An efficient Biginelli one-pot synthesis of new benzoxazole-substituted dihydropyrimidinones and thiones catalysed by alumina-supported trifluoromethane sulfonic acid under solvent free conditions

Article abstract of DOI:10.1002/jhet.29

An efficient synthesis of benzoxazole-substituted 3,4-dihydropyrimidinones (DHPMs) using alumina supported trifluoromethane sulfonic acid as the catalyst for the first time from an aldehyde, β-keto ester, and benzoxazole- substituted urea and thiourea und

Full text of DOI:10.1002/jhet.29

January 2009
An Efficient Biginelli One-Pot Synthesis of New Benzoxazole-
Substituted Dihydropyrimidinones and Thiones Catalysed by
Alumina-Supported Trifluoromethane Sulfonic Acid Under
Solvent Free Conditions
119
M. Arjun,a D. Sridhar,a M. Adharvana Chari,b and M. Sarangapanic*
aUniversity College of Pharmaceutical Sciences, Kakatiya University, Warangal 506009, India
bDepartment of Applied Chemistry, Kyung Hee University, South Korea
cDepartment of Chemistry, Kakatiya University, Warangal 506009, India
*E-mail: drmac_s@yahoo.com
Received January 29, 2008
DOI 10.1002/jhet.29
Published online 11 February 2009 in Wiley InterScience (www.interscience.wiley.com).
An efficient synthesis of benzoxazole-substituted 3,4-dihydropyrimidinones (DHPMs) using alumina
supported trifluoromethane sulfonic acid as the catalyst for the first time from an aldehyde, b-keto ester,
and benzoxazole-substituted urea and thiourea under solvent-free conditions is described. When com-
pared with the classical Biginelli reaction conditions, this new method consistently has the advantage of
excellent yields (80–93%) and short reaction time (30–120 minutes) at 120ꢀC temperature.
J. Heterocyclic Chem., 46, 119 (2009).
INTRODUCTION
Similarly, benzoxazole nucleus can also be frequently
recognized in the structure of numerous naturally occur-
ring compounds with interesting biological and pharma-
cological properties. Benzaxazoles have been found to
possess marked biological effects as anti inflammatory
[18,19], anticancer [20] and antimicrobial [21,22]
agents. In view of this benzoxazole-substituted urea and
thiourea are used in the synthesis of 3,4-dihydropyrimi-
dinones to get more biodynamic compounds.
The Biginelli (1893) reaction [1] is a simple one-pot
condensation of an aldehyde, keto ester, and urea or thi-
ourea in the presence of catalytic amount of acid to pro-
duce 3,4-dihydropyrimidin-2(1H)-ones. Dihydropyrimi-
dinones (DHPMs) and their derivatives exhibit wide
range of biological activities such as antibacterial, anti-
viral, antitumour, and anti-inflamatory actions [2]. Bigi-
nelli compounds exhibit pharmacological activities as
calcium channel blockers, antihypertensive agents, a -
1a–antagonists, and neuro peptide Y(NPY) antagonists
[3–6]. Biological activities of some marine alkaloids iso-
lated were also found to contain the dihydropyrimidi-
none-5-carboxylate core [7]. Most notably among them
are batezelladine alkaloids, which have been found to be
potent HIV gp-120-CD4 inhibitors [8–10]. Conse-
quently, syntheses of Biginelli compounds have gained
importance, which often suffer from low yields practi-
cally in case of substituted aromatic and aliphatic alde-
hydes [11–13]. Even though, high yields could be
achieved by following complex multistep procedures
[14–17], these methods lack the simplicity of original
one-pot Biginelli protocol. Therefore, Biginelli reaction
continues to attract the attention of researchers for the
discovery of a milder and efficient procedure for the
synthesis of dihydropyrimidinones.
In recent years, several synthetic procedures for pre-
paring of DHPMs have been reported including classical
conditions with microwave irradiation [23,24] and by
using Lewis acids as well as protic acids as promoters
such as [25–30] Conc. HCl, BF3.OEt2, PPE, KSF clay,
InCl3, LaCl3, lanthanide triflate, H2SO4, ceric ammo-
nium nitrate (CAN), Mn(OAc)3, ion-exchange resin, 1n-
butyl-3-methyl
imidazolium
tetra
fluoroborate
(BMImBF4), BiCl3, LiClO4, InBr3, FeCl3, ZrCl4,
Cu(OTf)2, Bi(OTf)3, LiBr, ytterbium triflates, NH4Cl,
MgBr2, SiO2/NaHSO4, CdCl2, and other reagents [31]
have been found to be effective. Many of these methods
involve expensive reagents, stochiometric amounts of
catalysts, strongly acidic conditions, long reaction times,
unsatisfactory yields, and incompatibility with other
functional groups. Therefore, the development of a neu-
tral alternative would extend the scope of the Biginelli
reaction.
