Directed Arylation of Unprotected Anilines Enabled by Continuous Flow Technology

通过连续流技术实现未保护苯胺的定向芳基化

• 批准号: 8912912
• 负责人: Yiming Wang
• 金额: $ 5.24万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8912912
• 关键词: Address; Amidines; Aniline; Aromatic Amines; Binding; Carbamates; Carbon; Carbon Dioxide; Carbonates; Cells; Chemicals; Chemistry; Complex; Coupling; Decarboxylation; Development; Future; Generations; Health; High temperature of physical object; Hydrogen Bonding; In Situ; Lead; Libraries; Ligands; Maintenance; Metals; Methods; Monitor; Palladium; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Process; Reaction; Reaction Time; Reagent; Reporting; Research; Route; Salts; Societies; Sodium Chloride; Structure; System; Techniques; Technology; Temperature; Transition Elements; Tube; amino group; base; cost; cost effective; flasks; functional group; pressure; prevent; residence; scaffold; success; tool; wasting

DESCRIPTION (provided by applicant): The direct functionalization of arene C-H bonds can be a powerful way of constructing biaryl motifs found in a variety of medicinally relevant molecules. Despite the potential utility of direct C-H arylation, control of regioselectivity remais a difficulty that limits its synthetic utility. One approach to address this issue is the use of an ortho directing group. Although many such directing groups are currently known, most are synthetically inflexible or require added protection/deprotection steps for their use. Due to the versatility of the amino group, an ortho-arylation using this functional group would be synthetically valuable, allowing access to diverse ortho-substituted biaryl derivatives. However, use of the amino group for ortho direction is challenging, the first example of which having been reported only very recently. The current proposal provides an approach to ortho-arylation of anilines and heteroarylamines utilizing continuous flow technology. Specifically, through the use of carbon dioxide as an abundant and inexpensive reagent, the amino group of an arylamine will be converted to the carbamate salt, which can serve as an in situ protecting and directing group for ortho-arylation. The use of continuous flow methods for this approach is uniquely advantageous, since 1) the thermally labile carbamate salts can be produced and immediately consumed, and 2) high carbon dioxide pressure can be conveniently and safely accessed, a condition necessary to prevent decarboxylation of the carbamate intermediates at the high temperatures required for C-H arylation. Taken together, these two features of continuous flow synthesis allow for an expedient ortho-arylation of anilines that eliminates the need for separate protection/deprotection steps. This advance could lead to more cost-effective syntheses of biaryl scaffolds that are ubiquitous in pharmaceutical agents.

描述（由申请人提供）：Arene C-H键的直接功能化可以是构建在多种药物相关分子中发现的二型序列的有力方法。尽管直接C-H芳基化具有潜在的实用性，但控制区域选择性的控制难度限制了其合成效用。解决此问题的一种方法是使用 Ortho指导小组。尽管目前已知许多这样的指导组，但大多数人在综合上不灵活或需要增加保护/脱保护步骤以供其使用。由于氨基组的多功能性，使用该功能组的正式化将在合成中有价值，从而允许访问各种矫正均取代的Biaryl衍生物。但是，将氨基组用于Ortho方向是具有挑战性的，第一个示例仅是最近报告的。当前的提案提供了一种利用连续流动技术的苯胺和异性胺的矫正方法。具体而言，通过将二氧化碳用作丰富且廉价的试剂，芳基胺的氨基群将转化为氨基甲酸盐，该氨基盐可以用作原位保护和指导型嫁接的原位和指导组。这种方法的连续流方法的使用具有独特的优势，因为1）可以立即生产并立即产生热不稳定的氨基甲酸盐盐，而2）可以方便且安全地访问高二氧化碳压力，以防止在高温下以高温为C-H-HATRATIONS CARBAMATE中间体脱羧所必需的条件。综上所述，连续流合成的这两个特征允许对苯胺的固定性截闭，从而消除了对单独的保护/脱身步骤的需求。这一进步可能导致更具成本效益的双脚架合成，这些支架无处不在，这些支架无处不在。