Development of decarboxylative coupling processes

杂芳烃在制药工业中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的挑战。常见反应的主要限制，如铃木和斯蒂尔交叉偶联，是使用化学计量数量的有机金属物质，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。自然界已经进化出了有效的脱羧偶联过程，用于制备碳-碳键，例如脂肪酸的合成。然而，直到最近，有机化学家们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。这种方法为进入一个新的研究领域提供了一个入口，其中羧酸现在在交叉偶联反应中作为有机金属替代品起作用。由于其固有的新颖性，以及由于这些耦合伙伴在商业上广泛可用且无限稳定，因此这种反应性非常重要。深入了解脱羧偶联的作用机制对于进一步利用该技术至关重要。长期目标将包括通过合成多功能杂芳烃产品以及快速筛选针对生物靶标的杂芳烃亚结构来强调偶联的实际用途。进一步的扩展将探索其他金属替代物，如亚磺酸，由于碳硫键较弱，它将比相应的羧酸更容易发生去亚砜化。我们的研究项目，脱羧金属催化偶联，还处于起步阶段，但这一新兴和最近突出的领域将标志着在合成具有重要药学意义的杂芳烃时选择偶联伙伴的范式转变。

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.