Development of decarboxylative coupling processes

脱羧偶联工艺的开发

• 批准号: 371540-2009
• 负责人: Forgione, Pat
• 金额: $ 2.91万
• 依托单位: Concordia University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=550065
• 关键词: Development; decarboxylative; coupling; processes

Heteroaromatics play a large role in the discovery of new molecules with important biological properties for the pharmaceutical industry. Thus, the development of novel synthetic methods remains a key challenge. The main limitation of common reactions, such as the Suzuki and Stille cross-couplings, is the employment of stoichiometric amounts of organometallic species that must be prepared in separate chemical transformations and generate chemical by-product waste. The primary goal of our research program is to explore carboxylic acids as surrogates for the organometallic species in carbon-carbon bond forming reactions. Nature has evolved effective decarboxylative coupling processes for the preparation of carbon-carbon bonds, such as in the synthesis of fatty acids. However, until recently, these have been under utilized by organic chemists as synthetic tools. My previous work revealed that 2-carboxylic acid-heteroaromatics are useful cross-coupling partners that undergo efficient coupling with aryl halides. This approach provides an entry into a new field of research, where carboxylic acids now function as organometallic surrogates in cross-coupling reactions. This reactivity is important due to the inherent novelty, as well as industrially since these coupling partners are widely available commercially and indefinitely stable. Gaining insight into the operative mechanism of the decarboxylative coupling is essential to capitalize further on this technology. Longer-term goals will involve highlighting the practical uses of the coupling through the synthesis of versatile heteroaromatic products as well as the rapid screening of heteroaromatic substructures against biological targets. Further extensions will explore other metal surrogates such as sulfinic acids, which will undergo de-sulfinylation more readily than the corresponding carboxylic acid due to the weaker carbon-sulfur bond. Our research program, decarboxylative metal catalyzed couplings, is in its infancy, but this burgeoning and recently highlighted field will mark a paradigm shift in the choice of coupling partners in the synthesis of pharmaceutically important heteroaromatics.

杂芳族化合物在发现具有重要生物学特性的新分子方面发挥着重要作用。因此，开发新的合成方法仍然是一个关键挑战。常见反应（例如Suzuki和Stille交叉偶联）的主要限制是使用化学计量量的有机金属物质，其必须在单独的化学转化中制备并产生化学副产物废物。我们研究计划的主要目标是探索羧酸作为碳-碳键形成反应中有机金属物种的替代物。自然界已经发展出用于制备碳-碳键的有效脱羧偶联方法，例如在脂肪酸的合成中。 然而，直到最近，有机化学家还没有充分利用它们作为合成工具。我以前的工作表明，2-羧酸-杂芳族化合物是有用的交叉偶联伙伴，与芳基卤化物进行有效的偶联。这种方法提供了一个进入一个新的研究领域，其中羧酸现在作为交叉偶联反应中的有机金属替代物。这种反应性是重要的，这是由于固有的新奇，以及工业上，因为这些偶联配偶体是广泛可商购的和无限稳定的。深入了解脱羧偶联的操作机制对于进一步利用这项技术至关重要。长期目标将涉及通过合成多功能杂芳族产物以及针对生物靶标快速筛选杂芳族亚结构来突出偶联的实际用途。进一步的扩展将探索其他金属替代物，如亚磺酸，由于较弱的碳-硫键，其将比相应的羧酸更容易进行脱亚磺酰化。我们的研究计划，脱羧金属催化偶联，是在其起步阶段，但这个新兴的和最近突出的领域将标志着在药学上重要的杂环化合物的合成偶联合作伙伴的选择范式转变。