Ferric chloride/tetraethyl orthosilicate as an efficient system for synthesis of dihydropyrimidinones by Biginelli reaction

Article abstract of DOI:10.1016/j.tet.2005.02.059

An efficient method for the Biginelli reaction of aldehydes, acetoacetate esters and urea employing tetraethyl orthosilicate in the presence of ferric chloride is described. These improved reaction conditions allow the preparation of a wide variety of substituted dihydropyrimidinones (including sterically encumbered ones) in high yields and purity under mild reaction conditions.

Full text of DOI:10.1016/j.tet.2005.02.059

Tetrahedron 61 (2005) 4275–4280
Ferric chloride/tetraethyl orthosilicate as an efficient system for
synthesis of dihydropyrimidinones by Biginelli reaction
Ivica Cepanec,
*
Mladen Litvi c´ , Anamarija Bartolin cˇ i c´ and Marija Lovri c´
BELUPO Pharmaceuticals, Research Department, Radni cˇ ka c. 224, 10000 Zagreb, Croatia
Received 28 October 2004; revised 27 January 2005; accepted 17 February 2005
Available online 17 March 2005
Abstract—An efficient method for the Biginelli reaction of aldehydes, acetoacetate esters and urea employing tetraethyl orthosilicate in the
presence of ferric chloride is described. These improved reaction conditions allow the preparation of a wide variety of substituted
dihydropyrimidinones (including sterically encumbered ones) in high yields and purity under mild reaction conditions.
q 2005 Elsevier Ltd. All rights reserved.
2
2
23
24
1
. Introduction
ZnI2, CdCl2, BiCl3 are active catalysts. The catalytic
effect of metal cations is even more pronounced with
methods based on metal salts with non-nucleophilic anions
1
The Biginelli reaction is a well-known, simple and
straightforward procedure for the synthesis of dihydropyri-
midinones by the three-component condensation of ali-
phatic or aromatic aldehyde, acetoacetate ester and urea.
Since dihydropyrimidinones exhibit significant biological
activity (e.g. as calcium channel blockers), their synthesis
has been the focus of much interest from organic and
2
5
15
26
27
such as LiClO , CuSO $5H O, Zn(OTf)2, Cu(OTf)2,
4
Al(HSO ) , BiONO3, or variuos lanthanide triflates,
4
29
2
2
8
4
3
3
0–32
Ln(OTf)3 (LnZYb, Sc, La).
catalysts are bismuth triflate
which allow the preparation of dihydropyrimidinones in
good to high yields at room temperature. Another effective
Biginelli reaction conditions employing stoichiometric
reagents are BF $Et O and catalytic AcOH/CuCl in
The most efficient
35
and trimethylsilyl triflate,
3
3,34
2
medicinal chemists. In its original version, the reaction is
conducted in boiling ethanol in the presence of catalytic
amounts of concentrated aqueous hydrochloric acid. This
simple procedure has been effective in a number of the
Biginelli reactions with simple unsubstituted, or para- and
3
2
3
6
37
38
refluxing THF, (CH ) SiCl (TMSCl), TMSCl/NaI, or
3
3
3
9
TMSCl/DMFA. Additionally, the Biginelli reaction can
be strongly accelerated by various ionic liquids in catalytic
amounts, e.g. 1-n-butyl-3-methylimidazolium tetrafluoro-
borate (BMImBF4). Finally the reaction can be performed
by simple heating a neat mixture of aldehyde, acetoacetate
3
–9
meta-substituted aldehydes and acetoacetate esters.
However, in cases of significant steric hindrance in both
counterparts the reaction yields drop drastically. In order to
improve the yield of dihydropyrimidinones, a few other
40
and urea (in slight excess) at 100–105 8C under solventless
conditions for a few hours with fair yields.
1
0
11
multistep approaches using aldehyde or acetoacetate
41
equivalents in modified Biginelli reactions have been
developed. Nevertheless, the original Biginelli reaction
offers the most simple, cost-effective and reasonable access
to these important compounds.
Although many of the above mentioned methods give pure
dihydropyrimidinone in good to excellent yields, in almost
all cases the model compounds were selected from simple
acetoacetate esters, either methyl or ethyl acetoacetate,
and, mainly, meta- and para-substituted aromatic aldehydes
with no significant steric demands. As a consequence, many
of these methods do not work with sterically encumbered
Biginelli counterparts.
