Ultrasound-accelerated synthesis of 3,4-dihydropyrimidin-2(1H)-ones with ceric ammonium nitrate

Article abstract of DOI:10.1039/b102565c

Ceric ammonium nitrate efficiently catalyzes the three component condensation of an aldehyde, β-ketoester and urea in methanol to afford the corresponding dihydropyrimidinones in excellent yields under sonication. Other oxidants such as manganese triaceta

Full text of DOI:10.1039/b102565c

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Ultrasound-accelerated synthesis of 3,4-dihydropyrimidin-2(1H)-
ones with ceric ammonium nitrate†
Jhillu S. Yadav,* Basi V. Subba Reddy, Kasireddy Bhaskar Reddy, Kavuda Sarita Raj
and Attaluri R. Prasad
1
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad, 500 007,
India. E-mail: yadav@iict.ap.nic.in; Fax: ϩ91-040-7170512
Received (in Cambridge, UK) 19th March 2001, Accepted 26th June 2001
First published as an Advance Article on the web 27th July 2001
Ceric ammonium nitrate efficiently catalyzes the three component condensation of an aldehyde, β-ketoester and urea
in methanol to afford the corresponding dihydropyrimidinones in excellent yields under sonication. Other oxidants
such as manganese triacetate and Oxone were also found to catalyze this transformation under similar conditions.
Introduction
the presence of CAN in methanol under sonication resulted in
the formation of 3,4-dihydropyrimidin-2(1H)-one in 92% yield.
Similarly, the treatment of several aromatic, aliphatic and
heterocyclic aldehydes with ethyl acetoacetate and urea gave
the corresponding dihydropyrimidinones in excellent yields
4
-Aryldihydropyrimidinones are known to exhibit a wide range
1
of biological activities such as antiviral, antitumor, anti-
bacterial and antiinflammatory properties. In addition, these
compounds have emerged as potent calcium channel blockers,
antihypertensives, α -adrenergic antagonists and neuropeptide
2
(
Scheme 1).
1a
antagonists. Furthermore, the 2-oxodihydropyrimidine-5-
carboxylate core unit is found in many marine natural prod-
3
ucts, including batzelladine alkaloids, which have been found
to be potent HIV gp-120-CD inhibitors. The simple and direct
4
4
method, originally reported by Biginelli, for the synthesis of
dihydropyrimidinones often suffers from low yields of products
5
in the case of substituted aromatic and aliphatic aldehydes.
Scheme 1
6
Subsequent multi-step syntheses produced somewhat higher
yields but these lack the simplicity of the original one-pot
Biginelli protocol. Therefore, the Biginelli reaction continues to
attract the attention of researchers in the hope of discovering
milder and efficient procedures for the synthesis of dihydro-
pyrimidinones. Recently, several improved procedures have
The cyclocondensation proceeded smoothly under sonication
to give the products in high to quantitative yields. Owing to the
vibrational energy of the water, the bath temperature reached
55–60 ЊC under sonication. Many of the pharmacologically
relevant substitution patterns on the aromatic ring could be
introduced with high efficiency. Aromatic aldehydes carrying
either electron-donating or electron-withdrawing substituents
reacted well under sonication to give the corresponding dihydro-
pyrimidinones in high yields with high purity. Acid-sensitive
aldehydes like 2-furaldehyde and phenylacetaldehyde worked
well without the formation of any side products, which are
generally observed under strongly protic or Lewis acidic con-
ditions. Another important feature of this procedure is the
survival of a variety of functional groups such as olefins, ethers,
esters, nitro groups and halides under the present reaction
conditions.
7
been reported using Lewis acids as well as protic acids as
promoters. However, in spite of their potential utility, many of
these methods involve expensive reagents, stoichiometric
amount of catalysts, strongly acidic conditions, longer reaction
times, high temperatures, unsatisfactory yields and incompat-
ibility with other functional groups. Therefore, the development
of a neutral alternative would extend the scope of the useful
Biginelli reaction. Recently, ultrasound has become a very
8
useful tool in organic synthesis. It has been used to enhance
9
reaction rates in a large number of classical organic reactions.
