41 (t, J = 7.1 Hz, 1H, H7); 7.60 (t, J
= 7.4 Hz, 1H, H6); 8.10 (d, J = 7.1 Hz, 1H, H8). 13C NMR (CDCl3-TFA): δ 24.4 (C3); 30.9 (C4); 127.4
(C7); 128.7 (C5); 128.8 (=CH-COOH); 128.9 (C8); 131.3 (C8a); 135.1 (C6); 144.0 (C4a); 153.1 (C2); 175.9
(COOH); 200.6 (C1). MS (CI): m/ z = 203 (MH+, 58%), 185 (100), 157 (32), 129 (31).
4.2.14. 2-(1,2,3,4-Tetrahydro-1-oxonaphthalen-2-yl)acetic acid (15).
To a solution of 14 (2.0 g, 9.9 mmol) in 70% aqueous solution of glacial AcOH (30 mL), zinc
(granules, 1.50 g, 22.8 mmol) was added and the suspension vigorously stirred at 75 ºC for 1h. After
cooling the inorganic material was filtered off and the filtrate extracted several times with EtOAc. The
combined organic extracts were distilled under reduced pressure and the residue recrystallized from
cyclohexane giving 15 as a white solid (1.93 g, 94%). Mp 107–109 ºC (Lit.: 94–100 ºC [9]). IR: 1603,
1685, 1702, 2921. 1H NMR (CDCl3): δ 2.00 (dq, J = 4.5 Hz, J = 12.9 Hz, 1H, H3); 2.30–2.25 (m, 1H, H3);
2.49 (q, J = 8.3 Hz, 1H, -HCH-COOH); 2.96–3.20 (m, 4H, H2, H4, HCH-COOH); 7.24–7.35 (q, J = 7.5
Hz, 2H, H5, H7); 7.49 (t, J = 7.4 Hz, 1H, H6); 8.03 (d, J = 7.8 Hz, 1H, H8). 13C NMR (CDCl3): δ 29.2 (C3
and C4): 35.0 (CH2-COOH); 44.6 (C2); 126.7 (C7); 127.5 (C5); 128.8 (C8); 131.9 (C8a); 133.6 (C6); 144.1
(C4a); 178.6 (COOH); 198.4 (C1);. MS (EI): m/z = 204.1 (M+, 28%), 186.1 (43); 158.1 (52); 144.1 (98);
118 (100). Anal. C12H12O3 (C, H).
4.2.15. 2-(1,2,3,4-Tetrahydro-7-nitro-1-oxonaphthalen-2-yl)acetic acid (16).
A 33% solution of HNO3 in conc. H2SO4 (1 mL) was added dropwise during 30 minutes at -20°C
to a stirred solution of acid 15 (0.50 g, 2.5 mmol) in conc. H2SO4 (2 mL), and stirring was continued at
the same temperature for 45 minutes. Then, the solution was poured into crushed ice, filtered and washed
with water. The cream solid obtained was partially dried on the filter and then purified by recrystallization
from 33% aqueous methanol to give 16 (0.37 g, 60%) as a white solid. Mp 149–150 ºC (H2O/MeOH). IR:
1523, 1607, 1686, 1709, 2878. 1H NMR ((CD3)2CO): δ 2.03–2.20 (m, 1H, 1H3); 2.32–2.38 (m, 1H, 1H3);
2.59 (dd, J = 6.4 Hz, J = 16.9 Hz, 1H, HCH-COOH); 2.93 (dd, J = 5.4 Hz, J = 16.8 Hz, 1H, HCH-
COOH); 3.06–3.36 (m, 3H, H2, H4); 7.67 (d, J = 8.5 Hz, 1H, H5); 8.36 (dd, J = 2.5 Hz, J = 8.5 Hz, 1H,
H6); 8.67 (d, J = 2.5 Hz, 1H, H8); 10.76 (br.s., 1H, -OH). 13C NMR ((CD3)2CO): δ 28.2 (C3); 29.7 (C4);
33.9 (CH2-COOH); 44.2 (C2); 121.5 (C8); 126.8 (C6); 130.9 (C5); 133.5 (C8a); 146.9 (C7); 151.5 (C4a);
172.5 (COOH); 196.4 (C1). MS (CI): m/z 250.1 (MH+, 29%), 231.2 (100), 220.1 (12), 202.1 (22). Anal.
C12H11NO5 (C, H, N).
4.2.16. 3,4-Dihydro-7-nitronaphthalen-1(2H)-one (17).
7-Nitrotetralone was synthesized by nitration of commercially available 1-tetralone following the
method previously described, and its spectroscopic data were consistent with those of the Literature [16].
1
Yield: 65%. Mp 106–108 ºC (Hexane). IR: 1355, 1519, 1607, 1681, 3085. H NMR (CDC13): δ 2.13–
2.30 (m, 2H, H3); 2.66–2.81 (m, 2H, H4); 3.10 (t, J = 6.0 Hz, 2H, H2); 7.50 (d, J = 8.4 Hz, 1H, H5); 8.30

ACCEPTED MANUSCRIPT
(dd, J = 2.5 Hz, J = 8.4 Hz, 1H, H6); 8.80 (d, J = 2.5 Hz, 1H, H8). 13C NMR (CDCl3): δ 22.4 (C3); 29.6
(C4); 38.4 (C2); 122.1 (C8); 126.9 (C6); 130.2 (C5); 133.2 (C8a); 146.8 (C7); 150.9 (C4a); 195.9 (C1). MS
(CI): m/z= 192.0 (MH+, 100%), 162.1 (29).
4.2.17. 2-(1,2,3,4-Tetrahydro-7-nitro-1-oxo-2-naphthylidene)acetic acid (18).
Acid 18 was synthesized from 17 following the procedure reported for 14. Yield: 90%. Mp >230
1
ºC. IR: 1519, 1606, 1672, 1696, 2927. H NMR (CD3OD): δ 3.20–3.22 (m, 2H, H3); 3.46–3.43 (m, 2H,
H4); 6.81 (t, J = 1.9 Hz, 1H, -C=CH-COOH); 7.71 (d, J = 8.4 Hz, 1H, H5); 8.39 (dd, J = 2.6 Hz, J = 8.5
Hz, 1H, H6); 8.70 (d, J = 2.2 Hz, 1H, H8). 13C NMR ((CD3)2CO): δ 26.0 (C3); 28.2 (C4); 122.4 (C8); 122.2
(=CH-COOH); 127.5 (C6); 130.7 (C5); 133.3 (C8a); 147.8 (C7); 151.2 (C2); 166.1 (C4a); 185.1 (COOH);
205.6 (C1). MS (CI): m/z= 248.1 (MH+, 52%), 230.1 (99), 201 (100). Naphthylideneacetic acid 18 was
reduced as for 14 to give nitroacid 16 in 84% yield.
4.2.18. 2-[2-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-2-oxoethyl]-3,4-dihydro-7-
nitronaphthalen-1(2H)-one (19).
A solution of acid 16 (0.50 g, 2.0 mmol), 1-HOBt (0.54 g, 4.0 mmol) and 4-(6-
fluorobenzo[d]isoxazol-3-yl)piperidine (0.44 g, 2.0 mmol) in anhydrous CH2Cl2 (25 mL) was stirred
under argon at room temperature for 15 min and then cooled to 0 °C. At this temperature, DCC (0.83 g,
4.0 mmol) was added, and the reaction mixture was stirred at the same temperature for 1 h, then allowed
to reach room temperature and stirred overnight. The precipitated dicyclohexylurea was filtered off, and
the filtrate was washed several times with 10% NaHCO3, dried (Na2SO4), and concentrated to dryness.
