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DOI: 10.1055/a-2367-1877
β-Nitroacrylates and Phenols as Key Precursors of Arenofuran-3-carboxylates
We gratefully acknowledge financial support from the Università degli Studi di Camerino (University of Camerino). The research network Consorzio Interuniversitario Nazionale di ricerca in Metodologie e Processi Innovativi di Sintesi - Bari (CINMPIS-Bari) is also gratefully acknowledged.
Abstract
Herein we report a new, practical and efficient preparation of benzofuran-3-carboxylates and naphthofuran-3-carboxylates starting from β-nitroacrylates and phenols. The reaction is promoted by indium trichloride and leads to the target compounds in good to very good yields under microwave irradiation.
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β-Nitroacrylates 1 belong to an important class of nitroalkenes that have served as key intermediates in organic synthesis for many years.[1] Their reactivity stems from the simultaneous presence of the nitro and ester groups at the α- and β-positions of the double bond, that synergistically enhance the electrophilicity of the double bond. Careful selection of the nucleophilic species makes this class of compounds amenable to Diels–Alder reactions and various domino processes for generating homo- and heterocyclic systems (Scheme [1]).[2]
In this context, arenofuran systems have recently attracted growing attention in medicinal chemistry due to their interesting structural features and biological activities, with potential applications for the treatment of various diseases.[3] For these reasons, the benzofuran core is now considered to be a privileged scaffold.[4] A particular interest pertains to benzofuran-3-carboxylate derivatives, which exhibit a plethora of biological activities such as anti-inflammatory, antifungal, antibacterial and anticancer. Furthermore, they have been strategically used as precursors of other biologically active molecules (Figure [1]).[5]
Notwithstanding the above-mentioned benefits, the preparation of this specific class of arenofuran derivatives usually requires the use of complex starting materials,[6`] [b] [c] harsh reaction conditions,[6d] [e] expensive catalysts,[6f] multistep approaches,[6g] and long reaction times.[6b] [h] [i]
Following our studies concerning the applications of β-nitroacrylates in organic synthesis, and inspired by the work of Hajra et al.[7] that highlighted the effectiveness of indium salts in promoting the Friedel–Crafts reaction between 2-naphthols and nitroalkenes, we have discovered that the reactions of β-nitroacrylates 1 with phenols 2 efficiently afford the desired arenofurans in the presence of indium(III) chloride. The probable reaction mechanism involves a preliminary Friedel–Crafts reaction of phenol 2 with the β-nitroacrylate 1 leading to adduct A. Next, adduct A undergoes intramolecular attack by the oxygen atom of the phenol moiety leading to the cyclic intermediate B. Finally, upon elimination of a molecule of water and a nitroxyl species, the arenofuran derivative 3 is obtained (Scheme [2]).[8]
In order to test the feasibility of this approach, β-nitroacrylate 1a was reacted with p-cresol (2a) under various reaction conditions (Table [1]). Initially, we explored the reaction in the presence of 0.5 equivalents of InCl3 at room temperature and under reflux conditions (entries a and b). However, in both cases the conversion appeared incomplete; in the former (entry a), the reaction proved to be very slow and product 3a was obtained in a yield of only 29% after 24 hours (unreacted starting materials were still present). Conversely, under reflux conditions (entry b), the reaction did not show any significant progress, and after 9 hours, product 3a was isolated in 58% yield. Full conversion of the reactants was achieved by increasing the amount of InCl3 up to 1 equivalent, and the desired product 3a was obtained in 72% yield (entry c).
Next, by utilizing a Biotage® Initiator microwave synthesizer, we explored the reaction at different temperatures. In particular, the reaction at 110 °C was complete after 2.5 hours and product 3a was obtained in 74% yield (Table [1], entry d). Raising the temperature to 130 °C led to a decrease of the reaction time (1.5 h) and a significant increase of the yield to 81% (entry e). A further increase of the temperature to 150 °C was still beneficial in reducing the reaction time (1 h), but at the expense of the yield (62%) (entry f). Next, we screened the reaction trend in the presence of respectively 0.7 and 1.3 equivalents of InCl3, but no improvements were noted (entries g and h). We also explored the effects of other solvents (entries i–m) as well as different Lewis acids (entries n–t). However, in each case, the results were inferior, with only InBr3 (1 equiv) providing 3a in a satisfactory 71% yield. Lastly, a Brønsted acid, p-toluenesulfonic acid, was employed but without any success (entry u).
a Entries d–q were conducted under microwave conditions.
b Yield of pure isolated product. NR = no reaction.
