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Synlett 2006(18): 3115-3119  
DOI: 10.1055/s-2006-951495
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Adrian L. Schwan*a, Petar A. Dusparaa, Michelle M. Paquettea, A. Rod Merrillb
a Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, Department of Chemistry, University of Guelph, Guelph, ON, N1G 2W1, Canada
Fax: +1(519)7661499; e-Mail: schwan@uoguelph.ca;
b Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, N1G 2W1, Canada
Further Information

Publication History

Received 25 May 2006
Publication Date:
25 October 2006 (online)

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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.

Key words

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

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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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Compound 5 and its isomer were not amenable to flash chromatography, but fortunately 5 could be cleanly separated from the more soluble isomer by toluene recrystallization.

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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.