1,1,3,3-Tetramethyldisiloxane and Potassium Tert-Butoxide as an Unconventional Reducing Agent and its Application in the Synthesis and Deconstruction of Carbon-Carbon Bonds

Abstract

Over the past decade, the combination of hydrosilanes and Lewis bases have seen a renaissance with chemists uncovering the mechanistic intricacies that underlying their reactivity. Owing to the diverse mechanistic reactivity showcased by these reagent combinations, various reductive defunctionalization reactions including C-O, C-N, and C-C bond cleavage have been reported as practical synthetic methods. Further investigation of these reagent combinations led to the development of C-H and N-H silylation reactions in addition to hydrosilylation reactions earning their place as versatile synthetic multi-tools. Despite this synthetic versatility, chemists have yet to extend the list of transformations facilitated by hydrosilanes and Lewis bases to the synthesis of carbon-carbon bonds - a fundamental transformation in organic synthesis. This thesis outlines the discovery and application of 1,1,3,3-tetramethyldisiloxane (TMDSO) and potassium tert-butoxide (KOᵗBu) as a unique reducing agent towards C-C bond cleavage and C-C bond formation. Chapter Two of this dissertation outlines the serendipitous discovery and development of the reductive C(sp²)-CF3 bond cleavage of 2-trifluoromethylpyridines. Using TMDSO and KOᵗBu the reductive cleavage of C(sp²)-CF₃ bonds was demonstrated to be regioselective for C2 on trifluoromethylpyridines and trifluoromethylquinolines bearing alkyl, amino, aryl, and chloro substituents. A small mechanistic investigation unveiled that TMDSO and KOᵗBu may display redox reactivity acting as a one-pot single-electron donor and hydrogen atom donor. The discovery of this redox reactivity manifold culminated in a hydroalkylation reaction discussed in chapter 3 of the dissertation. Chapter Three of this dissertation builds on a discovery made towards the end of Chapter Two where under the same reaction conditions trans-stilbene could be hydroalkylated using an alkyl halide as an electrophile, representing the first instance of C(sp³)-C(sp³) bond formation facilitated by the combination of a hydrosilane and Lewis base. This transition-metal-free approach is used to functionalize mono, di, and trisubstituted aryl olefins bearing alkyl, aryl, and halogen substituents and primary and secondary alkyl halides as electrophiles. An in-depth mechanistic analysis pointed towards the formation of a benzylic radical via HAT from what is presumed to be a potassium dihydridosilicate to styrene, followed by a key reductive radical polar crossover step to transform the benzylic radical into a benzylic carbanion. A subsequent bimolecular nucleophilic substitution reaction between the benzylic carbanion and alkyl halide leads to the desired product. Chapter Four of this dissertation highlights an unusual C(sp³)-H alkylation reaction facilitated by TMDSO and KOᵗBu that was discovered at the end of chapter three. In this chapter, TMDSO and KOᵗBu are used to facilitate the deprotonation and alkylation of weakly acidic C(sp³)-H bonds. A small scope of alkylpyridines, benzylic species, and dithiane were amenable to the reaction conditions. A unique feature of this reaction is the overalkylation of the intended product thought to occur through a subsequent deprotonation and alkylation step; this reactivity was exploited to synthesize novel spirocycles from alkylpyridines and dihaloalkanes. Control experiments, reaction kinetics, and substrate probes revealed the reaction proceeds through a key deprotonation step facilitated by a KH-like base derived from the hydrosilane, TMDSO. This thesis concludes with chapter five highlighting the significance of this work by demonstrating the expansion of hydrosilane and Lewis base reactivity towards the synthesis of C(sp³)-C(sp³) bonds. This chapter also serves to frame the future of this reactivity based on the opinions of the dissertation author.