New aspects in aluminium promoted organic synthesis

Glynn, Daniel Joseph (2011) New aspects in aluminium promoted organic synthesis. PhD thesis, University of Nottingham.

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Abstract

In the first chapter of this thesis the aluminium promoted zinc Schlenk equilibrium of FG-ArZnX/AlMe3 is shown to provide good access for the synthesis of chiral secondary alcohols. This practical asymmetric 1,2-addition to aliphatic and aromatic aldehydes uses only commercially available reagents and ligands. Enantioselectivity is provided by the use of (1R,2S)-dibutylnorephedrine (1,2-amino alcohol ligand) giving selectivity, in most cases, between 80-96% ee. Yields are moderate to good, typically alcohols are prepared in 50-97% yield.

Uniquely the FG-ArZnBr species can be prepared in situ directly from Ar-Br or Ar-I, via the cobalt catalysed zinc insertion. Optimisation of the zinc insertion allowed for rate acceleration and a subsequent slight reduction in enantiocontrol. Furthermore, enantioselectivity of the reaction can be enhanced via the simple addition of LiBr to the FG-ArZnBr species. A LiBr promoter can dramatically enhance the enantioselectivity of such ‘home made’ reagents (from 30 to ca. 90% ee in one case), however studies to explain this effect have not been investigated.

Further investigation into zinc source optimisation via electron microscopy and energy dispersive X-ray (EDX) spectroscopy, has highlighted the necessity to use small particulate zinc in the range of 2-10 muM and having little surface oxide.

Stereo correlations of the secondary alcohol products highlight a reverse in stereochemistry compared to the ‘classic Noyori’ transition state for the addition of ZnEt2 to PhCHO using chiral 1,2-aminoalcohol ligands. Analysis and investigation of our system showed there was no non-linear effect associated with the process, suggesting the catalyst to be monomeric in solution.

A second thesis chapter describes facile DABAL-Me3 mediated preparation of aromatic and aliphatic amides. This procedure allows the coupling of a wide range of functionalised primary and secondary amines and esters, secondary amines and allows formation of versatile Weinreb amides. Microwave irradiation provides an improved rate of reaction allowing excellent yields (51-99%) in short reaction times (8-16 min). Wide applicability is shown in the variation and tolerance of a wide range of functional groups in both coupling partners. Functional groups tolerated include: acetal, alcohol, alkene, alkyne, Ar-X, cyano and ethers. Furthermore the stereochemical integrity of the coupling partners is retained in two representative examples with an epimerisable carbon centre. This procedure enables the coupling of less nucleophillic amines such as anilines. However, the reaction yields are diminished when highly electron poor anilines are used, or when highly sterically hindered esters or amines are used.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Woodward, S.
Thomas, N.R .
Subjects: Q Science > QD Chemistry > QD241 Organic chemistry
Q Science > QD Chemistry > QD450 Physical and theoretical chemistry
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 12048
Depositing User: EP, Services
Date Deposited: 22 Dec 2011 15:09
Last Modified: 06 Apr 2016 15:33
URI: http://eprints.nottingham.ac.uk/id/eprint/12048

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