Download PDF
Synlett 2009(11): 1817-1821  
DOI: 10.1055/s-0029-1217377
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Palladium-Catalyzed Synthesis of Free-NH Indole 2-Acetamides and Derivatives from Ethyl 3-(o-Trifluoroacetamidoaryl)-1-propargylic Carbonates

Sandro Cacchi*, Giancarlo Fabrizi, Eleonora Filisti
Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi ‘La Sapienza’, P.le A. Moro 5, 00185 Rome, Italy
Fax: +39(06)49912780; e-Mail: sandro.cacchi@uniroma1.it;
Further Information

Publication History

Received 17 March 2009
Publication Date:
12 June 2009 (online)

    Permissions and Reprints All articles of this category

Abstract

The reaction of ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates with primary or secondary amines in the presence of Pd2(dba)3, dppf, and carbon monoxide in THF at 80 ˚C provides ready access to free-NH indole 2-acetamides. The reaction can be applied to the synthesis of free-NH indole 2-acetic acid methyl esters.

Key words

palladium - carbonylation - indoles - alkynes - propargylic esters

    References and Notes

  • For some selected recent reviews, see:
  • 1a Zeni G. Larock RC. Chem. Rev.  2004,  104:  2285 
    Google Scholar
  • 1b Alonso F. Beletskaya IP. Yus M. Chem. Rev.  2004,  104:  3079 
    Google Scholar
  • 1c Nakamura I. Yamamoto Y. Chem. Rev.  2004,  104:  2127 
    Google Scholar
  • 1d Cacchi S. Fabrizi G. Chem. Rev.  2005,  105:  2873 
    Google Scholar
  • 1e Humphrey GR. Kuethe JT. Chem. Rev.  2006,  106:  2875 
    Google Scholar
  • 1f Ackermann L. Synlett  2007,  507 
    Google Scholar
  • 1g Krüger K. Tillack A. Beller M. Adv. Synth. Catal.  2008,  350:  2153 
    Google Scholar
  • 2a Abou-Gharbia MA. US 4748247, Chem. Abstr.  1988,  109:  129055 
    Google Scholar
  • 2b Weber D. Berger C. Eickelmann P. Antel J. Kessler H. J. Med. Chem.  2003,  46:  1918 
    Google Scholar
  • 2c Mjalli AMM. Andrews RC. Yarragunta RR.
    Xie     R. Ren T. Subramanian G. Quada JC. WO 20040212 Chem. Abstr.  2004,  141:  225511 
    Google Scholar
  • 3a Sundberg RJ. Hong J. Smith SQ. Sabat M. Tetrahedron  1998,  54:  6259 
    Google Scholar
  • 3b Phillips AJ. Uto Y. Wipf P. Reno MJ. Williams DR. Org. Lett.  2000,  2:  11656 
    Google Scholar
  • 4 Kidwai M. Misra P. Bhushan KR. Saxena RK. Singh M. Monatsh. Chem.  2000,  131:  937 
    CrossrefGoogle Scholar
  • 5 Katritzky AR. Akutagawa K. J. Am. Chem. Soc.  1986,  108:  6808 
    CrossrefGoogle Scholar
  • 6a Ambrogio I. Cacchi S. Fabrizi G. Org. Lett.  2006,  10:  2083 
    Google Scholar
  • 6b Ambrogio I. Cacchi S. Fabrizi G. Tetrahedron Lett.  2007,  48:  7721 
    Google Scholar
  • For some recent selected references on the formation of urea derivatives via palladium-catalyzed reactions of amines with carbon monoxide, see:
  • 9a Gabriele B. Salerno G. Mancuso R. Costa M. J. Org. Chem.  2004,  69:  4741 
    Google Scholar
  • 9b Nishiyama Y. Kawamatsu H. Sonoda N. J. Org. Chem.  2005,  70:  2551 
    Google Scholar
7

Compounds 1b, 1c and 1f were prepared via Sonogashira cross-coupling of o-iodoanilines with the THP derivative of propargyl alcohol. The cross-coupling products were treated with (CF3CO)2O. The resultant trifluoroacetamido derivatives were deprotected and subjected to ethyl chlorocarbonate to give the title propargylic esters.

8

Typical Procedure for the Preparation of Free-NH Indole 2-Acetamides (3): A stainless steel reaction vessel was charged with 1a (94.5 mg, 0.3 mmol), Pd2 (dba)3 (6.9 mg, 0.0075 mmol), dppf (8.3 mg, 0.015 mmol), 2d (185.7 mg, 0.9 mmol), and anhydrous THF (10 mL). The reactor was pressured to 40 atm with CO, warmed to 80 ˚C, and stirred for 24 h. After cooling and eliminating CO, the volatile materials were evaporated at reduced pressure and the residue was purified by chromatography on neutral aluminum oxide (Brockmann 1; n-hexane-EtOAc, 90:10→70:30) to afford 3d (87 mg, 80% yield); viscous oil; IR (KBr): 3296, 3064, 2989, 2929, 2852, 1630 cm-¹; ¹H NMR (400 MHz, CDCl3): δ = 9.36 (br s, 1 H), 7.59-7.58 (m, 1 H), 7.36-7.34 (m, 1 H), 7.23 (d, J = 8.5 Hz, 2 H), 7.18-7.12 (m, 2 H), 6.90 (d, J = 8.5 Hz, 2 H), 6.31 (s, 1 H), 3.90 (s, 2 H), 3.84 (s, 3 H), 3.69-3.68 (m, 2 H), 3.58-3.56 (m, 2 H), 3.44 (s, 2 H), 2.43-2.40 (m, 2 H), 2.37-2.35 (m, 2 H); ¹³C NMR (100.6 MHz, CDCl3): δ = 168.4, 159.0, 136.5, 132.0, 130.4, 129.6, 128.4, 121.6, 120.0, 119.7, 113.8, 111.1, 101.0, 62.1, 55.3, 52.9, 52.5, 46.4, 42.1, 33.3; MS: m/z (%) = 121 (100) [M - C14H16N3O]+, 85 (50), 78 (44), 56 (52); Anal. Calcd. for C22H25N3O2: C, 72.70; H, 6.93; Found: C, 72.63; H, 6.91.

10

Typical Procedure for the Preparation of Free-NH Indole 2-Acetic Acid Methyl Esters (7): A stainless steel reaction vessel was charged with 1e (99 mg, 0.3 mmol),
Pd2 (dba)3 (6.9 mg, 0.0075 mmol), dppf (8.3 mg, 0.015 mmol), anhydrous THF (10 mL), and MeOH (1 mL). The reactor was pressured to 40 atm with CO, warmed to 80 ˚C, and stirred for 24 h. After cooling and eliminating CO, the volatile materials were evaporated at reduced pressure and the residue was purified by chromatography on silica gel (n-hexane-EtOAc, 80:20) to afford of 7b (40.2 mg, 66% yield); mp 90-93 ˚C; IR (KBr): 3356, 2952, 1714, 1458, 1427
cm-¹; ¹H NMR (400 MHz, CDCl3): δ = 8.55 (br s, 1 H), 7.60 (d, J = 7.8 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.18 (t, J = 8.0 Hz, 1 H), 7.12 (t, J = 7.9 Hz, 1 H), 6.41 (s, 1 H), 4.00 (q, J = 7.1 Hz, 1 H), 3.77 (s, 3 H), 1.66 (d, J = 7.2 Hz, 3 H); ¹³C NMR (100.6 MHz, CDCl3): δ = 174.1, 136.7, 136.2, 128.2, 121.9, 120.3, 119.9, 110.9, 100.3, 52.5, 39.2, 17.5; Anal. Calcd. for C12H13NO2: C, 70.92; H, 6.45; Found: C, 70.83; H, 6.47.