Organocatalyzed Michael Addition of Aldehydes to Nitro Alkenes – Generally Accepted Mechanism Revisited and Revised

The amine‐catalyzed enantioselective Michael addition of aldehydes to nitro alkenes ( Scheme 1 ) is known to be acid‐catalyzed ( Fig. 1 ). A mechanistic investigation of this reaction, catalyzed by diphenylprolinol trimethylsilyl ether is described. Of the 13 acids tested, 4‐NO 2 C 6 H 4 OH turned out to be the most effective additive, with which the amount of catalyst could be reduced to 1 mol‐% ( Tables 2 – 5 ). Fast formation of an amino‐nitro‐cyclobutane 12 was discovered by in situ NMR analysis of a reaction mixture. Enamines, preformed from the prolinol ether and aldehydes (benzene/molecular sieves), and nitroolefins underwent a stoichiometric reaction to give single all‐ trans ‐isomers of cyclobutanes ( Fig. 3 ) in a [2+2] cycloaddition. This reaction was shown, in one case, to be acid‐catalyzed ( Fig. 4 ) and, in another case, to be thermally reversible ( Fig. 5 ). Treatment of benzene solutions of the isolated amino‐nitro‐cyclobutanes with H 2 O led to mixtures of 4‐nitro aldehydes (the products 7 of overall Michael addition) and enamines 13 derived thereof ( Figs. 6 – 9 ). From the results obtained with specific examples, the following tentative, general conclusions are drawn for the mechanism of the reaction ( Schemes 2 and 3 ): enamine and cyclobutane formation are fast, as compared to product formation; the zwitterionic primary product 5 of C,C‐bond formation is in equilibrium with the product of its collapse (the cyclobutane) and with its precursors (enamine and nitro alkene); when protonated at its nitronate anion moiety the zwitterion gives rise to an iminium ion 6 , which is hydrolyzed to the desired nitro aldehyde 7 or deprotonated to an enamine 13 . While the enantioselectivity of the reaction is generally very high (>97% ee), the diastereoselectivity depends upon the conditions, under which the reaction is carried out ( Fig. 10 and Tables 1 – 5 ). Various acid‐catalyzed steps have been identified. The cyclobutanes 12 may be considered an off‐cycle ‘reservoir’ of catalyst, and the zwitterions 5 the ‘key players’ of the process (bottom part of Scheme 2 and Scheme 3 ).