Ynthesis of 6-piperazinyl-3,4-dihydroquinazolin-2(1H)-ones

Article abstract of DOI:10.14233/ajchem.2014.15639

A series of new 6-piperazinyl-3,4-dihydroquinazolin-2(1H)-ones have been synthesized. The described compounds are structurally related to adoprazine, a potential atypical antipsychotics bearing potent D2 receptor antagonist and 5-HT1A receptor agonist pro

Full text of DOI:10.14233/ajchem.2014.15639

Asian Journal of Chemistry; Vol. 26, No. 7 (2014), 2031-2036
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.15639
Synthesis of 6-Piperazinyl-3,4-dihydroquinazolin-2(1H)-ones
N. ULLAH
Department of Chemistry, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia
Corresponding author: Fax: +966 3 8604277; Tel: +966 3 8607527; E-mail: nullah@kfupm.edu.sa
Received: 15 April 2013;
Accepted: 8 August 2013;
Published online: 22 March 2014;
AJC-14955
A series of new 6-piperazinyl-3,4-dihydroquinazolin-2(1H)-ones have been synthesized. The described compounds are structurally related
to adoprazine, a potential atypical antipsychotics bearing potent D2 receptor antagonist and 5-HT1A receptor agonist properties. Buchwald-
Hartwig coupling of suitably modified aryl bromides with tert-butyl piperazine-1-carboxylate afforded the advanced intermediate
piperazinyl-3,4-dihydroquinazolin-2(1H)-one. The reductive amination of the latter with appropriately designed biarylaldehydes
accomplished the synthesis of 6-piperazinyl-3,4-dihydroquinazolin-2(1H)-ones.
Keywords: Schizophrenia, 6-Piperazinyl-3,4-Dihydroquinazolin-2(1H)-ones, Buchwald-Hartwig Coupling, 5-HT1A receptor.
complementary balance of pharmacological activity with
reduced undesirable responses5. Indeed, numerous mechanistic
considerations6-8 and preclinical evidence9-11 support the poten-
tial of such a combination. Consequently adoprazine (4) (SLV-
313) and bifeprunox (5), bearing potent D2 receptor antagonist
and 5-HT1A receptor agonist properties, were developed
(Fig. 1)12.
INTRODUCTION
Schizophrenia is a severe psychiatric illness afflicting 1 %
of the population worldwide. The diagnosis of the disease is
based on diverse and variably expressed symptoms which can
be grouped as positive and negative. The positive symptoms
include disorganized thought, delusions and auditory halluci-
nations whereas the most characteristic negative symptoms
are emotional flattening, poverty of speech and motivational
deficits1. The first-generation antipsychotics or typical anti-
psychotics such as chlorpromazine (1) and haloperidol (2)
are dopamine antagonists which alleviate positive symptoms
including hallucinations, agitation and delusions but fail to
control the negative symptoms such as blunted affect, emo-
tional withdrawal and cognitive deficits. In addition these
therapeutics develop extrapyramidal symptoms (EPS) and
hyperprolactinemia, respectively2. The 'second-generation' or
atypical antipsychotics, such as clozapine (3), combine D2
receptor antagonism with activity at other receptors, on the
premise that a suitable balance of pharmacological activity
should broaden the spectrum of therapeutic efficacy and reduce
extrapyramidal symptoms. With respect to classical neurolep-
tics, clozapine shows significantly greater efficacy, including
an improved effect on negative symptoms and causes a marked
increase in dopamine output in the prefrontal cortex3. Clozapine,
however, is associated with its own set of serious side effects
including weight gain, diabetes and an increased risk of seizures
and agranulocytosis4.
Although 5 has completed phase III clinical trials and has
satisfactory tolerance profile, the FDA did not grant marketing
approval. In addition, the failure of 4 and 5 to oppose phency-
clidine-induced social interaction deficits suggested that an
appropriate 'balance' of activity at these sites is necessary for
activity in this model13. Thus, the need to discover compounds
having varying ratios of D2 and 5-HT1A activities continued14.
In an ongoing efforts to develop new antipsychotics15-17, we
have synthesized a series of 6-piperazinyl-3,4-dihydroqui-
nazolin-2(1H)-ones (6a-f), which are structural analogs of
adopraine (4) (Fig. 2). Herein we wish to disclose the synthesis
of these compounds.
EXPERIMENTAL
Melting points were determined on a Büchi apparatus and
are uncorrected. Elemental analysis was carried out on a Perkin
Elmer Elemental Analyzer Series 11 Model 2400. IR spectra
were recorded on a Perkin Elmer 16F PC FTIR spectropho-
1
tometer. H and 13C NMR spectra were measured in CDCl3
and δ6-DMSO using TMS as internal standard on a JEOL
LA 500 MHz spectrometer. Mass spectra were recorded on a
GC-MS system (Agilent Technologies, 6890 N). Analytical
TLC was carried out on silica gel 60 F254 plates; column
Several preclinical observations suggest that combining
5-HT1A and D2 receptor properties may provide a mutually

2032 Ullah
Asian J. Chem.
