In-situ Generation of Diazomethane for the Late-Stage Functionalisation of Drug Candidates

重氮甲烷是一种强有力的试剂，可用于广泛的化学反应：从羧酸的简单甲基化，到更复杂的同系物羧酸和衍生物的Arbench-Arbenchtert合成。当敏感官能团存在于分子上时（例如在酸敏感化合物存在下羧酸的甲基化），此类方法可以提供温和和正交的条件。然而，其使用受到其毒性、致癌性和爆炸性的限制。因此，本项目旨在开发一种更简单，更安全，通过磺酰叠氮与烯胺反应原位生成和反应重氮化合物的方法。为实现这一目标，将考虑以下几个方面：反应应在有机溶剂中进行（理想情况下为绿色），只需在室温下将试剂混合在一起（或更低），而不需要催化剂或苛刻的试剂，如氢氧化物碱或昂贵的设置（根据Diazald方法）.1原位生成将有助于避免重氮甲烷的危险积聚和直接处理，叠氮化物和烯胺应该正交反应。该方法应尽可能简单，使用易于合成的固体，可称重和稳定的试剂。LS和Luke奥德尔教授（LO，乌普萨拉大学）先前的工作通过其（氘）-甲基化羧酸并原位形成重氮酮的能力证明了该方法的实用性，该方法不使用强碱和水（https：//doi.org/10.1002/adsc.202300132）。这种方法将进一步突出重氮甲烷的力量，导致更广泛的使用，以丰富药物发现的努力，这已经在合成抗病毒药物中得到了应用。

Diazomethane is a powerful reagent useful in a broad range of chemical reactions: from simple methylations of carboxylic acids, to more complex Arndt-Eistert syntheses of homologated carboxylic acids and derivatives. Such methods can offer mild and orthogonal conditions when sensitive functionalities are present on the molecule (e.g. methylation of carboxylic acids in the presence of acid-sensitive compounds). Its use however is limited by its toxicity, carcinogenicity, and explosive nature. This project hence aims to develop a method for the simpler, safer, in-situ generation and reaction of diazo compounds via the reaction of a sulfonyl azide with an enamine. To achieve this, several aspects will be considered: the reaction should be carried out in an organic solvent (ideally green) by simply mixing the reagents together at room temperature (or lower), without the need for catalysts or harsh reagents like hydroxide bases or expensive setups (as per the Diazald method).1 In-situ generation will help to avoid the dangerous build-up and direct handling of diazomethane, and the azide and enamine should react orthogonally. The method should be as simple as possible, using solid, weighable, and stable reagents that are easy to synthesise. Previous work by LS and Prof. Luke Odell (LO, Uppsala University) demonstrates the utility of this method via its ability to (deutero)-methylate carboxylic acids and form diazoketones in-situ that excludes the use of strong bases and water (https://doi.org/10.1002/adsc.202300132). Such a method will further highlight the power of diazomethane, leading to more widespread use to enrich drug discovery efforts, which has already seen use in the synthesis of antivirals.