RUI: Development of Bench-stable N-quaternized ketene N,O-acetals as Multifunctional Reagents for Organic Synthesis

在化学系化学合成项目的支持下，汉密尔顿学院的Max Majireck正在研究一类新的化合物，这种化合物可用于制造增值材料，如药剂、农用化学品和其他对社会有用的物质。这项研究的核心是Majireck研究小组最近的一项发现，即被称为N-季胺化酮N，O-缩醛的活性化合物通常过于微妙，无法处理，可以以稳定它们的方式进行制备。这一重要发现为这种材料首次用于合成一系列有价值的化合物打开了大门。例如，资助项目的一个目标是使用新获得的一类N，O-缩醛来制备生物活性的含氮环化合物，这些化合物通常是活性药物中的成分。此外，研究小组将调查涉及新试剂的各种工艺，以发现直接且不含贵金属催化剂等昂贵添加剂的有效化学制造方法。该项目的更广泛影响将延伸到支持汉密尔顿学院合成有机化学本科生的研究型学术课程和暑期研究经验，重点是招募、培训和留住代表人数较少的群体的学生从事科学、技术、工程和数学(STEM)。N-季胺基烯酮N，O-缩醛因其典型的不稳定性和/或特殊的原位生成方法而被忽视作为有机合成的试剂。然而，最近发现这类化合物中的某些化合物，特别是吡啶酮N，O-缩醛，具有长期的工作台稳定性，允许以直接的方式制备和纯化它们。这为在有机合成中利用N-季胺化烯酮N，O-缩醛作为多功能试剂提供了可能性。例如，这类化合物可以作为热生成O-烷基酮离子的来源，可用于无酸催化剂的Friedel-Craft酰化反应或各种环加成反应。除了对这类过程的持续探索，马吉雷克博士和他的本科生团队还将研究使用2-卤代-N-(1-烷氧基乙烯基)吡啶盐作为亲电剂，通过温和的亲核芳香取代反应生产2-氨基吡啶衍生物。这项研究将为本科生提供宝贵的机会，特别是那些来自STEM传统上代表性较低的群体的本科生，参与身临其境的研究体验，预计这将有助于加强和多样化美国科学工作者。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemical Synthesis program in the Division of Chemistry, Max Majireck of Hamilton College is studying a new class of compounds that is useful for the manufacture of value-added materials such as pharmaceutical agents, agrochemicals, and other substances of use to society. Central to this research is a recent discovery made by the Majireck research group that reactive compounds known as N-quaternized ketene N,O-acetals, typically too delicate to be handled, can be prepared in a manner that stabilizes them. This important finding opens the door for such materials to be employed for the first time in the synthesis of a broad range of valuable compounds. For example, a goal of the funded project is to use the newly available class of N,O-acetals for the preparation of biologically active nitrogen-containing cyclic compounds commonly found as components in active pharmaceuticals. Furthermore, the research team will investigate a variety of processes involving the new reagents to uncover efficient methods for chemical manufacture that are straightforward and devoid of expensive additives, such as precious metal catalysts. The broader impacts of the project will extend to supporting research-based academic courses and summer research experiences for undergraduate students in synthetic organic chemistry at Hamilton College, with an emphasis on recruiting, training, and retaining students from underrepresented groups for careers in science, technology, engineering, and mathematics (STEM).N-Quaternized ketene N,O-acetals have been overlooked as reagents in organic synthesis due to their typical instability and/or specialized means of generation in situ. However, it was recently discovered that certain compounds within this class, and particularly pyridinium ketene N,O-acetals, have long-term bench-stability that allows for their preparation and purification in a straightforward manner. This opens up the possibility of leveraging N-quaternized ketene N,O-acetals as versatile reagents in organic synthesis. For example, such compounds can act as a source of thermally-generated O-alkyl ketenium ions, which can be used in acid catalyst-free Friedel-Crafts acylations, or in various cycloaddition reactions. Beyond the continued explorations of these kinds of processes, Dr. Majireck and his team of undergraduate students will also study the use of 2-halo-N-(1-alkoxyvinyl)pyridinium salts as electrophiles for the production of 2-aminopyridine derivatives via mild nucleophilic aromatic substitution reactions. The research will provide valuable opportunities for undergraduate students, particularly those from groups traditionally underrepresented in STEM, to partake in immersive research experiences which are anticipated to contribute toward a strengthening and diversification of the U.S. scientific workforce.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.