4126
J. M. Khurana, S. Kumar / Tetrahedron Letters 50 (2009) 4125–4127
Table 3
Table 1
Synthesis of 3,4-dihydropyrano[c]chromenes by condensation of aldehydes, 4-
Evaluation of catalytic activity of different catalysts for the condensation of 4-
chlorobenzaldehyde and 4-hydroxycoumarin in water
hydroxycoumarin and malononitrile using TBAB (10 mol %) as catalyst17
Entry
R
Product
Method A
Yield
Method B
Yield
S.No.
Catalyst
Mol (%)
Time
Yield (%)
Time
(min)
Time
(min)
1
2
3
4
5
6
7
8
9
HBF4
pTSA
Sulfamic acid
NH4Cl
LiBr
TBAB
TBAB
TBAB
TBAB
10
10
10
10
10
10
5
1
0
10
10 h
10 h
10 h
10 h
3 h
25 min
2 h
5 h
55
48
45
40
71
95
87
65
40
88
(%)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
C6H5
4-ClC6H4
4-BrC6H4
3-ClC6H4
4-NO2C6H4
4-CH3C6H4
2,4-Cl2C6H3
4-FC6H4
4-(CH3)2NC6H4
4-HOC6H4
4-CH3OC6H4
–CH@CH–C6H5
4-
4a
4b
4c
4d
4e
4f
4g
4h
4i
45
45
50
50
45
50
50
60
50
60
60
45
45
91
93
91
89
86
88
87
84
88
85
85
87
91
40
40
40
40
40
40
40
40
40
40
40
40
40
88
85
85
78
89
82
87
81
78
82
78
75
81
10 h
30 min
10
TBAF
4j
4k
4l
selectivity under such conditions.16 Therefore, 4-chlorobenzalde-
lyde, 4-hydroxycoumarin and TBAB were mixed thoroughly in a
round-bottomed flask and the mixture was heated in an oil bath
maintained at 120 °C. Interestingly, the reaction was complete in
20 min and 87% of pure 2b was obtained.
Subsequently, the condensation of a series of aromatic, hetero-
aromatic and aliphatic aldehydes with 4-hydroxycoumarin was
carried out using TBAB as catalyst under both the conditions out-
lined above. All aldehydes reacted almost equally well to afford
biscoumarins (2a–o) in excellent yields. A comparison of aqua-
mediated synthesis with those performed under neat conditions
is drawn in Table 2. It can be inferred from Table 2 that high yields
of biscoumarins were obtained by both methods, though, the reac-
tion times were slightly shortened in neat conditions, and the
yields were also slightly lower.
Encouraged by these results, we tried to extend the scope of the
present protocol for condensation of aldehydes, 4-hydroxycouma-
rin and malononitrile to afford 2-amino-4-alkyl/aryl-5-oxo-4H,5H-
pyrano[3,2-c]chromene-3-carbonitrile derivatives. The desired
2-amino-4-chlorophenyl-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-
carbonitrile 4b was obtained in 93% yield by condensation of a one
mole of 4-chlorobenzaldehyde with 1 mole of 4-hydroxycoumarin
and 1.5 mol of malononitrile in presence of 10 mol % of TBAB as
catalyst in water under reflux after 45 min. The condensation un-
der solvent-free conditions yielded 88% of pure 4b in 40 min.
Thereafter, a series of differently substituted 3,4-dihydropyr-
ano[c]chromene derivatives were prepared successfully from dif-
ferent aliphatic, heteroaromatic and aromatic aldehydes bearing
4m
(CH3)2CHC6H4
1-Naphthyl
14
4n
45
87
40
78
Method A: Reaction carried out in water.
Method B: Reaction carried out under solvent-free conditions.
electron-withdrawing and electron-donating groups, 4-hydroxy-
coumarin and malononitrile in water and under solvent-free neat
conditions. These results are listed in Table 3.
The results clearly indicate that reactions can tolerate a wide
range of differently substituted aldehydes. The three-component
reactions proceeded smoothly and were complete within 1 h.
Excellent yields of products were obtained by both methods. How-
ever, in case of aliphatic aldehydes, reactions were not performed
under solvent-free conditions because of low boiling point of the
aldehydes.
