Benzoxazole-Directed Halogen Dance of Bromofuran

Abstract

A halogen dance of a benzoxazole-conjugated bromofuran derived from furfural is described. The reaction proceeds through a benzoxazole-directed lithiation to provide the α-lithiofuran, which is subjected to Negishi coupling to give α-arylated benzoxazole-conjugated furan derivatives. The synthetic utility of the reaction was demonstrated by transformation of the residual bromo group into a side chain bearing a siloxane moiety, which resulted in a significant improvement in solubility in organic solvents.

Key words

halogen dance - one-pot reaction - cross-coupling - Negishi coupling - furan - oxazole

• References and Notes

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• 8 2-(5-Bromo-2-furyl)-1,3-benzoxazole (1) A flame-dried 500 mL Schlenk tube equipped with a Teflon-coated magnetic stirrer bar and a rubber septum was charged with furfural (4.97 mL, 60 mmol, 1.0 equiv), 2-aminophenol (7.20 g, 66 mmol, 1.1 equiv), TEMPO (469 mg, 3.0 mmol, 5 mol%), and anhyd xylenes (150 mL).^7a The Schlenk tube was flushed with O₂ gas and then the mixture was heated at 120 °C for 18 h. The resulting dark-red mixture was treated with H₂O, and the mixture was partitioned with Et₂O. The organic layer was washed with H₂O, dried (Na₂SO₄), and filtered. The filtrate was concentrated under reduced pressure to give a crude material that was purified by column chromatography [silica gel, hexane–Et₂O (10:1)] to give 2-(2-furyl)-1,3-benzoxazole as a yellow solid; yield: 10.3 g (55.6 mmol, 93%). A 30 mL test tube equipped with a Teflon-coated magnetic stirrer bar was charged with 2-(2-furyl)-1,3-benzoxazole (559 mg, 3.0 mmol, 1.0 equiv) and anhyd THF (3.0 mL). NBS (587 mg, 3.3 mmol, 1.1 equiv) was then added in a portionwise manner at r.t., and the mixture was stirred at 60 °C for 2 h. Additional NBS (161 mg, 0.90 mmol, 0.3 equiv) was then added and the mixture was stirred at 60 °C for a further 2 h, until the substrate was consumed (TLC). The reaction was quenched with sat. aq NH₄Cl, and the resulting mixture was partitioned with Et₂O. The organic layer was washed with sat. aq NH₄Cl, dried (Na₂SO₄), and filtered. The filtrate was concentrated under reduced pressure to give a crude material that was purified by column chromatography [silica gel, hexane–Et₂O (5:1)] to give a beige solid; yield: 650 mg (2.45 mmol, 82%). The ¹H NMR spectrum of the product was identical to the reported spectrum;^7b mp 98–99 °C; R_f  = 0.30 (hexane–Et₂O, 5:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.79–7.73 (m, 1 H), 7.59–7.53 (m, 1 H), 7.40–7.34 (m, 2 H), 7.22 (d, J = 3.4 Hz, 1 H), 6.56 (d, J = 3.4 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 154.1, 150.0, 144.2, 141.5, 126.6, 125.5, 125.0, 120.2, 116.3, 114.2, 110.6.
