A -Heteroarenes

Palladium chemistry involving heterocycles has its unique characteristics stemming from the heterocycles inherently different structural and electronic properties in comparison to the corresponding carbocyclic aryl compounds. One example illustrating the striking difference in reactivity between a heteroarene and a carbocyclic arene is the heteroaryl Heck reaction (vide infra, see Section 1.4). We define a heteroaryl Heck reaction as an intermolecular or an intramolecular Heck reaction occurring onto a heteroaryl recipient. Intermolecular Heck reactions of carbocyclic arenes as the recipients are rare [12a-d], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles, pyrroles and indoles, etc. are excellent substrates. For instance, the heteroaryl Heck reaction of 2-chloro-3,6-diethylpyrazine (1) and benzoxazole occurred at the C(2) position of benzoxazole to elaborate pyrazinylbenzoxazole 2 [12e]. 

The close proximity of functional groups in 1,2-disubstituted benzenes can sometimes bring about an unexpected reactivity. Attempts to N-alkylate ortho-nitroani-lines under strongly basic reaction conditions, for instance, lead to the formation of N-alkoxybenzimidazoles (Scheme 6.10). The main force driving this reaction is the formation of an imidazole ring, a heteroarene with high resonance energy and thermal stability. 

A -Heteroarenes such as pyridine however photochemically add amines to yield oc-aminoalkyl substituted products even with secondary amines (Scheme 50) [280]. 

Recent efforts pertaining to direct attachment of chiral sidechain to a heteroarene show that enantioselective Pictet-Spengler reaction is achievable in the presence of a multifunctional thiourea An interesting observation is that annulation of pyrroles by this method (with 17) can give different isomers from CC bond formation at an a- or 3-carbon ... 

With this large group of heterocycles, ring strain is of little or no importance. Ring-opening reactions are, therefore, rarer than in three- and four-membered heterocycles. The crucial consideration is rather whether a compound can be regarded as a heteroarene or whether it has to be classified as a heterocycloalkane or heterocycloalkene (see p 2). Various aromaticity criteria apply to heteroarenes, and as a consequence, different opinions have been expressed on this matter [1]. As will be shown by means of examples of the various systems, the nature and number of heteroatoms are the critical factors. The parent compound of the five-membered heterocycles with one oxygen atom is furan. 

To summarize, the reactivity of oxazoles closely resembles that of the ftirans, especially in their readiness to undergo ring-opening reactions and [4+2] cycloadditions. The pyridine-like N-atom impedes electrophilic substitution reactions. On the other hand, it facilitates the attack of nucleophiles onto the C-2 atom. Although oxazole is considered to be a heteroarene, because of its six delocalized ring electrons, its aromaticity is low and comparable to that of furan. 

Its spectroscopic properties correspond to those of the parent compound 2//-pyran-2--one. Coumarin has the character of an enol lactone rather than that of a heteroarene, as is shown by its JR and NMR spectra ... 

The first cross-dehydrogenative intermolecular arylation of a heteroarene with an arene was reported by Fagnou in 2007. N-acetyl-lH-indoles were coupled with simple arenes and selective C3-arylation was obtained (88 89) in the presence of Pd(TFA)2 as catalyst in combination with superstoichiometric Cu(OAc)2 as terminal oxidant (Scheme 40) (2007SCI1172). The N-acetyl group proved to be crucial as no reaction product was achieved with IH-indoles, furthermore N-methyl-lH-indoles gave only self-dimerized products. 

Directed activation of a C(sp )-H bond by an iron complex was much less investigated than the reaction of C(sp )-H bonds. Li reported the phosphine-directed C (sp )-H to form an iron pincer complex (e.g., [80]). Ohki and Tatsumi reported that Cp Fe complexes bearing imidazolium salts undergo cyclometalation through C-H activation or can cleave the C-H bond of a heteroarene [81]. 

D. D. Vachhani, A. Sharma, E. Van der Eycken, Angew. Chem. Int. Ed. 2013, 52, 2547-2550. Copper-catalyzed direct secondary and tertiary C-H alkylation of azoles through a heteroarene-amine-aldehyde/ketone coupling reaction. 

Introduction. Zinc isopropylsulfinate (IPS) is a commercially available reagent that appends isopropyl units to heteroarenes under practical and mild conditions. Reactions are run at either room temperature (rt) or 50 °C, the reaction is tolerant of air and moisture, and the reaction solvent can even he H2O. Innately reactive (i.e., electrophihc) positions of a heteroarene undergo the transformation of carbon-hydrogen to carhon-isopropyl. C-H functionalization of these innate positions and methods to override this inherent reactivity as well as one-pot sequential functionalization of two different positions of a heteroarene wiU he discussed herein. 

Ru3(CO)i2 catalyzes a Murai-like reaction in which an acyl group is introduced (3 to nitrogen in a heteroarene. Cyclometalation in clusters is particularly easy, and instead of simply forming the Ru alkyl, as in the Murai case, an additional CO insertion step occurs, to produce an ct-acyl heterocycle (Eq. 14.39). ... 

The authors have proposed a plausible mechanism for the trifluoromethylation reaction (Scheme 13.31). They assumed that a SET reduction ofCF3S02Cl224 by the photoexcited catalyst gives the oxidatively active catalyst and a CF3SO2CI radical anion 227, which rapidly collapses to generate the CF3 radical by the release of SO2 and chloride. The CFg radical then adds to a heteroarene to form the radical 228. Single-electron oxidation and subsequent deprotonation of the resulting cation 229 furnishes the trrfluoromethyl-substituted heteroarene products. 

A possible catalytic cycle for this transformation, involving an oxidative quenching pathway, was proposed by the authors (Scheme 13.38). Single-electron transfer from photoexcited Ir(III) to trifluoromethylacyloxyphthalimide 261 generates the A/ -centered radical (PhthN) 263, trifluoroacetate anion, and Ir(IV). The addition of radical 263 to a heteroarene forms the carbon radical intermediate 264, which is then oxidized by Ir(IV) with subsequent deprotonation providing the aminated product 262a. 

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