The oily residue was purified by flash chromatography using EtOAc:hexane (1:2) as eluent to give the
1
title amide 19 (0.74 g, 82%). Mp 84–85 ºC. IR: 1343, 1495, 1522, 1611, 1636, 1688, 2925. H NMR
(CDCl3): δ 1.90–2.24 (m, 5H, -N(HCH-CH2)2CH-, 1H3); 2.35–2.41 (m, 1H, 1H3); 2.52–2.60 (m, 1H, -
HCH-CON<); 2.96 (q, J = 11 Hz, 1H, -N(HCH-CH2)2CH-); 3.20 (td, J = 4.7 Hz, J = 12.2 Hz, 4H, H2, H4,
-HCH-CON<); 3.38 (dt, J = 3.5 Hz, J = 11.1 Hz, 2H, -N(HCH-CH2)CH-, -N(HCH-CH2)CH-); 4.11–4.18
(m, 1H, -N(HCH-CH2)CH-); 4.70–4.72 (m, 1H, -N(HCH-CH2)CH-); 7.12 (dd, J = 2.2 Hz, J = 8.8 Hz, 1H,
H5 bzx); 7.26 (dd, J = 2.2 Hz, J = 8.5 Hz, 1H, H7 bzx); 7.45 (d, J = 8.5 Hz, 1H, H5); 7.70 (ddd, J = 5.0 Hz,
J = 8.5 Hz, J = 13.7 Hz, 1H, H4 bzx); 8.29 (dd, J = 2.5 Hz, J = 8.5 Hz, 1H, H6); 8.84 (d, J = 2.5 Hz, 1H,
H8). 13C NMR (CDCl3): δ 28.9 (C3); 29.6 (C4); 30.4 (N(CH2-CH2)CH); 33.4 (N(CH2-CH2)CH); 34.5
(CH2-CON<); 41.6 (CON(CH2-CH2)CH); 44.9 (C2); 130.3 (C5); 45.3 (N(CH2-CH2)CH); 45.6 (N(CH2-
CH2)CH); 97.6 (d, J = 26.5 Hz, C7 bzx); 112.7 (d, J = 25.4 Hz, C5 bzx); 117.0 (C3a bzx); 122.5 (d, J =
11.5 Hz, C4 bzx); 122.7 (C8); 127.0 (C6); 133.2 (C8a); 147.0 (C7); 150.7 (C4a); 160.2 (C3 bzx); 163.9 (d, J
= 7.0 Hz, C7a bzx); 164.2 (d, J = 251 Hz, C6 bzx); 169.2 (CON); 197.4 (C1). MS (CI): m/z= 451.0 (MH+,
45%); 232.0 (49); 219.0 (100). Anal. C24H22FN3O5 (C, H, N).
4.2.19. 3,4-Dihydro-2-[2-(4-(2-methoxyphenyl)piperazin-1-yl)-2-oxoethyl]-7-nitronaphthalen-1(2H)-one
(20).

ACCEPTED MANUSCRIPT
Amide 20 was similarly prepared in 83% yield. Mp 79–80 ºC. IR: 1521, 1609, 1636, 1686, 2915.
1H NMR (CDCl3): δ 2.05 (dq, J = 4.6 Hz, J = 12.9 Hz, 1H, H3); 2.40 (dd, J = 3.0 Hz, J = 13.2 Hz, 1H,
H3); 2.54 (dd, J = 7.6 Hz, J = 16.7 Hz, 1H, HCH-CON<); 3.05–3.23 (m, 8H, -CON(CH2CH2)2N-, HCH-
CON<, H2, H4); 3.71–3.86 (m, 4H, -CON(CH2CH2)2N-); 3.89 (s, 3H, -OCH3); 6.88–7.07 (m, 4H, Ph);
7.45 (d, J = 8.5 Hz, 1H, H5); 8.29 (dd, J = 2.5 Hz, J = 8.5 Hz, 1H, H6); 8.86 (d, J = 2.5 Hz, 1H, H8). 13
C
NMR (CDCl3): δ 27.9 (C3); 28.5 (C4); 32.3 (-CH2CON<); 41.1 (-N(CH2CH2)2N-); 43.7 (C2); 44.8 (-
N(CH2CH2)2N-); 49.5 (-N(CH2CH2)2N-); 49.9 (-N(CH2CH2)2N-); 54.4 (-OCH3); 110.3 (C6 Ph); 117.5 (C3
Ph); 120.1 (C4 Ph); 121.8 (C5 Ph); 122.6 (C8); 126 (C6); 129.2 (C5); 132.3 (C8a); 139.6 (C1 Ph); 146.1
(C7); 149.6 (C4a); 151.3 (C2 Ph); 168.2 (-CON); 196.3 (C1). MS (CI): m/z= 424.2 (MH+, 100%); 205.0
(48).
4.2.20. 2-[2-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl]-1,2,3,4-tetrahydro-7-
nitronaphthalen-1-ol (21).
Under argon atmosphere, a solution of amide 19 (0.1 g, 0.22 mmol) in dry THF (10mL) was
added dropwise at 0ºC to a freshly-prepared 1M solution of AlH3 (0.55 mL, 0.55 mmol) in anhydrous
THF. The resulted suspension was stirred at the same temperature for 1h, when TLC indicated the
absence of starting material. The reaction mixture was quenched by careful addition of H2O (0.5 mL),
10% aqueous Na2CO3 (2 mL) and H2O (0.5 mL) at 0ºC. The reaction mixture was filtered in vacuo and
the filtrate evaporated. The crude obtained was dissolved in CH2Cl2, dried over Na2SO4, concentrated
under reduced pressure and finally purified by preparative silica gel chromatography using
CH2Cl2:MeOH (99:1) as eluent to afford the required compound 21 as a off-white foam (29 mg, 30%).
Mp 133–135ºC. IR: 1494, 1516, 1613, 2928, 3066. 1H NMR (CDCl3): δ 1.64–1.89 (m, 5H, H2, H3, -CH2-
CH2N<); 2.06–2.34 (m, 5H, N(CH2CH2)2CH-, -CH2-HCH-N<); 2.50 (dt, J = 2.4 Hz, J = 11.5 Hz, 1H, -
HCH-N<); 2.62–2.67 (m, 2H, H4); 2.90–3.05 (m, 3H, N(HCHCH2)2CH-); 3.18–3.35 (m, 2H, N(HCH-
CH2)2CH); 4.20 (d, J = 7.7 Hz, H1); 7.19 (dd, J = 2.3 Hz, J = 8.8 Hz, 2H, H5, H5 bzx); 7.25 (dd, J = 2.2
Hz, J = 8.1 Hz, 1H, H7 bzx); 7.90 (dd, J = 5.2 Hz, J = 8.8 Hz, H4 bzx); 7.97 (dd, J = 2.2 Hz, J = 8.4 Hz,
1H, H6); 8.65 (d, J = 1.9 Hz, 1H, H8). 13C NMR (CDCl3): δ 29.6 (C3); 29.7 (-CH2CH2N<); 29.9 (C4); 34.2
(-N(CH2CH2)2CH-); 44.3 (C2); 51.4 (-N(CH2CH2)2CH-); 54.5 (-CH2N<); 57.7 (-N(CH2CH2)2CH-); 73.3
(C1); 97.6 (d, J = 26.5 Hz, C7 bzx); 112.9 (d, J = 25.4 Hz, C5 bzx); 116.9 (C3a bzx); 121.3 (C6); 122.9
(C8); 123.1 (C4 bzx); 128.9 (C5); 141.8 (C8a); 143.6 (C4a); 146.8 (C7); 160.6 (C3 bzx); 164.1 (d, J = 13.8
Hz, C7a bzx); 165.8 (d, J = 251 Hz, C6 bzx). MS (CI): m/z= 440.2 (MH+, 93%), 422.2 (24), 410.2 (68),
137.9 (100). Anal. C24H26FN3O4·0.6H2O: (C, H, N).
