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.

杂芳烃在制药工业中发现具有重要生物学性质的新分子方面发挥着重要的作用。因此，开发新的合成方法仍然是一个关键的挑战。常见反应的主要局限性，如铃木和斯蒂尔交叉偶联，是使用化学计量比的有机金属物种，必须在单独的化学转化中制备，并产生化学副产品废物。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品。自然界已经进化出有效的脱羧基偶联过程来制备碳-碳键，例如在脂肪酸的合成中。然而，直到最近，这些都没有被有机化学家作为合成工具充分利用。我以前的工作表明，2-羧酸-杂芳烃是有用的交叉偶联伙伴，可以与芳基卤化物进行有效的偶联。这种方法提供了进入一个新的研究领域，在这个领域中，羧酸现在作为交叉偶联反应中的有机金属替代品发挥作用。由于固有的新颖性，这种反应性很重要，而且在工业上也是如此，因为这些偶联伙伴在商业上广泛可用，并且无限稳定。深入了解脱羧基偶联的运行机制对于进一步利用这项技术是至关重要的。较长期的目标将包括通过合成多种杂芳烃产品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品，如亚磺酸，由于较弱的碳-硫键，亚磺酸将比相应的羧酸更容易进行脱硫化。我们的研究项目，脱羧金属催化偶联，还处于初级阶段，但这个新兴的和最近受到关注的领域将标志着在合成具有重要药用价值的杂芳烃时偶联伙伴的选择发生了范式转变。