Cascade Radical Reaction Induced by Polarity-Mismatched Perfluoroalkylation

Abstract

Cascade radical addition-cyclization-trapping reaction proceeded via the unfavorable polarity-mismatched addition of electrophilic perfluoroalkyl radicals to electron-deficient acceptors.

Key word

radical - fluoro - cyclization - enantioselective - cascade

References and notes

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15

The structures of cis-2a,b, trans-2a,b and 3a,b were confirmed by HMQC, HMBC, and NOESY experiments.

19

The electrophilicity of perfluoroalkyl radicals followed the order 1˚ < 2˚ < 3˚; see ref. 12.

21

The absolute configuration at the stereocenter of cis-2a-d was assumed by similarity between the present reaction and the previously reported study. See ref. 10a.

23

Both cis-9 and trans-9 were respectively obtained as two diastereomers concerning the newly generated stereocenter at iodinated carbon.

24

General Procedure for Enantioselective Radical Reaction: A solution of substrate 1 or 8 (100 mg or 106 mg, 0.43 mmol), Zn(OTf)₂ (156 mg, 0.43 mmol) and ligand 7 (153 mg, 0.43 mmol) in CH₂Cl₂ (4.3 mL) was stirred for 1 h under Ar atmosphere at 20 ˚C. To the reaction mixture were added RI (2.15 mmol) and Et₃B (1.05 M in hexane, 2.05 mL, 2.15 mmol) at -78 ˚C. After being stirred at the same temperature for 1-5 d, the reaction mixture was diluted with sat. NaHCO₃ and then extracted with CH₂Cl₂. The organic phase was dried over Na₂SO₄ and concentrated at reduced pressure. The residue was roughly purified by preparative TLC (hexane-EtOAc, 3:1) to give the mixture of products. The ratio of products was determined by ^¹H NMR analysis of the mixture. Second purification of the mixture by preparative TLC (benzene-EtOAc, 10:1 or hexane-EtOAc, 6:1, 2-fold development) afforded the isolated products.
Representative Products: cis -2a: colorless crystals; mp 99-99.5 ˚C (hexane). IR (KBr): 2948, 1717, 1458 cm^-¹. ^¹H NMR (CDCl₃): δ = 7.38-7.50 (m, 5 H), 5.04 (d, J = 11.0 Hz, 1 H), 5.02 (d, J = 11.0 Hz, 1 H), 3.50 (dd, J = 9.2, 6.6 Hz, 1 H), 3.19-3.30 (m, 2 H), 2.73 (t, J = 11.4 Hz, 1 H), 2.39-2.58 (m, 2 H), 2.26 (br dd, J = 37.0, 16.0 Hz, 1 H), 1.32 (d, J = 1.6 Hz, 3 H). ^¹³C NMR (CDCl₃): δ = 170.8, 134.7, 129.6, 129.3, 128.7, 118.3 (tt, J = 257, 31 Hz), 117.5 (qt, J = 289, 34 Hz), 108.4 (tsext, J = 265, 36 Hz), 76.9, 51.1, 44.5, 44.2, 31.0 (t, J = 21 Hz), 22.2, 4.1. ^¹9F NMR (CDCl₃): δ = -80.6 (t, J = 19.5 Hz, 3 F), -106.2 (dm, J = 273 Hz, 1 F), -116.0 (dm, J = 273 Hz, 1 F), -128.3 (br s, 2 F). MS (EI⁺): m/z = 528 (25)
[M + H⁺], 91 (100). HRMS (EI⁺): m/z [M + H⁺] calcd for C₁₇H₁₈F₇INO₂: 528.0270; found: 528.0260. Anal. Calcd for C₁₇H₁₇F₇INO₂: C, 38.73; H, 3.25; N, 2.66. Found: C, 38.74; H, 3.22; N, 2.60. HPLC (Chiralcel AD-H, hexane-2-propanol, 95:5; flow: 1.0 mL/min, l = 254 nm); t _R (major) = 6.7 min, t _R (minor) = 8.9 min. A sample of 87% ee by HPLC analysis gave [α]^²4 _D +28.3 (c = 0.40, CHCl₃). 3a: colorless oil. IR (KBr): 2968, 2932, 1714, 1455 cm^-¹. ^¹H NMR (CDCl₃): δ = 7.34-7.47 (m, 5 H), 5.09 (d, J = 11.0 Hz, 1 H), 5.04 (d, J = 11.0 Hz, 1 H), 3.48 (t, J = 8.5 Hz, 1 H), 3.37 (dd, J = 8.5, 1.8 Hz, 1 H), 3.23 (d, J = 11.0 Hz, 1 H), 3.05 (d, J = 11.0 Hz, 1 H), 2.45 (m, 1 H), 2.26-2.42 (br m, 2 H), 1.30 (s, 3 H). ^¹³C NMR (CDCl₃): δ = 170.1, 134.7, 129.5, 129.1, 128.6, 117.6 (qt, J = 288, 34 Hz), 117.4 (tt, J = 256, 32 Hz), 108.4 (tsext, J = 265, 38 Hz), 77.2, 50.1 (d, J = 5 Hz), 44.0, 33.9, 28.1 (t, J = 21 Hz), 25.0, 6.4. ^¹9F NMR (CDCl₃): δ =
-80.9 (t, J = 9 Hz, 3 F), -113.7 (dm, J = 273 Hz, 1 F), -116.0 (dm, J = 273 Hz, 1 F), -127.8 (dd, J = 290, 5 Hz, 1 F), -128.2 (dd, J = 290, 5 Hz, 1 F). HRMS (ESI): m/z [M + H⁺] calcd for C₁₇H₁₈F₇INO₂: 528.0270; found: 528.0269.