N acylhydrazones

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. 

In a related study, it has been shown that several aldehyde N-acylhydra-zones undergo oxidative cyclization with IBD in methanolic sodium acetate to give 2,5-disubstituted 1,3,4-oxadiazoles (Eq. 32). The oxidation of ketone N-acylhydrazones by IBD in methanol or ethanol affords the corresponding 2-alkoxy-A -l,3,4-oxadiazolines in excellent yields (Eq. 33), while oxidative cyclization of acetone 4-phenylsemicarbazone provides 2-(A -phenylimino)-A -l,3,4-oxadiazoline in 93% yield (Eq. 34) (93JOC3381). 

The presence of a heteroatom directly connected to the nitrogen atom of the imine activates it toward hydrogenation, while creating a second coordination site for the catalyst. Indeed, some successful results have been achieved for the hydrogenation of N-acylhydrazone, sulfonimide, and N-diphenylphosphinyl ketimines. The Et-DuPhos-Rh complex is an efficient catalyst for the asymmetric hydrogenation of a variety of N-acyl- ... 

A wide variety of /3-lactams are available by these routes because of the range of substituents possible in either the ketene or its equivalent substituted acetic acid derivative. Considerable diversity in imine structure is also possible. In addition to simple Schiff bases, imino esters and thioethers, amidines, cyclic imines and conjugated imines such as cinnamy-lidineaniline have found wide application in the synthesis of functionalized /3-lactams. N-Acylhydrazones can be used, but phenylhydrazones and O-alkyloximes do not give /3-lactams. These /3-lactam forming reactions give both cis- and rrans-azetidin-2-ones some control over stereochemistry can, however, be exercised by choice of reactants and conditions. 

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

Armed with a strong set of precedents, we applied this photolysis to the reaction of ethyl iodide with N-acylhydrazone 3a (Table 5) [69, 70], Irradiation (300 nm) with Mn2(CO)io using InCl3 as a Lewis acid furnished the ethyl adduct in 85% yield, a dramatic improvement over experiments using triethylborane or hexamethylditin. Control experiments revealed a requirement for both irradiation and Mn2(CO)io on the other hand, the reaction proceeded without InCl3, though sluggishly (21% yield, 2 days). 

Implementation with N acylhydrazones derived from 4 benzyl 2 oxazolidinone. 

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]. 

The scope of the reaction was evaluated by variations in both the radical and the radical acceptor. In the presence of ZnCb, the propionaldehyde N acylhydrazone 8a was subjected to radical additions of various organic iodides (Table 2.3, entries 1 4). Reaction conditions entailed addition of Bu3SnH (5 equiv) and O2 (7 ml/mmol) by syringe pump to a mixture of iPrI (10 equiv), 136 (10 equiv), and Lewis acid (2 equiv) in 2 1 CH2Cl2/ether at 78 °C, gradually bringing the mixture to ambient temper ature after the addition. Under these conditions, ethyl radical (from the triethylbor ane) can compete for the radical acceptor, and as a result, the separable ethyl radical adduct 17 (Scheme 2.2) was observed (<10% yield) in all cases. With simple secondary and tertiary alkyl iodides as radical precursors (entries 1 4), additions to 8a occurred with moderate yields to afford N acylhydrazines. Radical reactivity is... 

Table 2.3 Reactivity scope of tin mediated radical addition to N acylhydrazones (R Bn) in the presence of ZnCl2.

A variety of aldehyde hydrazones were screened [24b]. Branching at a saturated a carbon was detrimental in the tin mediated radical additions, but an aromatic benzaldehyde hydrazone 12 offered some success, with yields ranging from 30 to 83% (Table 2.3, entries 5 8). With the exception of 8a, which decomposed under the reaction conditions, the reactions were quite dean. Even in the examples with lower yields, the mass balance after recovery of the hydrazone precursor was generally 80 90%, demonstrating the excellent chemoselectivity of the reactions of radicals with N acylhydrazones. We were delighted to find that the radical additions had occurred with excellent stereocontrol in all secondary and tertiary radical additions to hydrazones 8 and 12 (Table 2.3), with diastereomer ratios ranging from 93 7 to 99 1 [24]. 

Next, the effects of varying the stereocontrol elements on the oxazolidinone moiety were assessed, with the main goal to examine the change in diastereoselectivity. Without optimizing for yield, isopropyl radical additions to several N acylhydrazones 8a 8e (See Scheme 2.1 for structures) were compared for stereo selectivity (Table 2.4). Although the measurement was not available for 8c, all auxiliaries gave very high diastereoselectivity in addition of isopropyl radical to propionaldehyde hydrazone [24b]. 

For the y amino acid 44 (Figure 2.5), phenylacetaldehyde N acylhydrazone 48 (Scheme 2.7) was employed as the radical acceptor. Mn mediated addition of difunctional iodide 49a (5 equiv) proceeded in 56% yield, affording SOa as a single diastereomer [39]. Recently, we found that the unprotected alcohol 49b couples with hydrazone 48 in 79% yield, using a modest excess (3.5 equiv) of the iodide. Considering that typical intermolecular radical additions often require large... 

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