Diversity oriented synthesis: substitution at C5 in unreactive pyrimidines by Claisen rearrangement and reactivity in nucleophilic substitution at C2 and C4 in pteridines and pyrido[2,3-d]pyrimidines

Abstract

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Therapeutic potential of pteridine derivatives: A comprehensive review

“…Several 2,4‐thibenzyl and 2,4‐dialkylamino pteridine derivatives showed antiparasite activities against T. brucei brucei when tested in cell‐based assays. The dialkylamino pteridines 66a and 66b reached MIC values of 3.1 μM, while 66c had a MIC of 6.3 μM …”

The diversity‐oriented synthesis of pteridines—achievements and potential for development

“…Phosphorylation can also lead to activation for nucleophilic substitution. In pteridines, phosphate forming activating agents such as BOP has been used to activate a series of 4‐oxo‐2‐thioalkyl‐ and 2‐amino‐4‐oxopteridines in a study of the introduction of multiple points of diversity using several different latent reactivities (27) (Scheme ). In contrast to the high temperatures typically required for halide displacement, substitution of the intermediate phosphate occurs at room temperature giving good yields over two steps for a series of primary and secondary amine nucleophiles.…”

“…In passing, it is worth noting that the same study found that the BOP reaction in related pyrido[2,3‐ d ]pyrimidines was selective for a 4‐oxo over a 7‐oxo substituent, a feature that may be reproducible in pteridines. The substrate for this reaction contains an additional site for diversification, the thioether, and experiments were also carried out using this leaving group; in practice, it was possible to choose the order of substitution between C2 and C4 by choice of appropriate reagents, an attractive feature in a diversity‐oriented synthesis (27).…”

“…As in solution, it was also possible to cleave the alkylthio link by either direct substitution or using the oxidized sulfone. Subsequent work has shown how these reactions can be combined in different orders to create small demonstration libraries of various 2,4‐diamino‐6,7‐diarylpteridines, some of which had significant antitrypanosomal activity (27). On the other hand, whilst this method and variations applied in the fields of the synthesis of pyrido[2,3‐ d ]pyrimidines and pyrrolo[2,3‐ d ]pyrimidines (33) were successful, alkylthio precursors are not suitable for the diversity synthesis of 7,7‐dialkyl‐7,8‐dihydropteridines because the required pyrimidine precursors could not be prepared.…”

Microwaves in Heterocyclic Chemistry

“…It was shown that this reaction is controlled by the nature of the solvent (DMF). Pyrido [2,3-d]pyrimidines have been also prepared from 2-alkylthiopyrimidines [72]. Transformation of 5-acyl-2H-pyran-2-ones with various amidines such as 1,3-binucleophiles in the presence of DBU (1,8-diazabicyclo [5.4.0]undec-7-ene) produced pyrano [2,3-d]pyrimidines [73].…”