Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), CNRS UMR 8182, Université Paris-Saclay, 91405, Orsay, France.
Laboratoire de Chimie Moléculaire (LCM), CNRS UMR 9168, Ecole Polytechnique, Institut Polytechnique de Paris, 91128, Palaiseau, France.
Angew Chem Int Ed Engl. 2021 Jan 11;60(2):946-953. doi: 10.1002/anie.202010846. Epub 2020 Nov 3.
Pyrrolidine and piperidine derivatives bearing halide functional groups are prevalent building blocks in drug discovery as halides can serve as an anchor for post-modifications. In principle, one of the simplest ways to build these frameworks is the haloamination of alkenes. While progress has been made in this field, notably with the development of enantioselective versions, this reaction is still fraught with limitations in terms of reactivity. Besides, a major question remaining is to understand the mechanism at work. The formation of a haliranium intermediate is typically mentioned, but limited mechanistic evidence supports it. Reported here is an efficient metal- and oxidant-free protocol to achieve the haloamidation of olefins, promoted by hexafluoroisopropanol, along with a DFT investigation of the mechanism. These findings should guide the future development of more complex transformations in the field of halofunctionalization.
吡咯烷和哌啶衍生物带有卤代官能团，是药物发现中常用的构建模块，因为卤代物可以作为后期修饰的锚点。原则上，构建这些骨架最简单的方法之一是烯烃的卤胺化。虽然在这一领域已经取得了进展，特别是开发了对映选择性版本，但该反应在反应性方面仍然存在局限性。此外，一个悬而未决的主要问题是了解起作用的机制。通常提到形成卤代锍中间体，但有限的机理证据支持它。本文报道了一种在六氟异丙醇促进下实现烯烃卤酰胺化的高效无金属和氧化剂的方法，并通过密度泛函理论（DFT）研究了其反应机理。这些发现应该指导卤官能团化领域中更复杂转化的未来发展。
