Directed Arylation of Unprotected Anilines Enabled by Continuous Flow Technology

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式。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。解决此问题的一种方法是使用 邻位定向基团。尽管目前已知许多这样的定向基团，但大多数在合成上是不灵活的或需要额外的保护/脱保护步骤来使用。由于氨基的多功能性，使用该官能团的邻位芳基化将是合成上有价值的，允许获得不同的邻位取代的联芳基衍生物。然而，将氨基用于邻位方向是具有挑战性的，其第一个例子仅在最近才被报道。本发明提供了一种利用连续流技术进行苯胺和杂芳基胺的邻位芳基化的方法。具体地，通过使用二氧化碳作为丰富且廉价的试剂，芳基胺的氨基将被转化为氨基甲酸盐，其可以用作邻位芳基化的原位保护和导向基团。对于该方法使用连续流动方法是独特有利的，因为1）热不稳定的氨基甲酸盐可以被生产并立即消耗，和2）高二氧化碳压力可以方便和安全地获得，这是防止氨基甲酸酯中间体在C-H芳基化所需的高温下脱羧所必需的条件。总之，连续流合成的这两个特征允许苯胺的有利的邻位芳基化，其消除了对单独的保护/脱保护步骤的需要。这一进展可能会导致更具有成本效益的合成联芳基支架，是无处不在的药剂。

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.