Design, synthesis and evaluation of organocatalysts in 1,4-conjugate additions to nitroolefins and alkylidene malonates

A family of cinchona-based and thiourea pyrrolidine-based organocatalysts were synthesised and fully characterised. Their catalytic activity and selectivity in 1,4-conjugate additions involving the Michael acceptor, nitrostyrene, was evaluated. Thiourea catalysts based upon the cinchona alkaloid framework were found to exhibit excellent activity and enantioselectivity (up to 95% yield and 97% ee) at loadings of 10 mol% when 1,3-diketones were employed as the pronucleophile. This result demonstrated that a thiourea cinchona catalyst was much more efficient at catalysing this Michael addition than previously reported. The same thiourea organocatalysts were employed in the first successful Michael addition of the sterically challenging dipivaloylmethane to β-nitrostyrene. Thiourea catalysts based upon the pyrrolidine motif were also employed in the Michael addition of cyclohexanone to nitrostyrene, furnishing up to 97% yield and 48% ee . The organocatalysed conjugate addition reactions involving less activated Michael acceptors, such as ,-unsaturated diesters, ketones and acrylate esters was also investigated. Although these acceptors are challenging substrates and are considerably less reactive than nitrostyrene, we herein report the first organocatalytic Michael addition to an ,-unsaturated diester using a H-bonding bifunctional catalyst. These thiourea catalysts were excellent promoters of the Michael addition of acetylacetone to dimethyl ethylidenemalonate and the yields were high (up to 99%) for all of the catalysts tested. Other Michael donors, such as nitromethane and malononitrile, were also successfully employed as nucleophiles in Michael additions to ,-unsaturated diesters, with yields and enantioselectivities of up to 88% and 48% respectively. Additionally, a family of -substituted aminoacrylates were synthesised. Ethyl-3-(dimethylamino)acrylate proved to be a good Michael acceptor in the 1,4-conjugate addition of phenyllithium (64% yield). Variable temperature NMR spectroscopy was used to analyse the restricted rotation about the C-N bond in these aminoacrylates. The barrier to rotation about the C-N bond was calculated for a series of compounds. The effect of the steric bulk associated with the various N-substitutions had on the barrier to rotation was evaluated using Charton values.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

National University of Ireland Maynooth

Year dc:date.issued

2012

Author dc:creator

• Gavin, Declan P.

• Chemistry

Language dc:language

en