Synlett 2012; 23(13): 1978-1984
DOI: 10.1055/s-0032-1316559
letter
© Georg Thieme Verlag Stuttgart · New York

Regiocomplementary Synthesis of Fluorinated Bridged Biphenyls

Hiroyuki Nemoto
School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526, Japan, Fax: +81(54)2645672   Email: akai@u-shizuoka-ken.ac.jp
,
Keita Takubo
School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526, Japan, Fax: +81(54)2645672   Email: akai@u-shizuoka-ken.ac.jp
,
Kazuki Shimizu
School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526, Japan, Fax: +81(54)2645672   Email: akai@u-shizuoka-ken.ac.jp
,
Shuji Akai*
School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526, Japan, Fax: +81(54)2645672   Email: akai@u-shizuoka-ken.ac.jp
› Author Affiliations
Further Information

Publication History

Received: 02 May 2012

Accepted after revision: 24 May 2012

Publication Date:
26 July 2012 (eFirst)

Abstract

Complementary synthesis of two kinds of fluorinated bridged biphenyls has been developed by the combination of oxidative carbon–carbon bond formation and deoxyfluorination.

Supporting Information

 
  • References and Notes

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      For recent successful examples, see:
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  • 13 The fluorinated bridged biphenyls have been prepared based on Ullmann couling reaction,14 ring contraction of colchicine,15 and carbanion-induced reaction.16
  • 14 Ahmed SR, Hall DM. J. Chem. Soc. 1960; 4165
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  • 17 In our previous study, the fluorination of ortho-quinones mainly proceeded at the less stabilized carbonyl groups, see ref. 7.
  • 18 The regioselectivity of the dienone–phenol rearrangement was reported to be completely controlled by electronic factors, see: Frimer AA, Marks V, Sprecher M, Gilinsky-Sharon P. J. Org. Chem. 1994; 59: 1831

