An Acid-Catalysed Hydroamination Approach to Isoindolines

Abstract

Acid-catalysed intramolecular hydroaminations of 2-­alkenylarylethylamine derivatives lead smoothly to isoindolines via benzylic carbenium ion generation.

Key words

cyclisation - sulfonamides - heterocycles - hydroamination - isoindolines

• References

• 1 Griffiths-Jones CM, Knight DW. Tetrahedron 2011; 67: 8515
• 2a Griffiths-Jones CM, Knight DW. Tetrahedron 2010; 66: 4150
• 2b Schlummer B, Hartwig JF. Org. Lett. 2002; 4: 1471

For recent reviews of alkene hydroamination, see:
• 3a Müller TE, Beller M. Chem. Rev. 1998; 98: 675
• 3b Nobis M, Driessen-Hölscher B. Angew. Chem. Int. Ed. 2001; 40: 3983
• 3c Pohlki F, Doye S. Chem. Soc. Rev. 2003; 32: 104
• 3d Müller TE, Hultzsch KC, Yus M, Foubelo F, Tada M. Chem Rev. 2008; 108: 3795
• 3e Majumdar KC, Debnath P, De N, Roy B. Curr. Org. Chem. 2011; 15: 1760
• 4 Bergman J, Janosik T. Comp. Heterocycl. Chem. . Vol. 3. Katritzky AR, Ramsden CA, Scriven EF. V, Taylor RJ. K. Elsevier; Oxford: 2008: 269-351 ; and references cited therein
• 5 Henderson, L.; Knight, D. W.; Williams, A. C. Tetrahedron Lett. 2012, submitted
• 6 Zhu M, Fujita K, Yamaguchi R. Org. Lett. 2010; 12: 1336
• 7 Preparation of Isoindolines 10b–d; Typical Procedures: 1-(4-Chlorobenzyl)-2-tosylisoindoline (10b)� i) (E)-N-[2-(4-Chlorostyryl)benzyl]-4-methylbenzene-sulfonamide 9b (95 mg, 0.238 mmol, 1.0 equiv) was dissolved in dry dichloromethane (10 ml), to which was added TfOH (0.20 ml, 0.119 mmol, 0.5 equiv). The resulting solution was heated to 40 °C for 24 h, then cooled to room temperature and quenched using saturated aqueous K₂CO₃. The quenched solution was then separated and the aqueous layer was extracted with dichloromethane (3 x 10 ml). The combined organic layers were dried over K₂CO₃, filtered through a plug of silica gel and the filtrates and washings evaporated to give the isoindole 10b as a yellow oil (77 mg, yield: 81%).�ii) (E)-N-[2-(4-Chlorostyryl)benzyl]-4-methylbenzene-sulfonamide 9b (106 mg, 0.267 mmol, 1.0 equiv) was dissolved in dichloromethane (10 ml), to which was added concentrated sulfuric acid (2 drops). The resulting suspension was stirred at 40 °C for 48 h, then cooled to room temperature and quenched with saturated aqueous K₂CO₃. The quenched solution was then separated and the aqueous layer was extracted with dichloromethane (3 x 10 ml). The combined organic layers were dried over K2CO₃, filtered through a plug of silica gel and the filtrates and washings evaporated to give the isoindole 10b as a yellow oil (74 mg, yield: 70%).�The two samples showed identical spectroscopic and analytical data. IR (film): 3277, 3062, 3028, 2923, 2855, 1598, 1448, 1274, 815, 750, 658 cm–1. 1H NMR (400 MHz, CDCl3) δ = 7.75–7.52 (m, 4 H, 2 × Ts CH and 2 × Ar CH), 7.35–6.88 (m, 8 H, 2 × Ts CH and 6 × Ar CH), 5.31 (d, 1 H, J = 15.4 Hz, CHaHbN), 4.59 (d, 1 H, J = 15.4 Hz, CH_aH_bN), 4.11 (t, 1 H, J = 6.2 Hz, CHN), 2.98 (app. br s, 2 H, CH2), 2.28 (s, 3 H, Ts CH3). ¹³C NMR (400 MHz, CDCl3) δ = 143.2 (C), 139.8 (C), 137.0 (C), 132.6 (C), 132.4 (C), 132.2 (C), 129.6 (ArCH), 129.5 (2 × TsCH), 128.6 (ArCH), 128.5 (ArCH), 128.4 (ArCH), 127.4 (ArCH), 127.2 (ArCH), 127.1 (2 × TsCH), 126.5 (ArCH), 125.9 (ArCH), 54.7 (CHN), 44.0 (CH2N), 32.3 (CH2), 21.6 (TsCH3). HRMS (APCI): m/z calcd. for C₂₂H₂₁ClNO₂S [M + H]⁺ = 398.0982 (Cl³⁵); found 398.0983 (Cl³⁵)�
• 8 AlHadi, A.; Knight, D. W. unpublished observations