Direct Organo-Catalytic Asymmetricα-Amination of Aldehydes—A Simple Approach to Optically Activeα-Amino Aldehydes,α-Amino Alcohols, andα-Amino Acids

L-Proline as the catalyst: The first direct asymmetric α-amination of aldehydes using L-proline as the catalyst is presented (see scheme; Pg=protecting group). This new reaction gives easy access to optically active α-amino aldehydes, α-amino alcohols, and α-amino acids from simple and easily available starting materials and catalysts. The reactions proceed in high yields and excellent enantioselectivities with as little as 2 mol % of the catalyst. One of the ultimate goals and challenges in chemistry is to develop stereoselective transformations for the creation of functionalized optically active molecules with structural diversity from simple and easily available starting materials. Several procedures to generate optically active molecules are known and among these asymmetric catalysis plays an important role. The importance of optically active α-amino acids, α-amino aldehydes, and α-amino alcohols, formed by asymmetric catalysis,1 has stimulated an enormous development in synthetic strategies, and two different catalytic, enantioselective approaches are attractive: the C−C and the C−N bond-forming reactions. The catalytic enantioselective C−C bond-forming reactions include the addition to imines, such as the Strecker2 and Mannich3 reactions. The catalytic, enantioselective, direct C−N bond-forming reaction using aldehydes and a nitrogen source, such as azodicarboxylates, would constitute one of the simplest procedures for the construction of a stereogenic carbon center attached to a nitrogen atom (Scheme 1). Recently, we presented the first direct, enantioselective α-amination of 2-keto esters catalyzed by chiral copper(II)–bisoxazoline complexes.4, 5 This development led to a simple synthetic approach to optically active syn-β-amino-α-hydroxy esters. Pg=protecting group. Herein we present the first catalytic, enantioselective, direct α-amination of aldehydes, that is, the successful and unprecedented use of unmodified aldehydes for the stereoselective creation of C−N bonds using L-proline3c,3d, 6, 7 as the catalyst (Scheme 1). These reactions give an easy and simple access to many classes of optically active molecules with high structural diversity. The molecules include α-amino aldehydes, α-amino alcohols, and α-amino acids, all key chiral elements in many natural products as well as in medicinal chemistry. The results for the direct α-amination of some representative aldehydes 1 a, b with different azodicarboxylates 2 a–c catalyzed by L-proline [Eq. (1)] under various reaction conditions are presented in Table 1. Entry Aldehyde Azodicarboxylate Solvent Cat. Load [%] Reaction time [min] Yield [%][b] ee [%][c] 1 R1=Me (1 a) R2=Et (2 a) CH2Cl2 50 45 3 a–93 92 2 R1=Me (1 a) R2=Et (2 a) CH2Cl2 20 55 3 a–82 92 3 R1=Me (1 a) R2=Et (2 a) CH2Cl2 5 105 3 a–87 91 4 R1=Me (1 a) R2=Et (2 a) CH2Cl2 2 300 3 a–92 84 5 R1=Me (1 a) R2=Et (2 a) ClCH2CH2Cl 50 120 3 a–87 89 6 R1=Me (1 a) R2=Et (2 a) MeCN 50 30 3 a–70 91 7 R1=Me (1 a) R2=Et (2 a) EtOAc 50 300 3 a–77 81 8 R1=Me (1 a) R2=Et (2 a) toluene 50 450 3 a–81 86 9 R1=Me (1 a) R2=Et (2 a) dioxane 50 50 3 a–86 68 10 R1=Et (1 b) R2=Et (2 a) CH2Cl2 10 120 3 b–77 90 11 R1=Me (1 a) R2=iPr (2 b) CH2Cl2 10 105 3 c–91 88 12 R1=Me (1 a) R2=tBu (2 c) CH2Cl2 10 205 3 d–99 89 Propanal 1 a reacts with diethyl azodicarboxylate (DEAD) 2 a catalyzed by L-proline at room temperature under ambient conditions in CH2Cl2 and the α-aminated product 3 a is formed in 93 % yield and with 92 % ee (Table 1, entry 1). The procedure for the isolation of the α-aminated product is remarkable: addition of H2O and extraction with Et2O followed by evaporation of the excess aldehyde and the solvent gives pure 3 a. At 0 °C the enantioselectivity of the reaction is not significantly improved (93 % ee). However, the reaction also proceeds with lower catalyst loadings (Table 1, entries 2–4) and a highly enantioselective reaction takes place using only 2 mol % of L-proline as the catalyst. A variety of other solvents can also be applied with success for the catalytic, enantioselective, direct α-amination reaction (Table 1, entries 5–9). Butanal 1 b is α-aminated, in good yield, and high enantioselectivity using DEAD 2 a to give 3 b in 77 % yield and 90 % ee (Table 1, entry 10). The direct α-amination of 1 a was also investigated for the azodicarboxylates 2 b, c (Table 1, entries 11 and 12) to introduce more useful N-protecting groups (see below). Further attractive features of the L-proline-catalyzed direct α-amination reactions are: 1) the neat reaction proceeds smoothly in, for example, propanal with only a slight decrease in enantioselectivity,8 and 2) the reaction can also be performed in gram scale with the same high yield and enantioselectivity (e.g. propanal reacts with DEAD (10 mmol scale) to give the α-aminated product 3 a in 98 % yield and 92 % ee). The enantiomeric excesses of the products formed by the direct α-amination of aldehydes decrease slowly because of the acidity of the α-position next to the carbonyl group. This problem can easily be solved by the in situ reduction of the aldehyde group of the α-aminated aldehydes. This approach leads to a simple, catalytic, enantioselective procedure for the formation of valuable α-amino alcohols [Eq. (2)]. To simplify the isolation and analytical procedures the α-amino alcohols were converted into the N-amino oxazolidinones 4. The results are presented in Table 2. Entry Aldehyde Azodicarboxylate Yield [%][b] ee [%][c] 1 R1=Me (1 a) R2=Et (2 a) 4 a–67 93 2 R1=Et (1 b) R2=Et (2 a) 4 b–77 95 3 R1=iPr (1 c) R2=Et (2 a) 4 c–83 93 4 R1=tBu (1 d) R2=Et (2 a) 4 d–57 91 5 R1=allyl (1 e) R2=Et (2 a) 4 e–92 93 6 R1=Bn (1 f) R2=Et (2 a) 4 f–68 89 7 R1=iPr (1 c) R2=Bn (2 d) 4 g–70 91 The various aldehydes 1 a–f all react with azodicarboxylates affording the α-aminated aldehydes in high yields and enantioselectivities in the presence of L-proline (10 mol %) as the catalyst. Further transformations give the N-amino oxazolidinones 4. The results given in Table 2, entries 1 and 2 show that the masked α-amino alcohols are obtained with excellent enantioselectivity and that a slightly higher enantioselectivity is obtained when the aldehyde is reduced to the alcohol prior to workup. The other aldehydes 1 c–f are directly α aminated in a highly enantioselective fashion with DEAD 2 a in the presence of L-proline as the catalyst to give, after reduction and cyclization, the corresponding oxazolidinones in high yields and very high enantioselectivities (Table 2, entries 3–6, 89 % to 93 % ee). To expand the scope of the reaction we also treated 1 c with dibenzyl azodicarboxylate 2 d in the presence of L-proline (10 mol %) as the catalyst. The N-Cbz protected (Cbz=phenylmethoxycarbonyl) N-amino oxazolidinone 4 g was isolated in 70 % yield and 91 % ee (Table 2, entry 7) thus showing that a readily removable protecting group can be introduced. Based on the absolute configuration of the α-aminated products, we propose the transition-state model 70 for the reaction. The approach of the azodicarboxylate might be directed by interaction of the incoming nitrogen atom with the proton of the carboxylic acid of the L-proline–enamine intermediate. In conclusion, we have demonstrated the first organo-catalytic, direct, asymmetric α-amination of aldehydes with azodicarboxylates as the nitrogen source and L-proline as the catalyst. The new reaction provides easy access to optically active α-amino aldehydes, α-amino alcohols, and α-amino acids from simple and easily available starting materials and catalyst. Aldehydes react with azodicarboxylates and the corresponding optically active α-aminated adducts are formed in high yields and enantiomeric excesses, with as little as 2 mol % of L-proline. It is also demonstrated that masked α-amino alcohols are formed in high yields and excellent enantioselectivities (up to 95 % ee). Furthermore, the formation of oxazolidinones and α-amino acids is demonstrated. This direct α-amination reaction uses readily available and inexpensive achiral starting materials, and can be carried out under environmentally friendly and operationally simple reaction conditions. Supporting information for this article is available on the WWW under http://www.angewandte.com or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.