C
V
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120
M. Arjun, D. Sridhar, M. A. Chari, and M. Sarangapani
Vol 46
Scheme 1
Recently, the use of solid supported reagents [32] has
alumina supported trifluoromethane sulfonic acid cata-
lyst. The results are listed in Table 1. Another important
feature of this procedure is the stability of a variety of
functional groups such as ether, hydroxy, halides, nitro,
etc., under these reaction conditions.
Benzoxazole-substituted urea and thiourea has been
used with similar success to provide the corresponding
dihydropyrimidinones and thiones in high yields, which
are also of much interest with regard to biological activ-
ity. An acid sensitive aldehyde, worked well without
formation of any side product. It is noteworthy which
the survival of a variety of functional groups such as
ether, hydroxy, halides, nitro, unsaturation, etc, under
the reaction conditions.
received considerable importance in organic synthesis
because of their ease of handling, enhanced reaction
rates, greater selectivity, simple workup, and recover-
ability of catalysts. Among the various heterogeneous
catalysts, particularly, alumina supported trifluorome-
thane sulfonic acid has advantages of low cost, ease of
preparation, and catalyst recycling. As the reaction is
heterogeneous in nature, the catalyst can conveniently
be separated by simple filtration. In view of the recent
surge in the use of heterogeneous catalysts [33–35], we
wish to report a simple, convenient, and efficient
method for the preparation of benzoxazole-substituted
dihydropyrimidinone derivatives using alumina [36] sup-
ported trifluoromethane sulfonic acid, as an inexpensive
and eco-friendly catalyst. This catalyst can act as eco-
friendly for a variety of organic transformations because
it is nonvolatile, recyclable, inexplosive, easy to handle,
and thermally robust. In view of the emerging impor-
tance of heterogeneous catalysts, we wish to explore the
use of alumina supported trifluoromethane sulfonic acid
[37] as recyclable catalyst in the synthesis of DHPMs
using substituted urea and thiourea.
The efficiency of the recovered catalyst was verified
with the reaction of benzaldehyde, benzoxazole -substi-
tuted urea and ethyl acetoacetate (Entry 1). Using fresh
catalyst, the yield of product (4a) was 90% while the
recovered catalyst in the three subsequent recyclization
the yields were 89, 87, and 86.
CONCLUSION
In summary, we have developed a new methodology
for the synthesis of substituted DHPMs by using substi-
tuted urea and thiourea in the presence of a catalytic
amount of alumina supported trifluoromethane sulfonic
acid at 120ꢀC temperature. Thus, alumina-supported
trifluoromethane sulfonic acid mediated one-pot synthe-
sis of DHPMs is, therefore, a simple, high yielding,
time saving, and eco-friendly process. The catalyst can
be prepared from available inexpensive reagents and can
be easy recycled, which is heterogeneous and
nonhazardous.
RESULTS AND DISCUSSION
Initially, we have studied the Bignelli’s one-pot con-
densation reaction of benzaldehyde (1.0 mmol) with
benzoxazole-substituted urea (1.2 mmol) and ethyl ace-
toacetate (1.2 mmol) using 5 mol % of alumina-sup-
ported trifluoromethane sulfonic acid as catalyst under
solvent free conditions (Scheme 1). The reaction is very
fast and 90% conversion was observed in 1 h.
Encouraged by these results, we examined several ar-
omatic and aliphatic aldehydes under optimized condi-
tions (Table 1). Furthermore, the use of just 5 mol %
alumina-supported trifluoromethane sulfonic acid as cat-
alyst is sufficient to promote the reaction. There are no
improvements in the reaction rates and yields by
increasing the amount of the catalyst from 5 to 10 mol
%. The best results were achieved when the reactions
were carried out at 120ꢀC temperature in an oil bath for
30–120 minutes in the presence of catalytic amount of
EXPERIMENTAL
All chemicals were A. R. grade obtained from Qualigens,
India. All the solvents were purified by standard techniques.