During the last decade, several efficient methods based on
metal-catalysed Biginelli reaction have been reported.
Among the simple metal (and ammonium) salts with
1
2
13
14
16
21
nucleophilic anions, e.g. LiBr, NH Cl, NiCl $6H O,
4
15
2
2
1
4
FeCl $6H O,
3
CuCl $2H O,
2
Mn(OAc) $2H O, ZrCl4, InCl3, InBr3, ZnCl2,
CeCl $7H O,
3 2
20
2
2
1
7
18
19
3
2
In contrast to simple catalytic methods, those employing
suitable dehydrating agents have proved more effective,
even in the cases of more complicated dihydropyrimidi-
Keywords: Biginelli reaction; Dihydropyrimidinones; Ferric chloride;
Tetraethyl orthosilicate.
4
2
*
Corresponding author. Fax: C385 1 2408 074;
e-mail: ivica.cepanec@belupo.hr
nones. Thus, Kappe and coworkers described a simple,
effective and general method for Biginelli reaction based on
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.059

4276
I. Cepanec et al. / Tetrahedron 61 (2005) 4275–4280
Scheme 1.
Scheme 2.
ethyl polyphosphate (PPE) mediated reaction under quite
mild reaction conditions (refluxing THF). Moreover, it has
been found that the procedure can be further speeded-up
using microwave heating. Except the work from Kappe’s
group, not much attention has been paid to the synthetic
methods applicable to all kinds of dihydropyrimidinones,
including the sterically hindered ones.
(1a, 1 equiv), methyl acetoacetate (2a, 1.05 equiv), and urea
(1.2 equiv) in the presence of Si(OEt) (1 equiv) affording
5-methoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimi-
din-2(1H)-one (3a) in various yields (Scheme 2). Since the
4
4
3
model reaction catalysed by PhSO H performed in refluxing
3
acetonitrile (80 8C) or THF (65 8C) gave significantly lower
yields than in isopropanol, all other reactions in this study
were conducted in the latter reaction solvent. The results are
presented in Table 1.
We decided to study the Biginelli reaction based on
tetraethyl orthosilicate (Si(OEt) ) in the presence of a
4
suitable acid catalyst. Si(OEt) is an extremely efficient
4
Table 1. Catalyst effect in the model Biginelli reaction (Scheme 2)
reagent in the synthesis of sterically encumbered Schiff’s
bases. Since the generally accepted Biginelli reaction
4
4
a
b
Entry
Catalyst
(10 mol%)
Time (h)
Yield (%)
4
5–47
mechanism
(Scheme 1) involves the formation of
C]N bond from the parent aldehyde (I) and urea followed
by (protic or Lewis) acid-catalysed addition of acetoacetate
ester (II) to the protonated aryl(or alkyl)idene–urea (Ia) and
cyclodehydration (via Ib) yielding dihydropyrimidinones
(III), Si(OEt) might promote the reaction by accelerating
4
the formation C]N bond (rate-determining step).
1
2
–
37% HCl aq.
24
5
4
20
20
20
20
4
8
47
c
d
e
3
4
5
6
7
8
9
PhSO
NiCl
3
H
59 (51, 43 )
2
72
65
52
64
71
75
41
88
94
CeCl
ZnCl
3
2
AlCl
CuCl
Cu(OTf)
Fe(OAc)
3
2
2
4
The same effect was successfully employed in the synthesis
of 1,4-dihydropyridines, where Si(OEt)4 dramatically
accelerates the acid-catalysed Hantzsch condensation of
aldehyde, acetoacetate ester and ammonium acetate furnish-
1
1
1
0
1
2
2
24
2.5
4
FeCl
FeCl
3
f
3
a
4
8
The reactions were monitored by TLC until the disappearance of starting
methyl acetoacetate (2a).
Yields of isolated and recrystallised product (from 96% EtOH).
This reaction was carried out in refluxing 96% EtOH, representing the
classical Biginelli conditions.
In refluxing MeCN.
In refluxing THF.
Methyl acetoacetate (2a) was added dropwise to the reaction mixture at
reflux temperature during 2 h, plus 2 h additional heating.
ing very pure 1,4-dihydropyridines in excellent yields.
b
c
2
. Results and discussion
d
e
f
First, we examined the effect of various Lewis acids and
0 mol % PhSO H on the model reaction of benzaldehyde
1
3

I. Cepanec et al. / Tetrahedron 61 (2005) 4275–4280
4277
Scheme 3.
