Direct arylations benzothiazoles

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. 

Direct Arylation of Heteroarenes, Aryl silicon reagents were employed to directly arylate heteroarenes via a Pd-catalyzed, ligand-free process. Silver(I) fluoride was the most effective source of fluoride (93%) compared with FeFs, KF, wBu4NF-H20, and CsF, although CuF2 gave a comparable performance (82%). In addition to activating the arylsilanes, silver(I) fluoride acts as a co-oxidant with Cu(0Ac)2-H20 to oxidize Pd° to Pd. The electron-rich and electron-deficient aryl (trimethoxy)silanes could be coupled to access arylated benzothiazoles in excellent yields (83-93%) (eq 19). 

Pd-catalyzed Direct Arylation of Heterocycles. Microwave conditions were developed to access biheteroaryls using PivOH and PCys. Heteroarenes, such as benzothiophene, N-methylimidazole, thiophene, furan, thiazole, and benzothiazole, reacted efficiently with aryl bromides containing varying electronic and sterically challenging substituents (eq 18). 

A cobalt-catalyzed method for arylation of heteroarenes including thiazole and benzothiazole was reported in 2003 <030L3607>. According to this report, the direct C-5 arylation of thiazole with iodobenzene was carried out in the presence of cobalt catalyst [Co(OAc)2/IMes] and cesium carbonate, and a complete reversal of arylation from C-5 to C-2 was observed with the bimetallic Co/Cu/IMes system. This report has been retracted as the laboratory of the senior author has not been able to reproduce the key results disclosed in the communication <06OL2899>. 

Several nickel-based catalyst systems have been proven to catalyse C-H arylation of heteroarenes with aryl halides. For example, a combination of Ni(OAc)2 and bipy or dppf catalyses the C-H arylation of azoles including thiazoles, benzothiazoles, oxazoles, benzoxazoles, and benzimidazoles with aryl chlorides, bromides and iodides as well as aryl triflates in the presence of LiOtBu or Mg(OtBu)2. The Ni(OAc)2/dppf/LiOtBu system is more effective for aryl chloride or triflate electrophiles. Nickel-catalysed direct allq ny-lation of azoles with all yl bromides was also carried out. Ni(COD)2/l,2-bis(diphenylphosphino)benzene (dppbz) is an effective catalyst and LiOtBu is a suitable base for this transformation. In some cases, a catalytic amount of Cul additive promotes the coupling. ... 

A variety of benzoxazoles (214) have been shown to selectively undergo copper-catalyzed direct ring-opening N-arylation over C-2 arylation when the coupling with aryl iodide (215) is conducted in a screw-capped vial rather than the standard round-bottomed flask (2015JOC3670). Two catalysts, copper cyanide and cyano bis(triphenylphosphine)copper(l), proved effective in generating the ring-opened products but displayed no activity with benzimidazoles and benzothiazoles. 

C2-Arylated 1,3-Azoles In 1998, Miura reported the first example of the catalytic C-H arylation of (benzo)azoles and thiophenes (at their C2 position) with aryl halides [98, 99a]. In the presence of catalytic Pd(OAc)2 and stoichiometric carbonate base at high temperature (140 °C), 1,3-azoles (oxazoles, N-alkylated imidazoles, fhiazoles) were coupled with various aryl bromides selectively at the C2 position. For the reactions of N-alkylated benzimidazoles, benzoxazoles, and benzothiazoles, addition of Cul was necessary to increase the yield of products. Furthermore, when N-methylbenzimidazole was used, Miura discovered that the coupling with aryl bromides proceeds without the palladium catalyst (i.e., by a copper-mediated C-H/C-X coupling of azoles with aryl halides). Thereafter, Miura enhanced the efficiency of the coupling reaction to allow for multiple arylations of azoles both C2 and C5 positions [99b]. In 2000, Rondo [100] prepared polymer-supported aryl iodides, with which the direct coupling reaction with 1,3-azoles (Miura s conditions) was conducted. 

In 2009, Patel and co-workers developed two ligand-assisted Cu(i)-cata-lyzed sequential intra- and intermolecular S-arylations for the synthesis of arylthiobenzothiazoles in a one-pot manner without an inert atmosphere (Scheme 2.140). Low catalyst loading, inexpensive metal catalyst and ligand, lower reaction temperature, and shorter reaction times make this method superior to all reported methods for the synthesis of aiylthio-benzothiazole. In detail, the reaction started with an intramolecular S-aiy-lation of a dithiocarbamate salt and yielded benzothiazol-2-thiol or MBT (2-mercaptobenzothiazole), which was then followed by an intermolecular C-S coupling giving 2-atylthiobenzothiazoles directly. In the communication, the authors found the following order of reactivity in aryl iodides P-NO2 > 0-NO2 > o-COOMe > m-Cl > H > p-Me > p-OMe. 

In 2013, Wang et al. [115] reported the direct thiolation of benzothiazole using Cul (30mol%) in the presence of elemental sulfur and aryl bromides and iodides. Significant reaction scope was demonstrated for the aryl halide reagent. 

Direct Carbonylative Coupling. Unsymmetrical diaryl ketones were synthesized via the direct carbonylative coupling of aryl iodides and heteroarenes in the presence of catalytic [PdCl(cinnamyl)]2, l,3-bis(diphenylphosphino)propane (dppp) as the ligand, and stoichiometric Cul. Thus, heterocycles such as oxazoles, benzoxazoles, thiazoles, benzothiazoles, and imidazoles reacted, with 4-iodoanisole in 56-75% yields (eq 1). Aryl iodides containing a variety of electron-donating or electron-withdrawing substitutents were tolerated in the reaction (eq 2) however, aryl bromides provided only traces of products. The role of the stoichiometric copper salt was to form a heteroaryl-Cu species, which could easily transmetallate to Pd. No reaction was observed in the absence of the Cul additive. 

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