A-Aminoxylation

Chiral non-racemic 0-(2-ketoalkyl) A-phenylhydroxylamines such as 115 (equation 84) can be prepared through catalytic enantioselective a-aminoxylation of carbonyl compounds catalyzed by proline. This reaction proceeds with a variety of ketones and aldehydes although it has been tried only with a nitrosobenzene component ... 

Bpgevig, A., Sund, H. and Cordova, A. Direct Catalytic Enantioselective a-Aminoxylation of Ketones A Stereoselective Synthesis of a-Hydroxy and a,a -Dihydroxy Ketones. Angew. Chem. Int. Ed. 2004, 43, 1109-1111. 

The direct catalytic enantioselective a-aminoxylation of carbonyl compounds is a synthetically useful method for the preparation of versatile a-hydroxy carbonyl compounds. We have developed the direct catalytic enantioselective a-aminoxyla-... 

This asymmetric a-aminoxylation can be applied to a wide range of aldehydes (Table 6.1) and six-membered cyclic ketones (Table 6.2). Because of the easy conversion of a-aminoxy moiety to the a-hydroxy group, " operational simplicity, and the... 

Table 6.1 Proline-catalyzed direct asymmetric a-aminoxylation of aldehydes.

Addition to N=0 double bonds (a-aminoxylation/ hydroxylation of carbonyl compounds [7.2]... 

Proline-derived sulfonylcarboxamides are excellent catalysts for the direct enan-tioselective a-oxidation of ketones and aldehydes with nitrosobenzene. The alkyl-and arylsulfonylcarboxamides furnished the corresponding a-aminoxylated products in good yields with up to >99% ee.82... 

Singh, R. Tsuneda, T Hirao, K. An examination of density functionals on aldol, Mannich and a-aminoxylation reaction enthalpy calculations, Theor. Chem. Acc. 2011,130,153-160. 

Enamine-based organocatalytic a-aminoxylation of carbonyl compounds using proline in ionic liquids. 

Strategy A. The enamine strategy to asymmetric transformations of carbonyl compounds is also exploited for the construction of carbon-heteroatom bonds using proline as catalyst, dissolved in ionic liquid media. Thus, a highly enantioselective a-aminoxylation of aldehydes and ketones has been reported based on the use of nitrosobenzene as the aminoxylating agent and catalysed by proline in [bmim] and [pmim] [BF4] and The reaction reported in Figure 6 affords poorer values in terms of yield and reaction rate when carried out in molecular solvents. Conversely, proline dissolved in the IL is recovered up to 6 times without appreciable loss of activity. 

Recently, some extensive research has been devoted to exploring a diastereo-selective and enantioselective route for the synthesis of a-hydroxyaldehydes or a-hydroxyketones because they are important building blocks for the construction of complex natural products and biologically active molecules [91]. In parallel with the transition-metal-catalyzed asymmetric nitroso-aldol reaction [92], much interest has also been expressed towards the proline-catalyzed direct asymmetric a-aminoxylation of aldehydes or ketones for the synthesis of optically active a-hydroxyladehydes and a-hydroxyketones [93]. Wang [94] and Huang [95] independently reported an L-proline-catalyzed asymmetric a-aminoxylation reaction in ionic liquids, whereby it was found tliat aldehydes and ketones could undergo... 

Very recently, Pericas reported a new strategy to immobihze trans-4-hydroxypro-line onto an insoluble Merrifield-type polymer by exploiting Cu(I)-catalyzed 1,3-dipolar cycloaddition ( click chemistry ) [42]. The supported catalyst 25 was successfully employed in the a-aminoxylation of ketones and aldehydes (Scheme 8.13). Under the optimized reaction conditions (20mol%/cat, 2 equiv. ketone, DMF, 23 °C, 3 h), the reaction of cyclohexanone with nitrosobenzene catalyzed by 25 gave the product in 60% yield and 98% ee (Scheme 8.13 Equation a). It should be noted that the reaction rates of cyclic ketones with supported catalyst are faster than those reported with (S)-proline. The use of a supported catalyst allowed for a simplification of the work-up procedure, as the product could often be obtained after simple filtration of the catalyst and evaporation of the solvents. Furthermore, 25 was recycled up to three times without any decrease in either the chemical and/or stereochemical efficiency. 