Column chromatographic separations were carried out on Sili-
cagel 100–200 mesh size. I.R Spectra were scanned on a Per-
kin-Elmer, 1310 Spectrophotometer with sodium chloride
optics. NMR spectra were recorded on a varian FT-200 MHz
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2009
An Efficient Biginelli One-Pot Synthesis of New Benzoxazole-Substituted
Dihydropyrimidinones and Thiones Catalysed
121
Table 1
Alumina-supported trifluoromethane sulfonic acid-catalyzed synthesis of dihydropyrimidinones and thio derivatives.
Entry
R
Ar
X
Products
Time (min)
M.P. (ꢀC)
Yield (%)
1
2
H
CH3
H
CH3
H
C6H5
C6H5
O
O
O
O
O
O
O
O
O
O
O
O
S
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
30
60
40
70
40
80
60
120
40
60
50
70
40
70
60
70
60
80
90
120
60
90
80
120
171–173
164–165
193–194
201–203
196–198
209–210
183–185
188–190
151–153
167–168
217–219
213–214
178–180
161–163
199–200
191–192
204–206
211–212
181–182
186–187
147–149
156–158
207–208
219–221
90
87
90
88
91
87
88
84
93
86
82
80
88
85
87
84
90
88
80
87
90
82
83
85
3
4
4-ClC6H4
4-ClC6H4
4-NO2C6H5
4-NO2C6H4
4-(CH3)2NC6H4
4-(CH3)2NC6H4
2-OHC6H4
2-OHC6H4
Furyl
5
6
7
CH3
H
8
9
CH3
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
Furyl
C6H5
C6H5
S
4-ClC6H4
4-ClC6H4
4-NO2C6H4
4-NO2C6H4
4-(CH3)2NC6H4
4-(CH3)2NC6H4
2-OHC6H4
2-OHC6H4
Furyl
S
S
S
S
S
CH3
H
S
S
4t
4u
4v
4w
4x
CH3
H
S
S
CH3
Furyl
S
(GEMINI) using tetramethyl silane (TMS) as the internal
standard. Mass spectra were obtained on micro Mass VG70-
70H spectrometer operating at 70 eV using a direct inlet
system.
C23H22N4O5 (434.16): C, 63.59; H, 5.10; N, 12.90. Found: C,
63.57; H, 5.06; N, 12.80.
Entry 3 (4c). Solid, m.p. 193–194ꢀC, 1H NMR (CDCl3): d
1.24 (t, 3H, J ¼ 7.0 Hz), 2.38 (s, 3H), 4.20 (q, 2H, J ¼ 7.0
Hz), 4.84 (s, 1H), 6.84–8.89 (m, 8H, ArAH), 9.42 (bs, 1H,
NH), 10.12 (bs, 1H, NH). EMS: m/z: 454(Mþ). IR (KBr): m ¼
3340, 1725, 1695, 1612, 1578. Anal. Calc. for C22H19ClN4O5
(454.1): C, 58.09; H, 4.21; N, 12.32; Cl, 7.79;. Found: C,
58.03; H, 4.18; N, 12.30; Cl, 7.70.
Preparation of the catalyst. The catalyst was prepared by
mixing alumina (5 mmol) with a trifluoromethane sulfonic
acid (5 mmol) in distilled water (10 mL). The resulting mix-
ture was stirred for 30 minutes to absorb triflouromethane sul-
fonic acid on the surface of alumina. After removal of water
in a rotary evaporator, the solid powder was dried at 120ꢀC
for 2–3 h under reduced pressure. The drying temperature was
maintained below the decomposition temperatures of the salts.
General procedure for the synthesis of DHPMs. A solu-
tion of an appropriate b-keto ester (1.2 mmol), corresponding
aldehyde (1.0 mmol), benzaxazole substituted urea or thiourea
(1.2 mmol), and alumina-supported trifluoromethane sulfonic
acid (5 mol %) under solvent-free conditions was heated at
120ꢀC (completion of reaction was monitored by TLC). The
reaction mixture was washed thoroughly with water, filtered
and recrystallized from methanol to afford pure product. The
spectral data of the compounds are given below.
Entry 1 (4a). Solid, m.p. 171–173ꢀC, 1H NMR (CDCl3): d
1.20 (t, 3H, J ¼ 7.0 Hz), 2.30 (s, 3H), 4.10 (q, 2H, J ¼ 7.0
Hz), 4.72 (s, 1H), 6.72–8.94 (m, 9H, ArAH), 9.64 (bs, 1H,
NH), 10.48 (bs, 1H, NH). EMS: m/z: 420(Mþ). IR (KBr): m ¼
3427, 1715, 1686, 1608, 1584. Anal. Calc. for C22H20N4O5
(420.14): C, 62.85; H, 4.79; N, 13.33. Found: C, 62.83; H,
4.76; N, 13.32.
