Late-Stage Sequential C-H Functionalization of Thiazolo[5,4-f]quina-zolin-9(8H)-one: Synthesis of a Library of Potential Kinase Inhibitors

Our research group was focused on the synthesis of a novel library of thiazolo[5,4-f]quinazolines  and thiazolo[5,4-f]quinazolin-9(8H)-one as potential kinase inhibitors involved to some extent in Alzheimer's disease.¹ We previously reported that 4-N-alkylated/arylated thiazolo[5,4-f]quinazolines displayed single-digit nanomolar IC₅₀ values and are among the most potent DYRK1A/1B inhibitors disclosed to date.² Following our effort for the construction of a broad range of substituted thiazoloquinazolin-4-one derivatives,³ the synthesis of an array of C2 and/or C7 arylated compounds was further envisioned. In this context, transition-metal-catalyzed C-C coupling of heteroarene through C-H arylation represents an extremely attractive approach.⁴ This methodology has emerged as an important tool for incorporating structural diversity into complex nitrogen containing heterocycles, without the need for prefunctionalized starting materials, useful in drug discovery.

Following our previous study on C-H arylation of quinazolinone skeleton,⁵ a selective palladium-catalyzed and copper-assisted direct C-H (hetero)-arylation of thiazolo[5,4-f]quinazolin-9(8H)-one has been developed with aryl iodides and bromides as coupling partners under microwave irradiation.⁶ This innovative sequential C-H functionalization tolerates a broad range of heteroaryl and aryl halides substituted by electronically different groups.⁷ Differently substituted N⁸-benzylated-2,7-diaryl-thiazoloquinazolin-9(8H)-ones were thereby obtained in a facile manner. A one-pot procedure has also been performed. b-bromostyrene was also an effective coupling partner as demonstrated by the alkenylation reaction leading exclusively to the corresponding (E)-isomer. These protocols provide a synthetically useful route for late-stage functionalization of this high valuable scaffold, required in drug discovery.

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