Substitutions of Aromatic Heterocycles

This chapter describes in general terms the types of reactivity found in the typical six- and five-membered aromatic heterocycles. We discuss electrophilic addition (to nitrogen) and electrophilic, nucleophilic and radical substitution chemistry. This chapter also has discussion of orf/to-quinodimethanes, in the heterocyclic context. Organometallic derivatives of heterocycles, and transition metal (especially palladium)-catalysed chemistry of heterocycles, are so important that we deal with these aspects separately, in Chapter 4. Emphasis on the typical chemistry of individual heterocyclic systems is to be found in the summary chapters (7, 10, 13, 15, 19 and 23), and a more detailed examination of typical heterocyclic reactivity and many more examples for particular heterocyclic systems are to be found in the chapters - Pyridines Reactions and Synthesis , etc. 

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It has also been argued10,40 that the second mechanism (rapid, reversible interconversion of II and IV) cannot be general. The basis for this contention is the fact that electrophilic catalysis is rare in nucleophilic aromatic substitution of non-heterocyclic substrates, an exception being the 2000-fold acceleration by thorium ion of the rate of reaction of 2,4-dinitrofluorobenzene with thiocyanate... 

Our study of heterocyclic compounds is directed primarily to an understanding of their reactivity and importance in biochemistry and medicine. The synthesis of aromatic heterocycles is not, therefore, a main theme, but it is useful to consider just a few examples to underline the application of reactions we have considered in earlier chapters. From the beginning, we should appreciate that the synthesis of substituted heterocycles is probably not best achieved by carrying out substitution reactions on the simple heterocycle. It is often much easier and more convenient to design the synthesis so that the heterocycle already carries the required substituents, or has easily modified functions. We can consider two main approaches for heterocycle synthesis, here using pyridine and pyrrole as targets. 

The Friedel-Crafts alkylation and acylation are of very little, if any, synthetic interest when applied to heterocyclic aromatic bases the substitution of protonated heterocycles by nucleophilic carbon-centered radicals is instead successful. This reaction, because of the dominant polar effect which is mainly related to the charge-transfer character of the transition state (Scheme 1), reproduces most of the aspects of the Friedel-Crafts aromatic substitution, but reactivity and selectivity are the opposite. 

The CIR is exceptionally well suited as an entry to multi-component syntheses of aromatic heterocycles and on this basis Muller and coworkers [91f, 92] designed a coupling-isomerization-Stetter-Paal-Knorr sequence as a diversity-oriented approach to highly substituted furans and pyrroles (Scheme 5.22). 

Among the wide variety of unsaturated functionalities which participate in the cobalt-mediated [2+2+2] cycloaddition that has proved to be a powerful tool for the assembly of complex polycyclic molecules are a number of aromatic heterocyclic double bonds, such as those in pyrrole and indole <20000L2479, 2001JA9324 and references therein>. Indoles, including those substituted at C-3, can be cyclized, both intra- and intermolecularly, with a wide variety of alkynes to yield functionalized products in moderate to good yields. A stereoselective cobalt-mediated [2+2+2] cycloaddition reaction between the W(pent-2-en-4-ynoyl)indole moiety of tryptamine derivative 1093 (R = (CH2)2NHAc) and acetylene has been employed for the formal total synthesis of strychnine 1097, the most famous Strychnos alkaloid and a commonly used rodenticide and animal stimulant (Scheme 213). 

In order to accelerate the slow metalation, several methods have been proposed (1) use of substitution reaction of cadmium(II) or mercuty(II) porphyrin, (2) use of N-substituted porphyrins at the pyrrole nitrogen, (3) addition of aromatic heterocyclic bases such as pyridine and imidazole, (4) introduction of functional groups to bind metal ions in the vicini of the porphyrin nucleus (e. g. tetracarboxylic add "picket-fence" porphyrins) and (5) use of reducing agents such as hydroxylamine and ascorbic add in copperfll) incorporation. 

