Direct arylations oxazole

Although examples for the arylation of oxazole itself are limited, reaction with 2-chloro-3,6-dialkylpyradines at the 5-position is known [6], 2-Phenyloxazole [3] and benzoxoazole [3, 10, 19, 21] are good substrates for the direct arylation (Eqs. 17 and 18) [3],... 

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. 

Miura et al. have described the nickel-catalyzed direct arylation of azoles with aryl bromides, using nickel(II) bromide or a nickel(II) bromide diglyme complex, in the presence of 1,10-phenanthroline as ligand, and lithium t-butoxide as base, in diglyme at elevated temperature. The systems were optimized for benzthiazoles, benzoxa-zoles, and 5-phenyl oxazoles benzthiazoles coupled efficiently without the addition of zinc to give 2-arylbenzthiazoles 3 (Scheme 5.1, Table 5.1). 

Pd(ll)-mediated direct arylation (with aryl halides) in the 2-position of oxazole-4-carboxylate 10 has been efficiently achieved to give the products 11, which allow a second arylation in the 5-position affording the diarylated 4-carboxylates 12 [256] ... 

Finally, Greaney recently reported the use of PEPPSI-IPr in the direct arylation of oxazoles, although the scope of this reaction was limited. ... 

Other catalysts employed in the direct arylation of oxazole include copper and nickel. " Aryl halides can be employed under nonoxidative conditions through benzyne intermediate, and, as with palladium, an oxidant is needed to couple Ar-M species. In all cases, the arylated products are obtained in moderate to good yields. 

Gorelsky has modeled the C-H activation step in the direct arylation of both free and Cu(I)-bound azoles at a Pd(Ph)(K -OAc)(PMej) intermediate [37c]. These two reactions provide complementary regioselectivities, with reaction at C5 favored for the free azoles but C2-arylation favored in the presence of Cu(I) salts. With A-methylimidazole and oxazole, the formation of A-bound... 

One class of transformations that illustrate the striking difference in reactivity between heteroarenes and carbocyclic arenes is the heteroaryl Heck reaction, in which an aryl or heteroaryl halide is coupled directly with a heteroaromatic compound to afford a biaryl product (formally a C—H bond functionalization process). Intermolecular Heck reactions involving the functionalization of aromatic carbocycles with aryVheteroaryl halides are rare [70], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles. 

Nicolaides and co-workers " conducted extensive studies on preparing 2-aryl- and 2-heteroarylphenanthro[9,10-(i]oxazoles. For instance, refluxing a solution of 10-(methoxyimino)phenanthrene-9-one 304 in an aromatic or heterocyclic methylated hydrocarbon affords a 2-aryl- or a 2-heteroarylphenanthro[9,10-d] oxazole 305 directly (Scheme 1.81). The yields are variable and poor to modest. However, using a substituted methyl analog, i.e., ArCH2Y in this reaction markedly improved the yield of 305 for several cases. Examples of 305 prepared from aromatic and heterocyclic alkanes are shown in Table 1.25. 

In a number of multicomponent condensation reactions, TMSCl has also been utilized to improve the yield or efficacy of the desired product, or is directly incorporated into the final molecules. Examples include the synthesis of Al-aryl-3-arylamino acids from a three-coir onent reaction of phenols, glyoxylates, and anilines, preparation of 2,4,5-trisubstituted oxazoles, or 4-cyanooxazoles, and the three-component BigmeUi reaction... 

Tin Derivatives A convenient and direct method for the preparation of metallated species in the azole series starts with lithiation, as in the case of rr-excessive systems. In thiazoles the initial lithiation is in the 2-position. Subseqnent qnenching with a stannyl halide will furnish a stannane snbstrate 100 to be used for Stille couplings with aryl or heteroaryl halides, in the present case with a bromide (Scheme 42). Stannylated oxazoles are similarly prepared and react in the same manner.The same applies to their benzannulated analogs 101. ... 

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). 

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. 

An alternative to the use of benzyl hahdes in direct C-H benzylations was disclosed by Ackermaim and coworkers. These authors optimized conditions for the C-H arylation and alkenylation of (benz)oxazoles with phosphate and sulfamate electrophiles and extended their results to the C-2 benzylation of (benz)oxazoles with benzyl phosphate (Scheme 19.21) [35]. More recently, the same group reported the use of a palladium catalyst containing an air- and moisture-stable secondary phosphine oxide ligand for this reaction [36]. 

In the homogeneous eatalysis domain, veiy recently Jia et al. examined the homogeneous eatalytie ability of one of their newly synthesised complexes [ (DMOX)CdCl 2(/t-Cl)2] (8) (DMOX = 4,5-dihydro-2-(4,5-dihydro-4,4-dime-thyloxazol-2-yl)-4,4-dimethyl-oxazole), for direct C-N crosscoupling of amine with aryl halide. The results point out that Cd(ii) complex 8 shows significant catal5dic activity in C-N crosscoupling of amines with aryl halide (Scheme 17.4). 

A novel Pd(OAc)2-NFSI-TFA system was developed recently by Xu and cowoilc-ers demonstrating highly selective, ortto-monofluorination. In this case Pd coordination was directed by a diverse range of aryl-Af-heterocyclic directing groups (Scheme 9.15), such as quinoxaline, pyrazole, benzo[rf]oxazole, and pyrazine derivatives. A Pd(ll/IV) catalytic cycle was proposed. 

In addition, oxazole-4-carboxylate 10 can be subjected to direct Pd-catalyzed alkenylation, benzylation, and alkylation in the 2-position [257]. Recently, direct 2-C-H-functionaUzation (alkylation and arylation) has been reported for oxazoles (as well as thiazoles and benzazoles) with free 2-position utihzing chelated Ni/Cu-catalysts derived from 2,2 -bis(dimethylamino)diphenylamine [258] or chelated Cu/Pd-complexes derived from Xantphos ]259] in the presence of a base. 

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. 

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. 

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 title compound was employed as a catalyst in the direct benzylation of thiazoles (eq 2), thiophenes, indolizines, im-idazopyridines, oxazoles, and furans. The Csp -Csp arylation was successful on a wide range of electron-rich and deficient... 

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