Download PDF
Synlett 2010(19): 2899-2904  
DOI: 10.1055/s-0030-1259027
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Syntheses of N-Alkylated Carbazolones via Pd(OAc)2-Mediated Intramolecular Coupling of N-Substituted 3-(Arylamino)cyclohex-2-enones

Wenying Bi, Xiliu Yun, Yanfeng Fan, Xiuxiang Qi, Yunfei Du*, Jianhui Huang*
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P. R. of China
Fax: +86(22)27404031; e-Mail: duyunfeier@tju.edu.cn; e-Mail: jhuang@tju.edu.cn;
Further Information

Publication History

Received 5 September 2010
Publication Date:
03 November 2010 (online)

    Permissions and Reprints All articles of this category

Abstract

A variety of functionalized N-alkylated carbazolones were prepared via N-alkylation of 3-(arylamino)cyclohex-2-enones followed by an intramolecular oxidative coupling mediated by Pd(OAc)2 under an oxygen atmosphere. This approach adopts an inverted sequence, consisting of the conventional annulation and subsequent N-alkylation.

Key words

N-substituted 3-(arylamino)cyclohex-2-enones - N-alkylated carbazolones - Pd(OAc)2 - oxygen - CH activation

    References and Notes

  • 1a Gant TG, and Sarshar S. inventors; US  2010119623. 
  • 1b Barta TE. Barabasz AF. Foley BE. Geng L. Hall SE. Hanson GJ. Jenks M. Ma W. Rice JW. Veal J. Bioorg. Med. Chem. Lett.  2009,  19:  3078 
    Google Scholar
  • 1c Barta TE. Veal JM. Rice JW. Partridge JM. Fadden RP. Ma W. Jenks M. Geng L. Hanson GJ. Huang KH. Barabasz AF. Foley BE. Otto J. Hall SE. Bioorg. Med. Chem. Lett.  2008,  18:  3517 
    Google Scholar
  • 1d Yan S. Wu H. Wu N. Jiang Y. Synlett  2007,  2699 
    Google Scholar
  • 1e Romeo G. Materia L. Pittala V. Modica M. Salerno L. Siracusa M. Russo F. Minneman KP. Bioorg. Med. Chem.  2006,  14:  5211 
    Google Scholar
  • 1f Li X. Vince R. Bioorg. Med. Chem.  2006,  14:  2942 
    Google Scholar
  • 1g Kukushkin SY. Ivanov PY. Alekseeva LM. Levina VI. Kobrakov KI. Grigor’ev NB. Granik VG. Russ. Chem. Bull.  2005,  54:  1887 
    Google Scholar
  • 1h Sorensen US. Pombo-Villar E. Helv. Chim. Acta  2004,  87:  82 
    Google Scholar
  • 2a Bunce RA. Nammalwar B. J. Heterocycl. Chem.  2009,  46:  172 
    Google Scholar
  • 2b Scott TL. Burke N. Carrero-Martínez G. Söderberg BCG. Tetrahedron  2007,  63:  1183 
    Google Scholar
  • 2c Scott TL. Yu X. Gorugantula SP. Carrero-Martinez G. Soederberg BCG. Tetrahedron  2006,  62:  10835 
    Google Scholar
  • 2d Czeskis BA. Wheeler WJ. J. Labelled Compd. Radiopharm.  2005,  48:  407 
    Google Scholar
  • 2e Sissouma D. Collet SC. Guingant AY. Synlett  2004,  2612 
    Google Scholar
  • 2f Scott TL. Söderberg BCG. Tetrahedron  2002,  43:  1621 
    Google Scholar
  • 2g Tietcheu C. Garcia C. Gardette D. Dugat D. Gramain J. J. Heterocycl. Chem.  2002,  39:  965 
    Google Scholar
  • 2h Dubois EA. van den Bos JC. Doornbos T. van Doremalen P. Somsen GA. Vekemans J. Janssen A. Batink HD. Boer GJ. Pfaffendorf M. van Royen EA. van Zwieten PA. J. Med. Chem.  1996,  39:  3256 
    Google Scholar
  • 2i Caubère C. Caubère P. Renard P. Bizot-Espiart J.-G. Jamart-Grégoire B. Tetrahedron Lett.  1993,  34:  6889 
    Google Scholar
  • 2j Oikawa Y. Yonemitsu O. J. Org. Chem.  1977,  42:  1213 
    Google Scholar
  • 2k Kawai H. Nagasu T. Takeda T. Fujiwara K. Tsuji T. Ohkita M. Nishida J. Suzuki T. Tetrahedron Lett.  1975,  45:  4533 
    Google Scholar
  • 3a Weng B. Liu R. Li J.-H. Synthesis  2010,  in press
    Google Scholar
  • 3b Punniyamurthy T. Velusamy S. Iqbal J. Chem. Rev.  2005,  105:  2329 
    Google Scholar
  • 3c Knölker H.-J. Reddy KR. Chem. Rev.  2002,  102:  4303 
    Google Scholar
  • 3d Hagelin H. Oslob JD. Åkermark B. Chem. Eur. J.  1999,  5:  2413 
    Google Scholar
  • 3e Knölker H.-J. Fröhner W. J. Chem. Soc., Perkin Trans. 1  1998,  173 
    Google Scholar
  • 4a Kudzma LV. Synlett  2003,  1661 
    Google Scholar
  • 4b Osuka A. Mori Y. Suzuki H. Chem. Lett.  1982,  2031 
    Google Scholar
  • 4c Iida H. Yuasa Y. Kibayashi C. J. Org. Chem.  1980,  45:  2938 
    Google Scholar
  • 4d Iida H. Yuasa Y. Kibayashi C. J. Org. Chem.  1979,  44:  1236 
    Google Scholar
  • 5a Ge H. Niphakis MJ. Georg GI. J. Am. Chem. Soc.  2008,  130:  3708 
    Google Scholar
  • 5b Rakshit S. Patureau FW. Glorius F. J. Am. Chem. Soc.  2010,  132:  9585 
    Google Scholar
  • 5c Neumann JJ. Suri M. Glorius F. Angew. Chem. Int. Ed.  2010,  49: In press
    Google Scholar
  • 6a Shi Z. Zhang C. Li S. Pan D. Ding S. Cui Y. Jiao N. Angew. Chem. Int. Ed.  2009,  48:  4572 
    Google Scholar
  • 6b Würtz S. Rakshit S. Neumann JJ. Dröge T. Glorius F. Angew. Chem. Int. Ed.  2008,  47:  7230 
    Google Scholar
  • 6c Humphrey GR. Kuethe JT. Chem. Rev.  2006,  106:  2875 
    Google Scholar
  • 6d Cacchi S. Fabrizi G. Chem. Rev.  2005,  105:  2873 
    Google Scholar
  • 6e Chen C. Lieberman DR. Larsen RD. Verhoeven TR. Reider PJ. J. Org. Chem.  1997,  62:  2676 
    Google Scholar
  • 6f Koerber-Plé K. Massiot G. Synlett  1994,  759 
    Google Scholar
  • 6g Sakamoto T. Nagano T. Kondo Y. Yamanaka H. Synthesis  1990,  215 
    Google Scholar
  • For recent selected examples using oxygen as oxidant, see:
  • 7a Hamada T. Ye X. Stahl SS. J. Am. Chem. Soc.  2008,  130:  833 
    Google Scholar
  • 7b Jiao N. Zhang C. J. Am. Chem. Soc.  2010,  132:  28 
    Google Scholar
  • 7c Shi Z. Zhang B. Cui Y. Jiao N. Angew. Chem. Int. Ed.  2010,  49:  4036 
    Google Scholar
  • 7d Jiao N. Zhang C. Angew. Chem. Int. Ed.  2010,  49:  6174 
    Google Scholar
  • 8 For the most similar N-methylation of 1 using NaH and methyl iodide in toluene, see: Aragon P.-J. Yapi A.-D. Pinguet F. Chezal J.-M. Teulade J.-C. Chapat J.-P. Blache Y. Chem. Pharm. Bull.  2004,  52:  659 
    CrossrefGoogle Scholar
  • 9a Sissouma D. Collet SC. Guingant AY. Synlett  2004,  2612 
    Google Scholar
  • 9b Dobbs AP. Jones K. Veal KT. Tetrahedron Lett.  1997,  38:  5379 
    Google Scholar
  • 11 Rodríguez JG. del Valle C. Esteban-Calderón C. Martinez-Ripoll M. J. Chem. Crystallogr.  1995,  25:  249 
    CrossrefGoogle Scholar
10

General Procedure for the Synthesis of N-Substituted Carbazolones 3
To a solution of N-substituted 3-(arylamino)cyclohex-
2-enones 2a-n (1 mmol) in AcOH (15 mL) was added Pd(OAc)2 (0.1 mmol), and the resulting solution was heated at 100 ˚C and passed through oxygen flow (1.0 L/min).
TLC was used to monitor the reaction progress. After the consumption of starting material, the reaction mixture was extracted by EtOAc (3 × 15 mL). The organic phase was combined, dried (anhyd Na2SO4). After filtration, the solvent was removed under reduced pressure to give the crude product. The residue was purified by flash column chromatography (EtOAc-PE, 1:3) on silica gel to give the desired products 3a-n. Compound 3a:¹¹ white solid; mp 195-196 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 8.27-8.23 (m, 1 H, ArH), 7.33-7.27 (m, 3 H, ArH), 3.72 (s, 3 H, NCH3), 2.95 (t, J = 6.0 Hz, 2 H, COCH2), 2.62 (t, J = 6.0 Hz, 2 H, CH2), 2.30-2.23 (m, 2 H, CH2). ESI-LRMS: m/z calcd for C13H13NO+: 200.1 [M + H+]; found: 200.1 [M + H+], 222 [M + Na+].
Compound 3b: brown solid; mp 230-231 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 8.38 (d, J = 2.0 Hz, 1 H, ArH), 7.34 (dd, J = 9.0, 2.0 Hz, 1 H, ArH), 7.18 (d, J = 9.0 Hz, 1 H, ArH), 3.68 (s, 3 H, NCH3), 2.92 (t, J = 6.0 Hz, 2 H, COCH2), 2.56 (t, J = 6.0 Hz, 2 H, CH2), 2.28-2.22 (m, 2 H, CH2). ¹³C NMR (100 MHz, CDCl3): δ = 193.8, 153.0, 137.6, 134.9, 127.2, 125.8, 124.4, 111.8, 110.8, 37.7, 35.6, 23.1, 21.9. ESI-LRMS: m/z calcd for C13H12 79BrNO+: 280.0 [M + H+]; found: 280.0. The spectroscopic data for all the new compounds can be found in the Supporting Information.