Download PDF
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)

    Permissions and Reprints All articles of this category

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

    References and Notes

  • 1 Albert JS. Ohnmacht C. Bernstein PR. Rumsey WL. Aharony D. Alelyunas Y. Russell DJ. Potts W. Sherwood SA. Shen L. Dedinas RF. Palmer WE. Russell K. J. Med. Chem.  2004,  47:  519 
    CrossrefGoogle Scholar
  • 2 Baldwin J. Michnoff CH. Malmquist NA. White J. Roth MG. Rathod PK. Phillips MA. J. Biol. Chem.  2005,  280:  21847 
    CrossrefGoogle Scholar
  • 3 Voets M. Antes I. Scherer C. Mueller-Vieira U. Biemel K. Barassin C. Marchais-Oberwinkler S. Hartmann RW. J. Med. Chem.  2005,  48:  6632 
    CrossrefGoogle Scholar
  • 4 Greco MN. Hawkins MJ. Powell ET. Almond HR. Corcoran TW. de Garavilla L. Kauffman JA. Recacha R. Chattopadhyay D. Andrade-Gordon P. Maryanoff BE. J. Am. Chem. Soc.  2002,  124:  3810 
    CrossrefGoogle Scholar
  • 5 de Garavilla L. Greco MN. Sukumar N. Chen Z.-W. Pineda AO. Mathews FS. Di Cera E. Giardino EC. Wells GI. Haertlein BJ. Kauffman JA. Corcoran TW. Derian CK. Eckardt AJ. Damiano BP. Andrade-Gordon P. Maryanoff BE. J. Biol. Chem.  2005,  280:  18001 
    Google Scholar
  • 6a Kohrt JT. Filipski KJ. Rapundalo ST. Cody WL. Edmunds JJ. Tetrahedron Lett.  2000,  41:  6041 
    CrossrefGoogle Scholar
  • 6b
    Jia     ZJ. Wu Y. Huang W. Goldman E. Zhang P. Woolfrey J. Wong P. Huang B. Sinha U. Park G. Reed A. Scarborough RM. Zhu B.-Y. Bioorg. Med. Chem. Lett.  2002,  12:  1651 
    CrossrefGoogle Scholar
  • 6c Parmee ER. He J. Mastracchio A. Edmondson SD. Colwell L. Eiermann G. Feeney WP. Habulihaz B. He H. Kilburn R. Leiting B. Lyons K. Marsilio F. Patel RA. Petrov A. Di Salvo J. Wu JK. Thornberry NA. Weber AE. Bioorg. Med. Chem. Lett.  2004,  14:  43 
    CrossrefGoogle Scholar
  • 6d Gyoergydeak Z. Hadady Z. Felfoeldi N. Krakomperger A. Nagy V. Toth M. Brunyanszki A. Docsa T. Gergely P. Somsak L. Bioorg. Med. Chem.  2004,  12:  4861 
    CrossrefGoogle Scholar
  • 7 Zhang J. Li J.-H. Drugs Fut.  2002,  27:  371 
    CrossrefGoogle Scholar
  • 8 Southan GJ. Szabo C. Curr. Med. Chem.  2003,  10:  321 
    Google Scholar
  • 9 Jagtap P. Szabo C. Nat. Rev. Drug Discovery  2005,  4:  421 
    CrossrefGoogle Scholar
  • 10 Lautier D. Lagueux J. Thibodeau J. Menard L. Poirier GG. Mol. Cell. Biochem.  1993,  122:  171 
    CrossrefGoogle Scholar
  • 11 Armstrong S. Li J.-H. Zhang J. Merrill AR. J. Enzyme Inhib. Med. Chem.  2002,  17:  235 
    CrossrefGoogle Scholar
  • 12 Yates SP. Taylor PL. Jørgensen R. Ferraris D. Zhang J. Andersen GR. Merrill AR. Biochem. J.  2005,  385:  667 
    CrossrefGoogle Scholar
  • 13 Dai W.-M. Zhang Y. Zhang Y. Tetrahedron: Asymmetry  2004,  15:  525 
    CrossrefGoogle Scholar
  • 14 Clayden J. Frampton CS. McCarthy C. Westlund N. Tetrahedron  1999,  55:  14161 
    CrossrefGoogle Scholar
  • 15 Metallinos C. Nerdinger S. Snieckus V. Org. Lett.  1999,  1:  1183 ; comparable results were found using TFA
    CrossrefGoogle Scholar
  • 17 Watanabe M. Snieckus V. J. Am. Chem. Soc.  1980,  102:  1457 
    CrossrefGoogle Scholar
  • 18 Chen CW. Beak P. J. Org. Chem.  1986,  51:  3325 
    CrossrefGoogle Scholar
  • 19 Bindal RD. Katzenellenbogen JA. J. Org. Chem.  1987,  52:  3181 
    CrossrefGoogle Scholar
