Copper-Catalyzed Annulation–Cyanotrifluoromethylation of 1,6-Enynes Toward 1-Indanones via a Radical Process

A new Cu(II)-catalyzed annulation–cyanotrifluoromethylation of 1,6-enynes with Togni's reagent and trimethylsilyl cyanide (TMSCN) has been established, enabling the direct construction of trifluoromethylated 1-indanones with an all-carbon quaternary center in good yields. This reaction was performed by using low-cost Cu(OTf)2 as the catalyst and Togni's reagent as both the radical initiator and a CF3 source, providing an efficient protocol for building up an 1-indanone framework with wide functional group compatibility. The reaction mechanism was proposed through a radical triggered addition/5-exo-dig cyclization/oxidation/nucleophilic cascade.


INTRODUCTION
Trifluoromethylation of organic molecular skeletons has attracted considerable attention in pharmaceutical chemistry, agrochemicals, and functional materials, owing to the fact that incorporation of the trifluoromethyl group into organic molecules can modulate their abilities including lipophilicity, bioavailability, and metabolic stability (Umemoto, 1996;Müller et al., 2007;Hagmann, 2008;Studer, 2012;Yang et al., 2015). Therefore, many efforts have been done in the past few decades, which mainly depended on transition-metal-catalyzed trifluoromethylation reactions. Such reactions enable direct construction of the C-CF 3 bond in an atom-economic manner and provide efficient and practical methods for the collection of trifluoromethyl-containing compounds, such as catalytic trifluoromethylation of alkane (Pan et al., 2011;Fu et al., 2012;Kuninobu et al., 2015;Wang et al., 2015;Xiao et al., 2019), alkenes (Chu and Qing, 2012;Shimizu et al., 2012;Zhu and Buchwald, 2013;Lin et al., 2016;He et al., 2018), and alkynes (Ge et al., 2014;Iqbal et al., 2014;Tomita et al., 2015;Wu et al., 2017;Huang et al., 2018). Among them, a vast majority of reports focused on the difunctionalization of alkenes or enynes (He et al., 2014a,b), such as hydrotrifluoromethylation (Wilger et al., 2013;Wu et al., 2013), carbotrifluoromethylation (Chen et al., 2013;Egami et al., 2013;Liu et al., 2013), and oxytrifluoromethylation Janson et al., 2012;Li and Studer, 2012;Zhu and Buchwald, 2012) for their high utilization by incorporating trifluoromethyl groups into target molecules across the unsaturated π system. On the other hand, 1-indanones are privileged structural motifs commonly present Graphical Abstract | A new Cu(II)-catalyzed annulation-cyanotrifluoromethylation of 1,6-enynes with Togni's reagent and TMSCN has been established, enabling the direct construction of trifluoromethylated 1-indanones with an all-carbon quaternary center in good yields. This reaction was performed by using low-cost Cu(OTf) 2 as the catalyst and Togni's reagent as both the radical initiator and a CF3 source, providing an efficieA new Cu(II)-catalyzed annulation-cyanotrifluoromethylation of 1,6-enynes with Togni's reagent and TMSCN has been established, enabling the direct construction of trifluoromethylated 1-indanones with an all-carbon quaternary center in good yields. This reaction was performed by using low-cost Cu(OTf) 2 as the catalyst and Togni's reagent as both the radical initiator and a CF 3 source, providing an efficient protocol for building up 1-indanone framework with wide functional group compatibility. The reaction mechanism was proposed through a radical triggered addition/5-exo-dig cyclization/oxidation/nucleophilic cascade. nt protocol for building up 1-indanone framework with wide functional group compatibility. The reaction mechanism was proposed through a radical triggered addition/5-exo-dig cyclization/oxidation/nucleophilic cascade. in many bioactive molecules and natural products such as Pterosin B and C (Nagle et al., 2000;Wessig and Teubner, 2006), pauciflorol F (Dai et al., 1998;Nitta et al., 2002;Ito et al., 2004), and (+)-indacrinone (DeSolms et al., 1978) (Figure 1). Consequently, many chemists made their contributions to establish numerous elegant protocols for their synthesis including Friedel-Crafts acylation (Koelsch, 1932;Frank et al., 1944), Grignard reactions (Bergmann, 1956;Manning et al., 1981), and transition metal-catalyzed annulation of arylalkynes (Shintani et al., 2007;Chernyak et al., 2011;He et al., 2018;Song et al., 2019), radical addition-cyclization of 1,6-enynes (Shen et al., 2018a, and other methods (Zhu et al., , 2018aShi et al., 2019a). To the best of our knowledge, introduction of a trifluoromethyl group into the 1-indanone framework via a radical-triggered annulationdifunctionalization strategy remains elusive.
Multicomponent reactions (MCRs) represent an attractive and powerful tool for building complex molecular architectures under usually mild conditions (Hao et al., 2016;Wang et al., 2016a,b;Ji et al., 2019;Liu et al., 2019;Qin et al., 2019;Shi et al., 2019b). Radical-triggered annulation-difunctionalization cascades, standing at the intersection of both radical and multicomponent transformations, constitute a unique reaction category, which enables direct assembly of difunctionalized cyclic systems containing both isocyclic and heterocyclic skeletons which are not available from other methods. As a result, lots of unsaturated compounds endowed with alkene and/or alkyne units are devised and prepared as radical acceptors to capture the various radical species (Chen et al., 2008;Liu et al., 2014;Kong et al., 2015;Wang F. et al., 2016;Zhang et al., 2019). Generally, the success of the radical annulationdifunctionalization relies on the radical continuous transfer across the unsaturated systems through a synergistic orientation process. Over the years, our group has been heavily involved in the development of new annulation-difunctionalization cascades for multiple ring formations. For example, we reported a copper-catalyzed annulation-halofluoroalkylation of 1,6-enynes, leading to the atom-economic and highly stereoselective protocol toward functionalized 1-indenones (Scheme 1, path a) . To continue our interest in this project, we approach a radical addition-cyclization strategy to install FIGURE 1 | 1-Indanone-containing natural products. SCHEME 1 | Profiles for annulation-difunctionalization of 1,6-enynes.
both trifluoromethyl and cyano moieties into the 1-indenone framework, due to the behaviors of trifluoromethyl and cyano groups in the wide application potentiality in assigning and discovering new biological lead compounds. An extensive literature survey revealed that the radical-triggered annulationcyanotrifluoromethylation of 1,6-enynes toward 1-indanones remains unreported to date. For this reason, the coppercatalyzed annulation-cyanotrifluoromethylation of 1,6-enynes 1 with Togni's reagent 2a and trimethylsilyl cyanide (TMSCN) was carried out by 1,10-phenanthroline (phen) as the ligand, enabling a radical-induced three-component cascade to access trifluoromethylated 1-indanones 3 with generally good yields (Scheme 1, path b). Remarkably, some cases showed complete stereoselectivity, and only E-selectivity was observed. Herein, we report this copper-catalyzed radical transformation.

