Vincenzo Frenna

Ring Transformations of Five-Membered Heterocycles*

Publisher Summary This chapter reviews that ring transformations of heterocycles constitute an interesting area that continues to be of great importance in mechanistic studies and in synthetic design. With reference to five-membered heterocycles, an enormous variety of ring transformations are known and there has always been some difficulty in rationalizing these reactions systematically. A greatly significant classification can be recognized in molecular rearrangements of heteromonocycles that involve the participation of a given number of side-chain atoms in the new ring formation, including special rearrangements where interchanges of annular atoms simply occur. This review is concerned with the rearrangements of five-membered heterocycles represented by the generalized pattern 5→ 6, where W pivotal center is a nitrogen (W=N), sulfur (W=S), or carbon atom (W=C), and the side-chain contains three or four participating atoms.

Mononuclear heterocyclic rearrangements. Part 11. Kinetic study of the rearrangement of (Z)-phenylhydrazones of some 5-alkyl-3-benzoyl-1,2,4-oxadiazoles into 4-acylamino-2,5-diphenyl-1,2,3-triazoles in benzene, dioxane–water, and acetonitrile

The kinetics of the title reactions have been measured at various catalyst concentrations. The 5-alkyl-substituted phenylhydrazones (alkyl = Me, Et, Pri, or But) rearrange more slowly than the 5-H parent compound; moreover the rearrangement rate is little affected by the structure of the 5-alkyl substituent. These facts are considered as evidence against a rearrangement mechanism involving catalyst addition to the C(5)–N(4) bond of the 1,2,4-oxadiazole ring. The observed reactivity pattern can be related to the influence of the 5-substituent on the leaving group ability of the substituent–C(5)–O system.

Acid- and Base-Catalysis in the Mononuclear Rearrangement of Some (Z)-arylhydrazones of 5-Amino-3-benzoyl-1,2,4-oxadiazole in Toluene: Effect of Substituents on the Course of Reaction

The reaction rates for the rearrangement of eleven (Z)-arylhydrazones of 5-amino-3-benzoyl-1,2,4-oxadiazole 3a-k into the relevant (2-aryl-5-phenyl-2H-1,2,3-triazol-4-yl)ureas 4a-k in the presence of trichloroacetic acid or of piperidine have been determined in toluene at 313.1 K. The results have been related to the effect of the aryl substituent by using Hammett and/or Ingold-Yukawa-Tsuno correlations and have been compared with those previously collected in a protic polar solvent (dioxane/water) as well as with those on the analogous rearrangement of the corresponding (Z)-arylhydrazones of 3-benzoyl-5-phenyl-1,2,4-oxadiazole 1a-k in benzene. Some light can thus be shed on the general differences of chemical reactivity between protic polar (or dipolar aprotic) and apolar solvents.

A GENERALIZED SYNTHESIS OF 3-AMINO-5-ARYL- , 3-AMINO-5- POLYFLUOROPHENYL-, AND 3-AMINO-5-ALKYL-1,2,4- OXADIAZOLES THROUGH RING-DEGENERATE REARRANGEMENTS

A generalized synthesis of 3-amino-5-aryl-, 3-amino-5-poly- fluorophenyl- and 3-amino-5-alkyl-1,2,4-oxadiazoles has been developed starting from the 3-amino-5-methyl-1,2,4-oxadiazole as a common synthon. Aroylation or alkanoylation of this aminooxadiazole, followed by thermally- induced ring-degenerate equilibration of resulting 3-acylamino compounds, and final acid hydrolysis of the 3-acetylamino-5-aryl- (or 5-polyfluorophenyl-), or 3- acetylamino-5-alkyl-1,2,4-oxadiazoles counterpart which is formed, gave the expected 3-amino-5-substituted 1,2,4-oxadiazoles. In the case of some 3- aroylamino compounds, yields of final 3-amino-5-aryloxadiazoles are higher than that expected on the basis of the thermally-induced equilibrium composition, since acid hydrolysis plays a significant role in the shift of the equilibrium itself. Satisfactory direct procedures have also been described. As expected, restrictions to the above methodology were found in the synthesis of 5-perfluoroalkyl derivatives.

