Abstract
Nitrogen-containing heteroaromatic cores are ubiquitous building blocks in organic chemistry. Herein, we present a family of metal-free intermolecular formal cycloaddition reactions that enable highly selective and orthogonal access to isoquinolines and pyrimidines at will. Applications of the products are complemented by a density functional theory mechanistic analysis that pinpoints the crucial factors responsible for the selectivity observed, including stoichiometry and the nature of the heteroalkyne.
Highlights
Nitrogen-containing heteroaromatic cores are ubiquitous building blocks in organic chemistry
We report a family of reactions that enable a high yielding, orthogonal access to either isoquinolines or pyrimidines at will (Fig. 1b), by Brønsted acid-mediated regioselective formal cycloaddition of ynamides and thioalkynes with nitriles
Initial experiments involving the reaction of ynamide 1a with various Brønsted acids in the presence of varying amounts of acetonitrile led to moderate yields of isoquinoline 3aa
Summary
Initial experiments involving the reaction of ynamide 1a with various Brønsted acids in the presence of varying amounts of acetonitrile led to moderate yields of isoquinoline 3aa. After optimization of conditions (see Supplementary Table 1 for details), we found that essentially equimolar amounts of 1a, 2a and TfOH in dichloroethane as solvent sufficed to enable preparation of 3aa in 89% yield (for a discussion of stoichiometry in these reactions, vide infra). Holding suitable conditions in hand, we examined several nitriles 2a-j under the optimized conditions. This direct formal cycloaddition is applicable to a broad range of substrates, generally affording good to excellent yields of isoquinoline products.
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