Synthesis of Novel 3,4-Dihydropyrimidinones on Water Soluble Solid Support Catalyzed by Indium Triflate

Article abstract of DOI:10.1002/jhet.5570400521

Syntheses of several new 3,4-dihydropyrimidinones (DHPMs) on sodium sulfate solid support have been reported. The microwave enhanced rapid synthesis of the title compounds yielded a good percentage of the DHPMs. The catalytic activity of indium triflate e

Full text of DOI:10.1002/jhet.5570400521

Sep-Oct 2003
879
Synthesis of Novel 3,4-Dihydropyrimidinones on Water Soluble Solid
Support Catalyzed by Indium Triflate
P. Shanmugam, G. AnnieandP. T. Perumal*
Organic Chemistry Division, Central Leather Research Institute,
Adyar, Chennai-600 020, INDIA
Fax No. 91-044-2491 1589 E-mail: ptperumal@hotmail.com
Received February 18, 2003
Syntheses of several new 3,4-dihydropyrimidinones (DHPMs) on sodium sulfate solid support have been
reported. The microwave enhanced rapid synthesis of the title compounds yielded a good percentage of the
DHPMs. The catalytic activity of indium triflate enables to prepare a wide range of DHPMs. Syntheses of
2-hydroxyphenyl, 2-hydroxy-4-methoxyphenyl pendant groups on DHPMs scaffold are advantages of the
present method, which are rather prone towards cyclization and the presence of free hydroxyl groups on the
phenyl ring is confirmed via D O exchange study. The mechanism of the reaction is expected to proceed via
2
absorption of substrates on the solid support followed by promotion of the reaction by In(OTf) coupled with
3
microwave irradiation.
J. Heterocyclic Chem., 40, 879 (2003).
Introduction.
by Lewis acid catalyst In(OTf) and accelerated manifolds
3
by microwave rapid heating. Various water-soluble solid
supports like sodium chloride, magnesium sulfate and
sodium sulfate were screened in the preliminary experi-
The growing need for novel methods in organic synthe-
sis is unmitigated. Eco-benign versions of organic reac-
tions are potential candidates for the synthesis of biologi-
cally active compounds [1,2]. In contemporary research,
methods such as microwave assisted synthesis [3a], soni-
cation [3b], and solid-phase reaction [3c,d] are proliferat-
ing in all frontiers of organic syntheses. Among the afore-
said methods, microwave assisted rapid syntheses of
organic compounds on solid supports are found to meet the
increasing needs of organic chemists [4].
3,4-Dihydropyrimidinones (DHPMs) [5a,b], also called
Biginelli compounds possess interesting biological applica-
tions [5c-e]. The apparent structural similarities of DHPMs
to the well-known Hantzsch type dihydropyridines, cal-
cium channel modulators suggest a good scope for this
class of compounds in the field of medicinal chemistry
[6a,b]. The classical one-pot condensation [7] of ethyl ace-
toacetate, benzaldehyde and urea for the preparation of
DHPMs had been subjected to several improvements [8].
Different Lewis acid and metal ion catalysts were exploited
for the enhancement of the yields [9a-e]. However, it is
observed that the scope for syntheses of DHPMs containing
sensitive, bulky and interesting heterocyclic groups at C-4
position have not been explored so far.
ments using In(OTf) as the catalyst. Sodium sulfate was
3
found to be the optimum solid support over the rest.
Microwave irradiation of different aldehydes with 1 and 3
using In(OTf) as the catalyst on sodium sulfate solid sup-
3
port provided the best results. The catalytic activities of
various Lewis acids on this reaction were evaluated by
considering InCl , FeCl , and ZnCl and In(OTf) , indi-
3
3
2
3
vidually in the above-mentioned procedure on sodium sul-
fate solid support. Indium triflate was found to be better
over other catalysts based on the yields obtained for differ-
ent DHPMs.
In the present work DHPMs containing significant pen-
dant groups, unlike usual substituted aryl groups, are con-
sidered. However the method is suitable for synthesizing
DHPMs with usual aryl groups at C-4 position such as 2-
nitrophenyl, 4-chlorophenyl- 4-anisyl-, etc. as well.
