Nitrones esters

Nitrones or aci-nitro esters react with alkenes to give in some cases A/-substituted isoxazolidines and in others 2-isoxazolines. When the intermediate isoxazolidines were observed, a number of procedures transformed them into the 2-isoxazolines. Acrylonitrile and phenyl rzcf-nitrone esters produced an A/-methoxyisoxazolidine. Treatment with acid generated a 2-isoxazole while treatment with base generated an oxazine (Scheme 118) (68ZOR236). When an ethoxycarbonyl nitrone ester was reacted with alkenes, no intermediate isoxazolidine was observed, only A -isoxazolines. Other aci-mtro methyl esters used are shown in Scheme 118 and these generate IV-methoxyisoxazolidines or A -isoxazolines which can be further transformed (72MI41605). 

The addition of nitronic esters to alkynes to produce aziridines was postulated to proceed through a 4-isoxazoline as one of the intermediates (Scheme 132). A biradical intermediate (492) was also included in the mechanistic pathway for the reaction (77JA6667). 

A newer method for the preparation of nitronic esters, namely utilizing the (9-trimethyl-silyl ester, has been reported and these are prepared by the reaction of alkylnitro compounds and (V,(V-bis(trimethylsilyl)acetamide. These nitronic esters also undergo cycloaddition with alkenes to produce isoxazolidines (equation 54) (74MIP41601, 74DOK109, 78ACS(B)ll8). 

Steroidal alkene (531a) reacted with a nitronic ester at 14 000 atmospheres to produce an isoxazolidine (532a) (80IZV1893). 

A" -Isoxazolines, which are readily accessible by 1,3-dipolar addition of nitrones and nitronic esters to activated alkynes, undergo facile rearrangement upon warming (<110 °C)... 

Alkylation gives nitronic esters, which are generally unstable to heat but break down to give an oxime and an aldehyde or ketone. 

Table 3.5 gives the most typical examples of acyclic nitronic esters, which have unusually high thermal stability. These data contradict the known data on fast thermal decomposition of alkyl nitronates derived from the simplest nitroalkanes (237) and relatively low thermal stability of nitronate (73a). On the basis of the available data, the following empirical mle can be derived an extension of the conjugation chain of the nitronate fragment increases stability of nitronates. 

However, in our opinion, the rigorous assignment of products to covalent nitronic esters rather than to their structural isomers, which are true nitro compounds or ionic salts, is a more important and complex problem This problem involves difficulties, because ambident anions of nitro compounds (which are evident precursors of nitronates) have comparable O- and C-nucleophilicities and, therefore, the resulting substrates can belong to any of the above mentioned series. Incorrect structure assignments of derivatives of polynitro compounds prepared from tetranitromethane were made in former studies. In addition, the structures of nitronates assigned to some products in early studies, should not have been accepted without the use of modem spectral methods. 

A second and related consequence in aliphatic nitro compounds is the acidification of the directly bonded CH unit through the attendant stabilization of the derived conjugate bases (5,6). As with all delocalized anions, reprotonation gives rise to tautomers, the original C-nitro compound (I) and the oci-nitro or isonitro form (II), Eq. 2.1. The aci-nitro tautomers are typically present in very minor concentrations, with equilibrium constants (A eq) between 10 and 10 (7). Alkylation of the delocalized anion leads to both a-substituted nitro compounds and the regioisomeric nitronic esters (nitronates). Nitronates were described as early as 1894 (8), however, the first isolated nitronic ester was obtained several years later upon the addition of diazomethane to phenylazonitromethane (1), Eq. 2.2 (9). 

Aside from the relatively trivial conversions of nitronates to the corresponding oxime and carbonyl compounds (10,11), the chemistry of nitronates remained relatively unexplored for much of the early 1900s. However, in 1964, Tartakovskii et al. (12) demonstrated that alkyl nitronate esters were competent partners in the newly discovered class of dipolar cycloadditions with alkenes (Scheme 2.1). Both cyclic and acyclic nitronates participated, thus providing a new functional group were the nitrogen atom existed at the center of an acetal (13). These compounds were subsequently referred to as nitroso acetals (14) or nitrosals (15). 

The tandem transesterification/[3 + 2]-cycloaddition methodology is be a powerful synthetic tool, since it guarantees high diastereoselectivity even under thermal conditions. It has been successfully apphed to synthetic work of the N-terminal amino acid component of Nikkomycin Bz (Scheme 11.53) (173). Thus, the sugar-based oxime is condensed with a glyoxylate hemiacetal to produce a chiral nitrone ester, which is then reacted with ( )-p-niethoxycinnamyl alcohol in the presence of a catalytic amount of TiCU at 100 °C. After the intramolecular cycloaddition, the... 

Application of the Franck reaction to acetoxymethyl dime thy lamine I synthesized by Bohme (10),gave a compound identified as the nitronate ester III of hydroxymethyl methylnitrosamine in 20% yield. 

In spite of variations in temperature and concentration, there was no evidence for the presence of the a-acetate II.At that time, we have no explanation for the formation of this nitronate ester although we may now have a possible rationalization which will be discussed later. 

Isoxazolidines result from 1,3-dipolar cycloadditions of nitrone or nitrone esters and alkenes (see Equation (1)) (95PHC179). 

Nitronate esters have been used for the same purpose of C=S to C=0 conversion, and the procedure was notably applied in a (+)-methynolide total synthesis [518]. 

In contrast to titanium(IV) tetrachloride, which causes polymerization of a,3-unsaturated esters, aluminum triflate88 or aluminum-impregnated montmorillonite87b are excellent promoters of silyl ketene acetal additions to a,(3-unsaturated esters (Scheme 35). Similarly, the addition of silyl ketene acetals and enol silyl ethers to nitroalkenes, followed by Nef-type work-up, affords y-keto esters (216) and y-di-ketones (218), respectively (Scheme 35).89a>89b Mechanistically, the y-diketones (218) arise from Nef-type hydrolysis of an initial nitronate ester (217).89e 89d Mukaiyama reports that SbCls-Sn(OTf)2 catalyzes diastereoselective anti additions of silyl ketene acetals, silyl thioketene acetals and enol silyl ethers to a,(3-unsaturated thioesters (219).90... 

Tandem Diels-Alder-Nitronic Ester Cyclization Reactions 1122... 

The earliest and to date most extensively studied class of intramolecular cycloadditions involves unsaturated nitrones.4 These are most readily available from condensation of an unsaturated aldehyde with a hydroxylamine or an unsaturated hydroxylamine with an aldehyde. Another approach is simply to oxidize an unsaturated hydroxylamine. Nitronic esters are nitrones containing an alkoxy substituent attached to the N-atom they can be prepared from nitro compounds. Frequently an unsaturated nitrone can be isolated and purified, although much work has been done with the nitrone generated in situ eventual cyclization can provide three new contiguous chiral centers, often with only one diastereomer actually formed. 

Allylic nitro compounds containing a suitable dipolarophile undergo Diels-Alder cycloaddition to alkenes in the presence of tin(lV) chloride affording cyclic nitronic esters (Scheme 16).26 Nitronic ester (59) could not be isolated but spontaneously cyclized to the 5,5-fiised cyclic product (60), isolated in 68% yield. The nitronic esters (61a) and (61b) were isolated from the Diels-Alder reaction and could be separated. Heating (61a) in refluxing benzene afforded the 5,6-fused dipolar cydization product (62a) in 93% (68% overall) yield (61b) likewise afforded (62b) in 62% (11% overall) yield. Either (62a) or (62b) could be converted to the tricyclic lactam (63) by catalytic hydrogenolysis followed by lactamiza-... 

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