N,N′-Dichlorobis(2,4,6-trichlorophenyl)urea (CC-2) as a new reagent for the synthesis of pyrimidone and pyrimidine derivatives via Biginelli reaction

Article abstract of DOI:10.1016/j.tetlet.2010.12.039

A simple and efficient method for the synthesis of 3,4-dihydropyrimidin-2- (1H)one and benzo[4,5]imidazo/thioazo[1,2-a]pyrimidine derivatives has been described using N,N′-dichlorobis(2,4,6-trichlorophenyl)urea (CC-2) as a new reagent. This method is foun

Full text of DOI:10.1016/j.tetlet.2010.12.039

Tetrahedron Letters 52 (2011) 809–812
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Tetrahedron Letters
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N,N0-Dichlorobis(2,4,6-trichlorophenyl)urea (CC-2) as a new reagent
for the synthesis of pyrimidone and pyrimidine derivatives via Biginelli reaction
⇑
G. B. Dharma Rao, B. N. Acharya, S. K. Verma, M. P. Kaushik
Discovery Centre, Process Technology Development Division, Defence R&D Establishment, Jhansi Road, Gwalior 474002, MP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient method for the synthesis of 3,4-dihydropyrimidin-2-(1H)one and benzo[4,5]imi-
dazo/thioazo[1,2-a]pyrimidine derivatives has been described using N,N0-dichlorobis(2,4,6-trichlorophe-
nyl)urea (CC-2) as a new reagent. This method is found to be efficient and convenient for the synthesis of
pyrimidone and pyrimidine derivatives.
Received 15 October 2010
Revised 6 December 2010
Accepted 9 December 2010
Available online 15 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Multi-component reactions
Biginelli reaction
N,N0-Dichlorobis(2,4,6-trichlorophenyl)urea
(CC-2)
Dihydropyrimidones
Benzimidazoles
Benzothiazoles
Multicomponent reactions have gained increasing attention for
the synthesis of new heterocycles of medicinal importance.1–3
Medicinal chemistry relies on robust, reliable reactions, facilitating
the rapid development of new chemical entities (NCE’s) available
for bio-evaluation. In this area, Biginelli reaction is one of the most
versatile reactions for the selective construction of heterocycles.
The simple and straightforward procedure reported by Biginelli4
in 1893 involves a three component condensation reaction of
b-ketoesters (1), arylaldehyde (2), and urea (3) to give 3,4-dihydro-
pyrimidin-2-(1H)one (DHPMs, 4) (Scheme 1) in one-pot. The
DHPMs derivatives have received considerable attention in recent
years essentially because of their importance in medicinal chemis-
try.5–8 Due to the pharmacological importance, several protocols
aimed to improve the Biginelli reaction have been reported using
commercially available reagents.9–15 However, most of reagents
have been used for conventional reactants (e.g., aryl aldehyde,
b-ketoesters, and urea/thiourea) only. The Biginelli reactions with
alternative reactants16–21 other than urea have gained wide inter-
est because of pharmaceutical significance. Recently, 2-amino-
benzimidazoles/2-aminobenzothioazoles derivatives as alternates
to urea have been reported.16 However, the reported methods of
Biginelli reaction with these alternates suffer from several draw-
backs, such as longer reaction time, harsh reaction conditions,
difficulties in the isolation of products, formation of by-products,
and lower yields. Therefore, development of a new reagent with
a wide range of structure diversity is needed. In continuation of
our work on the synthesis of biologically active compounds15b
there was a need to synthesize a library of Biginelli products with
urea and other substituents. We performed a number of reactions
with various reported reagents (Table 1). However, most of the
reagents were applicable only for a small range of reactants. So
the development of a new reagent with wide applicability was
required.
N,N0-Dichlorobis(2,4,6-trichlorophenyl)urea (CC-2),22,23 is
a
mild, stable, safe reagent and has high active chlorine content
(14.54%). The reagent has been used for various organic transfor-
mations.24,25 CC-2 releases active chlorine and gets converted into
an insoluble mass 1,3-bis(2,4,6-trichlorophenyl)urea. The insoluble
mass can be easily separated by simple filtration and can be
O
O
R
R'O
1
H2N
H2N
O
acid catalyst
reflux
+
X
R'O
NH
H
O
3
R
N
H
X
2
4
⇑
Corresponding author. Tel.: +91 751 2343972; fax: +91 751 2347542.
