Sodium benzenesulfinates: Novel and effective organo catalyst for three component synthesis 5,6,7,8-tetrahydro-4H-chromene derivatives under ultrasound irradiation

Article abstract of DOI:10.2174/1570178612666150203004727

Sodium benzenesulfinates, as a new organo catalyst, can be used to synthesize tetrahydro- 4H-chromene derivatives by three component reaction of cyclic β-dicarbonyl compounds, malononitrile, and aromatic aldehydes, in H₂O/EtOH, under ultrasound

Full text of DOI:10.2174/1570178612666150203004727

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Letters in Organic Chemistry, 2015, 12, 271-276
271
Sodium Benzenesulfinates: Novel and Effective Organo Catalyst for Three
Component Synthesis 5,6,7,8-Tetrahydro-4H-chromene Derivatives Under
Ultrasound Irradiation
Mehdi Abaszadeha,* and Mohammad Seifib
aPharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical
Sciences, Kerman 76175493, Iran; bDepartment of Chemistry, Faculty of Sciences, Najafabad Branch,
Islamic Azad University, Najafabad, Esfahan, Iran
Received October 08, 2014: Revised January 13, 2015: Accepted January 27, 2015
Abstract: Sodium benzenesulfinates, as a new organo catalyst, can be used to synthesize tetrahydro-
4H-chromene derivatives by three component reaction of cyclic ꢀ-dicarbonyl compounds, malononi-
trile, and aromatic aldehydes, in H2O/EtOH, under ultrasound irradiation at room temperature. Inex-
pensiveness, stability and the potential of being easily obtained can be noted as preponderance of
these catalysts. Furthermore, high conversions, short reaction times and cleaner reaction profiles are
some of the advantages of this method. Moreover, H2O/EtOH (7:3) was selected as a green solvent.
Keywords: Sodium benzenesulfinates, tetrahydro-4H-chromene derivatives, three component reactions, ultrasound irradiation,
cyclic ꢀ-dicarbonyl compounds, aromatic aldehydes.
INTRODUCTION
hypotensive [23] agents. They can also be used as cognitive
enhancers for the treatment of neurodegenerative diseases
such as Alzheimer’s disease, amyotrophic lateral sclerosis,
Huntington’s disease, Parkinson’s disease, AIDS associated
diseases [24].
Ultrasound irradiation has been increasingly used in or-
ganic synthesis in the last three decades as a green synthetic
approach for accelerating organic chemical reactions [1-3].
Moreover, formation of unadulterated products in high
yields, easier manipulation and waste minimization are some
prominent features of this approach [4, 5]. More recently,
ultrasonic irradiation has been used in the click chemistry
[6], synthesis of benzotriazoles and 1-acylbenzotriazoles [7]
and multicomponent reactions (MCRs) [8] as a clean, practi-
cal and of use protocol.
Due to the important properties of tetrahydro-4H-
chromene derivatives, considerable attention has been fo-
cused on the development of environmentally friendly pro-
cedures to synthesize tetrahydro-4H-chromenes, by three
component reaction of cyclic ꢀ-dicarbonyl compounds,
malononitrile and aromatic aldehydes. Various catalytic sys-
tems such as potassium phthalimide-N-oxyl (POPINO) [25],
CaCl2 under ultrasonic irradiation [26], high surface area
MgO [27], tetrabutylammonium bromide [28], N,N-
dimethylaminoethylbenzyldimethylammonium chloride [29],
diammonium hydrogen phosphate (DAHP) [30], K3PO4 [31],
Na2CO3 under grinding [32], SiO2 nanoparticles [33],
methanesulfonic acid [34] and 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) [35] have been used. Each of these methods
has its own merits, but the use of toxic organic solvents, ex-
pensive catalysts, containing transition metals, difficult work
up, high reaction times, and low yields are drawbacks of
these procedures. Thus, the exploitation of a simple and
green synthesis of tetrahydro-4H-chromene derivatives is
desirable to remove these restrictions.
MCRs are highly flexible and supply the opportunity of
building up complex molecules with exceptional synthetic
efficiency, frequently with high stereoselectivity, from sim-
ple and easily available substrates [9-11]. In fact, develop-
ment of MCRs can lead to new efficient synthetic method-
ologies to afford many small organic compounds in the field
of new organic, bioorganic, and medicinal chemistry [12-
14]. Hence, MCRs are considered as a vital technique in the
synthesis of many important heterocyclic compounds such as
tetrahydro-4H-chromene derivatives nowadays.
Tetrahydro-4H-chromenes have recently attracted atten-
tion as an important class of heterocyclic compounds in the
field of drugs and pharmaceuticals due to their useful bio-
logical and pharmacological properties. These compounds
are widely used as anticancer [15], antimalarial [16], an-
tileishmanial [17], antibacterial [18], antifungal [19],
antianaphylactic [20], antiallergenic [21], diuretic [22] and
Sodium benzenesulfinates (SBSs) have been used in
many organic reactions as traceless linkers [36] and as nu-
cleophiles [37]. SBSs have been never used as catalysts in
the synthesis of heterocyclic compounds via three compo-
nent reaction. Hence, we make our minds up to synthesize
tetrahydro-4H-chromene derivatives in H2O/EtOH by using
inexpensive and commercially available SBSs as catalysts
under ultrasound irradiation at room temperature.
*Address correspondence to this author at the Pharmaceutics Research
Center, Institute of Neuropharmacology, Kerman University of Medical
Sciences, Kerman 76175493, Iran; Tel: +98 341 3205001;
Fax: +98 341 3205215; E-mail: abaszadeh@kmu.ac.ir
1875-6255/15 $58.00+.00
© 2015 Bentham Science Publishers

272 Letters in Organic Chemistry, 2015, Vol. 12, No. 4
Abaszadeh and Seifi
O
O
Ar
CN
O
CN
i
R
R
Ar
H
CN
O
O
NH2
R
R
4a-z,a'-g'
1a (R = Me)
1b (R = H)
2
3a-r
i: H2O/EtOH, 4-chloroSBS (10 mol%), ultrasound irradiation at room temperature
Scheme 1.
Table 1. Optimization of the model reaction between dimedone (1a), malononitrile (2), and benzaldehyde (3a Ar = C6H5).
Entry
Solvent
Catalyst
Catalyst (mol%)
Time (min)
Yield (%)
1
2
H2O/EtOH
H2O
4-chloroSBS
4-chloroSBS
4-chloroSBS
4-chloroSBS
4-chloroSBS
4-chloroSBS
SBS
10
10
10
10
10
10
10
10
8
8
93
89
90
82
83
65
91
88
90
86
84
12
10
30
28
70
18
25
10
18
30
3
EtOH
4
Ethyl acetate
Acetonitrile
Toluene
5
6
7
H2O/EtOH
H2O/EtOH
H2O/EtOH
H2O/EtOH
H2O/EtOH
8
4-methylSBS
4-chloroSBS
4-chloroSBS
4-chloroSBS
9
10
11
6
4
RESULTS AND DISCUSSION
According to rely on our collected data, we decided to
apply this method for synthesizing 5,6,7,8-tetrahydro-4H-
chromene derivatives by using three component reaction of
dimedone (1a) or 1,3-cyclohexanedione (1b), malononitrile
(2) and aromatic aldehydes (3a-r), in H2O/EtOH, under ul-
trasound irradiation at room temperature, in the presence of
4-chloroSBS (Table 2).
In the present work and in continuing our interest in the
synthesis of heterocyclic compounds by three component
reaction [38], we report the synthesis of 5,6,7,8-tetrahydro-
4H-chromene derivatives 4a-x,a'-g' by three component re-
action of dimedone (1a) or 1,3-cyclohexanedione (1b), mal-
ononitrile (2) and aromatic aldehydes (3a-r) in H2O/EtOH
by using SBSs as new and effective organo catalyst under
ultrasound irradiation at room temperature (Scheme 1).
According to the literature [36], condensation of SBSs,
aromatic aldehydes (3a-r) and dimedone (1a), or 1,3-
cyclohexanedione (1b), provided ꢀ. Subsequent coupling of ꢀ
with malononitrile (2) gave the expected products
4a-z,a'-g' (5,6,7,8-tetrahydro-4H-chromene derivatives)
(Scheme 2).