Cl
H
N
O
O
HO
O
O
N
N
CH3
N
N
CH3
N
N
N
CH3
N
F
O
N
S
Cl
N
Cl
N
H
N
F
4
5
1
3
2
Fig. 1. Chlorpromazine, haloperidol, clozapine, adoprazine and bifeprunox
H
N
O
NH
N
N
R
6
(R = H)
f
6a- (R = a-f)
F
N
b
a
c
R =
F
N
N
d
f
e
Fig. 2. 6-Piperazinyl-3,4-dihydroquinazolin-2(1H)-ones (6a-f)
chromatography was carried out on Merck silica gel (200-
400 mesh).
(C-1), 131.45 (C-6), 132.50 (C-4), 139.00 (C-5), 145.99
(C-2). Calculated (%) for C7H7N2O2Br (229.97); C: 36.39, H:
3.05, N: 12.12, found (%); C: 36.33, H: 3.10, N: 12.02.
N-(5-Bromo-2-nitrobenzyl)acetamide (14): To a solution
of compound 13 (2.5 g, 10.82 mmol) in pyridine (20 mL) was
added acetic anhydride (2 mL, 21.60 mmol) and the mixture
was stirred at room temperature for 12 h. The reaction was added
ethyl acetate (30 mL) and the organic layer was washed
sequentially with H2O (20 mL), 1N HCl (15 mL × 3), brine (15
mL) and dried over Na2SO4 and evaporated to get N-(5-bromo-
2-nitrobenzyl)acetamide as an off-white solid (2.89 g, 98 %). IR
(KBr, νmax, cm-1): 3419 (NH), 3062 (Ar-H), 2925 (Alph-H), 1695
(C=O), 1604, 1564 (C=C), 1520, 1435 (NO2), 1232 (C-N), 1168
(C-O). 1H NMR (500 MHz, CDCl3) δ = 2.19 (s, 3H, CH3); 5.50
(s, 2H, CH2); 7.63 (dd, 1H, J = 2.3, 8.6 Hz, H-4); 7.75 (d, 1H,
J = 2.3, H-6), 8.00 (d, 1H, J = 8.6 Hz, H-3). 13C NMR (125.7
MHz, CDCl3) δ = 20.78 (CH3), 62.27 (CH2), 126.58 (C-3), 129.03
(C-1), 131.73 (C-6), 131.82 (C-4), 134.34 (C-5), 145.33 (C-2),
170.10 (CO). Calculated (%) for C9H9N2O3Br (271.98); C: 39.58,
H: 3.32, N: 10.26, found (%); C: 39.52, H: 3.36, N: 10.20.
(5-Bromo-2-nitrophenyl)methanamine (13): In a three
neck round bottom flask solution of aldehyde (12) (3 g, 13
mmol) in THF (25 mL) was prepared at room temperature. To
the solution were added ammonium hydroxide (28 %, 5 mL)
and sodium borohydride (1.47 g, 39 mmol) simultaneously in
portions in such a rate that addition of both was completed in
20 min. The mixture was left at room temperature for 4 h; ethyl
acetate (30 mL) and brine (15 mL) were added. The organic
layer was separated and washed with brine (15 mL), dried
over Na2SO4 and evaporated to get an off-white solid, which
was recrystallized from a mixture of ethanol and hexanes (3:7)
to afford (5-bromo-2-nitrophenyl)methanamine (13) as an off-
white solid (2.68 g, 89 %). IR (KBr, νmax, cm-1): 3431, 3319
(NH2), 3052 (Ar-H), 2925 (Alph-H), 1606, 1554 (C=C), 1521,
1
1432 (NO2), 1230 (C-N), 1188 (C-O). H NMR (500 MHz,
CDCl3) δ = 2.41 (br. s, 2H, NH2), 5.02 (s, 2H, CH2), 7.60 (dd,
1H, J = 2.2, 8.2 Hz, H-4), 7.99 (m, 2H, aromatic H). 13C NMR
(125.7 MHz, CDCl3) δ = 61.95 (CH2), 126.51 (C-3), 129.53

Vol. 26, No. 7 (2014)
Synthesis of 6-Piperazinyl-3,4-dihydroquinazolin-2(1H)-ones 2033
tert-Butyl 4-[3-(acetamidomethyl)-4-nitrophenyl]-
piperazine-1-carboxylate (15): To an oven-dried flask, 1-boc-
piperazine (3.19 g, 17.1 mmol), Cs2CO3 (5.82 g, 17.86 mmol),
Pd2(dba)3 (1.44 g, 1.57 mmol), rac-2,2'-bis(diphenylphos
phino)-1,1'-binaphthyl (0.89 g, 1.43 mmol), toluene (8 mL)
and compound 14 (3.89 g, 14.26 mmol) were added. While
stirring the reaction mixture at room temperature, the air in
the flask was removed and replaced by N2. This process was
