Synthesis of Novel Fluorinated Benzofurans and Dihydrobenzofurans

Abstract

Starting from easily accessible propargylic fluorides an intramolecular oxa-Michael addition affords, in good yields, new gem-difluo­rodihydrobenzofurans bearing an electrophilic double bond in position 2. On these intermediates nucleophilic additions and Diels–Alder reactions have been performed affording functionalized fluorinated dihydrobenzofurans. On the other hand, Pd-catalyzed defluorinations give the corresponding fluorine containing benzofurans.

Key words

fluorine - gem-difluoropropargyls - benzofurans - 2,3-dihy­drobenzofurans - oxa-Michael additions - heterocycles

• References and Notes


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• 12 For a concise and pertinent review of the main approaches to benzofuran synthesis, see the organic synthesis portal: http://www.organic-chemistry.org/synthesis/heterocycles/ furans/benzo[b]furans.shtm (accessed Oct. 3, 2016).

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• 16 CCDC 1491716 [(E)-8], 1491717 [(E)-8], 1491718 (13), and 1491719 (18) contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
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• 18 The isomer (E)-8 gave a similar defluorination reaction but benzofuran 14 proved to be inseparable by chromatography from remaining starting material (E)-8.
• 19 In some cases, a small amount (<15%) of acids corresponding to 15 and 16, can be obtained in these reactions.
• 20 Representative Experimental Procedures and Spectral/Analytical Data Cyclization Procedure To the fluorinated compound 5 or 6 (0.54 mmol) in THF (7 mL), were added a concentrated solution of H₂SO₄ (0.5 mL) and DDC (0.6 g, 2.18 mmol, 4 equiv). The reaction mixture was stirred for 3 d at r.t. and then extracted with EtOAc (3×). The organic layers were separated, washed with H₂O (3×), dried over Na₂SO₄, and concentrated under vacuum. After purification by chromatography on silica gel, the two isomers E and Z of compounds 7 (75%; E/Z = 3:1) and 8 (80%; E/Z = 2:1) were obtained. (E)-Methyl 2-[3,3-Difluorobenzofuran-2(3H)-ylidene]acetate [(E)-7] White crystals (69 mg, 56%); R_f = 0.43 (PE–EtOAc, 9:1); mp 65 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.62 (dd, J = 7.6, 1.2 Hz, 1 H), 7.50 (dt, J = 8.4, 1.2 Hz, 1 H), 7.21 (dt, J = 7.6, 0.6 Hz, 1 H), 7.06 (dd, J = 8.4, 0.6 Hz, 1 H), 6.03 (t, J = 3.3 Hz, 1 H), 3.82 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 