A careful analysis of the reactivity of alkylidene carbenes and their precursors formed from carbonyl compounds and lithium trimethylsilyldiazomethane has led to the discovery of overlooked reactivity. Dr. Daesung Lee and coworkers at the University of Illinois at Chicago aim at exploiting the selectivity profile of alkylidene carbenes, developing new valuable synthetic methods that rely on this selectivity trend, and gaining new mechanistic understanding of their reactions. With the support from the Chemical Synthesis Program in the Division of Chemistry, new CH2 homologation and ring expansion chemistry will be developed with concomitant garnering of new information about the regioselectivity of C-C bond migration. Unprecedented reactivity of alkylidene carbenes to develop new method for allene synthesis will be investigated. The fundamental aspects of regioselectivity of carbene insertion reaction will be studied. In addition, the reactivity and selectivity of strained methylene cyclopropane systems generated from alkylidene carbene precursors and their utility in cycloaddition reaction will be explored.
The new understanding of reactivity of certain reactive intermediates such as unsaturated carbene species and a good control over their behavior would improve chemists' ability to develop more effective synthetic methods to prepare compounds of complex structures (including chemicals of medicinal use), thus ultimately improve human health and have broad societal impacts. Furthermore, this research provides training for students in fundamental and applied chemical synthesis and prepares them for careers in either academia or industrial settings.
Exploration of new reactivity of certain reactive intermediates is of paramount importance because it not only provides a platform to develop useful new synthetic methods but also leads to an insight that has significant ramification for related species. The current research executed under three major aims and the outcomes are summarized below. Aim 1. Development of new methylene insertion reaction: The major goal in this study is to develop a new and efficient methylene insertion method to ketones. Although there are many methylene homologation methods available, generally they are either ineffective or involve multistep transformations, or suffer from selectivity problems. We addressed these problems by accommodating the prowess of lithium trimethylsilyldiazomethane, which lead to the development of an effective and selective methylene homologation for cyclic ketones. While expanding the scope of this homologation, we discovered that the reaction with more functionalized ketones containing a remote alkene provided a facile cycloaddition between the diazomethyl functionality and a tethered alkene to generate structurally novel pyrazoline structures. This reaction was further optimized to run under a catalytic protocol (5–10 mol % of KOtBu or TBAT, a fluoride source). Under this catalytic condition, both aldehydes and ketones with various substituent patterns participated to form pyrazolines efficiently. The stereoselectivity of the newly formed stereogenic centers ranges from 1:1 to single diastereomer formation depending on the substrate structure and the reaction conditions employed. Aim 2. Allene synthesis by trapping alkylidene carbenes with diazo compounds: Under this aim the unprecedented reactivity of alkylidene carbenes has been explored, which evolved to a new method for allene synthesis. This new protocol involves the association of the carbenic carbon with trimethylsilyldiazoalkane to generate various trimethylsilyl allenes in one-step starting from ketones. These silylallenes display unprecedented reactivity toward various oxidizing agents including triplet molecular oxygen. The scope of allene synthesis was further extended to ethyldiazoacetate with copper catalyst. The resulting allenes containing hydroxyl group at the delta-position were prone to undergo allylic transposition to generate the corresponding 1,3-diene containing vinylic triflate or vinylic chloride functionality. This new allylic transposition without the involvement of any metal catalyst was stereoselective in most cases, and the stereoselectivity was justified by DFT calculations. While exploring the reactivity of lithium trimethylsilyldiazomethane with conjugated carbonyl compounds, another new reaction involving a dipolar cycloaddition was discovered, which provides structurally novel pyrazoline products in high yields. This dipolar cycloaddition reactivity of lithium trimethylsilyldiazomethane was further expanded to unsaturated esters, and was used as a key step for the synthesis of various natural products. Aim 3. Exploration of selectivity in carbene insertion reactions: The selectivity of alkylidene carbenes insertion was studied. The selectivity trend is the result of an extremely electron-deficient nature of alkylidene carbene. We discovered that cyclic and conformationally constrained C–H bonds are less reactive than those in acyclic environments, and the allene formation favorably competes with the insertion into 1° C–H bond but insertion into acyclic 2° and 3° C–H bonds outcompetes the allene formation. Unexpectedly, we observed that steric hindrance plays only minor role for the regioselectivity of alkylidene insertion. In another competition experiment, we discovered that a more electron-rich C–Si bond could favorably undergo insertion by alkylidene carbenes to generate cyclopropenes. The selectivity between C–H vs C–Si bond was explored, and a good predictable trend was established. We also discovered that these silylated cyclopropenes show unique reactivity toward Lewis acids to generate 1,1-disubstituted silylallenes. With an effective excess to cyclopropenes, we investigated their C–H activation-based amination with azodicarboxylate, the mechanism of which was studied by DFT calculations. The theoretical calculations strongly indicate that the amination of silylated cyclopropenes proceeds through an initial ene-type reaction followed by 1,3-rearrangement. Our interests in the carbene-based reactivity to activate C–H bond was further explored by using arynes that are generated from triynes through the hexadehydro Diels-Alder reaction. Broader Impact: These accomplished results of the proposed research would broaden the reactivity lithium trimethylsilyldiazomethane and the scope of alkylidene carbene chemistry. The obtained new knowledge and information will guide chemist to develop more effective synthetic methods that ultimately contribute to the synthesis of medicine and related compounds, thus improving societal benefits. At the fundamental level, the study of structure–based selectivity control, understanding reactivity of alkylidene carbenes, and the development of new synthetic methods would provide an opportunity for involved students to develop knowledge and skills to become skillful researchers. Importantly, because most students trained through these project areas are pursuing careers in either academia or industry settings, their contributions will range from basic science to human health through their involvement in the preparation of medicinally important compounds and other products. This is one of the most important roles of the proposed research and its execution by the involved graduate and undergraduate students.
