Dichloro Dicyano Quinone (DDQ) as coupling reagent for high yield synthesis of 3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1002/jhet.5570450448

(Chemical Equation Presented) DDQ catalyzes efficiently the three-component condensation reaction of aldehyde, β-ketoester and urea in refluxing acetonitrile to afford the corresponding dihydropyrimidinones. Compared to the classical Biginelli reaction co

Full text of DOI:10.1002/jhet.5570450448

Jul-Aug 2008
1225
Dichloro Dicyano Quinone (DDQ) as Coupling Reagent for High
Yield Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones
D. Shobha, M. Adharvana Chari, P. Sadanandam and K. Mukkanti*
Dept.of Chemistry, Institute of Science and Technology, J.N.T.University, Kukatpally,
Hyderabad –500072, India.
drmac_s@yahoo.com
Received July 7, 2007
O
R
X
O
DDQ
O
NH
EtO
Me
RCHO
+
+
H2N
NH2
Me
OEt
N
H
O
CH3CN, reflux
X = O, S
1
2
DDQ catalyzes efficiently the three-component condensation reaction of aldehyde, ꢀ-ketoester and urea
in refluxing acetonitrile to afford the corresponding dihydropyrimidinones. Compared to the classical
Biginelli reaction conditions, this new approach consistently has the advantage of excellent yields (80-
92%) and short reaction times 1.5-2.5 h.
J. Heterocyclic Chem., 45, 1225 (2008).
INTRODUCTION
with microwave irradiation [19] and by using Lewis acids
as well as protic acids as promoters such as [20] Conc.
HCl, BF3.OEt2 , PPE , KSF clay , InCl3 , LaCl3, lanthanide
triflate, H2SO4, ceric ammonium nitrate (CAN),
Mn(OAc)3, ion-exchange resin, 1-n-butyl-3-methylimida-
zolium tetrafluoroborate (BMImBF4), BiCl3, LiClO4,
InBr3, FeCl3, ZrCl4 , Cu(OTf)2 , Bi(OTf)3 , LiBr, ytterbium
triflates, NH4Cl, MgBr2, SiO2/NaHSO4 and other reagents
[21-25] have been found to be effective. Many of these
methods involve expensive reagents, stochiometric
amounts of catalysts, strongly acidic conditions, long
reaction times, unsatisfactory yields and incompatibility
with other functional groups. Therefore, the development
of a neutral alternative would extend the scope of the
Biginelli reaction. In view of this, we have utilized DDQ
as an efficient reagent for the Biginelli three-component
one-pot synthesis in our laboratory.
The use of the 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ) [26] is well known for oxidation, in
dehydrogenation reactions as a coupling reagent and
recent papers report that DDQ acts as a Lewis acid
catalyst [27]. On the other hand we have developed DDQ
as a coupling reagent in this reaction. In this paper, we
wish to describe a simple and efficient procedure for the
synthesis of DPHMS via condensation of aldehyde, ꢀ-
ketoester and urea in refluxing acetonitrile in the presence
of DDQ.
Many aryl substituted 3,4–dihydropyrimidin–2-ones
(DHPMs) and their derivatives are an important class of
compounds in the field of drugs and pharmaceuticals [1].
They are found to exhibit a wide range of biological
activities [2] such as antibacterial, antiviral, antitumour,
antiinflamatory properties. Most of the DHPMs and their
derivatives are medicinally important as calcium channel
blockers, antihypertensive agents ꢁ1a-antagonists and anti
HIV agents [3]. The biological activities of some marine
alkaloids isolated recently have been attributed to the
presence of a dihydropyrimidinone moiety [4]. The
simplest and the most straightforward approach for
DHPMs involve one pot condensation of an aldehyde, ꢀ-
ketoester and urea or thiourea in the presence of acid
catalyst [5]. However, this so-called Biginelli reaction
often suffer from low yields practically in case of
substituted aromatic and aliphatic aldehydes [6]. Even
though high yields could be achieved by following
complex multi-step procedures [7], these methods lack the
simplicity of original one-pot Biginelli protocol.
Therefore, Biginelli reaction continues to attract the
attention of researchers for the discovery of milder and
efficient procedures for the synthesis of dihydro-
pyrimidinones.
Due to this, several workers [8-18] have been reported
the synthesis of DHPMs including classical conditions
Scheme 1
O
R
X
O
DDQ
O
NH
EtO
Me
RCHO
+
+
H2N
NH2
Me
OEt
N
H
O
CH3CN, reflux
X = O, S
1
2

