Heteroaryl halide

Heteroarylphenylalanines could be smoothly obtained via microwave-promoted Suzuki reaction of heteroaryl halides with 2-amino-3-[4-(dihy-droxyboryl)phenyl]propanoic acid (Scheme 28) [46]. Interestingly, the free amino acid could be used without any protection of the amine and carboxylic acid fimctionahty. When 4-(dihydroxyboryl)-L-phenylalanine was used as organometallic partner no racemization was observed. The carboxylate anion and free amino group seem to shield the a-C - H from deprotonation and thus hmit racemization. 

Disodium glyphosate has been reacted with activated heteroaryl halides, such as 2-chlorobenzothiazole or 2-chlorobenzoxazole 79, in aqueous alcohol at reflux to produce the N heteroaryl glyphosate derivadves 80 (2). Improved yields have often obtained in these reactions using the more soluble bis-quatcmary ammonium salt of glyphosate derived from tetrabutylammonium hydroxide (2). 

Hie Pd-catalysed coupling of aiyl and heteroaryl halides with 2-hydroxyphenyl 2-propynyl ethers leads to (Z)-2-arylidene-l,4-benzodioxanes <96CC1067>. 

If the stannane bears substituents at the position geminal to tin, the reaction requires activation by Cu1 (Section 9.6.3.2.1). The cross-coupling of aryl (or heteroaryl) stannanes with aryl (or heteroaryl) halides or triflates is a general route to various biaryls and their analogues, particularly useful in those cases when the Suzuki-Miyaura reaction is less effective for... 

In addition, complexes of P(/-Bu)3 have been shown to catalyze the formation of diaryl heteroarylamines from bromothiophenes.224 Aminations of five-membered heterocyclic halides such as furans and thiophenes are limited because their electron-rich character makes oxidative addition of the heteroaryl halide and reductive elimination of amine slower than it is for simple aryl halides. Reactions of diarylamines with 3-bromothiophenes occurred in higher yields than did reactions of 2-bromothiophene, but reactions of substituted bromothiophenes occurred in more variable yields. The yields for reactions of these substrates in the presence of catalysts bearing P(/-Bu)3 as ligand were much higher than those in the presence of catalysts ligated by arylphosphines. 

The stannylation and silylation of heteroaryl halides has also been studied. The stannylation of 4-iodo pyrimidine was conducted with hexamethyl and hexa-ra-butyl ditin in the presence of fluoride ion and Pd(PPh3)2(OAc)2 as catalyst. The stannylation of 5-bromopyrimidine occurred in the highest yields in the presence of the ligandless catalyst bis(7r-allylpalladium chloride).175 The silylation of bromopyridines, bromopyrimidines, and bromoquinolines also occurred after 96 h at 160 °C with Pd(PPh3)4 as catalyst in HMPT solvent.162... 

The second salient feature of heterocycles is the marked activation at positions a- and y- to the heteroatom. For N-containing heterocycles, the presence of the N-atom polarizes the aromatic ring, thereby activating the a and y positions, making them more prone to nucleophilic attack. The order of SNAr displacement of heteroaryl halides with EtO is [14] ... 

Pd-catalyzed carbonylation of heteroaryl halides provides a quick entry to heteroaryl carbonyl compounds such as heteroaryl aldehydes, carboxylic acids, ketones, esters, amides, a-keto esters and a-keto amides. In addition, Pd-catalyzed alkoxycarbonylation and aminocarbonylation are compatible with many functional groups, and therefore, are more advantageous than conventional methods for preparing esters and amides [78],... 

The mechanism for Pd-catalyzed C—O bond formation is similar to that of C—N bond formation. Application of this method to heterocyclic chemistry is yet to be seen, partially because the SnAt displacements of many heteroaryl halides with alkoxides are facile without the aid of palladium. 

Pyridylstannanes have been cross-coupled with numerous aryl- and heteroaryl halides as well as various other electrophiles. For example, an extension of Stille s original methodology to 3-trimethylstannylpyridine and acid chloride 73 gave the corresponding ketone 74, which was then converted to 2S-(+)-nicotinylalanine 75, a neuroprotection agent [62],... 

The furyl- and benzofurylstannanes can be coupled with a variety of electrophiles including aryl [53] and heteroaryl halides [54, 55]. In their synthetic studies towards lophotoxin and pukalide, Paterson and coworkers explored both intermolecular and intramolecular Stiile coupling reactions [56], The intermolecular approach between vinyl iodide 54 and furylstannane 55 was... 