Even though ultrasound has been used extensively in organic
synthesis, it has not been employed to improve the one-pot
Biginelli reaction. In recent years, ceric ammonium nitrate has
In addition to its simplicity and milder reaction conditions,
this method is even effective with aliphatic and α,β-unsaturated
aldehydes, which normally produce poor yields because of their
decomposition or polymerization under strongly acidic con-
ditions. Unlike the reported methods, the present procedure
10
emerged as a powerful one-electron transfer catalyst in many
carbon–carbon bond forming reactions. It has also been widely
used in carbon–hetero atom bond formation. However, the use
of CAN as a catalyst in the synthesis of pyrimidinones under
neutral conditions has not been reported. In this report we
describe an ultrasound-accelerated synthesis of pyrimidinones
using a catalytic amount of ceric ammonium nitrate under
sonic waves.
7e
does not require any additives or acidic promoters
or
anhydrous conditions. The procedure not only preserves the
simplicity of the Biginelli reaction but also gives excellent yields
of the products.
The reaction rates and yields were dramatically enhanced by
ultrasound. The rate enhancement under ultrasound may be
9
attributed to the cavitation and the activation of the catalyst
Results and discussion
by sonic waves. In the absence of sonic waves, the products were
formed in moderate yields (55–70%) in the presence of 10%
CAN in refluxing methanol after a long reaction time (8–12 h).
However, the reaction did not proceed in the absence of ceric
The reaction of benzaldehyde, ethyl acetoacetate and urea in
†
IICT Communication No. 4728.
DOI: 10.1039/b102565c
J. Chem. Soc., Perkin Trans. 1, 2001, 1939–1941
This journal is © The Royal Society of Chemistry 2001
1939

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a
b
Table 1 Ceric ammonium nitrate catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones under sonication
1
c
c
d
11
Compound 3
R
R
Time /h
Yield (%)
Observed melting point/ЊC (literature)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
C H
4-ClC H
CH3
CH3
CH3
CH3
CF3
CH3
CH3
CF3
CH3
CF3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
3.5 (5.0)
4.0 (6.5)
6.0 (6.0)
3.0 (4.5)
4.0 (5.0)
5.0 (7.5)
4.5 (6.0)
5.0 (8.0)
7.0 (9.5)
4.5 (4.0)
3.5 (5.0)
4.0 (5.5)
3.5 (3.0)
3.0 (4.5)
3.5 (4.0)
4.0 (6.0)
3.5 (4.5)
92 (88)
89 (85)
91 (87)
90 (92)
88 (80)
90 (83)
84 (78)
88 (81)
85 (73)
90 (85)
87 (80)
85 (82)
90 (78)
87 (73)
85 (77)
88 (70)
90 (85)
201–203 (203)
212–213 (214)
194–195 (195–196)
176–177 (177)
154–155 (156–157)
221–223 (223)
247–249 (248)
168–170 (—)
206–208 (208)
220–221 (—)
6
5
6
4
C H CH
6
5
2
3,4-(MeO) C H
4-MeOC H
3,4-Cl C H
2-Naphthyl
4-MeC H
4-NO C H
3,4-Methylenedioxyphenyl
Cyclohexyl
Cinnamyl
Thienyl
Furfuryl
Hexyl
4-N,N-(CH ) NC H
3,4,5-(MeO) C H
2
2
6
3
6
4
2
6
3
6
4
2
6
4
235–236 (235–237)
241–243 (242–244)
206–208 (208)
205–206 (205)
152–153 (151–152)
256–257 (257–258)
216–218 (217–219)
3
2
6
4
3
6
a
2
b
1
R = C H for all compounds. All products were characterized by H NMR, IR and mass spectra and also by comparison of their physical
2
5
1
1
c
d
characteristics with those of the authentic compounds. Yields and reaction times with Oxone are indicated in parentheses. Melting points are
uncorrected.