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• 13 2-(2-Bromo-2-furyl)-1,3-benzoxazole (2): Typical Procedure A flame-dried 20 mL Schlenk tube equipped with a Teflon-coated magnetic stirrer bar and a rubber septum was charged with bromofuran 1 (132 mg, 0.50 mmol, 1.0 equiv) and anhyd THF (3.3 mL), and the solution was cooled to –50 °C. A 1.5 M soln of LDA in THF–ethylbenzene–heptane (0.40 mL, 0.60 mmol, 1.2 equiv) was added dropwise to the Schlenk tube, and the resulting mixture was stirred at –50 °C for 1 h. The resulting dark-red mixture was then treated with H₂O (5 mL). After partitioning, the aqueous layer was extracted with Et₂O (2 × 5 mL). The combined organic extracts were washed with H₂O, dried (Na₂SO₄), and filtered. The filtrate was concentrated under reduced pressure to give a crude material that was purified by column chromatography [silica gel, hexane–Et₂O (10:1 to 5:1, gradient)] to give a colorless solid; yield: 83.8 mg (0.317 mmol, 64%); mp 86–87 °C (hexane); R_f  = 0.33 (hexane–Et₂O, 5:1). IR (ATR): 2959, 2927, 1536, 1450, 1261, 1241, 1087, 1052, 1029, 1005, 977, 883, 797, 756, 744 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.85–7.80 (m, 1 H), 7.64–7.58 (m, 2 H), 7.43–7.35 (m, 2 H), 6.71 (d, J = 2.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 154.3, 150.1, 145.6, 141.5, 139.9, 125.8, 125.1, 120.6, 117.1, 110.9, 104.6. HRMS (DART⁺): m/z [M + H]⁺ calcd for C₁₁H₇ ⁷⁹BrNO₂: 263.9660; found: 263.9657
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• 17 Freshly prepared Pd(PPh₃)₄ was used.
• 18 2-[3-Bromo-5-(4-methoxyphenyl)-2-furyl]-1,3-benzoxazole (5a); Typical Procedure A flame-dried 20 mL Schlenk tube equipped with a Teflon-coated magnetic stirrer bar and a rubber septum was charged with bromofuran 1 (132 mg, 0.50 mmol, 1.0 equiv) and anhyd THF (3.3 mL), and the solution was cooled to –50 °C. A 1.5 M soln of LDA in THF–ethylbenzene–heptane (0.40 mL, 0.60 mmol, 1.2 equiv) was added to the Schlenk tube, and the resulting mixture was stirred at –50 °C for 1 h. The dark-red solution was treated by addition of ZnCl₂·TMEDA complex (151.5 mg, 0.60 mmol, 1.2 equiv) at –50 °C, and stirred at r.t. for 15 min. p-Iodoanisole (140.4 mg, 0.60 mmol, 1.2 equiv) and Pd(PPh₃)₄ (28.9 mg, 25 μmol, 5 mol%) were added to the solution, and the resulting mixture was heated at 60 °C for 18 h. The mixture was then treated with sat. aq NH₄Cl (5 mL). After partitioning, the aqueous layer was extracted with Et₂O (2 × 5 mL). The combined organic extracts were washed with H₂O and filtered. The filtrate was concentrated under reduced pressure to give a crude material that was purified by column chromatography [silica gel, hexane–Et₂O (10:1)] to give a yellow solid; yield: 111.6 mg (0.301 mmol, 60%); mp 140–142 °C; R_f  = 0.19 (hexane–Et₂O, 5:1). IR (ATR): 1632, 1613, 1590, 1503, 1463, 1449, 1291, 1247, 1173, 1124, 1056, 1033, 1003, 920, 819, 801, 780, 735 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.87–7.81 (m, 1 H), 7.76 (d, J = 9.2 Hz, 2 H), 7.65–7.59 (m, 1 H), 7.41–7.34 (m, 2 H), 6.98 (d, J = 9.2 Hz, 2 H), 6.80 (s, 1 H), 3.87 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 160.6, 156.8, 154.5, 150.0, 141.7, 138.0, 126.4, 125.4, 124.9, 121.3, 120.3, 114.4, 110.7, 110.2, 106.7, 55.4. HRMS (DART⁺): m/z [M + H]⁺ calcd for C₁₈H₁₃ ⁷⁹BrNO₃: 370.0079; found: 370.0066.
