Synthesis and appetite suppressant activity of 1-aryloxy-2-substituted aminomethyltetrahydronaphthalenes as conformationally rigid analogues of fluoxetine

Article abstract of DOI:10.1016/j.bmc.2005.11.032

Several 1-aryloxy-2-substituted aminomethyltetrahydronaphthalenes (7-21) as conformationally rigid analogues of fluoxetine were synthesized and evaluated for their anorexigenic and antidepressant activities. For SAR studies the related acyclic analogues (

Full text of DOI:10.1016/j.bmc.2005.11.032

Bioorganic & Medicinal Chemistry 14 (2006) 2535–2544
Synthesis and appetite suppressant activity of
1-aryloxy-2-substituted aminomethyltetrahydronaphthalenes
as conformationally rigid analogues of fluoxetineq
Kalpana Bhandari,a,* Shipra Srivastava,a Girija Shankarb and Chandishwar Nathb
aMedicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
bPharmacology Division, Central Drug Research Institute, Lucknow 226001, India
Received 20 October 2005; revised 14 November 2005; accepted 15 November 2005
Available online 5 December 2005
Abstract—Several 1-aryloxy-2-substituted aminomethyltetrahydronaphthalenes (7–21) as conformationally rigid analogues of fluox-
etine were synthesized and evaluated for their anorexigenic and antidepressant activities. For SAR studies the related acyclic ana-
logues (22–27) were also prepared. Out of the 21 synthesized compounds, 10 compounds (9, 10, 11, 15, 16, 18, 21, 22, 23 and 27)
exhibited significant anorexigenic activity (at 75 lmol/kg). Interestingly, all the compounds (7–20, 22–26) were devoid of antidepres-
sant effect, except for compounds 21 and 27 in which the antidepressant activity was retained. Compound 16 emerged as the most
active compound of the series with better anorexigenic activity (97.92%) compared to fluoxetine (76.25%) and even with a clinically
used drug sibutramine, thus providing a new structural lead for appetite suppressants.
ꢀ 2005 Elsevier Ltd. All rights reserved.
N
1. Introduction
Me
NH2
Me
Me
N
Despite a rising worldwide epidemic of obesity1–3 there
are currently only a very small number of anti-obesity
drugs available to manage the problem.4 Some of these
drugs may assist weight loss by modifying the function-
ing of the appetite system as measured by subjective
changes in feelings of hunger and fullness (indices of
satiety). Such drugs can be considered as appetite sup-
pressants5 with clinical potential as anti-obesity agents.
Centrally acting appetite suppressant drugs (Fig. 1) used
in the treatment of obesity fall into two broad pharma-
cological categories:6 those, which act via catechol-
amine7 pathways, and those, which act via serotonin8
pathways. Of the former group, amphetamine and phen-
metrazine are no longer recommended because of their
stimulant properties and addictive potential.9,10 The
remaining drugs11 in this class include diethylpropion,
phentermine, mazindol and phenylpropanolamine, all
have been shown to reduce appetite and lower food
intake. They all have some sympathomimetic and
NEt2
HO
O
Diethylpropion
Phentermine
Mazindol
Cl
Me
Me
NHEt
NHEt
F3C
F3C
Dexfenfluramine
Fenflramine
Figure 1. Centrally acting appetite suppressant drugs.
stimulant properties. Anorectic drugs, which promote
serotonin neurotransmission8,12, have no such stimulant
or sympathomimetic properties. They are fenfluramine,
together with its dextrorotatory stereoisomers dexfen-
fluramine and fluoxetine.13,14 They reduce appetite and
food intake, and are effective in the treatment of obesity
but their use has been limited by side effects. This neces-
sitates the development of more effective drugs.
Keywords: Fluoxetine; Appetite suppressant; Antidepressant; Rigid
analogue.
The above report and our interest in fluoxetine ana-
logues15–17 have induced us to investigate how the ano-
rectic and antidepressant activities of fluoxetine would
be influenced by restricting the free movement of
q
CDRI Communication No. 6856.
Corresponding author. Tel.: +91 522 2212413; fax: +91 522
2223405; e-mail: bhandarikalpana@rediffmail.com
*
0968-0896/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.11.032

2536
K. Bhandari et al. / Bioorg. Med. Chem. 14 (2006) 2535–2544
in Scheme 1. Substituted aminomethyl-3,4-dihydro-
R
R
H
2H-naphthalen-1-one (5a–5h) was prepared from 1-
tetralone (3a)/6-methoxy-1-tetralone (3b) by Mannich
reaction using different secondary amines (4a–4e)
which on sodium borohydride reduction gave the
hydroxy intermediate (6a–6h) in a substantially pure
trans isomeric form. Condensation of the hydroxy
intermediate (6a–6h) with (i) 4-fluorobenzotrifluoride/
4-fluoroacetophenone in the presence of sodium hy-
dride in dimethylacetamide or with (ii) methanesulfo-
nyl chloride followed by condensation with the
sodium salts of phenol/4-methoxyphenol furnished
the desired ethers (7–20) with cis stereoselectivity.
The reaction typically proceeded with inversion of ste-
reochemistry, thus the trans hydroxy compounds (6a–
6h) yielded predominantly the cis phenoxy ethers of
formula (7–20). The cis stereochemistry with respect
to phenoxy and methylamine moieties of 1-aryloxy-
2-substituted aminomethyltetrahydronaphthalenes (7–
20) was established on the basis of 1H NMR
spectra.18 3-Aryl-3-aryloxypropanamines (22–25) were
synthesized from acetophenone/4-methoxyacetophe-
none and different secondary amines (4d, 4e) by the
method reported earlier (Scheme 2).19 Debenzylation
of 13 and 25 with methyl chloroformate and hydra-
zinehydrate gave 21 and 26, respectively (Schemes 1
and 2).16 Fluoxetine was treated with formaldehyde
followed by sodium borohydride to give N,N-dimeth-
yl-3-phenyl-3-(4-trifluoromethylphenoxy)propanamine
27 (Scheme 2).
R1
R1
N
N
N
Me
R2
R2
O
O
O
F3C
R3
R3
1
2
Fluoxetine
Figure 2.
propylamine chain. It has been carried out by linking
the C-2 carbon atom of propylamine chain and C-2 of
the phenyl ring through a two carbon spacer. Thus, we
herein report the synthesis, pharmacological evaluation
and SAR studies of 1-aryloxy-2-substituted aminometh-
yltetrahydronaphthalene derivatives (1) as conforma-
tionally rigid analogues of fluoxetine (Fig. 2). The
impact of the rigidity of the structure has been evaluated
with respect to the anorexigenic and antidepressant ef-
fects and compared with that of the parent compound
fluoxetine. In an attempt to explore the SAR of these
rigid analogues (1), we also prepared related acyclic
derivatives (2) (Fig. 2) and evaluated them for both
anorexigenic and antidepressant effects.
2. Chemistry
The synthetic route for 1-aryloxy-2-substituted
aminomethyltetrahydronaphthalenes (7–21) is depicted
R
R
R
a
b
NR1R2
NR1R2
O
3a,b
O
5a-h
OH
6a-h
c/(d, e)
H
13
f, g
N
R
Me
O
NR1R2
O
21
F3C
7-20
R3
Compd.No.
NR1R2
R
H
H
H
H
H
H
H
R3
Compd.No.
NR1R2
R
R3
7
4-[(4-methyl)phenyl]piperazino
4-[(4-methyl)phenyl]piperazino
CF3
14
benzylmethylamino
dibenzylamino
H
COCH3
COCH3
COCH3
COCH3
COCH3
OMe
8
COCH3 15
H
9
4-(3- , , -trifluorotolyl)piperazino
4-(3- , , -trifluorotolyl)piperazino
dimethylamino
CF3
16
17
18
19
20
4-[(4-methyl)phenyl]piperazino
dimethylamino
OMe
OMe
OMe
H
10
11
12
13
COCH3
CF3
benzylmethylamino
dimethylamino
dimethylamino
COCH3
CF3
benzylmethylamino
dimethylamino
H
H
Scheme 1. Reagents and conditions: (a) HNR1R2 (4a–4e), (HCHO)3, isopropanol, 95 ꢁC; (b) NaBH4, MeOH, rt; (c) NaH, 4-fluorobenzotrifluoride/
4-fluoroacetophenone, dry DMAC; (d) CH3SO2Cl, K2CO3, dry acetone, 0–4 ꢁC; (e) NaOH, phenol/4-methoxyphenol, EtOH, rt; (f) ClCOOMe, dry
benzene, reflux; (g) NH2–NH2ÆH2O, KOH, n-propanol, reflux.