Finally, we assessed the generality of our protocol by applying the optimized reaction conditions to several β-nitroacrylates and phenols. The corresponding benzofuran-3-carboxylate derivatives 3a–p were isolated in good to very good yields, except for compounds 3m and 3n, which were isolated in yields of 41% and 39%, respectively (Scheme [3]). In the former case, the presence of the methoxy group makes the conversion faster (1 h vs 1.5 h), however, in addition to the formation of 3m, an inseparable complex mixture of by-products was also observed. In contrast, the presence of the electron-withdrawing Cl atom made the reaction significantly less efficient, leading to an increase in the reaction time to 7 hours and the concomitant degradation of 1a. Moreover, the reaction was also investigated using methyl 4-hydroxybenzoate, however, this substrate was completely unreactive due to the strong deactivation effect of the ester group.
In conclusion, we have implemented an easy and practical strategy for the preparation of arenofuran-3-carboxylate systems starting from easily accessible substrates. Using our approach, the desired products can be obtained in good yields and in short reaction times in the presence of a range of different substituents on both the furan and benzene rings. Moreover, we have once again demonstrated the importance of β-nitroacrylates as key precursors of heterocyclic systems.
1H NMR analyses were recorded at 400 MHz on a Varian Mercury Plus 400. 13C NMR analyses were recorded at 100 MHz. IR spectra were recorded with a Perkin Elmer FTIR spectrophotometer Spectrum Two UATR. Microanalyses were performed with a CHNS-O analyzer Model EA 1108 from Fisons Instruments. GS-MS analyses were obtained on a Hewlett-Packard GC/MS 6890 N instrument operating under the EI technique (70 eV). Microwave irradiation was performed using a Biotage® Initiator. Compounds 1 were synthesized according to reported procedures.[9] Benzofurans 3a and 3j are known compounds.[6a] [10]
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Arenofuran-3-carboxylates 3a–p; General Procedure
β-Nitroacrylate 1 (1 mmol) and phenol 2 (1 mmol) were dissolved in dichloroethane (10 mL) in a 20 mL Biotage® vial and then treated with indium(III) chloride (0.221 g, 1 mmol). The resulting solution was irradiated at 130 °C for 1.5 h by employing a Biotage® Initiator microwave synthesizer. After cooling, the solution was transferred to a separating funnel, quenched with a 0.5 N aqueous solution of HCl (30 mL), extracted with DCM (3 × 30 mL), and the organic extracts were dried over anhydrous Na2SO4. Finally, after filtration and evaporation of the solvent under reduced pressure, the crude reaction product 3 was purified by flash column chromatography (hexane/EtOAc, 95:5).
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Ethyl 2-Ethyl-5-methylbenzofuran-3-carboxylate (3a)
Yellow oil; yield: 188 mg (81%).
IR (neat): 1707, 1587, 1463, 1373, 1248, 1148, 1094, 1039, 796 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.76 (s, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 7.08 (dd, J = 8.4, 1.8 Hz, 1 H), 4.41 (q, J = 7.2 Hz, 2 H), 3.19 (q, J = 7.6 Hz, 2 H), 2.46 (s, 3 H), 1.45 (t, J = 7.1 Hz, 3 H), 1.35 (t, J = 7.6 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 168.5, 164.7, 152.2, 133.4, 126.5, 125.5, 121.8, 110.4, 107.9, 60.3, 21.9, 21.6, 14.6, 12.2.
GC-MS (EI): m/z (%) = 232 (72) [M+], 203 (100), 187 (41), 185 (40), 159 (17), 131 (15), 115 (24), 91 (10).
Anal. Calcd for C14H16O3 (232.28): C, 72.39; H, 6.94. Found: C, 72.43; H, 6.97.
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Ethyl 2-Heptyl-5-methylbenzofuran-3-carboxylate (3b)
Yellow oil; yield: 257 mg (85%).
