An Update on Direct C–H Bond Functionalization of Nitrogen-Containing Fused Heterocycles

Abstract

This report highlights the recent advances in direct C–H bond functionalization of 5,5- and 6,5-fused heterocycles containing at least two nitrogen atoms. Besides C–C bond formation, C–N, C–S, C–P, and C–Si bonds can also be created via a metal-catalyzed process. Some examples, where a C–H functionalization approach was applied for the synthesis of drug candidates, will be presented as well.1 Introduction2 C–H Functionalization Reactions of N-Containing Heterocycles2.1 Imidazo[1,2-a]pyridines2.2 Pyrrolo[1,2-a]pyrazines2.3 Imidazo[1,2-b]pyrazoles2.4 Imidazo[1,2-a]pyrimidines2.5 Imidazo[1,2-a]pyrazines and Imidazo[1,5-a]pyrazines2.6 Imidazo[1,2-b]pyridazines2.7 Imidazo[4,5-b]pyridines and Imidazo[4,5-c]pyridines2.8 Pyrazolo[3,4-b]pyridines2.9 Pyrazolo[1,5-a]pyrimidines2.10 Pyrrolo[2,3-d]pyrimidines and Pyrrolo[3,2-d]pyrimidines2.11 Imidazo[1,2-b][1,2,4]triazines2.12 Imidazo[1,2-b][1,2,4,5]tetrazines3 Outlook4 Conclusion

Formation and Uses of Imidazo[1,2-a]pyrimidines and Related Compounds: A Review Comprising Years 2000-2021

“…Aziz and Piguel, in their mini-review published in 2017, studied C-H arylations of heterocycles, in which imidazo[1,2-a]pyrimidines played a major role. Some examples were provided (43). (See Figures 45-54).…”

Recent Developments in Transition‐Metal‐Catalyzed Regioselective Functionalization of Imidazo[1, 2‐a]pyridine

“…In early years, most of the functionalization reactions of imidazo[1, 2‐ a ]pyridine are palladium and copper based catalytic systems to form C−C,C−S,C−Se,C−N,C−P bonds at C‐3 position [32,33] . However with contemporary developments, a variety of transition metals are used for C−H functionalization at different positions of imidazopyridine scaffold [34] . The carbon‐carbon and carbon‐heteroatom bond formation of imidazo[1, 2‐ a ]pyridine is carried out by transition metal‐based catalysts (Pd, Cu, Rh, Fe, V, Ru, Ir, Co, Mn, Zn), metal‐free catalysts (PIDA, iodine, DEAD, DMAP, etc.)…”

Kinetic Solvent Isotope Effect in P450-Mediated Cyclization in Indolactams: Evidence for Branched Reactions and Guide for Their Modulation in Heterocycle Chemoenzymatic Synthesis

“…Natural heterocycles or their derivatives have attracted extensive attention because of their diverse biological activities. − Several heterocycles synthesized in laboratories have successfully passed clinical trials and have been used as approved drugs. − Hence, increasing efforts have been devoted to the development of concise synthetic routes to generate new bioactive heterocycles. − As a preferred strategy, direct selective C–H bond functionalization has been adopted in heterocyclic chemistry. − However, it is still challenging to control the regio- and stereoselectivity in the synthesis of heterocycles. − Cytochrome P450s (P450s) are versatile monoxygenases that can directly activate inert C–H bonds effectively, generating new skeletons with diversified bioactivities. − Actually, owing to the highly active catalytic intermediates and relaxed substrate specificity, except for the major products, P450s also can generate other novel heterocycle structures as the minor product, which also exhibited a potentially considerable pharmaceutical effect. ,− However, as the minor product, the biocatalysis of reactions leading to those minor heterocycles with novel structures is still difficult, also hindering their opportunities for drug discovery development.…”