Electron-deficient dipolarophiles

Gycloaddition reactions of betaine 64 with electron-deficient dipolarophiles, such as the extremely reactive 4-phenyl-1,2,4-triazoline-3,5-dione, gave the corresponding cycloadduct 65 isolated in quantitative yield (Equation 8) <1995T6651>. 

The 3 + 2-cycloaddition of 1,2-dithiophthalides with nitrilimines yields benzo[c]thio-phenespirothiadiazoles regioselectively. The azomethineimines isoquinolinium-iV-aryllimide and A-(2-pyridyl)imide readily undergo 1,3-dipolar cycloaddition with electron-deficient dipolarophiles, dimethyl fumarate and dimethyl maleate, to yield tetrahydropyrazolo[5,l-a]isoquinolines in high yield. ° The 1,3-dipolar cycloadditions of electron-poor 1,3-dipoles, bicyclic azomethine ylides (27), with ( )-l-A,A-dimethylaminopropene to yield cycloadducts (28) and (29) are examples of non-stereospecific cycloadductions (Scheme 9). The synthesis of protected... 

Yamamoto and co-workers (135,135-137) recently reported a new method for stereocontrol in nitrile oxide cycloadditions. Metal ion-catalyzed diastereoselective asymmetric reactions using chiral electron-deficient dipolarophiles have remained unreported except for reactions using a-methylene-p-hydroxy esters, which were described in Section 11.2.2.6. Although synthetically very useful and, hence, attractive as an entry to the asymmetric synthesis of 2-isoxazohnes, the application of Lewis acid catalysis to nitrile oxide cycloadditions with 4-chiral 3-(2-aIkenoyl)-2-oxazolidinones has been unsuccessful, even when > 1 equiv of Lewis acids are employed. However, as shown in the Scheme 11.37, diastereoselectivities in favor of the ffc-cycloadducts are improved (diastereomer ratio = 96 4) when the reactions are performed in dichloromethane in the presence of 1 equiv of MgBr2 at higher than normal concentrations (0.25 vs 0.083 M) (140). The Lewis acid... 

When acrylonitrile or ethyl acrylate was used as the dipolarophile, the azomethine adducts (134) and (135) were formed no thiocarbonyl ylide addition products were isolable in refluxing toluene or xylene, although the isoindoles (136a) and (136b) derived from them were isolated. In contrast to the reactions with fumaronitrile or AT-phenylmaleimide, the azomethine adducts (134) and (135) were still present at higher reaction temperatures — almost 50% in toluene and 4-5% in xylene. Under the same reaction conditions other electron-deficient dipolarophiles like dimethyl fumarate, norbornene, dimethyl maleate, phenyl isocyanate, phenyl isothiocyanate, benzoyl isothiocyanate, p-tosyl isocyanate and diphenylcyclopropenone failed to undergo cycloaddition to thienopyrrole (13), presumably due to steric interactions (77HC(30)317). 

The magnitude of the interaction between the high energy HOMO of the ylide system and the low energy LUMO of the electron-deficient dipolarophile is inversely proportional to the energy difference and is dependent on orbital overlap. The HOMO of the ylide has indeed nodal properties suitable for overlap with the antibonding orbitals of the dipolarophile. 

Calculations have shown that the HOMO in the [3,4-c]-annelated A,B-diheteropen-talenes is closely related to the nonbonding MO, thereby allowing ready reaction with electron-deficient dipolarophiles. In the case of the systems with two discrete ylide moieties as in thieno[3,4-c]pyrrole derivatives, it is not only the nature of the HOMO which directs the mode of addition, but also the thermodynamic stability of the adduct, leading to addition across the thiocarbonyl ylide at elevated temperatures and to the azomethine ylide at low temperatures (Section 3.18.4.2.1) (77T3203). 