163.9 (t, ⁴ J _CF = 2.3 Hz), 160.8 (t, ² J _CF = 29.3 Hz), 156.4 (t, ³ J _CF = 7.3 Hz), 134 (t, ⁴ J _CF = 1.3 Hz), 124.5, 124.1 (t, ⁴ J _CF = 1.5 Hz), 120.6 (t, ² J _CF = 25.9 Hz), 118.9 (t, ¹ J _CF = 247.2 Hz), 111.4, 102.6 (t, ³ J _CF = 1.1 Hz), 51.9. ¹⁹F NMR (470 MHz, CDCl₃): δ = –90.43 (s). ESI-HRMS: m/z calcd for C₁₁H₈O₃F₂Na [M + Na]⁺: 249.03337; found: 249.0334 (0 ppm). (Z)-Methyl-2 [3,3-Difluorobenzofuran-2(3H)-ylidene]acetate [(Z)-7] White crystals (23 mg, 19%); R_f = 0.41 (PE–EtOAc, 9:1); mp 72 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.61 (dd, J = 7.7, 1.2 Hz, 1 H), 7.55 (dt, J = 8.5, 1.2 Hz, 1 H), 7.22–7.24 (m, 2 H), 5.83 (t, J = 3.0 Hz, 1 H), 3.82 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 164.0 (t, ⁴ J _CF = 2.5 Hz), 159.2 (t, ² J _CF = 27.6 Hz), 157.7 (t, ³ J _CF = 7.8 Hz), 134.4 (t, ⁴ J _CF = 1.1 Hz), 124.4, 119.4 (t, ¹ J _CF = 244.9 Hz), 118.8 (t, ² J _CF = 25.0 Hz), 112.3, 97.8 (t, ³ J _CF = 1.4 Hz), 97.8 (t, ³ J _CF = 1.4 Hz), 51.9. ¹⁹F NMR (470 MHz, CDCl₃): δ = –86.5 (s). ESI-HRMS: m/z calcd for C₁₁H₈O₃F₂Na [M + Na]⁺: 249.03337; found: 249.0335 (0 ppm). (E)-Methyl 2-[5-Bromo-3,3-difluorobenzofuran-2(3H)-ylide-ne]acetate [(E)-8] White crystals (87 mg, 53%); R_f = 0.4 (PE–EtOAc, 9:1); mp 158 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.74 (d, J = 0.8 Hz, 1 H), 7.62 (dd, J = 8.7, 0.8 Hz, 1 H), 6.97 (d, J = 8.7 Hz, 1 H), 6.05 (t, J = 3.3 Hz, 1 H), 3.82 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 163.7 (t, ⁴ J _CF = 1.0 Hz), 160.4 (t, ² J _CF = 29.2 Hz), 155.3 (t, ³ J _CF = 7.1 Hz), 137.0 (t, ³ J _CF = 1.3 Hz), 127.6, 122.6 (t, ² J _CF = 26.3 Hz), 117.5 (t, ¹ J _CF = 248.6 Hz), 116.4 (t, ⁴ J _CF = 1.7 Hz), 113.2, 103.5 (t, ³ J _CF = 1.2 Hz), 52.1. ¹⁹F NMR (282 MHz, CDCl₃): δ = –90.23 (s). ESI-HRMS: m/z calcd for C₁₁H₇O₃F₂ ⁷⁹BrNa [M + Na]⁺: 326.94388; found: 326.9443 (1 ppm). (Z)-Methyl 2-[5-Bromo-3,3-difluorobenzofuran-2(3H)-ylide-ne]acetate [(Z)-8] White crystals (44 mg, 27%); R_f = 0.38 (PE–EtOAc, 9:1); mp 115 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.74 (d, J = 0.7 Hz, 1 H), 7.66 (dd, J = 8.7, 0.7 Hz, 1 H), 7.13 (d, J = 0.7 Hz, 1 H), 5.85 (t, J = 3.0 Hz, 1 H), 3.82 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 163.7 (t, ⁴ J _CF = 2.4 Hz), 158.6 (t, ² J _CF = 27.4 Hz), 156.6 (t, ³ J _CF = 7.5 Hz), 137.4 (t, ³ J _CF = 1.1 Hz), 127.5, 120.8 (t, ² J _CF = 25.2 Hz), 118.7 (t, ¹ J _CF = 246.3 Hz), 116.7 (t, ⁴ J _CF = 1.6 Hz), 114.0, 98.6 (t, ³ J _CF = 1.7 Hz), 52.0. ¹⁹F NMR (282 MHz, CDCl₃): δ = –86.39 (s). ESI-HRMS: m/z calcd for C₁₁H₇O₃F₂ ⁷⁹BrNa [M + Na]⁺: 326.94388; found: 326.9441 (1 ppm). Addition of 2-Mercaptoethanol A solution of 8 (20 mg, 0.066 mmol), 2-mercaptoethanol (10 μL, 2 equiv), and K₂CO₃ (30 mg, 3 equiv) in anhydrous MeCN (2 mL) was stirred at r.t., under nitrogen for 2 h. The reaction mixture was extracted with EtOAc (3×). The organic layers were separated, washed with H₂O (3×), dried over Na₂SO₄, and concentrated under vacuum. After purification by chromatography on silica gel, compound 9 was obtained. Methyl 2-[5-Bromo-3,3-difluoro-2-(2-hydroxyethylthio)-2,3-dihydrobenzofuran-2-yl]acetate (9) Colorless oil (22 mg, 88%); R_f = 0.33 (PE–EtOAc, 8:2). ¹H NMR (300 MHz, CDCl₃): δ = 7.55 (d, J = 2.3 Hz, 1 H), 7.42 (dd, J = 8.7, 2.3 Hz, 1 H), 7.09 (br s, 1 H), 6.82 (d, J = 8.7 Hz, 1 H), 4.21–4.26 (m, 2 H), 3.73 (s, 3 H), 3.14 (AB system, J = 15.0 Hz, 2 H), 2.90–2.97 (m, 1 H), 2.27–2.36 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): d = 168.9, 153.8 (t, ³ J _CF = 3.5 Hz), 135.2 (t, ³ J _CF = 0.8 Hz), 131.8 (t, ² J _CF = 8.6 Hz), 120.7 (t, ¹ J _CF = 254.9 Hz), 120.1 (2 C), 111.7, 96.3 (dd, ² J _CF = 31.1, 31.0 Hz), 74.2, 52.0, 39.8, 33.8. ¹⁹F NMR (282 MHz, CDCl₃): δ = –101.88 (AB system, J = 259.3 Hz). ESI-HRMS: m/z calcd for C₁₃H₁₃O₄F₂S⁷⁹BrNa [M + Na]⁺: 404.95782; found: 404.9579 (0 ppm). Addition of Piperidine Piperidine (28.6 mg, 0.34 mmol, 0.033 mL) was added dropwise at r.t. to compound 8 (mixture of E and Z isomers; 34 mg, 0.112 mmol) in MeCN (3 mL). The mixture was stirred at r.t., and the reaction was monitored by ¹⁹F NMR spectroscopy. After 4 h no more starting material was detected, a diluted solution of HCl was then added. The mixture was extracted with EtOAc, the organic layer was dried (Na₂SO₄), and the solvent was evaporated to give compound 12 after purification on silica gel chromatography. Methyl 2-(5-Bromo-3,3-difluoro-2-hydroxy-2,3-dihydrobenzofuran-2-yl)acetate (12) Colorless oil (28 mg, 77%); R_f = 0.2 (PE–EtOAc, 8:2). ¹H NMR (300 MHz, CDCl₃): δ = 7.62 (d, J = 0.9 Hz, 1 H), 7.54 (dd, J = 8.7, 0.9 Hz, 1 H), 6.80 (d, J = 8.7 Hz, 1 H), 6.24 (br s, 1 H exchanged with D₂O), 3.84 (s, 3 H), 3.01 (s, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 171.6 (d, ⁴ J _CF = 1.5 Hz), 157.4 (dd, ³ J _CF = 8.3, 8.1 Hz), 136.9 (t, ³ J _CF = 1.0 Hz), 128.3, 121.7 (dd, ¹ J _CF = 261.3, 248.6 Hz), 121.5 (t, ² J _CF = 26.2 Hz), 114.1 (t, ⁴ J _CF = 1.7 Hz), 