IR (neat): 1712, 1588, 1463, 1376, 1243, 1146, 1055, 799, 788 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.76 (s, 1 H), 7.30 (d, J = 8.4 Hz, 1 H), 7.07 (dd, J = 8.4, 1.8 Hz, 1 H), 4.41 (q, J = 7.1 Hz, 2 H), 3.15 (t, J = 7.6 Hz, 2 H), 2.46 (s, 3 H), 1.82–1.71 (m, 2 H), 1.44 (t, J = 7.1 Hz, 3 H), 1.41–1.20 (m, 8 H), 0.88 (t, J = 7.0 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 167.7, 164.7, 152.2, 133.3, 126.5, 125.5, 121.8, 110.4, 108.4, 60.3, 31.9, 29.4, 29.1, 28.4, 28.1, 22.7, 21.6, 14.6, 14.2.
GC-MS (EI): m/z (%) = 302 (43) [M+], 257 (9), 218 (19), 189 (100), 145 (22), 115 (16).
Anal. Calcd for C19H26O3 (302.41): C, 75.46; H, 8.67. Found: C, 75.50; H, 8.69.
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Ethyl 2-(3-Cyanopropyl)-5-methylbenzofuran-3-carboxylate (3c)
Orange solid; yield: 138 mg (51%); mp 40–42 °C.
IR (neat): 2247, 1706, 1591, 1461, 1377, 1244, 1146, 1078, 1036, 801, 789 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.76 (s, 1 H), 7.32 (d, J = 8.4 Hz, 1 H), 7.12 (dd, J = 8.4, 1.4 Hz, 1 H), 4.42 (q, J = 7.1 Hz, 2 H), 3.32 (t, J = 7.3 Hz, 2 H), 2.46 (s, 3 H), 2.43 (t, J = 7.3 Hz, 2 H), 2.11–2.08 (m, 2 H), 1.46 (t, J = 7.1 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 164.3, 164.1, 152.3, 133.7, 126.1, 126.0, 121.9, 119.2, 110.6, 109.7, 60.6, 27.1, 24.0, 21.6, 16.8, 14.5.
GC-MS (EI): m/z (%) = 271 (52) [M+], 226 (41), 225 (64), 202 (29), 185 (100), 189 (32), 115 (25).
Anal. Calcd for C16H17NO3 (271.32): C, 70.83; H, 6.32; N, 5.16. Found: C, 70.80; H, 6.30; N, 5.14.
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Ethyl 4,6-Dimethyl-2-pentylbenzofuran-3-carboxylate (3d)
Orange oil; yield: 173 mg (60%).
IR (neat): 1718, 1572, 1374, 1196, 1065, 1047, 834, 598 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.08 (s, 1 H), 6.88 (s, 1 H), 4.38 (q, J = 7.1 Hz, 2 H), 3.06–2.99 (m, 2 H), 2.62 (s, 3 H), 2.40 (s, 3 H), 1.81–1.68 (m, 2 H), 1.46–1.30 (m, 4 H), 1.41 (t, J = 7.2 Hz, 3 H), 0.90 (t, J = 7.1 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 165.0, 164.9, 154.5, 134.5, 131.7, 127.3, 122.3, 110.1, 108.9, 60.6, 31.6, 28.4, 28.0, 22.5, 21.5, 21.4, 14.5, 14.1.
GC-MS (EI): m/z (%) = 288 (100) [M+], 231 (49), 203 (98), 187 (20), 159 (35), 119 (15).
Anal. Calcd for C18H24O3 (288.39): C, 74.97; H, 8.39. Found: C, 75.00; H, 8.37.
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Ethyl 2-Pentyl-6-propylbenzofuran-3-carboxylate (3e)
Yellow oil; yield: 187 mg (62%).
IR (neat): 1712, 1591, 1534, 1376, 1180, 1103, 1052, 824 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.0 Hz, 1 H), 7.24 (s, 1 H), 7.12 (dd, J = 8.0, 1.1 Hz, 1 H), 4.40 (q, J = 7.1 Hz, 2 H), 3.18–3.12 (m, 2 H), 2.72–2.65 (m, 2 H), 1.83–1.60 (m, 4 H), 1.44 (t, J = 7.1 Hz, 3 H), 1.41–1.31 (m, 4 H), 0.95 (t, J = 7.3 Hz, 3 H), 0.90 (t, J = 7.0 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 167.2, 164.7, 154.1, 139.6, 124.6, 124.1, 121.4, 110.6, 108.6, 60.3, 38.2, 31.6, 28.2, 27.8, 25.0, 22.5, 14.6, 14.1, 13.9.
GC-MS (EI): m/z (%) = 302 (100) [M+], 273 (78), 245 (31), 217 (80), 187 (11).
Anal. Calcd for C19H26O3 (302.41): C, 75.46; H, 8.67. Found: C, 75.42; H, 8.70.