4.2.21. 1,2,3,4-Tetrahydro-2-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]-7-nitronaphthalen-1-ol (22).
Following the same procedure, compound 22 was synthesized from 20 as a colourless oily solid
in 30% yield. IR: 1499, 1518, 1577, 1625, 2850, 2926, 3322. 1H NMR (CDCl3): δ 1.61–1.88 (m, 5H, H2,
H3, -CH2-CH2N<); 2.58–2.73 (m, 4H, N(H2C-CH2)2N); 2.88–2.99 (m, 4H, H4, -CH2-CH2N<); 3.19 (br.s.,

ACCEPTED MANUSCRIPT
4H, -N(H2C-CH2)2N-); 3.87 (s, 3H, -OCH3); 4.40 (d, J = 7.8 Hz, 1H, H1); 6.86–7.06 (m, 4H, Ph); 7.17 (d,
J = 8.4 Hz, 1H, H5); 7.96 (dd, J = 2.3 Hz, J = 8.2 Hz, 1H, H6); 8.61 (d, J = 1.9 Hz, 1H, H8). 13C NMR
(CDCl3): δ 29.5 (C3); 29.7 (-CH2-CH2N<); 33.5 (C4); 44.1 (C2); 50.2 (-N(CH2CH2)2N-); 53.1 (-CH2N<);
55.4 (-OCH3); 57.7 (-N(CH2CH2)2N-); 73.1 (C1); 111.1 (C3 Ph); 118.6 (C6 Ph); 121.1 (C6); 121.3 (C4 Ph);
123.1 (C8); 123.3 (C5 Ph); 128.8 (C5); 140.8 (C8a); 141.9 (C1 Ph); 143.7 (C4a); 146.8 (C7); 152.2 (C2 Ph).
MS (EI): m/z= 411.2 (M+, 85%), 394.2 (39), 205.1 (100). Hydrochloride (22·HCl): Mp 193–194 ºC. Anal.
C23H29N3O4·2HCl·0.05H2O (C, H, N).
4.2.22. 7-Amino-2-[2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl]-1,2,3,4-
tetrahydronaphthalen-1-ol (24) and 7-Amino-2-[2-(4-(4-fluoro-2-hydroxybenzoyl)piperidin-1-yl)ethyl]-
1,2,3,4-tetrahydronaphthalen-1-ol (25).
To a suspension of 10% Pd/C (20 mg) in dry THF (2 mL), a solution of nitroalcohol 21 (0.2 g,
0.46 mmol) in THF (8 mL) was added and the mixture vigorously stirred under H2 at room temperature
for 12 h. Then, the reaction was filtered off through a pad of Celite and concentrated in vacuo. The crude
material was purified by aluminum dioxide column chromatography using 95% methanol:acetone as
eluent to yield alcohol 24 (47 mg, 25%) as a white solid and aminoketone 25 (38 mg, 20%) as an oily
colourless solid.
4.2.22.1. 7-Amino-2-[2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl]-1,2,3,4-
tetrahydronaphthalen-1-ol (24). Mp 137–139 ºC. IR: 1456, 1499, 1589, 1619, 2851, 2922. 1H NMR
(CDCl3): δ 1.61–1.80 (m, 5H, H2, H3, -CH2-CH2N<); 2.12–2.22 (m , 5H, N(CH2CH2)2CH-, -CH2-HCH-
N<); 2.41 (dt, J = 2.4 Hz, J = 11.5 Hz, 1H, -CH2-HCH-N<); 2.61–2.68 (m, 3H, N(HCH-CH2)2CH-, 1H4);
2.73–2.84 (m, 1H, 1H4); 3.03–3.33 (m, 3H, N(HCH-CH2)2CH-); 4.37 (d, J = 7.8 Hz, 1H, H1); 6.46 (dd, J
= 2.6 Hz, J = 8.1 Hz, 1H, H6); 6.87 (d, J = 8.0 Hz, 1H, H5); 7.08 (dt, J = 2.1 Hz, J = 8.8 Hz, 2H, H8, H5
bzx); 7.25 (dd, J = 2.1 Hz, J = 8.5 Hz, 1H, H7 bzx); 7.77 (dd, J = 5.0 Hz, J = 8.8 Hz, 1H, H4 bzx). 13
C
NMR (CDCl3): δ 28.8 (C3); 29.8 (-CH2CH2N<); 29.9 (C4); 33.7 (-N(H2C-CH2)2CH-); 44.3 (C2); 51.9 (-
N(CH2CH2)2CH-); 54.0 (-CH2N<); 57.8 (-N(CH2CH2)2CH-); 73.8 (C1); 97.5 (d, J =26.5 Hz, C7 bzx);
112.5 (d, J = 25.4 Hz, C5 bzx); 113.9 (C6); 114.3 (C8); 117.1 (C3a bzx); 122.8 (d, J = 11.6 Hz, C4 bzx);
126.4 (C4a); 128.8 (C5); 140.5 (C8a); 144.5 (C7); 160.7 (C3 bzx); 164.0 (d, J = 13.8 Hz, C7a bzx); 165.8 (d,
J = 251 Hz, C6 bzx). MS (CI): m/z= 410.1 (MH+, 100%), 392.1 (86); 233.1 (49), 201.1 (40). Anal.
C24H28FN3O2·0.5H2O·0.6C4H10O (C, H, N).
4.2.22.2. 7-Amino-2-[2-(4-(4-fluoro-2-hydroxybenzoyl)piperidin-1-yl)ethyl]-1,2,3,4-
tetrahydronaphthalen-1-ol (25). IR: 1504, 1616, 1633, 2847, 2924. 1H NMR (CDCl3): δ 1.52–1.79 (m,
5H, H2, H3, -CH2-CH2N<); 1.86–2.13 (m, 5H, N(H2C-CH2)2CH-, -CH2-HCH-N<); 2.32 (dt, J = 2.7 Hz, J
= 11.6 Hz, 1H, -CH2-HCH-N<); 2.57–2.82 (m, 4H, H4, N(HCH-CH2)2CH-); 3.01 (m, 1H, N(CH2-
CH2)2CH-); 3.23–3. 03 (m, 2H, N(HCH-CH2)2CH-); 4.34 (d, J = 7.8 Hz, 1H, H1); 6.51 (dd, J = 2.5 Hz, J
= 8.0 Hz, 1H, H6); 6.57–6.71 (m, 2H, H3 and H5 Ph); 6.84 (d, J = 8.0 Hz, 1H, H5); 7.05 (d, J = 2.3 Hz, 1H,

ACCEPTED MANUSCRIPT
H8); 7.76 (dd, J = 6.4 Hz, J = 8.9 Hz, 1H, H6 Ph); 12.77 (s, Ph-OH). 13C NMR (CDCl3): δ 28.7 (C3); 30.2
(-CH2-CH2N<); 33.7 (C4); 43.2 (-N(CH2-CH2)2CH-); 44.3 (C2); 51.7 (-N(CH2-CH2)CH-); 53.7 (-CH2N<);
57.8 (-N(CH2-CH2)2CH-); 73.8 (C1); 105.4 (d, J = 23.0 Hz, C3 Ph); 107.3 (d, J = 23.0 Hz, C5 Ph); 113.9
(C6); 114.2 (C8); 115.2 (C1 Ph); 126.3 (C4a); 128.8 (C5); 131.8 (d, J = 11.5 Hz, C6 Ph); 144.6 (C7); 140.5
(C8a); 165.8 (C2 Ph); 167.0 (d, J = 253 Hz, C4 Ph); 207.0 (CO). MS (CI): m/z= 413.2 (MH+, 87%), 395.2
(100), 236.0 (46). Hydrochloride (25·HCl): Mp >230ºC. Anal. C24H29FN2O3·2HCl·0.85CH4O (C, H, N).
