Development of a Continuous Flow Sulfoxide Imidation Protocol Using Azide Sources under Superacidic Conditions

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• 作者：Bernhard Gutmann ; Petteri Elsner ; Anne O鈥橩earney-McMullan ; William Goundry ; Dominique M. Roberge ; C. Oliver Kappe
• 刊名：Organic Process Research & Development
• 出版年：2015
• 出版时间：August 21, 2015
• 年：2015
• 卷：19
• 期：8
• 页码：1062-1067
• 全文大小：261K
• ISSN：1520-586X

文摘

The development of a continuous flow sulfoxide imidation protocol for a pharmaceutically relevant target molecule is described. Sulfoxide imidation is a key step in the preparation of certain ATR kinase inhibitors. Reactions with NaN₃ or TMSN₃ and concentrated sulfuric acid under literature conditions provided low conversions and poor selectivities. In contrast, reactions employing fuming sulfuric acid afforded the target sulfoximine with a selectivity of 鈭?0% after a reaction time of only 10鈥?5 min at 50 掳C. The imidation reaction using TMSN₃ as reagent was successfully performed in a flow reactor utilizing CH₂Cl₂/H₂SO₄ biphasic conditions. The mixture was subsequently quenched in-line with H₂O. Phase separation, neutralization, and re-extraction with an organic solvent furnished the product in excellent purity and good yields, albeit with loss of chirality.