Chiral N acylhydrazones

Fig. 1 Disconnecting a C-C bond of a chiral amine suggests a chiral N-acylhydrazone radical acceptor and a radical precursor...

Intermolecular Radical Addition Chiral N Acylhydrazones SS Table 2.1 Amination of oxazolidinones and condensation with aldehydes (Scheme 2.1). 

Chiral N acylhydrazone derivatives may also be prepared from various ketones by condensation with N aminooxazolidinone 7a (Table 2.2) [22]. Mixtures of E/Z isomers were usually obtained, although ketone N acylhydrazones 14d and 15d, with highly branched tertiary butyl (tBu) substituents, were formed as single isomers. Others have recently used the amination and condensation procedures to prepare very similar chiral N acylhydrazones from ketones with excellent results [23]. 

The first test of the chiral N acylhydrazones was in tin mediated radical addition [24]. 

Friestad etal. had reported the synthesis of chiral homoallylic amines and their derivatives through the diastereofacial selective addition of tetraallylsilane to chiral N-acylhydrazones [72]. These chiral N-acylhydrazones are essentially imines linked to a chiral auxilliary that could be removed to liberate the homoallylic amine moieties after allylation. The success of this novel strategy lies in the activation of the allyl nucleophile through the use of tetrabutylammonium triphenyldifluo-rosilicate (TBAT), and the activation and formation of cyclic rigid complexes of the N-acylhydrazones through the use of ln(OTf)3 (Figure 8.39). 

Friestad, G.K. and Qin, J., Intermolecular alkyl radical addition to chiral N-acylhydrazones mediated by manganese carbonyl,/. Am. Chem. Soc., 123, 9922, 2001. 

Burk et al. showed the enantioselective hydrogenation of a broad range of N-acylhydrazones 146 to occur readily with [Et-DuPhos Rh(COD)]OTf [14]. The reaction was found to be extremely chemoselective, with little or no reduction of alkenes, alkynes, ketones, aldehydes, esters, nitriles, imines, carbon-halogen, or nitro groups occurring. Excellent enantioselectivities were achieved (88-97% ee) at reasonable rates (TOF up to 500 h ) under very mild conditions (4 bar H2, 20°C). The products from these reactions could be easily converted into chiral amines or a-amino acids by cleavage of the N-N bond with samarium diiodide. 

Figure 2.6 Two point binding of N acylhydrazones involving Lewis acid and chiral ligand(s).

High diastereoselectivity in the allylated product is controlled through chelation of the allylfluorosilicate to the Lewis acid associated with the chiral A-acylhydrazone, causing Si-face addition. Cleavage of the N-N bond produced homoallylic amines. 

Recently, novel bifunctionalized zinc catalysts have been developed (compounds (N) and (P), Scheme 55). They have both Lewis-acid and Lewis-base centers in their complexes, and show remarkable catalytic activity in direct aldol reactions.233-236 A Zn11 chiral diamine complex effectively catalyzes Mannich-type reactions of acylhydrazones in aqueous media to afford the corresponding adducts in high yields and selectivities (Scheme 56).237 This is the first example of catalytic asymmetric Mannich-type reactions in aqueous media, and it is remarkable that this chiral Zn11 complex is stable in aqueous media. 

The enantioselective reduction of a C=N double bond is an interesting alternative for the production of chiral amines by hydrogenation of enamides. Required imines or oximes can be prepared by reaction of ketones with amines or hydroxylamines. However, to date, trials to reduce these substrates with ethyl-DuPHOS catalysts gave no satisfying results. Therefore, transformation of ketones or a-keto acids into acylhydrazones and subsequent enantioselective hydrogenation has proven advantageous (eq 12, Table 5). ... 

Most rhodium catalysts for the enantioselective reduction of the C=N group are prepared in situ from a dimeric Rh-diene complex and a chiral diphosphine. Only few of the tested diphosphine ligands exhibit enantioselectivities >70% bdpp, cycphos, and phephos for imines and duphos for acylhydrazones. The activity of most Rh-diphosphine complexes for imine hydrogenation is low and therefore most of them are of limited practical use. Although some catalysts work already at ambient reaction conditions, most Rh-diphosphine complexes show low tof s even at elevated hydrogen pressures (>60 bar). 

Tan, K.L. and Jacobsen, E.N. (2007) Indium-mediated asymmetric allylation of acylhydrazones using a chiral urea catalyst. Angewandte Chemie - International Edition, 46, 1315-1317. 

Acylhydrazones, R CH=N-NHCOR , undergo stereoselective Mannich reactions with silyl ketene acetals to give j8-hydrazido esters, using activation by a chiral silicon Lewis acid. Alternatively, the use of silyl ketene imine gives a /3-hydrazido nitrile. Enantioselective (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) hydrazone alkylation of aldehydes and ketones is the subject of a computational study, providing a useful screening method for possible new candidates. " ... 

---