Synthesis of new 4-aryl-1-(biarylmethylene)piperidines. Structural analogs of adoprazine (SLV313)

Article abstract of DOI:10.1515/znb-2012-0312

A series of new 4-aryl-1-(biarylmethylene)piperidines have been synthesized. They are structurally related to SLV-313, a potential atypical antipsychotic agent with potent D₂ receptor antagonist and 5-HT _1A receptor agonist properties. Suzuki-Miyaura reaction of cyclic vinyl boronates, derived from the vinyl triflates of N-protected tetrahydropyridines, with appropriate aryl halides yielded 4-arylpiperidines. The reductive amination of the latter with suitable biarylaldehdyes accomplished the synthesis of the new compounds.

Full text of DOI:10.1515/znb-2012-0312

Synthesis of New 4-Aryl-1-(biarylmethylene)piperidines.
Structural Analogs of Adoprazine (SLV313)
Nisar Ullah and Ali Ahmed Qaid Al-Shaheri
Chemistry Department & Centre of Research Excellence in Nanotechnology, King Fahd University
of Petroleum and Minerals, Dhahran 31261, Saudi Arabia
Reprint requests to Professor Nisar Ullah. Fax: + 966 3 860 4277. E-mail: nullah@kfupm.edu.sa
Z. Naturforsch. 2012, 67b, 253 – 262; received January 18, 2012
A series of new 4-aryl-1-(biarylmethylene)piperidines have been synthesized. They are structurally
related to SLV-313, a potential atypical antipsychotic agent with potent D2 receptor antagonist and
5-HT1A receptor agonist properties. Suzuki-Miyaura reaction of cyclic vinyl boronates, derived from
the vinyl triflates of N-protected tetrahydropyridines, with appropriate aryl halides yielded 4-aryl-
piperidines. The reductive amination of the latter with suitable biarylaldehdyes accomplished the
synthesis of the new compounds.
Key words: Aryl-(biarylmethylene)piperidines, Suzuki-Miyaura Reaction, Reductive Amination,
Schizophrenia
Introduction
HT1A receptor agonist properties could improve the
therapeutic window, side-effect profile and therapeutic
efficacy of antipsychotic agents [4]. As a result ado-
prazine (1) (SLV-313) and bifeprunox (2), possessing
potent D2 receptor antagonist and 5-HT1A receptor ag-
onist properties, were developed [5]. However, the fail-
ure of 1 and 2 to oppose phencyclidine-induced social
interaction deficits suggested that an appropriate ‘bal-
ance’ of activity at these sites is necessary for activ-
ity in this model [4]. Thus, the need to discover com-
pounds having varying ratios of D2 and 5-HT1A ac-
tivities continued [6]. This report describes the synthe-
sis of a series of new 4-aryl-1-(biarylmethylene)piperi-
dines 3a – f, 4a – f and 5a – f, structurally related to 1
(Fig. 1).
Schizophrenia is a complex lifelong chronic neu-
ropsychiatric illness, afflicting approximately 1 % of
the world population. The symptoms of the disease
can be grouped as positive and negative. Positive
symptoms include delusions, hallucinations, and con-
ceptual disorganization. The most characteristic neg-
ative symptoms are affective flattening, social with-
drawal, anhedonia, and poverty of thought and con-
tent of speech [1]. The typical antipsychotic drugs,
for example haloperidol or chlorpromazine, were the
most widely used drugs for this disease because they
block D2 receptors. However, although the blockade
of D2 receptors improves the positive symptoms, the
development of neurological side effects such as dys-
tonia, muscle rigidity, tremor and akathisia, and tar-
dive dyskinesia, and in particular of extrapyramidal
side effects (EPS) [2, 3] undermine compliance. Vari-
ous atypical or second-generation antipsychotics, such
as clozapine and more recently aripiprazole have been
developed to reduce EPS liability and to treat nega-
tive symptoms. The atypical antipsychotics combine
D2 receptor antagonism with activity at other recep-
tors such as serotonergic receptors, on the premise that
a suitable balance of pharmacological activity should
broaden the spectrum of therapeutic efficacy and re-
duce EPS. It has been demonstrated that the combi-
nation of a dopamine D2 receptor antagonist with 5-
Results and Discussion
The synthesis of compounds 3a – f, 4a – f and 5a –
f required the synthesis of aldehydes 6b – f. Suzuki
reaction of 4-bromobenzaldehyde with 4-fluorobor-
onic acid yielded 6b whereas the reaction between 5-
bromonicotinaldehyde(7) with the appropriate boronic
acid gave the desired aldehydes 6c and 6d [7 – 10].
The known aldehydes 6e and 6f were synthesized from
their corresponding bromides 8 and 9 by employing
literature-known procedures [11] (Scheme 1).
The synthesis of the required arylpiperidines was
commenced from lithiation of 10 in THF at −78 ◦C fol-
c
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254
N. Ullah and A. A. Q. Al-Shaheri et al. · 4-Aryl-1-(biarylmethylene)piperidines
Fig. 1. 1-Aryl-4-(biarylmethylene)piper-
idines 3a – f, 4a – f and 5a – f.
reaction yielded a mixture of products which were dif-
ficult to separate (Scheme 2).
Thus, the desired intermediates 4 and 5 were
synthesized by an alternative route as outlined in
Scheme 3. Suzuki-Miyaura reaction of cyclic vinyl
boronates 14 [12], derived from the vinyl triflates of N-
protected tetrahydropyridines,with bromoquinoline10
generated compound 15. Hydrogenation of intermedi-
ate 15 in a Parr apparatus at 50 psi for 6 h followed
by column-chromatographic purifications on silica gel
produced intermediates 16 and 17 in a ratio of 3 : 7. Ex-
posure of compounds 16 and 17 to trifluoroacetic acid
at room temperature smoothly furnished the desired in-
termediates 4 and 5 in high yields (Scheme 3).
Likewise, to synthesize the required intermediate 3,
Suzuki-Miyaura reaction of cyclic vinyl boronates 14
with bromoquinoline 18 [13] generated compound 19,
which in turn was hydrogenated at 50 psi for 7 h to
furnish intermediate 20. Exposure of the latter to tri-
fluoroacetic acid at r. t. smoothly produced the desired
intermediate 5 in an overall yield of 36 % from 18
(Scheme 4).
Scheme 1. Synthesis of aldehydes 6c – f.
lowed by quenching with N-protected piperidinone 11
to obtain alcohol 12 in 68 % yield. The dehydration of
the latter was ensued by refluxing it in concentrated
HCl and MeOH to generate compound 13 in a mode-
rate yield. To produce the desired intermediate 4 from
compound 13, removal of N-protection and reduction
of the double bond were required. Hence compound 13
was subjected to hydrogenation in a Parr apparatus
at 60 psi (1 psi = 6894.757 Pa) for 5 h. The benzyl
deprotection, however, proved to be stubborn, and the
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N. Ullah and A. A. Q. Al-Shaheri et al. · 4-Aryl-1-(biarylmethylene)piperidines
255
Scheme 2. Synthesis of arylpiperi-
dines 4 and 5.
Scheme 3. Synthesis of arylpiperi-
dines 4 and 5, an alternative route.
Scheme 4. Synthesis of arylpiperi-
dine
3 (dppf =
1,1ꢀ-bis(diphenyl-
phosphino)ferrocene).
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N. Ullah and A. A. Q. Al-Shaheri et al. · 4-Aryl-1-(biarylmethylene)piperidines
128.87, 129.08, 129.39, 129.93, 136.84, 141.18, 142.25,
144.64 (all Carom), 160.31 (C-2). – C42H44N4O3 (652.82):
calcd. C 77.27, H 6.79, N 8.58; found C 77.20, H 6.84,
N 8.51.