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Ethyl 2-Ethylnaphtho[2,1-b]furan-1-carboxylate (3f)
Orang waxy solid; yield: 188 mg (70%).
IR (neat): 1711, 1414, 1387, 1314, 1265, 1174, 1154, 1093, 1031, 802, 771, 746, 420 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.17 (d, J = 8.0 Hz, 1 H), 7.93 (d, J = 8.1 Hz, 1 H), 7.74 (d, J = 8.9 Hz, 1 H), 7.64–7.57 (m, 2 H), 7.53–7.47 (m, 1 H), 4.52 (q, J = 7.1 Hz, 2 H), 3.19 (q, J = 7.5 Hz, 2 H), 1.49 (t, J = 7.1 Hz, 3 H), 1.41 (t, J = 7.5 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 166.0, 165.2, 151.6, 131.4, 128.8, 128.0, 126.4, 126.3, 126.0, 124.7, 120.5, 111.8, 111.0, 61.0, 22.6, 14.4, 12.7.
GC-MS (EI): m/z (%) = 268 (100) [M+], 239 (46), 221 (78), 194 (27), 165 (30), 152 (26).
Anal. Calcd for C17H16O3 (268.31): C, 76.10; H, 6.01. Found: C, 76.13; H, 5.99.
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Methyl 2-(3-Acetoxypropyl)naphtho[2,1-b]furan-1-carboxylate (3g)
Orange solid; yield: 232 mg (71%); mp 62–64 °C.
IR (neat): 1732, 1710, 1436, 1389, 1244, 1101, 1030, 822, 773, 755 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.09 (d, J = 8.6 Hz, 1 H), 7.92 (d, J = 8.1 Hz, 1 H), 7.75 (d, J = 8.9 Hz, 1 H), 7.63–7.56 (m, 2 H), 7.54–7.46 (m, 1 H), 4.18 (t, J = 6.4 Hz, 2 H), 4.03 (s, 3 H), 3.24 (t, J = 7.5 Hz, 2 H), 2.21–2.11 (m, 2 H), 2.02 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 171.2, 165.4, 163.6, 151.8, 131.4, 128.9, 127.9, 126.8, 126.5, 125.9, 124.9, 120.3, 111.9, 111.8, 63.8, 52.0, 27.4, 25.8, 21.0.
GC-MS (EI): m/z (%) = 326 (50) [M+], 266 (100), 152 (49), 234 (26), 207 (23), 152 (22), 43 (15).
Anal. Calcd for C19H18O5 (326.35): C, 69.93; H, 5.56. Found: C, 69.96; H, 5.58.
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Methyl 2-Methyl-5-phenylbenzofuran-3-carboxylate (3h)
Yellow waxy solid; yield: 205 mg (77%).
IR (neat): 1709, 1594, 1460, 1437, 1170, 1084, 761, 699, 594 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.18 (s, 1 H), 7.67 (d, J = 8.2 Hz, 2 H), 7.55–7.45 (m, 4 H), 7.41–7.35 (m, 1 H), 3.99 (s, 3 H), 2.82 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 164.9, 164.3, 153.3, 141.6, 137.5, 129.1, 128.7, 127.6, 127.0, 124.0, 120.3, 110.9, 109.1, 51.4, 14.5.
GC-MS (EI): m/z (%) = 266 (100) [M+], 251 (26), 235 (43), 206 (15), 178 (29), 152 (12).
Anal. Calcd for C17H14O3 (266.30): C, 76.68; H, 5.30. Found: C, 76.72; H, 5.28.
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Butyl 2-Methyl-5-phenylbenzofuran-3-carboxylate (3i)
Yellow solid; yield: 271 mg (88%); mp 47–49 °C.
IR (neat): 1710, 1599, 1461, 1200, 1173, 1084, 761, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.20 (s, 1 H), 7.65 (d, J = 8.3 Hz, 2 H), 7.55–7.43 (m, 4 H), 7.40–7.32 (m, 1 H), 4.39 (t, J = 6.5 Hz, 2 H), 2.80 (s, 3 H), 1.87–1.76 (m, 2 H), 1.63–1.50 (m, 2 H), 1.03 (t, J = 7.4 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 164.6, 164.2, 153.2, 141.5, 137.3, 128.8, 127.4, 127.0, 126.8, 123.8, 120.3, 110.9, 109.3, 64.2, 30.9, 19.5, 14.5, 13.8.
