Selective Synthesis of 3-Methylene-2,3-dihydrofurans or 1,2,4-Trisubstituted Furans via Tandem Reactions of Allenic Ketones with α-Chloro β-Keto Esters or Ketones

Abstract

Novel and efficient synthesis of functionalized furan derivatives have been developed in this paper. Promoted by K₂CO₃, allenic ketones underwent tandem reactions with 2-chloroacetoacetate or 3-chloropentane-2,4-dione to afford 3-methylene-2,3-dihydrofurans with high efficiency under remarkably mild conditions. When the same substrates were treated with potassium carbonate and triphenylphosphine, on the other hand, 1,2,4-trisubstituted furans could be obtained in good yields.

Key words

allenic ketones - furan derivatives - phosphine catalysis - tandem reactions

• References and Notes

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• 5 Typical Procedure for the Preparation of Compounds 3aa–da,na,ab – Exemplified with 3aa (Table 1, Entry 1) To a flask containing 1-phenylbuta-2,3-dien-1-one (1a, 1 mmol) and ethyl 2-chloroacetoacetate (2, 1.1 mmol) in MeCN (3 mL) were added anhydrous K₂CO₃ (1.0 mmol). The solution was stirred at r.t. for 1 h. The reaction then was quenched with aq NH₄Cl and extracted with EtOAc (3 × 5 mL). The combined organic phases were dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography over silica gel using EtOAc–PE (1:15, v/v) as eluent to give 3aa (68%). 2-Acetyl-3-methylene-5-phenyl-2,3-dihydrofuran-2-carboxylate (3aa, Table 1, Entry 1) Eluent: EtOAc–PE (1:15), yellow oil; yield: 85%. ¹H NMR (400 MHz, CDCl₃): δ = 7.71–7.68 (m, 2 H), 7.42–7.38 (m, 3 H), 6.07 (s, 1 H), 5.18 (s, 1 H), 5.12 (s, 1 H), 4.29 (q, J = 6.8 Hz, 2 H), 2.31 (s, 3 H), 1.30 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 200.0, 166.1, 161.1, 144.7, 129.9, 129.1, 128.8, 128.6, 125.6, 104.9, 101.9, 94.1, 62.5, 25.1, 14.013. ESI-HRMS: m/z calcd for C₁₆H₁₇O₄ [M + H]⁺: 273.1127; found: 273.1137. Ethyl 2-Acetyl-5-(4-bromophenyl)-3-methylene-2,3-dihydrofuran-2-carboxylate (3ba, Table 1, Entry 2) Eluent: EtOAc–PE (1:15); yellow oil; yield: 82%. ¹H NMR (400 MHz, CDCl₃): δ = 7.54–7.53 (m, 4 H), 6.06 (s, 1 H), 5.20 (s, 1 H), 5.14 (s, 1 H), 4.28 (q, J = 7.2 Hz, 2 H), 2.30 (s, 3 H), 1.30 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 199.7, 166.0, 160.0, 144.3, 131.9, 128.0, 127.1, 124.0, 105.7, 102.5, 94.1, 62.7, 25.1, 14.0. ESI-HRMS: m/z calcd for C₁₆H₁₆BrO₄ [M + H]⁺: 351.0232; found: 351.0237. Ethyl 2-Acetyl-3-methylene-5-p-tolyl-2,3-dihydrofuran-2-carboxylate (3ca, Table 1, Entry 3) Eluent: EtOAc–PE (1:15); yellow oil; yield: 86%. ¹H NMR (400 MHz, CDCl₃): δ = 7.59 (d, J = 8.4 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 6.02 (s, 1 H), 5.51 (s, 1 H), 5.08 (s, 1 H), 4.29 (t, J = 6.8 Hz, 2 H), 2.38 (s, 3 H), 2.31 (s, 3 H), 1.30 (t, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 200.2, 166.2, 161.4, 144.8, 140.2, 129.3, 126.4, 125.6, 104.3, 101.1, 94.0, 62.5, 25.1, 25.5, 14.0. ESI-HRMS: m/z calcd for C₁₇H₁₉O₄ [M + H]⁺: 287.1283; found: 287.1280. Ethyl 2-Acetyl-3-methylene-5-(3-oxo-3-phenylpropyl)-2,3-dihydrofuran-2-carboxylate (3da, Table 1, Entry 4) Eluent: EtOAc–PE (1:15); yellow oil; yield: 81%. ¹H NMR (400 MHz, CDCl₃): δ = 7.31–7.27 (m, 2 H), 7.22–7.20 (m, 3 H), 5.38 (s, 1 H), 4.99 (s, 1 H), 4.95 (s, 1 H), 4.31–4.25 (m, 2 H), 2.96–2.91 (m, 2 H), 2.70–2.66 (m, 2 H), 2.23 (s, 3 H), 1.38 (t, J = 7.6 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 199.6, 166.2, 165.1, 144.6, 140.4, 128.5, 128.4, 128.3, 126.4, 103.1, 102.9, 94.1, 62.5, 32.6, 30.0, 24.9, 14.0. ESI-HRMS: m/z calcd for C₁₉H₂₁O₅ [M + H]⁺: 329.1389; found: 329.1383. 1,1′-(3-Methylene-5-phenyl-2,3-dihydrofuran-2,2-diyl)diethanone (3ab, Table 1, Entry 5) Eluent: EtOAc–PE (1:15); yellow oil; yield: 83%. ¹H NMR (400 MHz, CDCl₃): δ = 7.71–7.69 (m, 2 H), 7.44–7.42 (m, 3 H), 6.08 (s, 1 H), 5.13 (s, 1 H), 5.03 (s, 1 H), 2.31 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 199.9, 160.9, 144.0, 130.0, 129.1, 128.8, 128.7, 127.0, 125.4, 104.4, 102.3, 99.0, 25.5. ESI-HRMS: m/z calcd for C₁₅H₁₅O₃ [M + H]⁺: 243.1021; found: 243.1027. 1,1′-(3-Ethylidene-5-phenyl-2,3-dihydrofuran-2,2-diyl)diethanone (3na, Table 1, Entry 6) Eluent: EtOAc–PE (1:15); yellow oil; yield: 54%. ¹H NMR (400 MHz, CDCl₃): δ = 7.71–7.69 (m, 2 H), 7.42–7.36 (m, 3 H), 6.18 (s, 1 H), 5.51 (q, J = 7.6 Hz, 1 H), 4.31–4.23 (m, 2 H), 2.29 (s, 3 H), 1.85 (d, J = 7.2 Hz, 3 H), 1.29 (t, J = 7.6 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 200.8, 166.7, 159.6, 136.9, 129.5, 128.6, 125.4, 116.2, 98.6, 93.8, 62.4, 25.1, 15.4, 14.0. ESI-HRMS: m/z calcd for C₁₆H₁₇O₃ [M + H]⁺: 257.1178; found: 257.1183.
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• 11 Typical Procedure for the Preparation of Compounds 4aa–ma,jb–kb – Exemplified with 4aa (Table 3, Entry 1) To a flask containing 1-phenylbuta-2,3-dien-1-one (1a, 1 mmol) and triphenylphosphine (0.5 mmol) in toluene (5 mL) were added ethyl 2-chloroacetoacetate (2, 1.1 mmol) and anhydrous K₂CO₃ (1.0 mmol). The solution was stirred at r.t. for 1.5 h. The reaction then was quenched with aq NH₄Cl and extracted with EtOAc (3 × 5 mL). The combined organic phases were dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography over silica gel using EtOAc–PE (1:30, v/v) as eluent to give 4aa (65%). Ethyl 2-Methyl-5-(2-oxo-2-phenylethyl)furan-3-carboxylate (4aa, Table 3, Entry 1) Eluent: EtOAc–PE (1:30); yellow syrup; yield: 65%. ¹H NMR (400 MHz, CDCl₃): δ = 7.98 (d, J = 8.0 Hz, 2 H), 7.57 (t, J = 7.2 Hz, 1 H), 7.46 (t, J = 8.0 Hz, 1 H), 6.49 (s, 1 H), 4.24 (s, 2 H), 4.24 (q, J = 7.6 Hz, 2 H), 2.52 (s, 3 H), 