Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Haus F, 81377, München, Germany.
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 4057, Basel, Switzerland.
Chemistry. 2022 Jun 10;28(33):e202200733. doi: 10.1002/chem.202200733. Epub 2022 May 11.
DFT-calculations allow prediction of the reactivity of uncommon N-heterocyclic scaffolds of pyrazolo[1,5-a]pyrimidines and imidazo[1,2-b]pyridazines and considerably facilitate their functionalization. The derivatization of these N-heterocycles was realized using Grignard reagents for nucleophilic additions to 5-chloropyrazolo[1,5-a]pyrimidines and TMP Zn ⋅ 2 MgCl ⋅ 2 LiCl allowed regioselective zincations. In the case of 6-chloroimidazo[1,2-b]pyridazine, bases such as TMP Zn ⋅ MgCl ⋅ 2 LiCl, in the presence or absence of BF ⋅ OEt , led to regioselective metalations at positions 3 or 8. Subsequent functionalizations were achieved with TMPMgCl ⋅ LiCl, producing various polysubstituted derivatives (up to penta-substitution). X-ray analysis confirmed the regioselectivity for key functional heterocycles.
DFT 计算允许预测吡唑并[1,5-a]嘧啶和咪唑并[1,2-b]哒嗪中不常见的 N-杂环支架的反应性，并大大促进了它们的功能化。这些 N-杂环的衍生化是使用 Grignard 试剂进行亲核加成来实现的，对于 5-氯吡唑并[1,5-a]嘧啶，TMP Zn ⋅ 2MgCl ⋅ 2LiCl 允许区域选择性锌化。对于 6-氯咪唑并[1,2-b]哒嗪，TMP Zn ⋅ MgCl ⋅ 2LiCl 等碱，在存在或不存在 BF ⋅ OEt 的情况下，在 3 位或 8 位导致区域选择性金属化。随后使用 TMPMgCl ⋅ LiCl 进行功能化，生成各种多取代衍生物（最多五取代）。X 射线分析证实了关键功能杂环的区域选择性。
