Synlett 2005(20): 3071-3074  
DOI: 10.1055/s-2005-921917
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Nicolas Charrier, Emmanuel Demont*, Rachel Dunsdon, Graham Maile, Alan Naylor, Alistair O’Brien, Sally Redshaw, Pam Theobald, David Vesey, Daryl Walter
Neurology and Gastrointestinal Center of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK
Fax: +44(1279)627685; e-Mail: emmanuel.h.demont@gsk.com;
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Publikationsverlauf

Received 12 August 2005
Publikationsdatum:
28. November 2005 (online)

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.

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.