Six-Member Heterocyclic Systems

The steric interaction between any axial substituent and a 3-situated heteroatom is counted as zeroT Thus, in 3-substituted tetrahydropyrans, the destabilization due to an axial R substituent is computed as half of the A.  

Because of the shorter C-0 bond distance (C-0 1.43 A), the 1,3 R H interaction is expected to increase. This is especially evident when two heteroatoms are present in the cyclohexane ring, as in 1,3-dioxanes. For example, the conformational equilibrium in the following example favors the axial t-butyl group It should be noted that interference by bonded atoms or groups is more severe than by nonbonding (lone pairs) electrons. 

Alternatively, electrostatic repulsive forces between the dipoles due to the ring oxygen lone pairs and the exocyclic oxygen or halogen may account in part for the observed axial preferences.  

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Two types of reaction are known which involve ring contraction of six-membered heterocyclic systems and present mechanistically intriguing problems. One is the ring contraction of the diphenyltriazinone (10) Treatment with chloramine gives a 4,5-diphenyl-w-triazole in high yield. A mechanism (Scheme 26) involving a 2-carboxamidotriazole... 

As with the other procedures for the preparation of six-membered heterocyclic systems which proceed via formation of only one ring bond there are relatively few methods which involve formation of a ring bond y to the heteroatom and which can best be classified as [6 + 0] processes rather than [4 + 2], [3 + 3], etc, processes. Of those which can be so represented, however, a number are important processes which are widely used for the synthesis of saturated, partially saturated and aromatic six-membered heterocyclic systems and their benzo derivatives. Mechanistically, the nucleophile —> electrophile approach is by far the most common, but in contrast to the reactions discussed in the previous three sections, radical cyclizations are of considerable utility here. 

Synthetic methods for the preparation of six-membered heterocyclic systems which proceed via the formation of three or four bonds are virtually restricted in application to the monocyclic heterocycles and have been most widely applied to pyridine and pyrimidine derivatives. In principle, reactions which proceed with the formation of three ring bonds can be sub-classified into three groups, namely, those involving [4 + 1 + 1] atom fragments, [3 + 2 + 1] atom fragments and [2 + 2 + 2] atom fragments. 

There is a very wide variety of reactions in which five-membered heterocycles are transformed into six-membered heterocyclic systems and some of these processes are of... 

A number of very important synthetic methods are based on ring interconversions of six-membered heterocyclic systems. As with the transformations of five- into six-membered rings, examples are known of all of the possible atom fragments, but [5 + 1] and [4+2] processes are by far the most important. As described in Chapter 2.02, a number of [6+0] photoisomerizations of diazines have been discovered, but while these are of considerable mechanistic and theoretical importance they are of little preparative significance. 

There are two important general types of reaction by which six-membered heterocycles containing two or more heteroatoms can be transformed into other six-membered heterocyclic systems, namely reactions which involve an ANRORC mechanism, and reactions which proceed by a Diels-Alder/retro-Diels-Alder type of mechanism. Transformation of 1,3-oxazinones and -thiazinones into pyrimidones (equations 193 and 194) has been extensively used, especially in the conversion of isatoic anhydride into quinazolinones (e.g. equation 195). 2,4-Diaryl-l,2,3,5-oxathiadiazines, which are readily accessible by reaction of sulfur trioxide with aryl isocyanates, are useful precursors to pyrimidines and 1,3,5-triazines (equation 196). 

The conversion of a 1,4,3-oxathiazine 4,4-dioxide (268) by ethanolic ammonia into a 4H-l,2,4-thiadiazine 1,1-dioxide (269) is a rare example of the formation of a 1,2,4-thiadiazine by ring transformation from another six-membered heterocyclic system (Equation (23)) <888521 >. 

Six-membered heterocyclic systems which have been synthesised by similar methods include l,6-methano[10]annulenopyridines (214) from (213), y-carblines (215), lavendamycin methyl ester,a range of functionalised 2,3-dihydropyrido[3 ,2 4,5]thieno[3,2-d]pyrimidines (216), and the quinazolino[3,4-a]perimidine derivatives (e.g. 218) from 1,2-dihydro-properimidine azide (217). The previously unreported 4-methylene-4H-3,l-benzozazine ring (219) has been prepared from o-azidoacetophenone and the zwitterionic heteropolycyclic uracils (220) have been synthesised by a three-component reaction of iminophosphorane, isocyanate, and substituted pyridine. ... 

In fact, the experimentally determined conformation of these types of six membered heterocyclic systems is found to be dependent on the heteroatom as illustrated be-... 

Five-Membered Heterocycles Fused with Six-Membered Heterocyclic Systems 288... 

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