Copper-promoted hydration and annulation of 2-fluorophenylacetylene derivatives: from alkynes to benzo[b]furans and benzo[b]thiophenes

Summary An efficient copper-promoted hydration reaction and its application in the synthesis of benzo[b]furan and benzo[b]thiophene derivatives is presented starting from readily available 2-fluorophenylacetylene derivatives. The key annulation step involves the hydration of the C–F bond of 2-fluorophenylacetylene derivatives followed by an intramolecular annulation to afford benzo[b]furan and benzo[b]thiophene derivatives. Moreover, structurally important 2,2'-bisbenzofuran scaffolds are provided in good yields.

Ackermann et al. utilized bromo-and iodo-substituted phenylacetylene in their TiCl 4 -catalyzed intramolecular nucleophilic annulation process (Scheme 1b) [24]. But this method involves a two-step process and the usage of two different metal salts may complicate further processing. The direct design of a Pd or Cu-catalyzed one-pot synthesis of benzo[b]thiophenes from 2-bromoalkynylbenzenes and a thiol derivative has eliminated these problems to a large extent [25][26][27][28][29]. Nevertheless, the direct synthesis of benzo[b]furans from 2-haloalkynylbenzenes and the usage of 2-fluorophenylacetylene derivatives as substrates continues to represent a challenge. Indeed, Tsuji and co-workers have developed a transition metal-free process for the synthesis of benzo[b]furans from 2-fluorophenylacetylene derivatives. But the reaction requires conditions with a high reaction temperature for satisfactory yields. Unfortunately, only benzo[b]furans were obtained in this reaction [30].
Typically, the aryl halides used in the annulation reactions are iodides and bromides. It is rare to employ aryl fluorides because of their low reactivity [31][32][33]. To extend the application of our strategy of the copper-catalyzed synthesis of heterocycles, we report herein a one-pot process for the synthesis of benzo[b]furans and benzo[b]thiophenes with 2-fluorophenylacetylene derivatives as precursors (Scheme 1c).

Results and Discussion
We report an efficient synthesis of functionalized benzo[b]furans from commercially available alkynes by a copper-catalyzed, intramolecular annulation process. Initially, our investigation commenced with the annulation of (2-(2fluorophenyl)ethynyl)benzene (1a) to give the corresponding product 2-phenylbenzofuran (2a) by using 2 equiv KOH as a base under various conditions. In the presence of the Pd(PPh 3 ) 4 catalyst the reaction of (2-(2-fluorophenyl)ethynyl)benzene in CH 3 CN does not give any corresponding product (Table 1, entry 1). The usage of CuCl and 1,10-phenanthroline (1,10phen) as a ligand in CH 3 CN at 80 °C showed that 2a could be isolated in 35% yield (Table 1, entry 2). The screening of the various solvents revealed that the solvent played an important role in this hydration and annulation process. Compared with the other solvents, DMSO is more suitable for the annulation process (Table 1, entries 2-4). These investigations revealed that the usage of CuI instead of CuCl as a catalyst resulted in the isolation of 2a in a satisfactory 88% yield after 4 hour (Table 1, entry 5). To our delight, the use of 0.2 equiv of KI as an additive afforded 2a in a satisfactory 95% yield (Table 1, entry 6). The base loading had a strong influence on the yield with 2 equiv KOH being the optimal amount (Table 1, entries 7 and 12). Further screening of bases did not lead to better yields and confirmed that the reaction did not proceed in the presence of CsCO 3 ( Table 1, entry 8). Other catalytic systems, such as Cu(OAc) 2 , Cu(OTf) 2 and Cu(acac) 2 , were less effective for this annulation process (Table 1, entries 9-11). A decrease in the temperature lowered the yield of the reaction ( Table 1, entry 13). The importance of water was confirmed by a lower yield under dry conditions ( Table 1, entry 14). In the absence of CuI, we found that the reaction of (2-(2-fluorophenyl)ethynyl)benzene with KOH in DMSO at 80 °C for 4 h gave 55% yield of the annulation product (Table 1, entry 15). Next, we explored the scope and generality of the process by using the conditions for Tabe 1, entry 6. As shown in Scheme 2, substrates with either electron-donating or electron-withdrawing substituents on the benzene ring can undergo the reaction smoothly, and the corresponding benzo[b]furan products were obtained in good to excellent yields. The reaction tolerated a variety of substituents including -Cl, -Br, -F, -OMe, -NMe 2 and thiophenyl groups. The use of 2-fluorophenylacetylene derivatives with electron-withdrawing substituents as R 2 afforded benzo[b]furan products in higher yields. It is noteworthy that the 2-(2-(2-fluorophenyl)ethynyl)thiophene was also successfully converted to 2-(thiophen-2-yl)benzofuran (2j) in good yields. Subsequently, the R 1 substituent of the 2-fluorophenylacetylene derivatives was varied from hydrogen to other functional groups. Substituents at the ortho position of the benzyl group did not have an impact on the reaction yield. The presence of an additional electron-donating substituent marginally decreased the conversion of 2-fluorophenylacetylene derivatives resulting in products in moderate yields (Scheme 2, 2k and 2o). Interestingly, the p-fluoro atom was kept intact during the reaction and fluoro-substituted benzofuran was obtained (Scheme 2, 2q) [34][35][36][37]. This shows the good selectivity of the current reaction system. It should be emphasized that the 1,3-bis(2-(2-fluorophenyl)ethynyl)benzene was also successfully converted to benzo[b]furan 2r in good yield.
Unfortunately, when aliphatic alkynes were employed, the desired annulation products were formed in low yields.
To gain a deeper mechanistic understanding of the present catalytic process, the direct intramolecular annulation of 1-bromo-2-(2-(2-fluorophenyl)ethynyl)benzene and 1-chloro-2-  Reactions with Na 2 S·9H 2 O as a nucleophile were successful, and the corresponding benzo[b]thiophene products were obtained in high yields (Scheme 5). We obtained the best results with DMSO as the solvent and a reaction temperature of 60 °C. Using the optimized reaction conditions, 3-chloro and 4-chloro substituted 2-fluoroalkynylbenzenes were reacted with Na 2 S·9H 2 O to yield benzo[b]thiophenes in good yields.
The postulated reaction mechanism is depicted in Scheme 6 [25][26][27][28][29].  starting from 2-fluorophenylacetylene derivatives. The hydration and annulation is catalyzed by CuI with KOH or Na 2 S·9H 2 O as a base at 60-80 °C to give the corresponding products in moderate to good yields. Various functional groups are accepted resulting in a wide range of substituted benzo[b]furans and benzo[b]thiophenes. Further studies, which are focused on the extension of the scope and the application of the reaction to the synthesis of bioactive products, are currently ongoing in our laboratory.

Supporting Information
Supporting Information File 1 Full experimental details and copies of NMR spectral data.