Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Patrick J. Walsh

Abstract

Transition metal-catalyzed reactions are rapidly being developed for the synthesis complex natural and non-natural products. Among these, palladium-catalyzed reactions are both attractive and reliable. However, a formidable challenge at the forefront of organic chemistry is the control of selectivity to enable the selective formation of diverse structural motifs from readily available substrate classes. Herein, progress toward broadening the scope of palladium-catalyzed C–C bond-forming reactions is demonstrated, with a particular focus on controlling reactivity, regioselectivity, and chemoselectivity.

Chapters 1 and 2 describe detailed studies of chemoselectivity with palladium-based phosphine catalysts and readily available 2-B(pin)-substituted allylic acetates, benzoates, and carbonates. Depending on the choice of reagents, catalysts and reaction conditions, 2-B(pin)-substituted allylic acetates and derivatives can be steered into one of three reaction manifolds: allylic substitution, Suzuki-Miyaura cross-coupling, or elimination to form allenes, all with excellent chemoselectivity. Detailed study of this system indicates the relative order of reactivity toward Pd(0) is Ar–I > Ar–Br > allylic carbonate > allylic benzoate > allylic acetate, with the reactivity of allylic carbonates approaching that of aryl bromides. Additionally, we also probe the regioselectivity with 1,2,3-trisubstituted allylic substrates in Tsuji-Trost allylic substitution reactions. Bulkier C–2 substituents in 1,2,3-trisubstituted η3-allylpalladium intermediates provide stronger preference for nucleophilic attack at anti-oriented benzylic termini.

Chapters 3 and 4 describe a direct C–H functionalization approach to produce skeletally diverse aryl(pyridyl)methyl core structures. The novel arylation step is catalyzed by a Pd(OAc)2/NIXANTPHOS-based system via a deprotonative cross-coupling process. Under conditions where the azaarylmethyl amines or ethers’ benzylic C–H is reversibly deprotonated, a Pd(OAc)2/NIXANTPHOS-based catalyst couples the resulting carbanions with various aryl halides to provide new C–C bonds. The efficient and operationally simple protocols enable generation of either arylation products or tandem arylation/[1,2]-Wittig rearrangement products with remarkable selectivity and good to excellent yields. Choice of base, solvent, and reaction temperature play a pivotal role in tuning the reactivity of intermediates and controlling the relative rates of competing processes. These practical methods will be applicable for the synthesis of a broad array of pyridyl-containing amines, ethers and alcohols.

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