Selective Functionalization of Pyridines and Diazines via Heterocyclic Phosphonium Salts

项目摘要。 该建议的目的是开发一种使吡啶和二嗪官能化的通用方法， 可以以加速的方式接近生物活性分子。吡啶是第二常见的 在FDA批准的药物和相关的二嗪类（嘧啶、吡嗪和 使这些杂环官能化的传统方法受到以下限制： 官能团耐受性差、区域控制差和缺乏对复杂底物的适用性。的策略 官能化这些杂环将安装多功能官能团，其使得许多随后的 成键反应具体来说，我们将吡啶和二嗪转化为鏻盐并使用 磷鎓离子制备药用相关衍生物的独特反应性。4-选择性反应 制备磷鎓盐将使用普通的试剂，操作简单，并且具有广泛的底物范围。 我们还建议将这种方法用于药物的后期功能化。转化 将磷鎓盐转化为重要的吡啶和二嗪衍生物将通过不同的机理发生。 途径。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过程或在磷中心的配体偶联。金属催化的交叉偶联，使用镍和 钴催化剂将用于芳基化和烷基化反应。碱基介导的断裂反应 形成杂芳基阴离子，其将用于安装氘和氚同位素并形成有机金属。一 基于磷配体，将开发概念上新的方法来制备重要的双杂联芳基化合物 耦合过程总的来说，该计划将提供快速获得吡啶和二嗪衍生物的机会， 在制药科学中具有多种应用。长期目标是使这些方法 作为药物化学家的常规工具。

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.