• 19 2-[3-Allyl-5-(4-methoxyphenyl)-2-furyl]-1,3-benzoxazole (6a) A flame-dried 20 mL Schlenk tube equipped with a Teflon-coated magnetic stirrer bar and a rubber septum was charged with bromofuran 5a (105.1 mg, 0.284 mmol) and anhyd THF (1.4 mL). A 1.64 M soln of BuLi in hexane (208 μL, 0.341 mmol) was then added dropwise at –78 °C, and the mixture was stirred at –78 °C for 30 min. Allyl bromide (49 μL, 0.57 mmol) was added to the resulting solution at –78 °C, and the mixture was stirred at –78 °C for 30 min, then warmed to r.t. and stirred for 2 h. The resulting mixture was treated with sat. aq NH₄Cl (3 mL) then partitioned between Et₂O (3 mL) and sat. aq NH₄Cl. The aqueous layer was extracted with Et₂O (2 × 3 mL), and the combined organic extracts were washed with H₂O, dried ­(Na₂SO₄), and filtered. The filtrate was concentrated under reduced pressure to give a crude material that was purified by column chromatography [silica gel, hexane–Et₂O (10:1)] to give a yellow solid; yield: 51.6 mg (0.156 mmol, 55%); mp 93–95 °C; R_f  = 0.33 (hexane–Et₂O, 5:1). IR (ATR): 1628, 1612, 1562, 1532, 1511, 1491, 1453, 1303, 1252, 1244, 1175, 1032, 930, 919, 833, 805, 772, 745, 633 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.81–7.75 (m, 3 H), 7.60–7.56 (m, 1 H), 7.39–7.31 (m, 2 H), 6.96 (d, J = 9.2 Hz, 2 H), 6.64 (s, 1 H), 6.07 (ddt, J = 16.8, 10.0, 6.4 Hz, 1 H), 5.25 (dtd, J = 16.8, 2.0, 1.6 Hz, 1 H), 5.16 (dtd, J = 10.0, 2.0, 1.6 Hz, 1 H), 3.86 (s, 3 H), 3.81 (d, J = 6.4 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 160.2, 156.4, 156.2, 150.0, 142.0, 137.0, 135.6, 131.9, 126.4, 124.82, 124.79, 122.6, 119.9, 116.7, 114.4, 110.5, 108.0, 55.5, 30.2. HRMS (DART⁺): m/z [M + H]⁺ calcd for C₂₁H₁₈NO₃: 332.1287; found: 332.1302.
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• 21 2-{5-(4-Methoxyphenyl)-3-[3-(pentamethyldisiloxanyl)propyl]-2-furyl}-1,3-benzoxazole (7a) A 10-mL screw-top test tube equipped with a Teflon-coated magnetic stirrer bar was charged with terminal alkene 6a (33.1 mg, 0.10 mmol), disiloxane (24 μL, 0.12 mmol), and anhyd THF (0.50 mL). To the solution was added a 2 wt% solution of Karstedt catalyst [(1,1,3,3-tetramethyl-1,3-divinyldisiloxane)platinum(0)] [Pt(dvds)] in xylene (Aldrich; 2.2 μL, 0.1 μmol, 0.1 mol%) at r.t., and the mixture was stirred at r.t. for 24 h. The resulting mixture was then treated with H₂O. The mixture was partitioned between Et₂O (2 mL) and H₂O (2 mL) three times. The combined organic extracts were dried (Na₂SO₄) and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, 100% hexane to hexane–Et₂O (5:1)] to afford a pale-yellow oil; yield: 33.2 mg (0.069 mmol, 69%); R_f  = 0.40 (hexane–Et₂O, 5:1); IR (ATR): 2956, 1613, 1563, 1532, 1492, 1453, 1251, 1175, 1036, 839, 804, 758, 745, 689, 667, 624 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.82–7.75 (m, 3 H), 7.60–7.53 (m, 1 H), 7.37–7.29 (m, 2 H), 6.96 (d, J = 8.8 Hz, 2 H), 6.63 (s, 1 H), 3.86 (s, 3 H), 3.03 (t, J = 7.6 Hz, 2 H), 1.81–1.72 (m, 2 H), 0.72–0.65 (m, 2 H), 0.07 (s, 6 H), 0.05 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 160.1, 156.5, 156.2, 150.0, 142.1, 137.1, 134.5, 126.3, 124.7, 124.6, 122.8, 119.9, 114.3, 110.4, 107.9, 55.5, 29.2, 23.8, 18.4, 2.1, 0.5. HRMS (DART⁺): m/z [M + H]⁺ calcd for C₂₆H₃₄NO₄Si₂: 480.2026; found: 480.2025.
• 22 For details, see the Supporting Information.