The use of sulfoxide ligands for transition metal catalyzed transformations has recently been brought to the forefront in organic chemistry. The synthesis of a series of tri- and disulfoxides will be presented, and their applications investigated. Their use in rhodium catalyzed 1,4-additions of phenylboronic acid to 2-cyclohexen-1-one result in enantioselectivities up to 80%. The incorporation of β-amino acid residues into polypeptides has resulted in new foldamers whose structures and enhanced stability provide interesting opportunities for new biological applications. A novel strategy for an iterative peptide synthesis involving β-amino acids will be proposed. Lastly, a hydroamidation-type strategy for the construction of β3-amino acids, or more specifically of β-(N-acylamino)acrylates, will be presented as preliminary work towards the goal of dipeptide synthesis.

Despite the great abundance of C–H bonds in readily available starting materials, their use in synthesis of functionalized molecules has been hampered by the high bond strengths, rendering them inert to common organic reagents. However, recent progress in the field has addressed this issue, enabling selective C–H bond functionalizations to be performed using catalytic transition metal mediated processes. Herein, the use of sulfonyl chlorides as versatile reagents for C–H bond functionalizations is reported. Using chelation assistance, the regioselective conversion of C–H bonds to either C–S, C–Cl or C–C bonds was achieved. The methodology development, substrate scope determination and mechanistic investigations will be discussed.

The use of sulfoxide ligands for transition metal catalyzed transformations has recently been brought to the forefront in organic chemistry. The synthesis of a series of tri- and disulfoxides will be presented, and their applications investigated. Their use in rhodium catalyzed 1,4-additions of phenylboronic acid to 2-cyclohexen-1-one result in enantioselectivities up to 80%. The incorporation of β-amino acid residues into polypeptides has resulted in new foldamers whose structures and enhanced stability provide interesting opportunities for new biological applications. A novel strategy for an iterative peptide synthesis involving β-amino acids will be proposed. Lastly, a hydroamidation-type strategy for the construction of β3-amino acids, or more specifically of β-(N-acylamino)acrylates, will be presented as preliminary work towards the goal of dipeptide synthesis.

The research investigations presented herein are concerned with the syntheses and applications of arylboronic acids and their derivatives; with a particular focus on their accessibility or utility in certain of the most significant modern transition metal-catalysed reactions to involve organoborons. Chapter 1 provides an introduction to the field of organoboron chemistry, from its roots employing borane and related highly reactive derivatives for uncatalysed hydroboration of olefins and acetylenes, to the modern classes of organoboron reagents of the greatest significance to the related contemporary transition metal-catalysed methodologies. Furthermore particular emphasis is placed on the discussion of arylboronic acids, their synthesis, and application to transition metal catalysis as a result of their propensity to undergo useful transmetallation events. Chapter 2 details the use of a commercially available sulfonated monophosphine ligand in the rhodium-catalysed 1,2-addition reaction employing aryl aldehydes and arylboronic acids in aqueous media. The high and continued activity of the catalytic complex is demonstrated by it being successfully recycled five consecutive times in the arylation reaction of an aryl aldehyde; as well as being active for the arylations of more sterically demanding aryl methyl ketone substrates. Chapter 3 details the design and synthesis of a novel bench-stable azidomethylene substituted arylboronate ester. The reactivity of this compound and a related analogue in both the coppercatalysed azide alkyne cycloaddition reaction and the Suzuki coupling reaction are detailed, culminating in the proof-of-concept use of such versatile synthetic building blocks in the synthesis of a drug-substance derivative. Chapter 4 details alternative synthetic approaches to that used in Chapter 3 in order to access bifunctional azidomethylene substituted arylboronate esters. In particular the application of Miyaura borylation of arylhalides bearing benzylic azides is addressed as a means to rapidly access substrates which are otherwise shown to be incompatible with classical s-block synthetic intermediates.