Scheme 2
ammonium nitrate, even under thermal conditions. The efficacy
on a Finnigan-MAT 1020 mass spectrometer operating at 70
eV. CHN analyses were recorded on a Vario EL analyzer. TLC
was monitored on 0.25 mm E. Merck pre-coated silica gel plates
(60F-254). The CAN used for the reactions was purchased from
Aldrich Co. and was used without purification. The Bransonic
model 2210R-DTH ultrasound was operated at 335 W (47
KHz).
of other oxidants such as manganese() acetate and FeCl was
3
studied for this reaction. Among these catalysts, CAN was
found to be superior in terms of conversion and reaction time.
Similar results were also obtained using 10% Oxone in meth-
anol under identical reaction conditions and the results are
presented in Table 1. Furthermore, manganese() acetate
worked well when acetic acid was used as solvent. Thus, this
procedure provides easy access to substituted pyrimidinones
with a wide variety of substitution patterns. Several examples
illustrating this novel and rapid procedure for the synthesis of
dihydropyrimidinones are summarized in Table 1. The best
results were obtained with CAN when methanol was used as
solvent, because radical generation from CH acidic substrates
takes place in methanol at low temperatures. The reaction may
proceed through a single-electron transfer with initial form-
Ceric ammonium nitrate catalyzed synthesis of pyrimidinones
General procedure. Method A. A homogeneous solution of
aldehyde (5 mmol), ethyl acetoacetate (5 mmol), urea (10 mmol)
and ceric ammonium nitrate (10% w/w of aldehyde) in meth-
anol (15 ml) was sonicated (Bransonic model 2210R-DTH) for
the appropriate time (see Table 1). The reaction temperature
was raised to 55–60 ЊC after sonication for 3–7 h. On comple-
tion of the reaction, as indicated by TLC, the reaction mixture
was diluted with water and the resulting solid was filtered under
suction and recrystallized from hot methanol to afford the pure
product.
12
ation of a β-ketoester radical that adds to the imine inter-
mediate, as shown in Scheme 2.
In summary we have presented an ultrasound-accelerated
synthesis of dihydropyrimidinones using a catalytic amount of
ceric ammonium nitrate under neutral reaction conditions.
Mild reaction conditions, improved yields, enhanced reaction
rates, greater selectivity, compatibility with various functional
groups, operational simplicity, an inexpensive catalyst and
simple experimental/product isolation procedures are the main
advantages of this procedure over existing ones for the syn-
thesis of pyrimidinones.
Method B. A mixture of aldehyde (5 mmol), ethyl aceto-
acetate (5 mmol), urea (10 mmol) and Oxone (10% w/w of
aldehyde) in methanol (15 ml) was sonicated (Bransonic model
2
210R-DTH) for the appropriate time (see Table 1). The reac-
tion temperature was raised to 55–60 ЊC after sonication for
–7 h. On completion of the reaction, as indicated by TLC, the
3
reaction mixture was diluted with water and the resulting solid
was filtered under suction and recrystallized from hot methanol
to afford pure product.
Experimental
Melting points were recorded on a Büchi R-535 apparatus. IR
1
Compound 3c. Solid, mp 194–195 ЊC; H NMR (DMSO-d ):
6
spectra were recorded on a Perkin-Elmer FT-IR 240-c spectro-
δ 1.25 (t, 3H, J = 6.8 Hz), 2.25 (s, 3H), 2.60–2.70 (m, 2H), 4.15
(q, 2H, J = 6.7), 4.25 (m, 1H), 7.10–7.25 (m, 6H), 8.80 (br s,
1
13
photometer with KBr optics. H and C NMR spectra were
recorded on a Varian-Gemini-200 spectrometer in DMSO-d6
using TMS as an internal standard. Mass spectra were recorded
ϩ
NH); EIMS: m/z 274 (M ), 183, 155, 137, 91; IR (KBr): ν 3248,
Ϫ1
3117, 2975, 1724, 1652, 1495, 1287, 1226, 1092, 778 cm .