E-mail address: mpkaushik@rediffmail.com (M.P. Kaushik).
Scheme 1. Biginelli reaction.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.039

810
G. B. Dharma Rao et al. / Tetrahedron Letters 52 (2011) 809–812
Table 1
Table 2
Comparison of CC-2 with various reagentsa,b
Preparation of dihydropyrimidinonesa
Entry
Urea/alternate
Reagent
Time (h)
Yield (%)c,ref
O
O
Cl
Cl Cl
Cl
R
O
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Urea
Urea
Urea
Urea
Urea
Urea
CaCl2
SiOCl2
Ph3P
Yb(OTf)3
Bi(NO3)3
CC-2
CaCl2
SiOCl2
Ph3P
Yb(OTf)3
Bi(NO3)3
CC-2
CaCl2
SiOCl2
Ph3P
Yb(OTf)3
Bi(NO3)3
CC-2
2
3
10
6
6
3
10
9
12
15
15
5
12
11
14
16
16.5
6.5
9815a
9015b
5815c
9615d
8015e
98
35
15
45
65
60
82
28
30
30
45
40
75
N
N
R'O
O
1
Cl
Cl
Cl
Cl
H2N
H2N
CC-2
+
X
R'O
NH
EtOH, reflux/3hr
H
O
R
N
H
X
3
2-Aminobenzimidazole
2-Aminobenzimidazole
2-Aminobenzimidazole
2-Aminobenzimidazole
2-Aminobenzimidazole
2-Aminobenzimidazole
2-Aminobenzothioazole
2-Aminobenzothioazole
2-Aminobenzothioazole
2-Aminobenzothioazole
2-Aminobenzothioazole
2-Aminobenzothioazole
4
2
Entry
R
R0
X
Yieldb (%)
Mp (°C)
Observed
Reportedref
1
2
3
4
5
6
7
8
9
10
11
12
13
H
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
CH3
CH3
CH3
CH3
O
O
O
O
O
S
93
98
88
85
91
82
84
80
90
85
86
80
90
200–202
196–198
200–202
180–182
228–230
194–196
242–244
152–154
233–235
193–195
194–196
204–206
202–204
202–20415a
200–20115a
199–20015a
182–18415b
230–23215a
192–19415c
245–24613a
150–15213b
235–23715a
192–19413c
192–19415a
207–20813d
206–20715c
4-OCH3
4-OH
4-F
4-N(CH3)2
4-CH3
4-OH
4-OCH3
4-NO2
4-F
4-OCH3
3-OCH3
H
a
Reaction conditions: 4-methoxy benzaldehyde (1.0 equiv), ethyl acetoacetate
O
S
(1.0 equiv), urea/alternate (1.2 equiv) and CC-2 (0.3 equiv) in ethanol as solvent
under reflux conditions.
O
O
O
O
S
Reaction conditions for other reagents was same as in literature.15a–e
b
c
Isolated yield.
CH3
C2H5
converted back to CC-2 by the reaction with AcOH/Cl2/NaOH.26
Due to these advantages, we attempted the use of this reagent
for the Biginelli reaction with urea and other alternatives. Herein,
we describe N,N0-dichlorobis(2,4,6-trichlorophenyl)urea (CC-2) as
a versatile reagent for Biginelli and modified Biginelli reactions.
In order to optimize the reaction conditions, 4-methoxy benzal-
dehyde, ethyl acetoacetate and urea were taken as model reactants
in ethanol under reflux conditions (Table 1, entry 6). It was
observed that when aryl aldehydes, acetoacetate, urea, and CC-2
were used in the ratio of 1:1:1.2:0.3 in ethanol, it gave the best re-
sult. Additionally, we found that CC-2 was also compatible to carry
out Biginelli reaction with other alternatives (5) to urea (Table 1,
entries 12 and 18). The CC-2 was further compared with other
reported reagents of the Biginelli reaction (Table 1) and it was
revealed that only CC-2 gave the best results with urea and other
substituents with respect to reaction time and yield.
See Ref. 27 for general procedure.
a
Reaction conditions:
1 (1.0 equiv), 2 (1.0 equiv), 3 (1.2 equiv) and CC-2
(0.3 equiv) in refluxed ethanol for 3 h.
b
Isolated yield.
