Schwizer, Natascha (2019) Stereo-controlled lithiation-methylation and subsequent aminolysis of a chiral epoxide in continuous flow. Masters Thesis for the University of Applied Sciences NW-Switzerland.

Abstract

In this master thesis the lithiation and methylation of epoxide 1 was initially developed in batch and then transferred into a flow process. The lithiated epoxide 2 is an unstable species, and so is an ideal case for processing by flow chemistry. Various electrophiles and organometallic bases were screened in batch reactions before the transfer into flow was done. The stability of the oxiranyl anion 2 was studied with anisaldehyde as substitute electrophile, allowing us to overcome a probable clustering-effect of the lithiated epoxide 2. The stereo-retention of the methylation was shown. The flow process was then optimized to obtain acceptable conversion at accessible temperatures. The optimization of the deprotonation in flow was done with anisaldehyde as electrophile before the methylation was optimized. A large screening of parameters was conducted: concentration of starting solutions, equivalents of reagents, residence times for deprotonation and methylation as well as the temperature. It was possible to handle the low boiling points of these compounds by careful sampling which minimized losses to headspaces. The aminolytic ring opening of the methylated epoxide 3 was optimized in the batch microwave unit. A temperature and equivalent screening with NH4OH was done. The possibility of a one sequence approach from epoxide 1 to the amino alcohol 4 was shown. The optimized conditions for the ring opening were successfully used on samples from the flow lithiation methylation.

Item Type:	Article
Date Deposited:	02 Apr 2019 00:45
Last Modified:	02 Apr 2019 00:45
URI:	https://oak.novartis.com/id/eprint/38920