Synthesis of novel new 2-(2-(4-((3,4-dihydro-4-oxo-3-aryl quinazolin-2-yl)methyl)piperazin-1-yl)acetoyloxy)-2-phenyl acetic acid esters

Article abstract of DOI:10.1080/00397910902735381

Stereoselective diazotization of (S)-2-amino-2-phenyl acetic acid (L-phenyl glycine) (4) with NaNO2 in 6% H2SO4 in a mixture of acetone and water gave optically pure (S)-2-hydroxy-2-phenyl acetic acid (L-mandelic acid) (5). Esterification, gave (S)-2-hydroxy-2-phenyl acetic acid esters (6). The latter was treated with chloroacetyl chloride in the presence of triethylamine (TEA) in dichloromethane (DCM) to yield (S)-2-chloroacetyloxy phenyl acetic acid ester (2). In another sequence, the reaction of 2-(chloromethyl)-3-arylquinazolin- 4(3H)-one (9) treated with N-Boc piperazine, followed by deprotection of the Boc group, to obtain 3-aryl-2-((piperazin-1-yl)methyl) quinazolin-4(3H)-one (3). Reaction of 2 with 3 in the presence of K2CO3 and KI gave the title compound, 2-(2-(4-((3,4-dihydro-4-oxo-3-arylquinazolin-2-yl)methyl)piperazin-1-yl) acetoyloxy)-2-phenyl acetic acid esters (1). The structures of all the new compounds obtained in the present work are supported by spectral and analytical data. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910902735381

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Synthesis of Novel New
2-(2-(4-((3,4-Dihydro-4-
oxo-3-aryl quinazolin-2-
yl)methyl)piperazin-1-
yl)acetoyloxy)-2-phenyl Acetic
Acid Esters
Palle V. R. Acharyulu a , P. K. Dubey b , P. V. V.
Prasada Reddy c & Thatipally Suresh c
a Dr. Reddy's Laboratories , Bachupalli, Hyderabad,
India
b Department of Chemistry , College of Engineering,
JNT University , Hyderabad, India
c Aptuit Laurus, Shamerpet , Hyderabad, India
Published online: 12 Aug 2009.
To cite this article: Palle V. R. Acharyulu , P. K. Dubey , P. V. V. Prasada Reddy &
Thatipally Suresh (2009) Synthesis of Novel New 2-(2-(4-((3,4-Dihydro-4-oxo-3-
aryl quinazolin-2-yl)methyl)piperazin-1-yl)acetoyloxy)-2-phenyl Acetic Acid Esters,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:18, 3217-3231, DOI: 10.1080/00397910902735381
To link to this article: http://dx.doi.org/10.1080/00397910902735381
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Synthetic Communications1, 39: 3217–3231, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902735381
Synthesis of Novel New 2-(2-(4-((3,4-Dihydro-
4-oxo-3-aryl quinazolin-2-yl)methyl)piperazin-
1-yl)acetoyloxy)-2-phenyl Acetic Acid Esters
Palle V. R. Acharyulu,1 P. K. Dubey,2 P. V. V. Prasada Reddy,3
and Thatipally Suresh3
1Dr. Reddy’s Laboratories, Bachupalli, Hyderabad, India
2Department of Chemistry, College of Engineering, JNT University,
Hyderabad, India
3Aptuit Laurus, Shamerpet, Hyderabad, India
Abstract: Stereoselective diazotization of (S)-2-amino-2-phenyl acetic acid
(L-phenyl glycine) (4) with NaNO2 in 6% H2SO4 in a mixture of acetone and
water gave optically pure (S)-2-hydroxy-2-phenyl acetic acid (L-mandelic acid)
(5). Esterification, gave (S)-2-hydroxy-2-phenyl acetic acid esters (6). The latter
was treated with chloroacetyl chloride in the presence of triethylamine (TEA)
in dichloromethane (DCM) to yield (S)-2-chloroacetyloxy phenyl acetic acid ester
(2). In another sequence, the reaction of 2-(chloromethyl)-3-arylquinazolin-
4(3H)-one (9) treated with N-Boc piperazine, followed by deprotection of the
Boc group, to obtain 3-aryl-2-((piperazin-1-yl)methyl) quinazolin-4(3H)-one
(3). Reaction of 2 with 3 in the presence of K2CO3 and KI gave the title
compound, 2-(2-(4-((3,4-dihydro-4-oxo-3-arylquinazolin-2-yl)methyl)piperazin-
1-yl) acetoyloxy)-2-phenyl acetic acid esters (1). The structures of all the new
compounds obtained in the present work are supported by spectral and analytical
data.
Keywords: (S)-2-Amino-2-phenyl acetic acid, N-Boc-piperazine, chloroacetyl-
chloride, 2-(chloromethyl)-3-arylquinazolin-4(3H)-one, diazotization, K2CO3=KI
Received November 12, 2008.
Address correspondence to P. K. Dubey, Department of Chemistry, College
of Engineering, JNT University, Kukatpally, Hyderabad, A. P. 500 085, India.
E-mail: thatipally5@gmail.com
3217