Table 3
Biginelli reaction with 2-aminobenzimidazole/2-aminobenzothioazolea
R
H2N
1
CC-2
O
N
Y
+
EtOH, reflux
R'O
N
2
Y
N
H
5
6 a-n
Entry
R
R’
Y
Product
Time (h)
Yieldb,ref (%)
The optimized reaction conditions were further extended to a
wide range of reactants and the results have been summarized
(Table 2). In addition, various pyrimidine derivatives were also
synthesized using 2-aminobenzimidazole/ 2-aminobenzothioazole
as alternatives to urea using CC-2 in a Biginelli like reaction (Table
3). The conversion was found to be modest with 2-aminobenzim-
idazole/benzothioazole. This might be due to lower conversion to
the imine intermediate. The rate of formation of desired product
was also found to be modest with substituted benzaldehydes espe-
cially at position 3 (Table 3, entries 7 and 10) and with higher aryl
aldehydes (Table 3, entries 13 and 14). The modest yield might be
because of steric hindrance in the formation of Schiff’s base.
On the basis of the above observations and the literature
reports, a plausible mechanism for the Biginelli reaction with
CC-2 is depicted (Scheme 2). The first step of the reaction involves
the electrophilic attack of positive chlorine on the imine formed by
the reaction of urea and aldehyde.13c The activated imine (2)
attacks on alkyl acetoacetate to give final product DHPMs. The
nitronium ion formed on CC-2 after release of active chlorine picks
up the proton from water and results in the formation of 1,3-
bis(2,4,6-trichlorophenyl)urea.22
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4-OCH3
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
N
N
N
N
N
N
N
N
S
S
S
S
N
N
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
5
5
5.5
6.5
6
6
7
6
6.5
6.5
6.5
8
8
10
8216
78
4-OC2H5–
4-C2H5–
4-Me2CH–
4-F–
4-NO2–
3-NO2–
4-OH–
4-OCH3
3-OH–
4-Me2N–
4-CF3–
7616
7216
6816
7016
68
71
7516
66
65
5816
55
3,4,5-(OMe)3–
Indol-
CH3
55
a
Reaction conditions:
(0.3 equiv) using EtOH as solvent under reflux condition.
1
(1.0 equiv),
2
(1.0 equiv),
5
(1.2 equiv) and CC-2
b
Isolated yield.
component coupling in one-pot. According to the conversion and
reaction work-up, CC-2 was found to be an efficient and convenient
reagent. The important advantages of this method are a simple
work-up procedure, wide applicability and recyclability of the
by-product formed during the reaction.
In conclusion, we have demonstrated the application of CC-2 for
the synthesis of diversified pyrimidones and pyrimidines by three

G. B. Dharma Rao et al. / Tetrahedron Letters 52 (2011) 809–812
811
OC2H5
OH
O
O
H
H2N
NH2
Ph
H
H
Ph
H
O
OC2H5
Cl+
Cl
Ph
Cl
O
N
N
NH2
HO
Ph + H
N
O
NH2
NH2
O
O
OEt
NH
O
OEt
O
OEt
O
H
H
-H+
Ph
Cl
H
-H2O
Ph
H2O
OH
OH
Ph
N
HN
NH
N
NH
H
O
O
O
+
HOCl
H2O + Cl+
HOCl + H+
Scheme 2. Proposed mechanism with urea.
24. Shakya, P. D.; Dubey, D. K.; Pardasini, D.; Palit, M.; Gupta, A. K. J. Chem. Res.
2005, 12, 821–823.
Acknowledgments
25. Gupta, A. K.; Acharya, J.; Pardasini, D.; Dubey, D. K. Tetrahedron Lett. 2007, 48,
767–770.
26. Bag, B. C.; Sekhar, K.; Dubey, D. K.; Sai, M.; Dangi, R. S.; Kaushik, M. P.;
Bhattacharya, C. Org. Process Res. Dev. 2006, 10, 505–511.
27. General procedure: A 25 ml R.B flask was charged with urea (2.4 mmol) and
aromatic aldehyde (2 mmol). The mixture was stirred for ½ h. The b-ketoester
(2 mmol) and CC-2 in protic solvent (ethanol) was added to the above mixture.
The reaction mixture was refluxed at 70 °C with stirring till the reaction was
complete. The reaction mixture was then filtered and the solvent was
evaporated under reduced pressure. The solid mass was washed with cold
diethylether (15 ml ꢀ 3) and dried. The product was obtained in 55–98% yield.
The spectral data for some compounds are given below.
The authors are thankful to Dr. B.C. Bag for providing CC-2 and
Mr. Basant Lal for NMR. The authors express special thanks to Dr. R.
