I want to perform Michael addition (with O, N and S) to a a,b-conjugated system. I know that in the presence of copper, I can selectively have 1,4-addition. This works even in the presence of a slightly hindered system (trisubstituted alkene) or there are more favorable reactional conditions?
I would suggest that you might add TMSCl to trapp the enolate formed stopping the reverse reaction.
The key is to avoid the retro Michael, the addition itself is usually pretty easy. The problem is the thermodynamics/reversibility in cases when the adduct has higher energy than reactants separately. I do not see any necessity to have copper there, what carbonyl do you have?
I agree. For example, in an experiment I did, a primary amine was dissolved/suspended in 10 ml water. Methyl acrylate was added and the mixture heated for 3 h at 60°C, while stirring. After cooling to room temperature, the mixture was extracted with dichloromethane to yield, after drying (anhydrous K2CO3) and evaporation, the crude product. Straightforward, in my case.
Hello.
I have a ketone. The conjugated system is inserted in a macrocycle with 11 carbons, with a methyl group at alpha and a ciclopentane attached to the beta carbom (hindered).
Indeed, it was possible to form an adduct in MeOH/KOH 10%, but only in a small amount.
Ricardo Ferreira
Dear Ricardo, please see ACIE 28,3,351-353,1989 for the Cu(1) promoted Michael type addition of carbanions toesters, nitriles amnd aminoacids as one of the principal references to support your reaction conditions. Best regards.
The ease of Michael addition is very dependent upon the nucleophile. Sulfur nucleophiles are the easiest (RSH, Et3N often works well), followed by amines. Alcohols can be difficult but sometimes propargyl alcohol works quite well with a stronger base such as NaH or t-BuOK.
Ricardo: so probably the adduct will be very hindered, thus high in HOF energy and such hard to prepare. Catalyst will have only small chance to change it and what is the best option, is to find the way how to trap the product out of the reaction. Here you have 2 options: 1. react it off with some subsequent reaction e.g. slow reduction of the ketone (slower than the M.A.) 2. identify solvent and concentration for the precipitation of the product from the reaction environment. In case of O and N M.A. is the product more polar and hydrophilic than the Michael acceptor and thus less soluble in non polar/hydrophobic solvents.
I would suggest that you might add TMSCl to trapp the enolate formed stopping the reverse reaction.
Dear Ricardo
If you are interessted in Umpolung of the Michael acceptor reactivity here a few literatur cites:
Rainer Brehme in Synthesis 2010, No.20, pp 3556-3568 and furthermore: Keiji Maruoka in Angew. Chem. 2010, 122, 6996-6999 and in Angew. Chem. 2011, 123, 3551-3554. See also Rainer Brehme in Eur. J. Org. Chem. 2007, 5629.
Sincerely yours Rainer Brehme
Bifunctional (integration of weak acid + base moiety) organocatalysts are powerful catalysts for Michael addition reactions.
KF-Al2O3 is also very good for Michael addition reaction. Is worth considering it in neat (solvent-less) condition.
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