Tautomerism with enamines

There is a distinct relationship between keto-enol tautomerism and the iminium-enamine interconversion it can be seen from the above scheme that enamines are actually nitrogen analogues of enols. Their chemical properties reflect this relationship. It also leads us to another reason why enamine formation is a property of secondary amines, whereas primary amines give imines with aldehydes and ketones (see Section 7.7.1). Enamines from primary amines would undergo rapid conversion into the more stable imine tautomers (compare enol and keto tautomers) this isomerization cannot occur with enamines from secondary amines, and such enamines are, therefore, stable. 

We shall consider the sequence as firstly imine formation (an abbreviated form of this mechanism is shown), followed by imine-enamine tautomerism. This provides a nucleophilic centre and allows a subsequent aldol-type reaction with enamine plus ketone. The pyrrole ring is produced by proton loss and a dehydration. 

The solid-state interaction of enamines (428, 333a) with trans-l,2-diben-zoylethene (87) provides quantitative yields of the pyrrole derivatives 445 or 446 [140]. These remarkable 5-cascades consist of initial vinylogous Michael addition, enol/keto tautomerism, imine/enamine tautomerism, cyclization, and elimination, all within the crystal without melting. A waste-free extraordinary atom economy is achieved that cannot nearly be obtained in solution. The milling times are unusually long here (3 h) but it s certainly worth the effort... 

Ammo-5-thioformyluracils, e.g. (108a), have their thioaldehyde function stabilized by the amino group this may involve tautomerization to an imino-mercaptomethylene structure (108b). The reactivity of (108a) with enamines has been investigated.189... 

The ring-chain tautomerism of oxazolidines is discussed in Section 4.18.2.5.2. Oxazolidines form unstable salts which are easily hydrolyzed (equation 80) (77RRC1413). IV-Substituted oxazolidines react with enamines in the presence of trifluoroacetic acid to yield 1,4-oxazepines in a ring-opening 1,5-cycloaddition reaction (equation 8,1) (80LA1573). 

Tautomerization with concomitant protonation of the bridgehead Nsp3 and the less basic Nsp2 nitrogen generation of an enol i, which is also an enamine, and C8 N + R3 heterolysis The pyridine-type heterocycle is an electron-attracting moiety as exemplified by the spontaneous low-temperature enolization of 1-azabicyclic [3.2.2]ketones 115 and 116 described below (Scheme 12.43). 

In the above reactions of enamine derivatives with oxazolidines and oxazinanes, pyridine systems did not constitute direct targets but were formed, in a few cases, by air oxidation of initially formed dihydropyridine derivatives. Oxazolidines 30, possessing electron-withdrawing groups in C-2 substituents, exist mainly as tautomeric acyclic enamines 28 (Section II.C.2), which in the presence of an acid would also generate iminium cations such as 54 that should react with nucleophiles. Thus, it has been found that such oxazolidines in presence of an acid, react with acyclic, cyclic, and heterocyclic enamine derivatives in 1 1 stoichiometry to provide a unique synthesis of pyridine, quinolinone, and pyridopyrimidine derivatives (98T935). 

The proposed biosynthesis of piperazate residue of kutznerides, in analogy with monamycin and polyoxypeptin biosynthesis [213, 214], starts from the precursors glutamic acid and glutamine. The N—bond formation is achieved by the initial A-hydroxylation catalyzed by Ktzl, followed by the intramolecular displacement of the hydroxyl group by 5-amine as a nucleophile. The y,5-deidropiperazate is the common intermediate for all four piperazate moieties in kutznerides. Tautomerization of enamine to imine forms the -N unsaturated dehydropiperazate. Reduction of hydrazone leads to piperazate. The biosynthesis of y-chloro-substituted piperazate... 

The mechanism for the Hantzsch pyrrole synthesis begins with enamine formation. Condensation of ammonia (or an ammonia surrogate) and 3-ketoester 2 gives intermediate A. Intermediate A then undergoes dehydration and tautomerization (B) to produce enamine C. Michael addition of enamine C and a-haloketone 1 gives D, which forms E via P-elimination. Intramolecular nucleophilic substitution then generates F, which undergoes rapid isomerization to form the desired pyrrole 3. 

A similar conclusion can be drawn from an unexplained case of sonochemical switching (Fig. 29). The addition of primary aromatic amines to methyl pyruvate produces first the tautomeric imine-enamine condensation product. This step seems to be sonication independent. Under stirring at room temperature, the condensation goes on with the condensation of the enamine with the pyruvic ester to yield a lactone. In contrast, sonication under the same conditions... 

Aldehydes and ketones react with primary amines to form azomethines which are usually known as Schiff bases, or sometimes, if the amine is aromatic, as anils. Stable Schiff bases are formed with aromatic aldehydes and with aliphatic and aromatic ketones, those formed from ahphatic aldehydes are often subject to aldol-type polymerization and are not suitable for group protection. The Schiff bases formed from aliphatic ketones are potentially tautomeric with the corresponding enamines, but they exist as azomethines unless there is some other structural feature present to stabilize the enamine form (section 2.1.3.2). The condensation reaction by which these derivatives are formed is acid-catalyzed and easily reversible, thus this method of oup protection is only applicable under neutral or alkaline conditions. The condensation using aromatic aldehydes or aliphatic ketones take place readily without solvent or in refluxing ethanol, those with aryl-alkyl or diaryl ketones may require catalysis or azeotropic removal of the water formed in the reaction. 

Imines (like carbonyl compounds that form enols) are in equilibrium with their tautomeric forms, enamines (Section 17-9). If we write this form for our oxime, we arrive at an aminocarbonyl compound that is poised to undergo fast intramolecular formation of another hemiaminal. Dehydration produces a new cyclic enamine, which, upon inspection, is nothing but a hydrated pyridine. Finally, the driving force of aromaticity facilitates the rapid loss of water and generation of the pyridine product. 

Addition of an aromatic sulphonyl azide to an unstrained alkene gives the corresponding iV-arenesulphonylimine, which is tautomeric with the corresponding enamine, and which can be hydrolysed easily to a mixture of a ketone and a sulphonamide. Arenesulphonylimino-derivatives are formed, amongst other products, when an arenesulphonyl azide reacts with 1,4-dihydroquinolines and isoquinolines, indoles, and carbazoles. ... 

List and coworkers developed an excellent application of this method to a dynamic kinetic resolution approach (Scheme 11.12) [23]. In the presence of phosphoric acid catalyst la and 39, the reductive amination of racemic a,a-disubstituted aldehydes 46andpara-anisidine (17) proceeded through a tautomerization between enamine 48 and imine 49. The essential point of this protocol is that the hydrogenation of (R)-49 proceeded more rapidly than that of (S)-49 to give P-branched amine 47 in 87% yield with 96% ee. 

In spite of the usefulness of the Beirut reaction, mechanistically it is not well understood. It has been suggested that the first step involves the nucleophilic attack by the enolate or the enamine at N-3 of the benzofuroxan to yield an intermediate iV-oxide (Scheme 50) which subsequently undergoes tautomerism to an hydroxylamino derivative. This intermediate then cyclizes to the dihydroquinoxaline 1,4-dioxide. This suggestion has not been proven, and indeed there is evidence that benzofuroxan is in equilibrium with 1,2-dinitrosobenzene... 

Analogous compounds with a secondary amino group (a,j8-unsaturated secondary amines) can, in principle, exist in either the form of imines (6) or the tautomeric form of enamines (7). As they practically occur and react in the former structure, it is more convenient to use the group designation imines. ... 

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