Enantioselective Synthesis of Difluoroalkylated Isoindolinones via Chiral Spirocyclic Phosphoric Acid Catalyzed Mannich-Type Reaction

An enantioselective Mannich-type reaction of in situ generated cyclic ketimines with difluoroenoxysilanes catalyzed by chiral spirocyclic phosphoric acid has been developed. This methodology provides a facile route to difluoroalkyl-substituted chiral isoindolinones bearing a quaternary stereogenic center in high yields and up to 96% enantioselectivity.

Key words

enantioselective synthesis - Mannich-type reaction - chiral spirocyclic phosphoric acid - isoindolinone - difluoroenoxysilane

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15 General Procedure for the Reaction of 3-Hydroxyisoindolin-1-ones 1 with Difluoroenoxysilanes 2 To a mixture of 3-hydroxyisoindolin-1-ones 1 (0.05 mmol) and catalyst (S)-4e (0.005 mmol, 10 mol%) in toluene (0.5 mL) was added difluoroenoxysilanes 2 (0.1 mmol, 2 equiv). After stirring at 0 °C for 48 h, the residue was then purified by flash column chromatography with ethyl acetate/petroleum ether (1:4, v/v) on silica gel to give the desired product 3. 3-(1,1-Difluoro-2-oxo-2-phenylethyl)-3-phenylisoindolin-1-one (3a) White solid; mp 167–169 °C; 87% yield; 92% ee, determined by HPLC (Daicel Chiralcel OD-H column (250 × 4.6 mm), n-hexane/i-PrOH = 80:20, 0.8 mL/min, 254 nm; t _major = 8.176 min, t _minor = 7.063 min); [α]_D ²⁰ +143.2 (c 0.34, CH₂Cl₂). ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.03 (s, 1 H), 8.02 (d, J = 7.6 Hz, 1 H), 7.87–7.78 (m, 4 H), 7.71–7.39 (m, 9 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 188.19 (dd, J = 30.8, 27.6 Hz), 168.95, 143.52 (d, J = 3.8 Hz), 135.59, 134.49, 132.64, 132.37, 131.53, 129.67, 128.74, 128.56, 127.01, 125.69, 123.17, 120.12, 117.46, 114.84, 68.39 (t, J = 25.8 Hz). ¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –99.44 (d, J = 268.9 Hz, 1 F), –102.12 (d, J = 268.9 Hz, 1 F). IR (film): ν = 3432, 3054, 2970, 1701, 1266, 739, 704 cm^–1. HRMS (EI-TOF): m/z calcd for C₂₂H₁₅F₂NO₂: 363.1071; found: 363.1071.
16 Procedure for the 2 mmol Scale Reaction To a mixture of 3-hydroxyisoindolin-1-one 1a (450 mg, 2.0 mmol) and catalyst (S)-4e (0.2 mmol, 10 mol%) in toluene (40 mL) was added difluoroenoxysilane 2e (1.22 g, 4.0 mmol, 2 equiv). After stirring at 0 °C for 72 h, the solvent was removed under vacuo. The residue was then purified by flash column chromatography with ethyl acetate/petroleum ether (1:4, v/v) on silica gel to give the desired product 3q in 62% yield with 90% ee. Recovery of catalyst 4e was achieved after acidification of the relevant fractions as described previously (122 mg, 92%).
17 Procedure for the Synthetic Transformation of 3j To a solution of 3j (0.15 mmol, 95% ee) in THF (2.0 mL) was added NaOH (0.3 mmol, 2.0 equiv) at room temperature. The mixture was stirred until full consumption of 3j for 7 h, and then quenched by water, followed by extraction using DCM, and then dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluting with ethyl acetate/petrolem ether, 1:2) to afford 6 as white solid. 3-(Difluoromethyl)-3-(m-tolyl)isoindolin-1-one (6) White solid; mp 165–168 °C; 99% yield; 95% ee, determined by HPLC (Daicel Chiralcel AD-H column (250 × 4.6 mm), n-hexane/i-PrOH = 70:30, 0.8 mL/min, 254 nm; t _major = 10.131 min, t _minor = 6.871 min); [α]_D ²⁰ +156.2 (c 0.46, CH₂Cl₂). ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.69 (s, 1 H), 7.76 (dd, J = 16.8, 7.5 Hz, 2 H), 7.66 (t, J = 7.4 Hz, 1 H), 7.57 (t, J = 7.3 Hz, 1 H), 7.48 (s, 2 H), 7.32 (t, J = 7.9 Hz, 1 H), 7.19 (d, J = 7.3 Hz, 1 H), 6.96 (t, J = 54.4 Hz, 1 H), 2.32 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 169.37, 144.38, 138.05, 136.41, 132.30, 131.63, 129.42, 129.01, 128.68, 126.58, 123.97, 123.28 (d, J = 8.7 Hz), 117.81, 115.36, 112.91, 67.54, 21.11. ¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –125.16 (d, J = 273.4 Hz, 1 F), –127.96 (d, J = 273.4 Hz, 1 F). IR (film): ν = 3427, 3199, 3054, 2986, 1707, 1265, 1075, 741, 705 cm^–1. HRMS (EI-TOF): m/z calcd for C₁₆H₁₃F₂NO 273.0965; found: 273.0966. Procedure for the Synthetic Transformation of 3q A solution of benzyl bromide (0.24 mmol) in DMF (2.0 mL) was cooled to 0 °C. The mixture was charged with portion wise addition of NaH (0.24 mmol) at the same temperature. To the reaction mixture was then slowly added a cooled (0 °C) solution of 3q (0.2 mmol) in DMF (2.0 mL). Reaction mixture was allowed to stir for 3 h at room temperature. Upon completion of the reaction, the mixture was quenched with saturated aqueous NH₄Cl solution, and the solvent was removed in vacuo. The resulting aqueous solution was extracted with DCM, and then dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluting with ethyl acetate/petrolem ether, 1:50) to afford 7 as colorless oil. 2-Benzyl-3-[2-(4-bromophenyl)-1,1-difluoro-2-oxoethyl]-3-phenylisoindolin-1-one (7) Colorless oil; 88% yield; 94% ee, determined by HPLC (Daicel Chiralcel OD-H column (250 × 4.6 mm), n-hexane/i-PrOH = 99:1, 0.8 mL/min, 254 nm; t _major = 8.990 min, t _minor = 10.179 min); [α]_D ²⁰ +73.0 (c 0.33, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 8.07 (d, J = 7.7 Hz, 1 H), 7.97 (d, J = 7.8 Hz, 2 H), 7.92–7.82 (m, 2 H), 7.60–7.39 (m, 5 H), 7.38–7.26 (m, 8 H), 5.38 (d, J = 12.2 Hz, 1 H), 5.13 (d, J = 12.2 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.05, 151.94, 149.30, 137.34, 135.83, 134.27, 131.61, 130.93, 130.24, 129.88, 129.76, 129.61, 129.47, 129.40, 126.95, 122.55, 71.68. ¹⁹F NMR (376 MHz, CDCl₃): δ = –101.67, –102.34, –103.19, –103.85. IR (film): ν = 3054, 2985, 1695, 1624, 1575, 1351, 1265, 739, 704, 440 cm^–1. HRMS (EI-TOF): m/z calcd for C₂₉H₂₀BrF₂NO₂: 531.0645; found: 531.0641.

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