טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentShneider Orel
SubjectOxidative Umpolung Alpha- Alkylation of Ketones
DepartmentDepartment of Chemistry
Supervisor Professor Alex.m Szpilman


Abstract

   A novel alkylation reaction of ketones, has been designed, developed and mechanistically studied. The transformation entails an oxidative umpolung based reaction at the α position of a carbonyl compound, mediated by the hypervalent iodine oxidant, Koser reagent, while employing dialkylzinc reagents as alkyl nucleophiles.

   The reaction was found to be applicable to a wide range of carbonyl compounds, namely, simple ketones and 1,3-dicarbonyl compounds, β-keto esters and β-keto amides. The alkylated materials were formed in good to excellent yields of up to 93%. In all the tested cases, only mono-alkylated products were obtained, contrary to classical α-alkylation via enolate formation, where multiple alkylations may occur.

   The transformation was shown to have a broad functional group tolerance to functionalities such as halogens, methoxy, nitro, alkene and alkyne groups. Moreover, the alkylation reaction gave access to formation of quaternary carbon centers.

   Extensive mechanistic studies were performed, in order to examine possible carbene, radical, or ionic pathways. Based on meticulous product analysis, NMR studies, EPR and GC-HRMS analysis, computational model, and cross-over experiments, an ionic umpolung mechanism was deduced.  

   Following the symmetric alkylation method, an asymmetric single step oxidative umpolung alkylation of Evans’ β-keto imides was developed. The reaction afforded diastereomerically pure products in yields of up to 80% (for the major diastereomer), with diastereoselectivities ranging between 3:1 and 18:1. Based on the mechanistic studies in the symmetric transformation, a plausible mechanism for umpolung asymmetric alkylation was suggested.