The cycloaddition of azides to multiple -ir-bonds is an old and widely used reaction. Organic azides are well known to behave as 1,3-dipoles in thermal cycloaddition reactions.178 The first example of this reaction was observed by Michael in 1893.179 Since then the addition of azide to carbon-carbon double and triple bonds has become the most important synthetic route to 1,2,3-triazoles, -triazolines and their derivatives.180-184 The cycloadditions of simple organic azides with electron-rich dipolarophiles are LUMO controlled.3 Since the larger terminal coefficients are on the unsubstituted nitrogen in the azide and unsubstituted terminus in the dipolarophiles, the 5-substituted A2-triazolines are favored, in agreement with experiment.185-187 Reactions with electron-deficient dipolarophiles are HOMO controlled, and... 

Azide cycloaddition to electron-deficient dipolarophiles is normally HOMO-dipole LUMO-dipolaro-phile controlled, whereas the reverse is true for electron-rich dipolarophiles. Products with an electron-deficient group at the 5-position or an election-rich group at the 4-position are favored electronically in intramolecular cycloadditions, steric constraints can be expected to outweigh these considerations. 

A review on die inter- and intra-molecular cycloaddition of oxidopyridiniums and pyridinium ylides has appealed.117 The known 1,3-dipolar cycloaddition of 1 -methyl-4-phenyl-3-oxidopyridinium with electron-deficient dipolarophiles has been used to produce tropenones which can be transformed into 6- and 7-substituted 3-phenyltropanes, analogues of cocaine.118... 

Intermolecular cycloaddition also proceeds smoothly. The 2,8-dioxabicyclo-[3,2.1]octane core system 379 of zaragozic acid 380 was constructed by the intramolecular carbonyl ylide formation from 376 catalysed by Rh2(OAc)4, followed by intermolecular 1,3-dipolar cycloaddition of the electron-deficient dipolarophile 377 as shown by 378 as a single diastereomer out of four possible diastereomers [124],... 

As early as 1967, Huisgen and coworkers [37] had shown that, upon photolysis, certain aziridines of type 96 undergo C—C bond fragmentation stereospecifkally to produce octet-stabilized azomethine ylides which, on cycloaddition with electron-deficient dipolarophiles, produce pyrrolidine ring systems (Scheme 8.29). 

Diazomethane is an electron-rich 1,3-dipole, and it therefore engages in Sustmann type I 1,3-dipolar cycloadditions. In other words, diazomethane reacts with acceptor-substituted alkenes or alkynes (e.g., acrylic add esters and their derivatives) much faster than with ethene or acetylene (Figure 12.33). Diazomethane often reacts with asymmetric electron-deficient dipolarophiles with orientation selectivity, as exempli-... 

None of the ring-fused thiatriazole and selenatriazole derivatives undergo cycloaddition with electron deficient dipolarophiles (see Section 4.28.4.4.4) (81JOC4065). 

Table 1. Percentage of 4-substituted adduct ( 5%) obtained in cycloadditions of nitrones to electron-deficient dipolarophiles... 

The 1,3-dipolar cycloaddition of 7V-benzyl-C-ethoxycarbonylnitrone with (5)-5-hydroxymethyl-(577)-fiiran-2-one is regio- and stereo-selective. The intramolecular 1,3-dipolar cycloaddition of sugar ketonitrones (50) provides a convenient method for the stereoselective formation of carbohydrate derivatives (51) possessing nitrogenated quaternary centres. This methodology has been successfully used to prepare synthetic precursors of (—)-tetrodotoxin (52) (Scheme 18). The hydrophobic effect has been shown to influence the rate and selectivity of 1,3-dipolar cycloaddition reactions of C,iV-diphenylnitrone with electron-deficient dipolarophiles. ... 

With electron-deficient dipolarophiles and phenyl azide, the situation is again delicately balanced. The reaction is only just a dipole-HO-controlled one (9-5 eV against 10-7 eV). For the dipole-HO-controlled reaction, we should expect to get adducts orientated as shown on the left of Fig. 4-65. However, a phenyl group reduces the coefficient at the neighbouring atom both for the HOMO and for the LUMO, and this will reduce the polarization of the HOMO. Conversely, it will increase the polarization for the LUMO and hence increase the effectiveness of the dipole LUMO s interaction with... 

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