Systems retrosynthetic considerations

The synthesis of pyridazines follows from a simple retrosynthetic consideration, leading to the 1,4-dicarbonyl systems 5 and 6 and hydrazine as starting materials ... 

A bicyclic system consisting of two aneUated rings can be viewed as a monocycle, which carries two substituents that happen to be closed to the other ring. In terms of retrosynthetic considerations, the four exendo bonds are important, i.e., those bonds that are endocyclic in one ring and exocyclic with respect to the other ring (Scheme 6.17). 

The above retrosynthetic considerations are the basis for the majority of the actual syntheses [166] of the quinoline system. 

Intramolecular cycloadditions are among the most efficient methods for the synthesis of fused bicyclic ring systems [30]. From this perspective, the hetisine skeleton encompasses two key retro-cycloaddition key elements. (1) a bridging pyrrolidine ring accessible via a [3+2] azomethine dipolar cycloaddition and (2) a [2.2.2] bicyclo-octane accessible via a [4+2] Diels-Alder carbocyclic cycloaddition (Chart 1.4). While intramolecular [4+2] Diels—Alder cycloadditions to form [2.2.2] bicycle-octane systems have extensive precedence [3+2], azomethine dipolar cycloadditions to form highly fused aza systems are rare [31-33]. The staging of these two operations in sequence is critical to a unified synthetic plan. As the proposed [3+2] dipolar cycloaddition is expected to be the more challenging of the two transformations, it should be conducted in an early phase in the forward synthetic direction. As a result, a retrosynthetic analysis would entail initial consideration of the [4+2] cycloaddition to arrive at the optimal retrosynthetic C-C bond disconnections for this transformation. 

Two possible intramolecular disconnections are available for the [2.2.2] bicyclo-octane ring system (path A and path B, Scheme 1.4). The choice between the initial [4+2] disconnections A and B at first appears inconsequential leading to idealized intermediates of comparable complexity (54 and 57). However, when the [4+2] and [3+2] disconnections are considered in sequence, the difference becomes clear. For path A, retrosynthetic [3+2] disconnection of intermediate 54 leads to the conceptual precursor 56, which embodies a considerable simplification. In contrast, path B reveals a retrosynthetic [3+2] disconnection of intermediate 57 to provide the precursor 59, a considerably less simplified medium-ring bridged macrocycle. Thus, unification of the [3+2]/[4+2] dual cycloaddition strategy, using the staging... 

It must not be forgotten that the retrosynthetic bond-disconnections are only mental processes [27], which may however, coincide with actual processes in the laboratory provided that the reactions under consideration are reversible. Another immediate consequence is that only consonant systems (or molecules) can offer, properly speaking, reasonable bond-disconnection mechanisms, as it is required by "logical bond disconnections". 

If the azine structure is considered by itself, then the retrosynthetic analysis can start at the imine structural element (H2O addition O -> C-2, retrosynthetic path a). Suggestions for the cyclocondensation of various intermediates arise based on the 5-aminopentadienal or -one system 145, and further (path g, NH3 loss) on pent-2-endial (glutaconic dialdehyde) or its corresponding diketone 146. Consideration of a retro-cycloaddition (operation c) leads to the conclusion that a synthesis of pyridines by a cocyclooligomerization of alkynes with nitriles is possible. 

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