Entry 4 (4d). Solid, m.p. 201–203ꢀC, 1H NMR (CDCl3): d
1.19 (t, 3H, J ¼ 7.0 Hz), 2.36 (s, 3H), 2.56(s, 3H), 4.18 (q,
2H, J ¼ 7.0 Hz), 4.83 (s, 1H), 6.78–8.74 (m, 7H, ArAH), 9.24
(bs, 1H, NH), 10.76 (bs, 1H, NH). EMS: m/z: 468(Mþ). IR
(KBr): m ¼ 3319, 1722, 1895, 1605, 1592. Anal. Calc. for
C23H21ClN4O5 (468.12): C, 58.91; H, 4.51; N, 11.95; Cl, 7.56.
Found: C, 58.89; H, 4.48; N, 11.90; Cl, 7.47.
Entry 5 (4e). Solid, m.p. 196–198ꢀC, 1H NMR (CDCl3): d
1.22 (t, 3H, J ¼ 7.0 Hz), 2.34 (s, 3H), 4.25 (q, 2H, J ¼ 7.0
Hz), 4.81 (s, 1H), 6.78–8.92 (m, 8H, ArAH), 9.24 (bs, 1H,
NH), 10.67 (bs, 1H, NH). EMS: m/z: 465(Mþ). IR (KBr): m ¼
3470, 1725, 1682, 1602, 1573. Anal. Calc. for C22H19N5O7
(465.13): C, 56.77; H, 4.11; N, 15.05. Found: C, 56.75; H,
4.08; N, 15.04.
Entry 6 (4f). Solid, m.p. 209–210ꢀC, 1H NMR (CDCl3): d
1.21 (t, 3H, J ¼ 7.0 Hz), 2.41 (s, 3H), 2.62(s, 3H), 4.00 (q,
2H, J ¼ 7.0 Hz), 4.87 (s, 1H), 6.91 – 8.72 (m, 7H, ArAH),
9.24 (bs, 1H, NH), 10.96 (bs, 1H, NH). EMS: m/z: 479(Mþ).
IR (KBr): m ¼ 3345, 1723, 1695, 1605, 1592. Anal. Calc. for
C23H21N5O7 (479.14): C, 57.62; H, 4.41; N, 14.61. Found: C,
57.60; H, 4.38; N, 14.60.
Entry 7 (4g). Solid, m.p. 183–185ꢀC, 1H NMR (CDCl3): d
1.04 (t, 3H, J ¼ 7.0 Hz), 2.41 (s, 3H), 2.65(s, 6H, N(CH3)2),
4.08 (q, 2H, J ¼ 7.0 Hz), 4.83 (s,1H), 6.67–8.76 (m, 8H,
Entry 2 (4b). Solid, m.p. 164–165ꢀC, 1H NMR (CDCl3): d
1.22 (t, 3H, J ¼ 7.0 Hz), 2.34 (s, 3H), 2.51(s, 3H), 4.16 (q,
2H, J ¼ 7.0 Hz), 4.76 (s, 1H), 6.64–8.73 (m, 8H, ArAH), 9.46
(bs, 1H, NH), 10.24 (bs, 1H, NH). EMS: m/z: 434(Mþ). IR
(KBr): m ¼ 3345, 1721, 1682, 1610, 1589. Anal. Calc. for
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1
Entry 16 (4p). Solid, m.p. 189–191ꢀC, H NMR (CDCl3): d
1.21 (t, 3H, J ¼ 7.0 Hz), 2.34 (s, 3H),2.61(s, 3H), 4.26 (q, 2H,
J ¼ 7.0 Hz), 4.87 (s, 1H), 6.69–8.78 (m, 7H, ArAH), 9.56 (bs,
1H, NH), 10.84 (bs, 1H, NH). EMS: m/z: 484 (Mþ). IR (KBr):
m ¼ 3359, 1716, 1888, 1618, 1589, 1259. Anal. Calc. for
C23H21ClN4O4S (484.1): C, 56.96; H, 4.36; N, 11.55; Cl, 7.31.
Found: C, 56.90; H, 4.33; N, 11.50, Cl, 7.22.
ArAH), 9.18 (bs, 1H, NH), 10.86 (bs, 1H, NH). EMS: m/z:
463(Mþ). IR (KBr): m ¼ 3295, 1714, 1677, 1611, 1575. Anal.