The Biginelli reaction in the presence of Si(OEt) is actually
4
mode of reactant addition, a significant further improvement
of the reaction yield was achieved (entry 12).
catalysed by all catalysts probed but with significant
differences in their activity. Although Cu(OTf)2 and
CuCl2 (entries 8 and 9) were quite effective catalysts,
This method was further studied in several model Biginelli
reactions of various aromatic (1a–g) or aliphatic (1h)
aldehydes, and trans-cinnamaldehyde (1i) as a,b-unsatu-
rated aldehyde with acetoacetate esters (2a–e) and urea to
give the respective dihydropyrimidinones (3a–m) in good to
high yields (Scheme 3). As the reaction proceeds, the silica
gel precipitates from the reaction mixture indicating the
progress of the Biginelli reaction. The results are presented
in Table 2.
anhydrous FeCl was selected as the most efficient. As one
3
could predict, the decreased yields in the Biginelli
condensation is caused mainly due to acetoacetate ester
polymerisation prior to reaction with urea–aldehyde adduct
(
Biginelli reaction pathway). To overcome this side-
reaction, methyl acetoacetate (2a) was added dropwise to
the refluxing reaction mixture of urea, benzaldehyde,
Si(OEt) and FeCl (10 mol %). Employing this reverse-
4
3
3 4
Table 2. Synthesis of dihydropyrimidinones 3a–m by anhydrous FeCl -catalysed Biginelli reaction in the presence of Si(OEt)
1
2
a
b
Entry
Product
R
R
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
Ph
Ph
Ph
Ph
2-O
4-O
2-CH
4-CH
1-Naphthyl
9-Anthryl
2-Pr
Me
Et
2-Pr
i-Bu
Bn
Me
Me
Me
Me
Me
Me
Me
Et
2.5
3
3
4
6 (4 )
10
4
4 (3 )
4
4
19
3.5
2
94
88
85
92
79 (86 )
81
86
c
c
2
NC
NC
6
H
H
4
2
6
4
d
d
3
OC
OC
6
H
4
73 (88 )
3
6
H
4
92
86
95
71
80
1
1
1
1
0
1
2
3
3j
3k
3l
3m
PhCH]CH
a
b
c
d
Determined by TLC.
Yields of recrystallised products (0.1 mol scale).
In 2-butanol as reaction solvent.
In cyclohexanol as reaction solvent.

4278
I. Cepanec et al. / Tetrahedron 61 (2005) 4275–4280
Aromatic aldehydes bearing both electron-donating and
electron-withdrawing groups readily undergo the reaction
giving fair yields of the corresponding Biginelli compounds.
Steric demands of ortho-substituted aromatic aldehydes and
larger alkyl-moieties in the acetoacetate esters are also well
tolerated. The choice of isopropanol (secondary alcohol) as
reaction solvent was optimal since the primary alcohols
such as methanol, abs. ethanol, or 1-propanol (slightly less)
led to the formation of transesterification by-products. For
example, when the reaction of methyl acetoacetate (2a),
benzaldehyde (1a) and urea was conducted in refluxing
anhydrous ethanol, a mixture of methyl- and ethyl-esters of
the respective 1,4-dihydropyrimidinone, 3a and 3b was
was refluxed with stirring for the time indicated in the
Table 1. The reaction mixture was evaporated to dryness. To
a residue, 96% ethanol (40 mL) was added, followed by
sodium hydroxide (0.40 g, 0.01 mol) and stirred at room
temperature for 1 h. Then, concentrated hydrochloric acid
(1.1 mL, 0.48 g HCl, 13 mmol, 1.3 equiv to NaOH) was
added and the resulting suspension was evaporated to
dryness. The solid residue was extracted with boiling
ethanol (3!20 mL) followed by (hot) filtration through a
celite. Combined filtrates were evaporated to dryness.
The reaction conducted with PhSO H, and the classical
3
Biginelli reaction with 37% HCl (aq.) performed in
refluxing ethanol were only evaporated to dryness.
