Grup de Química Farmacèutica, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta, 390, E-08017 Barcelona, Spain.
Org Biomol Chem. 2020 Dec 23;18(48):9810-9815. doi: 10.1039/d0ob01785j.
Wheland intermediates are usually unstable compounds and only a few have been isolated at very low temperatures. During our work on tyrosine kinase inhibitors, we studied the bromination of 7 in order to obtain a dibromo substituted pyrido[2,3-d]pyrimidin-7(8H)-one which could be orthogonally decorated. Surprisingly, treatment of 7 with 3 equiv. of Br2 in acetic acid (AcOH) afforded 12, a captured room temperature stable Wheland bromination intermediate stabilized by the bromination of the imino tautomer of the amino group at C4 of the pyridopyrimidine skeleton. The structure was confirmed by crystal structure determination from powder X-ray diffraction data. Treatment of 12 with DMSO afforded the dibromo substituted compound 13 presenting a bromine atom at C6 and C5-C6 unsaturation. 13 was directly accessed by treating 7 with N-bromosuccinimide (NBS), a protocol extended to other compounds using NBS or N-iodosuccinimide (NIS) to afford 6-halo substituted systems. 26, bearing an iodine at C6 and a p-bromophenylamino at C2, allows the orthogonal decoration of pyridopyrimidines.
Wheland 中间体通常是不稳定的化合物，只有少数在极低温度下被分离出来。在研究酪氨酸激酶抑制剂的过程中，我们研究了 7 的溴化反应，以获得可以进行正交修饰的二溴取代的吡啶并[2,3-d]嘧啶-7(8H)-酮。令人惊讶的是，7 与 3 当量的 Br2 在乙酸（AcOH）中反应，得到了 12，这是一个捕获到的室温稳定的 Wheland 溴化中间体，由吡啶并嘧啶骨架上 C4 位的氨基的亚胺互变异构体的溴化稳定。该结构通过粉末 X 射线衍射数据的晶体结构确定得到证实。12 用 DMSO 处理得到二溴取代化合物 13，其在 C6 和 C5-C6 处呈现出不饱和键和溴原子。13 可以通过将 7 与 N-溴代丁二酰亚胺（NBS）直接反应得到，该方案扩展到使用 NBS 或 N-碘代丁二酰亚胺（NIS）处理其他化合物，以获得 6-卤代取代的系统。26 在 C6 处带有碘原子和 C2 处带有对溴苯氨基，允许对吡啶并嘧啶进行正交修饰。
