Zeolite catalyzed solvent-free one-pot synthesis of dihydropyrimidin-2(1H)- ones - A practical synthesis of monastrol

Article abstract of DOI:10.3762/bjoc.5.4

A zeolite-catalyzed, simple, one-pot, solvent-free, cost effective, and environmentally benign process for the synthesis of dihydropyrimidones is described. This reaction is scaleable to multigram scale and the catalyst is recyclable. This methodology has

Full text of DOI:10.3762/bjoc.5.4

Zeolite catalyzed solvent-free one-pot synthesis of
dihydropyrimidin-2(1H)-ones – A practical synthesis
of monastrol
Mukund G. Kulkarni*, Sanjay W. Chavhan, Mahadev P. Shinde,
Dnyaneshwar D. Gaikwad, Ajit S. Borhade, Attrimuni P. Dhondge,
Yunnus B. Shaikh, Vijay B. Ningdale, Mayur P. Desai
and Deekshaputra R. Birhade
Preliminary Communication
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 4.
Department of Chemistry, University of Pune, Ganeshkhind, Pune
411007, Maharashtra, India
doi:10.3762/bjoc.5.4
Received: 15 October 2008
Accepted: 23 January 2009
Published: 04 February 2009
Email:
Mukund G. Kulkarni* - mgkulkarni@chem.unipune.ernet.in
* Corresponding author
Editor-in-Chief: J. Clayden
Keywords:
© 2009 Kulkarni et al; licensee Beilstein-Institut.
License and terms: see end of document.
Biginelli reaction; DHPMs; neat; MCR; zeolite
Abstract
A zeolite-catalyzed, simple, one-pot, solvent-free, cost effective, and environmentally benign process for the synthesis of
dihydropyrimidones is described. This reaction is scaleable to multigram scale and the catalyst is recyclable. This methodology has
resulted in an efficient synthesis of monastrol, a potent inhibitor of kinesin Eg5.
Introduction
The Biginelli reaction is a well-known multicomponent reac- the synthesis of DHPMs. A one-pot cyclocondensation of ethyl
tion involving a one-pot cyclocondensation of an aldehyde, acetoacetate, an aromatic aldehyde and urea under strongly
β-ketoester and urea/thiourea [1-3]. Multicomponent reactions acidic conditions furnished the corresponding DHPMs [1].
(MCRs) have recently gained tremendous importance in organic Unfortunately this method led to low to moderate yields of the
and medicinal chemistry. The main contributing factors are the desired DHPMs, particularly when substituted aromatic or
high atom economy, wide application in combinatorial chem- aliphatic aldehydes and thiourea were employed [14-20].
istry and diversity-oriented synthesis [4-10]. In general, the
dihydropyrimidones (DHPMs) are known for their diverse To overcome this problem, various homogeneous as well as
important biological activities like antiviral, antitumor, antibac- heterogeneous catalysts have been utilized. Typical examples of
terial and antiinflammatory properties [11-13].
the various homogeneous catalysts employed are polyphos-
phate ester [18], LaCl3·7H2O [21] and LiClO4 [22]. Recently
The first report of the Biginelli reaction dates back to 1893. Lewis acid catalyzed Biginelli reactions have been extensively
This involved a very simple and straightforward procedure for reported in the literature. This involved the use of Lewis acids
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Beilstein Journal of Organic Chemistry 2009, 5, No. 4.
like Yb(OTf)3 [23], CuCl2 [24], Mn(OAc)3 [25], Bi(OTf)3 [26], reaction conditions, even on using excess of ethyl acetoacetate
CeCl3·7H2O [27], Cu(OTf)2 [28], FeCl3 [29], BF3·Et2O/ (2 mmol), no side product arising through Knoevenagel
Cu(OAc)2 [30], ZrCl4 [31], polymer supported ytterbium condensation [41] was observed.
reagents [32], TaBr5 [33], ZrCl4 or ZrOCl2 [34]. Baker’s yeast
has also been used recently for this purpose [35]. The Brønsted This methodology was effective for aliphatic as well as
acid mediated Biginelli reactions using p-TSA [36], H2SO4/ aromatic aldehydes in the preparation of dihydropyrimidones
SiO2 [37], and KHSO4 [38] are known in the literature. The (4a–4l) with uniformly high yields (Table 1).
heterogeneous catalysts used in this reaction involve the use of
KSF (montmorillonite) [39], bentonitic clay [40], and zeolites
Table 1: Titanium silicate (TS-1) catalyzed synthesis of DHPMs.
like HZSM-5, Hy, MCM–41 [41]. The limitations in using the
Prod No.
R
X
Time
(min)
Yield
(%)