K. Bhandari et al. / Bioorg. Med. Chem. 14 (2006) 2535–2544
2537
R
with the retention of weak anorexigenic activity
(10.42%) in compound 13, suggesting that the secondary
amino group may be responsible for the antidepressant
effect. We therefore attempted to minimize the antide-
pressant effect and to improve the anorexigenic activity
of 21 by replacing the secondary amino groups with var-
ious amino substructures (7–20). Interestingly, all the
rigid analogues (7–20) were devoid of antidepressant
activity. Among the 14 synthesized N-substituted rigid
analogues, compound nos. 9, 10, 11, 15, 16 and 18
showed significant anorexigenic activity (P 6 0.05) with
a significant decrease in milk intake (28.57–97.92%) in
comparison to the control group (Fig. 3). Compound
16 emerged as the most potent appetite suppressant with
97.92% anorexigenic activity, which was better than that
of the parent compound fluoxetine (76.25%). The
anorexigenic activity of the test compound 16 was also
found to be superior compared to the clinically used
drug sibutramine (80%).
R
NR1R2
a, b, c
O
O
22-25
R3
MeO
H
N
Me
d, e
O
25
26
F3C
Me
N
f
Me
Fluoxetine
O
27
SAR studies revealed that among the five groups substi-
tuted at NH, 4-(3-trifluorotolyl)piperazino group was
found to be the most effective in exhibiting a better
appetite suppressant activity profile followed by dimeth-
yl amino, dibenzyl amino, 4-(4-methylphenyl)piperazino
and benzylmethyl amino in decreasing order. Introduc-
tion of substituents different from trifluoromethyl in
the aryloxy ring of the rigid analogue led to a substantial
decrease of anorexigenic activity with the maximum
potency for CF3 following the decreasing order by
COCH3 > H > OMe. Only compound numbers 9 and
10 behaved differently in which acetyl analogue 10 was
more active than its CF3 analogue 9. Introduction of
methoxy functionality at the 6-position of the tetrahy-
dronaphthalene ring in compounds 16, 17 and 18 result-
ed in the enhancement of the percentage anorexia than
their unsubstituted counterparts 8, 12 and 14,
respectively.
F3C
Compd. no.
NR1R2
R
R3
22
23
24
25
Dibenzylamino
Dibenzylamino
H
COCH3
CF3
H
Benzylmethylamino
Benzylmethylamino
H
CF3
OMe
CF3
Scheme 2. Reagents and conditions: (a) HNR1R2 (4d, 4e), (HCHO)3,
n-propanol, reflux; (b) NaBH4, MeOH, rt; (c) NaH, 4-fluorobenzotri-
fluoride/4-fluoroacetophenone, dry DMAC; (d) ClCOOMe, dry ben-
zene, reflux; (e) NH2–NH2ÆH2O, KOH, n-propanol, reflux; (f) HCHO,
MeOH, NaBH4, rt.
3. Results and discussion
The synthesized compounds (7–27) were assessed for
gross behavioural, anorexigenic and antidepressant ef-
fects by standard methods.15 The results are summarized
in Table 1 and compared with the activity of the parent
compound fluoxetine. The tested compounds did not
show any significant effect on the gross behaviour, ex-
cept for 21 which showed mild stimulation (increased
locomotor activity) similar to that of fluoxetine.
Similarly, among the acyclic fluoxetine analogues in
which the secondary amino group was replaced by
dibenzyl (22 and 23), benzylmethyl (24) and dimethyl
(27) amino substructures showed significant anorexia
(except for 24) whereas the antidepressant activity was
either decreased (27), insignificant (24) or completely
lost (22 and 23). Surprisingly, contrary to rigid ana-
logues (16–18), the introduction of methoxyl group at
4-position of the aryl ring in acyclic analogues (25 and
26) resulted in the reduction of both anorexigenic as well
as antidepressant activities.
First, we focused our attention mainly on compound 21
the fluoxetine-like structure for a direct comparison of
its antidepressant and anorexigenic activities with that
of the lead fluoxetine. The results indicated that the con-
formationally restricted rigid analogue 21 at 75 lmol/kg
dose exhibited significant anorexigenic activity (66%)
with signs of stimulation. The stimulant activity may be
attributed to the propylamino chain in rigid frame. How-
ever, at half dose (37.5 lmol/kg), compound 21 showed
the dose-dependent activity pattern; it showed antidepres-
sant activity with insignificant anorexigenic and stimulant
effects; 21 was found to be better than fluoxetine (at
37.5 lmol/kg) in exhibiting antidepressant activity.
4. Conclusion
The current study was performed to evaluate a new ser-
ies of 1-aryloxy-2-substituted aminomethyltetrahydro-
naphthalenes as conformationally rigid analogues of
fluoxetine for appetite suppressant and antidepressant
activities. The following conclusions can be drawn from
the SARs of this series of compounds—(1) compound
21, the fluoxetine-like structure (with free NH), can be
presented as selective antidepressant as it showed better
activity than fluoxetine at lower doses (37.5 lmol/kg ip);
The substitution of hydrogen of the NH of 21 by benzyl
group resulted in complete loss of antidepressant effect

2538
K. Bhandari et al. / Bioorg. Med. Chem. 14 (2006) 2535–2544
Table 1. Pharmacological data of fluoxetine analogues (7–27) at 75 lmol/kg ip in a Swiss albino mice model
Compound
Anorexigenic activity
Antidepressant activitye
Sedation and crouching
(median score)
Means SEM of
milk intake (mL)
% decrease in milk
intake (anorexia)
Ptosis
(% incidence)
Control
0.49 0.01
0.33 0.06
0.34 0.06
0.27 0.08b
0.22 0.05b
0.23 0.07b
0
100
100
100
100
100
0
4
4
4
4
4
7
8
31.68
30.04
44.44
54.73
52.67
9
10
11
Control
12
13
0.48 0.01
0.34 0.09
0.43 0.03
0.47 0.02
0.24 0.08b
0.01 0.01b
0
100
100
100
100
100
0
4
4
4
4
4
29.17
10.42
2.08
14
15
50.42
97.92
16
Control
17
18
0.49 0.01
0.34 0.07
0.35 0.04b
0.38 0.09
0.37 0.07
0.17 0.05b
0.43 0.05
0
100
100
100
100
0d
0
30.61
28.57
22.45
24.49
66.90
12.24
4
4
19
20
4
4
21
21a
0d
1c
20c
Control
22
0.48 0.01
0.29 0.04b
0.29 0.03b
0.43 0.04
0.47 0.01
0.49 0.01
0.16 0.01b
0.11 0.06b
0.46 0.04
0.09 0.05b
0
100
100
80
0
38.54
40.40
11.43
2.08
4
23
24
4
4
25
26
100
80
40c
0c
40c
4
2.08
4
27
67.50
76.25
4.17
2c
0c
2c
—
4
Fluoxetine
Fluoxetinea
Sibutramine
Reserpine control
80
—
100
(—) not tested. Control: saline treated mice.
a Dose: 37.5 lmol/kg.
b Significant anorexigenic activity (P 6 0.05).
c Significant antidepressant activity.
d Stimulant action (increased locomotor activity).
e The antidepressant activity of Fluoxetine and the compounds was evaluated after 3 h of reserpine treatment.
the activity pattern; the methoxy substitution in the aryl
ring of rigid analogues enhanced the anorexigenic activ-
ity, whereas in the acyclic analogues both the activities
were reduced; however, substitutions in the aryloxy ring
followed the same pattern in both rigid as well as acyclic
analogues with the maximum potency for the CF3
substitution.
100
80
60
40
20
0
In conclusion, we have identified a novel lead compound
16 exhibiting better anorexigenic activity compared to
that of fluoxetine as well as sibutramine. The results of
the present study encourage further research in this ser-
ies of compounds in order to find the selective and more
potent appetite suppressant.
Compound
Figure 3. Comparative activity profile of the compounds at 75 lmol/
kg dose showing significant (P 6 0.05) anorexigenic and/or antide-
pressant (antireserpine) activities in terms of % decrease from the saline
and reserpine treated control, respectively; @at 37.5 lmol/kg dose.
(2) the substitution of NH by different amino substruc-
tures (7–20, 22–27) can lead to the development of po-
tent appetite suppressants as out of 21 synthesized
compounds ten exhibited significant anorexigenic activ-
ity; (3) different substituents introduced in the aryl and
aryloxy rings played an important role in influencing
5. Experimental
5.1. Chemistry
Melting points were determined in open capillaries
with an electrically heated block and are uncorrected.

