Palladium-mediated C–H Functionalization of Aliphatic Amines via High Valent Palladium(IV) Intermediates

The search for new and distinct disconnection strategies is one of the foremost challenges in synthetic organic chemistry. To this end, transition metal-catalyzed C–H functionalization represents a current area of research which aims to develop transformations that directly convert C–H bonds to C–C or C–heteroatom bonds, often enabling the synthesis of functionalized products that are not readily accessible using classical synthetic methods. The work disclosed in this thesis concerns the Pd-mediated C–H functionalization of unprotected aliphatic amines, in which the amine nitrogen coordinates to the Pd centre to promote cyclometalation to the key palladacycle intermediate. Specifically, research focused on the design and optimization of novel oxidants that would provide mild and general conditions to oxidize amine-derived palladacycles to high valent PdIV intermediates capable of undergoing a variety of reductive elimination pathways to afford a diverse range of functionalized products. Hypervalent iodine(III) reagents were initially investigated as oxidants in the development of a Pd-catalyzed intramolecular γ C–H amination process to form azetidine products from hindered cyclic amines. Following this, aryl halides containing coordinating groups at the ortho position were discovered as efficient palladacycle oxidants in which the ortho-group pre-coordinates to the palladium centre to facilitate the oxidative addition of the carbon–halogen bond. Employing 2-halobenzoic acid reagents, a Pd-catalyzed γ C–H arylation of acyclic secondary amines was developed involving in situ decarboxylation of the aryl group. Conversely, exchanging the ortho-carboxylic group for an acyl sulfonamide resulted in a switch in the selectivity of reductive elimination to form azetidines. Subsequently, organometallic studies using an aryl iodide reagent containing two ortho-carboxylic acid groups provided access to isolable aminoalkyl Pd(IV) complexes that were stable at room temperature, allowing for the study of the structure and reactivity of these previously elusive high valent intermediates. In addition to C(sp3)–H functionalization of all-alkyl amines, C(sp2)–H functionalization of benzylamines was investigated, with a modified aryl iodide reagent enabling a Pd-catalyzed C–H arylation-lactamization process to form a 7-membered ring lactam product. Finally, a stoichiometric study on benzylamine-derived palladacycles led to the discovery of an unprecedented dehydrogenative intramolecular C–C coupling reaction under oxidative conditions employing 2,6-pyridinedicarboxylic acid and an electrophilic fluorine oxidant. Preliminary investigations provided support for a Pd(IV)-mediated C–H activation step preceding C–C bond formation.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2020

Author dc:creator

• Whitehurst, William

Advisor dc:contributor.advisor

• Gaunt, Matthew

• Palladium
• Catalysis
• Amines
• Synthesis

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/769b412f-ca99-4781-b369-6c1ab51bd5eb/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0002-7214-608X

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/309480