Ionic liquid: An efficient and recyclable medium for the synthesis of octahydroquinazolinone and biscoumarin derivatives

Article abstract of DOI:10.1007/s00706-010-0306-4

A facile and environmentally benign procedure for the synthesis of octahydroquinazolinone and biscoumarin derivatives in ionic liquids is reported. Octahydroquinazolinones were synthesized in the presence of trimethylsilyl chloride (TMSCl) while the synthesis of biscoumarins required no additive. The ability to reuse the ionic liquid, the high yields, and ease of purification are the important features of this process.

Full text of DOI:10.1007/s00706-010-0306-4

Monatsh Chem (2010) 141:561–564
DOI 10.1007/s00706-010-0306-4
ORIGINAL PAPER
Ionic liquid: an efficient and recyclable medium for the synthesis
of octahydroquinazolinone and biscoumarin derivatives
Jitender M. Khurana Sanjay Kumar
•
Received: 22 August 2009 / Accepted: 17 March 2010 / Published online: 9 April 2010
Ó Springer-Verlag 2010
Abstract A facile and environmentally benign proce-
dure for the synthesis of octahydroquinazolinone and
biscoumarin derivatives in ionic liquids is reported. Octa-
hydroquinazolinones were synthesized in the presence of
trimethylsilyl chloride (TMSCl) while the synthesis of bis-
coumarins required no additive. The ability to reuse the ionic
liquid, the high yields, and ease of purification are the
important features of this process.
negligible vapour pressure, wide liquid range, tunable
polarity and potential for recycling circumvent many of the
problems associated with common organic solvents. In
view of the above observations and our continuing interest
in the synthesis of heterocyclic compounds [13–17], we
have investigated the synthesis of octahydroquinazolinones
(which have potential antibacterial activity and also act as
calcium antagonists [18–20]) and biscoumarin derivatives
(which have been reported to have anticoagulant [21, 22],
Keywords Octahydroquinazolinone ꢀ Biscoumarin ꢀ
Trimethylsilyl chloride ꢀ Ionic liquid
spasmolytic [23] and antifungal activity [24]) in ionic
liquids.
Introduction
Results and discussion
Heterocyclic systems are common structural motifs in
many biologically active substances and natural products
and therefore warrant the design of newer and efficient
protocols for their synthesis. In view of this, multicompo-
nent reactions (MCRs) are an important sub-class of
tandem reactions which can be used to rapidly generate
vast libraries of compounds [1, 2], and their highly flexible
and selective nature makes MCRs a convenient tool for the
construction of many heterocyclic compounds [3–6]. In
recent years, green chemistry [7, 8] has emerged as a
revolutionary concept and one of its tenets focuses on
providing alternative reaction conditions and reaction
media that are environmentally benign. In this context,
ionic liquids have gained recognition as possible ‘green’
alternatives to more volatile organic solvents [9–12]. Their
In this paper, we report a simple and convenient synthesis
of octahydroquinazolinone and biscoumarin derivatives in
ionic liquids. Our initial attempts were directed towards
the synthesis of octahydroquinazolinones. In order to
optimize the reaction conditions for the synthesis, a
reaction using benzaldehyde (2 mmol), dimedone
(2 mmol) and urea (3 mmol) was attempted in the ionic
liquid 1-butyl-3-methylimidazolium bromide ([bmim]Br)
at 100 °C. After 10 h, the reaction was found to be
incomplete and only 30% of 4,6,7,8-tetrahydro-7,7-dime-
thyl-4-phenyl-1H,3H-quinazoline-2,5-dione was obtained.
When this reaction was repeated in presence of TMSCl
(4 mmol), the yield improved remarkably to 92% in
2.5 h. Subsequently, the effect of different ionic liquids
on the rate of reaction and the yield of products was
investigated. It can be inferred from Table 1 that
[
bmim]Br and [bmim]BF were the preferred media for
4
J. M. Khurana (&) ꢀ S. Kumar
Department of Chemistry, University of Delhi,
Delhi 110007, India
high yields as compared with [bmim]Cl and [bmim]PF6.
Therefore, [bmim]Br was chosen as the reaction medium
for subsequent reactions.
e-mail: jmkhurana1@yahoo.co.in
123