1
isolated in almost equimolar ratio (determined by H NMR
spectroscopy). We believe that the transesterification side-
products are formed in relatively slower Biginelli reactions
by reaction of primary alcohols with the starting acetoace-
tate ester under the influence of FeCl as catalyst, prior to
3
the Biginelli condensation. The reaction of dihydropyrimi-
dinone 3a in refluxing ethanol in the presence of anhydrous
FeCl (10 mol %) did not afford the respective compound
3
3b at all. This clearly indicates that the transesterification
side-products are formed at the acetoacetate-stage. Accord-
The crude products were recrystallised from 96% ethanol
(6–8 mL) to give pure samples of 5-methoxycarbonyl-6-
methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one (3a) as
white crystals, mps in a range of 206–210 8C, all within
2
5
the interval of 2 8C (lit. mp 208–210 8C), and results are
presented in the Table 1. Analytical results (mp, IR, H and
1
1
3
C NMR) of products were identical to those reported in
the literature, and purities according to H NMR were
1
ing to our knowledge the FeCl -catalysed transesterification
3
generally O97%.
of acetoacetate esters has not been described so far. This
simple and interesting reaction is under investigation and
will be published elsewhere. Other secondary alcohols such
as 2-butanol or cyclohexanol can be also successfully used
as alternative reaction solvents since they give slightly
higher yields with sluggish Biginelli reactions, presumably
as a result of the higher temperatures that can be used
4.2. General procedure for the synthesis of
dihydropyrimidinones 3a–m
To a solution of anhydrous ferric chloride (1.62 g, 0.01 mol,
10 mol%) in 2-PrOH (100 mL) was added urea (7.21 g,
0.12 mol, 1.2 equiv), followed by solution of aldehyde 1a–i
(0.1 mol) in 2-PrOH (50 mL) and tetraethyl orthosilicate
(
entries 5 and 8).
(22.3 mL, 20.83 g, 0.01 mol, 1 equiv). The reaction mixture
was heated with stirring to a reflux temperature. Then, the
solution of acetoacetate ester 2a–e (0.105 mol, 1.05 equiv)
in 2-PrOH (50 mL) was added dropwise during 50% of
reaction time indicated in Table 2. Then the heating was
continued for the same additional period of time. The
reaction mixture was evaporated to dryness. To a residue,
96% ethanol (400 mL) was added, followed by sodium
hydroxide (4.00 g, 0.1 mol) and stirred at room temperature
for 1 h. Then, concentrated hydrochloric acid (11 mL,
3
. Conclusion
The Biginelli reaction can be efficiently performed employ-
ing tetraethyl orthosilicate as dehydrating agent in refluxing
isopropanol in the presence of catalytic amount of
anhydrous ferric chloride giving good to high yields of
pure dihydropyrimidinones.
4
.82 g HCl, 0.13 mol, 1.3 equiv to NaOH) was added and
4
. Experimental
the resulting suspension was evaporated to dryness. The
solid residue was extracted with boiling ethanol (3!
200 mL) followed by (hot) filtration through a celite.
Combined filtrates were evaporated to dryness. The crude
products were recrystallised from 96% ethanol to give
reasonably pure dihydropyrimidinones 3a–m whose
IR spectra were recorded on a Perkin-Elmer Spectrum One
1
13
spectrometer. H and C NMR spectra were recorded on a
AV Bruker (600 MHz) spectrometer, and shifts are given in
ppm downfield from TMS as an internal standard. TLC
analyses were performed on Merck’s (Darmstadt, Germany)
DC-alufolien with Kieselgel 60F254. Melting points were
determined using a B u¨ chi B-540 instrument.
1
purities, according to H NMR, were generally O97%.
Analytical results (mp, IR, H and C NMR) of products
1
13
2
5
25
49
20
20
20
3a, 3b, 3f, 3g, 3i, and 3m were identical to those
reported in the literature.
4.1. Synthesis of dihydropyrimidinones in the presence
of Si(OEt) and various Lewis acids and PhSO H
4.2.1. 5-Isopropyloxycarbonyl-6-methyl-4-phenyl-3,4-
dihydropyrimidin-2(1H)-one (3c). Colourless crystals;
mp 189.9–191.2 8C; yield 23.31 g (85%); Found: C, 65.4;
H, 6.4; N, 10.1. C H N O requires C, 65.68; H, 6.61; N,
4
3
To a solution of benzaldehyde (1a, 1.06 g, 0.01 mol),
methyl acetoacetate (2a, 1.22 g, 0.0105 mol, 1.05 equiv) in
1
5 18 2 3
2
1
0
-PrOH (20 mL) was added urea (0.72 g, 0.012 mol,
.2 equiv), tetraethyl orthosilicate (2.2 mL, 2.08 g,
.01 mol, 1 equiv), followed by metal salt: NiCl , CeCl ,
10.21; R (10% 2-PrOH/CH Cl ) 0.50; n
f
(KBr) 3251,
max
2
2
3120, 2980, 2939, 1722, 1706, 1651, 1468, 1423, 1385,
1348, 1314, 1289, 1227, 1091 cm ; dH (600 MHz,
K1
2
3
1
DMSO-d ) 9.12 ( H NMR, s, NH), 7.68 (1H, s, NH),
7.30–7.24 (2H, m, arom.), 7.22–7.12 (3H, m, arom.), 5.07
ZnCl , AlCl , CuCl , Cu(OTf) , Fe(OAc) or FeCl , or
2
PhSO H (1 mmol, 10 mol %) at once. The reaction mixture
3
3
2
2
2
3
6

I. Cepanec et al. / Tetrahedron 61 (2005) 4275–4280
4279
(
2
(
1H, d, JZ3.2 Hz, benzylic), 4.77–4.72 (1H, m, CHMe2),
.18 (3H, s, CH ), 1.09 (3H, d, JZ6.2 Hz, CH(CH ) ), 0.91
COOCH ), 2.42 (3H, s, CH ); d (600 MHz, DMSO-d6)
3 3 C
165.8, 151.9, 149.2, 139.9, 133.6, 130.1, 128.5, 128.0,
126.2, 125.7, 124.3, 124.0, 123.6, 98.8, 50.7, 49.8, 17.9.
3
3 2
3H, d, JZ6.2 Hz, CH(CH ) ); d (600 MHz, DMSO-d )
3 2 C 6
1
5
64.8, 152.1, 148.1, 145.0, 128.3, 127.2, 126.3, 99.6, 66.3,
4.1, 21.8, 21.4, 17.7.
4
3
.2.6. 5-Methoxycarbonyl-6-methyl-4-(9-anthracenyl)-
,4-dihydropyrimidin-2(1H)-one (3k). Colourless crys-
4
.2.2. 5-Isobutyloxycarbonyl-6-methyl-4-phenyl-3,4-
tals; mp 250.4–253.1 8C; yield 32.62 g (95%); Found: C,
2.6; H, 4.9; N, 7.9. C H N O requires C, 72.82; H, 5.24;
dihydropyrimidin-2(1H)-one (3d). Colourless crystals;
mp 143.7–145.8 8C; yield 26.52 g (92%); Found: C, 66.5;
H, 7.0; N, 9.6. C H N O requires C, 66.65; H, 6.99; N,
7
2
1 18 2 3
N, 8.09; R (10% 2-PrOH/CH Cl ) 0.58; n (KBr) 3351,
max
3228, 3108, 3052, 2948, 1694, 1639, 1526, 1488, 1453,
1430, 1372, 1309, 1234, 1189, 1158, 1143, 1101 cm ; dH
f
2
2
1
6
20
2
3
9
3
1
.72; R (10% 2-PrOH/CH Cl ) 0.53; n
(KBr) 3254,
121, 2963, 1721, 1707, 1682, 1648, 1464, 1421, 1393,
K1
f
2
2
max
(600 MHz, DMSO-d ) 9.46 (1H, s, NH), 8.57 (1H, s, NH),
6
K1
378, 1342, 1314, 1291, 1268, 1223, 1099 cm ; dH
8.51–8.49 (1H, m, arom.), 8.09 (2H, d, JZ8.6 Hz, arom.),
7.72–7.68 (1H, m, arom.), 7.65–7.47 (4H, m, arom.), 7.04–
6.99 (1H, m, arom.), 5.77 (1H, s, benzylic), 2.97 (3H, s,
COOCH ), 2.27 (3H, s, CH ); d (600 MHz, DMSO-d6)
166.3, 151.0, 146.5, 135.5, 131.6, 131.5, 129.8, 128.5,
126.2, 125.2, 124.7, 99.9, 50.6, 50.5, 18.2.
(
600 MHz, DMSO-d ) 9.17 (1H, s, NH), 7.69 (1H, s, NH),
6
7
5
.31–7.23 (2H, m, arom.), 7.22–7.13 (3H, m, arom.), 5.14–
.05 (1H, m, benzylic), 3.73–3.60 (2H, m, CO CH
2
2-
2-
3
3
C
CHMe ), 2.22 (3H, s, CH ), 1.73–1.65 (1H, m, CO CH
2
CHMe ), 0.75–0.62 (6H, m, CO CH CH(CH ) ); d
C
3
2
2
2
2
3 2
(
600 MHz, DMSO-d ) 165.3, 152.0, 148.7, 144.6, 128.4,
6
1
27.2, 126.2, 99.0, 69.2, 54.0, 27.2, 18.8, 17.8.