113.8, 105.3 (dd, ² J _CF = 20.5, 13.7 Hz), 52.8, 36.6 (d, ³ J = 7.8 Hz). ¹⁹F NMR (282 MHz, CDCl₃): δ = –105.96 (AB system, J = 251.9 Hz). ESI-HRMS: m/z calcd for C₁₁H₉O₄F₂ ⁷⁹BrNa [M + Na]⁺: 344.95445; found: 344.9546 (0 ppm). Diels–Alder Reaction A solution of (E)-8 (11.3 mg) and 2,3-dimethyl-1,3-butadiene (0.25 mL) were heated, in a pressure tube, at 170 °C for 10 h. The monitoring of the reaction by ¹⁹F NMR spectroscopy made it possible to observe the formation of the product. After the reaction was cooled to r.t., EtOAc was added, and some polymeric material was removed by filtration. After evaporation of the solvent in vacuo, and purification on silica gel chromatography, compound 13 was isolated. Spiro Compound 13 Colorless crystals (9 mg, 63%); R_f = 0.36 (PE–EtOAc, 9.5:0.5); mp 75 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.59 (m, 1 H), 7.49 (m, 1 H), 6.78 (m, 1 H), 3.68 (s, 3 H), 3.13 (d, J = 18.7 Hz, 1 H), 3.03 (d, J = 6.9 Hz, 1 H), 2.73 (dd, J = 18.7, 6.9 Hz, 1 H), 2.36 (d, J = 17.9 Hz, 1 H), 2.02 (d, J = 17.9 Hz, 1 H), 1.7 (s, 3 H), 1.69 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 171.8, 157.6 (t, ³ J _CF = 7.6 Hz), 136.5 (t, ³ J _CF = 1.2 Hz), 127.3, 125.3 (dd, ¹ J = 253.3, 250.1 Hz), 122.7 (t, ² J = 27.2 Hz), 122.6, 122.2, 113.5, 113.1 (t, ⁴ J _CF = 1.9 Hz), 89.2 (dd, ² J _CF = 24.6, 23.9 Hz), 51.9, 41.9 (dd, ³ J _CF = 7.5, 1.5 Hz), 34.5 (dd, ³ J _CF = 9.4, 2.4 Hz), 32.7, 18.9, 18.6. ¹⁹F NMR (282 MHz, CDCl₃): δ = –96.01 (AB system, J = 256.2 Hz). ESI-HRMS: m/z calcd for C₁₇H₁₇O₃F₂ ⁷⁹BrNa [M + Na]⁺: 409.02213; found: 409.0221 (0 ppm). Reductive Defluorination A solution of (Z)-8 (33 mg, 0.11 mmol), phenylsilane or triphenylsilane (2 equiv), palladium dichlorobis(triphenylphosphine) (1.9 mg, 2.5 mol %), and Et₃N (1.5 μL, 10 mol%) in a 1:2 methanol–dioxan mixture (3 mL) was stirred at 50 °C for 22 h. After addition of Na₂SO₄ and filtration, the residues were extracted with EtOAc and the solution concentrated in vacuo. After purification by chromatography on silica gel, the product 14 was separated from remaining (Z)-8 (56% yield) and isolated in 30% yield. Methyl 2-(5-Bromo-3-fluorobenzofuran-2-yl)acetate (14) Yellow oil (9.3 mg, 30%); R_f = 0.33 (PE–EtOAc, 9.5:0.5). ¹H NMR (500 MHz, CDCl₃): δ = 7.69 (d, J = 2.0 Hz, 1 H), 7.41 (dd, J = 8.8, 2.0 Hz, 1 H), 7.28 (d, J = 8.8 Hz, 1 H), 3.85 (d, J = 1.5 Hz, 2 H), 3.76 (s, 3H ). ¹³C NMR (125 MHz, CDCl₃): δ = 168.3 (d, ⁴ J _CF = 2.6 Hz), 150.4 (d, ³ J _CF = 