[(PhCH 2 O) 2 P(CH 3 ) 2 CHNCH(CH 3 ) 2 ] 2 PdCl 2 /CuI as Cocatalyst for Coupling-Cyclization of 2-Iodophenol with Terminal Alkynes in Water

: A new and efficient [(PhCH 2 O) 2 P(CH 3 ) 2 CHNCH(CH 3 ) 2 ] 2 PdCl 2 /CuI-co-catalyzed coupling-cyclization reactions of 2-iodophenol with terminal alkynes is described. Different 2-substitued benzo[b]furan derivatives are obtained in good to excellent yields. This protocol employs a relatively low palladium(II) catalyst loading in water under air conditions.


Introduction
Compounds which contain 2-substituted benzo [b]furan frameworks have been found in applications in areas ranging from pharmaceuticals to natural products owing to their various biological activities, such as antibacterial [1], antifungal [2], antitumor [3], antiviral [4], anti-inflammatory [5], antioxidant [6], and antiradical activities [7]. Various methods [8][9][10][11][12][13][14] have been developed for the synthesis of 2-substituted benzo[b]furan derivatives. Pd-catalyzed one-pot synthesis of benzo[b]furans from 2-halophenols and terminal alkynes by a Sonogashira coupling-cyclization sequence is aclassical, useful, and reliable method [10,11,[15][16][17]. Typically, this reaction is performed using a palladium catalyst in the presence of a copper salt as a co-catalyst [18][19][20]. However, most of these reactions are carried out in organic solvents and only several reactions on the synthesis of 2-substituted benzo [b]fuans are performed in water [19,21,22]. However, in the reactions which occurred in water, there are disadvantages, such as low isolated yield [21] and high loading of the palladium catalyst [19,22]. Hence, there is still need to develop a catalytic system performed in water with high yield and low loading of the palladium catalyst. Our group has recently synthesized and characterized a new palladium(II) complex(1) (Figure 1) via single-crystal X-ray crystallography. Owing to the inertness of the palladium(II) complex(1) towards oxygen and moisture, it has been used as catalyst in an aerobic coupling reaction [23]. Herein, we wish to report the use of a new Pd(II)/CuI co-catalytic system for the highly efficient synthesis of 2-substituted benzo[b]furans via coupling-cyclization reactions of 2-iodophenol with terminal alkynes in water under air conditions (Scheme 1).

