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

Abstract

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 ÀC 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 þ 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 aminonitro-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).

Structure‐Reactivity Studies of Simple 4‐Hydroxyprolinamide Organocatalysts in the Asymmetric Michael Addition Reaction of Aldehydes to Nitroolefins

“…Separately each ester was hydrolysed to give the free carboxylic acids 13 and 14. In order to compare directly with our previously developed prolinamide catalysts, [8] the a-methylbenzylamine-derived 4-hydroxyprolinamides were prepared. Coupling of 13 separately with (R)-or (S)-N,a-dimethylbenzylamine in the presence of HATU gave the N-methylated prolinamides 15b and 16b, in low yields of 33 and 31% respectively, due to the highly hindered nature of both coupling partners.…”

“…As the presence of the a-methyl group was previously found to be detrimental to efficient catalysis, [8] the analogous simple 4-hydroxy prolinamide N-H and N-methyl catalysts were prepared in a similar manner to that outlined (vide supra), but using the N-Boc TBDMS ether protected carboxylic acid 26, which was prepared from the methyl ester 10 by hydrolysis (Scheme 2). The N-H prolinamides 27 and 28 were 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 10 10 11 11 12 12 13 13 14 14 15 15 16 16 17 17 18 18 19 19 20 20 21 21 22 22 23 23 24 24 25 25 26 26 27 27 28 28 29 29 30 30 31 31 32 32 33 33 34 34 35 35 36 36 37 37 38 38 39 39 40 40 41 41 42 42 43 43 44 44 45 45 46 46 47 47 48 48 49 49 50 50 51 51 52 52 53 53 54 54 55 55…”

“…All the prepared compounds were assessed as organocatalysts in the model reaction of valeraldehyde with trans-b-nitrostyrene (Table 1). For comparison with our previously published results [8] the reaction conditions were kept constant, i.e., the solvent used was DCM, with 5 mol% catalyst, 1.5 mole equivalents of valeraldehyde, at room temperature for 48 h. The two a-methyl compounds 19b and 20b with the Nmethyl amide trans to the 4-hydroxy group (entries 1 and 2) show good yields, poor diastereoselectivity, but reasonable enantiomeric excesses of the major syn product. However, the two a-methyl compounds 24b and 25b with the N-methyl amide cis to the 4-hydroxy group show much reduced yields, diastereoselectivities and enantioselectivities (entries 3 and 4).…”

“…An understanding of the mechanisms [8] and structure-reactivity relationships of existing catalysts is also needed to help with the design and development of new catalytic systems.…”

Exploiting the benefits of continuous-flow processing for the development of novel sustainable catalytic procedures

“…We hypothesized that the N-terminal secondary amine residue of the peptidic catalyst may catalyze enolization of the γ-nitroaldehyde, and thus the catalyst itself is responsible for the configurational instability of the product. 205 To understand the observed decrease in diastereoselectivity, the isolated γ-nitroaldehyde 57 (8 mg mL …”