Halogenation of Indoles with Copper(II) Halides: Selective Synthesis of 2-Halo-, 3-Halo-, and 2,3-Dibromoindoles

Shi Tang; Jin-Heng Li; Ye-Xiang Xie; Nai-Xing Wang

doi:10.1055/s-2007-966030

PAPER

Halogenation of Indoles with Copper(II) Halides: Selective Synthesis of 2-Halo-, 3-Halo-, and 2,3-Dibromoindoles

Shi Tang^a,b, Jin-Heng Li*^b, Ye-Xiang Xie^b, Nai-Xing Wang*^a
^a Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100101, P. R. of China
^b Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education), College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, P. R. of China
Fax: +86(731)8872531; e-Mail: jhli@hunnu.edu.cn;

Abstract

All articles of this category

Abstract

A simple and selective protocol for the halogenation of indoles with copper(II) bromide or chloride to synthesize 2-halo-, 3-halo-, and 2,3-dibromoindoles was developed. It was found that both base and water could be used as switches for the selectivity of the halogenation reactions. In the presence of copper(II) halide and sodium hydroxide, 3-haloindoles were obtained as the major products, whereas the selectivity was shifted toward 2,3-dihaloindoles when water was added instead of sodium hydroxide. Moreover, 2-halogenations of 3-substituted indoles were also performed successfully in moderate to good yields under the standard conditions.

Key words

halogenation - indole - copper(II) halide - 2-haloindole - 3-haloindole - 2,3-dibromoindole

Full Text

References

For selected papers, see:

<A NAME="RF02307SS-1A">1a</A> Carter GT. Rinehart KL. Li HL. Connor SLKL. Tetrahedron Lett. 1978, 19: 4479

<A NAME="RF02307SS-1B">1b</A> Tarzia G. Diamantini G. Giacomo BD. Spadoni G. J. Med. Chem. 1997, 40: 2003

<A NAME="RF02307SS-1C">1c</A> He F. Foxman BM. Snider BB. J. Am. Chem. Soc. 1998, 120: 6417

<A NAME="RF02307SS-1D">1d</A> Fiumana A. Jones K. Chem. Commun. 1999, 1761

<A NAME="RF02307SS-1E">1e</A> Snider BB. Zeng HB. Org. Lett. 2000, 2: 4103

<A NAME="RF02307SS-1F">1f</A> Kanekiyo N. Kuwada T. Choshi T. Nobuhiro J. Hibino S. J. Org. Chem. 2001, 66: 8793

<A NAME="RF02307SS-1G">1g</A> Hooper MW. Utsunomiya M. Hartwig JF. J. Org. Chem. 2003, 68: 2861

<A NAME="RF02307SS-1H">1h</A> Rawat M. Wulff WD. Org. Lett. 2004, 6: 329

<A NAME="RF02307SS-1I">1i</A> Yue DW. Larock RC. Org. Lett. 2004, 6: 1037

<A NAME="RF02307SS-1J">1j</A> Nicolaou KC. Snyder SA. Huang XH. Simonsen KB. Koumbis AE. Bigot A. J. Am. Chem. Soc. 2004, 126: 10162

<A NAME="RF02307SS-1K">1k</A> Frohner W. Monse B. Braxmeier TM. Casiraghi L. Sahagun H. Seneci P. Org. Lett. 2005, 7: 4573

<A NAME="RF02307SS-1L">1l</A> Ludwig J. Bovens S. Brauch C. Elfringhoff AS. Lehr M. J. Med. Chem. 2006, 49: 2611

For reviews, see:

<A NAME="RF02307SS-2A">2a</A> Crisp GT. Chem. Soc. Rev. 1998, 27: 427

<A NAME="RF02307SS-2B">2b</A> Gribble GW. Chem. Soc. Rev. 1999, 28: 335

<A NAME="RF02307SS-2C">2c</A> Gribble GW. Environ. Sci., Pollut. Res. 2000, 7: 37

<A NAME="RF02307SS-2D">2d</A> Knölker HJ. Reddy KR. Chem. Rev. 2002, 102: 4303

<A NAME="RF02307SS-2E">2e</A> Chinchilla R. Nájera C. Yus M. Chem. Rev. 2004, 104: 2667

<A NAME="RF02307SS-2F">2f</A> Lloyd-Williams P. Giralt E. Chem. Soc. Rev. 2001, 30: 145

<A NAME="RF02307SS-2G">2g</A> Cacchi S. Fabrizi G. Chem. Rev. 2005, 105: 2873

For representative papers on the synthesis of 2- or 3-halo-indoles mediated by N-halosuccinimides, see:

<A NAME="RF02307SS-3A">3a</A> Saulnier MG. Gribble GW. J. Org. Chem. 1982, 47: 757

<A NAME="RF02307SS-3B">3b</A> Saulnier MG. Gribble GW. J. Org. Chem. 1983, 48: 2690

<A NAME="RF02307SS-3C">3c</A> Mistry AG. Smith K. Bye MR. Tetrahedron Lett. 1986, 27: 1051

<A NAME="RF02307SS-3D">3d</A> Zhang P. Liu R. Cook JM. Tetrahedron Lett. 1995, 36: 3103

<A NAME="RF02307SS-3E">3e</A> Liu R. Zhang P. Gan T. Cook JM. J. Org. Chem. 1997, 62: 7447

<A NAME="RF02307SS-3F">3f</A> Kobayashi Y. Fujimoto T. Fukuyama T. J. Am. Chem. Soc. 1999, 121: 6501

<A NAME="RF02307SS-3G">3g</A> Katayama S. Ae N. Nagata R. J. Org. Chem. 2001, 66: 3474

<A NAME="RF02307SS-3H">3h</A> Ma C. Liu XX. Li XY. Anderson JF. Yu S. Cook JM. J. Org. Chem. 2001, 66: 4525

<A NAME="RF02307SS-3I">3i</A> Nicolaou KC. Snyder SC. Huang XH. Simonsen KB. Koumbis AE. Bigot A. J. Am. Chem. Soc. 2004, 126: 10162

<A NAME="RF02307SS-3J">3j</A> de Koning CB. Michael JP. Pathak R. van Otterlo WAL. Tetrahedron Lett. 2004, 45: 1117

<A NAME="RF02307SS-3K">3k</A> Mejia-Oneto JM. Padwa A. Org. Lett. 2004, 6: 3241

<A NAME="RF02307SS-4A">4a</A> Bocchi V. Palla G. Synthesis 1982, 1096

<A NAME="RF02307SS-4B">4b</A> Martin P. Tetrahedron Lett. 1987, 28: 1645

<A NAME="RF02307SS-4C">4c</A> Martin P. Helv. Chim. Acta 1988, 71: 344

<A NAME="RF02307SS-4D">4d</A> Timms GH. Tupper DE. Morgan SE. J. Chem. Soc., Perkin Trans. 1 1989, 817

<A NAME="RF02307SS-4E">4e</A> Billimoria AD. Cava MP. J. Org. Chem. 1994, 59: 6777

<A NAME="RF02307SS-4F">4f</A> Katritzky AR. Xie L. J. Org. Chem. 1995, 60: 3707

<A NAME="RF02307SS-4G">4g</A> Morales-Rios MS. Santos-Sanchez NF. Suarez-Castillo OR. Joseph-Nathan P. J. Org. Chem. 2003, 68: 305

<A NAME="RF02307SS-4H">4h</A> Ohshita J. Lee K.-H. Kimura K. Kunai A. Organometallics 2004, 23: 5622

<A NAME="RF02307SS-4I">4i</A> Brennan MR. Erickson KL. Szmalc FS. Tansey MJ. Thornton JM. Heterocycles 1986, 24: 2879

<A NAME="RF02307SS-5A">5a</A> Akinori K. Tatsuya N. Synthesis 1980, 365

<A NAME="RF02307SS-5B">5b</A> Tarzia G. Diamantini G. Giacomo BDi. Spadoni G. J. Med. Chem. 2000, 43: 2449

For selected papers on other transformations for the synthesis of 2-halo- or/and 3-haloindoles, see:

<A NAME="RF02307SS-6A">6a</A> Bergman J. Carlsson R. Sjoberg B. J. Heterocycl. Chem. 1977, 14: 1123

<A NAME="RF02307SS-6B">6b</A> Akinori K. Tatsuya N. Synthesis 1980, 365

<A NAME="RF02307SS-6C">6c</A> Kubo A. Uchino K. Heterocycles 1981, 16: 1441

<A NAME="RF02307SS-6D">6d</A> Gribble GW. Allison BD. Conway SC. Saulnier MG. Org. Prep. Proced. Int. 1992, 24: 649

<A NAME="RF02307SS-6E">6e</A> Duan X.-G. Rees CW. J. Chem. Soc., Perkin Trans. 1 1997, 2695

<A NAME="RF02307SS-6F">6f</A> Witulsk B. Buschmann N. Bergstraßer U. Tetrahedron 2000, 56: 8473

<A NAME="RF02307SS-6G">6g</A> Zhang H. Laroch RC. Org. Lett. 2001, 3: 3083

<A NAME="RF02307SS-6H">6h</A> Zhang H. Laroch RC. J. Org. Chem. 2002, 67: 5318

<A NAME="RF02307SS-6I">6i</A> Liu YB. Gribble CW. J. Nat. Prod. 2002, 65: 748

<A NAME="RF02307SS-6J">6j</A> Yuen J. Fang Y.-Q. Lautens M. Org. Lett. 2006, 8: 653

<A NAME="RF02307SS-6K">6k</A> Zhang Z. Zhou G. Gao X. Li Y. Liao R. Synth. Commun. 2001, 31: 947

For selected papers on the synthesis of 2,3-dibromoindoles by bromination of indoles, see:

<A NAME="RF02307SS-7A">7a</A> Zajc B. Zupan M. Tetrahedron 1989, 45: 7869

<A NAME="RF02307SS-7B">7b</A> Bergman J. Venemalm L. J. Org. Chem. 1992, 57: 2495

<A NAME="RF02307SS-7C">7c</A> Liu Y. Gribble GW. Tetrahedron Lett. 2001, 42: 2949

<A NAME="RF02307SS-7D">7d</A> Liu Y. Gribble GW. J. Nat. Prod. 2002, 65: 748

<A NAME="RF02307SS-7E">7e</A> Beevers RE. Buckley GM. Davies N. Fraser JL. Galvin FC. Hannah DR. Haughan AF. Jenkins K. Mack SR. Pitt WR. Ratcliffe AJ. Richard MD. Sabin V. Sharpe A. Williams SC. Bioorg. Med. Chem. Lett. 2006, 16: 2535

<A NAME="RF02307SS-8A">8a</A> Balogh-Hergovich É. Speier G. J. Chem. Soc., Perkin Trans. 1 1986, 2305

<A NAME="RF02307SS-8B">8b</A> Gallou F. Reeves JT. Tan Z. Song JJ. Yee NK. Campbell S. Jones P.-J. Senanayake CH. Synlett 2005, 2400