5
62
J. M. Khurana, S. Kumar
Table 1 Effect of different ionic liquids on condensation reaction of
dimedone, benzaldehyde and urea
Table 2 Synthesis of various octahydroquinazolinone and octahy-
drothioquinazolinone derivatives using dimedone, aldehydes, and
urea or thiourea
Entry
Ionic liquid
Catalyst
Yield (%)
Entry
R
X
Product Time Isolated yield
(h)
Ref.
1
2
3
4
5
[bmim]Br
[bmim]Cl
TMSCl
TMSCl
TMSCl
TMSCl
–
92
62
84
65
30
(%)
a
92, (86, 84, 72) [26]
1
2
3
4
5
6
7
8
9
C
6
H
5
O
O
O
O
O
O
O
O
S
2a
2b
2c
2d
2e
2f
2.5
2.0
2.5
2.5
3.0
2.5
3.5
3.5
2.5
2.5
3.0
3.5
4.0
[bmim]BF
4
4-BrC
3-ClC
4-O NC
4-CH
2,4-Cl
4-(CH
(CH
6
H
4
93
84
85
81
86
77
85
91
89
81
82
74
[26]
[26]
[26]
[26]
[26]
[26]
[26]
[26]
[26]
[26]
[26]
[26]
[bmim]PF
6
6 4
H
[bmim]Br
2
6
H
4
3 6
C H
4
2 6 3
C H
Having established the reaction conditions for the mul-
ticomponent reaction, the scope and limitations of the
reaction with different aldehydes and cyclic b-diketones
was investigated. The reactions of dimedone with various
aromatic aldehydes containing electron-withdrawing and
electron-donating groups and urea or thiourea proceeded
smoothly in presence of TMSCl and were complete in 2–
3
)
2
NC
6
H
4
2g
2h
2i
3 2
)
CH
6 5
C H
1
1
1
1
a
0
1
2
3
4-BrC
3-ClC
4-CH
4-(CH
H
6 4
S
2j
6
H
4
S
2k
2l
3
C
6
H
4
S
3
)
2
NC
6
H
4
S
2m
4
h. The reactions were slightly faster for aromatic alde-
hydes bearing an electron-withdrawing group. A series of
octahydroquinazolinones and octahydrothioquinazolinones
were prepared (Scheme 1) and the results are listed in
Table 2. Some of these reactions were also attempted under
microwave irradiation [25] but these resulted in a mixture
of products and were discarded.
Yields in parentheses are the yields obtained by using the recovered
ionic liquid in successive runs
hydroxycoumarin) as characterized by its melting point and
spectral data, and urea was found unreacted in the reaction
mixture. Subsequently, it was observed that biscoumarins
could be obtained even without a catalyst by simply heat-
ing the aldehyde and 4-hydroxycoumarin in ionic liquid at
60–70 °C. Consequently, the condensation of a series of
aromatic, heteroaromatic and aliphatic aldehydes was car-
ried out with 4-hydroxycoumarin under similar conditions.
All aldehydes reacted almost equally fast to afford bis-
coumarins in excellent yields (Scheme 3). All these results
are listed in Table 4.
Cyclocondensation of 1,3-cyclohexanedione with alde-
hydes and urea was also investigated. The reaction of
benzaldehyde was performed with 1,3-cyclohexanedione
and urea under the same conditions in [bmim]Br at 100 °C.
Interestingly, the reaction was incomplete even after 15 h
and only 55% of the product was obtained. However, when
the reaction was performed in [bmim]BF at 60–70 °C,
9
4
4% of 1,2,3,4,5,6,7,8-octahydro-4-phenylquinazoline-2,5-
dione was obtained in 6.5 h. The generality of the con-
densation was confirmed by carrying out reactions of
different aldehydes with 1,3-cyclohexanedione and urea
In conclusion we have reported an easy and efficient
protocol for the synthesis of octahydroquinazolinones and
biscoumarins in the easily accessible ionic liquids
(
Scheme 2). These reactions were slow compared with
[bmim]Br and [bmim]BF . The method offers marked
4
reactions of dimedone. The results are listed in Table 3.
The scope of the present protocol was extended to
another active methylene compound, 4-hydroxycoumarin,
in place of dimedone or 1,3-cyclohexanedione. A pilot
reaction was performed by the condensation of benzalde-
improvement with its operational simplicity, short reaction
time and high isolated yield of pure products.
Experimental
hyde, 4-hydroxycoumarin and urea in [bmim]BF , using
4
TMSCl as catalyst. However, to our surprise, the isolated
0
The ionic liquids were prepared by reported procedures
[31, 32]. All products were confirmed by their m.p., IR,
product was identified to be 3,3 -benzylidenebis-(4-
Scheme 1
H
X
O
O
R
N
X
[
bmim]Br, 100 °C
C
R
CHO
+
+
H N
NH2
O
NH
2
TMSCl
1a-1m
X = O, S
2a-2m
1
23

