Exploration of the catalytic use of alkali metal bases
This PhD thesis project was concerned with the use of alkali metal amide Brønsted bases and alkali metal alkoxide Lewis bases in (asymmetric) catalysis. The first chapter deals with formal allylic C(sp3)–H bond activation of aromatic and functionalized alkenes for subsequent C–C and C–H bond formations. The second chapter is focused on C(sp3)–Si bond activation of fluorinated pro-nucleophiles in view of C–C bond formations. In the first chapter, a screening of various metal amides, hydrides, and alkyl reagents resulted in the observation that alkali metal amides were effective Brønsted bases to trigger allylic C(sp3)–H bond activation of aromatic alkenes at room temperature. Sodium hexamethyldisilazide was found to be most efficient compared with other s-, p-, d-, and fblock metal amides. This unique transition metal-free methodology was exploited to activate a variety of alkene pro-nucleophiles, which were shown to undergo γ-selective C–C bond formation with various aromatic aldimines as well as one aliphatic substrate. The corresponding homoallylic amine derivatives were obtained in high yields with excellent E:Z ratios. The reaction mechanism was investigated and attempts to detect and/or isolate key intermediates were undertaken. Importantly, it was shown that metal-free superbases of the Schwesinger or Verkade type were not apt to catalyse this challenging C–C bond formation. The asymmetric version of this rare sodium amide catalysis has been achieved by using a commercially available enantiopure bisoxazoline ligand (46% ee). Subsequently, the catalytic use of sodium and potassium amides was applied to the isomerization of terminal aromatic alkenes to generate the thermodynamically more stable internal olefins in excellent yields with high E:Z ratios. Furthermore, functionalized metalloid (B, Si) and metal-free alkenes were found to undergo alkali metal amide-triggered (chemoselective) allylic C(sp3)–H bond activation in view of isomerization and/or C–C bond formation with aldimines. In the second chapter, the catalytic C–Si bond activation of an important difluoromethylation reagent, HCF2SiMe3, was investigated. Here, alkali metal alkoxides were shown to be more effective Lewis base triggers than other metal alkoxides or metal-free superbases. This novel method was successfully used to transfer the nucleophilic difluoromethyl fragment to electrophiles such as a variety of amides and lactams, whereas unsaturated amides failed to undergo the intended conjugate C–C bond formation. In this context, it is noted that the α-hydrogen of certain amides was tolerated. This unprecedented catalytic difluoromethylation of unactivated carbonyl electrophiles was achieved using potassium tert-butoxide at room temperature, and the corresponding fluorinated ‘hemiaminal’ products were obtained in high yields.