Five-membered heterocyclics substitution

Table 32 Conformational Preference of 2-Substituted Five-membered Heterocycles...

Some examples of ring opening reactions with carbanions leading to five-membered heterocyclic ring formation are shown in Scheme 85. Pyrrole syntheses from functionally substituted oxiranes and amines are often described and typical examples are shown in Scheme 86. 

In the reactions of electrophilic substitution, isoxazole is far less active than the five-membered heterocycles with one hetero atom and pyrazole. It is closer to pyridine, but more reactive. 

As demonstrated above, nitro derivatives of five-membered heterocycles have found extensive use as antiinfective agents. It is therefore of interest that the nitro derivative of a substituted thiazole was at one time used as an antitrichomonal agent. Bro-mination of 2-aminothiazole (136) (obtained from condensation of thiourea with chloroacetaldehyde) gives the 4-bromo derivative (138) this is then acetylated to 139. Treatment of 139 with nitric acid leads to an interesting displacement of bromine by a nitro group to afford aminitrazole (140)... 

In addition to nitrones, azomethine ylides are also valuable 1,3-dipoles for five-membered heterocycles [415], which have found useful applications in the synthesis of for example, alkaloids [416]. Again, the groups of both Grigg [417] and Risch [418] have contributed to this field. As reported by the latter group, the treatment of secondary amines 2-824 with benzaldehyde and an appropriate dipolarophile leads to the formation of either substituted pyrrolidines 2-823, 2-825 and 2-826 or oxa-zolidines 2-828 with the 1,3-dipole 2-827 as intermediate (Scheme 2.184). However, the yields and the diastereoselectivities are not always satisfactory. 

All compounds reported within the review period are indolizines or their hetero-substituted derivatives, fused through the a- or -edge to a five-membered heterocyclic ring. 

In addition, complexes of P(/-Bu)3 have been shown to catalyze the formation of diaryl heteroarylamines from bromothiophenes.224 Aminations of five-membered heterocyclic halides such as furans and thiophenes are limited because their electron-rich character makes oxidative addition of the heteroaryl halide and reductive elimination of amine slower than it is for simple aryl halides. Reactions of diarylamines with 3-bromothiophenes occurred in higher yields than did reactions of 2-bromothiophene, but reactions of substituted bromothiophenes occurred in more variable yields. The yields for reactions of these substrates in the presence of catalysts bearing P(/-Bu)3 as ligand were much higher than those in the presence of catalysts ligated by arylphosphines. 

Dipolar cycloadditions are the most general method for the synthesis of five-membered heterocycles [51]. Various easily available and efficient 1,3-dipolar reagents are able to react with double or triple bonds to afford many different classes of structurally differentiated, selectively substituted heterocycles... 

There are several systematic nuclear magnetic resonance studies of the interaction between the substituents and the protons and ring atoms of five-membered heterocycles. In some 2-substituted furans, thiophenes, selenophenes, and tellurophenes there is a linear correlation between the electronegativity of the chalcogen and several of the NMR parameters.28 As there also is a good correlation between the shifts of the corresponding protons and carbons in the four heterocycles, the shifts of unknown selenophene and tellurophene derivatives can be predicted when those of thiophene are known. This is of special interest for the tellurophene derivatives, since they are difficult to synthesize. In the selenophene series, where a representative set of substituents can be introduced in the 2- as well as in the 3-position, the correlation between the H and 13C shifts and the reactivity parameters according to Swain and Lupton s two-parameter equation... 

The amino-substituted five-membered heterocycles are unstable compounds, but their acetyl and formyl derivatives can be isolated. N-(Selenienyl-3)formamide can be obtained via the reaction route shown in Scheme ll.134 An ortho, electron-attracting substituent, such as formyl or nitro, renders amino compounds stable. However, the yield of 2-nitro-3-aminoselenophene is quite low. 

In contrast to 6-substituted-bipyridine systems such as 49, attachment of a five-membered heterocycle to the 2-position of 1,10-phenanthroline, which is a structural modification similar to the replacement of one of the terminal rings of terpyridine, does generally bring the ligand field into the crossover region and spin transitions have been observed for such systems when the heterocycle is thiazole 51 [74], imidazoline [75], triazole [76], pyrazole [77] and oxadiazole [78]. 

The cydoaddition of different 1,3-dipoles such as azides [331, 341] and diazoalkanes [342-344] to acceptor-substituted allenes was thoroughly investigated early and has been summarized in a comprehensive review by Broggini and Zecchi [345], The primary products of the 1,3-dipolar cycloadditions often undergo subsequent fast rearrangements, for example tautomerism to yield aromatic compounds. For instance, the five-membered heterocycles 359, generated regioselectively from allenes 357 and diazoalkanes 358, isomerize to the pyrazoles 360 (Scheme 7.50) [331]. 

The reactions of 5-acyl-2,2-dimethyl-4,6-dioxo-l, 3-dioxanes (1373) with urea, thiourea, sulfamide, hydroxylamine, or 1-substituted hydrazines gave monocyclic six- and five-membered heterocycles (1374-1378) in good yields [79JAP(K) 106466],... 

No nucleophilic substitution in five membered heterocycles with hydroxylamines has been reported so far, although any nucleophilic substitution reaction known for amines should be suitable for hydroxylamines as well. 

Forty-four five-membered heterocycles of type A (13, 19) have been described (Table I). If the atoms or groups a, b, c, d, e, and f are selected from suitably substituted carbon, nitrogen, oxygen, and sulfur atoms, then with these conditions it can be shown that 144 structural possibilities are provided by the general formula 19. The number of structural possibilities can be deduced in various ways, but a very useful approach is to regard type A meso-ionic molecules (19) as being derived by the union (-<—u— ) of 1,3-dipoles (34) and heterocumulenes (35). 

This second class of five-membered heterocyclic meso-ionic compounds is represented by the type formula 14 20. So far, only eight representatives (Table II) of type B have been described, whereas acceptable combinations of the groupings a, b, c, d, e, and f derived from suitably substituted carbon, nitrogen, oxygen, or sulfur atoms lead, in principle, to 84 possibilities. However, not all these 84 possible structures are necess y well based because valence tautomerism (see Section VI) might well be associated with thermodynamic preference for the acyclic covalent valence isomer (46) rather than the cyclic meso-ionic alternative (20). 

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