Regioselectivity 4 + 2 cycloaddition, nitroalkenes

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

When ene-nitrile oxidoisoquinolium betaine 131 was heated as a dilute solution in toluene to 120 °C (Scheme 1.15), near quantitative conversion to the cycloadduct 133, resulting from the undesired regioselectivity, was observed. While the near complete conversion to cycloadduct 133 of oxidoisoquinolinium betaine 131 indeed demonstrated complete avoidance of the conjugate addition pathway in favor of cycloaddition, initial production of undesired isomeric cycloadduct 133 (instead of 136) was disappointing. Notably, cycloadduct 133 is expected to be less kinetically favored based on frontier molecular orbital (FMO) analysis (assuming dipole HOMO-controlled cycloaddition) of the putative transition state. This result stands in contrast to the cycloaddition of nitroalkene oxidoisoquinolinium betaine... 

In contrast to the complete regioselectivity observed in the 1,3-dipolar cycloaddition of nitronate 16b and methyl crotonate 42 or methyl cinnamate 44 shown in Scheme 9.14, the [3 -t 2] cycloaddition of yS-nitrostyrene (15a) and nitronate intermediate 16a was not completely regioselective. Regio-isomers 46 and 47 were formed in 83 % yield, as mixtures of diastereomers, in a 7 3 ratio after the high pressure-promoted domino cycloaddition of enol ether 14 with 2 equiv. fi-nitrostyrene (15a) (15 kbar, RT, 18 h, Scheme 9.15). The formation of regio-isomer 46 as major product was rather unexpected, since comparable 1,3-dipolar cycloadditions of nitrones and nitroalkenes [25] showed the opposite regio-isomer to be formed predominantly. This nitroso acetal (46) was converted to )S-lactam (48) via a base-catalyzed rearrangement (Scheme 9.16). This conversion appeared applicable to different hi- and tricyclic nitroso acetals and led to the formation of a novel class of bi- and tricyclic yS-lactams [26]. 

The relative reaction rates of the 1,3-dipolar cycloaddition reaction of phenyl azide to dipolarophiles containing the C=C bond can be predicted by using the Jaguar V. 3.0 ab initio electronic package. Thermodynamic analysis of the 1,3-dipolar cycloaddition of organic azides with conjugated nitroalkenes at 273-398 K shows that temperature does not affect the course of these reactions in the vapour phase. Density-functional procedures have been used to explain the regioselectivity displayed by the 1,3-dipolar cycloaddition of azides with substituted ethylenes. A density-functional theory study of the 1,3-dipolar cycloaddition of thionitroso compounds with fulminic acid and simple azides indicates that the additions are not stereospeciflc. ... 

The reactivity, regioselectivity and stereoselectivity of [3+2] cycloadditions of oxazoline 7V-oxides and a,P-unsaturated esters or nitroalkenes can be rationalized in terms of the FMO theory. The reactions are HOMO-dipole controlled and the preferred ewi/o-selectivity in those cycloadditions can be rationalized by stabilizing secondary orbital interactions only present in the en[Pg.105]

The use of oxygen-containing dienophiles in the form of silyl enol ethers, or ketene acetals has attracted considerable attention [66]. However, alkyl enol ethers are the most extensively employed dienophiles. The regioselectivity in the [4 + 2] cycloaddition step can be predicted in a straightforward way by FMO analysis. The larger coefficient in the LUMO of the nitroalkene (at the 3-carbon) will align with the... 

Unlike the regioselectivity of the [4 + 2] nitroalkene cycloaddition, the exo-Zendo-selectivity is less consistent. Thus, cyclohexadiene (45) reacts with a disubstimted... 

The two components of the [4 + 2] cycloaddition can be linked to react intramolecularly. The dienophile can be tethered to either a- or (3-carbon of the nitroalkene, which in turn creates bicyclic fused or bridged nitronates, depending upon the regioselectivity (Figure 16.4). To date, only cycloadditions of (3-tethered nitroalkenes are known. The reaction can be used to prepare five- and six-membered rings [58], which correspond to a three- or four-atom linker between the diene and dienophile. An attempted preparation of a seven-membered ring led to an intermolecular cycloaddition instead. 

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