Intermediate tautomer stabilization

Clearly, in the case of (66) two amide tautomers (72) and (73) are possible, but if both hydroxyl protons tautomerize to the nitrogen atoms one amide bond then becomes formally cross-conjugated and its normal resonance stabilization is not developed (c/. 74). Indeed, part of the driving force for the reactions may come from this feature, since once the cycloaddition (of 72 or 73) has occurred the double bond shift results in an intermediate imidic acid which should rapidly tautomerize. In addition, literature precedent suggests that betaines such as (74) may also be present and clearly this opens avenues for alternative mechanistic pathways. 

A large number of Brpnsted and Lewis acid catalysts have been employed in the Fischer indole synthesis. Only a few have been found to be sufficiently useful for general use. It is worth noting that some Fischer indolizations are unsuccessful simply due to the sensitivity of the reaction intermediates or products under acidic conditions. In many such cases the thermal indolization process may be of use if the reaction intermediates or products are thermally stable (vide infra). If the products (intermediates) are labile to either thermal or acidic conditions, the use of pyridine chloride in pyridine or biphasic conditions are employed. The general mechanism for the acid catalyzed reaction is believed to be facilitated by the equilibrium between the aryl-hydrazone 13 (R = FF or Lewis acid) and the ene-hydrazine tautomer 14, presumably stabilizing the latter intermediate 14 by either protonation or complex formation (i.e. Lewis acid) at the more basic nitrogen atom (i.e. the 2-nitrogen atom in the arylhydrazone) is important. 

Chatani s proposed mechanism bears some similarity to that of Jun s reaction (Scheme 9.12). They both begin with hydroamination of the C=C 7t-bond of a rhodium vinylidene. The resultant aminocarbene complexes (71 and 62) are each in equilibrium with two tautomers. The conversion of 71 to imidoyl-alkyne complex 74 involves an intramolecular olefin hydroalkynylation. Intramolecular syn-carbome-tallation of intermediate 74 is thought to be responsible for ring closure and the apparent stereospecificity of the overall reaction. In the light of the complexity of Chatani and coworkers mechanism, the levels of chemoselectivity that they achieved should be considered remarkable. For example, 5 -endo-cyclization of intermediate 72 was not observed, though it has been for more stabilized rhodium aminocarbenes bearing pendant olefins [27]. 

N-Unsubstituted 1//-azepines are rare since, like the parent system, they tautomerize readily to the 3H-isomers in whose preparation they are often considered as transient intermediates (see Section 5.16.4.1.2(h)). This rearrangement is particularly apparent with 2-amino- and 2-alkoxy derivatives since stabilization of the 37/-azepine is then possible by amidine and imidate type resonance. For the CH2-containing tautomers the order of stability appears to be 3H > AH > 2H, a fact attested to by the facile thermal and base-catalyzed rearrangements of AH- azepines to the 3H-tautomers (72CB982) and the rarity and inherent instability of 2H-azepines. The latter are well established as intermediates in the formation of 3H- azepines (74JOC3070) but have been characterized only as their benzologues. 

Orotidine 5 -phosphate undergoes an unusual decarboxylation (Fig. 25-14, step/), which apparently is not assisted by any coenzyme or metal ion but is enhanced over the spontaneous decarboxylation rate 1017-fold. No covalent bond formation with the enzyme has been detected.268 It has been suggested that the enzyme stabilizes a dipolar ionic tautomer of the substrate. Decarboxylation to form an intermediate ylid would be assisted by the adjacent positive charge.269,270 Alternatively, a concerted mechanism may be assisted by a nearby lysine side chain.270a d Hereditary absence of this decarboxylase is one cause of orotic aciduria. Treatment with uridine is of some value.271... 

Suelter90 has classified enzymes that are activated by monovalent cations into two groups. One involves the catalysis of phosphoryl-transfer reactions and the other a variety of elimination and/or hydrolytic reactions in which a keto-enol tautomer can be invoked as an intermediate. The M+ cation is then required to stabilize the enolate anion. It is still not possible to verify this hypothesis, but it seems unlikely in view of the comments above. 

Aldehydes or ketones with an a-hydrogen exist as an equilibrium mixture of keto (H-Ca-C=0) and enol (Ca=C-OH) tautomers. The keto form usually predominates. An a-hydrogen is weakly acidic and can be removed by a base to produce a resonance-stabilized enolate anion. Deuterium exchange of a-hydrogens provides experimental evidence for ends as reaction intermediates. 

The relatively easy decarboxylation of many azolecarboxylic acids is a result of inductive stabilization of intermediate zwitterions of type 608 (cf. Section 3.4.1.8.1). Kinetic studies show that oxazole-2- and -5-carboxylic acids are both decarboxylated via the zwitterionic tautomers. Thiazole-2-carboxylic acids, and to a lesser extent -5-carboxylic acids, are decarboxylated readily thiazole-4-carboxylic acids are relatively stable. Isothiazole-5-carboxylic acids are decarboxylated readily, the 3-isomers less so while the 4-isomers require high temperatures. The 1,2,4-, 1,2,5-, and 1,3,4-thiadiazolecar-boxylic acids are also easily decarboxylated their stability is increased by electron-donating substituents. Most 1,2,3-triazolecarboxylic acids lose carbon dioxide when heated above their melting points. Decarboxylation of 2-hydroxytetra-zole-5-carboxylic acid requires severe conditions (HC1, reflux, 90 h) to produce 2-hydroxytetrazole (40%) <1999TL6093>. 

Intermediate 3-33 reacts by a route completely analogous to the previous steps to give 3-35, a tautomer of the product. That is, the proton removed from the amino nitrogen of 3-33 leads to a resonance-stabilized anion, 3-34. (The anion formed by removal of a proton from the imide nitrogen would not be resonance stabilized.) The nucleophilic anion, 3-34, adds to the remaining ester carbonyl. Elimination of ethoxide then gives 3-35. 

In this initial step, an aldol condensation takes place. The solvent of this reaction is an ionic liquid. It is a very polar solvent that is able to stabilize polar molecules and can act as an acceptor for hydrogen bonds. Thus, it is able to shift the equilibrium towards the enol tautomers. After the aldol addition, the intermediate can eliminate water via a second enol intermediate. Although the substrates are both aldehydes, only one product is formed because 19 lacks an acidic position, so it cannot become a nucleophile. Owing to its tendency to form homodimers, a two-fold excess of propionaldehyde 20 is needed. 

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