Development of transition metal-catalyzed methods for the preparation of highly substituted nitroalkanes and axially chiral biarenes
Date
2024
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Publisher
University of Delaware
Abstract
Nitroalkanes are versatile reagents in organic synthesis. They can participate in various carbon-carbon bond forming reactions and can be transformed into important functional groups such as amines. Despite their significance, methods to prepare nitroalkanes via a simple alkylation process with alkyl electrophiles has remained a challenging task. Over the past decade, our group has sought to utilize metal-catalyzed radical-based approach to solve this general problem. ☐ In Chapter 1, I will describe the development of a nitroalkane propargylation reaction that is enabled by a commercially available and inexpensive copper catalyst system. The conditions are robust for the coupling of primary and secondary nitroalkanes with highly functionalized propargyl bromides. Homopropargylic nitroalkanes are accessed from this method, and the utility of the products are demonstrated through downstream functionalization to biologically relevant, five-membered nitrogen heterocycles such as pyrroles and 2-pyrrolines. ☐ In Chapter 2, the development of a photoredox-nickel dual-catalyzed nitroalkane alkylation with unactivated alkyl iodides is described. Our first-generation nickel-catalyzed condition that we previously discovered showed poor reactivity outside of primary nitroalkanes. However, with this new condition, an efficient mono-alkylation of nitromethane, primary, and secondary nitroalkanes is now realized. The conditions are scalable as well as air and moisture tolerant. Most importantly, complex tertiary nitroalkanes, which are direct precursors to important a-tertiary amines, can now be accessed. ☐ In Chapter 3, I will describe our mechanistic investigation on the photoredox-nickel dual-catalyzed nitroalkane alkylation reaction. We initially assumed that the photoredox catalyst was behaving as a reductant to initiate catalysis. However, after our in-depth mechanistic study it was revealed that its role in the reaction and the overall mechanism is more complicated than expected. In collaboration with Prof. Rosenthal’s group at UD and Prof. Guitierrez’s group at TAMU, a novel mechanism is proposed involving a unique photoexcited nickel(II) dinitronate intermediate. ☐ In Chapter 4, I will describe the development of an asymmetric nitroalkane alkylation reaction with α-bromoketones enabled by photoredox-nickel dual-catalysis. Recently, our group disclosed the first nickel-catalyzed asymmetric nitroalkane alkylation reaction. However, the method was found to be limited to α-bromoamides. The conditions developed herein now gives access to β-nitroketone products in good yields and stereoselectivity for the syn products. ☐ In Chapter 5, the development of a nickel-catalyzed atroposelective reductive homocoupling reaction of aryl halides is described in the context of phosphine ligand synthesis. Axially chiral biaryl bisphosphines are a valuable class of chiral ligands in the field of asymmetric catalysis. However, access to this class of ligands has been generally challenging. We showcase that the synthesis of highly enantioenriched biaryl bisphosphonate or bisphosphine oxides can be achieved by an asymmetric Ullmann-type reaction. Additionally, with slight modification of the conditions, we show that the asymmetric dimerization of other, non-phosphorus-containing aryl halides could be achieved as well. ☐ In Chapter 6, the nickel-catalyzed atroposelective reductive cross-coupling of aryl halides is described. Particularly, ortho-(bromo)arylethers and ortho- (chloro)arylphosphine oxides are coupled with high levels of cross-selectivity and atroposelectivity. This previously uninvestigated asymmetric nickel-catalyzed reaction shows a broad substrate scope and it offers a direct route to chiral biaryl monophosphine oxides. The products are of potential interest as precursors to MOP-type ligands.
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Keywords
Asymmetric catalysis, Atropisomers, Biaryl phosphine ligands, Nitroalkane alkylation, Reductive coupling, Transition-metal catalysis