3218
P. V. R. Acharyulu et al.
INTRODUCTION
The derivatives of a-hydroxy carboxylic acids relate to novel antiobesity
and hypocholesterolemic compounds. A few b-aryl-a-hydroxy propionic
acids, their derivatives, and their analogs have been reported to lower
total cholesterol (TC), increase high-density lipoprotein (HDL), and
decrease low-density lipoprotein (LDL), which have beneficial effects
on coronary heart disease and atherosclerosis. This would be useful in
the treatment of certain types of cancer, which express PPARc (peroxi-
some proliferator-activated receptor), and could lead to a nontoxic
chemotherapy. Some of such compounds are described in Fig. 1.[1]
4(3H)-Quinazolinones have emerged as an important class of nitro-
genated heterocycles and have attracted significant synthetic interest
because of their pharmacological and therapeutic properties, such as
antibacterial, antifungal, antimalarial, antihypertensive, anticonvulsant,
anti-Parkinson, antihistaminic, local anaesthetic, analgesic, anti-
inflammatory, antiviral, and anticancer activities.[2] Several bioactive
natural products such as febrifugine[3] and isofebrifugine[4] contain
quinazolinone moieties with potential antimalarial activity.
A number of quinazolinones have been reported as potent
chemotherapeutic agents in the treatment of tuberculosis, for example,
3-aryl-6,8-dichloro-2H-1,3-benzoxazine-2,4-(3H)-diones and 3-arylquina-
zolinones-2,4-(1H,3H)-diones as antimycobacterial agents and quinazoli-
nones derivatives as antitubercular agents.[5,6] The antihyperlipidemic
activities of these compounds were also investigated.[7]
Multicomponent organic reactions are of great importance in
organic synthesis. Likewise, quinazolinones fused with a piperizine ring
system may also be associated with a wide range of biological activities,
including the quinazolinones fused with simple piperzine ring systems
such as anacine[8] and quinazolinones fused with a piperzine ring, along
with a spiro-ring functionality such as fumiquinazoline[9] D and E.
We report here the synthesis of 2-(2-(4-((3,4-dihydro-4-oxo-3-aryl-
quinazolin-2-yl)methyl)piperazin-1-yl)acetoyloxy)-2-phenyl acetic acid
esters (1), incorporating three biologically active moieties (quinazoli-
nones, piperizine, and L-mandelic acid derivatives) in a single molecule.
Figure 1. b-Aryl-a-hydroxy propionic acids and their derivatives.

Synthesis of Quinazolinone Derivatives
RESULTS AND DISCUSSION
3219
The retrosynthetic analysis of the present route (Scheme 1) revealed that
the molecule could be dissected into two intermediates, namely 2-chlor-
oacetoxyphenyl acetic acid esters (2) and 3-aryl-2-(piperazin-1-yl)
quinazolin-4(3H)-one (3), which can be condensed conveniently to afford
the final product. Accordingly, we describe here a more efficient method
wherein the two key intermediates 2 and 3 are made simultaneously and
upon condensation produce 2-(2-(4-((3,4-dihydro-4-oxo-3-arylquinazo-
lin-2-yl)methyl)piperazin-1-yl)acetoyloxy)-2-phenyl acetic acid esters (1).
The synthetic strategy described was implemented by making the key
intermediates 2 and 3 simultaneously. The chiral intermediate 2 was
synthesized by a method developed by this group starting from L-phenyl
glycine 4 (Scheme 2). The crucial a-hydroxy compound was prepared by
a stereoselective diazotization of (S)-2-amino-2-phenyl acetic acid
(L-phenyl glycine) (4) in aqueous acetone, using sodium nitrite in the
presence of dil. H2SO4, to afford (S)-2-hydroxy-2-phenyl acetic acid (5)
in 70% yield with ee of more than 99%. These results are further
supported by comparison with known compound of (S)-2-hydroxy-2-
phenyl acetic acid by optical rotation and chiral high-performance liquid
chromatography (HPLC). When compared with the previous literature
reports, this method is very advantageous because the product is
obtained in good yields and no side products are formed. On treatment
with alcohols (such as methanol, ethanol, and isopropanol) in the
presence of a catalytic amount of conc. H2SO4 under refluxing condi-
tions, 5 gave the previously reported[10] (S)-2-hydroxy-2-phenyl acetic
acid esters (6). On treatment with chloroacetyl chloride in dichloro-
methane (DCM) using triethylamine (TEA) as a base at room tempera-
ture, the latter gave the desired (S)-2-chloroacetyloxy phenyl acetic acid
ester (2) (Scheme 2).
In another sequence of reactions, anthranilic acid (7) was treated
with chloroacetyl chloride in the presence of TEA in DCM at room
temperature to obtain the previously reported[11] 2-chloromethyl
benzo[d][1,3]oxazin-4-one (8). On treatment with aromatic amines in
Scheme 1. Retrosynthetic approach to the present work.

