Tetrahedron Letters
Synthesis of novel 5-monoalkylbarbiturate derivatives: new access
to 1,2-oxazepines
a
a
b,c
Assem Barakat a,c, , Mohammad Shahidul Islam , Abdullah M. Al-Majid , Saied M. Soliman
,
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Yahia N. Mabkhot a, Zeid Abdullah Al-Othman a, Hazem A. Ghabbour d, Hoong-Kun Fun d,e
a Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia
b Department of Chemistry, Rabigh College of Science and Art, PO Box 344, Rabigh 21911, Saudi Arabia
c Department of Chemistry, Faculty of Science, Alexandria University, PO Box 426, Ibrahimia, 21321 Alexandria, Egypt
d Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia
e X-ray Crystallography Unit, School of Physics, Universiti Sains Malaysia, Penang 11800, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and straightforward route to 5-monoalkylbarbiturates by the NHEt2 catalyzed Michael reaction
of 1,3-dimethylbarbituric acid and ,b-unsaturated ketones is described. Significantly, the reaction exclu-
sively furnished 5-monoalkylbarbiturates. Under neat conditions, the mixing and grinding of a represen-
tative 1,5-diketone and hydroxylamine hydrochloride gave the corresponding 1,2-oxazepine in very good
yield.
Received 19 April 2015
Revised 20 September 2015
Accepted 29 October 2015
Available online xxxx
a
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Michael addition
Barbituric acid
Nitrogen heterocycles
Oxazepines
DFT
Introduction
been described by Zoorob et al. but only three examples were
reported.10a
The pyrimidinetrione core has long been exploited by medicinal
chemists as a psychotropic drug, as well as an anti-seizure, anti-
cancer, and antimicrobial compound.1 Barbituric acid and its
derivatives are known to show biological activities and have
gained importance as potential chemotherapeutics,2 and for the
treatment of epilepsy.3 Substituted seven-membered heterocyclic
oxazepine4,5 derivatives have received much attention in recent
years owing to their wide range of biological and pharmaceutical
activities (Fig. 1). Appropriate substitution and functionalization
of oxazepines have improved their pharmacological properties
and they are known to be potential opioid analgesics.4b
Recently, a new series of hybrid compounds, containing indole
and barbituric acid moieties, possessing anticancer activities, have
been synthesized through C–C bond formation.6 The scope of this
Knoevenagel–Michael reaction is very broad;7–10 and it is suitable
for use in combinatorial chemistry for the preparation of libraries
with high diversity either in the solid phase or in solution. The
Michael addition of 1,3-dimethylbarbituric acid to chalcones has
Different protocols have been applied to the synthesis of these
5-monoalkylbarbiturates such as the condensation of alkylated
malonic esters and urea in the presence of sodium alkoxide,11
5-alkylation of unsubstituted barbituric acid,11 metal-catalyzed
alkylation,12 ring opening of spiro[2.5]barbiturates,13 and a multi-
component reaction.14 Recently, Deka and co-workers developed
an effective procedure to access 5-monoalkylbarbiturates by the
domino reaction of 6-aminouracils, water, and
a,b-unsaturated
ketones catalyzed by FeCl3Á6H2O.15
Aiming toward the development of a direct, and more efficient
reactions,16 herein, we report a mild, rapid, direct, and efficient
procedure promoted by NHEt2 for the synthesis of 5-monoalkyl-
barbiturates. This methodology could provide a broad scope of
5-monoalkylbarbiturate derivatives in high yields.
Results and discussion
In preliminary experiments; the reaction of 1,3-dimethylbarbi-
turic acid 1 with enone 2a was examined as a model substrate.
Stirring these compounds in water/diethylamine at room temper-
ature for 120 h (Table 1, entry 1), gave Michael addition product 3a
in 70% yield. The structure was identified by spectroscopy analysis
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0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.