RESULTS AND DISCUSSION
At the outset of our studies, we chose the preformed 1,6-enyne 1a, Togni's reagent 2a, and TMSCN as the model substrate ( Table 1). To our delight, the reaction of 1a with 2a and TMSCN in a 1:2:2 mol ratio catalyzed by 10 mol% Cu(OAc) 2 proceeded smoothly in acetonitrile at 50 • C by using 1,10phenanthroline (phen, L 1 ) as a ligand, and the target product 3a as a sole (E)-stereoisomer was obtained in 36% yield. The following screening of solvents showed that the use of DMSO and DMF led to a slightly decreased yield of 3a compared with acetonitrile (entries 2 and 3 vs. entry 1), whereas both 1,4dioxane and THF completely suppressed the formation of 3a (entries 4 and 5). Thus, acetonitrile was the best solvent for the reaction. An employment of NaOAc as the base facilitated the reaction process, delivering 40% yield of the desired product 3a (entry 6). After that, we conducted the screening of a variety of copper salts, such as Cu(CH 3 CN) 4 PF 6 , CuCN, CuI, and Cu(OTf) 2 , that are often utilized in catalytic transformations, for this addition-cyclization cascade by using acetonitrile as the reaction medium. All these catalysts could promote the conversion of 1a into 3a (entries 7-10), and the latter one showed the best catalytic performance in the current reaction, generating product 3a in 55% yield (entry 10). As the next optimization step, several ligands, such as 1,10-phenanthroline-5,6-dione (L 2 ), 2,2 ′ -bipyridine (L 3 ), and 2,2 ′ :6 ′ ,2 ′′ -terpyridine (L 4 ), were investigated and anticipated to enhance the yield of product 3a. Disappointingly, ligands L 2 -L 4 showed slightly weaker performance on the conversion of 1a into 3a as compared with L 1 (entries 11-13). Using Togni's reagent 2b to replace 2a resulted in a lower conversion (42%, entry 14 vs. entry 10). Different bases such as potassium phosphate tribasic (K 3 PO 4 ), trimethylamine (Et 3 N), and cesium carbonate (Cs 2 CO 3 ) were then screened. The results indicated that K 3 PO 4 could improve the reaction, providing product 3a in 64% yield. After careful optimizations, we found that fine-tuning the substrate ratio 1a/2a/TMSCN to 1:3:2 delivered product 3a in a higher 87% yield (entry 18).
to offer the corresponding (E)-1-indanones 3f and 3g with complete stereoselectivities, albeit with low yields. Due to the pharmacological significance of fluorine-containing molecules compared to their non-fluorinated analogs, we decided to prepare 1,6-enynes 1h-1j containing the fluoro group residing in the 5-position of the internal arene ring and employed them to react with 2a and TMSCN. The reaction worked well, accessing the corresponding polyfluoro products 3h-3j in 42-64% yields and 5:3 to 5:2 E/Z ratios. Other substituents including chloro (1k-1o, 1r, and 1s), methyl (1p and 1t-1x), and methoxy (1q) located at the C4-or C5-position on the internal arene ring did not hamper this copper-catalyzed reaction, and a range of new substituted 1-indanones 3k-3x can be isolated in synthetically useful yields, in which a complete diastereoselectivity was also observed in the cases of 3k, 3l, 3p, 3q, 3r, and 3t. However, unsatisfactory E/Z ratios were detected for the other products. Either electronically neutral (H), poor (fluoro, chloro, and bromo), or rich [methyl, ethyl, t-butyl, and methoxy (PMP = p-methoxyphenyl)] groups at the para-position of the arylalkynyl moiety (R 1 ) are well-tolerated with the catalytic conditions. Unfortunately, 1,6-enyne 1y carrying a 2-thienyl group was an ineffective reaction partner in this transformation. The structures of these resulting 1-indanones were fully characterized by NMR spectroscopy and HRMS data (Data Sheet 1).
To gain mechanistic insight into this transformation, radical trapping experiments were performed. When 2,2,6,6tetramethylpiperidine-1-oxyl (TEMPO) as a radical scavenger was subjected to the reaction conditions, the generation of 3a was completely suppressed (Scheme 3a). Similarly, BHT could inhibit the formation of 3a. These results showed that the reaction may include a radical process. Moreover, the developed transformation could be valorized through postfunctionalization of indanone 3q (Scheme 3b). The combination of NaBH 4 and I 2 was found to be effective to reduce 3q to give 2,3-dihydro-1H-inden-1-ol 4 (51% yield) (He et al., 2015;Chen et al., 2018). SCHEME 3 | Control experiments and application of compound 3q.

