Aqua mediated synthesis of substituted 2-amino-4H-chromenes catalyzed by green and reusable Preyssler heteropolyacid

Article abstract of DOI:10.1016/j.bmcl.2007.05.023

A simple, clean and environmentally benign route to the synthesis of 2-amino-4H-chromenes is described using Preyssler type heteropolyacid, H₁₄[NaP₅W₃₀O₁₁₀], as a green and reusable catalyst in water. The produc

Full text of DOI:10.1016/j.bmcl.2007.05.023

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4262–4265
Aqua mediated synthesis of substituted 2-amino-4H-chromenes
catalyzed by green and reusable Preyssler heteropolyacid
Majid M. Heravi,a,* Khadijeh Bakhtiari,a Vahideh Zadsirjan,a
Fatemeh F. Bamoharramb and Omid M. Heravic
aDepartment of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran 1234, Iran
bDepartment of Chemistry, Azad University of Mashhad, Mashhad, Iran
cMedical School, Azad University, Tehran, Iran
Received 18 February 2007; revised 18 April 2007; accepted 10 May 2007
Available online 16 May 2007
Abstract—A simple, clean and environmentally benign route to the synthesis of 2-amino-4H-chromenes is described using Preyssler
type heteropolyacid, H14[NaP5W30O110], as a green and reusable catalyst in water. The products were obtained in very good yields.
ꢀ 2007 Elsevier Ltd. All rights reserved.
2-Amino-chromenes represent an important class of
compounds being the main components of many natu-
rally occurring products. They can also widely be uti-
lised as cosmetics, pigments1 and potential
biodegradable agrochemicals.2 These compounds have
been of interest to the medicinal chemist for many years.
Fused chromenes are biologically active compounds
with a wide spectrum of activities such as antimicrobial,3
mutagenicitical,4 antiviral,5,6 antiproliferative,7 sex
pheromonal,8 antitumoral9 and central nervous system
activities.10 Furthermore, many bio-active compounds
(e.g., antioxidants,11 enzyme inhibitors12) incorporate
these key heterocycles. The basic structural framework
of chromenes for example is a common feature of many
tannins and polyphenols13 found in tea, fruits, vegeta-
bles and red wine and these compounds have become
more important as a result of their health-promoting
effects.
water is a cheap, safe and environmentally benign
solvent.15
2-Amino-chromenes are generally prepared by refluxing
malononitrile, aldehyde and activated phenol in the
presence of hazardous organic bases like piperidine in
organic solvents like ethanol and acetonitrile for several
hours.16 A literature survey revealed the recent reports
on several modified procedures using CTACl,17
TEBA,18 c- alumina19 and K2CO3 in water under micro-
wave irradiation.20
The use of clean solvents in combination with heteroge-
neous and reusable catalysts represents one of the more
powerful green chemical technology procedures.21
Aqua mediated reactions have received considerable
attention in organic synthesis due to environmental
safety reasons. Water is the cheapest, most abundant
and non-toxic chemical in nature. It has unique physical
and chemical properties such as a high dielectric con-
stant and cohesive energy density compared to organic
solvents. It has also special effects on reactions arising
from inter- and intramolecular non-covalent interac-
tions leading to novel salvation and assembly processes.
Many organic reactions have been performed success-
fully in water as reaction medium, and several books
and reviews have been devoted to such an application.22
One-pot multicomponent condensations represent as
possible instrument to perform a near ideal synthesis
because they possess one of the aforementioned quali-
ties, namely the possibility of building-up complex mol-
ecules with maximum simplicity and brevity.14 Recently
organic reactions in water without the use of harmful or-
ganic solvents have attracted much attention, because
Keywords: Substituted 2-amino-4H-chromenes; Heteropolyacid; Prey-
ssler; H14[NaP5W30O110]; Water.
Heteropolyacids, HPAs, have attracted increasing inter-
est because of their applications, For example, as cata-
*
Corresponding author. E-mail: mmh1331@yahoo.com
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.05.023

M. M. Heravi et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4262–4265
4263
lysts for organic reactions, corrosion resistant coatings,
dopants in sol–gel matrices, membranes in selective elec-
trodes, in gas detection apparatuses, in solid-state elec-
trochromic devices, in liquid and solid wx electrolytic
cells.23–28
C-alkylation of a-naphthol by reaction with the electro-
philic C@C double bond36 and the nucleophilic addition
of the phenolic OH group of the CN moiety37 producing
the final 2-amino-2-chromene, requires the intervention
of the catalyst, as the uncatalyzed reaction afforded
the final product in only 29% yield.
There are two kinds of protons in the HPA crystals. One
is the dissociated and hydrated proton that is combined
with the HPA anion; the other is the unhydrated proton
that is located on the bridge-oxygen in the HPA anion.
A screening of three different solvents was performed in
order to define the best solvent as a solvent of choice. As
reported in Table 1, water was found to be the superior
one affording the desired product in 91% yield.
Since the dissociated protons have good mobility, the
HPA crystals have some characteristics of a ‘‘pseudo-
liquid phase’’. Hence they are superionic protonic con-
ductors and promising solid electrolytes.
The scope and the generality of the present method were
then further demonstrated by the reaction of various
aldehydes with malononitrile and a- or b-naphthol. In
all cases good yields with good selectivity were obtained.
In view of the diverse therapeutic activity of chromenes
and based on our previous studies on the use of water as
solvent29,30 and Preyssler type heteropolyacid as cata-
lyst31 for carrying out organic reactions and in continu-
ation of our interest in the synthesis of heterocyclic
compounds32 we now report the three-component syn-
thesis of substituted 2-amino-chromenes using Preyssler
type heteropolyacid, H14[NaP5W30O110], as readily
available, green, reusable and inexpensive catalyst and
water as solvent (Scheme 1).
It is noteworthy to mention that, the effect of the nature
of the substituents on the aromatic ring showed no obvi-
ous effect on this conversion, because they were obtained
in high yields in relatively short reaction times. The
results are shown in Table 2.
Finally we investigated the reusability of the catalyst.
The catalyst is soluble in water and could be removed
easily by evaporation of the solvent. After evaporating
of water the catalyst was filtered, washed with diethyl
ether, dried at 130 ꢁC for 1 h, and re-used in another
reaction. The recycled catalyst was used for three con-
secutive reactions without observation of appreciable
loss in its catalytic activities.39
Preyssler type heteropolyacid, H14[NaP5W30O110], was
prepared by the passage of a solution of the potassium
salt in water through a column (50 cm · 1 cm) of Dowex
50 W · 8 in the H+ form and evaporation of the elute to
dryness under vacuum.
It was used three times to promote the model reaction
affording the corresponding chromene in 91, 89 and
87% yields, respectively, and with the same excellent
selectivity.
In a typical reaction39 a mixture of the H14[NaP5-
W30O110] (0.03 g), benzaldehyde (1 mmol), malononitrile
(1 mmol) and a-naphthol (1 mmol) in water (5 mL) was
refluxed for 3 h. After completion of the reaction, the
mixture was cooled to room temperature. The solid,
which separated, was filtered and then recrystallized
from methanol to afford pure product.
In conclusion, H14[NaP5W30O110] can serve as an effi-
cient catalyst for the synthesis of 2-amino-4H-chrom-
enes as biologically and pharmacologically active
compounds. This procedure offers several advantages
including mild reaction conditions, cleaner reaction,
high yields of products as well as a simple experimental
The process represents a typical cascade reaction33,34 in
which the benzylidene malononitrile, containing the
electron-poor C–C double bond, is fast and quantita-
tively produced by Knoevenagel addition of malononit-
rile to the aromatic aldehyde and subsequent water
elimination (Scheme 1).
Table 1. Synthesis of 3-amino-2-cyano-1-(phenyl)-1H-benzo[f]chro-
mene in different solvents in the presence of H14[NaP5W30O110]
Entry
Solvent
Time (h)
Yield (%)a
1
2
3
HOAc
CH3CN
H2O
8
6
5
50
80
91
It is well known that the first step, if carried out in protic
solvents like water, does not require any catalyst
although it results in a net dehydration.35 On the con-
trary, the second step, presumably involving the ortho
a Yields refer to isolated products.
NH2
CN
X
CN
R
R
NH2
O
CN
CN
Y
H14[NaP5W30O110
]
+
O
RCHO
+
or
H2O, reflux
X, Y=H or OH
1a-i
Scheme 1.

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M. M. Heravi et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4262–4265
Table 2. Synthesis of substituted 2-amino-chromenes catalyzed by H14[NaP5W30O110
]
Entry
R
Phenol
Time (h)
Yield (%)a
Mp (ꢁC)
Reported19,38
Found
1
2
3
4
5
6
7
8
9
C6H5
C6H5
a-Naphthol
b-Naphthol
a-Naphthol
b-Naphthol
a-Naphthol
b-Naphthol
a-Naphthol
b-Naphthol
a-Naphthol
3
91
93
90
93
91
92
90
91
92
209
280
210–211
278–280
239.5–241
188–189
190–191.5
182
2.75
4.5
4.25
3.25
3
4-NO2C6H4
4-NO2C6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
3-NO2C6H4
240
188
191
182–183
231–232
206–208
212
4
232
208
4
4.5
214.5–216
a Yields refer to isolated products.
16. Elagamay, A. G. A.; El-Taweel, F. M. A. A. Indian J.
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39. Preparation of 2-amino-4H-chromenes: General proce-
dure. A mixture of an appropriate benzaldehyde (1 mmol),
malononitrile (1 mmol), a- or b-naphthol (1 mmol) and
H14[NaP5W30O110] (0.03 g), in water (5 mL) were refluxed
for 3 h; After completion of the reaction which was
monitored by TLC, the mixture was cooled to room
temperature. The precipitate was collected by filtration
and recrystallized from MeOH. In order to show generality
of the procedure, the reaction was repeated with other
benzaldehyde derivatives. The results are summarized in
Table 1.Recyclibility of the catalyst: After evaporating of
water the catalyst was filtered, washed with diethyl ether,
dried at 130 ꢁC for 1 h, and re-used in another reaction.