Reactions heterocyclic aromatic compounds

From the preparative point of view, reactions of heterocyclic aromatic compounds with nucleophilic reagents are very important, especially the reactions of their quaternary salts containing a formal enamine grouping in the molecule. 

Since thiophene derivatives, heterocyclic aromatic compounds, are sensitive toward electrophilic substitution reactions, the bromination of these compounds generally gives a mixture of mono-, di-, and other poly-substituted bromination products (ref. 19). However, we have recently found that BTMA Br3 is a useful... 

Like the piperidones, a wide variety of TV-heterocyclic aromatic compounds show an ability to activate electrophilic functional groups. It is known that acetophenone is completely protonated in CF3SO3H, however in the presence of benzene there is no hydroxyalkylation (condensation) reaction.12 On the other... 

M n Part II we spend a lot of time and pages on aromatic systems, starting with benzene. You examine benzene s structure, its resonance stabilization, and its stability. Next you study benzene derivatives and heterocyclic aromatic compounds, and then we address the spectroscopy of these aromatic compounds. And in Chapters 7 and 8 we introduce you to aromatic substitution by both electrophiles and nucleophiles, and you get to see a lot of reactions and a lot of examples. In this part you also start working with many more named reactions. 

Cyclopentadienes, 1,3-cyclohexadienes, 1,3-cycloheptadienes, as well as furan and aklyl-substituted furans, have been investigated as substrates of photosensitized oxygenation reactions, while aromatic compounds such as anthracenes and tetracenes as well as aryl-substituted carbo-and heterocyclic pentadienes were studied in direct and indirect (photosensitized) photooxygenation reactions. 

Nucleophilic Reactions of Aromatic Heterocyclic Bases Heterocyclic aromatic compounds containing a formal imine group (pyridine, quinoline, isoquinoline, and acridine) also react readily with nucleophilic reagents. A dihydro-derivative results, which is readily dehydrogenated to a new heteroaromatic system. Since the nucleophile always attacks the a-carbon atom, the reaction formally constitutes an addition to the C=N double bond. An actual localization of the C=N double bond in aromatic heterocyclic compounds is incompatible with molecular orbital theory. The attack of the nucleophilic reagent occurs at a site of low 77-electron density, which is not... 

Organomagnesium compounds usually resemble organolithium compounds in their reactions with nitrogen heterocyclic aromatic compounds [E, G], but they generally give inferior results for preparative purposes. Thus, as in the case of organolithium compounds, addition normally occurs at the 2-position of pyridine, and subsequent elimination or oxidation gives the 2-substituted pyridine [1] ... 

The nucleophilic reaction with aromatic compounds in an inter-molecular reaction has been briefly explored in this laboratory26 with several phenols and alkoxybenzenes [Eq. (37)]. This reaction could well be extended to a number of interesting heterocyclic systems. 

Ambident anions are mesomeric, nucleophilic anions which have at least two reactive centers with a substantial fraction of the negative charge distributed over these cen-ters ) ). Such ambident anions are capable of forming two types of products in nucleophilic substitution reactions with electrophilic reactants . Examples of this kind of anion are the enolates of 1,3-dicarbonyl compounds, phenolate, cyanide, thiocyanide, and nitrite ions, the anions of nitro compounds, oximes, amides, the anions of heterocyclic aromatic compounds e.g. pyrrole, hydroxypyridines, hydroxypyrimidines) and others cf. Fig. 5-17. 

Friedel-Crafts Alkylation Reactions. The activation of glyoxylate esters,trifluoromethyl pyruvate esters, and unsaturated a-ketoesters by catalyst 2 converts these materials into effective electrophiles for asymmetric Friedel-Crafts alkylation reactions with activated arenes (eqs 16 and 17). In fact, bis(triflate) (2) is far superior to tbe bis(hexafluoroantimonate) complex at catalyzing the enantioselective alkylation of benzene derivatives. Aniline and anisole derivatives both give the reaction, as do heterocyclic aromatic compounds such as indole and furan. 

This section will encompass the reactions of carbocyclic and heterocyclic aromatic compounds in which oxidation affects the aromatic rings and the attached side chains. 

The reaction is applicable to saturated and unsaturated methyl ketones of the aliphatic and alicyclic series, to aryl methyl ketones, and to methyl ketones of heterocyclic aromatic compounds. 

Friedel-Crafts reaction of phosgene with heterocyclic aromatic compounds is also difficult to stop at the acid chloride stage. However, under selected conditions, heteroaromatics such as thiophene can be directly acylated to give thiophenecarbonyl chloride [Scheme T9] (Ref. 15) ... 

Conjugate addition of enolate-type nucleophiles ch29 Reactions of heterocyclic aromatic compounds ch43... 