Sensitive aldehydes such as salicylaldehyde, o-vanillin
and cyanobenzaldehyde were chosen to show the tolerabil-
ity of this method (Scheme 1, Table 1).
Results and Discussion.
Recently sodium sulfate supported reaction [10] has
been utilized for the synthesis of cyclophanes, which
encouraged us to probe into the application of the same to
synthesize DHPMs. In the present work, sodium sulfate is
used as the solid support along with 2 mol % of In(OTf)
3
to prepare DHPMs. The advantage of the method is that
the inert solid support can be easily removed by washing
with water and the crude reaction mixture can be purified
either by recrystallization or column chromatography,
leading to the desired products. The reaction is promoted

880
P. Shanmugam, G. AnnieandP. T. Perumal
Vol. 40
Table 1
Synthesis of DHPM Containing Sensitive and o-substituted Pendant Groups
1
2
3
Product
R
R
R
R
X
Irradiation Time (min)
Yield (%) [a,b]
4a
4b
4c
4d
4e
Me
Me
Me
Me
Ph
OEt
OEt
OEt
OEt
Me
OH
OH
H
Cl
Cl
H
O
O
O
S
11
13
15
8
91
87
93
86
89
OMe
CN
H
Cl
O
11
1
13
[a] yield of the product obtained by crystallization; [b] all the products were characterized by IR, H NMR, C NMR
and elemental analysis.
Interestingly, the products 4a,b (Table 1) were obtained
without cyclization as confirmed by IR and NMR spectra.
It is noteworthy to mention that 4a,b can not be prepared
by any of the previously reported one-pot condensation
methods due to tandem cyclization reaction (4f) [5a,11].
Atwal modification [12] a multi-step strategy to synthe-
size DHPMs, also does not afford the expected product
4a,b as it needs the Knoevenagel condensation product of
aldehyde and ethyl acetoacetate as the starting material.
But the Knoevenagel condensation does not stop with
enone product, which undergoes progressive cyclization to
form acylcoumarins (4g) [13].
Deuterium exchange study was carried out to confirm
that 4a,b synthesized through the present method are
uncyclized. H NMR spectra of the deuterium exchanged
Figure 1
1
However, this reaction requires excess of ethyl acetoac-
etate (3 moles) that enables acyliminium ion to intercept
with 1 to give product 6c. The heterocyclic aldehydes 5d,f
were prepared in the laboratory by following the reported
literature procedures through the Vilsmeier- Haack reac-
tion as they are not commercially available [14]. The alde-
hydes 5a-g when subjected to Biginelli reaction under
microwave irradiation yielded the required DHPMs 6a-g
in good percentage (Scheme 2, Table 2).
samples 4a,b do not contain three signals corresponding to
the two NH protons of DHPM skeleton and OH proton of
the phenyl ring. Deuterium exchange study authenticates
The products 4-quinolinyl-3,4-dihydropyrimidinone 6d
and 4-chromonyl-3,4-dihydropyrimidinone 6f are new in
the DHPM series reported as of now. The formation of 6d
is confirmed by proton resonance peaks at δ = 5.7 ppm (for
CH (4)) and NH protons resonating at δ = 9.39 ppm and δ
= 8.29 ppm. Similarly proton resonance peaks at δ = 5.22
ppm and NH protons resonating at δ = 9.39 ppm and δ =
8.1 ppm confirm the formation of 6g (Table 2). To synthe-
size 6d, conventionally, the necessary ingredients in acidi-
fied ethanolic solution were mixed and refluxed over oil
bath. However, the reaction yielded less than 30 % of
product after prolonged heating (>24 h) and excess of 1
(2.5 equiv).
It is presumed that the mechanism of the reaction pro-
ceeds via acyliminium ion as predicted by Kappe [15a].