To optimize the conditions, the reaction between dime-
done (1a), malononitrile (2), and benzaldehyde (3a Ar =
C6H5) was chosen as a model. When this three component
reaction was carried out in the presence of 4-chloroSBS (10
mol%), in H2O/EtOH (7:3), under ultrasound irradiation at
room temperature, 2-amino-5,6,7,8-tetrahydro-7,7-dimethyl-
5-oxo-4-phenyl-4H-chromene-3-carbonitrile (4a) was ob-
tained in 93% yield within 8 min. This reaction was also
carried out in different solvents such as H2O, EtOH, ethyl
acetate, acetonitrile and toluene, and the best results in terms
of reaction time and yield of the desired product 4a were
obtained when the reaction was conducted in H2O/EtOH
(Table 1, entries 1-6). Moreover SBS and 4-methylSBS were
used as a catalyst (Table 1, entries 7-8). Decreasing the cata-
lyst loading from 10 to 4 mol% significantly lowered the
yield of the reaction (Table 1, entries 9-11). The best catalyst
loading was found in 10 mol%, which gave an excellent
yield of 4a after only 8 min.
CONCLUSION
In summary, we have reported the use of SBSs as a new
and effective organo catalyst for three component reaction of
dimedone (1a) or 1,3-cyclohexanedione (1b), malononitrile
(2), and aromatic aldehydes (3a-r), which leads to the syn-
thesis of 5,6,7,8-tetrahydro-4H-chromene derivatives (4a-
z,a'-g'). These reactions were carried out in H2O/EtOH un-
der ultrasound irradiation at room temperature. High yields,
operational simplicity, clean reaction conditions in compari-
son with existing methods are advantages of this procedure
that make it a useful practical process for the synthesis of
these compounds.

Sodium Benzenesulfinates: Novel and Effective Organo Catalyst
Letters in Organic Chemistry, 2015, Vol. 12, No. 4 273
Table 2. Three component reactions of dimedone (1a), or 1,3-cyclohexanedione (1b), malononitrile (2), and aromatic aldehydes (3a-r).
O
Ar
CN
R
O
NH2
R
4a-z,a'-g'
Product
R
Ar
Time (min)
Yield (%)
Mp Observed (°C)
Mp Reported (°C)
4a
4b
4c
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
C6H5
4-ClC6H4
8
6
93
94
94
95
93
93
94
94
93
94
92
91
92
90
90
91
90
92
92
93
93
94
93
92
94
92
94
92
90
89
90
89
91
231-232
215-217
210-212
175-178
221-222
108-110
207-210
181-182
213-216
214-217
218-220
200-202
231-233
225-228
208-210
221-222
227-229
206-207
230-231
223-226
195-197
220-222
248-250
215-217
234-237
200-202
200-202
223-225
189-191
256-258
237-239
210-211
229-230
234-236 [25]
216-218 [25]
214-215 [25]
178-179 [27]
222-224 [26]
2-ClC6H4
7
4d
4e
2,4-Cl2C6H3
4-BrC6H4
5
6
4f
2-BrC6H4
7
4g
4h
4i
4-FC6H4
6
208-211 [25]
180-182 [25]
217-219 [25]
215-217 [27]
219-221 [25]
201-203 [25]
231-232 [26]
226-228 [25]
210-212 [25]
220-222 [25]
226-228 [25]
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CH3C6H4
4-CH3OC6H4
2-CH3OC6H4
4-HOC6H4
4-(CH3)2NC6H4
2-furanyl
5
7
4j
6
4k
4l
10
12
12
15
17
13
15
10
10
7
4m
4n
4o
4p
4q
4r
2-thienyl
3-pyridinyl
C6H5
4s
229-231 [27]
225-227 [27]
197-199 [26]
221-223 [27]
4t
H
4-ClC6H4
4u
4v
4w
4x
4y
4z
H
2-ClC6H4
8
H
2,4-Cl2C6H3
4-BrC6H4
6
H
8
H
2-BrC6H4
10
6
H
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CH3C6H4
4-CH3OC6H4
4-HOC6H4
2-furanyl
235-237 [27]
201-203 [27]
H
9
4a'
4b'
4c'
4d'
4e'
4f'
4g'
H
7
H
13
15
20
15
17
12
224-226 [26]
190-192 [27]
257-259 [26]
H
H
H
H
2-thienyl
H
3-pyridinyl

274 Letters in Organic Chemistry, 2015, Vol. 12, No. 4
Abaszadeh and Seifi
G
O
Ar
ArCHO
CH2(CN)2
O
Ar
CN
3a-r
2
SO2Na
G
S
R
O
O2
R
O
NH2
OH
R
R
SBS
4a-z,a'-g'
R
I
O
R
1a (R = Me)
1b (R = H)
Scheme 2.
EXPERIMENTAL
MHz, DMSO-d6) ꢀppm: 198.14 (C-5), 163.22 (C-2), 160.92
(C-8a), 157.34 (furan C-2'), 143.35 (furan C-5'), 135.21 (C-
4a), 131.12 (furan C-4'), 123.78 (furan C-3'), 112.05 (CN),
77.68 (C-3), 57.01 (C-6), 51.51 (C-8), 33.41 (C-4), 30.59 (C-
7), 30.02 (CH3), 28.16 (CH3). Anal. calcd. for C16H16N2O3:
C, 67.59; H, 5.67; N, 9.85%. Found: C, 67.23; H, 5.45; N,
9.64%.
Melting points were measured on an Electrothermal-9100
apparatus and are uncorrected. IR spectra were recorded on a
Bruker FT-IR Tensor 27 infrared spectrophotometer. 1H
NMR spectra were recorded on a Bruker Avance III 400
MHz spectrometer. 13C NMR spectra were recorded on the
same instrument at 100 MHz using TMS as an internal stan-
dard. Elemental analyses were performed using a Heracus
CHN-O-Rapid analyzer.
2-Amino-5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-4-(2-thien-
yl)-4H-chromene-3-carbonitrile (4q)
White powder; IR (KBr, ꢁmax/cm-1): 3392, 3328 (NH2),
Typical Procedure for the Preparation of 2-Amino-4-
aryl-5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-carbonit-
riles 4a-z,a'-g'
1
2192 (CN), 1673 (C=O), 1596, 1539 (C=C). H NMR (400
3
MHz, DMSO-d6) ꢀppm: 7.30 (d, JHH = 4.0 Hz, CH-Ar), 7.10
(s, 2H, NH2), 6.88-6.84 (m, 2H, CH-Ar), 4.51 (s, 1H, CH),
A mixture of dimedone (1a) or 1,3-cyclohexanedione
(1b) (2 mmol), malononitrile (2) (2 mmol), aromatic alde-
hydes (3a-r) (2 mmol), and 4-chloroSBS (10 mol%) in
H2O/EtOH (7:3) was refluxed for the reported time in Table
2 (the progress of the reaction being monitored by TLC us-
ing hexane / ethyl acetate as an eluent). After completion of
the reaction, the reaction mixture was poured into ice-cold
H2O; the crude product was filtered, dried and recrystallized
from EtOH.
2.45 (d, 2JHH = 8.0 Hz, CH), 2.40 (d, 2JHH = 8.0 Hz, CH), 2.28
2
2
(d, JHH = 7.9 Hz, CH), 2.13 (d, JHH = 7.9 Hz, CH), 1.02 (s,
3H, CH3), 0.95 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-
d6) ꢀppm: 197.58 (C=O), 164.10, 160.54, 150.88, 128.41,
125.99, 125.60, 121.20, 114.56 (CN), 68.42 (C3), 59.73
(CH2), 51.51 (CH2), 33.33 (CH), 32.04 (CMe2), 30.25 (CH3),
28.10 (CH3). Anal. calcd. for C16H16N2O2S: C, 63.98; H,
5.37; N, 9.33%. Found: C, 63.72; H, 5.18; N, 9.14%.
2-Amino-5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-4-(3-pyridi-
nyl)-4H-chromene-3-carbonitrile (4r)
2-Amino-4-(2-bromophenyl)-5,6,7,8-tetrahydro-7,7-dimeth-
yl-5-oxo-4H-chromene-3-carbonitrile (4f)
White powder; IR (KBr, ꢁmax/cm-1): 3392, 3312 (NH2),
Yellow powder; IR (KBr, ꢁmax/cm-1): 3440, 3328 (NH2),
2192 (CN), 1680 (C=O), 1596, 1574 (C=C). H NMR (400
1
1
2192 (CN), 1683 (C=O), 1590, 1542 (C=C). H NMR (400
MHz, DMSO-d6) ꢀppm: 8.37 (s, 2H, NH2), 7.52-7.10 (m, 4H,
2
MHz, DMSO-d6) ꢀppm: 7.83-7.02 (m, 6H, CH-Ar, NH2), 4.69
CH-Ar), 4.22 (s, 1H, CH), 2.47 (d, JHH = 8.0 Hz, CH), 2.39
2
2
2
2
(s, 1H, CH), 2.32 (d, JHH = 8.0 Hz, CH), 2.22 (d, JHH = 7.9
Hz, CH), 2.05 (d, 2JHH = 7.9 Hz, CH), 1.89 (d, 2JHH = 8.0 Hz,
CH), 1.02 (s, 3H, CH3), 0.96 (s, 3H, CH3). 13C NMR (100
MHz, DMSO-d6) ꢀppm: 197.72 (C=O), 160.22, 144.97,
137.58, 135.58, 134.24, 131.47, 130.04, 129.66, 124.36,
113.76 (CN), 70.00 (C3), 58.80 (CH2), 51.60 (CH2), 36.67
(CH), 33.63 (CMe2), 33.35 (CH3), 30.05 (CH3). Anal. calcd.
for C18H17BrN2O2: C, 57.92; H, 4.59; N, 7.51%. Found: C,
57.64; H, 4.37; N, 7.24%.
(d, JHH = 7.9 Hz, CH), 2.22 (d, JHH = 7.9 Hz, CH), 2.09 (d,
2JHH = 8.0 Hz, CH), 1.01 (s, 3H, CH3), 0.92 (s, 3H, CH3). 13C
NMR (100 MHz, DMSO-d6) ꢀppm: 197.33 (C=O), 164.21,
160.22, 150.30, 149.44, 141.66, 136.36, 125.30, 121.10,
113.43 (CN), 67.08 (C3), 58.98 (CH2), 51.53 (CH2), 35.04
(CH), 33.42 (CMe2), 29.85 (CH3), 28.52 (CH3). Anal. calcd.
for C17H17N3O2: C, 69.14; H, 5.80; N, 14.23%. Found: C,
68.92; H, 5.63; N, 14.04%.
2-Amino-4-(4-bromophenyl)-5,6,7,8-tetrahydro-5-oxo-4H-
chromene-3-carbonitrile (4w)
2-Amino-4-(2-furanyl)- 5,6,7,8-tetrahydro-7,7-dimethyl-5-
oxo-4H-chromene-3-carbonitrile (4p)
White powder; IR (KBr, ꢁmax/cm-1): 3424, 3344 (NH2),
Yellow powder; IR (KBr, ꢁmax/cm-1): 3408, 3328 (NH2),
2192 (CN), 1680 (C=O), 1593, 1539 (C=C). H NMR (400
1
1
3
2192 (CN), 1680 (C=O), 1600, 1555 (C=C). H NMR (400
MHz, DMSO-d6) ꢀppm: 7.44 (d, JHH = 4.0 Hz, CH-Ar), 7.10
3
3
MHz, DMSO-d6) ꢀppm: 7.46 (d, JHH = 3.9 Hz, furan H-5'),
(d, JHH = 3.9 Hz, CH-Ar), 7.04 (s, 2H, NH2), 4.15 (s, 1H,
7.07 (s, 2H, NH2), 6.30-6.04 (m, 2H, furan H-3',4'), 4.30 (s,
CH), 2.47-1.93 (m, 6H, 3CH2).13C NMR (100 MHz, DMSO-
d6) ꢀppm: 197.89 (C=O), 166.05, 160.06, 145.82, 132.79,
131.10, 124.54, 121.20, 114.92 (CN), 59.24 (C3), 37.89
(CH), 36.70 (CH2), 28.08 (CH2), 21.37 (CH2). Anal. calcd.
1H, H-4), 2.47 (d, 2JHH = 7.9 Hz, CH), 2.40 (d, 2JHH = 7.9 Hz,
2
2
CH), 2.27 (d, JHH = 8.0 Hz, CH), 2.15 (d, JHH = 8.0 Hz,
CH), 1.03 (s, 3H, CH3), 0.97 (s, 3H, CH3). 13C NMR (100

Sodium Benzenesulfinates: Novel and Effective Organo Catalyst
Letters in Organic Chemistry, 2015, Vol. 12, No. 4 275
for C16H13BrN2O2: C, 55.67; H, 3.80; N, 8.12%. Found: C,
55.48; H, 3.63; N, 7.91%.
MHz, DMSO-d6) ꢀppm: 8.38 (s, 2H, NH2), 7.53-7.09 (m, 2H,
CH-Ar), 4.21 (s, 1H, CH), 2.47-1.92 (m, 6H, 3CH2).13C
NMR (100 MHz, DMSO-d6) ꢀppm: 197.36 (C=O), 166.48,
160.15, 150.29, 149.38, 141.71, 136.36, 125.23, 121.14,
114.40 (CN), 58.92 (C3), 37.86 (CH), 34.96 (CH2), 28.11
(CH2), 21.35 (CH2). Anal. calcd. for C15H13N3O2: C, 67.40;
H, 4.90; N, 15.72%. Found: C, 67.19; H, 4.75; N, 15.53%.
2-Amino-4-(2-bromophenyl)-5,6,7,8-tetrahydro-5-oxo-4H-
chromene-3-carbonitrile (4x)
Yellow powder; IR (KBr, ꢂmax/cm-1): 3472, 3328 (NH2),
1
2192 (CN), 1680 (C=O), 1593, 1545 (C=C). H NMR (400
MHz, DMSO-d6) ꢀppm: 7.51-7.08 (m, 4H, ArH), 7.05 (s, 2H,
NH2), 4.69 (s, 1H, H-4), 2.27-1.94 (m, 6H, H2-6-8). 13C
NMR (100 MHz, DMSO-d6) ꢀppm: 197.12 (C-5), 166.58 (C-
2), 160.05 (C-8a), 145.09 (phenyl C-1'), 134.16 (phenyl C-
3'), 131.46 (phenyl C-6'), 129.98 and 129.75 (phenyl C-4',5'),
124.32 (phenyl C-2'), 120.75 and 114.77 (C-4a, CN), 58.67
(C-3), 37.93 (C-4), 36.57 (C-6), 28.10 (C-8), 21.42 (C-7).
Anal. calcd. for C16H13BrN2O2: C, 55.67; H, 3.80; N, 8.12%.
Found: C, 55.46; H, 3.65; N, 7.94%.
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
The authors express their great appreciation to the Phar-
maceutics Research Center, Institute of Neuropharmacology,
Kerman University of Medical Sciences for supporting this
investigation.
2-Amino-5,6,7,8-tetrahydro-4-(2-nitrophenyl)-5-oxo-4H-
chromene-3-carbonitrile (4a')
Yellow powder; IR (KBr, ꢂmax/cm-1): 3408, 3344 (NH2),
1
2192 (CN), 1680 (C=O), 1593, 1523 (C=C). H NMR (400
REFERENCES
MHz, DMSO-d6) ꢀppm: 7.78-7.36 (m, 4H, CH-Ar), 7.15 (s,
2H, NH2), 4.91 (s, 1H, CH), 2.48-1.82 (m, 6H, 3CH2).13C
NMR (100 MHz, DMSO-d6) ꢀppm: 197.88 (C=O), 166.22,
160.66, 150.54, 140.59, 134.99, 132.01, 129.38, 125.24,
120.73, 114.86 (CN), 58.04 (C3), 37.54 (CH), 31.73 (CH2),
27.96 (CH2), 21.30 (CH2). Anal. calcd. for C16H13N3O4: C,
61.73; H, 4.21; N, 13.50%. Found: C, 61.54; H, 4.04; N,
13.33%.
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