Tautomers derivatives

Fig. 4. Tautomers derived from monohydroxy cyclotriphosphazene, NjPjRjR jfOH)...

The preparation and study of tautomers derived from 2-(2 -pyridyl)indole, 2-(2 -pyrrolo)[l,8]naphthyridine, and related heterocycles has been undertaken using ultraviolet (UV) and nuclear magnetic resonance (NMR) spectroscopy and also by molecular orbital (MO) calculations <1998JOC4055>. 

Carroll, J. D. Jones, P. R. Ball, R. G. Novel ring-chain tautomers derived from (o-formyl-phenyljethylamines./. Org. Chem. 1991, 56, 4208-4213. 

Although the parent compound has not been described, several of its derivatives have been prepared in general, they exist as the 3,4-dihydro tautomers. Derivatives of the 5,6-dihydro compound 51 are also known they are normally obtained when the 2-position is disubstituted. 

That such a delicate balance exists between tautomers is not an obvious prediction based solely on ApK s. The 10 pK unit difference in 9 benzoate favors the amidine-carboxylic acid form by 0.6 eV. However, a simple electrostatic calculation [123] for a positive and negative charge at a salt bridge distance of 3.8 A translates into a stabilization energy of-0.50 eV in the solvent THF, which nearly offsets the stabilization of the amidine-carboxylic acid tautomer derived from the ApfQ. Electron-rich carboxylates such as benzoate are sufficiently basic that the amidine-carboxylic acid hydrogen bond interaction prevails while the interface retains its ionic nature for more acidic carboxylic acids and various sulfonic acids. 

Few hydroxythienopyridines have been described. A major point of interest is the extent to which the compounds exist as the hydroxy or keto tautomer. Derivatives in which the group is attached to the pyridine ring would be expected to resemble their quinoline or isoquinoline analogs, but, in view of the fact that hydroxythiophenes exist to some extent in keto forms, the genuinely phenolic properties of hydroxy groups on the benzene rings of the isosteric systems might not be reproduced in thienopyridines. 1-Hydroxyisoquinoline and 2- and 4-hydroxy-quinoline exist almost exclusively in the keto forms, whereas 3-hydroxyquinoline and 4-hydroxyisoquinoline are extensively enolized in 3-hydroxyisoquinoline the two forms are of comparable stability and which one predominates is dependent on the solvent. A similar pattern is... 

The symmetrical disubstituted thioureas such as 137 do not give a thiazolic ring (Scheme 66), but give compounds of type 138 or 139, which are derived from the tautomer imino form of the 2-aminothiazole (86). 

Nitroso dyes are metal-complex derivatives of o-nitrosophenols or naphthols. Tautomerism is possible in the metal-free precursor between the nitrosohydroxy tautomer (76) and the quinoneoxime tautomer (77). 

Preliminary IR spectral studies were said to suggest that pyrimidinones existed as pyrimidinols <50JCS3062) but this conclusion was promptly reversed <52JCS168) on better experimental evidence subsequent comparison with their N- and O-methyl derivatives showed that the pyrimidinones (39a R = H) and (40a R = H) along with their A-methyl derivatives (39a R = Me), (40a R = Me) and (40b R = Me) all exhibited vqo in the range 1600-1700 cm, whereas the methoxypyrimidines (39b R = Me) and (40c R = Me) showed no such absorptions <53JCS33l, 55JCS211). Closer analysis of the spectra for pyrimidin-4-one (40a R= H) showed that the ort/jo-quinonoid form (40a R = H) is the predominant tautomer (see Section 2.13.1.4). 

The O-alkyl derivatives of those A-oxides, which exist partly or entirely as (V-hydroxy tautomers, may be made by primary synthesis (as above) or by alkylation. Thus, 5,5-diethyl-1-hydroxybarbituric acid (936 R = H) with methyl iodide/sodium ethoxide gives the 1-methoxy derivative (936 R = Me) or with benzenesulfonyl chloride/ethoxide it gives the alkylated derivative (936 R = PhS02) (78AJC2517). 

In principle, aminopyrazine and 2-aminoquinoxaline are capable of existing in the form of the imino tautomers (81) and (82) however, comparison of the UV spectra of the amino, methylamino and dimethylamino derivatives indicates that in both systems the amino rather than the imino tautomer is favored (60JCS242, 58JCS108). 

Only the potentially 2,4-dihydroxy derivatives of furan and thiophene are known and these exist in the solid state and in polar solvents as the monoenols (82) (71T3839). However, in non-polar solvents the furan derivatives exist predominantly in the dioxo form (83). The 2,5-dioxo structure (84) is well established for X=0, NR, S and Se (71BSF3547) and there is no evidence for intervention of any enolic species. The formal tautomer (85) of succinimide has been prepared and is reasonably stable (62CI(L)1576). 

Examples of the remaining potential 3,4-dihydroxy heterocycles are presently restricted to furan and thiophene. Although the parent 3,4-dihydroxyfuran apparently exists as the dioxo tautomer (86), derivatives bearing 2-alkyl or 2,5-dialkyl substituents prefer the keto-enol structure (87) (71T3839, 73HCA1882). The thiophene analogues also prefer the tautomeric structure (87), except in the case of the 2,5-diethoxycarbonyl derivative which has the fully aromatic structure (88) (71T3839). 

Mercapto derivatives of furan, thiophene, selenophene (77ACS(B)198) and pyrrole (72AJC985) all exist predominantly in the thiol form. 2-Mercaptobenzothiophene is also a thiol (70JCS(C)243i) whereas 2-mercaptoindole is mainly indoline-2-thione (89) (69CPB550). The finely balanced nature of this system is indicated by the fact that a 3-aryl, but not a 3-alkyl, substituent will stabilize the 2-thiol form, whereas for 3-aryl-fV-methyl derivatives the 2-thione tautomer is preferred (71CC836). 

The known 3-mercapto derivatives of furan, thiophene, selenophene (77ACS(B)198), ben-zothiophene (70JCS(Q243i) and indole (69TL4465) all exist as the 3-thiol tautomers. 

These observations can be extrapolated to the pyrrole series the 2-amino derivatives are very unstable whereas 3-aminopyrroles appear to be more stable. 3-Amino-l-tritylpyr-role (162) appears to exist in solution exclusively in the imino-A -pyrroline form (163) (83JCS(P1)93). 2-Aminoindole (164) is unusual in that it exists mainly as the 3//-tautomer (165). 4-Alkylaminoindoles (166) undergo an unexpected rearrangement to 4-amino-1-alkylindoles (167) when heated with p-toluenesulfonic acid hydrate (82CC1356). 

Annular tautomerism (e.g. 133 134) involves the movement of a proton between two annular nitrogen atoms. For unsubstituted imidazole (133 R = H) and pyrazole (135 R = H) the two tautomers are identical, but this does not apply to substituted derivatives. For triazoles and tetrazoles, even the unsubstituted parent compounds show two distinct tautomers. Flowever, interconversion occurs readily and such tautomers cannot be separated. Sometimes one tautomeric form predominates. Thus the mesomerism of the benzene ring is greater in (136) than in (137), and UV spectral comparisons show that benzotriazole exists predominantly as (136). 

Compounds of types (286) and (287) are in tautomeric equilibria with 4- or 5-hydroxyazoles. However, the non-aromatic form is sometimes by far the most stable. Thus oxazolinone derivatives of type (287) have been obtained as optically active forms they undergo racemization at measurable rates with nucleophiles (77AHC(21)175). Reactions of these derivatives are considered under the aromatic tautomer. 

Following the classification of Chapter 4.01, three classes will be considered, (a) Compounds isomeric with aromatic compounds (6), (7) and (8). The quaternary, non-aromatic salts (Scheme 7, Chapter 4.01) will be discussed only in connection with protonation studies which lead to the conclusion of their non-existence. The carbonyl derivatives (9), (10), (13) and (14) will also be included here because it is possible to write an aromatic tautomer for each one, (9 )-(14 ), even if it is energetically unfavoured, (b) Dihydro compounds. In this class not only pyrazolines (15), (16) and (17) but also pyrazolidinones (18) and pyrazolinediones like (1) are included, (c) Tetrahydro compounds. Besides the pyrazolidines (19), the pyrazolidinetriones (2) are included here. 

The same group has published two articles on indazoles [indazole (36), 1-methyl- (106) and 2-methyl-indazole (107)]. The He-I and He-II spectra have been obtained and satisfactorily interpreted by means of ab initio LCGO calculations (78JST(43)33, 78JST(43)203). The PE spectra support the conclusion (Section 4.04.1.5.1) that the 1//-tautomer is by far the more stable. X-Ray photoelectron spectra of some pyrazole and pyrazoline derivatives have been reported (83MI40400). 

In a neutral azole, the apparent rate of formation of an A-substituted derivative depends on the rate of reaction of a given tautomer and on the tautomeric equilibrium constant. For example, with a 3(5)-substituted pyrazole such as (199), which exists as a mixture of two tautomers (199a) and (199b) in equilibrium, the product composition [(200)]/[(201)] is a function of the rate constants Ha and fcs, as well as of the composition of the tautomeric mixture (Scheme 16) <76AHC(Si)l). 

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