Vanadium(III) chloride catalyzed Biginelli condensation: Solution phase library generation of dihydropyrimidin-(2H)-ones

Article abstract of DOI:10.1016/S0040-4039(03)01564-8

The three component condensation of an aldehyde, a β-keto ester and urea (thiourea) in the presence of a catalytic amount of VCl₃ is disclosed for the solution phase synthesis of dihydropyrimidinones. The ease of synthesis and work-up allowed t

Full text of DOI:10.1016/S0040-4039(03)01564-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6497–6499
Vanadium(III) chloride catalyzed Biginelli condensation: solution
phase library generation of dihydropyrimidin-(2H)-onesꢀ
Gowravaram Sabitha,* G. S. Kiran Kumar Reddy, K. Bhaskar Reddy and J. S. Yadav
Organic Chemical Sciences, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 13 March 2003; revised 12 June 2003; accepted 20 June 2003
Abstract—The three component condensation of an aldehyde, a b-keto ester and urea (thiourea) in the presence of a catalytic
amount of VCl3 is disclosed for the solution phase synthesis of dihydropyrimidinones. The ease of synthesis and work-up allowed
the parallel synthesis of a 48-membered library of dihydropyrimidinones quickly and efficiently in good yields.
© 2003 Elsevier Ltd. All rights reserved.
Combinatorial chemistry is playing an increasingly
important role as one of the tools of modern medicinal
chemistry for the rapid discovery of new leads.1 The
preparation of libraries of small organic molecules is a
rapidly evolving area of research.2 Recently much
attention has been devoted towards dihydropyrimidine
derivatives due to their significant therapeutic and
medicinal properties.3 Several marine alkaloids having
the dihydropyrimidinone core unit were found to show
interesting biological activities such as antiviral, antitu-
mor, antibacterial and anti-inflammatory activities.4 In
particular, the batzelladine alkaloids have been found
to be potent HIV gp-120-CD4 inhibitors.5 Many func-
tionalised derivatives are used as calcium channel
blockers, antihypertensive agents and a-1a antagonists.6
Therefore, the preparation of this heterocyclic core unit
has gained much importance. The simple and direct
method originally reported by Biginelli7 involves the
one-pot condensation of a b-keto ester with an alde-
hyde and urea under strongly acidic conditions but
often suffers from low yields when substituted aromatic
and aliphatic aldehydes are employed. This has led to
the disclosure of several improved procedures using
strong Lewis acids such as BF3·Et2O, protic acids such
as HCl, and AcOH as additives; many other reagents8
have also been employed, including ionic liquids, for
the synthesis of these derivatives. More recently KSF
has been employed for this9 transformation but requires
long reaction times (10–48 h) to obtain good yields.
Most of these methods use expensive reagents, strongly
acidic conditions, require long reaction times, give
unsatisfactory yields and involve difficult product isola-
tion. To the best of our knowledge, there is no report
on the synthesis of a dihydropyrimidine library in solu-
tion phase.
In this communication, we disclose a simple but effec-
tive modification of the Biginelli reaction that produces
high yields of dihydropyrimidinones using a catalytic
amount of VCl3 while preserving the original one-pot
strategy. Vanadium(III) chloride is relatively unex-
plored as a reagent in organic synthesis.10 The reactivity
of VCl3 and also the effect of solvent, time and temper-
ature on the Biginelli reaction was explored using the
model reaction between 2a, 3a and 4A which gave
product 1aA (Scheme 1). The reaction was found to be
complete within 2 h in refluxing acetonitrile and the
product precipitated from the reaction mixture on cool-
ing to room temperature. A catalytic amount of VCl3
was sufficient to push the Biginelli reaction forward. To
demonstrate the advantages of this procedure, we car-
ried out the synthesis of a 48-compound library in a
Keywords: Biginelli condensation; VCl3; dihydropyrimidin-2(1H)-
ones; parallel synthesis.
ꢀ IICT Communication No: 030306
* Corresponding author. Fax: +91-40-27160512; e-mail: sabitha@
iict.ap.nic.in
Scheme 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01564-8

6498
G. Sabitha et al. / Tetrahedron Letters 44 (2003) 6497–6499
Table 1. A 48-membered library of dihydropyrimidinonesa,b
parallel fashion using a Multiple synthesizer11 in 4 sets
of reactions (Table 1). For this purpose 12 reaction
vessels were charged with different mixtures of sub-
strates and a catalytic amount of VCl3 was added to
each vessel which were then heated at acetonitrile reflux
temperature for 2 h after which the completed reactions
were taken out of the reaction block (see experimental
procedure12). On cooling to room temperature the
products precipitated out. The reaction mixtures were
then poured onto crushed ice, and the solid product
separated, filtered and recrystallized. In order to
increase diversity, 6 different ketoesters or 1,3-dicar-
bonyl substrates, 10 different aldehydes and urea or
thiourea were used. The scope of the methodology was
demonstrated as a variety of 1,3-dicarbonyl compounds
proved effective with this protocol. Similarly, the con-
densation reactions were repeated three times with dif-
ferent combinations. All 48 compounds were formed in
good yields (80–96%) and with high purity >95%. Due
to short reaction times, high yields and easy work-up
procedures combined with the use of the Multiple
synthesizer, it was also possible to synthesize the 48
compounds within a few hours.13
corresponding dihydropyrimidines in good yields in 2 h
(see Table 1).
In summary, a novel solution phase procedure for the
preparation of dihydropyrimidinones has been
reported. The short reaction times, simple work-up and
isolation of the products in high yields with high puri-
ties make this approach a feasible and attractive proto-
col for the generation of dihydropyrimidinone libraries
as is demonstrated in Table 1.
Acknowledgements
G.S.K.K. thanks CSIR, and KBR thanks UGC, New
Delhi for the award of fellowships.
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