Bismuth(III) triflate: an economical and environmentally friendly catalyst for the Nazarov reaction

We describe the use of bismuth(III) triflate as an efficient and environmentally friendly catalyst for the Nazarov reaction of aryl vinyl ketones, leading to the synthesis of 3-aryl-2-ethoxycarbonyl-1-indanones and 3-aryl-1-indanones. By changing the temperature and reaction time, it was possible to modulate the reactivity, allowing the synthesis of two distinct product classes (3-aryl-2-ethoxycarbonyl-1-indanones and 3-aryl-1-indanones) in good to excellent yield. The reaction did not require additives and was insensitive to both air and moisture. Preliminary biological evaluation of some indanones showed a promising profile against some human cancer line cells.


Introduction
Natural products are the source of inspiration for several research groups that develop new synthetic methodologies.The chemistry of five-membered rings plays an important role in organic chemistry, both because of the wide occurrence in nature [1][2][3][4][5][6] and the broad spectrum of biological activities.Among the five-membered ring compounds, we find indanone (1, Figure 1).Within the class of indanones, we can highlight some interesting compounds.For example, nakiterpiosinone (2), which inhibits the growth of P388 mouse leukemia cells with an average inhibitory concentration (IC 50 ) of 10 ng/mL, lepistatin A (3), along with two other new chlorinated analogs, that were isolated from Basidiomycete Lepista sordida culture, pauciflorol F (4), isolated from Vatica pauciflora, which is an important building block for the biosynthesis of bioactive polyphenols, in addition to having antiviral activity, indacrinone (5), which is related to ethacrynic acid and usually stimulates the reversible short-circuit current and the influx of sodium when applied to the epithelial surface of amphibian skin, and donepezil (6), a drug used to treat Alzheimer's disease [7][8][9][10][11][12].
Despite the numerous reports on catalytic versions of the Nazarov reaction, few of them describe the use of bismuth salts as catalysts for Nazarov-type reactions [50,51] and none for the classical Nazarov reaction.With the growing environmental concern and the need to use green reagents, interest in the use of bismuth in organic synthesis has increased significantly, as is reflected by the large number of works dedicated to this topic [52][53][54].In addition to the replacement of toxic heavy metals, the use of bismuth compounds to promote reactions has the advantages of low cost and insensitivity to water and air.As such, the handling does not require special experimental techniques, such as an inert atmosphere and anhydrous solvents [55].The use of bismuth salts in organic synthesis has been reported for several transformations, such as epoxide opening [56], ketal formation and deprotection [57,58], Mannich reaction [59], intramolecular Sakurai cyclization [60], alcohol oxidation [61], aromatic hydrocarbon nitration [62], imine allylation [63], Knoevenagel condensation [64], Reformatsky reaction [65], azalactone synthesis [66], nitro reduction [67,68], epoxide rearrangement, thiourea guanylation, and others [69,70].
In this article, we describe a simple and direct protocol for the preparation of indanones through a classical Nazarov reaction catalyzed by bismuth(III) triflate.In addition to the synthetic simplicity, the moisture stability of bismuth triflate allows the protocol to be carried out under ambient atmospheric conditions.

Preparation of β-ketoesters
We initiated our studies with the preparation of the β-ketoesters, which were synthesized according to well-established protocols [71][72][73][74].The β-ketoesters were obtained employing a sequence of two reactions, the formation of the benzylic alcohol derivative, through a Reformatsky reaction using In(0), followed by a pyridinium chlorochromate (PCC) oxidation, giving the β-ketoesters 7a-g in moderate to good yields.With the β-ketoesters prepared, we began the synthesis of the Knoevenagel derivatives.To do so, we employed an adapted protocol from the literature.Using 1.00 equiv of β-ketoester, 1.50 equiv of aldehyde, 0.60 equiv of acetic acid, and 0.25 equiv of piperidine, the desired products were obtained in good to excellent yields and E-selectivities (Figure 2) [71][72][73][74].Various substrates (9aa-gc), containing electron-donating, electron-withdrawing, electroneutral groups, and heteroaryl units (2-thiophene and 3-benzothiophene) were obtained in good to excellent yields.For derivatives 9af,ag,bq, we observed the formation of an E/Z mixture of products that was inseparable by column chromatography.

