Dipolarophiles alkyl nitronates

Elsewhere, Heaney et al. (313-315) found that alkenyloximes (e.g., 285), may react in a number of ways including formation of cyclic nitrones by the 1,3-APT reaction (Scheme 1.60). The benzodiazepinone nitrones (286) formed by the intramolecular 1,3-APT will undergo an intermolecular dipolar cycloaddition reaction with an external dipolarophile to afford five,seven,six-membered tricyclic adducts (287). Alternatively, the oximes may equilibrate to the corresponding N—H nitrones (288) and undergo intramolecular cycloaddition with the alkenyl function to afford five,six,six-membered tricyclic isoxazolidine adducts (289, R = H see also Section 1.11.2). In the presence of an electron-deficient alkene such as methyl vinyl ketone, the nitrogen of oxime 285 may be alkylated via the acyclic version of the 1,3-APT reaction and thus afford the N-alkylated nitrone 290 and the corresponding adduct 291. In more recent work, they prepared the related pyrimidodiazepine N-oxides by oxime-alkene cyclization for subsequent cycloaddition reactions (316). Related nitrones have been prepared by a number of workers by the more familiar route of condensation with alkylhydroxylamines (Scheme 1.67, Section 1.11.3). 

The nitroso acetals that result from the [3 + 2] cycloaddition of alkyl nitronates with dipolarophiles typically provide several characteristic spectroscopic signals for identification. As in the silyl counterparts, the O—N—O stretch in the alkyl nitroso acetals is observed in the IR ranges between 1000 and 1030 cm (Tables 2.22 and 2.23) (57,75-77). However, this resonance is usually not strong, and can be obscured by other functional group resonances with more substituted nitroso acetals. 

In addition to the regioselectivity of the cycloaddition, there also exists a question of stereoselectivity. This issue involves the location of the substituent X on the dipolarophile in either an exo or endo fashion (Scheme 2.3). In the case of simple alkyl nitronates bearing an electron-withdrawing substituent, the stereoselectivity is highly dependent on both the nature of the dipolarophile and the configuration of the nitronate (Scheme 2.5) (96). In the case of nitronate 47, either a mixture of diastereomers or only the exo adduct is observed. However, the cycloaddition of maleic anhydride with 47 provides only the endo stereoisomer (97). 

The combination of the geometrical preference of the tether and the stereochemical preference of the dipolarophile substituent can be seen in the intramolecular cycloadditions of alkyl nitronates, (Scheme 2.6) (99). When the tether is restricted to two atoms, only the endo approach of the tether is observed in up to a 100 1 ratio, independent of the configuration of the disubstituted dipolarophile. However, in the case of a three-atom linker, there exists a matched and mismatched case with respect to the observed stereoselectivities. With a (Z)-configured dipolarophile, only the exo isomer was observed since the ester moiety also approaches on the exo to the nitronate. However, with an ( )-configured dipolarophile, the ester group is forced to approach in an endo manner to accommodate an exo approach of the tether, thus leading to lower selectivity. 

The number of investigations on the enantioselective dipolar cycloaddition of nitronates is still rather limited. In the case of simple alkyl nitronates, the facial selectivity is controlled solely by the steric environment about the two faces of the chiral unit. For example, the reaction of steroid dipolarophile 270 proceeds with the nitronate approaching the Re face of the alkene (Eq. 2.23) (234). The facial selectivity is controlled by the C(19) methyl group, which blocks the Si face of the dipolarophile. Similarly, exposure of 279 to ethyl acrylate at 40 °C for 24 h, provides a single nitroso acetal (Scheme 2.21) (242). The facial selectivity is presumed to arise from steric shielding by the menthol group, however the full stereostructure has not been established. 

MacMillan s imidazolidinone salts, used successfully in the organocatalysed Diels-Alder reaction (see Section 8.1) also function as effective catalysts in the asymmetric nitrone cycloaddition with simple monodentate dipolarophiles. Thus acrolein (8.63) and crotonaldehyde (8.99) both react with acyclic C-aryl, N-benzyl nitrones and C-aryl N-alkyl nitrones such as (8.198) with high ees ranging from 90 to 99% in the presence of the perchlorate salt of imidazolidinone (8.91). 

The commonly accepted mechanism for these isoxazole syntheses assumes the formation of intermediate mixed anhydrides between nitronic acid 6a and the acyl moiety. Many authors have illustrated these intermediates 6b (Scheme 8.2) where the acyl group (X = acyl) in turn is PhNHCO [5], MeCO [31,32,47,48], t-BuCO [32], t-BuOCO [42], EtOCO [37], PhCHaOCO [32], ArCO [32], PhSOa [37], p-TsO [36]. These nitronic mixed anhydrides are intermediates that usually carmot be isolated, unlike die esters alkyl nitronates 6c and silylnitronates 6d (Scheme 8.2). These esters 6c [49,50] and 6d [51-54] behave as 1,3-dipoles toward suitable dipolarophiles, and the resulting cycloadducts 7c and 7d are then converted into the final isoxazole derivatives by elimination of alcohol or silanol respectively in these cases cycloadditions precede elimination. 

Dipolarophiles D15. Several examples employing N-alkyl- and /V-arylmalei-mides as dipolarophiles in the 1,3-dipolar addition to nitrones have been presented (257, 295b, 815, 816). 

Other Types of Nitronates in [3 + 2]-Cycloaddition Reactions with Olefins As mentioned above, of all known types of nitronates, only alkyl and silyl nitronates can be involved in [3 + 2]-cycloaddition reactions with olefins. However, furoxans (161), which can also be considered as cyclic nitronates, can react with active dipolarophiles under extreme conditions to give nitrosoacetals (162) (Scheme 3.131, Eq. 1). 

TABLE 2.34. DIPOLAR CYCLOADDITIONS OF ALKYL SUBSTITUTED NITRONATES WITH VARIOUS DIPOLAROPHILES... 

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. 

Since then researchers in the field of nitrone cycloaddition seem to have more or less tacitly assumed that secondary interactions play an important role in determining endo/exo selectivity also in the case of N-alkyl and N-arylnitrone cycloaddi-tions.2 However, our experimental endo/exo selectivity studies " for the reactions of cyclic and open-chain nitrones with Z-disubstituted dipolarophiles revealed a clear-cut dominance (77% in benzene) of the endo mode only in one case the reaction of 1-pyrroline-l-oxide with maleonitrile, a reaction where the steric effects... 

A very similar strategy has been used for the synthesis of (—)-7-epiaustraIine 272 (Scheme 16.57) and (—)-l-epicas-tanospermine (271) [142]. An important feature of the synthesis of (—)-l-epicastanospermine is that the alkylation has been used to constmct not the five-, but the six-membered ring of this indohzidine alkaloid. In this reaction sequence the [3 + 2] cycloaddition between the nitronate 248 (prepared as shown in Scheme 16.54) and dipolarophile 110 provides nitroso acetal 266 with very high yield and selectivity. L-Selectride reduction provides the common intermediate 267, which can be mesylated and used for the synthesis... 

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