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法。尽管直接C-H芳基化有潜在的用途，但区域选择性的控制仍然是限制其合成用途的一个困难。解决此问题的一种方法是使用 Ortho导演组。虽然目前已知许多这样的导向基团，但大多数合成上不灵活，或者需要额外的保护/解除保护步骤才能使用。由于氨基的多功能性，使用这种官能团的邻位芳基化反应将具有合成价值，从而可以获得各种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，第一个例子直到最近才被报道。目前的建议提供了一种利用连续流动技术进行苯胺和杂芳胺的邻位芳基化反应的方法。具体地说，通过使用二氧化碳作为一种丰富而廉价的试剂，芳胺的氨基将被转化为氨基甲酸酯盐，它可以作为邻位芳基化的原位保护和导向基团。对于这种方法使用连续流动方法是独特的优势，因为1)可以生产热不稳定的氨基甲酸盐并立即消费，以及2)可以方便和安全地获得高二氧化碳压力，这是防止在C-H芳基化所需的高温下氨基甲酸酯中间体脱羧所必需的条件。总而言之，连续流动合成的这两个特点使得苯胺可以方便地进行邻位芳基化反应，从而不需要单独的保护/去保护步骤。这一进展可能导致更具成本效益的联芳基支架的合成，这种支架普遍存在于药物中。

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.