Pyridine retrosynthetic analysis

To begin the retrosynthetic analysis, note that the acetate ester is easily produced from the corresponding alcohol A. Therefore conversion of A to M using acetic anhydride/pyridine could be used in the synthetic step. (Remember For each retrosynthetic step, a reaction must be available to accomplish the synthetic step.)... 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

Our retrosynthetic analysis of generalised pyridine 5.4 commences with an adjustment of the oxidation level to produce dihydropyridine 5.5. This molecule can now be disconnected very readily. Cleavage of the carbon-heteroatom bonds in the usual way leaves dienol 5.6 which exists as diketone 5.7. The 1,5-dicarbonyl relationship can be derived from a Michael reaction of ketone 5.8 and enone 5.9, which in turn can arise from condensation of aldehyde 5.10 and ketone 5.11. 

Completion of the synthesis of WS75624 B was more complicated than that of caerulomycin C due to the presence of the substituted thiazole. As previously mentioned, our retrosynthetic analysis involved the disconnection of the thiazole from the pyridine, and required that we synthesize an appropriately functionalized thiazole coupling partner bearing a metal at the 4-position. Our success with the halogen-dance reaction on pyridines prompted us to examine its use in the synthesis of substituted thiazoies. 

The retrosynthetic analysis of pyridine (see Fig. 10) can be carried out in several ways. 

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. 

Retrosynthetic analysis ch28 How to make pyridines and pyridones ... 

WORKED PROBLEM 16.26 Here is a specific example of using retrosynthetic analysis. Provide a retrosynthetic synthesis of 2-phenyl-2-butanol. Assume that you have benzene, ethanol, pyridine, and access to any inorganic reagents you might need. 

Abstract Retrosynthetic analysis as an imaginative process is introduced. Disconnection and functional group interconversion are discussed. l-(Pyridine-3-yl) propan-l-ol is selected as an exemplary target molecule for retrosynthetic analysis and its (5 -enantiomer for asymmetric synthesis. Interconversions of oxygen functionalities are overviewed. The acidity of the C-H bond as a key property for C-C disconnections is indicated. Some historical and environmental aspects of organic synthesis are concisely presented. 

A proposal for the synthesis of the target molecule, irrespective of its complexity, can be elaborated by retrosynthetic analysis based on the disconnection approach. For chiral molecules this approach results in a proposal for the synthesis of racemic target molecules. Preparation of one enantiomer, or optically pure target molecule, enables asymmetric synthesis. 1-(Pyridine-3-yl)propan-l-ol is selected to demonstrate various retrosynthetic approaches to this relatively simple target molecule and to show the complexity of asymmetric syntheses of the preferred enantiomer. An introductory example is elaborated in some detail to familiarize the reader with the philosophy behind retrosynthetic analysis and to underline the need for chiral information in the reacting system to complete asymmetric synthesis. Today chiral variants of synthetic reactions are the subject of intensive research, and it is said that their number is limited only by the creativity of the organic chemist. 

The target molecule of our first retrosynthetic analysis is racemic l-(pyridine-3-yl) propan-l-ol, TM 1. In Sect. 1.3.2, we discuss some possibilities for obtaining optically pure enantiomer (5)-TM 1 by application of asymmetric synthesis. 

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