After a general introduction about the properties and preparation of organofluorine compounds (Chapter 1), this thesis is divided into two parts focussing on the development of new methods for C-F bond formation (Part A) as well as studies towards the development of novel fluorinating reagents (Part B). Part A: New Methods for Carbon-Fluorine Bond Formation Part A consists of two chapters outlining the development of a Pd-catalysed hydrofluorination of alkenylarenes (Chapter 2) as well as a halofluorination of alkynes (Chapter 3). Chapter 2 This chapter describes the development of a novel, regioselective, syn-specific hydrofluorination of alkenylarenes under Pd-catalysis leading to the formation of benzylic fluorides. An extensive substrate scope is presented together with a model of the catalytic cycle, based on observations during the development of this reaction, deuterium labelling experiments as well as mechanistic control experiments starting from isolated palladacycles. Chapter 3 In this chapter the development of a novel iodo- as well as bromofluorination of internal and terminal alkynes, leading to the formation of (E)-halofluoroalkenes, is presented. For the former substrate class, the effects of steric as well as electronic bias on regioselectivity are discussed. For the latter substrate class, this methodology could be extended to the corresponding double iodofluorination, and for both transformations it was found to exclusively lead to the fluorination of the internal carbon. An extensive substrate scope as well as different iodofluorination-cross-coupling sequences including Suzuki, Sonogashira and Ullmann couplings, are illustrated. A representative reaction was successfully carried out on gram-scale and an iodofluorination-Suzuki-coupling sequence was used to prepare a fluorinated tamoxifen derivative. Part B: Hydrogen-Bonded Fluoride Complexes as Novel Reagents for Carbon-Fluorine Bond Formation Part B consists of two chapters describing structural as well as reactivity studies of fluoride-alcohol (Chapter 4) and fluoride-urea complexes (Chapter 5). Chapter 4 In this chapter the synthesis of 19 novel hydrogen-bonded tetraalkylammonium fluoride-alcohol complexes is described. For a subset of 15, the solid-state structures as determined by single-crystal X-ray diffraction experiments are presented. Trends of reactivity and selectivity were determined using these complexes as sources of fluoride anion in a model SN2 reaction. Preliminary results from in silico modelling of the fluoride-alcohol system provide a basis for explaining the results. Chapter 5 This chapter summarises the synthesis and solid-state structures of 20 hydrogen-bonded fluoride complexes using the urea and related squaramide and amide motifs. Also, the size of the tetraalkylammonium counter-cation was varied to study the influence on the solid-state structure. The reactivity and selectivity of a series of complexes was studied using the same model SN2 reaction as in Chapter 4 and results were compared accordingly. Different UV-vis and NMR spectroscopic techniques were used to study the behaviour of the fluoride-urea system in solution. Preliminary results demonstrate the use of 1,3-diarylureas as organocatalysts for nucleophilic fluorination.

The invention of catalytic processes that convert feedstock chemicals into pharmacologically-privileged amines is a landmark challenge in organic synthesis. This thesis describes the development of three novel transition-metal catalyzed processes for the synthesis of alkylamines that attempts to meet this challenge. The first Pd-catalyzed methylene β-C−H carbonylation of alkylamines to form substituted β-lactams is reported. Through the synergistic use of a Pd-catalyst and Xanpthos ligand, secondary amines underwent exclusive methylene β-C−H activation in high yields and diastereoselectivities. Subsequently, the development of a remarkably selective methylene β-C−H carbonylation of α-tertiary amines (ATAs), is detailed. This methodology enables the C−H carbonylation of methylene C−H bonds over traditionally more reactive methyl and C(sp2)−H bonds. Importantly, a range of functional groups previously incompatible with C−H technologies were tolerated in good yields. Finally, the development of a novel multicomponent synthesis of tertiary amines is described. The novel photocatalytic single-electron reduction of alkyl iminium ions furnishes -amino radicals that engage alkenes forming a new C-C bond. The reaction exhibits broad functional group tolerance and enables the synthesis of amines not readily accessible by existing methods.

In this thesis new synthetic routes towards perfluorinated compounds are described, as well as their radiolabelling with fluorine-18, with the aim of application in pharmaceutically interesting targets. Part A investigates late-stage fluorination, i.e. retrosynthetic C–F bond disconnections. A silver catalysed electrophilic fluorodecarboxylation of fluorinated carboxylic acids for the formation of difluoromethyl-, trifluoromethyl-, and pentafluoroethylarenes is developed and transferred to a radiochemistry setting using [¹⁸F]Selectfluor bis(triflate). Part B explores late-stage perfluoroalkylation via cross-coupling strategies. The use of visible light-mediated ruthenium catalysis is investigated for the radical trifluoromethylation and pentafluoroethylation of vinyl- and alkynylsilanes and alkynes. Finally, the first generally applicable copper-mediated cross-coupling of Ruppert-Prakash-like aryl(tetrafluoroethyl)trimethylsilanes (ArCF2CF2SiMe3) is presented.

No description available.

Thesis advisor: Marc M. Snapper / Thesis advisor: James J. Morken / This dissertation will present three main projects focusing on the catalytic enantioselective synthesis and stereospecific functionalization of tertiary alkylboronates. In the first project, acyl chlorides were incorporated as a new class of electrophile in conjunctive cross-coupling, from which, a variety of tertiary β-boryl amides were successfully synthesized with high enantioselectivity. The utility of the tertiary alkylboronates products was also demonstrated through several orthogonal functionalizations of the boronic ester group and amide groups. The project culminated in the enantioselective total synthesis of natural product (+)-adalinine that leveraged this newly developed methodology. In the second project, a conjunctive cross-coupling enabled ring closure was developed to synthesize tertiary alkylboronates residing on carbocyclic and heterocyclic scaffolds. A Phosphinooxazoline (Phox) ligand was identified as a non-expensive ligand that catalyzed the conjunctive cyclization reaction with high enantioselectivity. A Series of synthetically challenging enantimerically enriched spirocyclic and aryl bicyclic tertiary alkylboronates were efficiently generated using this method, and several cyclopentyl boronic esters with two continuous stereogenic centers were synthesized with high diastereoselectivity. In the third project, a Rh-catalyzed diboration reaction was successfully employed to diborate monosubstituted cyclobutenes with excellent enantioselectivity. The less sterically hindered secondary boronic ester units in the diboron products can be regioselectively functionalized using the newly developed tert-butyllithium activation-transmetallation strategy. As a result, a variety of stereochemically defined β-substituted cyclobutyl tertiary boronic esters were synthesized with high efficiency. / Thesis (PhD) — Boston College, 2024. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

No description available.