Heterocyclic Rearrangements — The Rearrangement of 3-Aroylaminoisoxazoles into 2-Aroylaminooxazoles

When treated with t-BuOK in DMF at 110-120°C, 3-aroylamino-5-methylisoxazoles gave good yields of 2-aroylamino-5-methyloxazoles as the ring rearrangement products. The same to oxazole ring isomerization has been also observed in a photoinduced reaction

Mononuclear heterocyclic rearrangements. Part 14. Rearrangement of some Z-arylhydrazones of 3-benzoyl-5-phenylisoxazole to 2-aryl-4-phenacyl-1,2,3-triazoles in dioxane–water

The kinetics of the title reaction have been measured at various pS+ values. The results show the occurrence of general base catalysis and furnish information about substituent effects on the studied reaction. A reaction mechanism analogous to that proposed for the rearrangement of the arylhydrazones of 3-benzoyl-5-phenyl-1,2,4-oxadiazole is suggested. The reactivity of isoxazole derivatives is much lower than that of 1,2,4-oxadiazole derivatives.

Mononuclear heterocyclic rearrangements. Part 7. Evidence for general base catalysis in the rearrangement of the Z-phenylhydrazone of 3-benzoyl-5-phenyl-1,2,4-oxadiazole into 2,5-diphenyl-4-benzoylamino-1,2,3-triazole in dioxan–water

The title reaction has been studied at various pS+ and buffer concentrations. Kinetic constants for uncatalysed and catalysed pathways have been calculated. A mechanism for the rearrangement is offered.

Amine basicities in benzene and in water

The constants for ion-pair formation with 2,4-dinitrophenol in benzene (KB), and the pKa, values in water, of thirty-three amines have been measured. According to the class of amine, two different situations can be observed: for primary amines and secondary cyclic amines, the effects of structural variations on basicity are higher in water than in benzene; on the other hand, for tertiary amines these effects are similar in the two solvents. KB, Values of primary amines give a good correlation with σ*. The Taft and Hancock equation allows a unifying treatment of KB, values of the various classes of amines.

Mononuclear heterocyclic rearrangements. Effect of the structure of the side chain on the reactivity. Part 3. Rearrangement of some N-(5-phenyl-1,2,4-oxadiazol-3-yl)-N′-arylformamidines into 1-aryl-3-benzoylamino-1,2,4-triazoles in acetonitrile in the presence of triethylamine

The apparent pseudo-first-order rate constants for the title reaction give a curvilinear plot versus tertiary amine concentration, according to the equation kA  (ku, + K1k2[TEA])/(1 + K1[TEA]). This shows the occurrence of two different reaction pathways; the one, independent of [TEA] and the other, dependent on [TEA], which involves a fast conversion of the substrate into an acid-base adduct or an ion pair followed by its slow conversion into the corresponding triazole. The substituent effects on these reactions have also been studied.

Mononuclear heterocyclic rearrangements. Effect of the structure of the side chain on the reactivity. Part 1. Rearrangement of some 3-arylureines of 5-pheny-1,2,4-oxadiazole into 1-aryl-3-benzoylamino-1,2,4-triazolin-5-ones in acetonitrile, benzene, and dioxane–water

The effect of the structure of the side chain both on the mechanism and the reactivity in mononuclear heterocyclic rearrangements has been studied by comparing the base-catalysed rearrangement of some 3-arylureines of 5-phenyl-1,2,4-oxadiazole with that of some arylhydrazones of 3-benzoyl-5-phenyl-1,2,4-oxadiazole. In acetonitrile and in benzene, in the presence of amines, on changing from the side chain CNN (arylhydrazones) to the side chain NCN (arylureines), a strong decrease of the reactivity has been observed (rate ratios ca. 103), but the reaction mechanism is the same for the two series of compounds. In contrast, in dioxane–water, the reactivity variation is much less (rate ratios ca. 25 in the pS+-dependent range) and a change of mechanism is observed. For arylureines and for arylhydrazones, specific- and general-base catalysis respectively has been shown. This is in keeping with the high acidity of arylureines, which in the presence of a strong base can be converted into the corresponding anions and then rearrange to the 1,2,4-triazolin-5-ones.