    • For examples, see:
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  • 24 The presence of the 3-hydroxyl moiety of 2a was found to be essential for the fluorination by the fact that a similar fluorination of the acetyl derivative 10 of 2a did not proceed at all (Scheme 4).
  • 25 Only one example has been reported of the migration of a phenyl group onto the more electron-rich carbon, see: Guinaudeau H, Elango V, Shamma M, Fajardo V. J. Chem. Soc., Chem. Commun. 1982; 1122
  • 26 Middleton WJ. J. Org. Chem. 1975; 40: 574
    • 27a L’Heureux A, Bealieu F, Bennett C, Bill DR, Clayton S, LaFlamme F, Mirmehrabi M, Tadayon S, Tovell D, Couturier M. J. Org. Chem. 2010; 75: 3401
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  • 29 For detailed discussion on a plausible reaction mechanism for the fluorination of 3-hydroxydienones 2 producing 4, 9, and 3, see Supporting Information.
  • 30 Similar fluorination reactions using three equivalents of the same fluorination reagents proceeded very slowly and provided the products in lower yields (<30%).
  • 31 3,3-Bis(methoxycarbonyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroxy-naphthalene-1-spiro-1′-[3′-hydrooxy-cyclohexa-2′,5′-dien-4′-one] (2a) – Typical Procedure for the Cyclization of 1 to 2 Under a nitrogen atmosphere, PhI(OAc)2 (78 mg, 0.24 mmol) was added to a solution of 1a (100 mg, 0.23 mmol) and MsOH (15 μL, 0.23 mmol) in DME (2.3 mL) at 0 °C. The reaction mixture was stirred for 24 h at 5°C before being quenched with a sat. aq Na2S2O3 solution and H2O. EtOAc was added, the layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The purification of the residue by flash column chromatography (silica gel, hexanes–EtOAc = 2:1) afforded 2a (95 mg, 95% yield) as a colorless solid; mp 159.0–162.0 °C. IR (CHCl3): 3447, 1734, 1647, 1238 cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.36 (1 H, d, J = 15.0 Hz), 2.49 (1 H, d, J = 15.0 Hz), 3.13 (1 H, d, J = 16.5 Hz), 3.37 (1 H, d, J = 16.5 Hz), 3.60 (3 H, s), 3.75 (6 H, s), 3.77 (3 H, s), 3.85 (3 H, s), 5.94 (1 H, d, J = 3.0 Hz), 6.26 (1 H, s), 6.38 (1 H, d, J = 10.0 Hz), 6.51 (1 H, s), 6.89 (1 H, dd, J = 3.0, 10.0 Hz). 13C NMR (125 MHz, CDCl3): δ = 35.0, 40.5, 42.7, 51.6, 52.9, 55.7, 60.5, 61.0, 107.3, 118.8, 122.9, 123.5, 129.0, 140.7, 146.0, 152.7, 153.2, 158.8, 171.1, 171.3, 181.5. HRMS: m/z calcd for C22H25O9 [M + H]+: 433.1493; found: 433.1503. Dimethyl 5,7-Dihydro-9,10-dihydroxy-1,2,3-trimethoxy-6H-dibenzo[a,c]cycloheptene-6,6-dicarboxylate (5a) – Typical Procedure for the Dienone–Phenol Rearrangement of 2 to 5 Under a nitrogen atmosphere, MsOH (15 μL, 0.23 mmol) was added to a solution of 2a (100 mg, 0.23 mmol) in DME (2.3 mL). The reaction mixture was stirred at 80 °C until 2a was completely consumed (monitored by TLC analysis). After cooling, the reaction was quenched with H2O. EtOAc was added, the layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The purification of the residue by flash column chromatography (silica gel, hexanes–EtOAc = 1:1) afforded 5a (100 mg, quant.) as a colorless solid; mp 162.5–164.0 °C. IR (CHCl3): 3595, 3554, 1732 cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.727 (1 H, d, J = 14.0 Hz), 2.731 (1 H, d, J = 14.0 Hz), 3.09 (1 H, d, J = 14.0 Hz), 3.10 (1 H, d, J = 14.0 Hz), 3.54 (3 H, s), 3.74 (3 H, s), 3.75 (3 H, s), 3.85 (3 H, s), 3.90 (3 H, s), 5.94 (1 H, br s), 6.21 (1 H, br s), 6.62 (1 H, s), 6.83 (1 H, s), 7.08 (1 H, s). 