Equilibria imine/enamine tautomeric

Imine-enamine tautomeric equilibrium was observed in different substituted dihydroazines by NMR spectroscopy. Pinson and co-workers46 reported, for example, that a solution of 3,6-diphenyl-1,2-dihydropyrazine (27b) in CDC13 contains a tautomeric mixture of 2,5- (27a) and 1,2- (27b) dihydro derivatives in the ratio 30 70. 

Instead of homoaromaticity in the CDC13 spectra of 4,6-diphenyl-1,2-dihydropyrimidine, two new triplets were observed at 8 3.56 (J = 6.6 Hz) and 8 5.79 (J = 6.6 Hz). These were assigned to 4,6-diphenyl-2,5-dihydropyrimidine (21b) (Fig. 8), the second tautomeric form of the imine-enamine tautomeric equilibrium. The ratio of 21a to 21b is 2 1. In DMSO-d6 solution, the equilibrium shifts completely toward 1,2-dihydropyrimidine 21a because of strong intermolecular hydrogen bonding with the solvent. An analogous effect was observed in 1,6-dihydropyrazine.46... 

Real-scale experiments confirmed the reactivity of ozone with some opiates such as morphine, codeine, and norcodeine (Boleda et al., 2009). EDDP behaved differently despite the presence of a double bond in its stmcture, it survived this treatment. This can be explained by the imine-enamine tautomeric equilibrium, which decreases the electron density of the C-C double bond, thus lowering its reactivity toward ozone. 

Reactions of Halogenation and Nitrosation Nitrones with protons in the a-alkyl group can occur in tautomeric nitrone-hydroxylamine equilibrium (Scheme 2.117) similar to keto-enol and imine-enamine tautomerisms. 

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]. 

Tautomers are isomers in which the site of a hydrogen atom and a double bond are different. The tautomers are in dynamic equilibrium with each other. We have already met keto-enol tautomerlsm, of which this is a variation, in Chapter 6. Imine-enamine tautomerism is another example ... 

The E-isomer is generally more stable than the Z-isomer due to diminished steric hindrance, so it is assumed that the E-isomer is the major product (shown for 83). Water, a reaction by-product, may be removed to give a better yield of product and azeotropic distillation is used as well as molecular sieves (see Section 18.6.3). Enamines are structurally related to an end (HO—C=C) in that the heteroatom is directly attached to the alkene unit. Enamines are often isolable compounds, whereas enols tautomerize spontaneously to the carbonyl form. Note that when imine 76 is formed from iminium salt 80, there is no enamine product. In fact, the C-H in 80 is much less acidic that the N-H unit, so the product is the imine rather than the enamine. It is noted that there is an equilibrium between an imine and an enamine, known as imine-enamine tautomerism, but it will be ignored in this book. Many different secondary amines can be used in this reaction, including cyclic amines (see Chapter 26, Section 26.4.1) such as pyrrolidine (90), piperidine (91), and morpholine (92). It is important to note that it is generally easier to form an enamine from a ketone than from an aldehyde. 

Dihydro-2/7- 74 and -4//-l,2-oxazines and thiazines 75 are interrelated by prototropy, being enamines and imines, respectively. In the case of oxazines, the imine form 75 is favored, and there are several well established examples of this system, including the parent heterocycle 75 (X = O) [84MI2]. No tautomeric equilibrium between the 2H and 4H forms has been observed under normal conditions in solution or in the solid state. However, the formation of intermediate 2H isomers 77 was proposed both for the conversion of 3-phenyl-5,6-dihydro-4//-l,2-oxazine 76 (R = Ph, r = R = H) into 2-phenylpyrrole(89TL3471) under strong basic conditions and for thermal decomposition of cyclopentene-fused 1,2-oxazine 76... 

The intramolecular Heck reaction presented in Scheme 8 is also interesting and worthy of comment. Rawal s potentially general strategy for the stereocontrolled synthesis of the Strychnos alkaloids is predicated on the palladium-mediated intramolecular Heck reaction. In a concise synthesis of ( )-dehydrotubifoline [( )-40],22 Rawal et al. accomplished the conversion of compound 36 to the natural product under the conditions of Jeffery.23 In this ring-forming reaction, the a-alkenylpalladium(n) complex formed in the initial oxidative addition step engages the proximate cyclohexene double bond in a Heck cyclization, affording enamine 39 after syn /2-hydride elimination. The latter substance is a participant in a tautomeric equilibrium with imine ( )-40, which happens to be shifted substantially in favor of ( )-40. 

The reaction of or//io-substituted anilines containing substituent groups, e.g., phenyl, cyano, and nitro, gives rise to simple enamine fumarates these in turn can be cyclized to the corresponding 4-quinolones. " Aromatic diamines such as o-phenylenediamine and 2,3-diaminonaphthalene, however, react with DMAD to give tetra-hydroquinoxaline derivatives (7) [Eq. (2)]. ° It has been suggested that these tetrahydroquinoxalines exist in tautomeric equilibrium between the imine and enamine forms and that the enamine form (7) is more favored in inert organic solvents. On the other hand, an iso-... 

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,... 

Imines (e.g. R CH2-CH=N R or R-CH2-C(R)=N-R) are derived from the reaction of primary amines with aldehydes or ketones respectively, and may exist in tautomeric equilibrium with the corresponding enamine form, but in which the imine form predominates. 

