Patrick J. Walsh group realizes palladium catalyzed direct C-H arylation of 3-methylsulfinylthiphene

Thiophene is an important structure in organic functional materials due to its unique photoelectric properties and biological activities Moreover, polysubstituted thiophenes containing sulfinyl groups are also important pharmacophores Therefore, the development of effective methods of thiophene regioselective functionalization has been widely concerned by researchers Although the direct functionalization of 3-substituted thiophene to produce C2 - or C5 arylated derivatives has been reported, there are few examples of selective diarylation of thiophene In 2002, Miura and his colleagues reported the diarylation method of thiophene in the presence of PD (OAC) 2 and johnphos or P (t-Bu) 3 (scheme 1, a); in 2015, Murai developed a method of direct C-H aromatization of thioamide substituted thiophene and aryliodide (scheme 1, b) Although some progress has been made in palladium catalyzed arylation of thiophene, direct selective continuous diarylation is still difficult Recently, Patrick J Walsh, Department of chemistry, University of Pennsylvania, published a palladium catalyzed selective monoaromatization and diarylation of 3-methylsulphonylthiphene to 2-arylation or 2,5-diarylthiphene (DOI: 10.1021/acs.orglett 8b00599) on org Lett (source: org Lett.) the author has long been committed to the development of α - arylation and related reactions of methylsulfoxide In the early stage of the study, the author found that in the presence of t-buoli, the catalyst PD (OAC) 2, Kwong's ligand L1 (Figure 1), bromobenzene 2A and 3-methylsulphonylthiphene were used for the arylation reaction, and only 3A was formed The product did not produce the desired sulfoxide α - arylation product (scheme 2) Considering the importance of sulfinyl thiophene in pharmaceutical chemistry, the author decided to optimize the conditions for this unexpected discovery After a lot of conditions optimization, the optimal reaction of C2 arylation of thiophene is: in the presence of PD (DBA) 2, phdavephos L4 and base t-buoli, the product 3A (Table 1, entry 1) is obtained with 90% separation yield The reduction of temperature, the amount of catalyst, the equivalence of aryl bromine 2A or t-buoli all lead to the decrease of 3A yield In the process of condition optimization, the author observed the generation of 2,5-diaryl compound 4a, so he continued to optimize the reaction conditions for the generation of diaryl product 4a Firstly, in the presence of PD (DBA) 2 and phdavephos L4, the author investigated a variety of bases and solvents, and found that csoac and cpme are the best combination, and 4a (Table 1, entry 7) of 2,5-diarylation product can be obtained in 65% yield Then, in the presence of the above-mentioned alkali and solvent, the ligands were investigated Using 10 mol% PD (DBA) 2 and 20 mol% L7, the product 4A with 95% separation yield was obtained (Table 1, entry 14) Reducing the amount of PD (DBA) 2 to 0.5 mol% can still obtain 4A in the same yield After obtaining the optimal conditions, the author studied the substrate range of aryl bromide 2 under the condition of single aromatization A series of substituted aryl or Heterocyclo bromides can react smoothly, and the monoaromatization product 3 can be obtained in medium to excellent yield (60% - 92%) (source: org Lett.) next, the author continued to investigate the range of aryl bromides 2 under the condition of diarylation Most of the aryl bromides also obtained diarylated derivatives (80% - 99%) in excellent yields (source: org Lett.) conclusion: Patrick J Walsh group has developed a palladium catalyzed direct C-H functionalization method for sulfinyl thiophenes with good regioselectivity This method has potential application value in materials science and pharmaceutical chemistry