Merck Serono S.A., 9 Chemin des Mines, 1202 Geneva, Switzerland.
J Org Chem. 2012 May 18;77(10):4586-95. doi: 10.1021/jo300189q. Epub 2012 May 2.
We report herein an efficient route for the synthesis of 2,4,8-trichloropyrido[3,2-d]pyrimidines 1 with R(1) substituents at C-6. The potential of such scaffolds was demonstrated by the possibility to displace regioselectively each aromatic chloride to introduce diversity. Sequential sulfur nucleophilic addition followed by Liebeskind-Srogl cross-coupling reaction yielded unprecedented aryl introduction at C-4 on a trichloropyrido[3,2-d]pyrimidine derivative. The reactivity difference of the remaining two chlorides toward S(N)Ar reactions was investigated. Amination yielded high C-2 regioselectivity, while thiolation was influenced by C-6 substituents, resulting in medium to high C-2 versus C-8 regioselectivity. The last chloride was efficiently displaced by S(N)Ar, Suzuki-Miyaura cross-coupling reaction, or reduction. C-2 arylation as a final step was also possible by Liebeskind-Srogl cross-coupling reaction on the previously introduced C-2 thioether. A concise and highly divergent synthetic use of 1 was developed, thereby providing an efficient approach to explore the structure-activity relationship of pyrido[3,2-d]pyrimidine derivatives such as 9, 10, 15, and 16.
我们在此报告了一种高效的合成 2,4,8-三氯吡啶并[3,2-d]嘧啶 1 的路线，其中 C-6 位具有 R(1)取代基。这种支架的潜力通过可能对每个芳基氯进行区域选择性取代以引入多样性来证明。顺序硫亲核加成后进行 Liebeskind-Srogl 交叉偶联反应，在三氯吡啶并[3,2-d]嘧啶衍生物的 C-4 上引入了前所未有的芳基。研究了剩余两个氯对 S(N)Ar 反应的反应性差异。胺化得到高 C-2 区域选择性，而硫代反应受 C-6 取代基影响，导致 C-2 与 C-8 的中等至高区域选择性。最后一个氯通过 S(N)Ar、Suzuki-Miyaura 交叉偶联反应或还原反应被有效地取代。通过之前引入的 C-2 硫醚进行 Liebeskind-Srogl 交叉偶联反应，也可以在 C-2 进行芳基化作为最后一步。开发了一种简洁且高度多样化的 1 合成用途，从而为探索吡啶并[3,2-d]嘧啶衍生物（如 9、10、15 和 16）的结构-活性关系提供了一种有效的方法。
