An eco-safe approach to benzopyranopyrimidines and 4H-chromenes in ionic liquid at room temperature

Article abstract of DOI:10.1016/j.tetlet.2011.11.116

An environmentally benign, ionic liquid promoted multicomponent protocol to benzopyrano(2,3-d)pyrimidines and 4H-chromenes has been developed at room temperature. Results of the reaction depend on the nature of the nucleophile used in the reaction. Second

Full text of DOI:10.1016/j.tetlet.2011.11.116

Tetrahedron Letters 53 (2012) 650–653
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An eco-safe approach to benzopyranopyrimidines and 4H-chromenes
in ionic liquid at room temperature
⇑
Amit Kumar Gupta, Kumkum Kumari, Neetu Singh, Dushyant Singh Raghuvanshi, Krishna Nand Singh
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221 005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An environmentally benign, ionic liquid promoted multicomponent protocol to benzopyrano(2,3-
d)pyrimidines and 4H-chromenes has been developed at room temperature. Results of the reaction
depend on the nature of the nucleophile used in the reaction. Secondary amines result in the formation
of benzopyrano(2,3-d)pyrimidines, whereas thiols give rise to 4H-chromenes under the same set of reac-
tion conditions.
Received 3 October 2011
Revised 22 November 2011
Accepted 24 November 2011
Available online 7 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Green chemistry
Ionic liquid
Multicomponent reactions
Benzopyrano[2,3-d]pyrimidines
4H-Chromenes
The challenging task of achieving ‘efficiency’ and ‘green creden-
tials’ in all aspects of chemical synthesis, can be realized by inno-
vative research which comprehensively addresses the issues of
atom-economy, economy of steps, and the avoidance of auxiliary
chemicals.1 Multi-component reaction (MCR) protocol with envi-
ronmentally benign solvents and catalytic systems is one of the
most suitable strategies, which meets the requirements of green
aspects of chemistry for developing libraries of medicinal scaf-
folds.2 Ionic liquids are attracting increasing attention as alterna-
tive solvents for a wide range of catalytic and organic reactions
due to their very low vapor pressure and non-explosive and ther-
mally stable nature in a wide temperature range.3 The recent years
have witnessed the potential of ionic liquids as catalysts as well as
reaction media aimed to develop green chemistry, avoiding the use
of volatile organic solvents and allowing its reuse. There are
numerous examples of all classes of organic reactions that have
been successfully carried out in ionic liquid as reaction media.4
Benzopyrano[2,3-d]pyrimidine is a potentially important phar-
macophore that exhibits in vivo antitumor activity, cytotoxic activ-
ity against cancer cell lines and can cause significant perturbation
in cell cycle kinetics.5 Relatively few papers have been reported
on the formation of benzopyrano[2,3-d]pyrimidines with a limited
substitution pattern. This core was initially synthesized by O’Calla-
ghan by condensation of 2-iminocoumarin-3-carboxamides with
aldehydes involving a multistep complex reaction procedure.6
Despite some attempts to overcome the drawbacks, no benign
method with promising green credentials has so far appeared for
the synthesis of this core.7 In view of the above and as a part of
our ongoing research on development of efficient protocols in
organic synthesis,8 we report herein an ionic liquid promoted, effi-
cient combinatorial synthesis of substituted benzopyrano[2,3-d]
pyrimidines in good to excellent yields adopting a three-compo-
nent one-pot tandem approach (Scheme 1). The investigations have
also been extended to achieve a library of some new 4H-chromenes,
which constitute another important class of core structures
featured in a number of naturally occurring and biologically active
molecules known for their antimicrobial and antifungal,9–13
antioxidant,14,15 antileishmanial,16 antitumor,17–19 hypotensive,20
antiproliferation,21 local anesthetic,22 antiallergenic,23,24 central
nervous system (CNS) activities,25 as well as for the treatment of
Alzheimer’s disease26 and schizophrenia disorders.27
In order to optimize the reaction conditions, the catalytic activ-
ity of ionic liquids was tested for a typical multicomponent reac-
tion of salicyldehyde 1a, malononitrile 2, and dimethylamine 3a
at room temperature. The results are given in Table 1.
To find out a suitable reaction medium, a number of molecular
solvents were tried with catalytic amount of [Bmim]BF4 and it was
found that use of [Bmim]BF4 with dual role of catalyst and solvent
dramatically reduces the reaction time with improved product
yield at room temperature (Table 1, entry 6). An elevated temper-
ature, however, could not enhance the product yield (Table 1, entry
10). Intrigued by these observations, the model reaction was also
investigated using other ionic liquids namely [Bmim]PF6 and [Bmi-
m]OH, but they could not afford good product yield (Table 1, en-
tries 7 and 8).
⇑
Corresponding author. Tel.: +91 542 6702485; fax: +91 542 2368127.
E-mail addresses: knsingh@bhu.ac.in, knsinghbhu@yahoo.co.in (K.N. Singh).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.116

