Cycloaddition, Normal-electron demand

The normal electron-demand reaction is a HOMOdiene-LUMOdienophUeelectron-rich dienes and electron-deficient dienophiles (Scheme 4.2, left dotted line). The inverse electron-demand cycloaddition reaction is primarily controlled by a LUMOdiene HOMOdienophiie inter-... 

NORMAL-ELECTRON DEMAND HOMO(jjene dienophile COntroll d cycloaddition reactions... 

Basic Aspects of Metal-catalyzed 1,3-Dipolar Cycloaddition Reactions 215 The normal electron-demand 1,3-dlpolar cycloaddition reaction... 

Several titanium(IV) complexes are efficient and reliable Lewis acid catalysts and they have been applied to numerous reactions, especially in combination with the so-called TADDOL (a, a,a, a -tetraaryl-l,3-dioxolane-4,5-dimethanol) (22) ligands [53-55]. In the first study on normal electron-demand 1,3-dipolar cycloaddition reactions between nitrones and alkenes, which appeared in 1994, the catalytic reaction of a series of chiral TiCl2-TADDOLates on the reaction of nitrones 1 with al-kenoyloxazolidinones 19 was developed (Scheme 6.18) [56]. These substrates have turned out be the model system of choice for most studies on metal-catalyzed normal electron-demand 1,3-dipolar cycloaddition reactions of nitrones as it will appear from this chapter. When 10 mol% of the catalyst 23a was applied in the reaction depicted in Scheme 6.18 the reaction proceeded to give a yield of up to 94% ee after 20 h. The reaction led primarily to exo-21 and in the best case an endo/ exo ratio of 10 90 was obtained. The chiral information of the catalyst was transferred with a fair efficiency to the substrates as up to 60% ee of one of the isomers of exo3 was obtained [56]. 

The normal electron-demand principle of activation of 1,3-dipolar cycloaddition reactions of nitrones has also been tested for the 1,3-dipolar cycloaddition reaction of alkenes with diazoalkanes [71]. The reaction of ethyl diazoacetate 33 with 19b in the presence of a TiCl2-TADDOLate catalyst 23a afforded the 1,3-dipolar cycloaddition product 34 in good yield and with 30-40% ee (Scheme 6.26). 

The relative FMO energies of the substrates of the 1,3-dipolar cycloaddition reaction of nitrones are important for catalytic control of the reaction. For the normal electron-demand 1,3-dipolar cycloaddition reactions the dominant FMO interac-... 

Normal electron-demand 1,3-dlpolar cycloaddition reaction... 

Nitrones can be activated mainly in two different ways for the 1,3-dipolar cycloaddition with alkenes. In the reaction between a nitrone and an electron-dehcient alkene, such as an a,p-unsaturated carbonyl compound (a normal electron-demand reaction), it is primarily controlled by the interaction between HOMOnitrone-LUMOaikene (Scheme 12.64). By coordination of a Lewis acid (LA) catalyst to the a,p-unsaturated carbonyl compound, the LUMOaikene energy decreases and a better interaction with the nitrone can take place (16,17). 

Several chiral Ti(IV) complexes are efficient catalysts and have been applied to numerous reactions, especially in combination with the TADDOL 244 ligands (350). Chiral TiCl2-TADDOLates were the first asymmetric catalysts to be applied in the normal electron-demand 1,3-dipolar cycloaddition of nitrones 225 with alkenoyl-oxazolidinones 241 (Scheme 12.73) (351). These substrates have turned... 

Thus, Ghosez et al. were successful in showing that A,iV-dimethyl hydrazones prepared from a,/3-unsaturated aldehydes react smoothly in normal electron demand Diels-Alder reactions with electron-deficient dienophiles [218, 219]. Most of the more recent applications of such 1-aza-l,3-butadienes are directed towards the synthesis of biologically active aromatic alkaloids and azaanthra-quinones [220-224] a current example is the preparation of eupomatidine alkaloids recently published by Kubo and his coworkers. The tricyclic adduct 3-19 resulting from cycloaddition of naphthoquinone 3-17 and hydrazone 3-18 was easily transformed to eupomatidine-2 3-20 (Fig. 3-6) [225]. 

Azo compounds like esters or imides of azo dicarboxylic acid act as reactive dienophiles in normal electron demand hetero Diels-Alder reactions due to the strong activation caused by two electron-withdrawing moieties. In the last years, considerable attention has focused on alkyl and phenyl derivatives of 1,2,4-tria-zoline-3,5-diones since their cycloadditions to chiral dienes proceed with often excellent facial selectivities. Thus, when reacting an oxapropellane derived diene with N -methyltriazolinedione, Paquette et al. obtained the cycloadduct as single diastereomer, but both maleic anhydride and N-phenyl maleimide were distinctly less reactive and turned out to undergo cycloadditions with poor selectivities [289]. 

Similarly to the homologous 1-oxa-1,3-butadienes, 1-thia-1,3-butadienes are known to be very suitable and reactive substrates for hetero Diels-Alder reactions. However, in contrast to the oxa-1,3-butadienes which in general act as electron-deficient component in such cycloadditions, thia-1,3-butadienes predominantly undergo normal electron demand Diels-Alder reactions with electron-deficient dienophiles. Nevertheless, also some reactions of thia-1,3-butadienes involving electron-rich dienophiles have been described [412,413], Thia-1,3-butadienes considerably tend to dimerize due to their high reactivity in hetero Diels-Alder reactions [414]. 

The dihydropyrans resulting from an oxa Diels-Alder reaction represent valuable intermediates for the synthesis of numerous natural compounds. In particular, they exhibit many structural elements of carbohydrates. It is therefore not surprising that both the normal electron demand cycloaddition of dienes to carbonyl dienophiles as well as the reaction of 1-oxa-l,3-butadienes with electron-rich alkenes have extensively been used for the synthesis of sugar derivatives. Nevertheless, various approaches to other natural products have been worked out by means of these powerful tools. 

The alkene (dienophile) component has two electrons in a Tt-bond thus, the FMO theory identifies both HOMO and LUMO (Fig. 8.16). Likewise, the diene which has four electrons in conjugated TT-system can have its HOMO and LUMO (Fig, 8,16), The most common situation finds electron-withdrawing substituents (X) on the dienophilic double bond and electron-donating substituents (R) on the diene. The bonding interaction in a normal electron demand will therefore have electrons flowing from the HOMO of the diene ( F2) to the LUMO of the dienophile (tt ). Various possible ways for the [4+2]-cycloaddition reaction to occur are shown in Fig. 8.27. 

Figure 8.28 Thermal [4s- -2s]-cycloaddition is symmetry matched for normal electron demand.

Some cycloadditions proceed thermally, whereas others require hv. The dependence of certain cycloadditions on the presence of light can be explained by examining interactions between the MOs of the two reacting components. Frontier MO theory suggests that the rate of cycloadditions is determined by the strength of the interaction of the HOMO of one component with the LUMO of the other. In normal electron-demand Diels-Alder reactions, HOMOdiene ( Ai) interacts with LUMOdienophiie (< >i ) There is positive overlap between the orbitals where the two cr bonds form when both components of the reaction react from the same face of the tt system (suprafacially). 

By contrast, under photochemical conditions and normal electron demand, I IOMOdiene changes from //1 to i//2. In this case, positive overlap at both termini of the 77 systems can occur only if one of the 77 components reacts antarafa-cially. This situation is very difficult to achieve geometrically, and hence six-electron cycloadditions do not proceed photochemically. 

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