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

基本信息

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
项目类别：
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

项目摘要

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）：芳烃C-H键的直接官能化可以是构建在各种医学相关分子中发现的联芳基基序的有效方法。尽管直接C-H芳基化具有潜在的用途，但区域选择性的控制仍然是限制其合成用途的困难。解决这个问题的一种方法是使用邻位指导组。尽管目前已知许多此类导向基团，但大多数在合成上是不灵活的或者需要额外的保护/脱保护步骤才能使用。由于氨基的多功能性，使用该官能团的邻位芳基化将具有合成价值，允许获得多种邻位取代的联芳基衍生物。然而，将氨基用于邻位是具有挑战性的，第一个例子最近才被报道。目前的提案提供了一种利用连续流技术对苯胺和杂芳胺进行邻位芳基化的方法。具体而言，通过使用二氧化碳作为丰富且廉价的试剂，芳胺的氨基将转化为氨基甲酸盐，其可以作为邻位芳基化的原位保护和导向基团。这种方法使用连续流动方法具有独特的优势，因为 1) 可以产生热不稳定的氨基甲酸盐并立即消耗，2) 可以方便、安全地获得高二氧化碳压力，这是防止脱羧的必要条件。在 C-H 芳基化所需的高温下生成氨基甲酸酯中间体。总而言之，连续流合成的这两个特征允许苯胺的方便的邻位芳基化，从而消除了单独的保护/脱保护步骤的需要。这一进展可能会导致药物中普遍存在的联芳基支架的合成更具成本效益。