Aryl iodides arylations, oxazole

Several new methods for the synthesis of the oxazole nucleus were published. A new consecutive three-component oxazole synthesis by an amidation-coupling-cycloisomerisation sequence was developed. The synthesis started from propargylamine 92 and acyl chlorides. To extend this process, a four component sequence involving a carbonylative arylation by substitution of one acyl chloride with an aryl iodide and a CO atmosphere was also performed <06CC4817>. 

Cacchi s group reported an elegant synthesis of 2,5-diaryloxazoles 1616 using a palladium-catalyzed reaction of A -propargyl benzamides 1615 and aryl iodides (Scheme 1.412). The authors had evidence to support two different mechanistic pathways, depending on the substitution pattern of 1615 and the aryl iodide. The optimal reaction conditions were found to be Pd2(dba)3, P(2-furyl)3 as the ligand, NaOtBu as the base, and acetonitrile as the solvent. These conditions significantly reduce the reaction time and favor oxazole formation. 

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). 

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. 

The extensive work carried out by Beller in recent years has contributed to the field with a series of interesting examples, most of them based on the system palladium/di-1 -adamantyl- -butylphosphine (BuPAdj). Thus, they reported the use of ammonia as the nitrogen source for the palladium-catalyzed aminocarbonylation of aryl halides, providing a straightforward method to prepare primary amides with excellent applicability and functional group tolerance [4]. In the same group, the first carbonylative C—H activation reactions of heteroarenes to form diaryl ketones 4 were developed [5], A series of nonpreactivated heteroarenes 3 (oxazoles, thiazoles, and imidazoles) were successfully carbonylative coupled to a wide range of aryl iodides (Scheme 3.2). To avoid the formation of the noncarbonylative... 

As described in Sect. 2.1.2, the a-functi(Mialization (tosylation, triflation) of ketones with hypervalent iodine, followed by nucleophilic attack by diverse nucleophiles in an intramolecular fashion offers a convenient entry to various heterocycles [6]. Such a transformation can also be realized in an intermolecular fashion. Along these lines, Togo and coworkers [97] reported an elegant one-pot synthesis of 2,4,5-trisubstituted oxazoles 142 from alkyl aryl ketones 140 and nitriles 141 via an iodoarene-catalyzed oxidation reaction (Scheme 35). In this reaction sequence, reactive aryliodonium species were generated in situ by the reaction of aryl iodide with mCPBA and trifluoromethanesulfonic acid (TfOH). Afterwards, aryliodOTiium species reacted with alkyl aryl ketone to form a fi-keto aryliodonium species. 

Disubstituted oxazoles have been prepared also through the reaction of A -propargylamides with aryl iodides in the presence of Pd2(dba)3, tri(2-furyl) phosphine, and NaOBu . The reaction appears to proceed through a palladium-catalyzed coupling step followed by the in situ cyclization of the resultant coupling product [45]. 

Multiple arylations of oxazole was demonstrated with a paUa-dium/phenanthroline catalyst. Electron-deficient aryl iodides tended to provide the triarylated product, while more rich substrates furnished a mixture of products (eq 26). 

Two regioselective palladium-catalyzed methods have been developed for the direct C-H arylation of oxazole at C-5 or C-2 using aryl and heteroaryl bromides, chlorides, iodides, and tri-flates (eq SS). " Under optimized conditions, minor amounts (<10%) of the bis(arylated) product are observed. The reaction works well with arenes containing electron-donating or electron-withdrawing substituents. 

The coupling of various oxazoles with aryl iodides proceeds under Irgandless conditions, employing Pd(OAc)2 as the catalyst and Cul as the additive (eq 166). In case of the oxazole, it was necessary to use the aryl iodide as the limiting reagent to obtain synthetically useful yields (23 versus 74%). Moreover, two complementary C-2 C-5 arylations were developed for oxazoles. On the one hand, it was demonstrated that in nonpolar solvents, such as toluene, in the presence of a phosphine, such as RuPhos, selectivities >100 1 were obtained for arylation at the C-2 position (eq 167). On the other hand, polar solvents and hindered phosphines led to predominantly C-5 arylation (eq 167). It was hypothesized that, for the C-5 arylation, a CMD-type mechanism is operative, while a deprotonation pathway is the more likely explanation for the C-2 arylation. A general, paUadium-catalyzed, sequential arylation of ethyl oxazole-4-carboxylates at the C-2 and C-5 positions with a variety of aryl halides has also been reported. 

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. 

The Merck process chemists found that 2-oxazolylzinc species 40, successfully prepared from oxazole 39 subsequently cross-coupled with aryl or heteroaryl bromides to oxazoles 41. The use of solid zinc chloride helped the transmetallation however, long reaction times were required for good yields. Anderson also reported 2-oxazolylzinc species 40 was successfully cross-coupled with aryl iodides and triflates to compounds 41. This methodology was employed in the synthesis of oxazole-containing partial ergot alkaloids. ... 

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. ... 

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