repeated three times. The reaction temperature was brought
to 110 °C and stirred for 8 h. Ethyl acetate (40 mL) was added
to the mixture at room temperature, washed with H2O (15 mL),
brine (10 mL), dried over Na2SO4 and evaporated. The brown
oily material was chromatographed on a silica column, eluting
with hexanes:ethyl acetate (3:7) and then changing to (1:1) to
obtain the title compound 15 as light yellow solid (3.88 g,
72 %). IR (KBr, νmax, cm-1): 3441 (NH), 3060 (Ar-H), 2963
(Alph-H), 1696 (C=O), 1607, 1577 (C=C), 1484, 1421 (NO2),
2936 (Alph-H), 1697 (C=O), 1606, 1578 (C=C), 1244 (C-N),
1
1166 (C-O). H NMR (500 MHz, CDCl3) δ = 1.47 (s, 9H,
(C(CH3)3), 3.10 (br. s, 4H, 2CH2), 3.22 (br. s, 4H, 2CH2), 4.08
(s, 2H, CH2), 4.58 (br. s, 2H, NH2), 5.18 (br. s, 2H, NH2), 6.68
(dd, 1H, J = 2.3, 9.3 Hz, H-6), 6.73 (br. s, 1H, H-2), 6.81 (d,
1H, J = 9.2 Hz, H-5). 13C NMR (125.7 MHz, CDCl3) δ = 28.05
(C(CH3)3), 42.43 (CH2), 45.26 (CH2), 50.54 (CH2), 79.75
(C(CH3)3), 112.01 (aromatic-C), 112.08 (aromatic-C), 117.00
(aromatic-C), 130.28 (aromatic-C), 134.08 (aromatic-C),
143.08 (aromatic-C), 154.70 (CO). Calculated (%) for
C16H26N4O2 (306.21); C: 62.72, H: 8.55, N: 18.29, found (%);
C: 62.66, H: 8.62, N: 18.20.
tert-Butyl 4-(2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)-
piperazine-1-carboxylate (10): To a solution of compound
17 (1.38 g, 4.5 mmol) in THF (20 mL) at room temperature
was CDI (0.80 g, 4.95 mmol) and the reaction was stirred at
80 °C for 6 h . The mixture was cooled to room temperature
and the solid formed was filtered, washed with diethyl ether
to afford 0.99g (72 %) of compound 10 as an off-white foam.
IR (KBr, νmax, cm-1): 3210, 3162 (NH), 3032 (Ar-H), 1691
(C=O), 1607, 1515, 1419 (C=C). 1H NMR (500 MHz, CDCl3)
δ = 1.47 (s, 9H, (CH3)3C); 3.06 (m, 4H, 2CH2); 3.52 (m, 4H,
2CH2); 4.49 (s, 2H, CH2); 6.69 (m, 2H, aromatic-H), 6.74 (m,
1H, aromatic-H); 7.82 (br.s, 1H, NH); 13C NMR (125.7 MHz,
CDCl3) δ = 28.60 (CH3)3C), 43.35 (CH2), 43.90 (CH2), 50.66
(CH2), 80.10 (CH3)3C), 112.11 (aromatic-C), 112.28 (aromatic-
C), 117.19 (aromatic-C), 130.18 (aromatic-C), 134.88
(aromatic-C), 143.18 (aromatic-C), 154.62 (CO), 155.93
(C=O). Calculated (%) for C17H24N4O3 (332.18); C: 61.43, H:
7.28, N: 16.86, found (%) C: 61.38, H: 7.32, N: 16.81.
6-(Piperazin-1-yl)-3,4-dihydroquinazolin-2(1H)-one
(6): To a solution of compound 10 (0.7 g, 2.11 mmol) in a
mixture of CH2Cl2 (15 mL) and THF (5 mL) at 0 °C was added
TFA (5 mL) and the mixture was stirred at room temperature
for 6 h. The solvent was evaporated under vacuum to afford
0.66 g (96 %) of compound 6 as a dark brown gum. 1H NMR
(500 MHz, DMSO-d6) δ = 3.17 (m, 4H, 2CH2), 3.40 (m, 4H,
2CH2), 4.28 (s, 2H, CH2), 6.70 (m, 2H, aromatic-H), 6.73 (m,
1H, aromatic-H), 8.81 (br. s, 1H, NH), 8.86 (br. s, 1H, NH).
13C NMR (125.7 MHz, DMSO-d6) δ = 46.11 (CH2), 46.70
(CH2), 48.68 (CH2), 112.21 (aromatic-C), 112.27 (aromatic-
C), 117.31 (aromatic-C), 130.28 (aromatic-C), 134.99
(aromatic-C), 143.38 (aromatic-C), 154.82 (C=O). Calculated
(%) for C14H16N4O2F3 (329.12); C: 51.06, H: 4.90, N: 17.01,
found (%); C: 51.01, H: 4.95, N: 16.95.