4.2.23. 7-Amino-1,2,3,4-tetrahydro-2-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]naphthalen-1-ol (23).
To a suspension of 10% PtO2 (20 mg) in dry THF (2 mL), a solution of 22 (0.1 g, 0.24 mmol) in
dry THF (8 mL) was added and the resulting suspension was vigorously stirred under H2 at room
temperature for 12 h. Then, the reaction mixture was filtered through a pad of Celite and the filtrate was
evaporated in vacuo. The residue was purified by silica gel preparative chromatography using
CH2Cl2:MeOH (95:5) as eluent to yield the alcohol 23 (64 mg, 70 %) as a colourless oil. IR: 1499, 1592,
1
1620, 2826, 2919. H NMR (CDCl3): δ 1.65–1.79 (m, 5H, H2, H3, -CH2-CH2N<); 2.59–2.69 (m, 6H, -
N(CH2CH2)2N, -CH2-CH2N<); 2.75 (dd, J = 4.7 Hz, J = 11.2 Hz, 2H, H4); 2.90 (s.a, 2H, -NH2); 3.17
(br.s. 4H, -N(CH2CH2)2N-); 3.87 (s, 3H, -OCH3); 4.37 (d, J = 7.8 Hz, 1H, H1); 6.51 (dd, J = 2.5 Hz, J =
8.0 Hz, 1H, H6); 6.83–7.04 (m, 6H, H8, H5, Ph). 13C NMR (CDCl3): δ 28.8 (C3); 29.7 (-CH2-CH2N<); 33.6
(C4); 44.4 (C2); 50.2 (N(CH2CH2)2N); 53.1 (CH2N<); 55.3 (-OCH3); 57.8 (-N(CH2-CH2)2N-); 73.8 (C1);
111.1 (C3 Ph); 113.9 (C6); 114.2 (C8); 118.4 (C6 Ph); 120.9 (C4 Ph); 123.1 (C5 Ph); 126.4 (C4a); 128.8
(C5); 140.6 (C8a); 140.9 (C1 Ph); 144.5 (C7); 152.2 (C2 Ph). MS (CI): m/z= 382.2 (MH+, 96%), 364.2
(100), 205.0 (90). Hydrochloride (23·HCl): Mp > 230 ºC. Anal. C23H31N3O2·2HCl·2.05CH4O·1.3H2O (C,
H, N).
4.2.24. 7-Amino-2-[2-(4-(4-fluoro-2-hydroxybenzoyl)piperidin-1-yl)ethyl]-1,2,3,4-tetrahydronaphthalen-
1-ol (25).
Alcohol 25 was also obtained from 21 in 57% yield applying the methodology described for
obtaining 23 from 22. Spectroscopic data were consistent with those abovementioned.
4.2.26. 7-Amino-2-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-2-oxoethyl)-3,4-
dihydronaphthalen-1(2H)-one (26).
To a solution of 19 (0.1 g, 0.22 mmol) in anhydrous THF (2 mL), tin(II) chloride dihydrate (0.26
g, 1.1 mmol) was added. The mixture was stirred at room temperature for 5 minutes and then at 50-60 °C
for 6 h. After cooling, the mixture was diluted with EtOAc and taken to pH 5-6 with 8% aqueous
NaHCO3 solution. The mixture was filtered and the aqueous layer separated, extracted with EtOAc and
the combined extracts washed with brine, dried over Na2SO4 and concentrated in vacuo to give the amide
1
26 as a white foam (90 mg, 99%). Mp 90–91 ºC. IR: 1497, 1612, 1678, 1732, 2927, 3351. H NMR
(CDCl3): δ 1.80–2.12 (m, 5H, -N(CH2-CH2)2CH-, 1H3); 2.19–2.34 (m, 1H, 1H3); 2.74–2.86 (m, 2H, -
HCH-CON<, -N(HCH-CH2)2CH-); 2.90–3.35 (m, 6H, H2, H4, -HCH-CON<, -N(HCH-CH2)2CH-); 3.66

ACCEPTED MANUSCRIPT
(br.s., 2H, -NH2); 4.03–4.08 (m, 1H; -N(HCH-CH2)CH-); 4.56-4.68 (m, 1H; -N(HCH-CH2)CH-); 6.76
(dd, J = 8.1 Hz, J = 2.6 Hz, 1H, H6); 6.94–7.05 (m, 2H, H5, H5 bzx); 7.19 (dd, J = 2.5, J = 8.0, 1H, H7
bzx); 7.24 (d, J = 2.5 Hz, 1H, H8); 7.64 (ddd, J = 5.0 Hz, J = 8.5 Hz, J = 13.7 Hz, 1H, H4 bzx). 13C NMR
(CDCl3): δ 28.5 (C3); 29.7 (C4); 30.4 and 33.5 (-N(CH2-CH2)2CH-); 34.2 (-N(CH2-CH2)2CH-); 41.7 (C2);
34.6 (CH2-CON<); 45.1 and 45.6 (-N(CH2-CH2)2CH-); 97.6 (d, J = 25.3 Hz, C7 bzx); 112.3 (C8); 112.6
(d, J = 28.2 Hz, C5 bzx); 117.0 (C3a bzx); 120.9 (C6); 122.3 (d, J = 10.4 Hz, C4 bzx); 129.7 (C5); 132.9
(C4a); 134.5 (C8a); 144.9 (C7); 160.3 (C3 bzx); 163.9 (d, J = 12.6 Hz, C7a bzx); 164.2 (d, J = 250 Hz, C6
bzx); 170.1 (CON); 199.7 (C1). MS (CI): m/z= 422.2 (MH+, 86%), 221.1 (50), 203.0 (100). Anal.
C24H24FN3O3 (C, H, N).
4.2.27. 7-Amino-2-[2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl]-1,2,3,4-
tetrahydronaphthalen-1-ol (24).
Aminoalcohol 24 was prepared from amide 26 in 25% yield following the procedure described
for the synthesis of 21. Spectroscopic data were consistent with those already reported.
4.2.28. 2-(1,1-Ethylenedioxy-1,2,3,4-tetrahydro-7-nitronaphthalen-2-yl)-1-[4-(6-fluorobenzo[d]isoxazol-
3-yl)piperidin-1-yl]ethanone (27).