8-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-2(1H)-
one (13)
A solution of compound 12 (1.5 g, 5.35 mmol) in a mix-
ture of methanol (15 mL) and concentrated HCl (15 mL)
was heated at reflux temperature for 5 h. The reaction mix-
ture was cooled, and the solvent was removed under reduced
pressure to give the crude product as a hydrochloride salt,
which was converted to the free base (aq. NaOH/ethyl ace-
tate) and purified by column chromatography eluting with
ethyl acetate/hexane (20 : 80 to 40 : 60) to afford the title
compound as a light-yellow gum (0.95 g, 56 %). – IR (neat):
ν = 3182, 3054, 3022, 2978, 1638, 1610, 1465 cm−1. –
1H NMR (500 MHz, CDCl3): δ = 2.15 (br. s, 2 H, piperi-
dine H), 2.97 (t, J = 5.5 Hz, 2 H, piperidine H), 3.34 (br. s,
2 H, piperidine H), 3.87 (s, 2 H, NCH2Ph), 5.79 (br. s, 1 H,
piperidine H), 6.62 (d, J = 9.5 Hz, 1 H, 3-H), 7.18 (t, J =
7.5 Hz, 1 H, aromatic H), 7.28 – 7.47 (m, 8 H, aromatic H),
7.76 (d, J = 9.5 Hz, 1 H, 4-H), 10.17 (br. s, 1 H, NHCO). –
13C NMR (125.7 MHz, CDCl3): δ = 31.52, 48.1, 51.9,
115.82 (all Cpiper), 120.93, 123.73, 124.66, 127.58, 128.07,
128.66, 128.88, 129.49, 129.99, 134.85, 136.44, 141.10,
141.85 (all Carom), 160.32 (C-2). – C21H20N2O (316.40):
calcd. C 79.72, H 6.37, N 8.85; found C 79.66, H 6.41,
N 8.80.
Scheme 5. Synthesis of 1-aryl-4-(biarylmethylene)piperi-
dines 3a – f, 4a – f and 5a – f, a representative example.
Having the desired arylpiperidines 4 and 5 and
biarylaldehdyes 6b – f in hand, we next performed
the reductive amination in 1,2-dichloroethane, using
NaBH(OAc)3 as reducing agent to obtain the desired
piperidines 3a – f, 4a – f and 5a – f (Scheme 5).
Conclusion
In conclusion we have accomplished the synthe-
sis of a series of new 1-aryl-4-(biarylmethylene)piper-
idines, 3a – f, 4a – f and 5a – f, structurally related to
SLV313.
Experimental Section
1-Benzyl-4-(2-(benzyloxy)quinolin-8-yl)piperidin-4-ol (12)
A solution of 2-(benzyloxy)-8-bromoquinoline 10 (2.0 g,
6.4 mmol) in THF (20 mL) was added dropwise over 10 min
to a solution of n-BuLi (2.5 M, 2.8 mL, 7 mmol) in hexane
cooled to −78 ◦C. The mixture was stirred for 1 h at −78 ◦C,
and a solution of 1-benzylpiperidone 11 (1.21 g, 6.4 mmol)
in THF (10 mL) was added dropwise over a period of 10 min,
maintaining the reaction temperature at −78 ◦C. The mixture
tert-Butyl 4-(2-(benzyloxy)quinolin-8-yl)-5,6-dihydropyri-
dine-1(2H)-carboxylate (15)
Nitrogen was flushed for 3 min in a flask containing a so-
was stirred at −78 ◦C for 0.5 h and at −10 ◦C for 1.5 h where- lution of boronate 14 (1.39 g, 4.5 mmol), K2CO3 (1.86 g,
upon a saturated solution of ammonium chloride (4 mL) was 13.5 mmol) and bromide 10 (1.49 g, 4.74 mmol) in DMF
added. The reaction mixture was stirred and warmed to r. t. (30 mL), followed by the addition of [PdCl2(dppf)] (0.23 g,
Water (50 mL) was added, and the reaction mixture was ex- 0.28 mmol) (dppf = 1,1ꢀ-bis(diphenylphosphino)ferrocene).
◦
tracted with dichloromethane (3×30 mL). The combined or- The reaction mixture was heated to 80 C and stirred un-
ganic extracts were washed with water, dried with Na2SO4 der N2 overnight, cooled to room temperature and filtered
and filtered. The solvent was removed under reduced pres- through a pad of celite. To the filtrate was added ethyl ac-
sure, and the crude product was purified by flash chromatog- etate (50 mL), and it was washed successively with water
raphy (1 M NH3 in MeOH/dichloromethane, 2 : 98 to 7 : 93) (20 mL) and brine (3 × 15 mL), dried over Na2SO4, and
to afford the title compound as a dark-brown thick oil (1.84 g, evaporated. Column chromatography of the brown oily mate-
68 %). – IR (neat): ν = 3365, 3042, 3032, 2971, 1607, 1485, rial on silica gel, eluting with ethyl acetate : hexanes (10 : 90,
1260, 1192 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 2.15 then 25 : 75) gave the title compound as a light-yellow amor-
(br. s, 4 H, piperidine H), 2.73 – 2.78 (m, 5 H, piperidine H, phous solid (0.97 g, 52 %). – IR (neat): ν = 3043, 3021,
OH), 3.62 (s, 2 H, NCH2), 5.43 (s, 2 H, OCH2), 6.99 (d, 2978, 1681, 1607, 1442, 1175 cm−−1. – 1H NMR (500 MHz,
J = 9.0 Hz, 1 H, 3-H), 7.23 – 7.47 (m, 11 H, aromatic H), CDCl3): δ = 1.49 (s, 9 H, OC(CH3)3), 2.76 (br. s, 2 H,
7.60 (m, 2 H, aromatic H), 8.04 (d, J = 8.5 Hz, 1 H, 4-H). – piperidine H), 3.68 (br. s, 2 H, piperidine H), 4.13 (br. s,
13C NMR (125.7 MHz, CDCl3): δ = 37.26, 49.46 (all Cpiper), 2 H, piperidine H), 5.49 (s, 2 H, OCH2Ph), 5.85 (br. s, 1 H,
53.02 (OCH2), 63.52 (NCH2), 68.48 (Cpiper), 113.21 (C-3), piperidine H), 6.95 (d, J = 8.8 Hz, 1 H, aromatic H), 7.30 –
124.75, 126.30, 127.48, 127.80, 128.05, 128.54, 128.70, 7.38 (m, 4 H, aromatic H), 7.46 – 7.48 (m, 3 H, aromatic H),
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257
7.63 (dd, J = 1.5, 7.9 Hz, 1 H, aromatic H), 7.99 (d, J = 8-(Piperidin-4-yl)quinolin-2(1H)-one (4)
8.8 Hz, 1 H, aromatic H). – 13C NMR (125.7 MHz, CDCl3):
To a solution of 17 (0.5 g, 1.52 mmol) in C◦H2Cl2 (15 mL)
was added trifluoroacetic acid (3 mL) at 0 C, and the re-
action mixture was stirred for 6 h at r. t. Solvents were
evaporated under reduced pressure, and triturating with di-
ethyl ether gave the title compound 4 as trifluoroacetic
acid salt as an off-white solid (0.45 g, 90 %). M. p. 256 –
258 ◦C. – IR (neat): ν = 3266, 3031, 3011, 2990, 1672, 1618,
1445 cm−−1. – 1H NMR (500 MHz, [D6]DMSO): δ = 1.86
(br. s, 4 H, piperidine H), 3.08 (m, 2 H, piperidine H), 3.42
(m, 2 H, piperidine H), 3.48 (m, 1 H, piperidine H), 6.51 (d,
J = 9.4 Hz, 1 H, 3-H), 7.19 (t, J = 8.1 Hz, 1 H, aromatic H),
7.37 (d, J = 8.0 Hz, 1 H, aromatic H), 7.54 (d, J = 7.9 Hz,
1 H, aromatic H H), 7.91 (d, J = 9.5 Hz, 1 H, 4-H), 8.49
(br. s, 1 H, NHCO). – 13C NMR (125.7 MHz, [D6]DMSO):
δ = 28.91, 31.68, 44.05 (all Cpiper), 119.91, 121.60, 122.31,
127.09, 127.56, 129.40, 136.09, 141.55 (all Carom), 162.92
(C=O). – C16H17F3N2O3 (342.31): calcd. C 56.14, H 5.01,
N 8.18; found C 56.08, H 5.06, N 8.11.