1
1243 (C-N), 1168 (C-O). H NMR (500 MHz, CDCl3) δ =
1.49 (s, 9H, (C(CH3)3), 2.17 (s, 3H, CH3), 3.42 (br. s, 4H,
2CH2), 3.61 (br. s, 4H, 2CH2), 5.54 (s, 2H, CH2), 6.76 (dd, 1H,
J = 2.3, 9.3 Hz, H-6), 6.88 (br. s, 1H, H-2), 8.17 (d, 1H, J = 9.4
Hz, H-5). 13C NMR (125.7 MHz, CDCl3) δ = 20.93 (CH3),
28.39 (C(CH3)3), 46.82 (CH2), 50.02 (CH2), 66.12 (CH2), 80.42
(C(CH3)3), 112.30 (aromatic-C), 112.48 (aromatic-C), 128.17
(aromatic-C), 135.60 (aromatic-C), 137.03 (aromatic-C),
153.02 (aromatic-C), 154.56 (CO), 170.29 (CO). Calculated
(%) for C18H26N4O5 (378.19); C: 57.13, H: 6.93, N: 14.81,
found (%); C: 57.07, H: 6.99, N: 14.71.
tert-Butyl 4-[3-(acetamidomethyl)-4-aminophenyl]-
piperazine-1-carboxylate (16): To a solution of compound
(15) (1.13 g, 3 mmol) in EtOH (30 mL) was added Raney-Ni
(0.20 g, 10 % wet basis) and the mixture was subjected to
hydrogenation in Parr apparatus at 20 psi for 6 h.After filtering
over the pad of celite, the solution was concentrated and purified
over silica column, eluting with CH2Cl2:MeOH (95:5) and then
changing to (92:8) afforded compound (16) as a light yellow
thick oil (0.85 g, 82 %). IR (KBr, νmax, cm-1): 3441, 3421 (NH),
3042 (Ar-H), 2960 (Alph-H), 1699, 1696 (C=O), 1607, 1577
(C=C), 1240 (C-N), 1165 (C-O). 1H NMR (500 MHz, CDCl3)
δ = 1.48 (s, 9H, (C(CH3)3), 2.16 (s, 3H, CH3), 3.38 (br. s, 4H,
2CH2), 3.52 (br. s, 4H, 2CH2), 5.28 (br. s, 2H, NH2), 5.49 (s,
2H, CH2), 6.78 (dd, 1H, J = 2.3, 9.3 Hz, H-6), 6.80 (br. s, 1H,
H-2), 6.87 (d, 1H, J = 9.2 Hz, H-5). 13C NMR (125.7 MHz,
CDCl3) δ = 20.97 (CH3), 28.35 (C(CH3)3), 42.53 (CH2), 46.26
(CH2), 62.54 (CH2), 79.85 (C(CH3)3), 112.10 (aromatic-C),
112.38 (aromatic-C), 117.09 (aromatic-C), 130.22 (aromatic-
C), 135.03 (aromatic-C), 143.02 (aromatic-C), 154.58 (CO),
170.51 (CO). Calculated (%) for C18H28N4O3 (348.22); C:
62.05, H: 8.10, N: 16.08, found (%); C: 62.00, H: 8.15, N:
16.00.
6-[4-(Biphenyl-4-ylmethyl)piperazin-1-yl]-3,4-dihydro-
quinazolin-2(1H)-one (6a): Representative procedure: To a
solution of compound 6 (0.15 g, 0.43 mmol) and biphenyl-4-
carbaldehyde a (0.1 g, 0.55 mmol) in DMSO (2 mL) at 0 °C
was added Et3N (0.13 mL, 0.97 mmol). After being stirred for
0.5 h at room temperature, NaBH(OAc)3 (0.11 g, 0.53 mmol)
was added and the mixture was stirred for 6 h. The reaction
was mixed with sat. NaHCO3 solution (5 mL) and stirred for
15 min, followed by the addition of ethyl acetate (20 mL).
The organic layer was separated and washed with sat. NaHCO3,
brine and dried over Na2SO4 and evaporated. Column chroma-
tography on silica gel, eluting with methanol: dichloromethane
(5:95) and then changing (10:90) afforded 0.102 g (60 %) of
compound 6a as an off-white solid. IR (KBr, νmax, cm-1): 3436
tert-Butyl 4-[4-amino-3-(aminomethyl)phenyl]piperazine-
1-carboxylate (17): To a solution of compound 16 (0.70 g,
2 mmol) in ethanol (20 mL) was added 4 M solution of KOH
in H2O (4 mL, 16 mmol) and the mixture was stirred at 90 °C
for 12 h. The mixture was concentrated under reduced pressure
to get a brown oil material, which was resolved over silica
column eluting with CH2Cl2:MeOH (95:5) and then changing
to (90:10) to get compound 17 as light brown thick oil (0.51 g,
84 %). IR (KBr, νmax, cm-1) : 3421, 3411 (NH), 3053 (Ar-H),

2034 Ullah
Asian J. Chem.
