Development of axially chiral 2-aryl-4-dialkylaminopyridine-N-oxide based catalysts for the sulfonylative kinetic resolution of amines
Author(s)
Bob-Egbe, Opetoritse
Type
Thesis
Abstract
Lewis base catalysis has been studied extensively in recent years as a powerful tool for introducing
asymmetry into a variety of reactions, avoiding the use of expensive and potentially toxic metal
catalysts. There is however still ample scope for the development of procedures for the non-enzymatic
catalytic kinetic resolution (KR) of amines. Unlike alcohols, the intrinsic high reactivity of amines
towards acyl and sulfonyl donors makes their KR highly challenging. As a result, there are relatively few
publications on non-enzymatic catalytic KR of amines via acylation1-8 and none via sulfonylation.
This thesis describes the development of a new class of chiral 2-aryl-(4-dialkylamino)pyridine-N-oxides
(2-Ar-(4-DAAP)-N-oxides) (A), which are chiral by virtue of atropisomerism around the biaryl axis, and
their application as catalysts for the KR of amines via sulfonylation.
[molecular structure diagram]
The use of C-H activation was explored for the development of a concise and modular synthetic
procedure to the target catalyst structure. As a result, the key step in our final synthesis is a
microwave (MW) assisted C-H halogenation procedure.(9) This reaction provides facile access to a di-ortho
functionalised late stage intermediate from which a subsequent Pd catalysed cross coupling
with a range of activated aryl partners provides access to an array of chiral catalyst structures.
[molecular structure diagram]
These catalysts were synthesised for assessment in the kinetic resolution of the axially chiral amine
NOBIN, a synthetically useful chiral ligand which suffers from a difficult enantioselective synthesis.
[molecular structure diagram]
This thesis will provide a description of the synthetic route developed to achiral and chiral
catalysts, the dependence of sulfonylation rates on the electronics of the catalyst and the key role
of C-H activation in achieving a successful efficient synthesis of the target chiral catalyst
structures.
*For molecular structure diagrams, please see the PDF of the thesis.
asymmetry into a variety of reactions, avoiding the use of expensive and potentially toxic metal
catalysts. There is however still ample scope for the development of procedures for the non-enzymatic
catalytic kinetic resolution (KR) of amines. Unlike alcohols, the intrinsic high reactivity of amines
towards acyl and sulfonyl donors makes their KR highly challenging. As a result, there are relatively few
publications on non-enzymatic catalytic KR of amines via acylation1-8 and none via sulfonylation.
This thesis describes the development of a new class of chiral 2-aryl-(4-dialkylamino)pyridine-N-oxides
(2-Ar-(4-DAAP)-N-oxides) (A), which are chiral by virtue of atropisomerism around the biaryl axis, and
their application as catalysts for the KR of amines via sulfonylation.
[molecular structure diagram]
The use of C-H activation was explored for the development of a concise and modular synthetic
procedure to the target catalyst structure. As a result, the key step in our final synthesis is a
microwave (MW) assisted C-H halogenation procedure.(9) This reaction provides facile access to a di-ortho
functionalised late stage intermediate from which a subsequent Pd catalysed cross coupling
with a range of activated aryl partners provides access to an array of chiral catalyst structures.
[molecular structure diagram]
These catalysts were synthesised for assessment in the kinetic resolution of the axially chiral amine
NOBIN, a synthetically useful chiral ligand which suffers from a difficult enantioselective synthesis.
[molecular structure diagram]
This thesis will provide a description of the synthetic route developed to achiral and chiral
catalysts, the dependence of sulfonylation rates on the electronics of the catalyst and the key role
of C-H activation in achieving a successful efficient synthesis of the target chiral catalyst
structures.
*For molecular structure diagrams, please see the PDF of the thesis.
Date Issued
2012
Date Awarded
2012-06
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Spivey, Allan
Sponsor
Engineering and Physical Sciences Research Council ; Imperial College London
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)