Regioselective, Polycouplings of Polyhaloheteraromatics

多卤杂芳族化合物的区域选择性多偶联

• 批准号: 6953946
• 负责人: SCOTT T HANDY
• 金额: $ 17.79万
• 依托单位: MIDDLE TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6953946
• 关键词: bromine; chemical kinetics; chemical reaction; chemical synthesis; combinatorial chemistry; crosslink; gas chromatography mass spectrometry; halogenation; heterocyclic polycyclic compound; high performance liquid chromatography; method development; nuclear magnetic resonance spectroscopy; pyridine; pyrroles; quinoline; thiazoles

DESCRIPTION (provided by applicant): The focus of this proposal is the development of a concise and versatile route for the preparation of differentially substituted hetero aromatics, based on the regioselective one-pot coupling of polyhalogenated heteroaromatics.The basic advantages of such an approach is that the starting polyhalogenated compounds can be readily prepared by a single halogenation reaction. Then, by applying a coupling reaction in the second step a wide range of functionalized substituents can be installed regioselectively in a single step. The end result is a two step method for the preparation of any regioisomer of a polysubstituted heteroaromatic. Preliminary results have already indicated that both regioselectivity and double couplings can be accomplished in one pot. To further application of this method, a hypothesis has been developed using the 1H NMR chemical shift information for the parent, non-halogenated heteroaromatic to predict the order of coupling as well as what reaction conditions will work with which substrates. Further, two sets of coupling conditions have been developed based on the structure of the starting heteroaromatic. One set works for substrates that lack strongly coordinating Lewis basic sites, while the other set works for coordinating and potentially weakly coordinating but bidentate systems. Most of the preliminary studies have focused on pyrrole and pyridine, but the efforts outlined in this proposal will expand this scope to include a wide range of other classes of heteroaromatics in an effort to demonstrate that the same reaction conditions can be expanded to the preparation of a wide range of heteroaromatic compounds of medicinal interest. Further, some trihalogenated heteroaromatics will be studied in an effort to extend the polycoupling method to even more complex systems and thereby reap the benefit of greater reduction to the overall length of the synthesis of these types of compounds. On the basis of these studies, future research will be able to both synthesize compounds of biological interest (such as the lamellarins and pyridine-based antibiotics) as well as extend this method to other types of coupling reactions.

描述（由申请人提供）：该提案的重点是开发一种基于差异化替代异质芳香族剂的简洁而多功能的途径，该途径是基于多面化异源性杂型化的一个蛋白质耦合的。这种方法的基本优势是，启动多核化的综合反应可以恢复为单个验证，可以单位地制成单位验证。然后，通过在第二步中应用耦合反应，可以在单个步骤中进行区域选择性地安装宽范围的功能化取代基。最终结果是用于制备多积分杂虫的任何区域异构体的两步方法。初步结果已经表明，可以在一个锅中完成区域选择性和双重耦合。为了进一步应用该方法，使用1H NMR化学移位信息为父母，非催化异芳族的杂型疗法提出了假设，以预测耦合的顺序以及哪些反应条件将与哪些底物起作用。此外，基于起始杂音的结构开发了两组耦合条件。一组适用于缺乏强烈协调刘易斯基本站点的底物，而另一组则用于协调和潜在的弱协调但可以协调但双齿系统。大多数初步研究都集中在吡咯和吡啶上，但是该提案中概述的努力将扩大此范围，以包括其他类别的异性植物学，以证明可以将相同的反应条件扩展到制备广泛的药物利益化合物。此外，将研究一些三氢型异源物质，以将多耦合方法扩展到更复杂的系统，从而获得更大的利益，从而使这些化合物合成的整体长度更大。在这些研究的基础上，未来的研究将能够综合生物学兴趣化合物（例如层层和基于吡啶的抗生素），并将这种方法扩展到其他类型的耦合反应。