Thiazoles palladium-catalyzed oxidative

A palladium-catalyzed oxidative C—H/C—H cross-coupling between benzothiazoles 70 and thiazoles 71 is carried out under base-free conditions (14CC3996).This reaction appears to be insensitive to air and moisture and displays high-functional group tolerance. 

As can be seen in the scheme below, a series of substituted 2-(2-aminothiazol-4-yl)-benzo[ ]furans with inhibitory activity for leukotriene B4 were made from benzofurans via acylation, followed by Hantzsch thiazole formation <070BC3083>. 2-Substituted benzo[ ]furans could also be generated via an aerobic oxidative coupling of 2-unsubstituted benzo[ ]furans with arenes through the palladium-catalyzed double C-H activation <07OL3137>. In addition, 2,3-diarylbenzo h I uran could be constructed by a palladium-catalyzed arylation of benzo[6]furan with an aryl chloride in the presence of a bulky, and electron-rich phosphine <07OL1449>. 

Abstract Azines, diazines or thiazole (V-oxides are highly reactive substrates in palladium-catalyzed direct arylation reaction. For these reactions, the results are inconsistent with an SEAr reaction pathway and may best fit with a concerted metalation-deprotonation-like (CMD) mechanism. 

Scheme 14 Thiazole N-oxides in palladium-catalyzed direct arylation...

In 2011, Itami and Studer [183] developed a palladium-catalyzed C4-selective arylation of thiophenes and thiazoles with arylboronic acids. Although they had already reported the C4(/J)-selective arylation of thiophenes with aryl iodides [88] (Scheme 17.18), this C-H/C-B coupling method [using a Pd"/hipy or phen/TEMPO ((2,2,6,6-tetramethylpiperidin-l-yl)oxyl) catalyst system] enabled the use of thiazoles as aryl nucleophiles. They also applied this coupling reaction to the synthesis of the core structure of SCH-785532, which is known as a BACE inhibitor. In the same year, Itami [184] reported a direct arylation of a PAH with arylboronic acids to generate a 7t-expanded PAH. Treatment of pyrene 142 with arylboroxine 143 in the presence of Pd(OAc)2 and o-chloranil as an oxidant, followed by cydiza-tion under stoichiometric FeClj, produced PAH 144. Key to the unprecedented C-H arylation was a notable combination of Pd" and o-chloranil. 

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. ... 

Joyce LL, Batey RA. Heterocycle formation via palladium-catalyzed intramolecular oxidative C—H bond functionalization an efficient strategy for the synthesis of 2-aminobenzo-thiazoles. Org. Lett. 2009 11 2792-2795. 

Thiazole is a jt-electron-excessive heterocycle. The electronegativity of the N-atom at the 3-position makes C(2) partially electropositive and therefore susceptible to nucleophilic attack. In contrast, electrophilic substitution of thiazoles preferentially takes place at the electron-rich C(5) position. More relevant to palladium chemistry, 2-halothiazoles and 2-halobenzothiazoles are prone to undergo oxidative addition to Pd(0) and the resulting o-heteroaryl palladium complexes participate in various coupling reactions. Even 2-chlorothiazole and 2-chlorobenzothiazole are viable substrates for Pd-catalyzed reactions. 

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