3220
P. V. R. Acharyulu et al.
Scheme 2. Reagents and conditions: (i) H2O, acetone, dil. H2SO4, NaNO2, rt;
(ii) R-OH, conc. H2SO4 (R¼Me, Et, ipr), D; and (iii) chloroacetylchloride,
TEA, DCM, rt.
refluxing pyridine for 5–6 h, followed by simple processing, the latter
resulted in the formation of 2-(chloromethyl)-3-arylquinazolin-4(3H)-
one (9). Compound 9 reacted with N-Boc-piperazine in acetonitrile
and K2CO3 as a base in the presence of a catalytic amount of KI under
refluxing conditions for 1–2 h, yielding a neat product, which has been
characterized as tert-butyl-4-((3,4-dihydro-4-oxo-3-arylquinazolin-2-yl)
methyl)-piperazine-1-carboxylate (10) on the basis of spectral and analy-
tical data (Scheme 3). Treatment of 10 with methanolic HCl (14% w=w)
solution at room temperature gave 3-aryl-2-((piperazin-1-yl)methyl)
quinazolin-4(3H)-one (3), by simple deprotection of the Boc group.
Having made two key intermediates 2 and 3 simultaneously, the
two units were condensed (Scheme 4) in the presence of potassium
carbonate and a catalytic amount of KI in refluxing acetonitrile to afford
the desired compound, 2-(2-(4-((3,4-dihydro-4-oxo-3-arylquinazolin-2-yl)
methyl)piperazin-1-yl)acetoyloxy)-2-phenyl acetic acid ester (1), in good
yields. During this reaction, racemization took place, which was
confirmed by checking isolated compounds for optical purity with a
Scheme 3. Reagents and conditions: (iv) chloroacetyl chloride, TEA, DCM; (v)
Ar-NH2,
(Ar ¼ a ¼ -C6H4-2-CF3;
b ¼ -C6H4-3-OCH3;
c ¼ -C6H4-2-CH3;
d ¼ -C6H5), pyridine, D; (vii) N-Boc-piperazine, K2CO3, KI, CH3CN, D; and
(vii) 10% methanolic HCl.

Synthesis of Quinazolinone Derivatives
3221
Scheme 4. Reagents and conditions: (viii) K2CO3, KI, CH3CN, D.
polarimeter, and the rotation value was 0ꢀ. The explanation for the race-
mization is that a-hydrogen is labile and thus causes racemization under
the given conditions.
In conclusion, we have achieved the synthesis of (2-(2-(4-((3,
4-dihydro-4-oxo-3-arylquinazolin-2-yl)methyl)piperazin-1-yl)acetoyloxy)-
2-phenyl acetic acid esters through the preparation of two key intermedi-
ates by incorporating three moieties such as quinazolinones, piperizine,
and L-mandelic acid derivatives in a single molecule.
EXPERIMENTAL
General Conditions
Melting points were determined in open glass capillaries using a Buchi
melting-point apparatus and are uncorrected. Infrared (IR) spectra were
recorded on a sample as diluted solutions (chloroform or carbon
tetrachloride) in matched sodium chloride cells or as potassium bromide
pellets with a Perkin IR spectrometer. All 1H NMR spectra were
recorded on a Varian 200-MHz instrument with an internal standard
of tetramethylsilane (TMS). Mass spectra (MS) were recorded on an
Agilent LC-MS instrument giving only Mþꢁ values using (Mþ þ 1) mode.
Analytical thin-layer chromatography (TLC) was performed with silica
gel GF-254 from Merck (Germany). Spots were detected with ultraviolet
(UV) light or in iodine. The following experimental procedures are repre-
sentative of the general procedures used to synthesize all compounds.
Preparation of 5
A mixture of optically pure (S)-2-amino-2-phenyl acetic acid 4 (2.0 g,
10.0 mmol) in acetone (10.0 mL) and dil. H2SO4 (6%, w=v 10.0 ml) was

