A Practical and Efficient Vilsmeier Synthesis of 3-Chloroindole-2-carboxaldehydes

The indole ring is regarded as a priviledged structural moiety in many naturally occurring alkaloids1 or synthetic drugs.2 In particular, 3-chloroindole-2-carboxaldehyde derivatives display important pharmacological properties such as anti-HIV3, antitumor4 and anticancer activities.5 Recently, some important papers have been published on the synthesis and functionalization of indoles.6–8 Although the Vilsmeier cyclization of 2[(carboxymethyl)amino]benzoic acids 1 has provided an effective and more convenient approach for the construction of indole derivatives without any metal catalysts, it suffers the disadvantages of low efficiency with some substrates and unsatisfactory yields.9 Herein, we disclose an efficient and practical process for the improved synthesis of 3-chloroindole2-carboxaldehydes 2 from readily accessible 2-[(carboxymethyl)amino]benzoic acids 1 (Scheme 1). Initially, 2-[(carboxymethyl)amino]benzoic acid (1a) was used as a representative substrate to examine the best reaction conditions. Treatment of 1a with the Vilsmeier reagent (6.0 equiv.) prepared from DMF and bis-(trichloromethyl) carbonate (BTC) at 75◦C proceeded smoothly in 1,2-dichloroethane as indicated by TLC and furnished only one product after work-up and purification by column chromatography. The product was characterized as 3-chloroindole-2-carboxaldehyde (2a, Scheme 1) by its 1H NMR, 13C NMR and MS data. Based on our previous studies10 and encouraged by these results, the reaction conditions including solvent, temperature and the ratio of 1a to DMF/BTC were investigated. In order to avoid the use of 1,2-dichloroethane, much effort was made to select a suitable solvent. To our delight, it was found that 2-methyltetrahydrofuran (2-MeTHF) was the better choice than 1,2-dichloroethane, toluene, CH3CN and THF. As an eco-friendly

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