Alkyl nitronates applications

On the basis of this successful application of 23d, this catalyst was applied in a series of reactions (Scheme 6.22). For all eight reactions of nitrones 1 and alkenes 19 in which 23d was applied as the catalyst, diastereoselectivities >90% de were observed, and most remarkably >90% ee is obtained for all reactions involving a nitrone with an aromatic substituent whereas reactions with N-benzyl and N-alkyl nitrones led to lower enantioselectivities [65]. 

This chapter is divided into four major sections. The first (Section 2.1) will deal with the structure of both alkoxy and silyl nitronates. Specifically, this section will include physical, structural, and spectroscopic properties of nitronates. The next section (Section 2.2) describes the mechanistic aspects of the dipolar cycloaddition including both experimental and theoretical investigations. Also discussed in this section are the regio- and stereochemical features of the process. Finally, the remaining sections will cover the preparation, reaction, and subsequent functionalization of silyl nitronates (Section 2.3) and alkyl nitronates (Section 2.4), respectively. This will include discussion of facial selectivity in the case of chiral nitronates and the application of this process to combinatorial and natural product synthesis. 

Nitronates have also been applied in intramolecular 1,3-dipolar cycloaddition reactions. Denmark and Thorarensen (64) extensively studied the application of cyclic alkyl nitronates in tandem[4+2]/[3+2] cycloadditions of nitroalkanes. In most cases, the stereoselectivity of these reactions is directed by a chiral auxiliary and will thus be outlined in Section 12.3.4. The reader is also directed to the excellent chapter by Denmark in Chapter 2. 

A convenient alternative to the Beckmann rearrangement is reported by Barton 1 Alkyl nitrones, readily available from the corresponding ketones, are smoothly transformed into A-alkylamides by treatment with toluene-/ -sulphonyl chloride, as shown in Scheme 36. Beckmann rearrangement of the oxime of (105) affords the isomeric lactam (106). This reaction is applicable also to saturated ketones. 

The presence in the heterocycle of additional basic centers or those open to alkylation can lead to a change in reaction directions. It essentially limits the application of this method in the formation of a-methoxy nitrones. In such cases, it is reasonable to use diazomethane and, depending on the structure of hydroxamic acid (198-201) the yields of a-methoxy nitrones (197), (202-204) can rise from 17% up to 62% (Scheme 2.70) (353). 

As indicated from computational studies, the catalyst-activated iminium ion MM3-2 was expected to form with only the (E)-conformation to avoid nonbonding interactions between the substrate double bond and the gem-dimethyl substituents on the catalyst framework. In addition, the benzyl group of the imidazolidinone moiety should effectively shield the iminium-ion Si-face, leaving the Re-face exposed for enantioselective bond formation. The efficiency of chiral amine 1 in iminium catalysis was demonstrated by its successful application in several transformations such as enantioselective Diels-Alder reactions [6], nitrone additions [12], and Friedel-Crafts alkylations of pyrrole nucleophiles [13]. However, diminished reactivity was observed when indole and furan heteroaromatics where used for similar conjugate additions, causing the MacMillan group to embark upon studies to identify a more reactive and versatile amine catalyst. This led ultimately to the discovery of the second-generation imidazolidinone catalyst 3 (Fig. 3.1, bottom) [14],... 

The dipolarophilicity of nitriles can be enhanced by coordination to a metal center, namely toward azides or nitrones, [-0+N(R3)=C(R1)(R2)], to yield, via [2 + 3] cycloadditions, the tetrazolate complexes (1) and (2) (Table 5, the latter derived from the former by sterically promoted linkage isomerization) with a wide variety of metal centers4 and the A4-l,2,4-oxadiazoline complexes (3) with Pt centers,175 respectively. The reactions normally proceed under mild conditions, even for nitriles with electron-donor alkyl groups (R). The tetrazoles177 and the oxadiazolines175 were liberated in some cases and the metal-mediated processes constitute promising routes for the synthesis of such heterocycles as exhibit medicinal and other applications. 

These reaction conditions were also applicable to substituted aryl and alkyl (Me, f-Bu) nitrones, although enantioselectivity was reduced for the latter ( 40%). Enantioselectivity was also found using chiral hw-BlNOL-boric acids (two equiv.). 

Silyl enol ethers and ketene silyl acetals add to aromatic nitro compounds in the presence of TASF(Me) to give intermediate dihydro aromatic nitronates which can be oxidized with bromine or 2,3-dichloro-5,6-dicyano-l,4-benzoquinone to give a-nitroaryl carbonyl compounds the latter are precursors for indoles and oxindoles. The reaction is widely applicable to alkyl-, halo-, and alkoxy-substituted aromatic nitro confounds, including heterocyclic and polynuclear derivatives (eq 7). 

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