Synthesis of acyl cyclohexenes by an interrupted hydrogen borrowing reaction
Keywords: lactol
diol
organic chemistry
Ph* ketone
aluminium
hydrogen borrowing
iridium
deuterium labelling
cyclohexene
transition metal catalysis
hydride shift

Chapter 1: Introduction
The introduction discusses the prevalence of cyclohexenes, as well as an overview of existing methods for their synthesis. This chapter also reviews the history and contemporary developments of hydrogen borrowing catalysis for carbon-carbon bond formation, with particular emphasis on the reactivity of Ph* methyl ketone.
Chapter 2: Synthesis of Acyl Cyclohexenes by an Interrupted Hydrogen Borrowing Reaction
An iridium-catalysed reaction between readily available 1,5-pentane diols and Ph* methyl ketone to prepare valuable cyclohexenes is described. An extensive optimisation found that [Ir(COD)Cl]2 bearing CataCXium® A ligand was essential for the success of this transformation, which preferentially promoted an acceptorless dehydrogenation over 1,4-reduction of the acyl cyclohexene products. The substrate scope of the reaction was then explored, with a range of primary and secondary diols used to prepare multisubstituted cyclohexenes in excellent yields, and chemo- and regioselectivity. The preparation of different ring sizes and acyl groups in place of Ph* methyl ketone was also explored. Mildly acidic conditions of 2 M HCl in HFIP were developed for the retro-Friedel Crafts acylation of the acyl cyclohexene products to afford the corresponding carboxylic acid. Further derivatisation of the enone motif was also explored, such as bromination, conjugate addition and cyclopropanation, to name but a few examples.
Chapter 3: Mechanistic Investigations of the [5+1] Annulation
To shed light on the reaction mechanism for the [5+1] annulation to prepare acyl cyclohexenes, a detailed mechanistic study was undertaken, which began with performing a time course experiment and measuring the evolution of hydrogen gas. Resubjecting reaction intermediates revealed that the reaction proceeded through an unusual transition metal-free hydride shift aldol cascade. This was confirmed to be an intramolecular process by performing a double label crossover experiment. This cascade process was then confirmed to be the prevailing pathway of three related hydrogen borrowing reactions to prepare cyclohexanes, contrary to their proposed mechanisms.
Chapter 4: Cyclohexene Synthesis by Aluminium Mediated [1,5]-Hydride Shift Aldol Cascade
Based on the mechanistic insight from chapter 3, a transition metal-free methodology to prepare cyclohexenes by a tandem Horner-Wadsworth-Emmons, [1,5]-hydride shift cascade was developed. Through the screening of a range of basic and Lewis acidic conditions, the reagents alumina and aluminium tert-butoxide were found to uniquely promote the transformation in excellent yields. A diverse range of phosphonates were prepared, which enabled the synthesis of alkyl and aryl substituted acyl cyclohexenes. The lactol partner of the reaction was also explored, which allowed access to a diverse range of cyclohexene substitution patterns in complete regio- and stereochemical fidelity.
Chapter 5: Experimental
This chapter contains the experimental procedures and spectroscopic data for all of the compounds described within this thesis.
Chapter 6: Appendix
The HPLC calibrations, time course experiment data and hydrogen evolution data can be found in this appendix
Chapter 7: References
The references cited within the thesis can be found in this chapter.