Halides, heteroaromatic

The same group found that heteroaromatic halides can be smoothly phenylated using NaBPh4 as the transmetallating agent and ligand-free Pd(OAc)2 as a catalyst with water or AT-methylformamide (NMF) as the solvent (Scheme 21) [39], The experiments were all performed using power control. 

This is a problem that has been reported by several researchers in other cya-nation methods on heteroaromatic halides. (Hetero)aryl chlorides have also been tackled via in situ halogen exchange to (hetero)aryl bromides followed by sequential cyanation (Scheme 71). For this microwave-assisted process an equimolar amount of NiBr2 and a two-fold excess of NaCN were used. The only heteroaromatic chloride tested was 2-chloropyridine. Although the procedures described involve the use of significant amounts of nickel salts, a clear advantage is that the reactions can be performed in air. Moreover, the cyanat-ing reagents are easily removed since they are water soluble. 

Our new approach has proven its initial value in both palladium-(Schareina et al. 2004) and copper-catalyzed cyanations (Schareina et al. 2005) and has been adopted by other groups. Very recently, in a joint collaboration with Saltigo GmbH we developed a new and improved copper-based catalyst system, which allows for efficient cyanations of a variety of aromatic and heteroaromatic halides. Importantly, notoriously difficult substrates react in excellent yield and selectivity, making the method applicable on an industrial scale. 

The cross-coupling of CF3Br with aromatic and heteroaromatic halides has also been achieved using a sacrificial copper anode (Eq. 11) [25]. 

Nucleophilic substitution of halogen atom in aromatic and heteroaromatic halides with a hydroxyamino group proceeds only in substrates that are activated by a strong electron-withdrawing substituent in the benzene ring (e.g. 27, equation 17). Despite this limitation this reaction is useful for synthesis of arylhydroxylamines and usually provides good yields of products. Along with activated aryl halides and sulfonates, activated methyl aryl ethers such as 28 can be used (equation 18). 

Very strong bases such as NaNH2 convert unactivated aryl halides into benzyne intermediates which react rapidly with nucleophiles to form the products of an apparently simple nucleophilic substitution. It is now clear that hetarynes are frequent intermediates in reactions of not too highly activated heteroaromatic halides. 

N-Arylations of amines have also been realized with support-bound heteroaromatic halides (Entries 9-11, Table 10.4). Several examples of the synthesis of substituted 1,3,5-triazines [83-85], purines [78,85-93], and pyrimidines [77,85,94—96] have been reported. The reactivity of these arylating agents depends strongly on their precise substitution pattern, and generally increases with decreasing electron density of the het-eroarene. Illustrative examples are given in Table 10.4. The arylation of amines with simultaneous cleavage of the product from the support is discussed in Section 3.8. 

A direct transformation of functionalized aromatic/heteroaromatic halides into sul-fones has been performed via reactions of organomagnesium intermediates with sulfur dioxide (Scheme 19).98 The ratio of sulfones has been considerably increased by the use of polar aprotic solvents such as DMF or DMSO and of allylic and primary halides. 

Participating substrates include unactivated aromatic and heteroaromatic halides. In addition to halides, other leaving groups are known (i.e., (EtO)2P(0), RS (R = Ar, alkyl), ArSO, ArS02, PhSe, Ph2S+, RSN2 (R = /-Bu, Ph), N2BF4, R3N+, and N+). 

Stoichiometric palladium-mediated cyclization was used in natural product synthesis by Boger a number of years ago, as was noted in the introduction. More recently, an intramolecular palladium-catalyzed amination of a heteroaromatic halide has been used as a step in the synthesis of an a-carboline natural product analog [146]. As discussed above, the diphenylhydrazone arylation can also be used for nitrogen heterocycle synthesis [140]. 

Among the halides that react through this process are unactivated aromatic and heteroaromatic halides, vinyl halides, activated alkyl halides [nitroalkyl, nitroallyl, nitro-benzyl and other benzylic halides substituted with electron-withdrawing groups (EWG) as well as the heterocyclic analogues of these benzylic systems] and non-activated alkyl halides that have proved to be unreactive or poorly reactive towards polar mechanisms (bicycloalkyl, neopentyl and cycloalkyl halides and perfluoroalkyl iodides). 

There is a substantial body of literature on the palladium- and nickel-catalyzed formation of aryl sulfides, selenides, and phosphines from aromatic and heteroaromatic halides. Progress on these reactions has continued with several recent contributions [47-50]. A review in 1997 covered the types of transformations that can be conducted and the types of catalysts used [51]. Particularly useful examples are the conversions ofbinaphthol to binaphthylphosphines... 