Although the Heck reactions of heteroaryl halides are now commonplace [76], few examples are found using organohalide substrates possessing a carboxylic acid moiety [77]. However, 4,5-dibromo-2-furancarboxylic acid (86) underwent a Heck reaction with ethyl acrylate to afford diacrylate 87 [78]. 

Many examples exist for Pd-catalyzed cross-couplings of alkenylzirconocenes with simple carbocyclic aryl or alkenyl halides, whereas few precedents are seen for the coupling of alkenylzirconocenes with heteroaryl halides. Undheim and coworkers reported a Pd-catalyzed cross-coupling of 2,4-dichloropyrimidine with alkenylzirconocene [50]. Hydrozirconation of hexyne readily took place at room temperature with zirconocene chloride hydride in benzene. The resulting hexenylzirconocene chloride (76) was then coupled with 2,4-dichloropyrimidine at the more electrophilic 4 position, giving rise to 2-chloro-4-[( )-l-hexenyl]pyrimidine (77). 

Palladium chemistry of heterocycles has its idiosyncrasies stemming from their different structural properties from the corresponding carbocyclic aryl compounds. Even activated chloroheterocycles are sufficiently reactive to undergo Pd-catalyzed reactions. As a consequence of a and y activation of heteroaryl halides, Pd-catalyzed chemistry may take place regioselectively at the activated positions, a phenomenon rarely seen in carbocyclic aryl halides. In addition, another salient peculiarity in palladium chemistry of heterocycles is the so-called heteroaryl Heck reaction . For instance, while intermolecular palladium-catalyzed arylations of carbocyclic arenes are rare, palladium-catalyzed arylations of azoles and many other heterocycles readily take place. Therefore, the principal aim of this book is to highlight important palladium-mediated reactions of heterocycles with emphasis on the unique characteristics of individual heterocycles. 

We have compiled important preparations of heteroaryl halides, boranes and stannanes for each heterocycle. The large body of data regarding palladium-mediated polymerization of heterocycles in material chemistry is not focused here neither is coordination chemistry involving palladium and heterocycles. 

Organolithium or Grignard compounds derived from aryl or heteroaryl halides react with diphenyl phosphorazidate to give labile phosphinoyltriazenes, which on reductive work-up with aluminium hydride afford good yields of aryl or heteroaryl amines (equation 7)34. 

The electroreductive couphng process can also been performed with heteroaryl halides as 2- or 3-bromothiophene or 3-bromofuran instead of aryl hahdes. 

Nucleophilic substitution with heteroaryl halides is a particularly useful and important reaction. Due to higher reactivity of heteroaryl halides (e.g. 35, equation 24) in nucleophilic substitution these reactions are widely employed for synthesis of Al-heteroaryl hydroxylamines such as 36. Nucleophilic substitution of halogen or sulfonate functions has been performed at positions 2 and 4 of pyridine , quinoline, pyrimidine , pyridazine, pyrazine, purine and 1,3,5-triazine systems. In highly activated positions nucleophilic substitutions of other than halogen functional groups such as amino or methoxy are also common. 

The general approach to 0-arylation of hydroxylamines involves N-protection followed by O-arylation. Activated aryl halides and heteroaryl halides easily alkylate oxime salts (equation 25), N-aUcyl hydroxamic acids and N-hydroxysuccinimide . N-Hydroxyph-thalimide can be also 0-phenylated through a reaction with diphenyliodonium salt, although in lower yield . ... 

As described in Section in.B.4.d, a palladium catalyst was required to couple ArZnX with AFX. Indeed, the remaining nickel(II) complex in the medium was unable to catalyze this coupling reaction even if it was reduced to the corresponding zero-valent nickel complex. In contrast, with 2-chloropyridine as the heteroaryl halide added in the second stage, the coupling reaction was efficiently catalyzed by Ni°(bpy). 2-Arylpyridine compounds were obtained in good yields. Results are reported in Table 5. 

TABLE 7. Preparation of aryl-zinc halides from heteroaryl halides... 

The preceding examples show the possibilities and also the present limitations of PTC. The conversion of the heterocycle to its /V-oxide or complex-ation of benzene with Cr(CO)3 promote reaction of unactivated compounds. But these approaches are based on a multistep procedure. A very promising new method is the one-step reaction of unactivated aryl (and heteroaryl) halides by way of the SRN1 mechanism developed by Bunnett.232,233 This has been applied to heterocyclic molecules mainly by Wolfe and Carver.234 A pyridine derivative serves as an example. 

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