To a solution of amide 19 (0.50 g, 1.1 mmol) in anhydrous benzene (20 mL), ethyleneglycol (2.70
mL, 48 mmol) followed by a catalytic amount of p-TSA were added. The reaction mixture was refluxed
in a Dean–Stark for 16h. After cooling to ambient, the organic layer was washed with 10% NaHCO3 (1 ×
20 mL) and the aqueous layer extracted with CH2Cl2 (3 × 20 mL). Next, the combined organic layers
were dried over Na2SO4 and concentrated under reduced pressure. The crude oil was purified by silica gel
column chromatography using EtOAc:hexane (1:1) as eluent to afford the desired compound 27 as a light
1
yellow oil (0.41g, 75%). IR: 1520, 1613, 1639, 2925, 3418. H NMR (CDCl3): δ 1.88–2.32 (m, 7H, H3,
1H4, -N(HCH-CH2)2CH-); 2.65–2.77 (m, 2H, -HCH-CON<, 1H4); 2.87–2.98 (m, 3H, H2, -HCH-CON<, -
N(HCH-CH2)2CH-); 3.20–3.38 (m, 2H, -N(HCH-CH2)2CH-); 3.98 (d, J = 12.8 Hz, 1H, -N(HCH-
CH2)CH-); 4.11–4.32 (m, 4H, -OCH2CH2O-); 4.68 (t, J = 12.6 Hz, 1H, -N(HCH-CH2)CH-); 7.03–7.13
(m, 1H, H5 bzx); 7.23–7.30 (m, 2H, H5, H7 bzx); 7.61–7.67 (m, 1H, H4 bzx); 8.08 (dd, J = 2.3 Hz, J = 8.5
Hz, 1H, H6); 8.31 (d, J = 2.4 Hz, 1H, H8). MS (CI): m/z= 496.1 (MH+, 98%), 361.2 (11), 260.1 (20),
232.0 (25).
4.2.29.
2-(1,1-Ethylenedioxy-1,2,3,4-tetrahydro-7-nitronaphthalen-2-yl)-1-[4-(2-
methoxyphenyl)piperazin-1-yl]ethanone (28).
Following the same procedure, ketal 28 was prepared from ketone 20 as a colourless oil in 65%
yield. IR: 1521, 1591, 1639, 2890. 1H NMR (CDCl3): δ 2.00 (dd, J = 6.6 Hz, J = 13.4 Hz, 1H, H3); 2.17
(dd, J = 8.8 Hz, J = 14.8 Hz, 1H, H3); 2.63–2.74 (m, 3H, -CH2-CON<, H2); 2.93 (t, J = 6.8 Hz, 2H, H4);
3.00 (br.s., 4H, (-N(CH2CH2)2N-); 3.60 (br.s., 3H, N(HCH-CH2)N-, N(HCH-CH2)2N-); 3.70–3.82 (m, 1H,
-N(HCH-CH2)N-); 3.85 (s, 3H, -OCH3); 4.10–4.30 (m, 4H, -OCH2CH2O-); 6.85–7.04 (m, 4H, -Ph); 7.28

ACCEPTED MANUSCRIPT
(d, J = 8.5 Hz, 1H, H5); 8.07 (dd, J = 2.4 Hz, J = 8.5 Hz, 1H, H6); 8.29 (d, J = 2.4 Hz, 1H, H8). MS (CI):
m/z= 467.9 (MH+, 85%), 437.9 (100), 233.9 (52).
4.2.30. 3-(1-(2-(1,1-Ethylenedioxy-1,2,3,4-tetrahydro-7-nitronaphthalen-2-yl)ethyl)piperidin-4-yl)-6-
fluorobenzo[d]isoxazole (29).
Under argon atmosphere, a solution of ketone 27 (0.2 g, 0.4 mmol) in dry THF (20mL) was added
dropwise at 0ºC to a freshly-prepared 1M solution of AlH3 (1.71 mL, 1.71 mmol) in anhydrous THF. The
resulted suspension was stirred at the same temperature for 1h, when TLC indicated the absence of
starting material. The reaction mixture was quenched by careful addition of 10% aqueous Na2CO3 (2 mL)
at 0ºC. The reaction mixture was filtered in vacuo and the filtrate evaporated. The crude obtained was
dissolved in CH2Cl2, dried over Na2SO4, concentrated under reduced pressure and finally purified by
preparative chromatography using EtOAc:hexane (2:1) as eluent to afford the required ketal 29 as
1
yellowish oil (0.13 g, 66%). IR: 1495, 1520, 1589, 1613, 2940. H NMR (CDCl3): δ 1.82–1.99 (m, 2H,
1H3, HCH-CH2-N<); 2.04–2.27 (m, 8H, H2, 1H3, -N(CH2-CH2)2CH-, -N(CH2-CH2)2CH-, HCH-CH2-N<);
2.50 (t, J = 7.2 Hz, 2H, CH2-CH2-N<); 2.91 (q, J = 6.7 Hz, 2H, H4); 3.00–3.12 (m, 4H, -N(CH2-CH2)2CH-
); 4.13–4.29 (m, 4H, -OCH2CH2O-); 7.04 (dt, J = 2.2 Hz, J = 8.8 Hz, 1H, H5 bzx); 7.22–7.28 (m, 2H, H5,
H7 bzx); 7.68 (dd, J = 5.0 Hz, J = 8.7 Hz, 1H, H4 bzx); 8.08 (dd, J = 2.2 Hz, J = 8.5 Hz, 1H, H6); 8.31 (d,
J = 2.5 Hz, 1H, H8). MS (CI): m/z= 482.2 (MH+, 100%), 452.2 (44), 233.0 (26).
4.2.31. 1-(2-(1,1-Ethylenedioxy-1,2,3,4-tetrahydro-7-nitronaphthalen-2-yl)ethyl)-4-(2-
methoxyphenyl)piperazine (30).
The title compound was prepared from 28 in a similar manner to that for 29 (62% yield) as a
1
yellow oil. IR: 1499, 1520, 1591, 2938. H NMR (CDCl3): δ 1.80–1.98 (m, 3H, H3, -HCH-CH2-N<);
2.06–2.09 (m, 1H, -HCH-CH2-N<), 2.10–2.25 (m, 1H, H2); 2.51 (t, J = 8.2 Hz, 2H, CH2-CH2-N<); 2.67
(br.s., 4H, -N(H2C-CH2)2N-); 2.87–3.02 (m, 2H, H4); 3.09 (br.s., 4H, -N(CH2-CH2)2N-); 3.85 (s, 3H, -
OCH3); 4.11–4.28 (m, 4H, -OCH2CH2O-); 6.85–7.04 (m, 4H, -Ph); 7.25 (d, J = 8.2 Hz, 1H, H5); 8.06 (dd,
J = 2.4 Hz, J = 8.5 Hz, 1H, H6); 8.31 (d, J = 2.3 Hz, 1H, H8). MS (CI): m/z= 454.2 (MH+, 12%), 424.2
(27), 262.1 (10), 218.0 (65).
4.2.32.
8,8-Ethylenedioxy-7-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-5,6,7,8-
tetrahydronaphthalen-2-amine (33) and (1-(2-(7-Amino-1,1-ethylenedioxy-1,2,3,4-tetrahydronaphthalen-
2-yl)ethyl)piperidin-4-yl)(4-fluoro-2-hydroxyphenyl)methanone (35).