GC-MS (EI): m/z (%) = 308 (74) [M+], 252 (100), 207 (40), 178 (32), 73 (26).
Anal. Calcd for C20H20O3 (308.38): C, 77.90; H, 6.54. Found: C, 77.93; H, 6.56.
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Ethyl 5-Ethyl-2-phenylbenzofuran-3-carboxylate (3j)
Orange oil; yield: 153 mg (52%).
IR (neat): 1713, 1469, 1445, 1225, 1089, 1043, 766, 690 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.05–7.99 (m, 2 H), 7.91 (br s, 1 H), 7.54–7.41 (m, 4 H), 7.21 (dd, J = 8.4, 1.6 Hz, 1 H), 4.43 (q, J = 7.1 Hz, 2 H), 2.81 (q, J = 7.6 Hz, 2 H), 1.42 (t, J = 7.1 Hz, 3 H), 1.33 (t, J = 7.6 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 164.3, 160.9, 152.5, 140.3, 130.2, 129.9, 129.6, 128.1, 127.3, 125.6, 121.3, 110.9, 108.9, 60.7, 29.2, 16.4, 14.4.
GC-MS (EI): m/z (%) = 294 (100) [M+], 279 (32), 249 (40), 207 (15), 178 (20).
Anal. Calcd for C19H18O3 (294.35): C, 77.53; H, 6.16. Found: C, 77.50; H, 6.14.
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Butyl 5-Ethyl-2-(3-phenylpropyl)benzofuran-3-carboxylate (3k)
Orange oil; yield: 288 mg (79%).
IR (neat): 1708, 1588, 1470, 1455, 1240, 1147, 1066, 811, 733, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.81 (s, 1 H), 7.37–7.06 (m, 7 H), 4.35 (t, J = 6.6 Hz, 2 H), 3.26–3.19 (m, 2 H), 2.81–2.69 (m, 4 H), 2.16–2.06 (m, 2 H), 1.83–1.73 (m, 2 H), 1.58–1.47 (m, 2 H), 1.30 (t, J = 7.6 Hz, 3 H), 1.02 (t, J = 7.4 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 167.0, 164.7, 152.4, 141.8, 140.0, 128.6, 128.5, 126.5, 126.0, 124.6, 120.7, 110.6, 108.9, 64.2, 35.7, 31.0, 29.7, 29.1, 28.1, 19.6, 16.4, 13.9.
GC-MS (EI): m/z (%) = 364 (50) [M+], 290 (93), 260 (100), 217 (68), 204 (90), 159 (50), 91 (69).
Anal. Calcd for C24H28O3 (364.49): C, 79.09; H, 7.74. Found: C, 79.12; H, 7.11.
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Ethyl 2-Phenethyl-6-propylbenzofuran-3-carboxylate (3l)
Orange waxy solid; yield: 212 mg (63%).
IR (neat): 1709, 1591, 1495, 1237, 1181, 1060, 822, 697 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.0 Hz, 1 H), 7.34–7.18 (m, 6 H), 7.15 (d, J = 8.0 Hz, 1 H), 4.40 (q, J = 7.3 Hz, 2 H), 3.51–3.45 (m, 2 H), 3.13–3.05 (m, 2 H), 2.75–2.68 (m, 2 H), 1.76–1.64 (m, 2 H), 1.44 (t, J = 7.2 Hz, 3 H), 0.97 (t, J = 7.3 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 165.6, 164.5, 154.2, 140.9, 139.9, 128.6, 128.5, 126.3, 124.8, 124.0, 121.5, 110.6, 109.0, 60.3, 38.2, 34.3, 30.4, 25.0, 14.6, 13.9.
GC-MS (EI): m/z (%) = 336 (23) [M+], 290 (13), 245 (100), 217 (48), 188 (10), 91 (13).
Anal. Calcd for C22H24O3 (336.43): C, 78.54; H, 7.19. Found: C, 78.57; H, 7.21.
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Ethyl 2-Ethyl-6-methoxybenzofuran-3-carboxylate (3m)
Pale yellow waxy solid; yield: 102 mg (41%).
IR (neat): 1701, 1625, 1591, 1496, 1272, 1222, 1146, 1105, 1094, 1024, 816, 580 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.6 Hz, 1 H), 6.98 (s, 1 H), 6.92 (d, J = 8.6 Hz, 1 H), 4.39 (q, J = 7.1 Hz, 2 H), 3.85 (s, 3 H), 3.16 (q, J = 7.6 Hz, 2 H), 1.43 (t, J = 7.1 Hz, 3 H), 1.33 (t, J = 7.6 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 167.5, 158.0, 154.6, 122.1, 119.6, 112.5, 108.1, 95.8, 60.3, 55.9, 35.6, 21.8, 14.6, 12.3.
GC-MS (EI): m/z (%) = 248 (72) [M+], 233 (10), 219 (100), 205 (32), 175 (9), 159 (9).
Anal. Calcd for C14H16O4 (248.28): C, 67.73; H, 6.50. Found: C, 67.70; H, 6.48.
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Ethyl 5-Chloro-2-ethylbenzofuran-3-carboxylate (3n)
Yellow oil; yield: 99 mg (39%).
IR (neat): 1696, 1612, 1580, 1444, 1220, 1169, 1039, 809, 707, 588 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 2.2 Hz, 1 H), 7.34 (d, J = 8.7 Hz, 1 H), 7.23 (dd, J = 8.7, 2.2 Hz, 1 H), 4.41 (q, J = 7.2 Hz, 2 H), 3.19 (q, J = 7.6 Hz, 2 H), 1.44 (t, J = 7.2 Hz, 3 H), 1.34 (t, J = 7.6 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 169.8, 164.0, 152.1, 129.6, 127.8, 124.6, 121.7, 112.0, 108.0, 60.6, 21.9, 14.6, 12.1.
GC-MS (EI): m/z (%) = 254 (21) [M + 2+], 252 (65) [M+], 223 (100), 207 (61), 189.
Anal. Calcd for C13H13ClO3 (252.69): C, 61.79; H, 5.19. Found: C, 61.83; H, 5.22.
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Ethyl 2-Ethyl-5-(3-methoxy-3-oxopropyl)benzofuran-3-carboxylate (3o)
Yellow oil; yield: 201 mg (66%).
IR (neat): 1736, 1708, 1589, 1469, 1454, 1244, 1146, 1040, 807, 789 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 1.8 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 1 H), 7.11 (dd, J = 8.4, 1.8 Hz, 1 H), 4.41 (q, J = 7.1 Hz, 2 H), 3.67 (s, 3 H), 3.18 (q, J = 7.6 Hz, 2 H), 3.05 (t, J = 7.8 Hz, 2 H), 2.70–2.63 (m, 2 H), 1.44 (t, J = 7.1 Hz, 3 H), 1.33 (t, J = 7.6 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 173.5, 168.8, 164.5, 152.5, 136.2, 126.7, 124.8, 121.3, 110.8, 108.0, 60.3, 51.7, 36.5, 31.2, 21.9, 14.6, 12.2.
GC-MS (EI): m/z (%) = 304 (29) [M+], 258 (100), 226 (52), 201 (50), 157 (21), 128 (19).
Anal. Calcd for C17H20O5 (304.34): C, 67.09; H, 6.62. Found: C, 67.12; H, 6.60.
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Ethyl 5-(3-Methoxy-3-oxopropyl)-2-phenethylbenzofuran-3-carboxylate (3p)
Yellow solid; yield: 232 mg (61%); mp 50–52 °C.
IR (neat): 1723, 1697, 1583, 1454, 1441, 1382, 1227, 1137, 1056, 787, 754, 607, 596 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 1.8 Hz, 1 H), 7.36 (d, J = 8.4 Hz, 1 H), 7.31–7.17 (m, 5 H), 7.13 (dd, J = 8.4, 1.8 Hz, 1 H), 4.40 (q, J = 7.1 Hz, 2 H), 3.68 (s, 3 H), 3.50–3.42 (m, 2 H), 3.11–3.02 (m, 4 H), 2.71–2.64 (m, 2 H), 1.44 (t, J = 7.1 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 173.5, 166.4, 164.4, 152.6, 140.8, 136.3, 128.6, 128.5, 126.6, 126.4, 125.0, 121.4, 110.9, 109.0, 60.5, 51.8, 36.5, 34.3, 31.2, 30.5, 14.6.
GC-MS (EI): m/z (%) = 380 (21) [M+], 334 (59), 289 (100), 261 (22), 187 (35), 91 (26).
Anal. Calcd for C23H24O5 (380.44): C, 72.61; H, 6.36. Found: C, 72.58; H, 6.34.
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Conflict of Interest
The authors declare no conflict of interest.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2367-1877.
- Supporting Information
-
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Corresponding Author
Publication History
Received: 07 May 2024
Accepted after revision: 16 July 2024
Accepted Manuscript online:
16 July 2024
Article published online:
05 August 2024
© 2024. Thieme. All rights reserved
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-
References
- 1a Ballini R, Gabrielli S, Palmieri A. Curr. Org. Chem. 2010; 14: 65
- 1b Gabrielli S, Chiurchiù E, Palmieri A. Adv. Synth. Catal. 2019; 36: 630
- 2a Palmieri A, Gabrielli S, Lanari D, Vaccaro L, Ballini R. Adv. Synth. Catal. 2011; 353: 1425
- 2b Chiurchiù E, Patehebieke Y, Gabrielli S, Ballini R, Palmieri A. Adv. Synth. Catal. 2019; 361: 2042
- 2c Palmieri A. Eur. J. Org. Chem. 2020; 4247
- 2d Zeng H.-W, Wu P.-Y, Wu H.-L. Org. Biomol. Chem. 2020; 18: 2991
- 3a Hiremathad A, Patil MR, Chetana KR, Chand K, Santos MA, Keri RS. RSC Adv. 2015; 5: 96809
- 3b Shamsuzzaman HK. Eur. J. Med. Chem. 2015; 97: 483
- 3c Miao Y.-H, Hu Y.-H, Yang J, Liu T, Sun J, Wang X.-J. RSC Adv. 2019; 9: 27510
- 3d Arce-Ramos L, Castillo J.-C, Becerra D. Pharmaceuticals 2023; 16: 1265
- 4a Horton DA, Bourne GT, Smythe ML. Chem. Rev. 2003; 103: 893
- 4b Welsch ME, Snyder SA, Stockwell BR. Curr. Opin. Chem. Biol. 2010; 14: 347
- 4c Patel P, Shakya R, Vishakha, Asati V, Kurmi BD, Verma SK, Gupta GD, Rajak H. J. Mol. Struct. 2024; 1299: 137098
- 5a Pieters L, Van Dyck S, Gao M, Bai R, Hamel E, Vlietinck A, Lemière G. J. Med. Chem. 1999; 42: 5475
- 5b Chen Y, Chen S, Lu X, Cheng H, Ou Y, Cheng H, Zhou G.-C. Bioorg. Med. Chem. Lett. 2009; 19: 1851
- 5c Ryu C.-K, Song AL, Lee JY, Hong JA, Yoon JH, Kim A. Bioorg. Med. Chem. Lett. 2010; 20: 6777
- 5d Thévenin M, Thoret S, Grellier P, Dubois J. Bioorg. Med. Chem. 2013; 21: 4885
- 5e Yadav P, Singh P, Tewari AK. Bioorg. Med. Chem. Lett. 2014; 24: 2251
- 6a Liu Y, Wang H, Wan J.-P. J. Org. Chem. 2014; 79: 10599
- 6b Wan J.-P, Wang H, Liu Y, Ding H. Org. Lett. 2014; 16: 5160
- 6c Qin Z, Liu W, Wang D, He Z. J. Org. Chem. 2016; 81: 4690
- 6d Kang B, Lee MH, Kim M, Hwang J, Kim HB, Chi DY. J. Org. Chem. 2015; 80: 8254
- 6e Rahaman M, Hossain MM. Org. Synth. 2019; 96: 98
- 6f Sun P, Gao S, Yang С, Guo S, Lin A, Yao Н. Org. Lett. 2016; 18: 6464
- 6g Qin L, Vo D.-D, Nakhai A, Andersson CD, Elofsson M. ACS Comb. Sci. 2017; 19: 370
- 6h Sha Q, Liu H, Li Y. Adv. Synth. Catal. 2019; 361: 1627
- 6i Litvinova VA, Tikomirov AS. Chem. Heterocycl. Compd. 2019; 55: 689
- 7 Kundu D, Samim M, Majee A, Hajira A. Chem. Asian J. 2011; 6: 406
- 8 Revial G, Lim S, Viossat B, Lemoine P, Tomas A, Duprat AF, Pfau M. J. Org. Chem. 2000; 65: 4593
- 9a Ballini R, Fiorini D, Palmieri A. Tetrahedron Lett. 2004; 45: 7027
- 9b Palmieri A, Gabrielli S, Ballini R. Green Chem. 2013; 15: 2344
