Novel Synthesis of Fused Indoles by the Palladium-Catalyzed Cyclization of N-Cycloalkenyl-o-haloanilines

Abstract

A new palladium-catalyzed cyclization of N-alkenyl-o-haloanilines with selective isomerization of a double bond followed by 5-endo cyclization was developed and used to synthesize fused indoles.

Key words

heterocycles - indole - palladium - synthesis

References

• 1a Handbook of Organopalladium Chemistry for Organic Synthesis   Vol. I and II:  Negishi E. John Wiley and Sons, Inc.; New York: 2002. 
• 1b Li JJ. Gribble GW. Palladium in Heterocyclic Chemistry   Elsevier Science Ltd.; Oxford: 2000. 
• 2 Mori M. Ban Y. Tetrahedron Lett.  1977,  18:  1037 
• Synthesis of indoles by palladium-catalyzed cyclization of N-alkenyl-o-haloanilines, see:
• 3a Caddick S. Kofie W. Tetrahedron Lett.  2002,  43:  9347 
• 3b Michael JP. de Koning CB. Petersen RL. Stanbury TV. Tetrahedron Lett.  2001,  42:  7513 
• 3c Latham EJ. Stanforth SP. J. Chem. Soc, Perkin Trans. 1  1997,  2059 
• 3d Blache Y. Sinibaldi-Troin M.-E. Voldoire A. Chavignon O. Gramain J.-C. Teulade J.-C. Chapat J.-P. J. Org. Chem.  1997,  62:  8553 
• 3e Chen LC. Yang SC. Wang HM. Synthesis  1995,  385 
• 3f Michael JP. Chang S.-F. Wilson C. Tetrahedron Lett.  1993,  34:  8365 
• 3g Sakamoto T. Nagano T. Kondo Y. Yamanaka H. Synthesis  1990,  215 
• 3h Kasahara A. Izumi T. Murakami S. Yanai H. Takatori M. Bull. Chem. Soc. Jpn.  1986,  59:  927 
• 3i Iida H. Yuasa Y. Kibayashi C. J. Org. Chem.  1980,  45:  2938 
• 4a Sato Y. Watanabe S. Shibasaki M. Tetrahedron Lett.  1992,  33:  2589 
• 4b Sato Y. Honda T. Shibasaki M. Tetrahedron Lett.  1992,  33:  2593 
• 4c Sato Y. Nukui S. Sodeoka M. Shibasaki M. Tetrahedron  1994,  50:  371 
• 6 Awang K. Sévenet T. Païs M. Hadi AHA. J. Nat. Prod.  1993,  56:  1134 
• 7 Pearson WH. Mi Y. Lee IY. Stoy P. J. Am. Chem. Soc.  2001,  123:  6724 
• 8 Lennon M. Proctor GR. J. Chem. Soc., Perkin Trans. 1  1979,  2009 

5

While other silver salts, such as Ag₂CO₃, AgPF₆, AgOTf, and AgBF₄, also promoted this reaction, they were less effective.

9

Experimental Procedure for the Synthesis of 13: A mixture of enamine 12 (0.15 g, 0.28 mmol), Ag₃PO₄ (0.12 g, 0.28 mmol), and Pd(PPh₃)₄ (32 mg, 28 µmol) was heated (18 h) with stirring in DMSO (1.0 mL) at 100 °C under Ar. The mixture was diluted with Et₂O at r.t., and filtered through a celite pad. The filtrate was concentrated and the residue was purified by silica gel column chromatography (EtOAc:n-hexane, 1:5) to give 13 as a colorless oil (79 mg, 69%). ¹H NMR (600 MHz, CDCl₃): δ = 1.35 (t, J = 7.1 Hz, 3 H), 1.87 (td, J = 2.8, 12.9 Hz, 1 H), 2.18 (ddd, J = 3.9, 12.6, 14.8 Hz, 1 H), 2.56 (t, J = 12.1 Hz, 1 H), 2.66 (tt, J = 5.0, 12.9 Hz, 1 H), 2.94 (ddd, J = 3.0, 12.1, 15.1 Hz, 1 H), 3.13 (ddd, J = 1.4, 3.6, 15.1 Hz, 1 H), 3.48 (dd, J = 4.1, 15.1 Hz, 1 H), 4.12 (dt, J = 3.9, 13.2 Hz, 1 H), 4.24-4.32 (m, 2 H), 4.37 (dd, J = 5.2, 12.7 Hz, 1 H), 7.06 (td, J = 1.1, 7.1 Hz, 1 H), 7.13 (td, J = 1.1, 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.47 (td, J = 1.4, 7.7 Hz, 2 H), 7.54 (tt, J = 1.4, 7.2 Hz, 1 H), 7.78-7.80 (m, 2 H), 9.11 (s, 1 H). ¹³C NMR (150 MHz, CDCl₃): δ = 14.3, 25.8, 36.5, 39.4, 48.5, 53.7, 61.6, 111.2, 111.3, 117.6, 119.5, 121.9, 127.0, 129.2, 130.9, 132.7, 135.5, 139.1, 174.8.