Diketene as an alternative substrate for a new Biginelli-like multicomponent reaction: one-pot synthesis of 5-carboxamide substituted 3,4-dihydropyrimidine-2(1H)ones

Article abstract of DOI:10.1016/j.tet.2010.04.028

5-Carboxamide substituted 3,4-dihydropyrimidine-2(1H)one derivatives were synthesized in a simple and efficient method from the one-pot four-component reactions of an aliphatic or aromatic amine, diketene, an aromatic aldehyde and urea or thiourea in the presence of p-toluenesulfonic acid as a catalyst under mild reaction conditions at ambient temperature.

Full text of DOI:10.1016/j.tet.2010.04.028

Tetrahedron 66 (2010) 4040e4042
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Diketene as an alternative substrate for a new Biginelli-like multicomponent
reaction: one-pot synthesis of 5-carboxamide substituted 3,4-dihydropyrimidine-
2(1H)ones
*
Ahmad Shaabani , Mozhdeh Seyyedhamzeh, Ali Maleki, Fatemeh Hajishaabanha
Department of Chemistry, Shahid Beheshti University, PO Box 19396-4716, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
5-Carboxamide substituted 3,4-dihydropyrimidine-2(1H)one derivatives were synthesized in a simple
and efficient method from the one-pot four-component reactions of an aliphatic or aromatic amine,
diketene, an aromatic aldehyde and urea or thiourea in the presence of p-toluenesulfonic acid as a cat-
alyst under mild reaction conditions at ambient temperature.
Received 15 January 2010
Received in revised form 15 March 2010
Accepted 6 April 2010
Available online 10 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
3,4-Dihydropyrimidine-2(1H)one
Multicomponent reaction
One-pot
Urea
Diketene
1. Introduction
O
O
O
O
O
O
O
The classic version of the Biginelli1 three-component conden-
sation reaction, which combines an aldehyde, urea or thiourea and
an open-chain b-dicarbonyl compound under acidic conditions in
C
O
I
III
II
IV
ethanol affords a 3,4-dihydropyrimidin-2(1H)one, has seen wide-
spread use for generating large collections of molecules in combi-
natorial synthesis.2 Very recently, for novel Biginelli-like scaffold
Scheme 1.
Due to the biological activity of 3,4-dihydropyrimidine deriva-
tives9e16 and in continuation of our interest in diketene-based
MCRs17e20 and Biginelli reactions,5,21 we describe herein the
synthesis, the use of the common open-chain
pounds in Biginelli reactions has been extended to the use of cyclic
-diketones,3 -ketolactones,4 cyclic -diesters5 or -diamides,5,6
benzocyclic ketones7 and -keto acids.7 Although the Biginelli
b-dicarbonyl com-
b
b
b
b
synthesis of
a new class of 3,4-dihydropyrimidine-2(1H)one
a
derivatives 5aef in a one-pot process by a four-component con-
densation reaction of an aliphatic or aromatic amine 1, diketene 2,
an aromatic aldehyde 3 and urea/thiourea 4 in the presence of
p-toluenesulfonic acid (p-TsOH$H2O) as a catalyst in CH2Cl2 at
ambient temperature (Scheme 2). Since the number of possible
reaction was described over 100 years ago, this process lacks
literature precedent for the synthesis of 3,4-dihydropyrimidine-2
(1H)ones using diketene as the same of the
b-dicarbonyl synthon
instead of the usual -dicarbonyl compounds under the four-
b
component reactions strategy.
Diketene is a strained molecule (Estrain¼22.5 kcal/mol),8 which is
readily ring-opened and therefore frequently appears to react as
acetylketene I or one of its dipolar tautomers (II and III). It is
important to note that each of dipolar tautomers is equal to
O
O
Ar
X
R
p-TsOH.H2O
CH2Cl2, rt
3-5 h
N
H
NH
R
NH2
O
ArCHO
H2N
NH2
a b-dicarbonyl synthon. On the other hand diketene is a reagent for
synthon IV (Scheme 1).
N
H
X
3
4
1
2
5
R = benzyl and allyl
Ar = Ph, 4-ClC6H4, 3-NO2C6H4, 4-BrC6H4 and 2-Furyl
X = O and S
67-76%
* Corresponding author. Fax: þ98 21 22403041; e-mail address: a-shaabani@cc.