K. Bhandari et al. / Bioorg. Med. Chem. 14 (2006) 2535–2544
2539
1
IR spectra of all the compounds were recorded on a Per-
kin-Elmer AC–1 spectrophotometer. H NMR spectra
204 ((M+1)+, 100%); H NMR (200 MHz, CDCl3): d
2.00 (m, 1H, H-3), 2.20–2.35 (m, 7H, H-3, N(Me)2),
2.5–2.76 (m, 3H, CO–CH–CH2–N), 2.97–3.04 (m, 2H,
H-4), 7.22–7.29 (m, 2H, H-5, H-7), 7.46 (m, 1H, H-6),
7.99–8.03 (d, 1H, J = 7.84 Hz, H-8); IR (Neat): 3423,
1
were recorded on a Brucker WM 200 MHz spectrometer
in deuterated solvents with TMS as internal reference.
Mass spectra were recorded on Jeol (JMS-D 300 spec-
trometer (70 eV). Microanalyses were determined on a
Carlo Erba EA-1108 element analyzer within 0.4% of
the theoretical value. Thin-layer chromatography was
performed on 7.5 · 3.0 cm precoated silica gel plastic
plates (Aldrich). For column chromatography, basic
alumina from Acmeꢀs Synthetic Chemicals and silica
gel of 60–120 mesh from Qualigen Fine Chemicals were
used.
2936, 2705, 2043, 1680, 1598, 1455, 1231, 746 cmÀ1
.
5.1.1.4. 2-Benzylmethylaminomethyl-3,4-dihydro-2H-
naphthalen-1-one (5d). With 1-tetralone (3a) and ben-
zylmethylammonium chloride (4d). Yield 85%; MS
(FAB) m/z: 280 ((M+1)+, 65%); H NMR (200 MHz,
1
CDCl3): d 1.85–1.92 (m, 1H, H-3), 2.15–2.47 (m, 7H,
H-3, Me–N–CH2–CH), 2.76–2.84 (m, 2H, H-4), 3.00–
3.03 (m, 1H, Ar–CH2–N), 3.17–3.20 (m, 1H, Ar–CH2–
N), 7.07–7.12 (m, 3H, ArH), 7.25–7.35 (m, 4H, ArH),
7.45–7.53 (m, 1H, H-6), 8.01–8.05 (d, 1H, J = 7.81 Hz,
H-8); IR (Neat): 3338, 3024, 2939, 2844, 2791, 1680,
5.1.1. General procedure for the preparation of Mannich
bases (5a–5h). A mixtute of 1-tetralone (3a)/6-methoxy-
1-tetralone (3b) (11 mmol), hydrochloride salt of
secondary amines (4a–4e) (10 mmol) and 1/5th of para-
formaldehyde (20 mmol) in isopropanol (15 mL) was
stirred and concd HCl was added dropwise to adjust
the pH of the solution to 4. The reaction mixture was
then heated in an oil bath at 90–95 ꢁC for 30 min with
stirring. Other four portions of the paraformaldehyde
were added at 15 min interval. The reaction mixture
was further refluxed for 4 h. The solvent was distilled
off. The residue obtained was washed with hexane (2·
5 mL), added sodium bicarbonate solution to make
the pH alkaline and extracted with dichloromethane
(3· 15 mL). Combined organic extracts were dried over
Na2SO4 and distilled to afford the Mannich bases
(5a–5h) in good yield.
1454, 1221, 757 cmÀ1
.
5.1.1.5. 2-Dibenzylaminomethyl-3,4-dihydro-2H-naph-
thalen-1-one (5e). With 1-tetralone (3a) and dibenzylam-
monium chloride (4e). Yield 83%; MS (FAB) m/z: 356
((M+1)+, 100%); H NMR (200 MHz, CDCl3): d 1.54–
1
1.61 (m, 1H, H-3), 2.1 (m, 2H, H-3, N–CH2–CH),
2.36–2.43 (m, 1H, N–CH2–CH), 2.61–2.72 (m, 3H, H-
4, H-2), 3.06–3.12 (m, 2H, Ar–CH2–N), 4.01–4.08 (m,
1H, Ar–CH2–N), 4.21–4.26 (m, 1H, Ar–CH2–N), 6.94–
7.29 (m, 13H, ArH), 7.50–7.54 (d, 1H, J = 7.36 Hz,
ArH); IR (Neat): 3433, 2923, 2789, 2737, 2595, 2435,
1675, 1573, 1455, 1424, 743 cmÀ1
.
5.1.1.6. 6-Methoxy-2-[1-(4-methylphenyl)-piperazi-
5.1.1.1. 2-[1-(4-Methylphenyl)-piperazinyl]-methyl-3,4-
dihydro-2H-naphthalen-1- one (5a). With 1-tetralone (3a)
and 1-(4-methylphenyl)piperazine.dihydrochloride (4a).
Yield 77%; Mp 171–175 ꢁC; MS (FAB) m/z: 335
nyl]-methyl-3,4-dihydro-2H-naphthalen-1-one (5f). With
6-methoxy-1-tetralone (3b) and 1-(4-methylphenyl)
piperazine.dihydrochloride (4a). Yield 68%; Mp 165–
169 ꢁC; MS (FAB) m/z: 365 ((M+1)+, 100%); 1H
NMR (200 MHz, CDCl3): d 2.00 (m, 1H, H-3), 2.27–
2.36 (m, 4H, Ar–CH3, H-3), 2.53–2.78 (m, 6H,
NCH2), 2.94–3.00 (m, 3H, H-2, H-4), 3.13–3.15 (m,
4H, piperazinyl NH2 adjacent to phenyl ring), 3.85 (s,
3H, OMe), 6.70 (s, 1H, H-5), 6.80–6.87 (m, 3H, ArH
ortho to N, H-7), 7.05–7.09 (d, 2H, J = 8.42 Hz, ArH
ortho to CH3), 7.98–8.02 (d, 1H, J = 8.78 Hz, H-8); IR
(KBr): 3360, 2916, 2707, 2477, 2365, 1675, 1603, 1453,
1
((M+1)+, 100%); H NMR (200 MHz, CDCl3): d 2.02
(m, 1H, H-3), 2.26 (s, 3H, Ar–CH3), 2.4 (m, 1H, H-3),
2.54–2.75 (m, 6H, N–CH2), 2.93–3.04 (m, 3H, H-4,
CO–CH), 3.12–3.17 (m, 4H, piperazinyl NCH2 adjacent
to phenyl ring), 6.82–6.86 (d, 2H, J = 8.54 Hz, ArH
ortho to N), 7.05–7.09 (d, 2H, J = 8.46 Hz, ArH ortho
to CH3), 7.23–7.33 (m, 2H, H-5, H-7), 7.43–7.51 (m,
1H, H-6), 8.01–8.04 (d, 1H, J = 6.84 Hz, H-8); IR
(KBr): 3418, 2980, 2917, 2364, 1684, 1601, 1451, 1231,
1276, 1248, 1023, 817 cmÀ1
.
740 cmÀ1
.
5.1.1.7. 6-Methoxy-2-dimethylaminomethyl-3,4-dihy-
dro-2H-naphthalen-1-one (5g). With 6-methoxy-1-tetr-
alone (3b) and dimethylammonium chloride (4c). Yield
5.1.1.2.
2-[1-(3-Trifluoromethylphenyl)-piperazinyl]
methyl-3,4-dihydro-2H-naphthalen-1-one (5b). With 1-
tetralone (3a) and 1-(3-trifluoromethylphenyl)pipera-
zine. dihydrochloride (4b). Yield 70%; MS (FAB) m/z:
1
69%; MS (FAB) m/z: 234 ((M+1)+, 100%); H NMR
(200 MHz, CDCl3): d 2.00 (m, 1H, H-3), 2.66–3.14 (m,
12H, H-3, CO–CH–CH2–N(Me)2, H-4), 3.86 (s, 3H,
OMe), 6.70 (s, 1H, H-5), 6.80–6.89 (m, 1H, H-7),
7.94–7.98 (d, 1H, J = 8.72 Hz, H-8); IR (Neat): 3433,
390 ((M+2)+, 100%); H NMR (200 MHz, CDCl3): d
1
2.020 (m, 1H, H-3), 2.4 (m, 1H, H-3), 2.53–2.74 (m,
5H, N–CH2), 2.90–3.03 (m, 4H, H-2, H-4, N–CH2),
3.19–3.24 (m, 4H, piperazinyl NCH2 adjacent to phenyl
ring), 6.99–7.05 (m, 3H, ArH ortho and para to N),
7.17–7.47 (m, 4H, ArH), 7.97–8.01 (d, 1H, J = 7.8 Hz,
H-8); IR (Neat): 3432, 2937, 2363, 1681, 1596, 1452,
3018, 2937, 2675, 1665, 1602, 1255, 1237, 1019 cmÀ1
.
