Synthesis of biscoumarins from 4-hydroxycoumarin and aromatic aldehydes - A comparative assessment of percentage yield under thermal and microwave-assisted conditions

Article abstract of DOI:10.1080/00397910802162942

A convenient synthesis of various biscoumarins by condensing a series of aldehydes with 4-hydroxycoumarin under microwave irradiation is reported for the first time along with a comparative account of the syntheses under conventional conditions. The react

Full text of DOI:10.1080/00397910802162942

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Synthesis of Biscoumarins
from 4-Hydroxycoumarin
and Aromatic Aldehydes—A
Comparative Assessment
of Percentage Yield Under
Thermal and Microwave-
Assisted Conditions
Saima Qadir a , Aijaz Ahmad Dar a & Khaliquz Zaman
Khan a
a Department of Chemistry, University of Kashmir,
Hazratbal, Srinagar, India
Published online: 29 Sep 2008.
To cite this article: Saima Qadir , Aijaz Ahmad Dar & Khaliquz Zaman Khan (2008):
Synthesis of Biscoumarins from 4-Hydroxycoumarin and Aromatic Aldehydes—A
Comparative Assessment of Percentage Yield Under Thermal and Microwave-
Assisted Conditions, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:20, 3490-3499
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Synthetic Communications1, 38: 3490–3499, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802162942
Synthesis of Biscoumarins from
4-Hydroxycoumarin and Aromatic Aldehydes—A
Comparative Assessment of Percentage Yield
Under Thermal and Microwave-Assisted
Conditions
Saima Qadir, Aijaz Ahmad Dar, and Khaliquz Zaman Khan
Department of Chemistry, University of Kashmir,
Hazratbal, Srinagar, India
Abstract: A convenient synthesis of various biscoumarins by condensing a series
of aldehydes with 4-hydroxycoumarin under microwave irradiation is reported
for the first time along with a comparative account of the syntheses under conven-
tional conditions. The reaction times have been reduced considerably with
improvement in yields in comparison to thermal conditions. The reactions have
been carried out in solvent as well as under solvent-free conditions, and the
adopted procedure provides an energy-and time-saving protocol.
Keywords: 4-hydroxycoumarin, biscoumarins, condensation, microwave irradia-
tion, solvent-free
INTRODUCTION
Coumarins form an important group of organic compounds. 4-Hydroxy-
coumarin and its derivatives are known for their anticoagulant,[1] spas-
molytic,[2] antibacterial, and antifungal activities.[3] In addition, certain
derivatives have also been reported as antitumor[4] and anti-HIV
agents.[5] Besides, coumarins find diverse applications as agrochemicals[6]
Received December 31, 2007.
Address correspondence to Khaliquz Zaman Khan, Department of Chemistry,
University of Kashmir, Hazratbal, Srinagar 190 006, India. E-mail: khaliq_ku@
yahoo.com
3490

Biscoumarins
3491
as well as analytical reagents.[7] Biscoumarins, the bridge substituted
dimers of 4-hydroxycoumarin, have enormous potential as anticoagu-
lants.[8,9] 3,30-Methylene-bis(4-hydroxycoumarin), commonly known as
dicoumarol, occurs naturally in moldy clover.[10] It is the hemorrhagic
agent responsible for the sweet clover disease of cattle[1] and has also been
employed for the prevention and treatment of thrombosis.[11] Dicou-
marol is also the starting material for the synthesis of various furocou-
marins and benzopyrans.[12] A number of biscoumarins have been
screened for anticoagulant activity and quite a few of them have also been
found to be urease inhibitors.[13] Urease is an enzyme that causes decom-
position of urea to ammonia and carbondioxide and is directly involved
in the formation of renal stones causing various urological disorders.
Additionally, bacterial ureases present in the soil devoid the agricultural
area of nitrogenous nutrients, and the toxicity of ammonia (along with an
increase in the level of CO2 in the atmosphere) poses a threat to both
animal and plant kingdoms.
Biscoumarins have generally been synthesized by refluxing 4-
hydroxycoumarin and various aldehydes in ethanol for several hours.
Attempts have also been made to condense 4-hydroxycoumarin with
various aromatic, heterocyclic, and a,b-unsaturated aldeyhdes to get cor-
responding dicoumarols using different catalysts and media. These meth-
ods usually require hours of stirring at room temperature with tedious
workup in certain cases.[8,9,13] In a recent report, molecular iodine has
been employed as catalyst for the synthesis of various biscoumarins in
water.[14] The aqueous workup has been followed by chromatographic
purification of biscoumarins.
Since the concept of green chemistry is gaining momentum in the
field of organic synthesis, emphasis is on devising new methods and
procedures of synthesizing potentially important compounds in an eco-
friendly environment. Keeping into consideration the enormous pharma-
cological potential of biscoumarins, it is of utmost importance that their
synthesis should be achieved by a simple, effective, environmentally
benign, and time-saving method.
Although much work has been done on the synthesis of biscoumarins
under classical conditions, the use of microwave dielectric heating for
their synthesis is novel. Since the first use of microwave ovens in organic
synthesis,[15] this technique has blossomed into an ecofriendly procedure
with the advantages of improved yields, easy workup, and considerable
shortening of reaction time. Several coumarins have been synthesized
in this manner;[15] however, there is no report of synthesis of biscoumar-
ins under these conditions.
In this background, we report herein the first microwave-assisted
synthesis of biscoumarins with the advantages of minimum solvent usage,

3492
S. Qadir, A. A. Dar, and K. Z. Khan
improved yields, and shortened reaction times and without the usage
of catalytic reagents employed in many conventional procedures. This
efficient ecofriendly procedure provides a green chemistry approach for
the synthesis of biscoumarins.
RESULTS AND DISCUSSION
For the convenient synthesis of biscoumarins, a range of aromatic alde-
hydes were condensed with 4-hydroxycoumarin (Scheme 1). The reactions
were carried out in solvent media (EtOH) as well as under solvent-free
(silica-gel-supported) conditions in the molar ratio of 1:2 taken in an
open vessel and irradiated in a multimode domestic microwave oven at
a power output of 75% at the corresponding times as shown in Table 1.
Optimum irradiation times were precisely achieved, but the reaction was
carried out with intervals of 30s in cases involving liquid media to avoid
solvent loss and bumps due to rapid rise in temperature. In solvent-free
conditions, irradiation intervals were 1 minute in duration. Reactions
were monitored periodically with the help of thin-layer chromatography
(TLC). The problems encountered while performing the reactions using
solvent were easily overcome by solvent-free technique and the yields
obtained were almost quantitative. However, in case of reactions in etha-
nol, yields get affected. This could be due to the solvent–microwave inter-
action in which heat transfer takes place from the solvent to the reactants,
confirming the observations made by various authors.[16] The general
Scheme 1. Reaction of 4-hydroxycoumarin with different aldehydes to yield
the corresponding biscoumarins: a, benzaldehyde; b, 2-chlorobenzaldehyde;
c, 3-chlorobenzaldehyde; d, 4-chlorobenzaldehyde; e, 2-nitrobenzaldehyde;
f, 3-nitrobenzaldehyde; g, 4-nitrobenzaldehyde; and h, 4-methoxybenzaldehyde.

Biscoumarins
3493
Table 1. Percentage yield of biscoumarins 2a–h under microwave conditions in
both solvent as well as solvent-free media at a 3:1.5-mmol ratio of 4-hydroxy
coumarin and the corresponding aldehydes (error ꢀ2)
Solvent media
Solvent-free media
Time (min) Yield (%)
71
Product
R
Time (min) Yield (%)
2a
2b
2c
2d
2e
2f
C6H5
2ClC6H4
3ClC6H4
4ClC6H4
2NO2C6H4
3NO2C6H4
4NO2C6H4
4CH3OC6H4
2
4
1
3
5
6
4
3
86
49
98
90
65
86
75
80
6
6
4
5
4
6
6
7
88
95
85
81
87
81
86
2g
2h
advantage of the procedure is evident as considerably shorter time is
required under microwave irradiation than reported so far for the synth-
esis of biscoumarins.
A comparison of microwave-assisted synthesis with those carried out
under conventional conditions has been drawn in Table 2. The reactions
were carried out at a constant time of 5 min and a constant power level of
Table 2. Percentage yield of biscoumarins under conventional and microwave
irradiation at constant concentrations of 4-hydroxycoumarin and aldehyde
(3:1.5-mmol) in a 2:1 molar ratio (error ꢀ2)
Conventional (D)
Yield (%)a in microwave
Product
R
Time (hrs) Yield (%)
Solventb
Solvent-freec
2a
2b
2c
2d
2e
2f
C6H5
2ClC6H4
3ClC6H4
4ClC6H4
2NO2C6H4
3NO2C6H4
4NO2C6H4
4CH3OC6H4
5
7
6
5
6
5
6
7
41
48
52
84
76
76
50
62
43
49
54
35
65
94
67
62
68
73
94
87
89
76
69
60
2g
2h
aIrradiation time: 5 min; Power: 75%.
bEthanol.
cSilica-gel supported.

3494
S. Qadir, A. A. Dar, and K. Z. Khan
75% to monitor an exact comparison in terms of yields. The yields of bis-
coumarins for three different concentrations of 4-hydroxycoumarin and
the corresponding aldehyde (1.5:0.77, 3:1.5, 6:3 mmol) were obtained.
For the same concentrations of 4-hydroxycoumarin and the correspond-
ing aldehydes, more or less the same yields were obtained under conven-
tional and microwave conditions when the reactions were carried out in
solvent media except that the reaction times were considerably shortened
(Fig. 1). The reason as postulated by various authors is that ethanol,
being highly polar, interacts more with microwave irradiation than the
reactants[16] and consequently heat generated under microwave condi-
tions gets transferred from the solvent to the reactants through convec-
tion as happens in conventional heating. However, the exceptional
result obtained in case of 2f contradicts this argument (Table 2). Getting
high yield in solvent media in this case may be due to the heterogeneous
field generated inside the multimode oven. A superheating effect[17] in the
case of polar solvents under microwave irradiation may also contribute
Figure 1. Graph showing the comparative account of percentage yields of biscou-
marins from 4-hydroxycoumarin and corresponding aldehydes (same as in
Scheme 1) taken in a 3:1.5-mmol ratio under three different conditions.

Biscoumarins
3495
to this kind of results. Such situations can be minimized using a mono-
mode oven, which produces a homogenous field. Because the results
obtained when the reactions are carried out in the liquid phase lack
consistent reproducibility, efforts were made to carry them out under
solvent-free conditions, which gave improved and consistent results
(Table 2). The direct interaction of microwaves with the reactants in
solvent-free conditions gave better results then the one in which the reac-
tions have been carried out in solvent media. Exceptions were the cases of
2h and 2f, where the yields under solvent media were more than the yields
obtained under solvent-free conditions. This may be as a result of uneven
irradiation of the reaction mixture, leading to temperature differences in
various parts of the reaction vessel. Such temperature gradients may be
minimized if a microwave oven with a provision for stirring the reaction
mixture is used.
A study of the effect of concentration of reactants on the yields of
the corresponding biscoumarins under solvent-free conditions is shown
in Table 3. The increase in the concentration of reactants has a significant
effect on the yield in general as indicated in the table. Three-fourths of the
reactions show an increase in yield on increasing the amount of reactants,
and exceptionally high yields were obtained when 4-hydroxycoumarin
and aldehydes e–g were used in a 6:3 mmol ratio. This indicates that
the percentage conversion of reactants into products under solvent-free
microwave conditions gets increased in most cases when the concentra-
tion of reactants is increased.
EXPERIMENTAL
All the reactions were carried out at atmospheric pressure in an open
vessel and irradiated in a Sharp Carousel (210B) multimode microwave
oven. The compounds were identified through the comparison of their
1H NMR, IR, and mass spectra with the data reported in the literature
wherever possible. Physical properties such as melting point, solubility,
color, and physical state were in agreement with those reported in the
literature.
General Procedure for the Synthesis of Biscoumarins 2a–h
In Solvent Media
4-Hydroxycoumarin and the corresponding aldehydes were taken in a 2:1
molar ratio and dissolved in a minimum amount of ethanol. The reaction

3496
S. Qadir, A. A. Dar, and K. Z. Khan
Table 3. Percentage yield of biscoumarins at three different concentrations of
reactants under solvent-free microwave irradiation at constant time (5 min) and
constant power (75%) (error ꢀ2)
1 (mmol)
a–h (mmol)
Product
R
Yield (%)
1.5
3
6
1.5
3
6
1.5
3
6
1.5
3
6
1.5
3
6
1.5
3
6
1.5
3
6
1.5
3
6
0.77
1.5
3
0.77
1.5
3
0.77
1.5
3
0.77
1.5
3
0.77
1.5
3
0.77
1.5
3
0.77
1.5
3
0.77
1.5
3
2a
C6H5
63
68
62
74
73
82
91
94
84
68
87
75
63
88
94
77
76
95
71
69
91
68
60
60
2b
2c
2d
2e
2f
2ClC6H4
3ClC6H4
4ClC6H4
2NO2C6H4
3NO2C6H4
4NO2C6H4
4CH3OC6H4
2g
2h
mixture was irradiated under the microwave oven at the corresponding
times. The product, which precipitated out as an insoluble residue, was
filtered, washed with ethanol, dried, and crystallized from the appropri-
ate solvent.
In Solvent-Free Media
4-Hydroxycoumarin and the corresponding aldehydes taken in a 2:1
molar ratio were adsorbed on silica gel (60–120 mesh) and irradiated in
the microwave oven. The reaction mixture was eluted with acetone, which
upon concentration yielded the product as a precipitate. It was filtered
and washed with alcohol to remove any unreacted 1, dried, and crystal-
lized from the appropriate solvent.

Biscoumarins
3497
Spectral Data of Biscoumarins 2a–h
3,30-Benzylidene-bis(4-hydroxycoumarin) (2a)
1H NMR (200 MHz, CDCl3): d6.2 IH, s (H-11); 7.2–8.3, 13H, m
(13 ꢁ CH). IR (KBr, cmꢂ1): 1661.1, 1618, 1604.7, 1569.5, 762.2. MS
(m=z): 412 (ESI); Mp 215 ꢃC.
3,30-(2-Chlorobenzylidene)-bis(4-hydroxycoumarin) (2b)
1H NMR (200 MHz, CDCl3): d 6.2, IH, s (H-11); 7.3–8.2, 12H, m
(12 ꢁ CH). IR (KBr, cmꢂ1): 1648.3, 1618.4, 1601.7, 1565.7, 767.9. MS
(m=z): 445.9 (ESI); Mp 198–199 ꢃC.
3,30-(3-Chlorobenzylidene)-bis(4-hydroxycoumarin) (2c)
1H NMR (200 MHz, CDCl3): d 6.1, IH, s (H-11); 7.2–8.1, 12H, m
(12 ꢁ CH). IR (KBr, cmꢂ1): 1663.9, 1617.7, 1568.5, 762. MS (m=z):
445.9 (ESI); Mp 222–224 ꢃC.
3,30-(4-Chlorobenzylidene)-bis(4-hydroxycoumarin) (2d)
1H NMR (200 MHz, CDCl3): d 6.1, IH, s (H-11); 7.2–8.2, 12H, m
(12 ꢁ CH). IR (KBr, cmꢂ1): 1667.9, 1618.2, 1603.9, 1564.2, 765.9. MS
(m=z): 445.9 (ESI); Mp 247–248 ꢃC.
3,30-(2-Nitrobenzylidene)-bis(4-hydroxycoumarin) (2e)
1H NMR (200 MHz, CDCl3): d 6.7, IH, s (H-11); 7.2–8.1, 12H, m
(12 ꢁ CH). IR (KBr, cmꢂ1): 1653.87, 1616.2, 1567.9, 762.6. MS (m=z):
456.9 (ESI); Mp 200–202 ꢃC.
3,30-(3-Nitrobenzylidene)-bis(4-hydroxycoumarin) (2f)
1H NMR (200 MHz, CDCl3): d 6.2, IH, s (H-11); 7.2–8.2, 12H, m
(12 ꢁ CH). IR (KBr, cmꢂ1): 1657.8, 1617.6, 1567.6, 762.9. MS (m=z):
457 (ESI); Mp 212–215ꢃC.
3,30-(4-Nitrobenzylidene)-bis(4-hydroxycoumarin) (2g)
1H NMR (200 MHz, CDCl3): d 6.2, IH, s (H-11); 7.2–8.2, 12H, m
(12 ꢁ CH). IR (KBr, cmꢂ1): 1654.5, 1617.8, 1563.7, 782.9. MS (m=z):
457 (ESI); Mp 242–245 ꢃC.

3498
S. Qadir, A. A. Dar, and K. Z. Khan
3,30-(4-Methoxybenzylidene)-bis(4-hydroxycoumarin) (2h)
1H NMR (200 MHz, CDCl3): d 3.9, 3H, s (OCH3); 6.2, IH, s (H-11), 6.9–
8.2, 12H, m (12 ꢁ CH). IR (KBr, cmꢂ1): 1654.3, 1636.3, 1560.4, 781.8.
MS (m=z): 442 (ESI); Mp 238–240 ꢃC.
CONCLUSIONS
Biscoumarins have been conveniently prepared with improved yields
under solvent-free microwave conditions in less time than reported so
far in the literature. This novel procedure is simple and efficient, and
the absence of a catalyst makes it an ecofriendly procedure. Moreover,
the use of a domestic microwave oven makes the procedure more conve-
nient and easily accessible.
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