Sequential C–C, C–O, and C–N Bond-Forming Reaction of Methyl (–)-3-Dehydroshikimate, Malononitrile, and Bromoalkanes: Simple Synthesis of 2-(Alkylamino)-3-cyanobenzofurans from a Biomass-Derived Substrate

Abstract

An interesting and simple method was developed for the synthesis of 2-(alkylamino)-3-cyanobenzofurans by consecutive C–C, C–O, and C–N coupling reaction of methyl (–)-3-dehydroshikimate with malononitrile and a bromoalkane or dibromoalkane under microwave conditions. This process represents a metal-free sustainable strategy for the construction of 2-(alkylamino)-3-cyanobenzofurans from a biomass-derived starting material.

Key words

benzofurans - coupling - nitriles - bromoalkanes - cascade reaction - green-chemistry

• References and Notes

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• 18 Methyl 2-(Alkylamino)-3-cyanobenzofuran-5-carboxylates 4a–j and 7a–g; General Procedure A 25 mL round-bottomed flask was charged with 3-MDHS (1; 0.19 g, 1 mmol), malononitrile (2; 1.5 mmol), and H₂O (10 mL). The flask was placed in a microwave synthesizer, and the mixture was irradiated (240 W) at 85 °C for 10 min. The mixture was then filtered under reduced pressure to give the crude intermediate A, which was used in step 2 without further purification. Intermediate A, inorganic base [NaHCO₃ (2 mmol) for 4a–j; K₂CO₃ (2 mmol) for 7a–g], bromoalkane 3 [monobromoalkane (2 mmol) for 4a–4; dibromoalkane for 7a–g], and DMSO (8 mL) were added to a flask and irradiated (240 W) at 120 °C for 5 min then cooled. The mixture was then poured into brine (40 mL), extracted with EtOAc (3 × 20 mL), and dried (MgSO₄). The organic layer was concentrated and the residue was purified by column chromatography (silica gel, EtOAc–PE). Methyl 3-Cyano-2-(ethylamino)-1-benzofuran-5-carboxylate (4a) Light-yellow solid; yield: 82%; mp 189–190 °C. IR (KBr): 3442, 3288, 3058, 2972, 2206, 1728, 1712, 1645, 1533, 1448, 1344, 1294, 1248, 1184, 1107, 997, 958, 885, 762, 729, 654, 584 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.93 (t, J = 5.60 Hz, 1 H), 7.74 (d, J = 1.60 Hz, 1 H), 7.71 (dd, J ₁ = 8.40 Hz, J ₂ = 1.60 Hz, 1 H), 7.49 (d, J = 8.40 Hz, 1 H), 3.86 (s, 3 H), 3.47 (m, 2 H), 1.25 (t, J = 4.00 Hz, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 165.9, 164.6, 150.4, 128.9, 125.8, 123.2, 116.5, 115.1, 110.0, 59.3, 52.1, 37.1, 14.8. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₃H₁₃N₂O₃: 245.0921; found: 245.0923. Methyl 3-Cyano-2-(propylamino)-1-benzofuran-5-carboxylate (4c) White solid; yield: 70%; mp 168–169 °C. IR (KBr): 3435, 3288, 3047, 2980, 2200, 1703, 1628, 1531, 1450, 1288, 1250, 1176, 1165, 1101, 976, 766, 731, 644, 600 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.89 (d, J = 8.40 Hz, 1 H), 7.75 (s, 1 H), 7.71 (dd, J ₁ = 8.40 Hz, J ₂ = 1.20 Hz, 1 H), 7.50 (d, J = 8.40 Hz, 1 H), 4.05 (m, 1 H), 3.86 (s, 3 H), 1.27 (d, J = 8.00 Hz, 6 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 166.0, 163.9, 150.5, 129.0, 125.9, 123.3, 116.5, 115.2, 110.0, 59.3, 52.2, 45.0, 22.6. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₄H₁₅N₂O₃: 259.1077; found: 259.1074. Methyl 2-(sec-Butylamino)-3-cyano-1-benzofuran-5-carboxylate (4e) White needles; yield: 83%; mp 142–143 °C. IR (KBr): 3427, 3278, 3224, 3095, 2964, 2214, 1714, 1649, 1460, 1298, 1246, 1184, 1082, 991, 899, 822, 764, 656 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.86 (d, J = 8.80 Hz, 1 H), 7.74 (d, J = 1.60 Hz, 1 H), 7.71 (dd, J ₁ = 8.80 Hz, J ₂ = 2.00 Hz, 1 H), 7.49 (d, J = 8.40 Hz, 1 H), 3.86 (s, 3 H), 3.82 (m, 1 H), 1.61 (m, 2 H), 1.25 (d, J = 6.40 Hz, 3 H), 0.92 (t, J = 7.60 Hz, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 166.0, 164.2, 150.4, 129.1, 125.9, 123.3, 116.5, 115.3, 110.0, 59.1, 52.2, 50.6, 29.0, 20.4, 10.3. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₅H₁₇N₂O₃: 273.1234; found: 273.1236. Methyl 3-Cyano-2-[(3-methylbutyl)amino]-1-benzofuran-5-carboxylate (4h) White needles; yield: 81%; mp 136–137 °C. IR (KBr): 3429, 3224, 3086, 2951, 2879, 2214, 1718, 1662, 1460, 1369, 1294, 1248, 1190, 1119, 1101, 991, 957, 895, 822, 764, 669, 623 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.94 (t, J = 6.00 Hz, 1 H), 7.74 (d, J = 1.20 Hz, 1 H), 7.70 (dd, J ₁ = 8.40 Hz, J ₂ = 1.60 Hz, 1 H), 7.49 (d, J = 8.40 Hz, 1 H), 3.86 (s, 3 H), 3.44 (m, 2 H), 1.69 (m, 1 H), 1.52 (m, 2 H), 0.92 (d, J = 6.40 Hz, 6 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 166.0, 164.7, 150.5, 129.0, 125.9, 123.3, 116.5, 115.2, 110.0, 59.3, 52.2, 40.7, 37.9, 25.1, 22.3. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₆H₁₉N₂O₃: 287.1396; found: 287.1397. Methyl 3-Cyano-2-[(3-hydroxypropyl)amino]-1-benzofuran-5-carboxylate (4j) Brown solid; yield: 60%; mp 150–151 °C. IR (KBr): 3469, 3286, 3242, 3084, 2947, 2881, 2202, 1713, 1651, 1456, 1363, 1302, 1244, 1190, 1144, 1099, 1063, 978, 885, 829, 760, 698, 658, 590 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.89 (t, J = 5.60 Hz, 1 H), 7.74 (d, J = 1.20 Hz, 1 H), 7.70 (dd, J ₁ = 8.40 Hz, J ₂ = 2.00 Hz, 1 H), 7.49 (d, J = 8.40 Hz, 1 H), 4.59 (s, 1 H), 3.86 (s, 3 H), 3.50 (m, 4 H), 1.78 (m, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 166.0, 164.8, 150.5, 129.0, 125.9, 123.2, 116.5, 115.2, 110.0, 59.4, 57.8, 52.2, 32.2. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₄H₁₅N₂O₄ : 275.1032; found: 275.1031. Methyl 3-Cyano-2-pyrrolidin-1-yl-1-benzofuran-5-carboxylate (7c) White needles; yield: 81%; mp 185–186 °C. IR (KBr): 3431, 3064, 2960, 2879, 2191, 1724, 1637, 1450, 1352, 1300, 1246, 1178, 1097, 960, 881, 858, 818, 764, 733, 662, 517 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.71 (d, J = 1.20 Hz, 1 H), 7.69 (dd, J ₁ = 8.40 Hz, J ₂ = 2.00 Hz, 1 H), 7.48 (d, J = 8.40 Hz, 1 H), 3.87 (s, 3 H), 3.68 (t, J = 6.00 Hz, 4 H), 2.00 (t, J = 6.40 Hz, 4 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 166.0, 161.8, 150.7, 129.3, 126.0, 123.3, 116.6, 115.8, 110.1, 60.2, 52.2, 48.1, 24.9. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₅H₁₅N₂O₃: 271.1083; found: 271.1085. Methyl 3-Cyano-2-piperidin-1-yl-1-benzofuran-5-carboxylate (7e) White crystals; yield: 87%; mp 147–148 °C. IR (KBr): 3448, 3425, 3107, 2939, 2856, 2197, 1724, 1610, 1585, 1450, 1383, 1363, 1302, 1234, 1186, 1142, 1097, 962, 851, 800, 760, 665, 609 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.76 (d, J = 1.20 Hz, 1 H), 7.73 (dd, J ₁ = 8.40 Hz, J ₂ = 1.60 Hz, 1 H), 7.50 (d, J = 8.40 Hz, 1 H), 3.87 (s, 3 H), 3.73 (s, 4 H), 1.67 (s, 6 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 165.9, 162.8, 150.2, 129.2, 126.0, 123.7, 116.7, 115.6, 110.2, 61.0, 52.2, 47.0, 24.8, 23.1. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₆H₁₇N₂O₃: 285.1239; found: 285.1238.