(NH), 3052 (Ar-H), 2953 (Alph-H), 1702 (C=O), 1614, 1515,
1
1425 (C=C), 1229 (C-N), 1162 (C-O). H NMR (500 MHz,
6-[4-{5-(4-fluorophenyl)pyridin-3-yl}methyl]piperazin-
1-yl)-3,4-dihydroquinazolin-2(1H)-one (6d): Following the
same procedure adopted for the synthesis of 6a, the reductive
amination of compound 6 with aldehyde d afforded 0.083 g
DMSO-d6) δ = 2.76 (m, 4H, 2CH2), 3.18 (m, 4H, 2CH2), 3.67
(s, 2H, CH2), 4.49 (s, 2H, CH2), 6.60 (d, 1H, J = 2.3 Hz,
aromatic H), 6.70 (dd, 1H, J = 2.2, 8.5 Hz, aromatic H), 7.43-
7.48 (m, 6H, aromatic H), 7.58-7.62 (m, 4H, aromatic H). 13C
NMR (125.7 MHz, DMSO-d6) δ = 43.70 (CH2), 48.23 (CH2),
53.03 (CH2), 62.64 (CH2), 114.56 (aromatic-C), 117.64 (aromatic-
C), 119.82 (aromatic-C), 124.58 (aromatic-C), 127.19 (aromatic-
C), 127.26 (aromatic-C), 127.55 (aromatic-C), 127.90 (aromatic-
C), 128.95 (aromatic-C), 129.26 (aromatic-C), 130.25 (aromatic-
C), 130.59 (aromatic-C), 136.66 (aromatic-C), 138.22 (aromatic-
C), 138.66 (aromatic-C), 140.95 (aromatic-C), 146.88 (aromatic-
C), 156.32 (C=O). Calculated (%) for C25H26N4O (398.21); C:
75.35, H: 6.58, N: 14.06, found (%); C: 75.27, H: 6.65, N:
13.96.
(49 %) of compound 6d as a light yellow solid. IR (KBr, νmax
,
cm-1): 3426, 3175 (NH), 3040 (Ar-H), 2962 (Alph-H), 1688
(C=O), 1622, 1525, 1420 (C=C), 1172 (C-O). 1H NMR (500
MHz, CDCl3) δ = 2.79 (m, 4H, 2CH2), 3.19 (m, 4H, 2CH2),
3.66 (s, 2H, CH2), 4.48 (s, 2H, CH2), 6.62-6.69 (m, 2H, aromatic
H), 6.70-6.72 (m, 2H, aromatic H), 7.17 (m, 1H, aromatic H),
7.56-7.58 (m, 2H, aromatic H), 7.89 (s, 1H, aromatic H), 8.54
(s, 1H, aromatic H), 8.70 (s, 1H, NH), 8.96 (s, 1H, aromatic H).
13C NMR (125.7 MHz, CDCl3) δ = 43.60 (CH2), 48.19 (CH2),
52.90 (CH2), 61.41 (CH2), 114.32 (aromatic-C), 114.48
(aromatic-C), 115.85 (aromatic-C), 116.76 (aromatic-C), 117.54
(aromatic-C), 119.70 (aromatic-C), 124.38 (aromatic-C), 128.61
(aromatic-C), 129.75 (aromatic-C), 135.28 (aromatic-C), 136.63
(aromatic-C), 146.89 (aromatic-C), 146.96 (aromatic-C), 148.83
(aromatic-C), 150.49 (aromatic-C), 152.80 ((aromatic-C)),
155.06 (C=O), 161.73 (aromatic-C), 163.68 (aromatic-C).
Calculated (%) for C24H24FN5O (417.20); C: 69.05, H: 5.79, N:
16.78, found (%); C: 68.96, H: 5.86, N: 16.71.