Synthesis of octahydroquinazolinone and biscoumarin derivatives
563
Scheme 2
H
N
O
C
O
O
R
O
[
bmim]BF , 60-70 °C
4
R
CHO
+
+
H2N
NH2
O
NH
TMSCl
3a-3f
4a-4f
Table 3 Synthesis of various octahydroquinazolinone derivatives
using 1,3-cyclohexanedione, aldehydes and urea
Table 4 Synthesis of various biscoumarins by condensation of
aldehydes and 4-hydroxycoumarin
Entry
R
Product
Time (h)
Yield (%)
Ref.
Entry
R
C
Product Time (h) Yield (%) Ref.
1
2
3
4
5
6
C
6
H
5
4a
4b
4c
4d
4e
4f
6.5
6.0
6.0
6.5
7.0
8.0
94
93
88
81
82
78
[19]
[19]
[19]
[19]
[19]
[19]
1
2
3
4
5
6
7
8
9
6
H
5
6a
6b
6c
6d
6e
6f
2.0
2.5
2.5
2.5
2.5
3.0
3.0
3.0
3.0
3.0
3.0
84
91
87
84
84
83
87
82
77
83
81
[27]
[27]
[27]
[28]
[27]
[29]
[28]
[27]
[28]
[27]
[30]
4-BrC
4-ClC
6
H
4
4-ClC
4-BrC
3-ClC
4-NO
6 4
H
H
4
6 4
H
6
4-NO
2
C
6
H
4
6 4
H
2,4-Cl
2
C
6
H
3
C
2 6
H
4
4-CH
3
C
6
H
4
4-CH
3
C
6
H
4
4-CH OC
3
6
H
4
6g
6h
6i
CH=CH–C
CH(CH
6
H
5
NMR and mass spectra and comparison with data in ref-
erences [19, 26–30]. All melting points were recorded on a
Tropical Labequip apparatus. IR spectra were recorded on
3 2
)
1
0
2-Furanyl
2-Pyridyl
6j
1
13
11
6k
Perkin-Elmer FTIR-1710 instrument. H and C NMR
spectra were recorded on Bruker Advance Spectrospin 300
and 400 MHz spectrometer using TMS as internal stan-
dard. Mass spectra were recorded on Jeol-JMS-D300 and
Jeol SX102 instruments.
diethyl ether and recycled in subsequent reactions. Second
and third runs using recovered ionic liquid afforded similar
yields to those obtained in the first run (see Table 2).
However, in the fourth and fifth runs, the yields decreased
gradually.
General procedure for the synthesis
of octahydroquinazolinone and
octahydrothioquinazolinone derivatives 2a–2m
and 4a–4f
General procedure for the synthesis of biscoumarins
6a–6k
In a typical experiment, in a round-bottomed flask aldehyde
In a typical experiment, an aldehyde (n mmol), 4-hy-
droxycoumarin (2n mmol) and [bmim]BF (4n mmol) were
(
n mmol), dimedone or 1,3-cyclohexanedione (n mmol),
4
urea or thiourea (1.5n mmol), TMSCl (2n mmol) and ionic
liquid (4n mmol) were heated at 100 °C under nitrogen
atmosphere with vigorous stirring. After completion of the
reaction as monitored by TLC, the reaction mixture was
cooled to room temperature. The product was extracted in
diethyl ether and washed well with water. The combined
heated in a round-bottomed flask at 60–70 °C with vigor-
ous stirring. After completion of the reaction as monitored
by TLC, the reaction mixture was cooled to room tem-
perature. The product was extracted in diethyl ether and
washed well with water. The combined extract was dried
over anhydrous MgSO4 and concentrated on a rotary
evaporator. The crude product was recrystallized from
ethanol to give the pure desired product. The rest of the
viscous ionic liquid was thoroughly washed with diethyl
ether and recycled in subsequent reactions.
extract was dried over anhydrous MgSO and concentrated
4
on a rotary evaporator. The crude product was recrystal-
lized from ethanol to give the pure desired product. The
rest of the viscous ionic liquid was thoroughly washed with
Scheme 3
OH
O
O
O O
O
[
bmim]BF , 60-70 °C
4
R
CHO +
2
O
OH
R
OH
5
a-5k
6a-6k
123

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64
J. M. Khurana, S. Kumar
Acknowledgments S. K. thanks CSIR, New Delhi, India, for junior
and senior research fellowship grants.
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