A rich coordination chemistry of aromatic diazine (N-N), especially pyridazine and phthalazine related ligands has emerged over the last three decades,1-72 and recently open-chain diazine (N-N) coordination chemistry has been well developed, especially by Thompson and others.62-113 Many types of aromatic heterocyclic compounds contain a 1,2-diazine (N-N) moiety, e.g., pyridazine and its 3,6-disubstituted derivatives (Scheme 1, Type 1), phthalazine, condensed phthalazines and their substituted derivatives (Scheme 1, Type 2), and other compounds such as pyrazole, triazole, thiadiazole, tetrazole, indazole, 1,2,4-triazine, 1,2,4,5-tetrazine, and thiadiazepines. Alternatively, the 1,2-diazine (N-N) moiety also exists as an open-chain entity in some related compounds, e.g., A-substituted-amide hydrazonimidates (Scheme 1, Type 3), A-substituted-amide hydrazonidates (Scheme 1, Type 4), A-substituted hydrazides (Scheme 1, Type 5), A-substituted amidrazones (Scheme 1, Type 6), and A-sub-stituted hydrazidates (Scheme 1, Type 7). 

The electron affinities of aromatic heterocyclic compounds have been measured by TCT and are included in the NIST tables [21]. At the same time the electron affinities of pyridine, the diazines, and aza-substituted phenanthrenes were... 

An example of a box-set of 25 amino acids that we now are marketing is shown in Figure 4. A range of aromatic, heterocyclic, (3, (l-di substituted, 7,8-unsaturated, and P-amino acids are represented in this sundry collection. Brominated derivatives are included to permit further functionalization through crosscoupling reactions such as those described in Section 18.3.1.5. 

The study of aromatic heterocyclic reactivity can be said to have begun with the results of electrophilic substitution processes - these were traditionally the means for the introduction of substitutents onto het-erocylic rings. To a considerable extent, that methodology has been superseded, especially for the introduction of carbon substituents, by methods relying on the formation of organometallic nucleophiles (4.1) and on palladium-catalysed processes (4.2). Nonetheless, the reaction of heterocycles with electrophilic reagents is still extremely useful in many cases, particularly for electron-rich, five-membered heterocycles. 

C-substitution of nitrogen heterocycles , Vorbriiggen, H. and Maas, M., Heterocycles, 1988, 27, 2659 (discusses electrophilic and radical substitutions, lithiations and the use of iV-oxides) Regioselective substitution in aromatic six-membered nitrogen heterocycles , Comins, D. L. and O Connor, S., Adv. Heterocycl. Chem., 1988, 44, 199 (discusses electrophilic, nucleophilic and radical substitution, and metallation). 

Oxazoles and benzoxazoles are viable participants in the heteroaryl Heck reaction, whereby the alkyl halide or aryl halide is coupled to the unfunctionalized oxazole. First developed by Ohta and colleagues, it was demonstrated that a diverse array of aromatic heterocycles can be substrates in the reaction with chloropyrazines. While substitution was expected to occur at the 2-position, the reaction with chloropyrazine as the aryl halide resulted in substitution at the 5-position. When benzoxazole is used as the coupling partner, substitution is effected at the 2-position. More recently, a systematic study by Strotman and co-workers has demonstrated that slight modifications of the reaction conditions can allow completely regioselective coupling at either the 2- or 5-position. ... 

SFs-Substituted fused aromatic heterocycles derived from various SFs-arenes and having an SFs-group attached to the benzene part of a ben-zannulated molecule represent the largest group of SFs-heteroarenes known to date. Wide commercial availability of various SFs-substituted benzenes and the possibihty of their further transformation into more complex... 

In order to overcome issues such as inductive and steric effects in polymerizing substituted monomers, less-reactive substituted monomers can be either copolymerized with unsubstituted monomers or homopolymerized under more controlled conditions. In addition, it is important for the substitution to avoid locations that will impede polymer growth. For example, in the case of aniline, the substitution should only be in the meta and/or ortho positions and in the case of aromatic heterocyclics such as thiophene and pyrrole, substitution should only occur in the p position. ... 

One of the most widely studied approaches to heterocyclic synthesis is the intermolecular Sj l substitution of aromatic compounds that have an appropriate substituent Z ortho to the leaving group, followed by ring closure reactions between the Nu and a Z group. 

You first met amines in Chapter 2, and you have continued to encounter them in almost every chapter since. Chapter 20 starts by extending the coverage of amines. You have seen that amines do not undergo addition, substitution, or elimination reactions their importance lies in their reactions as bases and nucleophiles with other organic compounds. Chapter 20 also covers the reactions of aromatic heterocyclic compounds. You will see that they undergo the same reactions that benzene and substituted benzenes undergo and by the same mechanisms. 

Gronowitz S, Rosen U (1971) Nuclear magnetic resonance of aromatic heterocycles. III. On the synthesis of substituted fluorothiophenes. Chem Scr 1 33-43... 

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