δ = 28.77 (OC(CH3)3), 30.18, 44.32, 67.73 (all Cpiper),
79.74 (OC(CH3)3), 113.18, 124.14, 125.55, 127.22, 128.04,
128.20, 128.66, 129.12, 137.51, 139.51, 140.12, 144.24
(all Carom), 155.60 (C=O), 161.02 (Carom). – C26H28N2O3
(416.51): calcd. C 74.97, H 6.78, N 6.73; found C 74.91,
H 6.83, N 6.67.
tert-Butyl 4-(2-oxo-1,2,3,4-tetrahydroquinolin-8-yl)piperi-
dine-1-carboxylate (16)
To a solution of compound 15 (0.7 g, 1.68 mmol) in a
mixture of THF (5 mL) and EtOH (10 mL) was added Pd-
C (10 % wet basis, 0.5 g), and the mixture was subjected to
hydrogenation in a Parr apparatus at 50 psi for 6 h (1 psi =
6894.757 Pa). After filtration through a pad of celite, the so-
lution was concentrated to give a brown oily material, which
was resolved over a silica column eluting with ethyl ac-
etate : hexanes (30 : 70, then 60 : 40) to get compound 16 as
◦
an off-white solid (0.15 g, 27 %). M. p. 132 – 134 C. – IR
(neat): ν = 3245, 3019, 2971, 1668, 1603, 1472 cm−1. –
1H NMR (500 MHz, CDCl3): δ = 1.49 (s, 9 H, OC(CH3)3),
1.61 (m, 2 H, piperidine H), 1.69 (m, 2 H, piperidine H),
2.61 (m, 2 H, 4-H), 2.79 (m, 1 H, piperidine H), 2.85 (br.
s, 2 H, piperidine H), 2.93 (m, 2 H, 3-H), 4.28 (br. s, 2 H,
piperidine H), 6.97 (t, J = 7.6 Hz, 1 H, aromatic H), 7.04 –
7.09 (m, 2 H, aromatic H), 8.30 (br. s, 1 H, NHCO). –
13C NMR (125.7 MHz, CDCl3): δ = 26.00 (C-4), 28.45
(OC(CH3)3), 30.68 (C-3), 32.13, 35.62 (all Cpiper), 79.56
(OC(CH3)3), 123.18, 124.48, 124.75, 126.02, 130.65, 134.23
(all Carom), 154.75 (C=O), 172.03 (C-2). – C19H26N2O3
(330.42): calcd. C 69.06, H 7.93, N 8.48; found C 69.00,
H 7.98, N 8.41.
8-(Piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (5)
Following the same procedure as adopted for the synthe-
sis of 4, the title compound was obtained from compound 16
as an off-white solid (0.70 g, yield 89 %). M. p. 247 –
248 ◦C. – IR (neat): ν = 3221, 3021, 2988, 1660, 1603,
1445, 1186 cm−1. – 1H NMR (500 MHz, [D6]DMSO): δ =
1.79 (m, 4 H, piperidine H), 2.51 (m, 2 H, 2-H), 2.85 (m,
2 H, 3-H), 2.99 – 3.06 (m, 3 H, piperidine H), 3.34 (m, 2 H,
piperidine H), 6.96 (m, 1 H, aromatic H), 7.07 (m, 1 H, aro-
matic H), 9.63 (s, 1 H, NHCO). – 13C NMR (125.7 MHz,
[D6]DMSO): δ = 25.88 (C-4), 29.22 (Cpiper), 30.88 (C-3),
32.29, 44.82 (all Cpiper), 123.05, 124.68, 125.63, 126.62,
130.45, 135.37 (all Carom), 170.02 (C=O). – C16H19F3N2O3
(344.33): calcd. C 55.81, H 5.56, N 8.14; found C 55.74,
H 5.62, N 8.08.
tert-Butyl 4-(2-oxo-1,2-dihydroquinolin-8-yl)piperidine-1-
carboxylate (17)
Compound 17 was obtained from the reaction described
for compound 16 as a light-yellow solid (0.36 g, yield 65 %).
M. p. 101 – 103 ◦C. – IR (neat): ν = 3172, 3031, 2965, 1645,
1603, 1461, 1112 cm−1. – 1H NMR (500 MHz, CDCl3):
tert-Butyl 4-(2-methoxyquinolin-8-yl)-5,6-dihydropyridine-
1(2H)-carboxylate (19)
Following the same procedure as adopted for the synthe-
δ = 1.50 (s, 9 H, OC(CH3)3), 1.69 (m, 2 H, piperidine H), sis of 15, the title compound was obtained from Suzuki reac-
1.91 (m, 2 H, piperidine H), 3.10 (br. s, 2 H, piperidine H), tion of boronate 14 and bromoquinoline 18 as a dark-brown
◦
3.42 (m, 1 H, piperidine H), 4.30 (br. s, 2 H, piperidine H), gum, (0.64 g, yield 42 %). M. p. 132 – 133 C. – IR (neat):
6.67 (d, J = 9.5 Hz, 1 H, 3-H), 7.20 (t, J = 7.6 Hz, 1 H, ν = 3037, 2978, 1677, 1604, 1486, 1176 cm−1. – 1H NMR
aromatic H), 7.40 – 7.45 (m, 2 H, aromatic H), 7.78 (t, (500 MHz, CDCl3): δ = 1.49 (s, 9H, OC(CH3)3), 2.85 (br. s,
J = 7.6 Hz, 1 H, 4-H). – 13C NMR (125.7 MHz, CDCl3): 2 H, piperidine H), 3.70 (m, 2 H, piperidine H), 4.02 (s, 3 H,
δ = 28.48 (OC(CH3)3), 30.29, 32.33, 34.70 (all Cpiper), OCH3), 4.13 (br. s, 2 H, piperidine H), 5.86 (br. s, 1 H, piperi-
79.49 (OC(CH3)3), 120.20, 121.24, 122.54, 123.84, 126.41, dine H), 6.90 (d, J = 8.5 Hz, 1 H, 3-H), 7.32 (t, J = 7.6 Hz,
127.76, 131.38, 135.78, 141.74 (all Carom), 154.83 (C=O), 1 H, aromatic H), 7.48 (dd, J = 1.5, 7.3 Hz, 1 H, aromatic H),
163.99 (Carom), 172.58 (C=O). – C19H24N2O3 (328.41): 7.63 (dd, J = 1.2, 7.8 Hz, 1 H, aromatic H), 7.97 (d, J =
calcd. C 69.49, H 7.37, N 8.53; found C 69.45, H 7.43, 8.8 Hz, 1 H, aromatic H). – 13C NMR (125.7 MHz, CDCl3):
N 8.46.
δ = 24.54 (Cpiper), 28.51 (OC(CH3)3), 29.84, 42.32 (all
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258
N. Ullah and A. A. Q. Al-Shaheri et al. · 4-Aryl-1-(biarylmethylene)piperidines
Cpiper), 53.37 (OCH3), 79.52 (OC(CH3)3), 112.71, 123.80, (0.13 mL, 0.97 mmol). After being stirred for 10 min at
125.13, 126.99, 128.81, 139.06, 139.74, 144.03, 161.37 (all r. t., NaBH(OAc)3 (0.11 g, 0.53 mmol) was added, and
Carom). – C20H24N2O3 (340.42): calcd. C 70.56, H 7.11, the reaction mixture was stirred for 6 h. A sat. solution
N 8.23; found C 70.50, H 7.16, N 8.17.
of NaHCO3(10 mL) was added, and the mixture stirred
for 15 min, followed by the addition of ethyl acetate (30 mL).