4
.2.7. 5-Methoxycarbonyl-6-methyl-4-isopropyl-3,4-
dihydropyrimidin-2(1H)-one (3l). Colourless crystals;
mp 211.8–213.9 8C; yield 15.09 g (71%); Found: C, 56.5;
H, 7.5; N, 13.2. C H N O requires C, 56.59; H, 7.60; N,
4.2.3. 5-Benzyloxycarbonyl-6-methyl-4-phenyl-3,4-dihy-
dropyrimidin-2(1H)-one (3e). Colourless crystals; mp
1
0 16 2 3
1
2
8
69.1–171.1 8C; yield 25.47 g (79%) in 2-PrOH, and
7.72 g (86%) in cyclohexanol; Found: C, 70.6; H, 5.6; N,
.5. C H N O requires C, 70.79; H, 5.63; N, 8.69; R
1
3
1
1
3.20; R (10% 2-PrOH/CH Cl ) 0.51; n
f
(KBr) 3364,
max
2
2
240, 3119, 3003, 2955, 2933, 2905, 2873, 1705, 1673,
650, 1463, 1428, 1381, 1341, 1285, 1233, 1179, 1159,
1
9
18
2
3
f
(
10% 2-PrOH/CH Cl ) 0.58; n
(KBr) 3357, 3219, 3115,
028, 2978, 2950, 1704, 1687, 1637, 1495, 1455, 1423,
2
2
max
K1
135, 1109, 1087 cm ; dH (600 MHz, DMSO-d ) 8.90
6
3
1
1
7
(
1H, s, NH), 7.27 (1H, s, NH), 3.97–3.94 (1H, m, benzylic),
3.59 (3H, s, COOCH ), 2.17 (3H, s, CH ), 1.72–1.62 (1H,
m, CHMe ), 0.81 (3H, d, JZ6.9 Hz, CH(CH ) ), 0.73 (3H,
378, 1321, 1294, 1265, 1223, 1176, 1138, 1105, 1084,
026 cm ; dH (600 MHz, DMSO-d ) 9.25 (1H, s, NH),
.75 (1H, s, NH), 7.36–7.20 (8H, m, arom.), 7.19–7.16 (2H,
K1
3
3
6
2
3 2
d, JZ6.8 Hz, CH(CH ) ); d (600 MHz, DMSO-d ) 166.2,
3
2
C
6
m, arom.), 5.22 (1H, d, JZ3.3 Hz, 4-CH), 5.09–5.02 (2H,
m, benzyls), 2.30 (3H, s, CH ); d (600 MHz, DMSO-d )
153.2, 148.6, 98.0, 55.6, 50.6, 34.5, 18.4, 17.7, 15.8.
3
C
6
1
1
65.0, 152.0, 149.2, 144.6, 136.5, 128.4, 128.2, 127.6,
27.5, 127.2, 126.3, 98.8, 64.8, 53.9, 17.8.
Acknowledgements
4
.2.4. 5-Methoxycarbonyl-6-methyl-4-(2-methoxyphe-
nyl)-3,4-dihydropyrimidin-2(1H)-one (3h). Colourless
crystals; mp 283.3–285.7 8C; yield 20.17 g (73%) in 2-
PrOH, and 24.31 g (88%) in 2-BuOH; Found: C, 60.7; H,
The authors wish to express their gratitude to the Belupo
Pharmaceuticals for financial support of this research.
5
1
3
1
.9; N, 10.0. C H N O requires C, 60.86; H, 5.84; N,
14 16 2 4
0.14; R (10% 2-PrOH/CH Cl ) 0.55; n (KBr) 3367,
max
f
2
2
263, 3109, 3023, 2964, 2952, 2837, 1700, 1643, 1598,
589, 1487, 1465, 1436, 1427, 1379, 1337, 1319, 1287K,
275, 1244, 1218, 1184, 1169, 1102, 1084, 1051, 1028 cm
References and notes
1
1
;
d (600 MHz, CDCl ) 9.16 (1H, s, NH), 7.27 (s, 1H, NH),
H
1. Kappe, C. O. Tetrahedron 1993, 49, 6938–6963.
2. Atwal, K. S.; Rovnyak, G. C.; Schwartz, J.; Moreland, S.;
Hedberg, A.; Gougoutas, J. Z.; Malley, M. F.; Floyd, D. M.
