CL-130732
Received: August 10, 2013 | Accepted: October 14, 2013 | Web Released: October 23, 2013
Propylphosphonic Anhydride-catalyzed Tandem Approach
for Biginelli Reaction Starting from Alcohols
Cigalli N. Revanna,1,2 Goravanalli M. Raghavendra,3 T. A. Jenifer Vijay,3 Kanchugarakoppal S. Rangappa,3
Doddamedur G. Badregowda,1 and Kempegowda Mantelingu*3
1Yuvaraja’s College, University of Mysore, Mysore-570005, India
2Syngene International Limited, Jigini Link Road, Bangalore 560099, India
3Department of Studies in Chemistry, University of Mysore, Mysore-570006, India
(E-mail: mantelingu@chemistry.uni-mysore.ac.in)
An efficient and highly convergent route to dihydropyrimi-
dinones (DHPMs) has been developed by one-pot three-
component oxidative cyclocondensation of a variety of alcohols,
β-ketoesters/β-oxodithioester and urea in the presence of T3Pμ/
DMSO. This new approach consistently has the advantage of
tandem and good yields (65-88%).
O
R
S
R
O
S
O
O
EtO
NH
Ph
SMe
OEt
urea, T3P/DMSO
MeS
NH
R
OH
N
H
O
urea, T3P/DMSO
Ph
N
H
O
2a−2l
3a−3c
1
Scheme 1.
Domino processes and multicomponent reactions (MCRs)
in an environmentally benign and atom-economic fashion play
important roles in organic synthesis especially for the synthesis
of bioactive heterocycles.1 3,4-Dihydropyrimidin-2-ones
(DHPMs) and their derivates have been receiving much attention
in recent years owing to their enormous application in the field
of drugs and pharmaceuticals.2-4 They occupy an important
place in the realm of natural and synthetic organic chemistry due
to their broad range of biological, including antiviral, antitumor,
antibacterial, and anti-inflammatory activities and as HIV
agents.5-9 They also attracted considerable interest due to their
promising activities as calcium channel blockers and orally
active antihypertensive agents. A very recent important highlight
in this aspect is the identification of the structurally rather simple
DHPM monastrol as a mitotic kinesis EG5 motor protein
inhibitor and potential new lead for the development of
anticancer drugs.10 In 1893, Italian chemist Pietro Biginelli first
reported the synthesis of DHPMs by multicomponent cyclo-
condensation,11 involving reaction among a β-ketoester, an
aldehyde, and urea under strong acidic conditions. Under strong
acidic conditions the yields are very low, around 20%. To
enhance the efficiency of the Biginelli condensation, various
catalysts and reaction conditions have been studied including
classical conditions, microwave-assisted irradiation, solid sup-
port, ionic liquids,12 Lewis acid well as protic acid promoters
such as BF3¢OEt2,13a InCl3,13b LaCl3¢7H2O,13c FeCl3¢6H2O,13d
Mn(OAc)2,14a LiClO4,14b H2SO4,14c HClO4¢SiO4.14d Zumpe et al.
reported propylphosphonic anhydride (T3Pμ)-catalysed synthe-
sis of 3,4-dihydropyrimidin-2(1H)-ones from aldehydes.14e
Recently, tandem oxidative processes (TOP) in which
oxidation of alcohols combined with the subsequent elaboration
of the carbonyl intermediates (aldehyde) have gained consid-
erable attention among synthetic chemists.15,16 Although a lot of
work has been done for developing bimolecular TOP processes,
the literature records only a few examples of combining alcohol
oxidation with a multicomponent reaction (MCR) in a one-pot
process.17
corresponding alcohols. Thus, in many cases aldehydes must be
purified just before their use because the presence of other
products affects not only the concentration of the active
aldehyde but also that the impurities often interfere with
chemical reactions involving the aldehyde. The difficulties
associated with the development of one-pot oxidation-MCR
processes are self-evident due to the presence of multifunction-
alities/multiintermediates and the complexity of the reaction
mechanism intrinsic to MCRs. Thus, the use of a single vessel
oxidation-MCR protocol would widen significantly the versa-
tility and scope of the aldehyde-based MCRs. There have been
only two reports on the Biginelli reaction starting directly from
alcohols.18 Very few reports on dihydropyrimidinones synthesis
using β-oxodithioesters have appeared. However, to best of our
knowledge this is the first report for the synthesis of dihydro-
pyrimidinones starting from alcohols and β-oxodithioesters
(Scheme 1).19,20
In continuation of our recent work on the synthesis of
heterocycles by the development of new methodology,21-24 in
this paper, we report for the first time T3Pμ-DMSO-mediated
tandem approach for the promoted Biginelli reactions. T3Pμ-
catalyzed Biginelli reaction applied to the one-pot three-
component oxidative condensations of a variety of alcohols,
β-ketoester, and urea for the synthesis of DHPMs which is
simple and high yielding. The one-pot procedure should prove
highly advantageous for labile aldehydes in particular.
Treatment of alcohol (2 mmol), ethyl acetoacetate (2 mmol),
and urea (3 mmol) in the presence of T3Pμ (4 mmol) in DMSO/
ethyl acetate (1:2) at room temperature for 1-2 h followed by
heating with ethyl acetate afforded the corresponding 3,4-
dihydropyrimidones. The results are summarized in Table 1. The
yields of products were generally >94% as assessed by LC-
MS.27,28 Another, important feature of this protocol is survival of
a variety of functional groups such as OCH3, OH, NO2, Br, and
Cl under the reaction conditions. To explore the scope and
limitations of these reactions, we extended the procedure to
various aryl-substituted alcohols carrying either electron-releas-
ing (2a-2e) or electron-withdrawing (2f-2h), heterocyclic (2i
and 2j), aliphatic (2k and 2l) substituents. The same process was
successfully extended to β-oxodithioesters to the corresponding
Aldehydes are ubiquitous substrates in many powerful
MCRs. However, they are in general, more volatile, toxic, or
unstable, especially because of aerial oxidation, than their
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