5.1.1.8. 6-Methoxy-2-benzylmethylaminomethyl-3,4-di
hydro-2H-naphthalen-1-one (5h). With 6-methoxy-1-tetr-
alone (3b) and benzylmethylammonium chloride (4d).
1353, 1118, 692 cmÀ1
.
1
Yield 89%; MS (FAB) m/z: 310 ((M+1)+, 100%); H
5.1.1.3. 2-Dimethylaminomethyl-3,4-dihydro-2H-
naphthalen-1-one (5c). With 1-tetralone (3a) and dimeth-
yl ammonium chloride (4c). Yield 72%; MS (FAB) m/z:
NMR (200 MHz, CDCl3): d 1.85 (m, 1H, H-3), 2.23
(s, 3H, N-Me), 2.44 (m, 1H, H-3), 2.58–2.68 (m,
2H, N–CH2–CH), 2.81–2.93 (m, 3H, H-4, CO–CH),

2540
K. Bhandari et al. / Bioorg. Med. Chem. 14 (2006) 2535–2544
3.37–3.43 (m, 1H, Ar–CH2–N), 3.62–3.76 (m, 1H, Ar–
CH2–N), 3.83 (s, 3H, OMe), 6.65 (s, 1H, H-5), 6.76–
6.82 (m, 1H, H-7), 7.21–7.31 (m, 5H, ArH), 7.94–7.99
(d, 1H, J = 8.71 Hz, H-8); IR (Neat): 3424, 2944, 2840,
7.98 (d, 1H, J = 7.36 Hz, ArH); IR (Neat): 3250, 2924,
2846, 2801, 1680, 1456, 1039, 742 cmÀ1
.
5.1.2.5.
2-Dibenzylaminomethyl-1,2,3,4-tetrahydro-
2708, 1667, 1598, 1458, 1252, 1026, 751 cmÀ1
.
naphthalen-1-ol (6e). Yield 96%; MS (FAB) m/z: 358
(M+, 60%); 1H NMR (200 MHz, CDCl3): d 1.2 (m,
1H, H-2), 1.65 (m, 1H, H-3), 2.15–2.16 (m, 1H, H-3),
2.44 (m, 1H, CH–CH2–N), 2.67–3.19 (m, 4H, H-4,
CH–CH2–N), 3.78–3.90 (m, 3H, N–CH2–Ph), 4.08–
4.14 (m, 1H, N–CH2–Ph), 4.25–4.29 (d, 1H, J = 8 Hz,
OH–CH), 7.04–7.34 (m, 13H, ArH), 7.6 (m, 1H, ArH);
IR (Neat): 3259, 3025, 2930, 2814, 2364, 1454, 1217,
5.1.2. General procedure for the preparation of 2-substi-
tuted aminomethyl-1,2,3,4-tetrahydronaphthalen-1-ol
(6a–6h). Sodium borohydride (30 mmol) was added in
portions to a stirred and cooled solution of Mannich
bases (5a–5h) (10 mmol) in methanol (25 mL) over a
period of 30 min. The reaction mixture was further stir-
red at room temperature for 4 h. Methanol was distilled
under reduced pressure. The residue was triturated with
water (25 mL) and extracted with dichloromethane (3·
15 mL). The combined organic layer was dried over
sodium sulfate and concentrated to give the hydroxy
compounds (6a–6h) in excellent yield.
1039, 757 cmÀ1
.
5.1.2.6. 6-Methoxy-2-[1-(4-methylphenyl)-piperazi-
nyl]-methyl-1,2,3,4- tetrahydronaphthalen-1-ol (6f). Yield
97%; Mp 50–55 ꢁC. MS (FAB) m/z: 367 (M+1)+, 70%);
1H NMR (200 MHz, CDCl3): d 1.46 (m, 1H, H-2), 1.67–
1.73 (m, 1H, H-3), 2.27 (s, 3H, Ar–CH3), 2.56–2.68 (m,
4H, NCH2), 2.81–2.97 (m, 4H, H-4, N–CH2), 3.16–3.19
(m, 4H, piperazinyl NCH2 adjacent to phenyl ring), 3.78
(s, 3H, OMe), 4.64–4.68 (d, 1H, J = 9.20 Hz, OH–CH),
6.59–6.60 (d, 1H, J = 2.4 Hz, H-5), 6.76–6.85 (m, 3H,
ArH ortho to N, H-7), 7.05–7.09 (d, 2H, J = 8.39 Hz,
ArH ortho to CH3), 7.47–7.52 (d, 1H, J = 8.49 Hz, H-
8); IR (KBr): 3266, 2928, 2822, 2364, 1615, 1517,
5.1.2.1. 2-[1-(4-Methylphenyl)-piperazinyl]-methyl-
1,2,3,4-tetrahydronaphthalen-1-ol (6a). Yield 98%; Mp
170–175 ꢁC; MS (FAB) m/z: 336 (M+, 90%), 337
1
(M+1)+, 80%); H NMR (200 MHz, CDCl3): d 1.47–
1.50 (m, 1H, H-2), 1.68–1.70 (m, 1H, H-3), 2.00–2.07
(m, 1H, H-3), 2.26 (s, 3H, Ar–CH3), 2.58–2.67 (m, 4H,
NCH2), 2.88–2.98 (m, 4H, H-4, N–CH2), 3.16–3.21
(m, 4H, piperazinyl NCH2 adjacent to phenyl ring),
4.67–4.71 (d, 1H, J = 9.25 Hz, OH–CH), 6.81–6.85 (d,
2H, J = 8.45 Hz, ArH ortho to N), 7.05–7.22 (m, 5H,
ArH), 7.57–7.60 (d, 1H, J = 7.26 Hz, ArH); IR (KBr):
3364, 3226, 2928, 2812, 1611, 1516, 1446, 1244,
1248, 1052, 802 cmÀ1
.
5.1.2.7. 6-Methoxy-2-dimethylaminomethyl-1,2,3,4-
tetra hydronaphthalen-1-ol (6g). Yield 97%; MS (FAB)
1
m/z: 236 ((M+1)+, 82%); H NMR (200 MHz, CDCl3):
808 cmÀ1
.
d 1.45 (m, 1H, H-2), 1.68 (m, 1H, H-3), 1.9 (m, 1H,
H-3), 2.27–2.41 (m, 7H, CH2-N–(Me)2), 2.54–2.81 (m,
3H, N–CH2, H-4), 3.77 (s, 3H, OMe), 4.58–4.63 (d,
1H, J = 9.188 Hz, OH–CH), 6.59 (s, 1H, H-5), 6.80–
6.81 (m, 1H, H-7), 7.48–7.52 (d, 1H, J = 8.55 Hz, H-
8); IR (Neat): 3206, 2997, 2929, 2831, 2792, 1501,
5.1.2.2. 2-[1-(3-Trifluoromethylphenyl)-piperazinyl]-
methyl-1,2,3,4-tetrahydronaphthalen-1-ol (6b). Yield
97%; MS (FAB) m/z: 391 ((M+1)+, 70%); 1H NMR
(200 MHz, CDCl3): d 1.43–1.57 (m, 2H, H-2, H-3),
2.02–2.06 (m, 1H, H-3), 2.64–2.76 (m, 4H, NCH2),
2.88–2.94 (m, 4H, H-4, N–CH2), 3.29 (m, 4H, piperazi-
nyl NCH2 adjacent to phenyl ring), 4.69–4.73 (d, 1H,
J = 9.09 Hz, OH–CH), 7.10–7.39 (m, 7H, ArH), 7.57–
7.61 (d, 1H, J = 6.72 Hz, ArH); IR (Neat): 3223, 2921,
2877, 2824, 2364, 1611, 1498, 1450, 1361, 1311, 1250,
1466, 1254, 1219, 1037, 757 cmÀ1
.
