Modularly Designed Organocatalytic Assemblies for Direct Nitro‐Michael Addition Reactions

Abstract

Organocatalysis has developed rapidly in recent years. [1] Among the catalysts developed for this purpose, proline derivatives have risen to prominence, and have been used to catalyze a wide range of reactions.[2] While covalent bonds are used to connect the stereocontrolling moiety and the pyrrolidine backbone in most of these derivatives, Clarke and Fuentes recently reported the first example of modularly designed prolinamide-based catalysts that self-assemble under the reaction conditions through hydrogen-bonding interactions.[3] Although the reported method only affords mediocre enantioselectivities in most cases, the advantage of this approach is obvious: Modification of the catalyst structure only needs simple replacement of the modules, while further chemical synthesis is avoided. Moreover, a library of diverse organocatalysts may be more efficiently obtained for catalyst screening and structure modification. [4] During our recent study of quinine derivative-catalyzed enantioselective reactions, [5,6] we envisioned that ionic interactions may be utilized for the self-assembly of modularly designed organocatalysts. Our hypothesis is shown in Equation (1) with proline as the reaction-center module. When proline and a tertiary amine carrying a thiourea moiety (the stereocontrolling module) [7] are mixed, an acid-base reaction between the carboxylic acid and the tertiary amine groups should lead to an ammonium salt.[8] Ionic interactions between the ammonium and the carboxylate should cause these two modules to self-assemble, [9] forming a potential organocatalyst incorporating both the proline reaction center and a stereocontrolling moiety. Michael addition is one of the most important CÀC bondforming reactions in organic synthesis, [10] and many proline derivatives [11] have been developed as catalysts for the direct addition of ketones/aldehydes to nitroalkenes since the proline-catalyzed direct nitro-Michael addition was discovered.[12] To test our hypothesis, the nitro-Michael addition reaction was adopted as a model. Herein we wish to report our preliminary results of using these self-assembled organocatalysts in the direct Michael addition of ketones and aldehydes to nitroalkenes.Acetone and trans-b-nitrostyrene were selected as the model substrates in the preliminary screening. Acetone is one of the most problematic substrates for the nitro-Michael addition. To our knowledge, enantiomeric excesses of over 90 % have been obtained for the Michael product with an acetone substrate in only two cases [11i-j] , despite the fact that numerous sophisticated proline derivatives have been reported as the organocatalysts for this reaction.[11p-q] Readily available a-amino acids, such as proline, glycine, alanine, ltert-leucine, and phenylglycine, [13] were selected as the reaction-center modules, whereas some readily accessible cinchona alkaloid derivatives were chosen as the stereocontrolling modules (Scheme 1). Some typical results [13] are summarized in Table 1.The enantiomers of proline show strong matching ...

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

“…Prepared from 2a and (E)-3-methyl-1-nitrobut-1-ene (4i) according to GP. NMR Data correspond to those published in [53]. (2R,3S)-2-Ethyl-4-nitro-3-phenylbutanal (7k).…”

A Novel Type of Mono-Substituted Polyacetylene: Synthesis and Characterization of Poly(N-Propargylthiourea)s

“…Another major application of thioureas is as universal anion receptors [11,12]. Particularly designed thiourea derivatives can perform self-assembly [13], chiral recognition and chiral separation abilities [14,15]. In the latter applications, strong hydrogen bonds formed between thioureas and the target compounds play significant roles.…”

(S)-Binam-L-prolinamide as organocatalyst for the enantioselective conjugate addition of α-alkoxyketones to β-nitrostyrene derivatives

“…Thus, while compound 5 (20 mol%) in the presence of 4-(dimethylamino)pyridine (DMAP, 20 mol%) in chloroform at room temperature gave the anti-isomer in low diasteroselectivity (33% de) and moderate enantioselectivity (41% ee), 15 the use of the quinidine thiourea 6 in combination with proline (5 mol% of each) in benzene at rt led mainly to the formation of the syn-isomer in moderate diastereoselectivity (64% de) and high enantioselectivity (90% ee). 16 As in the direct aldol reaction catalyzed by Binam-prolinamides such as 7 17 and 8 18 between aldehydes and alkoxyacetones provided the expected products with high regio-, diastereo-and enantioselectivity using different reaction media, 17d,e,i including solvent-free reaction conditions, 17j,k we thought that the application of these catalyst to the Michael addition of α-alkoxyketones as nucleophiles to β-nitrostyrene derivatives would be of interest.…”