Scheme 2. Synthesis of dihydropyrimidine-5-carboxamides 5aef.
sbu.ac.ir (A. Shaabani).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.028

A. Shaabani et al. / Tetrahedron 66 (2010) 4040e4042
4041
combinations in four-component reactions is greater than the
three-component reactions, the diversity of Biginelli reaction is
increased under four-component reaction strategy.22
2. Results and discussion
In an exploratory experiment, the reaction of N-alkyl-3-oxobu-
tanamide 6, which was prepared by addition of benzylamine 1 to
diketene 2, with 4-chlorobenzaldehyde and urea 4 in the presence
of p-TsOH$H2O as a catalyst was performed in dry dichloromethane
at ambient temperature. The progress of the reaction was moni-
tored by TLC. After completion of the reaction (3 h), the product,
N-benzyl-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-6-methyl-2-oxo-
pyrimidine-5-carboxamide 5a was obtained in 73% yield.
Scheme 3. Proposed mechanism.
We have shown that the use of a wide diversity of substituents
in amines 1 and aromatic aldehydes 3 in this multicomponent
reaction makes possible the synthesis of libraries under similar
circumstances. Two substituents in the products can be varied
independently of each other. The results are shown in Table 1. As
anticipated from our original results, these reactions proceeded
very cleanly under mild conditions at room temperature and no
undesirable side reactions were observed. All compounds,
described in the paper, were synthesized for the first time. The
structures of products 5aef are shown in Figure 1.
3. Conclusion
In summary, diketene as a new substrate for the Biginelli
reaction has been identified and a diverse set of 5-carboxamide
substituted 3,4-dihydropyrimidine-2(1H)ones has been synthe-
sized without using any activation in high yields at room temper-
ature. Our literature survey shows that this is the first example in
which diketene as an activated
a Biginelli reaction.
b-dicarbonyl synthon is used in
Table 1
Synthesis of dihydropyrimidine-5-carboxamides 5aef
4. Experimental
4.1. General
Entry
R
Ar
X
Product
Time (h)
Yielda (%)
1
2
3
4
5
6
Benzyl
Benzyl
Benzyl
Allyl
Benzyl
Benzyl
4-ClC6H4
3-NO2C6H4
Ph
4-BrC6H4
Furyl
O
O
O
S
O
S
5a
5b
5c
5d
5e
5f
3
3
4.5
4
5
73
75
69
74
67
76
Melting points were measured on an Electrothermal 9200
apparatus and are uncorrected. Mass spectra were recorded on
a FINNIGAN-MAT 8430 mass spectrometer operating at an ioni-
zation potential of 70 eV. IR spectra were recorded on a Shi-
madzu IR-470 spectrometer. 1H and 13C NMR spectra were
recorded on a BRUKER DRX-300 AVANCE spectrometer at 300.13
and 75.47 MHz. NMR spectra were obtained on solution in
DMSO-d6 using TMS as internal standard. The chemicals used in
this work were purchased from Merck and Fluka Chemical
Companies.
4-BrC6H4
3.5
a
Isolated yield.
Cl
NO2
O
O
O
N
NH
N
H
NH
N
H
NH
H
N
H
O
N
H
O
N
H
O
4.2. Typical procedure for the synthesis of N-benzyl-4-
(4-chlorophenyl)-1,2,3,4-tetrahydro-6-methyl-2-
oxopyrimidine-5-carboxamide (5a)
5b
5c
5a
Br
Br
O
O
O
A solution of benzylamine (0.107 g, 1.0 mmol) and diketene
(0.084 g, 1.0 mmol) was magnetically stirred in 5 mL of dry CH2Cl2
for 2 h. Then, 4-chlorobenzaldehyde (0.140 g, 1.0 mmol), urea
(0.060 g, 1.0 mmol) and p-TsOH$H2O (0.019 g, 0.1 mmol) were
added simultaneously. The reaction mixture was allowed to stir for
1 h until a precipitate appeared. After completion of the reaction, as
indicated by TLC (EtOAc/n-hexane, 1:2), the reaction mixture was
filtered and the residue was washed with water and then with
ethanol and dried in vacuo to give 5a as pure product. White
powder (0.26 g, yield 73%). Mp 234e236 ꢀC. IR (KBr) (nmax/cmꢁ1):
3437, 3397, 3105, 2929, 1673, 1619, 1536, 1457, 1454. MS, m/z (%):
355 (Mþ, 22), 342 (22), 340 (76), 264 (12), 247 (21), 221 (48), 137
(20), 91 (100), 65 (20). 1H NMR (300.13 MHz, DMSO-d6): dH (ppm)
2.01 (3H, s, CH3), 4.14e4.32 (2H, m, CH2), 5.44 (1H, br s, CH),
6.92e7.40 (9H, m, HeAr), 7.54 (1H, br s, NH), 8.12 (1H, br s, NH),
8.64 (1H, br s, NH). 13C NMR (75.47 MHz, DMSO-d6): dC (ppm) 17.4
(CH3), 42.5 (CH2), 55.0 (CH), 104.8, 126.9, 127.3, 128.4, 128.8, 129.0,
138.2, 140.1, 141.8, 143.6 (CeAr and C]C), 152.8, 166.6 (CO). Anal.
