An efficient one-pot synthesis of 3,4-dihydropyrimidin-2-ones catalyzed by methanesulfonic acid

Article abstract of DOI:10.1081/SCC-200026660

An efficient synthesis of 3,4-dihydropyrimidin-2-ones (DHPMs) from the aldehydes, β-ketoesters, and urea in ethanol using methanesulfonic acid (CH₃SO₃H) as the catalyst is described. Compared with the classical Biginelli reaction con

Full text of DOI:10.1081/SCC-200026660

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An Efficient One‐Pot
Synthesis of
3,4‐Dihydropyrimidin‐2‐ones
Catalyzed by Methanesulfonic
Acid
Tong‐Shou Jin a , Huan‐Xin Wang a , Chun‐Yong
Xing a , Xiao‐Liu Li a & Tong‐Shuang Li a
a Department of Chemistry, College of Chemistry
and Environmental Science , Hebei University ,
No. 88 Hezuo Road, Baoding, 071002, Hebei
Province, P.R. China
Published online: 06 Jan 2011.
To cite this article: Tong‐Shou Jin , Huan‐Xin Wang , Chun‐Yong Xing , Xiao‐Liu Li &
Tong‐Shuang Li (2004) An Efficient One‐Pot Synthesis of 3,4‐Dihydropyrimidin‐2‐ones
Catalyzed by Methanesulfonic Acid, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 34:16, 3009-3016,
DOI: 10.1081/SCC-200026660
To link to this article: http://dx.doi.org/10.1081/SCC-200026660
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 16, pp. 3009–3016, 2004
An Efficient One-Pot Synthesis of
3,4-Dihydropyrimidin-2-ones Catalyzed
by Methanesulfonic Acid
*
Tong-Shou Jin, Huan-Xin Wang, Chun-Yong Xing,
Xiao-Liu Li, and Tong-Shuang Li
Department of Chemistry, College of Chemistry and Environmental
Science, Hebei University, Baoding, Hebei Province, P.R. China
ABSTRACT
An efficient synthesis of 3,4-dihydropyrimidin-2-ones (DHPMs) from the
aldehydes, b-ketoesters, and urea in ethanol using methanesulfonic acid
(CH3SO3H) as the catalyst is described. Compared with the classical
Biginelli reaction conditions, this method has the advantage of excellent
yields and short reaction time.
Key Words: Dihydropyrimidin-2(1H)-ones; Methanesulfonic acid;
Synthesis.
*
Correspondence: Tong-Shou Jin, Department of Chemistry, College of Chemistry and
Environmental Science, Hebei University, No. 88 Hezuo Road, Baoding 071002,
Hebei Province, P.R. China; E-mail: orgsyn@mail.hbu.edu.cn.
3009
DOI: 10.1081/SCC-200026660
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Jin et al.
INTRODUCTION
In the past decade, dihydropyrimidine derivatives have exhibited import-
ant pharmacological properties, as the integral backbone of several calcium
channel blockers, antihypertensive agents,a-1a-antagonists, and neuropeptide
antagonists.[1] Recently, several natural marine alkaloids with interesting
biological activities were also found to contain the dihydropyrimidinone-5-
carboxylate core.[2] Most notably among them are the batzelladine alkaloids,
which have been found to be potent HIVgp-120-CD4 inhibitors.[3] Conse-
quently, the synthesis of compounds containing the heterocyclic nucleus has
gained importance.
The Biginelli reaction, first described more than a century ago and
recently reviewed,[4] consists of the acid-catalyzed cyclocondensation reac-
tion of ethyl acetoacetate, benzaldehyde, and urea. This reaction is performed
by simply heating a mixture of the above three components dissolved in
ethanol with a catalytic amount of hydrochloric acid at reflux temperature
for 18 hr. However, this one-pot, one step protocol often provides only low
to moderate yields of the desired products (20–50%), in particular when sub-
stituted aromatic or aliphatic aldehydes were used. Therefore, the discovery of
milder and practical routes for the synthesis of dihydropyrimidin-2(1H)-ones
(DHPMs) by the Biginelli reaction continues to attract the attention of
chemists. Recently, several improved procedures for the preparation
of DHPMs (Biginelli compounds) have been reported, either by modification
of the classical one-pot Biginelli approach itself, such as polyphosphate ester
(PPE),[5] Lewis acid,[6–8] lanthanide compounds,[9,10] or by the development
of novel but more complex multistep strategies.[11] In addition, significant
enhancements on reaction rate and yield were realized for Biginelli reactions
under microwave irradiation.[12] Several combinatorial approaches towards
DHPMs have been also done, using solid phase or fluorous phase reaction
conditions.[13] More recently, several other conditions for the one-pot synthesis
of DHPMs have also been reported.[14–17] However, in spite of their respective
advantage and potential utility, some of the reported methods suffer from draw-
backs such as longer reaction times, higher temperatures, expensive catalysts,
lower yields, and cumbersome product isolation procedures.
Methanesulfonic acid (CH3SO3H) has been widely used for the catalysis
of various syntheses,[18,19] for a variety of reasons, including good color in
final product, faster reaction rate, no undesirable decomposition byproducts,
and low molecular weight, therefore, low cost per acid functionality.
However, the use of CH3SO3H as a catalyst in the synthesis of pyrimidinones
has not been reported yet. In this paper, we would like to report a general and
practical approach for the Biginelli cyclocondensation reaction using
CH3SO3H as catalyst (Sch. 1).