Development of oxazolinium compounds via rhodium-catalyzed C-H functionalization and dual gold/photoredox catalysis

Abstract

Oxazolinium compounds have been extensively studied in the past decades due to their versatility in organic transformation reactions. To further explore the potential of oxazoliniums in various fields, it is of ongoing interest to develop novel oxazolinium compounds using an efficient approach under mild reaction conditions. Given its high selectivity, unique reactivity, and broad functional group tolerance, Rh(III)-catalyzed C-H functionalization has been widely adopted for the construction of polycyclic heterocycles. In Chapter one, the chemistry of oxazolinium salts, the development of Rh(III)-catalyzed C-H activation, cysteine-selective bioconjugation, and dual photoredox/gold catalysis were introduced. In Chapter two, a group of novel polycyclic oxazolinium compounds was prepared by Rh(III)-catalyzed C-H functionalization. Coupling of aryl oxazolines with internal alkynes in the presence of a transition metal catalyst [Cp*RhCl2]2 and a catalyst activator AgBF4 afforded the polycyclic oxazolinium compounds with up to 81% isolated yield. Electron donating groups, electron withdrawing groups and chiral bulky substituents are well tolerated in this reaction. Control experiments have shown the selectivity of this reaction towards internal alkynes. When treated with nucleophiles like methanol and cysteine, the oxazolinium ring was opened and the oxazoliniums salts were transformed into isoquinolones. Hydrolysis of oxazoliniums occurs when heated in the presence of water under a basic environment. Site-selective chemical modification of peptides and proteins is vital for biological studies and drug development. In Chapter two, bioconjugation of the cysteine-containing peptides with oxazolinium compounds has been investigated to demonstrate the potential ability of this reagent in site-selective modification of biomolecules. Up to 45% conversion to the modified peptides were obtained upon treatment of the peptide STSSSCNLSK with 5 equivalents of the oxazolinium reagent in aqueous media at 25 °C for 16 h. Chemoselectivity was observed with exclusive modification on the cysteine residue. The recent decade has witnessed the merge of visible light photoredox catalysis and gold catalysis as a promising approach for organic transformations. With the help of visible light in overcoming the high potential barrier of the Au(I)/Au(III) couple, the use of strong oxidants can be avoided. In Chapter three, novel trimethylsilyl-substituted oxazolinium compounds were synthesized via dual photoredox gold-catalyzed cyclization of chiral 2-aryloxazoline ortho-diazoniums and phenylethynylsilanes. With the aid of a photosensitizer Ir(ppy)3, the TMS-substituted oxazolinium compounds were afforded with up to 35% isolated yield. Control experiments have shown that this reaction is selective towards silyl-substituted alkynes. In reaction intermediate studies, novel chiral oxazoline trans-diphosphine gold(III) complexes were isolated.