The rate enhancement under microwave irradiation may
be attributed to the effective absorption of microwave by
polar sodium sulfate solid support thereby triggering the
reaction rate. In addition, the improved surface area and
that 4a,b have not undergone cyclization. The salient fea-
ture of this method is that the mild and environmentally
friendly reaction conditions employed by us enable the
preparation of DHPMs containing very sensitive aromatic
pendant groups. Synthesis of DHPM bearing benzonitrile
group, 4c lends additional support to the tolerability of
reaction conditions. IR (ν = 2229 cm ) and C NMR (δ =
116 ppm) spectra confirm the presence of cyano group in
4c (Table 1). The current procedure also yields good per-
centage of product when ortho-substituted aldehydes are
employed (4d and 4e).
-1
13
Attempts to synthesize 6c by any of the conventional lit-
erature reports result in poor yields, while the sodium sul-
fate supported synthesis afforded 6c in moderate yield.

Sep-Oct 2003
Synthesis of Novel 3,4-Dihydropyrimidinones
881
Table 2
Synthesis of DHPM Containing Different Aryl and Heterocyclic Pendant Groups
Entry
Y
Product
Irradiation Time (min)
Yield (%) [a]
1
2
3
4
5
6
7
Phenyl-
1-Naphthyl-
9-Anthryl-
2-Chloro-3-quinolyl
Thienyl-
6a
6b
6c
6d
6e
6f
8
15
30
15
9
91 [b]
84 [b]
63 [c,d]
76 [d]
85 [b]
81 [d]
83 [b]
6-Methoxy-3-chromonyl-
2-pyridyl-
21
13
6g
[a] All products were characterized by IR, NMR and MS techniques; [b] products obtained by recrystallization of crude product;
[c] 1:3:1.5 equivalents of anthraldehyde, ethyl acetoacetate, and urea were taken; [d] products obtained by column chromatography.
not dissolved). To this solution In(OTf) (0.106 g, 2 mol %) was
bringing the reagents in close proximity due to the pres-
ence of pores may be the reason for the rate enhancement
of the organic reactions by employing inorganic solid sup-
ported catalysts [15b].
3
added followed by 10 g of sodium sulfate and the mixture was
made into dry slurry. The slurry was transformed into 30 mL
Borosil bottle with tight screw cap, which was kept in an alumina
bath and irradiated in a domestic microwave oven for appropriate
time with a pulse rate of 40 sec. and 30 % of power. The total
consumption of aldehyde as monitored by TLC was an indication
of completion of the reaction. After the reaction was over, the
mixture was poured into 150 mL of water and heated over water
bath for 30 minutes followed by stirring one hour at room tem-
perature. The solid thus obtained in the reaction was collected by
filtration and column chromatographed with 1:3 petroleum ether
and ethylacetate mixture to give the required 4-phenyl-3,4-dihy-
dropyrimidinone. The same method was repeated for Magnesium
sulfate and Sodium chloride. Yields obtained on these solid sup-
ports are 90%, 56% and 67% respectively. For the optimization
Conclusion.
We have presented an environmentally friendly method
to synthesize DHPMs. The present study, in addition to
focus on usual aromatic aldehydes as building blocks to
prepare DHPMs, is also aimed at the aldehydes of sensi-
tive type (such as salicylaldehyde, o-vanillin and cyano
benzaldehyde), with bulky pendant groups (1-naphtha-
laldehyde and 9-anthraldehyde) and interesting heterocy-
cles (chromon-3-carboxaldehyde and quinolin-3-carbox-
aldehyde) to synthesize DHPMs. The fact that the DHPMs
with sensitive functional groups such as phenolics 4a,b
could be prepared by this method stands testimony to the
milder reaction conditions. An additional advantage of the
method is the solubility of sodium sulfate in water, making
the work-up methodology a convenient one. Sodium sul-
fate supported reaction would find enough scope in syn-
thetic organic chemistry as an eco-benign choice to
organic chemists.
of catalysts, ZnCl , InCl , FeCl and In(OTf) were considered.
2
3
3
3
Optimization of different catalysts on sodium sulfate solid sup-
port were performed and yields are 77%, 73%, 84%, and 91%
respectively; i.e. best with In(OTf) .
3
Ethyl 6-Methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one-5-
carboxylate (6a).
