Heteroaromatic compounds electrophilic aromatic substitution

In addition to benzene and naphthalene derivatives, heteroaromatic compounds such as ferrocene[232, furan, thiophene, selenophene[233,234], and cyclobutadiene iron carbonyl complexpSS] react with alkenes to give vinyl heterocydes. The ease of the reaction of styrene with sub.stituted benzenes to give stilbene derivatives 260 increases in the order benzene < naphthalene < ferrocene < furan. The effect of substituents in this reaction is similar to that in the electrophilic aromatic substitution reactions[236]. 

As described in the previous sections, a variety of nucleophiles attack the Cy atom of ruthenium-allenylidene intermediates. Aromatic compounds should also be suitable candidates and this was found to be the case [30]. Thus, reactions of propargylic alcohols with heteroaromatic compounds such as furans, thiophenes, pyrroles, and indoles in the presence of a diruthenium catalyst such as la proceeded smoothly to afford the corresponding propargylated heteroaromatic compounds in high yields with complete regioselectivity (Scheme 7.25). The reaction is considered to be an electrophilic aromatic substitution if viewed from the side of aromatic compounds. 

The same concept was applied in the synthesis of aryl-substituted piperidines by the TfOH-catalyzed reaction of piperi-dones with benzene (eq 35). In the TfOH-catalyzed reactions, acetyl-substituted heteroaromatic compounds, such as pyridines, thiazoles, quinolines, and pyrazines can condense with benzene in good yields via the dicationic intermediates (eq 36). Amino alcohols have also been found to ionize cleanly to the dicationic intermediates, which were directly observed by low-temperature NMR. Amino alcohols can react with benzene in triflic acid by electrophilic aromatic substitution with 70 99% yields (eq 37). Similarly, amino acetals can react with benzene in triflic acid medium to give l-(3,3-diphenylpropyl)amines or l-(2,2-diphenylethyl)amines in 50 99% yield (eq 38). ... 

Although heteroaromatic compounds generally have lower resonance energies than benzene (Table 14.1, p. 629), they also undergo electrophilic aromatic substitution rather than addition. 

The gold-catalyzed reaction of alkynes with aromatic units has been extensively studied [105-107]. This reaction allows the synthesis of polycyclic aromatic and heteroaromatic systems via Friedel-Crafts-type processes. Although, the C-H activation of aryl compounds by gold(lll) has been known for more than 70 years, it is accepted that the Friedel-Crafts-type reaction proceeds via [Au(alkyne)] complexes and subsequent electrophilic aromatic substitution with the arenes or heteroarene compounds. 

The thiazolyl radicals are, in comparison to the phenyl radical, electrophilic as shown by isomer ratios obtained in reaction with different aromatic and heteroaromatic compounds. Sources of thiazolyl radicals are few the corresponding peroxide and 2-thiazolylhydrazine (202, 209, 210) (see Table III-34) are convenient reagents, and it is the reaction of an alky] nitrite (jsoamyl) on the corresponding (2-, 4-, or 5-) amine that is most commonly used to produce thiazolyl radicals (203-206). The yields of substituted thiazole are around 40%. These results are summarized in Tables III-35 and IIT36. 

This awareness in a short time led to new homolytic aromatic substitutions, characterized by high selectivity and versatility. Further developments along these lines can be expected, especially as regards reactions of nucleophilic radicals with protonated heteroaromatic bases, owing to the intrinsic interest of these reactions and to the fact that classical direct ionic substitution (electrophilic and nucleophilic) has several limitations in this class of compound and does not always offer alternative synthetic solutions. Homolytic substitution in heterocyclic compounds can no longer be considered the Cinderella of substitution reactions. 

Semiempirical methods of calculation with consideration of all valence electrons have been used only recently but already have given results on the reactivities of some aromatic and heteroaromatic compounds.157,239 243 Thus, to analyze the reactivities of thiophene and the isomeric thienothiophenes 1-3 to electrophilic substitution,157 the semiempirical SCF LCAO MO method CNDO/2 was used, taking into account all valence electrons.244 The 3s, 3p, and 3d orbitals have been taken into account for the sulfur atom.245 The reactivities were estimated from the difference between bond energies of the initial and the protonated molecule (in a complex).157... 

