Of saturated heterocycles

Application of NMR spectroscopy to heterocyclic chemistry has developed very rapidly during the past 15 years, and the technique is now used almost as routinely as H NMR spectroscopy. There are four main areas of application of interest to the heterocyclic chemist (i) elucidation of structure, where the method can be particularly valuable for complex natural products such as alkaloids and carbohydrate antibiotics (ii) stereochemical studies, especially conformational analysis of saturated heterocyclic systems (iii) the correlation of various theoretical aspects of structure and electronic distribution with chemical shifts, coupling constants and other NMR derived parameters and (iv) the unravelling of biosynthetic pathways to natural products, where, in contrast to related studies with " C-labelled precursors, stepwise degradation of the secondary metabolite is usually unnecessary. 

The spectra of saturated heterocycles are generally fairly featureless, with amine n —>a absorptions and those transitions associated with sulfur showing up weakly, while saturated ethers are usually transparent down to 210 nm. 

PE spectroscopy has also been applied to the study of the conformational equilibria of saturated heterocyclic six-membered rings, and in particular of hexahydropyridazines. The... 

The chemistry of saturated heterocyclic compounds is characteristic of their functional group. For example, nitrogen compounds are amines, oxygen compounds arc ethers, sulfur compounds are sulfides. Differences in chemical reactivity are observed for three-membered rings, e.g., epoxides, whose enhanced reactivity is driven by the relief of their severe ring strain. This chapter discusses heterocycles that are aromatic and have unique chemical properties. 

The reductive route used to prepare heterocyclic enamines has the advantage of avoiding the hydroxylation reaction sometimes found in the mercuric acetate oxidation of saturated heterocyclic amines [126]. The lithium-n-propyl-amine reducing system has been used by Leonard to reduce julodine to A5-tetrahydrojulolidine (66% yield) and l-methyl-l,2,3,4-tetrahydroquinoline to a mixture of enamines (87% yield), consisting of l-methyl-A8-octahydro-quinoline and 1-methyl-A9-octahydroquinoline [135] (Eqs. 51, 52). 

One of the present authors has extensively used the dipole-moment method to calculate conformational equilibria of saturated heterocycles. In hindsight this has been a frustrating experience not so much because of the assumptions and approximations that must be made, but because the results in some cases are in good agreement with those derived from other methods, whereas for other groups of compounds the dipole-moment conclusions are clearly incorrect. In this discussion we first discuss the method, using piperidines as an example, and then attempt to assess its areas of applicability and causes of failure. 

The basicities of saturated heterocycles are similar to those of analogous open chain systems, with the exception of three-membered heterocycles, in which the basicity is markedly reduced. Table 1 gives pvalues for the equilibria between free and monoprotonated heterocycles. As the ring size increases, the protonated species become more stable and the pKa values approach those of the open chain analogues. Increasing basicity (thiirane < oxirane < aziridine) prevails in gas phase proton affinities (Table 2) (80JA5151). 

A general account of the NMR spectroscopy of six-membered ring heterocycles is given in Chapter 2.01. Proton and carbon NMR spectroscopy have been used extensively to determine the solution conformations of saturated heterocyclic rings containing three or... 

Wilier, R.L. and Eliel, E.L., Conformational analysis. 34. Carbon-13 nuclear magnetic resonance spectra of saturated heterocycles. 6. Methylthianes, J. Am. Chem. Soc., 99, 1925, 1977. 

Synthesis of saturated heterocycles 89GSM(11)547 90GSM(12)423 91GSM(13)372 92GSM(14)363 93GSM(15)301. 

Conformational Analysis of Saturated Heterocyclic Six-Membered Rings... 

The saturated heterocyclic rings are shown in black, and names for the most important ring types are given some (like piperidine, morpholine)you will need to remember others (tetrahydrofuran, pyrrolidine) are more obviously derived from the names for aromatic heterocycles that we wi II. discuss in the next chapter. Someef -these compounds (nicotine, coniine, cocaine) are plant products fall the class called alkaloids. Alkaloids are discussed in Chapter 51. Another important class of saturated heterocycles, sugars, will reappear rt Chapter 49. 

Some substituents of saturated heterocycles prefer to be axial the anomeric effect... 

Aminals are another class of saturated heterocycles that form very readily under thermodynamic control aminals are nitrogen analogues of acetals. They are usually made by refluxing a 1,2-diamine with an aldehyde in toluene (no acid catalyst is needed because the nitrogens are very nucleophilic), and this makes a very useful way of forming a chiral derivative of an achiral aldehyde. Here is an example the diamine is made from the amino acid proline. The product has a new chiral centre, and it forms as a single diastereoisomer because the phenyl ring prefers to be on the exo face of the bicyclic system (see Chapter 33). 

The Lolium alkaloids have a striking skeleton of saturated heterocycles. One way to make this skeleton is shown below. Explain both the mechanism and the stereochemistry. 

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