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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

Adcock, Jonathan Paul and Gibson, Colin and Huggan, Judith and Suckling, Colin (2011) 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. Tetrahedron, 67 (18). pp. 3226-3237. ISSN 0040-4020

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Abstract

Diversity oriented synthesis of fused pyrimidines leads to scaffolds with many biological activities. In the case of the preparation of pyrido[2,3-d]pyrimidines from 2-alkylthiopyrimidines, the formation of a new carbon-carbon bond at C5 is required, a reaction that is very limited in scope. However Claisen type rearrangement of simple 4-allylic ethers affords C5 substituted pyrimidines readily; in cases with an ester substituent, rearrangement occurs at room temperature. Subsequent cyclisation to afford 6-methylpyrido[2,3-d]pyrimidin-7(8H)-ones was achieved in high yield. Using allylic ethers derived from 3-chloromethyl-4-arylbut-3-en-2-ones as substrates, a new titanium[IV]chloride catalysed reaction affording 6-arylmethyl-7-methylpyrido[2,3-d]pyrimidines was discovered. In contrast, 2-alkylthiopteridines are readily available. In both cases, substitution at C2 and C4 to generate diversity has been carried out and the reactivity compared; yields of substitution products were generally higher with pteridine substrates. In biological assays unexpected hits were found for activity against the Gram positive bacterium, Nocardia farcinia, and against the parasite Trypanosoma brucei brucei, illustrating the value of diversity oriented synthesis in the discovery of biologically active compounds