5.1.2.8. 6-Methoxy-2-benzylmethylaminomethyl-
1,2,3,4-tetrahydronaphthalen-1-ol (6h). Yield 95%; MS
1
(FAB) m/z: 312 ((M+1)+, 70%); H NMR (200 MHz,
CDCl3): d 1.35–1.42 (m, 1H, H-2), 1.63–1.69 (m, 1H,
H-3), 1.96–2.03 (m, 1H, H-3), 2.28 (s, 3H, N–Me),
2.41–2.49 (m, 1H, N–CH2– CH), 2.66–2.89 (m, 3H,
N–CH2, H-4), 3.39–3.45 (d, 1H, J = 12.9 Hz, Ar–CH2–
N), 3.73–3.77 (m, OMe, Ar–CH2–N), 4.52–4.57 (d,
1H, J = 9.18 Hz, OH–CH), 6.58 (s, 1H, H-5), 6.76–
6.80 (d, 1H, J = 8.6 Hz, H-7), 7.33 (m, 5H, ArH),
7.50–7.54 (d, 1H, J = 8.56 Hz, H-8); IR (Neat): 3222,
3065, 3008, 2931, 2838, 2804, 1611, 1500, 1464, 1217,
1163, 1105, 950, 742 cmÀ1
.
5.1.2.3. 2-Dimethylaminomethyl-1,2,3,4-tetrahydro-
naphthalen-1-ol (6c). Yield 97%; MS (FAB) m/z: 206
1
((M+1)+, 100%); H NMR (200 MHz, CDCl3): d 1.45
(m, 1H, H-2), 1.7 (m, 1H, H-3), 2.00 (m, 1H, H-3),
2.19–2.43 (m, 7H, CH2-N-(Me)2), 2.55–2.61 (m, 1H,
N–CH2), 2.84–2.86 (m, 2H, H-4), 4.62–4.67 (d, 1H,
J = 9.58 Hz, OH–CH), 7.08–7.22 (m, 3H, ArH), 7.57–
7.61 (d, 1H, J = 7.05 Hz, ArH); IR (Neat): 3259, 2924,
757 cmÀ1
.
2827, 2788, 1605, 1466, 1382, 1259, 1042, 743 cmÀ1
.
5.1.3. General procedure for the preparation of 1-aryloxy-
2-substituted aminomethyltetrahydronaphthalene deriva-
tives (7–18). A solution of 2-substituted aminomethyl-
1,2,3,4-tetrahydronaphthalen-1-ol (6a–6h) (5 mmol) in
dry dimethyl acetamide (DMAC) (2 mL) was added
dropwise to stirred and cooled (0–4 ꢁC) suspension of
sodium hydride (50%, 15 mmol) in dry (DMAC)
(3 mL). It was further stirred with cooling for 30 min
after which the reaction mixture was allowed to
attain the rt and heated at 80–90 ꢁC for 2 h. The reaction
5.1.2.4. 2-Benzylmethylaminomethyl-1,2,3,4-tetrahy-
dro naphthalen-1-ol (6d). Yield 94%; MS (FAB) m/z:
1
282 (M+, 100%); H NMR (200 MHz, CDCl3): d 1.41
(m, 1H, H-2), 1.65 (m, 1H, H-3), 1.99 (m, 1H, H-3),
2.22–2.51 (m, 4H, CH–CH2–N–CH3), 2.79–3.04 (m,
3H, H-4, CH–CH2–N), 3.40–3.46 (m, 1H, N–CH2–
Ph), 3.74–3.80 (m, 1H, N–CH2–Ph), 4.57–4.61 (d, 2H,
J = 9.03 Hz, OH–CH), 7.07–7.39 (m, 8H, ArH), 7.64–

K. Bhandari et al. / Bioorg. Med. Chem. 14 (2006) 2535–2544
2541
1
mixture was cooled to rt and 4-fluorobenzotrifluoride/4-
fluoroacetophenone (7.5 mmol) was added dropwise
with stirring. The dark coloured reaction mixture was
heated at 100–110 ꢁC for 3–4 h. The reaction was dis-
continued, treated with water (15 mL) and extracted
with ethyl acetate (3· 10 mL). The combined organic
layer was washed with water (6· 10 mL), dried over
sodium sulfate and concentrated to give the crude prod-
uct, which was chromatographed on a silica gel column
using ethyl acetate–hexane (10–18%) as an eluent to get
the desired ethers (7–18) in good yield and converted
into the oxalate salt in dry methanol.
75%), 508 (M+, 78%); H NMR (200 MHz, CDCl3): d
1.67–1.74 (m, 1H, H-3), 2.35–3.06 (m, 13H, H-3, H-2,
NCH2, H-4, COCH3), 3.28 (m, 4H, piperazinyl NCH2
adjacent to phenyl ring), 5.47 (s, 1H, O–CH), 7.06–7.36
(m, 10H, ArH), 7.92–7.96 (d, 2H, J = 8.78 Hz, ArH ortho
to COCH3); IR (KBr): 2930, 2823, 1675, 1598, 1452, 1314,
1245, 1122, 752 cmÀ1. Anal. Calcd for C30H31F3N2O2Æ
2H2C2O4Æ2H2O: C, 56.35; H, 5.39; N, 3.87. Found: C,
56.19; H, 5.10; N, 3.51.
5.1.3.5.
Dimethyl-[1-(4-trifluoromethylphenoxy)-
1,2,3,4-tetrahydronaphthalen-2-yl-methyl]-amine oxalate
(11). With 6c and 4-fluorobenzotrifluoride. Yield 77%;
Mp 195–200 ꢁC; MS (FAB) m/z: 350 ((M+1)+, 100%);
1H NMR (200 MHz, CDCl3): d 1.7 (m, 1H, H-3),
2.23–2.35 (m, 10H, H-3, H-2, NCH2, N–(Me)2), 2.78–
2.80 (m, 2H, H-4), 5.32–5.33 (d, 1H, J = 2.49 Hz, O–
CH), 7.11–7.18 (m, 6H, ArH), 7.53–7.58 (d, 2H,
J = 8.49 Hz, ArH ortho to CF3); IR (KBr): 3021, 2927,
2708, 1737, 1659, 1614, 1325, 1216, 763 cmÀ1. Anal.
Calcd for C20H22F3NO. H2C2O4: C, 60.14; H, 5.47; N,
3.19. Found: C, 59.77; H, 5.38; N, 2.97.
5.1.3.1.
1-(4-Methylphenyl)-4-[1-(4-trifluoromethyl
phenoxy)-1,2,3,4-tetrahydronaphthalen-2-yl-methyl]-
piperazine dioxalate (7). With 6a and 4-fluorobenzotri-
fluoride. Yield 83%; Mp 185–190 ꢁC; MS (FAB) m/z:
481 ((M+1)+, 90%); 1H NMR (200 MHz, CDCl3): d
1.59–1.64 (m, 1H, H-3), 2.20–2.48 (m, 9H, Ar–CH3,
NCH2, H-3, H-2), 2.59–2.77 (m, 4H, NCH2, H-4),
3.11 (m, 4H, piperazinyl NCH2 adjacent to phenyl ring),
5.35 (s, 1H, O–CH), 6.77–6.81 (d, 2H, J = 8.06 Hz, ArH
ortho to N), 7.00–7.04 (d, 2H, J = 7.74 Hz, ArH ortho to
O), 7.14–7.18 (m, 6H, ArH), 7.44–7.48 (d, 2H,
J = 8.16 Hz, ArH ortho to CF3); IR (KBr): 3448, 3028,
2923, 2502, 2364, 1733, 1618, 1516, 1329, 1166,
5.1.3.6. Dimethyl-[1-(4-acetylphenoxy)-1,2,3,4-tetra-
hydronaphthalen-2-yl-methyl]-amine oxalate (12). With
6c and 4-fluoroacetophenone. Yield 65%; Mp 88–
707 cmÀ1
.
Anal. Calcd for C29H31F3N2OÆ2H2C
90 ꢁC; MS (FAB) m/z: 324 ((M+1)+, 100%); H NMR
1
2O4Æ0.75H2O: C, 58.79; H, 5.42; N, 4.16. Found: C,
58.98; H, 5.40; N, 4.12.
(200 MHz, CDCl3): d 1.69–1.73 (m, 1H, H-3), 2.31–
2.40 (m, 10H, H-3, H-2, NCH2, N–(Me)2), 2.57 (s, 3H,
COCH3), 2.84 (m, 2H, H-4), 5.38 (s, 1H, O–CH),
7.09–7.26 (m, 6H, ArH), 7.93–7.97 (d, 2H,
J = 8.65 Hz, ArH ortho to COCH3); IR (KBr): 2932,
2374, 1598, 1353, 1241, 768 cmÀ1. Anal. Calcd for
C21H25NO2ÆH2C2O4Æ0.75H2O: C, 64.71; H, 6.68; N,
3.28. Found: C, 64.41; H, 6.61; N, 2.89.
5.1.3.2.
