Abstract
Dearomatization is a technique that has been steadily gaining interest in the fields of natural product synthesis and medicinal chemistry due to its potential to access structurally complex molecules from cheap, readily available aromatic precursors. A method for carrying out these dearomative processes is by the coordination of aromatic molecules to a transition metal complex. Dihapto-coordination of aromatic molecules to an electron-rich metal fragment leads to a disruption of aromaticity due to the donation of electron density from the dπ-orbitals of the metal to the π*-orbitals of the arene. Such coordination allows for subsequent functionalization to be performed on the uncoordinated π-bonds of the aromatic ligand.
Chapter 1 surveys methods of dearomatization and highlights how the implementation of these techniques could help achieve the synthetic goals within medicinal chemistry. Emphasis is given on transition-metal mediated dearomatization reactions—specifically, those promoted via the hexahapto- and dihapto-coordination of aromatic substrates to transition metals.
Chapter 2 examines the double protonation of TpW(NO)(PMe3)(η2-benzene) and TpW(NO)(PMe3)(η2-anisole). The resulting "doubly protonated" species exhibit drastically different reactivities than their monoprotonated counterparts. Namely, the dicationic species have an enhanced electrophilicity, allowing them to participate in electrophilic aromatic substitution (EAS) reactions with a wide range of aromatic nucleophiles. Through this chemistry, the highly selective construction of Csp3-Csp2 bonds is achieved.
Chapter 3 describes the study of the addition of carbon nucleophiles to tungsten-stabilized oxocarbenium ions derived from TpW(NO)(PMe3)(η2-anisole). To date, the functionalization of such complexes is highly underdeveloped. Though deprotonation of these ions is highly competitive, success is found in using strong carbon nucleophiles at low temperatures or increasing the oxocarbenium ion's reduction potential via its fluorination.
Chapter 4 explores the scope of nucleophiles compatible with tungsten-stabilized pi-allyl complexes. An expansion of the scope of carbon- and nitrogen-based nucleophiles is reported. A highlight of this work is the successful employment of amide and imides. Historically, amines are often used as nitrogen nucleophiles. However, owing to the inherent sensitivity of the allylic amino substituted product, considerable care must be taken in their handling. Conversely, the use of amides and imides offers enhanced stability.
Chapter 5 applies the chemistry discussed in Chapter 3 and Chapter 4 toward developing a novel platform for the stereodivergent synthesis of cis-and trans-3,6-disubstituted cyclohexenes. Dihapto-coordination of anisole to {WTp(NO)(PMe3)} enables a triple nucleophilic addition sequence to the bound aromatic. While each nucleophilic addition occurs on the face of the arene opposite to the metal fragment, two nucleophilic additions occur on the same carbon. When the final nucleophile is added, an inversion of the stereochemistry set by the preceding nucleophile occurs. By reversing the order in which the last two nucleophiles are introduced into the system, complementary cis and trans isomers can be made. This work is the first example of a general platform for stereodivergent synthesis via the tungsten-mediated dearomatization of anisole.
Chapter 6 describes a heteroannulation strategy facilitated by an internal nucleophilic addition to tungsten-stabilized pi-allyl complexes. Complexes containing substituents with a pendant nucleophilic moiety can undergo cyclization reactions via their treatment with a base. Compared to current heteroannulation strategies that rely on precious metals and highly specific reagents, the EAS/internal nucleophilic addition discussed in this chapter achieves cyclization using a tungsten complex, anisole, and an aromatic substrate.
Chapter 7 examines the use of {TpW(NO)(PBu3)} as an alternative to {TpW(NO)(PMe3)}. TpW(NO)(PBu3)(η2-anisole) is found to exhibit identical reactivity to the PMe3 analogue while costing significantly less to produce.
Finally, Chapter 8 details the use of molecular rotational resonance spectroscopy (MRR) to optimize the synthesis of deuterated cyclohexenes via the dearomatization of benzene. The insight gained through MRR analysis aids in significantly minimizing or eliminating impurities.