8.4 Hz), 144.8 (d, ¹ J _CF = 254.1 Hz), 135 (d, ² J _CF = 26.3 Hz), 128.2, 121.4 (d, ² J _CF = 18.8 Hz), 120.3 (d, ³ J _CF = 3.1 Hz), 116.2, 113.4, 52.6, 31.0 (d, ³ J _CF = 3.2 Hz). ¹⁹F NMR (470 MHz, CDCl₃): δ = –175.38 (d, J = 1.5 Hz). ESI-HRMS: m/z calcd for C₁₁H₈O₃F⁷⁹BrNa: m/z [M + Na]⁺: 308.9533; found: 308.9533 (0 ppm). Suzuki Coupling Reaction A solution of 8 (mixture of E and Z isomers; 10 mg, 0.033 mmol), phenylboronic acid or isopropenylboronic acid pinacol ester (4 equiv), palladium dichlorobis(triphenylphosphine) (1.15 mg, 5 mol %), and K₂CO₃ (9 mg, 2 equiv) in a 5:1 mixture of dioxane and H₂O (1 mL/0.2 mL) was stirred at 90 °C for 22 h. The reaction mixture was then extracted with EtOAc (3×), the organic layers were separated, washed with H₂O (3×), dried over Na₂SO₄, and concentrated under vacuum. After purification by chromatography on silica gel, the products 15 and 16 were isolated. Methyl 2-(3-Fluoro-5-phenylbenzofuran-2-yl)acetate (15) Yellow oil (8.9 mg, 95%); R_f = 0.47 (PE–EtOAc, 9:1). ¹H NMR (300 MHz, CDCl₃): δ = 7.74 (m, 1 H), 7.62–7.63 (m, 1 H), 7.60 (m, 1 H), 7.53–7.54 (m, 1 H), 7.46–7.48 (m, 2 H), 7.44–7.45 (m, 1 H), 7.36–7.39 (m, 1 H), 3.88 (d, J = 1.8 Hz, 2 H), 3.77 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 168.6 (d, ⁴ J _CF = 2.6 Hz), 151.3 (d, ³ J _CF = 8.8 Hz), 145.9 (d, ¹ J _CF = 253.4 Hz), 141.0, 136.9, 134.1 (d, ² J _CF = 26.7 Hz), 128.8 (2 C), 127.4 (2 C), 127.2, 124.8, 120.1 (d, ² J _CF = 18.9 Hz), 115.9 (d, ³ J _CF = 3.1 Hz), 112.0 (d, ⁴ J _CF = 1.4 Hz), 52.6, 31.1 (d, ³ J = 3.2 Hz). ¹⁹F NMR (282 MHz, CDCl₃): δ = –176.03 (d, J = 1.8 Hz). ESI-HRMS: m/z calcd for C₁₇H₁₃O₃FNa [M + Na]⁺: 307.07409; found: 307.0742 (0 ppm). Methyl 2-[3-Fluoro-5-(prop-1-en-2-yl)benzofuran-2-yl]acetate (16) Yellow oil (5.7 mg, 70%); R_f = 0.36 (PE–EtOAc, 9:1). ¹H NMR (500 MHz, CDCl₃): δ = 7.60 (d, J = 1.3 Hz, 1 H), 7.45 (dd, J = 8.7, 1.8 Hz, 1 H), 7.34 (dd, J = 8.7, 1.8 Hz, 1 H), 5.36 (s, 1 H), 5.11 (s, 1 H), 3.85 (d, J = 1.8 Hz, 2 H), 3.76 (s, 3 H), 2.20 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 168.6 (d, ⁴ J _CF = 2.6 Hz), 151.2 (d, ² J _CF = 8.8 Hz), 145.9 (d, ¹ J _CF = 253.4 Hz), 143.0, 136.9, 133.8 (d, ³ J _CF = 26.8 Hz), 123.2, 119.5 (d, ² J _CF = 18.8 Hz), 114.3 (d, ³ J _CF = 3 Hz), 112.5, 111.5 (d, ⁴ J _CF = 1.3 Hz), 52.6, 31.0 (d, ³ J = 3.1 Hz), 22.3. ¹⁹F NMR (282 MHz, CDCl₃): δ = –176.2 (d, J = 1.3 Hz). ESI-HRMS: m/z calcd for C₁₄H₁₃O₃FNa [M + Na]⁺: 271.07409; found: 271.0742 (0 ppm).