Tautomerism and Rearrangements

Equation (1) is dictated by the sensitivity of current techniques to detect a minor tautomer in an equilibrium mixture. Equation (2) serves to define tautomeric rearrangements as those transformations in which the lifetimes of the isomers are too short to enable the preparative separation of the two forms. Obviously, the above criteria should be regarded as no more than guidelines. Nevertheless, they do form a useful basis for distinguishing tautomeric reactions from rearrangements. 

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Undoubtedly, the above-mentioned examples are just a start toward investigating migrations in dihydroazines. Detailed research of these processes will certainly provide a deeper understanding of the problems of tautomerism and rearrangements as a whole as well as of the energetics, reactivity, and mechanisms of the formation of a variety of dihydroazines. 

Syntheses from Phthalimidines Syntheses from Ortho-Disubstituted Benzenes Condensation of 1,4-Diketones with Amines and Pyrroles Other Reactions and Rearrangements Leading to Isoindoles IV. Properties of the Isoindole System A. Tautomerism... 

In this work the possibility of the existence of 1,2-dihydro isomer with the core structure 42 was not considered. Recently, however, it was shown that 1,2-dihydropyridazines could be prepared by careful electroreduction of the corresponding pyridazines, and that their stability depends significantly on the ring substitutions. Thus, dimethyl l,2-dihydropyridazine-3,6-dicarboxylate 43a (R = H) is reasonably stable and rearranges into the 1,4-dihydro tautomer 43b only at a more negative potential, while the tautomerization in its tetrasubstituted analog 43a (R = COOMe) occurs more readily (Scheme 14) [00TL647]. 

Oxo-a-tocopherol (55) proved to be a very interesting compound with regard to forming various intermediate tautomeric and quinoid structures. It undergoes an intriguing rearrangement of its skeleton under involvement of different o-QM structures. The 4-oxo-compound was prepared from 3,4-dehydro-a-tocopheryl acetate via its bromohydrin, which was treated with ZnO to afford 4-oxo-a-tocopherol (55). 

In a related example, reaction of N-hydroxy-N-methylthiophene-2-carboximidamide 56 with DMAD gave a double Michael addition product 57, which when heated at reflux in xylenes, afforded hydroxypyrimidinone 60 in 57% overall yield (Scheme 6.21) [9f]. The mechanism invoked was opening of the oxa-diazole 57 to 58, followed by a [3,3]-Claisen-type rearrangement to 59, which, after tautomerization and cyclization, afforded 60. 

Recently, the hydroxy derivatives of furan, thiophene, and selenophene have been studied with regard to their physical properties and reactions. These compounds are tautomeric and if the oxygen function is placed in the 2-position they exist as unsaturated lactones and undergo carbon-carbon rearrangement, whereas the 3-hydroxy derivatives form oxo-enol tautomeric systems. By NMR the structures of the different tautomeric forms have been determined as well as the position of the tautomeric equilibrium and the rate of isomerization. 

While at Leeds from 1924 to 1930, Ingold s laboratory focused on three main topics of research (1) the nature and mechanism of orienting effects of groups in aromatic substitution (mainly nitration) (2) the study of prototropic rearrangements (shifts of H+) and aniontropic rearrangements (shifts of anions) as the ionic mechanisms of tautomerism and (3) the effect of polar substituents on the velocity and orientation of addition reactions to unsaturated systems. One of Ingold s students at Leeds, John William Baker, wrote a widely read book on tautomerism. 16... 

In contrast to Nair, Bode and co-workers propose that cross-benzoin adduct LVII is formed which then undergoes an oxy-Cope rearrangement to form LVIII (Scheme 38). Tautomerization and indamolecular aldol reaction occurs following the catalytic cycle proposed by Nair. 

Finally, an unusual approach to pyrrolo[2,3- pyrimidines is seen in Equation (40). The dimethyluracil 113 is presumed to form the A -oxide at the exocyclic nitrogen atom. This then undergoes a [2,3]-sigmatropic rearrangement followed by a [3,3]-sigmatropic rearrangement, tautomerization, and cyclization to give 114 <200581164>. 

If 2-methylenecyclobutanones, which themselves are not capable of this tautomerization and the following rearrangement, bear alkyl substituents with an a-hydrogen in the 3-position, still another rearrangement, a [1,3] shift, precedes the actual ring-enlargement step. This is important, because either 3-alkyl-2-methylene- or 2-alkylidenecyclobutanones or mixtures of both may be formed via [2 + 2] cycloaddition of allenes92 and can all be used as precursors for the same cyclohexenones. 

Strong heating of 2-substituted 5-propargylsulfanyl-3-aryl-3//-pyrimidin-4-ones, and their 5-allylsulfanyl derivatives, has been shown to lead to 2-substituted 3-aryl-6-methyl-3//-thieno[3,2-d]pyrimidin-4-ones and their 6,7-dihydro derivatives. The proposed mechanism in both cases is a [3,3]-sigmatropic thia-Claisen rearrangement followed by tautomerization and a 5-exodig or 5-exo-trig cyclization.38... 

The list of publications in the obituary of the organic chemist Otto Dimroth (1872-1940)139 has eleven papers that are classified as physikalisch-organische Chemie. They are mainly about tautomerism, intramolecular rearrangements, and solvent effects on tautomeric equilibria. One paper,140 published in 1933, deals with relationships between reaction velocities and oxidation-reduction potentials for quinone systems and it is evident that Dimroth was a pioneer in developing linear free-energy relationships. He was Professor in Wurzburg from 1918 to 1940. 

The initial product has a hydroxy group attached to a carbon-carbon double bond. Compounds such as this are called enols (ene + ol) and are very labile—they cannot usually be isolated. Enols such as this spontaneously rearrange to the more stable ketone isomer. The ketone and the enol are termed tautomers. This reaction, which simply involves the movement of a proton and a double bond, is called a keto—enol tautomerization and is usually very fast. In most cases the ketone is much more stable, and the amount of enol present at equilibrium is not detectable by most methods. The mechanism for this tautomerization in acid is shown in Figure 11.6. The mercury-catalyzed hydration of alkynes is a good method for the preparation of ketones, as shown in the following example ... 

Interestingly, some systems, such as (1) itself, show a tautomeric equilibrium between an H2 complex and a classical dihydride form others show a stretched H2. In the first case we have a double minimum on the potential energy surface (PES) (H2 and dihydride) and in the other a single minimum. The difference appears to lie in the motion of the heavy ligands that produces a barrier to the dihydrogen/dihydride tautomerism and where there are no such heavy atom rearrangements, the barrier disappears and a stretched H2 becomes possible. 

Besides the annular tautomerism and the Dimroth rearrangement (Section 4.02.3.5) ring-chain tautomerism of certain 1,2,3-triazoles have been discussed and, in some cases, shown by means of spectroscopic methods. Thus, cyanogen azide reacts with acetylene to form a 1 1 adduct, which was proved by means of IR, UV and temperature-dependent... 

The carbapenems are mechanism-based inhibitors which involve acylation of the active-site residue and subsequent rearrangement to a more stable acyl-enzyme species. Knowles and co-workers [32, 33] have demonstrated that the progressive inhibition of the TEM S-lactamase by the olivanic acids is due to the rearrangement of the J -pyrroline intermediate (15) to the tautomeric and thermodynamically more stable zl -pyrroline (16) Scheme 6.3). The resultant acyl-enzyme complex is believed to be stable to subsequent hydrolytic breakdown, thereby disrupting the catalytic activity of the enzyme. 

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