Amination of Heteroaromatic Halides

The palladium-catalyzed amination of heteroaromatic halides, or the arylation of heteroaromatic containing amines, is complicated by the Lewis basicity of the heteroatom. The heterocycle may thus act as a ligand for palladium and cause catalyst inhibition and/or poisoning. R. Dommisse demonstrated that by using excess K2CO3 with the Pd/BINAP or L5 catalyst system, a series of pyridyl chlorides could be efficiently aminated by either anilines or aminopyridines.63... 

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. 

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]. 

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

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). ... 

Kaushik and coworkers developed a ligand-free heterogeneous Cu-catalyzed N-arylation of amines with diheteroaryl halides (Scheme 4.29) (Verma et al., 2011). In this case, benzyltributyl ammonium bromide was used as the phase transfer catalyst (PTC), and potassium hydroxide (KOH) was employed as the base. Under optimized conditions (Cu(l)/PTC/KOH, in H2O-CHCI3 or HjO-EtOH), a variety of heteroaromatic amines were obtained in high yields with good chemoselectivity at 35oC-40°C. 

Based on this concept, Whitby and co-workers [110] reported an interesting palladium-catalyzed three-component synthesis of aromatic and heteroaromatic amidines 133 starting from unsaturated halides, amines, and t-butylisocyanide (Scheme 8.53). The catalytic cycle for this iminocarbonylative coupling reaction is analogous to the reactions incorporating carbon monoxide-isoelectronic with isocyanides-as the third partner [111]. 

Some of these transformations were accompanied by additional reactions, e.g. formylation of the aromatic or heteroaromatic - nucleus or CH-acidic methyl groups further dehydration of amides to nitriles was observed. Adducts from amides and PCI3, sulfonyl halides or SO2CI2/SCXZI2 from which amidines can be obtained by reaction with amine derivatives (compare Section 2.7.2.5 and refs. 5 and 14) have not found wide application for this purpose. An interesting reaction is the preparation of the amidine (294 equation 158) from 7V-pentafluorophenylformamide. By thermal decomposition of the adducts from secondary amides and 7V,iV-dialkylcarbamoyl chlorides amidinium salts were synthesized from which the amidines (295 equation 159) were set free by treatment with bases. " ... 

The vast majority of ILs are usually prepared by simple N- or T-alkylation of amines, heteroaromatics, and phosphines, often employing alkyl halides or alkyl sulfonates as alkylating agents, followed by association with metal halides or anion metathesis (Scheme 1). 

As described above, the initial [Pd]—R complex can be formed by the transfer of R from another organometallic RM. Compounds of mercury, boron or tin have often been used. Alternatively an aryl, heteroaromatic or vinyl halide is added to PdL, generated in situ from PdL or by reduction of L PdX. In the second method a base such as a tertiary amine is also required to react with the hydrogen halide which is produced. 

Apart from halides, several neutral cocatalysts have been reported to increase the catalytic activity of Ruj(CO)i2 in carbonylation reactions of the kind here discussed [18, 19, 154, 170-172, 178-180]. In most cases, these cocatalysts are phosphines or heteroaromatic amines such as pyridine, Bipy or Phen, and are considered to act as ligands towards ruthenium. The question of the nuclearity of the active catalytic species has been examined only in the case of phosphines and it appears that the most active catalysts are mononuclear. In the case of nitrogen ligands, the question has not been examined in detail, but the same is probably also true. A more detailed discussion on this point is reported in Chapter 6. 

A three-component synthesis of pyrroles, which unites enolisable ketones, primary amines, and vicinal diols, was reported by Beller. Remarkably, these reactions generate two C-N bonds, one C-C bond, liberate one equivalent of H2, and two equivalents of water in a single synthetic operation. A broad range of substituents is tolerated, including heteroaromatics, esters, amides, and aryl halides. Primary drawbacks of these methods include high reaction temperatures and the inability to access certain regio-isomers, such as 2-ff-3-allqrl pyrroles. 

Hydrogen borrowing and dehydrogenative condensations provide new opportunities for the preparation of both saturated and aromatic heterocycles respectively. The ability to directly access azacycles from stable species such as alcohols and amines allows chemists to circumvent the preparation and use of relatively unstable carbonyls and alkyl halides that conventional methods require. Pyridines, pyrazines, pyrroles, as well as fused bicyclic heteroaromatics, may all be prepared by dehydrogenative condensation this reactivity will likely be extended to pyrimidines, imidazoles, pyrazoles, and triazoles in the near future. Continuous advances in scope and scalability will expand the role of hydrogen transfer in the discovery and production of small molecule therapeutics. 

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