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Molecules 2017, 22(7), 1197; https://doi.org/10.3390/molecules22071197

Article
Synthesis of 2H-Chromenones from Salicylaldehydes and Arylacetonitriles
1
Zhejiang Provincial Key Laboratory of Fiber Materials and Manufacturing Technology, Zhejiang Sci-Tech University, Xiasha Campous, Hangzhou 310018, China
2
Zhejiang Kertice Hi-Tech Fluor-Material Co., LTD, Huzhou 313000, China
*
Author to whom correspondence should be addressed.
Received: 30 June 2017 / Accepted: 13 July 2017 / Published: 18 July 2017

Abstract

:
An efficient and convenient protocol for the synthesis of 2H-chromenones has been developed. In the presence of tBuOK in DMF, good to excellent yields of various chromenones were obtained from the corresponding salicylaldehydes and arylacetonitriles. No protection of inert gas atmosphere is required here.
Keywords:
chromenones synthesis; metal-free; green chemistry; heterocycle synthesis; salicylaldehydes

1. Introduction

Coumarin is an important class of benzo-fused six-membered heterocycles, which was first isolated as a natural product in 1820, and has been found to have various interesting bioactivities (Figure 1) [1,2,3,4,5,6,7,8]. Due to its importance, many efforts have been made to develop new synthetic procedures for coumarin’s preparation. Classical routes to coumarins based on Pechmann- [9], Knoevenagel- [10], Perkin- [11], Reformatsky- [12] and Wittig- [13] reactions have been extensively investigated. Recently, procedures based on transition metal catalysts, ionic liquids and microwaves have been developed as well [14,15,16,17].
In the 21st century, the demands of sustainable development drive organic chemists to pay more attention to the principles of green chemistry in designing their new procedures. Among the various possible directions, the development of new transition metal-free methodologies will be one attractive choice. On one hand, transition metal catalysts are usually considered to be toxic and non-environmentally benign. On the other hand, special attention has to be taken to avoid the problem of transition metal contamination of the final products, especially when in heterocycles synthesis chemistry. With these points in mind and also based on our continual interests in the development of new procedures for the synthesis of heterocycles under transition metal-free conditions [18], we wish to report here a convenient methodology for the construction of coumarins from salicylaldehydes and arylacetonitriles. In the presence of tBuOK in DMF, good to excellent yields of the desired chromenones were obtained and no protection of inert gas atmosphere is required here.

2. Results and Discussion

Initially, we choose salicylaldehyde and 2-phenylacetonitrile as the model substrates to establish this reaction system (Table 1). As we expected, with two equivalents of tBuOK as the base in 2 mL of dimethylformamide (DMF) at 110 °C, 77% of the desired product can be isolated (Table 1, entry 1). No better results can be obtained with an increased amount of promotor and similar yield can be observed with a higher concentration (Table 1, entries 2 and 3). Then, several other inorganic bases were screened and none of them could give better results than tBuOK (Table 1, entries 5–10). The reaction temperature was also checked and yields were reduced when the reaction temperature was decreased or increased (Table 1, entries 11 and 12). Subsequently, various solvents were examined but without improved results (Table 1, entries 13–17).
With the optimal reaction conditions in hand, several substituted salicylaldehydes were tested and shown in Table 2. Moderate to good yields of 2H-chromenones can be obtained from the corresponding salicylaldehydes and 2-phenylacetonitrile.
Then, various arylacetonitriles were examined with salicylaldehyde (Table 3). Both electron-donating and electron-withdrawing substituted phenylacetonitriles afforded the corresponding products in moderate to good yields. Notably, when 2-(2-fluorophenyl)acetonitrile and 2-(2-chlorophenyl)acetonitrile were applied as the reaction partner, good yields of dibenzo(b,f)oxepine-10-carbonitrile can be obtained via intermolecular condensation and intramolecular nucleophilic substitution (Table 3, entries 6 and 9) [19]. It is also important to mention that 3-oxo-3-phenylpropanenitrile, 3-phenylpropanenitrile and malononitrile were tested under standard conditions but no desired products can be detected (Table 3, entries 14–16).
To demonstrate the potential utility of this method, we conducted the reaction in gram scale as well (Scheme 1). Thus, salicylaldehyde (6 mmol) was reacted with phenylacetonitrile (8 mmol) in the presence of two equivalents; for tBuOK at 110 °C for 20 h, 83% yield of 3-phenyl-2H-chromen-2-one was obtained (1.11 g).
In addition, analogues of the substrates have been tested as well (Scheme 2). Under the standard conditions, 50% of 3-phenyl-2H-chromen-2-one and 21% of 2H-chromen-2-one could be obtained from methyl 2-phenylacetate and dimethyl malonate, respectively (Scheme 2, equation. a and equation. b). Moreover, 2-hydroxybenzonitrile, 2-acetylphenol and 2-hydroxybenzophenone were taken into consideration as well. Unfortunately, no desired product could be detected from 2-hydroxybenzonitrile (Scheme 2, equation. c). Interestingly, 2-acetylphenol could afford acceptable yield of the goal product (Scheme 2, equation. d) and moderate yield of 3,4-diphenyl-2H-chromen-2-one was generated from 2-hydroxybenzophenone and phenylacetonitrile without any further optimization (Scheme 2, equation. e) [20].
In order to obtain more insight into the reaction pathway, control experiments were performed (Scheme 3). Benzaldehyde, phenol and 4-hydroxybenzaldehyde were reacted with phenylacetonitrile under the standard reaction conditions, respectively. When benzaldehyde was reacted with phenylacetonitrile, 67% of 2,3-diphenylacrylonitrile was obtained while no product could be detected with phenol (Scheme 3, equation. a and equation. b). Compared with salicylaldehyde, 4-hydroxybenzaldehyde is considered as a compound with the same electron properties. Under the same reaction conditions, 93% of 3-(4-hydroxyphenyl)-2-phenylacrylonitrile was generated as the sole product by the reaction of 4-hydroxybenzaldehyde with phenylacetonitrile (Scheme 3, equation. c), which indicated that the first step of this transformation is the intermolecular condensation instead of the nucleophilic addition [21].
Based on these results, a possible reaction pathway has been proposed (Scheme 4). In the presence of base, phenylacetonitrile transformed into cyano(phenyl)methanide, which subsequently reacted with salicylaldehyde to give intermediate I. With the assistance of the other equivalent base, the hydroxyl group of intermediate I was activated and then reacted with the cyano via an intramolecular addition. The final products will be formed after in situ hydrolysis.

3. Materials and Methods

3.1. Materials and General Procedures

3.1.1. Materials

General comments: All reactions were carried out under air. Reactions were monitored by TLC analysis (pre-coated silica gel plates with fluorescent indicator UV254, 0.2 mm) and visualized with 254 nm UV light. Chemicals were purchased from Aldrich (Tianjin, China), Alfa-Aesar (Tianjin, China), TCI (Shanghai, China) and unless otherwise noted were used without further purification. All compounds were characterized by 1H-NMR and 13C-NMR spectroscopy and recorded on Bruker (Beijing, China) AV 300 and AV 400 spectrometers. Gas-chromatography-mass-analysis was performed using an Agilent HP-5890 with an Agilent HP-5973 Mass Selective Detector (EI) and an HP-5-capillary column using helium as a carrier gas.

3.1.2. General Procedures

Salicylaldehyde (1 mmol) and two equivalents of tBuOK were added in a 25 mL tube equipped with a stirring bar. Then, 1 mL of DMF and 2-phenylacetonitrile (1.5 mmol) were injected by syringe. After that, the tube was closed and heated up to 110 °C for 16 h. When the reaction was completed, the reaction mixture was cooled to room temperature. The reaction was quenched with distilled water and the solution was extracted with ethyl acetate. The crude product was purified by column chromatography (ethyl acetate/pentane = 1:25–1:8).

3.2. Synthesis of Adducts (Specific Spectral Reference Supplementary Materials)

3-Phenyl-2H-chromen-2-one: 7t1H-NMR (300 MHz, Chloroform-d) δ 7.74 (d, J = 0.6 Hz, 1H), 7.66–7.60 (m, 2H), 7.50–7.41 (m, 2H), 7.41–7.32 (m, 3H), 7.29 (dq, J = 7.7, 0.9 Hz, 1H), 7.25–7.19 (m, 1H). 13C-NMR (75 MHz, Chloroform-d) δ 160.55, 153.48, 139.83, 134.67, 131.36, 128.83, 128.49, 128.44, 128.33, 127.87, 124.46, 119.64, 116.42. GC-MS (EI, 70 ev): m/z (%) = 222 (M+, 100), 195 (14), 194 (93), 166 (12), 165 (89), 164 (16), 163 (10), 82 (11).
6-Methyl-3-phenyl-2H-chromen-2-one: 7u1H-NMR (300 MHz, Chloroform-d) δ 7.70 (s, 1H), 7.67–7.58 (m, 2H), 7.48–7.33 (m, 3H), 7.31–7.24 (m, 2H), 7.23–7.14 (m, 1H), 2.36 (s, 3H). 13C-NMR (75 MHz, Chloroform-d) δ 160.74, 151.61, 139.84, 134.81, 134.11, 132.40, 128.71, 128.48, 128.40, 128.14, 127.65, 119.36, 116.11, 20.76. GC-MS (EI, 70 ev): m/z (%) = 236 (M+, 100), 209 (10), 208 (67), 207 (62), 179 (24), 178 (40), 152 (16), 139 (10), 89 (12), 77 (13), 76 (12), 51 (11).
6-Fluoro-3-phenyl-2H-chromen-2-one: 1H-NMR (300 MHz, Chloroform-d) δ 7.75 (s, 1H), 7.73–7.67 (m, 2H), 7.50–7.41 (m, 3H), 7.35 (dddd, J = 8.8, 4.5, 1.8, 1.1 Hz, 1H), 7.29–7.19 (m, 2H). 13C-NMR (75 MHz, Chloroform-d) δ 160.17, 149.63, 138.73, 134.28, 129.52, 129.16, 128.54, 128.53, 120.28, 118.76 (d, J = 24.6 Hz), 118.05, 117.94, 113.05 (d, J = 23.9 Hz). GC-MS (EI, 70 ev): m/z (%) = 240 (M+, 94), 213 (15), 212 (96), 184 (15), 183 (100), 182 (12), 181 (10), 163 (11), 157 (13), 91 (10). HRMS (EI): Calcd. for [[M + H]+: C15H9FO2]+: 241.06593, found: 241.06566.
6-Chloro-3-phenyl-2H-chromen-2-one: 7t1H-NMR (300 MHz, Chloroform-d) δ 7.73 (t, J = 0.5 Hz, 1H), 7.72–7.66 (m, 2H), 7.53 (d, J = 2.4 Hz, 1H), 7.50–7.41 (m, 4H), 7.31 (dt, J = 8.8, 0.6 Hz, 1H). 13C-NMR (75 MHz, Chloroform-d) δ 160.02, 151.88, 138.45, 134.25, 131.31, 129.75, 128.69–128.43 (m), 129.56, 129.25, 128.58, 127.10, 120.73, 117.93. GC-MS (EI, 70 ev): m/z (%) = 256 (M+, 100), 230 (30), 229 (15), 166 (10), 165 (77), 164 (20), 163 (28), 139 (18), 82 (18), 63 (15).
Methyl-2-oxo-3-phenyl-2H-chromene-6-carboxylate: 7t1H-NMR (300 MHz, Chloroform-d) δ 8.28 (d, J = 2.0 Hz, 1H), 8.19 (dd, J = 8.7, 2.0 Hz, 1H), 7.89–7.84 (m, 1H), 7.76–7.65 (m, 2H), 7.55–7.34 (m, 5H), 3.96 (s, 3H). 13C-NMR (75 MHz, Chloroform-d) δ 165.70, 159.85, 156.21, 139.23, 134.17, 132.28, 129.94, 129.19, 128.56, 128.50, 128.35, 126.59, 119.39, 116.65, 52.47. GC-MS (EI, 70 ev): m/z (%) = 280 (M+, 100), 252 (11), 249 (30), 221 (45), 193 (29), 165 (27), 164 (12), 163 (14), 139 (22), 83 (15).
8-Methyl-3-phenyl-2H-chromen-2-one: 7t1H-NMR (300 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.75–7.64 (m, 2H), 7.51–7.27 (m, 5H), 7.19 (dd, J = 8.1, 7.0 Hz, 1H), 2.49 (s, 3H). 13C-NMR (75 MHz, Chloroform-d) δ 160.59, 151.78, 140.19, 134.76, 132.61, 129.02, 128.64, 128.43, 128.35, 127.80, 125.78, 125.56, 123.97, 119.29, 15.38. GC-MS (EI, 70 ev): m/z (%) = 236 (M+, 100), 209 (12), 208 (76), 207 (45), 179 (19), 178 (36), 165 (30), 152 (12), 89 (14), 77 (10), 76 (12).
6,8-Dichloro-3-phenyl-2H-chromen-2-one: 7v1H-NMR (300 MHz, Chloroform-d) δ 7.75–7.63 (m, 3H), 7.57 (d, J = 2.3 Hz, 1H), 7.48–7.39 (m, 4H). 13C-NMR (75 MHz, Chloroform-d) δ 158.81, 147.77, 137.89, 133.72, 131.20, 130.23, 129.50, 129.48, 128.60, 128.51, 125.61, 122.27, 121.44. GC-MS (EI, 70 ev): m/z (%) = 291 (M+, 63), 290 (94), 266 (11), 265 (10), 264 (65), 263 (16), 262 (100), 201 (20), 200 (10), 199 (62), 164 (28), 163 (60), 162 (10), 139 (10), 99 (16), 87 (11), 81 (19), 63 (10).
7-Chloro-3-phenyl-2H-chromen-2-one: 1H-NMR (300 MHz, Chloroform-d) δ 7.66 (s, 1H), 7.61–7.52 (m, 2H), 7.44–7.30 (m, 4H), 7.28–7.24 (m, 1H), 7.21–7.09 (m, 1H). 13C-NMR (75 MHz, Chloroform-d) δ 159.84, 153.66, 138.90, 137.23, 134.30, 129.03, 128.64, 128.49, 128.44, 128.26, 125.08, 124.91, 118.21, 116.73. GC-MS (EI, 70 ev): m/z (%) = 256 (M+, 100), 230 (16), 228 (100), 166 (12), 165 (85), 164 (27), 163 (28), 139 (16), 115 (14), 114 (12), 82 (11), 63 (15). HRMS (EI): Calcd. for [[M + H]+: C15H9ClO2]+: 257.03638, found: 257.03614.
2-Phenyl-3H-benzo[f]chromen-3-one: 7u1H-NMR (300 MHz, Chloroform-d) δ 8.36 (d, J = 1.7 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.83–7.68 (m, 2H), 7.67–7.59 (m, 2H), 7.50 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H), 7.42–7.26 (m, 5H). 13C-NMR (75 MHz, Chloroform-d) δ 160.55, 153.04, 135.60, 135.00, 132.62, 130.23, 129.01, 128.80, 128.50 (d, J = 2.1 Hz), 128.12, 127.10, 125.96, 121.34, 116.58, 113.65. GC-MS (EI, 70 ev): m/z (%) = 272 (M+, 92), 245 (23), 244 (100), 243 (23), 215 (60), 213 (27), 189 (10), 122 (10), 107 (25), 94 (18).
3-(o-Tolyl)-2H-chromen-2-one: 7x1H-NMR (300 MHz, Chloroform-d) δ 7.65 (s, 1H), 7.60–7.46 (m, 2H), 7.39 (ddt, J = 8.2, 1.2, 0.6 Hz, 1H), 7.36–7.28 (m, 3H), 7.28–7.22 (m, 2H). 13C-NMR (75 MHz, Chloroform-d) δ 160.21, 153.80, 141.59, 136.82, 134.66, 131.41, 130.30, 129.73, 128.81, 127.81, 125.85, 124.43, 119.28, 116.55, 19.92. GC-MS (EI, 70 ev): m/z (%) = 236 (M+, 100), 220 (12), 219 (64), 208 (37), 207 (86), 189 (27), 179 (26), 178 (53), 177 (10), 176 (11), 165 (24), 152 (21), 117 (12), 115 (23), 89 (18), 76 (14), 63 (18), 39 (11).
3-(m-Tolyl)-2H-chromen-2-one: 7t1H-NMR (300 MHz, Chloroform-d) δ 7.76 (s, 1H), 7.55–7.43 (m, 4H), 7.37–7.22 (m, 3H), 7.22–7.16 (m, 1H), 2.39 (s, 3H). 13C-NMR (75 MHz, Chloroform-d) δ 160.55, 153.42, 139.70, 138.03, 134.59, 131.24, 129.59, 129.09, 128.44, 128.32, 127.81, 125.60, 124.40, 119.65, 116.36, 21.45. GC-MS (EI, 70 ev): m/z (%) = 236 (M+, 100), 209 (14), 208 (81), 207 (18), 179 (14), 178 (30), 165 (38), 152 (13), 117 (11), 89 (13), 63 (10).
3-(p-Tolyl)-2H-chromen-2-one: 7t1H-NMR (300 MHz, Chloroform-d) δ 7.67 (s, 1H), 7.55–7.47 (m, 2H), 7.45–7.35 (m, 2H), 7.25 (dt, J = 7.8, 0.9 Hz, 1H), 7.21–7.09 (m, 3H), 2.29 (s, 3H). 13C-NMR (75 MHz, Chloroform-d) δ 160.60, 153.32, 139.12, 138.82, 131.71, 131.10, 129.09, 128.31, 128.17, 127.74, 124.36, 119.68, 116.30, 21.23. GC-MS (EI, 70 ev): m/z (%) = 236 (M+, 100), 209 (10), 208 (62), 207 (37), 179 (13), 178 (28), 165 (26), 152 (12), 89 (11), 63 (10), 114 (12), 82 (11), 63 (15).
3-(Naphthalen-1-yl)-2H-chromen-2-one: 7t1H-NMR (300 MHz, Chloroform-d) δ 7.97–7.87 (m, 2H), 7.84–7.76 (m, 2H), 7.64–7.41 (m, 7H), 7.38–7.30 (m, 1H). 13C-NMR (75 MHz, Chloroform-d) δ 160.77, 153.97, 142.77, 133.66, 132.64, 131.65, 131.53, 129.36, 128.53, 128.37, 127.93, 127.63, 126.48, 126.07, 125.23, 124.54, 119.32, 116.68. GC-MS (EI, 70 ev): m/z (%) = 272 (M+, 100), 273 (19), 271 (79), 255 (11), 244 (24), 243 (50), 216 (11), 215 (58), 214 (10), 213 (28), 189 (17), 107 (18), 95 (17), 63 (11).
3-(4-Methoxyphenyl)-2H-chromen-2-one: 7t1H-NMR (300 MHz, Chloroform-d) δ 7.75 (s, 1H), 7.71–7.63 (m, 2H), 7.56–7.44 (m, 2H), 7.34 (ddd, J = 8.0, 1.3, 0.7 Hz, 1H), 7.31–7.23 (m, 1H), 7.02–6.90 (m, 2H), 3.85 (s, 3H). 13C-NMR (75 MHz, Chloroform-d) δ 160.74, 160.10, 153.24, 138.43, 130.95, 129.78, 127.81, 127.65, 127.02, 124.38, 119.79, 116.32, 113.87, 55.32. GC-MS (EI, 70 ev): m/z (%) = 252 (M+, 100), 224 (10), 210 (10), 209 (65), 181 (41), 152 (35).
3-(3-Methoxyphenyl)-2H-chromen-2-one: 7t1H-NMR (300 MHz, Chloroform-d) δ 7.81 (s, 1H), 7.53 (td, J = 7.4, 1.6 Hz, 2H), 7.40–7.32 (m, 2H), 7.32–7.25 (m, 3H), 6.95 (ddd, J = 8.1, 2.6, 1.2 Hz, 1H), 3.85 (s, 3H). 13C-NMR (75 MHz, Chloroform-d) δ 160.41, 159.48, 153.45, 139.94, 135.96, 131.40, 129.43, 128.09, 127.89, 124.44, 120.86, 119.55, 116.38, 114.47, 114.16, 55.32. GC-MS (EI, 70 ev): m/z (%) = 252 (M+, 100), 224 (46), 194 (10), 182 (10), 181 (68), 167 (10), 165 (21), 153 (13), 152 (62), 151 (16), 127 (10), 126 (14), 63 (16), 39 (10).
3-(4-Fluorophenyl)-2H-chromen-2-one: 7u1H-NMR (300 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.75–7.64 (m, 2H), 7.54 (ddt, J = 7.6, 6.0, 1.8 Hz, 2H), 7.37 (dt, J = 8.8, 0.8 Hz, 1H), 7.34–7.27 (m, 1H), 7.19–7.06 (m, 2H). 13C-NMR (75 MHz, Chloroform-d) δ 164.70, 160.51, 153.47, 139.65, 131.48, 130.70, 130.39 (d, J = 8.3 Hz), 127.87, 127.30, 124.56, 119.54, 116.47, 115.46 (d, J = 21.6 Hz). GC-MS (EI, 70 ev): m/z (%) = 240 (M+, 93), 212 (100), 184 (14), 183 (81), 181 (14), 157 (19), 107 (12), 106 (21), 92 (12), 91 (13).
3-(3-Fluorophenyl)-2H-chromen-2-one: 7y1H-NMR (300 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.56–7.47 (m, 2H), 7.47–7.38 (m, 2H), 7.38–7.28 (m, 2H), 7.27–7.19 (m, 1H), 7.05 (tdd, J = 8.3, 2.6, 1.1 Hz, 1H). 13C-NMR (75 MHz, Chloroform-d) δ 164.24, 160.57 (d, J = 61.2 Hz), 153.54, 140.38, 136.63 (d, J = 8.1 Hz), 131.78, 129.95 (d, J = 8.4 Hz), 128.04, 126.99 (d, J = 2.4 Hz), 124.61, 124.13 (d, J = 3.1 Hz), 119.36, 116.49, 115.84 (d, J = 7.0 Hz), 115.55 (d, J = 8.9 Hz). GC-MS (EI, 70 ev): m/z (%) = 240 (M+, 80), 212 (90), 183 (100), 157 (10), 63 (10).
Dibenzo[b,f]oxepine-10-carbonitrile: 91H-NMR (300 MHz, Chloroform-d) δ 7.62 (dd, J = 8.1, 1.7 Hz, 1H), 7.54–7.41 (m, 3H), 7.35–7.18 (m, 5H). 13C-NMR (75 MHz, Chloroform-d) δ 158.30, 157.43, 142.37, 132.86, 131.91, 130.42, 128.29, 128.03, 126.17, 125.60, 125.41, 121.91, 121.67, 118.46, 113.99.GC-MS (EI, 70 ev): m/z (%) = 219 (M+, 100), 191 (25), 190 (93), 165 (12), 164 (30), 163 (25), 82 (10), 63 (12).
3-(3-Chlorophenyl)-2H-chromen-2-one: 1H-NMR (300 MHz, Chloroform-d) δ 7.83 (s, 1H), 7.70 (td, J = 1.7, 1.0 Hz, 1H), 7.64–7.59 (m, 1H), 7.59–7.51 (m, 2H), 7.42–7.37 (m, 2H), 7.37–7.28 (m, 2H). 13C-NMR (75 MHz, Chloroform-d) δ 160.15, 153.59, 140.43, 136.35, 134.38, 131.82, 129.68, 128.89, 128.54, 128.05, 126.96, 126.74, 124.63, 119.37, 116.53. GC-MS (EI, 70 ev): m/z (%) = 256 (M+, 100), 230 (27), 229 (17), 228 (95), 166 (10), 165 (80), 164 (22), 163 (27), 139 (12), 110 (10), 82 (13), 75 (12), 63 (12). HRMS (EI): Calcd. for [[M + H]+: C15H9ClO2]+: 257.03638, found: 257.03614.
3-(4-Chlorophenyl)-2H-chromen-2-one: 7t1H-NMR (300 MHz, Chloroform-d) δ 7.82 (d, J = 0.6 Hz, 1H), 7.71–7.62 (m, 2H), 7.59–7.50 (m, 2H), 7.46–7.40 (m, 2H), 7.37 (dt, J = 8.9, 0.8 Hz, 1H), 7.34–7.28 (m, 1H). 13C-NMR (75 MHz, Chloroform-d) δ 160.32, 153.52, 139.91, 134.92, 133.05, 131.66, 129.82, 128.67, 127.95, 127.15, 124.60, 119.46, 116.50. GC-MS (EI, 70 ev): m/z (%) = 256 (M+, 100), 230 (24), 229 (10), 228 (73), 165 (60), 164 (18), 163 (20).
3-(Pyridin-3-yl)-2H-chromen-2-one: 7z1H-NMR (300 MHz, Chloroform-d) δ 8.80 (d, J = 2.4 Hz, 1H), 8.61 (dd, J = 4.9, 1.7 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.28–7.22 (m, 1H), 7.44–7.31 (m, 3H), 7.25 (s, 1H), 7.14 (td, J = 7.6, 1.0 Hz, 2H). 13C-NMR (75 MHz, Chloroform-d) δ 153.33, 149.55, 149.14, 136.43, 134.27, 132.25, 130.90, 127.68, 123.61, 122.92, 119.62, 115.38. GC-MS (EI, 70 ev): m/z (%) = 221 (M+, 100), 222 (26), 139 (12).
4-Methyl-3-phenyl-2H-chromen-2-one: 7t1H-NMR (300 MHz, Chloroform-d) δ 7.69 (dd, J = 8.0, 1.5 Hz, 1H), 7.55 (ddd, J = 8.6, 7.2, 1.5 Hz, 1H), 7.50–7.36 (m, 4H), 7.36–7.28 (m, 3H), 2.32 (s, 3H). 13C-NMR (75 MHz, Chloroform-d) δ 160.93, 152.66, 147.59, 134.42, 131.29, 129.99, 128.40, 128.18, 127.33, 125.08, 124.22, 120.54, 116.85, 16.56. GC-MS (EI, 70 ev): m/z (%) = 236 (M+, 96), 235 (82), 208 (60), 207 (100), 179 (24), 178 (62), 177 (11), 176 (13), 165 (22), 152 (22), 151 (10), 139 (15), 131 (28), 115 (20), 102 (12), 89 (23), 77 (21), 75 (10), 63 (21), 51 (17), 50 (10), 39 (15).
3,4-Diphenyl-2H-chromen-2-one: 101H-NMR (300 MHz, Chloroform-d) δ 7.54 (ddd, J = 8.6, 6.6, 2.2 Hz, 1H), 7.44 (ddd, J = 8.3, 1.2, 0.6 Hz, 1H), 7.34–7.28 (m, 3H), 7.23–7.10 (m, 9H). 13C-NMR (75 MHz, Chloroform-d) δ 161.26, 153.22, 151.57, 134.46, 133.84, 131.43, 130.51, 129.35, 128.33, 128.25, 127.78, 127.73, 127.63, 126.99, 124.11, 120.51, 116.76. GC-MS (EI, 70 ev): m/z (%) = 298 (M+, 100), 297 (90), 281 (11), 270 (28), 269 (28), 268 (16), 255 (13), 253 (17), 252 (11), 241 (32), 240 (10), 239 (47), 165 (12), 119 (19).
2H-Chromen-2-one: 7m1H-NMR (300 MHz, Chloroform-d) δ 7.62 (d, J = 9.6 Hz, 1H), 7.50–7.35 (m, 2H), 7.30–7.13 (m, 2H), 6.34 (d, J = 9.5 Hz, 1H). 13C-NMR (75 MHz, Chloroform-d) δ 160.74, 154.03, 143.39, 131.80, 127.83, 124.39, 118.81, 116.88, 116.69. GC-MS (EI, 70 ev): m/z (%) = 146 (M+, 56), 118 (100), 90 (44), 89 (41), 64 (10), 63 (28), 62 (12).
(Z)-2,3-Diphenylacrylonitrile: 111H-NMR (300 MHz, Chloroform-d) δ 7.98–7.85 (m, 2H), 7.73–7.64 (m, 2H), 7.55 (s, 1H), 7.52–7.39 (m, 6H). 13C-NMR (75 MHz, Chloroform-d) δ 142.20, 134.41, 133.66, 130.49, 129.22, 129.16, 129.02, 128.91, 125.95, 117.95, 111.64. GC-MS (EI, 70 ev): m/z (%) = 205 (M+, 100), 204 (92), 203 (26), 190 (52), 178 (23), 177 (27), 176 (24), 165 (13), 151 (13), 102 (12), 89 (14), 88 (11), 77 (11), 76 (16), 75 (11), 63 (13), 51 (22), 50 (14), 39 (11).
(Z)-3-(4-Hydroxyphenyl)-2-phenylacrylonitrile: 111H-NMR (300 MHz, DMSO-d6) δ 10.29 (s, 1H), 7.93–7.76 (m, 3H), 7.75–7.64 (m, 2H), 7.54–7.43 (m, 2H), 7.42–7.31 (m, 1H), 6.92 (d, J = 8.7 Hz, 2H). 13C-NMR (75 MHz, DMSO-d6) δ 160.02, 142.91, 134.37, 131.44, 129.14, 128.61, 125.41, 124.79, 118.64, 115.89, 105.85. GC-MS (EI, 70 ev): m/z (%) = 221 (M+, 100), 206 (18), 204 (10), 203 (11), 202 (24), 192 (11), 191 (14) 190 (19), 177 (11), 165 (40), 164 (13), 63 (12), 51 (16), 39 (10).

4. Conclusions

In summary, a practical procedure for the synthesis of 3-aryl-2H-chromen-2-ones from salicylaldehydes and arylacetonitriles has been established. With tBuOK as the promotor and DMF as the solvent, good to excellent yields of chromenones were obtained. Additionally, no protection of inert gas atmosphere is required here.

Supplementary Materials

Supplementary materials are available online.

Acknowledgments

We gratefully thank the National Natural Science Foundation of China (grant No. 21406207) for support of this program.

Author Contributions

Chengcai Li and Hailin Zhu conceived and designed the experiments; Chengcai Li and Hang Zhang performed the experiments; Chengcai Li and Yongfeng Yang analyzed the data; Feng Wang contributed reagents/materials/analysis tools; Chengcai Li and Hailin Zhu wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Musa, M.A.; Cooperwood, J.S.; Khan, M.O.F. A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer. Curr. Med. Chem. 2008, 15, 2664–2679. [Google Scholar] [CrossRef] [PubMed]
  2. Thakur, A.; Singla, R.; Jaitak, V. Coumarins as anticancer agents: A review on synthetic strategies, mechanism of action and SAR studies. Eur. J. Med. Chem. 2015, 101, 476–495. [Google Scholar] [CrossRef] [PubMed]
  3. Swarnakar, N.K.; Jain, A.K.; Singh, R.P. Oral bioavailability, therapeutic efficacy and reactive oxygen species scavenging properties of coenzyme Q10-loaded polymeric nanoparticles. Biomaterials 2011, 32, 6860–6874. [Google Scholar] [CrossRef] [PubMed]
  4. Matos, M.J.; Vazquez-Rodriguez, S.; Santana, L.; Uriarte, E.; Fuentes-Edfuf, C.; Santos, Y.; Munoz-Crego, A. Looking for new targets: Simple coumarins as antibacterial agents. Med. Chem. 2012, 8, 1140–1145. [Google Scholar] [PubMed]
  5. Shi, Y.; Zhou, C.H. Synthesis and evaluation of a class of new coumarin triazole derivatives as potential antimicrobial agents. Bioorg. Med. Chem. Lett. 2011, 42, 956–960. [Google Scholar] [CrossRef] [PubMed]
  6. Choochuay, K.; Chunhacha, P.; Pongrakhananon, V. Imperatorin sensitizes anoikis and inhibits anchorage-independent growth of lung cancer cells. J. Nat. Med. 2013, 67, 599–606. [Google Scholar] [CrossRef] [PubMed]
  7. Basanagouda, M.; Vishwanath, B.; Barigidad, N.; Laxmeshwar, S.; Devaru, S.; Venkatesh, N. Synthesis, structure–activity relationship of iodinated-4-aryloxymethyl-coumarins as potential anti-cancer and anti-mycobacterial agents. Eur. J. Med. Chem. 2014, 74, 225–233. [Google Scholar] [CrossRef] [PubMed]
  8. Kostova, I.; Raleva, S.; Genova, P. Structure-Activity Relationships of Synthetic Coumarins as HIV-1 Inhibitors. Bioinorg. Chem. Appl. 2006, 2006, 68274. [Google Scholar] [CrossRef] [PubMed]
  9. Sugino, T.; Tanaka, K. Solvent-Free Coumarin Synthesis. Chem. Lett. 2001, 30, 110–111. [Google Scholar] [CrossRef]
  10. Fringuelli, F.; Pani, G.; Piermatti, O. ChemInform Abstract: Low-Polluting Chemical Processes-Aldol and Allylation Reactions in Water. Cheminform 1996, 27. [Google Scholar] [CrossRef]
  11. Johnson, J.R. The Perkin Reaction and Related Reactions. Org. React. 1942, 1, 210. [Google Scholar]
  12. Shriner, R.L. The reformatsky reaction. Org. React. 1942, 1, 1. [Google Scholar]
  13. Yavari, I.; Hekmat-Shoar, R.; Zonouzi, A. ChemInform Abstract: A New and Efficient Route to 4-Carboxymethylcoumarins Mediated by Vinyltriphenylphosphonium Salt. Tetrahedron Lett. 1998, 29, 2391–2392. [Google Scholar] [CrossRef]
  14. Song, C.E.; Jung, D.U.; Choung, S.Y. Dramatic enhancement of catalytic activity in an ionic liquid: Highly practical Friedel-Crafts alkenylation of arenes with alkynes catalyzed by metal triflates. Angew. Chem. 2004, 43, 6183–6185. [Google Scholar] [CrossRef] [PubMed]
  15. Reddy, M.S.; Thirupathi, N.; Babu, M.H. ChemInform Abstract: Synthesis of Substituted 3-Iodocoumarins and 3-Iodobutenolides via Electrophilic Iodocyclization of Ethoxyalkyne Diols. J. Org. Chem. 2013, 78, 5878–5888. [Google Scholar] [CrossRef] [PubMed]
  16. Mi, X.; Wang, C.; Huang, M. ChemInform Abstract: Preparation of 3-Acyl-4-arylcoumarins via Metal-Free Tandem Oxidative Acylation/Cyclization between Alkynoates with Aldehydes. J. Org. Chem. 2015, 80, 148–155. [Google Scholar] [CrossRef] [PubMed]
  17. Reddy, M.S.; Thirupathi, N.; Haribabu, M. Tandem aldehyde–alkyne–amine coupling/cycloisomerization: A new synthesis of coumarins. Beilstein. J. Org. Chem. 2013, 9, 180–184. [Google Scholar] [CrossRef] [PubMed]
  18. Dong, F.; Feng, X.; Zhang, Y. An anion-exchange strategy for 3D hierarchical (BiO)2CO3/amorphous Bi2S3 heterostructures with increased solar absorption and enhanced visible light photocatalysis. RSC Adv. 2015, 5, 11714–11723. [Google Scholar] [CrossRef]
  19. Feng, J.B.; Wu, X.F. Oxidative Synthesis of Quinazolinones under Metal-free Conditio. J. Heterocycl. Chem. 2016. [Google Scholar] [CrossRef]
  20. Choi, Y.L.; Lim, H.S.; Lim, H.J.; Heo, J.-N. One-Pot Transition-Metal-Free Synthesis of Dibenzo[b,f]oxepins from 2-Halobenzaldehydes. Org. Lett. 2012, 14, 5102–5105. [Google Scholar] [CrossRef] [PubMed]
  21. Zhang, L.; Meng, T.; Fan, R.; Wu, J. General and efficient route for the synthesis of 3,4-disubstituted coumarins via Pd-catalyzed site-selective cross-coupling reactions. J. Org. Chem. 2007, 72, 7279–7286. [Google Scholar] [CrossRef] [PubMed]
Sample Availability: Samples of the compounds are not available from the authors.
Figure 1. Selected examples of bioactive chromenones.
Figure 1. Selected examples of bioactive chromenones.
Molecules 22 01197 g001
Scheme 1. Gram scale synthesis of 3-phenyl-2H-chromen-2-one.
Scheme 1. Gram scale synthesis of 3-phenyl-2H-chromen-2-one.
Molecules 22 01197 sch001
Scheme 2. Substrate analogues testing. (a) methyl 2-phenylacetate (b) dimethyl malonate (c) 2-hydroxybenzonitrile (d) 2-acetylphenol (e) 2-hydroxybenzophenone.
Scheme 2. Substrate analogues testing. (a) methyl 2-phenylacetate (b) dimethyl malonate (c) 2-hydroxybenzonitrile (d) 2-acetylphenol (e) 2-hydroxybenzophenone.
Molecules 22 01197 sch002
Scheme 3. Control experiments. (a) Benzaldehyde (b) phenol (c) 4-hydroxybenzaldehyde.
Scheme 3. Control experiments. (a) Benzaldehyde (b) phenol (c) 4-hydroxybenzaldehyde.
Molecules 22 01197 sch003
Scheme 4. Proposed mechanism of the synthesis of chromenone.
Scheme 4. Proposed mechanism of the synthesis of chromenone.
Molecules 22 01197 sch004
Table 1. Optimization of the reaction conditions [a].
Table 1. Optimization of the reaction conditions [a].
Molecules 22 01197 i001
EntryBaseSolventT (°C)Yield (%) [b]
1tBuOKDMF [c]11077
2tBuOK [d]DMF [c]11075
3tBuOKDMF11081
4tBuOKDMF11048
80
5K2CO3DMF11034
6K3PO4DMF11055
7KOHDMF11027
8tBuOLiDMF11075
9NaOMeDMF11055
10tBuONaDMF11074
11tBuOKDMF9073
12tBuOKDMF13041
13tBuOKDMAc11054
14tBuOKDMSO11030
15tBuOKToluene1109
16tBuOKo-xylene11012
17tBuOK1,4-dioxane11015
[a] Reaction conditions: 1 (1 mmol), 2 (1.5 mmol), base (2.0 equiv.), solvent (1 mL), 110 °C, 16 h. [b] Isolated yields. [c] DMF (2 mL). [d] tBuOK (3 equiv.).
Table 2. Synthesis of chromenones from salicylaldehydes [a].
Table 2. Synthesis of chromenones from salicylaldehydes [a].
Molecules 22 01197 i002
EntrySubstrateProductYield (%) [b]
1 Molecules 22 01197 i004 Molecules 22 01197 i00581
2 Molecules 22 01197 i006 Molecules 22 01197 i00777
3 Molecules 22 01197 i008 Molecules 22 01197 i00965
4 Molecules 22 01197 i010 Molecules 22 01197 i01193
5 Molecules 22 01197 i012 Molecules 22 01197 i01366
6 Molecules 22 01197 i014 Molecules 22 01197 i01596
7 Molecules 22 01197 i016 Molecules 22 01197 i01752
8 Molecules 22 01197 i018 Molecules 22 01197 i01940
9 Molecules 22 01197 i020 Molecules 22 01197 i02190
[a] Reaction conditions: 1a (1 mmol), 2 (1.5 mmol), tBuOK (2.0 equiv.), DMF (1 mL), 110 °C, 16 h. [b] Isolated yields.
Table 3. Synthesis of chromenones from 2-arylacetonitriles [a].
Table 3. Synthesis of chromenones from 2-arylacetonitriles [a].
Molecules 22 01197 i003
EntrySubstrateProductYield (%) [b]
1 Molecules 22 01197 i022 Molecules 22 01197 i02381
2 Molecules 22 01197 i024 Molecules 22 01197 i02577
3 Molecules 22 01197 i026 Molecules 22 01197 i02765
4 Molecules 22 01197 i028 Molecules 22 01197 i02970
5 Molecules 22 01197 i030 Molecules 22 01197 i03170
6 Molecules 22 01197 i032 Molecules 22 01197 i03386
7 Molecules 22 01197 i034 Molecules 22 01197 i03578
8 Molecules 22 01197 i036 Molecules 22 01197 i03793
9 Molecules 22 01197 i038 Molecules 22 01197 i03968
10 Molecules 22 01197 i040 Molecules 22 01197 i04166
11 Molecules 22 01197 i042 Molecules 22 01197 i04370
12 Molecules 22 01197 i044 Molecules 22 01197 i04540
13 Molecules 22 01197 i046 Molecules 22 01197 i04751
14 Molecules 22 01197 i048 Molecules 22 01197 i0490
15 Molecules 22 01197 i050 Molecules 22 01197 i0510
16 Molecules 22 01197 i052 Molecules 22 01197 i0530
[a] Reaction conditions: 1 (1 mmol), 2b (1.5 mmol), tBuOK (2.0 equiv.), DMF (1 mL), 110 °C, 16 h. [b] Isolated yields.

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