J. Med. Chem. 1990, 33, 1510–1515.
3
7
7
.24–7.21 (1H, m, arom.), 7.10–6.98 (2H, m, arom.), 7.24–
.21 (1H, m, arom.), 5.51–5.47 (1H, m, benzylic), 3.80 (3H,
s, OCH ), 3.47 (3H, s, COOCH ), 2.29 (3H, s, CH ); d
C
3
3
3
(
1
600 MHz, CDCl ) 165.9, 156.6, 152.3, 149.3, 131.2, 128.8,
3
26.8, 120.2, 111.3, 97.2, 55.4, 50.8, 48.8, 17.8.
3. Zigeuner, G.; Hamberger, H.; Blaschke, H.; Sterk, H.
Monatsch. Chem. 1966, 97, 1408–1421.
4
. Chiba, T.; Sato, H.; Kato, T. Heterocycles 1984, 22, 493–496.
4
.2.5. 5-Methoxycarbonyl-6-methyl-4-(1-naphthyl)-3,4-
5. Valpuesta-Fernandez, M.; L o´ pez Herrera, F. J.; Lupi o´ n Cobos,
T. Heterocycles 1988, 27, 2133–2140.
dihydropyrimidin-2(1H)-one (3j). Colourless crystals;
mp 233.8–236.0 8C; yield 25.47 g (86%); Found: C, 68.9;
H, 5.3; N, 9.3. C H N O requires C, 68.91; H, 5.44; N,
6. Hinkel, L. E.; Hey, D. H. Recl. Trav. Chim. 1929, 48,
1280–1286.
1
7 16 2 3
9
3
1
1
.45; R (10% 2-PrOH/CH Cl ) 0.57; n (KBr) 3363,
f
7. George, T.; Tahilramani, R.; Mehta, D. V. Synthesis 1975,
404–407.
2
2
max
244, 3119, 2951, 1699, 1645, 1603, 1511, 1463, 1427,
399, 1377, 1320, 1278, 1267, 1231, 1221, 1181, 1140,
8. Ertan, M.; Balkan, A.; Sara c¸ , C.; Uma, S.; R u¨ bseman, K.;
Renaud, J. F. Arzneim.-Forsch. 1991, 41, 725–727.
9. Konyukov, V. N.; Sakovich, G. S.; Krupnova, L. V.;
Pushkareva, Z. V. Zh. Org. Khim. 1965, 1, 1487–1489.
10. Abdel-Fattah, A. A. A. Synthesis 2003, 2358–2362.
K1
115, 1088, 1036 cm ; dH (600 MHz, DMSO-d ) 9.35
6
(
1H, s, NH), 8.35 (1H, d, JZ8.2 Hz, NH), 7.96 (1H, d, JZ
.6 Hz, arom.), 7.89–7.84 (2H, m, arom.), 7.63–7.42 (4H,
m, arom.), 6.10 (1H, d, JZ2.8 Hz, benzylic), 3.38 (3H, s,
7

4
280
I. Cepanec et al. / Tetrahedron 61 (2005) 4275–4280
30. Ma, Y.; Qian, C.; Wang, L.; Yang, M. J. Org. Chem. 2000, 65,
1
1
1
1. Singh, K.; Singh, J.; Deb, P. K.; Singh, H. Tetrahedron 1999,
5, 12873–12880.
2. Maiti, G.; Kundu, P.; Guin, C. Tetrahedron Lett. 2003, 44,
757–2760.
3. Shaabani, A.; Bazgir, A.; Teimouri, F. Tetrahedron Lett. 2003,
4, 857–860.
5
3864–3868.
31. Wang, L.; Qian, C.; Tian, H.; Ma, Y. Synth. Commun. 2003,
33, 1459–1468.
2
32. Dondoni, A.; Massi, A.; Minghini, E.; Sabbatini, S.; Bertolasi,
V. J. Org. Chem. 2003, 68, 6172–6183.
4
1
1
1
4. Lu, J.; Bai, Y. Synthesis 2002, 466–470.
5. Gohain, M.; Prajapati, D.; Sandhu, J. S. Synlett 2004, 235–238.
6. Bose, D. S.; Fatima, L.; Mereyala, H. B. J. Org. Chem. 2003,
3
3. R e´ pichet, S.; Zwick, A.; Vendier, L.; Le Roux, C.; Dubac, J.
Tetrahedron Lett. 2002, 43, 993–995.
