Selective Functionalization of Pyridines and Diazines via Heterocyclic Phosphonium Salts

通过杂环鏻盐选择性官能化吡啶和二嗪

• 批准号: 10300452
• 负责人: Andrew McNally
• 金额: $ 28.05万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300452
• 关键词: Aldehyde oxidase; Alkylation; Anions; Carbonates; Catalysis; Chemicals; Cobalt; Complex; Coupling; Deuterium; Drug Industry; Electrons; FDA approved; Gases; Goals; Hydrogen; Ions; Isotope Labeling; Isotopes; Laboratories; Ligands; Mediating; Metabolism; Metals; Methods; Nickel; Nitrogen; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phosphines; Phosphorus; Positioning Attribute; Process; Protocols documentation; Pyrazines; Pyridazines; Pyrimidines; Reaction; Reagent; Research; Salts; Science; Scientist; Sodium Chloride; Source; Therapeutic; Transition Elements; Translating; Tritium; base; catalyst; diazine; drug discovery; functional group; interest; novel strategies; pharmacophore; programs; pyridine; small molecule; tool

Project Abstract. The aim of this proposal is to develop a general process to functionalize pyridines and diazines so that biologically active molecules can be accessed in an accelerated fashion. Pyridines are the second most common nitrogen heterocycle observed in FDA approved drugs and related diazines (pyrimidines, pyrazines and pyridazines) are also widely found. Traditional methods to functionalize these heterocycles are limited by functional group tolerance, poor regiocontrol and lack of applicability to complex substrates. Our strategy to functionalize these heterocycles will install a versatile functional group that enables a number of subsequent bond-forming reactions. Specifically, we will transform pyridines and diazines into phosphonium salts and use the unique reactivity of the phosphonium ion to make medicinally relevant derivatives. The 4-selective reaction to make phosphonium salts will use common reagents, be trivial to perform and have a broad substrate scope. We also propose to use this approach for late-stage functionalization of pharmaceuticals. Transforming phosphonium salts into important pyridine and diazine derivatives will occur through distinct mechanistic pathways. Direct reactions with nucleophiles will form C–C, C–O, C–S, C–N, and C–Hal bonds that occur via SNAr processes or ligand coupling at the phosphorus center. Metal-catalyzed cross-coupling, using nickel and cobalt catalysts, will be exploited for arylation and alkylation reactions. Base-mediated fragmentation reactions form heteroaryl anions that will be used to install deuterium and tritium isotopes and form organometallics. A conceptually new approach to make important bis-heterobiaryls will be developed base on phosphorus ligand coupling processes. Collectively, this program will provide rapid access to pyridine and diazine derivatives that have multiple applications in the pharmaceutical sciences. The long-term objective is for these methods to be used as routine tools by medicinal chemists.

项目摘要。 这项提议的目的是开发一种使吡啶和二氮杂物功能化的一般过程，以便 生物活性分子可以以加速的方式获得。吡啶类化合物是第二常见的 在FDA批准的药物和相关的二氮类(嘧啶、吡嗪和 并氮)也被广泛发现。将这些杂环功能化的传统方法受到以下限制 官能团耐受性差，区域控制差，缺乏对复杂底物的适用性。我们的战略是 官能化这些杂环将安装一个多功能官能团，使许多后续 成键反应。具体地说，我们将把吡啶和二氮杂物转化为膦盐并使用 膦离子独特的反应性，可制成与医药相关的衍生物。4-选择性反应 要制作膦盐将使用普通试剂，操作简单，底物范围广。 我们还建议将这种方法用于药物的后期功能化。转型 膦盐生成重要的吡啶和二氮杂衍生物将通过不同的机理发生 小路。与亲核试剂的直接反应将形成C-C、C-O、C-S、C-N和C-Hal键，这些键通过 SNAR过程或磷中心的配体偶联。金属催化的交叉偶联，使用镍和 钴催化剂将被开发用于芳基化和烷基化反应。碱基介导的裂解反应 形成杂芳基阴离子，这些阴离子将被用来安装氚和氚同位素，并形成有机金属。一个 从概念上讲，将开发一种新的方法来制备重要的双杂二芳基化合物 耦合过程。总而言之，该计划将提供快速获得吡啶和二氮杂衍生物的途径， 在制药科学中有多种应用。这些方法的长期目标是 被药用化学家用作常规工具。