Room-Temperature Direct β-Arylation of Thiophenes and Benzo[b]thiophenes and Kinetic Evidence for a Heck-type Pathway

The first example of a regioselective β-arylation of benzo[b]thiophenes and thiophenes at room temperature with aryl iodides as coupling partners is reported. This methodology stands out for its operational simplicity: no prefunctionalization of either starting material is required, the reaction is insensitive to air and moisture, and it proceeds at room temperature. The mild conditions afford wide functional group tolerance, often with complete regioselectivity and high yields, resulting in a highly efficient catalytic system. Initial mechanistic studies, including 13C and 2H KIEs, suggest that this process occurs via a concerted carbo-palladation across the thiophene double bond, followed by a base-assisted anti-elimination.


CHCl 3
Pd 2 (dba) 3 . CHCl 3 was synthesized according to the procedure of Ananikov et al. 1 Pd(OAc) 2 (500 mg, 2.23 mmol, 1 equiv), sodium acetate trihydrate (3.08 g, 22.6 mmol, 10 equiv), dibenzylideneacetone (1.03 g, 4.46 mmol, 2 equiv) were weighted in a 250 mL round-bottom flask followed by the addition of 50 mL of MeOH. The reaction mixture was stirred at 40 °C for 3 hours. After completion of the reaction a brown solid was formed. The solid was filtered off and washed with MeOH (2 x 3 mL) and water (3 x 3 mL). The residue was washed with CHCl 3 and the solution was evaporated. The solid obtained was redissolved in a minimum amount of CHCl 3 and acetone (~ 20 mL) was slowly added to the solution.

General procedures
General procedure A. Pd 2 (dba) 3 . CHCl 3 (2.5 mol %), silver carbonate (0.75 equiv), aryl iodide (1.50 equiv) and (benzo)thiophene (1.0 equiv) were stirred in hexafluoro-2-propanol at 24 °C for 16 h. After this time, the resultant mixture was diluted with EtOAc (5 mL) and filtered through a plug of silica. The silica plug was flushed with EtOAc (30 mL) and the filtrate was evaporated to dryness under reduced pressure. The crude product was purified by automated column chromatography using the specified eluent to afford the product.
General procedure B. Pd 2 (dba) 3 . CHCl 3 (2.5 mol %), silver carbonate (0.75 equiv), tris(4methoxyphenyl)phosphine (5 mol %), aryl iodide (1.50 equiv) and (benzo)thiophene (1.0 equiv) were stirred in hexafluoro-2-propanol at 50 °C for 16 h. After this time, the resultant mixture was diluted with EtOAc (5 mL) and filtered through a plug of silica. The silica plug was flushed with EtOAc (30 mL) S-9 and the filtrate was evaporated to dryness under reduced pressure. The crude product was purified by automated column chromatography using the specified eluent to afford the product.
General procedure C. Pd 2 (dba) 3 . CHCl 3 (2.5 mol %), silver carbonate (0.75 equiv), aryl iodide (1.50 equiv) and (benzo)thiophene (1.0 equiv) were stirred in hexafluoro-2-propanol at 50 °C for 16 h. After this time, the resultant mixture was diluted with EtOAc (5 mL) and filtered through a plug of silica. The silica plug was flushed with EtOAc (30 mL) and the filtrate was evaporated to dryness under reduced pressure. The crude product was purified by automated column chromatography using the specified eluent to afford the product.
General procedure D. Pd 2 (dba) 3 . CHCl 3 (2.5 mol %), silver carbonate (0.5 equiv), tris(4methoxyphenyl)phosphine (5 mol %), aryl iodide (1.0 equiv) and (benzo)thiophene (3.0 equiv) were stirred in hexafluoro-2-propanol at 50 °C for 16 h. After this time, the resultant mixture was diluted with EtOAc (5 mL) and filtered through a plug of silica. The silica plug was flushed with EtOAc (30 mL) and the filtrate was evaporated to dryness under reduced pressure. The crude product was purified by automated column chromatography using the specified eluent to afford the product.
General procedure E. Pd 2 (dba) 3 . CHCl 3 (2.5 mol %), silver carbonate or silver oxide (0.5 equiv), aryl iodide (1.0 equiv) and (benzo)thiophene (2.0 equiv) were stirred in hexafluoro-2-propanol at 24 °C for 16 h. After this time, the resultant mixture was diluted with EtOAc (5 mL) and filtered through a plug of silica. The silica plug was flushed with EtOAc (30 mL) and the filtrate was evaporated to dryness under reduced pressure. The crude product was purified by column chromatography using the specified eluent to afford the product.

3-(4-acetylphenyl)benzo[b]thiophene (3af)
The product 3af was obtained via the general procedure A using benzo [ Data is in accordance with the literature. 3 Alternatively, product 3af can be obtained in 90% yield using 0.5 mol% of Pd 2 (dba) 3 . CHCl 3 at 50 °C in S-13

Methyl 4-(benzo[b]thiophen-3-yl)benzoate (3ag)
The product 3ag was obtained via the general procedure A using Data is in accordance with the literature. 2 Alternatively, product 3aa can be obtained in 83% yield using 0.5 mol% of Pd 2 (dba) 3 . CHCl 3 at 50 °C in 16 h (NMR yield determined against internal standard).

3-(m-tolyl)benzo[b]thiophene (3am)
The product 3am was obtained via the general procedure A using

S-29
silica plug was flushed with EtOAc (30 mL) and the filtrate was evaporated to dryness under reduced pressure. Yields were calculated by 1 H-NMR using an internal standard. using an internal standard.

Formulas for the Determination of KIEs
The formulas applied for the determination of KIEs and their errors were reported by Saunders 13 and Singleton 14

Quantitative 13 C NMR
All NMR samples were prepared using benzo[b]thiophene (50 mg) in 0.5 mL of CDCl 3 . The 13 C spectra were recorded at 125.81 MHz using inverse gated decoupling, 51 s delays between calibrated π/2 pulses, 1.4 s acquisition time and 64 scans collecting 32768 complex points. Six spectra were recorded for each sample. A zero order baseline correction was generally applied, but in no case a first or higher correction was tested. Integrations were numerically determined using a constant region for each peak corresponding to a multiple of the peak widths at half height (± 5w 1/2 ) and referred to C7 of benzo[b]thiophene, which was set with an integration of 1000.

Experimental Procedure for Large Scale Reactions
In order to measure the 2 H KIEs using the same analytic technique, we partially deuterated the benzothiophene starting material at C-2 and C-3 (ca 1% each). The same procedure described for the 13 C KIEs determination was applied in the following reactions, in this case in the presence of an internal standard (1-methoxy-3-nitro-4-deuterobenzene). A conversion of 66.7 ± 0.7% was obtained for the first sample and 68.2 ± 0.6% for the second sample.

Quantitative 2 H NMR
All NMR samples were prepared using benzo[b]thiophene (60 mg) in 0.25 mL of CHCl 3 . 150 µl of a solution of 456 mg of 1-methoxy-3-nitro-4-deuterobenzene in 10 mL of CHCl 3 were then added to each sample as external standard for the integration. The 2 H{ 13 C} spectra were recorded at 77 MHz using inverse gated decoupling, 6.2 s delays between calibrated π/2 pulses, 2.7 s acquisition time and 256 scans collecting 8192 complex points. Each spectrum was obtained by taking the sum of five subspectra; six spectra were recorded for each sample. A zero order baseline correction was generally applied, but in no case a first or higher correction was tested. Integrations were numerically determined using by fitting the data to a Lorenztian function using the line shape fitting tool of Bruker's Topspin v.3.2 software.

Olefin insertion
The olefin insertion was modeled starting from benzo

C-H activation via concerted metalation deprotonation process
The

VII. Crystallographic data of 3ak
The crystal structure was deposit at the Cambridge Crystallographic Data Centre.