Synthesis of 3-aryl-2-ethoxycarbonyl-1indanones and 3-aryl-1-indanones
With the starting materials prepared, we began evaluating the use of bismuth salts to promote the Nazarov reaction, using models already studied in the literature [33][34][35][36][37][38][39][40][41][42][43].We investigated several conditions, such as the type of catalyst, temperature, solvent, and amount of catalyst (Table 1).Our optimization studies began with the reaction of substrate 9aa with Bi(OTf) 3 (10 mol %) in acetonitrile at room temperature (Table 1, entry 1).The desired product was obtained in 72% after 12 h.When the reaction was carried out at 40 °C for 8 h, the yield increased slightly to 76% (Table 1, entry 2).When the reaction was carried out at 60 °C, the yield increased to 93%, in addition to a marked decrease in the reaction time (Table 1, entry 3).Despite this excellent result, we continued to evaluate other catalysts to improve the yield and reaction time further.For this purpose, a series of Lewis acids, such as Bi(NO) 3 , BiBr 3 , BiCl 3 , Yt(OTf) 3 , Dy(OTf) 3 , ZrCl 4 , In(OTf) 3 , InCl 3 , and AlCl 3 were selected as catalysts (Table 1, entries 5-13), and even after this screening, the best result still remained the one obtained with Bi(OTf) 3 .The Brønsted acids TFA and TsOH were also tested for the transformation but gave worse results (Table 1, entries 14 and 15).Once the catalyst was chosen, we investigated the influence of the solvent.For this purpose, we evaluated dichloroethane (DCE), dichloromethane (DCM), toluene, and tetrahydrofuran (THF) as solvents for the transformation (Table 1, entries [16][17][18][19], but acetonitrile remained the best solvent.Finally, we evaluated the amount of catalyst, using two different catalyst loadings (5 and 20 mol %), but these variations also did not improve the yield (Table 1, entries 20 and 21).After this screening, the optimum conditions employed 10 mol % of bismuth triflate (Bi(OTf) 3 ) in acetonitrile at 60 °C (Table 1, entry 3).
With the optimized conditions in hand, we explored the substrate scope (Figure 3).In general, substrates with electron donor groups provided a better yield when compared to those obtained with electroneutral or electron-withdrawing groups.Particularly for substrates 9ai,fc,gc, there was no formation of the corresponding indanones even though the reaction remained at 60 °C for a longer time (48 h), but the starting materials could be recovered.For substrate 9ah, there was complete decomposition of the starting material, along with the formation of several byproducts.Surprisingly, when using the optimized conditions for substrates 9dc,dl, we found that in addition to the products of interest, they also formed the decarboxylated products as inseparable mixtures.Given this result, we investigated milder conditions to avoid decarboxylation.In doing so, we reacted the substrate 9dc for 24 h at room temperature.Despite this long reaction time, we still observed formation of the decarboxylated derivative, and we could also partly recover the starting material (Table 2).Nazarov cyclization of 3-substituted thiophene derivatives.When carrying out the reactions at 60 °C for 24 h, the formation of a 9:1 mixture of the products 13 and 14 in 61% combined yield was observed (Scheme 1) [75].Under more vigorous conditions (100 °C for 5 h), there was a slight increase in the yield of decarboxylated product 14.In 2010, Zhang et al. [76] developed a methodology catalyzed by In(OTf) 3 for the synthesis of bicycles, and they also verified that decarboxylation occurred when the reaction remained at 80 °C for 6 h (Scheme 1).The same behavior was observed by France during the synthesis of the lilolidone nucleus [77] and by Jung in the stereoselective synthesis of podophyllotoxin derivatives (Scheme 1) [78].Although the decarboxylation reaction of indanones has been observed and described in the literature, there are few extensive studies aimed at exploring this transfor-mation.The only exception is a report by Rajesh and Prajapati from 2015 [79].In this work, the authors aimed at obtaining substituted β,β-indanones, and the decarboxylation step was a mandatory part of the methodology, with no interest in controlling the process.

