Conjugate Addition of Indoles to α,β-Unsaturated Ketones Using Bismuth (III) Bromide

An efficient method for the conjugate addition of 
indoles to a variety of chalcones using BiBr3 in ethanol (190 proof) 
is reported. Products are isolated by a simple procedure that avoids an aqueous 
work up and extensive chromatography, thus minimizing waste. Bismuth (III) 
compounds are especially attractive from a 
green chemistry perspective because they are remarkably nontoxic, 
non-corrosive and relatively inexpensive.

conjugate addition of indoles to simple enones (but not chalcones) has been reported using Bi(NO 3 ) 3 ·5H 2 O as a catalyst [28] [29]. The conjugate addition of indole to chalcone has also been reported with Bi(OTf) 3 as a catalyst in CH 3 CN as the solvent [30] [31]. These bismuth salts-catalyzed methods involve product isolation via an aqueous work-up followed by chromatographic purification that generates significant solvent waste. In an effort to develop a method in a green solvent that would eliminate waste from aqueous work-up and extensive column chromatography, we investigated the utility of BiBr 3 as a catalyst in ethanol (190 proof) for the addition of indoles to chalcones. Bismuth compounds are remarkably nontoxic, relatively stable to moisture and air, and easy to handle. As a result there has been considerable interest in the use of bismuth compounds in organic synthesis in the last two decades [32] [33] [34] [35] [36]. Herein we report the conjugate addition of indoles to a variety of chalcones using bismuth bromide, BiBr 3 , in a relatively green and inexpensive solvent, ethanol (190 proof). The product was isolated by evaporation of the solvent, filtration of the residue (using minimal CH 2 Cl 2 ) through a short plug of silica to remove the catalyst, and concentration of the filtrate followed by trituration of the residue with CH 3 CH 2 OH (190 proof). This method avoids the use of elaborate chromatography for product purification and also eliminates an aqueous waste stream.
During optimization of the reaction conditions we found that both 2-propanol ( i PrOH) and absolute ethanol are also suitable solvents, but we chose CH 3 CH 2 OH (190 proof) as it was easier to remove than i PrOH, and is considerably cheaper and easier to obtain than absolute ethanol. The results are summarized in Table   1. Electron withdrawing groups on the phenyl ring proximal to the carbonyl required a higher catalyst loading for optimal reaction time and yield (entries 8, 9, 11 and 12). Similarly, a strongly electron donating group on the phenyl group distal to the carbonyl (entry 4) required a higher catalyst loading. When the nucleophilicity of the indole was lowered by an electron withdrawing group (entry 3) a higher catalyst loading was required. A solution of BiBr 3 in CH 3 CH 2 OH (190 proof) has a pH of ~3.0, suggesting that some HBr is generated by hydrolysis.
Hence, Bronsted acid catalysis by HBr cannot be ruled out. When the conjugate addition of indole to 4'-methylchalcone (Table 1,  Similarly, no product was formed when the same reaction was carried out in the presence of solid K 2 CO 3 . Both these results suggest that the primary role of BiBr 3 is to act as a convenient source of HBr [22]. Aqueous HBr is very corrosive and difficult to handle unlike BiBr 3 , which is an air stable and easy to handle solid. A representative procedure is given here: A mixture of 4-methylchalcone (0.5000 g, 2.2493 mmol) and indole (0.3162 g, 2.6992 mmol, 1.2 equivalents) in CH 3 CH 2 OH (190 proof, 10.0 mL) was stirred at room temperature as BiBr 3 (0.2018 g, 0.4497 mmol, 20.0 mol%) was added. The mixture was then heated at 70˚C (temperature controlled hot plate), and the reaction progress was monitored a Chalcones were purchased commercially or synthesized in lab using standard procedures [39]. b Reaction progress was monitored using TLC and spots were visualized under UV light, and by spraying with phosphomolybdic acid followed by heating. c Refers to yield of isolated product that was deemed to be ≥98% by 1 H and 13 C NMR spectroscopy. All products have been previously reported in the literature. Superscript against yield refers to literature reference for spectral data.
by TLC (20/80, EtOAc/heptane). After 26 h, the reaction was cooled to room temperature, and concentrated on a rotary evaporator to yield a pale red solid. The solid was filtered through a plug of silica gel (7.00 g, 20 mL of CH 2 Cl 2 ). The filtrate was concentrated on a rotary evaporator to yield a pale-yellow oily residue that was triturated with CH 3 CH 2 OH (190 proof, 6 mL) to yield 0.6500 g (85%) of a pale-pink solid. The product was characterized by comparison of 1 H and 13 C NMR spectral data to literature data and deemed to be >98% pure.
In summary, a new procedure for the conjugate addition of indoles to a variety of chalcones using BiBr 3 has been developed. The low toxicity of bismuth salts, and a product isolation method that avoids waste generated from an aqueous work up and elaborate column chromatography, make this procedure particularly attractive from a green chemistry perspective.
trometer. RM would like to acknowledge an Artistic and Scholarly grant from Illinois Wesleyan University.