A. K. Gupta et al. / Tetrahedron Letters 53 (2012) 650–653
651
R2
R1
R2
R1
N
N
N
H
3
N
OH
X
O
X
4
CHO
OH
CN
CN
[Bmim]BF4
RT
X
R3
S
R3SH
2
1
CN
NH2
5
X
O
7
Scheme 1. Synthesis of benzopyranopyrimidines 4 and 4H-chromenes 5 using [Bmim]BF4.
Table 1
Optimization of reaction conditions
Me
O
Me
N
N
CHO
CN
Me
Ionic liquid
RT
Me
N
OH
N
H
3a
OH
CN
2
1a
4a
Entry
Catalyst (mol %)
[Bmim]BF4 (20)
[Bmim]BF4 (20)
[Bmim]BF4 (20)
[Bmim]BF4 (20)
[Bmim]BF4 (20)
—
—
—
—
—
Solvent
Time
Yielda (%)
1
2
3
4
5
6
7
8
9
1,4-dioxane
EtOH
Toluene
4 h
4 h
4 h
4 h
4 h
20 min
20 min
20 min
40 min
20 min
17
79
27
nrb
23
88
45
45
19
85c
Water
Acetonitrile
[Bmim]BF4
[Bmim]PF6
[Bmim]OH
—
10
[Bmim]BF4
a
b
c
Isolated yield.
nr = no reaction.
Reaction carried out at 60 °C.
Under the optimized set of reaction conditions, a number of sal-
icylic aldehydes viz. salicyldehyde (1a), 5-bromosalicyldehyde (1b),
and 2-hydroxynaphthaldehyde (1c) were allowed to react with
malononitrile (2) and different secondary amines namely dimethyl-
amine (3a), piperidine (3b), morpholine (3c), diethylamine (3d) to
afford a variety of benzopyrano[2,3-d]pyrimidines 4a–i. The out-
come is described in Table 2. A perusal of Table 2 shows that salicyl-
dehyde (3a) and 5-bromosalicyldehyde (3b) underwent the
reaction smoothly affording reasonably good yields (entries 1–6).
However, a considerable decrease in the product yield was ob-
served with 2-hydroxynaphthaldehyde (1c) (entries 7, 8). As is evi-
dent, the secondary amines do also have profound effect on the
course of overall reaction. Dimethylamine (3a) works well in all
its reactions (entries 1, 4 and 7), but all the efforts to carry out
the reaction with diethylamine (3d) failed (entry 9). The probable
reason for this anomaly may be the presence of two extra arms,
R3
S
N
OH
X
O
N
X
6
CHO
OH
SH
CN
CN
2
[Bmim]BF4
30 min
R3
X
X
R3
S
1
5
CN
NH2
5a, R3= H
O
7
5b,
5C,
R
3 = CH3
3
R = OCH3
Scheme 2. Synthesis of 4H-chromenes using thiols 5.

652
A. K. Gupta et al. / Tetrahedron Letters 53 (2012) 650–653
Table 2
Table 3
Synthesis28 of substituted benzopyrano[2,3-d]pyrimidines (4)
Synthesis28 of 2-amino-4-arylsulfanyl-4H-chromene-3-corbonitriles (7)
Entry Aldehyde
Amine
Product
Yielda
(%)
Entry
Aldehyde (1)
Thiol (5)
Product (7)
Yielda (%)
1
2
3
4
5
6
7
1a
1a
1b
1b
1b
1c
1c
5a
5b
5a
5b
5c
5b
5c
7a
7b
7c
7d
7e
7f
80
85
82
80
78
72
81
CHO
OH
NMe2
N
H
3a
N
N
OH
OH
1
2
90
84
O
1a
4a
7g
CHO
OH
1a
a
Isolated yield.
N
H
N
N
N
3b
benzopyrano[2,3-d]pyrimidines, but to our utmost surprise, we
could not achieve the formation of the expected product 6. Careful
analysis of the spectral data rather revealed the formation of 2-
amino-4-arylsulfanyl-4H-chromene-3-corbonitriles (7), thereby
approving a different reaction pathway (Scheme 2). The outcome
of the reaction of different thiols viz. thiophenol (5a), p-methyl-
thiophenol (5b), p-methoxythiophenol (5c) with salicylic alde-
hydes 1 and malononitrile 2 is described in Table 3. It is evident
from Table 3 that all the salicylic aldehydes and thiophenols show
more or less similar reactivity and product yields. The reaction was
also tried with heteroaromatic and aliphatic thiols (2-mercapto-
benzothiazole and 2-mercaptoethanol) but it did not succeed.
The role of phenols as nucleophile in the aforementioned reaction
was also tried, but it did not give any impressive results.
It is worthwhile to mention that the IL [Bmim]BF4 was recycled
up to five times without any significant loss and diminution in its
amount and efficacy. After each and every recycle, the purity of the
IL was affirmed by spectroscopic data.
O
N
4b
O
CHO
OH
O
N
H
3c
N
1a
OH
3
4
5
76
78
80
O
N
4c
Br
Br
NMe2
CHO
N
H
3a
Br
N
N
OH
Br
OH
O
1b
4d
CHO
OH
N
H
N
N
N
Br
Br
1b
1b
OH
Br
3b
O
In conclusion, we have demonstrated an efficient use of ionic li-
quid for multicomponent synthesis of benzopyrano(2,3-d)pyrimi-
dines at room temperature under solvent-free conditions in an
environmentally benign and one-pot fashion. The reaction has also
been extended to the synthesis of 2-amino-3-arylsulfanyl-4H-
chromene-3-corbonitriles.
4e
Br
O
O
CHO
OH
N
H
3c
N
N
N
OH
Br
6
7
75
61
O
Acknowledgment
4f
NMe2
We are thankful to the Department of Biotechnology, New Delhi
for financial assistance.
CHO
OH
N
H
3a
N
N
OH
O
O
References and notes
1c
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1c
8
9
65
4h
NEt2
N
CHO
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1a
Et
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N
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a
Isolated yield.
b
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nr = no reaction.
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28. General procedure for preparation of benzopyrano[2,3-d]pyrimidine 4:
Salicylaldehyde 1 (2 mmol), malononitrile 2 (1 mmol), secondary amine 3
(1 mmol), and [Bmim]BF4 (0.2 mL) were taken in a 25 mL round bottomed
flask. The reaction mixture was stirred at room temperature for 20 min. After
completion of the reaction as indicated by TLC, ethanol (1 mL) and water
(1 mL) were successively added while stirring. The product was filtered and
washed with water and ethanol to afford pure product 4. The aqueous phase
containing the ionic liquid was washed with ether (10 mL) to remove the
organic impurities, and then dried under vacuum at 90–95 °C for 2 h to afford
[Bmim]BF4, which was used in the subsequent runs without further
purification.
yl)}phenol (4c) Yellow solid, mp: 196–197 °C; IR (KBr):
2858, 1581, 1390, 1246, 1118 cmÀ1 1H NMR (300 MHz, CDCl3): d 3.48 (t, 4H,
2-{4-(Morpholine-4-yl)-5H-benzopyrano[2,3-d]pyrimidin-2-
m
3449, 3049, 2962,
;
J = 4.2 Hz), 3.89 (m, 6H), 6.89–6.98 (m, 2H, Ar), 7.09–7.28 (m, 4H, Ar), 7.33 (t,
1H, J = 7.6 Hz, Ar), 8.38 (d, 1H, J = 7.8 Hz, Ar), 13.11 (s, 1H); 13C NMR (75 MHz,
CDCl3): d 25.4, 48.5, 66.5, 97.5, 116.9, 117.5, 118.2, 118.7, 118.9, 124.4, 128.1,
128.4, 129.0, 132.8, 150.2, 160.2, 161.8, 164.0, 164.5; Anal. Calcd for
C21H19N3O3: C, 69.79; H, 5.30; N, 11.63. Found: C, 69.68; H, 5.24; N, 11.55.
General procedure for preparation of 2-amino-4-arylsulfanyl-4H-chromene-3-
corbonitriles (7): A mixture of salicylaldehyde 1 (1 mmol), malononitrile 2
(1 mmol), thiol
5 (1 mmol) and [Bmim]BF4 (0.2 mL) was stirred at room
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temperature for 30 min. After completion of the reaction as indicated by TLC,
the product was isolated and purified adopting the same method as given in
Ref. 28. 2-Amino-6-bromo-4-p-tolylsulfanyl-4H-chromene-3-carbonitrile (7d)
White solid, mp: 168–169 °C; IR (KBr):
m ;
3449, 3329, 2199 cmÀ1 1H NMR
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(300 MHz, CDCl3): d 2.32 (s, 3H), 4.54 (s, 2H), 4.89 (s, 1H), 6.60 (d, 1H, J = 8.7 Hz,
Ar), 7.01 (m, 4H, Ar), 7.28 (m, 1H, Ar), 7.42 (m, 1H, Ar); 13CNMR (75 MHz,
DMSO-d6): d 20.8, 46.1, 53.1, 115.7, 117.6, 119.5, 123.8, 126.6, 129.3, 131.2,
131.3, 136.1, 138.7, 148.2, 161.8; Anal. Calcd for C17H13BrN2OS: C, 54.70; H,
3.51; N, 7.50. Found: C, 54.60; H, 3.56; N, 7.43.
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