1
This compound has mp 198-199 °C; H NMR (CDCl +
3
DMSO-d ): δ 8.93 (s, 1H, NH(1)), 7.40 (s, 1H, NH(3)), 7.30 (m,
6
5H, Ar-H), 5.28 (s, 1H, CH(4)), 4.03 (q, J = 7.5 Hz, 2H, -
OCH CH ), 2.30 (s, 3H, 6-Me), 1.12 (t, 3H, J = 7.5 Hz, -
2
3
13
OCH CH ); C NMR: δ 165.53, 152.69, 144.64, 128.03,
EXPERIMENTAL
2
3
127.07, 126.29, 99.83, 59.23, 54. 41, 17.85, 13.83; IR (KBr)
-1
+
3310, 2950, 1728, 1700 cm ; MS (EI, m/z): 260 (M ).
Anal. Calcd. for C H N O : C, 64.60; H, 6.15; N, 10.76.
Melting points were determined in open capillary tubes and are
uncorrected. IR measurements were obtained as KBr pellets
using Perkin Elmer Spectrum RXI FT-IR. The H NMR and
14 16
2 3
1
13
Found: C, 64.85; H, 6.32; N, 10.78.
C
The above-mentioned procedure was followed for the other
remaining substituents to obtain DHPMs.
NMR were recorded in CDCl + DMSO-d with JEOL 400 MHz
3
6
(model GSX 400) high resolution NMR spectrometer with TMS
as an internal standard. Mass spectra were obtained using JEOL
DX- 303 in EI ionization mode at 70 eV. The reaction was carried
out in commercial BPL-SANYO microwave oven operating at
2.45 GHz. TLC was performed on precoated polygram SIL G/
Ethyl 6-Methyl-4-(2-hydroxyphenyl)-3,4-dihydropyrimidin-
2(1H)-one-5-carboxylate (4a).
1
This compound has mp 224-226 °C; H NMR (DMSO-d ): δ
6
9.57 (s, 1H, OH), 9.09 (s, 1H, NH (1)), 7.08 (t, 1H, J = 8 Hz, Ar-
H), 7.04 (d, 1H, J = 7.6 Hz, Ar-H), 6.97 (s, 1H, NH (3)), 6.79 (d,
1H, J = 8 Hz, Ar-H), 6.70 (t, 1H, J = 7.6 Hz, Ar-H), 5.47 (s, 1H,
UV sheets.
254
Optimization and General Method of Preparation of 4-Aryl-3,4-
dihydropyrimidinone.
CH (4)), 3.93 (q, 2H, J = 6.8 Hz, CH CH ), 2.29 (s, 3H, 6- Me),
3
2
1
Benzaldehyde (1 g, 9.43 mmol), ethylacetoacetate (1.84 g,
14.15 mmol) and urea (0.6792 g, 11.32 mmol) were dissolved in
10 mL of chloroform (a few drops of methanol is added if urea is
1.04 (t, 3H, J = 7.2 Hz, CH CH - ); H NMR (DMSO-d + D O):
3 2 6 2
δ 7.08 (t, 1H, J = 8 Hz, Ar-H), 6.99 (d, 1H, J = 7.6 Hz, Ar-H)),
6.82 (d, 1H, J = 8.0 Hz, Ar-H), 6.74 (q, 1H, J = 7.6 Hz, Ar-H),

882
P. Shanmugam, G. AnnieandP. T. Perumal
Vol. 40
5.49 (s, 1H, CH (4)), 3.93 (q, 2H, J = 6.8 Hz, CH CH ), 2.29 (s,
Ethyl 4-(1-Naphthyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-
one-5-carboxylate (6b).
3
2
13
3H, 6-Me), 1.04 (t, 3H, J = 7.2 Hz, CH CH -); C NMR: δ
3
2
166.52, 155.09, 153.70, 149.32, 130.01, 118.73, 111.84, 98.79,
1
This compound has mp 243-245 °C; H NMR (DMSO-d ): δ
6
-1
60.21, 49.86, 18.29, 14.67; IR (ν, cm ): 3410, 3343, 3108, 2915,
9.05 (s, 1H, NH (1)), 8.21 (m, 1H Ar-H), 7.39 (m, 7H, Ar-H),
6.06 (s, 1H, CH(4)), 3.77 (q, 2H, J = 7.2 Hz, CH CH -), 2.29 (s,
+
1660, 1592, 1488. MS (EI, m/z): 275 (M - 1).
