Tetrahedron Letters 51 (2010) 966–969
Tetrahedron Letters
Lithium perchlorate-induced electrophilic activation: one-pot synthesis
of 3-aryl-2-thioxotetrahydropyrimidin-4-one derivatives from aryl
isothiocyanates
*
Varun Kumar, Vipin A. Nair
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160 062, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel methodology for the synthesis of N-substituted-3-aryl-2-thioxotetrahydropyrimidin-4(1H)-one
derivatives had been developed by the condensation of aryl isothiocyanates with b-amino esters using
lithium perchlorate as a catalyst and triethylamine as a base. This strategy not only overcomes the dis-
advantages of the reported methods but also provides high yield of the product in short span of time
by an easily workable procedure.
Received 13 November 2009
Revised 8 December 2009
Accepted 10 December 2009
Available online 13 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
reported for the synthesis of these compounds employs ionic
liquid-phase organic synthesis (IoLiPOS) methodology under
3-Aryl-2-thioxotetrahydropyrimidin-4-one derivatives are an
important class of heterocyclic compounds which had found
extensive use in pharmaceutical and agrochemical researches.
These scaffolds have been used to increase HDL cholesterol con-
centration and as therapeutic compositions for treating atheroscle-
rotic conditions such as dyslipoproteinemias and coronary heart
disease.1 Moreover these derivatives had shown interesting anti-
cancer properties as well.2 3-Aryl dihydrothiouracils are known
for their herbicidal and anticonvulsant activities.3,4 Their homo-
logues, the thiohydantoins are highly promising candidates for
androgen-dependent conditions such as prostate cancer which is
one of the most frequently diagnosed cancers and the second lead-
ing cause of cancer deaths in men after lung cancer.5
In our efforts to develop selective androgen receptor modula-
tors, we have focused on 3-aryl-2-thioxotetrahydropyrimidin-4-
one derivatives, their homologues the thiohydantoins being well
known for their binding affinity with the androgen receptor. The
rigid conformation of the thiohydantoin and the aryl substituent
at the 3-position with electron-withdrawing group are expected
to play an important role in the ligand-binding interactions.5
Unfortunately there are not many literature reports available on
the synthesis of 3-aryl-2-thioxotetrahydropyrimidin-4-one deriv-
atives. The classical method for the synthesis of these compounds
involves the condensation of b-amino acids or b-amino nitriles
with aryl isothiocyanates to give the corresponding thiourea
derivatives which are cyclized in a separate step to afford the de-
sired product under acidic condition.6–8 But this method suffers
from harsh reaction conditions and poor yields. Another method
microwave condition.9 Although this method affords better yields
of the products, it suffers from the disadvantage of involving
stoichiometric amount of ionic liquid for the condensation with
acryloyl chloride followed by Michael addition of amines to give
b-amino esters which were further reacted with isothiocyanates
to give the thioureido esters and finally cyclization using diethyl-
amine under microwave irradiation. Thus the multiple steps
involved, microwave conditions employed, longer reaction time,
and the stoichiometric amount of ionic liquid used have
restricted the synthetic applicability of the reaction. To overcome
these difficulties it was necessary to develop an alternate method
and this prompted us to reinvestigate the condensation reaction
between aryl isothiocyanates and b-amino esters so that the de-
sired product could be obtained by a straight-forward procedure
in high yields, short reaction time, and with operational
simplicity.
2. Results and discussion
The present Letter discusses the synthesis of N-substituted
3-aryl-2-thioxotetrahydropyrimidin-4(1H)-one derivatives by di-
rect condensation of aryl isothiocyanates and b-amino esters using
lithium perchlorate as the catalyst and triethylamine as the base.
The possible retrosynthetic routes for 3-aryl-2-thioxotetrahydro-
pyrimidin-4-one derivatives are depicted in Scheme 1. Out of the
two strategies, route B was considered better as route A involves
additional step of hydrolysis of cyano group to carboxylic acid
and harsh conditions. Route B proceeds by the condensation of aryl
isothiocyanates and b-amino esters to afford the 3-aryl-2-thioxo-
tetrahydropyrimidin-4-one derivatives with the intermediacy of
the corresponding thioureido ester.
* Corresponding author. Tel.: +91 172 2292045; fax: +91 172 2214692.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.