Synlett 2004(11): 1965-1969  
DOI: 10.1055/s-2004-830861
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 2-Substituted Indoles via Pd/C-Catalyzed Reaction in Water [1]

Manojit Pal*, Venkataraman Subramanian, Venkateswara Rao Batchu, Indu Dager
Chemistry-Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500049, India
Fax: +91(40)23045438; Fax: +91(40)23045007; e-Mail: manojitpal@drreddys.com ;
Further Information

Publication History

Received 7 March 2004
Publication Date:
06 August 2004 (online)

Abstract

A general and one-pot synthesis of 2-alkyl/aryl substituted indoles via a tandem Pd/C mediated coupling/5-endo-dig cyclization of terminal alkynes (including acetylenic carbinols) with o-iodoanilides in water is reported. The reaction is carried out using PPh3 and CuI as co-catalysts and 2-aminoethanol as a base. The reaction appears to tolerate a variety of functional groups present in the alkynes and does not require the use of any organic co-solvent.

1

DRL publication No 427.

    References

  • For a review, see:
  • 2a Sundberg RJ. Pyrroles and their Benzo Derivatives: Synthesis and Applications, In Comprehensive Heterocyclic Chemistry   Vol. 4:  Katritzky AR. Rees CW. Pergamon; Oxford: 1984.  p.313-376  
  • 2b Lounasmaa M. Tolvanen A. Nat. Prod. Rep.  2000,  17:  175 
  • 3 Young WB. Kolesnikov A. Rai R. Sprengeler PA. Leahy EM. Shrader WD. Sangalang J. Burgess-Henry J. Spencer J. Elrod K. Cregar L. Bioorg. Med. Chem. Lett.  2001,  11:  2253 
  • 4 Mackman RL. Hui HC. Breitenbucher JG. Katz BA. Luong C. Martelli A. McGee D. Radika K. Sendzik M. Spencer JR. Sprengeler PA. Tario J. Verner E. Wang J. Bioorg. Med. Chem. Lett.  2002,  12:  2019 
  • 5 Chai W. Breitenbucher JG. Kwok A. Li X. Wong V. Carruthers NI. Lovenberg TW. Mazur C. Wilson SJ. Axe FU. Jones TK. Bioorg. Med. Chem. Lett.  2003,  13:  1767 
  • 6 For a recent review on indole ring synthesis, see: Gribble GW. J. Chem. Soc., Perkin Trans. 1  2000,  1045 
  • For Cu-mediated process, see:
  • 7a Cacchi S. Fabrizi G. Parisi LM. Org. Lett.  2003,  5:  3843 
  • 7b Ezquerra J. Pedregal C. Lamas C. Barluenga J. Perez M. Garcia-Martin MA. Gonzalez JM. J. Org. Chem.  1996,  61:  5804 
  • 7c Hiroya K. Itoh S. Ozawa M. Kanamori Y. Sakamoto T. Tetrahedron Lett.  2002,  43:  1277 
  • 8a Hong KB. Lee CW. Yum EK. Tetrahedron Lett.  2004,  45:  693 
  • 8b Dai W.-M. Sun L.-P. Guo D.-S. Tetrahedron Lett.  2002,  43:  7699 
  • 8c Dai W.-M. Guo D.-S. Sun L.-P. Tetrahedron Lett.  2001,  42:  5275 
  • 8d Zhang HC. Ye H. White KB. Maryanoff BE. Tetrahedron Lett.  2001,  42:  4751 
  • 8e Zhang HC. Ye H. Moretto AF. Brumfield KK. Maryanoff BE. Org. Lett.  2000,  2:  89 
  • 8f Fagnola MC. Candiani I. Visentin G. Cabri W. Zarini F. Mongelli N. Bedeschi A. Tetrahedron Lett.  1997,  38:  2307 
  • 8g Arcadi A. Cacchi S. Marinelli F. Tetrahedron Lett.  1992,  33:  3915 
  • 8h Sakamoto T. Kondo Y. Yamanaka H. Heterocycles  1988,  27:  2225 
  • 8i Kabalka GW. Wang L. Pagni RM. Tetrahedron  2001,  57:  8017 
  • 9a Roesch KR. Larock RC. Org. Lett.  1999,  1:  1551 
  • 9b Larock RC. Yum EK. Refvik MD. J. Org. Chem.  1998,  63:  7652 
  • 9c Zhang H.-C. Brumfield KK. Maryanoff BE. Tetrahedron Lett.  1997,  38:  2439 
  • 9d Chen CY. Lieberman DR. Larsen RD. Reamer RA. Verhoven TR. Reider PJ. Cottrell IF. Houghton PG. Tetrahedron Lett.  1994,  35:  6981 
  • 9e Jeschke T. Wensbo D. Annby U. Gronowitz S. Cohen LA. Tetrahedron Lett.  1993,  34:  6471 
  • 9f Larock RC. Yum EK. J. Am. Chem. Soc.  1991,  113:  6689 
  • For Pd-mediated coupling reactions of haloindoles; see:
  • 10a Liu Y. Gribble GW. Tetrahedron Lett.  2000,  41:  8717 
  • 10b Zhang H.-C. Ye H. White KB. Maryanoff BE. Tetrahedron Lett.  2001,  42:  4751 
  • 11a Sakamoto T. Kondo Y. Iwashita S. Nagano T. Yamanaka H. Chem. Pharm. Bull.  1988,  36:  1305 
  • 11b Amjad M. Knight DW. Tetrahedron Lett.  2004,  45:  539 
  • 11c Mackman RL. Katz BA. Breitenbucher JG. Hui HC. Verner E. Luong C. Liu L. Sprengeler PA. J. Med. Chem.  2001,  44:  3856 
  • 11d Kundu NG. Mahanty JS. Das P. Das B. Tetrahedron Lett.  1993,  34:  1625 
  • 11e For palladium mediated cyclization of 2-alkynylanilines see: Takeda A. Kamijo S. Yamamoto Y. J. Am. Chem. Soc.  2000,  122:  5662 
  • 12a Leadbeater NE. Marco M. Tominack BJ. Org. Lett.  2003,  5:  3919 
  • 12b Aqueous-Phase Organometallic Catalysis, Concepts and Applications   Cornils B. Herrmann WA. Wiley-VCH; Weinheim: 1998. 
  • 13a Lopez-Deber MP. Castedo L. Granja JR. Org. Lett.  2001,  3:  2823 
  • 13b Pierre Genet J. Savignac M. J. Organomet. Chem.  1999,  576:  305 
  • 13c Mori A. Ahmed MSM. Sekiguchi A. Masui K. Koike T. Chem. Lett.  2002,  756 
  • 13d Bumagin NA. Sukhomlinova LI. Luzikova EV. Tolstaya TP. Beletskaya IP. Tetrahedron Lett.  1996,  37:  897 
  • 13e Uozumi Y. Kobayashi Y. Heterocycles  2003,  59:  71 
  • 13f Amatore C. Blart E. Genet JP. Jutand A. Lemaire-Audoire S. Savignac M. J. Org. Chem.  1995,  60:  6829 
  • 13g Casalnuovo AL. Calabrese JC. J. Am. Chem. Soc.  1990,  112:  4324 
  • 13h Dibowski H. Schmidtchen FP. Tetrahedron Lett.  1998,  39:  525 
  • 14 De la Rosa MA. Velarde E. Guzman A. Synth. Commun.  1990,  20:  2059 
  • 15a Novak Z. Szabo A. Repasi J. Kotschy A. J. Org. Chem.  2003,  68:  3327 
  • 15b For the use of Pd(OH)2/C as catalyst, see: Mori Y. Seki M. J. Org. Chem.  2003,  68:  1571 
  • 15c Heidenreich RG. Köhler K. Krauter JGE. Pietsch J. Synlett  2002,  1118 
  • 15d Felpin F.-X. Vo-Thanh G. Villiéras J. Lebreton J. Tetrahedron: Asymmetry  2001,  12:  1121 
  • 15e Bates RW. Boonsombat J. J. Chem. Soc., Perkin Trans. 1  2001,  654 
  • 15f Bleicher LS. Cosford NDP. Herbaut A. McCallum JS. McDonald IA. J. Org. Chem.  1998,  63:  1109 
  • 15g Bleicher L. Cosford NDP. Synlett  1995,  1115 
  • 15h Potts KT. Horwitz CP. Fessak A. Keshavarz KM. Nash KE. Toscano PJ. J. Am. Chem. Soc.  1993,  115:  10444 
  • 16a Pal M. Parasuraman K. Subramanian V. Dakarapu R. Yeleswarapu KR. Tetrahedron Lett.  2004,  45:  2305 
  • 16b Pal M. Parasuraman K. Yeleswarapu KR. Org. Lett.  2003,  5:  349 
  • 16c Pal M. Subramanian V. Parasuraman K. Yeleswarapu KR. Tetrahedron  2003,  59:  9563 
  • 16d Pal M. Parasuraman K. Gupta S. Yeleswarapu KR. Synlett  2002,  1976 
  • 16e Pal M. Kundu NG. J. Chem. Soc., Perkin Trans. 1  1996,  449 
  • 17a Pal M. Subramanian V. Yeleswarapu KR. Tetrahedron Lett.  2003,  44:  8221 
  • 17b Kundu NG. Pal M. J. Chem. Soc., Chem. Commun.  1993,  86 
  • 17c Kundu NG. Pal M. Mahanty JS. Dasgupta SK. J. Chem. Soc., Chem. Commun.  1992,  41 
  • 18a Radl S. Hezky P. Urbankova J. Vachal P. Krejci I. Collect. Czech. Chem. Commun.  2000,  65:  280 
  • 18b For biological activities of 5-methylindoles, see: Dai J. Sun B. Zhang A. Lin K. Wang L. Bull. Environ. Contam. Toxicol.  1998,  61:  591 
  • 18c Kon-Ya K. Shimidzu N. Miki W. Endo M. Biosci. Biotechnol. Biochem.  1994,  58:  2178 
  • 18d For our recent synthesis of indole derivatives, see: Pal M. Dakarapu R. Padakanti S. J. Org. Chem.  2004,  69:  2913 
  • 19a o-Iodoanilides were prepared according to the procedure described in the literature, see: Xiao W.-J. Alper H. J. Org. Chem.  1999,  64:  9646 
  • 19b

    All the terminal alkynes used are commercially available.

  • 19c

    General Procedure for the Preparation of 2-Substituted Indoles(4): A mixture of 1e (1.60 mmol), 10% Pd/C (51 mg, 0.05 mmol), PPh3 (50 mg, 0.19 mmol), CuI (18 mg, 0.09 mmol) and 2-aminoethanol (4.83 mmol) in H2O (8 mL) was stirred at 25 °C for 1 h under nitrogen. The acetylenic compound 2 (4.00-5.00 mmol) was added slowly to the mixture with stirring. The reaction mixture was then stirred at 80 °C for the time indicated in Table [1] . The mixture was cooled to r.t., diluted with EtOAc (120 mL) and filtered through celite. The filtrate was collected, washed with cold H2O (2 × 75 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue thus obtained was purified by column chromatography (hexane-EtOAc) to afford the desired product.
    Spectral and analytical data for 4a: light brown solid; yield 70%; mp 128-130 °C (hexane). 1H NMR (200 MHz, CDCl3): δ = 7.98 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 2.5 Hz, 1 H), 7.43-7.38 (m, 5 H), 7.19 (d, J = 8.4 Hz, 1 H), 6.65 (s, 1 H), 2.69 (s, 3 H, SO2CH3), 2.46 (s, 3 H, CH3). MS (CI): m/z = 286 (100) [M + 1]. IR (neat): 1586.1, 1462.5, 1361.1 cm-1. 13C NMR (50 MHz, CDCl3): δ = 142.08, 136.24, 134.20, 131.99, 130.55, 129.96 (2 C), 128.68, 127.60 (2 C), 126.39, 120.88, 115.50, 112.98, 38.91 (SO2CH3), 21.18 (CH3). HPLC: 97.3% [Symmetry Shield RP18 (250 × 4.6 mm), 0.01 M KH2PO4:MeCN, 1 mL/min 225 nm, retention time 13.7 min]. Elemental analysis found C, 67.39; H, 5.35; N, 4.89; C16H15NO2S requires C, 67.34; H, 5.30; N. 4.91%.
    Compound 4g: light brown solid; yield 80%; mp 78-80 °C (hexane). 1H NMR (200 MHz, CDCl3): δ = 7.89 (d, J = 8.7 Hz, 1 H), 7.34 (s, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 6.62 (s, 1 H), 5.02 (d, J = 7.9 Hz, 1 H), 3.09 (s, 3 H), 2.94 (d, J = 5.9 Hz, D2O exchangeable, OH), 2.43 (s, 3 H), 2.07-1.97 (m, 2 H), 1.09 (t, J = 7.3 Hz, 3 H). MS (CI): m/z = 250 (100) [M+ - OH]. IR (neat): 3540.1, 1462.4, 1358.0, 1159.6 cm-1. 13C NMR (50 MHz, CDCl3): δ = 143.42, 135.06, 133.29, 129.16, 126.19, 121.01, 113.67, 108.36, 67.76 (CHOH), 40.12 (SO2CH3), 28.59 (CH2), 20.98 (CH3), 10.53 (CH3). HPLC: 99.3% [Inertsil ODS 3V (250 × 4.6 mm), 0.01 M KH2PO4 in MeCN, 1 mL/min, 220 nm, retention time 16.6 min]. Elemental analysis found C, 58.38; H, 6.40; N, 5.27; C13H17NO3S requires C, 58.40; H, 6.41; N. 5.24%.

  • 20 Although the methanesulfonyl group of iodoarene 1e was tolerated under the present reaction conditions this group was removed efficiently from 4 using tetrabutylammonium fluoride in THF at elevated temperature to afford the corresponding indoles in good yields, see: Yasuhara A. Sakamoto T. Tetrahedron Lett.  1998,  39:  595 
  • 21a Sonogashira K. Tohda Y. Hagihara N. Tetrahedron Lett.  1975,  16:  4467 
  • 21b Novak Z. Szabo A. Repasi J. Kotschy A. J. Org. Chem.  2003,  68:  3327 
  • 21c Mori Y. Seki M. J. Org. Chem.  2003,  68:  1571 
  • 21d De la Rosa MA. Velarde E. Guzman A. Synth. Commun.  1990,  20:  2059 
  • 22a Amatore C. Jutand A. Acc. Chem. Res.  2000,  33:  314 
  • 22b Amatore C. Jutand A. Khalil F. M’Barki MA. Mottier L. Organometallics  1993,  12:  3168 
  • 22c The anionic species generated from Pd(PPh3)2Cl2 is thought to be the key intermediate and participates as active palladium species in these cross-coupling reactions, see: Grosshenny V. Romero FM. Ziessel R. J. Org. Chem.  1997,  62:  1491 
  • 22d Amatore C. Jutand A. J. Am. Chem. Soc.  1993,  115:  9531 
  • 23 Indole 4h was converted to the corresponding ketone using MnO2 in CH2Cl2 according to the procedure described in the literature. These ketones are of interest as analgesics.18a See: Jiang J. Gribble GW. Synth. Commun.  2002,  32:  2035 
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DRL publication No 427.