Silyl nitronates preparation

The classical Henry reaction conditions (base catalyzed addition) have some drawbacks sometimes the nitro alcohols are obtained in low yields and diastereoselectivities are not always high. To improve these results, a number of modifications were introduced. One of them is the Seebach s silyl nitronate method,25 that involves a reaction between an aldehyde with a silyl nitronate prepared by metalation of the corresponding nitro alkane with LDA, followed by reaction of the resulting nitronate with tert-butyldimethylsilyl chloride.26... 

Method G Highruiri-selecdvity is also observed in the fluoride-catalyzed reacdonof silyl nitronates v/ith aldehydes. Trialkyl silyl nitronates are prepared in good yield from primary nitroalkanes by consecndve treatment v/ith iithiiim dusopropylamide and trialkylsilyl chloride at -78 C in THF. 

A series of 3-substituted-2-isoxazoles are prepared by the following simple procedure in situ conversion of nitroalkane to the silyl nitronate is followed by 1,3-dipolar cycloaddition to produce the adduct, which undergoes thermal elimination during distillation to furnish the isoxazole (Eq. 8.74). 5 Isoxazoles are useful synthetic intermediates (discussed in the chapter on nitrile oxides Section 8.2.2). Furthermore, the nucleophilic addition to the C=N bond leads to new heterocyclic systems. For example, the addition of diallyl zinc to 5-aryl-4,5-dihydroi-soxazole occurs with high diastereoselectivity (Eq. 8.75).126 Numerous synthetic applications of 1,3-dipolar cycloaddition of nitronates are summarized in work by Torssell and coworker.63a... 

By contrast, softer nucleophiles, such as thiols (111), evidently do react with SENAs at the a-C atom (307) (see Scheme 3.94). This interpretation is confirmed by a substantial difference in the configuration of thiohydroxamate 112a isolated in the reaction with silyl nitronate (a) and analogous product 112b (b) prepared from authentic nitrile oxide. 

Intramolecular cyclizations of silyl nitronates were also used in the preparation of aminosugars. In 2003 Kudoh et al. reported the stereoselective conversion of 2-nitroalkanols by silyl nitronate generation followed by an intramolecular nitronate-olefin [3 + 2] cycloaddition reaction (Scheme 51).88... 

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. 

A more common method for the preparation of silyl nitronates is the use of trimethylsilyl chloride (TMSCl) in the presence of a base. With triethylamine, silyl nitronates are prepared from primary nitroalkanes in moderate yields however, it is necessary to conduct the silylation in acetonitrile for good yields with secondary nitroalkanes (18,101). In several cases, this silylation has been done in the presence of the dipolarophile for both inter- and intramolecular processes, or the nitronate has been used in subsequent reactions without purification (18,22). Employment of l,8-diazabicyclo(5.4.0)undec-7-ene (DBU) as the base allows this procedure to be general for most nitroalkanes (19). 

The wide variety of methods for the preparation of alkyl nitronates, gives rise to a broader diversity of structures compared to silyl nitronates. Alkyl nitronates can be grouped into two subclasses, acyclic and cyclic. Both subclasses participate in dipolar cycloadditions with similar reactivity, however, minor differences are manifest in their stability and stereoselectivity. Additionally, the ability to prepare cyclic nitronates allows access to a wide variety of novel, multicyclic ring stractures. 

The nitroaldol reaction of silyl nitronates with aldehydes promoted by ammonium fluorides, which was originally introduced by Seebach and Colvin in 1978 [24], is a useful method for the preparation of 1,2-functionalized nitroalkanols. Recently, the present authors have succeeded in developing an asymmetric version of high efficiency and stereoselectivity by using a designer chiral quaternary ammonium bifluoride of type 6 as catalyst, which was readily prepared from the corresponding bromide by the modified method C in Scheme 9.5 [25]. 

Kobayashi et al. found that lanthanide triflates were excellent catalysts for activation of C-N double bonds —activation by other Lewis acids required more than stoichiometric amounts of the acids. Examples were aza Diels-Alder reactions, the Man-nich-type reaction of A-(a-aminoalkyl)benzotriazoles with silyl enol ethers, the 1,3-dipolar cycloaddition of nitrones to alkenes, the 1,2-cycloaddition of diazoesters to imines, and the nucleophilic addition reactions to imines [24], These reactions are efficiently catalyzed by Yb(OTf)3. The arylimines reacted with Danishefsky s diene to give the dihydropyridones (Eq. 14) [25,26], The arylimines acted as the azadienes when reacted with cyclopentadiene, vinyl ethers or vinyl thioethers, providing the tet-rahydroquinolines (Eq. 15). Silyl enol ethers derived from esters, ketones, and thio-esters reacted with N-(a-aminoalkyl)benzotriazoles to give the /5-amino carbonyl compounds (Eq. 16) [27]. The diastereoselectivity was independent of the geometry of the silyl enol ethers, and favored the anti products. Nitrones, prepared in situ from aldehydes and N-substituted hydroxylamines, added to alkenes to afford isoxazoli-dines (Eq. 17) [28]. Addition of diazoesters to imines afforded CK-aziridines as the major products (Eq. 18) [29]. In all the reactions the imines could be generated in situ and the three-component coupling reactions proceeded smoothly in one pot. 

Preparation of a-fluoro ketones or aldehydes can also be achieved by cerium ammonium nitrate oxidation of the corresponding silyl nitronates. C-acylation compounds derived from nitroalkanes can be... 

The total synthesis of (+)-cyclophellitol containing a fully oxygenated cyclohexane ring was accomplished by T. Ishikawa and co-workers. The synthetic strategy was based on the intramolecular silyl nitronate [3+2] cycloaddition reaction. The cycloaddition precursor was prepared by the Henry reaction starting from a D-glucose-derived aldehyde. 

Significant improvements to the Henry reaction have been achieved by using silyl nitronates and catalytic amounts of fluoride ion or, alternatively, a,a doubly deprotonated primary nitroalkanes. Both of these procedures, discovered by the Seebach group, have proved to be useful for the stereoselective preparation of vicinal amino alcohols. 

Dihydrofuraldehydes were prepared by an intramolecular silyl nitronate olefin cycloaddition with subsequent acidic workup <94JOC3783>. 

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