Electron-poor aromatic heterocycles

Pyrazines, with 6 Ji-electrons, are cXoctron-d cient (also known as electron-poor) aromatic heterocycles because of the increased electronegativity of the nifrogen atoms. Due to the presence of the electronegative nitrogen atoms, the electron density on the ring carbons is less than one. The lone-pair electrons do not take part in the delocalization so this molecule can act as a mild base. 

Direct perfluoroalkylatwn of electron poor aromatic and heterocyclic systems with perfluorocarboxylic acids is mediated by xenon difluonde [165] (equation 142)... 

Benzylic desilylation and destannation have been often used in the alkylation of electron-poor aromatics (see Sect. 2.1.3), but are obviously useful in other contexts, a particularly well developed example being the benzylation of iminium salts for the synthesis of new heterocycles [236-238], including protoberberine alkaloids (Scheme 45) [239],... 

Aromatic Chlorination. Many aromatic and heteroaromatic chlorinations using NCS are catalyzed by acetic acid. Ferric chloride and ammonium nitrite have also been used to catalyze the chlorination of various heterocycles with NCS. Although NCS has been used for halogenation of electron-rich aromatics, the halogenation of electron-poor aromatic systems with NCS has been difficult to achieve. However, the chlorination of various deactivated aromatic systems can be achieved when NCS is acid catalyzed with boron trifiuoride monohydrate. The reaction is impressive in that even the deactivated 1-fiuoro-2-nitrobenzene is chlorinated to afford 4-chloro-l-fiuoro-2-nitrobenzene in 81% yield after 18 h at 100 °C (eq 24). ... 

Pyridine is the prototypic electron-poor 6-membered ring heterocycle conceptually obtained by replacing one of the CH units of benzene with nitrogen (Figure 8.1.1). The aromaticity originally found in the benzene framework is maintained in... 

Ethylene disulfonyl-1,3-butadiene (43) is an example of an outer-ring diene with a non-aromatic six-membered heterocyclic ring containing sulfur. It is prepared by thermolysis of sulfolenes in the presence of a basic catalyst. It is very reactive [43] and even though it is electron-deficient, it readily reacted with both electron-rich and electron-poor dienophiles (Equation 2.15). 

In a separate report, the regioselectivity and reactivity problems in the substitution of pyrimidines were avoided using 4,6-dichloro-5-nitropyrimi-dine as starting material,17 a very electron-poor heterocycle, which is highly reactive in nucleophilic aromatic substitutions. It reacts readily with the free amino group of the (trialkoxybenzhydrylamine) Rink linker on solid phase. This heterocycle could serve as a scaffold by itself and could also be used as a building block (precursor) to make other heterocycles such as purines. 

Pyridine is the six-membered-ring, nitrogen-containing heterocyclic analog of benzene. The pyridine ring is electron-poor and undergoes electrophilic aromatic substitution reactions with difficulty. Nucleophilic aromatic substitutions of 2- or 4-halopyridines take place readily, however. 

The first high yielding one-pot tandem Hartwig-Buchwald-Heck cyclization was reported and applied to the synthesis of 2,3-disubstituted indoles [201]. Commercially available enone 123 was coupled with 1,2-dibromobenzene to provide A -arylcncaminonc 124 which subsequently cyclized to indole derivative 125 [201]. This reaction was widely applicable to a variety of electron rich, electron poor and neutral aromatic bromides and chlorides as well as heterocyclic halides. Excellent yields were obtained regardless of the substitution pattern on the aromatic halide. 

The ability of boranes to coordinate and activate an incoming substrate was also proposed recently by Lu and Williams.The di(pyrazolyl)borohydride was first coordinated to mthenium. Chloride abstraction in acetonitrile then afforded the imido complex 46c as a result of intramolecular hydroborafion of the CN triple bond (Scheme 15). The process is amenable to catalysis using excess of NaBH and 1 equiv. of NaOfBu (Table 1). A broad variety of electron-poor and electron rich-aromatic nitriles were thereby reduced into primary amines using 5 mol% of 46c. With electron-rich heterocycles, hydration instead of hydrogenation is observed and amides are obtained. 

The inverse electron demand Diels-Alder [4+2]-cycloaddition of imidazoles to electron-poor dienes to )deld imidazo[4,5-d]pyridazines, reported in Comprehensive in heterocyclic chemistry II (CHEC-2), has been further developed. The reaction of 153 with tetrazines 142 was fruitless. However, 153 reacted with an excess of 142 to yield aromatic 155 along with 1,4-dihydrotetrazine 156. Most likely, 155 arose from... 

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