To a suspension of palladium on activated charcoal 10% (40 mg) in dry THF (2 mL), a solution
of 7-nitro ketal 29 (0.20 g, 0.42 mmol) in THF (8 mL) was added and the mixture vigorously stirred
under H2 at room temperature for 12 h. Afterwards, the reaction was filtered off through a pad of Celite to
remove the catalyst and subsequently evaporation of the filtrate gave a residue that was purified by
column chromatography on aluminum dioxide using methanol:acetone (95:5) as eluent yielding the ketals
33 (72 mg, 35%) and 35 (56 mg, 25%) as oily solids.

ACCEPTED MANUSCRIPT
4.2.32.1.
8,8-Ethylenedioxy-7-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-5,6,7,8-
1
tetrahydronaphthalen-2-amine (33). IR: 1446, 1496, 1614, 2927, 3356. H NMR (CDCl3): δ 1.74–1.84
(m, 3H, H3, HCH-CH2-N<); 1.90–2.14 (m, 8H, H2, HCH-CH2-N(HCH-CH2)2CH-); 2.42 (t, J = 7.8 Hz,
2H, CH2-CH2-N<); 3.01 (dd, J = 5.4 Hz, J = 12.1 Hz, 2H, N(HCH-CH2)2CH-); 2.53–2.77 (m, 2H, H4);
3.99–4.13 (m, 4H, -OCH2CH2-O-), 6.53 (dd, J = 2.5 Hz, J = 8.3 Hz, 1H, H6); 6.70 (d, J = 2.4 Hz, 1H, H8);
6.84 (d, J = 8 Hz, 1H, H5); 6.97 (dt, J = 2.1 Hz, J = 8.9 Hz, 1H, H5 bzx); 7.16 (dd, J = 2.2 Hz, J = 8.5 Hz,
1H, H7 bzx); 7.62 (dd, J = 5.2 Hz, J = 8.8 Hz, 1H, H4 bzx). 13C NMR (CDCl3): δ 24.3 (-CH2-CH2-N<);
24.7 (C4); 25.0 (C3); 29.7 (-N(CH2-CH2)CH-); 30.6 (-N(CH2-CH2)CH-); 34.7 (-N(CH2-CH2)2CH-); 40.1
(C2); 53.3 (-N(CH2-CH2)CH-); 53.9 (N(CH2-CH2)CH-); 57.4 (-CH2-N<); 65.2 (-OCH2CH2O-); 65.6 (-
OCH2CH2O-); 97.4 (d, J = 27.7 Hz, C7 bzx); 109.4 (C1); 111.9 (C6); 112.3 (d, J = 25.3 Hz, C5 bzx); 116.2
(C8); 117.3 (C3a bzx); 122.6 (d, J = 11.5 Hz, C4 bzx); 127.7 (C4a); 129.6 (C5); 138.1 (C8a); 144.3 (C7);
161.1 (C3 bzx); 163.8 (d, J = 12.6 Hz, C7a bzx); 164.1 (d, J = 251 Hz, C6 bzx). MS (CI): m/z= 452.2
(MH+, 100%), 432.2 (16), 390.2 (8).
4.2.32.2.
(1-(2-(7-Amino-1,1-ethylenedioxy-1,2,3,4-tetrahydronaphthalen-2-yl)ethyl)piperidin-4-yl)(4-
fluoro-2-hydroxyphenyl)methanone (35). IR: 1447, 1504, 1633, 2936. 1H NMR (CDCl3): δ 1.73-1.83 (m ,
5H, 1H3, -CH2-CH2N(CH2-HCH)2CH-); 1.92–2.10 (m, 4H, H2, 1H3, N(HCH-CH2)2CH-,); 2.38 (t, J = 7.8
Hz, 2H, CH2-CH2-N<); 2.54–2.74 (m, 2H, H4); 2.98 (t, J = 10.8 Hz, 2H, -N(HCH-CH2)2CH-); 3.07–3.15
(m, 1H, N(CH2-CH2)2CH-); 3.48 (s, 2H, -NH2); 3.97–4.14 (m, 4H, -OCH2CH2-O-); 6.50–6.62 (m, 3H, H6,
H5 and H7 Ph); 6.70 (d, J = 2.5 Hz, 1H, H8); 6.83 (d, J = 8.1 Hz, 1H, H5); 7.69 (dd, J = 6.4 Hz, J = 8.9 Hz,
1H, H4 Ph); 12.75 (s, 1H, -OH). 13C NMR (CDCl3): δ 24.3 (-CH2-CH2-N<); 24.7 (C4); 25.0 (C3); 28.9 (-
N(CH2-CH2)2CH-); 39.9 (-N(CH2-CH2)2CH-); 43.8 (C2); 52.9 and 53.5 (-N(CH2-CH2)2CH-); 57.2 (-CH2-
N<); 65.1 (-OCH2CH2O-); 65.5 (-OCH2CH2O-); 105.3 (d, J = 24.2 Hz, C6 Ph); 107.1 (d, J = 23 Hz, C5
Ph); 109.3 (C1); 111.9 (C6); 115.3 (C1 Ph); 116.1 (C8); 127.7 (C4a); 129.6 (C5); 138.1 (C8a); 144.3 (C7);
165.6 (C3 Ph); 165.8 (C2 Ph); 167.0 (d, J = 255 Hz, C4 Ph); 207.7 (C=O). MS (CI): m/z= 455.1 (MH+,
100%), 435.1 (24), 411.1 (21), 236.0 (58).
4.2.33. 8,8-Ethylenedioxy-7-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydronaphthalen-
2-amine (34).
To a suspension of PtO2 10% (20 mg) in dry THF (2 mL), a solution of 7-nitro ketal 30 (100 mg,
0.22 mmol) in THF (8 mL) was added and the mixture vigorously stirred under H2 at room temperature
for 12 h. Afterwards, the reaction was filtered off through a pad of Celite to remove the catalyst.
Evaporation of the filtrate gave a residue that was purified by preparative chromatography in
CH2Cl2:methanol (95:5) yielding the ketal 34 as an oily colourless solid (56 mg, 60%). IR: 3636, 2950,
1
2816, 1623, 1595, 1499 cm-1. H NMR (CDCl3): δ 1.92–1.79 (m, 2H, 1H3, -HCH-CH2-N<); 1.97–2.18
(m, 3H, H2, 1H3, -HCH-CH2-N<); 2.51 (t, J = 7.8 Hz, 2H, CH2-CH2-N<); 2.62–2.74 (m, 6H, -N(H2C-
CH2)N-, H4); 3.09 (br.s., 4H, -N(H2C-CH2)N-); 3.85 (s, 3H, -OCH3); 3.99–4.13 (m, 4H, -OCH2CH2O-);
6.60 (dd, J = 2.5 Hz, J = 8.3 Hz, 1H, H6); 6.76 (d, J = 2.5 Hz, 1H, H8); 6.84–7.02 (m, 5H, -Ph, H5). 13C

ACCEPTED MANUSCRIPT
NMR (CDCl3): δ 24.4 (-CH2-CH2-N<); 24.7 (C4); 25.1 (C3); 40.1 (C2); 50.6 (N(CH2-CH2)2N); 53.5
(N(CH2-CH2)2N); 55.3 (-OCH3); 57.2 (-CH2-N<); 65.1 (-OCH2CH2O-); 65.6 (-OCH2CH2O-); 109.4 (C1);
111.1 (C3 Ph); 111.9 (C6); 116.1 (C8); 118.2 (C6 Ph); 120.9 (C4 Ph); 122.8 (C5 Ph); 127.7 (C4a); 129.6
(C5); 138.2 (C8a); 141.4 (C1 Ph); 144.3 (C7); 152.3 (C2 Ph). MS (CI): m/z= 424.2 (MH+, 100%), 380.2
(16), 205.0 (48).
Ketal 35 was also obtained following the same procedure.
4.2.34.
(1-(2-(7-Amino-1,1-ethylenedioxy-1,2,3,4-tetrahydronaphthalen-2-yl)ethyl)piperidin-4-yl)(4-
fluoro-2-hydroxyphenyl)methanone (35).
Yield: 35% (oily yellow solid). Spectroscopic data were consistent with those already reported.
4.2.35.
2-[2-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl]-3,4-dihydro-7-nitronaphthalen-
1(2H)-one (31).
Ketal 29 (50 mg, 0.1 mmol) was dissolved in THF (2 mL) and 1M HCl (2 mL) was added
dropwise. The mixture was stirred for 24 h at room temperature and then concentrated in vacuo. The
resultant crude was dissolved in CH2Cl2 and washed with 10% aqueous NaOH. The organic layer was
dried (Na2SO4), concentrated under reduced pressure and the corresponding keto compound purified by
silica gel preparative chromatography using EtOAc as eluent giving nitroketone 31 (40 mg, 91%) as a
1
light yellow oil. IR: 3323, 1688, 1610, 1520, 1492 cm-1. H NMR (CDCl3): δ 1.75–1.84 (m, 1H, HCH-
CH2-N<); 8.83 (d, J = 2.5 Hz, 1H, H8); 1.91–2.11 (m, 4H, -N(CH2-CH2)2CH-); 2.19–2.37 (m, 4H, H3,
HCH-CH2-N<, N(CH2-CH2)CH-,); 2.56–2.73 (m, 3H, -CH2-CH2-N<, H2); 3.04–3.16 (q, J = 4.2 Hz, 6H, -
N(CH2-CH2)2CH-, H4); 7.05 (dt, J = 2.2 Hz, J = 8.8 Hz, 1H, H5 bzx); 7.23 (dd, J = 2.2 Hz, J = 8.5 Hz, 1H,
H7 bzx); 7.44 (d, J = 8.4 Hz, 1H, H5); 7.69 (dd, J =8.4 Hz, J = 5.1 Hz, 1H, H4 bzx); 8.30 (dd, J = 2.5 Hz, J
= 8.4 Hz, 1H, H6). 13C NMR (CDCl3): δ 23.2 (-CH2-CH2-N<); 24.9 (C4); 25.0 (C3); 29.3 (N(CH2-
CH2)CH-); 29.7 (N(CH2-CH2)CH); 32.4 (N(CH2-CH2)2CH); 45.8 (C2); 62.9 (N(CH2-CH2)CH); 64.2
(N(CH2-CH2)CH); 68.6 (-CH2-N<); 97.6 (d, J = 26.5 Hz, C7 bzx); 112.9 (d, J = 25.4 Hz, C5 bzx); 116.5
(C3a bzx); 122.6 (C8); 122.9 (d, J = 11.5 Hz, C4 bzx); 127.3 (C6); 130.4 (C5); 133.0 (C8a); 147.0 (C7);
150.6 (C4a); 159.5 (C3 bzx); 164.2 (d, J = 13.6 Hz, C7a bzx); 165.9 (d, J = 251 Hz, C6 bzx); 197.8 (C1).
MS (CI): m/z= 436.0 (MH+, 3%), 259.9 (100), 220.9 (38). Hydrochloride (31·HCl): Mp 230 ºC. Anal.
C24H24FN3O4·HCl·1.05H2O (C, H, N).
4.2.36. 3,4-Dihydro-2-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]-7-nitronaphthalen-1(2H)-one (32).
Following the procedure described for the cleavage of the ketal group in the preparation of 31,
compound 30 gave, after purification by silica gel preparative chromatography (EtOAc), nitroketone 32
(95%) as an oily colourless solid. IR: 2923, 1687, 1610, 1429, 1018 cm-1. 1H NMR (CDCl3): δ 1.64–1.74
(m, 1H, HCH-CH2-N); 1.84–1.98 (m, 1H, HCH-CH2-N<); 2.14–2.30 (m, 2H, H3); 2.49 (t, J = 7.4 Hz, 3H,
H2, -CH2-CH2-N<); 2.61 (br.s. 4H, -N(H2C-CH2)N-); 2.99 (br.s., 4H, -N(H2C-CH2)N-); 3.03–3.07 (m, 2H,
H4); 3.79 (s, 3H, -OCH3); 6.77–6.95 (m, 4H, -Ph); 7.36 (d, J = 8.2 Hz, 1H, H5); 8.21 (dd, J = 2.4, 8.6 Hz,

ACCEPTED MANUSCRIPT
1H, H6); 8.79 (d, J = 2.5 Hz, 1H, H8). 13C NMR (CDCl3): δ 26.7 (C3); 27.8 (-CH2-CH2-N<); 45.4 (C2);
28.8 (C4); 50.6 (CH2-N<); 53.4 (N(CH2-CH2)2N); 55.3 (-OCH3); 55.7 (N(CH2-CH2)2N); 111.2 (C6 Ph);
118.1 (C3 Ph); 120.9 (C4 Ph); 122.8 (C8); 122.9 (C5 Ph); 126.9 (C6); 130.1 (C5); 133.5 (C8a); 141.3 (C1
Ph); 147.0 (C7); 150.3 (C4a); 152.9 (C2 Ph); 197.8 (C1). MS (CI): m/z= 410.2 (MH+, 23%), 380.2 (40),
364.2 (21), 218.1 (38), 188.1 (100). Hydrochloride (32·HCl): Mp 210-212 ºC. IR: νmax= 3323, 2200,
1688, 1610, 1520, 1492 cm-1. Anal. C23H27N3O4·2HCl·0.5H2O (C, H, N).
4.2.37. 7-Amino-2-[2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl]-3,4-dihydronaphthalen-
1(2H)-one (36).