Vijayaraghavan, Director, DRDE, Gwalior for his keen interest and
encouragement.
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4-(4-Ethoxyphenyl)-2-methyl-1,4-dihydro-benzo[4,5]imidazo[1,2,a]-3-
ethylcarboxylate 6b: mp = 290–291 °C, 1H NMR (400 MHz, CDCl3) d 1.28 (t,
J = 7.2 Hz, 3H), 1.36 (t, J = 6.8 Hz, 3H), 2.73 (s, 3H), 3.97 (q, J = 6.8 Hz, 2H), 4.17
(q, J = 7.2 Hz, 2H), 6.40 (s, 1H), 6.77 (d, J = 6.0 Hz, 2H), 7.02–7.06 (m, 1H), 7.13–
7.17 (m, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 6.0 Hz, 2H), 7.53 (d, J = 7.6 Hz,
1H). 13C NMR (CDCl3) d = 14.3, 14.75, 19.02, 55.33, 61.02, 63.85, 98.96, 110.03,
114.29, 119.78, 122.52, 128.36, 128.56, 133.31, 140.92, 145.51, 146.42, 158.15,
165.70. ESI-MS: m/z = 378. Anal. Calcd for C22H23N3O3: C, 70.01; H, 6.14; N,
11.13; O, 12.72. Found: C, 70.08; H, 6.07; N, 11.18; O, 12.67.
4-(3-Nitrophenyl)-2-methyl-1,4-dihydro-benzo[4,5]imidazo[1,2,a]-3-
methylcarboxylate 6g: mp P 300 °C, 1H NMR (400 MHz, DMSO-d6) d 2.49 (s,
3H), 3.58 (s, 3H), 6.66 (s, 1H), 6.93–6.97 (m, 1H), 7.03–7.07 (m, 1H), 7.29 (d,
J = 8.0, 1H), 7.37 (d, J = 8.0, 1H), 7.55–7.59 (m, 1H), 7.78 (d, J = 8.0, 1H), 8.06 (d,
J = 8.0, 1H), 8.21 (s, 1H), 10.98 (s, 1H). 13C NMR (DMSO-d6) d = 18.77, 50.86,
55.07, 97.04, 109.80, 116.96, 120.52, 121.45, 122.06, 122.84, 130.17, 131.26,
133.43, 142.18, 144.09, 145.33, 147.56, 147.76, 165.45. ESI-MS: m/z = 365.41.
Anal. Calcd for C19H16N4O4: C, 62.63; H, 4.43; N, 15.38; O, 17.56. Found: C,
62.68; H, 4.38; N, 15.45; O, 17.49.
4-(4-Hydroxyphenyl)-2-methyl-1,4-dihydro-benzo[4,5]imidazo[1,2,a]-3-
ethylcarboxylate 6h: mp P 300 °C, 1H NMR (400 MHz, DMSO-d6) d 1.16 (t,
J = 6.8 Hz, 3H), 2.43 (s, 3H), 4.01 (q, J = 6.8 Hz, 2H), 6.30 (s, 1H), 6.63 (d,
J = 8.4 Hz, 2H), 6.92–6.96 (m, 1H), 7.00–7.04 (m, 1H), 7.15 (d, J = 8.4 Hz, 2H),
7.24 (d, J = 8.0, 1H), 7.33 (d, J = 8.0, 1H), 9.35 (s, 1H), 10.68 (s,1H). 13C
NMR(DMSO-d6) d = 18.52, 56.07, 75.39, 79.82, 83.90, 98.33, 113.67, 114.50,
114.99, 119.66, 127.73, 128.65, 131.13, 132.50, 145.91, 156.84, 165.29. ESI-MS:
m/z = 304.63. Anal. Calcd for C20H19N3O3: C, 68.75; H, 5.48; N, 12.03; O, 13.74.
Found: C, 68.72; H, 5.46; N, 12.07; O, 13.75.
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3667.
