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Synlett 2009(5): 808-812  
DOI: 10.1055/s-0028-1087951
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Palladium-Catalyzed Direct C-3 Arylations of Indoles with an Air-Stable HASPO

Lutz Ackermann*, Sebastian Barfüßer
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstr. 2, 37077 Göttingen, Germany
Fax: +49(551)396777; e-Mail: Lutz.Ackermann@chemie.uni-goettingen.de;
Further Information

Publication History

Received 11 December 2008
Publication Date:
24 February 2009 (online)

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Abstract

Efficient direct arylations of indoles occurred highly ­regioselectively at position C-3 with an in situ generated palladium complex derived from an air-stable HASPO, which enabled syntheses of diversely functionalized indoles, also with sterically hindered substrates.

Key words

C-H bond functionalization - heteroarenes - indoles - ­regioselectivity - palladium

    References and Notes

  • 1 Horton DA. Bourne GT. Smythe ML. Chem. Rev.  2003,  103:  893 
    CrossrefPubMedGoogle Scholar
  • 2 Humphrey GR. Kuethe JT. Chem. Rev.  2006,  106:  2875 
    CrossrefPubMedGoogle Scholar
  • 3 Eicher T. Hauptmann S. The Chemistry of Heterocycles   2nd ed.:  Wiley-VCH; Weinheim: 2003. 
    Google Scholar
  • 4 Gilchrist TL. Heterocyclic Chemistry   3rd ed.:  Addison Wesley Longman; Harlow: 1997. 
    Google Scholar
  • 5 Joule JA. Milles K. Heterocyclic Chemistry   4th ed.:  Blackwell Science Ltd; Oxford: 2000. 
    Google Scholar
  • 6 Ackermann L. Synlett  2007,  507 
    Article in Thieme ConnectGoogle Scholar
  • 7 Cacchi S. Fabrizi G. Chem. Rev.  2005,  105:  2873 
    CrossrefPubMedGoogle Scholar
  • 8 Krüger K. Tillack A. Beller M. Adv. Synth. Catal.  2008,  350:  2153 
    CrossrefGoogle Scholar
  • 9 Ackermann L. Modern Arylation Reactions   Wiley-VCH; Weinheim: 2009. 
    Google Scholar
  • Palladium-catalyzed cross-dehydrogenative arylations can proceed regioselectively at indoles. However, they display limited selectivities with respect to the coupling partner and rely on the use of (over)stoichiometric amounts of Cu(OAc)2 or AgOAc as terminal oxidants:
  • 10a Potavathri S. Dumas AS. Dwight TA. Naumiec GR. Hammann JM. DeBoef B. Tetrahedron Lett.  2008,  49:  4050 
    Google Scholar
  • 10b Stuart DR. Villemure E. Fagnou K. J. Am. Chem. Soc.  2007,  129:  12072 
    Google Scholar
  • 10c Dwight TA. Rue NR. Charyk D. Josselyn R. DeBoef B. Org. Lett.  2007,  9:  3137 
    Google Scholar
  • 10d Stuart DR. Fagnou K. Science  2007,  316:  1172 ; and references cited therein
    Google Scholar
  • For rhodium-catalyzed direct arylations of indoles, occurring largely with C-2 regioselectivity, see:
  • 11a Yanagisawa S. Sudo T. Noyori R. Itami K. Tetrahedron  2008,  64:  6073 
    Google Scholar
  • 11b Yanagisawa S. Sudo T. Noyori R. Itami K. J. Am. Chem. Soc.  2006,  128:  11748 
    Google Scholar
  • 11c Wang X. Lane BS. Sames D. J. Am. Chem. Soc.  2005,  127:  4996 
    Google Scholar
  • 12 Stoichiometrically magnesiated indoles were shown to give rise to C-3 arylated indoles: Lane BS. Brown MA. Sames D. J. Am. Chem. Soc.  2005,  127:  8050 
    CrossrefGoogle Scholar
  • 13 de Mendoza P. Echavarren AM. In Modern Arylation Methods   Ackermann L. Wiley-VCH; Weinheim: 2009.  p.363 
    Google Scholar
  • 14a Seregin IV. Gevorgyan V. Chem. Soc. Rev.  2007,  36:  1173 
    Google Scholar
  • 14b Alberico D. Scott ME. Lautens M. Chem. Rev.  2007,  107:  174 
    Google Scholar
  • Selected recent representative examples of palladium-catalyzed direct arylations of indoles:
  • 15a Lebrasseur N. Larrosa I. J. Am. Chem. Soc.  2008,  130:  2926 
    Google Scholar
  • 15b Zhao J. Zhang Y. Cheng K. J. Org. Chem.  2008,  73:  7428 
    Google Scholar
  • 15c Yang S.-D. Sun C.-L. Fang Z. Li B.-J. Li Y.-Z. Shi Z.-J. Angew. Chem. Int. Ed.  2008,  47:  1473 
    Google Scholar
  • 15d Bellina F. Calandri C. Cauteruccio S. Rossi R. Eur. J. Org. Chem.  2007,  2147 
    Google Scholar
  • 15e Deprez NR. Kalyani D. Krause A. Sanford MS. J. Am. Chem. Soc.  2006,  128:  4972 ; and references cited therein
    Google Scholar
  • 16 For elegant site-selective copper-catalyzed direct C-3 arylations of indoles employing [Ar2I]X as arylating reagents, see: Phipps RJ. Grimster NP. Gaunt MJ. J. Am. Chem. Soc.  2008,  130:  8172 
    Google Scholar
  • 17 For an early example of regioselective direct arylations of indoles, see: Akita Y. Itagaki Y. Takizawa S. Ohta A. Chem. Pharm. Bull.  1989,  37:  1477 
    CrossrefGoogle Scholar
  • 18 Ackermann L. Synthesis  2006,  1557 
    Article in Thieme ConnectGoogle Scholar
  • 19 Zhang Z. Hu Z. Yu Z. Lei P. Chi H. Wang Y. He R. Tetrahedron Lett.  2007,  48:  2415 
    CrossrefGoogle Scholar
  • For the recent use of a heterogenous palladium catalyst for direct C-3 arylations of 2-substituted indoles, see:
  • 20a Cusati G. Djakovitch L. Tetrahedron Lett.  2008,  49:  2499 
    Google Scholar
  • 20b For a direct C-3 arylation of a 2-substituted indole, see: Djakovitch L. Dufaud V. Zaidi R. Adv. Synth. Catal.  2006,  348:  715 
    Google Scholar
  • 21 For a recent report on the application of PCy3 or Bn(n-Bu)3NCl to palladium-catalyzed direct C-3 arylations of indoles, including 2-substituted ones, see: Bellina F. Benelli F. Rossi R. J. Org. Chem.  2008,  73:  5529 
    CrossrefGoogle Scholar
  • 22a Ackermann L. Org. Lett.  2005,  7:  439 
    Google Scholar
  • 22b Kaspar LT. Ackermann L. Tetrahedron  2005,  61:  11311 
    Google Scholar
  • 23 Ackermann L. Kaspar LT. Gschrei CJ. Chem. Commun.  2004,  2824 
    CrossrefGoogle Scholar
  • 24 Ackermann L. Sandmann R. Villar A. Kaspar LT. Tetrahedron  2008,  64:  769 
    CrossrefGoogle Scholar
  • 25a Ackermann L. Born R. Angew. Chem. Int. Ed.  2005,  44:  2444 
    Google Scholar
  • 25b Ackermann L. Gschrei CJ. Althammer A. Riederer M. Chem. Commun.  2006,  1419 
    Google Scholar
  • 25c Ackermann L. Spatz JH. Gschrei CJ. Born R. Althammer A. Angew. Chem. Int. Ed.  2006,  45:  7627 
    Google Scholar
  • 26 Ackermann L. Org. Lett.  2005,  7:  3123 
    CrossrefPubMedGoogle Scholar
  • 27 Ackermann L. Althammer A. Born R. Angew. Chem. Int. Ed.  2006,  45:  2619 
    CrossrefPubMedGoogle Scholar
  • For recent examples of palladium-catalyzed direct arylations from our laboratories, see:
  • 28a Ackermann L. Althammer A. Fenner S. Angew. Chem. Int. Ed.  2009,  48:  201 
    Google Scholar
  • 28b Ackermann L. Vicente R. Born R. Adv. Synth. Catal.  2008,  350:  741 
    Google Scholar
  • 28c Ackermann L. Althammer A. Angew. Chem. Int. Ed.  2007,  46:  1627 
    Google Scholar
  • 29 Unfortunately, under otherwise identical reaction conditions catalytic amounts of Bn(n-Bu)3NCl²¹ provided product 3a with lower isolated yields, as did the P-para-tolylated phosphonate derived from HASPO 4h (63%)
  • Carboxylic acids were used as additives in palladium- and ruthenium-catalyzed direct arylation reactions, which are believed to proceed through a concerted metalation-deprotonation mechanism: [Pd]:
  • 30a Lafrance M. Fagnou K. J. Am. Chem. Soc.  2006,  128:  16496 
    Google Scholar
  • 30b [Ru]: Lafrance M. Gorelsky SI. Fagnou K. J. Am. Chem. Soc.  2007,  129:  14570 
    Google Scholar
  • 30c Ackermann L. Vicente R. Althammer A. Org. Lett.  2008,  10:  2299 
    Google Scholar
  • 30d Ackermann L. Mulzer M. Org. Lett.  2008,  10:  5043 ; and references cited therein
    Google Scholar
31

Representative Procedure - Synthesis of 3a (Table 1, Entry 10)
A suspension of Pd(OAc)2 (5.6 mg, 0.025 mmol, 5.0 mol%) and 4h (28.4 mg, 0.05 mmol, 10 mol%) in dry dioxane (1 mL) was stirred for 30 min under N2 at ambient temperature. K2CO3 (207.0 mg, 1.50 mmol), indole (1a, 59.0 mg, 0.50 mmol), and 4-bromotoluene (2a, 106.0 mg, 0.62 mmol) were added, and the suspension was stirred at 95 ˚C for 20 h. After the reaction mixture was cooled to ambient temperature, Et2O (50 mL) and brine (50 mL) were added. The aqueous phase was extracted with Et2O (2 × 50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The remaining residue was purified by column chromatography on SiO2 (n-hexane-EtOAc, 10:1) to yield 3a (97.0 mg, 94%) as a pale yellow solid; mp 107.4-108.3 ˚C). ¹H NMR (300 MHz, DMSO-d 6): δ = 11.27 (br s, 1 H), 7.86 (d, J = 7.6 Hz, 1 H), 7.64-7.56 (m, 3 H), 7.47 (d, J = 7.8 Hz, 1 H), 7.24 (d, J = 8.2 Hz, 2 H), 7.19-7.07 (m, 2 H), 2.34 (s, 3 H). ¹³C NMR (75 MHz, DMSO-d 6): δ = 136.8 (Cq), 134.1 (Cq), 132.9 (Cq), 129.2 (CH), 126.3 (CH), 125.0 (Cq), 122.8 (CH), 121.2 (CH), 119.4 (CH), 118.9 (CH), 115.6 (Cq), 111.8 (CH), 20.6 (CH3). IR (KBr): 3387, 2361, 2337, 1653, 1617, 1116, 802, 747 cm-¹. MS (EI): m/z (%) = 207 (100) [M+], 206 (37), 117 (12), 90 (8). ESI-HRMS: m/z calcd for C15H14N 208.1121: found: 208.1121. The spectral data are in accordance with those reported in the literature. [¹9]

32

Analytical Data Indole 3i: mp 80.3-82.2 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 8.19 (br s, 1 H), 7.62 (t, J = 1.8 Hz, 1 H), 7.53 (dt, J = 7.7, 1.6 Hz, 1 H), 7.39-7.23 (m, 5 H), 6.93 (dd, J = 8.8, 2.4 Hz, 1 H), 3.88 (s, 3 H). ¹³C NMR (126 MHz, CDCl3): δ = 154.9 (Cq), 137.5 (Cq), 134.6 (Cq), 131.7 (Cq), 130.0 (CH), 127.1 (CH), 125.9 (Cq), 125.8 (CH), 125.3 (CH), 123.0 (CH), 116.8 (Cq), 112.7 (CH), 112.2 (CH), 101.5 (CH), 56.0 (CH3). IR (KBr): 3391, 1620, 1594, 1485, 1440, 1271, 1214, 791 cm-¹. MS (EI): m/z (%) = 257 (100) [M+], 242 (26), 215 (33), 178 (13), 152 (15) 128 (11). ESI-HRMS: m/z calcd for C15H13ClNO: 258.0680; found: 258.0682.
Indole 3k: mp 134.1-135.8 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 8.07 (br s, 1 H), 7.84 (d, J = 7.9 Hz, 1 H), 7.53-7.50 (m, 2 H), 7.40-7.32 (m, 2 H), 7.18-7.07 (m, 3 H), 2.52 (s, 3 H), 2.46 (s, 3 H). ¹³C NMR (126 MHz, CDCl3): δ = 138.2 (Cq), 136.1 (Cq), 135.5 (Cq), 128.6 (CH), 128.1 (CH), 126.7 (CH), 125.2 (Cq), 124.5 (CH), 122.8 (CH), 121.4 (CH), 120.4 (Cq), 120.4 (CH), 118.8 (Cq), 117.6 (CH), 21.7 (CH3), 16.6 (CH3). IR (KBr): 3411, 1653, 1635, 1540, 1457, 1113, 789, 751 cm-¹. MS (EI): m/z (%) = 221 (100) [M+], 204 (10), 178 (10), 110 (6), 102 (7). ESI-HRMS: m/z calcd for C16H16N: 222.1277; found: 222.1277.
Indole 3l: mp 113.0-115.2 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 7.92 (br s, 1 H), 7.65 (d, J = 7.4 Hz, 1 H), 7.38-7.28 (m, 4 H), 7.18-7.07 (m, 3 H), 2.50 (s, 3 H), 2.42 (s, 3 H). ¹³C NMR (126 MHz, CDCl3): δ = 137.9 (Cq), 135.2 (Cq), 135.1 (Cq) 131.2 (Cq), 130.0 (CH), 128.3 (CH), 127.8 (Cq), 126.5 (CH), 126.4 (CH), 121.4 (CH), 119.8 (CH), 118.8 (CH), 114.5 (Cq), 110.2 (CH), 21.7 (CH3), 12.7 (CH3). IR (KBr): 3392, 1682, 1653, 1559, 1457, 1306, 792, 746 cm-¹. MS (EI): m/z (%) = 221 (100) [M+], 204 (20), 178 (9), 130 (15), 102 (15). ESI-HRMS: m/z calcd for C16H16N: 222.1277; found: 222.1272.