In conclusion, we have reported an easy, efficient and green
protocol for the synthesis of biscoumarins and 3,4-dihydropyr-
ano[c]chromenes in water and solvent-free neat conditions. The
method offers marked improvement with its operational simplic-
ity, low reaction time and high yields of pure products without
use of any organic solvent.
Acknowledgment
S.K. thanks C.S.I.R., New Delhi, India for grant of Junior and Se-
nior research fellowships.
Table 2
References and notes
Synthesis of biscoumarins by condensation of aldehydes and 4-hydroxycoumarin
using TBAB (10 mol %) as catalyst17
1. (a) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879; (b) Liu, F.; Evans, T.; Das, B. C.
Tetrahedron Lett. 2008, 49, 1578; (c)Multicomponent Reactions; Zhu, J.,
Bienayme, H., Eds.; Wiley-VCH: Weinheim, 2005; (d) Domling, A.; Ugi, I.
Angew. Chem., Int. Ed. 2000, 39, 3168.
Entry
R
Product
Method A
Yield
Method B
Yield
Time
Time
2. (a) Polshettiwar, V.; Varma, R. S. Chem. Soc. Rev. 2008, 37, 1546; (b)
Polshettiwar, V.; Varma, R. S. Tetrahedron Lett. 2007, 48, 7343; (c) Sayyafi, M.;
Seyyedhamzeh, M.; Khavasi, H. R.; Bazgir, A. Tetrahedron 2008, 10, 2375.
3. Kantevari, S.; Chary, M. V.; Das, A. P. R.; Srinavasu, V. N. V.; Lingaiah, N. Catal.
Commun. 2008, 1575.
4. Chary, M. V.; Keerthysri, N. C.; Vapallapati, S. V. N.; Lingaiah, N.; Kantevari, S.
Catal. Commun. 2008, 9, 2013.
5. Siddiqui, S. A.; Narkhede, U. C.; Palimkar, S. S.; Daniel, T.; Loholi, R. J.;
Srinivasan, K. V. Tetrahedron 2005, 61, 3539.
6. Ranu, B. C.; Das, A.; Samanta, S. J. Chem. Soc., Perkin Trans. 1 2002, 1520.
7. Ranu, B. C.; Dey, S. S.; Hajra, A. Tetrahedron 2003, 59, 2417.
8. Kostava, I.; Manolov, I.; Nicolova, I.; Konstantonov, S.; Karaivanova, M. Eur. J.
Med. Chem. 2001, 36, 339.
9. Chohan, Z. H.; Shaikh, A. U.; Rauf, A.; Supuran, C. T. J. Enzym. Inhib. Med. Chem.
2006, 21, 741.
10. Zhao, H.; Neamati, N.; Hong, H.; Mazumdar, A.; Wang, S.; Sunder, S.; Milne, G.
W. A.; Pommier, Y.; Burke, T. R. J. Med. Chem. 1997, 40, 242.
11. Manolov, I.; Moessmer, C. M.; Danchev, N. Eur. J. Med. Chem. 2006, 41, 882.
12. Kadir, S.; Dar, A. A.; Khan, K. Z. Synth. Commun. 2008, 38, 3490.
13. Kidwai, M.; Bansal, V.; Mothsra, P.; Saxena, S.; Somvanshi, R. K.; Dey, S.; Singh,
T. P. J. Mol. Catal. 2007, 268, 6.
(min)
(%)
(min)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
C6H5
4-ClC6H4
4-BrC6H4
3-ClC6H4
4-NO2C6H4
4-CH3C6H4
4-CH3OC6H4
–CH@CH–C6H5
3,4-(CH3O)2C6H3
3,4,5(CH3O)3C6H2 2j
4-(CH3)2CHC6H4
Piperonyl
2a
2b
2c
2d
2e
2f
2g
2h
2i
25
30
30
30
25
30
30
35
40
40
30
30
35
35
35
92
95
88
87
91
92
84
82
87
84
91
88
88
90
82
20
20
20
20
20
20
20
20
20
20
20
20
20
20
—
85
87
87
85
91
88
78
81
77
75
85
85
77
78
—
2k
2l
2m
2n
2o
2-Furanyl
2-Pyridyl
CH(CH3)2
Method A: Reaction carried out in water.
Method B: Reaction carried out under solvent-free conditions.