Enamines tautomeric forms

The aminomethylenemalonates (1 and 2) may exist in imine or enamine tautomeric forms of R1 or R2 is a hydrogen atom. In some early papers, the imine tautomer (see below) was given for the structure of the products, usually without any explanation or evidence (e.g., 1885CB319 37JCS867 49JIC171 88KGS931). 

The acetic anhydride-induced cyclodehydration of the symmetrical diamide 411, derived from the tetrahydro-benzothiophene / -amino ester 410 and diethyl malonate, afforded the thieno[2,3-r7 [h3]oxazine derivative 413 rather than the expected bis-oxazine 412 (Scheme 78). The reaction probably takes place through sequential cyclizations, in which the pyridine ring of 413 is produced by condensation of the exocyclic double bond of the enamine tautomeric form of the 1,3-oxazine moiety and the mixed anhydride formed by the carboxylic group and acetic anhydride <2003PS245>. 

A high density of electrons associated with atoms C(3) and C(5) of 1,4-dihydropyridines and 1,4-dihydropyrimidines is also observed when these heterocycles undergo electrophilic substitutions such as Friedel-Crafts [315, 316, 317, 318, 319, 320] and Vilsmeier [297, 321] reactions (Scheme 3.99). In [315] it was shown that treatment of dihydropyridines 371 with aroyl or acyl chlorides 372 in the presence of SnCl4 leads to acylation of the heterocycle at position 3 (compounds 373). Dihydropyridines 374 and dihydroazolopyrimidines 376 undergo Vilsmeier reaction with the formation of the corresponding derivatives 375 and 377. It is interesting that imine heterocycle 376 after Vilsmeier reaction exists in the enamine tautomeric form. The tautomerism of dihydroazines and factors influencing it will be discussed in detail in Sect. 3.8. 

The influence of steric factors is more significant for dihydroazolopyrimi-dines 430 fused with a hydrogenated carbocycle [156] (Scheme 3.141). Regardless of the nature of the azole and carbocycle moieties, these compounds usually exist in the enamine tautomeric form. 

The problem of tautomeric equilibriums in annelated 1,5-diazepines was studied in [68] by means of NMR spectroscopy, X-ray analysis and quantum-chemical calculations. It was shown that the electron-withdrawing rings (e.g., pyrimidine moiety) fused with the diazepine cycle increase the stability of the antiaromatic enamine tautomeric forms A and C, while in the case of benzodiazepine, a diimine tautomer B was found to be the most stable. Ab initio quantum-chemical calculations and NMR spectroscopic data showed that solvation of seven-membered heterocycles with polar solvents contributes considerably to the stabilization of the enamine forms A and C. This assumption was also proven by X-ray analysis, which showed that in the solid state these diazepines exist in the diimine form B. 

A series of substituted salicylaldimines 54 was prepared by the condensation of various hydroxy and methoxy salicylaldehydes and 2,6-di-terr-butyl-4-aminophenol. It was shown by UV-Vis and H NMR spectroscopy investigations that compounds 54 exist in solutions both in the phenol-imine and keto-enamine tautomeric forms. ... 

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. ... 

Heterocyclic enamines A -pyrroline and A -piperideine are the precursors of compounds containing the pyrrolidine or piperidine rings in the molecule. Such compounds and their N-methylated analogs are believed to originate from arginine and lysine (291) by metabolic conversion. Under cellular conditions the proper reaction with an active methylene compound proceeds via an aldehyde ammonia, which is in equilibrium with other possible tautomeric forms. It is necessary to admit the involvement of the corresponding a-ketoacid (12,292) instead of an enamine. The a-ketoacid constitutes an intermediate state in the degradation of an amino acid to an aldehyde. a-Ketoacids or suitably substituted aromatic compounds may function as components in active methylene reactions (Scheme 17). 

C3 and N11 are nucleophilic, C4 and C8 are electrophilic. Which bond forms first Once the N11-C4 bond forms, C3 is made much less nucleophilic. So form the C3-C8 bond first (Michael reaction). C3 is made nucleophilic by tautomerization to the enol. The Michael reaction must be preceded by protonation of N11 to make C8 electrophilic enough. After the Michael reaction, the enamine is formed by the mechanism discussed in the text. 

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. 

Tautomeric equilibrium between imine 18 and enamine 19 forms of 2(l//)-quinoxalinonyl acetic acid derivatives (Scheme 4) has been recognized already but found to be affected by the substituent R on the side chain. When R is hydrogen and X is alkoxy or arylamino group, both tautomers 18 and 19 exist in DMSO-r4 or CDCI3 <1994ZOR1681,... 

Imido-enamine tautomery. Isolation of the polar tautomeric form of propyl j3-aminovinyl ketone [167]. 

The A-acylimine-enamide tautomerism of methyl 2-acetamidoacrylate has been studied641 by means of ab initio calculations. A 13C NMR investigation has been undertaken to study the tautomerism between the hydrazone imine and diazenylen-amine forms of 3-(arylhydrazono)methyl-2-oxo-l,2-dihydroquinoxalines,642 and the effects of temperature and side-chain on the imine-enamine tautomerism in quinoxalinone and pyridopyrazinone systems have been studied.643 A detailed... 

Fused diazepines like 54 and 56 can exist in several tautomeric forms (Scheme 4.16)—enamine 1H (A), enamine 5H (C) and diimine 3H (B) (Scheme 4.16). 

Notwithstanding, conformational factors apparently play a part in the enamine-imine equilibrium of the SchifF base prepared from cyclohexanone and cyclohexylamine, as shown by their infrared spectra 28 the base appears to be a mixture of both tautomeric forms, N-cyclo-hexylidenecyclohexylamine and N-1 -cyclohexenyIcyclohexylamine. Replacement of the cyclohexyl group by a phenyl group appears to stabilize the imino form.24... 

The behaviour of compounds 49 where R = H and CH3 from is even more complicated. For example, 4-methylamino-3-(4-X-phenylazo)pent-3-ene-2-one (49) contains two isomers. The tautomeric form of both isomers was confirmed with the help of 2D H-15N GHMQC spectra. The minor isomer is very similar to the tautomeric form of azo-enamine ( j(15N, H) = 89.6 Hz) the major isomer possesses a somewhat stronger character of hydrazono-ketimine form ( /(15N,1H) = 74.5 Hz about 80% azo and 20% hydrazone). These conclusions are confirmed by the values of <5(15NH2) in the minor isomer it is 6(15N) = —269.0 ppm (i.e. almost the same as in the starting enaminone with... 

The review starts with a discussion of the mechanism of keto-enol tautomerisation and with kinetic data. Included in this section are results on stereochemical aspects of enolisation (or enolate formation) and on regioselec-tivity when two enolisation sites are in competition. The next section is devoted to thermodynamic data (keto-enol equilibrium constants and acidity constants of the two tautomeric forms) which have greatly improved in quality over the last decade. The last two sections concern two processes closely related to enolisation, namely the formation of enol ethers in alcohols and that of enamines in the presence of primary and secondary amines. Indeed, over the last fifteen years, data have shown that enol-ether formation and enamine formation are two competitive and often more favourable routes for reactions which usually occur via enol or enolate. 

Spectroscopic studies of imine-enamine tautomerism have shown that the equilibrium is almost completely in favour of the imine form for simple aldehydes and ketones372-374. Nevertheless, some secondary enamines are sufficiently stable to exist in detectable amounts in equilibrium with the corresponding imines for example, the f-butylamine imine of cyclohexanone shows signals due to the secondary enamine tautomer in the NMR spectrum (<5=CH 4.6)375. Studies of the imine-enamine equilibria have shown, as expected, that the enamine form is stabilized by methyl or aryl substituents at the -position (Scheme 189). 

The ketimine (13a), prepared from desoxybenzoin and aniline, is also subject to a solvent-dependent tautomerism called imine/enamine tautomerism. The enamine content of a solution of (13a) increases in the order tetrachloromethane (31 cmol/mol at 35 °C), [Dsjpyridine (47.5 cmol/mol at 55 °C), and [Dejdimethyl sulfoxide (67 cmol/mol at 55 °C) [69], Hydrogen-bond acceptor solvents favour the enamine form (13b) due to hydrogen-bonding, whereas in less polar and apolar solvents the equilibrium is shifted towards the imine form / 13a) [69]. 

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