Tetrabutylammonium bromide (TBAB): a neutral and efficient catalyst for the synthesis of biscoumarin and 3,4-dihydropyrano[c]chromene derivatives in water and solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2009.04.125

A simple, efficient and ecofriendly procedure has been developed using tetrabutylammonium bromide as catalyst for the synthesis of biscoumarin and dihydropyrano[c]chromene derivatives in water and solvent-free neat conditions. The present methodology offe

Full text of DOI:10.1016/j.tetlet.2009.04.125

Tetrahedron Letters 50 (2009) 4125–4127
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Tetrahedron Letters
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Tetrabutylammonium bromide (TBAB): a neutral and efficient catalyst
for the synthesis of biscoumarin and 3,4-dihydropyrano[c]chromene derivatives
in water and solvent-free conditions
*
Jitender M. Khurana , Sanjay Kumar
Department of Chemistry, University of Delhi, Delhi 110 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, efficient and ecofriendly procedure has been developed using tetrabutylammonium bromide as
catalyst for the synthesis of biscoumarin and dihydropyrano[c]chromene derivatives in water and sol-
vent-free neat conditions. The present methodology offers several advantages such as excellent yields,
short reaction time and environmentally benign milder reaction conditions.
Received 1 March 2009
Revised 25 April 2009
Accepted 28 April 2009
Available online 3 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
O
O
O
O
O
O
Introduction
Water / Neat
R
CHO +
2
TBAB (10 mol%)
Multicomponent reactions (MCRs) have attracted the attention
of synthetic organic chemists for building highly functionalized or-
ganic molecules and pharmacologically important heterocyclic
compounds.1 Application of environmentally benign water- and
solvent-free solid state organic reactions represents powerful
green procedure.2 Recently tetrabutylammonium bromide (TBAB)
has emerged as mild, water-tolerant, inexpensive and environmen-
tally compatible homogenous catalyst in various organic transfor-
mations.3–7 Biscoumarins and dihydropyrano[c]chromenes are of
considerable interest due to their widespread biological proper-
ties.8–10 A number of methods have been reported for the synthesis
of biscoumarins.11–13 However, comparatively fewer methods have
been described for the synthesis of 3,4-dihydropyrano[c]chrom-
enes.14,15 Most of these procedures require refluxing for hours in
organic solvents, use of expensive catalysts and tedious work-up.
In view of the above-mentioned observations, we decided to inves-
tigate the application of TBAB as a catalyst for synthesis of bis-
coumarins and 3,4-dihydropyrano[c]chromenes in water and
under solvent-free neat conditions (Schemes 1 and 2).
OH
OH
R
2 a-o
OH
1a-o
Scheme 1.
NH2
CN
R
OH
O
O
CN
CN
Water / Neat
TBAB (10 mol%)
R
CHO
+
+
O
O
O
3 a-q
4 a-q
Scheme 2.
for example, HBF4, pTSA, sulfamic acid, NH4Cl, LiBr, TBAB and TBAF
to afford 3,30-(4-chlorophenylmethylene)-bis-(4-hydroxycouma-
rin) 2b. The results with different catalysts are given in Table 1.
The best results were obtained with the condensation of one
mole of 4-chlorobenzaldehyde with 2 mol of 4-hydroxycoumarin
using 10 mol % of TBAB as catalyst in water under reflux. Ninety-
five percent of 3,30-(4-chlorophenylmethylene)-bis-(4-hydroxy-
coumarin) 2b was obtained by simple recrystallization from
ethanol. Reaction with 5 mol % of catalyst required longer reaction
time while reaction with 1 mol % of catalyst was incomplete even
after 5 h and only 65% of the product was obtained. TBAF was
found to be equally effective as catalyst while the reactions with
other catalysts such as HBF4, pTSA, sulfamic acid, NH4Cl and LiBr
were sluggish.
Results and discussion
We report herein a green approach for the synthesis of some
novel biscoumarins and dihydropyrano[c]chromenes catalyzed by
TBAB in water and solvent-free neat conditions. In order to opti-
mize the reaction conditions and to evaluate catalytic activity of
TBAB, reactions of 4-chlorobenzaldehyde and 4-hydroxycoumarin
were carried out in water under reflux in presence of catalysts,
We have also investigated the synthesis of our target com-
pounds under solvent-free neat conditions since a number of reac-
tions have been reported to proceed efficiently and with higher
* Corresponding author. Tel.: +91 11 27667725; fax: +91 11 27667624.
E-mail address: jmkhurana1@yahoo.co.in (J.M. Khurana).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.125

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.

J. M. Khurana, S. Kumar / Tetrahedron Letters 50 (2009) 4125–4127
4127
14. Shaker, R. M. Pharmazie 1996, 51, 148.
was decanted and hot ethanol (15 mL) was added. The solid product obtained
was filtered using pump and dried. The crude product was recrystallized from
ethanol to yield pure product. For the preparation of pyrano[c]chromene
derivatives, the reaction of 4-hydroxycoumarin (5 mmol), aldehyde
(2.5 mmol), malononitrile (7.5 mmol) and TBAB (10 mol %) was carried out as
described above for reaction times given in Table 3.
15. Abdolmohammadi, S.; Balalaie, S. Tetrahedron Lett. 2007, 48, 3299.
16. (a) Bazgir, A.; Tisseh, Z. N.; Mirzaei, P. Tetrahedron Lett. 2008, 49, 5165; (b) Bazgir,
A.; Seyyedhamzeh, M.; Yasaei, Z.; Mirzaei, P. Tetrahedron Lett. 2007, 48, 8790.
17. General procedure for the synthesis of 3,3’-arylmethylenebis-(4-hydroxycoumarin)
and 2-amino-4-aryl/alkyl-5-oxo-4H, 5H-pyrano[3,2-c]chromene-3-carbonitrile:
Method A: In
a
typical reaction for the preparation of biscoumarins,
a
Method B: In another procedure, the components as mentioned above were
mixed thoroughly and heated in an oil bath maintained at 120 °C for
appropriate time. The reaction mixture was then cooled to room
temperature. Hot ethanol was added to the solid mass thus obtained and the
reaction was worked up as described in Method A.
mixture of 4-hydroxycoumarin (5 mmol), aldehyde (2.5 mmol), TBAB
(10 mol %) and 20 mL of water was stirred magnetically at 100 °C for
appropriate time as mentioned in Table 2. After completion of the reaction
as monitored by TLC, reaction mixture was cooled to room temperature. Water