New Synthetic Methods towards the Nucleobase Moiety of Remdesivir
Snead et al. and the groups of Sarpong and Garg have reported new synthetic methods towards pyrrolo[2,1-f][1,2,4]-triazin-4-amine, the nucleobase moiety of Remdesivir. Snead’s work involved the use of pyrrole as a starting material to give the intermediate by cyanation at the 2-position and subsequent amination at the 1-position. The intermediate is then treated with formamidine to obtain the desired product through the formation of a 1,2,4-triazine ring. On the other hand, Sarpong and Garg et al. chose a different approach by synthesizing the formamide in two steps using 2,5-dimethoxytetrahydrofuran[D0986] as a starting material and converting it into the cyanoamidine by addition of cyanamide. Upon treatment of the cyanoamidine with Lewis acid the synthesis of a desired product is completed with the formation of a 1,2,4-triazine.
The Bucherer reaction is a well-known method for the synthesis of amines from phenols using the reagent combination of NaHSO3 and NH3. 2-Bromoisobutyramide [B3380] is an effective alternate reagent for the synthesis of aromatic amines from phenols, via a one pot Smiles rearrangement under mild conditions. For example, phenol can react with B3380 under alkaline conditions to give the phenoxyether derivative. Further addition of NaOH and heating of the mixture provides the rearrangement product which upon hydrolysis yields the desired aniline derivative.
The Claisen rearrangement is a [3,3]-sigmatropic rearrangement which provides γ,δ-unsaturated carbonyl compounds from allyl vinyl ethers and allyl phenols. The reaction is considered to proceed via a chair-like transition state and has the advantage that the final product’s stereochemistry can be predicted from the substrate’s stereochemistry. Modified Claisen rearrangement reactions such as aza-Claisen, Johnson-Claisen, Eschenmoser-Claisen and Ireland-Claisen rearrangements are used according to the desired properties of substrates and products.
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