Calc. for C24H25N5O5 (463.19): C, 62.19; H, 5.44; N, 15.10.
Found: C, 62.17; H, 5.39; N, 15.09.
Entry 8 (4h). Solid, m.p. 188–190ꢀC, 1H NMR (CDCl3): d
1.19 (t, 3H, J ¼ 7.0 Hz), 2.35 (s, 3H), 2.52(s, 3H), 2.67(s, 6H,
N(CH3)2), 4.16 (q, 2H, J ¼ 7.0 Hz), 4.78 (s,1H), 6.89–8.72
(m, 7H, ArAH), 9.24 (bs, 1H, NH), 10.98 (bs, 1H, NH). EMS:
m/z: 477(Mþ). IR (KBr): m ¼ 3485, 1727, 1682, 1610, 1586.
Anal. Calc. for C25H27N5O5 (477.2): C, 62.88; H, 5.70; N,
14.67. Found: C, 62.86; H, 5.23; N, 14.66.
1
Entry 17 (4q). Solid, m.p. 191–193ꢀC, H NMR (CDCl3): d
1.18 (t, 3H, J ¼ 7.0 Hz), 2.31 (s, 3H), 4.28 (q, 2H, J ¼ 7.0
Hz), 4.76 (s, 1H), 6.82–8.88 (m, 8H, ArAH), 9.21 (bs, 1H,
NH), 10.89 (bs, 1H, NH). EMS: m/z: 491 (Mþ). IR (KBr): m ¼
3478, 1720, 1679, 1598, 1559, 1242. Anal. Calc. for
C22H19N5O6S(481.11): C, 54.88; H, 3.98; N, 14.55. Found: C,
54.87; H, 3.94; N, 14.54.
Entry 9 (4i). Solid, m.p. 151–153ꢀC, 1H NMR (CDCl3): d
1.15 (t, 3H, J ¼ 7.0 Hz), 2.36 (s, 3H), 4.20 (q, 2H, J ¼ 7.0
Hz), 4.84 (s, 1H), 6.91–8.72 (m, 8H, ArAH), 9.24 (bs, 1H,
NH), 10.78 (bs, 1H, NH), 11.12 (bs, 1H, OH). EMS: m/z:
436(Mþ). IR (KBr): m ¼ 3395, 1716, 1680, 1614, 1581. Anal.
Calc. for C22H20N4O6 (436.14): C, 60.55; H, 4.62; N, 12.84.
Found: C, 60.53; H, 4.58; N, 12.83.
1
Entry 18 (4r). Solid, m.p. 207–208ꢀC, H NMR (CDCl3): d
1.16 (t, 3H, J ¼ 7.0 Hz), 2.39 (s, 3H), 2.58 (s, 3H), 4.09 (q,
2H, J ¼ 7.0 Hz), 4.69 (s, 1H), 6.87–8.79 (m, 7H, ArAH), 9.32
(bs, 1H, NH), 10.76 (bs, 1H, NH). EMS: m/z: 495 (Mþ). IR
(KBr): m ¼ 3338, 1724, 1689, 1611, 1582, 1256. Anal. Calc.
for C23H21N5O6S (495.12): C, 55.75; H, 4.27; N, 14.13.
Found: C, 55.74; H, 4.24; N, 14.10.
1
Entry 10 (4j). Solid, m.p. 167–168ꢀC, H NMR (CDCl3): d
1.08 (t, 3H, J ¼ 7.0 Hz), 2.36 (s, 3H), 2.61(s, 3H), 4.12 (q,
2H, J ¼ 7.0 Hz), 4.89 (s, 1H), 6.84–8.67 (m, 7H, ArAH), 9.14
(bs, 1H, NH), 10.29 (bs, 1H, NH), 11.20 (bs, 1H,OH). EMS:
m/z: 450(Mþ). IR (KBr): m ¼ 3410, 1712, 1692, 1607, 1575.
Anal. Calc. for C23H22N4O6 (450.15): C, 61.33; H, 4.92; N,
12.44. Found: C, 61.31; H, 4.88; N, 12.40.
1
Entry 19 (4s). Solid, m.p. 182–183ꢀC, H NMR (CDCl3): d
1.14 (t, 3H, J ¼ 7.0 Hz), 2.46 (s, 3H), 2.58(s, 6H, N(CH3)2),
4.16 (q, 2H, J ¼ 7.0 Hz), 4.74 (s, 1H), 6.69–8.59 (m, 8H,
ArAH), 9.24 (bs, 1H, NH), 10.89 (bs, 1H, NH). EMS: m/z:
479 (Mþ). IR (KBr): m ¼ 3291, 1718, 1659, 1602, 1561, 1269.
Anal. Calc. for C24H25N5O4S (479.16): C, 60.11; H, 5.25; N,
14.60. Found: C, 60.10; H, 5.21; N, 14.56.
1
Entry 11 (4k). Solid, m.p. 217–219ꢀC, H NMR (CDCl3): d
1.18 (t, 3H, J ¼ 7.0 Hz), 2.24 (s, 3H), 4.23 (q, 2H, J ¼ 7.0
Hz), 4.76 (s, 1H), 7.12–8.53 (m, 7H, ArAH), 9.20 (bs, 1H,
NH), 10.76 (bs, 1H, NH). EMS: m/z: 410(Mþ). IR (KBr): m ¼
3317, 1719, 1675, 1610, 1594. Anal. Calc. for C20H18N4O6
(410.12): C, 58.53; H, 4.42; N, 13.65. Found: C, 58.51; H,
4.38; N, 13.60.
1
Entry 20 (4t). Solid, m.p. 185–187ꢀC, H NMR (CDCl3): d
1.21 (t, 3H, J ¼ 7.0 Hz), 2.24 (s, 3H), 2.56 (s, 3H), 2.71 (s,
6H, N(CH3)2), 4.12 (q, 2H, J ¼ 7.0 Hz), 4.69 (s,1H), 6.79 –
8.77 (m, 7H, ArAH), 9.31 (bs, 1H, NH), 11.04 (bs, 1H, NH).
EMS: m/z: 493 (Mþ). IR (KBr): m ¼ 3481, 1718, 1675, 1602,
1569, 1262. Anal. Calc. for C25H27N5O4S (493.18): C, 60.83;
H, 5.51; N, 14.19. Found: C, 60.82; H, 5.47; N, 14.15.
1
Entry 12 (4l). Solid, m.p. 213–214ꢀC, H NMR (CDCl3): d
1.19 (t, 3H, J ¼ 7.0 Hz), 2.37 (s, 3H), 2.65(s, 3H), 4.16 (q,
2H, J ¼ 7.0 Hz), 4.78 (s, 1H), 7.19–8.42 (m, 6H, ArAH), 9.75
(bs, 1H, NH), 10.95 (bs, 1H, NH). EMS: m/z: 424 (Mþ). IR
(KBr): m ¼ 3347, 1716, 1689, 1612, 1589. Anal. Calc. for
C21H20N4O6 (424.14): C, 59.43; H, 4.75; N, 13.20. Found: C,
59.41; H, 4.71; N, 13.18.
1
Entry 21 (4u). Solid, m.p. 165–165ꢀC, H NMR (CDCl3): d
1.12 (t, 3H, J ¼ 7.0 Hz), 2.46 (s, 3H), 4.26 (q, 2H, J ¼ 7.0
Hz), 4.79 (s, 1H), 6.86–8.82 (m, 8H, ArAH), 9.36 (bs, 1H,
NH), 10.89 (bs, 1H, NH), 11.14(bs, 1H, OH). EMS: m/z: 452
(Mþ). IR (KBr): m ¼ 3386, 1712, 1669, 1609, 1579, 1248.
Anal. Calc. for C22H20N4O5S (452.12): C, 58.40; H, 4.46; N,
12.38. Found: C, 58.39; H, 4.42; N, 12.35.
1
Entry 13 (4m). Solid, m.p.178–180ꢀC, H NMR (CDCl3): d
1.24 (t, 3H, J ¼ 7.0 Hz), 2.32 (s, 3H), 4.18 (q, 2H, J ¼ 7.0
Hz), 4.81 (s, 1H), 6.74–8.92 (m, 9H, ArAH), 9.42 (bs, 1H,
NH), 10.29 (bs, 1H, NH). EMS: m/z: 436 (Mþ). IR (KBr): m ¼
3489, 1717, 1689, 1602, 1591, 1242. Anal. Calc. for
C22H20N4O4S (436.12): C, 60.54; H, 4.62; N, 12.84. Found: C,
60.53; H, 4.58; N, 12.80.
1
Entry 22 (4v). Solid, m.p. 171–173ꢀC, H NMR (CDCl3): d
1.10 (t, 3H, J ¼ 7.0 Hz), 2.31 (s, 3H), 2.49(s, 3H), 4.08 (q,
2H, J ¼ 7.0 Hz), 4.74 (s, 1H), 6.69–8.66 (m, 7H, ArAH), 9.19
(bs, 1H, NH), 10.21 (bs, 1H, NH), 11.18 (bs, 1H,OH). EMS:
m/z: 466 (Mþ). IR (KBr): m ¼ 3402, 1718, 1688, 1598, 1563,
1253. Anal. Calc. for C23H22N4O5S (466.13): C, 59.22; H,
4.75; N, 12.01. Found: C, 59.21; H, 4.71; N, 12.00.
1
Entry 14 (4n). Solid, m.p. 161–163ꢀC, H NMR (CDCl3): d
1.10 (t, 3H, J ¼ 7.0 Hz), 2.22 (s, 3H), 2.46(s, 3H), 4.18 (q,
2H, J ¼ 7.0 Hz), 4.92 (s, 1H), 6.84–8.86 (m, 8H, ArAH), 9.82
(bs, 1H, NH), 10.46 (bs, 1H, NH). EMS: m/z: 450 (Mþ). IR
(KBr): m ¼ 3310, 1723, 1685, 1612, 1592, 1256. Anal. Calc.
for C23H22N4O4S (450.14): C, 61.32; H, 4.92; N, 12.44.
Found: C, 61.31; H, 4.88; N, 12.40.
Entry 15 (4o). Solid, m.p. 199–200ꢀC, 1H NMR (CDCl3):
d 1.09 (t, 3H, J ¼ 7.0 Hz), 2.39 (s, 3H), 4.24 (q, 2H, J
¼ 7.0 Hz), 4.86 (s, 1H), 6.89–8.87 (m, 8H, ArAH), 9.24
(bs, 1H, NH), 10.74 (bs, 1H, NH). EMS: m/z: 470 (Mþ).
IR (KBr): m ¼ 3320, 1721, 1686, 1608, 1584, 1262. Anal.
Calc. for C22H19ClN4O4S (470.93): C, 56.11; H, 4.07; N,
11.90; Cl, 7.53. Found: C, 56.05; H, 4.03;; N, 11.89; Cl,
7.43.
1
Entry 23 (4w). Solid, m.p. 212–214ꢀC, H NMR (CDCl3): d
1.14 (t, 3H, J ¼ 7.0 Hz), 2.29 (s, 3H), 4.21 (q, 2H, J ¼ 7.0
Hz), 4.58 (s, 1H), 7.16–8.59 (m, 7H, Ar-H), 9.28 (bs, 1H,
NH), 10.81 (bs, 1H, NH). EMS: m/z: 426 (Mþ). IR (KBr): m ¼
3326, 1723, 1665, 1612, 1598, 1264. Anal. Calc. for
C20H18N4O5S (426.1): C, 56.33; H, 4.25; N, 13.14. Found: C,
56.32; H, 4.22; N, 13.10.
1
Entry 24 (4x). Solid, m.p. 206–207ꢀC, H NMR (CDCl3): d
1.23 (t, 3H, J ¼ 7.0 Hz), 2.41 (s, 3H), 2.71 (s, 3H), 4.12 (q,
2H, J ¼ 7.0 Hz), 4.72 (s, 1H), 7.12–8.56 (m, 6H, ArAH), 9.89
(bs, 1H, NH), 10.89 (bs, 1H, NH). EMS: m/z: 440 (Mþ). IR
(KBr): m ¼ 3352, 1721, 1679, 1603, 1576, 1261. Anal. Calc.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2009
An Efficient Biginelli One-Pot Synthesis of New Benzoxazole-Substituted
Dihydropyrimidinones and Thiones Catalysed
123
[17] Shutalev, A. D.; Kishko, E. A.; Sivova, N.; Kuznetsov, A.
Y. Molecules 1998, 3, 100.
for C21H20N4O5S (440.12): C, 57.26; H, 4.58; N, 12.72.
Found: C, 57.25; H, 4.54; N, 12.70.
[18] Sridhar, D.; Arjun, M.; Jyothi, M.; Ravi Prasad, T.; Saraga-
pani, M. J Heterocyclic Chem 2006, 16, 99.
[19] Safak, C.; Simek, R.; Erol, K.; Vural, K. Pharmazie 1996, 51, 180.
[20] Cox, O.; Jackson, H.; Vanessa Vargas, A.; Adriana, B.; Julio
Colon, I.; Balacac Gonaliz, C.; de Leon, M. J Med Chem 1982, 25, 1378.
[21] Temiz, O.; Yalcin, I.; Sener, E.; Altanlar, N. Eur J Pharm
Sci 1999, 7, 153.
Acknowledgments. The authors are thankful to Principal, Uni-
versity College of Pharmaceutical Sciences, Kakatiya University,
Warangal, India, for affording facilities.
REFERENCES AND NOTES
[22] Temiz, O.; Sener, E.; Yalcin, I.; Altanlar, N. Archivder
Pharmazie 2003, 325, 283.
[1] Biginelli, P. Gazz Chim Ital 1893, 23, 360.
[2] Kappe, C. O. Tetrahedron 1993, 49, 6937.
[3] Atwal, K. S.; Rovnyak, G. C.; O’Reilly, B. C.; Schwartz, J.
J Org Chem 1989, 54, 5898.
[23] Gupta, R.; Gupta, A. K.; Paul, S.; Kachroo, P. L. Ind J
Chem 1995, 34B, 151.
[24] Yadav, J. S.; Subba Reddy, B. V.; Jagan Reddy, E.; Rama-
lingam, T. J Chem Res (S) 2000, 354.
[4] Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.;
Moreland, S.; Hedberg, A.; O’Reilly, B. C. J Med Chem 1991, 34, 806.
[5] Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.;
Moreland, S.; Gougoutas, J. Z.; O’Reilly, B. C.; Schwartz, J.; Malley,
M. F. J Med Chem 1992, 35, 3254.
[25] Adharvana Chari, M.; Syamasundar, K. J Mol Catal A
2004, 221, 137.
[26] Venkat Narsaiah, A.; Basak, A. K.; Nagaiah, K. Synthesis
2004, 8, 1253.
[6] Kappe, C. O.; Fabian, W. M. F. Tetrahedron 1997, 53,
2803.
[27] Amini, M. M.; Shaabani, A.; Bazgir, A. Catal Commun
2006, 7, 843.
[7] Snider, B. B.; Shi, Z. J Org Chem 1993, 58, 3828 and refer-
ences therein.
[28] Heravi, M. M.; Behbahani, F. K.; Zadsirjan, V.; Oskooie,
H. A. Heterocyclic Commun 2006, 12, 369.
[29] Chen, W.; Qin, S.; Jin, J. Catal Commun 2007, 8, 123.
[30] Legeay, J. C.; Vanden Eynde, J. J.; Bazureau, J. P. Tetrahe-
dron Lett 2007, 48, 1063.
[8] Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.;
Freyer, A. J.; De Brosse, C.; Mai, S.; Truneh, A.; Faulkner, D. J. J
Org Chem 1995, 60, 1182.
[9] Snider, B. B.; Chen, J.; Patil, A. D.; Freyer, A. Tetrahedron
Lett 1996, 37, 6977.
[31] Adharvana Chari, M.; Shobha, D.; Mukkanti, K. Catal
Commun 2006, 7, 787.
[10] Rama Rao, A. V.; Gurjar, M. K.; Vasudevan, J. J Chem
Soc Chem Commun 1995, 1369.
[32] Nishiguchi, T.; Kamio, C. J. J Chem Soc Perkin Trans
1989, 1, 707.
[11] Folkers, K.; Harwood, H. J.; Johnson, T. B. J Am Chem
Soc 1932, 54, 3751.
[33] Adharvana Chari, M.; Shobha, D.; Syamasundar, K. J Het-
erocyclic Chem 2007, 44, 929.
[12] Wipf, P.; Cunningham, A. Tetrahedron Lett 1995, 36, 7819.
[13] Folkers, K.; Johnson, T. B. J Am Chem Soc 1934, 56, 1180.
[14] O’Reilly, B. C.; Atwal, K. S. Heterocycles 1987, 26, 1185.
[15] Atwal, K. S.; O’Reilley, B. C.; Gougoutas, J. Z.; Malley,
M. F. Heterocycles 1987, 26, 1189.
[34] Breton, G. W. J Org Chem 1997, 62, 8952.
[35] Gupta, R.; Paul, S.; Gupta, R. J Mol Catal A: Chem 2007,
266, 50.
[36] Jain, S. L.; Prasad, V. V. D. N.; Sain, B. Catal Commun
2008, 9, 499.
[16] Shutalev, A. D.; Kuksa, V. A. Khim Geterotsikl Soedin
1997, 33, 105.
[37] Hommeltoft, S. I.; Ekelund, O.; Zavilla, J. Ind Eng Chem
Res 1997, 36, 3491.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet