Carbinolamine, tautomerism

The study of structure and reactivity of tertiary heterocyclic enamines is associated with the problem of equilibrium of the cyclic enamine form (70) and the tautomeric hydration products 173,174) quaternary hydroxide (71), pseudo base (so-called carbinolamine) (72) and an opened form of amino aldehyde or amino ketone (73). 

The position of the equilibrium is determined not only by ring size and polar and steric factors but also by the environment of the molecule. The experimental evidence for the existence of three tautomeric forms has been based on the study of their reactivity and, to a lesser degree, on physicochemical measurements 175-177). Often the existence of the corresponding carbinolamine or its acyclic tautomeric form in addition to the basic dehydrated form is quite important. 

The salts of some enamines crystallize as hydrates. In such cases it is possible that they are derived from either the tautomeric carbinolamine or the amino ketone forms. Amino ketone salts (93) ( = 5, 11) can serve as examples. The proton resonance spectra of 93 show that these salts exist in the open-chain forms in trifluoroacetic acid solution, rather than in the ring-closed forms (94, n = 5, 11). The spectrum of the 6-methylamino-l-phenylhexanone cation shows a multiplet at about 2.15 ppm for phenyl, a triplet for the N-methyl centered at 7.0 ppm and overlapped by signals for the methylene protons at about 8.2 ppm. The spectrum of 93 ( = 11) was similar. These assignments were confirmed by determination of the spectrum in deuterium oxide. Here the N-methyl group of 93 showed a sharp singlet at about 7.4 ppm since the splitting in —NDjMe was much reduced from that of the undeuterated compound. 

However, a critical examination of the enormous amount of the experimental material that has piled up over more than 80 years leads to the conclusion that the three tautomeric forms postulated by Gada-mer have not been proven in one single case. The so-called evidence is based on chemical reactions, " which are noncompelling, or on physical constants that have been interpreted in a biased manner. For the simultaneous existence of both forms of the ring-chain proto-tropic system, i.e., the carbinolamine and the amino-aldehyde, evidence is available only for one single case. ... 

In the case of the bases derived from quaternary heterocyclic ammonium salts, the carbinolamines (5) can react as cyclic aldehyde-ammonias with many reagents with which the amino-aldehyde (7) could react. However, reactions of the carbinolamines which are not characteristic of amino-aldehydes are also known. Carbinolamines can easily be reconverted into the quaternary salts by the action of dilute acids, and they form alkyl ethers very easily with alcohols. If these last reactions do not occur, then this is convincing evidence for the base possessing the amino-aldehyde structure. However, if these reactions do occur this does not provide unambiguous confirmation of the carbinolamine structure. They are also given by the bi-molecular ethers (8), and, in the case of a tautomeric equilibrium... 

These structural problems are also insoluble by physical methods alone. The infrared spectrum often gives an unambiguous decision about the structure in the solid state the characteristic bands of the carbonyl or the hydroxyl group decided whether the compound in question is a carbinolamine or an amino-aldehyde. However, tautomeric equilibria occur only in solution or in the liquid or gaseous states. Neither infrared nor ultraviolet spectroscopy are sufficiently sensitive to investigate equilibria in which the concentration of one of the isomers is very small but is still not negligible with respect to the chemical reaction. 

On the basis of the dissociation constant values, it seems sensible to conclude that, in these moderately basic carbinolamines, the hydrogen atom of the hydroxyl group is suflQciently acid to be eliminated under the influence of an alkali and by its transfer to the nitrogen atom of the mesomeric anion, the formation of the amino-aldehyde form may result. Instead of the amino-aldehyde, however, the corresponding bimolecular ether (15a-c) can be obtained. " It can be concluded that the formation of the bimolecular ether (S l or 8 2 mechanism) and the formation of the amino-aldehyde (B-SeI or B-Se2 mechanism) are competitive reactions. It seems probable that where the first reaction can occur the latter one is pushed into the background. The triple tautomeric system postulated by Gadamer... 

The great majority of the compounds investigated belong to types a and b, i.e., they occur in the carbinolamine form. The possibility that the triple tautomerism postulated by Gadamer exists cannot, therefore, be completely eliminated, but its existence has not been demonstrated in one single case. In complete contrast to the usual view, it certainly cannot be considered as a general or frequent... 

The tautomeric system aminoaldehyde (or, more rarely, aminoketone) vs. carbinolamine 61A 61B can be formed by the covalent addition of... 

It has been pointed out that 6-hydroxybuphanidrine (222) and 6-hydroxypowelline (227) could exist in solution as a mixture of tautomeric carbinolamine and open chain amino aldehyde, but investigation using physical methods did not reveal aldehydic forms. However, both alkaloids, upon treatment with NaN02 in diluted acetic acid, were converted into iV-nitroso aldehyde derivatives 230 and 231 which seems to suggest the existence in solution of an amino aldehyde form. 

The study of the enamine structure may be associated, to a certain degree, with the problem of the so-called pseudobases an instructive, but somewhat specialized, review of these compounds was contributed by the late Professor Beke 47 to the first volume of this series. The name pseudobases was given by Hantzsch,48 towards the end of the last century, to those a-aminocarbinols which undergo a structural change during salt formation and yield salts with the loss of one molecule of water. The liberation of pseudobases from their salts is accompanied by rehydration. This behavior has been observed with a,/3-unsaturated heterocyclic compounds and, to a certain degree, with aromatic heterocyclic pyridine derivatives. As formulated by Gadamer,49 the pseudobases represent a potential tautomeric system of three components, the quaternary hydroxide A, the carbinolamine B, and the open-chain amino-carbonyl derivative C, in which all three components exist in a mobile equilibrium ... 

The Gadamer system of three tautomeric components does not necessarily take for granted the simultaneous action of all three tautomeric equilibria, but rather it assumes two consecutive equilibria with the carbinolamine form (B) as an intermediate. 

The salts of some enamines crystallize as hydrates. It is possible that these salts are actually derived from either the tautomeric carbinol-amine or the amino-ketone forms. Steric factors should again be decisive. The salts obtained by an intramolecular cyclization of a bicyclic amino-ketone (13)55 belong to the carbinolamine type their infrared spectra reveal the presence of a hydroxyl group. 

Tetrahydro-6-phenylimidazo[2,l-6]thiazoIe hydrochloride (tetramisole) is a broad-spectrum anthelmintic the D-form is an antidepressant the L-form (levamisole) is known to possess immunoregulatory or immunostimulatory activity. Some phenacylthio-imidazolines which are tautomeric to cyclic carbinolamines are very potent antagonists of reserpine-induced hypothermia in mice. The corresponding 3-aryl-5,6-dihydroimidazo[2,l-6]thiazoles are also potent antidepressants. 5,6-Bis(4-methylsulfinylphenyl)-2,3-dihy-droimidazo[2,1 -b Jthiazole is used especially in the treatment of rheumatic arthritis. 

Cycloneosamandione did not contain the oxazolidine ring, but rather a tautomeric aminocarbonyl carbinolamine system (34). Two structures were proposed, one a carbinolamine formed with a C-19 aldehyde, the other a carbinolamine formed with a 6-keto group. Ultimately, the cyclone-... 

One other samandarine alkaloid, namely cycloneosamandaridine, contained a tautomeric aminocarbonyl carbinolamine system, and it was initially thought to be related to samandaridine just as cycloneosamandi-one was related to samandarone 34). However, synthetic cycloneosamandaridine with the carbinolamine formed with a C-19 aldehyde was not identical with the natural compound 36), which thus appears to have a carbinolamine formed with a 6-keto group. Retention of the original name, cycloneosamandaridine, for the natural compound would be unfortunate, since it implies the presence of the cycloneosamandione A,B ring system. The name isocycloneosamandaridine, proposed in Ref. 5, is used in this chapter (see Fig. 2). The name cycloneosamandaridine was retained for the synthetic material, which is shown in Fig. 3 it has not been reported in Nature. 

The behavior of the 1 -methiodide (179) is more difficult to explain as its spectrum in alcohol is nearly identical to that in alkaline solution, and these both show the same pattern as the 2-methylene indoline, i.e., with an intensified band II and a band III shifted to the red as compared to its methiodide. It seems possible that these compounds exist as the carbinolamine, or pseudobase, in hydroxylic solvents and are in tautomeric equilibrium (179 181). The direction of this equilibrium has been attributed by Beke to the basicity of the nitrogen, as well as other factors. B14ha and Cervinka discuss the importance of steric and polar structural factors, citing examples of stable pyrrolidine pseudobases. Indeed, Ficken and Kendall isolated the 4-azaindoline pseudobase (123), characterizing it by analysis and infrared spectral evidence. They similarly characterized the 2-methylene base (121), and it is unfortunate that their ultraviolet spectra were not determined. The 2-methylene-7-azaindoline... 

We chose the four above-mentioned reaction schemes specifically to indicate that, despite the wide use of these synthetic approaches and the relatively well-known chemistry of Schiff bases, they actually remain widely unstudied. For over a century, the mechanisms by which these reactions were suggested had no experimental justification. It is easy to note the similarities in formation of the intermediate cyclic N,0 hemiacetals (carbinolamines) (26a-d). These compounds are usually found to be relatively stable and isolable34 (see also Section V,B,l,a), in contrast to the unstable acyclic carbinolamines. The dehydration step also requires further investigation because the initial dehydration product may be stable, it may exist in tautomeric equilibrium, or it may be converted spontaneously to the more stable isomer ring, depending on the relative stabilities of the various isomers. If a detailed mechanism for these reactions is known, control of experimental conditions can be used to direct reaction products and improve yields. 

Final evidence for the tropan-l-ol hydrochloride structure in the crystal lattice was provided by X-ray analysis of physoperuvine hydrochloride. The tautomerism (6a)J(6b) was corroborated by the weak, positive Cotton effect, [0J288 = +174 (MeOH), compared to that of N-benzoylphysoperuvine, [Glass +7809 (MeOH), which can only exist as the benzamido-ketone form (7). A 1 45 ratio of the ketone (6b) to the carbinolamine (6a) was inferred from these data. ... 

Examples of ring-chain tautomerism in this ring system have been observed by spectral methods. Thus, 3-hydroxy-2,3-dihydrothiazolo-[3,2-a]benzimidazole and its 3-trifluoromethyl analogue exist exclusively as the cyclic carbinolamines (283a R = H or CFj) in both the solid and dissolved states. The 3-methyl homologue (283 R = Me) exists as (283a) in the solid state, but as a 1 2-mixture of (283a) and the open-chain... 

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