Switching Regioselectivity in the Asymmetric Bromocyclization of Difluoroalkenes Catalyzed by a Chiral Bisphosphine Oxide

Dedicated to Professor Hisashi Yamamoto on the occasion of his 80^th birthday

Abstract

We present an efficient approach for the enantioselective synthesis of difluoromethylene-containing oxazine compounds through 6-endo-selective bromocyclization of difluoroalkenes by using a chiral proton-bridged bisphosphine oxide complex as a catalyst precursor. The regioselectivity is significantly influenced by the solvent and the catalyst structure, and 6-endo cyclization products can be obtained preferentially with moderate to high enantioselectivity. This protocol offers complementary regioselectivity to our previously reported 5-exo-selective reaction, permitting the synthesis of diverse medicinally interesting compounds.

Key words

asymmetric catalysis - Brønsted bases - cyclization - organocatalysis - Lewis bases - oxazines

• References and Notes

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• 10 (5S)-5-Bromo-6,6-difluoro-2-phenyl-5-(p-tolyl)-5,6-dihydro-4H-1,3-oxazine (4a):Typical ProcedurePrecatalyst 1e (12.9 mg, 0.010 mmol, 10 mol%) and difluoroalkene 2a (28.7 mg, 0.10 mmol, 1.0 equiv) were placed in a well-dried Schlenk test tube under an argon atmosphere and dissolved in anhyd toluene (1.8 mL) and CH₂Cl₂ (0.2 mL). The mixture was cooled to –50 °C, and NBP (33.9 mg, 0.15 mmol, 1.5 equiv) was added. The mixture was stirred for 48 h at –50 °C, and then the reaction was quenched by adding a 1.5 M solution of butyl vinyl ether in MeOH (1.0 mL, precooled to –78 °C) through a cannula. The mixture was then gradually warmed to rt and diluted with brine (5.0 mL). The aqueous phase was extracted with CH₂Cl₂ (3 × 10 mL). The combined extracts were dried (MgSO₄) and concentrated under reduced pressure, and the residue was subjected to ¹H NMR analysis to determine the regioisomeric ratio. The crude product was purified by column chromatography [silica gel, hexane–EtOAc (100:0 to 9:1)] to give a white solid; yield: 32.4 mg (88%, 3a/4a = 1:7.2, 86% ee); mp 103–104 °C; [α]_D ²⁰ = –0.8 [c 1.00, CHCl₃, 86% ee, (S)].HPLC (Method 1) [IJ-3, hexane–i-PrOH (99:1), flow rate 1.0 mL/min, column temp. 40 °C, λ = 254 nm]: t _R = 13.2 min (minor, R), 14.5 min (major, S); (Method 2) [OD-H, hexane/i-PrOH (99.5:0.5), flow rate 1.0 mL/min, column temp. 40 °C, λ = 254 nm]: t _R = 6.5 min (major, S), 6.9 min (minor, R). IR (neat): 2919, 1674, 1448, 1353, 1234, 1149, 1084, 1054 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.99–7.98 (m, 2 H), 7.58 (d, J = 8.0 Hz, 2 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.44–7.41 (m, 2 H), 7.20 (d, J = 8.0 Hz, 2 H), 4.61 (dt, J = 17.8, 3.3 Hz, 1 H), 4.52 (dt, J = 17.8, 3.8 Hz, 1 H), 2.36 (s, 3 H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ = 150.8, 139.7, 132.2, 131.9, 130.1, 129.3 (2 C), 128.4 (2 C), 127.8 (2 C), 127.6 (2 C), 120.9 (t, J = 261.7 Hz), 56.7 (t, J = 26.9 Hz), 56.1, 21.1. ¹⁹F NMR (470 MHz, CDCl₃): δ = –74.9 (br, 2 F).The spectral data for 4a were consistent with those reported in ref. 7a