The most widespread and convenient method for the preparation of nitrobenzazoles is the reaction of nitration. Electrophilic substitution of azoles is a complex reaction in which the experimental conditions can modify the product orientation. The ability of azoles to electrophilic substitution is determined by the activity of reagents, the basicity of substrates, and the acidity of medium. This caused some uncertainty in interpreting the results and complicated comparison of the reactivity of various azoles among them. The situation has changed after Katritzky and Johnson [7] had reported the criteria allowing, with a sufficient degree of reliance, the establishment in what form (base or conjugative acid) the compound reacts. The information on the mechanism of nitration of azoles is basically borrowed from the extensive literature on the nitration of aromatic and heteroaromatic compounds [8] therefore, it does not make sense to discuss this point in the review. 

Udenfriend et al. observed that aromatic compounds are hydroxyl-ated by a system consisting of ferrous ion, EDTA, ascorbic acid, and oxygen.122 Aromatic and heteroaromatic compounds are hydroxylated at the positions which are normally most reactive in electrophilic substitutions. For example, acetanilide gives rise exclusively to the o-and p-hydroxy isomers whereas quinoline gives the 3-hydroxy product.12211 The products of the reaction of this system with heterocyclic compounds are shown in Table XIII. 

Iodine in combination with [bis(acyloxy)iodo]arenes is a classical reagent combination for the oxidative iodination of aromatic and heteroaromatic compounds [99], A typical iodination procedure involves the treatment of electron-rich arenes with the PhI(OAc)2-iodine system in a mixture of acetic acid and acetic anhydride in the presence of catalytic amounts of concentrated sulfuric acid at room temperature for 15 min [100,101]. A solvent-free, solid state oxidative halogenation of arenes using PhI(OAc)2 as the oxidant has been reported [102]. Alkanes can be directly iodinated by the reaction with the PhI(OAc)2-iodine system in the presence of f-butanol under photochemical or thermal conditions [103]. Several other iodine(in) oxidants, including recyclable hypervalent iodine reagents (Chapter 5), have been used as reagents for oxidative iodination of arenes [104-107]. For example, a mixture of iodine and [bis(trifluoroacetoxy)iodo]benzene in acetonitrile or methanol iodinates the aromatic ring of methoxy substituted alkyl aryl ketones to afford the products of electrophilic mono-iodination in 68-86% yield [107]. 

Heterocycles with conjugated n systems have a propensity to react as saturated rather than as unsaturated systems. The most familiar qualitative expression of the aromaticity of heteroaromatic systems is their reaction by electrophilic substitutions. However, the presence of two or more heteroatoms tends to decrease the electron availability at the ring carbons of a heteroaromatic compound and thus... 

Since heteroaromatic compounds sometimes exhibit interesting physical properties and biological activities, construction of substituted heteroaromatics has drawn some attention. Heteroaromatics can be divided into two major categories. One is the tt-electron-sufhcient heteroaromatics, such as pyrrole, indole, furan, and thiophene those easily react with electrophiles. The other is the 7r-electron-deficient heteroaromatics, such as pyridine, quinoline, and isoquinoline those have the tendency to accept the nucleophilic attack on the aromatic ring. Reflecting the electronic nature of heteroaromatics, the TT-electron-deflcient ones are usually used as the electrophiles.t The rr-electron-sufficient heteroaromatics having simple structures, such as 2-iodofuran and 2-iodothio-phene, have also been utilized as the electrophiles. Not only the electronic nature of the heteroaromatics but also coordination of the heteroatom to the palladium complexes influence catalytic activity. This is another reason why the couphng reaction did not proceed efficiently in some cases. 

Several reviews have been published on electrophilic homocyclic and heterocyclic aromatic substitution. Other reviews and books of relevance include polychloro-aromatic compounds, annulenes and related compounds, cyclobutadiene-metal complexes/ substitution via heteroaromatic N-oxide rearrangements/ 7T-excessiveness in heteroaromatic compounds/ and special topics in heterocyclic chemistry. The book by Jones and Bean is a mine of information on pyrrole chemistry. ... 

Reactions of aromatic and heteroaromatic rings are usually only found with highly reactive compounds containing strongly electron donating substituents or hetero atoms (e.g. phenols, anilines, pyrroles, indoles). Such molecules can be substituted by weak electrophiles, and the reagent of choice in nature as well as in the laboratory is usually a Mannich reagent or... 

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