6-[4-{(4'-fluorobiphenyl-4-yl)methyl}piperazin-1-yl]-
3,4-dihydroquinazolin-2(1H)-one (6b): Following the same
procedure adopted for the synthesis of 6a, the reductive
amination of compound 6 with aldehyde b afforded 0.101 g
(55 %) of compound 6b as an off-white solid. IR (KBr, νmax
,
cm-1): 3421 (NH), 3048 (Ar-H), 2953 (Alph-H), 1702 (C=O),
1615, 1515, 1420 (C=C), 1228 (C-N), 1161 (C-O). 1H NMR
(500 MHz, DMSO-d6) δ = 2.71 (m, 4H, 2CH2), 3.17 (m, 4H,
2CH2), 3.65 (s, 2H, CH2), 4.43 (s, 2H, CH2), 6.66 (d, 1H, J =
2.3 Hz, aromatic H), 6.73 (dd, 1H, J = 2.2, 8.5 Hz, aromatic
H), 7.13-7.15 (m, 3H, aromatic H), 7.40-7.45 (m, 2H, aromatic
H), 7.44-7.56 (m, 4H, aromatic H). 13C NMR (125.7 MHz,
DMSO-d6) δ = 43.76 (CH2), 48.28 (CH2), 53.08 (CH2), 62.66
(CH2), 114.66 (aromatic-C), 115.29 (aromatic-C), 116.18
(aromatic-C), 117.69 (aromatic-C), 119.88 (aromatic-C), 124.65
(aromatic-C), 127.52 (aromatic-C), 129.39 (aromatic-C), 129.46
(aromatic-C), 130.85 (aromatic-C), 131.15 (aromatic-C), 136.69
(aromatic-C), 136.79 (aromatic-C), 138.79 (aromatic-C), 140.89
(aromatic-C), 146.89 (aromatic-C), 156.38 (C=O), 161.64
(aromatic-C). Calculated (%) for C25H25N4OF (416.20); C: 72.09,
H: 6.05, N: 13.45, found (%); C: 72.00, H: 6.11, N: 13.37.
6-[4-{(5-Phenylpyridin-3-yl)methyl}piperazin-1-yl]-3,4-
dihydroquinazolin-2(1H)-one (6c): Following the same
procedure adopted for the synthesis of 6a, the reductive amination
of compound 6 with aldehyde c afforded 0.082 g (48 %) of
compound 6c as light yellow gum. IR (KBr, νmax, cm-1): 3436,
3192 (NH), 3042 (Ar-H), 2932 (Alph-H), 1690 (C=O), 1622,
1518, 1440 (C=C), 1175 (C-O). 1H NMR (500 MHz, CDCl3) δ
= 2.72 (m, 4H, 2CH2), 3.12 (m, 4H, 2CH2), 3.62 (s, 2H, CH2),
4.45 (s, 2H, CH2), 6.64-6.72 (m, 3H, aromatic H), 7.10-7.13 (m,
2H, aromatic H), 7.40-7.42 (m, 2H, aromatic H), 7.44-7.48 (m,
3H, aromatic H), 7.62 (m, 2H, aromatic H), 7.91 (s, 1H, aromatic
H), 8.55 (s, 1H, aromatic H), 8.92 (s, 1H, aromatic H). 13C NMR
(125.7 MHz, CDCl3) δ = 43.67 (CH2), 48.13 (CH2), 52.92 (CH2),
62.40 (CH2), 114.46 (aromatic-C), 117.54 (aromatic-C), 119.70
(aromatic-C), 124.38 (aromatic-C), 126.94 (aromatic-C), 127.86
(aromatic-C), 128.38 (aromatic-C), 128.70 (aromatic-C), 128.78
(aromatic-C), 128.89 (aromatic-C), 132.98 (aromatic-C), 133.16
(aromatic-C), 136.18 (aromatic-C), 136.49 (aromatic-C), 136.60
(aromatic-C), 137.36 (aromatic-C), 146.10 (aromatic-C), 146.87
(aromatic-C), 148.86 (aromatic-C), 155.41 (C=O). Calculated
(%) for C24H25N5O (399.21); C: 72.16, H: 6.31, N: 17.53, found
(%); C: 72.07, H: 6.37, N: 17.41.
6-[4-(3-cyclopentenylbenzyl)piperazin-1-yl]-3,4-
dihydroquinazolin-2(1H)-one (6e): Following the same
procedure adopted for the synthesis of 6a, the reductive amina-
tion of compound 6 with aldehyde e afforded 0.111 g (60 %)
of compound 6e as light brown foam. IR (KBr, νmax, cm-1):
3416, 3182 (NH), 3045 (Ar-H), 2933 (Alph-H), 1690 (C=O),
1
1622, 1518, 1421 (C=C), 1167 (C-O). H NMR (500 MHz,
CDCl3) δ = 2.00-2.04 (m, 2H, CH2), 2.51 (m, 2H, CH2), 2.60
(m, 2H, 2CH2), 2.73 (m, 4H, 2CH2), 3.12 (m, 4H, 2CH2), 3.60
(s, 2H, CH2), 4.46 (s, 2H, CH2), 6.19 (s, 1H, CH), 6.58-6.75
(m, 3H, aromatic H), 7.18 (m, 1H, aromatic H), 7.24 (m, 1H,
aromatic H), 7.31 (m, 1H, aromatic H), 7.40 (s, 1H, aromatic
H), 7.95 (br. s, 1H, NH). 13C NMR (125.7 MHz, CDCl3) δ =
23.52 (CH2), 33.46 (CH2), 33.58 (CH2), 43.62 (CH2), 48.18
(CH2), 52.90 (CH2), 62.48 (CH2), 114.48 (aromatic-C), 115.12
(aromatic-C), 117.58 (aromatic-C), 119.72 (aromatic-C), 123.52
(aromatic-C), 124.42 (aromatic-C), 126.59 (aromatic-C), 128.06
(aromatic-C), 128.45 (aromatic-C), 130.07 (aromatic-C), 136.60
(aromatic-C), 137.79 (aromatic-C), 142.58 (aromatic-C), 146.92
(aromatic-C), 156.19 (C=O). Calculated (%) for C24H28N4O
(388.23); C: 74.20, H: 7.26, N: 14.42, found (%); C: 74.13, H:
7.33, N: 14.33.
6-[4-{(5-cyclopentenylpyridin-3-yl)methyl}piperazin-
1-yl]-3,4-dihydroquinazolin-2(1H)-one (6f): Following the
same procedure adopted for the synthesis of 6a, the reductive
amination of compound 6 with aldehyde f afforded 0.090 g
(54 %) of compound 6f as an off-white solid. IR (KBr, νmax
,
cm-1): 3412, 3190 (NH), 3061 (Ar-H), 2961 (Alph-H), 1690
(C=O), 1626, 1523, 1422 (C=C), 1170 (C-O). 1H NMR (500
MHz, CDCl3) δ = 2.00-2.06 (m, 2H, CH2), 2.50 (m, 2H, CH2),
2.61 (m, 2H, 2CH2), 2.71 (m, 4H, 2CH2), 3.15 (m, 4H, 2CH2),
3.61 (s, 2H, CH2), 4.45 (s, 2H, CH2), 6.20 (s, 1H, CH), 6.58-
6.75 (m, 3H, aromatic H), 6.78 (m, 1H, aromatic H), 7.71 (s,
1H, NH), 8.09 (s, 1H, aromatic H), 8.42 (s, 1H, aromatic H),
8.58 (s, 1H, aromatic H). 13C NMR (125.7 MHz, CDCl3) δ =
23.92 (CH2), 33.56 (CH2), 33.88 (CH2), 43.69 (CH2), 48.12
(CH2), 52.92 (CH2), 62.68 (CH2), 114.43 (aromatic-C), 115.92

Vol. 26, No. 7 (2014)
Synthesis of 6-Piperazinyl-3,4-dihydroquinazolin-2(1H)-ones 2035
(aromatic-C), 117.44 (aromatic-C), 119.76 (aromatic-C), 124.39
(aromatic-C), 130.92 (aromatic-C), 133.09 (aromatic-C), 133.69
(aromatic-C), 136.60 (aromatic-C), 140.37 (aromatic-C), 146.90
(aromatic-C), 147.91 (aromatic-C), 149.46 (aromatic-C), 156.90
(C=O). Calculated (%) for C23H27N5O (389.22); C: 70.92, H:
6.99, N: 17.98, found (%); C: 70.86, H: 7.06, N: 17.91.
of bromides 9 with tert-butyl piperazine-1-carboxylate, under
different reaction conditions (PdCl2dppf, KOAc, DMF, 80 °C;
Pd(PPh3)4, toluene, ethanol, Na2CO3, reflux) were not successful;
the desired 10 was not observed in any case (scheme-I).
Therefore an alternative approach was adopted in which
benzaldehyde 11 was nitrated to the known benzaldehyde 1218,
which in turn was subjected to reductive amination by conden-
sing it with ammonium hydroxide, using sodium borohydride
as reducing agent to produce amine 13 in high yield. Acety-
lation amine 13 generated acetamide 14, which was reacted
with tert-butyl piperazine-1-carboxylate under Buchwald-
Hartwig conditions to afford intermediate 15 in good yield.
Reduction of nitro group of 15 over Pd-C in a Parr apparatus
produced intermediate 16 in 91 % yield high yield. Exposure
of intermediate 16 under basic conditions rendered the desired
diamine 17 in good yield after column purifications. Reaction
of 17 with CDI in THF, heating the mixture at 80 °C for 6 h,
RESULTS AND DISCUSSION
To accomplish the synthesis of the desired compounds
6a-f, synthesis of the key intermediate 10 was required, which
in turn was envision from the Buchwald-Hartwig coupling
reaction of known 6-bromo-3,4-dihydroquinazolin-2(1H)-one
(9)18 with tert-butyl piperazine-1-carboxylate. Thus the synthesis
of compound 9 was commenced with the reduction of bromo-
benzonitrile with borane to afford diamine (8), which was
reacted with triphosgene to get the desired bromide (9) in 23 %
overall yield from (7). However, the Buchwald-Hartwig coupling
O
O
NH2
NH2 NH2
HN
NH
HN
NH
CN
Triphosgene, Et3N
BH3.Me2S, THF
Buchwald-Hartwig
o
0 C to r.t., 16 h
o
0 C to r.t., 24 h
Br
(55%)
Br
(42%)
N
N
Br
7
8
9
Boc
10
Scheme-I: Synthesis of intermediate 10
NO2
NO2 NH2
CHO
H2SO4, HNO3
CHO
NH3
Ac2O, pyridine
0 oC, 45 min
(56%)
NaBH4, r.t, 2 h
(89%)
r.t., 16 h
(98%)
Br
11
Br
Br
12
13
NH2 NHR
NO2 NHAc
NO2 NHAc
1-boc-piperazine, BINAP,
Pd2(dba)3, Cs2CO3, Toluene
Ra-Ni, H2, EtOH
100 oC, 8 h
(72%)
20 psi, 6 h
(82%)
N
N
Br
14
N
N
Boc
Boc
O
O
15
R = Ac, 16
R = H, 17
KOH, EtOH,
90 oC, 12 h
HN
NH
HN
NH
(84%)
TFA, CH2Cl2
CDI, THF
N
N
o
r.t., 4 h
(98%)
N
N
65 C, 8 h
(66%)
Boc
10
H.TFA
6
Scheme-II: Synthesis of intermediate 10, an alternative route

2036 Ullah
Asian J. Chem.
