Department of Chemistry, Wellesley College, 106 Central Street, Wellesley, Massachusetts 02481, United States.
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Bauer B06, Cambridge, Massachusetts 02138, United States.
J Org Chem. 2022 Aug 5;87(15):10018-10025. doi: 10.1021/acs.joc.2c00980. Epub 2022 Jul 25.
Inspired by crystal structures, we designed and achieved a catalyst-free Michael reaction for the preparation of an N1-alkyl pyrazole in a high yield (>90%) with excellent regioselectivity (N1/N2 > 99.9:1). The scope of this protocol has been extended to accomplish the first general regioselective N1-alkylation of 1-pyrazoles to give di-, tri-, and tetra-substituted pyrazoles in a single step. The resulting pyrazoles bear versatile functional groups such as bromo, ester, nitro, and nitrile, offering opportunities for late-stage functionalization. This efficient methodology will have an impact on drug discovery, as several Food and Drug Administration-approved drugs are pyrazole derivatives. A working hypothesis for the regioselectivity is proposed. X-ray crystal structures of the products that highlight the attractive interactions are discussed. This report provides a rare source for the further elucidation of the attractive interactions because the isomeric ratios and the crystal structures are directly related.
受晶体结构的启发，我们设计并实现了一种无催化剂的迈克尔反应，以高产率（>90%）和优异的区域选择性（N1/N2 >99.9:1）制备 N1-烷基吡唑。该方案的范围已扩展到完成 1-吡唑的首次一般区域选择性 N1-烷基化，以一步法得到二、三、四取代的吡唑。所得的吡唑具有多种官能团，如溴、酯、硝基和腈，为后期的官能化提供了机会。这种高效的方法将对药物发现产生影响，因为几种获得美国食品和药物管理局批准的药物是吡唑衍生物。提出了区域选择性的工作假设。讨论了突出吸引力相互作用的产物的 X 射线晶体结构。由于异构比和晶体结构直接相关，因此该报告为进一步阐明吸引力相互作用提供了一个罕见的来源。
