Heterocycles with heteroatoms

Ortho-Fused Tricyclic Heterocycles with Heteroatoms at the 5 5 Ring Junction 793... 

Recently novel information on cyclizations to phosphorus-containing heterocycles with heteroatomic arrangement has appeared. These ring closures are shown in Scheme 46. 

Most benzo-fused heterocyclic systems are constructed from a substituted benzene by synthesis of the heterocyclic ring. Similarly most bicyclic heterocycles with heteroatoms in both rings commence with a monoheterocycle and build on the second heterocycle. However, substituent modification and, to a lesser extent, substituent introduction are also important, particularly in the later stages of a synthesis, and we now survey available methods for this. 

One can also determine the reactivity of two isomeric heterocycles in regard to their stability, with the notion that the less stable heterocycle will also be more reactive. That is, of course, not true because the reactivity of these two groups of heterocycles in Diels-Alder reactions do not depend only on their relative energies but also on the nature of the bonds that are formed in the course of reaction. Heterocycles with heteroatoms in the 1 and 2 positions of the ring form one bond... 

Addition of acetylene, ethylene, and cyclopropene to heterocycles with heteroatoms in the 1 and 2 positions... 

The other method to determine reactivity for reactions with synchronous concerted cyclic transition state structures is evaluation of the transition state ring aromaticity through bond order deviation. The results of the exo cyclopropene addition to the heterocycles and to cyclopentadiene are presented in Table 33. The higher the sum of bond order deviation from average bond order (x) is, the lower aromatic character the transition state structure has. The most reactive dienophile was cyclopentadiene, followed by furan, and then heterocycles. The most reactive heterocycle with heteroatoms in 1,3-position was 1,3-oxazole as was predicted on the basis of the FMO energy changes (Table 32). The least reactive was 1,3-diazole, as one would expect on the basis of experimental observations. It is very difficult to rely on the transition state structure bond order deviation to determine the experimental feasibility of a reaction but, because SBOD for furan and 1,3-oxadiazole were very similar, one can conclude that the cycloaddition with 1,3-oxadiazole is also experimentally feasible. 

Let us now explore the relative energies of these three groups of heterocycles. We have to be aware of the fact that only for heterocycles with heteroatoms simultaneously in the 1,3, and 4 positions two CC bonds are formed, while in the case of heterocycles with heteroatoms in 1,2, and 5 positions, two CN bond should be formed. The heterocycles with heteroatoms in the 1,2, and 3 positions are between these two cases. We have demonstrated above that heterocycles that have heteroatom-heteroatom bonds are usually less stable when compared with those that have heteroatoms separated by carbon atoms. As a result, one can... 

Here we present only activation barriers for heterocycles with heteroatoms in 1,2,5- positions in reaction with the most reactive dienophile, cyclopropene (Table 40). It demonstrates our previous postulate that the activation barriers were too high, even with very reactive dienophiles such as cyclopropene. The most reactive was 1,2,5-oxadiazole but not 1,2,5-tbiadiazole as predicted on the basis of FMO energy gap between reactants. The results indicated that the reaction should not be experimentally achievable. To the best of our knowledge, there is no experimental evidence that heterocycles with heteroatoms in 1,2,5- positions might be acceptable dienes for Diels-Alder reactions. 

The heterocycles with heteroatoms in 1, 2, and 4 positions (Scheme 8) have the highest probability to be engaged in Diels-Alder reactions as dienes because two new CC bonds should be formed in the course of the reaction. Due to their symmetry, one can also expect that transition states for reactions with symmetric dienophiles should be symmetric and support synchronous formation of both C-C bonds. The AMI computed transition state structures... 

As our computational results presented above demonstrate, it is highly unlikely that heterocycles would be good dienes for Diels-Alder reactions if formation of one or two C-N bonds were involved in the course of the reaction. This automatically eliminates some tautomeric forms of five-membered heterocycles with heteroatoms in 1 and 2 positions as well as five-membered heterocycles with heteroatoms in 1,2,3 and 1,2,5 positions. A major reason for the low reactivity of the heterocycles is because of their high aromaticity. It is obvious that diminishing or eliminating the aromaticity in these heterocycles would make them better dienophiles for Diels-Alder reactions. 

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