Universität zu Köln

Guillén Moralejo, María de los Ángeles ORCID: 0000-0001-5769-5147 (2025). Catalytic Oxy-aminomethylation of Alkenes. PhD thesis, Universität zu Köln.

PDF Dissertation_MGuillen_2025.pdf Download (8MB)

Abstract

The direct difunctionalization of C=C bonds is a particularly powerful strategy for the transformation of feedstock olefins into structurally complex building blocks. Olefin 1,2-functionalizations take an important place in chemical synthesis, with dihydroxylation and aminohydroxylation serving as notable examples of their significance. The transformation of olefins into 1,3-dioxygenated moieties through their reaction with aldehydes (Prins reaction) has been extensively documented and several catalytic methodologies thereof are available nowadays. Nonetheless, an analogous, straightforward strategy that enables the oxy-aminomethylation of alkenes remains underexplored, despite its significant potential for the synthesis of marketed blockbuster antidepressant drugs such as duloxetine, fluoxetine, and atomoxetine. The first part of this PhD work discloses the three-component reaction of aryl olefins, formaldehyde, and ammonia surrogates, such as sulfonamides or carbamates, to yield the corresponding 1,3-oxazinanes using the strong Brønsted acid HPF6 as catalyst. The proposed transformation not only contributes to the field of olefin functionalization but also benefits from the wide availability of sulfonamides and carbamates, which are common and widely used pharmacophores. This method affords a variety of 1,3-oxazinanes in moderate to good yields under mild reaction conditions. Mechanistic investigations suggest the intermediacy of an in situ generated 1,3,5-dioxazinane and a subsequent reaction with the olefin. The second part of this PhD work discloses the highly enantioselective, inverse-electron-demand hetero-Diels−Alder reaction of olefins with in situ generated N-Boc-formaldimine catalyzed by strong and confined Brønsted acids. This transformation provides direct access to valuable enantioenriched oxazinanones, common motifs in biologically active molecules and direct precursors of 1,3-amino alcohols. The synthetic utility of the obtained cycloaddition products has been demonstrated by the multigram-scale synthesis of the antidepressant (R)-fluoxetine hydrochloride. Isotope labeling studies and kinetic analysis reveal an unusual mechanism involving an oxazinium intermediate and a catalyst order greater than one.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Guillén Moralejo, María de los Ángeles guillen@kofo.mpg.de https://orcid.org/0000-0001-5769-5147 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-749952
Date:	2025
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Weitere Institute, Arbeits- und Forschungsgruppen > Other Central Institutions
Subjects:	Chemistry and allied sciences
Uncontrolled Keywords:	Keywords Language Organocatalysis English Asymmetric catalysis English Amino alchohol English Olefins English
Date of oral exam:	11 February 2025
Referee:	Name Academic Title List, Benjamin Prof. Dr. Kath-Schorr, Stephanie Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/74995