CHO
HN
HN
HN
HN
O
O
N
N H.TFA
N
N
DMSO, Et3N, NaBH(OAc)3,
rt, 6 h
( a)
6
Scheme-III: Synthesis of 6a, a representative example
2. D.C. Goff and R.I. Shader, in eds.: S.R. Hirsch and D. Weinberger,
Non-Neurological Side-Effects of Antipsychotic Drugs, In: Schizo-
phrenia, Blackwell Publishing, Oxford, edn 2, p. 573-88 (2002).
3. H.Y. Meltzer, Psychopharmacology, 99(S1), S18 (1989).
4. L.H. Lindstrom, Acta Psychiatr. Scand., 77, 524 (1988).
5. E.P. Prinssen, F.C. Colpaert and W. Koek, Eur. J. Pharmacol., 453,
217 (2002).
gave access to the key intermediate 10 in an overall yield of
33 % from 14. Exposure of intermediate 10 to trifluoroacetic
acid in a mixture of methanol and dichloromethane finally
furnished the desired key intermediate 18 (Scheme-II).
Having the desired intermediates 18 in hands, we next
performed reductive amination of 18 with aldehydes (a-f)15 in
DMSO, using NaBH(OAc)3 as reducing agent to accomplish
the synthesis of final compounds (6a-f) (Scheme-III).
6. A. Newman-Tancredi, M.B. Assie, N. Leduc, A.M. Ormiere, N. Danty
and C. Cosi, Int. J. Neuropsychopharmacol., 8, 341 (2005).
7. M.B. Assie, V. Ravailhe, V. Faucillon and A. Newman-Tancredi, J.
Pharmacol. Exp. Ther., 315, 265 (2005).
Conclusion
8. L.A. Bruins Slot, L. De Vries, A. Newman-Tancredi and D. Cussac,
Eur. J. Pharmacol., 534, 63 (2006).
A series of new 6-piperazinyl-3,4-dihydroquinazolin-
2(1H)-ones have been synthesized. The described compounds
are structurally related to adoprazine, a potential atypical
antipsychotics bearing potent D2 receptor antagonist and 5-
HT1A receptor agonist properties.
9. L.A. Bruins Slot, M.S. Kleven and A. Newman-Tancredi, Neurophar-
macology, 49, 996 (2005).
10. M.S. Kleven, C. Barret-Grevoz, L.A.B. Slot and A. Newman-Tancredi,
Neuropharmacology, 49, 135 (2005).
11. R.A. Bantick, J.F.W. Deakin and P.M. Grasby, J. Psychopharmacol.,
15, 37 (2001).
12. A.C. McCreary, J.C. Glennon, C.R. Ashby Jr., H.Y. Meltzer, Z. Li, J.-H.
Reinders, M.B. Hesselink, S.K. Long,A.H. Herremans, H. van Stuivenberg,
R.W. Feenstra and C.G. Kruse, Neuropsychopharmacology, 32, 78
(2007).
ACKNOWLEDGEMENTS
The financial support from National Plan for Science,
Technology and Innovation (NSTIP) project # 11-BIO2138-04
and facilities provided by KFUPM are gratefully acknowl-
edged.
13. A. Newman-Tancredi, Curr. Opin. Investig. Drugs, 11, 802 (2010).
14. S. Cuisiat, N. Bourdiol, V. Lacharme,A. Newman-Tancredi, F. Colpaert
and B. Vacher, J. Med. Chem., 50, 865 (2007).
15. N. Ullah, Z. Naturforsch, 67, 75 (2012).
16. N. Ullah and A.A.Q. Al-Shaheri, Z. Naturforsch, 67, 253 (2012).
17. N. Ullah, J. Enzym. Inhib. Med. Chem., 29, 281 (2014).
18. H. Venkatesan, F.M. Hocutt, T.K. Jones and M.H. Rabinowitz, J. Org.
Chem., 75, 3488 (2010).
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