Abstract
Reaction of thiazoline fused 2-pyridones with alkyl halides in the presence of cesium carbonate opens the thiazoline ring via S-alkylation and generates N-alkenyl functionalized 2-pyridones. In the reaction with propargyl bromide, the thiazoline ring opens and subsequently closes via a [2 + 2] cycloaddition between an in situ generated allene and the α,β-unsaturated methyl ester. This method enabled the synthesis of a variety of cyclobutane fused thiazolino-2-pyridones, of which a few analogues inhibit amyloid β1–40 fibril formation. Furthermore, other analogues were able to bind mature α-synuclein and amyloid β1−40 fibrils. Several thiazoline fused 2-pyridones with biological activity tolerate this transformation, which in addition provides an exocyclic alkene as a potential handle for tuning bioactivity.
Highlights
We demonstrated that the thiazoline ring can be opened by reaction with an aryne to generate N-alkenyl-2pyridones (Scheme 1).8e Knowing that ring opening results in the formation of a Michael acceptor, we envisaged that reaction of thiazolino-2-pyridones with alkyl halides would generate N-alkenyl-S-alkyl-2-pyridones, which could be used as synthons to build structurally diverse scaffolds
To develop the thiazoline ring opening reaction, we commenced our studies by investigating the reaction of 1a with simple alkyl halides such as methyl iodide
A few bases and solvents were screened to open the ring with methyl iodide (Scheme S1, Supporting Information)
Summary
The direct modification of an existing bioactive scaffold rather than the positioning of substituents is an important strategy to develop compounds with diverse shapes and properties.1Cyclobutanes are an important class of rigid motifs present in a variety of natural products and other biologically important molecules. A plethora of reactions like [2 + 2] cycloadditions2c−e,3 and rearrangements have been developed to construct structurally diverse cyclobutane containing scaffolds.Due to their rigid architecture, annulation of a cyclobutane ring with biologically relevant scaffolds like 2-pyridones, quinolones, and indoles2c has recently become popular (Figure 1).Thiazoline fused 2-pyridones have found various applications in developing biologically active compounds againstEscherichia coli, Chlamydia trachomatis, Listeria monocytogenes, and Mycobacterium tuberculosis infections. We have demonstrated that rigidification, either by functionalizing the compounds with sterically demanding aryl groups or annulation with heterocycles, has resulted in ring fused 2pyridones capable of modulating or binding amyloid fibrils. In a recent report, we demonstrated that the thiazoline ring can be opened by reaction with an aryne to generate N-alkenyl-2pyridones (Scheme 1).8e Knowing that ring opening results in the formation of a Michael acceptor, we envisaged that reaction of thiazolino-2-pyridones with alkyl halides would generate N-alkenyl-S-alkyl-2-pyridones, which could be used as synthons to build structurally diverse scaffolds. A plethora of reactions like [2 + 2] cycloadditions2c−e,3 and rearrangements have been developed to construct structurally diverse cyclobutane containing scaffolds. Due to their rigid architecture, annulation of a cyclobutane ring with biologically relevant scaffolds like 2-pyridones, quinolones, and indoles2c has recently become popular (Figure 1). We have demonstrated that rigidification, either by functionalizing the compounds with sterically demanding aryl groups or annulation with heterocycles, has resulted in ring fused 2pyridones capable of modulating or binding amyloid fibrils.. We demonstrated that the thiazoline ring can be opened by reaction with an aryne to generate N-alkenyl-2pyridones (Scheme 1).8e Knowing that ring opening results in the formation of a Michael acceptor, we envisaged that reaction of thiazolino-2-pyridones with alkyl halides would generate N-alkenyl-S-alkyl-2-pyridones, which could be used as synthons to build structurally diverse scaffolds
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