Date of Graduation

12-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemistry (PhD)

Degree Level

Graduate

Department

Chemistry & Biochemistry

Advisor/Mentor

Zheng, Nan

Committee Member

Durham, Bill

Second Committee Member

Allison, Neil T.

Third Committee Member

Kilyanek, Stefan M.

Keywords

Cycloalkylaniline; Deconstruction; Difunctionalization; Hypervalent iodine; Photoredox catalysis; Visible light

Abstract

The exploitation of ring strain as a driving force to facilitate chemical reactions is a well-appreciated principle in organic chemistry. Of the strained carbocycles frequently explored in this respect, cyclopropane ring systems have drawn considerably more interest among synthetic chemists than their homolog, the cyclobutane ring systems, even though the strain energy of cyclobutane (26.7 kcal/mol) is similar to that of cyclopropane (27.5 kcal/mol). We have previously developed a [4+2] annulation reaction for the synthesis of aniline-substituted six-membered carbocycles under photoredox catalysis via the oxidative cleavage of N-cyclobutylanilines. The key reaction involved in this method is a ring-opening process of cyclobutylanilines via single-electron oxidation of the anilines under visible light photoredox conditions to presumably generate distonic radical cation intermediates which possess bimodal reactivity due to the presence of a nucleophilic carbon radical moiety (site Y) and an electrophilic iminium ion moiety (site X) that are spatially separated. We have hitherto successfully achieved orthogonal 1,4-difunctionalization of the two reactive sites by using phenyl allyl sulfone or α-CF3-styrene as radical acceptor to capture the radical at Y and TMSCN as nucleophile to intercept the iminium ion at X respectively. The first of the three works described in this dissertation further exploits isocyanides (or isonitriles)—“stereoelectronic chameleons” that exhibit dichotomous reactivity—as radical acceptors in the difunctionalization of the bimodal amine distonic radical cations to afford both symmetrical and unsymmetrical N-substituted 2,6-diaminopimelonitriles in poor to good yields. This represents the first-ever report of a successful synthetic methodology that exploits the ambivalent reactivities of both distonic radical cations and isocyanides.Again, we report the development of a novel methodology for the synthesis of aminoalkynes from various N-substituted cyclobutane substrates via a sequential visible-light-assisted ring-opening and distal alkynylation with alkynyl hypervalent iodine (III) reagents. An in situ-generated distonic radical cation intermediate possessing resonance-stabilized iminium ion site mediates the transformation of the substrates into various pharmaceutically important nitrogen heterocycles. This methodology constitutes only the second example of aminoalkyne synthesis employing the cycloalkylamine deconstruction/refunctionalization strategy. Finally, we report the first-ever aromatization-promoted, visible-light-assisted deconstructive functionalization of unstrained medium-to-large-sized cycloalkanones using diamines as an activator of the ring cleavage for the synthesis of remotely functionalized quinazolinones. The protocol features an amido radical-mediated C(sp3)-C(sp3) cleavage via an aromatization/radical acceptor-driven ring-opening synergy, without the involvement of transition metals, exogenous oxidants, or chelation assistance. In addition, the reaction exhibits a broad substrate scope, good to excellent product yields, and high regioselectivities.

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