Results and Discussion
In our initial experiments, we observed that the coupling of 2-iodophenol (0.5 mmol, 1a) with phenylacetylene (0.6 mmol, 2a) in the presence of Pd(II) complex(1) (1 mol %)/CuI (2 mol %) and NEt 3 (1.5 mmol) in water (2 mL) at 80 • C for 4 h proceeded to give the desired product 3a in a moderate isolated yield (51%) ( Table 1, entry 1). In the same condition, after addition of the traditional ligand PPh 3 (2 mol %), the yield was up to 60% (entry 2). This observation prompted us to investigate the effects of different loadings of the ligand PPh 3 on the reaction, finding that the yield was increased to 97% in the presence of PPh 3 (4 mol %) as a ligand (entry 3). In the following experiments, we further investigated the impacts of different amounts of CuI and different bases on the yields. Consequently, we found that no product 3a was detected in the absence of CuI (entry 6). However, when 1 mol %CuI was used as a co-catalyst, the yield was obviously enhanced to 66% (entry 7). Compared to entries 1 and 3, the results show that both co-catalyst CuI and ligand PPh 3 play important roles in this protocol. As for the effects of base on the reaction, we discovered that the yield of product 3a was 28%, 19%, 21%, and 31% when using Cs 2 CO 3 , KOH, NaOH, and t-BuOH as a base, respectively (entries [10][11][12]15), and only a trace yield of product 3a in the presence of pyridine or K 2 CO 3 as bases (entries [13][14]. In comparison with entry 3, it is presumed that triethylamine functions not only as a base, but also as a co-solvent to help the organic substrates to disperse in water. We continued to examine the influence of time and temperature on the yields. As can be seen in Table 1, the desired product 3a was obtained in a higher yield of 97% at 80 • C, but in a lower yield of 70% at 60 • C (entry 19). With a slightly higher temperature, the yields were close to those obtained at 80 • C (entries 20-21). Prolonging the reaction time from 2 h to 4 h, the yields range from 90% to 97% (entries 16,3). In addition, the palladium-catalyzed ligand-free coupling-cyclization of 2-iodophenol with terminal alkynes in water was also tested. Using PdCl 2 , Pd(OAc) 2 instead of palladium(II) complex(1) as the catalyst, respectively, only moderate yields of 53% and 51% were achieved (entries [23][24]. In a word, the best yield was obtained to perform the reaction in the presence of 1 mol %Pd(II) complex catalyst (1), 2 mol % CuI, and 4 mol % PPh 3 using triethylamine as a base at 80 • C for 4 h under air conditions in water.
Encouraged by the efficiency of the reaction protocol described above, we expanded the substrate scopes. The reactions of a variety of aromatic terminal alkynes with 2-iodophenol were tested to obtain the corresponding 2-phenylbenzo[b]furan derivatives in good to excellent yields under the optimized conditions. The results are summarized in Table 2. As we can see from Table 2, the reactions of various aromatic acetylenes with electron-donating groups on aromatic rings, such as methyl, methoxy, and butyl gave almost the same high yields (87-96%) (entries 2-6). Additionally, no significant difference was observed in yields at the same reaction conditions when the effect of different positions of the substituent groups on aromatic rings was studied (entries 2-4,7-8). In addition, when aromatic acetylenes with electron-withdrawing groups on aromatic rings reacted with 2-iodophenol under optimized conditions, the yields of the desired products were also up to 80% (entries 9-10).

Reagents and Machine
The Pd(II) complex catalyst (1) was prepared according to a procedure reported in the literature [23]. Aromatic acetylene derivatives were obtained commercially from J&K Chemical Technology (Shanghai, China) and CCIS-CHEM (Shanghai, China). All reagents employed in the reaction were analytical grade, and other chemicals were obtained commercially and used without any prior purification. All products were isolated using thin-layer chromatography (Qingdao Haiyang Chemical CO, Ltd., Qingdao, China) with GF254 silica gel using hexane and ethyl acetate unless otherwise noted. Products described in the literature were characterized using 1 H-NMR and 13 C-NMR spectra and compared with previously-reported data. 1 H-NMR and 13 C-NMR spectra were recorded with a Bruker Avance II 400 spectrometer (Fallanden, Switzerland) using tetramethylsilane as the internal standard and CDCl 3 as the solvent.

General Experimental Procedure for the Coupling-Cyclization Reaction of 2-Iodophenol with Various Aromatic Acetylenes
All reactions were carried out under air conditions. A mixture of 2-iodophenol (0.5 mmol), aromatic acetylene (0.6 mmol), Pd(II) complex catalyst (1) (1 mol %), CuI (2 mol %), PPh 3 (4 mol %), triethylamine (1.5 mmol), and water (2 mL) was stirred at 80 • C for 4 h and then extracted with ethyl acetate (3 × 15 mL). The combined organic phase was dried with anhydrous Na 2 SO 4 , filtrated, and then the solvent was removed by a rotary evaporator. The product was isolated by thin-layer chromatography. The purified products were identified by 1 H-NMR and 13 C-NMR spectroscopy.

Conclusions
In summary, we have developed a new and efficient Pd(II)/CuI co-catalytic system for the coupling and cyclization of 2-iodophenol with various aromatic acetylenes. It is noteworthy that our protocol employs a relatively low-palladium catalyst loading in water under air conditions to obtain the desired products in good to excellent yields. Currently, further efforts to study the mechanism and apply the new approach in other transformations are under way in our laboratory.