13C NMR (125 MHz, CDCl3): δ = 36.2, 37.1, 52.8, 52.9, 56.0, 60.8, 61.2, 64.5, 109.5, 116.5, 116.8, 125.7, 128.0, 128.2, 131.6, 141.3, 142.4, 143.0, 150.3, 151.9, 171.2, 171.3. HRMS: m/z calcd for C22H24NaO9 [M + Na]+: 455.1313; found: 455.1339. Typical Procedure for the Fluorination of 2 Under a nitrogen atmosphere, Xtalfluor-E (95 mg, 0.41 mmol) was added to a solution of 2a (30 mg, 0.069 mmol) and Et3N·HF (0.41 mmol), in situ prepared from Et3N·3HF (22 μL, 0.14 mmol) and Et3N (38 μL, 0.28 mmol), in i-Pr2O–CHCl3 (1:1, 0.35 mL) at 0 °C. The reaction mixture was stirred for 1.5 h at 50 °C before being quenched with ice water. CH2Cl2 was added, the layers were separated, and the aqueous layer was extracted three times with CH2Cl2. The combined organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The purification of the residue by flash column chromatography (silica gel, hexanes–EtOAc = 3:1) afforded 4a (22 mg, 74% yield) and 9a (6.0 mg, 18% yield). Dimethyl 10-Fluoro-5,7-dihydro-9-hydroxy-1,2,3-trimethoxy-6H-dibenzo[a,c]cycloheptene-6,6-dicarboxylate (4a) Colorless solid; mp 146.0–147.0 °C. IR (CHCl3): 3578, 1734, 1254 cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.72 (1 H, d, J = 14.5 Hz), 2.76 (1 H, d, J = 14.5 Hz), 3.13 (2 × 1 H, d, J = 14.5 Hz), 3.60 (3 H, s), 3.76 (6 H, s), 3.87 (3 H, s), 3.90 (3 H, s), 5.39 (1 H, br), 6.63 (1 H, s), 6.93 (1 H, d, J = 9.0 Hz), 7.26 (1 H, d, J = 11.5 Hz). 13C NMR (125 MHz, CDCl3): δ = 36.2, 37.0, 52.8, 52.9, 56.0, 60.8, 61.1, 64.4, 109.4, 117.1 (d, J = 18.0 Hz), 118.3, 124.8, 128.5 (d, J = 7.0 Hz), 131.4, 132.3 (d, J = 3.5 Hz), 141.6, 142.2 (d, J = 14.5 Hz), 150.0 (d, J = 238 Hz), 150.6, 152.4, 170.8, 171.0. 19F NMR (470 MHz, CDCl3): δ = –146.5 (1 F, dd, J = 9.0, 11.5 Hz). HRMS: m/z calcd for C22H23FNaO8 [M + Na]+: 457.1269; found: 457.1289. Dimethyl 10-Fluoro-5,7-dihydro-11-hydroxy-1,2,3-trimethoxy-6H-dibenzo[a,c]cycloheptene-6,6-dicarboxylate (9a) Colorless solid; mp 104.0–109.0 °C. IR (CHCl3): 3327, 1732, 1240 cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.71 (1 H, d, J = 14.0 Hz), 2.73 (1 H, d, J = 14.0 Hz), 3.13 (1 H, d, J = 14.0 Hz), 3.20 (1 H, d, J = 14.0 Hz), 3.70 (3 H, s), 3.76 (3 H, s), 3.77 (3 H, s), 3.90 (3 H, s), 3.93 (3 H, s), 6.70 (1 H, s), 6.81 (1 H, dd, J = 5.0, 8.0 Hz), 6.99 (1 H, s), 7.01 (1 H, d, J = 8.0, 10.0 Hz). 13C NMR (125 MHz, CDCl3): δ = 36.8, 36.9, 52.88, 52.92, 56.1, 61.3, 62.2, 64.2, 110.9, 115.1 (d, J = 18.0 Hz), 121.3 (d, J = 2.0 Hz), 122.1 (d, J = 7.0 Hz), 126.4, 131.9 (d, J = 3.5 Hz), 132.4, 141.4, 141.5 (d, J = 12.0 Hz), 149.4, 152.9 (d, J = 241 Hz), 153.1, 170.6, 170.8. 19F NMR (470 MHz, CDCl3): δ = –138.9 (1 F, dd, J = 5.0, 10.0 Hz). HRMS: m/z calcd for C22H23FNaO8 [M + Na]+: 457.1269, found: 457.1271. Typical Procedure for the Fluorination of 5 Under a nitrogen atmosphere, PhI(OAc)2 (78 mg, 0.24 mmol) was added to a mixture of 5a (100 mg, 0.23 mmol) and MgO (21 mg, 0.53 mmol) in CHCl3 (1.2 mL) at 0 °C, and the reaction mixture was stirred at the same temperature for 5 min. Deoxofluor (0.25 mL, 1.4 mmol) was added, and the reaction mixture was stirred for 1 h at 40 °C before being quenched with ice water. CH2Cl2 was added, the layers were separated, and the aqueous layer was extracted three times with CH2Cl2. The combined organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in EtOH (1.2 mL), and NaBH4 (44 mg, 1.2 mmol) was added to the solution at 0 °C. The reaction mixture was stirred overnight at r.t. before being quenched with 1 M HCl. EtOAc was added, the layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, hexanes–EtOAc–Et3N = 33:66:1) afforded 4a (24 mg, 23% yield) and 7a (43 mg, 43% yield). Dimethyl 9-Fluoro-5,7-dihydro-10-hydroxy-1,2,3-tri-methoxy-6H-dibenzo[a,c]cycloheptene-6,6-dicarboxylate (7a) Colorless solid; mp 188.5–189.5 °C. IR (CHCl3): 3580, 1732, 1238 cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.68 (1 H, d, J = 14.0 Hz), 2.73 (1 H, d, J = 14.0 Hz), 3.13 (1 H, d, J = 13.0 Hz), 3.15 (1 H, d, J = 13.0 Hz), 3.61 (3 H, s), 3.76 (6 H, s), 3.88 (3 H, s), 3.90 (3 H, s), 5.26 (1 H, br), 6.64 (1 H, s), 7.03 (1 H, d, J = 11.0 Hz), 7.17 (1 H, d, J = 9.0 Hz). 13C NMR (125 MHz, CDCl3): δ = 36.0, 37.0, 52.8, 52.9, 56.0, 60.9, 61.1, 64.3, 109.4, 116.7 (d, J = 18.0 Hz), 119.0, 124.9, 128.3 (d, J = 6.0 Hz), 131.3, 132.5 (d, J = 3.5 Hz), 141.6, 142.1 (d, J = 13.0 Hz), 149.6 (d, J = 237 Hz), 150.7, 152.5, 170.9, 171.0. 19F NMR (470 MHz, CDCl3): δ = –145.4 to –145.2 (1 F, m). HRMS: m/z calcd for C22H23FNaO8 [M + Na]+: 457.1269; found: 457.1292.