Calcd for C19H18ClN3O2: C, 64.13; H, 5.10; N, 11.81%. Found C, 64.23;
H, 5.16; N, 11.75%.
O
N
H
NH
N
H
NH
N
H
NH
N
H
O
N
H
S
N
H
S
5e
Figure 1. Structures of products 5aef.
5f
5d
Compounds 5aef are stable solids whose structures were
established by IR, 1H and 13C NMR spectroscopy, mass spectrometry
and elemental analysis. The mass spectra of products 5aef
displayed molecular ion peaks at appropriate values, which were
consistent with the proposed products.
The possible mechanism for the formation of products 5aef is
shown in Scheme 3. It is reasonable to assume that 7 results from
initial addition of an aldehyde 3 to N-alkyl-3-oxobutanamide 6,
which derived from the addition of an amine 1 to diketene 2. Then,
the subsequent Michael-type addition of the urea/thiourea 4 to 7,
followed by an intramolecular condensation reaction of in-
termediate 8 to afford the corresponding products 5aef (Scheme 3).

4042
A. Shaabani et al. / Tetrahedron 66 (2010) 4040e4042
4.2.1. N-Benzyl-1,2,3,4-tetrahydro-6-methyl-4-(3-nitrophenyl)-2-ox-
opyrimidine-5-carboxamid (5b). White powder (0.27 g, yield 75%).
Mp 206e207 ꢀC. IR (KBr) (nmax/cmꢁ1): 3437, 3385, 3282, 3086,
2925, 1720, 1641, 1522, 1422. MS, m/z (%): 349 (Mþꢁ17, 100), 318
(32), 261 (10), 232 (15), 202 (27), 176 (63), 137 (30), 106 (100), 91
(78), 43 (62). 1H NMR (300.13 MHz, DMSO-d6): dH (ppm) 2.07 (3H, s,
CH3), 3.96e4.29 (2H, m, CH2), 5.34e5.44 (1H, m, CH), 6.62e7.76
(10H, m, HeAr, NH), 8.16 (1H, br s, NH), 8.75 (1H, br s, NH). 13C NMR
(75.47 MHz, DMSO-d6): dC (ppm) 17.2 (CH3), 42.4 (CH2), 53.4 (CH),
106.3,122.6,127.1,127.3,128.4,129.1,129.9,134.8,139.0,140.3,144.1,
147.9 (CeAr and C]C), 165.7, 166.4 (CO). Anal. Calcd for
C19H18N4O4: C, 62.29; H, 4.95; N, 15.29%. Found C, 62.23; H, 4.91; N,
15.39%.
1671,1612,1535,1457,1365. MS, m/z (%): 416 (Mþþ1, 3), 415 (Mþ, 8),
400 (15), 326 (28), 310 (30), 263 (27), 209 (74),107 (26), 91 (100), 65
(35), 39 (29). 1H NMR (300.13 MHz, DMSO-d6): dH (ppm) 2.03 (3H, s,
CH3), 4.12e4.32 (2H, m, CH2), 5.29 (1H, br s, CH), 6.90e7.54 (9H, m,
HeAr), 8.30e8.34 (1H, m, NH), 9.35 (1H, br s, NH), 9.91 (1H, br s,
NH). 13C NMR (75.47 MHz, DMSO-d6): dC (ppm) 16.9 (CH3), 42.6
(CH2), 55.1 (CH), 106.7, 126.0, 127.4, 128.5, 128.8, 129.5, 138.9, 140.2,
142.7, 145.0 (CeAr and C]C), 166.4, 174.2 (CO). Anal. Calcd for
C19H18BrN3OS: C, 54.81; H, 4.36; N, 10.09%. Found C, 54.92; H, 4.54;
N, 10.18%.
Acknowledgements
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
4.2.2. N-Benzyl-1,2,3,4-tetrahydro-6-methyl-2-oxo-4-phenyl-
pyrimidine-5-carboxamide (5c). White powder (0.23 g, yield 69%).
Mp 202e204 ꢀC. IR (KBr) (nmax/cmꢁ1): 3293, 3064, 2925, 1727, 1681,
1617, 1535, 1491. MS, m/z (%): 321 (Mþ, 27), 306 (100), 275 (10), 230
(20), 214 (65), 137 (18), 91 (100), 42 (35). 1H NMR (300.13 MHz,
DMSO-d6): dH (ppm) 2.02 (3H, s, CH3), 4.20e4.24 (2H, m, CH2), 5.31
(1H, br s, CH), 6.93e7.36 (10H, m, HeAr), 7.57e7.66 (1H, m, NH),
References and notes
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732e735.
3
8.07e8.16 (1H, t, JHH¼5.6 Hz, NH), 8.59 (1H, br s, NH). 13C NMR
(75.47 MHz, DMSO-d6): dC (ppm) 17.4 (CH3), 42.5 (CH2), 55.5 (CH),
105.3, 126.9, 127.3, 128.5, 128.8, 129.0, 138.0, 140.1, 141.9, 144.7
(CeAr and C]C), 153.1, 166.8 (CO). Anal. Calcd for C19H19N3O2: C,
71.01; H, 5.96; N, 13.08%. Found C, 71.23; H, 5.76; N, 13.15%.
5. Shaabani, A.; Bazgir, A.; Bijanzadeh, H. R. Mol. Diversity 2004, 8, 141e145.
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Gougoutas, J. Z.; O’Reilly, B. C.; Schwartz, J.; Malley, M. F. J. Med. Chem. 1992,
35, 3254e3263.
4.2.3. N-Allyl-4-(4-bromophenyl)-1,2,3,4-tetrahydro-6-methyl-2-thi-
oxopyrimidine-5-carboxamide (5d). White powder (0.27 g, yield
74%). Mp 182e183 ꢀC. IR (KBr) (nmax/cmꢁ1): 3446, 3325, 3201, 3058,
2925, 1710, 1660, 1619, 1547, 1489, 1425. MS, m/z (%): 366 (Mþþ1,
10), 365 (Mþ, 10), 352 (50), 326 (40), 309 (53), 281 (40), 153 (30),
115 (27), 67 (25), 41 (100). 1H NMR (300.13 MHz, DMSO-d6):
dH (ppm) 2.03 (3H, s, CH3), 3.57e3.67 (2H, m, CH2), 4.82e5.28 (3H,
m, H2C]CH), 5.62e5.75 (1H, m, CH), 6.92e7.40 (9H, m, HeAr),
7.91e7.98 (1H, t, 3JHH¼5.4 Hz, NH), 9.36 (1H, br s, NH), 9.90 (1H, br s,
NH). 13C NMR (75.47 MHz, DMSO-d6): dC (ppm) 16.8 (CH3), 41.5
(CH2), 54.8 (CH), 106.7, 115.3, 121.3, 129.2, 131.9, 135.5, 135.6, 142.7
(CeAr and C]C), 166.1, 174.4 (CO). Anal. Calcd for C15H16BrN3OS: C,
49.19; H, 4.40; N, 11.47%. Found C, 49.31; H, 4.53; N, 11.58%.
11. Rovnyak, G. C.; Kimball, S. D.; Beyer, B.; Gucinotta, G.; DiMarco, J. D.; Gougoutas,
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J.; Schreiber, S. L. Chem. Biol. 2000, 7, 275e286.
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4.2.4. N-Benzyl-4-(furan-2-yl)-1,2,3,4-tetrahydro-6-methyl-2-
oxopyrimidine-5-carboxamide (5e). White powder (0.21 g, yield
67%). Mp 232e234 ꢀC. IR (KBr) (nmax/cmꢁ1): 3334, 3279, 3090,
2925, 1724, 1665, 1626, 1553, 1499, 1456. MS, m/z (%): 310 (Mþꢁ1,
8), 308 (100), 264 (10), 228 (8), 201 (47),175 (50),106 (25), 91 (100),
65 (25). 1H NMR (300.13 MHz, DMSO-d6): dH (ppm) 1.19 (3H, s,
CH3), 4.26e4.30 (2H, m, CH2), 4.96 (1H, br s, CH), 6.96e7.23 (9H, m,
HeAr), 7.53 (1H, br s, NH), 8.23 (1H, br s, NH), 8.56 (1H, br s, NH). 13C
NMR (75.47 MHz, DMSO-d6): dC (ppm) 28.8 (CH3), 42.3 (CH2), 60.3
(CH), 107.7, 110.6, 126.9, 127.2, 127.5, 128.5, 128.6, 139.1, 139.6, 142.4
(CeAr and C]C), 154.1, 167.6 (CO). Anal. Calcd for C17H17N3O3: C,
65.58; H, 5.50; N, 13.50%. Found 65.63; H, 5.59; N, 13.65%.
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4.2.5. N-Benzyl-4-(4-bromophenyl)-1,2,3,4-tetrahydro-6-methyl-2-
thioxopyrimidine-5-carboxamide (5f). White powder (0.31 g, yield
76%). Mp 126e128 ꢀC. IR (KBr) (nmax/cmꢁ1): 3492, 3399, 3070, 2819,