A BF₃-Mediated Nitrogen-to-Carbon Rearrangement of N-Protected 2,3-Dihydro-3-hydroxy-1H-benzisoindol-1-ones, and Its Interception for a Facile Preparation of 3-Substituted Benzisoindolones

Abstract

A BF₃-mediated release of the hydroxy and the nitrogen-protecting group of N-(cumyl or 1,1-diphenylethyl)-2,3-dihydro-3-hydroxy-1H-benzisoindol-1-ones is accompanied by recombination of the nitrogen-protecting unit to the 3-position of the ring system. The addition of sulfur or carbon nucleophiles affords products of preferential capture of the rearrangement intermediate offering a convenient and rapid synthetic route to N-unprotected 2,3-dihydro-3-substituted-1H-benzisoindol-1-ones.

rearrangements - iminium ions - nucleophile - aromatic metalation - PARP inhibitors

References and Notes

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Rearrangement products 7 and 8 could be identified through spectral analysis including the observation of vinylic resonances in the ¹H NMR spectra. Tertiary alcohols 6, obtained as mixtures of diastereomers, were identified with the assistance of IR spectroscopy and mass spectrometry where applicable. Strong M⁺ peaks were seen under CI conditions. Full characterization data including elemental analysis or HRMS was obtained for all new compounds. Sample procedure for rearrangement: Isoindolone 3a (154 mg, 0.406 mmol, 1.0 equiv) was dissolved in 2.5 mL dry CH₂Cl₂ in a flame-dried flask under argon and cooled to 0 °C. Then, BF₃·OEt₂ (0.06 mL, 0.570 mmol, 1.4 equiv) was dissolved in 2.5 mL of dry CH₂Cl₂ in a flame-dried flask under argon and transferred to the solution of 3a via cannula, followed by a 2.5 mL CH₂Cl₂ rinse. The resulting dark brown solution quickly became clear and colorless, and was stirred overnight at r.t. The reaction was quenched with H₂O, extracted with CH₂Cl₂, dried with brine and MgSO₄ and concentrated. Flash chromatography with 15% EtOAc in hexane gave 69.0 mg (47% yield) of 7c and 39.6 mg (26% yield) of 6ac.
3-(2,2-Diphenylethenyl)-2,3-dihydro-1H-benzo[e]isoindol-1-one (7c): mp: 199-200 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.08 (d, J = 8.3 Hz, 1 H), 8.14 (d, J = 8.4 Hz, 1 H), 8.04 (d, J = 8.2 Hz, 1 H), 7.68-7.65 (m, 1 H), 7.61-7.41 (m, 9 H), 7.29-7.19 (m, 3 H), 5.81 (d, J = 9.9 Hz, 1 H), 5.04 (d, J = 9.9 Hz, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.6, 170.5, 147.1, 145.3, 140.6, 138.5, 132.9, 132.7, 129.7, 128.83, 128.77, 128.4, 127.9, 127.8, 127.0, 126.5, 125.5, 125.4, 122.9, 120.8, 55.4. IR (neat) 3447, 1690 cm^-1. MS (EI): m/z (%) = 362 (29), 361 (100) [M⁺], 284 (37). Anal. Calcd (%): C, 86.40; H, 5.30; N, 3.88. Found: C, 86.20; H, 5.54; N, 3.95.
3-(2,2-Diphenyl-2-hydroxyethyl)-2,3-dihydro-1H-benzo[e]isoindol-1-one (6ac): ¹H NMR (400 MHz, CDCl₃): δ = 8.88 (d, J = 8.3 Hz, 1 H), 7.84 (d, J = 8.3 Hz, 1 H), 7.74 (d, J = 8.1 Hz, 1 H), 7.47-7.36 (m, 4 H), 7.25-7.20 (m, 5 H), 7.15-7.03 (m, 4 H), 4.32 (d, J = 10.4 Hz, 1 H), 2.96 (d, J = 13.8 Hz, 1 H), 2.17 (dd, J = 13.8, 10.4 Hz, 1 H). ¹³C NMR (75.5 MHz, acetone-d ₆): δ = 170.8, 151.8, 149.9, 148.9, 148.8, 147.3, 134.1, 133.2, 130.4, 129.1, 129.0, 128.4, 127.9, 127.6, 127.1, 127.0, 124.3, 121.2, 78.6, 54.2, 47.4. IR (nujol): 3426, 3353, 1668 cm^-1. MS (EI): m/z (%) = 379 (8) [M⁺], 361 (32), 284 (16), 196 (42), 184 (27), 183 (32), 182 (59), 105 (27). MS (CI): m/z (%) = 380 (90) [M + H]⁺, 362 (44), 213 (53), 200(100), 196 (55), 183 (39). HRMS (EI): m/z calcd for C₂₆H₁₉NO [M - 18]⁺: 361.1468; found: 361.1470.

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Representative Procedure.
Isoindolone 3b (125 mg, 0.395 mmol, 1.0 equiv) and allyltrimethylsilane (0.25 mL, 1.57 mmol, 4.0 equiv) were slurried in 2.5 mL of dry CH₂Cl₂ in a flame-dried flask under argon and cooled to 0 °C. Then, BF₃·OEt₂ was dissolved in 2.5 mL of dry CH₂Cl₂ in a flame-dried flask under argon and transferred to the solution of 3b and thiol via cannula, followed by a 2.5 mL CH₂Cl₂ rinse. The clear colorless reaction mixture was stirred at r.t. overnight before quenching with H₂O, extracting with CH₂Cl₂, drying with brine and MgSO₄ and concentrating. Flash chromatography with 20% EtOAc in hexane gave 71 mg (80% yield) of 13.
3-Allyl-2,3-dihydro-1H-benz[e]isoindol-1-one (13): ¹H NMR (400 MHz, CDCl₃): δ = 9.22 (d, J = 8.4 Hz, 1 H), 8.02 (d, J = 8.4 Hz, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.67 (t, J = 7.2 Hz, 1 H), 7.57 (t, J = 7.2 Hz, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 5.89-5.78 (m, 1 H), 5.19 (d, J = 16.4 Hz, 1 H), 5.16 (d, J = 10.0 Hz, 1 H), 4.72 (dd, J = 8.0, 4.5 Hz, 1 H), 2.85-2.79 (m, 1 H), 2.42-2.35 (m, 1 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 171.9, 147.5, 133.1, 133.0, 132.7, 129.5, 128.1, 127.9, 126.5, 125.9, 123.9, 119.6, 119.1, 55.7, 38.7. IR: 3448, 3215, 1690 cm^-1. MS (EI): m/z (%) = 223 (8) [M⁺], 183 (14), 182 (100), 127 (13). Anal. Calcd: C, 80.69; H, 5.87. Found: C, 80.90; H, 5.85.

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