The organic layer was separated and washed with sat.
NaHCO3, brine, and dried over Na2SO4. Purification of the
brown oily material on a silica column, eluting with ethyl
acetate : hexanes (70 : 30) and then changing to ethyl acetate
(100 %) yielded the titled compound 3a as a light-yellow
solid 0.126 g, yield 45 %). M. p. 84 – 85 ◦C. – IR (neat): ν =
3031, 3021, 2936, 1609, 1444, 1186, 1120 cm−1. – 1H NMR
(500 MHz, CDCl3): δ = 2.15 (m, 2 H, piperidine H), 2.36
(m, 2 H, piperidine H), 2.85 (br. s, 2 H, piperidine H), 3.64
(m, 2 H, piperidine H), 4.03 (s, 3 H, OCH3), 4.20 (s, 2 H,
NCH2), 6.88 (d, J = 8.8 Hz, 1 H, 3-H), 7.32 – 7.38 (m, 2 H,
aromatic H), 7.45 (t, J = 7.3 Hz, 2 H, aromatic H), 7.51 (d, J =
7.3 Hz, 1 H, aromatic H), 7.56 – 7.59 (m, 4 H, aromatic H),
7.63 (m, 2 H, aromatic H), 7.95 (d, J = 8.5 Hz, 1 H, aro-
matic H). – 13C NMR (125.7 MHz, CDCl3): δ = 29.47, 34.92
(all Cpiper), 53.14 (OCH3), 61.71 (NCH2), 112.62 (C-3),
123.98, 124.98, 126.21, 127.06, 127.72, 128.85, 131.30,
139.31, 139.55, 140.02, 142.37, 143.86 (all Carom), 161.44
(C-2). – C28H28N2O (408.53): calcd. C 82.32, H 6.91,
N 6.86; found C 82.25, H 6.96, N 6.79.
tert-Butyl 4-(2-methoxyquinolin-8-yl)piperidine-1-carboxy-
late (20)
To a solution of compound 19 (0.6 g, 1.76 mmol) in a
mixture of THF (5 mL) and EtOH (10 mL) was added Pd-C
(10 % wet basis, 0.4 g), and the mixture was subjected to
hydrogenation in a Parr apparatus at 60 psi for 7 h (1 psi =
6894.757 Pa). After filtration through a pad of celite, the so-
lution was concentrated and chromatographed on a silica col-
umn, eluting with ethyl acetate:hexanes (20 : 80) to get the
title compoun◦d as an off-white solid (0.57 g, yield 94 %).
M. p. 72 – 73 C. – IR (neat): ν = 3031, 2935, 1675, 1608,
1484 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.42 (s, 9 H,
OC(CH3)3), 1.71 (m, 2 H, piperidine H), 1.95 (m, 2 H, piperi-
dine H), 2.88 (m, 2 H, piperidine H), 3.82 (m, 1 H, piperi-
dine H), 3.99 (s, 3 H, OCH3), 4.22 (br. s, 2 H, piperidine H),
6.84 (d, J = 8.5 Hz, 1 H, 3-H), 7.28 (m, 1 H, aromatic H), 7.38
(m, 1 H, aromatic H), 7.51 (m, 1 H, aromatic H), 7.97 (d, J =
8.8 Hz, 1 H, aromatic H). – 13C NMR (125.7 MHz, CDCl3):
δ = 28.48 (OC(CH3)3), 32.15, 36.84, 42.84 (all Cpiper), 53.23
(OCH3), 79.30 (OC(CH3)3), 112.38, 123.89, 124.96, 125.64,
126.04, 139.40, 143.93 (all Carom), 155.21 (C=O), 161.67
(Carom). – C20H26N2O3 (342.43): calcd. C 70.15, H 7.65,
N 8.18; found C 70.10, H 7.70, N, 8.11.
8-(4-((4ꢀ-Fluorobiphenyl-4-yl)methyl)piperazin-1-yl)-2-
methoxyquinoline (3b)
Following the same procedure as adopted for the syn-
thesis of 3a, the title compound was obtained by reduc-
tive amination of compounds 3 and 6b as an off-white
2-Methoxy-8-(piperidin-4-yl)quinoline (3)
◦
Following the same procedure as adopted for the synthesis
of 4, the title compound was obtained from compound 20 as
an off-white solid (0.46 g, yield 92 %). M. p. 142 – 144 ◦C. –
IR (neat): ν = 3031, 2982, 1612, 1441, 1213 cm−1. –
1H NMR (500 MHz, [D6]DMSO): δ = 1.99 (m, 2 H, piperi-
dine H), 2.14 (m, 2 H, piperidine H), 3.16 (m, 2 H, piperi-
dine H), 3.45 (m, 2 H, piperidine H), 4.01 (s, 3 H, OCH3),
7.01 (d, J = 8.2 Hz, 1 H, 3-H), 7.41 (m, 1 H, aromatic H),
7.51 (m, 1 H, aromatic H), 7.92 (d, J = 8.3 Hz, 1 H,
aromatic H). – 13C NMR (125.7 MHz, [D6]DMSO): δ =
28.72, 31.00, 34.40, 36.02, 44.33 (all Cpiper), 53.28 (OCH3),
112.76, 114.52, 116.83, 124.23, 126.19, 126.48, 140.10,
158.76, 161.23 (all Carom). – C17H19F3N2O3 (356.34):
calcd. C 57.30, H 5.37, N 7.86; found C 57.24, H 5.42,
N 7.80.
solid (yield 37 %). M. p. 94 – 95 C. – IR (neat): ν = 3042,
3011, 2926, 1603, 1440, 1183, 1132 cm−1
–
1H NMR
(500 MHz, CDCl3): δ = 1.92 (m, 2 H, piperidine H), 2.02
(m, 2 H, piperidine H), 2.30 (m, 2 H, piperidine H), 3.18
(m, 2 H, piperidine e H), 3.70 (s, 2 H, NCH2), 3.83 (m,
1 H, piperidine H), 4.05 (s, 3 H, OCH3), 6.88 (d, J =
8.5 Hz, 1 H, 3-H), 7.09 – 7.12 (m, 2 H, aromatic H), 7.32
(t, J = 7.6 Hz, 1 H, aromatic H), 7.45 – 7.56 (m, 8 H, aro-
matic H), 7.94 (d, J = 8.8 Hz, 1 H, aromatic H). – 13C NMR
(125.7 MHz, CDCl3): δ = 32.03, 36.07 (all Cpiper), 53.07
(OCH3), 54.66 (Cpiper), 62.95 (NCH2), 112.36 (C-3), 115.49,
115.66, 123.85, 124.91, 125.41, 125.81, 126.84, 128.52,
128.57, 129.97, 136.71, 136.98, 139.17, 142.32, 144.13
(all Carom), 161.20 (C-2). – C28H27FN2O (426.53): calcd.
C 78.85, H 6.38, N 6.57; found C 78.79, H 6.44, N 6.50.