3222
P. V. R. Acharyulu et al.
added to the reaction mixture at 0ꢀC to ꢂ5ꢀC. NaNO2 (4.62 g, 0.066 mol,
in 10 mL of water) was added to the reaction mixture dropwise during
10–15 min at 0ꢀC to ꢂ5ꢀC. The reaction mixture was stirred at 0ꢀC to
ꢂ5ꢀC for 2 h, and slowly the reaction mixture was brought to rt and
then stirred overnight. The progress of reaction was monitored by TLC
for disappearance of 4. After the completion of reaction, the mixture
was poured into ice-cold dil. HCl. The aqueous layer was extracted
into ethyl acetate (3 ꢃ 15 mL); combined organic layers were washed
with water and brine and dried over anhyd. Na2SO4. The organic
layer was distilled off under reduced pressure to give the crude 5. The
crude product was purified by column chromatography, and the product
was eluted with a mixture of hexane and ethyl acetate to yield a white
solid (75%).
Preparation of 6
A few drops of conc. H2SO4 were added to a solution of 5 (1.52 g,
10 mmol) in alcohol (20 mL), and the mixture was refluxed on a water
bath for 3 h. At the end of this period, the excess solvent was removed
by distillation. The residue was dissolved in water, cooled to 0ꢀC, and
gradually neutralized with solid NaHCO3. Reaction mass was extracted
into DCM (3 ꢃ 20 mL). Combined organic layers were washed with water
(25 mL) and dried over anhyd. Na2SO4. Finally, the solvent was distilled
off under reduced pressure to dryness to give the desired product 6
(Scheme 2).
Preparation of 2
A mixture of 6 (10 mmol) and triethyl amine (4.17 mL, 30 mmol) in
DCM (20 mL) was cooled to 0–5ꢀC. Chloroacetyl chloride (0.956 ml,
12 mmol) was added slowly at 0–5ꢀC during 15–20 min. After complete
addition, the reaction mass was brought to rt and maintained for 5–6 h.
The progress of the reaction was monitored by thin-layer chromatogra-
phy (TLC) for disappearance of 6. After completion of the reaction,
water (20 mL) was added, and the layers were separated. The aq. layer
was further extracted into DCM (2 ꢃ 10 mL). Combined organic layers
were washed with water (20 mL) and dried over anhyd. Na2SO4. The
organic layer was evaporated to dryness to give crude product 2. This
was purified by column chromatography, and the product was eluted
with a mixture of hexane and ethyl acetate to yield colorless liquids
(Scheme 2).

Synthesis of Quinazolinone Derivatives
3223
Representative Spectral Data
Compound 2a
R ¼ ꢂCH3; yield 82%; colorless liquid; IR (KBr): 1754.9 (COO) cmꢂ1; 1H
NMR (CDCl3, 200 MHz): d 3.8 (s, 3H, ꢂOCH3), 4.18–4.22 (d, 2H,
–CH2), 6.20 (S, 1H, –CH), 7.40–7.50 (m, 5H, Ar-H); M=Z (Mþ þ 1):
243. Anal. calcd. for C11H11ClO4; C, 54.45; H, 4.57; Found: C, 54.41;
H, 4.51%.
Compound 2b
R ¼ ꢂC2H5; yield 76%; colorless liquid; IR (KBr): 1747.19 (COO) cmꢂ1
;
1H NMR (CDCl3, 200 MHz): d 1.09–1.30 (t, 3H, –CH3), 4.05–4.25 (q,
2H, –CH2), 5.90–6.0 (s, 1H, –CH), 7.30–7.50 (m, 5H, Ar-H); M=Z
(Mþ þ 1): 257. Anal. calcd. for C12H13ClO4; C, 56.15; H, 5.10. Found:
C, 56.09; H, 5.02%.
Compound 2c
R ¼ ꢂCH(CH3)2; yield 82%; colorless liquid; IR (KBr): 1768.5 (COO)
cmꢂ1
;
1H NMR (CDCl3, 200 MHz): d 1.10–1.15 (d, 3H, –CH3),
1.22–1.30 (dd, 3H, –CH3), 4.07–4.25 (q, 2H, –CH2), 5.00–5.10 (m, 1H,
–CH), 5.90–5.95 (s, 1H, –CH), 7.38–7.50 (m, 5H, Ar-H); M=Z
(Mþ þ 1): 271. Anal. calcd. for C13H15ClO4; C, 57.68; H, 5.59. Found:
C, 57.62; H, 5.54%.
Preparation of 10
A mixture of 9 (10 mmol), N-Boc-piperazine (2.66 g, 15 mmol), K2CO3
(2.76 g, 20 mmol), KI (0.016 g, 0.01 mmol), and CH3CN (20 mL) was
heated at 80ꢀC for 90–120 min. The progress of reaction was monitored
by TLC for complete disappearance of 9. On completion of the
reaction, the mixture was diluted with water and extracted with ethyl
acetate (2 ꢃ 25 mL). The combined organic layer was washed with
water, saturated solution of NH4Cl (25 mL) (to remove unreacted
Boc-piperazine), and brine and then dried with anhydrous Na2SO4.
The organic layer was distilled under reduced pressure to give 10
(Scheme 3).

