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

重氮甲烷是一种强大的试剂，可用于广泛的化学反应：从简单的羧酸甲基化，到更复杂的同系化羧酸及其衍生物的Arndt-Eistert合成。当分子上存在敏感官能团时，这种方法可以提供温和和正交的条件(例如，在酸敏感化合物存在的情况下羧酸的甲基化)。然而，它的使用受到其毒性、致癌性和爆炸性的限制。因此，本项目旨在开发一种通过磺酰叠氮与烯胺反应来更简单、更安全、原位生成和反应重氮化合物的方法。为了实现这一点，将考虑几个方面：反应应在有机溶剂中(理想情况下是绿色的)中进行，只需在室温(或更低温度)下将试剂混合在一起，而不需要催化剂或苛刻的试剂，如氢氧化碱或昂贵的装置(根据Diazald方法)。1原位生成将有助于避免危险的重氮甲烷积聚和直接处理，叠氮和烯胺应垂直反应。该方法应尽可能简单，使用易于合成的固体、重量和稳定的试剂。LS和卢克·奥德尔教授(卢克·奥德尔，乌普萨拉大学)之前的工作证明了这种方法的实用性，它通过(重氢)甲基化羧酸和原位形成重氮酮的能力，排除了强碱和水的使用(https://doi.org/10.1002/adsc.202300132).这种方法将进一步突出重氮甲烷的威力，导致更广泛地用于丰富药物发现工作，这种方法已经在抗病毒药物的合成中使用。

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.