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Domino Knoevenagel condensation, Michael addition, and cyclization using ionic liquid, 2-hydroxyethylammonium formate, as a recoverable catalyst
Journal of Molecular Liquids 158 (2011) 145–150
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Journal of Molecular Liquids j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / m o l l i q
Domino Knoevenagel condensation, Michael addition, and cyclization using ionic liquid, 2-hydroxyethylammonium formate, as a recoverable catalyst H.R. Shaterian ⁎, M. Arman, F. Rigi Department of Chemistry, Faculty of Sciences, University of Sistan and Baluchestan PO Box 98135-674, Zahedan, Iran
a r t i c l e
i n f o
Article history: Received 11 November 2010 Received in revised form 18 November 2010 Accepted 19 November 2010 Available online 26 November 2010 Keywords: Benzylidenemalononitriles 2-Benzylidene-5,5-dimethylcyclohexane-1,3diones 2-Amino-5-oxo-4-aryl-4,5-dihydropyrano [3,2-c]chromene-3-carbonitrile Tetrahydrobenzo[b]pyran Ionic liquid Spirooxindole
a b s t r a c t The Knoevenagel condensation reaction of aromatic aldehydes with malononitrile or dimedone was investigated. Also, the three-component and one-pot synthesis of 2-amino-5-oxo-4-aryl-4,5-dihydropyrano [3,2-c]chromene-3-carbonitrile derivatives by condensing 4-hydroxycoumarin, aldehydes and malononitriles using a catalytic amount of 2-hydroxyethylammonium formate as an effective ionic liquid without using any additional co-catalyst under solvent-free conditions at room temperature is reported. Furthermore, the domino Knoevenagel condensation, conjugate addition, and cyclization for the preparation of tetrahydrobenzo[b]pyran, and spirooxindole derivatives in high atomic efficiency take place in excellent yields. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Low melting point salts consisting of ions, which are often classified as ionic liquids exist in the liquid state at ambient temperatures and have received a significant attention from research groups and industry for a range of novel applications [1]. Ionic liquids show several properties such as good solvents (green and environmentally benign solvent) for a large variety of organic as well as inorganic substances, polar, non-volatile, non-flammable, immiscible with many commonly used solvents, low vapor pressure (stable in high vacuum), no toxic, low melting point (liquid below 100 °C), thermal stability, and recyclability [2]. There has been an increasing interest in exploiting the potential of ionic liquids as a reaction medium to develop green methodologies; allowing reuse of the catalysts or reagents [3]. This properties and applications prompted us to initiate a systematic exploration on the preparation of organic compounds with the help of ionic liquids [4–6]. In continuation to our research on application of catalysts in several organic transformations [7–10], we herein report some applications of 2-hydroxyethylammonium formate, [H3N+–CH2–CH2–OH][HCOO−], as a recoverable ionic liquid. The ionic liquid showed weak basic character and was used as a green catalyst for the preparation of several organic compounds. It
⁎ Corresponding author. Tel.: +98 541 2446565; fax: +98 541 2431067. E-mail address: [email protected] (H.R. Shaterian). 0167-7322/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.molliq.2010.11.010
was synthesized for the first time by Bicak and showed heat stability up to 150 °C [11]. 2. Experimental All reagents were purchased from Merck and Aldrich and used without further purification. All yields refer to isolated products after purification. Products were characterized by comparison with authentic samples and by spectroscopy data (IR, 1H NMR spectra). The NMR spectra were recorded on a Bruker Avance DPX 500 MHz instrument. The spectra were measured in DMSO-d6 relative to TMS (0.00 ppm). Elemental analyses for C, H, and N were performed using a Heraeus CHN–O-Rapid analyzer. FT-IR spectra were recorded on a JASCO FT-IR 460 plus spectrophotometer. Mass spectra were recorded on an Agilent technologies 5973 network mass selective detector (MSD) operating at an ionization potential of 70 eV. TLC was performed on silica-gel Poly Gram SIL G/UV 254 plates. 2.1. Preparation of benzilidenemalononitriles and 2-benzylidene-5,5-dimethylcyclohexane-1,3-diones A mixture of an aromatic aldehyde (1 mmol), malononitrile (1 mmol) or dimedone (1 mmol), and ionic liquid (0.27 mmol), was stirred at room temperature under solvent-free condition for appropriate time (Table 1). After completion of the reaction which was monitored by TLC, the mixture was washed with water and the solid product was purified by recrystallization from ethanol.
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Table 1 Knoevenagel condensation for different substituted benzaldehydes with malononitrile or dimedone in the presence of ionic liquid under ambient conditions. Entry Substrate
Product Time Yield m.p (Lit.m.p 0C) [ref] (min) (%)a
1
1a
b1
91
82–83 (82–85) [19]
2
1a
4
83
160–161 (160) [19]
3
1a
6
79
140–141 (141–143) [26]
4
1a
3
66
103–105 (100–102) [26]
5
1a
2
75
132–133 (132–133) [19]
6
1a
1
82
93–95 (80–82) [19]
7
1a
4
61
155–157 (160–162) [23]
8
1a
3
96
113–114 (111–115) [19]
9
2a
45
58
138–140 (127–129) [24]
10
2a
30
63
123–125 (108–110) [22]
a Yields refer to isolated a pure products. The known products were characterized and their physical properties (M.p, 1H NMR, 13C NMR and IR) with authentic samples [19,22–26] were compared.
2.2. Preparation of 2-amino-5-oxo-4-aryl-4,5-dihydropyrano[3,2-c] chromene-3-carbonitrile A mixture of an aromatic aldehyde (1 mmol), malononitrile (1.2 mmol), 4-hdroxycoumarine (1 mmol) and ionic liquid (0.27 mmol), was stirred at room temperature under solvent-free condition for appropriate time (Table 3). After completion of the reaction which was monitored by TLC, the mixture was washed with water and the solid was product purified by recrystallization from ethanol. All of the desired product(s) were characterized by comparison of their physical data with those of known compounds and characterization data for novel products are given below. 2-Amino-5-oxo-4-(3-flourophenyl)-4,5-dihydropyrano[3,2-c] chromene-3-carbonitrile (Table 3, Entry 12): 1H NMR (DMSO-d6, 500 MHz): δ 4.50 (s, 1H, CH), 7.01–7.14 (m, 3H, Ar), 7.31–7.41 (m, 5H, NH2 and Ar), 7.63–6.69 (m, 1H, Ar), 7.87 (dd, J = 7.9, 1.2 Hz, 1H, Ar) ppm; 13C NMR (DMSO-d6, 125 MHz): δ 57.5, 103.2, 112.9, 113.8, 113.9, 114.4, 114.5, 116.4, 119.0, 122.5, 123.7, 124.5, 130.3, 130.3, 132.8, 146.1, 146.2, 152.1, 153.6, 157.9, 159.5, 161.2, and 163.1 ppm; IR (KBr, cm−1): 3375, 3315, 3191, 2195, 1711, 1675, 1619, 1489, 1370,
1252, 1062, and 763; MS (EI, 70 eV) m/z (%) = 334 (M+, 22), 267 (13), 239 (100), 121 (21), and 92 (8).; Anal. Calcd for: C19H11FN2O3: C, 68.26; H, 3.32; N, 8.38%. Found: C, 68.35; H, 3.30; N, 8.40%. 2-Amino-5-oxo-4-o-tolyl-4,5-dihydropyrano[3,2-c]chromene-3carbonitrile (Table 3, Entry 13): 1H NMR (DMSO-d6, 500 MHz): δ 2.48 (s, 3H, CH3), 4.73 (s, 1H, CH), 6.90–7.20 (m, 4H, Ar), 7.34 (s, 2H, NH2), 7.41 (d, J = 8.3 Hz, 1H, Ar), 7.46 (t, J = 7.6 Hz, 1H, Ar), 7.66–7.73 (m, 1H, Ar), 7.89 (d, J = 7.8 Hz, 1H, Ar) ppm; 13C NMR (DMSO-d6, 125 MHz): δ 19.0, 57.9, 104.5, 122.8, 116.4, 119.1, 122.3, 124.6, 126.6, 123.6, 126.7, 127.8, 130.0, 132.7, 135.2, 142.2, 152.0, 153.4, 157.7, 159.5 ppm; IR (KBr, cm−1): 3400, 3283, 3179, 2202, 1709, 1675, 1637, 1603, 1490, 1457, 1377, 1171, 1059, 957, 753; MS (EI, 70 eV) m/z (%) = 330 (M+, 18), 249 (24), 240 (17), 239 (100), 121 (21).; Anal. Calcd for: C20H14N2O3: C, 72.72; H, 4.27; N, 8.48%. Found: C, 72.80; H, 4.30; N, 8.50%. 2-Amino-5-oxo-4-(2,5-dimethoxyphenyl)-4,5-dihydropyrano [3,2-c]chromene-3-carbonitrile (Table 3, Entry 14): 1H NMR (DMSOd6, 500 MHz): δ 3.63 (s, 3H, CH3), 3.64 (s, 3H, CH3), 4.64 (s, 1H, CH), 6.66 (d, J = 2.3 Hz, 1H, Ar), 6.75–6.79 (m, 1H, Ar), 6.90 (d, J = 8.8 Hz, 1H, Ar), 7.25 (s, 2H, NH2), 7.41–7.49 (m, 2H, Ar), 7.67 (t, J = 7.7 Hz, 1H, Ar), 7.89 (d, J = 7.7 Hz, 1H, Ar) ppm; 13C NMR (DMSO-d6, 125 MHz): δ 55.2, 56.4, 56.8, 103.1, 112.2, 112.9, 113.1, 115.7, 116.4, 119.2, 122.2, 124.5,125, 131.9, 132.6, 151.5, 152.0, 153.1, 153.9, 158.5, and 159.4 ppm; IR (KBr, cm−1): 3403, 3322, 3192, 2195, 1708, 1672, 1605, 1501, 1380, 1224, 1054, 959, and 620; MS (EI, 70 eV) m/z (%) = 376 (M+, 23), 361 (14), 345 (42), 279 (100), 239 (26), 215 (13), and 121 (24).; Anal. Calcd for: C21H16N2O5: C, 67.82; H, 4.28; N, 7.44%. Found: C, 67.92; H, 4.36; N, 7.55%. 2-Amino-5-oxo-4-phenethyl-4,5-dihydropyrano[3,2-c] chromene-3-carbonitrile (Table 3, Entry 15): 1H NMR (DMSO-d6, 500 MHz): δ 1.81–1.87 (m, 1H,), 2.09–2.16 (m, 1H,), 2.45–2.52 (m, 1H,), 2.54–2.62 (m, 1H), 3.50–3.6 (m, 1H,), 7.00 (t, J = 8.1, 1H, Ar), 7.08 (d, J = 7.0 Hz, 2H, Ar), 7.13 (t, J = 7.5 Hz, 2H, Ar), 7.34–7.45 (m, 4H, NH2 and Ar), 7.62–7.67 (m, 1H, Ar), 7.76 (dd, J = 5.9, 1.2 Hz, 1H, Ar) ppm; 13C NMR (DMSO-d6, 125 MHz): δ 30.4, 30.7, 54.8, 103.7, 112.9, 116.3, 119.5, 122.1, 124.3, 125.5, 127.93 (2 C), 128.1, 132.5, 141.2, 152.0, 154.0, 159.4, and 159.8 ppm; IR (KBr, cm−1): 3382, 3315, 3189, 2198, 1694, 1671, 1608, 1396, 1315, 1179, 1211, 1112, and 759; MS (EI, 70 eV) m/z (%) = 344 (M+, 7), 240 (20), 239 (100), 187 (8), 138 (21), 91 (10), 43 (17).; Anal. Calcd for: C21H16N2O3: C, 73.24; H, 4.68; N, 8.13%. Found: C, 73.28; H, 4.70; N, 8.20%. 2.3. Preparation of tetrahydrobenzo[b]pyrans A mixture of an aromatic aldehyde (1 mmol), malononitrile (1.2 mmol), dimedone (1 mmol) and ionic liquid (0.27 mmol), was stirred at room temperature under solvent-free condition for appropriate time (Table 4). After completion of the reaction which was monitored by TLC, the mixture was washed with water and the solid product was purified by recrystallization from ethanol. 2.4. Preparation of spirooxindole derivatives A mixture of isatin (1 mmol), malononitrile (1 mmol), dimedone or 4-hydroxycoumarin (1 mmol) and ionic liquid (0.27 mmol), was stirred at room temperature under solvent-free condition for appropriate time. After completion of the reaction which was monitored by TLC, the mixture was washed with water and the solid product was purified by recrystallization from ethanol. 3. Results and discussion The Knoevenagel condensation is a very useful reaction and generates double bonds from a carbonyl compound and an active methylene compound in the presence of a catalytic amount of weak base [12–17]. Recently, the Knoevenagel condensation of carbonyl
H.R. Shaterian et al. / Journal of Molecular Liquids 158 (2011) 145–150
Scheme 1. The Knoevenagel condensation for preparation of benzilidenemalononitriles and 2-benzylidene-5,5-dimethylcyclohexane-1,3-diones.
Table 2 Comparison results of 2-hydroxyethylammonium formate with MgO [26], Ninanoparticles [22], Ti-TUD-1 [25] and porous calcium [23] in the synthesis of benzylidenemalononitriles from benzaldehyde and malononitrile. Entry Catalyst
Conditions
Time Yield (%) (min)
1 2
H2O, EtOH as solvent at r.t EtOH as solvent at r.t
7 19
3 4 5
MgO Ninanoparticles Ti-TUD-1 Porous calcium Ionic liquid
EtOH as solvent at r.t 30 CH2Cl2 as solvent under MW 2 Solvent-free at r.t b1
94 98 91 87 91 (present work)
compounds with rhodanine to afford arylalkylidene rhodanines in the presence of 2-hydroxyethylammonium formate was reported [18]. First report, the Knoevenagel condensation reaction of aromatic aldehydes with malononitrile or dimedone produces benzilidenemalononitriles [19–26] and 2-benzylidene-5,5-dimethylcyclohexane1,3-diones [22,24] respectively in the presence of 0.029 g (0.27 mmol) of ionic liquid as catalyst at ambient conditions (Scheme 1). The efficiency and versatility of the ionic liquid as catalyst for the Knoevenagel condensation for different substituted benzaldehydes using malononitrile or dimedone were investigated (Table 1). Using catalytic amount of the ionic liquid as catalyst, different substituted benzaldehydes got readily condensed with malononitrile to give corresponding product at short reaction times (b6 min) with excellent yield. The substrates when condensed with dimedone using similar amount of ionic liquid as catalyst gave desired condensed products consumed at longer times (30, 45 min). This may be attributed to the fact that the abstraction of proton from the active methylene group of malononitrile is easier compared to dimedone (Table 1, Entries 9, 10). All two Knoevenagel condensation reactions produced the dehydrated products without any side reactions such as self condensation, Cannizaro products or hydrated products of Knoevenagel adducts. The reaction of aliphatic aldehydes with malononitrile yielded a mixture of hydrated and dehydrated products, while the reaction of dimedone with aliphatic aldehydes
147
didn't progress after 24 h and starting materials were intact using ionic liquid. To show the merit of the present work in comparison with the reported results in the literature, we compared the results of 2hydroxyethylammonium formate with MgO [26], Ni-nanoparticles [22], Ti-TUD-1[25], and porous calcium [23] in the synthesis of benzylidenemalononitriles. As shown in Table 2, the ionic liquid can act as suitable catalyst with respect to reaction times and yields of the products. Next, as part of our program aimed at developing useful new synthesis methods based on the use of mentioned ionic liquid as a catalyst, we have studied the three-component one-pot synthesis of 2-amino-4-aryl-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile derivatives [27–33] by condensing 4-hydroxycoumarin, aldehydes and malononitriles using a catalytic amount of 2hydroxyethylammonium formate at room temperature. Furthermore, the three-component reaction of dimedone, aldehydes, and malonitrile for preparation of tetrahydrobenzo[b] pyrans [34–37] was investigated (Scheme 2). Subsequently, a series of differently substituted 2-amino-4-aryl-5oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile and tetrahydrobenzo[b]pyrans derivatives was prepared successfully under solventfree neat conditions. These results are listed in Tables 3 and 4. The results clearly indicate that reactions can tolerate a wide range of differently substituted aldehydes. The reactions were complete within 2–15 min and excellent yields of products were obtained by both methods. However, in case of aliphatic aldehydes, reactions were not completed under solvent-free conditions and desired products were obtained in low yields. The proposed mechanism for the reaction using ionic liquid as catalyst is also described in Scheme 3. According to literature report [27–33], ionic liquid with weak base character [11] is an effective catalyst for the readily in-situ formation of Knoevenagel product from activated aryl aldehyde and carboanion of malononitrile. Afterward, enamine is formed from 2-hydroxyethylammonium formate and 4hydroxycoumarin, which then reacts with protonated Knoevenagel product (formic acid formed and acts as protonated source) via 1,4conjugted addition, followed by cyclization to give desired cyclic product after hydrolysis (Scheme 3). In this mechanism cation and anion of IL are catalytically act and reformed to prepare 2hydroxyethylammonium formate in each cycles. In continuation to this research, a simple and an efficient one-pot synthetic approach was used for the preparation of biologically interesting spirooxindole derivatives [38,39] in high yields by means of three-component reactions of isatin, malononitrile, and dimedone or 4-hydroxycoumarin catalyzed by mentioned ionic liquid as catalyst under mild solvent-free and ambient conditions (Scheme 4). We suggested a mechanism according to the literature [38,39], the formation of spirooxindole can be explained by a formation of isatylidene malononitrile via a domino Knoevenagel condensation of isatin and malononitrile. Then, similar to Scheme 3, Michael addition
Scheme 2. The one-pot synthesis of 2-amino-5-oxo-4-aryl-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile and tetrahydrobenzo[b]pyran.
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Table 3 Preparation of a series of differently substituted 2-amino-4-aryl-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile in the presence of 2-hydroxy ethylammonium formate as catalyst from aryl aldehyde, malononitrile and hydroxycoumarine 4- at ambient conditions. Entry Substrate
product Time Yield m.p(Lit.m.p0C) [ref] (min) (%)a
1
1b
15
73
255–256 (257–258) [27]
2
1b
13
89
261–262 (261–262) [27]
3
4
5
1b
1b
1b
5
8
6
75
67
74
Table 4 Preparation of a series of differently substituted tetrahydrobenzo[b]pyrans in the presence of 2-hydroxy ethylammonium formate as catalyst from aryl aldehyde, malononitrile and dimedone at ambient conditions. Product
Time (min)
Yield (%)a
m.p(Lit.m.p0C) [ref]
1
2b
5
70
227–229 (226–228) [34]
2
2b
2
70
195–196 (197–199) [34]
3
2b
4
86
169–171 (175–176) [34]
4
2b
3
57
208–211 (201–205) [34]
5
2b
6
79
203–206 (202–203) [34]
6
2b
3
85
212–215 (209–211) [34]
7
2b
6
43
174–177 (198–200) [35]
8
2b
10
87
113–115 (115–117) [36]
Entry
Substrate
280–283 (280–282) [28]
245–247 (255–257) [28]
261–262 (258–260) [28]
6
1b
12
79
244–245 (247–248) [32]
7
1b
20
62
254–255 (254–255) [33] a
8
1b
12
73
273–274 (266–268) [33]
9
1b
7
60
261–262 (260–262) [28]
10
1b
15
70
258–259 (260–262) [33]
11
1b
10
71
222–224 (247–249) [29]
12
1b
10
40
241–242b
b
Yields refer to isolated pure products. The known products were characterized and their physical properties (M.p, 1H NMR, 13C NMR and IR) with authentic samples [34– 37] were compared.
of dimedone or 4-hydroxycoumarin with isatylidene malononitrile followed by cyclization in the presence of ionic liquid as catalyst produce desired spirooxindole (Scheme 5). We also investigated the recycling of the catalyst under solventfree conditions using a model reaction of 4-chlorobenzaldehde, malononitrile and 4-hydroxycoumarin (Table 3, entry 2). After completion of the reaction, water was added and the precipitated mixture was filtered off for separation of crude products. After washing solid products with water completely, the water containing ionic liquid (IL is soluble in water) was evaporated under reduce pressure and ionic liquid was recovered and reused. The recovered catalyst was reused for at least five runs without any loss of its activities (Fig. 1). 4. Conclusions
13
1b
7
65
260–261
14
1b
6
68
230–233b
In summary, we have successfully developed a simple, facile and efficient method for the synthesis of benzylidenmalononitrile, 2benzylidene-5,5-dimethylcyclohexane-1,3-dione, 2-amino-4-aryl-5Table 3 (continued) Entry Substrate
15
1b
7
98
179–182b
product Time Yield m.p(Lit.m.p0C) [ref] (min) (%)a
Notes to Table 3: a Yields refer to isolated pure products. The known products were characterized and their physical properties (M.p, 1H NMR, 13C NMR and IR) with authentic samples [27– 30,32,33] were compared. b Four new unknown products was synthesized.
H.R. Shaterian et al. / Journal of Molecular Liquids 158 (2011) 145–150
149
Scheme 3. The proposed mechanism for one-pot synthesis of 2-amino-5-oxo-4-aryl-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile.
oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile, tetrahydrobenzo[b] pyran, spirooxindole using a catalytic amount of 2hydroxyethylammonium formate as an inexpensive and available
ionic liquid under solvent-free and ambient conditions. The recovered ionic liquid was reused for 5 cycles. The method offered several advantages such as high yields, broader substrate scope, an easy and
Scheme 4. Preparation of spirooxindole derivatives.
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H.R. Shaterian et al. / Journal of Molecular Liquids 158 (2011) 145–150
Yield (%)
Scheme 5. The proposed mechanism for one-pot synthesis of spirooxindoles.
100 90 80 70 60 50 40 30 20 10 0
98100
96 99
95 98
93
97
91
96
Reaction Yield (%) Catalyst Yield (%)
1
2
3
4
5
Numbera of runs Fig. 1. The recycling of the catalyst under solvent-free conditions using a model reaction of 4-chlorobenzaldehde, malononitrile and 4-hydroxycoumarin.
environmentally benign experimental procedure, cheap, and being amenable to large-scale operation, which make it a useful and attractive process for the synthesis of these important compounds. Acknowledgment We are thankful to the University of Sistan and Baluchestan Research Council for the partial support of this research. References [1] [2] [3] [4] [5]
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Domino Knoevenagel condensation, Michael addition, and cyclization using ionic liquid, 2-hydroxyethylammonium formate, as a recoverable catalyst H.R. Shaterian ⁎, M. Arman, F. Rigi Department of Chemistry, Faculty of Sciences, University of Sistan and Baluchestan PO Box 98135-674, Zahedan, Iran
a r t i c l e
i n f o
Article history: Received 11 November 2010 Received in revised form 18 November 2010 Accepted 19 November 2010 Available online 26 November 2010 Keywords: Benzylidenemalononitriles 2-Benzylidene-5,5-dimethylcyclohexane-1,3diones 2-Amino-5-oxo-4-aryl-4,5-dihydropyrano [3,2-c]chromene-3-carbonitrile Tetrahydrobenzo[b]pyran Ionic liquid Spirooxindole
a b s t r a c t The Knoevenagel condensation reaction of aromatic aldehydes with malononitrile or dimedone was investigated. Also, the three-component and one-pot synthesis of 2-amino-5-oxo-4-aryl-4,5-dihydropyrano [3,2-c]chromene-3-carbonitrile derivatives by condensing 4-hydroxycoumarin, aldehydes and malononitriles using a catalytic amount of 2-hydroxyethylammonium formate as an effective ionic liquid without using any additional co-catalyst under solvent-free conditions at room temperature is reported. Furthermore, the domino Knoevenagel condensation, conjugate addition, and cyclization for the preparation of tetrahydrobenzo[b]pyran, and spirooxindole derivatives in high atomic efficiency take place in excellent yields. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Low melting point salts consisting of ions, which are often classified as ionic liquids exist in the liquid state at ambient temperatures and have received a significant attention from research groups and industry for a range of novel applications [1]. Ionic liquids show several properties such as good solvents (green and environmentally benign solvent) for a large variety of organic as well as inorganic substances, polar, non-volatile, non-flammable, immiscible with many commonly used solvents, low vapor pressure (stable in high vacuum), no toxic, low melting point (liquid below 100 °C), thermal stability, and recyclability [2]. There has been an increasing interest in exploiting the potential of ionic liquids as a reaction medium to develop green methodologies; allowing reuse of the catalysts or reagents [3]. This properties and applications prompted us to initiate a systematic exploration on the preparation of organic compounds with the help of ionic liquids [4–6]. In continuation to our research on application of catalysts in several organic transformations [7–10], we herein report some applications of 2-hydroxyethylammonium formate, [H3N+–CH2–CH2–OH][HCOO−], as a recoverable ionic liquid. The ionic liquid showed weak basic character and was used as a green catalyst for the preparation of several organic compounds. It
⁎ Corresponding author. Tel.: +98 541 2446565; fax: +98 541 2431067. E-mail address: [email protected] (H.R. Shaterian). 0167-7322/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.molliq.2010.11.010
was synthesized for the first time by Bicak and showed heat stability up to 150 °C [11]. 2. Experimental All reagents were purchased from Merck and Aldrich and used without further purification. All yields refer to isolated products after purification. Products were characterized by comparison with authentic samples and by spectroscopy data (IR, 1H NMR spectra). The NMR spectra were recorded on a Bruker Avance DPX 500 MHz instrument. The spectra were measured in DMSO-d6 relative to TMS (0.00 ppm). Elemental analyses for C, H, and N were performed using a Heraeus CHN–O-Rapid analyzer. FT-IR spectra were recorded on a JASCO FT-IR 460 plus spectrophotometer. Mass spectra were recorded on an Agilent technologies 5973 network mass selective detector (MSD) operating at an ionization potential of 70 eV. TLC was performed on silica-gel Poly Gram SIL G/UV 254 plates. 2.1. Preparation of benzilidenemalononitriles and 2-benzylidene-5,5-dimethylcyclohexane-1,3-diones A mixture of an aromatic aldehyde (1 mmol), malononitrile (1 mmol) or dimedone (1 mmol), and ionic liquid (0.27 mmol), was stirred at room temperature under solvent-free condition for appropriate time (Table 1). After completion of the reaction which was monitored by TLC, the mixture was washed with water and the solid product was purified by recrystallization from ethanol.
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Table 1 Knoevenagel condensation for different substituted benzaldehydes with malononitrile or dimedone in the presence of ionic liquid under ambient conditions. Entry Substrate
Product Time Yield m.p (Lit.m.p 0C) [ref] (min) (%)a
1
1a
b1
91
82–83 (82–85) [19]
2
1a
4
83
160–161 (160) [19]
3
1a
6
79
140–141 (141–143) [26]
4
1a
3
66
103–105 (100–102) [26]
5
1a
2
75
132–133 (132–133) [19]
6
1a
1
82
93–95 (80–82) [19]
7
1a
4
61
155–157 (160–162) [23]
8
1a
3
96
113–114 (111–115) [19]
9
2a
45
58
138–140 (127–129) [24]
10
2a
30
63
123–125 (108–110) [22]
a Yields refer to isolated a pure products. The known products were characterized and their physical properties (M.p, 1H NMR, 13C NMR and IR) with authentic samples [19,22–26] were compared.
2.2. Preparation of 2-amino-5-oxo-4-aryl-4,5-dihydropyrano[3,2-c] chromene-3-carbonitrile A mixture of an aromatic aldehyde (1 mmol), malononitrile (1.2 mmol), 4-hdroxycoumarine (1 mmol) and ionic liquid (0.27 mmol), was stirred at room temperature under solvent-free condition for appropriate time (Table 3). After completion of the reaction which was monitored by TLC, the mixture was washed with water and the solid was product purified by recrystallization from ethanol. All of the desired product(s) were characterized by comparison of their physical data with those of known compounds and characterization data for novel products are given below. 2-Amino-5-oxo-4-(3-flourophenyl)-4,5-dihydropyrano[3,2-c] chromene-3-carbonitrile (Table 3, Entry 12): 1H NMR (DMSO-d6, 500 MHz): δ 4.50 (s, 1H, CH), 7.01–7.14 (m, 3H, Ar), 7.31–7.41 (m, 5H, NH2 and Ar), 7.63–6.69 (m, 1H, Ar), 7.87 (dd, J = 7.9, 1.2 Hz, 1H, Ar) ppm; 13C NMR (DMSO-d6, 125 MHz): δ 57.5, 103.2, 112.9, 113.8, 113.9, 114.4, 114.5, 116.4, 119.0, 122.5, 123.7, 124.5, 130.3, 130.3, 132.8, 146.1, 146.2, 152.1, 153.6, 157.9, 159.5, 161.2, and 163.1 ppm; IR (KBr, cm−1): 3375, 3315, 3191, 2195, 1711, 1675, 1619, 1489, 1370,
1252, 1062, and 763; MS (EI, 70 eV) m/z (%) = 334 (M+, 22), 267 (13), 239 (100), 121 (21), and 92 (8).; Anal. Calcd for: C19H11FN2O3: C, 68.26; H, 3.32; N, 8.38%. Found: C, 68.35; H, 3.30; N, 8.40%. 2-Amino-5-oxo-4-o-tolyl-4,5-dihydropyrano[3,2-c]chromene-3carbonitrile (Table 3, Entry 13): 1H NMR (DMSO-d6, 500 MHz): δ 2.48 (s, 3H, CH3), 4.73 (s, 1H, CH), 6.90–7.20 (m, 4H, Ar), 7.34 (s, 2H, NH2), 7.41 (d, J = 8.3 Hz, 1H, Ar), 7.46 (t, J = 7.6 Hz, 1H, Ar), 7.66–7.73 (m, 1H, Ar), 7.89 (d, J = 7.8 Hz, 1H, Ar) ppm; 13C NMR (DMSO-d6, 125 MHz): δ 19.0, 57.9, 104.5, 122.8, 116.4, 119.1, 122.3, 124.6, 126.6, 123.6, 126.7, 127.8, 130.0, 132.7, 135.2, 142.2, 152.0, 153.4, 157.7, 159.5 ppm; IR (KBr, cm−1): 3400, 3283, 3179, 2202, 1709, 1675, 1637, 1603, 1490, 1457, 1377, 1171, 1059, 957, 753; MS (EI, 70 eV) m/z (%) = 330 (M+, 18), 249 (24), 240 (17), 239 (100), 121 (21).; Anal. Calcd for: C20H14N2O3: C, 72.72; H, 4.27; N, 8.48%. Found: C, 72.80; H, 4.30; N, 8.50%. 2-Amino-5-oxo-4-(2,5-dimethoxyphenyl)-4,5-dihydropyrano [3,2-c]chromene-3-carbonitrile (Table 3, Entry 14): 1H NMR (DMSOd6, 500 MHz): δ 3.63 (s, 3H, CH3), 3.64 (s, 3H, CH3), 4.64 (s, 1H, CH), 6.66 (d, J = 2.3 Hz, 1H, Ar), 6.75–6.79 (m, 1H, Ar), 6.90 (d, J = 8.8 Hz, 1H, Ar), 7.25 (s, 2H, NH2), 7.41–7.49 (m, 2H, Ar), 7.67 (t, J = 7.7 Hz, 1H, Ar), 7.89 (d, J = 7.7 Hz, 1H, Ar) ppm; 13C NMR (DMSO-d6, 125 MHz): δ 55.2, 56.4, 56.8, 103.1, 112.2, 112.9, 113.1, 115.7, 116.4, 119.2, 122.2, 124.5,125, 131.9, 132.6, 151.5, 152.0, 153.1, 153.9, 158.5, and 159.4 ppm; IR (KBr, cm−1): 3403, 3322, 3192, 2195, 1708, 1672, 1605, 1501, 1380, 1224, 1054, 959, and 620; MS (EI, 70 eV) m/z (%) = 376 (M+, 23), 361 (14), 345 (42), 279 (100), 239 (26), 215 (13), and 121 (24).; Anal. Calcd for: C21H16N2O5: C, 67.82; H, 4.28; N, 7.44%. Found: C, 67.92; H, 4.36; N, 7.55%. 2-Amino-5-oxo-4-phenethyl-4,5-dihydropyrano[3,2-c] chromene-3-carbonitrile (Table 3, Entry 15): 1H NMR (DMSO-d6, 500 MHz): δ 1.81–1.87 (m, 1H,), 2.09–2.16 (m, 1H,), 2.45–2.52 (m, 1H,), 2.54–2.62 (m, 1H), 3.50–3.6 (m, 1H,), 7.00 (t, J = 8.1, 1H, Ar), 7.08 (d, J = 7.0 Hz, 2H, Ar), 7.13 (t, J = 7.5 Hz, 2H, Ar), 7.34–7.45 (m, 4H, NH2 and Ar), 7.62–7.67 (m, 1H, Ar), 7.76 (dd, J = 5.9, 1.2 Hz, 1H, Ar) ppm; 13C NMR (DMSO-d6, 125 MHz): δ 30.4, 30.7, 54.8, 103.7, 112.9, 116.3, 119.5, 122.1, 124.3, 125.5, 127.93 (2 C), 128.1, 132.5, 141.2, 152.0, 154.0, 159.4, and 159.8 ppm; IR (KBr, cm−1): 3382, 3315, 3189, 2198, 1694, 1671, 1608, 1396, 1315, 1179, 1211, 1112, and 759; MS (EI, 70 eV) m/z (%) = 344 (M+, 7), 240 (20), 239 (100), 187 (8), 138 (21), 91 (10), 43 (17).; Anal. Calcd for: C21H16N2O3: C, 73.24; H, 4.68; N, 8.13%. Found: C, 73.28; H, 4.70; N, 8.20%. 2.3. Preparation of tetrahydrobenzo[b]pyrans A mixture of an aromatic aldehyde (1 mmol), malononitrile (1.2 mmol), dimedone (1 mmol) and ionic liquid (0.27 mmol), was stirred at room temperature under solvent-free condition for appropriate time (Table 4). After completion of the reaction which was monitored by TLC, the mixture was washed with water and the solid product was purified by recrystallization from ethanol. 2.4. Preparation of spirooxindole derivatives A mixture of isatin (1 mmol), malononitrile (1 mmol), dimedone or 4-hydroxycoumarin (1 mmol) and ionic liquid (0.27 mmol), was stirred at room temperature under solvent-free condition for appropriate time. After completion of the reaction which was monitored by TLC, the mixture was washed with water and the solid product was purified by recrystallization from ethanol. 3. Results and discussion The Knoevenagel condensation is a very useful reaction and generates double bonds from a carbonyl compound and an active methylene compound in the presence of a catalytic amount of weak base [12–17]. Recently, the Knoevenagel condensation of carbonyl
H.R. Shaterian et al. / Journal of Molecular Liquids 158 (2011) 145–150
Scheme 1. The Knoevenagel condensation for preparation of benzilidenemalononitriles and 2-benzylidene-5,5-dimethylcyclohexane-1,3-diones.
Table 2 Comparison results of 2-hydroxyethylammonium formate with MgO [26], Ninanoparticles [22], Ti-TUD-1 [25] and porous calcium [23] in the synthesis of benzylidenemalononitriles from benzaldehyde and malononitrile. Entry Catalyst
Conditions
Time Yield (%) (min)
1 2
H2O, EtOH as solvent at r.t EtOH as solvent at r.t
7 19
3 4 5
MgO Ninanoparticles Ti-TUD-1 Porous calcium Ionic liquid
EtOH as solvent at r.t 30 CH2Cl2 as solvent under MW 2 Solvent-free at r.t b1
94 98 91 87 91 (present work)
compounds with rhodanine to afford arylalkylidene rhodanines in the presence of 2-hydroxyethylammonium formate was reported [18]. First report, the Knoevenagel condensation reaction of aromatic aldehydes with malononitrile or dimedone produces benzilidenemalononitriles [19–26] and 2-benzylidene-5,5-dimethylcyclohexane1,3-diones [22,24] respectively in the presence of 0.029 g (0.27 mmol) of ionic liquid as catalyst at ambient conditions (Scheme 1). The efficiency and versatility of the ionic liquid as catalyst for the Knoevenagel condensation for different substituted benzaldehydes using malononitrile or dimedone were investigated (Table 1). Using catalytic amount of the ionic liquid as catalyst, different substituted benzaldehydes got readily condensed with malononitrile to give corresponding product at short reaction times (b6 min) with excellent yield. The substrates when condensed with dimedone using similar amount of ionic liquid as catalyst gave desired condensed products consumed at longer times (30, 45 min). This may be attributed to the fact that the abstraction of proton from the active methylene group of malononitrile is easier compared to dimedone (Table 1, Entries 9, 10). All two Knoevenagel condensation reactions produced the dehydrated products without any side reactions such as self condensation, Cannizaro products or hydrated products of Knoevenagel adducts. The reaction of aliphatic aldehydes with malononitrile yielded a mixture of hydrated and dehydrated products, while the reaction of dimedone with aliphatic aldehydes
147
didn't progress after 24 h and starting materials were intact using ionic liquid. To show the merit of the present work in comparison with the reported results in the literature, we compared the results of 2hydroxyethylammonium formate with MgO [26], Ni-nanoparticles [22], Ti-TUD-1[25], and porous calcium [23] in the synthesis of benzylidenemalononitriles. As shown in Table 2, the ionic liquid can act as suitable catalyst with respect to reaction times and yields of the products. Next, as part of our program aimed at developing useful new synthesis methods based on the use of mentioned ionic liquid as a catalyst, we have studied the three-component one-pot synthesis of 2-amino-4-aryl-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile derivatives [27–33] by condensing 4-hydroxycoumarin, aldehydes and malononitriles using a catalytic amount of 2hydroxyethylammonium formate at room temperature. Furthermore, the three-component reaction of dimedone, aldehydes, and malonitrile for preparation of tetrahydrobenzo[b] pyrans [34–37] was investigated (Scheme 2). Subsequently, a series of differently substituted 2-amino-4-aryl-5oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile and tetrahydrobenzo[b]pyrans derivatives was prepared successfully under solventfree neat conditions. These results are listed in Tables 3 and 4. The results clearly indicate that reactions can tolerate a wide range of differently substituted aldehydes. The reactions were complete within 2–15 min and excellent yields of products were obtained by both methods. However, in case of aliphatic aldehydes, reactions were not completed under solvent-free conditions and desired products were obtained in low yields. The proposed mechanism for the reaction using ionic liquid as catalyst is also described in Scheme 3. According to literature report [27–33], ionic liquid with weak base character [11] is an effective catalyst for the readily in-situ formation of Knoevenagel product from activated aryl aldehyde and carboanion of malononitrile. Afterward, enamine is formed from 2-hydroxyethylammonium formate and 4hydroxycoumarin, which then reacts with protonated Knoevenagel product (formic acid formed and acts as protonated source) via 1,4conjugted addition, followed by cyclization to give desired cyclic product after hydrolysis (Scheme 3). In this mechanism cation and anion of IL are catalytically act and reformed to prepare 2hydroxyethylammonium formate in each cycles. In continuation to this research, a simple and an efficient one-pot synthetic approach was used for the preparation of biologically interesting spirooxindole derivatives [38,39] in high yields by means of three-component reactions of isatin, malononitrile, and dimedone or 4-hydroxycoumarin catalyzed by mentioned ionic liquid as catalyst under mild solvent-free and ambient conditions (Scheme 4). We suggested a mechanism according to the literature [38,39], the formation of spirooxindole can be explained by a formation of isatylidene malononitrile via a domino Knoevenagel condensation of isatin and malononitrile. Then, similar to Scheme 3, Michael addition
Scheme 2. The one-pot synthesis of 2-amino-5-oxo-4-aryl-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile and tetrahydrobenzo[b]pyran.
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Table 3 Preparation of a series of differently substituted 2-amino-4-aryl-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile in the presence of 2-hydroxy ethylammonium formate as catalyst from aryl aldehyde, malononitrile and hydroxycoumarine 4- at ambient conditions. Entry Substrate
product Time Yield m.p(Lit.m.p0C) [ref] (min) (%)a
1
1b
15
73
255–256 (257–258) [27]
2
1b
13
89
261–262 (261–262) [27]
3
4
5
1b
1b
1b
5
8
6
75
67
74
Table 4 Preparation of a series of differently substituted tetrahydrobenzo[b]pyrans in the presence of 2-hydroxy ethylammonium formate as catalyst from aryl aldehyde, malononitrile and dimedone at ambient conditions. Product
Time (min)
Yield (%)a
m.p(Lit.m.p0C) [ref]
1
2b
5
70
227–229 (226–228) [34]
2
2b
2
70
195–196 (197–199) [34]
3
2b
4
86
169–171 (175–176) [34]
4
2b
3
57
208–211 (201–205) [34]
5
2b
6
79
203–206 (202–203) [34]
6
2b
3
85
212–215 (209–211) [34]
7
2b
6
43
174–177 (198–200) [35]
8
2b
10
87
113–115 (115–117) [36]
Entry
Substrate
280–283 (280–282) [28]
245–247 (255–257) [28]
261–262 (258–260) [28]
6
1b
12
79
244–245 (247–248) [32]
7
1b
20
62
254–255 (254–255) [33] a
8
1b
12
73
273–274 (266–268) [33]
9
1b
7
60
261–262 (260–262) [28]
10
1b
15
70
258–259 (260–262) [33]
11
1b
10
71
222–224 (247–249) [29]
12
1b
10
40
241–242b
b
Yields refer to isolated pure products. The known products were characterized and their physical properties (M.p, 1H NMR, 13C NMR and IR) with authentic samples [34– 37] were compared.
of dimedone or 4-hydroxycoumarin with isatylidene malononitrile followed by cyclization in the presence of ionic liquid as catalyst produce desired spirooxindole (Scheme 5). We also investigated the recycling of the catalyst under solventfree conditions using a model reaction of 4-chlorobenzaldehde, malononitrile and 4-hydroxycoumarin (Table 3, entry 2). After completion of the reaction, water was added and the precipitated mixture was filtered off for separation of crude products. After washing solid products with water completely, the water containing ionic liquid (IL is soluble in water) was evaporated under reduce pressure and ionic liquid was recovered and reused. The recovered catalyst was reused for at least five runs without any loss of its activities (Fig. 1). 4. Conclusions
13
1b
7
65
260–261
14
1b
6
68
230–233b
In summary, we have successfully developed a simple, facile and efficient method for the synthesis of benzylidenmalononitrile, 2benzylidene-5,5-dimethylcyclohexane-1,3-dione, 2-amino-4-aryl-5Table 3 (continued) Entry Substrate
15
1b
7
98
179–182b
product Time Yield m.p(Lit.m.p0C) [ref] (min) (%)a
Notes to Table 3: a Yields refer to isolated pure products. The known products were characterized and their physical properties (M.p, 1H NMR, 13C NMR and IR) with authentic samples [27– 30,32,33] were compared. b Four new unknown products was synthesized.
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149
Scheme 3. The proposed mechanism for one-pot synthesis of 2-amino-5-oxo-4-aryl-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile.
oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile, tetrahydrobenzo[b] pyran, spirooxindole using a catalytic amount of 2hydroxyethylammonium formate as an inexpensive and available
ionic liquid under solvent-free and ambient conditions. The recovered ionic liquid was reused for 5 cycles. The method offered several advantages such as high yields, broader substrate scope, an easy and
Scheme 4. Preparation of spirooxindole derivatives.
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Yield (%)
Scheme 5. The proposed mechanism for one-pot synthesis of spirooxindoles.
100 90 80 70 60 50 40 30 20 10 0
98100
96 99
95 98
93
97
91
96
Reaction Yield (%) Catalyst Yield (%)
1
2
3
4
5
Numbera of runs Fig. 1. The recycling of the catalyst under solvent-free conditions using a model reaction of 4-chlorobenzaldehde, malononitrile and 4-hydroxycoumarin.
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