This may imply that the intermolecular coupling of various aryl halides with other heteroaromatic compounds may proceed. Indeed, it is now known that not only the special heteroaromatic halides but also usual aryl halides can react with a variety of five-membered aromatic heterocycles, including furans, thiophenes, and azole compounds such as M-substituted imidazoles, oxazoles, and thiazoles [133-137]. The arylation of azoles can be carried out using iodobenzoate immobilized on an insoluble polymer support [138]. Related intermolecular reactions of indole [139] and imidazole [140] derivatives have also been reported. 

MAP and its analogues considerably accelerate the Hartwig-Buchwald amination of aromatic and heteroaromatic halides and triflates (eq simiiai- acceleration is observed for Suzuki-... 

Water-soluble palladium(O) complexes have also been used as homogeneous catalysts in aqueous-solution alkylation reactions. The particular complex that has been used is Pd(TPPMS>3. Aryl or heteroaromatic halides can be coupled with aryl or vinyl boronic acids, alkynes, alkenes, or dialkyl phosphites with this palladium(0) complex. This complex in aqueous solution can also be used for the coupling of alkynes with unprotected iodonucleotides, iodonucleosides, and iodoamino acids (133). 

For the coupling reaction of less-reactive heteroaromatic halides, diaryldichlorosilanes are conveniently employed to give heterobiaryls in high yields [Eq.(20)] [19]. 

The Suzuki coupling reaction is a powerful tool for the construction of biaryl compounds and their homologues, which are key structural elements of various natural products, polymers, and compounds of medicinal interest. Aryl boronic acids and their esters are the usual substrates in reactions with aryl or heteroaromatic halides and... 

The Castro-Stephens reaction entails coupling of alkynylcopper(I) reagents with aryl or heteroaromatic halides in refluxing pyridine to furnish arylacetylenes. The cuprous alkynylides are prepared by adding the 1-alkynes to an aqueous ammonia solution of cuprous iodide. Since dry copper alkynylides have the tendency to explode, they must be handled with great care and should only be used in a slightly damp state. ... 

Pd-catalyzed Miyaura boration Pd-catalyzed cross-coupling of aromatic and heteroaromatic halides or triflates with tetraalkoxydiboron compounds to give arylboronic and heteroarylboronic esters. 296... 

COUPLING OF C(ip )-ORGANOMETALUCS WITH ARYL O, S AND Se COMPOUNDS COUPLING OFC(jp )-ORGANOMETALLICS WITH POLYFUNCTIONAL AROMATICS COUPLING OFC(jp )-ORGANOMETALUCS WITH HETEROAROMATIC HALIDES AND SULFIDES Furans and Thiophenes... 

COUPLING OF C(s/ 3).orgANOMETALLICS WITH HETEROAROMATIC HALIDES AND SULFIDES... 

Nickel- or palladium-catalyzed coupling reactions of alkyl Grignard or zinc reagents can be applied to heteroaromatic halides and sulfides. The characteristic features are, therefore, based on those described in the preceding sections and hence details are not repeated in this section. Aspects are summarized by the types of heteroaromatic compounds NiCh(DPPP) is used as catalyst, unless stated otherwise hereafter. 

Nishida employed boronic acid 106 and the corresponding TV-TBS boronic acid in Suzuki reactions with a series of heteroaromatic halides [118], The TV-TIPS group proved superior to TV-TBS. 3-Indoleboronic acid 96 was employed by Neel to prepare bis(indolyl)maleimides such as 109 [119]. However, since the standard Suzuki conditions failed (triflate 108 apparently decomposing under the reaction conditions), the use of a phosphine-free Pd catalyst [120] and cesium fluoride [121] was necessary and gave 109 in an acceptable yield of 55%. 

For heteroaromatic systems, this reaction complements nucleophilic aromatic substitutions. The Pd-catalyzed reaction of 19 with 69 afforded 410 in excellent yield [145]. The use of bis-chelating ligands in this chemistry prevented ligand exchange with the pyridine substrate, thereby preventing formation of a bis(pyridyl)palladium species that would terminate the catalytic cycle. As a result of these specific catalytic conditions, this represented the first example of amination of a heteroaromatic halide. 

Various heteroaromatic alkylamines, such as (di)alkylamino derivatives of pyridine, quinoline and pyrimidine, which are difficult to prepare at normal pressure, have been obtained in good to high yields by high-pressure S nAi reactions of the corresponding heteroaromatic halides with various amines. 4-(Di)alkylaminopyridine derivatives 140 have been synthesized via the high-pressure-promoted (0.8 GPa) iS nAf of 4-chloropyridine hydrochloride (138) with primary and secondary amines 139 (Scheme 7.34). ... 

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