3224
P. V. R. Acharyulu et al.
Representative Spectral Data
Compound 10a
R1 ¼ ꢂC6H4-2-CF3; yield 86%; mp 166–68; IR (KBr): 1684 (C¼O), 1695
1
(COO) cmꢂ1; H NMR (CDCl3, 200 MHz): d 1.4 (t, 9H, BOC -CH3),
2.1–2.4 (m, 4H, piperazine), 3.1–3.2 (dd, 2H, –CH2), 3.2–3.4 (m, 4H,
piperazine), 7.45–7.85 (m, 7H, ArꢂH), 8.30 (m, 1H, Ar-H); M=Z
(Mþþ1): 489. Anal. calcd. for C25H27F3N4O3; C, 61.47; H, 5.57; N,
11.47. Found C, 61.38; H, 5.49; N, 11.41%.
Compound 10b
R1 ¼ ꢂC6H4-3-OCH3; yield 78%; mp 152–154ꢀC; IR (KBr): 1680 (C¼O),
1
1697 (COO) cmꢂ1; H NMR (CDCl3, 200 MHz): d 1.4 (s, 9H, BOC
ꢂCH3), 2.0–2.4 (m, 4H, piperazine), 3.1–3.2 (dd, 2H, ꢂCH2), 3.3–3.4
(m, 4H, piperazine), 3.7 (s, 3H, ArꢂOCH3), 7.1–8.3 (m, 7H, ArꢂH);
M=Z (Mþ þ 1): 451.5. Anal. calcd. for (C25H30N4O4): C, 66.65; H,
6.71; N, 12.44. Found: C, 66.58; H, 6.65; N, 12.38%.
Compound 10c
R1 ¼ ꢂC6H4-2-CH3; yield 74%; mp 132–134ꢀC; IR (KBr): 1680 (C¼O),
1
1694 (COO) cmꢂ1; H NMR (CDCl3, 200 MHz): d 1.4 (s, 9H, BOC
CH3), 2.10–2.35 (m, 4H, piperazine), 2.2 (s, 3H, ArꢂCH3), 3.1–3.2 (dd,
2H, ꢂCH2), 3.2–3.4 (m, 4H, piperazine), 7.18–7.20 (d, 1H, ArꢂH),
7.3–7.4 (m, 3H, Ar-H), 7.45–7.70 (t, 1H, Ar-H), 7.75–7.81 (m, 2H,
ArꢂH), 8.3 (d, 1H, ArꢂH); M=Z (Mþ þ 1): 435. Anal. calcd. for
C25H30N4O3; C, 69.10; H, 6.96; N, 12.89. Found: C, 69.00; H, 6.92; N,
12.83%.
Compound 10d
R1 ¼ ꢂC6H5; yield 84%; mp 126–130ꢀC; IR (KBr): 1687 (C¼O), 1696
1
(COO) cmꢂ1; H NMR (CDCl3, 200 MHz): d 1.4 (s, 9H, BOC CH3),
2.2–2.3 (m, 4H, piperazine), 3.2 (d, 2H, -CH2), 3.2–3.3 (m, 4H, pipera-
zine), 7.30–7.35 (d, 2H, Ar-H), 7.42–7.55 (m, 4H, Ar-H), 7.75–7.80 (m,
2H, Ar-H), 8.28 (d, 1H, Ar-H); M=Z (Mþ þ 1): 421. Anal. calcd. for
C24H28N4O3; C, 68.55; H, 6.71; N, 13.32. Found: C, 68.48; H, 6.65; N,
13.28%.

Synthesis of Quinazolinone Derivatives
3225
Preparation of 3 (Deprotection of Boc)
Compound 10 (10 mmol) was suspended in methanolic HCl (15 mL,
10–12% w=v) at ambient temperature. The mixture was stirred at the
same temperature for 1–2 h. After completion of the reaction, MTBE
(15 mL) was added, and the mixture was stirred for another 30 min at
rt. The separated solid was filtered and washed with methyl-tert-butyl
ether (MTBE) (5 mL) to remove excess HCl. The solid was dissolved in
water (5 mL), and pH was adjusted to ꢄ 8–9 by adding a sufficient
amount of saturated aqueous Na2CO3 solution. The aq. layer was
extracted in to DCM (3 ꢃ 20 mL). The organic layers were combined,
washed successively with water (2 ꢃ 10 mL until aq. layer pH is neutral)
and brine, and then dried with anhydrous Na2SO4. The organic layer
was distilled under reduced pressure to obtain a residue of 3 (Scheme 3).
Representative Spectral Data
Compound 3a
R1 ¼ ꢂC6H4-2-CF3; yield 80%; mp 142–145ꢀC; IR (KBr): 1754.9 (COO)
cmꢂ1; 1H NMR (CDCl3, 200MHz): d 2.2–2.4 (m, 4H, piperazine), 2.7–2.8
(m, 4H, piperazine), 3.15–3.25 (dd, 2H, ꢂCH2), 7.5–7.9 (m, 7H, Ar-H),
8.3 (m, 1H, Ar-H); M=Z (Mþ þ 1): 389. Anal. calcd. for C20H19F3N4O;
C, 61.85; H, 4.93; N, 14.43. Found: C, 61.81; H, 4.89; N, 14.38%.
Compound 3b
R1 ¼ ꢂC6H4-3-OCH3; yield 78%; mp 112–114ꢀC; IR (KBr): 1674 (C¼O)
cmꢂ1 1H NMR (CDCl3, 200 MHz): d 2.0–2.4 (m, 4H, piperazine),
;
2.6–2.8 (m, 4H, piperazine), 3.1–3.4 (dd, 2H, ꢂCH2), 3.7 (s, 3H,
ArꢂOCH3), 7.1–7.85 (m, 7H, ArꢂH), 8.3 (m, 1H, Ar-H); M=Z
(Mþþ1): 351.5. Anal. calcd. for C20H22N4O2; C, 68.55; H, 6.33; N,
15.99. Found: C, 68.51; H, 6.28; N, 15.93%.
Compound 3c
R1 ¼ ꢂC6H4-2-CH3; yield 72%; mp 170–174ꢀC; IR (KBr): 1684 (C¼O)
cmꢂ1
;
1H NMR (CDCl3, 200 MHz): d 2.1 (s, 3H, ArꢂCH3), 2.2–2.4
(m, 4H, piperazine), 2.7–2.9 (m, 4H, piperazine), 3.05–3.4 (dd, 2H,
ꢂCH2), 7.1–7.4 (m, 4H, Ar-H), 7.4–7.6 (m, 1H, Ar-H), 7.7–7.8 (m, 2H,
Ar-H), 8.3 (d, 1H, Ar-H); M=Z (Mþ þ 1): 335.5. Anal. calcd. for