1
940
J. Chem. Soc., Perkin Trans. 1, 2001, 1939–1941

View Article Online
Analysis calcd. for C H N O (274.318) C, 65.68; H, 6.61; N,
(s, 3H), 4.15 (m, 2H), 4.25 (m, 1H), 6.05 (br s, NH), 8.55 (br s,
15
18
2
3
ϩ
1
0.21. Found: C, 65.7; H, 6.63; N, 10.24%.
NH); EIMS: m/z 253 (M ), 209, 183, 155, 137, 91, 40; IR (KBr):
Ϫ1
ν 3249, 2933, 1730, 1646, 1433, 1331, 1288, 1086, 779 cm .
1
Compound 3d. Solid, mp 176–177 ЊC; H NMR (DMSO-d ):
Analysis calcd. for C H N O (254.327) C, 61.39; H, 8.72; N,
6
13 22
2
3
δ 1.15 (t, 3H, J = 7.0 Hz), 2.30 (s, 3H), 3.80 (s, 6H), 4.05 (q, 2H,
J = 7.0 Hz), 5.25 (s, 1H), 6.80 (m, 2H), 6.85 (m, 1H), 7.25 (br s,
NH), 8.95 (br s, NH); EIMS: m/z 320 (M ), 292, 276, 247, 232,
11.01. Found: C, 61.40; H, 8.75; N, 11.08%.
ϩ
1
Compound 3p. Solid, mp 256–257 ЊC; H NMR (DMSO-d ):
6
1
1
83, 155, 137, 97, 69; IR (KBr): ν 3253, 3118, 2956, 1723, 1682,
654, 1519, 1461, 1237, 1139, 1095, 790 cm . Analysis calcd.
δ 1.25 (t, 3H, J = 6.8 Hz), 2.30 (s, 3H), 3.05 (s, 6H), 4.05 (q, 2H,
J = 6.8 Hz), 5.20 (d, 1H, J = 2.1 Hz), 6.65 (d, 2H, J = 8.0 Hz),
7.15 (br s, NH), 7.20 (d, 2H, J = 8.0 Hz), 8.90 (br s, NH); IR
Ϫ1
for C H N O (320.342) C, 59.99; H, 6.29; N, 8.74. Found: C,
16
20
2
5
Ϫ1
ϩ
6
0.05; H, 6.30; N, 8.76%.
(KBr): ν 3243, 1725, 1673 cm ; EIMS: m/z 303 (M ). Analysis
calcd. for C H N O (305.375) C, 62.93; H, 7.59; N, 13.76.
16
23
3
5
1
Compound 3h. Solid, mp 168–170 ЊC; H NMR (DMSO-d ):
Found: C, 62.91; H, 7.60; N, 13.75%.
Compound 3q. Solid, mp 216–218 ЊC; H NMR (DMSO-d ):
6
6
δ 1.20 (t, 3H, J = 6.8 Hz), 2.20 (s, 3H), 4.05 (q, 2H, J = 6.9 Hz),
.20 (d, 1H, J = 2.0 Hz), 7.25 (br s, NH), 7.30–7.42 (m, 4H), 9.0
br s, NH); IR (KBr): ν 3243, 1705, 1689 cm ; EIMS: m/z 228
M ). Analysis calcd. for C H N F O (330.305) C, 54.55; H,
.19; N, 8.48; F, 17.26. Found: C, 54.57; H, 5.20; N, 8.47; F,
7.28%.
1
5
(
(
5
1
Ϫ1
δ 1.20 (t, 3H, J = 7.0 Hz), 2.35 (s, 3H), 3.85 (s, 9H), 4.05 (q, 2H,
J = 7.0 Hz), 5.25 (br s, 1H), 6.50 (m, 2H), 7.05 (br s, NH), 8.85
ϩ
15
17
2
3
3
Ϫ1
(br s, NH); IR (KBr): ν 3240, 1717, 1680 cm ; EIMS: m/z 350
ϩ
(M ). Analysis calcd. for C17
H N O (352.384) C, 57.44; H,
24 2 6
6
.86; N, 7.95. Found: C, 57.50; H, 6.89; N, 7.97%.
