'High' temperature lithiation-trapping of nitrogen and oxygen heterocycles

• Main Author: Kwong, Wai Sze Alice
• Other Authors: O'Brien, Peter ; Farmer, Thomas
• Published: University of York 2016
• Subjects: 547
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.703382

This thesis describes some novel aspects of the lithiation-trapping of nitrogen and oxygen heterocycles, including a systematic study of new methodologies at temperature above ‒78 °C and the use of the sustainable solvent, 2-MeTHF, as an alternative to Et2O and THF. Chapter 2 describes a detailed exploration of the s-BuLi-mediated lithiation-trapping of N-Boc heterocycles (pyrrolidine, piperidine, piperazine and azepane) using different conditions (diamine, solvent, temperature and time). For N-Boc pyrrolidine, two new high temperature lithiation conditions were optimised: (i) 0 °C for 5 sec is best for flow system; (ii) ‒20 ° C for 2 min is best for batch conditions. The stability of the lithiated N-Boc pyrrolidine at 0 °C was also investigated. In Chapter 3, the development of novel methodology for the lithiation-trapping of oxygen heterocycles (THF and THP) is presented. Different conditions were optimised for THF and THP lithiation to give trapped products in 20-32% yield. The newly developed methodology was extended to the lithiation-trapping of N-substituted morpholines. A full study of the reaction conditions and scope of the methodology was carried out for three different N-alkyl groups. The best substrate was the N-methyl morpholine and the optimised conditions were s-BuLi/TMEDA in hexane at 0 °C for 1 h, giving yields of trapped products in 75-90%. A procedure that is catalytic in TMEDA was also discovered.