Transition metal-catalyzed enantioselective C-alkylation of nitroalkanes and trifluoromethylation of nitroalkanes
Date
2018
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Publisher
University of Delaware
Abstract
This dissertation focused on the development of new methods to synthesize enantioenriched complex nitroalkanes using transition metal catalysis. Nitroalkanes are useful intermediates in several C–C bond forming reactions and serve as precursors for several functional groups including amines and carbonyls. Despite this rich chemistry, the seemingly simple C-alkylation of nitroalkanes with alkyl electrophiles (such as alkyl halides) has remained a highly challenging task due to competing O-alkylation. Using the advent of transition metal catalysis our group has addressed this century old problem. ☐ In this regard, I was involved in four main projects during my graduate career. Chapter 1 describes the synthetic utility of nitroalkanes in organic synthesis and include a summary of base metals known to undergo C–C bond forming reactions using simple alkyl electrophiles via a radical mechanism. ☐ Chapter 2, describes the development of metal-free trifluoromethylation of secondary nitroalkanes using commercially available reagent reagent 5-(trifluoromethyl)dibenzothiophenium triflate (Umemoto’s reagent). These conditions provide high yielding access to fully substituted -(trifluoromethyl)nitroalkanes and I showed that these compounds can be easily converted into medicinally relevant -(trifluoromethyl)amines. ☐ Chapter 3, describes the discovery and development of the first nickel-catalyzed conditions for the enantioselective synthesis of beta-nitroamides using racemic alpha-bromoamides as electrophiles. In this work, I showed the stereocenter alpha to the nitro group could be controlled and I also showed that the enantioenriched beta-nitroamides can be used as a handle for further C–C bond forming reactions such as conjugate addition, trifluoromethylation and Tsuji-Trost allylation to set a fully substituted nitro stereocenters without erosion of enantiomeric excess and producing the product with excellent diastereoselectivity. ☐ Chapter 3, also describes the development of a first, nickel-catalyzed C-alkylation of nitroalkanes using unactivated alkyl iodides. This method allowed the preparation of a diverse array of complex nitroalkanes using simple starting materials. Significantly, this system allows for the alkylation of primary, secondary, and tertiary alkyl iodides without the requirement of radical stabilizing groups. ☐ Preliminary results in the copper and nickel catalyzed enantioselective C-alkylation of nitroalkanes using additional radical stabilizing substrate classes such as benzyl bromide and alpha-bromoketones will be discussed in detail in Appendix D and E.
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Keywords
Pure sciences, 2 diamines, Asymmetric nitroalkane alkylation, Enantioenriched beta nitroamides, Enantioselective nickel catalysis, Nickel catalysis for synthesis of complex nitroalkanes, Novel chiral 1, Trifluoromethylation