1
Compound 3j. Solid, mp 220–221 ЊC; H NMR (DMSO-d ):
6
δ 1.20 (t, 3H, J = 6.9 Hz), 4.05 (q, 2H, J = 6.9 Hz), 5.20 (d, 1H,
J = 2.1 Hz), 6.05 (s, 2H), 6.70 (m, 3H), 7.25 (br s, NH), 9.0 (br s,
NH); IR (KBr): ν 3245, 1700, 1690 cm ; EIMS: m/z 358 (M ).
Acknowledgements
Ϫ1
ϩ
BVS and KBR thank CSIR, New Delhi for the award of
fellowships.
Analysis calcd. for C H N F O (360.28) C, 50.0; H, 4.20; N,
15
15
2
3
5
7
.78; F, 15.82. Found: C, 50.05; H, 4.27; N, 7.76; F, 15.85%.
References
1
Compound 3k. Solid, mp 235–236 ЊC; H NMR (DMSO-d ):
6
1
C. O. Kappe, Tetrahedron, 1993, 49, 6937 and references cited
therein.
δ 1.05 (m, 4H), 1.25 (t, 3H, J = 6.8 Hz), 1.45 (m, 3H), 1.75 (m,
H), 2.3 (s, 3H), 4.15 (m, 3H), 6.15 (br s, NH), 8.45 (br s, NH);
EIMS: m/z 266 (M ), 183, 137, 155, 40; IR (KBr): ν 3236, 3118,
920, 2850, 1726, 1702, 1647, 1450, 1230, 1095, 789 cm .
Analysis calcd. for C H N O (266.338) C, 63.14; H, 8.33; N,
0.82. Found: C, 63.17; H, 8.35; N, 10.80%.
4
2
(a) K. S. Atwal, B. N. Swanson, S. E. Unger, D. M. Floyd,
S. Moreland, A. Hedberg and B. C. O’Reilly, J. Med. Chem., 1991,
34, 806; (b) C. O. Kappe and W. M. F. Fabian, Tetrahedron, 1997, 53,
2803; (c) K. S. Atwal, G. C. Roonyak, B. C. O’Reilly and J. Schwartz,
J. Org. Chem., 1989, 54, 5898.
(a) A. D. Patil, N. V. Kumar, W. C. Kokke, M. F. Bean, A. J. Freyer,
C. De Brosse, S. Mai, A. Truneh and D. J. Faulkner, J. Org. Chem.,
ϩ
Ϫ1
2
14
22
2
3
1
3
1
Compound 3l. Solid, mp 241–243 ЊC; H NMR (DMSO-d ):
6
1
995, 60, 1182; (b) B. B. Snider, J. Chen, A. D. Patil and A. Freyer,
δ 1.05 (t, 3H, J = 7.0 Hz), 2.50 (s, 3H), 3.95 (q, 2H, J = 7.0 Hz),
.25 (d, 1H, J = 6.0 Hz), 6.05 (dd, 1H, J = 16.4 and 1.8 Hz), 6.2
d, 1H, J = 16.4 Hz), 7.25 (m, 5H), 7.45 (d, NH, J = 1.7 Hz),
.95 (br s, NH); EIMS: m/z 286 (M ), 252, 224, 196, 149, 84; IR
KBr): ν 3335, 3242, 3098, 2978, 1689, 1642, 1492, 1373, 1218,
121, 785. Analysis calcd. for C H N O (286.229) C, 67.12;
Tetrahedron Lett., 1996, 37, 6977.
4 P. Biginelli, Gazz. Chim. Ital., 1893, 23, 360.
4
(
8
(
5 (a) K. Folkers and T. B. Johnson, J. Am. Chem. Soc., 1934, 1180; (b)
K. Folkers, H. J. Harwood and T. B. Johnson, J. Am. Chem. Soc.,
ϩ
1
932, 54, 3751; (c) P. Wipf and A. Cunningham, Tetrahedron Lett.,
1
995, 36, 7819.