  • 21 The ketimine arising from loss of styryl or 1,1-diphenylethyl cation from 9 may also be implicated in this mechanism. However, efforts to detect or isolate the ketimine and a more stabilized version of it proved fruitless. The analogous cyclic sulfonimines(benzisothiazoles) exhibit more stability and can be obtained by a related N-decumylation/dehydration treatment. See: Metallinos C. Synlett  2002,  1556 
    Article in Thieme ConnectGoogle Scholar
  • 22 Ent H. De Koning H. Speckamp WN. J. Org.Chem.  1986,  51:  1687 
    Google Scholar
  • 23 Ent H. De Koning H. Speckamp WN. Tetrahedron Lett.  1985,  26:  5105 
    CrossrefGoogle Scholar
  • 24 Maryanoff BE. Zhang H.-C. Cohen JH. Turchi IJ. Maryanoff CA. Chem. Rev.  2004,  104:  1431 
    CrossrefPubMedGoogle Scholar
  • 25 Speckamp WN. Moolenaar MJ. Tetrahedron  2000,  56:  3817 
    CrossrefGoogle Scholar
  • Generally cyclic N-acyliminium ion chemistry involves carbon substitution and then introduction of another reagent for nitrogen deprotection, if desired. Some examples of the one-pot realization of both reactions are known:
  • 26a Pinder JL. Weinreb SM. Tetrahedron Lett.  2003,  44:  4141 
    CrossrefGoogle Scholar
  • 26b Reichelt A. Bur SK. Martin SF. Tetrahedron  2002,  58:  6323 
    CrossrefGoogle Scholar
  • 26c Lundkvist JRM. Wistrand LG. Hacksell U. Tetrahedron Lett.  1990,  31:  719 
    CrossrefGoogle Scholar
  • 26d Botman PNM. Dommerholt FJ. de Gelder R. Broxterman QB. Schoemaker HE. Rutjes FPJT. Blaauw RH. Org. Lett.  2004,  6:  4941 
    CrossrefGoogle Scholar
  • 26e Granier T. Vasella A. Helv. Chim. Acta  1998,  81:  865 
    CrossrefGoogle Scholar
  • 26f Lundkvist JRM. Vargas HM. Caldirola P. Ringdahl B. Hacksell U. J. Med. Chem.  1990,  33:  3182 
    CrossrefGoogle Scholar
  • 27 Stajer G. Csende F. Curr. Org. Chem.  2005,  9:  1277 
    CrossrefGoogle Scholar
  • This general family of compounds has biological significance in a variety of areas:
  • 28a Wrobel J. Dietrich A. Woolson SA. Millen J. McCaleb M. Harrison MC. Hohman TC. Sredy J. Sullivan D. J. Med. Chem.  1992,  35:  4613 
    CrossrefPubMedGoogle Scholar
  • 28b Andrews MD. Brewster AG. Chuhan J. Ibbett AJ. Moloney MG. Prout K. Watkin D. Synthesis  1997,  305 
    CrossrefPubMedGoogle Scholar
  • 28c Toyooka K, Kanamitsu N, Yoshimura M, Kuriyama H, and Tamura T. inventors; WO  048332.  ; Chem. Abstr. 2004, 141, 38525
    CrossrefPubMedGoogle Scholar
  • 28d Guillaumel J. Leonce S. Pierre A. Renard P. Pfeiffer B. Peruchon L. Arimondo PB. Monneret C. Oncol. Res.  2003,  13:  537 
    CrossrefPubMedGoogle Scholar
  • 28e Mertens A. Zilch H. Koenig B. Schaefer W. Poll T. Kampe W. Seidel H. Leser U. Leinert H. J. Med. Chem.  1993,  36:  2526 
    CrossrefPubMedGoogle Scholar
  • 30a Duggan HME. Hitchcock PB. Young DW. Org. Biomol. Chem.  2005,  3:  2287 
    CrossrefPubMedGoogle Scholar
  • 30b He Y. Moningka R. Lovely CJ. Tetrahedron Lett.  2005,  46:  1251 
    CrossrefPubMedGoogle Scholar
  • 30c Aggarwal VK. Astle CJ. Iding H. Wirz B. Rogers-Evans M. Tetrahedron Lett.  2005,  46:  945 
    CrossrefPubMedGoogle Scholar
  • 30d Huang P.-Q. Wei B.-G. Ruan Y.-P. Synlett  2003,  1663 
    CrossrefPubMedGoogle Scholar
  • 30e Gloanec P. Herve Y. Bremand N. Lecouve J.-P. Breard F. De Nanteuil G. Tetrahedron Lett.  2002,  43:  3499 
    CrossrefPubMedGoogle Scholar
  • 30f Okitsu O. Suzuki R. Kobayashi S. J. Org. Chem.  2001,  66:  809 
    CrossrefPubMedGoogle Scholar
16

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.

20

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.

29

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.