3226
P. V. R. Acharyulu et al.
C20H22N4O; C, 71.83; H, 6.63; N, 16.75. Found: C, 71.78; H, 6.58; N,
16.68%.
Compound 3d
R1 ¼ ꢂC6H5; yield 76%; mp 152–154ꢀC; IR (KBr): 1676 (C¼O) cmꢂ1; 1H
NMR (CDCl3, 200 MHz): d 2.2–2.45 (m, 4H, piperazine), 2.7–2.8 (m, 4H,
piperazine), 3.2 (s, 2H, ꢂCH2), 7.3–7.4 (d, 2H, Ar-H), 7.42–7.60 (m, 4H,
Ar-H), 7.7–7.80 (m, 2H, Ar-H), 8.3 (d, 1H, Ar-H); M=Z (Mþ þ 1): 321.5.
Anal. calcd. for C19H20N4O; C, 71.23; H, 6.29; N, 17.49. Found: C,
71.18; H, 6.25; N, 17.45%.
Preparation of 1
A mixture of 2 (10 mmol, 1.0 equiv.) and 3 (10 mmol, 1.0 equiv) was dis-
solved in CH3CN (20 mL), and then K2CO3 (2.76 g, 20 mmol) and KI
(0.016 g, 0.1 mmol) were added in order. The mixture (a suspension)
was heated at 80ꢀC for 90–120 min. The progress of the reaction was
monitored by TLC. On completion of the reaction, the mixture was
diluted with water and extracted with ethyl acetate (2 ꢃ 25 mL). The
combined organic layer was washed with water and brine and then dried
with anhydrous Na2SO4. The organic layer was distilled under reduced
pressure to obtain the final compound 1 (Scheme 4).
Representative Spectral Data
Compound 1a
R ¼ ꢂCH3; R1 ¼ ꢂC6H4-2-CF3; yield 78%; liquid; IR (KBr): 1670 (C¼O),
1
1754.9 (COO) cmꢂ1; H NMR (CDCl3, 200 MHz): d 2.2–2.4 (m, 4H,
piperazine), 2.4–2.6 (m, 4H, piperazine), 3.10–3.20 (d, 2H, N-CH2),
3.30–3.50 (d, 2H, N–CH2ꢂCO), 3.75 (s, 3H, ꢂOCH3), 5.95–6.00 (s,
1H, –CH), 7.40–7.9 (m, 12H, Ar-H), 8.3 (m, 1H, Ar-H); M=Z (Mþ þ
1): 595.4. Anal. calcd. for C31H29F3N4O5: C, 62.62; H, 4.92; N, 9.42.
Found: C, 62.58; H, 4.89; N, 9.36%.
Compound 1b
R ¼ ꢂCH3; R1 ¼ ꢂC6H4-3-OCH3; yield 80%; liquid; IR (KBr): 1688.4
1
(C¼O), 1749.1 (COO) cmꢂ1; H NMR (CDCl3, 200 MHz): d 2.4–2.5

Synthesis of Quinazolinone Derivatives
3227
(m, 4H, piperazine), 2.5–2.6 (m, 4H, piperazine), 3.20–3.30 (d, 2H,
N-CH2), 3.30–3.40 (d, 2H, N–CH2ꢂCO), 3.75 (s, 3H, ꢂOCH3), 3.82 (s,
3H, ꢂOCH3), 5.95–6.00 (s, 1H, –CH), 6.8–7.0 (m, 3H, Ar-H), 7.4–7.5
(m, 7H, Ar-H), 7.75–7.80 (m, 2H, Ar-H), 8.3 (m, 1H, Ar-H); M=Z
(Mþ þ 1): 557.4. Anal. calcd. for C31H32N4O6; C, 66.89; H, 5.79; N,
10.07. Found: C, 66.85; H, 5.74; H, 10.01%.
Compound 1c
R ¼ ꢂCH3; R1 ¼ ꢂC6H4-2-CH3; yield 82%; liquid; IR (KBr): 1698
1
(C¼O), 1750 (COO) cmꢂ1; H NMR (CDCl3, 200 MHz): d 2.2 (s, 3H,
–CH3), 2.4–2.5 (m, 4H, piperazine), 2.5–2.6 (m, 4H, piperazine),
3.10–3.20 (dd, 2H, NꢂCH2), 3.30–3.40 (d, 2H, N–CH2ꢂCO), 3.75 (s,
3H, –OCH3), 5.95 (s, 1H, –CH), 7.1–7.2 (m, 1H, Ar-H), 7.3–7.4 (m,
8H, Ar-H), 7.4–7.5 (m, 1H, Ar-H), 7.7–7.8 (m, 2H, Ar-H), 8.3 (m, 1H,
Ar-H); M=Z (Mþ þ 1): 541. Anal. calcd. for C31H32N4O5; C, 68.87; H,
5.97; N, 10.36. Found: C, 68.81; H, 5.95; N, 10.32%.
Compound 1d
R ¼ ꢂCH3; R1 ¼ ꢂC6H5; yield 89%; liquid; IR (KBr): 1683 (C¼O), 1753
(COO) cmꢂ1; 1H NMR (CDCl3, 200 MHz): d 2.3–2.4 (m, 4H, piperazine),
2.4–2.5 (m, 4H, piperazine), 3.20–3.25 (d, 2H, N-CH2), 3.30–3.40 (d, 2H,
N–CH2ꢂCO), 3.75 (s, 3H, OCH3), 5.95 (s, 1H, –CH), 7.3–7.6 (m, 11H,
Ar-H), 7.75–7.8 (m, 2H, Ar-H), 8.35 (m, 1H, Ar-H); M=Z (Mþ þ 1):
527.5. Anal. calcd. for C30H30N4O5; C, 68.43; H, 5.74; N, 10.64. Found:
C, 68.39; H, 5.70; N, 10.58%.
Compound 1e
R ¼ ꢂC2H5; R1 ¼ ꢂC6H4-2-CF3; yield 80%; liquid; IR (KBr): 1692.2
1
(C¼O), 1747.2 (COO) cmꢂ1; H NMR (CDCl3, 200 MHz): d 1.19–1.20
(t, 3H, –CH3), 2.2–2.3 (m, 4H, piperazine), 2.4–2.6 (m, 4H, piperazine),
3.05–3.20 (dd, 2H, ꢂCH2), 3.2–3.4 (dd, 2H, N–CH2ꢂCO), 4.10 (q, 2H,
–CH2), 5.95 (s, 1H, –CH), 7.2–7.8 (m, 12H, Ar-H), 8.3 (m, 1H, Ar-H);
M=Z (Mþ þ 1): 609.0. Anal. calcd. for C32H31F3 N4O5; C, 63.15; H,
5.13; N, 9.21. Found: C, 63.15; H, 5.08; N, 9.17%.
Compound 1f
R ¼ ꢂC2H5; R1 ¼ -C6H4-3-OCH3; yield 84%; liquid; IR (KBr): 1688.4
1
(C¼O), 1746.2 (COO) cmꢂ1; H NMR (CDCl3, 200 MHz): d 1.19–1.20