MECHANISM
According to these results and related literature (Kamigata et al., 1990;Liu et al., 2012;Pair et al., 2013;Yasu et al., 2013;He et al., 2014b;Shen et al., 2019), a plausible mechanism was proposed (Scheme 4). The copper(II) catalyst activates Togni's reagent 2a to give the activated complex A, which releases a Cu(III) species and the trifluoromethyl radical. The latter rapidly adds to 1,6-enyne 1a to give the radical intermediate B.
In the presence of ligands and TMSCN, Cu(III) species activates an alkyne unit of intermediate B to drive 5-exo-dig cyclization, giving favorable anti-Cu(III) species C , some of which is converted into syn-Cu(III) species C ′ , together with trimethylsilyl 2-iodobenzoate D. Finally, anti-Cu(III) species C undergoes reductive elimination to give the desired (E)-product 3a as a major isomer and regenerate a Cu(II) complex to complete a catalytic cycle through the release of ligands (He et al., 2014b), whereas syn-Cu(III) species C ′ undergoes the same reductive elimination to access minor (Z)-product 3a.

CONCLUSION
In summary, we have established a copper-catalyzed annulationcyanotrifluoromethylation of 1,6-enynes with easily available Togni's reagent and TMSCN, by which a wide range of 1indanones with a quaternary carbon center were stereoselectively synthesized in generally good yields. Notably, a complete stereoselectivity could be detected in most cases. This approach is efficiently induced by Togni's reagent as a radical donor and ultimately terminated by TMSCN as the nucleophilic reagent. The transformation offered a new entry to prepare the CF 3containing 1-indanone skeleton via a complex radical additioncyclization cascade. Further investigations into the mechanism and its application will be conducted in due course.

General Procedure for the Synthesis of 3
Example for the Synthesis of 3a Under Ar conditions, a mixture of Togni's reagent 2 (0.6 mmol), Cu(OTf) 2 (0.02 mmol), K 3 PO 4 (0.4 mmol), and ligand L1 (0.04 mmol) was added in a Schlenk tube. Acetonitrile was added into the tube. Then, 2-methyl-1-[2-(phenylethynyl)phenyl]prop-2en-1-one 1a (0.2 mmol) and TMSCN (0.4 mmol) were put in the system, stirred for 3 h at 50 • C until thin-layer chromatography (TLC) revealed that conversion of the starting material 1a was complete. Next, the reaction mixture was concentrated in vacuum, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 25:1, v/v) to afford the desired product 3a.

DATA AVAILABILITY STATEMENT
The datasets generated for this study are available on request to the corresponding author.

AUTHOR CONTRIBUTIONS
T-SZ, BJ, and P-JC designed the project. T-SZ performed the experiments. T-SZ, W-JH, S-JT, and P-JC analyzed the data. T-SZ, BJ, and GL wrote the manuscript.