The UV spectra of 9-(phenylamino)tetrahydro-4f/-pyrido[ 1,2-a] pyrimidin-4-ones 23 indicated the presence of an imine-enamine type of tautomerism in solution. A carboxyl or ester group in position 3 (R1 = COOR3 R3 = H, Et) and a methyl group in position 6 (R = Me) shifted the equilibrium toward the enamine form in a polar solvent [85JCS(P1) 1015]. For the imine tautomer, UV maxima at 235-250 nm and 280-300 nm and for the enamine absorbances at 260-265 nm and 355— 365 nm are characteristic. 

A tautomeric equilibrium between enamine and methylene imine forms has been demonstrated to exist in 2-(3,4-dihydro-3-oxo-2(l//)-quinoxalinylidene)-Al-phenylacetamides and 3,4-dihydro-3-oxo-/V-phenyl-2-quinoxaline acetamides when these are in DMSO solution either in the absence or presence of TFA [95JHC671]. The reduction potentials of some pyrazines and their benzo-fused analogs have been summarized as part of an EPR study of the electron transfer interaction between nitrogen heterocycles and n-B N+BHf [95JOM123]. 

In general, the tautomeric equilibrium (equation 1) is completely on the enamine side when an unsaturated electron-accepting substituent substitutes the /Tcarbon of 1 otherwise, the equilibrium lies far on the side of imine 1. However, apart from the two extreme cases above, some secondary enamines are sufficiently stable to exist in detectable amounts in equilibrium with the corresponding imines and thus it becomes possible to investigate the factors affecting the enamine-imine equilibrium51-53. 

It has been demonstrated that imines 410 are in tautomeric equilibrium with their secondary enamine forms 4111,249 (equation 86). Except where the enamine tautomer is stabilized by further conjugation250,251, the equilibrium is almost completely in favor of the imine form. 

Although this methodology is widely applicable for the preparation of many 1,1-enediamines, 2-(aroylmethylene)benzimidazolines (29) cannot be obtained from the reaction of benzoyl-substituted ketene dithioacetals 30 and o-phenylenediamine. Instead of 29, 3H- 1,5-benzodiazepines 31 are isolated from the reaction64. Similar results have been reported for the reaction of 30 and other primary aromatic diamines70,71. A recent study64 has revealed that an enamine-imine tautomeric equilibrium is involved in the reaction process (Scheme 2). This equilibrium between 33A and 33B is affected by the... 

Horvath et reported that the tricyclic formyl derivatives 390 n = 0-2) exhibit triple tautomerism between forms 451 and 453. The imine-enamine-enol tautomerism depends greatly on the ring size ( ). A significant solvent dependence was observed only for the pyirolo[2,l-i ]-quinazolinones 390 n = 0), which in ethanolic solution exist predominantly in the imino form (451), and in chloroform in the enol form (453). H-NMR spectroscopy showed that in chloroform the proportion of the imine tautomer 451 was about 5%. The fast equilibrium between the en-amine and enol forms 452 and 453 was shifted considerably toward the enamine tautomer 452 in the case of the pyrido[2,l-fi]quinazolinones 390 ( = 1). The azepino[2,1 -6]quinazoline ( = 2, R = 2-NO2) is a 2 3 mixture of the imine and the enamine tautomers 451 and 452. 

Thus, it was shown that the tautomerization may be of importance in the thermal dehalogenation of chloroaromatics14. The formation of diarylamines in this reaction can be also explained by the presence of aniline tautomers in the reaction mixtures14. One of the well-known types of aniline tautomerism is the enol-imine-keto-amine equilibrium. In effect, it is a reversible conversion of Schiff bases into enamines that is frequently employed for the synthesis of photochromic compounds, as well as of mesomorphic... 

Tautomerization is the shift of an H from a carbon adjacent to a carbon-heteroatom double bond to the heteroatom itself (and the reverse). It is an acid- or base-catalyzed equilibrium. Two examples are the keto/enol pair (Z = oxygen) and the imine/enamine pair (Z = nitrogen). Base catalysis goes via the enolate anion. 

The tautomeric equilibrium between the phenol imine structure (OH N form) and the keto-enamine structure (O HN form) was determined by UV-Vis spectroscopy in polar solvents for the bis(crown ether) ligands 48 which contain recognition sites for Na and Ni guest cations . 

It should be noted that the keto-enamine tautomers of Schiff bases are observed always when the latter are derived from 2-hydroxynaphthaldehyde and aniline. However, in Schiff bases derived from salicylaldehyde and aniline, the new band at >400 nm in UV-Vis spectra was not observed in both polar and non-polar solvents, but it appeared in acidic media. In this workl which contains a quite good survey of the investigations of tautomerism in Schiff bases, the effects of the solvent polarity and acidic media on the phenol-imine keto-amine tautomeric equilibrium in systems 55 and 56 were reported. It was shown by H NMR and UV-Vis spectra that compound 55 is in tautomeric equilibrium of structures 55a and 55b in both polar and non-polar solvents (equation 17), whereas the tautomer 56b was not observed for compound 56 (equation 18) . ... 

Extensive studies have shown that the enamine-imine tautomeric equilibrium of equation 1 shifts almost completely to the enamine side when an unsaturated electron-withdrawing group including nitrile nitro °, carbonyl, thiocarbonyP etc. ° is attached to the -carbon. Reviews related to these enamines which include enaminoni-triles 2, nitroenamines 3, enaminones 4 and the enaminothioketones 5, have appeared in the literature, ... 

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