Copper-catalyzed C–S direct cross-coupling of thiols with 5-arylpenta-2,4-dienoic acid ethyl ester

A selective copper (Cu)-catalyzed C–S bond direct cross-coupling of thiols with 5-arylpenta-2,4-dienoic acid ethyl ester was developed. Notably, various biologically active 5-phenyl-3-phenylsulfanylpenta-2,4-dienoic acid ethyl ester derivatives were efficiently synthesized under moderate conditions. Finally, a plausible Cu(i)/Cu(iii) reaction mechanism was proposed.


Introduction
As one of the most important compounds, organic thioethers are being widely applied in organic synthesis, the pharmaceutical industry, and functional materials. 1 C-H bonds functionalization has considerably progressed. 2 In theory, due to larger atomic radius and higher electron density, sulfur has more reactivity and is easy to modify (Scheme 1). 3 In comparison with the state art of C-C coupling, 4 acylation 5 and amination, 6 C-H bond direct thiolation has been seldom described in the literature. The main reason is that sulfur easily poisons transition metals. 7 Therefore, developing more efficient strategies for C-H bond thiolation is still required.
Selective C-H bond functionalization, either chemoselective or regioselective, has been long pursued. 8 The progress on transition-metal catalyzed C-N and C-O crosscoupling has been prompted. However C-H bonds activated by alkenes is rarely reported. 9 Considering the signicance of diversifying synthetic strategies, we focused our interest on sulfur-directed C-H bond functionalization. 10 5-Arylpenta-2,4-dienoic acid ethyl esters is an excellent scaffold which ubiquitous in natural biological products, the pharmaceutical chemistry and functionalized materials. 11 However, the earlier reported synthetic methods have many disadvantages, such as low efficiency, inconvenience, and requiring harsh conditions. Efficient synthetic methods of 5-phenylpenta-2,4dienoic acid ethyl esters are still required. Due to the functional group tolerance and economic attractiveness, copper catalysts have been extensively used in C-H bonds functionalization. 12 Herein, we report a selective copper-catalyzed C-S bond direct cross-coupling reaction of thiols with 5arylpenta-2,4-dienoic acid ethyl ester. In this reaction, various biological activity 5-aryl-3-arylsulfanylpenta-2,4dienoic acid ethyl ester derivatives were efficiently synthesized under moderate conditions. Finally, a plausible reaction mechanism was proposed.

Results and discussion
The reaction conditions were screened based on a model reaction of thiophenol 1a with 5-arylpenta-2,4-dienoic acid ethyl ester 2a. These reactions are mainly based on the use of the enaminone ligand, which was previously discovered in our laboratory as an effective ligand for the C-N coupling of Ullmann reactions between aryl halides and various azoles. 10 At the beginning, various structurally similar enaminone ligands L1-L9 were investigated (Scheme 2). The yields increased by changing the substituent R to R 0 . Additionally, other enaminone ligands, such as L7, L8, and L9, were observed to be less effective. Analyzing the results, L4 was considered the best ligand.
Furthermore, other reaction parameters were optimized (Table 1). Experimental results demonstrated that the Cu(I) salt resulted in a higher yield than the Cu(II) salt (entries 1-4). Additionally, the results also demonstrated that the reaction temperature was as an important parameter. The desired product had a 63% yield at 50 C (entry 8) and a 75% yield at 70 C (entry 9). Furthermore, the reaction in the absence of the ligand did not occur (entry 11). Finally, the desired product 3a was formed with 81% yield when used the catalyst system L4 with CuI at 60 C (entry 10).
Under the optimized conditions, the reaction scope was next investigated. A wide array of aryl thiols 1 and 5-arylpenta-2,4-dienoic acid ethyl esters 2 were obtained as the productivity with good to excellent yields (Table 2). We found that both the electron-donating and electron-withdrawing aryl thiols 1 reacted smoothly with 5-arylpenta-2,4-dienoic acid ethyl esters 2. The aryl thiols 1 bearing electron-donating groups showed better activity than those with electron-withdrawing groups. 5-Arylpenta-2,4-dienoic acid ethyl esters 2 bearing electronwithdrawing groups showed better activity than those bearing electron-donating groups. The C]C conguration of the 5arylpenta-2,4-dienoic acid ethyl esters 2 was retained in the corresponding products.
Next, we focused on other thiols (Table 3). Aliphatic thiols worked well in this reaction. The corresponding products were isolated with 76-88% yields. The C]C conguration of the 5phenylpenta-2,4-dienoic acid ethyl esters 2 were also retained in corresponding products.
There were two reasons of the ester group essential for the regioselectivity in those reactions. First, ethyl ester was more common and more meaningful than other alkyl esters in the eld of synthetic industry and functional materials. Secondly, ethyl ester had better coordination ability than other alkyl ester. Based on the above results, a reaction mechanism was proposed (Scheme 3). Aer the coordination of CuI with L4, a corresponding intermediate 6 was generated. 13 Next, an intermediate 7 was formed from intermediate 6 with aryl thiols through a ligand exchange step. Next, intermediate 7 Scheme 2 Ligand performance in copper-catalyzed C-S direct cross coupling.     a Reactions conditions: 4 (0.3 mmol), 2 (0.36 mmol), CuI (10 mol%), L4 (10 mol%), Cs 2 CO 3 (2 equiv.), DCE (4 mL), 60 C for 24 h, in N 2 . b Isolated yield.

Conclusions
In conclusion, a selective copper-catalyzed C-S bond direct cross-coupling of thiols with 5-arylpenta-2,4-dienoic acid ethyl esters was developed. Using this methodology, various biological activity 5-aryl-3-phenylsulfanylpenta-2,4-dienoic acid ethyl ester derivatives were efficiently synthesized. The process used inexpensive catalysts and under mild conditions. The reaction mechanism of the Cu(I)/Cu(III) catalysis cycle was proposed.

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