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Synlett 2008(16): 2547-2551  
DOI: 10.1055/s-2008-1078053
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 3-Fluoro-2,5-Disubstituted Furans and Further Derivative Reactions to Access Fluorine-Containing 3,3′-Bifurans and Tetrasubstituted Furans

Peng Li, Zhuo Chai, Gang Zhao*, Shi-Zheng Zhu*
Key Laboratory of Organofluorine Chemistry and Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. of China
Fax: +86(21)64166128; e-Mail: zhaog@mail.sioc.ac.cn; e-Mail: zhusz@mail.sioc.ac.cn;
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Publikationsverlauf

Received 29 May 2008
Publikationsdatum:
12. September 2008 (online)

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Abstract

2,5-Disubstituted 3-fluorofurans were synthesized in 42-99% yield via DBU-promoted cyclization reactions of electron-deficient gem-difluorohomopropargyl alcohols. Starting from these compounds, a series of fluorinated 3,3′-bifurans and tetrasubstituted furans were also prepared through a fluorine-directed ortho-functionalization process.

Key words

fluorinated furans - neighboring-group effects - cyclization reaction - DBU - coupling

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12

Typical Procedure for the Synthesis of 2c from 1c: To a solution of 1c (337 mg, 1 mmol) in anhyd THF (3 mL) was added DBU (3 equiv, 0.45 mL), and the mixture was stirred at 60 ˚C for 8 h. Then the reaction was quenched with H2O (2 mL), and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine and dried over anhyd Na2SO4. After evaporation of the solvent under reduced pressure, the crude product was purified by column chromatography on silica gel to afford 2c as a white solid (279 mg, 88%).
2c: mp 95-96 ˚C. IR: 1631, 1598, 1490, 1430, 1397, 1075, 922, 691 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.67-7.75 (m, 4 H), 7.10-7.44 (m, 5 H), 6.66 (s, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 150.7 (d, ¹ J CF = 256.0 Hz), 150.5 (d, ³ J CF = 8.2 Hz), 134.9 (d, ² J CF = 20.1 Hz), 131.8, 130.0, 128.7, 128.2, 127.7 (d, ³ J CF = 5.2 Hz), 124.8 (d, 4 J CF = 5.2 Hz), 123.7, 120.6, 99.2 (d, ² J CF = 20.1 Hz). ¹9F NMR (282 MHz, CDCl3, CFCl3 as the external standard): δ = -160.4 (s). LRMS: m/z (%) = 316 (100) [M+], 318 (98.47) [M+ + 2], 319 (17.59), 209 (21.35), 207 (14.17), 189 (14.46), 159 (14.64), 133 (27.90). Anal. Calcd for C16H10BrFO (315.99): C, 60.59; H, 3.18. Found: C, 60.40; H, 3.37.

15

Typical Procedure for the Synthesis of 3b from 2b: Under an atmosphere of argon, n-butyllithium (0.63 mL, 1.0 mmol) was added dropwise to a stirred solution of 2b (136 mg, 0.5 mmol) in THF (3 mL) at -78 ˚C. Then the reaction mixture was stirred for 40 min at this temperature before CuBr (81 mg, 0.60 mmol) was added and stirred for another 40 min. Then the system was equipped with an oxygen balloon and was allowed to warm to r.t. (the reaction solution slowly turned black during this process). After 8 h, 1.0 N HCl (2 mL) was added to quench the reaction and the aqueous layer was extracted with CH2Cl2 and dried over Na2SO4. The crude product was purified by column chromatography on silica gel to afford 3b as a white solid (64 mg, 47%).
3b: mp 177-178 ˚C. IR: 3143, 1636, 1492, 1400, 919, 824, 687 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.60-7.70 (m, 8 H), 7.42-7.45 (m, 4 H), 7.26-7.36 (m, 6 H). ¹³C NMR (100 MHz, CDCl3): δ = 148.8 (d, ¹ J CF = 257.0 Hz), 147.7 (d, ³ J CF = 9.0 Hz), 135.2 (d, ² J CF = 18.6 Hz), 133.1, 129.9, 129.1, 128.8, 128.7, 127.0, 126.9, 124.9, 103.2 (d, ² J CF = 15.6 Hz). ¹9F NMR (282 MHz, CDCl3, CFCl3 as the external standard): δ = -160.8 (s). LRMS: m/z (%) = 542 (100) [M+], 543 (42.97), 544 (72.01), 545 (25.67), 546 (14.78), 383 (15.56), 338 (6.20), 320 (12.79). HRMS: m/z calcd for C32H18Cl2F2O2: 542.0652; found: 542.0661.

16

Typical Procedure for the Synthesis of 4a from 2a: Under an atmosphere of argon, n-butyllithium (0.38 mL, 0.6 mmol) was added dropwise to a stirred solution of 2a (119 mg, 0.5 mmol) in THF (3 mL) at -78 ˚C. Then the reaction mixture was stirred for 40 min at this temperature before benzal-dehyde (64 mg, 0.6 mmol) was added and the system was allowed to warm to r.t. After disappearance of the substrate benzaldehyde (monitored by TLC), the reaction was quenched with sat. NH4Cl. The aqueous layer was extracted with EtOAc and dried over Na2SO4. The crude product was purified by column chromatography on silica gel to afford 4a as a colorless oil (122 mg, 71%).
4a: IR: 3366, 3059, 1640, 1495, 1437, 1170, 1015, 839, 693 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.54-7.76 (m, 6 H), 7.30-7.44 (m, 9 H), 6.13 (d, J = 6.0 Hz, 1 H), 2.44 (d, J = 6.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 148.8 (d, ¹ J CF = 260.0 Hz), 147.1 (d, ³ J CF = 7.0 Hz), 135.9 (d, ² J CF = 18.7 Hz), 141.5, 130.1, 128.7, 128.5, 127.8, 127.2, 126.6, 126.1, 123.6, 123.5, 116.0 (d, ² J CF = 13.4 Hz), 67.7. ¹9F NMR (282 MHz, CDCl3, CFCl3 as the external standard): δ = -161.7 (s). LRMS: m/z (%) = 344 (100) [M+], 105 (48.91), 77 (41.89), 345 (27.06), 133 (11.84), 267 (11.09), 79 (9.95), 189 (7.16). HRMS: m/z calcd for C23H17FO2: 344.1206; found: 344.1213.