3
2
Anal. Calcd. for C H N O : C, 60.85; H, 5.84; N, 10.14.
-1
14 16
2 4
3H, 6- Me), 1.12 (t, 3H, J = 7.3, CH CH - ); IR (ν, cm ): 3336,
3
2
Found: C, 60.74; H, 5.47; N, 10.12.
3226,3110,1694,1636.
Anal. Calcd. for C H N O : C, 69.65; H, 5.85; N, 9.03.
Ethyl 6-Methyl-4-(4-methoxy-2-hydroxyphenyl)-3,4-dihydropy-
rimidin-2(1H)-one-5-carboxylate (4b).
18 18
2 3
Found: C, 69.35; H, 5.91; N, 8.87.
1
Ethyl 4-(9-Anthryl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one-
5-carboxylate (6c).
This compound has mp 204-206 °C; H NMR (DMSO-d ):
6
δ 9.08 (s, 1H, OH), 8.72 (s, 1H, NH (1)), 7.05 (s, NH (3)), 6.84
(d, 1H, J = 8 Hz, Ar-H), 6.68 (q, 1H, J = 7.6 Hz, Ar-H), 6.61 (q,
1H, J = 7.6 Hz, Ar-H), 5.52 (s, 1H, CH (4)), 4.17 (q, 2H, J =
1
This compound has mp 235-237 °C; H NMR (DMSO-d ): δ
6
9.41 (s, 1H, NH (1)), 8.58 (d, 2H, J = 6.8 Hz), 8.42 (s, 1H,
NH(3)), 8.08 (d, 2H, J = 6.8 Hz), 7.71 (s, 1H, Ar-H), 7.50 (d, 4H,
J = 6.8 Hz), 7.01 (s, 1H, CH(4)), 3.35 (q, 2H, J= 6.8 Hz,
6.8 Hz, CH CH -), 3.93 (s, 3H, -OMe), 2.27 (s, 3H, 6-Me),
3
2
1
1.03 (t, 3H, J = 7.2 Hz, CH CH -); H NMR (DMSO-d
3
2
6
+D O): δ 6.84 (d, 1H, J = 8 Hz, Ar-H), 6.68 (q, 1H, J = 7.6 Hz,
Ar-H), 6.61 (q, 1H, J = 7.6 Hz, Ar-H), 5.20 (s, 1H, CH (4)),
3.92 (q, 2H, J = 6.8 Hz, CH CH -), 3.73 (s, 3H, -OMe), 2.29
(s, 3H, 6- Me), 1.03 (t, 3H, J = 7.2 Hz, CH CH - ): C NMR:
δ 166.88, 153.70, 149.32, 148.37, 144.04, 130.49, 120.04,
2
CH CH -), 2.24 (s, 3H, 6- Me), 0.18 (t, 3H, J = 6.8 Hz, CH CH -
3
2
3
2
-1
); IR (ν, cm ): 3483, 3387, 3331, 2923, 1693, 1640,1445. MS
(EI, m/z): 360 (M ).
+
3
2
13
3
2
Anal. Calcd. for C H N O : C, 73.30; H, 5.60; N, 7.78.
22 20
2 3
Found: C, 72.97; H, 5.63; N, 7.81.
119.73, 111.84, 99.28, 60.64, 56.71, 49.71, 18.45, and 14.82.
IR (ν, cm ): 3380, 3235, 3108, 2937, 1693, 1644, and 1488.
Ethyl 4-(2-Chloro-3-quinolinyl)-6-methyl-3,4-dihydropyrim-
idin-2(1H)-one-5-carboxylate (6d).
-1
+
MS (m/z): 306 (M ).
Anal. Calcd. for C
Found: C, 58.63; H, 5.81; N, 9.12.
H N O : C, 58.82; H, 5.92; N 9.15.
