Direct arylations benzoxazoles

The direct arylation of heteroaryls is particularly attractive due to the fact that these moieties are present in many biologically active compounds [58], Recently, etinkaya and co-workers reported the direct arylation of benzoxazoles and ben-zothiazoles with aryl bromides catalysed by a bis-NHC-palladium complex [59], Also, Sames and co-workers have described the C-H arylation of different SEM-protected heteroarenes, catalysed by NHC-Pd complex 28 (Scheme 7.12, pathway a) [60],... 

Phenyloxazole and benzoxazole (Eq. 60) are good substrates for the direct arylation [128]. 

Although, examples of the arylation of oxazole itself are Umited, the reaction with 2-chloro-3,6-dialkylpyridazines at the 5-position is known [58]. 2-Phenyloxa-zole [78] and benzoxazole [58, 78,91,92] are good substrates for the direct arylation (Equations 10.58 and 10.59) [78]. The arylation of oxazolo[4,5-fe]pyridine can be carried out under mild conditions (Equation 10.60) [93]. Treatment of ethyl 4-oxazolecarboxylate with iodobenzene in the presence of a catalyst system consisting of Pd(OAc)2 and IMes affords its 2-phenylated product predominantly (Equation 10.61) [94]. The regjoselectivity may be attributable to steric reasons. 

Many examples exist of synthetically useful intermolecular paUadium-catalyzed arylations of Jt-excessive heterocycles [4, 7, 50-56]. The reaction has also been extended to the direct arylation of pyridine, diazine and azole N-oxides with aryl halides [57]. Interestingly, tuning the ligand and base allows selective sp or sp activation of alkyl pyridine or pyrazine N-oxides [58], Palladium-catalyzed sp activation of alkylanines [59] and benzyUc arylation of benzoxazoles has also been described [60]. 

Direct Arylation of Benzoxazoles and Related Heterocycles. Benzoxazole 3 was functionalized with a variety of arenes and heteroarenes in the presence of catal)4ic amounts of [Pd(phen)2](PFe)2 (eq 3). In particular, heteroaryl iodides provided excellent yields of the comesponding products. The reaction... 

Direct Arylation. The direct functionalization of C—H bonds is an attractive area of research due to both economical and environmental concerns. It has been shown that the direct arylation of various heterocycles is feasible in the presence of a copper catalyst, a ligand, and employing LiO/Bu as a base. 7 The lithium aUcoxide base has proven to be superior to its potassium counterpart. For the arylation of benzoxazoles (eq 7), both electron-rich and electron-poor aryl iodides are good coupling partners, and the corresponding arylated benzoxazoles are obtained in good yields. ... 

Newman et al. reported an approach to 2-bromobenzofurans using an intramolecular copper catalyzed C—O coupling of gm-dibromovinyl phenols (Scheme 24.29, disconnection D-2 and Scheme 24.31) [115]. This process is directly analogous to their palladium-catalyzed route to indoles via gem-dihalovinylaniline precursors (Scheme 24.3). Like the indole synthesis, further development of this chemistry has focused on harnessing the synthetic potential of the second bromine atom. To this end, several research groups have reported routes incorporating a tandem direct arylation leading to 2-aryl [116] and heteroaryl [27,117] benzoxazoles. 

An interesting result has been obtained in a study of the dechlorination of polychlorobenzenes by direct irradiation in acetonitrile in addition to dechlorination, products resulting from rearrangement of the chlorine atoms to positions mefa to their original point of attachment are observed. Thus orfho-dichlorobenzene was found to yield mainly chlorobenzene along with small amounts of para-dichlorobenzene the authors speculate that the rearrangement products are formed by recombination of an aryl-chlorine radical pair. In another novel result photolysis of pentachlorophenol in acetonitrile is found to give small amounts of the benzoxazole (160). ... 

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. ... 

Further elaborations/modifications of the oxazole ring were also described. For example, a new POCN-pincer palladium catalyst was used in the copper-mediated arylation of the C-2 position of benzoxazoles and oxazoles with aryl iodides in satisfactory yields (14DT16084). An original method for the direct amination of heteroarenes including benzoxazoles was reported involving a one-pot heteroarene C-H zincation followed by a copper catalyzed electrophilic amination (14AGE4667). 

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. 

Fukuzawa, S.-L, Shimizu, E., Atsuumi, Y., Haga, M. and Ogata, K. 2009. Copper-catalyzed direct thiolation of benzoxazole with diaryl disulfides and aryl thiols. Tetrahedron Lett. 50(20) 2374-2376. 

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. 

Direct 2-arylation (i.e., 2-C-H functionalization) of benzoxazole has been achieved (a) by Cu-mediated reaction with aryl iodides in the presence of Na2C03 [281] and (b) by Pd-mediated reaction with aryl chlorides or bromides in the presence of CS2CO3 [282]. 

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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