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Synlett 2010(6): 934-938  
DOI: 10.1055/s-0029-1219392
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Preparation of 3-Alkyl-Oxindoles by Copper(II)-Mediated C-H, Ar-H Coupling Followed by Decarboxyalkylation

David. S. Pugh, Johannes E. M. N. Klein, Alexis Perry, Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Fax: +44(1904)434523; e-Mail: rjkt1@york.ac.uk;
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Publication History

Received 14 December 2009
Publication Date:
18 February 2010 (online)

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Abstract

A novel route for the conversion of anilides into 3-alkyl-oxindoles is described in which a copper(II)-mediated cyclization process is followed by an acid-mediated decarboxyalkylation. Scope and limitation studies are reported together with a telescoped variant which incorporates in situ N-deprotection.

Key words

oxindoles - 3-alkyl-oxindoles - anilides - cyclisation - copper(II) catalysis - C-H activation - decarboxyalkylation

    References and Notes

  • 1 Perry A. Taylor RJK. Chem. Commun.  2009,  3249 
    CrossrefGoogle Scholar
  • For related processes, see:
  • 2a Jia Y.-X. Kündig EP. Angew. Chem. Int. Ed.  2009,  48:  1636 
    Google Scholar
  • 2b Miura T. Ito Y. Murakami M. Chem. Lett.  2009,  38:  328 
    Google Scholar
  • 2c Liang J. Chen J. Du F. Zeng X. Li L. Zhang H. Org. Lett.  2009,  11:  2820 
    Google Scholar
  • 2d Teichert A. Jantos K. Harms K. Studer A. Org. Lett.  2004,  6:  3477 
    Google Scholar
  • 3a Bui T. Borregan M. Barbas CF. Org. Lett.  2009,  11:  8935 
    Google Scholar
  • 3b Qian Z.-Q. Zhou F. Du T.-P. Wang B.-L. Ding M. Zhao X.-L. Zhou J. Chem. Commun.  2009,  6753 
    Google Scholar
  • 3c Jiang K. Peng J. Cui H.-L. Chen Y.-C. Chem. Commun.  2009,  3955 
    Google Scholar
  • 3d Kato Y. Furutachi M. Chen Z. Mitsunuma H. Matsunaga S. Shibasaki M. J. Am. Chem. Soc.  2009,  131:  9168 
    Google Scholar
  • 3e Sano D. Nagata K. Itoh T. Org. Lett.  2008,  10:  1593 
    Google Scholar
  • 3f Nakazawa N. Tagami K. Iimori H. Sano S. Ishikawa T. Nagao Y. Heterocycles  2001,  55:  2157 
    Google Scholar
  • 3g Miah S. Moody CJ. Richards IC. Slawin AMZ. J. Chem. Soc., Perkin Trans. 1  1997,  2405 
    Google Scholar
  • 3h Damavandy JA. Jones RAY. J. Chem. Soc., Perkin Trans. 1  1981,  712 
    Google Scholar
  • 4a Shimazawa R. Kuriyama M. Shirai R. Bioorg. Med. Chem. Lett.  2009,  18:  3350 
    Google Scholar
  • 4b Rizzi E. Cassinelli G. Dallavalle S. Lanzi C. Cincinelli R. Nannei R. Cuccuru G. Zunino F. Bioorg. Med. Chem. Lett.  2007,  17:  3962 
    Google Scholar
  • 5a Henderson D. Richardson KA. Taylor RJK. Saunders J. Synthesis  1983,  996 ; and references therein
    Google Scholar
  • 5b Successful decarboxyalkylation of related systems under acidic conditions is precedented: Tani M. Matsumoto S. Aida Y. Arikawa S. Nakane A. Yokoyama Y. Murakami Y. Chem. Pharm. Bull.  1994,  42:  443 
    Google Scholar
  • 6 All novel compounds were fully characterised.
  • 7 Bald E. Saigo K. Mukaiyama T. Chem. Lett.  1975,  4:  1163 
    Google Scholar
  • 8 Millemaggi A. Perry A. Taylor RJK. Eur. J. Org. Chem.  2009,  2947 
    CrossrefGoogle Scholar
9

Prepared by the alkylation of amide 8 using the route shown in Scheme  [4] ; all yields were greater than 88% with the exceptions of i-Pr (5c, 55%), PhCH2CH2 (5f, 63%), PhCH2O(CH2)3 (5h, 69%), and 4-PyCH2 (5i, 46%).

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Representative Procedure for the Copper-Mediated Cyclisation: tert -Butyl 1-Methyl-3-(naphthalen-2-yl-methyl)-2-oxoindoline-3-carboxylate (5g) A 100 mL round-bottomed flask fitted with a condenser
and stirrer-bar was charged with tert-butyl ester 4g (R = naphthalen-2-yl-methyl, 195 mg, 0.50 mmol) and DMF (10 mL). KOt-Bu (62 mg, 0.55 mmol) was added in a single portion, followed by copper(II) acetate monohydrate (100 mg, 0.50 mmol). The green-black suspension was heated to 110 ˚C (oil bath temperature) over 15 min. After stirring at 110 ˚C for 18 h, the reaction was cooled to r.t. and quenched with a sat. solution of NH4Cl (10 mL), diluted with H2O (20 mL), and extracted with EtOAc (20 mL). The organic layer was washed with a sat. brine solution (2 × 20 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give an orange oil. Purification by flash column chromatography (SiO2, 7:2:1 PE-CH2Cl2-EtOAc) gave product 5g (141 mg, 73%) as a colorless gum; R f = 0.44 (3:1 PE-EtOAc). IR (film): νmax = 3056, 2978, 2932, 1734, 1715, 1610, 1493, 1471, 1370, 1351, 1306, 1251, 1155, 1086, 997, 909, 750 cm-¹. ¹H NMR (400 MHz, CHCl3-d 1): δ = 1.41 (9 H, s, CMe3), 2.89 (3 H, s, NMe), 3.64 (1 H, d, J = 13.5 Hz, CH2), 3.69 (1 H, d, J = 13.5 Hz, CH2), 6.50 (1 H, d, J = 7.5 Hz, ArH), 6.98 (1 H, dd, J = 8.5, 2.0 Hz, ArH), 7.06 (1 H, ddd,
J = 7.5, 7.5, 1.0 Hz, ArH), 7.17 (1 H, ddd, J = 7.5, 7.5, 1.5 Hz, ArH), 7.33-7.37 (3 H, m, ArH), 7.38 (1 H, ddd, J = 7.5, 1.5, 0.5 Hz, ArH), 7.48 (1 H, d, J = 8.5 Hz, ArH), 7.60 (1 H, dd, J = 6.0, 3.5 Hz, ArH), 7.67 (1 H, dd, J = 6.0, 3.5 Hz, ArH). ¹³C NMR (100 MHz, CHCl3-d 1): δ = 26.1 (NMe), 27.8 (CMe3), 39.7 (CH2), 61.8 (C), 82.6 [OC(CH3)3], 108.1 (ArH), 122.3 (ArH), 123.6 (ArH), 125.4 (ArH), 125.5 (ArH), 126.9 (ArH), 127.3 (ArH), 127.7 (ArH), 127.8 (Ar), 128.3 (ArH), 128.8 (2 × ArH), 132.1 (Ar), 132.5 (Ar), 132.9 (Ar), 144.1 (Ar), 168.1 (C=O), 173.8 (C=O). ESI-MS: m/z =
410 [MNa]+. ESI-HRMS: m/z calcd for C25H25NNaO3: 410.1727; found: 410.1731 [MNa]+; 0.6 ppm error.

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Representative Procedure for Decarboxyalkylation: 1-Methyl-3-(naphthalen-2-ylmethyl) indolin-2-one (3g) A 10 mL round-bottomed flask with stirrer bar was charged with tert-butyl ester 5g (97 mg, 0.25 mmol) and anisole (82 µL, 0.75 mmol), a septum was fitted and the flask purged with argon(balloon). TFA (1 mL) was added, and the resulting brown solution was stirred for 2 h. The reaction mixture was concentrated in vacuo to give a yellow gum. Purification by flash column chromatography (SiO2, 4:1 PE-EtOAc) gave oxindole 3g (67 mg, 93%) as a yellow solid. R f = 0.39 (3:1 PE-EtOAc); mp 91-93 ˚C. IR (film): νmax = 3053, 2920, 2853, 1709, 1612, 1493, 1469, 1422, 1375, 1350, 1256, 1127, 1089, 750, 732 cm-¹. ¹H NMR (400 MHz, CHCl3-d 1): δ = 3.04 (1 H, dd, J = 13.5, 9.5 Hz, CH2), 3.17 (3 H, s, NMe), 3.67 (1 H, dd, J = 13.5, 4.5 Hz, CH2), 3.84 (1 H, dd, J = 9.5, 4.5 Hz, CH), 6.71-6.77 (2 H, m, J = 7.5 Hz, ArH), 6.88 (1 H, ddd, J = 7.5, 7.5, 1.0 Hz, ArH), 7.21 (1 H, dd, J = 8.0, 8.0 Hz, ArH), 7.34 (1 H, dd, J = 8.5, 1.5 Hz, ArH), 7.43-7.47 (2 H, m, ArH), 7.60 (1 H, br s, ArH), 7.73-7.82 (3 H, m, ArH). ¹³C NMR (100 MHz, CHCl3-d 1): δ = 26.2 (NMe), 37.0 (CH2), 46.9 (CH), 107.9 (ArH), 122.1 (ArH), 124.5 (ArH), 125.5 (ArH), 126.0 (ArH), 127.6 (3 × ArH), 127.9 (2 × ArH), 128.0 (ArH), 128.3 (Ar), 132.3 (Ar), 133.3 (Ar), 135.5 (Ar), 144.1 (Ar), 177.0 (C=O). ESI-MS: m/z = 310 [MNa]+. ESI-HRMS: m/z calcd for C20H17NNaO: 310.1202; found: 310.1196 [MNa]+; 1.6 ppm error.