A variety of electrophilic alkenes will accept enol(ate) nucleophiles
المؤلف:
Jonathan Clayden , Nick Greeves , Stuart Warren
المصدر:
ORGANIC CHEMISTRY
الجزء والصفحة:
ص610-611
2025-06-29
597
The simplest and best Michael acceptors are those α,β-unsaturated carbonyl compounds with exposed unsaturated β carbon atoms, such as exo-methylene ketones, lactones, and vinyl ketones. However, their extreme reactivity can make than hard to handle (they polymerize readily), you will meet a method that makes them in situ to circumvent these problems.
One trick to persuade a stubborn enolate to do conjugate rather than direct substitution is to add an extra anion-stabilizing substituent in the α position. The margin shows a selection of reagents that do this. In each case the extra group (CO2Et, SPh, SOPh, SO2Ph, SiMe3, and Br) can be removed after the conjugate addition is complete. Unsaturated esters are good Michael acceptors because they are not very electrophilic. Unsaturated amides are even less electrophilic and (provided they are tertiary and have no acidic NH protons) will even give conjugate addition products with lithium enolates.
The nitrile group is not as reactive towards direct attack by nucleophiles as its carbonyl cousins but is equally able to stabilize an adjacent negative charge. Alkenes conjugated with nitriles are thus activated towards nucleophilic attack without the complications of competing direct addition to the activating group.
With base, methyl benzyl ketone forms its more stable enolate, which undergoes smooth and rapid conjugate addition to acrylonitrile. Acrylonitrile is one of the best Michael acceptors for enolates.
The cyanide group can also act as an anion-stabilizing group in the nucleophile. In combi nation with an ester group, the enolizable proton is acidified to such an extent that potassium hydroxide can be used as base.
The simplest amino acid, glycine, would be an ideal starting material for the synthesis of more complicated amino acids but it does not easily form enols or enolates. By conversion to the methyl ester of its benzaldehyde imine, two electron-withdrawing groups are introduced to help stabilization of the enolate and conjugate addition of acrylonitrile is now possible. The base used was solid potassium carbonate. Simple hydrolysis of the alkylated product leads to the extended amino acid.
You saw on p. 606 how two ester groups in fumarate diesters encourage conjugate addition, but what if there are two different groups at the ends of the Michael acceptor? Then you must make a judgement as to which is more electron-withdrawing. One case is clear-cut. The nitro group is worth two carbonyl groups so that conjugate addition occurs β to the nitro group in this case.
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