8-(1-(Biphenyl-4-ylmethyl)piperidin-4-yl)-2-methoxyquino-
2-Methoxy-8-(4-((5-phenylpyridin-3-yl)methyl)piperazin-1-
line (3a)
yl)quinoline (3c)
To a solution of compound 3 (0.15 g, 0.42 mmol)
Following the same procedure as adopted for the synthe-
and biphenyl-4-carbaldehyde (6a, 0.1 g, 0.55 mmol) in sis of 3a, the title compound was obtained by reductive am-
1,2-dichloroethane (5 mL) at 0 ◦C was added Et3N ination of compounds 3 and 6c as an off-white solid (yield
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259
35 %). M. p. 135 – 137 ◦C. – IR (neat): ν = 3021, 2945, 1601, piperidine H), 3.60 (s, 2 H, NCH2), 3.79 (m, 1 H, piperi-
1433, 1263, 1228 cm−1. – 1H NMR (500 MHz, CDCl3): δ = dine H), 4.05 (s, 3H, OCH3), 6.20 (s, 1 H, cyclopent H), 6.85
1.90 (m, 2 H, piperidine H), 2.02 (m, 2 H, piperidine H), (d, J = 8.8 Hz, 1 H, 3-H), 7.24 – 7.34 (m, 4 H, aromatic H),
2.30 (m, 2 H, piperidine H), 3.09 (m, 2 H, piperidine H), 7.45 – 7.54 (m, 3 H, aromatic H), 7.91 (d, J = 8.8 Hz,
3.67 (s, 2 H, NCH2), 3.82 (m, 1 H, piperidine H), 4.07 (s, 1 H, aromatic H). – 13C NMR (125.7 MHz, CDCl3): δ =
3 H, OCH3), 6.88 (d, J = 8.8 Hz, 1 H, 3-H), 7.33 (t, J = 23.33 (Ccyclopent), 32.33 (Cpiper), 33.22, 33.30 (all Ccyclopent),
7.6 Hz, 1 H, aromatic H), 7.41 (d, J = 7.3 Hz, 1 H, aro- 36.32 (Cpiper), 53.05 (OCH3), 54.74 (Cpiper), 63.62 (NCH2),
matic H), 7.47 – 7.53 (m, 3 H, aromatic H), 7.64 (m, 2 H, 112.34 (Ccyclopent), 123.80, 124.27, 124.87, 125.28, 125.80,
aromatic H), 7.94 (m, 2 H, aromatic H), 8.59 (d, J = 1.8 Hz, 126.12, 126.46, 127.88, 128.10, 136.67, 138.29, 139.11,
1 H, aromatic H), 8.77 (d, J = 2.1 Hz, 1 H, aromatic H). – 142.41, 142.67, 144.13, 161.12 (all Carom). – C27H30N2O
13C NMR (125.7 MHz, CDCl3): δ = 32.33, 36.36 (all Cpiper), (398.54): calcd. C 81.37, H 7.59, N 7.03; found C 81.31,
53.05 (OCH3), 54.79 (Cpiper), 60.65 (NCH2), 112.32 (C-3), H 7.64, N 6.97.
124.88, 125.33, 125.77, 127.16, 127.98, 128.97, 134.08,
135.05, 136.23, 137.81, 139.11, 142.49, 144.13, 146.95,
149.17 (all Carom), 161.13 (C-2). – C27H27N3O (409.52):
calcd. C 79.19, H 6.65, N 10.26; found C 79.12, H 6.71,
N 10.19.
8-(4-((5-Cyclopentenylpyridin-3-yl)methyl)piperazin-1-yl)-
2-methoxyquinoline (3f)
Following the same procedure as adopted for the syn-
thesis of 3a, the title compound was obtained by reductive
amination of compounds 3 and 6f as a light-yellow amor-
8-(4-((5-(4-Fluorophenyl)pyridin-3-yl)methyl)piperazin-1-
yl)-2-methoxyquinoline (3d)
◦
phous solid (yield 39 %). M. p. 85 – 86 C. – IR (neat): ν =
3021, 2992, 2828, 1601, 1472, 1445, 1255 cm−1. – 1H NMR
Following the same procedure as adopted for the syn- (500 MHz, CDCl3): δ = 1.89 – 194 (m, 2 H, piperidine H),
thesis of 3a, the title compound was obtained by reductive 2.02 – 2.09 (m, 4 H, piperidine H, cyclopent H), 2.26 – 2.31
amination of compounds 3 and 6d as a light-brown solid (m, 2 H, cyclopent H), 2.73 (m, 2 H, cyclopent H), 3.09
(yield 32 %). M. p. 156 – 158 ◦C. – IR (neat): ν = 3025, 2931, (m, 2 H, piperidine H), 3.61 (s, 2 H, NCH2), 3.80 (m, 1 H,
1607, 1431, 1266 cm−1. – 1H NMR (500 MHz, CDCl3): piperidine H), 4.05 (s, 3 H, OCH3), 6.30 (s, 1 H, cyclopent
δ = 1.89 (m, 2 H, piperidine H), 2.01 (m, 2 H, piperi- H), 6.87 (d, J = 8.5 Hz, 1 H, 3-H), 7.32 (m, 1 H, aro-
dine H), 2.28 (m, 2 H, piperidine H), 3.05 (m, 2 H, piperi- matic H), 7.49 (d, J = 7.3 Hz, 1 H, aromatic H), 7.55 (d,
dine H), 3.65 (s, 2 H, NCH2), 3.81 (m, 1 H, piperidine H), J = 7.9 Hz, 1 H, aromatic H), 7.76 (s, 1 H, aromatic H),
4.06 (s, 3 H, OCH3), 6.88 (d, J = 8.5 Hz, 1 H, 3-H), 7.16 7.95 (d, J = 8.8 Hz, 1 H, aromatic H), 8.42 (s, 1 H, aro-
(m, 2 H, aromatic H), 7.33 (t, J = 7.6, 1 H, aromatic H), matic H), 8.59 (s, 1 H, aromatic H). – 13C NMR (125.7 MHz,
7.51 (dd, J = 1.2, 7.3 Hz, 1 H, aromatic H), 7.54 – 7.59 (m, CDCl3): δ = 23.16 (Ccyclopent), 32.09 (Cpiper), 32.88, 33.36
3 H, aromatic H), 7.89 (m, 1 H, aromatic H), 7.94 (d, J = (all Ccyclopent), 36.24 (Cpiper), 53.03 (OCH3), 54.57 (Cpiper),
8.8 Hz, 1 H, aromatic H), 8.59 (d, J = 1.5 Hz, 1 H, aro- 60.46 (NCH2), 112.32 (Ccyclopent), 123.77, 124.87, 125.36,
matic H), 8.77 (d, J = 2.1 Hz, 1 H, aromatic H). – 13C NMR 125.78, 128.35, 132.04, 133.14, 133.59, 139.10, 139.38,
(125.7 MHz, CDCl3): δ = 32.33, 36.35 (all Cpiper), 53.04 142.34, 144.10, 145.74, 148.46 (all Carom), 161.14 (C-2). –
(OCH3), 54.82 (Cpiper), 60.62 (NCH2), 112.34 (C-3), 115.86, C26H29N3O (399.53): calcd. C 78.16, H 7.32, N 10.52; found
116.03, 123.78, 124.90, 125.36, 125.77, 128.80, 128.85, C 78.10, H 7.38, N 10.45.
133.92, 134.22, 134.89, 135.33, 139.12, 142.47, 144.13,
146.76, 149.17, 161.13, 163.82 (all Carom). – C27H26FN3O
(427.51): calcd. C 75.85, H 6.13, N 9.83; found C 75.79,
H 6.19, N 9.76.
