Homo Diels-Alder reaction regioselectivity

Homo-Diels-Alder reactions of norbornadiene, In the presence of Ni(COD)2 and P(C6H5)3 (1 2) norbornadienes can react with activated alkenes at 80° to give [2 + 2 + 2] adducts. Preliminary studies of the regioselectivity indicate that this homo-Diels-Alder reaction can be useful for synthesis of complex molecules. Thus reaction of methyl norbornadiene-2-carboxylate with acrylonitrile results in only two... 

These preliminary results indicate that substituent groups can exert a marked effect on the regioselectivity of this homo-Diels-Alder reaction with a general preference for ortho- and para-isomers. 

When both the 1,3-dipoIe and the dipolarophile are unsymmetrical, there are two possible orientations for addition. Both steric and electronic factors play a role in determining the regioselectivity of the addition. The most generally satisfactory interpretation of the regiochemistry of dipolar cycloadditions is based on frontier orbital concepts. As with the Diels-Alder reaction, the most favorable orientation is that which involves complementary interaction between the frontier orbitals of the 1,3-dipole and the dipolarophile. Although most dipolar cycloadditions are of the type in which the LUMO of the dipolarophile interacts with the HOMO of the 1,3-dipole, there are a significant number of systems in which the relationship is reversed. There are also some in which the two possible HOMO-LUMO interactions are of comparable magnitude. 

Fig. 6.2. HOMO-LUMO interactions rationalize regioselectivity of Diels-Alder reactions.

In the [4 + 2] cycloadditions discussed so far, the enol ether double bond of alkoxyallenes is exclusively attacked by the heterodienes, resulting in products bearing the alkoxy group at C-6of the heterocycles. This regioselective behavior is expected for [4+2] cycloadditions with inverse electron demand considering the HOMO coefficients of methoxyallene 145 [100]. In contrast, all known intramolecular Diels-Alder reactions of allenyl ether intermediates occur at the terminal C=C bond [101], most probably because of geometric restrictions. 

These same features can ensure regioselective Diels-Alder reactions. The same orbital of the dienophile is used and, if the HOMO of the diene is also unsymmetrical, the regioselectivity of the reaction will be controlled by the two largest coefficients bonding together. 

The Regioselectivity ofHetero Diels-Alder Reactions. In a few cases, carbonyl, nitrosyl, cyano, and other double bonds with one or more electronegative heteroatoms have acted as dienophiles in Diels-Alder reactions. The carbonyl group has a HOMO and a LUMO as shown in Fig. 1.51. The energies of both orbitals are relatively low, and most of their Diels-Alder reactions will therefore be guided by the interaction between the HOMO of the diene and the LUMO of the carbonyl compound. This explains the regioselectivity in the cycloaddition of dimethylbutadiene 6.176 and formaldehyde, and between 1-substitituted butadienes 6.177 and nitrosobenzenes. 

Secondary orbital interactions have also been invoked to explain regiochemistry as well as stereochemistry. Whereas 1 -substituted dienes sometimes have only a small difference between the coefficients on C-l and C-4 in the HOMO, they can have a relatively large difference between the coefficients on C-2 and C-3. Noticing this pattern, Alston suggested that the regioselectivity in Diels-Alder reactions may be better attributed, not to the primary interactions of the frontier orbitals on C-l and C-4 that we have been using so far, but to a... 

Among the few examples of simple 1-azadiene Diels-Alder reactions is a dihydropyridine synthesis using the stable azadiene 39 (prepared from cinnamaldehyde and aniline) with the dienophile 38 prepared from the isoxazole 35 by elimination. This is a reverse-electron-demand cycloaddition, the HOMO of the dienophile 38 combining with the LUMO of the azadiene 39 to give the cycloadduct 40 and hence the dihydropyridine 41 with complete regioselectivity and in very high yield.3... 

The regioselectivity of the addition is determined by the HOMO of the azadiene 62 which is dominated by the two electron-donating silyloxy groups. The nitrogen atom is almost irrelevant. The LUMO of the unsaturated ester is typical for any Diels-Alder reaction. 

The Alder ene reaction is like a Diels Alder reaction in which one Jt-bond in the diene has been replaced by a C-H bond 121. It does not therefore form a ring and does not fit easily into any of the three classes of pericyclic reaction (cycloaddition, electrocyclic, and sigmatropic). Since a hydrogen atom is transferred from one component to the other it is best described as a group transfer reaction.21 The regioselectivity is determined by the interaction 123 with the Jt-bond of the ene (the HOMO) with the LUMO of the enophile. ... 

Activated dienes are also highly regioselective. This is due to the unsymmetrical polarization of the HOMO that is caused by the placement of substituents on the diene. The use of activated dienes is well documented in classical Diels-Alder reactions. They provide for high reactivity, good regioselectivity and introduce useful functionality into the cycloadducts."... 

It is significant that if an electron-poor diene is utilized, the preference is reversed and electron-rich alkenes, such as vinyl ethers and enamines, are the best dienophiles. Such reactions are called inverse electron demand Diels-Alder reactions, and the reactivity relationships are readily understood in terms of frontier orbital theory. Electron-rich dienes have high-energy HOMOs that interact strongly with the LUMOs of electron-poor dienophiles. When the substituent pattern is reversed and the diene is electron poor, the strongest interaction is between the dienophile HOMO and the diene LUMO. The FMO approach correctly predicts both the relative reactivity and regioselectivity of the D-A reaction for a wide range of diene-dienophile combinations. 

In orbital terms, this must mean that the HOMO of the diene is distorted so that the end that reacts has the larger coefficient. When the unsymmetricai diene and the unsymmetricai dienophile combine in a Diels-Alder reaction, the reaction itself becomes unsymmetricai. It remains concerted but, in the transition state, bond formation between the largest coefficients in each partner is more advanced and this determines the regioselectivity of the reaction. 

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