An Al(OTf) 3 -catalyzed environmentally benign process for the propargylation of indoles Mukut Gohain, Charlene Marais, Barend C. B. Bezuidenhoudt ⇑ Department of Chemistry, University of the Free State, PO Box 339, Bloemfontein 9300, South Africa article info Article history: Available online 3 July 2012 Keywords: Aluminum triflate Indole Nucleophilic substitution 3-Propargylated indole Secondary/tertiary propargylic alcohols abstract Al(OTf) 3 catalyzed the alkylation of indoles using secondary/tertiary propargylic alcohols to produce 3- propargylated indoles in excellent yields with high selectivity. The reactions were performed in air with commercial grade solvents, and water was the only side product of the process. The catalyst was recov- ered after completion of the reaction and re-used with minimum loss of activity over three cycles. Ó 2012 Elsevier Ltd. All rights reserved. The indole moiety is a very common heterocyclic structure found in nature 1 and is present in many pharmacologically and biologi- cally active compounds. 2 Among these, 3-substituted indoles show significant biological activity and as such are precursors for the syn- thesis of various natural and synthetic pharmaceuticals. 3,4 In this re- gard, propargylation of indoles is an important process to give access to various pharmaceutical intermediates and other impor- tant heterocycles via simple functionalization of the triple bond. 5 Several approaches for the preparation of 3-propargyl indoles have been described in recent years. The most useful are based on transi- tion metal, 6 Lewis 7 and Brønsted acid 8 catalyzed methods for the di- rect nucleophilic substitution reactions of alcohols with indoles, which, furthermore, produces only water as the byproduct. Silveira et al. 9 recently described the CeCl 3 -catalyzed propargy- lation of indoles where ZnO was used as an additive in equivalent amounts. From an environmental point of view, this process is unattractive as it produces excessive amounts of metal waste. Sanz et al. 8c disclosed a Bronsted acid catalyzed propargylation method- ology, though the isolated yields of the products were not satisfac- tory. The aforementioned procedures and other reported methods 10 are hampered by the cost and availability of the catalysts, excessive catalyst loading, and reagents being toxic and/or moisture-sensi- tive, thus rendering them impractical for large-scale industrial synthesis. From a recent literature search, we did not find any efficient general synthetic methods for the direct nucleophilic substitution of propargylic alcohols with indoles which were equally efficient for both 2 o and 3 o propargylic alcohols. In most reports of catalyzed propargylation reactions, benzylic propargylic alcohols (1-aryl- prop-2-yn-1-ol derivatives) are employed as alkylating agents. Only a few methods have been reported for 3 o propargylic alcohols, which might be attributed to the tendency of 3 o propargylic alco- hols to form allenium intermediates, 11 or to eliminate water in acidic medium. 8a Therefore, to find an efficient general methodol- ogy for C3 propargylation of indoles with 3° as well as 2 o propar- gylic alcohols is a challenge. Metal triflates have received wide attention for their role as Le- wis acids in a number of reactions. 12 Water-tolerant metal triflates are especially attractive from an environmental point of view as they can be easily and repeatedly recycled. In this regard, Al(OTf) 3 was found to be a potent, water-tolerant, efficient, and reusable catalyst. 13 To date, it has not been explored as extensively as other metal triflates, the rare earth metal triflates in particular, despite it being comparatively more affordable. We now report that this ver- satile catalyst is also highly efficient for the direct nucleophilic substitution of propargylic alcohols with a variety of indoles in or- der to prepare the corresponding 3-propargylated indoles. Initially, to optimize the conditions, we performed the reaction with indole (1a) (1 mmol) and alkynol 2a (1.15 mmol) using 5 mol % of aluminum triflate in CH 3 CN (1.5 ml) at temperatures ranging from room temperature to reflux. Though the reaction did proceed at room temperature, it progressed very slowly and re- quired more than 10 h for completion. The rate of the reaction was accelerated by increasing the temperature; at reflux conditions (ca. 85 °C) the reaction proceeded to completion (monitored by GC– MS and TLC) within 90 min to give 3-substituted indole 3aa in 88% yield (Scheme 1). Since the 3-position of indoles is highly electron- rich and serves as the primary nucleophilic site during reactions with electrophiles, 14 electrophilic attack by the Lewis acid activated 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.06.095 ⇑ Corresponding author. Tel.: +27 51 4019021; fax: +27 51 4446384. E-mail address: bezuidbc@ufs.ac.za (B.C.B. Bezuidenhoudt). Tetrahedron Letters 53 (2012) 4704–4707 Contents lists available at SciVerse ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet