Bicyclic Heteroaromatics

Polycyclic aromatics with more than two aromatic rings, or more than one heteroatom are relatively easy to reduce and several reviews have summarized works on their electrochemical behavior. Bicyclic heteroaromatics with one heteroatom are reduced close to or beyond the decomposition of the electrolyte unless acidic solutions are used. Very few compounds of this kind have been preparatively reduced in neutral media. Their cathodic reduction could be carried out at mercury cathodes with TA A+ electrolytes. Depending on the heteroatom and the amount of charge transferred, hydrogenated and/or reductive cleavage products were obtained. 

Cathodic reductive cleavages have been reviewed 69> and most of the reported reactants were electroactive within the potential window . However, some reductive cleavages took place at very negative potentials, where the TAA+ electrolyte is decomposed and it is feasible that TAA-mercury were involved. The reductive cleavage of bicyclic heteroaromatics was presented in Sect. 6. Other cleavages at potentials < — 2.8 V (SCE) are discussed in this section. 

Methoxide addition has also been reported for two bicyclic heteroaromatic ring systems. 3-Methoxy-2-nitro- and 2-methoxy-3-nitrobenzothiophene add methoxide ion at C-3 and C-2, respectively, to give 183 and 184. Spectral, equilibrium, and kinetic studies of these reactions have been made.337... 

The bicyclic heteroaromatic bases 191 possess arrays of complementary donor-donor-acceptor and acceptor-acceptor-donor hydrogen bond sites and an additional benzocrown ether moiety. Structure and dimension of the nanotubes were determined by NMR, dynamic light scattering, small-angle X-ray scattering, and transmission electron microscopy. Addition of sodium or potassium ions did not interfere with the stability of the multichannel... 

The addition of nucleophiles to bicyclic heteroaromatic systems usually proceeds more easily thus, activation of isoquinoline by the cyano group is sufficient for the VNS hydroxylation (Scheme 45) [41]. 

Ochiai K, Takita S, Eiraku T, Kojima A, Iwase K, Kishi T, Fukuchi K, Yasue T, Adams DR, Allcock RW, Jiang Z, Kohn Y (2012) Phosphodiesterase inhibitors. Part 3 design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-(fihydropyridazinones with anti-inflammatory and bronchodilatory activity. Bioorg Med Chem 20 1644-1658... 

Dehydrogenative condensations have also been utilised for the synthesis of bicyclic heteroaromatic systems. The reaction of alcohols with o-aminoani-lines in the presence of a ruthenium catalyst and a hydrogen acceptor was shown to provide benzimidazoles. Mechanistically, this transformation requires dehydrogenation to form an aldehyde, condensation to generate an imine/dihydrobenzimidazole, which is likely followed by a second dehydrogenation to afford the benzimidazole products (Scheme 12.38). Two equivalents of crotonitrile are employed as the hydrogen acceptor. The authors also note that the coupling of aldehydes with o-aminophenols under modified conditions enables the synthesis of benzoxazoles. 

Hydrogen borrowing and dehydrogenative condensations provide new opportunities for the preparation of both saturated and aromatic heterocycles respectively. The ability to directly access azacycles from stable species such as alcohols and amines allows chemists to circumvent the preparation and use of relatively unstable carbonyls and alkyl halides that conventional methods require. Pyridines, pyrazines, pyrroles, as well as fused bicyclic heteroaromatics, may all be prepared by dehydrogenative condensation this reactivity will likely be extended to pyrimidines, imidazoles, pyrazoles, and triazoles in the near future. Continuous advances in scope and scalability will expand the role of hydrogen transfer in the discovery and production of small molecule therapeutics. 

Sahili, S., B. Erank, B. Schweizer, E. Diderich, D. Kaelin, J. Aebi, H. Bohm, H. Oefner, and G. Dale. 2005. Second-generation inhibitors for the metalloprotease neprilysin based on bicyclic heteroaromatic scaffolds synthesis, biological activity, and X-ray crystal-structure analysis. Helv. Chim. Acta 88 731-750. 

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