Exploiting Highly Reactive Intermediates as Opportunities for New Amination Methodologies: N-Isocyanates, O-Isocyanates and Carbamoyl Nitrenes
Creators: name: Ivanovich, Ryan A.
Publisher: name: Université d'Ottawa / University of Ottawa
Year: 2021
Subjects: Amination
Nitrene
Isocyanates
Photoredox

description: Nitrogen atoms play a distinctive role in eliciting a host of biological functions. Consequently, the efficient synthesis of nitrogen-containing molecules remains an important challenge for synthetic chemists. In view of these challenges, a variety of new methods for the incorporation of important N-containing motifs have been studied. The research efforts described in the present thesis were directed towards the development of novel amination methodologies via concerted cycloadditions, hydroamination, cascade reactions of N-, and O-isocyanates and photocatalytic C-H amination. In Chapter 2 alkene aminocarbonylation reactions of N-isocyanates and cascade reactions of N-isocyanates were investigated. Improved conditions for concerted intramolecular alkene aminocarbonylation with N-isocyanates were developed. The use of βN-benzyl carbazate precursors allowed minimization of N-isocyanate dimerization. Diminished dimerization led to higher yields of alkene aminocarbonylation products, to reactivity at lower temperatures, and to an improved scope for a reaction sequence involving alkene aminocarbonylation followed by 1,2-migration of the benzyl group. Furthermore, fine-tuning of the blocking group on the N-isocyanate precursor, and base catalysis resulted in room temperature reactivity, consequently minimizing the competing hydroamination pathway. Conditions for milder N-isocyanate generation and reactivity enabled new cascade reactions using N-isocyanates. Two new cascade processes were reported. First, a one-pot sequence for the synthesis of aza-diketopiperazines involving carbazate acylation with chloroacetyl chloride, SN2 with a primary amine, N-isocyanate formation and cyclization. This approach highlighted that βN-acyl carbazates could act as blocked N-isocyanates, thus allowing a challenging intermolecular SN2 reaction of a primary amine to proceed while the N-isocyanate was “protected”, then cyclization once it was deblocked. Control experiments showed that the alternate pathway — N-isocyanate substitution then cyclization by intramolecular SN2 reaction — was not operating. Second, ynone—derived carbazones engaged in a base catalyzed, room temperature substitution / 5-endo-dig cyclization to afford carbamoyl pyrazoles. The ability to use benzyl hydroxylamine as a nucleophile set the stage for subsequent investigations of O-isocyanates. Collectively, work in this chapter highlighted that controlled reactivity of amino-isocyanates was possible and provided a broadly applicable approaches to heterocycles possessing the N-N-C-O motif. In Chapter 3, new O-isocyanate reagents were developed. Oxy-carbamate O-isocyanate precursors facilitated access to synthetically valuable N-oxyureas via substitution reactions with amines. The development of blocked O-isocyanate precursors provided controlled reactivity, allowing the first examples of cascade reactions involving O-isocyanates. Complex hydroxylamine-derived hydantoins and dihydrouracil compounds were rapidly obtained from α- and β-amino esters, via substitution / intramolecular cyclization cascade reactions. Such reactivity illustrated the convenience of blocked O-isocyanates as hydroxylamine derived building blocks. Using allylamines as nucleophiles, the first Cope-type hydroamination of hydroxyureas was also developed. The cycloaddition reactivity of O-isocyanates was also assessed. O-Isocyanates were investigated as novel uncharched 1,3-dipole equivalents in [3+2] cycloadditions reactions. This enabled the first study of O-isocyanate cycloadditions both experimentally and by DFT calculations. This unique cycloaddition strategy allowed access to a novel class of heterocycle—aza-oxonium ylides via intramolecular and intermolecular cycloadditions with alkenes. This exploratory effort allowed a systematic study of the reactivity of the transient aza-oxonium ylide intermediate, which underwent N-O bond cleavage followed by nitrene C-H insertion, or the formation of β-lactams or isoxazolidinones by varying the structure of the alkene or O-isocyanate reagents. Collectively work in this chapter outlines some of the first synthetic uses of O-isocyanates. A variety of useful molecules were synthesized incorporating the O-N-C=O motif, or by taking advantage of the lability of the N-O bond for subsequent reactivity. In Chapter 4, the N-O bond cleavage / nitrene C-H insertion of O-isocyanate reagents was assessed. O-Isocyanate precursors were developed to act as both isocyanates (carbon electrophiles) and nitrenes (nitrogen electrophiles). Initial efforts were targeted at the cascade reactions of such precursors (e.g. substitution / C-H amination cascade reactions); however, this strategy was abandoned due to competing side reactions. Ultimately, an alternative strategy emerged using the same precursors, but under photocatalysis. While triplet nitrenes had been accessed via energy transfer catalysis using organic azides, hydroxylamine precursors had not previously been studied as nitrene precursors in a photocatalytic context. The combined use of photocatalysis with careful engineering of the precursor enabled C-H amination forming imidazolones and related nitrogen heterocycles from readily accessible hydroxylamine precursors. Preliminary mechanistic results were consistent with the formation of free carbamoyl triplet nitrenes as reactive intermediates. Overall, the collection of this work demonstrates the broad synthetic utility conferred by developing new reactions with rare amphoteric N- and O-isocyanate reagents.