A facile trifluoromethylthiolation of 3-chloro-1 H -inden-1-ones employing AgSCF 3 and KI

An efficient method for trifluoromethylthiolation of functionalized 3-chloro-1 H -inden-1-ones was described. Within this method, AgSCF 3 was employed as a nucleophilic reagent and KI was functionalized as an activator. This reaction provided the trifluoromethylthiolated indenones with excellent yields under moderate conditions


Introduction
Fluorinated compounds have received increasing attention within organic synthesis and medicinal/pharmaceutical science because of special properties of fluorine atoms, which are the most electronegative elements with a small atomic radius.Among these fluorine-containing groups, the trifluoromethylthio group (SCF3) is of particular interest.2] Some SCF3 group-containing pharmaceutical products or pesticides have been reported [shown in Figure 1 ], 3 including toltrazuril, 4 tiflorex, 5 and fiptonil. 6And the increasing number of the SCF3-containing bioactive lead compounds, such as amebiasis trifloromethionine 7 and potential hypotensive agents of losartan and nifedipin analogues 8 also prove the importance of introducing the SCF3 moiety into drug candidates.Many research groups have been managed to explore efficient methods introducing the SCF3 group to small heterocyclic molecules. 9Earlier trifluoromethylthiolation strategies can be classified as indirect and direct methods.The indirect methods include halogen-fluorine exchange 10 and trifluoromethylation of sulfur-containing compounds. 11However, both of the indirect methods require harsh conditions and have a narrow substrate scope.The direct trifluoromethylthiolation methods are based on either electrophilic or nucleophilic pathways.As for heterocyclic scaffolds, such as benzofurans/ benzothiophenes, 12 isocoumarin, 13 indole [14][15][16][17] and oxidine, [18][19][20] they can be trifluoromethylthiolated by N-trifluoromethanesulfanylamides or hypervalent iodine trifluoromethanesulfenate reagent and N-trifluoromethylthiosaccharin.AgSCF3, as the most common SCF3 -containing nucleophilic reagent, 21 plays a key role in trifluoromethylthiolation of various bioactive structures in medicinal chemistry.And trifluoromethylthiolation of chromone derivatives using AgSCF3 was achieved by our group. 22he indenone moiety is one of the privileged scaffolds in medicinal chemistry owing to its various biological activities.Indenone-containing compounds were widely employed as agonists for estrogen receptor 23 and peroxisome proliferator-activated receptor γ (PPARγ). 24They also has been used as cyclooxygenase-2 (COX-2) 25 and topoisomerase I (Top I) 26 inhibitors and so on . 27herefore, incorporation of the SCF3 group into the indenone moiety can lead to novel series of heterocyclic scaffolds and will bring about further advances in the pharmacological applications.Inspired by previous work, [28][29] we proposed a simple synthetic route to generate substituted indenone analogues in this work.

Results and Discussion
Compound 1a, which was synthesized from phenylacetic acid, phthalic anhydride, and phosphorus oxychloride, 30 was selected as the model substrate for optimal conditions' screening (shown in Table1).However, reactions did not occur when AgSCF3 was simply added even at different temperatures (entries1-3).This may be caused by the low activity of AgSCF3 to proceed this reaction.Considering the application of KI for trifluoromethylthiolation as the addition, 31-32 KI (2 Equiv.) was introduced to accelerate reaction.Then compound 2a was obtained at 60 o C in 51% yield (entry 4).Based on this, a series of solvents were tested.The results showed that the utilization of CH3CN as solvent provided 2a with the highest yield (entries 4-6).This solvent was confirmed to have a significant impact on yields.Additionally, the replacement of KI to the NaI can lead to the decease of yields (entry 7).It was also found that reactions tend to have better yields under nitrogen environment compared with no inert gas protection (entry 8).Under the optimized reaction conditions (2 equiv.AgSCF3 and 2 equiv.KI in CH3CN at 60 o C), a variety of indenone derivatives were applied as substrates.As shown in Figure 2, this reaction was compatible with both electron-withdrawing groups (fluoro, bromo, chloro, nitro, trifluoromethyl group) and electron-donating groups (methyl, methoxy, dimethoxy moities).The yields for different electron-withdrawing groups-containing substrates were similar.Besides, electron-withdrawing substituents at different positions of the aromatic ring provide desire products with excellent yields (2d, 2e, 2f).However, substrates containing electron-donating groups were different (2j, 2k, 2l).Compound 2k has the lowest yield at 60 o C. At first we think this reaction was sensitive for steric hindrance (2e vs 2k).To our surprise, the yields are almost the same when the bulkier naphthalenyl group was employed instead of the phenyl group (2n, 2o vs 2a).This result suggests that trifluoromethylthiolation of 3-chloro-1H-inden-1-ones via AgSCF3 and KI to functional 2-aryl-3-((trifluoromethyl)thio)-1H-inden-1-ones have broader application due to its wide substrates tolerance.Compared with previous work, [28][29] the experimential conditions are milder and the synthetic method has broad scope of substrates and excellent compatibility of functional-groups for the presence of the activated chlorine atom on indenone core.

Conclusions
A novel and facile method for synthesis of SCF3-substituted indenones via AgSCF3/KI was discovered.This novel method only requires mild conditions and short time without employment of Pd or Ni catalysts.Moreover, this novel synthetic method was followed by simple work up and provided with superior yields.

Experimental Section
General.All reactions were performed under an argon atmosphere.Solvents and reagents are commercially available and without pretreatment.Column chromatography was employed by silica gel (200-300 mesh). 1 H NMR spectra were recorded on a Bruker Avance 300 or a Bruker Avance 400 spectrometer in CDCl3 (δ 7.26 ppm) ,respectively. 13C NMR spectra were recorded on a Bruker Avance 400 or Bruker Avance 500 spectrometer in CDCl3 (δ77.16 ppm).
General procedure for the synthesis of compounds 1 Compound 1 were prepared from corresponding unsubstituted/substituted phenylacetic acid, phthalic anhydride and phosphorus oxychloride.

General procedure for the synthesis of compounds 2a-2o
To a reaction flask were added AgSCF3 (1 mmol), KI (1 mmol), compound 1(0.5 mmol), CH3CN (2 mL).The mixture was stirred at 60 o C for 2-4 h.Afterward, the reaction mixture was poured into water and extracted with EtOAc and dried with Na2SO4.The solution was concentrated in vacuo to get a crude mixture, which was purified by flash column chromatography on silica gel (petroleum ether: acetate 100:1) to pure products.

Figure 2 .
Figure 2. Exploration of reaction scope.a,b