Mohr's salt hexahydrate: A novel, cheap and powerful reagent for green synthesis of biscoumarins on water

Article abstract of DOI:10.1002/jccs.201200489

Anew and convenient method for the synthesis of biscoumarins based on the condensation of 4-hydroxycoumarin and aromatic aldehydes in the presence of Mohr's salt hexahydrate (ferrous ammonium sulfate hexahydrate) as a novel catalyst on water is developed.

Full text of DOI:10.1002/jccs.201200489

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Mohr’s Salt Hexahydrate: A Novel, Cheap and Powerful Reagent for Green Synthesis
of Biscoumarins on Water
Saeed Khodabakhshi* and Mojtaba Baghernejad
Young Researchers Club, Gachsaran Branch, Islamic Azad University, Gachsaran, Iran
(Received: Sept. 11, 2012; Accepted: Dec. 21, 2012; Published Online: Feb. 1, 2013; DOI: 10.1002/jccs.201200489)
A new and convenient method for the synthesis of biscoumarins based on the condensation of 4-hydroxy-
coumarin and aromatic aldehydes in the presence of Mohr’s salt hexahydrate (ferrous ammonium sulfate
hexahydrate) as a novel catalyst on water is developed. This method has advantages such as the use of in-
expensive and available reagent, avoidance of organic solvents, short reaction times, and high product
yields.
Keywords: Mohr’s salt; Biscoumarin; On-water; Aldehyde; Ferrous ammonium sulfate
hexahydrate.
INTRODUCTION
Coumarins have attracted the attention of chemists
RESULTS AND DISCUSSION
As a part of our continual efforts toward the develop-
ment of novel, efficient, and green procedures for organic
reactions,15-18 we turned our attention toward the condensa-
tion of 4-hydroxycoumarin (1) and aromatic aldehydes 2 in
the presence of Mohr’s salt hexahydrate as catalyst to pro-
duce bis-4-hydroxycoumarin derivatives 3 (Scheme I).19
because they are biologically active so that they reduce the
HIV activity and some coumarins have shown cytostatic
activity and therefore can be considered as potential candi-
dates for anti-cancer therapy.1 Biscoumarins, the bridge
substituted dimers of 4-hydroxycoumarin, have enormous
potential as anticoagulants.2 Dicoumarol is also an antico-
agulant that functions as a vitamin K antagonist.3 It is the
hemorrhagic agent responsible for the sweet clover disease
of cattle,4 and has also been employed for the prevention
and treatment of thrombosis.5 There are some methods de-
scribed in the literature for the synthesis of bis-4-hydroxy-
coumarins using different catalysts or reagents in various
conditions.6-12 Bis-4-hydroxycoumarins have been gener-
ally synthesized by refluxing 4-hydroxycoumarin and vari-
ous aldehydes in ethanol for several hours. However, some
of the reported methods suffer from drawbacks, such as the
use of expensive or synthetic reagents and organic sol-
vents.6,8 Also, some of them require harsh conditions,10 te-
dious work-up in certain cases12 and long reaction times to
complete.11
Synthesis of biscoumarins using Mohr’s
salt under reflux in water
Scheme I
O
O
O
O
X
O
H
H
Fe2+
S
O
N
HO
OH
O
O
O
H
H
O
O
O
2
2
H2O, Reflux
25-40 min.
+
OHHO
1
1
O
3
H
X
2
To identify the suitable reaction conditions for the
synthesis of 3 using Mohr’s salt, the reaction of 4-hydroxy-
coumarin (1) and benzaldehyde (2a) was selected as a
model (Scheme II).
As can be seen in Table 1, we found that in the ab-
sence of the catalyst, the reaction was not completed, even
at long reaction times in several solvents (Entry 1-3). In an-
other experiment, in order to show the effect of solvent or
media on the reaction progress, we employed several sol-
vents which the results have been shown in Table 1. It can
be concluded that protonic solvents such as EtOH, MeOH,
and H2O can accelerate the condensation reaction. It should
be also noted that 4-hydroxycoumarin is soluble in alcohol,
acetone and ether, but it has low solubility in water.
With an objective to develop environmentally benign
reaction conditions and media for organic transformations
with excellent efficiency and selectivity, water has been
shown to be a useful solvent or media.13 Recently, organic
synthesis on water was reviewed by Fokin and co-work-
ers.14 In this context, we report the use of Mohr’s salt hexa-
hydrate (ferrous ammonium sulfate hexahydrate) as an
eco-friendly and readily available reagent for the synthesis
of substituted biscoumarins on water.
* Corresponding author. Tel: +98 742 333923; Fax: +98 742 3332003; E-mail: saeidkhm@yahoo.com
J. Chin. Chem. Soc. 2013, 60, 495-498
© 2013 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
495

Article
Khodabakhshi and Baghernejad
Table 2. Synthesis of biscoumarin derivatives in the presence of
Mohr's salt under reflux in water
Reaction of benzaldehyde with 4-hydroxy-
coumarin in various conditions
Scheme II
Entry
X
Time (min) Yield [a] (%) M.p. (ºC)Ref.
3a
3b
3c
3d
3e
3f
H
4-F
30
25
35
40
20
25
25
30
35
40
25
25
98
90
98
90
97
95
90
95
90
85
90
90
229-2316
267-2696
253-2556
265-2676
232-2346
241-2436
227-2297
226-2286
268-2706
245-24720
265-2677
243-2457
4-Cl
4-Br
4-NO2
4-OMe
4-PhCH2O
2-Cl
3g
3h
3i
4-Me
3j
4-iPr
Through screening, we found that this reaction was
completed with Mohr’s salt (5 mol%) under refluxing H2O
about 30 min (Entry 6). Higher loadings of catalyst did not
affect a marked influence on the product yield or reaction
rate (Entry 8). After optimization of the reaction condi-
tions, to prove the general applicability of this method, dif-
ferent aldehydes and 4-hydroxycoumarin were examined
(Table 2).
3k
3l
4-Cl-3-NO2
3,4,5-(OMe)3
[a] Yields of isolated products.
Table 3. Comparison of our method with other methods for the
synthesis of 3a
Entry
Conditions
Time/Yield (%)Ref.
1
2
NaHSO4 SiO2/toluene/100 ºC
Indion 190 resin/toluene/100 ºC
Silica-supported Preyssler
nanoparticles/EtOH/r.t.
30 min/896
30 min/926
.
The nature of X group on the aldehydes showed no
significant effect on the reaction rate or product yield. It
should be mentioned that our efforts for the synthesis of
biscoumarins using aliphatic aldehydes were unsuccessful.
The problem with alkyl aldehydes is likely due to their
enolization during the reaction.
3
30 min/928
4
5
SO3H-functionalized ILs/70 ºC
H6[PMo9V3O40]/EtOH:H2O
Catslyst-free/microwave/H2O/150 W,
150 ºC
2 h/959
15 h/3010
6
7
9 min/ 8511
In order to show the merit of present method in com-
parison with other methods used for the similar reaction,
we have tabulated some of the results in Table 3. As it is ev-
idence from the results, the use of Mohr’s salt as catalyst
and water as a media can be considerable from the environ-
mental and economic aspects.
Mohr's salt/H2O/reflux
30 min/98 [a]
[a] This work.
have been reported for this type of condensation, the use of
Mohr’s salt seems to be attractive and provides another
valuable option for chemists because it is a safe and easily
accessible reagent. Besides, the use of water instead of or-
ganic solvents is more reasonable because of its safety and
cheapness. All of these factors are in accord with green
chemistry principles. The structures and purity of the ob-
tained products were deduced from their IR, elemental
analysis, and NMR spectral data.
Although so many different reagents and catalysts
Table 1. Optimization of the reaction conditions through various
solvents and temperatures
Time Yield
Entry
Conditions
(min) (%)
1
Catalyst-free/EtOH/reflux
Catalyst-free/EtOH:H2O/reflux
Catalyst-free/H2O/reflux
300
300
300
45
25
25
25
85
95
98
90
95
90
85
75
50
2
3
CONCLUSION
4
Mohr's salt (5 mol%)/EtOH/reflux
Mohr's salt (5 mol%)/EtOH:H2O/reflux
Mohr's salt (5 mol%)/H2O/reflux
Mohr's salt (2 mol%)/H2O/reflux
Mohr's salt (10 mol%)/H2O/reflux
Mohr's salt (5 mol%)/MeOH/reflux
Mohr's salt (5 mol%)/THF/reflux
Mohr's salt (5 mol%)/CH2Cl2/reflux
In summary, we have introduced a condensation reac-
tion leading to biscoumarin derivatives starting from sim-
ple and readily available precursors. This reaction can be
regarded as a new approach for the preparation of syntheti-
cally and pharmaceutically relevant heterocyclic systems.
This approach includes some important aspects such as
high yields, short reaction times, simple work-up proce-
5
40
6
30
7
70
8
35
9
40
10
11
12
60
120
Mohr's salt (5 mol%)/solvent-free/100 ºC 120
496
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J. Chin. Chem. Soc. 2013, 60, 495-498

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Mohr’s Salt Catalyzed Synthesis of Biscoumarins
dures, and use of water as a clean media, which make this
protocol a useful and an attractive procedure for the synthe-
sis of biscoumarin derivatives.
124.98, 124.41, 116.87, 116.68, 116.39, 115.63, 115,41, 105.49,
103.95, 35.68. Anal. Calcd. for C25H15NO8: C, 65.65; H, 3.31; N,
3.06. Found: C, 65.89; H, 3.24; N, 3.17.
Compound 3g
EXPERIMENTAL
1H NMR (DMSO-d6, 400 MHz) d ppm: 11.59 (b, 2H),
7.93-7.81 (m, 2H), 7.63-7.58 (m, 2H), 7.44-7.31 (m, 5H), 7.22-
7.06 (m, 2H), 6.90 (d, 2H, J = 8.8 Hz), 6.31 (s, 2H), 5.04 (s, 2H).
13C NMR (DMSO-d6, 100 MHz) d ppm: 164.97, 164.78, 156.44,
152.13, 137.21, 132.68, 131.90, 131.77, 128.48, 128.35, 127.84,
127.75, 127.71, 127.64, 123.90, 123.83, 123.76, 123.16, 117.76,
116.34, 115.95, 115.23, 114.31, 104.32, 90.96, 69.09, 35.21.
Anal. Calcd. for C32H22O7: C, 74.12; H, 4.28. Found: C, 74.29; H,
4.15.
General
All chemicals were purchased from Merck and Aldrich.
The reactions were monitored by thin layer chromatography
(TLC; silica-gel 60 F254, n-hexane: ethyl acetate). IR spectra were
recorded on a FT-IR JASCO-680 and the 1H NMR spectra were
obtained on a Bruker-Instrument DPX-400 MHz Avance 2 model.
The varioEl CHNS Isfahan Industrial University was used for ele-
mental analysis. All products were characterized by comparison
of their spectra and physical data with those reported in the litera-
ture.6,7
ACKNOWLEDGEMENTS
Preparation of bis-4-hydroxycoumarins
The authors are very grateful to Haj Khodadad
Taghipour (the head of Young Researchers Club, Islamic
Azad University of Gachsaran, Iran) for his kind coopera-
tion.
A mixture of 4-hydroxycoumarin 1 (2 mmol), aromatic al-
dehydes 2 (1 mmol) and Mohr’s salt (5 mol%) in water (10 mL)
was refluxed for the appropriate time mentioned in Tables 2. The
progress of reaction was monitored by TLC. After completion of
reaction, the solid compound obtained was filtered off and the
crude products were purified by recrystallization from EtOH.
Selected spectral data
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J. Chin. Chem. Soc. 2013, 60, 495-498