Synthetic strategies for pyrrolo[2,1-f][1,2,4]triazine: the parent moiety of antiviral drug remdesivir

Recent synthetic journey on pyrrole-fused compounds

“…[10][11][12] In the recent review by S. C. Philkhanarevie et al, they presented selected examples of the synthesis of functionalized pyrroles reported between 2014 and 2019. 13 In 2020, G. S. Rai published a summary on the synthetic reports related to pyrrolo[2,1-f ]-[1,2,4]triazine 14 but pyrroles fused with carbocycles or other heterocycles were not highlighted in their report. Another recent advanced approach was presented by T. Nemoto et al in 2018, in which they described the various synthetic routes for 3,4-fused tricyclic indole derivatives.…”

Evolution of the Synthesis of Remdesivir. Classical Approaches and Most Recent Advances

“…Klein et al (Scheme ) provided the first concise and efficient approach to this long known heterocycle ( 12 ) . 2-Formylpyrrole ( 8 ) was treated with hydroxylamine- O -sulfonic acid (HOSA) in aqueous KOH to give 1-amino-2-pyrrolonitrile ( 10 ) in 43% yield, along with 37% yield of 2-pyrrolonitrile ( 11 ).…”

“…Klein et al (Scheme 2) provided the first concise and efficient approach 8 to this long known heterocycle (12). 9 2-Formylpyrrole (8) was treated with hydroxylamine-O-sulfonic acid (HOSA) in aqueous KOH to give 1-amino-2-pyrrolonitrile (10) in 43% yield, along with 37% yield of 2-pyrrolonitrile (11). Next, 10 was cyclocondensed with formamidine acetate in refluxing ethanol under mild basic conditions (K 2 CO 3 ), furnishing 12 in 66% yield.…”

“…However, the approach of Snead et al 18 is the best one. It is based on a one-pot oxidative Vilsmeier cascade from pyrrole (9) to afford 10 through the intermediacy of 8 and further cyclocondensation of 10 to 12 with formamidine acetate (59% overall yield).…”

Synthesis, Reactivity, and Anticancer Activity Evaluation of 4‐Amino‐3‐Mercapto‐6‐Methyl‐1,2,4‐Triazin‐5(4H)‐One Derivatives

“…1,2,4‐Triazine is a nitrogen heterocyclic system that is among the well‐documented class of compounds, and a wide variety of synthetic approaches can be taken to prepare its derivatives. 1,2,4‐Triazine and its derivatives have been found to display a remarkably broad spectrum of biological activities, [1–3] involving antimicrobial, [4–10] antibacterial, [11] antifungal, [12–15] antioxidants, [16] anticancer, [17–21] anti‐inflammatory, [22–32] antimalarial, [33–39] α‐glucosidase inhibition, [40] antiproliferative, [41–47] antidepressant, [48] anticonvulsant, [49–58] antiviral, [59–66] and anti‐HIV [67–71] . The biological activities of 1,2,4‐triazines have also been shown to respond to minor changes in the compound's substituents [72] .…”