3228
P. V. R. Acharyulu et al.
(t, 3H, –CH3), 2.4–2.5 (m, 4H, piperazine), 2.5–2.6 (m, 4H, piperazine),
3.25–3.30 (dd, 2H, ꢂCH2), 3.3–3.4 (dd, 2H, N–CH2ꢂCO), 3.85 (s, 3H,
ꢂOCH3), 4.15 (q, 2H, –CH2), 5.95 (s, 1H, –CH), 6.8–7.0 (m, 3H,
Ar-H), 7.3–7.5 (m, 7H, Ar-H), 7.75–7.80 (m, 2H, Ar-H), 8.3 (m, 1H,
Ar-H); M=Z (Mþ þ 1): 571.5. Anal. calcd. for C32H34N4O6; C, 67.35;
H, 6.01; N, 9.82. Found: C, 67.29; H, 5.98; N, 9.78%.
Compound 1g
R ¼ ꢂC2H5; R1 ¼ ꢂC6H5; yield 86%; liquid; IR (KBr): 1686.4 (C¼O),
1
1748.2 (COO) cmꢂ1; H NMR (CDCl3, 200 MHz): d 1.19–1.20 (t, 3H,
–CH3), 2.4–2.5 (m, 4H, piperazine), 2.5–2.6 (m, 4H, piperazine),
3.25–3.30 (dd, 2H, ꢂCH2), 3.3–3.4 (dd, 2H, N–CH2ꢂCO), 4.15 (q, 2H,
–CH2), 5.95 (s, 1H, –CH), 7.2–7.5 (m, 11H, Ar-H), 7.75–7.8 (m, 2H,
Ar-H), 8.3 (m, 1H, Ar-H); M=Z (Mþþ1): 541.5. Anal. calcd. for
C31H32N4O5; C, 68.87; H, 5.97; N, 10.36. Found: C, 68.82; H, 5.92; N,
10.30%.
Compound 1h
R ¼ ꢂCH(CH3)2; R1 ¼ ꢂC6H4-2-CF3; yield 76%; liquid; IR (KBr): 1691.2
1
(C¼O), 1746.2 (COO) cmꢂ1; H NMR (CDCl3, 200 MHz): d 1.10–1.15
(d, 3H, –CH3), 1.22–1.30 (d, 3H, CH3), 2.2–2.4 (m, 4H, piperazine),
2.4–2.6 (m, 4H, piperazine), 3.1–3.2 (d, 2H, NꢂCH2), 3.3–3.4 (d, 2H,
N–CH2ꢂCO), 4.90–5.1 (m, 1H, –CH), 5.9 (s, 1H, –CH), 7.35–7.8 (m,
10H, Ar-H), 7.75–7.80 (m, 2H, Ar-H), 8.3 (m, 1H, Ar-H); M=Z
(Mþ þ 1): 623.5. Anal. calcd. for C33H33 F3N4O5; C, 63.66; H, 5.34; N,
9.00. Found: C, 63.63; H, 5.29; N, 8.95%.
Compound 1i
R ¼ ꢂCH(CH3)2; R1 ¼ ꢂC6H4-3-OCH3; yield 80%; liquid; IR (KBr):
1693.2 (C¼O), 1747.2 (COO) cmꢂ1
;
1H NMR (CDCl3, 200 MHz): d
1.10–1.15 (d, 3H, –CH3), 1.22–1.30 (d, 3H, –CH3), 2.4–2.5 (m, 4H,
piperazine), 2.5–2.6 (m, 4H, piperazine), 3.2–3.3 (d, 2H, N-CH2),
3.3–3.4 (d, 2H, N–CH2ꢂCO), 3.85 (s, 3H, ꢂOCH3), 5.00–5.10 (m,
1H, –CH), 5.9 (s, 1H, –CH), 6.8–7.0 (m, 3H, Ar-H), 7.35–7.45 (m,
7H, Ar-H), 7.75–7.80 (m, 2H, Ar-H), 8.35 (m, 1H, Ar-H); M=Z
(Mþ þ 1): 585.0. Anal. calcd. for C33H36N4O6; C, 67.79; H, 6.21; N,
9.58. Found: C, 67.75; H, 6.15; 9.54%.

Synthesis of Quinazolinone Derivatives
3229
Compound 1j
R ¼ ꢂCH(CH3)2; R1 ¼ ꢂC6H4-2-CH3; yield 80%; liquid; IR (KBr): 1698
(C¼O), 1750 (COO) cmꢂ1
;
1H NMR (CDCl3, 200 MHz): d 1.10–1.15
(d, 3H, –CH3), 1.22–1.30 (d, 3H, –CH3), 2.15 (s, 3H, –CH3), 2.2–2.3
(m, 4H, piperazine), 2.4–2.6 (m, 4H, piperazine), 3.15–3.2 (d, 2H,
NꢂCH2), 3.25–3.4 (dd, 2H, N–CH2ꢂCO), 5.0–5.10 (m, 1H, –CH), 5.9
(s, 1H, –CH), 7.15–7.2 (m, 2H, Ar-H), 7.3–7.55 (m, 8H, Ar-H),
7.75–7.80 (m, 2H, Ar-H), 8.35 (m, 1H, Ar-H); M=Z (Mþ þ 1): 569.0.
Anal. calcd. For C33H36N4O5; C, 69.70; H, 6.38; N, 9.85. Found: C,
69.66; H, 6.34; N, 9.82%.
Compound 1k
R ¼ ꢂCH(CH3)2; R1 ¼ ꢂC6H5; yield 88%; liquid; IR (KBr): 1695.1
1
(C¼O), 1747.2 (COO) cmꢂ1; H NMR (CDCl3, 200 MHz): d 1.25–1.20
(d, 3H, –CH3), 1.4–1.50 (d, 3H, –CH3), 2.15 (s, 3H, –CH3), 2.5–2.6 (m,
4H, piperazine), 2.6–2.8 (m, 4H, piperazine), 3.40–3.50 (d, 2H, NꢂCH2),
3.5–3.6 (d, 2H, N–CH2ꢂCO), 5.15–5.25 (m, 1H, –CH), 6.05 (s, 1H,
CH), 7.5–7.75 (m, 11H, Ar-H), 7.9–8.0 (m, 2H, Ar-H), 8.4 (m, 1H,
Ar-H); M=Z (Mþ þ 1): 555.0. Anal. calcd. for C32H34N4O5; C, 69.30;
H, 6.18; N, 10.10. Found: C, 69.26; H, 6.14; N, 10.04%.
ACKNOWLEDGMENT
We are thankful to Dr. H. R. Mohan (Aptuit-Laurus) for his useful
discussions about this work.
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