1.30 (t, J = 7.6 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.6, 164.0, 158.8, 146.2, 136.0, 133.6, 128.8, 128.5, 114.5, 109.3, 60.1, 38.0, 14.4, 13.8. ESI-HRMS: m/z calcd for C₁₆H₁₇O₄ [M + H]⁺: 273.1127; found: 273.1130. Ethyl 5-[2-(4-Fluorophenyl)-2-oxoethyl]-2-methylfuran-3-carboxylate (4ba, Table 3, Entry 2) Eluent: EtOAc–PE (1:30); yellow solid; yield: 58%. ¹H NMR (400 MHz, CDCl₃): δ = 8.03–8.00 (m, 2 H), 7.313–7.308 (m, 1 H), 7.15–7.11 (m, 2 H), 6.49 (s, 1 H), 4.24 (q, J = 7.6 Hz, 2 H), 4.21 (s, 2 H), 2.52 (s, 3 H), 1.30 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 193.1, 167.2, 164.7, 164.0, 158.9, 146.0, 133.8, 133.6, 132.4, 132.4, 132.1, 131.3, 131.2, 128.8, 128.6, 128.6, 128.5, 116.0, 115.8, 114.5, 109.4, 60.1, 38.0, 14.4, 13.8. ESI-HRMS: m/z calcd for C₁₆H₁₆FO₄ [M + H]⁺: 291.1033; found: 291.1037. Ethyl 5-[2-(4-Chlorophenyl)-2-oxoethyl]-2-methylfuran-3-carboxylate (4ca, Table 3, Entry 3) Eluent: EtOAc–PE (1:30); yellow solid; yield: 52%. ¹H NMR (400 MHz, CDCl₃): δ = 7.96 (d, J = 8.8 Hz, 2 H), 7.44 (d, J = 8.8 Hz, 2 H), 6.49 (s, 1 H), 4.24 (q, J = 7.2 Hz, 2 H), 4.22 (s, 2 H), 2.52 (s, 3 H), 1.31 (t, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 193.5, 164.0, 159.0, 145.8, 140.1, 134.3, 123.0, 129.1, 114.5, 109.5, 60.1, 38.1, 14.4, 13.8. ESI-HRMS: m/z calcd for C₁₆H₁₆ClO₄ [M + H]⁺: 307.0737; found: 307.0742. Ethyl 5-[2-(4-Bromophenyl)-2-oxoethyl]-2-methylfuran-3-carboxylate (4da, Table 3, Entry 4) Eluent: EtOAc–PE (1:30); yellow solid; yield: 53%. ¹H NMR (400 MHz, CDCl₃): δ = 7.83 (d, J = 8.4 Hz, 2 H), 7.58 (d, J = 8.4 Hz, 2 H), 6.47 (s, 1 H), 4.23 (q, J = 6.8 Hz, 2 H), 4.20 (s, 2 H), 2.51 (s, 3 H), 1.29 (t, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 193.6, 163.9, 158.9, 145.8, 134.7, 132.1, 130.1, 128.8, 114.5, 109.5, 60.1, 38.0, 14.4, 13.8. ESI-HRMS: m/z calcd for C₁₆H₁₆BrO₄ [M + H]⁺: 351.0232; found: 351.0237. Ethyl 5-[2-(4-Cyanophenyl)-2-oxoethyl]-2-methylfuran-3-carboxylate (4ea, Table 3, Entry 5) Eluent: EtOAc–PE (1:10); white solid; yield: 40%. ¹H NMR (400 MHz, CDCl₃): δ = 8.08 (d, J = 8.4 Hz, 2 H), 7.79 (d, J = 8.4 Hz, 2 H), 6.51 (s, 1 H), 4.27 (s, 2 H), 4.25 (q, J = 7.2 Hz, 2 H), 2.53 (s, 3 H), 1.32 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 193.3, 163.9, 159.1, 145.0, 138.9, 132.7, 129.0, 117.8, 116.8, 114.6, 109.8, 60.2, 38.4, 14.4, 13.8. ESI-HRMS: m/z calcd for C₁₇H₁₆NO₄ [M + H]⁺: 298.1079; found: 298.1083. Ethyl 2-Methyl-5-(2-oxo-2-p-tolylethyl)furan-3-carboxylate (4fa, Table 3, Entry 6) Eluent: EtOAc–PE (1:15); white solid; yield: 82%. ¹H NMR (400 MHz, CDCl₃): δ = 7.87 (d, J = 8.2 Hz, 2 H), 7.24 (d, J = 8.0 Hz, 2 H), 6.47 (s, 1 H), 4.23 (q, J = 7.2 Hz, 2 H), 4.20 (s, 2 H), 2.51 (s, 3 H), 2.38 (s, 3 H), 1.29 (t, J = 7.6 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.3, 164.1, 158.8, 146.4, 144.5, 133.5, 129.4, 128.7, 114.4, 109.2, 60.0, 37.9, 21.7, 14.4, 13.8. ESI-HRMS: m/z calcd for C₁₇H₁₉O₄ [M + H]⁺: 287.1283; found: 287.1289. Ethyl 5-[2-(4-Methoxyphenyl)-2-oxoethyl]-2-methylfuran-3-carboxylate (4ga, Table 3, Entry 7) Eluent: EtOAc–PE (1:10); white solid; yield: 80%. ¹H NMR (400 MHz, CD₃OD and DMSO-d ₆): δ = 8.07 (d, J = 8.8 Hz, 2 H), 7.09 (d, J = 8.8 Hz, 2 H), 6.53 (s, 1 H), 4.38 (s, 2 H), 4.28 (q, J = 6.8 Hz, 2 H), 3.92 (s, 3 H), 2.55 (s, 3 H), 1.35 (t, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 193.8, 164.1, 163.8, 158.4, 148.0, 130.9, 129.1, 114.2, 114.0, 108.9, 60.0, 55.2, 37.3, 13.8, 12.3. ESI-HRMS: m/z calcd for C₁₇H₁₉O₅ [M + H]⁺: 303.1232; found: 303.1236. Ethyl 5-[2-(3-Bromophenyl)-2-oxoethyl]-2-methylfuran-3-carboxylate (4ha, Table 3, Entry 8) Eluent: EtOAc–PE (1:30); white solid; yield: 40%. ¹H NMR (400 MHz, CDCl₃): δ = 8.12 (s, 1 H), 7.91 (d, J = 7.6 Hz, 1 H), 7.71 (d, J = 8.4 Hz, 1 H), 7.36 (t, J = 8.4 Hz, 1 H), 6.50 (s, 1 H), 4.26 (q, J = 7.6 Hz, 2 H), 4.23 (s, 2 H), 2.54 (s, 3 H), 1.32 (t, J = 7.6 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 193.3, 164.0, 159.0, 145.5, 137.7, 136.4, 131.6, 130.4, 127.1, 123.1, 114.5, 109.6, 60.1, 38.1, 14.4, 13.8. ESI-HRMS: m/z calcd for C₁₆H₁₆BrO₄ [M + H]⁺: 351.0232; found: 351.0237. Ethyl 2-Methyl-5-(2-oxo-2-m-tolylethyl)furan-3-carboxylate (4ia, Table 3, Entry 9) Eluent: EtOAc–PE (1:15); yellow oil; yield: 74%. ¹H NMR (400 MHz, CDCl₃): δ = 7.79–7.77 (m, 2 H), 7.37–7.26 (m, 2 H), 6.48 (s, 1 H), 4.25 (q, J = 7.2 Hz, 2 H), 4.22 (s, 2 H), 2.53 (s, 3 H), 2.40 (s, 3 H), 1.31 (t, J = 7.6 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.7, 164.0, 158.7, 146.3, 138.6, 136.2, 134.3, 129.0, 128.6, 125.8, 114.5, 109.3, 60.0, 38.0, 21.3, 14.3, 13.7. ESI-HRMS: m/z calcd for C₁₇H₁₉O₄ [M + H]⁺: 287.1283; found: 287.1289. Ethyl 5-[2-(2-Methoxyphenyl)-2-oxoethyl]-2-methylfuran-3-carboxylate (4ja, Table 3, Entry 10) Eluent: EtOAc–PE (1:10); white solid, yield 72%. ¹H NMR (400 MHz, CDCl₃): δ = 7.73–7.71 (m, 1 H), 7.47–7.42 (m, 1 H), 6.99–6.93 (m, 2 H), 6.43 (s, 1 H), 4.26 (s, 2 H), 4.23 (q, J = 6.8 Hz, 2 H), 3.89 (s, 3 H), 2.51 (s, 3 H), 1.29 (t, J = 6.8 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 196.5, 164.1, 158.7, 158.4, 147.3, 134.1, 130.8, 127.2, 120.8, 114.3, 111.6, 108.8, 59.9, 55.5, 42.6, 14.3, 13.7. ESI-HRMS: m/z calcd for C₁₇H₁₉O₅: [M + H]⁺: 303.1232; found: 303.1236. Ethyl 2-Methyl-5-(2-oxo-3-phenylpropyl)furan-3-carboxylate (4ka, Table 3, Entry 11) Eluent: EtOAc–PE (1:15); white solid; yield: 83%. ¹H NMR (400 MHz, CDCl₃): δ = 7.33–7.25 (m, 3 H), 7.17–7.15 (m, 2 H), 6.43 (s, 1 H), 4.25 (q, J = 6.8 Hz, 2 H), 3.73 (s, 2 H), 3.67 (s, 2 H), 2.51 (s, 3 H), 1.32 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 202.8, 163.9, 158.8, 145.9, 133.6, 129.4, 128.8, 127.2, 114.5, 109.4, 60.0, 49.1, 41.2, 14.3, 13.7. ESI-HRMS: m/z calcd for C₁₇H₁₉O₄ [M + H]⁺: 287.1283; found: 287.1288. Ethyl 2-Methyl-5-(2-oxo-4-phenylbutyl)furan-3-carboxylate (4la, Table 3, Entry 12) Eluent: EtOAc–PE (1:15); colorless oil; yield: 88%. ¹H NMR (400 MHz, CDCl₃): δ = 7.29–7.25 (m, 2 H), 7.20–7.15 (m, 3 H), 6.43 (s, 1 H), 4.26 (q, J = 7.2 Hz, 2 H), 2.89 (t, J = 7.2 Hz, 2 H), 2.79 (t, J = 7.2 Hz, 2 H), 2.53 (s, 3 H), 1.33 (t, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 204.8, 164.0, 158.9, 146.0, 140.7, 133.9, 133.7, 128.5, 128.4, 126.2, 114.5, 109.3, 60.1, 43.5, 42.2, 29.6, 14.4, 13.8. ESI-HRMS: m/z calcd for C₁₈H₂₁O₄ [M + H]⁺: 301.1440; found: 301.1446. Ethyl 5-[2-(Furan-2-yl)-2-oxoethyl]-2-methylfuran-3-carboxylate (4ma, Table 3, Entry 13) Eluent: EtOAc–PE (1:10); yellow solid; yield: 42%. ¹H NMR (400 MHz, CDCl₃): δ = 7.61 (d, J = 1.2 Hz, 1 H), 7.26–7.25 (m, 1 H), 6.56–6.55 (m, 1 H), 6.50 (s, 1 H), 4.25 (q, J = 6.8 Hz, 2 H), 4.10 (s, 2 H), 2.52 (s, 3 H), 1.31 (t, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 183.5, 164.1, 158.9, 151.9, 147.0, 145.6, 118.3, 114.5, 112.6, 109.4, 60.1, 37.8, 14.4, 13.8. ESI-HRMS: m/z calcd for C₁₄H₁₅O₅ [M + H]⁺: 263.0919; found: 263.0915. 2-(4-Acetyl-5-methylfuran-2-yl)-1-(2-methoxyphenyl)-ethanone (4jb, Table 3, Entry 14) Eluent: EtOAc–PE (1:30); white solid; yield: 40%. ¹H NMR (400 MHz, CDCl₃): δ = 7.78–7.76 (m, 1 H), 7.51–7.47 (m, 1 H), 7.03–6.97 (m, 2 H), 6.43 (s, 1 H), 4.30 (s, 2 H), 3.93 (s, 3 H), 2.54 (s, 3 H), 2.36 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 196.6, 194.4, 158.8, 157.8, 147.3, 134.3, 130.9, 126.9, 122.2, 120.9, 111.6, 108.7, 59.9, 55.6, 42.6, 29.2, 14.5. ESI-HRMS: m/z calcd for C₁₆H₁₇O₄ [M + H]⁺: 273.1127; found: 273.1125. 1-(4-Acetyl-5-methylfuran-2-yl)-3-phenylpropan-2-one (4kb, Table 3, Entry 15) Eluent: EtOAc–PE (1:10) yellow oil; yield: 42%. ¹H NMR (400 MHz, CDCl₃): δ = 7.33–7.26 (m, 3 H), 7.18–7.17 (m, 2 H), 6.39 (s, 1 H), 3.76 (s, 2 H), 3.70 (s, 2 H), 2.52 (s, 3 H), 2.36 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 203.0, 194.1, 158.1, 145.8, 133.4, 129.5, 128.9, 127.3, 122.3, 109.2, 49.4, 41.0, 29.2, 14.4. ESI-HRMS: m/z calcd for C₁₆H₁₇O₃ [M + H]⁺: 257.1178; found: 257.1184. 1-(4-Acetyl-5-methylfuran-2-yl)-4-phenylbutan-2-one (4lb, Table 3, Entry 16) Eluent: EtOAc–PE (1:10); yellow oil; yield: 44%. ¹H NMR (400 MHz, CDCl₃): δ = 7.29–7.25 (m, 2 H), 7.21–7.15 (m, 3 H), 6.38 (s, 1 H), 3.64 (s, 2 H), 2.90 (t, J = 7.6 Hz, 2 H), 2.81 (t, J = 8.0 Hz, 2 H), 2.53 (s, 3 H), 2.36 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 204.7, 194.1, 158.1, 145.9, 140.7, 128.6, 128.4, 126.3, 122.3, 109.1, 43.7, 42.1, 29.6, 29.2, 14.4. ESI-HRMS: m/z calcd for C₁₇H₁₉O₃ [M + H]⁺: 271.1334; found: 271.1341.