Following the procedure described for the cleavage of the ketal group in the preparation of 31,
compound 33 gave, after purification by silica gel preparative chromatography (EtOAc), aminoketone 36
(98%) as a cream solid. Mp 120–122 ºC. IR: 2925, 1672, 1612, 1498 cm-1. 1H NMR (CDCl3): δ 1.66–1.78
(m, 1H, -HCH-CH2-N<); 1.84–1.95 (m, 1H, -HCH-CH2-N<); 2.04 (dd, J = 3.2, 7.7 Hz, 3H, -HCH-N<, -
N(H2C-HCH)2CH); 2.13–2.24 (m, 5H, H3, -HCH-N<, N(HCH-CH2)2CH-); 2.53 (t, J = 7.8 Hz, 3H, -CH2-
CH2-N<, H2); 2.90 (dd, J = 4.7 Hz, 2H, H4); 3.03–3.12 (m, 3H, -N(HCH-CH2)2CH-); 3.72 (br.s., 2H, -
NH2); 6.83 (dd, J = 2.6, 8.1 Hz, 1H, H6); 7.05 (dt, J = 2.9, 8.9 Hz, 2H, H5, H5 bzx); 7.23 (dd, J = 2.1, 8.5
Hz, 1H, H7 bzx); 7.32 (d, J = 2.6 Hz, 1H, H8); 7.68 (dd, J = 5.1, 8.7 Hz, 1H, H4 bzx). 13C NMR (CDCl3):
δ 26.8 (C3); 27.9 (-CH2-CH2-N<); 28.7 (C4); 29.4 (-N(CH2-CH2)CH-); 33.6 (-N(CH2-CH2)2CH-); 44.8
(C2); 52.5 (CH2-N<); 55.2 (-N(CH2-CH2)CH-); 96.4 (d, J = 26.5 Hz, C7 bzx); 111.4 (C8); 111.5 (d, J =
24.2 Hz, C5 bzx); 116.3 (C3a bzx); 119.7 (C6); 121.6 (d, J = 11.5 Hz, C4 bzx); 128.6 (C5); 132.1 (C4a);
133.2 (C8a); 143.9 (C7); 160.1 (C3 bzx); 162.9 (d, J = 12.7 Hz, C7a bzx); 164.7 (d, J = 250 Hz, C6 bzx);
199.3 (C1). MS (CI): m/z= 408.2 (MH+, 88%), 390.2 (100), 188.0 (62). Anal. C24H26FN3O2·0.45H2O (C,
H, N).
4.2.38. 7-Amino-3,4-dihydro-2-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]naphthalen-1(2H)-one (37).
Following the general procedure described for the cleavage of the ketal group in the preparation
of 31, compound 34 gave, after purification by silica gel preparative chromatography (EtOAc),
aminoketone 37 (99%) as an oily colourless solid. IR: 2925, 1671, 1612, 1498 cm-1.1H NMR (CDCl3): δ
1.57–1.69 (m, 1H, -HCH-CH2-N<); 1.76–1.87 (m, 1H, -HCH-CH2-N<); 2.12–2.22 (m, 2H, H3); 2.48 (t, J
= 7.4 Hz, 3H, H2, CH2-CH2-N<); 2.63 (br.s., 4H, N(CH2CH2)2N); 2.82 (q, J = 4.7 Hz, 2H, H4); 3.02 (br.s.,
4H, N(CH2CH2)2N); 3.79 (s, 3H, -OCH3); 6.72–6.98 (m, 6H, H6, H7, -Ph); 7.24 (d, J =2.7 Hz, 1H, H8).
13C NMR (CDCl3): δ 26.3 (C3); 27.8 (-CH2-CH2-N<); 29.3 (C4); 45.8 (C2); 49.9 (CH2-N<); 53.1 (N(CH2-
CH2)2N); 55.4 (-OCH3); 55.9 (N(CH2-CH2)2N); 111.2 (C6 Ph); 112.1 (C8); 118.3 (C3 Ph); 120.8 (C6);
121.0 (C4 Ph); 122.9 (C5 Ph); 129.6 (C5); 132.9 (C4a); 134.8 (C8a); 138.1 (C1 Ph); 144.9 (C7); 152.2 (C2
Ph); 200.1 (C1). MS (CI): m/z= 380.2 (MH+, 100%), 218.2 (44), 205.2 (30), 188.1 (50). Hydrochloride
(37·HCl): Mp 180-182 ºC. Anal. C23H29N3O2·3HCl·0.85H2O (C, H, N).

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4.2.39. 7-Amino-2-[2-(4-(4-fluoro-2-hydroxybenzoyl)piperidin-1-yl)ethyl]-3,4-dihydronaphthalen-1(2H)-
one (38).
Following the general procedure described for the cleavage of the ketal group in the preparation
of 31, compound 35 gave, after purification by silica gel preparative chromatography (97:3
CH2Cl2/MeOH), aminoketone 38 (97%) as an oily colourless solid. IR: 3357, 2924, 1672, 1612, 1497 cm-
1
1. H NMR (CDCl3): δ 1.62–1.74 (m, 1H, -HCH-CH2N<); 1.80–1.93 (m, 5H, H3, H4 -HCH-CH2N<);
2.10–2.24 (m, 4H, N(H2C-CH2)2CH-); 2.50–2.55 (m, 3H, CH2-CH2N<, H2); 2.86–2.90 (m, 2H, N(HCH-
CH2)2CH-); 3.06–3.10 (m, 2H, N(HCH-CH2)2CH-); 3.16–3.26 (m, 1H, N(CH2CH2)2CH-); 6.56–6.70 (m,
2H, H5 and H7 Ph); 6.81 (dd, J = 2.6, 8.0 Hz, 1H, H6); 7.03 (d, J = 8.1 Hz, 1H, H5); 7.3 (d, J = 2.7 Hz, 1H,
H8); 7.76 (dd, J = 6.5, 9.0 Hz, 1H, H4 Ph); 12.80 (br.s., 1H, OH). 13C NMR (CDCl3): δ 26.8 (C3); 28.6 (-
CH2-CH2N<); 28.7 (N(CH2-CH2)CH-); 28.9 (C4); 43.5 (-N(CH2-CH2)2CH-); 45.8 (C2); 52.9 (-CH2N<);
56.1 (-N(H2C-CH2)2CH); 105.4 (d, J = 23.0 Hz, C3 Ph); 107.3 (d, J = 23.0 Hz, C5 Ph); 112.4 (C8); 115.3
(C1 Ph); 120.7 (C6); 129.5 (C5); 129.7 (C4a); 131.9 (d, J = 11.5 Hz, C6 Ph); 144.8 (C8a); 144.9 (C7); 165.8
(C2 Ph); 168.9 (d, J = 256 Hz, C4 Ph); 200.4 (C1); 207.6 (C=O). MS (CI): m/z= 411.0 (MH+, 100%), 250.1
(35), 161.1 (35). Hydrochloride (38·HCl): Mp > 230ºC. IR: 3328, 2938, 1681, 1633, 1495 cm-1. Anal.
C24H27FN2O3·2HCl·1.95H2O (C, H, N).
4.2.40.
7-Amino-2-[2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl]-3,4-dihydronaphthalen-
1(2H)-one (36).
The aminoketone 36 was synthesized from nitroketone 31 following the methodology described
for obtaining 26 from 19. Yield: 67% (white foam). Spectroscopic data were consistent with those
abovementioned.
4.3. Biological assay methods
The affinities of the new compounds for cloned human D2 and 5-HT2A receptors were evaluated
in in vitro binding assays using the radioligands [3H]spiperone and [3H]ketanserin, respectively, according
to our previously described procedures [6]. Ki values (expressed as pKi) were calculated according to the
Cheng-Prusoff equation [17].
The potency of the compounds at human D2 and 5-HT2A receptors were evaluated in in vitro
assays by measuring cAMP and inositol phosphate release, respectively. Cells transfected with the human
receptors were seeded in 96-well plates and incubated with compounds and agonists for 30 min at 37ºC.
After this time the cAMP and inositol phosphate release were quantitated by using HTRF assay kits
(CisBio, France).
Acknowledgment

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This work was supported by Spanish Ministerio de Educación, Cultura y Deporte (Grant SAF2009-
13609-C04) and Xunta de Galicia (Grant INCITE09 203 184PR). A PhD fellowship (FPU) has been
granted to L. Carro by the Ministerio de Educación, Cultura y Deporte. The authors gratefully
acknowledge the technical assistance of Rocío Piña and José Manuel Santamaría.
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