Ultrasound promoted one-pot synthesis of 2-amino-4,8-dihydropyrano[3,2-b] pyran-3-carbonitrile scaffolds in aqueous media: A complementary 'green chemistry' tool to organic synthesis

Article abstract of DOI:10.1016/j.ultsonch.2012.07.007

A green and simple approach to assembling of 2-amino-4,8-dihydropyrano[3,2- b]pyran-3-carbonitrile scaffolds via three-component reaction of kojic acid, malononitrile, and aromatic aldehydes in aqueous media under ultrasound irradiation is described. The combinatorial synthesis was achieved for this methodology with applying ultrasound irradiation while making use of water as green solvent. In comparison to conventional methods, experimental simplicity, good functional group tolerance, excellent yields, short routine, and selectivity without the need for a transition metal or base catalyst are prominent features of this green procedure.

Full text of DOI:10.1016/j.ultsonch.2012.07.007

Ultrasonics Sonochemistry 20 (2013) 401–407
Contents lists available at SciVerse ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultson
Ultrasound promoted one-pot synthesis of 2-amino-4,8-dihydropyrano
[3,2-b]pyran-3-carbonitrile scaffolds in aqueous media: A complementary ‘green
chemistry’ tool to organic synthesis
c
Sayed Hossein Banitaba a, Javad Safari b, , Shiva Dehghan Khalili
⇑
a Department of Chemistry, Majlesi Branch, Islamic Azad University, Isfahan, Iran
b Laboratory of Organic Chemistry Research, Department of Organic Chemistry, College of Chemistry, University of Kashan, 87317-51167, Kashan, Iran
c Department of Chemistry, Najafabad Branch, Islamic Azad University, Isfahan, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A green and simple approach to assembling of 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile
scaffolds via three-component reaction of kojic acid, malononitrile, and aromatic aldehydes in aqueous
media under ultrasound irradiation is described. The combinatorial synthesis was achieved for this meth-
odology with applying ultrasound irradiation while making use of water as green solvent. In comparison
to conventional methods, experimental simplicity, good functional group tolerance, excellent yields,
short routine, and selectivity without the need for a transition metal or base catalyst are prominent fea-
tures of this green procedure.
Received 26 January 2012
Received in revised form 9 July 2012
Accepted 17 July 2012
Available online 26 July 2012
Keywords:
2-Amino-4,8-dihydropyrano[3,2-b]pyran-3-
carbonitrile
Ó 2012 Elsevier B.V. All rights reserved.
Multicomponent reactions (MCRs)
Ultrasound irradiation
Kojic acid
Green chemistry
1. Introduction
of organic synthesis [4]. As a one-pot reaction, ultrasound assisted
multi-component reactions generally afford good yields in short
Green chemistry is a quickly developing new field that provides
us a proactive path for the sustainable progress of future science
and technologies [1]. Green chemistry uses highly efficient and
environmental benign synthetic procedures to deliver life saving
medicines, accelerating guide optimization processes in drug
discovery, with reduced needless environmental impact. Green
chemistry also offers enhanced chemical process economics con-
comitant with a reduced environmental burden [2]. In addition
the use of green solvents like water shows both economical and
synthetic advantages: not only the chemical processes needed to
produce organic solvents will be reduced, the atmospheric pollu-
tion by escaping volatile organic solvents will be decreased and
the waste treatment will be reduced, but also dramatic rate
enhancements can be achieved in many organic reactions, that is
Claisen rearrangement, aldol condensation, Diels–Alder cyclo-
addition [3]. The developing of new multi-component reactions
(MCRs) and improving the known MCRs by ultrasonic irradiation
are an area of considerable current interest. However, if the one-
pot MCRs could be carried out under ultrasonic irradiation and cat-
alyst-free conditions, it would be most efficient synthetic methods
reaction time and are fundamentally different from simple multi-
component reactions in several aspects [5,6] and permitted a rapid
access to combinatorial libraries of complex organic molecules for
an efficient lead structure identification and optimization in drug
discovery [7–9].
Ultrasonic-assisted organic synthesis (UAOS) as a green syn-
thetic approach is a powerful technique that is being used more
and more to accelerate organic reactions [10–14]. UAOS can be ex-
tremely efficient and it is applicable to a broad range of practical
syntheses. The notable features of the ultrasound approach are en-
hanced reaction rates, formation of purer products in high yields,
easier manipulation and considered a processing aid in terms of
energy conservation and waste minimization which compared
with traditional methods, this technique is more convenient taking
green chemistry concepts into account [15,16]. However, the use of
ultrasound in heterocyclic system is not fully explored [17,18].
Polysubstituted 2-amino-4H-pyran-3-carbonitrile derivatives
are very important heterocyclic compounds, which frequently ex-
hibit a variety of biological activities [19–24]. Recently, several
methods have been reported for the facile and efficient synthesis
of important polysubstituted 2-amino-4H-pyran-3-carbonitrile
scaffolds [25–28]. Any of these methods, however, suffer from
longer reaction times, unsatisfactory yields, harsh reaction
⇑
Corresponding author. Tel.: +98 361 591 2320; fax: +98 361 591 2397.
E-mail address: safari@kashanu.ac.ir (J. Safari).
1350-4177/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ultsonch.2012.07.007

402
S.H. Banitaba et al. / Ultrasonics Sonochemistry 20 (2013) 401–407
NC
CN
Ar
O
2
+
O
O
O
CN
HO
HO
Ultrasonic irradiation
Water, 50 oC, 5-30 min
Ar CHO
OH
NH2
O
1
3
4a-m
Scheme 1. Synthesis of 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-carbonitriles in water under ultrasonic irradiation.
NC
CN
Ph
O
2
+
O
O
O
CN
HO
HO
Ultrasonic irradiation
Conditions
Ph CHO
OH
NH2
O
1
3
4a
Scheme 2. Standard model reaction.
conditions and excessive use of reagents and catalysts. It is there-
fore important to find more convenient methods for the prepara-
tion of these compounds. Among these compounds, the ready
availability, potential biological activity and high reactivity of kojic
acid makes it an attractive molecule in pharmaceutical chemistry
and multi-component reactions [29,30]. Consequently, a large
number of kojic acid derivatives have been prepared for biological
evaluation [31,32]. The combination of two important scaffolds
such as kojic acid and pyran, may lead to new and alternative drug
candidates with improved pharmacological profile.
In continuation of our interest in exploring the synthetic of het-
erocyclic compound in water [33,34], the broad spectrum of appli-
cations of kojic acid 1 and its derivatives as biologically active
compounds, has prompted us to explore its reaction with malono-
nitrile 2, aldehydes 3 in a mild and efficient three-component reac-
tion in aqueous media under ultrasound irradiation (Scheme 1).
residue was filtered and was recrystallized from ethanol to pro-
duce the desired product 4a as white solid in 75% yield.
2.2. Typical procedure for synthesis of 2-amino-4,8-
dihydropyrano[3,2-b]pyran-3-carbonitriles (4a) under ultrasound
irradiation
A 25 mL Erlenmeyer flask was charged with malononitrile
(66 mg, 1 mmol), benzaldehyde (1 mmol), and kojic acid (1 mmol)
and water (5 mL). The reaction flask was located in the ultrasonic
bath, where the surface of reactants is slightly lower than the level
of the water, and irradiated under 20%, 40%, 60%, 80% and 100% of
the power of the ultrasonic bath at 50 °C (bath temperature, the
temperature inside the reactor was also 50 °C) for the period of
time (The reaction was monitored by TLC) separately as indicated
in Table 3. The reaction temperature was controlled by addition or
removal of water from ultrasonic bath. After completion of the
reaction, the mixture was diluted with water (10 mL), the solid
was filtered, washed with water and dried to give crude product,
which was further purified by recrystallization from ethanol to of-
fer pure product 4a in 95% yield.
2. Experimental
All reagents were purchased from Merck (Germany) and were
used without further purification. Melting points were measured
on an Electrothermal 9100 apparatus and are uncorrected. Infrared
(IR) spectra were recorded using a Perkin-Elmer FT-IR 550 spec-
trometer. 1H NMR and 13C NMR spectra were recorded with a Bru-
ker DRX-400 spectrometer at 400 and 100 MHz respectively. NMR
spectra were obtained in DMSO-d6 solutions and are reported as
parts per million (ppm) downfield from a tetramethylsilane inter-
nal standard. The following abbreviations are used; singlet (s),
doublet (d), triplet (t) and multiplate (m). The element analyses
for C, H, and N were performed using a Carlo ERBA Model EA
1108 analyzer carried out on Perkin-Elmer 240c analyzer, Sonica-
tion was performed in Shanghai Branson-BUG40-06 ultrasonic
cleaner (with a frequency of 40 kHz and a nominal power 200 W).
3. Results and discussions
To achieve the suitable conditions for the synthesis of 2-amino-
4,8-dihydropyrano [3,2-b]pyran-3-carbonitriles, various reaction
conditions have been investigated in the standard reaction of kojic
acid 1, malononitrile 2, and benzaldehyde 3a as a model reaction
(Scheme 2).
3.1. Effects of the solvents under ultrasound irradiation
Initially, we try to optimize the model process mentioned above
by detecting the efficiency of several classic solvents chosen as the
medium for comparison through some experiments. In each case,
the substrates were mixed together with 5 ml solvent under ultra-
sonic irradiation (power intensity: 40%). Among the tested solvents
such as methanol, ethanol, acetonitrile, THF, dichloromethane,
water and solvent-free conditions, the formation of product 4a
was more facile and proceeded to give not only in high yield but
also with high reaction rate in water (78 yield in 25 min) (Table 1,
entry 7). Polar protic solvents such as ethanol and methanol
2.1. Typical procedure for the synthesis of 2-amino-4,8-
dihydropyrano[3,2-b]pyran-3-carbonitriles (4a) in water under silent
conditions
A 50 mL flask was charged with malononitrile (66 mg, 1 mmol),
benzaldehyde (1 mmol), and kojic acid (1 mmol) in water (5 mL).
The mixture was stirred at 50 °C. After the completion of the reac-
tion (monitored by TLC), the reaction was allowed to cool. The

S.H. Banitaba et al. / Ultrasonics Sonochemistry 20 (2013) 401–407
403
Table 1
The effect of reaction condition on the synthesis of 4a under various conditions.a
3.2. Effects of reaction temperature under ultrasonic irradiation
To study the effect of temperature on this synthesis, we inves-
tigated the model reaction at different temperatures. The product
was obtained in yields ranging from 78% to 88% (Table 1, entries
7–10). It was observed that a lower reaction temperature led to a
lower yield. As shown in Table 1, entry 7, we found that high tem-
perature could improve the reaction yield and shorten the reaction
time. It can be seen from the results that with increasing media
temperatures, the formation of product increased rapidly in 30 to
50 °C in terms of reaction time and yield. One reason is possibly
due to the decrease of the surface tension and viscosity of the solu-
tion, so that the generations of bubbles become easier. Another is
the increment kinetic energy of liquid due to increase of tempera-
ture convert into heating contents of bubbles that caused to rela-
tively higher yield and shorter reaction time. On the other hand
with increasing of temperature from 60 to 70 °C, the yield was de-
creased to 89% (Table 1, entries 9 and 10). Probably, a higher reac-
tion temperature might induce a decrease in cavities growth,
lifetime and results in a dramatic increase of the vapor pressure
of the liquid, which results in higher vapor content of the cavitat-
ing bubbles. Under these conditions, the maximum temperature
and pressure created in such vaporous transient cavitation bubbles
have been shown to be much lower [35]. With having these results
in hand, we selected the water as solvent under ultrasound irradi-
ation conditions for the one-pot reaction of malononitrile,
benzaldehyde derivatives, and kojic acid to give corresponding
2-amino-4,8-dihydropyrano[3,2-b]pyran-3-carbonitriles at 50 °C.
These results were indicated that there was remarkable ultrasonic
temperature effect on this reaction.
Entry
Solvent
Temperature (oC)
Time (min)
Isolated yield (%)
A
B
1
2
3
4
5
6
7
8
9
10
Ethanol
Methanol
Acetonitrile
Dioxane
DCM
Solvent-free
Water
Water
30
30
30
30
30
30
30
50
60
70
50
70
60
45
45
35
50
78
88
88
80
55
52
Trace
25
Trace
30
50
75
74
74
55
120
90
130
85
25
20
Water
water
20
20
a
Substrate: kojic acid (1 mmol), malononitrile (1 mmol), benzaldehyde
(1 mmol), and solvent (5 mL); Conditions: A, under ultrasonic irradiation with
power intensity of 40%; B, under high stirring condition.
afforded moderate yields of desired products but took compara-
tively longer reaction time (Table 1, entries 1 and 2). When the
reaction was performed in acetonitrile, dioxane and dichlorometh-
ane, unfortunately, the desired product was only obtained in 45%,
45% and 35% yield respectively (Table 1, entries 3, 4, 5). In sol-
vent-free conditions the desert products 4a was obtained in low
yield 50% (Table 1, entry 6).
In order to verify the effect of ultrasound irradiation, the reac-
tion was also performed in mentioned solvents by high stirring
alone under silent condition (Table 1). As shown in Table 1, in all
cases, the experimental results show that the yields of the products
are lower than sonication within same reaction times. Based on the
results of this study, it’s clear that the ultrasound improves the
yields of products. According to our opinion, the possible nuclei
for occurrence of cavitation in water to other solvents can be done
faster and wider. Also the transfer of ultrasonic energy in water is
higher than in other solvents. Therefore water was chosen as sol-
vent of reaction.
3.3. Effect of intensity power of ultrasonic on reaction
After this, we have studied the effect of the ultrasound power
intensity; the reaction was also performed at 20%, 40%, 60%, 80%
and 100% of the rate power of the ultrasonic bath (40, 80, 120,
160 and 200 W). The results were showed in Table 2. Generally,
Table 2
The effect of ultrasonic power on the synthesis of 4a.
Max power intensity (W) 20% (40 W) 40% (80 W) 60% (120 W) 80% (160 W) 100% (200 W)
Time (min)/Yield (%)a
25/75 20/88 10/95 10/95 10/90
a
Isolated yields.
Table 3
Synthesis of 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile derivatives under sonication and conventional conditions.a
Entry
Product
Ar
With sonicationa
Time (min)
Without sonicationb
Time (h)
Yield (%)c
Yield (%)c
79
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
2-FC6H4
10
20
25
25
15
5
15
5
6
95
85
88
89
93
97
95
96
98
98
90
98
97
1.2
3.0
3.0
3.0
2.5
1.0
1.7
2.5
1.5
1.2
2.0
1.5
1.0
d
-
-
-
d
2-ClC6H4
2,4-Cl2C6H3
3-FC6H4
3-MeC6H4
3-BrC6H4
3,5-(MeO)2C6H3
4-FC6H4
3-Pyridyl
4-Pyridyl
2-Furyl
d
65
68
67
53
60
56
55
60
62
9
10
11
12
13
4j
4k
4l
5
15
5
4m
2-Thienyl
6
a
b
c
Reaction condition: reaction of aryl or heteroaryl aldehydes, malononitrile, kojic acid in water at 50 °C under ultrasound irradiation.
Reaction condition: reaction of aryl or heteroaryl aldehydes, malononitrile, kojic acid in water at 50 °C under high stirring condition.
Yields of isolated products.
d
Only obtained the intermediate benzylidenemalononitrile.

404
S.H. Banitaba et al. / Ultrasonics Sonochemistry 20 (2013) 401–407
increase of ultrasonic power means that higher intensity of ultra-
sound was introduced into the reaction vessel, which would accel-
erate the reactions. It can be seen from Table 2 that increase of
ultrasonic power led to relatively higher yield and shorter reaction
time before the ultrasound power intensity reached 80%, and then
the yield decreased slightly with increasing ultrasound power
intensity.
As we know, more energy was provided to reaction system to
accelerate cavitation effect with ultrasonic power increasing. The
increase in the acoustic power could increase the number of activ-
ecavitation bubbles and also the size of the individual bubbles.
Both increases can be expected to result in an increase in the max-
imum collapse temperature [35], and the respective reaction could
be accelerated. However, when ultrasonic intensity exceeded the
optimal value, a large number of gas bubbles exist in the solution
and a lesser level of energy is focused on the reaction vessel be-
cause of the scattering effect of gas bubbles on the sound waves.
On the other hand, it is possible the coalescence of the cavities in
the presence of large number of cavities resulting in the formation
of a large cavity which collapses less violently. So with the inordi-
nate increase in the operating intensity, the utilization efficiency of
ultrasound decrease and the reaction yield decreased too [35].
immiscible liquids. This is possible because cavitational collapse
at or near the interface disrupts it and impels jets of one liquid into
the other to form the emulsion [10]. These can cause the reaction
to take place rapidly. Therefore, in the present system, ultrasound
was found to have beneficial effect on solubility behavior and the
synthesis of 4a.
The structures of isolated new products 4a-m were deducted by
physical and spectroscopic data such as: IR, 1H NMR and 13C NMR
spectroscopy, and elemental analysis [36]. In IR spectra, symmetri-
cal and unsymmetrical stretching frequency of NH2 is formed in re-
gion between
C„N in nitrile group was appeared in the region between
= 2190–2210 CmÀ1. In the 1H NMR spectra in DMSO-d6 was
m
= 3330–3350 CmÀ1. The stretching vibration of
m
shown the two singlet signals around d = 7.2–7.35 and d = 4.60–
4.80 ppm corresponding to NH2 group and Ar–C–H pyran ring in
2-amino-4,8-dihydropyrano [3,2-b]pyran-3-carbonitriles was con-
firmed the formation of desired products in reaction (Fig. 1).
In the H–H COSY spectra (Fig. 2) in DMSO-d6 was shown the
two coupled signals around d = 4.10–4.30 and d = 5.50–5.80 ppm
corresponding to CH2 and OH group of compound 4f. The methy-
lene group on the methylenoxy substituent shows a rather more
complex splitting pattern than a simple doublet. This behavior is
due to a non-equivalence of the two hydrogens of the methylene
group. As shown, the diastereotopic hydrogens of methylene
group were found as coupling partners on both the vertical and
the horizontal lines from the hydrogen of OH with coupling
3.4. High efficiency and generality of synthesis by ultrasound
irradiation
3
In order to demonstrate the efficiency and scope of the present
method and to delineate the role of ultrasound, this methodology
was examined by the reaction of several substituted aryl or hetero-
aryl aldehydes, malononitrile, and kojic acid with and without
ultrasonic irradiation at the same temperature (50 °C) in water (Ta-
ble 3). When the reaction was carried out under conventional
method it gave comparatively low yields of products and took
longer reaction time, while the same reaction carried in the influ-
ence of ultrasonic irradiation gave excellent yields of product in
short reaction time (Table 3). Thus, ultrasonic irradiation was
found to have beneficial effect on the synthesis of 2-amino-4,8-
dihydropyrano[3,2-b]pyran-3-carbonitrile derivatives which was
superior to the traditional method with respect to yield, reaction
time. From the results shown in Table 3, it is evident that electron-
rich aromatic aldehydes afford fairly high yields of the desired
products than electron-deficient ones in reaction with malononit-
rile, and kojic acid under ultrasonic irradiation in water at 50 °C.
The results in Table 3 highlight a variety of structures accepted
by the method to give fairly excellent yields of the desired prod-
ucts, the scope of the method is expected to be even wider due
to its mild conditions with applying ultrasonic energy without
any base, or acid catalysts. Through the experiments mentioned
above, it was observed that there was a great amount of liquid in
this system originally because of the bad solubility benzaldehyde
in water at 50 °C. As the reaction went on under sonication, the
reactants were gradually dispersed in the reaction solvent and then
disappeared after about 5 min, while the classical condition needs
1 h. When the reaction was over (monitored by TLC), more and
more solids had appeared which TLC spot (RF) was different with
that of benzaldehyde. After separation and analysis such as 1H
NMR, it was surprising to find that the product is the desired
one. Then, we put two experiments to further study the accelera-
tion mechanism under sonication. After dissolution of insoluble
substrates which were irradiated under sonication, we carry out
the comparison between with and without ultrasound. We found
that the reaction without sonication for follow-up process took a
long time and the yields were relatively low. In the heterogeneous
reactions involving immiscible liquid, the reaction between these
species can only occur in the interfacial region between the liquids.
Sonication can be used to produce very fine emulsions from
constant of Jvic = 6.3 Hz (Fig. 2).
3.5. The study of acceleration mechanism under irradiation of
ultrasound
We have not established an exact mechanism for the formation
of 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-carbonitriles, how-
ever, a plausible mechanism explaining the aforementioned results
and the selectivity is depicted in Scheme 3. The reaction is thought
to proceed through Knoevenagel condensation, Michael addition,
and a cyclocondensation, which might initiate via two pathways,
namely A and B (Scheme 3). The effect of ultrasonic irradiation
can be foreseen when considering the following step where the
cyclization of 9 or 10 occur via a dipolar transition states TS1
and TS’1 amenable to establish favored interaction with the ultra-
sound in hot cavities. Thus, ultrasound irradiation activates the
reaction mixture by inducing high local temperatures and pressure
generated inside the cavitation bubble and its interfaces when it
collapses and accelerates the reaction rate and shortens the reac-
tion time. Also this phenomena, cavitation, cause to remove water
in condensation and cyclization steps and accelerate reaction in
water efficiently. Cavitation is the origin of sonochemistry, a phys-
ical process that creates, enlarges, and implodes gaseous and
vaporous cavities in an irradiated liquid, thus enhancing the mass
transfer and allowing chemical reactions to occur. The creation of
the so-called hot spots in the reaction mixture produces intense
local temperatures and high pressures generated inside the cavita-
tion bubble and its interfaces when it collapses. Therefore the very
reactive chemical species such as 7, 8 with short lifetime giving
rise to the 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-carbonitriles
(4a–m) in shorter times under ultrasound irradiation, thus facili-
tating the cyclization, and dehydration step that is critical in this
type of multi-component reactions. Furthermore, compared with
traditional methods, this technique is more efficient and environ-
mental-friendly, particularly when considering the basic green
chemistry concepts. It is noteworthy to mention that, the effect
of the nature of the substituent on the aromatic aldehydes ring
showed obvious effect on this conversion. The electron-releasing
groups not only obvious effect on the yield of this conversion but
also effect on the reaction time (Table 3, entries 6, 10). The

S.H. Banitaba et al. / Ultrasonics Sonochemistry 20 (2013) 401–407
405
Fig. 1. 1H NMR spectra of compound 4f.
Fig. 2. Hydrogen’s correlation in H–H COSY of product 4f.

406
S.H. Banitaba et al. / Ultrasonics Sonochemistry 20 (2013) 401–407
O
Pathway A
OH
Pathway B
OH
1
Ph
O
O
O
H
NC
NC
H
2
HO
NC
U.S
CN
H
O
Ph
Ph
-H2O
-H2O
U.S
3a
O
5
6
O
O
OH
1
Micheal
addition
NC
CN Micheal
addition
HO
2
Ph
Ph
NC
N
O
O
NC
N
O
OH
OH
O
HO
O
8
7
Ph
O
Ph
H
NC
NC
O
OH
OH
d+
d+
O
d-
N
d-
N
O
H
O
O
TS'1
TS 1
Cyclization
Cyclization
U.S
U.S
Ph
H
Ph
Ph
NC
HN
O
O
H
OH
NC
HN
O
NC
O
OH
OH
O
O
H2N
O
O
O
9
10
4a
Scheme 3. Plausible mechanism of the reaction.
electron-releasing groups on aromatic aldehydes ring facile Mi-
chael addition of malononitrile to (E)-2-benzylidene-6-(hydroxy-
methyl)-2H-pyran-3,4-dione 5 in pathway A or kojic acid to 6 in
pathway B.
Acknowledgment
The project was supported by research foundation of University
of Kashan (No. 159198/I).
4. Conclusion
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1H, 2J = 15.2, 4J = 5.2 Hz, CHaliph), 4.23 (dd, 1H, 2J = 15.2, 4J = 5.2 Hz, CHaliph),
4.88 (t, 1H, 4J = 5.2 Hz, OH), 5.64 (s, 1H, CHvinyl), 6.35 (s, 1H, CHaliph), 7.11–7.21
(m, 2H, CHarom), 7.30 (s, 2H, NH2), 7.40–7.80 (m, 2H, CHarom); 13C NMR
(100 MHz, DMSO-d6) dc = 55.2, 59.2, 111.4, 114.7 (d, 2J = 12.0 Hz, C–F), 114.8
(d, 2J = 20.0 Hz, C–F), 119.1, 123.8 (d, 4J = 2.0 Hz, C–F), 130.3 (d, 3J = 8.0 Hz, C–
F), 136.4, 143.2 (d, 3J = 7.0 Hz, C–F), 159.3, 162.1 (d, 1J = 264.0 Hz, C–F), 168.2,
169.5, 195.9; Anal. Calcd. for C16H11FN2O4: C, 61.23; H, 3.59; N, 8.94. Found: C,
61.15; H, 3.53; N, 8.91. Compound 4f: Colorless crystals; m.p = 219–221 °C; IR
(KBr, m ;
, CmÀ1): 3350 and 3366 (NH2), 3345 (OH), 2221 (CN), 1462 (C@O) cmÀ1
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D. Labrecque, R. Denis, S. Lamothe, G. Attardo, H. Gourdeau, B. Tseng, J. Drewe,
S.X. Cai, Bioorg. Med. Chem. Lett. 18 (2008) 603–607.
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Bubenick, G. Attardo, R. Denis, S. Lamothe, H. Gourdeau, B. Tseng, S. Kasibhatla,
S.X. Cai, J. Med. Chem. 51 (2008) 417–423.
1H NMR (400 MHz, DMSO-d6) d = 2.31 (s, 3 H, CH3), 4.11 (dd, 1H, 2J = 15.6,
4J = 6.4 Hz, CHaliph), 4.25 (dd, 1H, 2J = 15.6, 4J = 6.4 Hz, CHaliph), 4.73 (t, 1H,
4J = 6.4 Hz, OH), 5.69 (s, 1H, CHvinyl), 6.34 (s, 1H, CHaliph), 6.72 (d, 1H,
3J = 7.6 Hz, CHarom), 7.12 (d, 1H, 3J = 7.6 Hz, CHarom), 7.08 (s, 2H, NH2), 7.28 (t,
1H, 3J = 7.2 Hz, CHarom); 13C NMR (100 MHz, DMSO-d6) dc = 20.9, 55.7, 59.0,
111.3, 119.3, 124.9, 128.1, 128.7, 136.3, 138.2, 140.8, 149.1, 159.1, 168.2,
169.6, 195.4; Anal. Calcd. for C17H14N2O4: C, 65.01; H, 4.16; N, 9.05. Found: C,
65.80; H, 4.55; N, 9.03. Compound 4g: Colorless crystals; m.p = 242–244 °C; IR
(KBr, m ;
, CmÀ1): 3431 and 3325 (NH2), 3443 (OH), 2207 (CN), 1639 (C@O) cmÀ1
1H NMR (400 MHz, DMSO-d6) d = 4.15 (dd, 1H, 2J = 15.1, 4J = 6.0 Hz, CHaliph),
4.23 (dd, 1H, 2J = 15.1, 4J = 6.0 Hz, CHaliph), 5.88 (t, 1H, 4J = 6.0 Hz, OH), 5.69 (s,
1H, CHvinyl), 6.34 (s, 1H, CHaliph), 7.31 (s, 2H, NH2), 7.35–7.60 (m, 4H, CHarom);
13C NMR (100 MHz, DMSO-d6) dc = 55.1, 59.1, 114.2, 119.2, 122.1, 127.2, 130.6,
130.8, 131.5, 136.2, 143.3, 143.8, 159.2, 168.2, 169.3, 195.9; Anal. Calcd. for
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Lett. 51 (2010) 5677–5679.
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[33] J. Safari, S.H. Banitaba, S. Dehghan Khalili, J. Mol. Catal. A: Chem. 335 (2011)
46–50.
C
16H11BrN2O4: C, 51.33; H, 2.99; N, 7.48. Found: C, 51.22; H, 2.96; N, 7.47.
Compound 4h: Colorless crystals; m.p = 271–273 °C; IR (KBr,
, CmÀ1): 3434
and 3320 (NH2), 3442 (OH), 2116 (CN), 1640 (C@O) cmÀ1 1H NMR (400 MHz,
m
;
DMSO-d6) d = 3.73 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 4.17 (dd, 1H, 2J = 15.1,
4J = 4.8 Hz, CHaliph), 4.22 (dd, 1H, 2J = 15.1, 4J = 4.8 Hz, CHaliph), 7.72 (t, 1H,
4J = 4.8 Hz, OH), 5.70 (s, 1H, CHvinyl), 6.33 (d, 2H, 4J = 2.0 Hz, CHarom), 6.42 (s,
1H, CHaliph), 6.46 (d, 2H, 4J = 2.0 Hz, CHarom), 7.23 (s, 2H, NH2); 13C NMR
(100 MHz, DMSO-d6) dc = 55.2, 55.3, 59.1, 99.1, 105.8, 111.3, 119.1, 136.4,
143.3, 148.7, 159.3, 160.7, 168.3, 169.5, 195.6; Anal. Calcd. for C18H16N2O6: C,
60.77; H, 4.59; N, 7.88. Found: C, 60.67; H, 4.53; N, 7.86. Compound 4i:
Colorless crystals; m.p = 248–250 °C; IR (KBr,
m
, CmÀ1): 3466 and 3352 (NH2),
1H NMR (400 MHz, DMSO-d6)
3551 (OH), 2195 (CN), 1633 (C@O) cmÀ1
;
[34] J. Safari, S.H. Banitaba, S. Dehghan Khalili, Ultrason. Sonochem. 19 (2012)
1061–1069.
[35] X. Wang, Y. Wei, J. Wang, W. Guo, C. Wang, Ultrason. Sonochem. 19 (2012) 32–
37.
d = 4.15 (dd, 1H, 2J = 15.3, 4J = 6.0 Hz, CHaliph), 4.23 (dd, 1H, 2J = 15.3, 4J = 6.0 Hz,
CHaliph), 4.85 (t, 1H, 4J = 6.0 Hz, OH), 5.71 (s, 1H, CHvinyl), 6.34 (s, 1H, CHaliph),
7.18–7.25 (m, 2H, CHarom), 7.27 (s, 2H, NH2), 7.32–7.40 (m, 2H, CHarom); 13C
NMR (100 MHz, DMSO-d6) dc = 55.5, 59.1, 111.5, 115.6 (d, 2J = 21.0 Hz, C–F),
119.2, 129.8 (d, 3J = 9.0 Hz, C–F), 136.3, 136.9 (d, 4J = 3.0 Hz, C–F), 148.7, 159.9,
161.9 (d, 1J = 295.0 Hz, C–F), 168.2, 169.3, 198.7; Anal. Calcd. for C16H11FN2O4:
C, 61.26; H, 3.59; N, 8.93. Found: C, 61.15; H, 3.53; N, 8.91. Compound 4j:
[36] Data spectra of products: compound 4a: Colorless crystals; m.p = 220–222 °C;
IR (KBr,
m
, CmÀ1): 3353 and 3361 (NH2), 3340 (OH), 2218 (CN), 1460 (C@O)
cmÀ1
;
1H NMR (400 MHz, DMSO-d6) d = 4.14 (dd, 1H, 2J = 15.1, 4J = 6.0 Hz,
CHaliph), 4.23 (dd, 1H, 2J = 15.1, 4J = 6.0 Hz, CHaliph), 5.23 (t, 1H, 4J = 6.0 Hz, OH),
5.62 (s, 1H, CHvinyl), 6.29 (s, 1H, CHaliph), 7.11 (s, 2H, NH2), 7.22-7.50 (m, 5H,
CHarom); 13C NMR (100 MHz, DMSO-d6) dc = 45.3, 58.6, 111.2, 117.9,
118.2,128.5, 130.5, 132.2, 136.5, 137.7, 147.9, 158.3, 168.2, 169.2, 194.2;
Anal. Calcd. for C16H12N2O4: C, 64.92; H, 4.12; N, 9.44. Found: C, 64.86; H, 4.08;
Colorless crystals; m.p = 251–253 °C; IR (KBr,
m
, CmÀ1): 3313 and 3199 (NH2),
1H NMR (400 MHz, DMSO-d6)
3369 (OH), 2198 (CN), 1629 (C@O) cmÀ1
;
d = 4.15 (dd, 1H, 2J = 15.0, 4J = 6.4 Hz, CHaliph), 4.42 (dd, 1H, 2J = 15.0, 4J = 6.4 Hz,
CHaliph), 4.95 (t, 1H, 4J = 6.4 Hz, OH), 5.70 (s, 1H, CHvinyl), 6.35 (s, 1H, CHaliph),
7.34 (s, 2H, NH2), 7.43 (dd, 1H, 3J = 7.6, 4J = 4.8 Hz, CHarom), 7.41 (dt, 1H, 3J = 7.6,
4J = 6.0 Hz, CHarom), 8.52–8.58 (m, 2H, CHarom); 13C NMR (100 MHz, DMSO-d6)
dc = 54.7, 59.4, 111.6, 119.1, 124.2, 145.5, 136.2, 136.4, 141.9, 149.0, 149.2,
159.3, 168.3, 169.6, 195.7; Anal. Calcd. for C15H11N3O4: C, 60.76; H, 3.78; N,
14.16. Found: C, 60.61; H, 3.73; N, 14.14. Compound 4k: Colorless crystals;
N, 9.46. Compound 4b: Colorless crystals; m.p = 207–208 °C; IR (KBr,
m
, CmÀ1):
1H NMR
3352 and 3365 (NH2), 3349 (OH), 2220 (CN), 1465 (C@O)cmÀ1
;
(400 MHz, DMSO-d6) d = 4.13 (dd, 1H, 2J = 15.2, 4J = 5.6 Hz, CHaliph), 4.25 (dd,
1H, 2J = 15.2, 4J = 5.6 Hz, CHaliph), 4.91 (t, 1H, 4J = 5.6 Hz, OH), 5.71 (s, 1H,
CHvinyl), 6.36 (s, 1H, CHaliph), 7.11 (s, 2H, NH2), 7.36 (m, 4H, CHarom); 13C NMR
(100 MHz, DMSO-d6) dc = 54.4, 59.1, 111.4, 115.5 (d, 2J = 21.0 Hz, C–F), 119.3,
125.8 (d, 2J = 12.0 Hz, C-F), 127.3, 130.2 (d, 3J = 8.0 Hz, C-F), 130.4 (d,
3J = 4.0 Hz, C-F), 136.7, 147.9, 159.3, 159.5, 168.2, 169.5, 195.3; Anal. Calcd.
for C16H11FN2O4: C, 61.23; H, 3.59; N, 8.93. Found: C, 61.15; H, 3.53; N, 8.91.
m.p = 233–235 °C; IR (KBr,
m
, CmÀ1): 3377 and 3171 (NH2), 3351 (OH), 2119
1H NMR (400 MHz, DMSO-d6) d = 4.13 (dd, 1H,
(CN), 1640 (C@O) cmÀ1
;
2J = 15.2, 4J = 5.6 Hz, CHaliph), 4.25 (dd, 1H, 2J = 15.2, 4J = 5.6 Hz, CHaliph), 4.91 (t,
1H, 4J = 5.6 Hz, OH), 5.71 (s, 1H, CHvinyl), 6.36 (s, 1H, CHaliph), 7.35 (d, 2H,
3J = 5.6, CHarom),7.38 (s, 2H, NH2), 8.59 (d, 2H, 3J = 5.6, CHarom); 13C NMR
(100 MHz, DMSO-d6) dc = 54.3, 59.1, 111.5, 118.6, 122.9, 136.6, 136.4, 147.5,
149.1, 150.2, 159.4, 168.3, 169.5, 195.8; Anal. Calcd. for C15H11N3O4: C, 60.69;
H, 3.78; N, 14.16. Found: C, 60.61; H, 3.73; N, 14.14. Compound 4l: Colorless
Compound 4c: Colorless crystals; m.p = 210-213 °C; IR (KBr,
m
, CmÀ1): 3371
1H NMR (400 MHz,
and 3331 (NH2), 3351 (OH), 2217 (CN), 1613 (C@O) cmÀ1
;
DMSO-d6) d = 4.19 (dd, 1H, 2J = 15.3, 4J = 6.0 Hz, CHaliph), 4.22 (dd, 1H, 2J = 15.3,
4J = 6.0 Hz, CHaliph), 5.27 (t, 1H, 4J = 6.0 Hz, OH), 5.68 (s, 1H, CHvinyl), 6.36 (s, 1H,
CHaliph), 7.14 (s, 2H, NH2), 7.20-7.50 (m, 4H, CHarom); 13C NMR (100 MHz,
DMSO-d6) dc = 54.6, 59.0, 111.4, 118.9, 128.1, 129.7, 130.1, 130.8, 132.2, 136.9,
137.4, 147.9, 159.4, 168.2, 169.5, 194.9; Anal. Calcd. for C16H11ClN2O4: C,
58.21; H, 3.40; N, 8.49. Found: C, 58.11; H, 3.35; N, 8.47. Compound 4d:
crystals; m.p = 223–225 °C; IR (KBr,
m
, CmÀ1): 3317 and 3191 (NH2), 3368
1H NMR (400 MHz, DMSO-d6) d = 4.16 (dd,
(OH), 2189 (CN), 1629 (C@O) cmÀ1
;
1H, 2J = 15.3, 4J = 6.1 Hz, CHaliph), 4.19 (dd, 1H, 2J = 15.3, 4J = 6.1 Hz, CHaliph),
4.95 (t, 1H, 4J = 6.1 Hz, OH), 5.23 (s, 1H, CHvinyl), 6.35 (s, 1H, CHaliph), 7.08 (s, 2H,
NH2), 7.46 (d, 2H, 3J = 4.1, CHarom), 7.50–7.55 (m, 2H, CHarom); 13C NMR
(100 MHz, DMSO-d6) dc = 33.4, 55.3, 59.1, 106.5, 110.6, 111.9, 112.6, 119.4,
142.5, 142.1, 152.2, 159.4, 168.7, 196.6; Anal. Calcd. for C14H10N2O5: C, 58.83;
H, 3.57; N, 9.81. Found: C, 58.74; H, 3.52; N, 9.79. Compound 4m: Colorless
Colorless crystals; m.p = 240-242 °C; IR (KBr,
m
, CmÀ1): 3465 and 3353 (NH2),
1H NMR (400 MHz, DMSO-d6)
3560 (OH), 2211 (CN), 1609 (C@O) cmÀ1
;
d = 4.13 (dd, 1H, 2J = 15.3, 4J = 6.0 Hz, CHaliph), 4.21 (dd, 1H, 2J = 15.3, 4J = 6.0 Hz,
CHaliph), 5.28 (t, 1H, 4J = 6.0 Hz, OH), 5.68 (s, 1H, CHvinyl), 6.35 (s, 1H, CHaliph),
7.34 (s, 2H, NH2), 7.44 (d, 1H, 3J = 8.4 Hz, CHarom), 7.67 (d, 1H, 4J = 2.4 Hz,
CHarom), 7.82 (dd, 1H, 3J = 8.4, 4J = 2.0 Hz, CHarom); 13C NMR (100 MHz, DMSO-
d6) dc = 54.3, 59.5, 112.1, 118.3, 128.6, 129.7, 130.6, 131.3, 132.4, 136.7, 138.3,
148.1, 159.9, 168.8, 169.3, 194.5; Anal. Calcd. for C16H10Cl2N2O4: C, 52.72; H,
2.80; N, 7.69. Found: C, 52.63; H, 2.76; N, 7.67. Compound 4e: Colorless
crystals; m.p = 235–237 °C; IR (KBr,
m
, CmÀ1): 3182 and 3191 (NH2), 3361
1H NMR (400 MHz, DMSO-d6) d = 4.18 (dd,
(OH), 2110 (CN), 1631 (C@O) cmÀ1
;
1H, 2J = 15.6, 4J = 5.9 Hz, CHaliph), 4.25 (dd, 1H, 2J = 15.5, 4J = 5.9 Hz, CHaliph),
4.96 (t, 1H, 4J = 5.9 Hz, OH), 5.29 (s, 1H, CHvinyl), 6.34 (s, 1H, CHaliph), 6.98 (s,
2H, NH2), 7.39 (d, 2H, 3J = 4.7, CHarom), 7.45–7.60 (m, 2H, CHarom); 13C NMR
(100 MHz, DMSO-d6) dc = 32.9, 58.3, 58.9, 111.5, 112.6, 119.5, 123.6, 119.4,
127.5, 139.4, 142.5, 159.4, 169.2, 197.2; Anal. Calcd. for C14H10N2O4S: C, 55.70;
H, 3.36; N, 9.29. Found: C, 55.62; H, 3.33; N, 9.27.
crystals; m.p = 220–223 °C; IR (KBr,
m
, CmÀ1): 3425 and 3325 (NH2), 3463
(OH), 2214 (CN), 1642 (C = O) cmÀ1 1H NMR (400 MHz, DMSO-d6) d = 4.12 (dd,
;