A regioselective protocol for the synthesis of substituted allylic chlorides, bromides, and fluorides has been established. Remarkably, the method can be applied to the enantioselective synthesis of challenging chiral allylic chlorides. When the allylic halides are treated with the base triazabicyclodecene as the catalyst, a [1,3]-proton shift takes place, giving the corresponding vinyl halides in excellent yields with excellent Z:E ratios. Furthermore, the [1,3]-proton shift takes place with an outstanding level of chirality transfer from chiral allylic alcohols (<= 98%) to give chiral trifluoromethylated vinyl chlorides.

We have used experimental studies and DFT calculations to investigate the IrIII-catalyzed isomerization of allylic alcohols into carbonyl compounds, and the regiospecific isomerization–chlorination of allylic alcohols into α-chlorinated carbonyl compounds. The mechanism involves a hydride elimination followed by a migratory insertion step that may take place at Cβ but also at Cα with a small energy-barrier difference of 1.8 kcal mol−1. After a protonation step, calculations show that the final tautomerization can take place both at the Ir center and outside the catalytic cycle. For the isomerization–chlorination reaction, calculations show that the chlorination step takes place outside the cycle with an energy barrier much lower than that for the tautomerization to yield the saturated ketone. All the energies in the proposed mechanism are plausible, and the cycle accounts for the experimental observations.

The selective synthesis of a-functionalized ketones with two similar enolizable positions can be accomplished using allylic alcohols and iridium(III) catalysts. A formal 1,3-hydrogen shift on allylic alcohols generates catalytic iridium-enolates in a stereospecific manner, which are able to react with electrophiles to yield alpha-functionalized ketones as single constitutional isomers. However, the employment of nucleophiles to react with the nucleophilic catalytic enolates in this chemistry is still unknown. Herein, we report an umpolung strategy for the selective synthesis of alpha-alkoxy carbonyl compounds by the reaction of iridium enolates and alcohols promoted by an iodine(III) reagent. Moreover, the protocol also works in an intra-molecular fashion to synthesize 3(2H)-furanones from gamma-keto allylic alcohols. Experimental and computational investigations have been carried out, and mechanisms are proposed for both the inter- and intramolecular reactions, explaining the key role of the iodine(III) reagent in this umpolung approach.

The isomerization of dienyl alcohols and polyenyl alkyl ethers catalyzed by TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) under metal-free conditions is presented. Two reaction pathways have been observed. For dienyl alcohols, the reaction proceeds by a [1,3]-proton shift to give γ,δ-unsaturated ketones exclusively. On the other hand, the reaction with polyenyl alkyl ethers gives the corresponding conjugated vinyl ethers in good yields (up to 85%), with regioselectivities up to >20:1. Experimental and computational investigations suggest that the mechanism proceeds through consecutive “chain-walking” proton shifts (“base walk”) mediated by TBD.

The present thesis describes the development of new catalytic protocols to transform allylic substrates into a wide variety of versatile carbonyl and vinyl organic compounds. All procedures that are described in this work have in common the existence of one or more hydrogen shifts as key steps in the mechanism of the reactions. The thesis is divided into two mayor sections depending on the strategy employed, metal catalysis or organocatalysis. 

The introductory chapter (Chapter 1) starts with an overview of the different types of catalysis and the importance of allylic substrates in organic chemistry. The chapter continues with an extensive description of the isomerization of allylic alcohols and finishes with a short introduction about hypervalent iodine chemistry. The goals of the thesis are also depicted at the end of this chapter.

Chapters 2, 3 and 4 embody the use of iridium catalysis as an effective tool to synthesize α-functionalized carbonyl compounds selectively as single constitutional isomers from allylic alcohols. The first two chapters of this section describe the employment of several electrophiles to trap enolate derivatives formed from the corresponding allylic alcohols. Chapter 2 shows the development of two new protocols for the preparation of challenging α-iodinated carbonyl compounds. In chapter 3, the synthesis of α-aminooxy and α-hydroxyketones is investigated by employing an N-oxoammonium salt as electrophilic agent. Chapter 4 describes the development of an umpolung strategy that allows the synthesis of α-functionalized carbonyls through the reaction of two formal nucleophiles: enolate derivatives and alcohols. Mechanistic investigations performed in this section point to the presence of an iridium-catalyzed hydride shift operating in the reaction pathways.

The last three chapters (5, 6 and 7) describe the development of metal-free methods for the conversion of allylic substrates into valuable products by means of base catalysis. Chapter 5 and 6 depict the stereospecific isomerization of a large scope of allylic alcohols, ethers and halides. A simple guanidine-type base, TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene), is an effective catalyst to isomerize allylic substrates with excellent levels of transfer of chirality. The mechanism of this transformation is studied in detail experimentally and computationally and it is suggested to involve a [1,3]-proton shift through the formation of a tight ion-pair. Chapter 7 shows that base-catalysis allows the isomerization of conjugated polyenyl alcohols and ethers which has been proved to be challenging with metal–catalysis. Experimental and computational investigations in this last chapter suggests that the mechanism may proceed through a series of iterative [1,3]-proton shifts or “base-walk”. 

The first method to access unsymmetrical aliphatic acyloins is presented. The method relies on a fast 1,3-hydride shift mediated by an Ir-III complex in allylic alcohols followed by oxidation with TEMPO+. The direct conversion of allylic alcohols into acyloins is achieved in a one-pot procedure. Further functionalization of the C alpha' of the alpha-amino-oxylated ketone products gives access to highly functionalized unsymmetrical aliphatic ketones, which further highlights the utility of this transformation.

An efficient method for the synthesis of alpha-iodoketones from allylic alcohols and elemental iodine is reported. We show in this paper that the isomerization of allylic alcohols catalyzed by iridium(III) complexes can be combined with an aerobic oxidative iodination protocol, resulting in a straightforward method for the synthesis of a wide range of alpha-iodoketones as single constitutional isomers and in high yields under mild reaction conditions.

2,2-Diiodo-5,5-dimethylcyclohexane-1,3-dione is reported as a new electrophilic iodinating agent that selectively iodinates electron-rich aromatics. In contrast to other common electrophilic iodinating reagents, its mild nature allows it to be used for the selective synthesis of alpha-iodinated carbonyl compounds from allylic alcohols through a 1,3-hydrogen shift/iodination process catalyzed by iridium(III) complexes.

A mild base-catalyzed strategy for the isomerization of allylic alcohols and allylic ethers has been developed. Experimental and computational investigations indicate that transition metal catalysts are not required when basic additives are present. As in the case of using transition metals under basic conditions, the isomerization catalyzed solely by base also follows a stereospecific pathway. The reaction is initiated by a rate-limiting deprotonation. Formation of an intimate ion pair between an allylic anion and the conjugate acid of the base results in efficient transfer of chirality. Through this mechanism, stereochemical information contained in the allylic alcohols is transferred to the ketone products. The stereospecific isomerization is also applicable for the first time to allylic ethers, yielding synthetically valuable enantioenriched (up to 97% ee) enol ethers.