8-(4-(Biphenyl-4-ylmethyl)piperazin-1-yl)quinolin-2(1H)-
one (4a)
Following the same procedure as adopted for the synthesis
of 3a, the title compound was obtained by reductive amina-
tion of compounds 4 and 6a as a light-yellow solid (yield
45 %). M. p. 146 – 148 ◦C. – IR (neat): ν = 3193, 3038, 3021,
8-(4-(3-Cyclopentenylbenzyl)piperazin-1-yl)-2-methoxy-
quinoline (3e)
Following the same procedure as adopted for the syn- 2938, 1641, 1601, 1437, 1218 cm−1. – 1H NMR (500 MHz,
thesis of 3a, the title compound was obtained by reductive CDCl3): δ = 1.81 (m, 4 H, piperidine H), 2.26 (m, 2 H,
amination of compounds 3 and 6e as a light-yellow solid piperidine H), 3.00 (br. s, 3 H, piperidine H), 3.60 (s, 2 H,
(yield 46 %). M. p. 125 – 126 ◦C. – IR (neat): ν = 3028, NCH2), 6.65 (d, J = 9.4 Hz, 1 H, 3-H), 7.10 (t, J = 8.7 Hz,
2982, 2898, 1605, 1472, 1445, 1263, 1258 cm−1. – 1H NMR 1 H, aromatic H), 7.34 – 7.55 (m, 5 H, aromatic H), 7.61
(500 MHz, CDCl3): δ = 1.85 – 192 (m, 2 H, piperidine H), (d, J = 9.4 Hz, 1 H, 4-H), 10.12 (br. s, 1 H, NHCO). –
1.98 – 2.04 (m, 4 H, piperidine H, cyclopent H), 2.24 (m, 13C NMR (125.7 MHz, CDCl3): δ = 32.41, 34.93, 53.83
2 H, cyclopent H), 2.72 (m, 2 H, cyclopent H), 3.05 (m, 2 H, (all Cpiper), 63.03 (NCH2), 119.99, 121.17, 122.47, 126.18,
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260
N. Ullah and A. A. Q. Al-Shaheri et al. · 4-Aryl-1-(biarylmethylene)piperidines
126.92, 127.03, 127.16, 127.78, 128.73, 129.75, 131.41, tion of compounds 4 and 6d as a light-yellow solid (yield
135.71, 137.02, 139.95, 140.92, 141.61 (all Carom), 163.46 34 %). M. p. 161 – 163 ◦C. – IR (neat): ν = 3373, 3058, 3040,
(C=O). – C27H26N2O (394.51): calcd. C 82.20, H 6.64, 2928, 1640, 1602, 1430, 1228 cm−1. – 1H NMR (500 MHz,
N 7.10; found C 82.14, H 6.70, N 7.03.
CDCl3): δ = 1.91 (m, 4 H, piperidine H), 2.39 (m, 2 H,
piperidine H), 3.09 (m, 3 H, piperidine H), 3.71 (s, 2 H,
NCH2), 6.62 (d, J = 11.8 Hz, 1 H, 3-H), 7.18 – 7.22 (m, 4 H,
aromatic H), 7.44 – 7.48 (m, 2 H, aromatic H), 7.59 – 7.62
(m, 2 H, aromatic H), 7.80 (d, J = 11.2 Hz, 1 H, 4-H), 7.91
(br. s, 1 H, NH), 8.59 (d, J = 1.8 Hz, 1 H, aromatic H), 8.75
(d, J = 1.8 Hz, 1 H, aromatic H), 10.20 (br. s, 1 H, NHCO). –
13C NMR (125.7 MHz, CDCl3): δ = 32.26, 34.89, 53.99
(all Cpiper), 60.46 (NCH2), 115.97, 116.18, 120.07, 121.15,
123.63, 126.38, 127.85, 128.89, 131.10, 133.87, 135.03,
135.48, 141.77, 147.01, 149.24, 163.50, 164.36 (all Carom). –
C26H24FN3O (413.49): calcd. C 75.52, H 5.85, N 10.16;
found C 75.46, H 5.91, N 10.09.
8-(4-((4ꢀ-Fluorobiphenyl-4-yl)methyl)piperazin-1-yl)quino-
lin-2(1H)-one (4b)
Following the same procedure as adopted for the synthe-
sis of 3a, the title compound was obtained by reductive ami-
nation of compounds 4 and 6b as an off-white solid (yield
41 %). M. p. 159 – 161 ◦C. – IR (neat): ν = 3213, 3028,
2928, 1637, 1609, 1447, 1171 cm−1. – 1H NMR (500 MHz,
CDCl3): δ = 1.88 (m, 4 H, piperidine H), 2.24 (m, 2 H,
piperidine H), 2.90 (m, 1 H, piperidine H), 3.08 (m, 2 H,
piperidine H), 3.65 (s, 2 H, NCH2), 6.62 (d, J = 9.4 Hz,
1 H, 3-H), 7.12 (t, J = 8.7 Hz, 1 H, aromatic H), 7.20 (t, J =
8.5 Hz, 1 H, aromatic H), 7.41 – 7.44 (m, 4 H, aromatic H),
7.52 – 7.58 (m, 5 H, aromatic H), 7.73 (d, J = 9.4 Hz, 1 H,
4-H), 9.55 (br. s, 1 H, NHCO). – 13C NMR (125.7 MHz,
CDCl3): δ = 32.32, 35.36, 54.03 (all Cpiper), 63.02 (NCH2),
115.52, 115.73, 120.06, 121.21, 122.62, 126.32, 126.86,
127.82, 128.56, 128.64, 129.77, 130.08, 135.66, 137.05,
137.07, 139.03, 141.70 (all Carom), 161.32 (C=O), 163.11
(Carom). – C27H25FN2O (412.50): calcd. C 78.62, H 6.11,
N 6.79; found C 78.56, H 6.16, N 6.72.
8-(4-(3-Cyclopentenylbenzyl)piperazin-1-yl)quinolin-2(1H)-
one (4e)
Following the same procedure as adopted for the synthe-
sis of 3a, the title compound was obtained by reductive am-
ination of compounds 4 and 6e as a colorless solid (yield
42 %). M. p. 123 – 125 ◦C. – IR (neat): ν = 3164, 3110, 3022,
3011, 2936, 2886, 1639, 1599, 1471, 1116 cm−1. – 1H NMR
(500 MHz, CDCl3): δ = 1.83 – 191 (m, 6 H, piperidine H,
cyclopent H), 2.21 – 2.29 (m, 2 H, cyclopent H), 2.51 – 2.59
(m, 2 H, piperidine H), 2.73 (m, 2 H, cyclopent H), 2.83 (m,
1 H, piperidine H), 3.08 (m, 2 H, piperidine H), 3.60 (s, 2 H,
NCH2), 6.22 (s, 1 H, cyclopent H), 6.60 (d, J = 9.4 Hz,
1 H, 3-H), 7.11 – 7.28 (m, 2 H, aromatic H), 7.29 (t, J =
7.8 Hz, 1 H, aromatic H), 7.33 (m, 1 H, aromatic H), 7.42
(m, 2 H, aromatic H), 7.52 (m, 1 H, aromatic H), 7.75 (d,
J = 9.4 Hz, 1 H, 4-H), 9.36 (br. s, 1 H, NHCO). – 13C NMR
(125.7 MHz, CDCl3): δ = 23.37 (Ccyclopent), 32.27 (Cpiper),
33.28, 33.34 (all Ccyclopent), 35.47, 53.99 (all Cpiper), 63.44
(NCH2), 119.94, 121.21, 122.58, 124.37, 126.26, 126.43,
127.81, 128.18, 130.84, 135.47, 136.77, 137.01, 141.64,
142.42 (all Carom), 162.98 (C=O). – C26H28N2O (384.51):
calcd. C 81.21, H 7.34, N 7.29; found C 81.15, H 7.40,
N 7.22.
