Recent Advances in Functionalization of Pyrroles and their Translational Potential

Abstract

Among the known aromatic nitrogen heterocycles, pyrrole represents a privileged aromatic heterocycle ranging its occurrence in the key component of “pigments of life” to biologically active natural products to active pharmaceuticals. Pyrrole being an electron‐rich heteroaromatic compound, its predominant functionalization is legendary to aromatic electrophilic substitution reactions. Although a few excellent reviews on the functionalization of pyrroles including the reports by Baltazzi in 1963, Casiraghi and Rassu in 1995, and Banwell in 2006 are available, they are fragmentary and over fifteen years old, and do not cover the modern aspects of catalysis. A review covering a comprehensive package of direct functionalization on pyrroles via catalytic and non‐catalytic methods including their translational potential is described. Subsequent to statutory yet concise introduction, the classical functionalization on pyrroles using Lewis acids largely following an ionic mechanism is discussed. The subsequent discussion follows the various metal‐catalyzed C−H functionalization on pyrroles, which are otherwise difficult to implement by Lewis acids. A major emphasize is given on the radical based pyrrole functionalization under metal‐free oxidative conditions, which is otherwise poorly highlighted in the literature. Towards the end, the current development of pyrrole functionalization under photocatalyzed and electrochemical conditions is appended. Only a selected examples of substrates and important mechanisms are discussed for different methods highlighting their scopes and limitations. The aromatic nucleophillic substitution on pyrroles (being an electron‐rich heterocycle) happened to be the subject of recent investigations, which has also been covered accentuating their underlying conceptual development. Despite great achievements over the past several years in these areas, many challenges and problems are yet to be solved, which are all discussed in summary and outlook.

Regioselective oxidative C–H heptafluoroisopropylation of heteroarenes with heptafluoroisopropyl silver

“…The pyrrole motif represents a privileged class of heterocyclic skeletons found in various natural products and pharmaceuticals. 14 However, no method is available for the direct introduction of a CF(CF 3 ) 2 group into pyrroles. Thus, phenyl(1 H -pyrrol-2-yl)methanone ( 1a ) was chosen as the model substrate to react with AgCF(CF 3 ) 2 /MeCN 15 in situ generated from hexafluoropropylene and AgF in MeCN (Table 1).…”

N-Heterocyclic Carbene-Photocatalyzed Tricomponent Regioselective 1,2-Diacylation of Alkenes Illuminates the Mechanistic Details of the Electron Donor–Acceptor Complex-Mediated Radical Relay Processes

“…1,4-Dicarbonyl compounds are centrally important synthetic intermediates that provide access to a variety of nitrogen, oxygen, and sulfur heterocycles, as well as other diverse products with applications in medicinal chemistry and materials science . However, the synthesis of 1,4-dicarbonyls remains challenging because of the mismatch in the polarity-driven reactivities of the carbonyl precursors (Figure ).…”

Chemical Reactivity and Skin Sensitization Studies on a Series of Chloro- and Fluoropyrroles—A Computational Approach

“…Several biologically active compounds with useful properties such as antipsychotic, anticancer, and antimalarial were obtained with various pharmacophores combination in a pyrrole ring system . Direct functionalization on electron-rich heteroaromatic compound, namely, the pyrroles via catalytic and noncatalytic methods were presented in a recent review . The possibility of developing densely functionalized pyrroles from inexpensive and commonly obtainable carbohydrates has been discussed …”

“…29 Direct functionalization on electron-rich heteroaromatic compound, namely, the pyrroles via catalytic and noncatalytic methods were presented in a recent review. 30 The possibility of developing densely functionalized pyrroles from inexpensive and commonly obtainable carbohydrates has been discussed. 31 Polypyrrole (PPy) has drawn distinct attention due to its conductivity and other prospective applications.…”