Copper(i) reagent-promoted hydroxytrifluoromethylation of enamides: flexible synthesis of substituted-3-hydroxy-2-aryl-3-(2,2,2-trifluoro-1-arylethyl)isoindolin-1-one

A novel CuBr-catalyzed hydroxytrifluoromethylation reaction was investigated. Substituted 3-benzylidene-2-arylisoindolin-1-ones was reacted with sodium trifluoromethanesulfinate to afford substituted-3-hydroxy-2-aryl-3-(2,2,2-trifluoro-1-arylethyl)isoindolin-1-one. The reaction proceeded at 25 °C in air atmosphere in the absence of base and ligands. Our results indicate that trifluoromethyl free radical tends to attack a double bond rather than aryl in this reaction.


Introduction
Isoindoles are a series of notable nitrogen-containing compounds known for their bioactivity in nature. 1 In particular, 3-hydroxyisoindolin-1-ones such as I and II are the core structural motifs of several compounds of medicinal value (Fig. 1). 3-Hydroxy isoindolin-1-ones are known for their use as diuretic and anticancer drugs. 2 As substituted 3-benzylidene-2arylisoindolin-1-ones have double bonds, we try to nd a catalytic system for direct hydroxytriuoromethylation of substituted 3-benzylidene-2-arylisoindolin-1-one.
Hydroxytriuoromethylation of organic molecules has become a research focus in the eld of organic synthesis for its unique biological activities. 3 In 1991, Langlois and co-workers reported the rst use of CF 3 SO 2 Na as the triuoromethyl radical source. 4 Since then, a series of triuoromethylation of olens by using Langlois reagent has been published in the last twenty years. 5 In these reactions, CF 3 SO 2 Na was excited by single electron oxidations to generate CF 3 free radicals. The oxidative partners included TBHP, 6 K 2 S 2 O 8 , 7 PhI(OAc) 2 , 8 DTBP, 9 I 2 O 5 , 10 metal (Cu, Mn), 11 photoinducers 12 and so on. There have only been several examples involving hydroxytri-uoromethylation of olens to afford useful b-triuoromethyl alcohols. 13 Moreover, there were also studies of the metal-freecatalyzed hydroxytriuoromethylation reactions of styrenes. 14 Recently, manganese-catalyzed direct hydroxytri-uoromethylation reaction of styrene derivatives has been established. 15 On the other hand, the CuCF 3 system has been used for the synthesis of direct hydroxytriuoromethylation reaction. 16 Visible light promoted C-F functionalization has been developed under mild reaction condition. 17 Until now, hydroxytriuoromethylation of enamides has not been reported. As part of our research on the transition metal-catalyzed free radical reaction of substituted 3-benzylidene-2-arylisoindolin-1-one, 18 this communication reports the rst example of hydroxytriuoromethylation reaction of 3-benzylidene-2arylisoindolin-1-one (the special structure of enamide) with sodium triuoromethanesulnate catalyzed by CuBr in the presence of K 2 S 2 O 8 (Scheme 1).

Results and discussion
When the model reaction of 3-benzylidene-2-phenylisoindolin-1-one (1a) with sodium triuoromethanesulnate (2) was performed in CH 3 CN/H 2 O in the presence of oxidants such as TBHP, DTBP, Mn(OAc) 3 and PhI(OAc) 2 , no desired products were obtained (Table 1, entries 1, 2, 3 and 4). Aer the addition of K 2 S 2 O 8 (4 eq.), the reaction proceeded smoothly to afford the desired product, 3-hydroxy-2-phenyl-3-(2,2,2-triuoro-1phenylethyl)isoindolin-1-one (3a) in 48% yield (Table 1, entry 5). Further investigation of copper catalysts, the yield of 3a was improved to 72% when we used CuBr as the catalyst (Table 1, entries 9). On the other hand, when we use FeCl 3 in place of CuBr, the reaction afforded the desired product in a lower yield (  [15][16][17][18][19], we found that CH 3 CN/H 2 O (2 : 1) works best for the reaction. Apart from the above-mentioned factors, the effects of catalyst loading, reaction temperature and time were also investigated, and the optimal reaction conditions were determined to be room temperature reaction for 0.5 h in air atmosphere, with the addition of 20 mol% CuBr as catalyst, K 2 S 2 O 8 as single electron oxidation regent and CH 3 CN/H 2 O as solvent (Table 1, entries 20-27).
In order to understand the reaction mechanism, following control experiments were carried out. We repeated the reaction in the presence of radical quencher 2,2,6,6tetramethylpiperidin-1-oxyl (TEMPO) and none of 3a was obtained (Scheme 2a). The result suggested that free radical were probably generated during the reaction. Furthermore, 3a was also not detected when the reaction was performed with the addition of butylated hydroxytoluene (BHT, 3.0 equiv.) under the standard conditions (Scheme 2b). Tri-uoromethylation products was obtained when 1,1-diyldibenzene and Langlois reagent were carried out in standard condition (Scheme 2c). On the other hand, neither aryl amine nor benzylamine substrate produced the ortho-position C-H activated products (Scheme 2d). 18 These results indicated that the reaction is only suitable for enamine substrates which have enough electron cloud density.
As the hydroxytriuoromethylation always took place under argon atmosphere in the above experiments, we wondered whether the reaction would proceed if isotopically labelled molecular H 2 18 O was used. Hence, we did further reactions (Scheme 2e). Surprisingly, the corresponding 18 O-containing

Conclusions
In summary, we have developed a novel catalytic system for direct hydroxytriuoromethylation of substituted 3benzylidene-2-arylisoindolin-1-ones via a radical pathway. The reaction has a high regioselectivity as the CF 3 free radical is prone to attacking a double bond rather than the aryl. The method has a broad scope and offers a good yield. The corresponding products are potentially useful in drug discovery.

Conflicts of interest
There are no conicts to declare.