8-(4-((5-Phenylpyridin-3-yl)methyl)piperazin-1-yl)quinolin-
2(1H)-one (4c)
Following the same procedure as adopted for the syn-
thesis of 3a, the title compound was obtained by reductive
amination of compounds 4 and 6c as a light-yellow solid
(yield 38 %). M. p. 158 – 160 ◦C. – IR (neat): ν = 3363,
3051, 3018, 2932, 1643, 1600, 1433, 1208 cm−1. – 1H NMR
(500 MHz, CDCl3): δ = 1.90 (m, 4 H, piperidine H), 2.17
(m, 2 H, piperidine H), 3.07 (m, 3 H, piperidine H), 3.71
(s, 2 H, NCH2), 6.59 (d, J = 9.5 Hz, 1 H, 3-H), 7.21 (t,
J = 7.6 Hz, 1 H, aromatic H), 7.41 – 7.43 (m, 2 H, aro-
matic H), 7.47 – 7.51 (m, 4 H, aromatic H), 7.64 (m, 2 H,
aromatic H), 7.7 (d, J = 9.4 Hz, 1 H, 4-H), 7.92 (s, 1 H, aro-
matic H), 8.57 (d, J = 1.8 Hz, 1 H, aromatic H), 8.78 (d,
J = 1.6 Hz, 1 H, aromatic H), 10.52 (br. s, 1 H, NHCO). –
13C NMR (125.7 MHz, CDCl3): δ = 32.28, 34.67, 53.84
(all Cpiper), 60.47 (NCH2), 120.03, 121.06, 122.55, 126.26,
127.19, 127.81, 128.07, 129.02, 131.34, 133.55, 135.16,
135.69, 136.31, 137.71, 141.73, 147.06, 149.16 (all Carom),
163.65 (C=O). – C26H25N3O (395.50): calcd. C 78.96,
H 6.37, N 10.62; found C 78.90, H 6.43, N 10.57.
8-(4-((5-Cyclopentenylpyridin-3-yl)methyl)piperazin-1-
yl)quinolin-2(1H)-one (4f)
Following the same procedure as adopted for the synthe-
sis of 3a, the title compound was obtained by reductive am-
ination of compounds 4 and 6f as an off-white solid (yield
31 %). M. p. 133 – 135 ◦C. – IR (neat): ν = 3169, 3026, 2934,
1639, 1601, 1411, 1190, 1127 cm−1. – 1H NMR (500 MHz,
CDCl3): δ = 1.81 – 191 (m, 4 H, piperidine H), 1.98 – 2.10
(m, 2 H, cyclopent H), 2.25 – 2.36 (m, 2 H, cyclopent H),
8-(4-((5-(4-Fluorophenyl)pyridin-3-yl)methyl)piperazin-1-
yl)quinolin-2(1H)-one (4d)
Following the same procedure as adopted for the synthesis 2.52 – 2.59 (m, 2 H, piperidine H), 2.72 (m, 2 H, cyclopent
of 3a, the title compound was obtained by reductive amina- H), 3.00 (m, 3 H, piperidine H), 3.59 (s, 2 H, NCH2), 6.30
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261
(s, 1 H, cyclopent H), 6.57 (d, J = 9.4 Hz, 1 H, 3-H), 161.32, 163.62 (all Carom), 170.87 (C=O). – C27H27FN2O
7.18 (t, J = 8.8 Hz, 1 H, aromatic H), 7.41 (m, 2 H, aro- (414.51): calcd. C 78.23, H 6.57, N 6.76; found C 78.26,
matic H), 7.68 (s, 1 H, aromatic H), 7.76 (d, J = 9.4 Hz, H 6.62, N 6.69.
1 H, 4-H), 8.40 (s, 1 H, aromatic H), 8.59 (s, 1 H, aro-
matic H), 10.18 (br. s, 1 H, NHCO). – 13C NMR (125.7 MHz,
8-(4-((5-Phenylpyridin-3-yl)methyl)piperazin-1-yl)-3,4-
CDCl3): δ = 23.33 (Ccyclopent), 32.33 (Cpiper), 33.22, 33.30
(all Ccyclopent), 36.32 (Cpiper), 53.05 (OCH3), 54.74 (Cpiper),
63.62 (NCH2), 113.98 (Ccyclopent), 120.14 (Ar-C), 122.26,
122.41, 124.11, 128.50, 132.05, 132.59, 133.36, 133.58,
138.80, 139.29, 140.65, 145.98, 148.45 (all Carom), 162.28
(C-2). – C25H27N3O (385.50): calcd. C 77.89, H 7.06,
N 10.90; found C 77.83, H 7.12, N 10.83.
dihydroquinolin-2(1H)-one (5c)
Following the same procedure as adopted for the synthe-
sis of 3a, the title compound was obtained by reductive am-
ination of compounds 5 and 6c as a light-yellow gum (yield
34 %). – IR (neat): ν = 3213, 3032, 2922, 1662, 1608, 1472,
1201 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 1.76 – 189
(m, 4 H, piperidine H), 2.27 (m, 2 H, piperidine H), 2.56 –
2.66 (m, 3 H, piperidine H, 4-H), 2.93 (m, 2 H, 3-H), 3.05
(m, 2 H, piperidine H), 3.67 (s, 2 H, NCH2), 6.97 (m, 2 H,
aromatic H), 7.07 (m, 1 H, aromatic H), 7.43 (m, 1 H, aro-
matic H), 7.50 (t, J = 7.5 Hz, 2 H, aromatic H), 7.89 (s, 1 H,
aromatic H), 8.41 (s, 1 H, aromatic H), 8.54 (s, 1 H, NHCO),
8.72 (s, 1 H, aromatic H). – 13C NMR (125.7 MHz, CDCl3):
δ = 25.93 (C-4), 30.63 (C-3), 31.93, 35.26, 53.85 (all Cpiper),
60.13 (s, 2 H, NCH2), 115.99, 116.20, 123.34, 124.43,
124.91, 125.96, 128.87, 128.95, 130.99, 133.68, 134.21,
135.43, 146.80, 148.93, 161.76, 164.22 (all Carom), 172.50
(C=O). – C26H27N3O (397.51): calcd. C 78.56, H 6.85,
N 10.57; found C 78.50, H 6.91, N 10.50.
8-(4-(Biphenyl-4-ylmethyl)piperazin-1-yl)-3,4-dihydroqui-
nolin-2(1H)-one (5a)
Following the same procedure as adopted for the synthe-
sis of 3a, the title compound was obtained by reductive am-
ination of compounds 5 and 6a as an off-white solid (yield
41 %). M. p. 116 – 118 ◦C. – IR (neat): ν = 3217, 3053, 2912,
2872, 1668, 1601, 1482, 1211 cm−1. – 1H NMR (500 MHz,
CDCl3): δ = 1.76 – 184 (m, 4 H, piperidine H), 2.15 (m,
4 H, piperidine H), 2.53 (m, 1 H, piperidine H), 2.59 (t, J =
7.6, 2 H, 4-H), 2.94 (t, J = 6.7, 2 H, 3-H), 3.05 (m, 2 H,
piperidine H), 3.60 (s, 2 H, NCH2), 6.97 – 7.03 (m, 2 H,
aromatic H), 7.15 (m, 1 H, aromatic H), 7.34 (m, 1 H, aro-
matic H), 7.41 – 7.45 (m, 4 H, aromatic H), 7.55 (d, J = 7.3,
1 H, aromatic H), 7.60 (d, J = 7.3, 1 H, aromatic H), 7.87 (br.
s, 1 H, NHCO). – 13C NMR (125.7 MHz, CDCl3): δ = 25.95
(C-4), 30.62 (C-3), 32.24, 35.82, 54.07 (all Cpiper), 63.00
(NCH2), 123.09, 124.21, 124.80, 125.69, 126.92, 127.01,
127.12, 128.69, 129.62, 130.91, 134.20, 137.22, 139.95,
140.91 (all Carom), 171.68 (C-2). – C27H28N2O (396.52):
calcd. C 81.78, H 7.12, N 7.06; found C 81.72, H 7.17,
N 7.00.
