Synthesis of 3,5,7-Substituted Indoles via Heck Cyclisation

Abstract

Traditional strategies in indole chemistry do not allow high yielding access to some substitution patterns such as 3,5,7-trisubstituted indoles. We report in this article the efficient synthesis of this type of indole. The Heck cyclisation strategy we used allows the synthesis of 7-iodo-, 7-nitro-, 7-amino- or 7-alkoxy indoles bearing other functionalities in the 3- and 5-positions. We believe the mild conditions used should allow preparation of indoles with a wide range of substituents in these two positions.

Key words

indoles - Heck reaction - palladium - anilines - hydroxybenzimidazole

References

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  See also ref. 13.

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  See also ref. 9b.

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2

A search for the indole core in WDI database retrieved more than 3700 hits. See also ref. 5.

14

Aniline 2 is also commercially available from Maybridge.

18

The NOE experiment proved that the stereochemistry of the exocyclic double bond is as shown in Scheme [3] .

22

Removal of the TFA proved more difficult than in the case of amide 11 and was not complete after 2 d using similar conditions (deprotection of 11 takes 15 min at r.t.). We therefore did not attempt the Heck cyclisation on the unprotected aniline.

23

Typical Procedure.
To a solution of methyl 3-bromo-4-[(2E,Z)-2-buten-1-yl(trifluoroacetyl)amino]-5-[(phenylmethyl)oxy]benzoate (20, 12.3 g, 25.3 mmol, 1 equiv) in DMF (150 mL) were added Na₂CO₃ (6.7 g, 63.3 mmol, 2.5 equiv), Bu₄NCl (7.7 g, 27.8 mmol, 1.1 equiv) and Pd(OAc)₂ (570 mg, 2.53 mmol, 0.1 equiv) and the resulting mixture was stirred under nitrogen at 100 °C for 2 h then cooled to r.t. and concentrated in vacuo. The residue was partitioned between EtOAc and H₂O and the layers were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with H₂O and brine, dried over MgSO₄ and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane-EtOAc, 9:1 to 3:1) gave methyl 3-ethyl-7-[(phenylmethyl)oxy]-1H-indole-5-carboxylate (21, 6.7 g, 86%) as a white solid; mp 96-98 °C. MS (ES): m/z = 310.0 [M + H]⁺. ¹H (400 MHz, CDCl₃): δ = 1.33 (t, 3 H, J = 7.2 Hz), 2.79 (q, 2 H, J = 7.2 Hz), 3.93 (s, 3 H), 5.23 (s, 2 H), 6.98 (s, 1 H), 7.31-7.51 (m, 6 H), 8.07 (s, 1 H), 8.43 (br s, 1 H). ¹³C (100.6 MHz, CDCl₃): δ = 14.6, 18.3, 52.0, 70.5, 103.6, 115.9, 120.8, 121.2, 121.7, 128.1, 128.2, 128.3, 128.7, 129.8, 136.7, 144.8, 168.4. MS: m/z calcd for C₁₉H₂₀NO₃: 310.14377; found: 310.14372.