4-(3-Hydroxyphenyl)-2-methyl-1,4-dihydro
benzo[4,5]thioazo[1,2,a]-3-ethyl-
carboxylate 6j: mp = 210–212 °C, 1H NMR (400 MHz, DMSO-d6)
d
1.18 (t,
J = 7.2 Hz, 3H), 2.44 (s, 3H), 4.03 (q, J = 7.2 Hz, 2H), 5.81 (s,1H), 6.33 (s, 1H),
6.66–6.67 (m, 1H), 6.95 (s, 1H), 7.02 (d, J = 8.0 Hz, 2H), 7.06 (s, 1H), 7.21 (s, 1H),
7.35 (d, J = 8.0 Hz, 2H), 9.34 (s, 1H), 10.74 (s, 1H). 13C NMR (DMSO-d6) d = 14.13,
14.72, 56.42, 59.37, 80.13, 97.98, 113.14, 116.34, 117.17, 117.94, 128.58,
129.77, 131.58, 142.30, 143.31, 146.21, 157.34, 165.23. ESI-MS: m/z = 369.
Anal. Calcd for C20H20N2O3S: C, 65.16; H, 5.72; N, 7.95; O, 12.08; S, 9.09%.
Found: C, 65.14; H, 5.73; N, 7.96; O, 12.11; S, 9.06%.
4-(4-Dimethylaminophenyl)-2-methyl-1,4-dihydro-benzo[4,5]thioazo[1,2,a]-3-
ethylcarboxylate 6k: M.P = 232–234 °C, 1H NMR (400 MHz, CDCl3) d 1.29 (t,
J = 7.2 Hz, 3H), 2.72 (s, 3H), 2.87 (s, 6H), 4.16 (q, J = 7.2 Hz, 2H), 5.81 (s, 1H),
6.37 (s, 1H), 6.59 (d, J = 8.0 Hz, 2H), 7.17–7.20 (m, 1H), 7.24–7.26 (m, 3H), 7.51
(d, J = 8.0 Hz, 2H). 13C NMR (CDCl3) d = 14.32, 14.96, 56.00, 59.23, 98.46, 109.57,
111.34, 112.24, 120.57, 120.87, 127.10, 128.22, 129.42, 131.58, 142.32, 145.59,
149.71, 165.30. ESI-MS: m/z = 396.42. Anal. Calcd for C22H24N4O2: C, 70.19; H,
6.43; N, 14.88; O, 8.50. Found: C, 70.22; H, 6.38; N, 14.93; O, 8.47.
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23. Vijayaraghavan, R.; Praveen Kumar; Dubey, D. K.; Singh, R. Biomed. Enviro. Sci.
2002, 15, 25–35.
4-(3,4,5-Trimethoxyphenyl)-2-methyl-1,4-dihydro-benzo[4,5]imidazo[1,2,a]-3-
methylcarboxylate 6m: mp P 300 °C, 1H NMR (400 MHz, DMSO-d6) d 2.45 (s,

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3H), 3.56 (s, 3H), 3.61 (s, 3H), 3.68 (s, 6H), 6.39 (s, 1H), 6.63 (s, 2H), 6.96–7.00
mp P 300 °C, 1H NMR (400 MHz, DMSO-d6) d 2.43 (s, 3H), 3.55 (s, 3H), 6.75
(s, 1H), 6.86–6.90 (m, 2H), 6.95–6.99 (m, 2H), 7.21 (d, J = 8 Hz, 1H), 7.26–7.29
(m, 3H), 7.58 (s, H), 10.83 (s, 1H), 11.00 (s, 1H). 13C NMR (DMSO-d6) d = 18.51,
49.14, 61.20, 97.40, 97.44, 109.26, 114.83, 119.62, 120.80, 120.92, 121.38,
124.46, 131.75, 134.81, 136.32, 142.27, 145.23, 145.94, 166.00. ESI-MS: m/z =
359.59. Anal. Calcd for C21H18N4O2: C, 70.38; H, 5.06; N, 15.63; O, 8.93. Found:
C, 70.42; H, 5.01; N, 15.69; O, 8.88.
(m, 1H), 7.03–7.07 (m, 1H), 7.34–7.39 (m, 2H), 10.76 (s, 1H). 13C NMR (DMSO-
d6) d = 18.5, 50.7, 55.8, 59.8, 97.7, 104.3, 110.0, 116.7, 120.2, 121.7, 131.5,
137.5, 142.2, 145.6, 152.7, 165.7. ESI-MS: m/z = 409. Anal. Calcd for
C22H23N3O5: C, 64.54; H, 5.66; N, 10.26; O, 19.54. Found: C, 64.39; H, 5.63;
N, 10.31; O, 19.57.
4-Indol-2-methyl-1,4-dihydro-benzo[4,5]imidazo[1,2,a]-3-methylcarboxylate 6n: