Download PDF
Synthesis 2006(20): 3467-3477  
DOI: 10.1055/s-2006-950223
PAPER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Indoles: Efficient Functionalisation of the 7-Position

Nicolas Charrier, Emmanuel Demont*, Rachel Dunsdon, Graham Maile, Alan Naylor, Alistair O’Brien, Sally Redshaw, Pam Theobald, David Vesey, Daryl Walter
Neurology and Gastrointestinal Center of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, CM19 5AW, Essex, UK
Fax: +44(1279)627685; e-Mail: emmanuel.h.demont@gsk.com;
Further Information

Publication History

Received 8 June 2006
Publication Date:
04 September 2006 (online)

    Permissions and Reprints All articles of this category

Abstract

Traditional strategies in indole chemistry do not allow high-yielding access to some substitution patterns such as 3,5,7-trisubstituted indoles. We report in this article the efficient synthesis of this type of indole. The Heck cyclisation strategy we used allows the synthesis of 7-iodo-, 7-alkoxy-, 7-amino-, and 7-nitroindoles bearing other functionalities at the 3- and 5-positions. We believe that the mild conditions used should allow the preparation of indoles with a wide range of substituents in these two positions as shown by the synthesis of a 5-bromo-7-iodoindole. However, this strategy has some limitations in the case of very electron-deficient indoles such as a 7-nitroindole where the aromatisation of the 7-nitrodihydroindole intermediate is not complete. In this case, Larock’s indole synthesis from disubstituted acetylenes proved to be more appropriate.

Key words

indoles - Heck reaction - palladium - 2-vinylanilines - Larock’s cyclisation

    References

  • 1 Saxton JE. The Chemistry of Heterocyclic Compounds   Vol. 25, Part IV:  Wiley; New York: 1983. 
    Google Scholar
  • 3 Charrier N. Demont E. Dunsdon R. Maile G. Naylor A. O’Brien A. Redshaw S. Theobald P. Vesey D. Walter D. Synlett  2005,  3071 
    Article in Thieme ConnectGoogle Scholar
  • 4a Heath-Brown B. Philpott PG. J. Chem. Soc.  1965,  7185 
    CrossrefGoogle Scholar
  • 4b McKittrick B. Failli A. Steffan RJ. Soll RM. Schmid J. Asselin AA. Shaw CC. Noureldin R. Gavin G. J. Heterocycl. Chem.  1990,  27:  2151 
    CrossrefGoogle Scholar
  • 5 Bartoli G. Palmieri G. Bosco M. Dalpozzo R. Tetrahedron Lett.  1989,  30:  2129 
    CrossrefGoogle Scholar
  • 6a Clark RD. Repke DB. Heterocycles  1984,  22:  195 
    CrossrefGoogle Scholar
  • 6b Moyer MP. Shiurba JF. Rapoport H. J. Org. Chem.  1986,  51:  5106 
    CrossrefGoogle Scholar
  • For a review on the use of transition metals in the synthesis and functionalisation of indoles, see:
  • 7a Hegedus LS. Angew. Chem., Int. Ed. Engl.  1988,  27:  1113 
    CrossrefPubMedGoogle Scholar
  • For a recent and very well-documented review on the synthesis of indoles through palladium-catalysed reactions, see:
  • 7b Cacchi S. Fabrizi G. Chem. Rev.  2005,  105:  2873 
    CrossrefPubMedGoogle Scholar
  • 8 Hartung CG. Fecher A. Chapell B. Snieckus V. Org. Lett.  2003,  5:  1899 
    CrossrefGoogle Scholar
  • 9a Somei M. Saida Y. Heterocycles  1985,  23:  3113 
    CrossrefGoogle Scholar
  • 9b Somei M. Yamada F. Hamada H. Kawasaki T. Heterocycles  1989,  29:  643 
    CrossrefGoogle Scholar
  • 10 Iwao M. Heterocycles  1994,  38:  45 
    CrossrefGoogle Scholar
  • 11 This list is not exhaustive. For example, since the completion of this work, a one-pot synthesis of indoles via enamines has been reported, see: Barluenga J. Fernandez MA. Aznar F. Valdes C. Chem. Eur. J.  2005,  11:  2276 ; see also ref. 7b
    CrossrefPubMedGoogle Scholar
  • For a very comprehensive overview of the challenges posed by the synthesis of 7-substituted indoles, see:
  • 12a Ezquerra J. Pedregal C. Lamas C. Barluenga J. Perez M. Garcia-Martin MA. Gonzales JM. J. Org. Chem.  1996,  61:  5804 ; and references cited therein
    CrossrefGoogle Scholar
  • 12b Rodriguez AL. Koradin C. Dohle W. Knochel P. Angew. Chem. Int. Ed.   2000,  39:  2488 ; and references cited therein
    CrossrefGoogle Scholar
  • 12c Koradin C. Dohle W. Rodriguez AL. Schmid B. Knochel P. Tetrahedron  2003,  59:  1571 
    CrossrefGoogle Scholar
  • It is possible to functionalise the 3-position in situ, but it needs concomitant substitution at the 2-position:
  • 13a Arcadi A. Cacchi S. Marinelli F. Tetrahedron Lett.  1992,  33:  3915 
    Google Scholar
  • 13b Arcadi A. Cacchi S. Carcinelli V. Marinelli F. Tetrahedron  1994,  50:  437 
    Google Scholar
  • 14 Okauchi T. Itonaga M. Minami T. Owa T. Kitoh K. Yoshino H. Org. Lett.  2000,  2:  1485 
    CrossrefPubMedGoogle Scholar
  • 15 Iwao M. Motoi O. Fukuda T. Ishibashi F. Tetrahedron  1998,  54:  8999 
    CrossrefGoogle Scholar
  • 16 Heydari A. Mehrdad M. Maleki A. Ahmadi N. Synthesis  2004,  1563 
    Article in Thieme ConnectGoogle Scholar
  • 17a Odle R. Blevins B. Ratcliff M. Hegedus LS. J. Org. Chem.  1980,  45:  2709 
    Google Scholar
  • 17b Yang S. Chung W. Indian J. Chem., Sect. B  1999,  38:  897 
    Google Scholar
  • 18a Larock RC. Yum EK. Refvik MD. J. Org. Chem.  1998,  63:  7652 
    CrossrefGoogle Scholar
  • For application to total synthesis, see:
  • 18b Chen C. Lieberman DR. Larsen RD. Reamer RA. Verhoeven TR. Reider PJ. Tetrahedron Lett.  1994,  35:  6981 
    CrossrefGoogle Scholar
  • 18c Liu X. Deschamp JR. Cook JM. Org. Lett.  2002,  4:  3339 
    CrossrefGoogle Scholar
  • 19 Hegedus LS. Allen GF. Bozell JJ. Waterman EL. J. Am. Chem. Soc.  1978,  100:  5800 
    Google Scholar
  • 20a O’Shea DF. Kerins F. J. Org. Chem.  2002,  67:  4968 
    CrossrefPubMedGoogle Scholar
  • 20b Coleman CM. O’Shea DF. J. Am. Chem. Soc.  2003,  125:  4054 
    CrossrefPubMedGoogle Scholar
  • 22 Macor JE. Ogilvie RJ. Wythes MJ. Tetrahedron Lett.  1996,  37:  4289 
    CrossrefGoogle Scholar
  • 23a Jeffery T. David M. Tetrahedron Lett.  1998,  39:  5751 
    CrossrefGoogle Scholar
  • 23b Jeffery T. Tetrahedron  1996,  52:  10113 
    CrossrefGoogle Scholar
  • Reviews:
  • 23c De Meijere A. Meyer FE. Angew. Chem., Int. Ed. Engl.  1994,  33:  2379 
    CrossrefGoogle Scholar
  • 23d Jeffery T. In Advances in Metal-Organic Chemistry   Vol. 5:  Liebeskind LS. JAI Press; Greenwich CT: 1996.  p.153-260  
    CrossrefGoogle Scholar
  • 24 For a recent synthesis of 7-hydroxy-indole, see: Lerman L. Weinstock-Rosin M. Nudelman A. Synthesis  2004,  3043 
    Article in Thieme ConnectGoogle Scholar
  • 25 Bosch J. Roca T. Armengol M. Fernandez-Forner D. Tetrahedron  2001,  57:  1041 ; see also ref. 22
    CrossrefGoogle Scholar
  • 26 For a review on iodination of aryl compounds, see: Merkushev EB. Synthesis  1988,  923 
    Article in Thieme ConnectGoogle Scholar
  • 27 This side reaction is not observed with 2-nitro aniline: Ragagnin G. Knochel P. Synlett  2004,  951 
    Article in Thieme ConnectGoogle Scholar
  • Bis(pyridine)iodonium(I) tetrafluoroborate is also efficient for high-yielding selective iodination of aniline; see ref. 12a and:
  • 28a Barluenga J. Gonzalez JM. Garcia-Martin MA. Campos PJ. Asensio G. J. Org. Chem.  1993,  58:  2058 
    CrossrefGoogle Scholar
  • 28b Barluenga J. Rodriguez MA. Campos PJ. J. Org. Chem.  1990,  55:  3104 
    CrossrefGoogle Scholar
  • 29 Gardiner JM. Loyns CR. Schwalbe CH. Barrett GC. Lowe PR. Tetrahedron  1995,  51:  4101.  Methyl 4-bromo-1-hydroxy-2-[(E)-prop-1-enyl]-1H-benzimidazole-6-carboxylate(23a) has the following characteristics: white solid; mp 186-188 °C; 1H NMR (400 MHz, DMSO-d 6): δ = 2.02 (dd, J = 7.2, 2.0 Hz, 3 H), 3.89 (s, 3 H), 6.68 (dd, J = 14.0, 2.0 Hz, 1 H), 7.17 (dq, J = 14.0, 7.2 Hz, 1 H), 7.95 (s, 1 H), 8.00 (s, 1 H), 12.70 (br s, 1 H); 13C NMR (100.6 MHz, DMSO-d 6): δ = 18.7, 52.3, 110.2, 111.4, 116.0, 124.1, 125.1, 132.4, 138.6, 139.5, 150.2, 165.3; ESI-MS: m/z = 310.9, 312.9 [M + H+]
    CrossrefGoogle Scholar
  • 31 Hegedus LS. Mulhern TA. Mori A. J. Org. Chem.  1985,  50:  4282 ; See also ref. 17b
    CrossrefGoogle Scholar
  • 32 Sakamoto T. Kondo Y. Uchiyama M. Yamanaka H. J. Chem. Soc., Perkin Trans. 1  1993,  1941 
    CrossrefGoogle Scholar
  • Sulfonamide:
  • 35a Krolski ME. Renaldo AF. Rudisill DE. Stille JK. J. Org. Chem.  1988,  53:  1170 
    CrossrefGoogle Scholar
  • Acetanilide:
  • 35b Kasahara A. Izumi T. Murakami S. Miyamoto K. Hino T. J. Heterocycl. Chem.  1989,  26:  1405 
    CrossrefGoogle Scholar
  • Anilines:
  • 35c Yamaguchi M. Arisawa M. Hirama M. Chem. Commun.  1998,  1399 
    CrossrefGoogle Scholar
  • 35d Adams DR. Duncton MAJ. Roffey JRA. Spencer J. Tetrahedron Lett.  2002,  43:  7581 
    CrossrefGoogle Scholar
  • 36 The synthesis of indoles from 2-halogenated anilines and a (2-alkoxyvinyl)boronic ester, followed by hydrolysis and in situ cyclisation has also been described. However, the synthesis of the (2-alkoxyvinyl)boronic ester requires two steps and we felt this route would not offer significant advantages compared to the others (see below): Satoh M. Miyaura N. Suzuki A. Synthesis  1987,  373 
    Article in Thieme ConnectGoogle Scholar
  • 41 Wheeler L. Am. Chem. J.  1909,  42:  457 
    Google Scholar
  • 42 Dains V. Vaughan J. J. Am. Chem. Soc.  1918,  40:  932 
    Google Scholar
  • 43 Borsche W. Stackmann L. Makaroff-Semljanski J. Chem. Ber.  1916,  49:  2230 
    Google Scholar
2

A search for the indole core in the WDI database retrieved more than 3700 hits. See also ref. 12a.

21

The synthesis of the 7-substituted indoles will be described with ethyl or n-propyl at the 3-position. The synthetic routes described in this paper are applicable to both substituents.

30

An NOE experiment proved that the stereochemistry of the exocyclic double bond is as shown in Scheme [7] .

33

See references 133d and 136a-e cited in ref. 7b.

34

Compounds 28a and 28b are drawn as acids for convenience, but are isolated as trimers. See ref. 20a.

37

The structure of 30 was assigned by an NOE experiment.

38

We ensured that we were able to reproduce Larock’s results on 2-iodoaniline. Under the same conditions, methyl 4-amino-3-iodo-benzoate gave a 94:6 mixture of isomers. Within this set of examples, the selectivity appears related to the electron deficiency of the aromatic ring.

39

We did not attempt to increase the yield of the ring formation by using substituents more stable than trimethylsilyl to the reaction conditions, since the yield obtained was adequate for our purposes.

40

Removal of the trifluoroacetamido group proved easier for 25 (deprotection takes 45 minutes at room temperature) than for 14 (deprotection not complete after two days under similar conditions).