Discovery of new reaction modes in organic synthesis triggered by HFIP

Identifier:  TDX:4343

Handle: https://hdl.handle.net/20.500.11797/TDX4343

Authors:  Zhang, Jiayu

Abstract:
This dissertation has expanded the repertoire of roles that 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) can play in organic synthesis, untapping unprecedented reaction modes in metal-free transformations and TM catalysis. In Chapter II, we have engineered a general and mild PIFA-mediated intramolecular C(sp3)–H functionalization protocol facilitated by HFIP that enables the preparation of valuable pyrrolidines, piperidines and O-heterocycles. Our strategy complements the traditional Hofmann-Löffler-Freytag reactions by circumventing existing synthetic shortcomings related to the preparation saturated heterocycles via hydrogen atom transfer (HAT). The success of this reaction relies on a SET event between PIFA and the substrate that leads to a key aromatic radical cation intermediate. Experimental and computational studies support two different pathways for the generation of the corresponding radical cation depending on the electron density of the starting material. In Chapter III, we have disclosed a “non-excited” singlet-triplet intersystem crossing (ISC) via secondary-coordination sphere interactions with HFIP. We uncovered the light-free access to a long-lived reactive triplet Cp*Co(CO) species, after CO dissociation, by simply dissolving Cp*Co(CO)2 in this perfluorinated alcohol. This behavior has no precedents in the literature and provides proof-of-principle for new concepts and prospects in the intriguing behavior of ISC in organometallics. Indeed, we have capitalized on this unusual phenomenon to develop a versatile site-selective cobalt-catalyzed Mizoroki-Heck protocol, which features (i) a wide range of starting materials, including readily available aryl chlorides; (ii) a great functional group tolerance and (iii) enables the employment of targeted drug derivatives. For the first time, we provide experimental and computational evidence that the solvent-induced SCO is responsible for the C–X bond-cleavage. This opens the door to explore the effect of HFIP in additional cross-coupling reactions and the application of ISC events in first-row transition metal catalysis.