1-(4-Methylphenyl)-4-[1-(4-acetylphenoxy)-
1,2,3,4-tetrahydronaphthalen-2-yl-methyl]piperazine
dioxalate (8). With 6a and 4-fluoroacetophenone. Yield
60%; Mp 142–144 ꢁC; MS (FAB) m/z: 454 ((M+1)+,
1
90%); H NMR (200 MHz, CDCl3): d 1.69 (m, 1H, H-
3), 2.17–2.35 (m, 4H, Ar–CH3, H-3), 2.39–2.56 (m,
8H, NCH2, H-2, COCH3), 2.66–2.82 (m, 4H, NCH2,
H-4), 3.19 (m, 4H, piperazinyl NCH2 adjacent to phenyl
ring), 5.48 (s, 1H, O–CH), 6.85–6.89 (d, 2H,
J = 8.03 Hz, ArH ortho to N), 7.07–7.31 (m, 8H,
ArH), 7.91–7.95 (d, 2H, J = 7.58 Hz, ArH ortho to
COCH3); IR (KBr): 3038, 2925, 2692, 1734, 1614,
5.1.3.7. Benzylmethyl-[1-(4-trifluoromethylphenoxy)-
1,2,3,4-tetrahydronaphthalen- 2-yl-methyl]-amine oxalate
(13). With 6d and 4-fluorobenzotrifluoride. Yield 67%;
Mp 110–115 ꢁC; MS (FAB) m/z: 425 (M+, 70%); 1H
NMR (200 MHz, CDCl3): d 1.64–1.68 (m, 1H, H-3),
2.23–2.47 (m, 7H, H-3, H-2, NCH2, N–Me), 2.60–2.77
(m, 2H, H-4), 3.41–3.56 (m, 2H, Ar–CH2–N), 5.34 (s,
1H, O–CH), 7.13–7.41 (m, 11H, ArH), 7.50–7.54 (d,
2H, J = 8.22 Hz, ArH ortho to CF3); IR (KBr): 3759,
3622, 3436, 1326, 1218, 1164, 767 cmÀ1. Anal. Calcd
for C26H26F3NO. H2C2O4Æ0.5H2O: C, 64.12; H, 5.53;
N, 2.67. Found: C, 64.21; H, 5.21; N, 2.38.
1325, 1243, 1114, 842 cmÀ1
.
Anal. Calcd for
C30H34N2O2Æ2H2C2O4Æ0.5H2O: C, 63.45; H, 6.07; N,
4.35. Found: C, 63.07; H, 5.68; N, 4.39.
5.1.3.3. 1-(3-Trifluoromethylphenyl)-4-[1-(4-trifluoro-
methylphenoxy)-1,2,3,4-tetrahydronaphthalen-2-yl-meth-
yl]piperazine dioxalate (9). With 6b and 4-fluorobenzotri-
fluoride. Yield 66%; Mp 135–140 ꢁC; MS (FAB) m/z: 534
(M+, 70%); 1H NMR (200 MHz, CDCl3): d 1.72–1.74 (m,
1H, H-3), 2.17–2.82 (m, 10H, H-3, H-2, NCH2, H-4), 3.27
(m, 4H, piperazinyl NCH2 adjacent to phenyl ring), 5.42
(s, 1H, O–CH), 7.12–7.36 (m, 10H, ArH), 7.53–7.57 (d,
2H, J = 8.07 Hz, ArH); IR (KBr): 3754, 3449, 2951,
2819, 2363, 1601, 1352, 1115 cmÀ1. Anal. Calcd for
C29H28F6N2OÆ2H2C2O4: C, 55.46; H, 4.48; N, 3.92.
Found: C, 55.80; H, 4.84; N, 4.05.
5.1.3.8. Benzylmethyl-[1-(4-acetylphenoxy)-1,2,3,4-
tetra hydronaphthalen-2-yl-methyl]-amine oxalate (14).
With 6d and 4-fluoroacetophenone. Yield 76%; Mp 100–
104 ꢁC; MS (FAB) m/z: 400 ((M+1)+, 100%); H NMR
1
(200 MHz, CDCl3): d 1.61–1.70 (m, 1H, H-3), 2.17–2.35
(m, 5H, N–Me, H-3, H-2), 2.39–2.55 (m, 5H, COCH3,
NCH2), 2.69–2.80 (m, 2H, H-4), 3.41–3.50 (m, 2H,
Ar–CH2–N), 5.39 (s, 1H, O–CH), 6.63–6.67 (d, 1H,
J = 8.92 Hz, ArH), 7.10–7.33 (m, 9H, ArH), 7.85–7.93
(m, 3H, ArH); IR (KBr): 3025, 2932, 2796, 1675, 1598,
1505, 1361, 1277, 1172, 749 cmÀ1. Anal. Calcd for
C27H29NO2ÆH2C2O4Æ0.5H2O: C, 69.88; H, 6.43; N,
2.81. Found: C, 70.01; H, 6.81; N, 2.78.
5.1.3.4. 1-(3-Trifluoromethylphenyl)-4-[1-(4-acetyl phen-
oxy)-1,2,3,4-tetrahydronaphthalen-2-yl-methyl] piperazine
dioxalate (10). With 6b and 4-fluoroacetophenone. Yield
58%; Mp 130–135 ꢁC; MS (FAB) m/z: 509 ((M+1)+,

2542
K. Bhandari et al. / Bioorg. Med. Chem. 14 (2006) 2535–2544
5.1.3.9. Dibenzyl-[1-(4-acetylphenoxy)-1,2,3,4-tetrahy-
dro naphthalen-2-yl-methyl]-amine oxalate (15). With 6e
and 4-fluoroacetophenone. Yield 50%; oil; MS (FAB)
wise under stirring over a period of 15 min. The reaction
mixture was further stirred for 2 h at 0–4 ꢁC. After
completion of reaction, the solid was filtered and the
filtrate was concentrated to give the mesylate residue.
The sodium salt of 4-methoxy phenol/phenol was
prepared by adding the corresponding phenol (11 mmol)
to a solution of sodium hydroxide (12 mmol) in ethanol
(20 mL) The solution of mesylate in alcohol (5 mL) was
then added dropwise to the sodium salt. The reaction
mixture was further stirred for 12 h at room tempera-
ture. Then solvent was distilled off, treated with brine
(20 mL), extracted with chloroform (3· 15 mL) and
dried (anhyd Na2SO4). The solvent was then removed
under reduced pressure to give the crude, which was
chromatographed on silica gel using ethyl acetate–hex-
ane (10–15%) as an eluent to afford 19 and 20 as an
oil which were converted into oxalate salt in dry
methanol.
1
m/z: 476 (M+, 25%); H NMR (200 MHz, CDCl3): d
1.6 (m, 1H, H-3), 2.09–2.28 (m, 2H, H-3, H-2), 2.39–
2.48 (m, 5H, COCH3, NCH2), 2.65 (m, 2H, H-4),
3.40–3.64 (m, 2H, Ar–CH2–N), 5.09–5.11 (d, 1H,
J = 2.84 Hz, O–CH), 6.87–7.06 (m, 4H, ArH), 7.11–
7.20 (m, 12H, ArH), 7.76–7.80 (d, 2H, J = 8.76 Hz,
ArH ortho to COCH3); IR (Neat): 3468, 3020, 2401,
1677, 1598, 1216, 770 cmÀ1
.
Anal. Calcd for
C33H33NO2Æ H2C2O4Æ1.5H2O: C, 70.95; H, 6.42; N,
2.36. Found: C, 70.59; H, 6.53; N, 2.48
5.1.3.10. 1-(4-Methylphenyl)-4-[6-methoxy-1-(4-acetyl
phenoxy)-1,2,3,4-tetrahydronaphthalen-2-yl-methyl]-
piperazine dioxalate (16). With 6f and 4-fluoroacetophe-
none. Yield 91%; Mp 165–170 ꢁC; MS (FAB) m/z: 484
1
(M+, 60%); H NMR (200 MHz, CDCl3): d 1.63 (m,
1H, H-3), 2.17–2.77 (m, 16H, H-2, H-3, H-4, NCH2,
Ar–CH3, COCH3), 3.19 (m, 4H, piperazinyl NCH2 adja-
cent to phenyl ring), 3.80 (s, 3H, OMe), 5.44 (s, 1H, O–
CH), 6.69–6.89 (m, 4H, ArH), 7.07–7.19 (m, 5H, ArH),
7.90–7.94 (d, 2H, J = 8.2 Hz, ArH ortho to COCH3); IR
(KBr): 3433, 3018, 2936, 1672, 1598, 1505, 1218, 1171,
765 cmÀ1. Anal. Calcd for C31H36N2O3Æ2H2C2O4Æ2H2O:
C, 60.00; H, 6.29; N, 4.00. Found: C, 59.69; H, 5.90; N,
4.16.
