Microwave-assisted efficient synthesis of dihydropyrimidines in solvent-free condition

Article abstract of DOI:10.1081/SCC-200030577

An efficient synthesis of 3,4-dihydropyrimidinones from an aldehyde, a ketoester, and a urea or thiourea using a catalytic amount of ferric chloride hexahydrate is described. Microwave irradiation has been used to accelerate the synthesis of the Biginelli

Full text of DOI:10.1081/SCC-200030577

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Microwave‐Assisted
Efficient Synthesis of
Dihydropyrimidines in
Solvent‐Free Condition
Maryam Mirza‐Aghayan a , Mohammad
Bolourtchian a & Maryam Hosseini a
a Chemistry and Chemical Engineering Research
Center of Iran (CCERCI), P.O. Box 14335‐186,
Tehran, Iran
Published online: 10 Jan 2011.
To cite this article: Maryam MirzaAghayan , Mohammad Bolourtchian & Maryam
Hosseini (2004) Microwave‐Assisted Efficient Synthesis of Dihydropyrimidines in
Solvent‐Free Condition, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 34:18, 3335-3341, DOI:
10.1081/SCC-200030577
To link to this article: http://dx.doi.org/10.1081/SCC-200030577
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 18, pp. 3335–3341, 2004
Microwave-Assisted Efficient Synthesis of
Dihydropyrimidines in Solvent-Free
Condition
*
Maryam Mirza-Aghayan, Mohammad Bolourtchian,
and Maryam Hosseini
Chemistry and Chemical Engineering Research Center of Iran
(CCERCI), Tehran, Iran
ABSTRACT
An efficient synthesis of 3,4-dihydropyrimidinones from an aldehyde,
a ketoester, and a urea or thiourea using a catalytic amount of ferric chlor-
ide hexahydrate is described. Microwave irradiation has been used to
accelerate the synthesis of the Biginelli compounds under solvent-free
conditions and in a short reaction time and with good yield.
Key Words: Microwave irradiation; Biginelli compounds; Solvent-free
condition; Ferric chloride hexahydrate.
*
Correspondence: Maryam Mirza-Aghayan, Chemistry and Chemical Engineering
Research Center of Iran (CCERCI), P.O. Box 14335-186, Tehran, Iran; E-mail:
m.mirzaaghayan@ccerci.ac.ir.
3335
DOI: 10.1081/SCC-200030577
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3336
Mirza-Aghayan, Bolourtchian, and Hosseini
Dihydropyrimidinones are an important class of compounds, which is
becoming increasingly important due to their therapeutic and pharmacological
properties.[1] They have emerged as the integral backbones of several calcium
channel blockers, antihypertensive agents, and alpha-1a-antagonists.[2]
Recently, several isolated marine alkaloids with interesting biological activi-
ties were also found to contain the dihydropyrimidinone-5-carboxylate core.[3]
Most notably among them are the batzelladine alkaloids, which have been
found to be potent human immunodeficiency virus (HIV) gp-120-CD4 inhibi-
tors.[4] Consequently, synthesis of the heterocyclic nucleus contained in such
compounds has gained importance. The simple and direct method originally
reported by Biginelli involving three-component condensation reaction
often suffers from low yield, particularly in case of substituted aromatic alde-
hydes.[1,5] The Biginelli reaction has been reviewed.[6] Subsequently reported
multistep protocols afford somewhat higher yields but these do not have the
simplicity of the original one-pot Biginelli protocol.[7] However, some of
the newer reported methods also suffer from drawbacks such as unsatisfactory
yield, cumbersome product isolation procedures, and environmental
pollution.[8]
Several groups have demonstrated that chemical synthesis may be
dramatically accelerated using microwave irradiation. The conditions
caused by this kind of heating lead directly to acceleration in the reaction
times compared with conventional reflux conditions.
Reactions carried out in dry media offer a number of advantages, consid-
ering solvents are often expensive, toxic, and, in the case of aprotic solvents
with high boiling point, difficult to remove.[9]
In recent years, ferric chloride hexahydrate has emerged as an efficient
catalyst in carbon-carbon bond-forming reactions.[10] In continuation of our
interest in microwave-assisted organic transformation,[11] herein we report a
simple but effective modification of the Biginelli reaction using ferric chloride
hexahydrate under solvent-free conditions using microwave irradiation that
produces good yields of the desired dihydropyrimidines while preserving
the original one-pot strategy.
Microwave irradiation can be applied to synthesis of a number of 3,4-
dihydropyrimidinones, via a simple and fast procedure based on the reaction of
ethyl acetoacetate, aldehydes, and urea or thiourea in solvent-free conditions
(Sch. 1).
An equimolar quantity of an aldehyde, a b-keto ester, and 1.5 equimolar
equivalents of urea or thiourea were mixed and subjected to microwave
irradiation for an appropriate time. After cooling to room temperature, water
was added and the product was extracted with ethyl acetate. After the organic
layer was dried (Na2SO4) and evaporated, the residue was recrystallized by
ethyl acetate. The results were disappointing because of the low yield and

Synthesis of Dihydropyrimidines in Solvent-Free Condition
3337
Scheme 1.
long reaction time (Table 1). However, in order to obtain better yields, an
alternative procedure using the catalyst was developed. As previously, to
a mixture of an equimolar of aldehyde, b-keto ester, and 1.5 equimolar of
urea or thiourea was added a catalytic amount of ferric chloride hexahydrate
(10%).
With the catalyst (ferric chloride hexahydrate), the reaction was faster
and the yields were higher. The yields of the one-pot Biginelli reaction can
be increased to 38%–68% while the reaction time is shortened from 18 hr
to 48 hr to 20 s to 30 s by this procedure. Table 1 summarizes the results for
the application of this procedure to a series of aldehydes, showing the time
in which the reactions were done.
In conclusion, a novel method for the synthesis of dihydropyrimidinones
by three-component Biginelli condensation of aldehyde with b-keto ester and
urea or thiourea using ferric chloride hexahydrate as catalyst under solvent-
free and microwave irradiation conditions was developed on good yield.
We have described a simple modification of the Biginelli dihydropyrimidine
.
synthesis by using FeCl3 6H2O as the catalyst. The main advantages of this
methodology are simple catalyst system and shorter time reaction, which is
free of organic solvent.
EXPERIMENTAL
Nuclear magnetic resonance (1H-NMR) spectra were registered on a
Bruker 80-MHz in DMSO utilizing tetramethylsilane as the internal standard.
Mass spectra were obtained on a FISON GC 8000/Trio 1000 gas chromato-
graphy under 70 eV. Melting points were determined in evacuated capillaries
with a Buchi 530 melting points apparatus. Microwave irradiation was carried
out in a National oven Model 6755 at 900 W.

3338
Mirza-Aghayan, Bolourtchian, and Hosseini

Synthesis of Dihydropyrimidines in Solvent-Free Condition
3339
Typical Procedure for 3,4-dihydropyrimidin-2(1H)-ones
Preparation
Aldehyde (1 mmol), ethyl acetoacetate (1 mmol), and urea or thiourea
.
(1.5 mmol) was added to FeCl3 6H2O (0.1 mmol). The reaction mixture was
irradiated in a microwave oven for the indicated time (Table 1). After cooling
to room temperature, water was added and the product was extracted with
ethyl acetate. After the organic layer was dried (Na2SO4) and evaporated,
the residue was recrystallized from ethyl acetate to afford pure products.
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Received in the UK January 19, 2004