1226
D. Shobha, M. A. Chari, P. Sadanandam and K. Mukkanti
Vol 45
RESULTS AND DISCUSSION
catalyst from 5-mol% to 10-mol%. The best results were
achieved when the reactions were carried out at reflux
temperature in an oil bath for 90 -150 minutes in the
presence of catalytic amount of DDQ. Another important
feature of this procedure is the stability of a variety of
functional groups such as ether, hydroxy, halides, nitro
etc., under these reaction conditions. This procedure not
only preserves the simplicity of Biginelli reaction but also
produces DHPMs in excellent yields. Thus this procedure
offers an easy access to substituted DHPMs with a variety
of substitution patterns. Among various solvents like
acetonitrile, methanol, ether and THF used for this
transformation, methanol and acetonitrile were the best
choice. Thiourea has been used to obtain the
corresponding thio-derivatives of dihydropyrimidinones
that possess good biological activities. Several examples
illustrating this novel and general method for the
synthesis of dihydropyrimidinones are summarized in
Table 1.
Initially, we have studied the Bignelli’s one-pot
condensation reaction of benzaldehyde (1.0 mmol) with
urea (1.2 mmol) and ethyl acetoacetate (1.2 mmol) using
5-mol% of DDQ as coupling reagent under reflux and
acetonitrile solvent conditions(Scheme 1).
Table 1
DDQ catalysed synthesis of dihydropyrimidinones and thio derivaties.
R
X
Entry(1)
a
Time (h)
Yield(%)
CHO
CHO
O
1.5
92
b
c
O
O
2.0
2.0
89
91
Cl
Cl
CHO
CHO
Cl
d
e
O
1.5
90
OH
CHO
CONCLUSION
O
O
1.5
2.0
88
90
OH
We have developed a simple, convenient and effective
method for the synthesis of 3,4-dihydropyrimidinones by
using DDQ. This method is applicable to a wide range of
substrates including aromatic, aliphatic, ꢀ,ꢁ-unsaturated
and heterocyclic aldehydes. To our knowledge, this is the
first report of an efficient general method for the synthesis
of DHPMs by using DDQ.
CHO
f
H3CO
CHO
CHO
g
h
i
O
O
2.5
2.5
84
88
H3C
O2N
CHO
O
O
O
2.0
85
EXPERIMENTAL
CHO
CHO
j
2.5
2.5
85
80
O
Typical procedure: A solution of ethyl acetoacetate (156 mg,
1.2 mmol), aldehyde (1.0 mmol) and urea (72 mg, 1.2 mmol) in
acetonitrile (8 ml) was heated under reflux conditions in the
presence of catalyst (5 mol%) for 2.5 h. Completion of the
reaction was monitored by TLC. The reaction mixture was then
poured onto crushed ice and the solid product separated was
filtered and recrystallised from methanol. The spectral data of
some of the compounds are given below.
Compound (l). Solid, m.p. 193-194°C. 1H NMR (DMSO-d6):
ꢂ 1.14 (t, 3H, J = 6.8 Hz), 2.36 (s, 3H), 4.10 (q, 2H, J = 6.8 Hz),
5.35 (s, 1H), 5.80 (brs, NH), 6.85 (m, 1H), 7.05 ~ 7.10 (m, 5H),
7.45 (m, 3H), 8.40 (brs, NH). EIMS: m/z 352 (M+), 323, 279,
183, 155, 137, 91, 69. IR (KBr): ꢃ 3242, 3112, 2981, 1712,
1654, 1582, 1487, 1245, 1097, 786. Anal. Calcd. for C20H22N2O4
(354.16): C, 67.78; H, 6.26; N, 7.90; O, 18.06. Found: C, 67.79;
H, 6.26; N, 7.94; O, 18.10.
k
CHO
l
O
2.5
2.5
2.5
91
85
85
PhO
CHO
CHO
O
O
m
n
Ph
HO
HO
OH
CHO
CHO
o
p
S
1.5
92
S
S
2.0
2.0
90
90
Cl
CHO
OH
q
Compound (m). Solid, m.p. 229-231°C (lit. 232-235). 1H
NMR (DMSO-d6): ꢂ 1.06 (t, 3H, J = 7.0 Hz), 2.50 (s, 3H), 3.95
(q, 2H, J = 7.0 Hz), 4.24 (d, 1H, J = 6.0 Hz), 6.05 (dd, 1H, J =
16.4 Hz), 6.2 (d, 1H, J = 16.4 Hz), 7.20 ~ 7.25 (m, 5H), 7.45 (d,
NH, J = 1.7 Hz), 8.95 (brs, NH). EIMS: m/z 286 (M+), 252, 224,
196, 149, 84. IR (KBr): ꢃ 3335, 3242, 3098, 2978, 1689, 1642,
1492, 1373, 1218, 1121, 785. Anal. Calcd. for C16H20N2O3
(288.15): C, 66.65; H, 6.99; N, 9.72; O, 16.65. Found: C, 66.68;
H, 6.99; N, 9.75; O, 16.67.
Encouraged by these results, we examined several
aromatic and aliphatic aldehydes under the optimized
conditions. Furthermore, the use of just 5-mole% DDQ as
coupling reagent is sufficient to promote the reaction. The
three-component condensations proceeded smoothly in
refluxing acetonitrile and also are complete with in 1-2.5
h of reaction time. There are no improvements in the
reaction rates and yields by increasing the amount of the
All other products were characterized by spectral (NMR &
IR) data and by comparison with those of authentic samples and

Jul-Aug 2008
Dichloro Dicyano Quinone (DDQ) as Coupling Reagent
1227
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Acknowledgement. The authors are thankful to Director,
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