8-(4-((5-(4-Fluorophenyl)pyridin-3-yl)methyl)piperazin-1-
yl)-3,4-dihydroquinolin-2(1H)-one (5d)
Following the same procedure as adopted for the syn-
thesis of 3a, the title compound was obtained by reductive
amination of compounds 5 and 6d as a light-yellow solid
(yield 30 %). M. p. 136 – 138 ◦C. – IR (neat): ν = 3198, 3051,
2931, 1660, 1608, 1468, 1186 cm−1. – 1H NMR (500 MHz,
CDCl3): δ = 1.74 – 189 (m, 4 H, piperidine H), 2.31 (m,
2 H, piperidine H), 2.56 (m, 2 H, 4-H), 2.72 (m, 1 H, piperi-
dine H), 2.89 (m, 2 H, 3-H), 3.07 (m, 2 H, piperidine H),
3.70 (s, 2 H, NCH2), 6.93 – 7.06 (m, 2 H, aromatic H),
7.13 (d, J = 8.2 Hz, 1 H, aromatic H), 7.35 – 7.55 (t, J =
9.0 Hz, 3 H, aromatic H), 7.62 (m, 2 H, aromatic H), 7.93
(s, 1 H, aromatic H), 8.54 (s, 1 H, aromatic H), 9.61 (br. s,
1 H, NHCO). – 13C NMR (125.7 MHz, CDCl3): δ = 25.95
(C-4), 30.68 (C-3), 31.95, 35.04, 53.69 (all Cpiper), 60.07
(NCH2), 123.30, 124.46, 124.93, 125.90, 127.20, 128.23,
129.10, 131.25, 133.00, 134.37, 135.69, 136.55, 137.51,
146.91, 148.90 (all Carom), 172.66 (C=O). – C26H26FN3O
(415.50): calcd. C 75.16, H 6.31, N 10.11; found C 75.10,
H 6.37, N 10.03.
8-(4-((4ꢀ-Fluorobiphenyl-4-yl)methyl)piperazin-1-yl)-3,4-
dihydroquinolin-2(1H)-one (5b)
Following the same procedure as adopted for the synthesis
of 3a, the title compound was obtained by reductive amina-
tion of compounds 5 and 6b as a light-yellow solid (yield
33 %). M. p. 132 – 134 ◦C. – IR (neat): ν = 3223, 3050, 2902,
2862, 1667, 1600, 1489, 1231 cm−1. – 1H NMR (500 MHz,
CDCl3): δ = 1.67 – 173 (m, 4 H, piperidine H), 2.07 (m,
2 H, piperidine H), 2.50 (m, 3 H, piperidine H, 4-H), 2.83
(t, J = 7.6, 2 H, 3-H), 2.96 (m, 2 H, piperidine H), 3.51
(s, 2 H, NCH2), 6.88 – 6.94 ((m, 2 H, aromatic H), 7.01 –
7.12 ((m, 3 H, aromatic H), 7.32 (d, J = 7.6 Hz, 2 H, aro-
matic H), 7.39 – 7.49 ((m, 4 H, aromatic H), 7.94 (br. s, 1 H,
NHCO). – 13C NMR (125.7 MHz, CDCl3): δ = 26.02 (C-4),
30.71 (C-3), 32.30, 35.78, 54.10 (all Cpiper), 63.02 (NCH2),
115.52, 115.73, 123.16, 124.31, 124.87, 125.87, 126.84,
8-(4-(3-Cyclopentenylbenzyl)piperazin-1-yl)-3,4-dihydro-
quinolin-2(1H)-one (5e)
Following the same procedure as adopted for the synthe-
128.56, 129.78, 131.05, 134.31, 137.08, 137.24, 139.04, sis of 3a, the title compound was obtained by reductive am-
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262
N. Ullah and A. A. Q. Al-Shaheri et al. · 4-Aryl-1-(biarylmethylene)piperidines
ination of compounds 5 and 6e as a light-green solid (yield amination of compounds 5 and 6f as a light-yellow solid
45 %). M. p. 115 – 117 ◦C. – IR (neat): ν = 3191, 3067, 2922, (yield 39 %). M. p. 123 – 125 ◦C. – IR (neat): ν = 3195,
2842, 1665, 1603, 1431, 1188 cm−1. – 1H NMR (500 MHz, 3057, 2932, 2832, 1667, 1600, 1437, 1182 cm−1. – 1H NMR
CDCl3): δ = 1.71 – 189 (m, 4 H, piperidine H), 1.98 – 2.08 (500 MHz, CDCl3): δ = 1.73 – 188 (m, 4 H, piperidine H),
(m, 2 H, cyclopent H), 2.11 – 2.18 (m, 2 H, cyclopent H), 2.00 – 2.11 (m, 2 H, cyclopent H), 2.12 – 2.16 (m, 2 H, cy-
2.48 – 2.56 (m, 5 H, piperidine H, 4-H), 2.74 (m, 2 H, cy- clopent H), 2.51 – 2.66 (m, 4 H, piperidine H, 4-H), 2.69 –
clopent H), 2.95 (m, 2 H, 3-H), 3.03 (m, 2 H, piperidine H), 2.76 (m, 2 H, cyclopent H), 2.92 – 3.06 (m, 4 H, piperi-
3.57 (s, 2 H, NCH2), 6.22 (br. s, 1 H, cyclopent H), 6.94 – dine H, 3-H), 3.57 (s, 2 H, NCH2), 6.31 (br. s, 1 H, cy-
7.13 (m, 2 H, aromatic H), 7.16 (d, J = 7.7 Hz, 1 H, aro- clopent H), 6.92 – 7.12 (m, 2 H, aromatic H), 7.16 (d, J =
matic H), 7.23 (d, J = 7.6 Hz, 1 H, aromatic H), 7.25 – 7.32 7.7 Hz, 1 H, aromatic H), 7.69 (s, 1 H, aromatic H), 8.12
(m, 2 H, aromatic H), 7.41 (s, 1 H, aromatic H), 7.98 (br. s, (br. s, 1 H, NHCO), 8.41 (s, 1 H, aromatic H), 8.59 (s,
1 H, NHCO). – 13C NMR (125.7 MHz, CDCl3): δ = 23.40 1 H, aromatic H). – 13C NMR (125.7 MHz, CDCl3): δ =
(Ccyclopent), 26.04 (C-4), 30.71 (C-3), 32.31 (Cpiper), 33.29, 23.25 (Ccyclopent), 26.03 (C-4), 30.71 (C-3), 32.25 (Cpiper),
33.37 (all Ccyclopent), 35.83, 54.07 (all Cpiper), 63.49 (NCH2), 32.99, 33.44 (all Ccyclopent), 35.62, 54.04 (all Cpiper), 60.57
123.13 (Ccyclopent), 124.28, 124.37, 124.88, 125.83, 126.27, (NCH2), 123.13 (Ccyclopent), 124.34, 124.84, 125.88, 128.35,
126.26, 127.88, 128.18, 131.11, 134.30, 136.82, 137.04, 130.98, 132.02, 133.07, 133.31, 134.33, 139.49, 146.02,
142.42 (all Carom), 171.82 (C=O). – C26H30N2O (386.53): 148.68 (all Carom), 171.87 (C=O). – C25H29N3O (387.52):
calcd. C 80.79, H 7.82, N 7.25; found C 80.73, H 7.88, calcd. C 77.48, H 7.54, N 10.84; found C 77.42, H 7.60,
N 7.18.
N 10.77.
8-(4-((5-Cyclopentenylpyridin-3-yl)methyl)piperazin-1-yl)-
3,4-dihydroquinolin-2(1H)-one (5f)
Acknowledgements
The financial support from KACST Project No: AR-28-38
and lab facilities from KFUPM are gratefully acknowledged.
Following the same procedure as adopted for the syn-
thesis of 3a, the title compound was obtained by reductive
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