C1 Building Blocks: New Approaches for Thiomethylations and Esterification

Abstract: The thioether motif is found in numerous pharmaceuticals. The simplest form of this motif, the methyl-thioether is similarly found in many biologically active compounds and has exhibited many advantageous properties. The installation of the thiomethyl moiety can be troublesome due to the toxicity and malodor of small sulfur reagents. To avoid these issues, many alternative sources and methods have been developed, although these often require metal catalysis, or operate via electrophilic species as the sulfur source.The first section of this thesis covers the discovery and development of BF3SMe2 as a Lewis acid and non-malodorous source for nucleophilic installation of the thiomethyl moiety. In paper I, this reagent is leveraged for the Lewis acid activation and the nucleophilic thiomethylation of electron-deficient haloarenes. The reagent was also found to be a selective reductant for nitropyridines and could in some instances perform concomitant thiomethylation via C-H substitution. The nucleophilic installation of the thiomethyl moiety was continued in paper II, where BF3SMe2 was developed for the conversion of aromatic aldehydes into methyl-dithioacetals. The dithioacetal is an important protecting group, and a useful intermediate, and since there are only a handful of reported strategies for the synthesis of the methyl-analog, this method represents an important addition to existing methods. In addition, BF3SMe2 was able to promote Friedel-Crafts reactions between aldehydes and electron-rich arenes, resulting in unsymmetrical, thiomethylated diarylmethanes. In the final part of this section, BF3SMe2 was used for the activation of trifluoromethylarenes for defluorination and sulfur incorporation, resulting in the methyl-dithioester moiety. This functional group is a useful intermediate, but current methodology for its synthesis suffers from several drawbacks, including multistep reactions. The method developed in paper III is a convenient one-step approach to reach the methyl-dithioester, and was also expanded to one-pot synthesis of thioamides and different heterocyclic systems starting from the trifluoromethyl moiety.In the second section of this thesis, an in situ method for diazomethane release and consumption was investigated and applied. Diazomethane is a useful reagent with a unique reactivity profile, including mild and selective O-methylation of carboxylic acids. The reactivity of this gaseous reagent however comes with hazards, such as high toxicity. Therefore, earlier efforts have been made for in situ generation of diazomethane, although with limitations such as specific solvent requirements or alkaline conditions. The method developed in paper IV however is an improvement upon these with base-free conditions, and wide solvent compatibility, and was successfully applied to the methylation of carboxylic acids, solvent-mediated deuterium labeling without any a priori deuterium incorporation, and synthesis of diazoketones.