Heterocyclic aromatic compounds such as pyrrole are readily metallated with Grignard reagents. The resulting compounds have N"Mg bonds and are, therefore, not organometallic compounds, but on reaction with electrophiles give 2-substituted pyrroles [14] (eq (4)). The reaction of chloroform or bromoform with PrMgCl at -78 °C in THF-HMPA (4 1) is mild and convenient method for the generation of an unstable carbenoid in the solution [15] (eq (5)). 

There is, for example, no end-of-text chapter entitled Heterocyclic Compounds. Rather, heteroatoms are defined in Chapter 1 and nonaromatic heterocyclic compounds introduced in Chapter 3 heterocyclic aromatic compounds are included in Chapter 11, and their electrophilic and nucleophilic aromatic substitution reactions described in Chapters 12 and 23, respectively. Heterocyclic compounds appear in numerous ways throughout the text and the biological role of two classes of them—the purines and pyrimidines—features prominently in the discussion of nucleic acids in Chapter 27. 

The reaction has been shown to be of very broad scope with a multitude of nucleophiles Nu such as imides.23,24,29,32,33,36,37,42 amines,10,32 cyanide,25,32 hydroxide,10,32 alkox-ide,10,26,32 electron-rich isocyclic or heterocyclic aromatic compounds,28 carboxamides,31 lactams,31 ureas,31 sulfonamides,31 cyanate,31 formate (to give products with Nu = H),34 C-H acidic compounds,35 hydrazines and hydrazides,38 and sulfinates.38 The amino group NR R2 of cyclopropane-1,1-diamines and the nucleophile Nu in bicycles 8, 9 or 12, respectively, can be easily replaced with other nucleophiles Nu, such as water,10,32,33 alkoxide,10,32-34,42 Grignard compounds,27,42 amines,29,30,36,37,42,43 cyanide,29,33,42,44 hydride,34,42,44 and C-H acidic compounds39-41,43,44 (see Section 5.2.1.). Therefore, it is currently the most important method for the preparation of substituted bicyclic cyclopropylamines. The toxic and costly reagent methyl fluorosulfate can be avoided in a modified synthetic route, which instead of the fluorosulfate 5 proceeds via the corresponding tetraphenylborate, hexafluorophosphate, or (most conveniently) via the tosylate.23 The different steps of the method can often be combined in a one-pot procedure. Results are summarized in Table 3. 

Some heterocyclic aromatic compounds—particularly those containing nitrogen—are degraded by reactions involving hydroxy-lation rather than dioxygenation before rupture of the rings (Section 6.3.1.1). 

The chemical reactivity of simple heterocyclic aromatic compounds varies widely in electrophilic substitution reactions, thiophene is similar to benzene and pyridine is less reactive than benzene, while furan and pyrrole are susceptible to polymerization reactions conversely, pyridine is more readily susceptible than benzene to attack by nucleophilic reagents. These differences are to a considerable extent reflected in the susceptibility of these compounds and their benzo analogues to microbial degradation. In contrast to the almost universal dioxygenation reaction used for the bacterial degradation of aromatic hydrocarbons, two broad mechanisms operate for heterocyclic aromatic compounds ... 

Compounds in the two groups differ in a number of ways. The two differ chemically in that the aliphatic undergo free-radical substitution reactions and the aromatic undergo ionic substitution reactions. In this chapter you examine the basics of both aromatic and heterocyclic aromatic compounds, concentrating on benzene and related compounds. 

Cycloaddition to five-membered heterocyclic aromatic compounds is well documented. Examples reported this year include the formation of azetidine adducts (67) by irradiation of 3-(p-cyanophenyl)-2-isoxazoline with furan or thiophen (and also with benzene) benzophenone-sensitized reaction of selenophen with dimethylmaleic anhydride (68) to give 1 1 and 1 2 adducts and oxetan formation from benzophenone and 1-acylimidazoles (69), thiazoles, or isoxazoles. ... 

As mentioned above, a major problem in using heterocyclic aromatic compounds as dienes in the Diels-Alder reaction is their highly aromatic character which hinders their involvement in reactions that include direct participation of their 7c-bonds. Some heterocycles such as pyrrole would, in many instances, rather participate in Michael-addition type of reactions than in Diels-Alder... 

Regioselectivity ch24 Conjugate addition of enolates ch26 Reactions of heterocyclic aromatic compounds ch29 ch30... 

In contrast to facile reactions of aryl halides with alkenes and alkynes, reactions of aromatic compounds with aryl halides have received less attention. Only intramolecular arylation of benzene derivatives, except phenols, is known [1]. On the other hand, electron-rich heterocycles such as ffirans, thiophenes, pyrroles, oxa-zoles, imidazoles, and thiazoles undergo facile inter- and intramolecular arylation with aryl halides. These are called heteroaryl Heck reactions [2]. 

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