15 18 2 5
1
This compound has mp > 265 °C (decomp); H NMR (DMSO-
d ): δ 9.39 (s, 1H, NH (1)), 8.29 (s, 1H, NH (3)), 8.09 (d, 1H, J =
6
Ethyl 4-(4-Cyanophenyl)-6-methyl-3,4-dihydropyrimidin-
2(1H)-one-5-carboxylate (4c).
8.4 Hz), 7.95 (d, 1H, J = 8.4 Hz, Ar-H), 7. 79 (m, 2H, Ar-H), 7.63
(q, 1H, J = 7.2 Hz, Ar-H), 5.75 (s, 1H, CH (4)), 3.86 (q, 2H, J =
7.2 Hz, CH CH )), 2.38 (s, 3H, 6-Me), 0.94 (t, 3H, J = 7.2 Hz,
1
This compound has mp 180-182 °C; H NMR (DMSO-d ): δ
6
3
2
13
9.21 (s, 1H, NH (1)), 7.75 (s, 1H, NH (3)), 7.67 (d, 2H, J = 8.3
Hz, Ar-H), 7.45 (d, 2H, J = 8.3 Hz, Ar-H), 5.28 (s, 1H, CH(4)),
4.01 (q, 2H, J = 7.3 Hz, CH CH -), 2.29 (s, 3H, 6- Me), 1.12 (t,
CH CH ); C NMR δ: 165.76, 148.34, 139.86, 133.67, 130.26,
3
2
128.60, 128.00, 126.16, 125.62, 125.50, 95.58, 59.37, 50.41,
-1
18.20, 13.88; IR (ν, cm ): 3490, 3331, 3232, 2915, 1697, 1638,
3
2
13
+
3H, J = 7.3 Hz, CH CH -); C NMR: δ 163.55, 150.52, 148.37,
and 1443. MS (EI, m/z): 344 (M ).
3
2
147.49, 130.52, 125.80, 116.90, 108.81, 96.85, 57.70, 52.48,
Anal. Calcd. for C H N O Cl: C, 59.12; H, 4.67; N, 12.17.
17 16
3 3
-1
16.39, and 12.45; IR (ν, cm ): 3233, 3111, 2929, 2229, 1735,
Found: C, 59.02; H, 4.74; N, 12.29.
1708, 1648.
Ethyl 4-(2-Thienyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one-
5-carboxylate (6e).
Anal. Calcd. for C H N O : C, 63.15; H, 5.30; N, 14.73;
15 15
3 3
Found: C, 63.12; H, 5.19; N, 14.70.
1
This compound has mp 215-217 °C; H NMR (DMSO-d ): δ
6
Ethyl4-(2-Chlorophenyl)-6-methyl-2-thioxo-3,4-dihydropyrim-
idin-2(1H)-one-5-carboxylate (4d).
9.33 (s, NH (1)), 7.92 (s, NH (3)), 7.35 (d, 1H, J = 4.9 Hz, Ar-H),
6.94 (d, 1H, J = 3.54 Hz, Ar-H), 6.89 (d, 1H, J = 10.2 Hz, Ar-H),
5.41 (d, 1H, J = 3.54 Hz, CH(4)), 4.01 (q, 2H, J = 7.1 Hz,
CH CH -), 2.22 (s, 3H, 6- Me), 1.15 (t, 3H, J = 7.1 Hz, CH CH -
This compound has mp 168-168 °C; IR (KBr) 3235, 3050,
-1 1
1674, 1636 cm ; H NMR (CDCl + DMSO-d ): δ 1.02 (t, 3H, J
3
6
3
2
3
2
-1
= 7.6 Hz, -OCH CH ), 2.45 (s, 3H, 6-Me), 3.98 (q, 2H, J = 7.6
); IR (ν, cm ): 3344, 3250, 2922, 1696, 1646 , 1484. MS (EI,
m/z): 266 (M ).
2
3
+
Hz, -OCH CH ), 5.90 (d, 1H, J = 2.7 Hz, 4 - CH), 7.34 (s, 1H,
2
3
NH (3)), 7.36 - 7.41 (m, 4H, Ar-H), 8.25 (s, 1H, NH (1)).
Anal. Calcd. for C H N O S: C, 54.12; H, 5.30; N, 10.52.
Found: C, 54.08; H, 5.26; N, 10.39.
12 14
2 3
Anal. Calcd. for C H ClN O S: C, 54.10; H, 4.86; N, 9.01.
14 15
2 2
Found: C, 54.18; H, 4.88; N, 8.99.
Ethyl 4-(6-Methoxy-3-chromonyl)-6-methyl-3,4-dihydropyrim-
5-Acetyl-4-(2,4-dichlorophenyl)-6-phenyl-3,4-dihydropyrim-
idin-2(1H)-one-5-carboxylate (6f).
idin-2(1H)-one (4e).
1
This compound has mp > 250 °C (decomp); H NMR (DMSO-
1
This compound has mp 220-222 °C; H NMR (DMSO-d ): δ
d ): δ 9.23 (s, 1H, NH (1)), 8.15 (s, 1H, NH (3)), 7.61 (d, 1H, J =
6
6
1.67 (s, 3H), 5.43 (d, 1H, J = 3.5Hz), 6.84 (s, 1H, NH(3)), 7.42-
7.65 (m, 6H), 7.76 - 8.13 (m, 2H), 9.39 (s, 1H, NH(1)). C NMR
9.2 Hz, Ar-H), 7.46 (d, 1H, J = 3.2 Hz, Ar-H), 7.38 (q, 2H, J = 3.2
Hz & 9.2 Hz, Ar-H), 7.21 ( s, 1H, pyran-H), 5.23 (s, 1H, CH(4)),
13
δ: 19.43, 55.08, 108.32, 121.56, 122.94, 127.95, 128.30, 129.20,
3.97 (q, 2H, J = 6.8 Hz, CH CH -), 3.86 (s, 3H, Ar-OMe), 2.25
3
2
13
129.33, 130.80, 132.08, 133.63, 142.21, 147.51, 148.04, 148.65,
(s, 3H, 6- Me), 1.07 (t, 3H, J = 6.8 Hz, CH CH - ); C NMR: δ
3
2
-1
152.23, 195.06. IR (ν, cm ): 3315, 3154, 2924, 1716, 1694,
161.58, 158.09, 155.02, 151.16, 150.11, 147.98, 138.94, 137.12,
124.13, 119.26, 117.32, 109.58, 97.85, 60.12, 57.82, 53.48,
1643.
-1
Anal. Calcd. for C H Cl N O : C, 59.99; H, 3.92; N, 7.78.
17.49, 13.92; IR (ν, cm ): 3435, 3233, 3069, 2922, 1720, 1672,
18 14
2 2 2
Found: C, 59.83; H, 3.95; N, 7.71.
1624. MS (EI, m/z): 358.

Sep-Oct 2003
Synthesis of Novel 3,4-Dihydropyrimidinones
883
Acc. Chem. Res. 33, 879 (2000); [c] C. O. Kappe, Eur. J. Med. Chem., 35,
1043 (2000); [d] L. E. Overman, M. H. Rabinowitz and P. A. Renhowe,
J. Am. Chem. Soc., 117, 2657 (1995); [e] B. B. Snider and Z. Shi, J. Org.
Chem., 58, 3828 (1993).
[6a] G. C. Rovnyak, K. S. Atwal, A. Hedberg, S. D. Kimball, S.
Moreland, J. Z. Gougoutas, B. C. O’Reilly, J. Schwartz, and M. F. Malley,
J. Med. Chem., 35, 3254 (1992); [b] G. C. Rovnyak, S. D. Kimball, B.
Beyer, G. Cucinotta, J. D. DiMarco, J. Z. Gougoutas, A. Hedberg, M.
Malley, J. P. McCarthy, R. Zhang, and S. Moreland, J. Med. Chem., 38,
119 (1995).
[7a] P.Biginelli, Gazz. Chim. Ital., 23, 360 (1893); [b] K. Folkers,
and T. B. Johnson, J. Am. Chem. Soc., 55, 3781 (1933).
[8a] A. D. Shutalev, E. A. Kishko, N. V. Sivova, A. Yu. and A.
