1.3.4- Thiazoles, arylations, palladium acetate

Two methodologies for the direct C-2 arylation of thiazoles have been reported. The first one is mediated by both palladium and copper <07T1970>. Thus, the C-2 arylation of thiazole and benzothiazole with aryl iodides is carried out using copper iodide (2 equiv.) and a catalytic amount of palladium acetate under base-free conditions. The other method involves copper-catalyzed arylation with aryl iodides in the presence of lithium t-butoxide <07JA12404>. In general, reactions with lithium tert-butoxide provide better yields than those with potassium fert-butoxide. In addition, arylation with phenyl bromide, chloride or tosylate fails to provide any desired arylation products. 

Imidazole /V-oxide substrates may be used in a similar fashion. Initial investigations revealed that the use of palladium acetate in conjunction with an electron deficient 4-fluorophenylphosphine in acetonitrile at 70 °C provides C2 arylation in high yields. With the goal of achieving the same reactivity at or near room temperature it was determined that the use of palladium acetate in conjunction with a Buchwald ligand, catalytic copper bromide and 30 mol% pivalic acid in acetonitrile could also achieve high yields of C2 arylation at 25 °C. As was the case with thiazole V-oxides. if the C2 and C5 positions of the imidazole are blocked C4 arylation may also be achieved in synthetically useful yield (Scheme 15). 

Arylation of Thiazoles and Oxazoles. The protocol that was previously developed for the C-H activation of azine and diazine (V-oxides with aryl triflates was used to effect the arylation of flve-membered ring heterocycles, such as oxazoles and thiazoles. In contrast to another protocol that was previously reported by the same group, the transformation did not require an V-oxide function. However, in order to direct the arylation at the C4-position, to prevent the formation of a mixture of regioisomers, and to minimize the generation of diarylated products, a C5-chloride was used as a blocking group. The procedure, which is promoted by palladium acetate and di-tert-butyl(methyl)phosphonium tetrafluoroborate, uses an aryl bromide as the electrophile. 

The C5-arylation is usually preferred in the C-H activation of thiazoles. For instance, upon using di-tert-butyl(methyl)phosphonium tetrafluoroborate in conjunction with palladium acetate, theregioselectiveCS-arylation of unsubstituted thiazoles was observed (eq 15). ... 

Palladium-catalyzed Direct Arylation of Pyridine N-Oxides, Pyrazine N-Oxides, Pyridazine N-Oxides, Pyrimidine N-Oxides, and Thiazole N-Oxides. Pyridine W-oxides can be efficiently ary-lated at the C2 position using aryl halides as the electrophile, palladium acetate as the catalyst, tri-tert-butylphosphonium tetraflu-oroborate as the ligand, and potassium carbonate as the base (eq 19). In this protocol, 3 equiv of pyridine Al-oxide are utilized to generate the corresponding 2-aryl derivatives. ... 

Other classes of heterocycles that have been arylated using the C-H activation method and involving palladium acetate and tri-tert-butylphosphonium tetrafluorohorate include the quinoline N-oxides (eq 25) and the thiazoleiV-oxides (eq 26). In the case of quinoline (V-oxides, the regioselectivity of arylation is as expected and leads to the corresponding 2-aryl derivatives. However, in the case of thiazole IV-oxides, the nature of the phosphine has a dramatic influence on the regioselectivity of the arylation process, with tri-terf-butylphosphine providing the product of C5 arylation. 

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