5.1.4.1. Dimethyl-[1-(4-methoxyphenoxy)-1,2,3,4-tetra
hydronaphthalen-2-yl-methyl]-amine oxalate (19). Yield
50%; Mp 140–142 ꢁC; MS (FAB) m/z: 312 ((M+1)+,
1
100%); H NMR (200 MHz, CDCl3): d 1.69–1.75 (m,
1H, H-3), 2.30–2.44 (m, 10H, H-3, H-2, CH2–N–
(Me)2), 2.87 (m, 2H, H-4), 3.8 (s, 3H, OMe), 5.11 (s,
1H, O–CH), 6.83–6.88 (d, 2H, J = 8.84 Hz, ArH ortho
to O), 6.97–7.01 (d, 2H, J = 8.92 Hz, ArH ortho to O),
7.18–7.37 (m, 4H, ArH); IR (KBr): 3410, 2935, 2859,
2771, 1668, 1504, 1458, 1220, 1036, 748 cmÀ1. Anal.
Calcd for C20H25NO2ÆH2C2O4: C, 65.84; H, 6.73; N,
3.49. Found: C, 65.52; H, 6.38; N, 3.28.
5.1.3.11. Dimethyl-[6-methoxy-1-(4-acetylphenoxy)-
1,2,3,4-tetrahydronaphthalen-2- yl-methyl]-amine oxalate
(17). With 6g and 4-fluoroacetophenone. Yield 52%; Mp
90–95 ꢁC; MS (FAB) m/z: 354 ((M+1)+, 60%); 1H NMR
(200 MHz, CDCl3): d 1.7 (m, 1H, H-3), 2.07–2.34 (m,
10H, H-3, H-2, CH2–N–(Me)2), 2.56 (s, 3H, COCH3),
2.75–2.77 (m, 2H, H-4), 3.79 (s, 3H, OMe), 5.33–5.35
(d, 1H, J = 2.48 Hz, O–CH), 6.68–6.78 (m, 2H, ArH),
7.07–7.12 (d, 2H, J = 8.87 Hz, ArH), 7.17–7.21 (d, 1H,
J = 8.42 Hz, ArH), 7.92–7.97 (d, 2H, J = 8.85 Hz, ArH
ortho to COCH3); IR (KBr): 3011, 2937, 1673, 1599,
5.1.4.2. Dimethyl-[1-phenoxy-1,2,3,4-tetrahydronaph
thalen-2-yl-methyl]-amine oxalate (20). Yield 52%; Mp
1
168–170 ꢁC; MS (FAB) m/z: 282 ((M+1)+, 100%); H
NMR (200 MHz, CDCl3): d 1.7 (m, 1H, H-3), 2.18–
2.29 (m, 10H, H-3, H-2, CH2–N–(Me)2), 2.78–2.80 (m,
2H, H-4), 5.21–5.22 (d, 1H, J = 3.86 Hz, O–CH), 6.95–
7.34 (m, 9H, ArH); IR (KBr): 3403, 2932, 2362, 2339,
1657, 1588, 1219, 771 cmÀ1
.
Anal. Calcd for
1506, 1246, 1169, 761 cmÀ1
.
Anal. Calcd for
C19H23NO. H2C2O4: C, 67.92; H, 6.74; N, 3.77. Found:
C, 68.13; H, 6.60; N, 4.11.
C22H27NO3ÆH2C2O4Æ1.5H2O: C, 61.28; H, 6.81; N,
2.98. Found: C, 61.41; H, 7.19; N, 2.61.
5.1.5. Methyl-[1-(4-trifluoromethylphenoxy)-1,2,3,4-tetra-
hydronaphthalen-2-yl-methyl]-amine oxalate (21). It was
prepared by known methods reported in the literature
starting from 13.16 Yield 73%; Mp 225–227 ꢁC; MS
5.1.3.12.
Benzyl-[6-methoxy-1-(4-acetylphenoxy)-
1,2,3,4-tetrahydronaphthalen-2-yl-methyl]-methylamine
oxalate (18). With 6h and 4-fluoroacetophenone. Yield
58%; Mp 75–80 ꢁC; MS (FAB) m/z: 430 ((M+1)+,
1
(FAB) m/z: 336 ((M+1)+, 100%); H NMR (200 MHz,
1
20%); H NMR (200 MHz, CDCl3): d 1.60 (m, 1H, H-
CDCl3): d 1.76 (m, 1H, H-3), 2.17–2.41 (m, 5H, H-3,
H-2, N-Me), 2.54–2.74 (m, 2H, NCH2), 2.80–2.88 (m,
2H, H-4), 5.39–5.42 (d, 1H, J = 5.26 Hz, O–CH), 7.11–
7.28 (m, 6H, ArH), 7.54–7.58 (d, 2H, J = 8.58 Hz,
ArH ortho to CF3); IR (KBr): 3323, 2931, 2852, 2798,
3), 2.13–2.45 (m, 7H, H-2, H-3, CH–CH2–NMe), 2.55
(s, 3H, COCH3), 2.60–2.77 (m, 2H, H-4), 3.47–3.50
(m, 2H, Ar–CH2–N), 3.78 (s, 3H, OMe), 5.36 (s, 1H,
O–CH), 6.64–6.75 (m, 2H, ArH), 7.09–7.37 (m, 8H,
ArH), 7.88–7.93 (d, 2H, J = 8.7 Hz, ArH ortho to
COCH3); IR (KBr): 3164, 2372, 1658, 1401, 1279,
1229, 1112 cmÀ1. Anal. Calcd for C28H31NO3ÆH2-
C2O4Æ1H2O: C, 67.04; H, 6.52; N, 2.61. Found: C,
66.94; H, 6.36; N, 2.57.
1675, 1613, 1516, 1326, 1249, 1162, 1114, 749 cmÀ1
.
Anal. Calcd for C19H20F3NOÆH2C2O4Æ0.25H2O: C,
58.67; H, 5.24; N, 3.26. Found: C, 58.79; H, 5.09; N,
3.59.
5.1.6. N,N-Dibenzyl-3-phenyl-3-(4-acetylphenoxy) prop-
anamine hydrochloride (22). It was prepared by known
methods reported in the literature using acetophenone,
dibenzylammonium chloride (4e) and 4-fluoroacetophe-
none.19 Yield 60%; Mp 55 ꢁC; MS (FAB) m/z: 450
5.1.4. General procedure for the preparation of 19 and 20.
To a precooled (0–4 ꢁC) suspension of 6c (10 mmol) and
anhyd. K2CO3 (25 mmol) in dry acetone (25 mL)
was added methanesulfonyl chloride (25 mmol) drop-

K. Bhandari et al. / Bioorg. Med. Chem. 14 (2006) 2535–2544
2543
1
((M+1)+, 70%); 1H NMR (200 MHz, CDCl3): d 2.00 (m,
2H, CH–CH2), 2.4–2.5 (m, 4H, COCH3, CH–CH2–
CH2), 2.7 (m, 1H, CH–CH2–CH2), 3.44–3.70 (m, 4H,
Ar–CH2–N), 5.24–5.31 (m, 1H, O–CH), 6.67–6.72 (d,
2H, J = 8.86 Hz, ArH ortho to COCH3), 7.10–7.34 (m,
15H, ArH), 7.74–7.78 (d, 2H, J = 8.86 Hz, ArH ortho
to COCH3); IR (KBr): 3447, 3028, 2927, 2082, 2363,
100%); H NMR (200 MHz, CDCl3): d 1.99–2.07 (m,
1H, NCH2–CH2), 2.12–2.21 (m, 1H, NCH2–CH2), 2.44
(s, 3H, NMe), 2.72–2.77 (t, 2H, J = 6.28 Hz, NCH2),
3.77 (s, 3H, OMe), 5.22–5.30 (m, 1H, OCH), 6.81–6.89
(m, 4H, ArH ortho to O), 7.19–7.25 (m, 2H, ArH),
7.39–7.44 (d, 2H, J = 8.64 Hz, ArH ortho to CF3); IR
(Neat): 3427, 2955, 2840, 2481, 1613, 1514, 1327, 1249,
1143, 1033, 836 cmÀ1. Anal. Calcd for C18H20F3NO2ÆH-
ClÆ0.5H2O: C, 56.18; H, 5.72; N, 3.64. Found: C, 55.95;
H, 6.03; N, 3.38.
