Organocatalytic a-amination

The sequential use of the organocatalytic a-amination of aldehydes by azodicar-boxylates with another process has provided a useful tool for the synthesis of complex molecules. Thus, the combination of the amination of linear aldehydes catalyzed by (5)-proline (20) and the Passerini reaction allowed the rapid access to norstatine based peptidomimetics albeit with low diastereoselectivities (36-98% yield, up to 4 1 dr) [27]. Moreover, the enantioselective synthesis of y-amino-a,P-unsaturated esters can be performed via the sequential a-amination-Homer-Wadsworth-Emmons olefination of aldehydes catalyzed by (5)-proline (20,10mol%) affording the expected products in high yields and enantioselectivities (85-90% yield, ee 92-99%) [28]. 

An enantioselective organocatalytic reductive amination has been achieved using Hantzsch ester for hydrogen transfer and compound (21) as catalyst. This mild and operationally simple fragment coupling has been accomplished with a wide range of ketones in combination with aryl and heterocyclic amines.359... 

In conclusion, the organocatalytic asymmetric a-amination of aldehydes and ketones using proline as catalyst is a new and attractive access to optically active N-protected a-amino aldehydes and ketones and related derivatives, e.g. a-amino acid esters. 

In the following sections we will describe recent developments and applications in the organocatalytic a-heteroatom functionalization of aldehydes and ketones catalyzed by chiral amines [1]. Notably, the C-H to C-Het transformations associated with amination, oxygenation, halogenation (fluorination, chlorination, bro-mination), and sulfenylation will be outlined (Scheme 2.24). 

Barbas and colleagues have applied the organocatalytic direct amination of aldehydes in a series of reports [7]. By combining acetone, various aldehydes, dibenzyl azodicarboxylate and i-proline as the catalyst, a one-pot synthesis of functionalized /Tamino alcohols was achieved [7a]. The scope of the reaction was found to be quite general for various aldehydes, and the optically active / -amino alcohols were obtained in high yields with low diastereoselective control. However, excellent enantioselectivity of especially the anti-adduct was obtained. 

Scheme 2.29 The application of organocatalytic enantioselective a-amination reaction of 3-(4-bromophenyl)-2-methylpropanal 8 for the total synthesis of the optically active cell-adhesion inhibitor BIRT-377 [7b].

Based on the above activation mechanism we wondered whether it would be possible to develop a biomimetic, organocatalytic reductive amination or transfer hydrogenation of ketimines. We reasoned that the activation of the imine by catalytic protonation through the Brpnsted acid should enable the hydrogen transfer from a suitable NADH mimic to yield the corresponding amine (Fig. 2). Hence, initial experiments focused on the examination of various Brpnsted acids in combination with different hydride sources (Rueping et al. 2005a). 

In 2008, Zhang, Ying, and co-workers reported an organocatalytic p-amination reaction of a,p-unsaturated aldehydes with nitrosobenzene catalyzed by an NHC. Specifically, the addition of NHC to a,p-unsaturated aldehyde generates a homoenolate intermediate that reacts with nitrosobenzene to afford Af-phenylisoxazolidin-5-ones, followed by an acid-catalyzed esterification and Bamberger-type rearrangement to produce Af-PMP-protected p-amino esters. A preliminary study on the enantioselective reaction of... 

Enantioselective organocatalytic a-chlorination of aldehydes, via enamine catalysis, was independently reported by the groups of MacMillan and Jprgensen in 2004 (Scheme 13.20) [46, 47]. MacMillan utilized his imidazolidinone catalyst and a perchlorinated quinone as the chlorine source, to obtain the S-enantiomer of the a-chloroaldehyde products. Jprgensen employed NCS as the chlorine source, and either a prolinamide catalyst to access the / -enantiomer of the a-chloroaldehyde products, or a Ci-symmetric amine catalyst to access the 5-enantiomer. A recyclable fluorous pyrrolidine-thiourea bifunctional organocatalyst was later employed as an enamine catalyst in this transformation [48]. 

Soon afterward, MacMillan s group properly explored this organocatalytic reductive amination, observing that the ortho-triphenylsilyl phosphoric acid 17n in the presence of 5-A MS facilitates the desired coupling of acetophenone and 4-OMe-aniline in high conversion and with excellent levels of enantiocontrol at 40 C (87% yield, 94% ee) [55]. Authors report also the reduction of the pyruvic acid-derived cyclic imino ester with excellent enantioselectivity. However, implementation of the corresponding ethyl-substituted imine resulted in a dramatic decrease in... 

Bogevig A, Juhl K, Kumaragurubaran N, Zhuang W, J0rgensen KA (2002) Direct Organocatalytic Asymmetric a-Amination of Aldehydes - A Simple Approach to Optically Active a-Amino Aldehydes, a-Amino Alcohols, and a-Amino Acids. Angew Chem Int Ed 41 1790... 

A new organocatalytic Michael/a-amination sequence based on double enamine activation of aldehydes produces a-hydrazino-aldehydes bearing a quaternary stereocentre in high yield and ee ... 

In addition, Erase et al. have studied the thermal elfects in the L-proline-catalysed asymmetric a-amination of disubstituted aldehydes with azodi-carboxylates, demonstrating that this reaction was accelerated under micro-wave conditions at 60 Compared to the results previously obtained at room temperature, both the yield and the enantioselectivity could be significantly increased and the reaction time considerably reduced. As shown in Scheme 5.15, this improved protocol allowed the fast and efficient synthesis of chiral a,a-disubstituted amino aldehydes with enantioselectivities of up to 90% ee, providing the best results for the a-amination of a-branched aldehydes to date. Significantly, the amination of branched aldehydes is one of the few organocatalytic reactions where good to moderate levels of enantioselection can be achieved at high temperatures (60-70 °C). 

Desmarchelier, A., Marrot, J., Moreau, X., Greek, C. (2011). Asymmetric organocatalytic Michael-a-amination sequence for the construction of a quaternary stereocenter. Organic Biomolecular Chemistry, 9, 994-997. 

Diels-Alder Reactions The organocatalytic Diels-Alder reaction of a,P-unsaturated carbonyl compounds can be performed either via iminium (see Section 11.3) or enamine catalysis. The first highly selective enamine-promoted cycloaddition reaction was reported by Jprgensen and coworkers, who developed an amine-catalyzed inverse-electron-demand hetero-Diels-Alder (HDA) reaction (Scheme ll.lOa). ... 

Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones have been extensively stndied with chiral secondary amine catalysts. These secondary amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active enamine or imininm intermediate species [44], Cinchona alkaloids were previonsly shown to be active catalysts in malonate additions. The conjngate addition of malonates and other 1,3-dicarbonyls to imines, however, is relatively nnexplored. Snbseqnently, Schans et al. [45] employed the nse of Cinchona alkaloids in the conjngate addition of P-ketoesters to iV-acyl aldimines. Highly enantioselective mnltifnnctional secondary amine prodncts were obtained with 10 mol% cinchonine (Scheme 5). 

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

---