Decarboxylation reactions of indanones have previously been described in the literature. In 2008, Itoh et al. investigated the
The indanone core is a privileged structure, as it is often found in a series of natural products and synthetic molecules with different biological activities [11,80,81].In particular, 1-indanones substituted in position 3 are important synthons for some drugs and natural products [82][83][84].A bibliographic survey revealed that some methods were developed for the synthesis of 3-aryl-1-indanones.In this context, due to the formation of the previously shown derivatives 11dc,dl, we decided to explore the Nazarov reaction-decarboxylation sequence cata- lyzed by Bi(OTf) 3 to prepare variously substituted 3-aryl-1indanones from substrate 9.
We initially investigated the behavior of substrate 9aa under the conditions established for the Nazarov cyclization (60 °C).
However, despite the reaction remaining under these conditions for a long period (24 h), only partial decarboxylation of the Nazarov product was observed.Thus, we decided to increase the temperature to 100 °C, and the reaction was maintained under these conditions in a sealed tube for 12 h.To our delight,  we obtained only the decarboxylated indanone in an excellent yield (93%).These conditions were chosen as the optimal conditions, and the scope for the synthesis of 3-aryl-1indanones derivatives is summarized in Figure 4.
Simply by controlling the reaction temperature, it was possible to obtain indanones with different substitution patterns.At the lower temperature (60 °C), 2,3-substituted indanones could be obtained, while at the higher temperature (100 °C), 3-substituted indanones were achieved.Under both conditions, virtually no product mixtures were observed.

Preliminary biological evaluation
To investigate the cytotoxic activity of the indanone derivatives, in total 20 compounds were tested at a concentration of 5 and 50 μg/mL for 72 h in a panel of four histologically unrelated tumor lines, HCT116 (colon adenocarcinoma), MCF7 (breast adenocarcinoma), SK-MEL-28 (melanoma), and NB4 (acute leukemia) by methylthiazol tetrazolium (MTT) assay, as previously described [85].Among the tested cells, NB4 cells were the most sensitive ones, with 7 compounds (10aa,bk and 11aa,ad,ae,dc,bj) being active at 5 μg/mL, using a 75% cutoff inhibition at each concentration.On the other hand, MCF-7 and SK-MEL-28 cells were the most resistant ones, with no compound being active at the lower concentration (Figure 5).This evidence of selective cytotoxicity for a specific histological tumor subtype may drive further structure-activity relationship studies to identify indanone targets of pharmacological interest.

Conclusion
In summary, we developed a simple and efficient methodology for the Nazarov reaction of aryl vinyl ketones, leading to 3-aryl-2-ethoxycarbonyl-1-indanones and 3-aryl-1-indanones.The reactions were catalyzed by bismuth triflate, an environmentally friendly metal.By simply changing the temperature and reaction time, it was possible to modulate the reactivity.In this methodology, no additives were used, and the reaction was insensitive to both air and moisture.To the best of our knowledge, this study is unique in the sense that there are no previous reports on the use of bismuth triflate as catalyst for a classic Nazarov reaction.There is also no reported precedent for the preparation of indanones with different substitution patterns through simple control of the reaction temperature.
The initial biological profile of 20 indanones was assessed, revealing promising activity against certain human cancer cell lines in some cases.To enhance the anticancer potential of these compounds, it is imperative to carry out additional comprehensive studies.

Figure 1 :
Figure 1: Examples of different compounds containing the indanone moiety.

Figure 5 :
Figure 5: Impact of indanone derivatives on cell viability of tumor cells.Cell viability was determined by MTT assay.Data is expressed as reduction in viability in relation to the vehicle, and the dotted line indicates 75% reduction in cell viability.Compounds that reduced cell viability by at least 75% at 5 µg/mL are highlighted in the graph.

Table 1 :
Optimization of the reaction conditions.
a Isolated yield after purification using silica gel column chromatography.b Recovery of starting material.

Table 2 :
Evaluation of the reactivity of 9dc,dl.Yield determined by 1 H NMR analysis using dimethyl terephthalate as internal standard.b Ratio determined by 1 H NMR analysis.Previous methods describing decarboxylation reactions of indanones and xanthenones. a