Yamamoto and coworkers have developed an asymmetric a-aminoxylation of cyclic tributyltin enolates using nitrosobenzene (5.85) as oxygen source in the presence of Lewis acidic 1 1 silver-BINAP complexes. For example, the enolate (5.86) is converted into the a-aminoxyketone with high ee using this procedure. Cleavage of the N-0 bond is then effected with no racemization, using catalytic copper sulfate in methanol. 

Scheme 9.41 Direct a-aminoxylation of aldehydes and ketones with nitrosobenzene.

Proline-catalyzed a-aminoxylation reaction in the synthesis of biologically active compounds 13ACR289. 

Chirality amplification in the proline-catalyzed a-aminoxylation of aldehydes was uncovered and analyzed by Blackmond and co-workers in 2004 [29]. These researchers found that, contrary to what happens in proline-catalyzed aldol reactions, when the reaction was carried out with non-enantiopure proline, the enantiomeric excess of the product was higher than that expected from a linear relationship, and this enantiomeric excess rose over the course of the reaction. These results were rationalized by assuming an autoinductive behavior of the a-aminoxylation product, which formed a new catalytic species via enamine formation with proline, with the additional hypothesis of a matched interaction of L-Pro with the (/ )-enantiomer of the product (Scheme 2.3). 

SCHEME 23. Blackmond s mechanism for product induction and kinetic resolution in the proline-catalyzed a-aminoxylation of aldehydes. 

McQuade and co-workers [41] found that while the rate of proline-catalyzed a-aminoxylation of aldehydes in chloroform or ethyl acetate is significantly increased by the presence of a bifunctional urea, this effect is not observed when the catalyst is a 2-pyrrolidine-tetrazole, which cannot form an oxazolidinone. On the other hand, a similar rate acceleration was observed when the catalyst was the preformed Seebach oxazolidinone derived from proline and hexanal, or the soluble trans-A- tert- saiy di-methylsilyloxy)proline. NMR studies also showed that the role of the urea was to promote both (a) pro line solubilization by formation of the oxazolidinone (not by direct... 

SCHEME 2.8. MacQuade s merging of Seebach and Blackmond pathways for proline-catalyzed aldehyde a-aminoxylation. 

The a-aminoxylation of aldehydes has been successfully applied by different groups to the synthesis of biologically important compounds such as (+)-strictifo-lione [21], brasoside and littoralisone [22], ethambutol [23], levetiracetam [24], halipeptin A [25], brevicomin [26], linezolid [27], (+)-harzialactone A [28], tarchonanthuslactone [29], (+)-neosymbioimine [30], propranolol [31], thysanone [32], and (-l-)-disparlure [33]. 

Other secondary amines (11-14) have also been used in this transformation (Figure 12.2). Among proline derivatives [40-42], catalyst 11 afforded good yields and enantioselectivities for a broad scope of aldehydes and ketones, with lower catalyst loading and shorter reaction times [40]. Interestingly, binaphthyl-based secondary amine 14 also proved to be successful in the a-aminoxylation of aldehydes [43,44]. Recently, Pericas and co-workers reported the use of an insoluble. 

In 2008, Itoh and co-workers [66] successfully developed the first organocata-lyzed a-aminoxylation of oxyindoles using a cinchonidine-derived phase-transfer catalyst 29 and molecular oxygen (Scheme 12.7). In 2010, Barbas III and co-workers [67] designed a new dimeric quinidine catalyst 28 to synthesize the same kind of... 

A sequence involving an L-proKne-catalysed a-aminoxylation of an aldehyde followed by treatment with NaBH4 was used as a key step in a total synthesis of the HRV 3C-protease inhibitor (lR,35)-thysanone. This reaction provided the corresponding enantiopure 1,2-diol in a good yield, as shown in Scheme 4.6. 

---