3
3
3
4. Varala, R.; Alam, M. M.; Adapa, S. R. Synlett 2003, 67–70.
5. Bose, D. S.; Kumar, R. K.; Fatima, L. Synlett 2004, 279–282.
6. Hu, E. H.; Sidler, D. R.; Dolling, U.-H. J. Org. Chem. 1998,
68, 587–590.
1
1
7. Kumar, K. A.; Kasthuraiah, M.; Reddy, C. S.; Reddy, C. D.
Tetrahedron Lett. 2001, 42, 7873–7875.
6
3, 3454–3457.
7. Zhu, Y.; Pan, Y.; Huang, S. Synth. Commun. 2004, 34,
167–3174.
8. Reddy, C. V.; Mahesh, M.; Raju, P. V. K.; Ramesh Babu, T.;
Narayana Reddy, V. V. Tetrahedron Lett. 2002, 43,
3
3
3
3
2
657–2659.
9. Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65,
270–6272.
8. Sabitha, G.; Reddy, G. S. K. K.; Reddy, C. S.; Yadav, J. S.
Synlett 2003, 858–860.
1
2
2
6
9. Zavyalov, S. I.; Kulikova, L. B. Khim.-Farm. Zh. 1992, 26,
0. Fu, N.-Y.; Yuan, Y.-F.; Cao, Z.; Wang, S.-W.; Wang, J.-T.;
Peppe, C. Tetrahedron 2002, 58, 4801–4807.
1
655–1658.
4
0. Peng, J.; Deng, Y. Tetrahedron Lett. 2001, 42, 5917–5919.
1. Ranu, B. C.; Hajra, A.; Dey, S. S. Org. Proc. Res. Dev. 2002, 6,
1. Sun, Q.; Wang, Y.-q.; Ge, Z.-m.; Cheng, T. -m; Li, R.-t.
Synthesis 2004, 1047–1051.
4
8
17–818.
2
2. Jenner, G. Tetrahedron Lett. 2004, 45, 6195–6198.
3. Narsaiah, A. V.; Basak, A. K.; Nagaiah, K. Synthesis 2004,
4
4
2. Kappe, C. O.; Falsone, S. F. Synlett 1998, 718–720.
2
3. Kappe, C. O.; Kumar, D.; Varma, R. S. Synthesis 1999,
1
253–1256.
4. Ramaliga, K.; Vijayalakshmi, P.; Kaimal, T. N. B. Synlett
001, 863–865.
1
799–1803.
2
2
4
4. Love, B. E.; Ren, J. J. Org. Chem. 1993, 58, 5556–5557.
5. Folkers, K.; Johnson, T. B. J. Am. Chem. Soc. 1933, 55,
2
4
5. Yadav, J. S.; Reddy, B. V. S.; Srinivas, R.; Venugopal, C.;
Ramalingam, T. Synthesis 2001, 1341–1345.
3
784–3791.
6. Sweet, F.; Fissekis, J. D. J. Am. Chem. Soc. 1973, 95,
741–8749.
7. Kappe, C. O. J. Org. Chem. 1997, 62, 7201–7204.
, M.; Cepanec, I.; Vinkovi c´ , V. Heterocycl. Commun.
4
4
2
6. Xu, H.; Wang, Y.-G. Indian J. Chem. 2003, 42B, 2604–2607.
7. Paraskar, A. S.; DewKar, G. K.; Sudalai, A. Tetrahedron Lett.
8
2
2003, 44, 3305–3308.
48. Litvic
´
2
2
8. Khodaei, M. M.; Salehi, P.; Zolfigol, M. A.; Sirouszadeh, S.
Pol. J. Chem. 2004, 78, 385–388.
2003, 9, 385–390.
9. Reddy, Y. T.; Rajitha, B.; Reddy, P. N.; Kumar, B. S.; Rao,
V. P. Synth. Commun. 2004, 34, 3821–3825.
49. Tu, S.; Fang, F.; Miao, C.; Jiang, H.; Feng, Y.; Shi, D.; Wang,
X. Tetrahedron Lett. 2003, 44, 6153–6155.