Jackson Oliver D, Reyes Albert, Stein Collin D, Larson Nathaniel G, Andrews Calvin T, Neufeldt Sharon R
Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana 59717, United States.
J Am Chem Soc. 2025 Jan 29;147(4):3017-3022. doi: 10.1021/jacs.4c17020. Epub 2025 Jan 19.
Under most conditions, 2,4-dihalopyrimidines undergo substitution reactions at C4. Here we report that Pd(II) precatalysts supported by bulky -heterocyclic carbene ligands uniquely effect C2-selective cross-coupling of 2,4-dichloropyrimidine with thiols. The regioselectivity of this reaction stands in stark contrast to ∼1500 previously reported Pd-catalyzed cross-couplings that favor C4 in the absence of other substituents on the pyrimidine ring. Selectivity in the catalytic system reported herein is extremely sensitive to the structure of the Pd(II) precatalyst, largely due to competing C4-selective nucleophilic aromatic substitution. C2-selectivity is high with most 1° thiols and thiophenols, and a range of substituted dichloropyrimidines can be used. The atypical selectivity of this transformation may facilitate diversity-oriented synthesis, as demonstrated for derivatives of an antiviral agent. Under these conditions, C2─Cl cleavage may not take place through a typical oxidative addition pathway.
在大多数情况下，2,4-二卤嘧啶在C4位发生取代反应。在此我们报道，由大位阻杂环卡宾配体支撑的Pd(II)预催化剂能独特地实现2,4-二氯嘧啶与硫醇的C2选择性交叉偶联。该反应的区域选择性与之前报道的约1500例Pd催化的交叉偶联反应形成鲜明对比，在嘧啶环上没有其他取代基时，那些反应倾向于C4位。本文报道的催化体系中的选择性对Pd(II)预催化剂的结构极为敏感，这主要是由于存在竞争性的C4选择性亲核芳香取代反应。对于大多数一级硫醇和硫酚，C2选择性较高，并且可以使用一系列取代的二氯嘧啶。这种转化的非典型选择性可能有助于多样性导向合成，如一种抗病毒剂的衍生物所示。在这些条件下，C2-Cl键的断裂可能不是通过典型的氧化加成途径发生的。