1
16
18
2
3
6
7
(a) B. C. O’Reilly and K. S. Atwal, Heterocycles, 1987, 26, 1185; (b)
K. S. Atwal, B. C. O’Reilly, J. Z. Gougoutas and M. F. Malley,
Heterocycles, 1987, 26, 1189; (c) A. D. Shutalev, E. A. Kishko, N.
Sivova and A. Y. Kuznetsov, Molecules, 1998, 3, 100.
H, 6.34; N, 9.78. Found: C, 67.15; H, 6.37; N, 9.80%.
1
Compound 3m. Solid, mp 206–208 ЊC; H NMR (DMSO-d ):
6
(a) E. H. Hu, D. R. Sidler and U.-H. Dolling, J. Org. Chem., 1998,
δ 1.25 (t, 3H, J = 7.0 Hz), 2.30 (s, 3H), 4.10 (q, 2H, J = 7.0 Hz),
.50 (d, 1H, J = 2.2 Hz), 6.85 (m, 2H), 7.15 (m, 1H), 7.30 (br s,
NH), 8.90 (br s, NH); IR (KBr): ν 3245, 1720, 1690 cm ;
EIMS: m/z 266 (M ). Analysis calcd. for C H N O S (268.33)
C, 53.7; H, 6.0; N, 10.44; S, 11.95. Found: C, 53.78; H, 6.05; N,
0.47; S, 11.97%.
6
3, 3454; (b) C. O. Kappe and S. F. Falsone, Synlett, 1998, 718; (c)
5
B. C. Ranu, A. Hajra and U. Jana, J. Org. Chem., 2000, 65, 6270; (d )
Y. Ma, C. Qian, L. Wang and M. Yang, J. Org. Chem., 2000, 65,
3864; (e) J. Lu and H Ma, Synlett, 2000, 1, 63; ( f ) F. Bigi, S. Carloni,
B. Frullanti, R. Maggi and G. Sartori, Tetrahedron Lett., 1999, 40,
3465.
Ϫ1
ϩ
12
16
2
3
1
8
9
(a) C. Einhorn, J. Einhorn and J.-L. Luche, Synthesis, 1989,
787; (b) B. H. Han and P. Boudjouk, J. Org. Chem., 1982, 40,
1
Compound 3n. Solid, mp 203–205 ЊC; H NMR (DMSO-d ):
6
6
731.
δ 1.20 (t, 3H, J = 6.8 Hz), 2.25 (s, 3H), 4.15 (q, 2H, J = 6.8 Hz),
.20 (br s, 1H), 6.10 (m, 1H), 6.25 (m, 1H), 7.30 (m, 1H), 7.40
br s, NH), 9.10 (br s, NH); IR (KBr): ν 3242, 1710, 1685 cm ;
EIMS: m/z 250 (M ). Analysis calcd. for C H N O (252.268)
C, 57.13; H, 6.39; N, 11.10. Found: C, 57.15; H, 6.40; N,
1.13%.
T. J. Mason, Chem. Soc. Rev., 1997, 26, 443.
0 V. Nair, J. Mathew and J. Prabhakaran., Chem. Soc. Rev., 1997,
5
(
1
Ϫ1
127.
ϩ
11 (a) K. Folkers, H. J. Harwood and T. B. Johnson, J. Am. Chem. Soc.,
12
16
2
4
1
932, 54, 3751; (b) K Folkers and T. B. Johnson, J. Am. Chem. Soc.,
1
933, 55, 3361; (c) K. Singh, J. Singh, P. K Deb and H. Singh,
1
Tetrahedron, 1999, 55, 12873.
1
2 (a) E Baciocchi, B. Giese, H Farshchi and R. Ruzziconi, J. Org.
Chem., 1990, 55, 5688; (b) V. Nair and J. Mathew, J. Chem. Soc.,
Perkin Trans. 1, 1995, 1881.
1
Compound 3o. Solid, mp 151–153 ЊC; H NMR (DMSO-d ):
6
δ 0.95 (t, 3H, J = 6.8 Hz), 1.25–1.40 (m, 9H), 1.55 (m, 2H), 2.30
J. Chem. Soc., Perkin Trans. 1, 2001, 1939–1941
1941