above mentioned catalysts were elevated reaction temperatures,
solvent mediated reactions and moderate yields of the products.
Apart from these, the heterogeneous catalysts were required in
stoichiometric amounts. Furthermore, when aliphatic aldehydes
and thiourea were used low yields of DHPMs were realized.
4a
4b
4c
4d
4e
4f
Ph
O
O
O
O
O
O
O
O
O
O
O
O
S
10
10
12
15
30
25
35
20
10
18
12
15
20
33
20
14
98
93
97
97
94
95
90
96
96
96
95
95
95
94
95
95
CH3
CH3-CH2
CH3-CH2-CH2
4-(OH)-C6H4
3-(OH)-C6H4
2-(NO2)-C6H4
4-(Cl)-C6H4
Ph-CH=CHa
3,4-di-(OMe)C6H3
2-furyl
Results and Discussion
We herein report a one-pot synthesis of DHPMs using a cata-
lytic amount of zeolite under solvent-free conditions. In our
quest to bring about the Biginelli reaction, we attempted the
reaction using zeolite under solvent-free conditions. The well-
known titanium silicate TS-1 (also known as titanium silicalite)
[42] is a widely used heterogeneous catalyst. Therefore we
decided to explore its suitability in the Biginelli reaction. For
this purpose, a mixture of an aldehyde 1 (1 mmol), ethyl aceto-
acetate (2, 1 mmol), urea 3 (1.5 mmol) and TS-1 (10 wt %) was
stirred at room temperature for 10 min (TLC check). The solid
product 4 obtained was extracted in hot ethanol and on concen-
trating the extract the product was obtained albeit in low yield
(25%). Even after stirring the reaction mixture for prolonged
4g
4h
4I
4j
4k
4l
5-methyl-2-furyl
CH3
4m
4n
4o
4p
3-(OH)-C6H4
4-(Cl)-C6H4
Ph-CH=CH
S
S
S
acommercially available cinnamic aldehyde was used.
time, no substantial increase in the yield was observed. Hence This catalyst also worked well even with an acid-sensitive alde-
the reaction mixture was heated at 50 °C for 10 min (TLC hyde such as furfural (4k–4l) without leading to the formation
check). Following the above workup procedure, the product was of any side products. The structural variations in the aldehydes
obtained in 98% yield (Scheme 1).
employed in the reaction has no effect on the yield of the reac-
tion, which is uniformly high. Significantly, a variety of sens-
itive functional groups like the NO2, Cl, OH, OCH3 and conjug-
ated double bonds affect neither the course nor the yield of the
reaction.
The scope of the reaction was further expanded when the reac-
tion was carried out successfully using thiourea to provide the
corresponding dihydropyrimidin-2(1H)-thiones (4m–4p). These
thiones are also of much interest with regard to biological
activity. One of the well-known examples of dihydropyrimidin-
2-(1H)-thiones is the compound monastrol (4n), a potent inhib-
Scheme 1: General procedure for the synthesis of DHPMs.
Next we explored the effect of the amount of catalyst on the itor of kinesin Eg5 (Figure 1).
yield of the product obtained in the reaction. After several runs
using diminishing quantities of the catalyst it was found that We could achieve the synthesis of this compound in one step
there is no effect on the product yield even when the catalyst using 3-hydroxybenzaldehyde, thiourea, ethyl acetoacetate and
was used to the extent of 2 wt %. So all the further reactions TS-1 under the above mentioned reaction conditions. Monastrol
were conducted using 2 wt % of catalyst. Under the present was obtained in 94% yield.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 4.
Supporting Information
Supporting Information File 1
13C NMR spectra of compounds 4a–4p
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-5-4-S1.doc]
Supporting Information File 2
Figure 1: Monastrol (4n).
Experimental procedures for compounds 4a–4p
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-5-4-S2.doc]
The most important and salient feature of the present reaction is
the recyclability of the catalyst and the scaleability of the reac-
tion. It was observed that the catalyst could be reused at least
seven times. Use of the recycled catalyst in the reaction had no Acknowledgments
effect either on the yield of the product or the quality of the The authors SWC, APD, ASB, YBS, DDG, VBN, DRB thank
product. Moreover no side products were observed in these CSIR and MPD thanks UGC for Fellowships.
reactions. Furthermore, the reaction can be scaled up to a multi-
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