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

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.

Key words

indoles - Sonogashira coupling/5-endo-dig cyclization - palladium catalyst - water

1

DRL publication No 427.

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• 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 
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1

DRL publication No 427.