Kuznetsov, Molecules, 3, 100 (1998); [b] P. Wipf, and A. Cunningham,
Tetrahedron Lett., 36, 7819 (1995).
Anal. Calcd. for C H N O : C, 60.33; H, 5.06; N, 7.82.
Found: C, 60.19; H, 5.21; N, 7.73.
Ethyl 4-(2-Pyridyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-
18 18
2 6
one-5-carboxylate (6g).
This compound has mp 212 - 214 °C; H NMR (DMSO-d ): δ
1
6
9.51 (m, 2H), 9.17 (s, 1H, NH (1)), 8.06 (s, 1H, NH (3)), 7.38 (m,
2H), 5.41 (s, 1H, CH(4)), 3.96 (q, 2H, J = 6.84 Hz, CH CH -),
3
2
13
2.24 (s, 3H, 6- Me), 1.11 (t, 3H, J = 6.84 Hz, CH CH - );
C
3
2
NMR: δ 165.02, 159.54, 151.20, 148.62, 126.11, 123.06, 122.50,
-1
121.42, 94.69, 58.38, 45.92, 17.66, 13.97; IR (ν, cm ): 3422,
3210, 3072, 2932, 1718, 1675, 1625.
Anal. Calcd. for C H N O : C, 59.76; H, 5.79; N, 16.08.
13 15
3 3
Found: C, 59.70; H, 5.83; N, 15.99.
[9a] E. H. Hu, D. R Sidler, and U.- H. Dolling, J. Org. Chem., 63,
3454 (1998); [b] B. C. Ranu, A. Hajra, and U. Jana, J. Org. Chem., 65,
6270 (2000); [c] J. Lu, and Y. Bai, Synthesis, 466 (2002); [d] K. A.
Kumar, M. Kasthuraiah, C. S. Reddy, and C. D.Reddy, Tetrahedron Lett.,
42, 7873 (2001); [e] Y. Ma, C. Qian, L. Wang, and M. Yang, J. Org.
Chem., 65, 3864 (2000).
[10] P. Rajakumar, andV.Murali, Chem. Commun., 2710 (2001).
[11] J. Svetlik, V. Hanus, and J. Bella, J. Chem. Research (M), 4
(1991).
Acknowledgment.
This work was supported by Council of Scientific and
Industrial Research (CSIR), New Delhi, India.
REFERENCES AND NOTES
[1] A. Studer, S. Hadida, R. Ferritto, S. -Y. Kim, P. Jeger, P. Wipf
andD. P. Curran, Science, 275, 823 (1997).
[12] B. C. O’Reilly, and K. S. Atwal, Heterocycles, 26, 1185
(1987).
[2] J. S. Wilkes, Green Chem., 4, 73 (2002).
[3a] B. C. Ranu, A. Hajra and U. Jana, Tetrahedron Lett., 41, 531
(2000); [b] Y. Peng and G. Song, Green Chem., 4, 349 (2002); [c] B. C.
Ranu, A. Hajra and U. Jana, Org. Lett., 1, 1141 (1991); [d] G. A.
Strohmeier and C. O. Kappe, J. Comb. Chem. 4, 154 (2002).
[4a] N. Kuhnert, Angew. Chem. Int. Ed., 41, 1863 (2002); [b] C. O.
Kappe, Am lab, 13 (2001).
[13] R. Jones, Org. React., 15, 250 (1967).
[14a] O. Meth-Cohn, B. Narine, and B. Tarnowski, J. Chem. Soc.,
Perkin Trans. 1, 1520 (1981); [b] A. Nohara, T. Umetani, and Y.Sanno,
Tetrahedron, 30, 3553 (1974).
[15a] C. O. Kappe, J. Org. Chem., 62, 7201 (1997); [b] J. R. Hwu,
M. L. Jain, F.-Y. Tsai, S.-C. Tsay, A. Balakumar, and G. H. Hakimelahi, J.
Org. Chem., 65, 5077 (2000).
[5a] C. O. Kappe, Tetrahedron, 49, 6937 (1993); [b] C. O. Kappe,