1675, 1599, 1249, 749 cmÀ1
.
Anal. Calcd for
C31H31NO2ÆHClÆ1.5H2O: C, 72.59; H, 6.83; N, 2.73.
Found: C, 72.83; H, 6.89; N, 3.11.
5.1.7. N,N-Dibenzyl-3-phenyl-3-(4-trifluoromethylphen-
oxy)propanamine hydrochloride (23). It was prepared
by known methods reported in the literature using ace-
tophenone, dibenzylammonium chloride (4e) and 4-
chlorobenzotrifluoride.19 Yield 70%; Mp 162–166 ꢁC;
5.1.11. N-Methyl-3-phenyl-3-(4-trifluoromethylphenoxy)-
propanamine hydrochloride (fluoxetine). It was prepared
by known methods reported in the literature.16
5.1.12. N,N-Dimethyl-3-phenyl-3-(4-trifluoromethylphen-
oxy)propanamine hydrochloride (27). A mixture of fluoxe-
tine (618 mg, 2 mmol) and formaldehyde solution (40%,
2.1 mL) in dry methanol (5 mL) was allowed to stir for
1 h , which was followed by the addition of sodium boro-
hydride (200 mg) in portions. The reaction mixture was
further stirred for overnight. The solvent was distilled
off under reduced pressure. The residue obtained was
treated with water (15 mL), extracted with dichlorometh-
ane (3· 10 mL) and chromatographed on silica gel col-
umn using methanol:chloroform (2:98) as an eluant to
afford 27 as an oil, which was converted into hydrochlo-
ride salt using methanolic hydrochloric acid. Yield 85%;
MS (FAB) m/z: 324 ((M+1)+, 100%); 1H NMR
(200 MHz, CDCl3): d 1.95 (m, 2H, CH-CH2), 2.23 (s,
6H, N(Me)2), 2.38–2.42 (m, 2H, CH–CH2–CH2), 5.3
(m, 1H, CH), 6.86–6.90 (d, 2H, J = 8.6 Hz, ArH ortho
to O), 7.25–7.33 (m, 5H, ArH), 7.39–7.43 (d, 2H,
J = 8.6 Hz, ArH ortho to CF3); IR (Neat): 2949, 2819,
2771, 1615, 1516, 1327, 1251, 1066, 836, 702 cmÀ1. Anal.
Calcd for C18H20F3NOÆHClÆ1.75H2O: C, 55.24; H, 6.27;
N, 3.58. Found: C, 55.58; H, 6.54; N, 3.26.
1
MS (FAB) m/z: 475 (M+, 70%); H NMR (200 MHz,
CDCl3): d 2.1 (m, 2H, CH–CH2), 2.5 (m, 1H, CH–
CH2–CH2), 2.7 (m, 1H, CH–CH2–CH2), 3.43–3.70 (m,
4H, Ar–CH2–N), 5.25 (m, 1H, O–CH), 6.70–6.74 (d,
2H, J = 8.54 Hz, ArH ortho to O), 7.16–7.40 (m, 17H,
ArH), IR (KBr): 3029, 2930, 2803, 1614, 1452, 1326,
1252, 1117, 755 cmÀ1. Anal. Calcd for C30H28F3NOÆH-
ClÆH2O: C, 67.99; H, 5.85; N, 2.64. Found: C, 67.67;
H, 5.90; N, 2.41.
5.1.8. N-Benzyl-N-methyl-3-phenyl-3-(4-trifluoromethyl-
phenoxy)propanamine hydrochloride (24). It was pre-
pared by known methods reported in the literature using
acetophenone, benzylmethylammonium chloride (4d)
and 4-chlorobenzotrifluoride.19 Yield 77%; Mp 145–
147 ꢁC; MS (FAB) m/z: 400 ((M+1)+, 30%), 399 (M+,
1
100%); H NMR (300 MHz, CDCl3): d 2.01–2.06 (m,
1H, CH–CH2), 2.18–2.29 (m, 4H, N–Me, CH–CH2),
2.45–2.51 (m, 1H, CH–CH2–CH2), 2.60–2.67 (m, 1H,
CH–CH2–CH2), 3.44–3.57 (m, 2H, Ar–CH2–N), 5.33–
5.37 (m, 1H, O–CH), 6.87–6.90 (d, 2H, J = 8.7 Hz,
ArH ortho to O), 7.23–7.36 (m, 10H, ArH), 7.42–7.45
(d, 2H, J = 8.7 Hz, ArH ortho to CF3); IR (KBr):
5.2. Pharmacology
3440, 2937, 2619, 1614, 1517, 1461 cmÀ1
.
All the synthesized compounds were tested for anorexi-
genic and antidepressant activities by standard meth-
ods.15 The present study was carried out in a group of
five Swiss albino mice (weighing 16–20 g) of either sex.
Each mouse was individually caged and the compounds
were administered intraperitoneally at 75 lmol/kg dose
(as oxalate or hydrochloride salt) either as aqueous solu-
tion or suspension in gum acacia. After ip administra-
tion of the compounds, the animals were observed for
gross behaviour. The mice were examined continuously
for 3 h after ip administration of compounds, then every
30 min for next 3 h and finally after 24 h. CNS stimula-
tion was judged by increased spontaneous motor activi-
ty (SMA), pilorection, exopthalamous, clonic or tonic
convulsions. Reduced SMA, sedation, ptosis, crouching
and catalepsy assessed CNS depression. Autonomic ef-
fects—pilorection, urination, defecation, salivation and
lachrymation were also observed. For anorexigenic
activity, mice were fasted for 24 h and pretreated with
75 lmol/kg dose of the compound intraperitoneally.
After 1 h, each mouse was exposed to 0.5 mL of the milk
(sweetened and reconstituted as 25% aqueous suspen-
sion from powdered milk manufactured by Nestle) for
5.1.9. N-Benzyl-N-methyl-3-(4-methoxyphenyl)-3-(4-tri-
fluoromethylphenoxy)propanamine hydrochloride (25). It
was prepared by known methods reported in the litera-
ture using 4-methoxy acetophenone, benzylmethylam-
monium chloride (4d) and 4-chlorobenzotrifluoride.19
Yield 72%; MS (FAB) m/z: 268 ((M-(O–Ar–CF3))+,
50%); 1H NMR (200 MHz, CDCl3): d 1.89–2.00 (m,
1H, CH–CH2), 2.09–2.19 (m, 4H, N-Me, CH–CH2),
2.33–2.39 (m, 1H, CH–CH2–CH2), 2.49–2.56 (m, 1H,
CH–CH2–CH2), 3.43–3.45 (m, 2H, Ar–CH2–N), 3.74
(s, 3H, OMe), 5.21–5.28 (m, 1H, O–CH), 6.74–6.82
(m, 4H, ArH ortho to O), 7.13–7.23 (m, 7H, ArH),
7.36–7.41 (d, 2H, J = 8.61 Hz, ArH ortho to CF3); IR
(Neat): 3417, 3020, 2958, 2363, 1614, 1514, 1326, 1249,
1217, 761 cmÀ1. Anal. Calcd for C25H26F3NO2ÆHClÆ0.5-
H2O: C, 63.22; H, 5.90; N, 2.95. Found: C, 62.96; H,
6.28; N, 3.10.
5.1.10.
N-Methyl-3-(4-methoxyphenyl)-3-(4-trifluoro-
methylphenoxy)propanamine hydrochloride (26). It was
prepared by known methods in the literature starting
from 25.16 Yield 67%; MS (FAB) m/z: 340 ((M+1)+,

2544
K. Bhandari et al. / Bioorg. Med. Chem. 14 (2006) 2535–2544
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treated group was noted and the significance of differ-
ence between them was determined by unpaired Stu-
dentꢀs t test (two-tailed P value) with Welch correction
wherever required (Table 1 and Fig. 3). For antidepres-
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Acknowledgments
S.S. thanks the Council of Scientific and Industrial
Research (India) for the award of Senior Research
Fellowship. The authors are thankful to Mr. Anoop
K. Srivastava for providing technical assistance.
References and notes
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L. JAMA 2002, 288, 1723.